Peptidic compounds, ie. compounds having or incorporating a peptide structure, eg. proteins, glycopeptides, phosphopeptides and oligopeptides, have an enormously important role in many biological processes. Many such compounds are produced commerically as therapeutic or diagnostic agents. Where naturally occurring amino acids are used however, eg. in the production of a therapeutic agent designed to prevent or provoke the effect of a naturally occurring peptidic compound, the resultant peptidic product may have less than optimal properties, eg. in terms of efficacy or stability, and thus it is well known to substitute synthetic (ie. non naturally occurring) amino acids for various natural amino acids in the preparation of biologically active peptidic compounds.

We have now developed certain novel analogs of the natural hydroxyl side chain containing a-amino acids serine and threonine.

Thus viewed from one aspect the invention provides compounds of formula I (where D is a bridging group which together with the carbon atom to which it is attached forms a four to ten, especially 5 to 7, membered carbocyclic ring which is optionally but preferably substituted and/or saturated, eg. optionally substituted by at least one hydroxy, oxo, amino, or carboxy group or by one or more optionally substituted C14 alkyl or alkenyl groups) and stereoisomers, stereoisomer mixtures, salts, esters, amides and protected derivatives thereof.

In one preferred embodiment of the invention, the bridging group D in the compounds of formula I is preferably substituted, eg. by a hydroxy or hydroxylated group, by a Ci. alkenyl group, by a C14 alkyl group or by an oxo group.

Where such substituents are or contain hydroxy, amino or carboxy groups, these may if desired be esterified or amidated, eg. with C14 alkyl or acyl groups.

Viewed from a further aspect the invention provides the use of an optionally protected compound of formula I (either a ring or side-chain hydroxylated compound or a deshydroxyl analog) for the manufacture of a peptidic compound, eg. a therapeutic or diagnostic agent.

For the manufacture of such peptidic compounds, conventional peptide building techniques, eg. solid state peptide syntheses, may be used.

The compounds of formula I provide rigidified analogs of the natural hydroxylated side chain a-amino acids which are suitable for incorporation into small peptides and peptidomimetic compounds and which can provide stabilizing conformational restrictions in conformations such as (3-turnes, a-helical and extended conformations.

Particularly suitably, the compounds may be used as substitutes for serine or threonine, for example at the last C-terminal turn of an a-helix, or at an 0- glycosylation or O-phosphonation site, eg. in an artifical enzyme, growth factor, growth factor receptor, immunosuppressant, immunostimulant, blood clotting agent, etc. Of particular interest are the blood clot formation reducing agents which act to inhibit one or more of the cascade of reactions involved in blood clot formation. By way of example, the compounds of the invention may be used in place of serine in the low molecular weight hemoregulatory peptides of Bhatnagar et al. (see J. Med. Chem. 39: 3814-3819 (1996)). Similarly the hydroxy-containing amino acid in the immuno depressant cyclosporin may conveniently be replaced by one of the amino acids of formula I.

In one preferred embodiment of the compounds of the invention, D carries a single hydroxyl at the 2-or 3- position (the 1 position being the attachment point of D itself and of the amino and carboxy groups). It is also preferred that the carbocyclic ring be unsaturated, preferably mono-unsaturated at a bond other than the bonds to the 1 and 2 positions.

Thus for example the amino acids of the invention may be of formula II where a and b, which may be the same or different, are 0,1,2 or 3 and each ring carbon in the alkenylene group (CH2) aCH=CH (CH2) b may optionally be substituted by an optionally substituted (eg. hydroxylated, aminated or carboxylated or oxo-substituted) C14 alkyl or alkenyl group and one of the carbons at the 2 and any 2+b positions (preferably the 2 or 3 position) may optionally carry a hydroxyl, oxo, carboxyl or amino group, preferably a hydroxyl group. Alternatively the amino acids may be of formula III where a and b are as defined above, one, two or three of the ring carbon atoms, preferably at positions 2,3,3+b and 4+b, carry hydroxyl or amino groups and one or more of the ring carbons is optionally substituted by an optionally substituted C14 alkyl or alkenyl group or an oxo or carboxyl group.

Where the carbocyclic ring in the amino acid compounds of the invention carries an alkyl substituent, this may for example be an optionally hydroxylated methyl, ethyl, n-propyl, isopropyl, n-butyl or t-butyl group.

Thus for example the ring atoms of the D chain may be substituted by hydroxy, amino, oxo, CHO and carboxyl groups (which may be esterified or amidated or otherwise protected) or by alkyl or alkenyl groups which themselves may carry substituents such as hydroxy, amino, carboxyl and oxo groups-which again may be esterified or amidated or otherwise protected.

Preferably the ring atoms have at least one hydroxy, amino or carboxy substituent, especially preferably at least one hydroxy substituent.

Where the carbocyclic ring in the amino acid compounds of the invention carries an alkenyl substituent, this may for example be a group CH2=C-R"where R"is hydrogen or optionally hydroxy substituted alkyl, eg. methyl or ethyl.

Unsaturated side chains can be produced by a catalysed ring closing reaction as described below in which one of the unsaturated ring forming groups is an alkynyl group.

Such unsaturated side chains can then be substituted, eg. to introduce hydroxyl groups into the side chain.

Examples of unsaturated side chains include methylene, ethenyl and propenyl.

One or more of the hydroxy, carboxy and amino groups in the compounds of the invention may be protected before they are used to construct a peptidic compound of interest. In this regard conventional hydroxyl, carboxy and amine protecting groups may be used and they may be removed when appropriate by conventional deprotection reactions (see for example McOmie"Protective groups in organic chemistry", Plenum, 1973, and Greene"Protective groups in organic synthesis", Wiley-Interscience, 1981).

Such singly or multiply protected amino acids fall within the scope of the present invention. By way of example hydroxy protection may be by an alkyl (eg. Cl-, alkyl) or acyl (eg. C16 acyl) group.

The amino acids of the invention may be used in the synthesis of peptidic compounds in which they will be bound by peptide bonds (amide linkages). Accordingly the resulting peptidic compounds will be amides of compounds of formula I and thus fall within the scope of the present invention. Typically the amino acids of the invention will be used in place of natural amino acids such as serine or threonine or even lysine or glutamic acid. In general, the ring-hydroxylated compounds will be used in place of serine or threonine and the ring- aminated or ring-carboxylated compound, will be used in place of lysine or glutamic acid.

The compounds of formula I may be prepared by cyclization of an a-amino acid disubstituted at the a position by unsaturated groups, eg. alkenyl or alkynyl groups, followed if desired by reduction or substitution of the resulting unsaturated bond in the carbocyclic ring. Such a process forms a further aspect of the invention.

The cyclization is conveniently metal catalysed, eg. with ruthenium, and can be carried out before or after introduction of the ring hydroxyl substituent.

In such a process the amino acid compounds of the invention may be prepared with desired stereoselectivity if the carboxy and amino groups are held in a cyclic structure which is selectively substituted with the unsaturated groups before the ring closure is effected.

This technique for producing cyclic 1-amino-1-carboxylic acids forms a further aspect of the present invention.

Viewed from this aspect the invention provides a process for the preparation of a cyclic 1-amino-1-carboxylic acid (preferably a compound of formula I) having a 4 to 10 membered, preferably carbocyclic, ring, which process involves the steps of (i) bisalkenylating (or alkenylating and alkynylating, etc.) a compound of formula IV (where E is an organic bridging group not susceptible to alkenylation under the conditions used and R* is a hydroxy protecting group); (ii) cyclizing the product of step (i), optionally after removal of group E, to yield an optionally protected bisalkenylated a-amino acid; (iii) if required removing group E to yield an optionally protected cyclic 1-amino-l-carboxylic acid; (iv) if required deprotecting the resulting product; and (v) optionally reducing or substituting the ring double bond and any side chain double bonds in the product of any one of steps (ii) to (iv).

In this process, E is preferably such that the two hydrogens at the substitution site in the starting compound are not sterically equivalent. Thus for example the compound of formula IV may be Such compounds may be stereoselectively substituted and so stepwise bisalkenylation according to step (i) will allow stereoselective preparation of the final cyclic 1- amino-1-carboxylic acid. However single isomers, as well as isomer mixtures, of the compounds of formula I are deemed to fall within the scope of the invention.

The ring closing reaction of step (ii) is preferably catalyzed by a transition metal, such as for example ruthenium, molybdenum or tungsten, especially ruthenium (see Grubbs et al. Acc. Chem. Res. 28: 446-452 (1995), JACS 118: 100-112 (1996), Angew. Chem. Int. Ed. Engl.

34 : 2039-2041 (1995), JACS 117: 5855-5856 (1995), J.

Org. Chem. 59: 4029-4031 (1994), JACS 114: 5426-5427 (1992), and JACS 115: 9856-9857 (1993), and Schuster et al. Angew. Chem. Int. Ed. Engl. 35 : 1979-1980 (1996)).

Where step (v) is effected, this may be for example to simply reduce the bond (ie. add in hydrogens), to add one or more C14 alkyl substituents, to add one or more hydroxyl substituents or to add alkyl and hydroxyl substituents. Conventional reduction or substitution techniques may be used.

Where for example the cyclized structure contains a hydroxyl precursor, eg. a carbonyl group, this may be converted to a hydroxyl group by standard technique (eg. reduction, or carbometallation by an organic reagent).

The compounds according to the invention in which the ring carbons of bridging group D are amino substituted or carry amino substituted substituents may be produced for example by: (i) epoxidation of a cycloalkenyl or alkenyl precursor (eg. compound 4 below) followed by epoxide ring opening, eg. with an azide (for example a metal azide or a TMS azide) followed by reduction, or with a cyanide followed by hydrolysis, or with an amine; (ii) reductive amination of an oxo substituted precursor (eg. compound 47 below); (iii) alkenylation of bislactim precursors with imine rather than aldehyde substituted reagents (see Scheme E below for example); or (iv) amination of a hydroxylated analog or precursor, eg. by activation using a Mitsunobu reaction followed by reaction with an amine or by bromination followed by reaction with an amine.

The compounds in which the ring atoms of D are carboxy substituted or carry carboxy-substituted substituents may be prepared for example by: (i) oxidation of a primary alcohol (eg. a hydroxymethyl substituent), for example by Swern reaction to an aldehyde followed by standard mild oxidation; or (ii) alkenylation of bislactim precursors with a carboxylated alkenylating agent (generally with the carboxy group present as an ester).

The process for the preparation of compounds of formula I (or protected derivatives thereof) may be illustrated by the following reaction schemes in which a and b, which may be the same or different are 0,1,2 or 3, each Rl and R2 independently is H or C14 alkyl, and OR3, M, X, V, U and Y are leaving or protecting groups as appropriate: As can be seen from the above, ring formation can be effected by initial monoalkylation with a difunctional reagent (reaction S to T) with the intermediate (T) being cyclized on remetallation.

In the reactions set out above, it may be desirable to facilitate the hydrolytic opening of the pyrazine ring (ie. A to B or C to D) by forming the a-keto rather than a-hydroxy intermediate (ie. C rather than A) as this will reduce steric crowding in the ring opening precursor. Also as set out above, it may be seen that hydrolytic opening of the pyrazine may be effected before or after the RCM reaction. Where the pyrazine opening is effected first the amine should be N- protected (group NHY in intermediate N).

The spiro compounds produced by the RCM reaction in the schemes above are particularly useful as intermediates for stereoselective substitution of the ring double bond due to the steric control exerted by the pyrazine chiral auxiliary.

The schemes set out above deal with preparation of 2- hydroxy derivatives. Compounds with the hydroxy group more remote can be produced by alkenylation with an a- halo oxo agent, rather than with an acylating agent, or by hydroxylating the ring double bond in the RCM product. Thus further schemes are as follows (wherein m is 0,1 or 2, p is 0,1,2 or 3 and R4 is a protecting residue): For this scheme, the acyclic precursors can be constructed by alkylation with an a-halo oxo derivative as in the formation of Y; subsequent RCM reaction yield a spiro-ketone Z as a target molecule. The latter provides secondary hydroxy derivatives on reduction with a metal hydride, or tertiary hydroxy derivatives on reaction with organometallics; epimeric hydroxy isomers are conveniently separated by flash chromatography.

Epoxides provide an alternative approach. The metallated substrate opens the epoxide ring at the least substituted carbon to form the (3-hydroxy derivatives AA; the latter are substrates for subsequent RCM reactions. This scheme shows hydrolytic reactions leading to target amino acid esters as the oxo derivatives AC or the hydroxy derivatives AD.

Hydrolysis can be effected before ring closure as shown for the preparation of AC ; similarly the hydrolyzed ester product AE is N-protected and subjected to RCM reaction to furnish AD.

The scheme shown below shows an alternative route to hydroxylated saturated cyclic amino acids based on the synthesis of cycloalkene structures AF by RCM. Epoxidation can be effected as in the preparation of AG; reductive ring opening leads to monohydroxy derivatives AH: Organometallics will introduce a vicinal carbosubstituent (not drawn).

Saturated hydroxylated cyclic amino acids may be produced by hydroxylation of spiro-structures AF.

(i) Epoxidation conditions (ii) Reductive opening of epoxide (iii) Sharpless asymmetric dihydroxylation AD-mix-a or P- (iv) Acid or base catalyzed hydroxyl opening of epoxide Acid or base can be used to produce a trans derivative AK. cis-Derivatives are alternative products using appropriate hydroxylating reagents. Stereochemical control may be achieved. Flash chromatography may be used for stereoisomer separations.

Hydroxylated compounds from the scheme above may be hydrolyzed under conventional conditions working with weak TFA solution. In case of problems caused by the OH-groups, the latter have to be protected, e. g. by acylation. Alternatively, hydroxylation reactions can be effected as shown below on cyclic amino ester AS after initial N-protection.

(i) TFA/H2=hydrolysis (ii) Reductive opening of epoxide (iii) Acid or base catalyzed hydroxyl opening of epoxide (iv) Epoxidation conditions (v) Sharpless asymmetric dihydroxylation AD-mix-a or ß- Tri-or dihydroxy derivatives may be prepared from spiro structures A' : (i) Sharpless asymmetric epoxidation (ii) Reductive opening of epoxide (iii) Sharpless asymmetric dihydroxylation AD-mix-a or ß- (iv) Acid or base catalyzed hydroxyl opening of epoxide The scheme above shows an important series of hydroxylation reactions from the a-hydroxy derivatives A'. The latter represent substrates well suited for Sharpless asymmetric epoxidation to furnish AV which can be reductively opened to a hydroxy derivative, i. e. the dihydroxy derivative AY. Acid or base can be used for to form a vicinal trans diol, i. e. the trihydroxy derivative AZ. Sharpless asymmetric dihydroxylation may yield the triols AX and AY.

Conventional hydrolytic reaction of spiro-structures AV, AX and AV provide the compounds BB, BC and BD.

(i) TFA/H2O hydrolysis (ii) Acid or base catalyzed hydroxyl ring opening of epoxide Tri or dihydroxy derivatives can also be prepared by analogous hydroxylation reactions as shown below: (i) Sharpless asymmetric epoxidation (ii) Acid or base catalyzed hydroxyl opening of epoxide (iii) Sharpless asymmetric dihydroxylation AD-mix-a or - Hydrolytic cleavage of the pyrazine ring in the -oxy series in the desired fashion may be effected conventionally using mild conditions with dilute TFA.

(where Rs is H or C14 alkyl).

As shown in the scheme above, the RCM reaction can also be effected in the presence of a triple bond. The reaction takes a different course, however, in that the product arises through a cyclic rearrangement to form a product with the same number of carbons. The product is a cyclic unsaturated structure with an additional exocyclic conjugated double bond.

Hydroxy derived structures may be formed from alkyne reagents as shown in the scheme above yielding cyclic hydroxylated conjugated dienes, and finally the target amino acid ester (BS).

The preparation of ring hydroxylated and unhydroxylated compounds using a ruthenium catalysed cyclization technique is discussed further below.

The substrates for the ring closing metathesis (RCM) reactions discussed in the Examples below were a, a- disubstituted glycine derivatives with the desired stereochemistry already built into the stereogenic center.

Carbenoid ruthenium (II) complexes are excellent catalysts in RCM reactions. More reactive, but less selective molybdenum complexes can be used. Tungsten complexes also effect RCM reactions.

The reaction scheme (A) shown below was used: The substrates for the RCM reaction were geminal diolefins 3 derived from (2R)-2,5-dihydro-3,6-dimethoxy- 2-isopropylpyrazine 1. Bisalkylation of the latter was effected in a stepwise manner which allowed for the 3a m=n=l 3b m=l, n=2 3cm=2, n=1 3d m=n=2 3e m=3, n=1 Compound Yield % d. e. % 2a 83 96 2b 92 75 2c 80 82 3a 81 3b 87 >95 3c 76 >95 3d 73 3e 65 >95 (i) nBuLi/THF/-78°C CH2CH (CH2) ber/-78 to 20°C (ii)nBuLi/THF/-50°C CH2CH (CH2) nBr/-78 to 20°C introduction of two different alkenes. The first alkylation step was effected by lithiation at-78°C using allyl, 4-bromo-1-butene and 5-bromo-1-pentene.

The yields of the monoalkylated products 2 were in the range 80-92%, the diastereomeric excess (d. e.) in the range 75-96%. The minor isomer can be removed and isolated by flash chromatography, but separation is not necessary since the overall stereochemistry in the reaction sequence is determined during the second alkylation step. The lithiation of the monalkylated products is slower than before the first alkylation, and was effected at-50°C. The lithiated species were subsequently cooled to-78°C and the second alkylating agent added. Once lithiated the second time, the stereochemistry at the initial alkylating site is lost.

The new alkylating agent will approach the reactive carbanionic center at the 5-position from the side of the ring opposite to the isopropyl group. The d. e. of the product 3 after the second alkylation step was excellent, as seen when different alkylating agents were used in the two steps (3b, 3c, 3e), in excess of 95%; the chemical yields were in the range 65-87%.

The RCM reactions were effected by adding catalytic amounts of bis (tricyclohexylphosphine)-benzylidine ruthenium dichloride, usually 2%, to a solution of the bis-olefin 3 in benzene or toluene (Scheme B below).

The progress of the reaction was monitored by GLC or TLC. The time and temperature varied for the reaction to go to completion; the rate was monitored by the disappearance of the substrate. The results from the RCM experiments are shown in Table 1. The catalyst complex seems sensitive to steric interaction from the isopropyl group of the substrate. An allyl group cis to the isopropyl group seems to be less reactive than in the trans position, and when the double bond is further removed by extension of the alkene; the formation of the six-membered ring structure 4b proceeded more readily than the formation of its isomer 4c. Support was further found in the relative ease of formation of the seven-membered ring structure 4d whereas formation of the five-membered ring structure 4a proceeded less readily from its diallyl precursor by RCM.

SCHEME B: Table 1. Formation of Cycloalkenes in Ru (II)-Catalyzed RCM Reactions Compound Temp (°C) Time (hours) Yield (%) 4a 100 18 53 4b 60 5 95 4c 20 23 99 4d 20 23 go 4e 80 8 60 Solvent: 4a toluene; 4b-4d benzene In the slow reaction for the formation of the five- membered ring structure 4a the reaction was effected in toluene at 100°C. The catalyst under these conditions became inactive after a few hours and a second 2% portion of the catalyst was added after 4 hours; 53% yield was obtained after 18 hours.

The low reactivity of the bisallyl derivative 3a in the formation of its RCM five-membered ring product 4a led to an alternative approach (Scheme C below) for the preparation of the amino acid target 8.

SCHEME C: The bisallyl derivative 3a was hydrolyzed under mild acid conditions with trifluoroacetic acid in acetonitrile at room temperature over 5 days. Mild conditions were necessary to avoid alternative reaction paths which lead to dipeptides. Prior to the RCM reaction the amino group was protected by acetylation.

There was a very significant change in the ease of the RCM reaction for the acyclic amino acid 6 and its precursor 3a; the RCM reaction for 3a gave 89% of the cyclic amino acid 7 after 4 hours at ambient temperature.

The bislactim ethers are generally hydrolyzed by acid under mild conditions, 0.25-0.50M HC1, to furnish their respective amino acid methyl esters. For the cyclic products 4, however, hydrolysis was slow under these conditions and the formation of dipeptides was a problem. Better results were obtained using slow 0.2M trifluoroacetic acid in acetonitrile allowing the reaction to proceed at ambient temperature for several days.

According to NMR and GLC, the RCM products 4b, 4c and 4e were diastereomerically pure. Accordingly the specific rotations of the enantiomeric pairs 8b and 8c after acid hydrolysis were found to be approximately the same with opposite rotational sign (see Scheme D below). Only one of the enantiomeric seven-membered rings, viz 8e, was prepared. The other enantiomer would be available by changing the order of the stepwise alkylation used in the preparation of the intermediate substrate 3, or by using the chiral auxiliary 1 with the opposite (2S)- configuration and retaining the order of the stepwise alkylation.

SCHEME D: To produce ring hydroxylated compounds, ring formation was again effected from geminal alkenyl derivatives (9 and 10) (Scheme E below). The chiral auxiliary was the bislactim ether reagent, (2R)-2,5-dihydro-3,6-dimethoxy- 2-isopropylpyrazine 1 which had the desired stereochemistry built into the stereogenic centre. The ring closing reactions were effected using a carbenoid ruthenium (II) complex as catalyst in the ring closure metathesis (RCM) reactions.

SCHEME E: The substrate 1 as its lithiated species was monalkylated with allyl, 4-bromo-1-butene and 5-brom-1- pentene at-78°C as described above. The diastereomeric excess (d. e.) is in the range 75-95%, but separation of the isomers was not effected since the overall stereochemistry in the reaction is determined during the subsequent aldol reaction. Acrolein used in the present work was exclusively involved in 1,2-addition to form the aldols 9 and 10. The lithiated bislactam ethers 2 formed exclusively trans-aldols relatively to the 2- isopropyl group (GLC, NMR). At the a-carbon, the hydroxyl carbon, the stereoselectivity was low. The a- (S) isomers 9 are characterised by H-bonding from the OH-group to the nearby 6-methoxy group; the hydrogen bonding was not seen in the a- (R) isomers. With lithium as counterion the isomer ratio 9: 10 was about 1: 2.

After exchange of the metal ion from lithium to tri- isopropoxytitanium, formation of the a- (R)-isomer 10 was favoured but the yield in the reaction was markedly reduced because of competing polymerization reactions of the acrolein. The complex with tris (diethylamide) titanium as counterion was found to provide strong stereoselective control over the aldol reactions. The aldol reaction of monoalkenylated bislactim ethers 2 were best effected at-50°C ; lower temperature decreased the yield.

The RCM reactions were effected according to Scheme F below in refluxing benzene solution using 2% bis (tricyclohexylphosphine) benzylidine ruthenium dichloride [Ru (II)] without protection of the hydroxyl group to yield the six-membered ring structures llb and 12b in yields 89 and 88%, respectively. The reaction time for the conversion of the a- (S)-isomer 9b to the RCM product llb was 14 hours, for the (R)-isomer 10b to 12b 3 days.

For the formation of the seven-membered rings lie and 12c by 2% Ru (II) promotion, reflux in 1,2-dichloroethane were the best conditions. The yields of the a- (S)- isomer llc and the a- (R)-isomer 12c were 59 and 47% after reflux for 17 hours and 24 hours, respectively.

Hydrolytic cleavage of the bislactim ether in the RCM products llb and 12b was effected with dilute TFA in acetonitrile at ambient temperature for 3 days; the isolated yields of the methyl esters of the target molecules 13a and 14a were 81 and 60%, respectively.

The conditions for generation of the seven-membered ring analogues of serine, viz 13b and 14b differed significantly. The a-(S)-isomer llc was the more reactive and yielded the cyclic serine ester in 66% yield with aqueous TFA in acetonitrile after 5 days.

The reaction with the less reactive a- (R)-isomer 12c was stopped after 10 days; the desired cyclic serine analogue 14b was isolated in 26% yield after flash chromatography. The other products were the dipeptides 15 and 1-6 which were formed in almost equimolar amounts (ca. 20%) by the two possible ways for ring opening of the pyrazine ring in 12c (see Scheme G below).

SCHEME G: Hydrolytic cleavage of the a- (R)-isomer 10a was attempted (see Scheme H below).

SCHEME H: (i) 10 eqv. 0.2M TFA/CH3CN, 8 days, 20°C (ii) Ac2O, DMAP/CH2C12, 2.5 hours, 20°C (iii) 2% Ru (II), CH2C12, 1 hour, 20°C The steric crowding is such that the desired hydrolysis was not effected; instead the dipeptide was formed in 61% yield after 8 days under the standard hydrolytic conditions. The latter was protected as the N-acetyl derivative before cyclization was attempted. The RCM reaction proceeded smoothly by reflux in dichloromethane to yield the five-membered serine analogue as a dipeptide 19.

Compounds of formula I with unsaturated side chains on the carbocyclic ring may be produced by reactions outlined in Scheme I below. The pathway is basically as discussed above. The stereochemistry at C-1 is determined by the order of alkenylation/alkynylation.

SCHEME I: Compounds of formula I in which D carries an alkenyl group may be prepared as described below using Schemes J, K and L using the bis (tricyclohexylphosphine)- benzylidene ruthenium dichloride (Ru (II)) catalyst system in the metathesis rearrangement (RCM) of enynes into the precursors for the cyclic amino acids.

SCHEME J: (a) nBuLi/THF,-78 to 20°C, 14 hours (b) nBuLi/THF,-50°C/alkyl.-78 to-20°C, 14 hours (i) CH2=CH (CH2) iBr (ii) propargyl bromide (iii)1-bromo-2-butyne (iv)4-bromo-1-butene The enyne substrates for the RCM reactions were prepared in a stereoselective manner by alkylation reactions of the Schollkopf chiral auxiliary, the bislactim ether 1.

(See Goodman et al. Pure Appl. Chem 68: 1303-1308 (1996) and Degrado in Adv. Protein Chem. 39 : 51-124 (1988)).

The alkylating agent was either an alkenyl or an alkynyl halide. The diastereomeric excess (d. e.) in the first alkylation step was variable. The stereochemical yield in this step, however, is of little importance in this context since the stereochemistry at C-5 in the initial products 2 or 25 is lost when the monoalkylated species are metallated again for the second alkylation. The d. e. in the second alkylation was invariably very high using propargyl bromide for the formation of the enyne 21. The isomer with the propargyl group in a trans- relationship to the isopropyl group was obtained.

When the alkenylation/alkynylation sequence of the bislactim ether is changed, the enynes formed have the opposite stereochemistry at C-5 allowing for the synthesis of enantiomeric target compounds without changing the configuration of the chiral auxiliary used in the reaction.

A methyl group was introduced indirectly on the acetylenic carbon by using 1-bromo-2-butyne for the alkylation of 2b, the product being the enyne 24a. Its isomer 24b with the opposite stereochemistry at C-5, was available by initial alkynylation of the bislactim ether 1 with 1-bromo-2-butyne to give 25 in high yield, but the d. e. was low (79%). The stereochemistry at C-5, however, is lost on lithiation. After the subsequent alkylation with 4-bromo-1-butene, the stereoisomer 24b was obtained (70% yield).

SCHEME K: (i) BuLi,-78 to 20°C/(CH2O) nl 14 hours (ii) Ac2O, DMAP, CH2Cl2, 20°C, 30 min In the enynes 21, an acidic and readily removable proton is situated on the terminal actylenic carbon. Hence substitution on the terminal alkyne carbon in the enyne 21 can be effected by lithiation and treatment with an electrophile; formaldehyde from paraformaldehyde was the reagent used for hydroxymethylation of the lithiated species of 21c with formation of the alcohol 26. The hydroxyl group in 26 was protected as the acetyl derivative 27 before the subsequent metathesis rearrangement.

SCHEME L: The amino acid products include compounds of formula where i is 0 or 1, Ru vis hydroxyl or an ester or amide forming group (eg. CH30 or an amino acid residue for example a valine residue) and Ry is H, CH3 or HOCH2 or an acylated hydroxymethyl group.

The metathesis reactions of the enyne substrates were effected in refluxing dry and deoxygenated benzene solution with 5% of the ruthenium carbene catalyst.

Benzene was a better choice than 1,2-dichloroethane and toluene (reflux) as solvent. In this manner the 1- vinylcyclohexenyl derivative 21c was formed in 81% yield and the five-membered ring derivative 28a in 73% yield.

The enyne with a terminal methyl group on the acetylenic carbon (S)-24a gave the cyclic product (5S)-28c in only 50% yield. In the analogous (R)-series, the yield of the cyclic product was significantly higher, viz. 86%, presumably due to differences in the non-bonded interactions in the formation of the two diastereomers 28c and 28d. If desired, in the process for the generation of 26c, the stereochemistry of the chiral bislactim auxiliary which is used for generating the enyne substrate may be changed.

The hydroxymethyl enyne 27 was protected as an acetyl derivative before ring-closure (71% yield) to the product 28e.

The spirane metathesis products 28 were all cleaved to the desired amino acid methyl esters 29 under mild acid conditions (Scheme L). 0.2 M trifluoroacetic acid in acetonitrile effected the hydrolysis. The five-membered ring derivative 28a was most difficult to hydrolyze; the yield of the amino acid ester 29a was 42%. An additional product (8% yield) from this reaction was identified as the partially hydrolyzed dipeptidic valine derivative 30. Hydrolysis of the acetyl derivative 28e gave the amino acid ester 29e in 65% yield. In accordance with the enantiomeric assignments, the stereoisomers 29c and 29d showed approximately the same figures for the optical rotations which were of opposite sign.

Thus it is clear that there is a useful ruthenium (II)- catalysed pathway to cyclic amino acids from enyne substrates. The latter are available by highly stereoselective alkylation reactions from bislactim ether chiral auxiliaries, eg. from 1 or its enantiomer.

The configuration at the new stereogenic centre in the cyclic amino acids is controlled either by the configuration of the chiral auxiliary or by the order of alkylation used in the preparation of the intermediate enyne substrates.

The Ru (II) metathesis cyclization reaction functions even where the double bonds in the pendant alkenyl groups are not in the terminal position. This is illustrated in Scheme M SCHEME M: This provides an alternative route to compounds such as 4c. The allylic alcohol substrate for the cyclization reaction is available by reaction of lithiated lactim ether 2b with vinyloxirane; the nucleophilic attack was on the terminal carbon of the double bond with concurrent opening of the epoxide ring to furnish the allylic alcohol 29.5% catalyst was used in the subsequent RCM reaction with formation of 4c.

Schemes N and O below demonstrate that hydroxylation at the ß-carbon of the cycloalkane portion of the RCM formed spiranes eventually translates into the 3 or portion of the cyclic amino acid compounds.

SCHEME N: Thus with BF3-etherate as catalyst, the attack on vinyloxirane by metallated bislactim ether 2b was at the terminal epoxide carbon to furnish secondary alcohols with 32a as the major alcohol isomer. In competitive reactions with attack on the other epoxide carbon, the epimeric hydroxymethyl derivatives 33a and 33b were formed in almost equimolar amounts.

A more convenient route for the preparation of the epimeric alcohols 32 has been found. For this purpose the butenyl lactim ether 2b, after lithiation, was alkylated using ethylene oxide to furnish the ethanol derivative 34. Subsequent oxidation of the primary alcohol function using Swern conditions furnished the aldehyde 35. Addition to the latter of vinylmagnesium bromide in ethereal solution at 0°C furnished a high yield of the epimeric alcohols 32a and 32b in a ratio of about 1: 1. Separation of the epimeric alcohols was by flash chromatography. Simple acylations of the alcohols furnished the acetates 36a and 36b, respectively.

After protection as acetate, the cyclization of the acetate 36 proceeded to the extent of 90-93-% yield of isolated cyclic product 37. Mild basic hydrolysis gave the cyclic spiro-alcohol 38. The bislactim ether in the spirane 38 was cleaved under the usual mild acid conditions with TFA. The products were the lactone 39a which can be opened to the acid form, and the hydroxy aminoacid 39b. Lactone formation is an acid catalyzed re-esterification process of the methyl ester. In this connectin it is important to point out that lactone formation is the basis for the assignment of stereochemistry to the hydroxy group in the lactone 39a and subsequently to the stereochemistry of its hydroxy precursors 38a, 37a, 36a and 32a.

SCHEME P: Referring to Scheme P, the hydroxymethyl derivatives 33a and 33b have also been cyclized using Ru (II)-catalysis producing the spiro compounds 40 and 41 in good yields.

The former, viz. 40, is a tricyclic structure. It is formed by an exchange of two alcoholic groups, ie. by displacement of the 5-methoxy group with insertion of the 2-hydroxymethyl function. The cyclization is rationalized as due to ruthenium catalysis under the conditions used to effect RCM. For the interchange to take place, the stereochemistry of the hydroxymethyl group must be such that five-membered ring formation is favourable. In the other isomer there was no exchange of alcoholic functions.

Using mild acidic conditions for cleavage of the bislactim ether, the tricyclic structure 40 gave the dipeptide 42 as the major product in which the cyclic amino acid is the N-terminal in the dipeptide with valine.

Dipeptides can be cleaved by acid hydrolysis to their respective amino acids.

When the bicyclic derivative 41 was subjected to the same acid conditions, the two dipeptides 43 and 44 were formed. The former arises by opening of the bislactim ring at the 3, 4-imino bond, the latter at the 5,6-imino bond, the former pathway being favoured.

In the cyclic amino compounds of formula I, D may carry an oxygen function. This oxygen function can either be a hydroxy functionality or an oxo group. The oxo derivative is either a target molecule in itself or acts as an intermediate for hydroxylation by a reductive process, by organometal additions, or is suitable for aminations.

In Scheme Q above, it is shown that oxo derivatives undergo the RCM reaction with formation of cyclic ketones, in this case a, a-unsaturated ketones 46. The substrates for the cyclization reactions were available from the hydroxy-alkenyl derivatives 9. The latter were converted to the ketones 45 under Swern oxidation conditions. Ru (II)-catalyst was used for the ring closing metathesis reactions which proceeded well. Mild acid hydrolysis furnished the oxo amino acid derivatives 47. Where RCM is used to generate spiro compounds containing a cycloalkene, the double bond in the cycloalkene may be used to introduce hydroxyl groups which will appear in the cyclic amino acid product.

Thus for example, hydroxylation may be achieved by epoxide formation (eg. effected by peracid oxidation) and subsequent ring opening, or by vicinal bishydroxylation, eg. by osmium tetroxide glycolation.

This is illustrated in Scheme R.

SCHEME R : OCH3 opening ofepoxide ring N 48 CH30 NX XAc02H (AcOH), NaOAc, CH2CI2 OOC, Shrs, S3% N OCH3 CH30NT). 2. S% Os04 (tBuOH) NMO acetone, water, OOC FCH3 XcH3 + H CH30 <) H 50a (59%) OH SOb (18%) OH O I M TFA H20,CH3CN 60% 200C, 3days HO"AcO, ,"NHZ Ac20 11 ; ,, NHCOCH3 I y---i I 7. HO COOCH3 DMAP, CHzCIz Ac0 COOCH3 20oc, 2days, 60% sol 52 After the reaction between the cyclopentenyl spirane 4a with peracetic acid at 0°C there was isolated an epoxide product. The reaction was stereoselective. The stereochemistry at the epoxide carbons has been assigned as shown in structure 48.

Subsequent reactions of the epoxide will lead to hydroxylated structures either before or after hydrolysis of the bislactim ring with formation of cyclic amino acid derivatives.

Glycolation has been effected using osmium tetroxide in reaction with the cyclopentene derivative 4a. The hydroxylation reaction proceeded well with the osmium reagent as catalyst and with NMO as cooxidant in aqueous acetone at about 0°C ; overall yield of isolated material was 77%. Two stereoisomers, 50a and 50b, were formed, in a ratio of about 3: 1. Mild acid hydrolysis carried out on the major glycol isomer furnished the highly water soluble bishydroxylated amino acid ester 51. For simple isolation and characterization, the latter was acetylated and isolated as the N-acetyl derivative 52.

The present invention will now be described further with reference to the following non-limiting Examples.

1H NMR spectra were recorded in CDCl3 at 300 MHz or 200 MHz with a Bruker DPX 300 or DPX 200. The 13C NMR spectra were recorded in CDCl3 at 75 MHz or 50 MHz.

Chemical shifts are reported in ppm using residual CHCl3 (7.24 ppm) and CDCl3 (77.00 ppm) as references. The mass spectra under electron impact conditions (EI) were recorded at 70 eV ionizing potential; methane or isobutane was used for chemical ionization (CI). The spectra are presented as m/z (% rel. int.). Dry THF, benzene and toluene were distilled from sodium and benzophenone. Dry 1,2-dichloroethane and dichloromethane were distilled from calcium. Benzene, toluene, 1,2-dichloroethane and dichloromethane were degassed by bubbling argon through the solvents.

Bis (tricyclohexylphosphine) benzylidine ruthenium dichloride was purchased from Strem Chemicals Inc., 7 Mulliken Way, Newburyport, MA.

Example 1 (2R. 5S)-5-Allyl-3, 6-dimethoxy-2.5-dihydro-2- isopropylpyrazine (2a) Prepared as described by Rose et al. J Chem. Soc. Perkin Trans. 1 1995, 157-165. Example 2 (2R, 5S)-5-(3-Butenyl)-2 5-dihydro-3 6-dimethoxy-2- isopropylpyrazine (2b) and (2R. 5R)-5- (3-butenyl)-2. 5- dihydro-3 6-dimethoxy-2-isopropylpyrazine nBuLi (5.30 ml, 11.13 mmol, 2.1 M in hexane) was added to a solution of (R)-2,5-dihydro-3,6-dimethoxy-2- isopropylpyrazine (2.00 g, 10.86 mmol) in THF (20 ml) under argon at-78°C. After 25 min, 4-bromo-1-butene (1.10 ml, 11.00 mmol) in THF (5 ml) was added dropwise over 20 minutes. The mixture was left to reach ambient temperature overnight before the reaction was quenched by addition of 0.1 M phosphate buffer (pH 7,15 ml).

The aqueous layer was extracted with dichloromethane (3 x 20 ml). The combined organic layers were dried (MgSO4) and evaporated to dryness. The residual product was purified by flash chromatography using 3% and 5% ethyl acetate in hexane as eluents; yield 1.36 g (92%, d. e. 75%) of a colourless oil. Found: C, 65.22; H, 9.09. Calc. for C13H22N202 : C, 65.51; H, 9.30%. [a] D = +6.9° (c = 1.04, CHCl3). 1H NMR (300 MHz): 5 0.64 (d, J7 Hz, 3H, CH3), 0.82 (d, J7 Hz, 3H, CH3), 1.69--2.25 (m, 5H, CH, 2 x CH2), 3.64 (s, 3H, CH30), 3.65 (s, 3H, CH30), 3.88 (m, 1H, H-2), 3.99 (m, 1H, H-5), 4.95 (m, 2H, CH2=), 5.75 (m, 1H, CH=). 13C NMR (75 MHz) : 6 16.50 (CH3), 19.00 (CH3), 28.92 (CH2), 31.63 (CH), 33.35 (CH2), 52.22 (2 x CH30), 54. 85 (C-5), 60. 71 (C-2), 114.40 (CH2=), 138.36 (CH=), 163.46 (C), 163.68 (C). MS (EI) : 238 (8, M+), 223 (41), 196 (29), 195 (100), 183 (17), 166 (16), 153 (64), 141 (95). MS (EI): M 238.1674. Calc. for C13H22N202 : 238.1681. The slower moving component isolated after flash chromatography was (2R 5R)-5-(3-butenvl)-2 5-dihydro- 3 6-dimethoxy-2-isopropylpyrazine : Colourless oil [a] D = -82.2° (c = 1.03, CHCl3). 1H NMR (300 MHz): 6 0.68 (d, J7 Hz, 3H, CH3), 1.02 (d, J7 Hz, 3H, CH3), 1.49-2.23 (m, 5H, CH, 2 x CH2), 3.62 (s, 3H, CH30), 3.63 (s, 3H, CH30), 3.87-3.97 (m, 2H, H-2, H-5), 4.97 (m, 2H, CH2=), 5.82 (m, 1H, CH=). 13C NMR (75 MHz): 5 17.35 (CH3), 19.48 (CH3), 30.18 (CH2), 31. 16 (CH), 34. 75 (CH2), 52. 09 (2 x CH30), 55.05 (C-5), 60.81 (C-2), 114.61 (CH2=), 138.35 (CH=), 162.91 (C), 163.63 (C). Example 3 (2R, 5S)-2, 5-Dihydro-3 6-dimethoxy-2-isopropyl-5- (4- pentenyl) pyrazine (2c) and (2R, 5R)-2, 5-dihydro-3. 6- dimethoxy-2-isopropvl-5- (4-pentenvl) pyrazine nBuLi (2.6 ml, 5.46 mmol, 2.1 M in hexane) was added dropwise to a solution of (R)-2,5-dihydro-3,6-dimethoxy- 2-isopropylpyrazine (971 mg, 5.27 mmol) in dry THF (15 ml) under argon at-78°C. After 20 minutes, 5-brom-1- pentene (0.65 ml, 5.46 mmol) in THF (2 ml) was added dropwise with stirring, the mixture allowed to reach ambient temperature overnight, 0.1 M phosphate buffer (pH 7,10 ml) added, the phases separated and the aqueous phase extracted with dichloromethane (3 x 20 ml). The combined organic extracts were dried (MgSO4), evaporated and the two residual isomers separated by flash chromatography using 3% and then 5% ethyl acetate in hexane as eluents: yield 1.07 g (80%, d. e. 82%). The product was a colourless oil. Found. C, 66.49, H, 9.49. Calc. for C14N24N202 : C, 66.23; H, 9.59%. [a] D = +6.1° (c = 1.45, CHCl3). 1H NMR (300 MHz): 6 0.63 (d, J7 Hz, 3H, CH3), 0.98 (d, J7 Hz, 3H, CH3), 1.31 (m, 2H, CH2), 1.71 (m, 2H, CH2), 1.95 (m, 2H, CH2), 2.19 (m, 1H, CH), 3.61 (s, 3H, CH30), 3.62 (s, 3H, CH30), 3.87 (m, 1H, H-2), 3.96 (m, 1H, H-5), 4.89 (m, 2H, CH2=), 5.73 (m, 1H, CH=). 13C NMR (75 MHz): 16.44 (CH3), 18.99 (CH3), 23.80 (CHO), 31.55 (CH), 33.52 (CH2), 33. 62 (CH2), 52.17 (2 x CH30), 55.27 (C-5), 60.61 (C-2), 114.28 (CH2=), 138.66 (CH=), 163.36 (C), 163.75 (C). MS (EI) : 252 (34, M+), 209 (58), 184 (11), 183 (100), 153 (26), 141 (45). The second product eluted on flash chromatography was (2R. 5R)-2, 5-dihydro- 3. 6-dimethoxy-2-isopropyl-5- 4-pentenyl) pyrazine : Colourless oil. [a] D =-88.6° (c = 0.57, CHCl3). 1H NMR (300 MHz): 5 0.70 (d, J7 Hz, 3H, CH3), 1.03 (d, J7 Hz, 3H, CH3), 1.45-2.16 (m, 6H, 3 x CH2), 2.18 (m, 1H, CH), 3.63 (s, 3H, CH30), 3.64 (s, 3H, CH30), 3.93 (m, 2H, H-2, H-5), 4.95 (m, 2H, CH2=), 5. 80 (m, 1H, CH=). 13C NMR (75 MHz): 5 17.52 (CH3), 19.57 (CH3), 25.31 (CH2), 31.32 (CH), 33.60 (CH2), 35.00 (CH2), 52.19 (2 x CH30), 55.69 (C-5), 60.89 (C-2), 114.34 (CH2=), 138.78 (CH=), 162.99 (C), 163.79 (C). Example 4 (2R)-5. 5-Diallyl-2, 5-dihydro-3 6-dimethoxy-2- isopropylpyrazine (3a) nBuLi (2.7 ml, 5.94 mmol, 2.2 M in hexane) was added to a solution of (R)-2,5-dihydro-3,6-dimethoxy-2- isopropylpyrazine (1.00 g, 5.43 mmol) in dry THF (10 ml) under nitrogen at-78°C. After 20 minutes, a solution of allyl bromide (0.51 ml, 5.97 mmol) in THF (2 ml) was added dropwise with stirring. The reaction mixture was left overnight to reach ambient temperature. The mixture was subsequently cooled to-78°C, and nBuLi (2.7 ml, 5.94 mmol, 2.2 M in hexane) was added. After 20 minutes, a solution of allyl bromide (0.51 ml, 5.97 mmol) in dry THF (2 ml) was added. The mixture was stirred at-78°C for 3 hours, the cold bath removed and the mixture stirred for 1 hour at ambient temperature before 0.1 M phosphate buffer (pH 7,20 ml) was added.

The phases were separated, the aqueous phase extracted with dichloromethane (3 x 20 ml) and the combined organic phases dried (MgSO4), evaporated and the residual product purified by flash chromatography using 2% ethyl acetate in hexane as eluent; yield 1.16 g (81%) of a colourless oil. Found: C, 67.95; H, 8.78. Calc. for C15H24N202 : C, 68.15; H, 9.15%. [a] D =-28.4° (c = 0.62, CHCl3). 1H NMR (200 MHz): 5 0.61 (d, J 6.8 Hz, 3H, CH3), 1.03 (d, J 6.8 Hz, 3H, CH3), 2.19-2.28 (m, 5H, CH, 2 x CH2), 3.61 (s, 3H, CH30), 3.63 (s, 3H, CH30), 3.79 (d, J 3.3 Hz, 1H, H-2), 4.90-5.02 (m, 4H, 2 x CH2=), 5.39-5.67 (m, 2H, 2 x CH=). 13C NMR (50 MHz): 5 17.08 (CH3), 19.49 (CH3), 30.45 (CH), 44.46 (CH2), 44.74 (CH2), 51.96 (CH30), 52.21 (CH30), 60.54 (C-2), 62.02 (C-5), 117.39 (CH2=), 118.12 (CH2=), 133.40 (CH=), 134.48 (CH=), 162.60 (C), 163.31 (C). MS (EI) : 264 (0.3, M+), 223 (59), 182 (11), 181 (100). Example 5 (2R. 5R)-5-Allyl-5- (3-butenyl)-2, 5-dihydro-3. 6-dimethoxy- 2-isopropylpyrazine (3b) nBuLi (1.10 ml, 2.31 mmol, 2.1 M in hexane) was added to a solution of (2R, 5S)-5-allyl-2,5-dihydro-3,6-dimethoxy- 2-isopropylpyrazine (514 mg, 2.29 mmol) in dry THF (15 ml) under argon at-50°C. After 30 minutes, the mixture was cooled to-78°C and 4-bromo-1-butene (0.25 ml, 2.40 mmol) in THF (1 ml) added dropwise. The solution was left to reach ambient temperature overnight, 0.1 M phosphate buffer (pH 7,10 ml) added, the phases separated, the aqueous phase extracted with dichloromethane (2 x 15 ml), the combined organic extracts dried (MgSO4) evaporated and the crude product purified by flash chromatography using 2% ethyl acetate in hexane as eluent; yield 554 mg (87%, d. e. >95%) of a colourless oil. [a] D =-32.8° (c = 1.27, CHCl3). Found: C, 68.61; H, 9.43. Calc. for C16H26N202 : C, 69.03; H, 9.41%. 1H NMR (200 MHz) : 5 0.63 (d, J 7 Hz, 3H, CH3), 1.05 (d, J 7 Hz, 3H, CH3), 1.59-2.56 (m, 7H, CH, 3 x CH2), 3.62 (s, 3H, CH30), 3.63 (s, 3H, CH30), 3.81 (d, J3 Hz, 1H, H-2), 4.81-5.01 (m, 4H, 2 x CH2=), 5.50-5.77 (m, 2H, 2 x CH=). 13C NMR (50 MHz): b 17.21 (CH3), 19.56 (CH3), 28. 61 (CH2), 30. 54 (CH), 39. 54 (CH2), 45. 09 (CH2), 52.03 (CH30), 52.18 (CH30), 60.75 (C-2), 61.73 (C-5), 114.13 (CH2=), 117.35 (CH2=), 134.56 (CH=), 138.32 (CH=), 162.47 (C), 163.65 (C). MS (EI) : 278 (1, M+), 237 (23), 235 (30), 223 (17), 196 (18), 195 (100), 153 (39), 141 (35), 123 (10). MS (EI) : M 278.1981. Calc. for C16H26N202 : 278. 1994. Example 6 (2R,5S)-5-Allyl-5- (3-butenyl)-2, 5-dihydro-3, 6-dimethoxy- 2-isopropylpyrazine (3c) nBuLi (1.20 ml, 2.52 mmol, 2.1 M in hexane) was added dropwise to a solution of (2R, 5S)-5- (3-butenyl)-2, 5- dihydro-3,6-dimethoxy-2-isopropylpyrazine and (2R, 5R)-5- (3-butenyl)-2,5-dihydro-3,6-dimethoxy-2- isopropylpyrazine (578 mg, 2.43 mmol) in THF under argon (15 ml) at-50°C. After 30 minutes, the solution was cooled to-78°C, allyl bromide (0.21 ml, 2.52 mmol) in THF (2 ml) added dropwise with stirring, the mixture allowed to reach ambient temperature overnight, phosphate buffer (pH 7,10 ml) added, the two phases separated and the aqueous phase extracted with dichloromethane (3 x 20 ml). The combined organic extracts were dried (MgSO4), evaporated and the residual product purified by flash chromatography using 2% ethyl acetate in hexane as eluent; yield 516 mg (76%, d. e.

>95%) of a colourless oil. Found: C, 69.30; H, 9.27. Calc. for C16H26N202 : C, 69.03; H, 9.41%. [a] D =-20.5° (c = 1. 00, CHCl3). 1H NMR (300 MHz): b 0.63 (d, J7 Hz, 3H, CH3), 1.05 (d, J7 Hz, 3H, CH3), 1.61-2.47 (m, 7H, 3 x CH2, CH), 3.63 (s, 3H, CH30), 3.64 (s, 3H, CH30), 3.81 (d, J3 Hz, 1H, H-2), 4.96 (m, 4H, 2 x CH2=), 5.43--5.82 (m, 2H, 2 x CH=). 13C NMR (75 MHz): 5 16.91 (CH3), 19.52 (CH3), 29. 11 (CH2), 30. 49 (CH), 38. 98 (CH2), 45. 37 (CH2), 52. 06 (CH30), 52.26 (CH30), 60.66 (C-2), 61.87 (C-5), 114.08 (CH2=), 118.16 (CH2=), 133.40 (CH=), 138.77 (CH=), 162.88 (C), 163.57 (C). MS (EI) : 278 (1, M+), 237 (51), 235 (23), 196 (12), 195 (100), 181 (12), 153 (27). MS (EI): M 278.1978. Calc. for C16H26N202 : 278. 1994. Example 7 (2R)-5, 5-Bis (3-butenyl)-2, 5-dihydro-3 6-dimethoxy-2- isopropylpyrazine (3d) nBuLi (1.10 ml, 2.31 mmol, 2.1 M in hexane) was added dropwise to a solution of (2R, 5S)-5- (3-butenyl)-2, 5- dihydro-3,6-dimethoxy-2-isopropylpyrazine and (2R, 5R)-5- (3-butenyl)-2,5-dihydro-3,6-dimethoxy-2- isopropylpyrazine (529 mg, 2.22 mmol) in THF (15 ml) under argon at-50°C. After 30 minutes, the solution was cooled to-78°C, 4-bromo-1-butene (0.25 ml, 2.31 mmol) in THF (2 ml) added dropwise with stirring, the reaction mixture allowed to reach ambient temperature overnight, 0.1 M phosphate buffer (pH 7,10 ml) added, the two phases separated, the aqueous phase extracted with dichloromethane (3 x 20 ml), the combined organic extracts dried (MgS04), evaporated and the residual product purified by flash chromatography using 2% ethyl acetate in hexane as eluent; yield 475 mg (73%) of a colourless oil. Found: C, 69.47; H, 9.41. Calc. for C17H28N202 : C, 69.82; H, 9.65%. [a] D =-26.0° (c = 1.09, CHCl3). 1H NMR (300 MHz): S 0.65 (d, J7 Hz, 3H, CH3), 1.07 (d, J7 Hz, 3H, CH3), 1.61-1.90 (m, 8H, 4 x CH2), 2.32 (m, 1H, CH), 3.64 (s, 3H, CH30), 3.65 (s, 3H, CH30), 3.85 (d, J3 Hz, 1H, H-2), 4.90 (m, 4H, 2 x CH2=), 5.74 (m, 2H, CH=). 13C NMR (75 MHz) : å 16.99 (CH3), 19.56 (CH3), 28. 53 (CH2), 29. 07 (CH2), 30. 55 (CH), 39. 51 (CH2), 40. 15 (CH2), 52. 12 (CH30), 52.22 (CH30), 60.79 (C-2), 61.50 (C-5), 114.05 (CH2=), 114.11 (CH2=), 138.38 (CH=), 138.84 (CH=), 162.65 (C), 163.89 (C). MS (EI) : 292 (1, M+), 277 (14), 249 (10), 237 (36), 196 (13), 195 (100), 153 (14). MS (EI): M 292.2163. Calc. for C17H28N202 : 292.2151 Example 8 (2R, 5S)-5-Allyl-2. 5-dihydro-3 6-dimethoxy-2-isopropyl-5- (4-pentenyl) vrazine ! 3e) nBuLi (1.30 ml, 2.73 mmol, 2.1 M in hexane) was added to a solution of (2R, 5S)-2,5-dihydro-3,6-dimethoxy-2- isopropyl-5- (4-pentenyl) pyrazine and (2R, 5S)-2,5- dihydro-3,6-dimethoxy-2-isopropyl-5- (4-pentenyl) pyrazine (622 mg, 2.46 mmol) in dry THF (20 ml) under argon at -50°C. After stirring for 1 hour, the solution was cooled to-78°C, allyl bromide (0.25 ml, 2.89 mmol) in THF (2 ml) added dropwise with stirring, the mixture left to reach ambient temperature overnight, 0.1 M phosphate buffer (pH 7,10 ml) added, the phases separated, the aqueous phase extracted with dichloromethane (3 x 20 ml) and the combined organic extracts dried (MgS04), evaporated and the residual product purified by flash chromatography using 2% ethyl acetate as eluent; yield 466 mg (65%, d. e. >95%) of a colourless oil. Found: C, 69.47; H. 9.81. Calc. for C17H28N202 : C, 69.82; H, 9.65%. [a] D =-13.6° (c = 0.96, CHCl3). 1H NMR (300 MHz): 5 0.62 (d, J7 Hz, 3H, CH3), 1.04 (d, J7 Hz, 3H, CH3), 1.07-2.45 (m, 9H, 4 x CH2, CH), 3.61 (s, 3H, CH30), 3.62 (s, 3H, CH30), 3.79 (d, J3 Hz, 1H, H-2), 4.90 (m, 4H, 2 x CH2=), 5. 50 (m, 1H, CH=), 5.70 (m, 1H, CH=). 13C NMR (75 MHz): 5 16.88 (CH3), 19. 50 (CH3), 23. 86 (CH2), 30. 49 (CH), 33. 67 (CH2), 39. 24 (CH2), 45. 41 (CH2), 51. 96 (CH30), 52.16 (CH30), 60.63 (C-2), 62.10 (C-5), 114.11 (CH2=), 118.00 (CH2=), 133.47 (CH=), 138.73 (CH=), 162.68 (C), 163.70 (C),. MS (EI) : 292 (10, M+), 252 (19), 251 (100), 209 (62), 195 (20). MS (EI) : M: 292.2152. Calc. for C17H28N202 : 292.2151. Example 9 (2R)-2, 5-Dihydro-3, 6-dimethoxy-2-isopropylpyrazine-5- spiro (3-cyclopentene) (4a) Bis (tricyclohexylphosphine) benzylidine ruthenium dichloride (24 mg, 0.029 mmol) in dry toluene (1 ml) was added to a solution of (2R)-5,5-diallyl-2,5-dihydro-3,6- dimethoxy-2-isopropylpyrazine (193 mg, 0.73 mmol) in dry toluene (10 ml) under argon, the mixture was heated at 100°C for 4 hours, and another portion of bis (tricyclohexylphosphine) benzylidine ruthenium dichloride (24 mg, 0.029 mmol) in dry toluene (1 ml) was added. The solution was heated under argon at 100°C with stirring overnight, the solvent evaporated at reduced pressure and the product isolated from the residual material by flash chromatography using 2% ethyl acetate in hexane as eluent; yield 92 mg (53%) of a colourless oil. Found: C, 65.88; H, 8.44. Calc. for C13H2oN202 : C, 66.07; H, 8.53%. [a] D =-43.2° (c = 0.47, CHCl3). 1H NMR (300 MHz): 5 0.66 (d, J7 Hz, 3H, CH3), 1.03 (d, J7 Hz, 3H, CH3), 2.17 (m, 1H, CH), 2.27 (m, 2H, CH2), 2.85 (m, 2H, CH2), 3.61 (s, 3H, CH30), 3.67 (s, 3H, CH30), 3.96 (d, J3 Hz, 1H, H-8), 5.65 (m, 2H, 2 x CH=). 13C NMR (75 MHz) : b 16.80 (CH3), 19.25 (CH3), 31. 21 (CH), 48.95 (CH2), 49.09 (CH2), 52.23 (CH30), 52.48 (CH30), 61.06 (C-8), 62.45 (C-5), 127.73 (CH=), 128.26 (CH=), 161.35 (C), 165.96 (C). MS (EI) : 236 (10, M+'), 221 (8), 194 (19), 193 (100), 179 (11), 178 (14). MS (EI): M 236.1504. Calc. for C13H20N202 : 236.1525. Example 10 (2R, 5R)-2, 5-Dihydro-3, 6-dimethoxy-3-isopropylpyrazine-5- spiro (3-cyclohexene) (4b) Bis (tricyclohexylphosphine) benzylidine ruthenium dichloride (17 mg, 0.020 mmol) in dry degassed benzene (1 ml) was added to a solution of (2R, 5R)-5-allyl-5- (3- butenyl)-2,5-dihydro-3,6-dimethoxy-2-isopropylpyrazine (291 mg, 1.05 mmol) in dry degassed benzene (30 ml) under argon at 60°C. After 5 hours, the solvent was evaporated and the product purified by flash chromatography using 2% ethyl acetate in hexane as eluent; yield 249 mg (95%) of a colourless oil. Found: C, 66.89; H, 8.61. Calc. for C14H22N202 : C, 67.17; H, 8.86%. [a] D = +24.6° (c = 0. 82, CHCl3). 1H NMR (300 MHz): 5 0.68 (d, J7 Hz, 3H, CH3), 1.04 (d, J7 Hz, 3H, CH3), 1.41-2.71 (m, 7H, 3 x CH2, CH), 3.61 (s, 3H, CH30), 3.64 (s, 3H, CH30), 3.92 (d, J3 Hz, H-3), 5.59 (m, 1H, CH=), 5.75 (m, 1H, CH=). 13C NMR (75 MHz): 5 16.96 (CH3), 19.33 (CH3), 21.35 (CH), 32.75 (CH2), 36.47 (CH2), 52.01 (CH30), 52.36 (CH30), 55.83 (C-6), 60.58 (C-3), 123.66 (CH=), 126.28 (CH=), 161.17 (C), 166.34 (C). MS (EI) : 250 (54, M+), 208 (13), 207 (100), 154 (21), 153 (40). MS (EI): M 250.1681. Calc. for C14H22N202 : 250.1681. Example 11 (2R, 5S)-2, 5-Dihydro-3 6-dimethoxy-3-isopropylpyrazine-5- spiro (3-cyclohexene) (4c) Bis (tricyclohexylphosphine) benzylidine ruthenium dichloride (10 mg, 0.013 mmol) in dry degassed benzene (1 ml) was added to a solution of (2R, 5S)-5-allyl-5- (3- butenyl)-2,5-dihydro-3,6-dimethoxy-2-isopropylpyrazine (175 mg, 0.63 mmol) in dry degassed benzene (15 ml). The mixture was stirred under argon for 23 hours at ambient temperature, the solvent evaporated and the product purified by flash chromatography using 5% ethyl acetate in hexane as eluent; yield 156 mg (99%) of a colourless oil. Found: C, 66.99; H, 8.40. Calc. for C14H22N202 : C, 67.17; H, 8.86%. [a] D =-102.3° (c = 1.45, CHC13). 1H NMR (300 MHz): 5 0.65 (d, J7 Hz, 3H, CH3), 1.05 (d, J7 Hz, 3H, CH3), 1.40-2.66 (m, 7H, 3 x CH2, CH), 3.59 (s, 3H, CH30), 3.63 (s, 3H, CH30), 3.93 (d, J3 Hz, 1H, H-3), 5.58 (m, 1H, CH=), 5.72 (m, 1H, CH=). 13C NMR (75 MHz): b 16.88 (CH3), 19.34 (CH3), 21.56 (CH2), 30.82 (CH), 32.71 (CH2), 36.65 (CH2), 51.94 (CH30), 52.26 (CH30), 55.82 (C-6), 60.51 (C-3), 123.57 (CH=), 126.17 (CH=), 160.96 (C), 166.15 (C). MS (EI) : 250 (50, M+), 208 (13), 207 (100), 196 (11), 154 (36), 153 (61), 123 (11). MS (EI): M 250.1679. Calc. for C14N22N202 : 250.1681. Example 12 (2R)-2. 5-Dihydro-3 6-dimethoxy-2-isopropylpyrazine-5- spiro- (4-cycloheptene) (4d) Bis (tricyclohexylphosphine) benzylidine ruthenium dichloride (13 mg, 0.015 mmol) in dry degassed benzene (1 ml) was added to a solution of (2R)-5,5-bis (3- butenyl)-2,5-dihydro-3,6-dimethoxy-2-isopropylpyrazine (230 mg, 0.79 mmol) in dry degassed benzene (20 ml) under argon at ambient temperature. The solution was stirred for 23 hours, the solvent evaporated and the residual product purified by flash chromatography using 2% ethyl acetate in hexane as eluent; yield 186 mg (90%) of a colourless oll. Found: C, 68.21; H, 8.95. Calc. for C15H24N202 : C, 68.15; H, 9.15%. 1H NMR (300 MHz): 0.62 (d, J7 Hz, 3H, CH3), 1.04 (d, J7 Hz, 3H, CH3), 1.52 (m, 2H, CH2), 2.02 (m, 4H, 2 x CH2), 2.21 (m, 1H, CH), 2.59 (m, 2H, CH2), 3.63 (s, 3H, CH30), 3.66 (s, 3H, CH30), 3.88 (d, J3 Hz, 1H, H-3), 5.74 (m, 2H, 2 x CH=). 13C NMR (75 MHz): 16.89 (CH3), 19.37 (CH3), 23.03 (CH2), 23.25 (CH2), 30. 87 (CH), 38. 30 (CH2), 38. 45 (CH2), 52. 03 (CH30), 52. 23 (CH30), 59. 88 (C-6), 60.34 (C-3), 131.86 (2 x CH=), 160.14 (C), 167.05 (C). MS (EI) : 264 (25, M+), 249 (26), 222 (18), 221 (100), 193 (40), 153 (21). MS (EI): 264.1849. Calc. for C15H24N202 : 264.1838. Example 13 (2R, 5S)-2, 5-Dihydro-3 6-dimethoxy-2-isopropylpyrazine-5- spiro (3-cycloheptene) (4e) Bis (tricyclohexylphosphine) benzylidine ruthenium dichloride (11 mg, 0.013 mmol) in dry benzene (1 ml) was added to a solution of (2R, 5S)-5-allyl-2, 5-dihydro-3,6- dimethoxy-2-isopropyl-5- (4-pentenyl) pyrazine (188 mg, 0.64 mmol) in benzene (10 ml) at 80°C. The mixture was refluxed for 8 hours, the solvent evaporated and the residual product purified by flash chromatography using 2% ethyl acetate in hexane as eluent; yield 101 mg (60%) of a colourless oil. Found: C, 68.38; H, 8.97. Calc. for C15H24N202 : C, 68. 15 ; H, 9.15%. [a] D = 79.8° (c = 0.5, CHCl3). 1H NMR (200 MHz): 5 0.64 (d, J7 Hz, 3H, CH3), 1.04 (d, J7 Hz, 3H, CH3), 1.49-2.75 (m, 9H, 4 x CH2, CH), 3.60 (CH30), 3.64 (CH30), 3.88 (d, J3 Hz, H-3), 5.50 (m, 1H, CH=), 5.78 (m, 1H, CH). 13C NMR (50 MHz): 5 16.96 (CH3), 19.35 (CH3), 20.37 (CH2), 29.21 (CH2), 30.93 (CH), 38.73 (CH2), 42.05 (CH2), 52.01 (CH30), 52.27 (CH30), 58.50 (C-6), 60.32 (C-3), 126.65 (CH=), 131.56 (CH=), 159.99 (C), 167.04 (C). MS (EI) : 264 (21, M+), 249 (11), 222 (17), 221 (100), 207 (12), 196 (26). MS (EI): M 264.1823. Calc. for C15H24N202 : 264.1838. Example 14 Methyl 2-allyl-2-amino-4-pentenoate (5) A solution of (2R)-5,5-diallyl-2,5-dihydro-3,6- dimethoxy-2-isopropylpyrazine (1.30 g, 4.92 mmol) in MeCN (40 ml) and 0.2 M TFA (250 ml, 50.00 mmol) was stirred at ambient temperature for 5 days, the solution evaporated almost to dryness at reduced pressure and water (20 ml) and dichloromethane (40 ml) added. The phases were separated, the aqueous layer brought to pH 10 by addition of conc. aq. ammonia, the aqueous mixture extracted with dichloromethane (3 x 50 ml), the combined dichloromethane extracts dried (MgSO4), evaporated and the product isolated by flash chromatography using dichloromethane/diethyl ether 2: 1 as eluent; yield 0.59 g (75%) of a colourless oil. Found: C, 64.37; H, 8.75. Calc. for CgH15NO2 : C, 63.88; H, 8.93%. 1H NMR (200 MHz) : 5 1.57 (s, 2H, NH2), 2.12,2.19 and 2.42,2.49 (2 x dd, J8 Hz and 6 Hz, 4H, 2 x CH2), 3.61 (s, 3H, CH30), 5.05 (m, 4H, 2 x CH2=), 5.57 (m, 2H, CH=). 13C NMR (50 MHz): 5 43. 89 (2 x CH2), 51. 88 (CH30), 60. 43 (C), 119.25 (2 x CHz=), 132.40 (2 x CH=), 176.50 (C=O). MS (CI-CH4) : 170 (65, M+ 1), 128 (100), 110 (40). Example 15 Methyl 2-acetamido-2-allyl-4-pentenoate (6) A solution of (2R)-5,5-diallyl-2,5-dihydro-3,6- dimethoxy-2-isopropylpyrazine (229 mg, 0.87 mmol) in 0.2 M TFA (43.5 ml, 8.70 mmol) and MeCN (10 ml) was stirred at ambient temperature for 5 days, the solution concentrated to about 10 ml under reduced pressure, brought to pH 10 using conc. aq. ammonia, extracted with dichloromethane (3 x 20 ml), the combined organic extracts dried (MgS04) and evaporated. The residual mixture was dissolved in dichloromethane (5 ml), N, N- dimethyl-4-aminopyridine (244 mg, 2.00 mmol) and acetic anhydride (0.20 ml, 2.00 mmol) added, the mixture stirred at ambient temperature overnight, the solution evaporated and the residual mixture subjected to flash chromatography. The desired product was isolated using dichloromethane/diethyl ether 9: 1 and 4: 1 as eluents; yield 144 mg (81%) ; white needles, m. p. 60°C. Found: C, 62.96; H, 8.03. Calc. for C1lHl7NO3 : C, 62.54; H, 8.11%. 1H NMR (200 MHz): 5 1.97 (s, 3H, CH3), 2.45,2.52 and 3.11, 3.17 (2 x dd, J7 Hz, 4H, 2 x CH2), 3.72 (s, 3H, CH30), 4.99 (m, 4H, 2 x CH2=), 5.45-5.59 (m, 2H, 2 x CH=), 6.25 (s, 1H, NH). 13C NMR (50 MHz): 5 23.74 (CH3), 38.78 (2 x CH2), 52.51 (CH30), 64.04 (C), 118.87 (2 x CH2=), 132.12 (2 x CH=), 169.13 (C=O), 173.29 (C=O). MS (CI-iBu): 212 (100, M+1), 196 (10), 184 (6). MS (EI) : M 211.1194. Calc. for C1lHl7NO3 : 211.1208. Example 16 Methyl l-acetamido-3-cyclopentene-carboxylate (7) Bis (tricyclohexylphosphine) benzylidine ruthenium dichloride (13 mg, 0.016 mmol) in dry degassed benzene (1 ml) was added to a solution of methyl 2-acetamido-2- allyl-4-pentenoate (166 mg, 0.79 mmol) in dry degassed benzene (20 ml) under argon, the mixture stirred for 4 hours at ambient temperature, the solvent evaporated and the residual product purified by flash chromatography using dichloromethane/diethyl ether 1: 1 as eluent; yield 127 mg (89%), white solid material, m. p. 155°C. Found: C, 59.31; H, 7.02. Calc. for CgH13NO3 : C, 59.00; H, 7.15%. 1H NMR (300 MHz): 5 1.95 (s, 3H, CH3), 2.61,3.04 (2 x d, J14 Hz, 4H, H-2 and H-5), 3.71 (s, 3H, CH30), 5.63 (s, 2H, H-3 and H-4), 6.15 (s, 1H, NH). 13C NMR (75 MHz) : 5 23.13 (CH3), 44.48 (C-2 and C-5), 52.70 (CH30), 64.10 (C- 1), 127.77 (C-3 and C-4), 169.82 (C=O), 174.20 (C=O). MS (CI-iBu): 184 (100, M+1), 152 (12). MS (E1) : M 183.0909. Calc. for CgH13NO3 : 183.0895. Example 17 Methyl 1-amino-3-cyclopentene-1-carboxylate (8a) A solution of (2R)-2,5-dihydro-3,6-dimethoxy-2- isopropylpyrazine-5-spiro (3-cyclopentene) (98 mg, 0.42 mmol) in TFA (21 ml, 4.20 mmol, 0.2 M) and MeCN (5 ml) was left at ambient temperature for 8 days, the solution concentrated to about 10 ml and dichloromethane (20 ml) added. The two phases were separated, the pH of the aqueous solution brought to 10 by adding conc. aq. ammonia, the mixture extracted with dichloromethane (3 x 15 ml), the organic solution dried (MgS04), evaporated and the product isolated by flash chromatography using 3% methanol in dichloromethane as eluent; yield 26 mg (45%) of a colourless oil. Found: C, 61.20; H, 8.14. Calc. for C7H1lNO2 : C, 59.99; H, 7.85%. 1H NMR (200 MHz): 5 1.40 (s, 2H, NH2), 2.29,2.97 (dd, J16 Hz, 4H, 2 x CH2), 3.72 (s, 3H, CH30), 5.68 (s, 2H, 2 x CH=). 13C NMR (50 MHz): 5 47.16 (C-2, C-5), 52.39 (CH30), 63.36 (C-1), 127.80 (C-3, C-4), 177.76 (C=O). MS (EI) : 115 (7), 112 (4), 82 (M+-CO2CH3, 100), 81 (7), 80 (15). Example 18 (R) Methyl 1-amino-3-cyclohexene-1-carboxylate (8b) A solution of (2R, 5R)-2,5-dihydro-3,6-dimethoxy-3- isopropylpyrazine-5-spiro (3-cyclohexene) (177 mg, 0.71 mmol) in TFA (36 ml, 7.20 mmol, 0.2 M) and MeCN (36 ml) was stirred at ambient temperature for 3 days, the solution concentrated to about 10 ml and dichloromethane (20 ml) added. The aqueous phase was separated and brought to pH 10 with conc. aq. ammonia, the mixture extracted with dichloromethane (2 x 20 ml), the combined organic solutions dried (MgSO4), evaporated and most of the methyl valinate removed from the residual material by bulb to bulb distillation, 25°C/0. 6 mmHg (10 min). The residual product was purified by flash chromatography using 3% methanol in dichloromethane as eluent; yield 64 mg (58%) of a colourless oil. Found: C, 60.72; H, 8.18. Calc. for C8H13NO2 : C, 61.91; H, 8.44%. [a] D =-19.2° (c = 0.50, CHCl3). 1H NMR (300 MHz): 5 1.61-2.61 (m, 8H, 3 x CH2, NH2), 3.69 (s, 3H, CH30), 5.58-5.71 (m, 2H, 2 x CH=). 13C NMR (50 MHz): 5 21.73 (CH2), 31.13 (CH2), 35.27 (CH2), 52.11 (CH30), 55.58 (C- 1), 123.54 (CH=), 125.87 (CH=), 177.19 (C=O). MS (EI) : 155 (1, M+), 101 (29), 95 (100), 79 (22). MS (EI) : M 155.0941. Calc. for C8H13NO2 : 155.0946. Example 19 (S) Methyl 1-amino-3-cyclohexene-l-carboxylate (8c) A solution of (2R, 5S)-2,5-dihydro-3,6-dimethoxy-3- isopropylpyrazine-5-spiro (3-cyclohexene) (118 mg, 0.47 mmol) in TFA (23.5 ml, 4.70 mmol, 0.2 M) and MeCN (23.5 ml) was kept at ambient temperature for 3 days, the solution evaporated almost to dryness at reduced pressure, water (5 ml) and dichloromethane (10 ml) added and the two layers separated. The aqueous solution was brought to pH 10 by addition of conc. aq. ammonia, the mixture extracted with dichloromethane (3 x 20 ml), the organic extracts dried (MgSO4), evaporated and the product isolated by flash chromatography using 3% methanol in dichloromethane as eluent ; yield 31 mg (42%) of a colourless oil. [a] D = +19.5° (c = 0. 62, CHCl3). 1H NMR (300 MHz): 5 1.61-2.61 (m, 8H, 3 x CH2, NH2), 3.69 (s, 3H, CH30), 5.58-5.71 (m, 2H, 2 x CH=). 13C NMR (75 MHz): 5 21.82 (CH2), 31.24 (CHO), 35.39 (CH2), 52.18 (CH30), 55.67 (C), 123.63 (CH=), 125.96 (CH=), 177.30 (C=0). MS (EI) : 101 (28), 96 (100), 79 (31). MS (EI): M 155.0956. Calc. for C8H13NO2 : 155.0946. Example 20 Methylw 1-amino-4-cycloheptene-l-carboxylate (8d) A solution of (2R)-2,5-dihydro-3,6-dimethoxy-2- isopropylpyrazine-5-spiro (4-cycloheptene) (186 mg, 0.70 mmol) in MeCN (35 ml) and TFA (35 ml, 7.00 mmol, 0.2 M) was stirred at ambient temperature for 3 days, the solution concentrated to about 10 ml and dichloromethane (20 ml) added. The two phases were separated, the aqueous phase brought to pH 10 by addition of conc. aq. ammonia, extracted with dichloromethane (3 x 20 ml), the solvent removed by distillation, and most of the methyl valinate removed from the residue by careful bulb to bulb distillation at 25°C/0. 05 mmHg (45 min). The residual product was purified by flash chromatography using 3% methanol in dichloromethane as eluent; yield 83 mg (69%) of a colourless oil. Found: C, 62.61; H, 8.39. Calc. for CgN15NO2 : C, 63.88; H, 8.94%. 1H NMR (300 MHz) : 5 1.53-2.30 (m, 10H, 4 x CH2, NH2), 3.67 (s, 3H, CH30) 5.66 (m, 2H, 2 x CH=). 13C NMR (75 MHz): 5 23.45 (2 x CH2), 36.50 (2 x CH2), 52.07 (CH30), 60.71 (C), 131.13 (2 x CH=), 178.13 (C=O). MS (EI) : 169 (1, M+), 110 (100), 93 (11). MS (EI) : M 169.1101. Calc. for C9H15NO2 : 169.1103. Example 21 (S) Methyl l-amino-3-cycloheptene carboxylate (8e) A solution of (3R, 6S)-2,5-dihydro-3,6-dimethoxy-2- isopropylpyrazine-5-spiro (3-cycloheptene) (100 mg, 0.38 mmol) in MeCN (19 ml) and 0.2 M TFA (19 ml, 3.70 mmol) was stirred for 5 days at ambient temperature. The solution was concentrated to about 10 ml, dicliloromethane (10 ml) added, the layers separated, the aqueous solution brought to pH 10 by addition of conc. aq. ammonia, the mixture extracted with dichloromethane (3 x 10 ml), the organic extracts dried (MgSO4), evaporated and the methyl valinate removed from the residual material by bulb to bulb distillation at 25°C/0. 05 mmHg (10 min). The residual product was purified by flash chromatography using 3% methanol in dichloromethane as eluent; yield 46 mg (73%) of a colourless oil. [a] D =-12.8° (c = 0.78, CHCl3). 1H NMR (200 MHz): 5 1.46-2.58 (m, 10H, 4 x CH2, NH2), 3.65 (s, 3H, CH30), 5.57 (m, 1H, CH=), 5.90 (m, 1H, CH=). 13C NMR (50 MHz): (5 21.54 (CH2), 28.30 (CH2), 37.27 (CH2), 41.51 (CH2), 51.97 (CH30), 57.81 (C-1), 126.31 (CH=), 134.49 (CH=), 176.97 (C=O). MS (EI) : 154 (8, M+-Me), 114 (28), 110 (100). Example 22 (2R. 5S, l'S)-5-Allyl-2, 5-dihydro-3 6-dimethoxy-5- (l- hydroxy-2-propenyl) 2-isopropylpyrazine (9a) and (2R, 5S. I'R)-5-allyl-2Z5-dihydro-3B6-dimethoxy-5-( hydroxy-2-propenyl)-2-isopropylpyrazine (l0a) nBuLi (3.90 ml, 8.61 mmol, 2.2 M in hexane) was added dropwise to a solution of (2R, 5S/R)-allyl-2,5-dihydro- 3,6-dimethoxy-2-isopropylpyrazine (1.76 g 7.83 mmol) in dry THF (10 ml) at-50°C under argon. Acrolein (0.80 ml, 11.74 mmol) in THF (3 ml) was added dropwise after 1 hour. The mixture was left to slowly reach ambient temperature overnight. Acetic acid (1 ml) and phosphate buffer (10 ml, pH 7,0.1 M) were added and the aqueous layer was extracted with dichloromethane (3 x 30 ml). The combined organic layers were dried (MgSO4) and concentrated. The products were separated by flash chromatography using hexane/ethyl acetate 7: 1 and 4: 1 as eluents. First eluted was (2R, 5S, 1'S)-5- allyl-2, 5- dihydro-36-dimethoxy-5- (l-hydroxy-2-propenyl)-2- isopropylpyrazine (9a): yield 532 mg (24%), white crystalline material, mp. 58°C. [a] D =-63.0° (c = 1.07, CHCl3). 1H NMR (300 MHz) : 5 0.64 (3H, d, J7 Hz, CH3), 1. 03 (3H, d, J7 Hz, CH3), 2.23 (1H, m, CH), 2.65 (1H, d, J7 Hz, OH), 2.65-2.93 (2H, m, CH2), 3.63 (3H, s, CH30), 3.67 (3H, s, CH30), 3.81 (1H, d, J3 Hz, H-2), 4.19 (1H, m, H-1'), 4.91-5.21 (4H, m, 2 x CH2=) 5.50-5.56 (2H, m, 2 x CH=). 13C NMR (75 MHz) : 5 17.48 (CH3), 19.56 (CH3), 30.65 (CH), 41.48 (CH2), 52.57 ( 2 x CH30), 61.17 (C-2), 65.26 (C-5), 76.39 (C-1'), 116.60 (CH2=), 118.03 (CH2=), 134.08 (CH=), 136.72 (CH=), 161.76 (2 x C). The second product eluted was (2R, 5S, l'R)-5-allyl-2 5- dihydro-36-dimethoxy-5- (1-hydroxy-2-propenyl)-2- isopropylpyrazine (10a) : yield 847 mg (39%) of a colourless oil. Found: C, 63.48; H, 8.32. Calc. for C1sH24N2o3 C, 64.26; H, 8.63%. [a] D =-16.9° (c = 0.75, CHCl3). 1H NMR (300 MHz): 5 0.60 (3H, d, J7 Hz, CH3), 1.01 (3H, d, J7 Hz, CH3), 2.21 (4H, m, CH, OH, CH2), 3.61 (3H, s, CH30), 3.62 (3H, s, CH30), 3.82 (1H, d, J3 Hz, H- 2), 4.04 (1H, m, H-1'), 4.88-5.17 (4H, m, 2 x CH2=), 5.22 (1H, m, CH=), 5.74 (1H, m, CH=). 13C NMR (75 MHz): 5 17.15 (CH3), 19.37 (CH3), 30.33 (CH), 40.35 (CH2), 52.25 (CH30), 52.32 (CH30), 60.35 (C-2), 65.11 (C-5), 77.82 (C- 1'), 177.19 (CH2=), 117.75 (CH2), 133.81 (CH=), 136.23 (CH=), 162.00 (C), 163.92 (C). MS (EI): 239 (12, M+ -CH2=CHCH2), 224 (10), 223 (35), 222 (37), 197 (22), 183 (30), 182 (13), 181 (100), 141 (69). Example 23 (2R, 5S, 1'S)-5- (3-Butenvl)-2, 5-dihydro-3, 6-dimethoxy-5- (1-hydroxy-2-propenyl)-2-isopropylpyrazine (9b) and (2R, 5S, l'R)-5-(3-butenyl)-2 5-dihydro-3 6-dimethoxy-5- (1-hydroxy-2-propenyl)-2-isopropylpyrazine (10b) nBuLi (1.90 ml, 3.99 mmol, 2.1 M in hexane) was added dropwise to a solution of (2R, 5R/S)-5- (3-butenyl)-2, 5- dihydro-3,6-dimethoxy-2-isopropylpyrazine (788 mg, 3.31 mmol) in dry THF (10 ml) at-50°C under argon. Acrolein (0.33 ml, 4.87 mmol) in THF (2 ml) was added dropwise after 45 minutes. The temperature was kept at-50°C for 30 minutes, and the reaction mixture was then left to slowly reach ambient temperature overnight. The reaction was quenched by addition of a saturated solution of ammonium chloride (10 ml). The aqueous layer was extracted with dichloromethane (3 x 20 ml), the combined organic layers dried (MgSO4), concentrated and the two products separated by flash chromatography using hexane/ethyl acetate 9: 1 and 4: 1 as eluent. (2R, 5S, 1'S)-5- (3-butenyl)-2, 5-dihydro-3, 6-dimethoxy-5- (1-hydroxy-2-propenyl-2-isopropylpyrazine (9b) was first eluted; yield 212 mg (22%) of a white oily material. [a] D =-53.5° (c = 1.90, CHCl3). 1H NMR (300 MHz) : 5 0.61 (3H, d, J7 Hz, CH3), 1.04 (3H, d, J7 Hz, CH3), 1.66-1.98 (4H, m, 2 x CH2), 2.26 (1H, m, CH), 2.83 (1H, d, J10 Hz, OH), 3.63 (3H, s, CH30), 3.65 (3H, s, CH30), 3.77 (1H, d, J3 Hz, H-2), 4.14 (1H, dd, H-1'), 4.87-5.18 (4H, m, 2 x CH2=), 5.51-5.80 (2H, m, 2 x CH=). 13C NMR (75 MHz): 5 17.16 (CH3), 19.52 (CH3), 29. 05 (CH2), 30. 59 (CH), 35. 48 (CH2), 52.19 (CH30), 52.56 (CH30), 60.76 (C-2), 64.63 (C- 5), 76.90 (C-1'), 114.22 (CH2=), 116.45 (CH2=), 136.86 (CH=), 138.40 (CH=), 162.13 (C), 164.66 (C). The slower moving component was (2R, 5S, 1'R)-5- (3-butenyl)-2. 5- dihydro-36-dimethoxy-5- (l-hydroxy-2-propenyl)-2- isopropylpyrazine (lOb) ; yield 464 mg (48%) of a colourless oily material. Found: C, 64.94; H, 8.93. Calc. for C16H26N203 : C, 65.27; H, 8.90%. [a] D =-10.1° (c = 1. 69, CHCl3). 1H NMR (300 MHz): 5 0.64 (3H, d, J7 Hz, CH3), 1.06 (3H, d, J7 Hz, CH3), 1. 66-2. 02 (4H, m, 2 x CH2), 2.17 (1H, d, J8 Hz, OH), 2.33 (1H, m, CH), 3.66 (3H, s, CH30), 3.67 (3H, s, CH30), 3.86 (1H, d, J3 Hz, H- 2), 4.06 (1H, t, J6 Hz, H-1'), 4.87-5.28 (4H, m, 2 x CH2=), 5.71-5.91 (2H, m, 2 x CH=). 13C NMR (75 MHz): 5 17.02 (CH3), 19.53 (CH3), 28.71 (CH2), 30.51 (CH), 34.98 (CH2), 52.36 (CH30), 52.47 (CH30), 60.61 (C-2), 64.91 (C- 5), 78.21 (C-1'), 114.25 (CH2=), 117.39 (CH2=), 136.35 (CH=), 138.63 (CH=), 162.27 (C), 164.24 (C). MS (EI) : 294 (0.2, M+), 237 (47), 196 (14), 195 (100), 153 (32), 141 (14). Example 24 (2R, 5S, 1'S)-2, 5-dihydro-3 6-dimethoxy-5- (l-hydroxy-2- propenyl)-2-isopropyl-5- (4-pentenyl) pyrazine (9c) and (2R, 5S, 1'R)-2, 5-dihydro-3 6-dimethoxy-5- (l-hydroxy-2 propenyl)-2-isopropyl-5- (4-pentenyl) pyrazine (10c) nBuLi (2.00 ml, 4.40 mmol, 2.2 M in hexane) was added to a solution of (2R, 5R/S)-2,5-dihydro-3,6-dimethoxy-2- isopropyl-5- (4-pentenyl) pyrazine (1.00 g, 3.98 mmol) in THF (10 ml) at-50°C under argon. Acrolein (0.40 ml, 6.03 mmol) in THF (3 ml) was added dropwise after 1 hour. The mixture was left to slowly reach ambient temperature overnight. Acetic acid (0.5 ml) and a solution of phosphate buffer (10 ml, 0.1 M, pH 7) was added, the aqueous layer extracted with dichloromethane (3 x 20 ml), the combined organic layers dried (MgSO4), concentrated and the products separated by flash chromatography using hexane/ethyl acetate 9: 1 and 7: 1 as eluents. First eluted was (2R, 5S. 1'S)-2, 5-dihydro-3 6- dimethoxy-5- (1-hydroxy-2-propenyl)-2-isopropyl-5- (4- pentenyl) pyrazine (9c): yield 272 mg (22%) of a colourless oily material. [a] D =-45.2° (c = 0.82, CHCl3). 1H NMR (300 MHz): 5 0.65 (3H, d, J7 Hz, CH3), 1.05 (3H, d, J7 Hz, CH3), 1.08-1.21 (2H, m, CH2), 1.85- 1.98 (4H, m, 2 x CH2), 2.27 (1H, m, CH), 2.83 (1H, d, J10 Hz, OH), 3.63 (3H, s, CH30), 3.65 (3H, s, CH30), 3.81 (1H, d, J3 Hz, H-2), 4.14 (1H, m, H-1'), 4.88-5.17 (4H, m, 2 x CH2=), 5.50-5.78 (2H, m, 2 x CH=). 13C NMR (75 MHz) : ã 17.21 (CH3), 19.54 (CH3), 23.94 (CH2), 30.67 (CH), 33. 65 (CH2), 35. 82 (CH2), 52. 18 (CH30), 52. 57 (CH30), 60.78 (C-2), 64.86 (C-5), 76.90 (C-1'), 114.24 (CH2=), 116.39 (CH2=), 136.94 (CH=), 138. 61 (CH=), 162.30 (C), 164.52 (C). The second eluted product was (2R, 5S. 1'R)-2, 5-dihydro-3 6-dimethoxy-5- (1-hydroxy-2- propenyl)-2-isopropyl-5- (4-pentenyl) pyrazine (10c) ; yield 530 mg (43%) of a colourless oily material. Found: C, 65.96; H, 88.4. Calc. for C17H28N203 : C, 66.20; H, 9.15%. [a] D =-3.2° (c = 1.40, CHC13). 1H NMR (300 MHz) : ã 0.63 (3H, d, J 7 Hz, CH3), 1.05 (3H, d, J 7 Hz, CH3), 1.04-2. 32 (7H, m, 3 x CH2, CH), 2.25 (1H, d, J 8 Hz, OH), 3.64 (3H, s, CH30), 3.66 (3H, s, CH30), 3.86 (1H, d, J 3 Hz, H-2), 4.02 (1H, m, H-1'), 4.86-5.24 (4H, m, 2 x CH2), 5.75-5.81 (2H, m, 2 x CH=). 13C NMR (75 MHz) : ã 16.99 (CH3), 19.48 (CH3), 23.50 (CH2), 30.50 (CH), 33.65 (CH2), 35.13 (CH2), 52.28 (CH30), 52.37 (CH30), 60.54 (C-2), 65.14 (C-5), 78.17 (C-1'), 114.17 (CH2=), 117.18 (CH2=), 136.44 (CH=), 138.64 (CH=), 162.44 (C), 163.99 (C). MS (EI) : 308 (1.4, At), 252 (15), 251 (56), 250 (14), 210 (14), 209 (100), 196 (47), 195 (14). MS (EI): M 308.2103. Calc. for C17H28N203 : 308.2100. Example 25 (2R. 5S, 2'S)-2, 5-Dihydro-3 6-dimethoxy-2- isopropvlpvrazine-5-spiro (2-hydroxy-3-cyclohexene) (llb) Bis (tricyclohexylphosphine) benzylidine ruthenium dichloride (12 mg, 0.015 mmol) in dry degassed benzene (1 ml) was added to a solution of (2R, 5S, 1'S)-5-3- butenyl)-2,5-dihydro-3,6-dimethoxy-5- (l-hydroxy-2- propenyl)-2-isopropylpyrazine (222 mg, 0.75 mmol) in dry degassed benzene (10 ml). The mixture was stirred at ambient temperature under argon for 14 h, the solvent distilled off and the product purified by flash chromatography using hexane/ethyl acetate 4: 1 as eluent; yield 178 mg (89%) of white crystalline material, mp. 66°C. Found: C 63.17, H, 8.15. Calc. for C14H22N203 : C 63.13, H 8.33%. [a] D = +53.7° (c = 1.49, CHCl3). 1H NMR (300 MHz): 5 0.65 (3H, d, J 7 Hz, CH3), 1.04 (3H, d, J 7Hz, CH3), 1.64-1.95 (2H, ABX, CH2), 2.13-2.28 (4H, m, CH2, OH, CH), 3.59 (3H, s, CH30), 3.64 (3H, s, CH30), 3.86 (1H, bs, H-2'), 3.92 (1H, d, J 3 Hz, H-3), 5.62 (1H, m, CH=), 5.78 (1H, m, CH=). 13C NMR (75 MHz): 5 16.85 (CH3), 19.42 (CH3), 23.07 (CH2), 30.68 (CH), 30.92 (CH2), 52.23 (CH30), 52.35 (CH30), 60.48 (C-5), 60.51 (C- 2), 73.02 (C-2'), 127.20 (CH=), 129.47 (CH=), 163.31 (C), 163.84 (C). MS (EI) : 266 (2.5, M). 224 (14), 223 (100), 221 (16), 197 (18), 154 (26), 153 (55), 123 (14). MS (EI): M 266.1627. Calc. for C14H22N203 : 266.1630. Example 26 (2R, 5S, 2'S)-2, 5-Dihydro-3. 6-dimethoxy-2- isopropylpyrazine-5-spiro (2-hydroxy-3-cycloheptene) (llc) Bis (tricyclohexylphosphine) benzylidine ruthenium dichloride (3 mg, 0. 004 mmol) in dry degassed 1,2- dichloroethane (0.5 ml) was added to a solution of (2R, 5S, 1'S)-2, 5-dihydro-3,6-dimethoxy-5- (l-hydroxy-2- propenyl)-2-isopropyl-5- (4-pentenyl) pyrazine (56 mg, 0.18 mmol) in dry degassed 1,2-dichloroethane (5 ml) under argon at ambient temperature. The mixture was stirred at this temperature for 1 h, heated at 80°C for 14 h, the solvent distilled off and the crude product purified by flash chromatography using hexane/ethyl acetate 4: 1 eluent; yield 30 mg (59%) of a white solid material, mp. 108-110°C. Found: C, 64.00; H, 8.50. Calc. for C15H24N203 : C, 64.26; H, 8.63%. [a] p = +53.7° (c = 0. 60, CHC13). 1H NMR (200 MHz): 5 0.67 (3H, d, J 7 Hz, CH3), 1.03 (3H, d, J 7 Hz, CH3), 1.54-2.28 (8H, m, 3 x CH3, CH, OH), 3.66 (6H, s, 2 x CH30), 3.95 (1H, d, J 3 Hz, H-3), 4.49 (1H, bs, H-2'), 5.59 (2H, m, 2 x CH=). 13C NMR (50 MHz): b 17.19 (CH3), 19.41 (CH3), 19.72 (CH2), 28.62 (CH2), 31.24 (CH), 38.46 (CH2), 52.56 (2 x CH30), 60.81 (C-2), 64.40 (C-5), 75.82 (C-2'), 127.47 (CH=), 132.11 (CH=), 163.48 (C), 163.74 (C). MS (EI) : 280 (10, AT), 238 (15), 237 (100). MS (EI) : M 280.1786. Calc. for ClsH24N2°3: 280. 1787. Example 27 (2R. 5S. 2'S)-2, 5-Dihydro-3, 6-dimethoxy-2- isopropylpyrazine-5-spiro (2-hydroxy-3-cyclohexene) (12b) Bis (tricyclohexylphosphine) benzylidine ruthenium dichloride (22 mg, 0.027 mmol) in dry degassed benzene (1 ml) was added to a solution of (2R, 5S, 1'R)-5- (3- butenyl)-2,5-dihydro-3,6-dimethoxy-5- (l-hydroxy-2- propenyl)-2-isopropylpyrazine (383 mg, 1.30 mmol) in dry degassed benzene (15 ml). The mixture was stirred at ambient temperature under argon for 3 d at ambient temperature, the solvent distilled off and the product purified by flash chromatography using hexane/ethyl acetate 4: 1 as eluent; yield 306 mg (88%) of a colourless oily material. Found: C 62.81, H, 8.13. Calc. for C14H22N203 : C 63.13, H 8.33%. [a] p =-127.5° (c = 1.02, CHCl3). 1H NMR (200 MHz): 5 0.68 (3H, d, J 7 Hz, CH3), 1.04 (3H, d, J 7Hz, CH3), 1.51-2.30 (6H, m, 2 x CH2, CH, OH), 3.63 (3H, s, CH30), 3.67 (3H, s, CH30), 3.99 (1H, d, J 3 Hz, H-3), 4.51 (1H, m, H-2'), 5.50 (1H, m, CH=), 5.75 (1H, m, CH=). 13C NMR (50 MHz): 6 17.20 (CH3), 19.33 (CH3), 19.33 (CH3), 21. 66 (CH2), 31.17 (CH), 33. 23 (CH2), 52. 25 (CH30), 52. 56 (CH30), 59. 96 (C-5), 60. 88 (C-2), 69.77 (C-2'), 128.41 (CH=), 128.95 (CH=), 163.80 (C), 165.60 (C). MS (EI) : 266 (1.7, M+), 223 (100), 205 (11), 197 (15), 154 (17), 153 (37), MS (EI): M 266.1618. Calc. for C14H22N203 : 266.1630. Example 28 (2R, 5S, 2'R)-2, 5-Dihydro-3, 6-dimethoxy-2- isopropylpyrazine-5-spiro (2-hydroxy-3-cycloheptene) (12c) Bis (tricyclohexylphosphine) benzylidine ruthenium dichloride (16 mg, 0. 019 mmol) in dry degassed 1,2- dichloroethane (1 ml) was added to a solution of (2R, 5S, 1'R)-2, 5-dihydro-3,6-dimethoxy-5- (l-hydroxy-2- propenyl)-2-isopropyl-5- (4-pentenyl) pyrazine (290 mg, 0.94 mmol) in dry degassed 1,2-dichloroethane (20 ml), the mixture was stirred under argon for 17 h at 80°C, the solvent distilled off and the product purified by flash chromatography using hexane/ethyl acetate 4: 1 eluent; yield 165 mg (63%) of a colourless oil material. Found: C, 64.00; H, 8.50. Calc. for C15H24N203 : C, 64.26; H, 8.63%. [a] D =-133.3° (c = 0.89, CHC13), 1H NMR (300 MHz): 5 0.65 (3H, d, J 7 Hz, CH3), 1.03 (3H, d, J 7 Hz, CH3), 1.03 (3H, d, J 7 Hz, CH3), 1,49-2.23 (8H, m, 3 x CH2, CH, OH), 3.62 (3H, s, CH30), 3.68 (3H, s, CH30), 3.95 (1H, d, J 3 Hz, H-3), 4.75 (1H, m, H-2'), 5.33 (1H, m, CH=), 5.68 (1H, m, CH=). 13C NMR (75 MHz): 6 17.14 (CH3), 19.34 (CH3), 19. 99 (CH2), 29. 12 (CH2), 31. 08 (CH), 39.88 (CH2), 52.22 (CH30), 52.50 (CH30), 60.51 (C-2), 63.74 (C-5), 74.26 (C-2'), 127.89 (CH=), 134.34 (CH=), 163.10 (C), 164.45 (C), MS (EI) : 280 (6, AT), 266 (19), 248 (30), 237 (75), 223 (100), 209 (54), 195 (42), 177 (100). Example 29 (lS 2S) Methyl 1-amino-2-hydroxy-3-cyclohexene-1- carboxylate (13a) (2R, 5S, 2'S)-2,5-Dihydro-3,6-dimethoxy-2- isopropylpyrazine-5-spiro (2-hydroxy-3-cyclohexene) (127 mg, 0.48 mmol) was stirred with trifluoroacetic acid (23.8 ml, 4.76 mmol, 0. 2 M) and acetonitrile (23.8 ml) at ambient temperature for 3 d. The solution was evaporated almost to dryness at reduced pressure, water (10 ml) and dichloromethane (20 ml) added, the aqueous layer made alkaline (pH 10) by addition of conc. ammonia, extracted with dichloromethane (2 x 20 ml), the combined organic layers dried (MgSO4), evaporated and the product isolated by flash chromatography using 5% and 10% methanol in dichloromethane; yield 66 mg (81%) of a colourless oily material. Found: C, 56.00; H, 7.50. Calc. for C8Hl3NO3 : C, 56.13; H. 7.65%. [a] D = +24.8° (c = 0.46, CHCl3). 1H NMR (300 MHz): b 1.81-2.11 (2H, m, CH2), 2.11 (2H, bs, NH2), 3.15 (3H, bs, CH2, OH), 3.73 (3H, s CH30), 4.14 (1H, bs, H-2), 5.68-5.79 (2H, m, 2 x CH=). 13C NMR (75 MHz): 5 22.61 (CH2), 28.42 (CH2), 52.26 (CH30), 60.18 (C-1), 71.78 (C-2), 127.84 (CH=), 128.97 (CH=), 175.40 (C=O). MS (EI) : 171 (0.7, AT), 103 (9), 102 (100), 101 (38), 94 (29), MS (EI): 171.0896. Calc. for C8H13NO3 : 171.0895. Example 30 (lS, 2S) Methyl 1-amino-2-hydroxy-3-cycloheptene-1- carboxylate (13b) (2R, 5S, 2'S)-2, 5-Dihydro-3,6-dimethoxy-2- isopropylpyrazine-5-spiro (2-hydroxy-3-cycloheptene) (116 mg, 0.41 mmol) was stirred with trifluoroacetic acid (21 ml, 4.20 mmol, 0.2 M) and acetonitrile (21 ml) at ambient temperature for 5 d, the mixture concentrated almost to dryness, water (10 ml) and dichloromethane (20 ml) added, the aqueous layer made alkaline (pH 10) by addition of conc. ammonia, the aqueous phase extracted with dichloromethane (2 x 15 ml), the organic phases combined, dried (MgSO4), evaporated and the product isolated by flash chromatography using 5% methanol in dichloromethane as eluent; yield 50 mg (66%) of a colourless oily material. [a] D =-11. 8° (c = 1.00, CHCl3). 1H NMR (300 MHz): b 1.28-2.53 (9H, m, 3 x CH2, NH2, OH), 3.68 (3H, s, CH30), 4.17 (1H, m, CH-OH), 5.59-5.79 (2H, m, 2 x CH=). 13C NMR (75 MHz): 5 22.91 (CH2), 27.91 (CH2), 38.95 (CH2), 51.90 (CH30), 61.97 (C-1), 75.32 (C- 2), 130.14 (CH=), 134.71 (CH=), 175.62 (C=O). Example 31 (1S 2R) Methyl 1-amino-2-hydroxy-3-cyclohexene-1- carboxylate (14a) (2R, 5S, 2'R)-2,5-Dihydro-3,6-dimethoxy-2- isopropylpyrazine-5-spiro (2-hydroxy-3-cyclohexene) (112 mg, 0. 42 mmol) was stirred with trifluoroacetic acid (21 ml, 4.20 mmol, 0.2 M) and acetonitrile (21 ml) at ambient temperature for 3 d, the acetonitrile evaporated, water (10 ml) and dichloromethane (20 ml) added, the aqueous layer made alkaline (pH 10) by addition of conc. ammonia, extracted with dichloromethane (2 x 20 ml), the combined organic layers dried (MgSO4), concentrated and the product isolated by flash chromatography using 5% and 10% methanol in dichloromethane; yield 43 mg (60%) of a colourless oily material. [a] D=-66. 4° (c = 0.84, EtOH). 1H NMR (300 MHz): 5 1.78-2.17 (7H, m, 2 x CH2, OH, NH2), 3.72 (3H, s, CH30), 4.47 (1H, bs, H-2), 5.53 (1H, m, CH=), 5.72 (1H, m, CH=). 13C NMR (75 MHz): 5 21.20 (CH2), 30.48 (CH2), 52.53 (CH30), 59.30 (C-1), 68.65 (C-2), 127.54 (CH=), 129.28 (CH=), 176.06 (C=O). MS (CI-CH4) : 172 (62, M + 1), 168 (71), 155 (11), 154 (100), 137 (15), 122 (25), 112 (26). Example 32 (1S. 2R) Methyl 1-amino-2-hydroxy-3-cycloheptene-1- carboxylate (14b) (2R, 5S, 2'R)-2, 5-Dihydro-3,6-dimethoxy-2- isopropylpyrazine-5-spiro (2-hydroxy-3-cycloheptene) (167 mg, 0.60 mmol) was stirred with trifluoroacetic acid (30 ml, 6.00 mmol. 0.2 M) and acetonitrile (30 ml) at ambient temperature for 10 days, the mixture concentrated almost to dryness, water (10 ml) and dichloromethane (20 ml) added, the aqueous layer made alkaline (pH 10) by addition of conc. ammonia, the aqueous phase extracted with dichloromethane (2 x 20 ml), the combined organic phases dried (MgSO4), evaporated and the product isolated by flash chromatography using 3% and 5% methanol in dichloromethane as eluent; yield 29 mg (26%) of a white solid mp. 74°C. Found: C, 59.08; H, 8.15. Calc. for C9Hl5NO3 : C, 58.36; H, 8.16%. [a] D =-69.8° (c = 0.56, CHCl3). 1H NMR (300 MHz): 5 1.43-2.39 (9H, m, 3 x CH2, NH2, OH), 3.73 (3H, s, CH30), 4.72 (1H, bs, H-2), 5.46 (1H, m, CH=), 5. 80 (1H, m, CH=). 13C NMR (75 MHz): 5 20.05 (CH2), 28.42 (CH2), 38.66 (CH2), 52.44 (CH30), 63.34 (C-1), 73.96 (C-2), 130.22 (CH=), 134.50 (CH=), 176.02 (C=O). (1S. 2'R) Methyl N-rl-amino-2-hydroxy-3-cycloheptene-1- carbonyl)-D-valinate (15) The second product eluted on flash chromatography of the reaction mixture yielding 14b (vide supra) was identified as the dipeptide 15,21%. 1H NMR (300 MHz): 5 0.89 (3H, d, J 7 Hz, CH3) 0.93 (3H, d, J7 Hz, CH3), 1.30- 2.25 (lOH, m, 3 x CH2, OH, NH2, CH), 3.71 (3H, s, Cl30) 4.37,4.40 (1H, dd, J 4 Hz, CH-NH), 4.99 (bs, CH-OH), 5.48 (1H, m, CH=), 5.85 (1H, m, CH=), 8.12 (1H, d, J 8 Hz, NH). 13C NMR (75 MHz): 5 17.69 (CH3), 19.17 (CH3), 20.75 (CH2), 28.07 (CH2), 30.79 (CH), 37.93 (CH2), 52 19 (CH30), 57. 16 (CH), 73. 93 (CH), 130. 23 (CH=), 133.79 (CH=), 172.32 (C=O), 177.30 (C=O). MS (EI) : 284 (0.3, M), 255 (3), 126 (100), 109 (32), 108 (36). (1S2R) Methyl 1- (R)-valinylamido-2-hydroxy-3- cycloheptene-1-carboxylate (16) The third product eluted on flash chromatography of the reaction mixture yielding 14b (vide supra) was identified as the dipeptide 16, yield 18%. 1H NMR (300 MHz): 5 0. 85 (3H, d, J 7 Hz, CH3), 1. 02 (3H, d, J Hz, CH3), 1.36-2.43 (lOH, m, 3 x CH2, OH, NH2), 3. 36 (1H, d, J 7 Hz, CH), 3.78 (3H, s, CH30), 4.80 (1H, s, CH-OH), 5.57-5.76 (2H, m, 2 x CH=), 7.87 (1H, s, NH). 13C NMR (75 MHz) 5 15.80 (CH3), 19.77 (CH3), 20.38 (CH2), 27.71 (CH2), 30. 61 (CH), 37. 62 (CH2), 52. 64 (CH30), 59. 99 (CH), 66.61 (C), 73.34 (CH), 128.54 (CH=), 136.44 (CH=), 172.34 (C), 175.99 (C). MS (CI-isobutane): 285 (100, M+1), 267 (62), 253 (11), 186 (11), 168 (15). Example 33 (2R, 1S 2''R) Methyl N-n-allyl-l-amino-l- (2-hydroxy-3- butene)-carbonyllvalinate(17) (2R, 5S, l'R)-5-allyl-2, 5-dihydro-3,6-dimethoxy-5- (l- hydroxy-2-propenyl)-2-isopropyl-pyrazine (847 mg, 3.02 mmol) was stirred in trifluoroacetic acid (150 ml, 30.00 mmol, 0.2 M) and acetonitrile (150 ml) for 8 d. The reaction mixture was then concentrated almost to dryness, water (20 ml) and dichloromethane (40 ml) added, the aqueous layer brought to pH 10 by addition of conc. ammonia, extracted with dichloromethane (3 x 25 ml), the combined organic layers dried (MgSO4), the solution concentrated and the product isolated by flash chromatography using 3% methanol in dichloromethane as eluent; yield 520 mg (61%) of a colourless oily material. Found: C, 58.42; H, 8.22. Calc. for C14H24N204 : C, 59.14; H, 8.51%. [a] D = +8.3° (c = 1.38, CHCl3). 1H NMR (300 MHz) : 0.88 (3H, d, J 7 Hz, CH3). 0. 91 (3H, d, J7 Hz, CH3), 1.40 (2H, bs, NH2), 2.12-2.61 (4H, m, CH2 CH, OH), 3.69 (3H, s, CH30), 4.11 (1H, d, J 7 Hz, CH-NH), 4.37 (1H, m, CH-OH), 5.08-5.34 (4H, m, 2 x CH2=), 5.67- 5.81 (2H, m, 2 x CH=), 8.10 (1H, d, J 8 Hz, NH). 13C NMR (75 MHz): 5 17.69 (CH3), 19. 09 (CH3), 30.52 (CH), 41.09 (CH2) 52.11 (CH30), 57.10 (CH), 61.86 (C), 77.95 (CH-OH), 119.16 (CH2=), 119.53 (CH2=), 132.33 (CH=), 135.57 (CH=), 172.14 (C=O), 176.06 (C=O). MS (CI-CH4) : 285 (100, M+1), 267 (72), 243 (12), 227 (42) 167 (19). Example 34 (2R, 1'S 2''R) Methyl N-r1-allyl-1-acetamido-1-(2- hydroxy-3-butene)-carbonyllvalinate (18) Acetic anhydride (35 Al, 0.37 mmol) was added dropwise to a solution of (2R, 1'S, 2"R) Methyl N- [l-allyl-l- amino-1-(2-hydroxy-3-butene)-carbonyl] valinate (87 mg, 0.31 mmol) in dry dichloromethane (3 ml) at ambient temperature, the mixture stirred under argon for 2.5 h, the solution evaporated to dryness at reduced pressure and the product isolated by flash chromatography using 3% methanol in dichloromethane as eluent; yield 79 mg (80%) of a white crystalline mateial, mp. 107-109°C. Found: C, 58.98; H, 7.94. Calc. for C16H26N205 : C, 58.88; H, 8.03%. [a] D = +6.1° (c = 0. 80, CHCl3). 1H NMR (300 MHz): 5 0. 90 (3H, d, J7 Hz, CH3), 0.92 (3H, d, J 7 Hz, CH3), 1.94 (3H, s, CH3), 2.15 (2H, m, CH, OH), 2.80,3.39 (2H, ABX, CH2), 3.69, (3H, s, CH30), 4.40 (1H, dd, CH- NH), 5.00-5.82 (7H, m, 2 x CH2, 2 x CH=, CH-OH), 6.92 (1H, s, NH), 7.73 (1H, d J 8 Hz, NH). 13C NMR (75 MHz): 1 17. 73 (CH3), 19.22 (CH3), 24.17 (CH3), 30. 74 (CH), 37. 21 (CH2), 52. 02 (CH30), 57. 82 (CH), 65. 87 (C), 71. 49 (CH), 117.62 (CH2=), 118.98 (CH2=), 132.00 (CH=), 135.28 (CH=), 169.99 (C=O), 171.23 (C=O), 171.85 (C=O). MS (EI) : 325 (0.5, At), 252 (17), 249 (10), 193 (11), 150 (85), 136 (21), 109 (48). Example 35 (2R, 1'S, 2''R) Methyl N-rl-acetamido-l- (2-hydroxy-3- cyclopentene)-1-carbonyllvalinate (19) Bis (tricyclohexylphosphine) benzylidine ruthenium dichloride (3 mg, 0.004 mmol) in dry degassed dichloromethane (0.5 ml) was added to a solution under argon of (2R, 1'S, 2''R) methyl N- [l-allyl-l-acetamido-l- (2-hydroxy-3-butene)-1-carbonyl] valinate (64 mg, 0.20 mmol) in dry degassed dichloromethane (5 ml) at ambient temperature. The mixture was stirred at ambient temperature for 18 h, the solution evaporated to dryness at reduced pressure and the crude product purified by flash chromatography using 5% methanol in dichloromethane as eluent: yield 50 mg (86%) of a white solid material, mp. 128-130°C. Found: C, 56.78; H, 7.35. Calc. for C, 4H22N205 : C, 56.36; H, 7.43%. [a] D =-12.1° (c = 0. 70, CHCl3). 1H NMR (300 MHz) : S 0.84 (3H, d, J 7 Hz, CH3), 0. 91 (3H, d, J 7 Hz, CH3), 2.03 (3H, s, CH3), 2.17 (1H, m, CH), 2.95,3.09 (2H, dd, J 17 Hz, CH2), 3.68 (3H, s, CH30), 3.92 (1H, bs, OH), 4.41,4.44 (1H, dd, J 5 Hz, CH-NH), 5.06 (1H, bs, CH-OH), 5.71 (1H, d, J 4 Hz, CH=), 5.88 (1H, d, J 4 Hz, CH=), 7.07 (1H, s, NH), 7.20 (1H, d, J 8 Hz, NH). 13C NMR (75 MHz): 5 17.50 (CH3), 19.05 (CH3), 23.70 (CH3), 30.73 (CH), 40.34 (CH2), 52.18 (CH30), 57.50 (CH), 66.83 (C), 80.68 (CH), 130.87 (CH=), 132.59 (CH=), 171.35 (C=O), 172.63 (C=O), 173.21 (C=O). MS (EI) : 298 (4, M+), 238 (14), 168 (11), 167 (12), 140 (21), 132 (47), 123 (50), 98 (93), 72 (100). Example 36 (2R, 5S)-5- (3-butenyl)-2, 5-dihvdro-3, 6-dimethoxy-2- isopropyl-5- (2-propynyl) pyrazine (21a) nBuLi (2.20 ml, 4.84 mmol, 2.2 M in hexane) was added to a solution of (2R, 5R/S)-5- (3-butenyl)-2, 5-dihydro-3,6- dimethoxy-2-isopropylpyrazine (1.06g, 4.44 mmol) in THF (15 ml) at-50°C under argon. The mixture was stirred for 45 minutes and cooled to-78°C. Propargyl bromide (0.75 ml, 6.66 mmol, 80% in toluene) in THF (2 ml) was added dropwise and the mixture was left to slowly reach ambient temperature overnight, 0.1 M phosphate buffer (pH 7,10 ml) added, the aqueous phase extracted with dichloromethane (3 x 20 ml). The combined organic extracts dried (MgSO4) and evaporated. The crude product was purified by flash chromatography using 5% diethyl ether in hexane as eluent; yield 1.04g (85%) of a colourless oil. Found: C, 69.13; H, 8.70. Calc. for C16H24N202 : C, 69.53; H, 8.75%. [a] D =-20.4° (c = 1.11, CHCl3). 1H NMR (200 MHz): 5 0.63 (d, J7 Hz, 3H, CH3), 1.07 (d, J7 Hz, 3H, CH3), 1.62-2.64 (m, 8H, 3 x CH2, 2 x CH), 3.67 (s, 6H, 2 x CH30), 3.99 (d, J3 Hz, 1H, H-2), 4.90 (m, 2H, CH2=), 5.75 (m, 1H, CH=). 13C NMR (50 MHz): 5 16.88 (CH3), 19.51 (CH3), 29. 09 (CH2), 30. 47 (CH), 31. 65 (CH2), 38. 54 (CH2), 52. 31 (CH30), 52. 39 (CH30), 60.90 (CH), 61.32 (C), 70.01 (C), 80.35 (C), 114.30 (CH2=), 138.31 (CH=), 162.46 (C), 164.01 (C). MS (EI) : 276 (2, M+), 261 (14), 237 (76), 233 (43), 196 (12), 195 (100), 179 (23), 153 (35). Example 37 (2R, 5S)-5- (3-butenyl)-5- (2-butynyl)-2, 5-dihydro-3, 6- dimethoxy-2-isopropylpyrazine (21b) To a solution of 2-butyn-1-ol methanesulphonate (657 mg, 4.44 mmol) in dry THF (10 ml) at-78°C was added a solution of (2R, 5R/S)-5- (3-butenyl)-2, 5-dihydro-3,6- dimethoxy-2-isopropylpyrazine (881 mg, 3.70 mmol) and nBuLi (2.71 ml, 4.07 mmol, 1.5 M in hexane) in THF (15 ml) at 78°C via a teflon tube. The solution was kept at -78°C for 4 hours and reached ambient temperature overnight. Phosphate buffer (10 ml, pH 7,0.1 M) was added. The aqueous phase was extracted with dichloromethane (3 x 30 ml). The combined organic phases were dried (MgSO4) and evaporated. The product was isolated by flash chromatography using 3% diethyl ether in hexane as eluent; yield 239 mg (18%) of a colourless oily material. Found: C, 70.28; H, 9.08. Calc. for C17H26N202 : C, 70.31; H, 9.02%. [a] D =-16.5° (c = 1. 56, CHCl3). 1H NMR (300 MHz): 5 0.64 (d, J7 Hz, 3H, CH3), 1.08 (d, J7 Hz, 3H, CH3), 1.61-2.55 (m, 10H, 3 x CH2, CH3, CH), 3.66 (s, 3H, CH30), 3.68 (s, 3H, CH30), 3.93 (d, J3 Hz, 1H, H-2), 4.90 (m, 2H, CH2=), 5.77 (m, 1H, CH=). 13C NMR (75 MHz): 5 3.53 (CH3), 16.90 (CH3), 19.53 (CH3), 29.23 (CH2), 30.54 (CH), 32.12 (CH2), 38.44 (CH2), 52.30 (CH30), 52.40 (CH30), 60.84 (C-2), 61.59 (C-5), 74.92 (C), 77.24 (C), 114.19 (CH2=), 138.56 (CH=), 162.85 (C), 163.69 (C). MS (EI) : 290 (2, M+), 275 (6), 247 (7), 238 (10), 237 (63), 196 (12), 195 (100), 153 (29). Example 38 (2R. 5S)-2, 5-dihydro-3. 6-dimethoxy-2-isopropylpyrazine-5- spiro (3-vinyl-3-cyclohexene) (22a) Bis (tricyclohexylphosphine) benzylidine ruthenium dichloride (6 mg, 0.008 mmol) in dry degassed benzene (1 ml) was added to a solution of (2R, 5R/S)-5- (3-butenyl)- 2,5-dihydro-3,6-dimethoxy-2-isopropyl-5- (2-propynyl)- pyrazine (70 mg, 0.25 mmol) in dry degassed benzene (5 ml) at 80°C under argon. The solution was stirred under argon at 80°C for 12 hours, the solvent evaporated and the residue purified by flash chromatography using 3% diethyl ether in hexane as eluent; yield 49 mg (70%) of a colourless oily material. 1H NMR (300 MHz): 5 0.66 (d, J7 Hz, 3H, CH3), 1.06 (d, J7 Hz, 3H, CH3), 1.23-2.70 (m, 7H, 3 x CH2, CH), 3.56 (s, 3H, CH30), 3.66 (s, 3H, CH30), 3.95 (d, J3 Hz, 1H, H-2), 4.90 (m, 2H, CH2=), 5.81 (bs, 1H, CH=), 6.35,6.41 (dd, J11 Hz, 1H, CH=). 13C NMR (75 MHz) 5 16.88 (CH3), 19.36 (CH3), 22.19 (CH2), 30.84 (CH), 32.69 (CH2), 35.55 (CH2), 52.05 (CH30), 52.37 (CH30), 55.90 (C-5), 60.53 (C-2), 109.38 (CH2=), 128.67 (CH=), 132.90 (CH=), 140.07 (C=), 161.01 (C), 166.04 (C). Example 39 (2R, 5S)-2, 5-dihydro-3. 6-dimethoxy-2-isopropylpyrazine-5- spirof3-(2-propenyl)-3-cyclohexenel (22b) Bis (tricyclohexylphosphine) benzylidine ruthenium dichloride (17 mg, 0.02 mmol) in dry degassed benzene (2 ml) was added to a solution of (2R, 5S)-5- (3-butenyl)-5- (2-butynyl)-2,5-dihydro-3,6-dimethoxy-2-isopropyl- pyrazine (118 mg, 0.41 mmol) in dry degassed benzene (10 ml) under argon at 80°C. The solution was stirred at 80°C for 18 hours. The solvent was then evaporated and the product purified by flash chromatography using 3% diethyl ether in hexane as eluent; yield 51 mg (43%) of a colourless oily material. [a] D =-11.4° (c = 0.51, CHC13). 1H NMR (300 MHz): 5 0.67 (d, J7 Hz, 3H, CH3), 1.07 (d, J7 Hz, 3H, CH3), 1. 41-2. 77 (m, 7H, 3 x CH2, CH), 1.91 (s, 3H, CH3), 3.56 (s, 3H, CH30), 3.66 (s, 3H, CH30), 3.95 (d, J3 Hz, 1H, H-2), 4.80 (d, J12 Hz, 2H, CH2=), 5.94 (m, 1H, CH=). 13C NMR (75 MHz): 5 16.88 (CH3), 19.38 (CH3), 20.78 (CH3), 22. 27 (CH2), 30. 84 (CH), 32.21 (CH2), 37.12 (CH2), 52.07 (CH30), 52.39 (CH30), 56.31 (C-5), 60.50 (C-2), 109.27 (CH2=), 123.94 (CH=), 133.29 (C=), 143.69 (C=), 160.89 (C), 166.23 (C). Example 40 (S) Methyl 1-amino-3-vinyl-3-cyclohexene-1-carboxylate (23a) A solution of (2R, 5S)-2,5-dihydro-3,6-dimethoxy-2- isopropylpyrazine-5-spiro (3-vinyl-3-cyclohexene) (0.5 mmol) in TFA (25 ml, 5.0 mmol, 0.2 M) and MeCN (25 ml) is kept at ambient temperature for 3 days, the solution evaporated almost to dryness at reduced pressure, water (5 ml) and dichloromethane (10 ml) added and the two layers separated. The aqueous solution is brought to pH 10 by addition of conc. aq. ammonia, the mixture extracted with dichloromethane (3 x 20 ml), the organic extracts dried (MgSO4), evaporated and the product isolated by flash chromatography using 3% methanol in dichloromethane as eluent; yield 40% of the title compound as a colourless oily material. Example 41 (S) Methyl 1-amino-3-(2-propenyl)-3-cyclohexene-1- carboxylate (23b) Prepared from (2R, 5S)-2, 5-dihydro-3,6-dimethoxy-2- isopropylpyrazine-5-spiro[3-(2-propenyl)-3-cyclohexene] by hydrolysis in aq. TFA/MeCN as described for 23a. Example 42 General procedure for the preparation of (2R, 5S)-5- alkenyl-2, 5-dihydro-3 6-dimethoxy-2-isopropyl-5-(2- propynyl) pyrazine (24) nBuLi (4.40 mmol, 2.2 M in hexane) was added to a solution of (2R, 5S)-5-alkenyl- 2, 5-dihydro-3,6- dimethoxy-2-isopropylpyrazine (4.00 mmol) in dry THF (15 ml) under argon at-50°C. The mixture was stirred for 45 min and cooled to-78°C. Propargyl bromide (6.00 mmol, 80% in toluene) in THF (2 ml) was added dropwise, the mixture left to slowly reach ambient temperature overnight, 0.1 M phosphate buffer (pH 7,10 ml) added and the aqueous layer extracted with dichloromethane (3 x 20 ml). The combined organic extracts were dried (MgSO4) and evaporated. The crude product was purified by flash chromatography using 2% diethyl ether in hexane as eluent. Example 42a (2R, 5S)-5-Allyl-2, 5-dihydro-3 6-dimethoxy-2-isopropyl-5- (2-propynyl) pyrazine (21a) was obtained from (2R, 5S)-5- allyl-2,5-dihydro-3,6-dimethoxy-2-isopropylpyrazine in 80% yield as a colourless oil. Found: C, 68.84; H, 8.40. Calc. for C15H22N202 : C, 68.67; H, 8.45%. [a] D = -32.5° (c = 1.23, CHCl3). 1H NMR (300 MHz): 5 0.62 (d, J7 Hz, 3H, CH3), 1. 05 (d, J7 Hz, 3H, CH3), 1.83 (t, J3 Hz, 1H, CH), 2.26-2.62 (m, 5H, 2 x CH2, CH), 3.66 (s, 3H, CH30), 3.67 (s, 3H, CH30), 3.98 (d, J3 Hz, 1H, H-2), 4.97 (m, 2H, CH2=), 5.63 (m, 1H, CH=). 13C NMR (75 MHz) : 5 17.09 (CH3), 19.52 (CH3), 30. 51 (CH), 31. 07 (CH2), 44. 01 (CH2), 52.29 (CH30), 52.41 (CH30), 60.82 (C-2), 61.47 (C- 5), 70.09 (CH), 80.42 (C), 117.92 (CH2=), 133.94 (CH=), 162.33 (C), 163.70 (C). MS (EI) : 262 (0.7, M+), 223 (54), 222 (11), 221 (42), 219 (25), 181 (100), 179 (72), 164 (22), 149 (46). MS (EI): M 262.1676. Calc. for C15N22N202 : 262.1681. Example 42b (2R. 5S)-5- (3-Butenyl)-2, 5-dihydro-3, 6-dimethoxy-2- isopropvl-5- (2-propynyl) pyrazine (21c) was obtained from (2R, 5S)-5- (3-butenyl)-2, 5-dihydro-3,6-dimethoxy-2- isopropylpyrazine in 85% yield as a colourless oil. Found: C, 69.13; H, 8.70. Calc. for C16H24N202 : C, 69.53; H, 8.75%. [a] D=-20.4° (c = 1.11, CHCl3). 1H NMR (200 MHz) : 6 0.63 (d, J7 Hz, 3H, CH3), 1.07 (d, J7 Hz, 3H, CH3), 1.62-2.64 (m, 8H, 3 x CH2, 2 x CH), 3.67 (s, 6H, 2 x CH30), 3.99 (d, J3 Hz, 1H, H-2), 4.90 (m, 2H, CH2=), 5.75 (m, 1H, CH=). 13C NMR (50 MHz): 5 16.88 (CH3), 19.51 (CH3), 29. 09 (CH2), 30. 47 (CH), 31. 65 (CH2), 38. 54 (CH2), 52.31 (CH30), 52.39 (CH30), 60.90 (CH), 61.32 (C), 70.01 (CH), 80.35 (C), 114.30 (CH2=), 138.31 (CH=), 162.46 (C), 164.01 (C). MS (EI) : 276 (2, M+). 261 (14), 237 (76), 233 (43), 196 (12), 195 (100), 179 (23), 153 (35). Example 43 (2R. 5S)-5- (3-Butenyl)-5- (2-butynyl)-2, 5-dihvdro-3, 6- dimethoxy-2-isopropylpyrazine (24a) nBuLi (1. 62 ml, 3.73 mmol, 2.3 M in heptane) was added to a solution of (2R, 5R/S)-5- (3-butenyl)-2, 5-dihydro-3,6- dimethoxy-2-isopropylpyrazine (807 mg, 3.37 mmol) in dry THF (15 ml) under argon at-50°C. The solution was cooled to-78°C after 45 min and 1-bromo-2-butyne (see Marson et al. J. Org. Chem 59: 284-290 (1994)) (585 mg, 4.40 mmol) in THF (0.5 ml) added dropwise. The solution was allowed to reach ambient temperature overnight, 0.1 M phosphate buffer (10 ml, pH 7) added, the aqueous phase extracted with dichloromethane (3 x 30 ml) and the combined organic phases dried (MgSO4) and evaporated. The pure product was flash chromatographed using 3% diethyl ether in hexane as eluent; yield 877 mg (89%) of a colourless oil. Found: C, 70.28; H, 9.08. Calc. for C17H26N202 : C, 70.31; H, 9.02%. [a] D =-16.5° (c = 1.56, CHCl3). 1H NMR (300 MHz): 6 0.64 (d, J7 Hz, 3H, CH3), 1.08 (d, J7 Hz, 3H, CH3), 1.61-2.55 (m, 10 H, 3 x CH2, CH3, CH), 3.66 (s, 3H, CH30), 3.68 (s, 3H, CH30), 3.93 (d, J3 Hz, 1H, H-2), 4.90 (m, 2H, CH2=), 5.77 (m, 1H, CH=). 13C NMR (75 MHz): 5 3.53 (CH3), 16.90 (CH3), 19.53 (CH3), 29.23 (CH2), 30.54 (CH), 32.12 (CH2), 38.44 (CH2), 52.30 (CH30), 52. 40 (CH30), 60. 84 (C-2), 61. 59 (C-5), 74.92 (C), 77.24 (C), 114.19 (CH2=), 138.56 (CH=), 162.85 (C), 163.69 (C). MS (EI) : 290 (2, M+), 275 (6), 247 (7), 238 (10), 237 (63), 196 (12), 195 (100), 153 (29). This is the same as the compound of Example 37 Example 44 (2R. 5S)-5- (2-Butynyl)-2, 5-dihydro-3, 6-dimethoxy-2- isopropylpyrazine (25) and (2R, 5R)-5-(2-butynyl)-2 5- dihydro-36-dimethoxy-2-isopropylpyrazine nBuli (2.00 ml, 2.30 mmol, 2.3 M in heptane) was added dropwise to a solution of (R)-2,5-dihydro-3,6-dimethoxy- 2-isopropylpyrazine (764 mg, 4.15 mmol) in dry THF (15 ml) at-78°C under argon. 1-Bromo-2-butyne (716 mg, 5.39 mmol) in THF (0.5 ml) was added dropwise after 15 min, the mixture allowed to reach ambient temperature overnight, the reaction quenched by addition of 0.1 M phosphate buffer (10 ml, pH 10), the aqueous layer extracted with dichloromethane (3 x 30 ml) and the combined organic layers dried (MgS04) and evaporated. The crude product was purified by flash chromatography using hexane/diethyl ether 9: 1 as eluent; yield 744 mg (76%, d. e. 79%) of a colourless oil (25). Found: C, 65.66; H, 8.35%. Calc. for Cl3H20N202 : C, 66.07, H, 8.53%. [a] D = +16.5° (c = 0.60, CHCl3). 1H NMR (300 MHz) : õ 0.62 (d, J7 Hz, 3H, CH3), 1. 00 (d, J7 Hz, 3H, CH3), 1. 65 (t, J2.5 Hz, 3H, CH3), 2.22 (m, 1H, CH), 2.57 (m, 2H, CH2), 3.65 (s, 6H, 2 x CH30), 3.92-4.03 (m, 2H, H-2, H- 5). 13C NMR (75 MHz): 6 3.45 (CH3), 16.40 (CH3), 19.02 (CH3), 25.28 (CH2), 31.45 (CH), 52.35 (CH30), 52.41 (CH30), 54.73 (C-5), 60.73 (C-2), 74.84 (C), 77.23 (C), 162.00 (C), 164.44 (C). MS (EI) : 236 (5, M+), 221 (6), 183 (52), 141 (100). MS (EI) : M236.1522. Calc. for C13H2oN202 : 236. 1525. A slower moving component during flash chromatography was was identified as (2R, 5R)-5- (2-butynyl)-2, 5-dihydro- 3,6-dimethoxy-2-isopropyl-pyrazine: Colourless oil. 1H NMR (300 MHz): b 0.73 (d, J7 Hz, 3H, CH3), 1.03 (d, J7 Hz, 3H, CH3), 1.67 (t, J3 Hz, 3H, CH3), 2.24 (m, 1H, CH), 2.63 (m, 2H, CH2), 3.66 (s, 3H, CH30), 3.67 (s, 3H, CH30), 3.88,4.05 (2 x m, 2H, H-2 and H-5). 13C NMR (75 MHz): 5 3.58 (CH3), 17.31 (CH3), 19.61 (CH3), 25.10 (CH2), 31. 08 (CH), 52. 32 (CH30), 52. 53 (CH30), 54.82 (C-5), 60.77 (C-2), 75.68 (C), 77.41 (C), 161.64 (C), 163.77 (C). Example 45 (2R, 5R)-5- (3-Butenyl)-5- (2-butynyl)-2, 5-dihydro-3, 6- dimethoxy-2-isopropylpyrazine (24b) nBuLi (1.33 ml, 3.08 mmol, 2.3 N in heptane) was added to a solution of (2R, 5S)-5- (2-butynyl)-2, 5-dihydro-3,6- dimethoxy-2-isopropylpyrazine (661 mg, 2.80 mmol) in dry THF (10 ml) under argon at-50°C. The solution was cooled to-78°C after 45 min and 4-bromo-1-butene (0.35 ml, 3.36 mmol) in THF (0.5 ml) was added dropwise. The mixture was left to slowly reach ambient temperature overnight. A 0.1 M phosphate bar solution (10 ml, pH 7) was addded and the aqueous phase was extracted with dichloromethane (3 x 20 ml). The combined organic layers were dried (MgSO4) and evaporated. The residue was purified by flash chromatography using 3% diethyl ether in hexane as eluent; yield 568 mg (70%) of a colourless oily material. Found: C, 70.09; H, 9.15. Calc. for C17H26N202 : C, 70.31; H, 9.02%. [a] D =-35.3° (c = 1. 13, CHCl3). 1H NMR (300 MHz): 5 0. 72 (d, J7 Hz, 3H, CH3), 1.08 (d, J7 Hz, 3H, CH3), 1.63 (t, J3 Hz, 3H, CH3), 1.61-2.68 (m, 7H, 3 x CH3, CH), 3.66 (s, 3H, CH30), 3.67 (s, 3H, CH30), 3.85 (d, J3 Hz, 1H, H-2), 4.88 (m, 2H, CH2=), 5.70 (m, 1H, CH=). 13C NMR (75 MHz): 5 3.60 (CH3), 16.99 (CH3), 19.61 (CH3), 28. 58 (CH2), 30. 58 (CH), 31. 39 (CH2), 39. 48 (CHz), 52.38 (2 x CH30), 60.91 (C-2), 61.58 (C-5), 75.82, (C), 77.28 (C), 114.29 (CH2=), 138.08 (CH=), 162.92 (C), 163.09 (C). MS (EI) : 290 (3, M+), 247 (20), 237 (34), 196 (12), 195 (100), 193 (13), 153 (22). MS (EI): M 290.2022, Calc. for C17H26N202 : 290.1994. Example 46 (2R,5S)-5- (3-Butenyl)-2, 5-dihydro-3. 6-dimethoxy-5- (4- hydroxy-2-butynyl)-2-isopropylpyrazine (26) nBuLi (2.00 ml, 4.60 mmol, 2.3 M in heptane) was added to a solution of (2R, 5S)-5- (3-butenyl)-2, 5-dihydro-3,6- dimethoxy-2-isopropyl-5- (2-propynyl) pyrazine (1.16 g, 4.18 mmol) in dry THF (10 ml) at-78°C under argon. The solution was transferred after 30 min via a Teflons tubing to a suspension of paraformaldehyde (188 mg, corresponding to 6.27 mmol of monomer) in THF (5 ml). The mixture was allowed to slowly reach ambient temperature overnight, 0.1 M phosphate buffer solution (pH 7,10 ml) added and the aqueous layer extracted with dichloromethane (3 x 15 ml). The combined organic layers were dried (MgSO4), evaporated and flash chromatographed using hexane/ethyl acetate 4: 1 as eluent; yield 964 mg (74%) of a white waxy material melting at 48°C. Found: C, 67.19; H, 8.43. Calc. for C17H26N203 : C, 66. 64 ; H, 8.55%. [a] D =-10.3° (c = 1.94, CHCl3). 1H NMR (200 MHz) : ã 0.63 (d, J7 Hz, 3H, CH3), 1.07 (d, J7 Hz, 3H, CH3), 1.63-2.67 (m, 8H, 3 x CH2, CH, OH), 3.67 (s, 6H, 2 x CH30), 3.97 (d, J3 Hz, 1H, H-2), 4.11 (s, 2H, CH20), 4.92 (m, 2H, CH2=), 5.77 (m, 1H, CH=). 13C NMR (50 MHz): 5 16.87 (CH3), 19.48 (CH3), 29.13 (CH2), 30. 54 (CH), 32. 12 (CH2), 38. 40 (CH2), 50. 98 (CH2O), 52.45 (2 x CH30), 60.80 (C-2), 61.51 (C-5), 80.32 (C), 82.04 (C), 114.33 (CH2=), 138.32 (CH=), 162.91 (C), 163.87 (C). MS (EI) : 306 (0.6, M+), 289 (22), 237 (65), 195 (100), 153 (27). MS (EI): M 306. 1922. Calc. for : 306.1943. Example 47 (2R, 5S)-5- (4-Acetoxy-2-butynyl)-5- (3-butenyl)-2, 5- dihydro-3 6-dimethoxy-2-isopropylpyrazine (27) Acetic anhydride (0.10 ml, 1.02 mmol) was added dropwise to a solution of (2R, 5S)-5- (3-butenyl)-2, 5-dihydro-3,6- dimethoxy-5- (4-hydroxy-2-butynyl)-2-isopropylpyrazine (285 mg, 0.93 mmol) and 4-dimethylaminopyridine (125 mg, 1.02 mmol) in dichloromethane (10 nml) at ambient temperature under argon. The solvent was evaporated after 30 min and the product isolated by flash chromatography using hexane/ethyl acetate (4: 1) as eluent; yield 299 mg (92%) of a colourless oily material. Found: C, 66.31; H, 8.16. Calc. for C1gH28N204 : C, 65.49; H, 8.10%. [a] D =-13.4° (c = 1.03, CHCl3). 1H NMR (300 MHz): 5 0. 63 (d, J7 Hz, 3H, CH3), 1.07 (d, J7 Hz, 3H, CH3), 1.62-1.90 (m, 4H, 2 x CH2), 2.04 (s, 3H, CH3C=O), 2.30-2.65 (m, 3H, CH2, CH), 3.66 (s, 3H, CH30), 3.67 (s, 3H, CH30), 3.97 (d, J3 Hz, 1H, H-2), 4.54 (t, J2 Hz, 2H, CHO), 4.95 (m, 2H, CH2=), 5.75 (m, 1H, CH=). 13C NMR (75 MHz): 16.88 (CH3), 19.54 (CH3), 20.68 (CH3), 29.13 (CH2), 30.46 (CH), 32.03 (CH2), 38.46 (CH2), 52.39 (2 x CH30), 52.53 (CH2O), 60.77 (C-2), 61.31 (C-5), 75.75 (C), 83.43 (C), 114.34 (CH2=), 138.34 (CH=), 162.29 (C), 164.05 (C), 170.21 (C=O). MS (EI) : 348 (0.6, M+), 305 (10), 289 (42), 237 (77), 195 (100), 153 (18). MS (EI): M 348.2059. Calc. for C1gH28N204 348. 2049. Example 48 General procedure for the preparation of (2R, 5S/R)-2, 5- dihydro-3 6-dimethoxy-2-isopropylpyrazine-5-spiro (3- alkenyl-3-cycloalkenes) (28) Bis (tricyclohexylphosphine) benzylidene ruthenium dichloride (0.036 mmol) in dry degassed benzene (3 ml) was added to a solution of (2R, 5S/R)-5-alkenyl-5- alkynyl-2,5-dihydro-3,6-dimethoxy-2-isopropylpyrazine (0.72 mmol) in dry degassed benzene (10 ml) and the mixture refluxed under argon for 14 h. The solvent was then evaporated, and the residue purified by flash chromatography using 2% diethyl ether in hexane as eluent. Example 48a (2R, 5S)-2, 5-Dihydro-3 6-dimethoxy-2-isopropylpyrazine-5- spiro (3-vinyl-3-cyclopentene) (28a) was obtained from (2R,5S)-5-allyl-2,5-dihydro-3,6-dimethoxy-2-isopropyl-5- (2-propynyl) pyrazine in 73% yield as a colourless oily material. Found: C, 68.65; H, 8.23. Calc. for C1sH22N2o2 : C, 68.67; H, 8.45%. [a] D = +13.1° (c = 1.35, CHCl3). 1H NMR (300 MHz): 5 0.66 (d, J7 Hz, 3H, CH3), 1.03 (d, J7 Hz, 3H, CH3), 2.21 (m, 1H, CH), 2.42 (m, 2H, CH2), 3.03 (m, 2H, CH2), 3.61 (s, 3H, CH30), 3.67 (s, 3H, CH30), 3.98 (d, J3 Hz, 1H, H-2), 5.03 (m, 2H, CH2), 5.62 (bs, 1H, CH=), 6.51,6.56 (dd, J 10 Hz, 1H, CH=). 13C NMR (75 MHz): 6 16.75 (CH3), 19.24 (CH3), 31.14 (CH), 47.08 (CH2), 49.13 (CH2), 52.22 (CH30), 52.44 (CH30), 61.03 (C- 2), 62.47 (C-5), 114.29 (CH2=), 127.45 (CH=), 133.24 (CH=), 140.48 (C=), 161.32 (C), 165.72 (C). MS (EI) : 262 (9, M+), 220 (15), 219 (100), 153 (20), 149 (12). MS (EI) : M 262.1666. Calc. for C15H22N202 : 262.1681. Example 48b (2R, 5S)-2, 5-Dihydro-3 6-dimethoxy-2-isopropylpyrazine-5- spiro (3-vinyl-3-cyclohexene) (28b) was obtained from (2R, 5S)-5- (3-butenyl)-2, 5-dihydro-3,6-dimethoxy-2- isopropyl-5- (2-propynyl) pyrazine in 81% yield as a white solid material, m. p. 68°C. Found: C, 69.00; H, 8.74. Calc. for C16H24N202 : C, 69.53; H, 8.75%. [a] D = +7.7° (c = 0.87, CHCl3). 1H NMR (300 MHz): 5 0.66 (d, J7 Hz, 3H, CH3), 1.06 (d, J7 Hz, 3H, CH3), 1.23-2.70 (m, 7H, 3 x CH2, CH), 3.56 (s, 3H, CH30), 3.66 (s, 3H, CH30), 3.95 (d, J3 Hz, 1H, H-2), 4.90 (m, 2H, CH2=), 5.81 (bs, 1H, CH=), 6.35,6.41 (dd, J11 Hz, 1H, CH=). 13C NMR (75 MHz) : b 16.88 (CH3), 19.36 (CH3), 22.19 (CH2), 30.84 (CH), 32.69 (CH2), 35.55 (CH2), 52.05 (CH30), 52.37 (CH30), 55.90 (C-5), 60.53 (C-2), 109.38 (CH2=), 128.67 (CH=), 132.90 (C=), 140.07 (CH=), 161.01 (C), 166.04 (C). MS (EI) : 276 (74, M+), 250 (12), 233 (98), 153 (93), 149 (95). MS (EI) M 276. 1843. Calc. for C16H24N202 : 276.1838. Example 48c (2R, 5S)-2, 5-Dihydro-3 6-dimethoxy-2-isoproylpyrazine-5- spiro (3-isopropenyl-3-cyclohexene) (28c) was obtained from (2R, 5S)-5- (3-butenyl)-5- (2-butynyl)-2, 5-dihydro- 3,6-dimethoxy-2-isopropylpyrazine in 51% yield as a colourless oil. [a] D =-11.4° (c = 0.51, CHCl3). 1H NMR (300 MHz): 5 0.67 (d, J7 Hz, 3H, CH3), 1.07 (d, J7 Hz, 3H, CH3), 1.41-2.77 (m, 7H, 3 x CH2, CH), 1.91 (s, 3H, CH3), 3.56 (s, 3H, CH30), 3.66 (s, 3H, CH30), 3.95 (d, J3 Hz, 1H, H-2), 4.80 (d, J12 Hz, 2H, CH2=), 5.94 (m, 1H, CH=). 13C NMR (75 MHz): 5 16.88 (CH3), 19.38 (CH3), 20.78 (CH3), 22. 27 (CH2), 30.84 (CH), 32.21 (CH2), 37.12 (CH2), 52.07 (CH30), 52.39 (CH30), 56.31 (C-5), 60.50 (C-2), 109.27 (CH2=), 123.94 (CH=), 133. 29 (C=), 143.69 (C=), 160.89 (C), 166.23 (C). MS (EI) : 290 (53, M+), 249 (14), 247 (69), 195 (30), 153 (100). MS (EI): M 290.1981. Calc. for C17H26N202 : 290. 1994. Example 48d (2R, 5R)-2, 5-Dihydro-3 6-dimethoxy-2-isopropylpyrazine-5- spiro (3-isopropenyl-3-cyclohexene) (28d) was obtained from (2R, 5R)-5- (3-butenyl)-5- (2-butynyl)-2, 5-dihydro- 3,6-dimethoxy-2-isopropylpyrazine in 86% yield as a colourless oil. Found: C, 70.21; H, 9.10. Calc. for C17N26N202 : C, 70.31; H, 9.02%. [a] D =-74.3° (c = 1.81, CHCl3). 1H NMR (300 MHz): 5 0.71 (d, J7 Hz, 3H, CH3), 1.06 (d, J7 Hz, 3H, CH3), 1.40-2.81 (m, 7H, 3 x CH2, CH), 1.91 (s, 3H, CH3), 3.57 (s, 3H, CH30), 3.66 (s, 3H, CH30), 3.94 (d, J3 Hz, 1H, H-2), 4.80 (d, J9 Hz, 2H, CH2=), 5.94 (m, 1H, CH=). 13C NMR (75 MHz): 5 17.00 (CH3), 19.36 (CH3), 20.76 (CH3), 21.98 (CH2), 31.08 (CH), 32.30 (CH2), 36.84 (CH2), 52.06 (CH30), 52.39 (CH30), 56.23 (C-5), 60.55 (C-2), 109.20 (CH2=), 124.08 (CH=), 133.24 (C=), 143.63 (C=), 161.00 (C), 166.29 (C). MS (EI) : 290 (100, M+), 247 (100), 153 (83). MS (EI) : M 290.1985. Calc. for C17H26N202 : 290.1994. Example 48e (2R. 5S)-2, 5-Dihydro-3 6-dimethoxy-2-isopropylpyrazine-5- spirof3- (3-acetoxy-l-propen-2-yl)-3-cyclohexenel (28e) was obtained from (2R, 5S)-5- (4-acetoxy-2-butynyl)-5- (3- butenyl)-2,5-dihydro-3,6-dimethoxy-2-isopropylpyrazine in 71% yield as a colourless oil. Found; C, 64.43; H, 8.04. Calc. for C19H28N204 : C, 65.49; H, 8.10. [a] D = -19.2° (c = 0.65, CHCl3). 1H NMR (300 MHz): 6 0.65 (d, J7 Hz, 3H, CH3), 1.05 (d, J7 Hz, 3H, CH3), 1.04-2.76 (m, 7H, 3 x CH2, CH), 2. 04 (s, 3H, CH3), 3.54 (s, 3H, CH30), 3.65 (s, 3H, CH30), 3.94 (d, J3 Hz, 1H, H-2), 4.77 (s, 2H, CH2-OAc), 5.04 (s, 2H, CH2=), 5.90 (m, 1H, CH=). 13C NMR (75 MHz): 5 16.84 (CH3), 19.31 (CH3), 20.98 (CH3), 22.20 (CH2), 30. 79 (CH), 32. 08 (CH2), 37. 23 (CH2), 52. 01 (CH30), 52.41 (CH30), 56.09 (C-5), 60.46 (C-2), 65.14 (CH2O), 111.45 (CH2=), 124. 46 (CH=), 130. 63 (C=), 142. 29 (C=), 161.00 (C), 165.88 (C), 170.71 (CO). MS (EI) : 348 (100, M+), 305 (48), 263 (12), 245 (78), 153 (61). MS (EI): M 348.2057. Calc. for Cl9H28N204 : 348.2049. Example 49 General procedure for the preparation of methyl (S/R)-3- alkenyl-l-amino-3-cycloalkene-l-carboxylate (29) The (2R, 5S/R) 2,5-dihydro-3,6-dimethoxy-2- isopropylpyrazine-5-spiro (3-alkenyl-3-cycloalkene) (0.50 mmol) was added dropwise to a solution of TFA (25 ml, 5.00 mmol, 0.2M) and MeCN (25 ml) and the mixture stirred for 3 d at ambient temperature. The acetonitrile was then evaporated off and the aqueous residue made alkaline by addition of conc. ammonia (pH 10). The resultant suspension was extracted with dichloromethane (3 x 20 ml), the combined dichloromethane layers dried (MgS04) and evaporated. The title compound was isolated by flash chromatography using 2% methanol in dichloromethane as eluent. Example 49a Methyl(S)-1-amino-3-vinyl-3-cyclopentene-l-carboxylate (29a) was obtained from (2R, 5S)-2,5-dihydro-3,6- dimethoxy-2-isopropylpyrazine-5-spiro (3-vinyl-3- cyclopentene) in 42% yield as a colourless oily material. [a] D =-36.9° (c = 0.90, CHC13). 1H NMR (300 MHz): 5 1.78 (bs, 2H, NH2), 2.38 (m, 2H, CH2), 3.02 (d, J 15 Hz, 2H, CH2), 3.70 (s, 3H, CH30), 5.02 (m, 2H, CH2=), 5.60 (bs, 1H, CH=), 6.46,6.51 (dd, 11 Hz, 1H, CH=). 13C NMR (75 MHz): 5 45.04 (CH2), 46.93 (CH2), 52.36 (CH30), 63.26 (C-1), 114.68 (CH2=), 126.92 (CH=), 132.86 (CH=), 140.04 (C=), 177.50 (C=O). MS (EI) : 135 (8, M-CH30H, 119 (15), 118 (15), 108 (100). Example 49b Methyl(S)-l-amino-3-vinyl-3-cyclohexene-l-carboxylate (29b) was obtained from (2R, 5S)-2,5-dihydro-3,6- dimethoxy-2-isopropylpyrazine-5-spiro (3-vinyl-3- cyclohexene) in 83% yield as a colourless oily material. [a] D = +3.6° (c = 0. 80, CHCl3). 1H NMR (300 MHz): 5 1.72-2.68 (m, 8H, 3 x CH2, NH2), 3.72 (s, 3H, CH30), 4.90 (d, J 11 Hz, 1H, 1/2 CH2=), 5.04 (d, J 18 Hz, 1H, 1/2 CH2=), 5.74 (bs, 1H, CH=), 6.32,6.38 (dd, J 10 Hz, 1H, CH=). 13C NMR (75 MHz): 5 22.70 (CH2), 31. 50 (CH2), 34. 52 (CH2), 52.75 (CH30), 56.43 (C), 110.98 (CH2), 128.04 (CH=), 133.37 (C=), 139.71 (CH=), 177.49 (CO). MS (EI) : 181 (25, M+), 164 (9), 122 (100), 105 (75), 101 (29). MS (EI): M 181.1116. Calc. for CloHlsNO2 : 181. 1103. Example 49c Methyl(S)-l-amino-3-isopropenyl-3-cyclohexene-l- carboxylate (29c) was obtained from (2R, 5S)-2,5- dihydro-3,6-dimethoxy-2-isopropylpyrazine-5-spiro (3- isopropenyl-3-cyclohexene) in 80% yield as a colourless oil. [a] D = +5.1° (c = 0.85, CHCl3). 1H NMR (200 MHz): 5 1.64-2.75 (m, 8H, 3 x CH2, NH2), 1.87 (s, 3H, CH3), 3.71 (s, 3H, CH30), 4.86 (d, J 16 Hz, 2H, CH2), 5.86 (bs, 1H, CH=). 13C NMR (50 MHz): 5 20.66 (CH3), 22.34 (CH2), 30.54 (CH2), 35.62 (CH2), 52.30 (CH30), 56.31 (C-1), 110.19 (CH2=), 122.99 (CH=), 133.48 (C=), 143.00 (C=), 177.20 (C). MS (EI) : 195 (20, M+), 178 (9), 136 (68), 119 (52), 101 (39). MS (EI) : M 195.1241. Calc. for C1lNl7NO2 : 195.1259. Example 49d Methyl(R)-l-amino-3-isopropenyl-3-cyclohexene-l- carboxylate (29d) was obtained from (2R, 5R)-2,5- dihydro-3,6-dimethoxy-2-isopropylpyrazine-5-spiro (3- isopropenyl-3-cyclohexene) in 73% yield as a colourless oil. 1H NMR (300 MHz): 5 1.64-2.73 (m, 8H, 3 x CH2, NH2), 1.87 (s, 3H, CH3), 3.71 (s, 3H, CH30), 4.86 (d, J 16 Hz, 2H, CH2=), 5.86 (bs, 1H, CH=). 13C NMR (75 MHz): 520. 66 (CH3), 22. 33 (CH2), 30. 53 (CH2), 35. 63 (CH2), 52.29 (CH30), 56.23 (C-1), 110.17 (CHz=), 122.98 (CH=), 133.44 (C=), 142.96 (C=), 177.32 (C=O). MS (EI): 195 (16, M+), 136 (51), 119 (22), 101 (26). MS (EI): M 195.1249. Calc. for C1lNl7NO2 : 195.1259. Example 49e Methyl(S)-l-amino-3- (3-acetoxy-l-propen-2-yl)-3- cyclohexene-l-carboxylate (29e) was obtained from (2R, 5S)-2, 5-dihydro-3,6-dimethoxy-2-isopropylpyrazine-5- spiro [3- (3-acetoxy-l-propen-2-yl)-3-cyclohexene] in 65% yield as a colorless oily material. [ot] D = +3.9° (c = 0.70, CHCl3). 1H NMR (300 MHz): 5 1.65-2.72 (8 H, m, 3 x CH2, NH2), 2.06 (s, 3H, CH3), 3.71 (s, 3H, CH30), 4.73 (s, CH20), 5.13 (d, J9 Hz, 2H, CH2=), 5.84 (bs, 1H, CH=). 13C (75 MHz): 5 21.00 (CH3), 22.31 (CH2), 30.49 (CH2), 35.71 (CH2), 52.34 (CH2O), 56.12 (C-1), 65.03 (CH20), 112.61 (CH2=), 123.68 (CH=), 130.90 (C=), 141.67 (C=), 170.72 (C=O), 176.98 (C=O). MS (EI) : 253 (26, M+), 195 (13), 194 (100), 176 (26), 134 (73), 117 (33). MS (EI): M 253.1301. Calc. for C13HlgNO4 : 253.1314. Example 50 Methyl(S)-N- (l-amino-3-vinyl-3-cyclopentene-l- carbonyl)- (R)-valinate (30) A second product ftom the reaction mixture which gave 29a, was the dipeptide 28. It was eluated before 29a during flash chromatography. Yield 12 mg (8%). 1H NMR (300 MHz): 5 0.89 (d, J7 Hz, 3H, CH3), 0.92 (d, J 7 Hz, 3H, CH3), 2.18 (m, 1H, CH), 2.30 (m, 4H, CH2, NH2), 3.13, 3.22 (dd, J 16 Hz, 2H, CH2), 3.72 (s, 3H, CH30), 4.47, 4.50 (dd, J5 Hz, 1H, CH-NH), 5.03 (d, J 11 Hz, 1H, 1/2 CH2=), 5.08 (d, J4 Hz, 1H, 1/2 CH2), 5.61 (bs, 1H, CH=), 6.48,6.54 (dd, J 11 Hz, 1H, CH=), 7.98 (d, J9 Hz, 1H, NH). 13C NMR (75 MHz): 5 17.77 (CH3), 19.08 (CH3), 31.31 (CH), 45.75 (CH2), 47.84 (CH2), 52.05 (CH30), 57.18 (CH), 64.21 (C), 115.11 (CH2=), 125.73 (CH=), 132.90 (CH=), 140.59 (C=), 172.52 (C=O), 175.96 (=CO). Example 51 (2R,5S)-5- (3-Butenyl)-2, 5-dihydro-3, 6-dimethoxy-5- (4- hydroxy-2-butenyl)-2-isopropylpyrazine (31) nBuLi (0.75 ml, 1.80 mmol, 2.4 M in heptane) was added dropwise to a solution of (2R, 5S)-5- (3-butenyl)-2, 5- dihydro-3,6-dimethoxy-2-isopropylpyrazine (385 mg, 1.62 mmol) in dry THF (10 ml) under argon at-50°C. The solution was cooled to-78°C, stirred at this temperature for 45 min before vinyloxirane (0.145 ml, 1.80 mmol) in THF (2 ml) was added dropwise. The mixture was allowed to slowly reach ambient temperature overnight. 0.1 M Phosphate buffer (pH 7,10 ml) was added and the aqueous phase extracted with dichloromethane (3 x 20 ml). The combined organic layers were dried (MgSO4) and evaporated. The residue was purified by flash chromatography using dichloromethane/diethyl ether 9: 1 and 4: 1 as eluents. Yield 270 mg (54%) as a colourless oil. Found: C, 66.03; 9.37. Calc. for C17H28N203 : C, 66.20; H, 9.15%, [a] D =-2. 7° (c = 1.11, CHCl3). 1H NMR (300 MHz): 5 0. 61 (d, J7 Hz, 3H, CH3), 1.03 (d, J7 Hz, 3H, CH3), 1.60-2.44 (m, 8H, 3 x CH2, CH, OH), 3.62 (s, 3H, CH30), 3.65 (s, 3H, CH30), 3.71 (d, J3 Hz, 1H, 1/2 CH2), 3.76 (d, J3 Hz, 1H, CH), 3.95 (d, J6 Hz, 1H, 1/2 CH2), 4.91-5.85 (m, 5H, CH2=, 3 x CH). 13C NMR (75 MHz) 5 16.89 (CH3), 19.47 (CH3),29. 07 (CH2), 30. 53 (CH), 38. 81 (CH2), 43. 80 (CH2), 52.17 (CH30), 52.37 (CH30), 60.60 (C-2), 61.99 (C-5), 63.34 (CH2-OH), 114.14 (CHO=), 127.14 (CH=), 133.00 (CH=), 138.64 (CH=), 162.87 (C), 163.79 (C). MS (EI) : 308 (0.5, M+), 237 (57), 196 (12), 195 (100), 153 (27). Example 52 (2R, 5S)-2, 5-Dihydro-3, 6-dimethoxy-2-isopropylpyrazine-5- spiro (3-cyclohexene) (4c) Bis (tricyclohexylphosphine) benzylidene ruthenium dichloride (39 mg, 0. 047 mmol) in dry degassed toluene (1 ml) was added to a solution of (2R, 5S)-5- (3-butenyl)- 2,5-dihydro-3,6-dimethoxy-5- (4-hydroxy-2-butenyl)-2- isopropylpyrazine (289 mg, 0.94 mmol) in dry degassed toluene (10 ml) under argon at 60°C. The solvent was evaporated after 18 h and the residue purified by flash chromatograhy using 2% ethyl acetate in hexane as eluent. Yield 95 (41%); colourless oil. Analytical data identical to Example 11. There was also isolated 100 mg (35%) of unreacted stating material. Example 53 (2R, 5S, 2'R)-5- (3-Butenyl)-5- (2-hydroxy-3-butenyl)-2, 5- dihydro-3, 6-dimethoxy-2-isopropylpyrazine (32a), (2R, 5S, 1'S)-5- (3-butenyl)-2, 5-dihydro-3. 6-dimethoxy-2- isopropyl-5- (l-hydroxymethyl-2-propenyl) pyrazine (33a) and (2R, 5S, 1'R)-5- (3-butenyl)-2, 5-dihydro-3, 6-dimethoxy- 2-isopropyl-5- (l-hydroxymethyl-2-propenyl)-pyrazine (31b) nBuLi (2.92 ml, 7.00 mmol, 2.4 M in heptane) was added to a solution of (2R, 5S)-5- (3-butenyl)-2, 5-dihydro 3,6- dimethoxy-2-isopropylpyrazine (1.56 g, 6.56 mmol) in dry THF (15 ml) under argon at-50°C. The solution was cooled to-78°C, stirred at this temperature for 45 min before vinyloxirane (0.56 ml, 7.00 mmol) in dry THF (0.5 ml) was added dropwise followed by dropwise addition of boron trifluoride ethyl etherate (0.88 ml, 7.00 mmol). Acetic acid (1 ml) was added after 3 h at-78°C and the cold bath removed. 0.1 M Phosphate buffer (pH 7,10 ml) was added and the aqueous layer extracted with dichloromethane (3 x 30 ml). The combined organic layers were dried (MgSO4) and evaporated. The three alcohols were separated by repeated use of flash chromatography with hexane/ethyl acetate 7: 1 and 4: 1 as eluents. First eluated was (2R, 5S, 2'R)-5- (3-butenyl)-5- (2- hydroxy-3-butenyl)-2, 5-dihydro-3 6-dimethoxy-2- isopropylpyrazine (32a) ; yield 473 mg (23%); colourless oil. Found: C, 66.17; H, 9.23. Calc. for C17H28N203 : C, 66.20; H, 9.15%. [a] D =-14.3° (c = 1.03, CHCl3). 1H NMR (300 MHz): 6 0.65 (d, J7 Hz, 3H, CH3), 1.04 (d, J7 Hz, 3H, CH3), 1.61-1.99 (m, 6H, 3 x CH2), 2.30 (m, 1H, CH), 3.61 (s, 3H, CH30), 3.62 (s, 3H, CH30), 3.86 (d, J3 Hz, 1H, H-2), 4.44 (m, 1H, CH-OH), 4.55 (bs, 1H, OH), 4.86- 5.21 (m, 4H, 2 x CH2=), 5.70 (m, 2H, 2 x CH=). 13C NMR (75 MHz): 5 17.10 (CH3), 19.47 (CH3), 29. 05 (CH2), 30. 44 (CH), 36.81 (CH2), 46.57 (CH2), 52.26 (CH30), 52. 41 (CH30), 60.14 (C-2), 61.19 (C-5), 69.69 (CH), 113.80 (CH2=), 114.42 (CH2=), 138.12 (CH=), 140.60 (CH=), 163.32 (C), 163.43 (C). MS (EI) : 308 (0.82, M+), 237 (27), 211 (18), 197 (12), 196 (13), 195 (100). The second product eluated was (2R, 5S, 1'S)-5- (3- butenyl)-2, 5-dihydro-3, 6-dimethoxy-2-isopropyl-5- (l- hydroxymethyl-2-propenyl)-pyrazine (33a): yield 122 mg (6%). Found: C, 66.13; H, 8.92. Calc. for C17H28N203 : C, 66.20; H, 9.15%. [a] D = +9.1° (c = 0.95, CHCl3). 1H NMR (200 MHz): 5 0.62 (d, J7 Hz, 3H, CH3), 1.03 (d, J7 Hz, 3H, CH3), 1.63-2.01 (m, 4H, 2 x CH2), 2.21-2.50 (m, 2H, 2 x CH), 3.59 (s, 3H, CH30) ; 3.61 (s, 3H, CH30), 3.82 (d, J3 Hz, 1H, H-2), 4.10,4.15 (dd, J4 Hz, 2H, CH2), 4.86- 5.10 (m, 4H, CH2=), 5. 68-5.82 (m, 2H, 2 x CH=). 13C NMR (50 MHz): 6 17.14 (CH3), 19.46 (CH3), 29.22 (CH2), 30.37 (CH), 36.56 (CH2), 52.04 (CH30), 52.47 (CH30), 52.50 (CH), 59.98 (C-2), 63.05 (CH2OH), 65.41 (C-5), 114.44 (CH2=), 118.14 (CH2=), 135.52 (CH=), 138.14 (CH=), 161.85 (C), 164.08 (C). MS (EI) : 208 (0.4, M+), 237 (60), 234 (10), 196 (12), 195 (100), 153 (21). The final compound eluated was (2R, 5S, 1'R)-5- (3- butenyl)-2, 5-dihydro-3, 6-dimethoxy-2-isopropyl-5- (l- hydroxymethyl-2-propenyl) pyrazine (33b); yield 263 mg (13%). Found: C, 66.58; H, 8.90. Calc. for C17H28N203 : C, 66.20; H, 9.15%. [a] D =-36.4° (c = 1.36, CHCl3). 1H NMR (200 MHz): 6 0.63 (d, J7 Hz, 3H, CH3), 1.05 (d, J7 Hz, 3H, CH3), 1.58-2.01 (m, 4H, 2 x CH2), 2.31 (m, 1H, CH), 2.54 (m, 1H, CH), 3.17-3.50 (m, 2H, CH20), 3.63 (s, 3H, CH30), 3.64 (s, 3H, CH30), 3.81 (d, J3 Hz, 1H, H-2), 4.84-5.24 (m, 4H, 2 x CH2=), 5.66-5.88 (m, 2H, CH=). 13C NMR (50 MHz): 5 17.06 (CH3), 19.48 (CH3), 28.93 (CH2), 30.45 (CH), 37.08 (CH2), 52.27 (CH30), 52.34 (CH30), 55.00 (CH), 60.36 (CH), 61.91 (CH2), 62.37 (C-5), 114.23 (CH2=), 119.75 (CH2=), 135.43 (CH=), 138.52 (CH=), 163.02 (2 x C). MS (EI) : 308 (1, M+), 265 (11), 238 (10), 237 (63), 235 (11), 233 (22), 196 (12), 195 (100), 153 (23). Example 54 (2R, 5S, 2'R)-5-(3-Butenyl)-2 5-dihydro-3 6-dimethoxy-5- (2-hydroxy-3-butenyl)-2-isopropylpyrazine (32a) and (2R, 5S, 2'S)-5- (3-butenyl)-2, 5-dihydro-3, 6-dimethoxy-5- (2-hydroxy-3-butenyl)-2-isopropylpyrazine (32b) Vinylmagnesium bromide (1.70 ml, 1.70 mmol, 1.0 M in THF) was added dropwise to a solution of (2R, 5S)-5- (3- butenyl)-2,5-dihydro-3,6-dimethoxy-2-isopropyl-5- (2- oxoethyl) pyrazine (318 mg, 1.13 mmol) in dry diethyl ether (10 ml) under argon at 0°C. 0.1 M phosphate buffer (pH 7,10 ml) was added after 5 min and the aqueous layer extracted with dichloromethane (3 x 20 ml). The combined organic layers were dried (MgSO4) and evaporated. The two alcohols were separated by flash chromatography using hexane/ethyl acetate 4: 1 as eluent. First eluated was (2R, 5S, 2'R)-5- (3-butenyl)-2, 5 dihydro- 3,6-dimethoxy-5- (2-hydroxy-3-butenyl)-2- isopropylpyrazine (32a) 126 mg (36%). Analytical data as in Example 53. The final product eluated was (2R, 5S, 2'S)-5- (3-butenyl)- 2, 5-dihydro-3 6-dimethoxy-5- (2-hydroxy-3-butenyl)-2- isopropylpyrazine (32b); yield 152 mg (43%). [a] D = -6.5° (c = 0.95, CHCl3). 1H NMR (200 MHz): 6 0.69 (d, J7 Hz, 3H, CH3), 1.06 (d, J7 Hz, 3H, CH3)-1. 73-2.13 (m, 6H, 3 x CH2), 2.25 (m, 1H, CH), 2.75 (bs, 1H, OH), 3.64 (s, 3H, CH30), 3.67 (s, 3H, CH30), 3.94 (d, J3 Hz, 1H, H-2), 3.94 (m, 1H, H-2'), 4.85-5.19 (m, 4H, 2 x CH2=), 5.72 (m, 2H, 2 x CH=). 13C NMR (50 MHz): 6 17.44 (CH3), 19.61 (CH3), 28.60 (CH2), 30.88 (CH), 40.49 (CH2), 46.65 (CH2), 52.33 (2 x CH30), 60.95 (C-2), 61.44 (C-5), 70.44 (C-2'), 113.84 (CH2=), 114.36 (CH2=), 138.38 (CH=), 140.49 (CH=), 163.53 (C), 164.21 (C). MS (EI) : 308 (2, M+), 238 (10), 237 (49), 211 (35), 197 (13), 196 (14), 195 (100), 193 (15). MS (EI): 308.2112. Calc. for C17H28N203 : 308.2100 Example 55 (2R,5S)-5-(3-Butenyl)-2 5-dihydro-3 6-dimethoxy-5-(2- hydroxyethyl)-2-isopropylpyrazine (34) nBuLi (2.80 ml, 6.72 mmol, 2.4 M in heptane) was added dropwise to a solution of (2R, 5S)-5- (3-butenyl)-2, 5- dihydro-3,6-dimethoxy-2-isopropylpyrazine (1.52 g, 6.39 mmol) in dry THF (15 ml) under argon at-50°C. The solution was cooled to-78°C, stirred at this temperature for 45 min before an excess of ethylene oxide was introduced through a syringe needle by condensing the gas on the glass wall of the reaction vessel. The condensed gas was subsequently washed into the mixture using dry THF (1 ml) in a syringe. Boron trifluoride ethyl etherate (0.84 ml, 6.72 mmol) was then added dropwise. Acetic acid (1 ml) was added after 3 h at-78°C, the cold bath removed, and 0.1 M phosphate buffer (pH 7,10 ml) added. The aqueous layer was extracted with dichloromethane (3 x 20 ml). The combined organic layers were dried (MgSO4) and evaporated. The residue was purified by flash chromatography using hexane/ethyl acetate 2: 1 and 1: 1 as eluents. Yield 1.14 g (63%) ; colourless oil. [a] D = -34.8° (c = 0.92, CHCl3). 1H NMR (300 MHz): 6 0.66 (d, J7 Hz, 3H, CH3), 1.06 (d, J7 Hz, 3H, CH3), 1. 70-2. 01 (m, 6H, 3 x CH2), 2.31 (m, 1H, CH), 3.51-3.80 (m, 2H, CH2), 3.63 (s, 6H, 2 x CH30), 3.90 (d, J3 Hz, 1H, H-2), 4.91 (m, 2H, CH2=), 5.74 (m, 1H, CH=). 13C NMR (75 MHz): 6 17.10 (CH3), 19.53 (CH3), 28. 92 (CH2), 30. 58 (CH), 37. 80 (CH2), 42.28 (CH2), 52.27 (CH30), 52.37 (CH30), 59.58 (CH2OH), 60.35 (C-2), 61.14 (C-5), 114.34 (CH2=), 138.41 (CH=), 163.31 (C), 163.71 (C). MS (EI) : 282 (0.3, M+), 267 (19), 238 (16), 237 (91), 196 (13), 195 (100), 185 (57). MS (EI): M 282.1939. Calc. for C15H26N203 : 282.1943. Example 56 (2R, 5S)-5- (3-Butenyl)-2, 5-dihydro-3, 6-dimethoxy-2- isopropvl-5- (2-oxoethyl) pyrazine (35) DMSO (0.63 ml, 8.88 mmol) in dichloromethane (5 ml) was added dropwise to a solution of oxalyl chloride (0.38 ml, 4.34 mmol) in dichloromethane (20 ml) at-60°C under argon. A solution of (2R, 5S)-5- (3-butenyl)-2, 5-dihydro- 3,6-dimethoxy-2-isopropylpyrazine (1.12 g, 3.95 mmol) in dichloromethane (10 ml) was added dropwise after 5 min. The mixture was kept at this temperature for 5 min, warmed to-15°C for 20 min and then cooled to-60°C for addition of triethylamine (2.00 ml, 14.21 mmol). The cold-bath was removed after 5 min and the mixture allowed to reach ambient temperature. Water (20 ml) was added and the aqueous phase extracted with dichloromethane (3 x 20 ml). The dichloromethane layers were dried (MgSO4), evaporated, diethyl ether added and the suspension filtered and evaporated. The residue was purified by flash chromatography using hexane/ethyl acetate 9: 1 as eluent. Yield 831 mg (75%); colourless oil. Found: C, 63.96; H, 8.61. Calc. for C15N24N203 : C, 64.26; H, 8.63%. [oc] D =-42.4° (c = 0.99, CHCl3). 1H NMR (300 MHz): 6 0.66 (d, J7 Hz, 3H, CH3), 1.06 (d, J7 Hz, 3H, CH3), 1.71-1.91 (m, 4H, 2 x CH2), 2.30 (m, 1H, CH), 2.64 (m, 2H, CH2), 3.60 (s, 3H, CH30), 3.64 (s, 3H, CH30), 3.91 (d, J3 Hz, 1H, H-2), 4.95 (m, 2H, CH2=), 5.72 (m, 1H, CH=), 9.57 (t, J3 Hz, 1H, CHO). 13C NMR (75 MHz): 5 17.14 (CH3), 19.52 (CH3), 28.48 (CH2), 30.52 (CH), 39.17 (CH2), 52.39 (CH30), 52.42 (CH30), 53.13 (CH2), 58.91 (C-5), 60.75 (C-2), 114.52 (CH2=), 138.04 (CH=), 162.56 (C), 163.57 (C), 200.82 (CHO). MS (EI) : 280 (1, M+), 265 (9), 238 (15), 237 (100), 209 (29), 197 (15), 195 (23), 183 (41), 181 (11). Example 57 (2R, 5S, 2'R)-5- (2-Acetoxy-3-butenyl)-5- (3-butenyl)-2, 5- dihydro-3 6-dimethoxy-2-isopropylpyrazine (36a) Acetic anhydride (0.23 ml, 2.46 mmol) was added dropwise to a solution of (2R, 5S, 2'R)-5- (3-butenyl)-2, 5-dihydro- 3,6-dimethoxy-5- (2-hydroxy-3-butenyl)-2- isopropyl- pyrazine (689 mg, 2.23 mmol) and 4-dimethylaminopyridine (300 mg, 2.46 mmol) in dichloromethane (15 ml). The solvent was evaporated after 2 h and the residue purified by flash chromatography using hexane/ethyl acetate 9: 1 as eluent. Yield 715 mg (91%); colourless oil. Found: C, 65.13; H, 8.41. Calc. for C1gH30N204 : C, 65.12; H, 8.63%. [a] D = + 0. 8° (c = 1.12, CHC13). 1H NMR (200 MHz): 6 0.64 (d, J7 Hz, 3H, CH3), 1.03 (d, J7 Hz, 3H, CH3), 1. 59-2. 33 (m, 7H, 3 x CH2, CH), 1.94 (s, 3H, CH3), 3.65 (s, 6H, 2 x CH30), 3.73 (d, J3 Hz, 1H, H-2), 4.85-5.14 (m, 5H, 2 x CH2=, H-2'), 5.68 (m, 2H, 2 x CH=). 13C NMR (50 MHz): 5 17.09 (CH3), 19.54 (CH3), 21.03 (CH3), 28.62 (CH2), 30.38 (CH), 40.44 (CH2), 44.00 (CH2), 52.01 (CH30), 52.33 (CH30), 59.13 (C-5), 60.69 (C-2), 71.20 (C- 2'), 114.24 (CH2=), 115.61 (CH2=), 136.76 (CH=), 138.51 (CH=), 163.34 (C), 163.64 (C), 170.19 (CO). MS (EI) : 350 (2, M+), 335 (7), 291 (20), 253 (19), 238 (10), 237 (41), 196 (13), 195 (100), 193 (31). Example 58 (2R, 5S, 2'S)-5- (2-Acetoxy-3-butenyl)-5- (3-butenyl)-2, 5- dihydro-3, 6-dimethoxy-2-isopropylpyrazine (36b) Acetic anhydride (67 Al, 0.71 mmol) was added to a solution of (2R, 5S, 2'S)-5- (3-butenyl)-2, 5-dihydro-3,6- dimethoxy-5- (2-hydroxy-3-butenyl)-2-isopropyl-pyrazine (200 mg, 0.65 mmol) and 4-dimethylaminopyridine (87 mg, 0.71 mmol) in dichloromethane (10 ml) at ambient temperature under argon. The solvent was evaporated after 2 h and the product isolated by flash chromatography using hexane/ethyl acetate 9: 1 as eluent. Yield 160 mg (70%); colourless oil. Found: C, 65.10; N, 8.70. Calc. for C1gN30N204 : C, 65.12; N, 8.63%. [a] D = -5.3° (c = 1.22, CHC13). 1H NMR (300 MHz): 6 0.63 (d, J7 Hz, 3H, CH3), 1.05 (d, J7 Hz, 3H, CH3), 1.63-2.03 (m, 6H, 3 x CH2), 1.96 (s, 3H, CH3), 2.30 (m, 1H, CH), 3.61 (s, 3H, CH30), 3.65 (s, 3H, CH30), 3.83 (d, J3 Hz, 1H, H-2), 4.85-5.11 (m, 5H, 2 x CH2=, H-2'), 5.58-5.69 (m, 2H, 2 x CH=). 13C NMR (75 MHz:): 5 17.15 (CH3), 19.53 (CH3), 21.10 (CH3), 28.71 (CH2), 30.47 (CH), 39.96 (CH2), 44.34 (CH2), 52.09 (CH30), 52.23 (CH30), 60.23 (C-5), 60.58 (C- 2), 71.96 (C-2'), 114.21 (CH2=), 115.94 (CH2=), 136.60 (CH=), 138.48 (CH=), 162.66 (C), 162.98 (C), 169.72 (C). MS (EI) : 350 (5, M+), 335 (11), 307 (18), 291 (41), 253 (49), 237.8 (15), 237 (52), 196 (14), 195 (100), 194 (12), 193 (50). Example 59 (2R, 5S, 3'R)-2, 5-Dihydro-3 6-dimethoxy-2- isopropylpyrazine-5-spiro (3-acetoxy-4-cycloheptene) (37a) Bis (tricyclohexylphosphine) benzylidene ruthenium dichloride (29 mg, 0.036 mmol) in dry degassed dichloroethane (2 ml) was added to a solution of (2R, 5S, 2'R)-5- (2-acetoxy-3-butenyl)-5- (3-butenyl)-2, 5- dihydro-3,6-dimethoxy-2-isopropylpyrazine (624 mg, 1.78 mmol) in dry degassed dichloroethane (20 ml) at 40°C. The solvent was evaporated after 16 h and the residue purified by flash chromatography using hexane/ethyl acetate 9: 1 as eluent. Yield 533 mg (93%) ; colourless oil. Found: C, 63.00; H 7.92,. Calc. for C17H26N204 : C, 63.33 ; H, 8.13. [a] D =-10.5° (c = 0.83, CHCl3). 1H NMR (200 MHz): 0.65 (d, J7 Hz, 3H, CH3), 1.05 (d, J7 Hz, 3H, CH3), 1.46-2.57 (m, 7J, 3 x CH2, CH), 2.00 (s, 3H, CH3C=O), 3.63 (s, 3H, CH30), 3.70 (s, 3H, CH30), 3.91 (d, J3 Hz, 1H, H-2), 5.60-6-05 (m, 3H, 2 x CH=, H-3'). 13C NMR (50 MHz): 5 17.01 (CH3), 19.37 (CH3), 21.36 (CH3), 22.76 (CH2), 30.90 (CH), 38.00 (CH2), 43.31 (CH2), 52.43 (CH30), 52.53 (CH30), 58.18 (C-5), 60.31 (C-2), 69.96 (C- 3'), 130.31 (CH=), 134.65 (CH=), 160.87 (C), 165.55 (C), 170.16 (C). MS (EI) : 322 (32, M+), 307 (19), 280 (14), 279 (75), 263 (99), 238 (14), 237 (100), 197 (18), 195 (16), 193 (59), 153 (27). Example 60 (2R 5S, 3'R)-2, 5-Dihydro-3 6-dimethoxy-2- isopropylpyrazine-5-spiro (3-hydroxy-4-cycloheptene) (38a) (2R, 5S, 3'R)-2,5-Dihydro-3,6-dimethoxy-2-isopropyl- pyrazine-5-spiro (3-acetoxy-4-cycloheptene) (533 mg, 1.65 mmol) was stirred with 1M NaOH (15 ml) and dioxane (15 ml) at ambient temperature for 3 h. Dichloromethane was added, the aqueous layer separated and extracted with dichloromethane (2 x 20 ml). The combined organic layers were dried (MgSO4), evaporated, and the residue purified by flash chromatography using hexane/ethyl acetate 4: 1 as eluent. Yield 371 mg (80%); white solid material, mp. 98-100°C. Found: C, 64.07; N, 8.50. Calc. for, C15H24N203 : C, 64.26; H 8.63%. [a] D =-3.2° (c = 0.91, CHCl3). 1H NMR (300 MHz, CDCl3) : 6 0.63 (d, J7 Hz, 3H, CH3), 1.04 (d, J7 Hz, 3H, CH3), 1.48-2.50 (m, 8H, 3 x CH3, CH, OH), 3.63 (s, 3H, CH30), 3.65 (s, 3H, CH30), 3.90 (d, J3 Hz, 1H, H-2), 4.92 (m, 1H, H-3'), 5.75 (m, 2H, 2 x CH=). 13C NMR (75 MHz): 6 17.89 (CH3), 19.33 (CH3), 22. 84 (CH2), 30. 86 (CH), 38. 03 (CH2) ; 47. 00 (CH2), 52.19 (CH30), 52.41 (CH30), 58.37 (C-5), 60.15 (C-2), 66.69 (C-3'), 129.45 (CH=), 138.29 (CH=), 160.63 (C), 165.93 (C). MS (EI): 280 (16, M+), 265 (26), 238 (15), 237 (100), 197 (15), 193 (52). Example 61 (lS, 3R)-3-Hydroxy-4-cycloheptene-l-carboxylic acid y- lactone(39a) (2R, 5S, 3'R)-2, 5-Dihydro-3,6-dimethoxy-2-isopropyl- pyrazine-5-spiro (3-hydroxy-4-cycloheptene) (155 mg, 0.55 mmol) was stirred with TFA (28 ml, 5.60 mmol, 0.2 M) and acetonitrile (28 ml) for 3 d at ambient temperature. The solvents were evaporated almost to dryness and water (5 ml) and dichloromethane (10 ml) were added. The aqueous layer was brought to pH 10 by addition of conc. ammonia and extracted with dichloromethane (3 x 10 ml). The combined dichloromethane layers were dried (MgSO4) and evaporated. The residue was purified by flash chromatography using 3% and 5% methanol in dichloromethane as eluents. Yield 52 mg (62%); white solid, mp. 60°C. [a] D =-95.1° (c = 0.80, CHCl3). 1H NNR (300 MHz): 6 1.79-2.44 (m, 8H, 3 x CH2, NH2), 4.81 (m, 1H, CH), 5.94 (m, 2H, 2 x CH=). 13C NMR (75 MHz): 5 24.08 (CH2), 40.22 (CH2), 42.87 (CH2), 59.29 (C), 72.31 (CH), 130.25 (CH=), 134.27 (CH=), 181.42 (C=O). Example 62 (2R, 5S 3'S)-2, 5-Dihydro-3, 6-dimethoxy-2-isopropyl- pyrazine-5-spiro (3-acetoxy-4-cycloheptene) (37b) Bis (tricyclohexylphosphine) benzylidene ruthenium dichloride (8 mg, 0.010 mmol) in dry degassed dichloroethane (1 ml) was added to a solution of (2R, 5S, 2'S)-5- (2-acetoxy-3-butenyl)-5- (3-butenyl)-2, 5- dihydro-3,6-dimethoxy-2-isopropylpyrazine (175 mg, 0.50 mmol) in dry degassed dichloroethane (10 ml) at 40°C. The solvent was evaporated after 16 h and the residue purified by flash chromatography using hexane/ethyl acetate 9: 1 as eluent. Yield 126 mg (90%); colourless oil. [a] D =-24.4° (c = 1.26, CHCl3). 1H NMR (300 MHz): 6 0.61 (d, J7 Hz, 3H, CH3), 1.02 (d, J7 Hz, 3H, CH3), 1.39,1.44 (dd, J7 Hz, 1H, 1/2 CH2), 1.78-2.75 (m, 6H, 2 x CH2, 1/2 CH2, CH), 1.98 (s, 3H, CH3), 3.64 (s, 3H, CH30), 3.68 (s, 3H, CH30), 3.87 (d, J3 Hz, 1H, H-2), 5.51 (m, 1H, CH=), 5.76 (m, 1H, CH=), 5.96 (m, 1H, H-3'). 13C NMR (75 MHz): 6 16.76 (CH3), 19.29 (CH3), 21. 29 (CH3), 23.16 (CH2), 30.79 (CH), 38.15 (CH2), 46.44 (CH2), 51.99 (CH30), 52.41 (CH30), 57.31 (C-5), 60.41 (C-2), 70.77 (C- 3'), 131.79 (CH=), 131.89 (CH=), 161.47 (C), 166.10 (C), 169.98 (C). MS (EI) : 322 (2, M), 307 (5), 279 (7), 264 (17), 263 (100), 193 (18). Example 63 (2R, 5S, 3'S)-2, 5-Dihydro-3 6-dimethoxy-2-isopropyl- pyrazine-5-spiro (3-hydroxy-4-cycloheptene) (38b) (2R, 5S, 3'S)-2,5-Dihydro-3,6-dimethoxy-2-isopropyl- pyrazine-5-spiro (3-acetoxy-4-cycloheptene) (190 mg, 0.59 mmol) was stirred with 1 M NaOH (10 ml) and dioxane (10 ml) at ambient temperature for 2 h. Dichloromethane (20 ml) was added and the aqueous layer separated and extracted with dichloromethane (2 x 10 ml). The combined organic layers wer dried (MgSO4) and evaporated. The residue was purified by flash chromatography using hexane/ethyl acetate 2: 1 as eluent. Yield 120 mg (73%); colourless oil. [a] D =-52.0° (c = 0.88, CHCl3). 1H NMR (300 MHz): 5 0.62 (d, J7 Hz, 3H, CH3), 1.02 (d, J7 Hz, 3H, CH3), 1.20-2.51 (m, 7H, 3 x CH3, CH), 3.62 (s, 6H, 2 x CH30), 3.92 (d, J3 Hz, 1H, H-2), 4.42 (m, 1H, H-3'), 5.40 (bs, 1H, OH), 5.84 (m, 2H, 2 x CH=). 13C NMR (75 MHz) : 5 17.07 (CH3), 19.31 (CH3), 23.66 (CH2), 30.92 (CH),40. 08 (CH2), 42. 32 (CH2), 52. 39 (CH30), 52. 47 (CH30), 60.11 (C-2), 61.26 (C-5), 68.99 (C-3'), 132.19 (CH=), 133.74 (CH=) 162.19 (C), 165.25 (C). Example 64 Methyl (lS, 3S)-1-amino-3-hydroxy-4-cycloheptene-1- carboxylate (39b) (2R, 5S, 3'S)-2,5-Dihydro-3,6-dimethoxy-2-isopropyl- pyrazine-5-spiro (3-hydroxy-4-cycloheptene) (120 mg, 0.43 mmol) was stirred with TFA (21.5 ml, 4.30 mmol, 0.2 M) and acetonitrile (21.5 ml) at ambient temperature for 3 d. The solution was evaporated almost to dryness and water (5 ml) and dichloromethane (10 ml) added. The aqueous layer was brought to pH 10 by addition of conc. ammonia and the mixture extracted with dichloromethane (3 x 10 ml). The combined dichloromethane layers were dried (MgSO4) and evaporated. The residue was purified by flash chromatography using 5% and 10% methanol in dichloromethane as eluent. Yield 32 mg (41%) colourless oil. 1H NMR (300 MHz): 5 1.78-2.80 (m, 9H, 3 x CH2, OH, NH2), 3.72 (s, 3H, CH30), 4.45 (m, 1H, H-3), 5.80 (m, 2H, 2 x CH=). 13C NMR (75 MHz): 5 23.52 (CH2), 36.99 (CH2), 40.93 (CH2), 52.52 (CH30), 60.48 (C-1), 68.05 (C-3), 131.54 (CH=), 134.48 (CH=), 177.32 (C=O). Example 65 (2R, 5S, 2'S)-6, 2'-Oxymethylene-r2, 5-dihydro-3 6- dimethoxy-2-isopropypyrazine-5-spirol (3-cyclohexene) (40) Bis (tricyclohexylphosphine) benzylidene ruthenium dichloride (47 mg, 0.057 mmol) in dry degassed 1,2- dichloroethane (2 ml) was added to a solution of (2R, 5S, 1'S)-5- (3-butenyl)-2,5-dihydro-3,6-dimethoxy-2- isopropyl-5- (l-hydroxymethyl-2-propenyl) pyrazine (350 mg, 1.14 mmol) in dry degassed 1,2-dichloroethane (20 ml) at 60°C. TLC monitoring showed the presence of unreacted substrate after 18 h at 60°C whereas the catalyst had been deactivated. Another portion of catalyst (47 mg, 0.057 mmol) in 1,2-dichloroethane (2 ml) was added and the stirring was continued at 60°C for 4 h. The solvent was evaporated and the residue purified by flash chromatography using hexane/ethyl acetate 1: 1 as eluent. Yield 185 mg (66%); colourless oil. Found: C, 67.32; H, 8.13. Calc. for C14H2oN202 : C, 67.72; H, 8.12%. [a] D =-152.3° (c = 1.21, CHCl3). 1H NMR (300 MHz): 6 1.02 (d, J7 Hz, 3H, CH3), 1.04 (d, J7 Hz, 3H, CH3), 1.45-2.74 (m, 6H, 2 x CH2, 2 x CH), 364 (s, 3H, CH30), 3.75 (d, J8 Hz, 1H, CH), 3.93,3.97 (dd, J8 Hz, 1H, 1/2 CH20), 4.41,4.44 (dd, J8 Hz, 1H, 1/2 CH2O), 5.64 (m, 1H, CH=), 5.96 (m, 1H, CH=). 13C NMR (75 MHz): b 20. 46 (CH3), 20. 78 (CH3), 21. 06 (CH2), 29. 93 (CH2), 35. 54 (CH), 43. 64 (CH), 52. 88 (CH30), 57. 07 (C), 64. 89 (CH), 73.39 (CH2), 122.04 (CH=), 129.64 (CH=), 167.76 (C), 172.83 (C). MS (EI) : 249 (11), 248 (63, M+), 206 (31), 205 (100), 191 (37), 177 (16). MS (EI): 248.1520. Calc. for C14H2oN202 : 248.1525. Example 66 (2R, 5S, 2'R)-2, S-Dihydro-3 6-dimethoxy-2-isopropyl- pyrazine-5-spiro (2-hydroxymethyl-3-cycloheptene) (41) Bis (tricyclohexylphosphine) benzylidene ruthenium dichloride (12 mg, 0.015 mmol) in dry degassed dichloroethane (1 ml) was added to a solution of (2R, 5S, 1'R)-5- (3-butenyl)-2,5-dihydro-3,6-dimethoxy-2- isopropyl-5- (l-hydroxymethyl-2-propenyl) pyrazine (93 mg, 0.30 mmol) in dry degassed dichloroethane (5 ml) at 60°C. The solvent was evaporated after 6 h and the residue purified by flash chromatography using hexane/diethyl ether 1: 1 and 1: 2 as eluents; yield 60 mg (71%) of a colourless oil. Found: C, 64.20; 8.60. Calc. for C1sH24N2o3 C, 64.26; H, 8.63%. [a] D =-86.2° (c = 0.60, CHCl3). 1H NMR (300 MHz): 5 0.70 (d, J7 Hz, 3H, CH3), 1.06 (d, J7 Hz, 3H, CH3), 1. 40-2. 32 (m, 6H, 2 x CH2, CH, OH), 2.30 (bs, 1H, CH), 3.48 (m, 2H, CH2OH), 3.61 (s, 3H, CH30), 3.65 (s, 3H, CH30), 4.01 (d, J4 Hz, 1H, H-2), 5.56 (m, 1H, CH=), 5.86 (m, 1H, CH=). 13C NMR (75 MHz): 5 17.45 (CH3), 19.41 (CH3), 21.41 (CH2), 31.29 (CH), 34.74 (CH2), 43.51 (CH), 52.15 (CH30), 52.66 (CH30), 59.29 (C-5), 60.86 (C-2), 63.52 (CH20H)), 125.84 (CH=), 127.66 (CH=), 163.51 (C), 165.23 (C). MS (EI) : 280 (9, M+), 250 (19), 238 (14), 237 (100), 219 (15), 196 (16), 154 (48), 153 (79), 125 (9), 123 (14). Example 67 Methyl N-r (lS, 2S)-1-amino-2-hydroxymethyl-3-cyclohexene- 1-carbonyll-(R)-valinate (42) (2R, 5S, 2'S)-6,2'-Oxymethylene- [2,5-dihydro-3,6- dimethoxy-2-isopropylpyrazine-5-spiro] (3-cyclohexene) (103 mg, 0.42 mmol) was stirred with trifluoroacetic acid (21 ml, 4.20 mmol, 0.2 M) and acetonitrile (21 ml) at ambient temperature for 3 d. The mixture was evaporated almost to dryness and water (5 ml) and dichloromethane (10 ml) were added. The aqueous phase was made alkaline by addition of conc. ammonia (pH 10) and the aqueous layer extracted with dichloromethane (3 x 10 ml). The combined dichloromethane layers were dried, evaporated and the residue purified by flash chromatography using 3% and 5% methanol in dichloromethane as eluent. Yield 41 mg (35%); colourless oil. [a] D = 70.2° (c = 0. 54, CHCl3). 1H NMR (300 MHz): 0.88 (d, J7 Hz, 3H, CH3), 0.94 (d, J7 Hz, 3H, CH3), 1.47-2.46 (m, 9H, 2 x CH2, NH2, 2 x CH, OH), 3.62 (m, 2H, CH2), 3.70 (s, 3H, CH30), 4.37,4.40 (dd, J5 Hz, 1H, CH), 5.51 (m, 1H, CH=), 5.81 (m, 1H, CH=), 8.29 (d, J7 Hz, 1H, NH). 13C NMR (75 MHz): 5 17.82 (CH3), 19.13 (CH3), 21. 67 (CH2), 30. 62 (CH2, CH), 47. 71 (CH), 52. 11 (CH30), 57. 26 (CH), 58. 00 (C), 63. 67 (CH2OH), 125. 93 (CH=), 127.90 (CH=), 172.32 (C=O), 176.96 (CO). Example 68 Methyl N-r (lS, 2R)-l-amino-2-hydroxymethyl-3-cyclohexene- 1-carbonyll-(R)-valinate (43) and methyl (lS, lR)-l-r (R)- valinylaminol-2-hydroxymethyl-3-cyclohexene-l- carboxylate (44) (2R, 5S, 2'R)-2,5-Dihydro-3,6-dimethoxy-2-isopropyl- pyrazine-5-spiro (2-hydroxymethyl-3-cycloheptene) (158 mg, 0.56 mmol) was stirred with trifluoroacetic acid (28 ml, 5.60 mmol) and acetonitrile (28 ml) at ambient temperature for 7 d, the mixture concentrated almost to dryness and water (10 ml) and dichloromethane (20 ml) were added before the aqueous layer was brought to pH 10 by addition of conc. ammonia. The aqueous phase was extracted with dichloromethane (2 x 20 ml), the organic phases combined, dried (MgSO4) and evaporated. The products were isolated by flash chromatography using 3% and 10% methanol in dichloromethane. The product first eluated was methyl Nf (lS, 2R)-l-amino- 2-hydroxymethyl-3-cyclohexene-l-carbonyll- (R)-valinate (43) ; yield 73 mg (46%). [a] D =-59.9° (c = 0.73, CHCl3). 1H NMR (300 MHz): 5 0.87 (d, J7 Hz, 3H, CH3), 0. 91 (d, J7 Hz, 3H, CH3), 1.52-2.20 (m, 8H, 2 x CH2, NH2, CH, OH), 2.96 (m, 1H, CH), 3.53-3.70 (m, 2H, CH2), 3.68 (s, 3H, CH30), 4.42,4.43 (dd, J5 Hz, 1H, CH), 5.50 (m, 1H, CH=), 5.77 (m, 1H, CH=), 8.11 (d, J9 Hz, 1H, NH). 13C NMR (75 MHz): 5 17.64 (CH3), 19.06 (CH3), 21.38 (CH2), 30.76 (CH), 32.85 (CH2), 42.99 (CH), 52.04 (CH30), 56.96 (CH), 58.05 (C), 63.11 (CH2OH), 126.35 (CH=), 126.81 (CH=), 172.49 (CO), 177.60 (CO). MS (EI) : 225 (2.5, M+-CH30CO), 127 (8), 126 (100), 108 (18). MS (CI-CH4 : 285 (15, M + 1), 126 (100). The second product eluated was methyl (1S, 2R)-2- hydroxymethyl-l-r(R)-valinylaminol-3-cyclohexene-l- carboxylate (44); yield 28 mg (18%). 1H NMR (500 MHz): 5 0.86 (d, J7 Hz, 3H, CH3), 0.94 (d, J7 Hz, 3H, CH3), 1.47 (bs, 4H, NH2, NH, OH), 1.64-2.21 (m, 5H, 2 x CH2, CH), 3.09 (m, 1H, CH), 3.17 (d, J5 Hz, 1H, CH), 3.72 (s, 3H, CH30), 3.94-4.23 (m, 2H, CH2), 5.35 (m, 1H, CH=), 5.82 (m, 1H, CH=). 13C NMR (125 MHz): 5 17.00 (CH3), 19.37 (CH3), 21.33 (CH2), 31.84 (CH), 32.74 (CH2), 40.84 (CH), 56.92 (C), 59.84 (CH), 64.35 (CH2OH), 124.04 (CH=), 127.77 (CH=), 175.43 (CO), 177.34 (CO). MS (EI) : 284 (0.4, M+), 224 (18), 223 (81), 167 (21), 152 (16), 108 (98), 72 (100). MS (EI): M 284.1726. Calc. for C14H24N204 : 284.1736. Example 69 (2R. 5S)-5- (3-Butenyl)-2, 5-dihydro-3, 6-dimethoxy-2- isopropyl-5- (l-oxo-2-propenyl)-pyrazine (45a) A solution of oxalyl chloride (86 mg, 0.678 mmol) in CH2Cl2 (1.8 ml) under argon was cooled to-60°C and a solution of DMSO (105 mg, 1. 356 mmol) in CH2Cl2 (0. 34 ml) added. The resultant mixture was stirred for 2 min before a solution of (2R, 5S, 1'S/R)-5- (3-butenyl)-2, 5-dihydro-3,6- dimethoxy-5- (l-hydroxy-2-propenyl)-2-isopropylpyrazine (200 mg, 0.680 mmol) in CH2Cl2 (1. 5 ml) was added dropwise. The reaction mixture was stirred at-10°C for 15 min, colled to-60°C and triethylamine (0.360 ml) added. The reaction mixture was stirred for 5 min and allowed to reach ambient temperature. Yield 145 mg (73%); colourless oil. [a] D=-21.44° (c= 0.90, CHC13). Found: C 65.75; H, 8.22. Calc. for C16H24N203 : C, 65.92; H, 8.21%. 1H NMR (200 MHz): 5 0.67 (d, J7 Hz, 3H, CH3), 1.05 (d, J7 Hz, 3H, CH3), 1.82-2.12 (m, 4H, 2 x CH2), 2.33 (m, 1H, CH), 3.63 (s, 3H, CH30), 3.68 (S, 3H, CH30), 3.92 (d, J3 Hz, 1H, CH), 4.88 (m, 2H, CH2=), 5.61-5.67 (m, 2H, CH2=), 6.27-6.62 (m, 2H, 2 x CH=). 13C NMR (50 MHz): b 17.62 (CH3), 20.18 (CH3), 29.02 (CH2), 31.25 (CH), 34.66 (CH2), 53.44 (CH30), 53.51 (CH30), 61.35 (C-2), 70.84 (C- 5), 115.11 (CH2=). 130. 32 (CH2=), 131.31 (CH=), 138.94 (C=), 160.76 (C), 165 (C), 194 (C=O). MS (EI) : 292 (0.47, M+), 237 (55), 195 (100), 153 (34), 123 (10), 55 (22), 43 (13), 27 (13). Example 70 (2R, 5S)-2, 5-dihydro-3, 6-dimethoxy-2-isopropyl-5 (1-oxo-2- propenyl)-5- (4-pentenyl) pyrazine (45b) A solution of oxalyl chloride (123 mg, 0.969 mmol) in CH2C12 (3 ml) under argon was cooled to-60°C and a solution of DMSO (151 mg, 1.938 mmol) in CH2C12 (0.5 ml) added. The mixture was stirred at this temperature for 2 min before dropwise addition of a solution of (2R, 5S, 1'R/S)-2, 5-dihydro-3,6-dimethoxy-5- (l-hydroxy-2- propenyl)-2-isopropyl-5- (4-pentenyl) pyrazine (300 mg, 0.974 mmol) in CH2C12 (2.5 ml). The reaction mixture was stirred at-10°C for 15 min, cooled to-60°C and triethylamine (0.54ml) added. The stirring was continued for 5 min at this temperature before the reaction mixture was allowed to reach ambient temperature. Yield 212 mg (71%); colourless oil. [a] D=- 30.24° (c = 0.85 CHC13). 1H NMR (200 MHz): 5 0. 66 (d, J7 z, 3H, CH3), 1.06 (d, J7 Hz, 3H, CH3), 1.27 (m. 2H, CH2), 1.90-2.05 (m, 4H, 2 x CH2), 2.33 (m, 1H, CH), 3.63 (s, 3H, CH30), 3.65 (s, 3H, CH30), 3.94 (d, J 3 Hz, 1H, CH), 4.86 (m, 2H, CH2=), 5.59-5.70 (m, 2H, CH2=), 6.27-6.57 (m, 2H, 2 x CH=). 13C NMR (50 MHz): 5 16.97 (CH3), 19.54 (CH3), 23. 28 (CH2), 30. 63 (CH), 33. 63 (CH2), 34. 19 (CH2), 52.74 (CH30), 52.80 (CH30), 60.68 (C-2), 70.45 (C-5), 114.36 (CH2=), 129.54 (CH2=), 130.71 (CH=), 138.51 (CH=), 160.26 (C), 164.56 (C), 193.57 (C=O). MS (EI) : 306 (3, M+), 251 (100), 209 (43), 195 (17), 153 (18). Example 71 (2R, 5S)-2, 5-Dihydro-3 6-dimethoxy-2-ispropylpyrazine-5- spiro (2-oxo-3-cyclohexene) (46a) Bis (tricyclohexylphosphine) benzylidene ruthenium dichloride (18 mg, 0. 022 mmol, 2%) in dry degassed 1,2- dichloroethane (1 ml) was added to a solution of (2R, 5S)-5- (3-butenyl)-2, 5-dihydro-3,6-dimethoxy-2- isopropyl-5- (1-oxo-2-propenyl) pyrazine (313 mg, 1.072 mmol) in dry 1,2-dichlorethane (15 ml). The reaction mixture was stirred at 40°C for 4 h before the solvent was evaporated and the product purified by flash chromatography using hexane: ethyl acetate 4: 1. Yield 194 mg (69%); colourless oil. [a] D=-21. 74° (c = 0.70, CHC13). Found: C, 63.88; H, 7.70. Calc. for C14H2oN203 : C, 63.64; H, 7.58%. 1H NMR (200 MHz): 5 0.62 (d, J7 Hz, 3H, CH3), 1.05 (d, J7 Hz, 3H, CH3), 1.90-2.63 (m, 5H, 2 x CH2, CH), 3.60 (s, 3H, CH30), 3.67 (s, 3H, CH3), 4.30 (d, J3 Hz, 1H, CH), 5.90 (d, 1H, CH=), 6.99-7.06 (m, 1H, CH=). 13C NMR (50 MHz): 5 16.61 (CH3), 19.30 (CH3), 22.4 (CH2), 30.57 (CH), 34.20 (CH2), 52.47 (CH30), 52.55 (CH30), 60.70 (C-2), 65.0 (C-5), 127.56 (=CH), 151.41 (=CH), 161.06 (C), 164.47 (C), 193.63 (C=O). MS (EI): 264 (8, M+), 221 (100), 193 (17), 153 (35), 80 (29). Example 72 (2R, 5S)-2, 5-Dihydro-3 6-dimethoxy-2-isopropylpyrazine-5- spiro (2-oxo-3-cycloheptene) (46b) Bis (tricyclohexylphosphine) benzylidene ruthenium dichloride (14 mg, 0. 016 mmol) in dry degassed 1,2- dichloroethane (1 ml) was added to a solution of (2R, 5S)-2,5-dihydro-3,6-dimethoxy-2-isopropyl-5- (l-oxo- 2-propenyl)-5- (4-pentenyl) pyrazine (100 mg, 0.327 mmol) in dry 1,2-dichloroethane (7 ml). The reaction mixture was stirred at 80°C for 22 h before the solvent was evaporated and the product purified by flash chromatography using hexane: ethyl acetate 9: 1. Yield 25 mg (28%); colourless oil. 1H NMR (300 MHz): 5 0.63 (d, J7 Hz, 3H, CH3), 1.04 (d, J7 Hz, 3H, CH3), 1.69-1.83 (m, 2H, CH2), 2.25-2. 56 (m, 5H, 2 x CH2, CH), 3.60 (s, 3H, CH30), 3.67 (s, 3H, CH30), 4.04 (d, J3 Hz, 1H, CH), 5.93 (d, J3 Hz, 1H, CH=), 6.36-6.44 (m, 1H, CH=). 13C NMR (75 MHz); 5 16.78 (CH3), 19.40 (CH3), 20. 21 (CH2), 30.67 (CH), 33. 15 (CH2), 35.25 (CH2), 52.48 (CH30), 52.67 (CH30), 60.55 (C-2), 70.20 (C-5), 129.72 (CH=), 144.66 (CH=), 161.77 (C), 163.39 (C), 200.26 (C=O). MS (EI) : 278 (20, M+), 235 (100), 207 (46), 153 (30). Example 73 Methyl(S)-1-amino-2-oxo-3-cyclohexene-1-carboxylate (47a) (2R,5S)-2,5-Dihydro-3,6-dimethoxy-2-isopropylpyrazine-5- spiro (2-oxo-3-cyclohexene) (200 mg, 0.758 mmol) was added to a solution of trifluoracetic acid (38 ml, 7.50 mmol, 0.2 M) in acetonitrile (38 ml) at ambient temperature and the mixture stirred for 5 d. The solution was evaporated almost to dryness at reduced pressure, water (16 ml) and dichloromethane (30 ml) added. The two layers were separated, the aqueous layer made alkaline (pH 10) by addition of conc. ammonia, extracted with dichlormethane (2 x 30 ml), the combined organic layers dried (MgS04), evaporated and the product isolated after flash chromotography using 3% methanol in dichloromethane. Yield 47 mg (37%); colourless oil. [a] D=-59° (c = 0.30, CHC13). Found: C, 56.11; H, 6.30. Calc. for C8H1lNO3 : C, 56.81; H, 6.51%. 1H NMR (300 MHz): 5 1.88-2.34 (m, 6H, 2 x CH2, NH2), 3.68 (s, 3H, CH30), 6.06 (m, 1H, CH=), 6.95 (m, 1H, CH=). 13C NMR (75 MHz): 5 23.70 (CH2). 33.69 (CH2), 52.73 (CH30), 64.23 (C-1), 127.39 (CH=), 150.27 (CH=), 172.48 (C=O), 194.77 (C=O). MS (EI) : 169 (10, M+), 110 (100), 101 (63), 82 (37), 68 (33). Example 74 Methyl(S)-1-amino-2-oxo-3-cycloheptene-1-carboxylate (47b) (2R,5S)-2,5-Dihydro-3,6-dimethoxy-2-isopropylpyrazine-5- spiro (2-oxo-3-cycloheptene) (0.5 mmol) was added to a solution of trifluoracetic acid (5 mmol, 0.2M) in acetonitrile (25 ml) at ambient temperature and the mixture was stirred for 5 d. The solution was evaporated almost to dryness at reduced pressure, and water (10 ml) and dichloromethane (20 ml) were added. The two layers were separated, the aqueous layer made alkaline (pH 10) by addition of conc. ammonia, extracted with dichloromethane (2 x 25 ml), the combined organic layers dried (MgSO4), evaporated and the product isolated after flash chromatography using 3% methanol in dichloromethane. Yield 30%, colourless oil. 1H NMR (300 MHz): 5 1.72-2.00 (m, 8H, 3 x CH2, NH2), 3.72 (s, 3H, CH30), 6.06 (m, 1H, CH=), 6.42 (m, 1H, CH=). 13C NMR (75 MHz): 5 21. 77 (CH2), 32. 63 (CH2), 34. 66 (CH2), 52. 77 (CH30), 59.92 (C-1), 129.41 (CH=), 144.42 (CH=), 173.92 (CO), 200.94 (CO). Example 75 (2R)-2, 5-Dihydro-3, 6-dimethoxy-2-isopropylpyrazine-5- spiro (cis-3, 4-epoxycyclopentane) (48) Peracetic acid (0.48 ml, 2.79 mmol, 39% in acetic acid) was added dropwise to a suspension of (2R)-2,5-dihydro- 3,6-dimethoxy-2-isopropylpyrazine-5-spiro (3- cyclopentene) (220 mg, 0.93 mmol) and anhydrous sodium acetate (534 mg, 6.52 mmol) in dry dichloromethane (10 ml) at 0°C. 0.1 M phosphate buffer (pH 7,10 ml) was added after 5 h at 0°C, the aqueous layer extracted with dichloromethane (3 x 15 ml), the dichloromethane solution dried and evaporated. The residue was purified by flash chromatography using hexane/ethyl acetate 9: 1 and 4: 1 as eluents. Yield 122 mg (53%), white solid, mp; 36°C. Found: C, 62.19; H, 7.92. Calc. for C13N20N203 : C, 61.88; H, 7.99%. [a] D =-27.8° (c = 1.16, CHCl3). 1H NMR (200 MHz): 5 0.60 (d, J7 Hz, 3H, CH3), 0.98 (d, J7 Hz, 3H, CH3), 1.89 (m, 5H, 2 x CH2, CH), 3.57 (m, 2H, 2 x CH- O), 3.60 (s, 3H, CH30), 3.63 (s, 3H, CH30), 3.85 (d, J3 Hz, 1H, H-2). 13C NMR (50 MHz): 5 16.74 (CH3), 19.18 (CH3), 31. 04 (CH), 43. 19 (CH2), 43. 61 (CH2), 52. 20 (CH30), 52. 54 (CH30), 59. 54 (CH), 59. 79 (CH), 60. 47 (CH), 64. 21 (C-5), 160.97 (C), 164.32 (C). MS (EI) : 252 (43, M+), 251 (15), 210 (16), 209 (69), 196 (67), 180 (45), 167 (30), 154 (67), 153 (100). Example 76 (2R)-2. 5-Dihydro-3 6-dimethoxy-2-isopropylpyrazine-5- spiro (cis-3 4-dihydroxycyclopentane) (50a) and (2R)-2, 5- dihydro-3 6-dimethoxy-2-ispropylpyrazine-5-spiro (trans- 3, 4-dihydroxycyclopentane) (50b) Osmium tetroxide (0.15 ml, 0.011 mmol, 2.5% in tBuOH) was added to a solution of (2R)-2,5-dihydro-3,6- dimethoxy-2-isopropylpyrazine-5-spiro (3-cyclopentene) (267 mg, 1.13 mmol) and 4-methylmorpholine-4-oxide monohydrate (168 mg, 1.24 mmol) in acetone (20 ml) and water (5 ml) at 0°C. Sodium bisulphite (125 mg, 1.24 mmol) was added after 6 h and the mixture stirred for 15 min. Dichloromethane (20 ml) was added and the aqueous layer extracted with dichloromethane (3 x 10 ml), the combined organic layers were dried (MgS04), evaporated, and the two diols were separated by flash chromatography using 5% methanol in dichloromethane. The product first eluated was (2R)-2, 5-Dihvdro-3, 6- dimethoxy-2-isopropvpvrazine-5-spiro (cis-3, 4- dihydroxycyclopentane) (50a); yield 180 mg (59%); white solid, mp., 76°C. Found: C, 57. 90 ; H, 8.40. Calc. for C13H22N204 : C, 57.76; H, 8.20%. [a] D =-42.2° (c = 0.87, CHCl3). 1H NMR (200 MHz): 5 0.60 (d, J7 Hz, 3H, CH3), 0.97 (d, J7 Hz, 3H, CH3), 1.57-1.74 (m, 2H, CH2), 2.16 (m, 1H, CH), 2.35,2.42 (dd, 6 Hz, 2H, CH2), 3.55 (s, 3H, CH30), 3.59 (s, 3H, CH30), 3.81 (d, J9 Hz, 1H, OH), 3.91 (d, J3 Hz, 1H, H-2), 4.20 (bs, 3H, 2 x CH, OH). 13C NMR (50 MHz): 5 16.66 (CH3), 19.07 (CH3), 31.11 (CH), 45.45 (CH2), 46.41 (CH2), 52.38 (CH30), 52.51 (CH30), 60.44 (C- 2), 63.91 (C-5), 74.53 (CH-OH), 74.68 (CH-OH), 161.43 (C), 162.98 (C). MS (EI) : 270 (3, M+), 227 (8), 226 (14), 184 (10), 183 (100). The second product eluated was (2R)-2, 5-dihydro-3 6- dimethoxy-isopropylpyrazine-5-spiro (trans-3 4- dihydroxycyclopentane) (50b) yield 54 mg (18%); white solid, mp. 104°C. [a] D =-34.6° (c 0.54, CHCl3). 1H NMR (200 MHz): 5 0.61 (d, J7 Hz, 3H, CH3), 1.00 (d, J7 Hz, 3H, CH3), 1. 85-2. 27 (m, 5H, 2 x CH2, CH), 2.87 (m, 2H, 2 x OH), 3.57 (s, 3H, CH30), 3.70 (s, 3H, CH30), 3.92 (d, J3 Hz, H-2), 4.25 (m, 2H, 2 x CH). 1 3C NMR (50 MHz) : 5 16.72 (CH3), 19. 19 (CH3), 30. 98 (CH), 46. 58 (CH2), 46. 75 (CH2), 52. 18 (CH30), 52. 89 (CH30), 60. 86 (C-5, C-2), 73.65 (2 x CH-OH), 160.92 (C), 163.73 (C). MS (EI) : 270 (19), 253 (10), 228 (14), 227 (100), 209 (20), 195 (26), 183 (50). Example 77 Methyl cis-l-acetamido-3 4-diacetoxy-cyclopentane-l- carboxylate (52) (Prepared without isolation of the dihydroxy compound 51) (2R)-2,5-Dihydro-3,6-dimethoxy-2-isopropylpyrazine-5- spiro (cis-3,4-dihydroxycyclopentane) (162 mg, 0.60 mmol) was stirred with TFA (30 ml, 6.00 mmol, 0.2 M) and acetonitrile (30 ml) at ambient temperature for 3 d. Most of the solvents were evaporated and water (1 ml) and dichloromethane (10 ml) were added. The aqueous phase was brought to pH 10 by addition of conc. ammonia and extracted with dichloromethane (2 x 20 ml). The combined dichloromethane layers were dried (MgSO4) and concentrated by evaporation. The residue was dissolved in dichloromethane (10 ml) and 4-dimethylaminopyridine (450 mg, 3.68 mmol) and acetic anhydride (0.35 ml, 3.68 mmol) was added. The solvent was evaporated after stirring at ambient temperature for 2 ddays and the residue was purified by flash chromatoaraphy using 3% methanol in dichloromethane as eluent. Yield 107 mg (60%); colourless oil. 1H NMR (300 MHz): 5 1.96 (s, 3H, CH3), 2.01 (s, 6H, 2 x CH3), 2.05,2.10 (dd, J5 Hz, 2H, CH2), 2.69,2.73 (dd, J6 Hz, 2H, CH2), 3.69 (s, 3H, CH30), 5.25 (m, 2H, 2 x CH), 6.30 (s, 1H, NH). 13C NMR (75 MHz): 5 20.75 (2 x CH3), 22.81 (CH3), 40.09 (2 x CH2), 53.00 (CH30), 61.25 (C-1), 72.50 (2 x CH), 169.86 (CO), 169.93 (CO), 173.37 (CO). Example 78 Methyl cis-1-amino-3 4-dihydroxy-cyclopentane-1- carboxylate (51) (2R)-2,5-Dihydro-3,6-dimethoxy-2-isopropylpyrazine-5- spiro (cis-3,4-dihydroxycyclopentane) (161 mg, 0.60 mmol) was stirred with TFA (30 ml, 6.00 mmol, 0.2 M) and acetonitrile (30 ml) at ambient temperature for 3 days. Most of the solvents were evaporated and water (5 ml) and dichloromethane (10 ml) were added. The aqueous phase was brought to pH 10 by addition of conc. ammonia and extracted with dichloromethane (3 x 20 ml). The combined dichloromethane layers were dried (MgS04) and evaporated. The residue is isolated by flash chromatography using 5% methanol in dichloromethane.'H NMR (300 MHz): 5 1.92-2.34 (m, 8H, 2 x CH2, 2 x OH, NH2), 3.67 (s, 3H, CH30), 4.14 (m, 2H, 2 x CH). 13C NMR (75 MHz): 5 44.18 (C-2 and C-5), 52.52 (CH30), 59.81 (C-1), 74.01 (C-3 and C-4), 176.45 (CO).