The present invention relates to novel cyclic chiral compounds. Much research is currently devoted to methods of producing optically active compounds. Some compounds can be synthesised directly in a form containing an excess of a desired isomer, using optically active starting materials or an optically active catalyst. Other materials are more conveniently prepared in isomeric form by separation of the desired isomer from a mixture. A number of chiral reagents useful in such separations are known.

We have now found a family of novel cyclic optically active compounds useful in asymmetric synthesis and in the separation of particular isomers from mixtures.

Accordingly, the present invention provides a compound of the general formula:

in which each of R--, R^, R ³ and R ^*+ independently represent a hydrogen atom or a group -(C0) _n R^ in which n is 0 or 1 and R represents an alkyl, aryl, cycloalkyl, alkaryl or aralkyl group, or R* and R^ together and/or R ³ and R ^*+ together represent an alkylene group; Q

represents an oxygen or sulphur atom; and Y represents a hydrogen atom, an alkali metal atom or a group of the general formula -COA in which A represents a halogen atom or an alkyl, alkenyl or alkoxy group optionally substituted by a phenyl, cycloalkyl, alkoxy or alkylcarbonyl group.

An alkyl group R- preferably has up to 17, especially up to 6, carbon atoms. A cycloalkyl group R-> is preferably a cyclopentyl or, especially, cyclohexyl, group. An aryl group R^ is preferably a phenyl group. An aralkyl or alkaryl group R^ preferably contains a phenyl group and an alkyl moiety having 1 to 4 carbon atoms.

Where R* and R^ or R^ and R" ⁺ together represent an alkylene group, such group preferably completes a 5 or 6 numbered ring. Preferably, both R^ and R^ together and R^ and R ^* * together represent an alkylene group, especially a CH(CI_3)2 group. The number of carbon atoms in an alkyl, alkenyl or alkoxy group A is not crucial. Preferably such a group has up to 30 carbon atoms. Where a higher alkyl or alkoxy group is preferred, such a group may for example have from 15 to 30 carbon atoms. Where a lower alkyl or alkoxy group is preferred, such a group preferably has up to 6, especially up to 4, carbon atoms. A cycloalkyl substituent on an alkyl, alkenyl or alkoxy group A is preferably a cyclopentyl or cyclohexyl group and an alkoxy or alkylcarbonyl substituent preferably has up to 6, especially up to 4, carbon atoms in the alkyl moiety. Preferably Q represents an oxygen atom. Compounds of the formula (I) may be prepared by ring closure of a suitable precursor. Accordingly, the invention further provides a process for the preparation of a compound of the general formula I, which comprises inducing ring closure in a compound of the general formula II:

in which R*, R^, R-* and R ^* * have the meanings given for the general formula I except hydrogen, and Z represents an -N3 group or a group of the general formula -NH.0.S02.R^, in which R^ represents an aryl, especially phenyl group, and if desired, converting the resulting compound of the general formula I into any other desired compound of the general formula I. The compounds of the general formula II are novel, and form a further aspect of the present invention.

A compound of the general formula II in which Z is an -N3 group may be cyclised by heating, for example to a temperature in the range of from 100 to 300*C. The heating may be carried out in the presence or absence of a solvent. The spray pyrolysis apparatus described in Accts. Chem. Res., 1987, 1_ , 18 or the flash vacuum pyrolysis apparatus described in EP-A-259103 may be used. If a solvent is used, this may for example be a hydrocarbon or a chlorohydrocarbon, preferably tetrachloroethane. A preferred method of carrying out the cyclisation comprises adding the compound of the general formula II dropwise to boiling tetrachlorethane. Ultra-violet photolysis or microwaves may also be used, again preferably in the presence of a hydrocarbon or chlorohydrocarbon solvent. A compound of the general formula II in which Z represents a group of the general formula -NH.0.S02.R^ _f may be cyclised by treatment with a base in a homogeneous or two-phase system. Examples of the homogeneous system are the use of araine bases such as triethylamine, or sodium bicarbonate in a chlorinated solvent such as dichloromethane or hydrocarbon/substituted hydrocarbon solvent such as nitromethane. Reaction in an organic-aqueous two-phase system is performed using a similar selection of organic solvents with, preferably, aqueous sodium bicarbonate as the basic solution. In addition a quaternary ammonium or phosphonium salt as phase-transfer catalyst, preferably benzyltriethylammonium chloride, may be employed. The temperature may be for example in the range 20-100°C, preferably 20-30'C. The aryl group R ⁶ may if desired contain one or more substituents, especially electron-withdrawing substituents, such as nitro groups, halogen atoms, or alkylcarbonyl groups. A p-N02 substituent represents a typical substituent.

A compound of the general formula I in which Y represents a hydrogen atom may be converted into the corresponding compound in which Y represents an alkali metal atom by reaction with a suitable strong base, and into the corresponding compound in which Y represents a group COA by reaction with a compound of formula HalCOA, in which

Hal represents a halogen atom. Such conversions may be carried out by known methods.

A compound of the general formula I in which Q represents an oxygen atom may be converted into the corresponding compound in which Q represents a sulphur atom by methods analogous to known methods, for example by reaction with phosphorus pentasulphide or with Lawesson's reagent.

A compound of the general formula I prepared by cyclisation of a compound of the general formula II can be converted into another compound of the general formula I containing one or more free hydroxy groups by methods analogous to known methods. For example, a compound in which R and R^ together and/or R^ and R* together represent an alkylene group can be so converted by reaction with a base. Compounds containing ester groups can be converted by hydrolysis of the ester linkage.

A compound of the general formula II may be prepared by reaction of a compound of the general formula III:

in which R , R ^z , R ³ and R ^*+ have the meanings given for the general formula II, with an alkali or alkaline earth metal azide, preferably sodium azide, to produce a compound of the general formula II in which Z represents an -N3 group, or with hydrox ammonium chloride followed

by a compound of the general formula CI.SO2.R , or with a compound of formula NH2O.SO2. , in which R^ has the meaning given for the general formula II, to produce a compound of the general formula II in which Z represents an -NH.0.S02.R^ group.

A compound of the general formula III may be prepared by reaction of a compound of the general formula IV:

in which R*, R^, R3 and R"* have the meanings given for the general formula II, with phosgene. The reaction is suitably carried out in the presence of a suitable solvent, for example an ether such as diethyl ether, tetrahydrofuran or 1,4-dioxan and in the presence or absence of a base such as pyridine or triethylamine, at a temperature in the range of from -lO'C to 20'C, preferably -5*C to 10 C. The reaction is preferably carried out under an inert atmosphere.

The compounds of the general formula IV may be prepared from galactose by protection of the hydroxy groups attached directly to the ring, by known methods, For example, reaction with a ketone will produce a compound in which R^- and R^ together and/or R^ and R ^*+ together represent an alkylene group. Reaction with an etherifying agent will produce compounds in which the -OH groups are etherified, and the hydroxy groups can be esterified in known manner. Compounds of the general formula I may be used as resolving agents for other optically-active compounds, or as intermediates for the production of chiral compounds. For example, compounds in which Y represents -COHal where Hal is a halogen atom may be used to separate enantiomers of amines, amino-acids, alcohols or thiols whilst compounds in which Y represents an alkali metal atom may be used to

separate enantiomers of acid halides or amino-acid halides. In addition, a compound of the general formula I in which Y represents a group - COA where A is an optionally substituted alkyl or alkenyl group, may be used to react with optically inactive compounds, for example aldehydes, ketones, keto-acids, epoxides and dienes, generating optical centres stereoselectively.

Accordingly, the present invention also provides a process for separating enantiomers of a compound capable of reacting with a compound of the general formula I, which comprises contacting a mixture of said enantiomers with a compound of the general formula I, and separating the resulting components of the mixture.

The invention further provides a process for generating an optically active carbon atom from an optically inactive carbon atom, which comprises reacting a compound of the general formula I in which A is an optionally substituted alkyl group, with an alkylating agent such as an aldehyde, ketone, keto-acid, alkyl halide or epoxide, or an acylating. agent or an halogenating agent or in which A is an optionally substituted alkenyl group, with a diene. These Diels-Alder, alkylations, Michael or aldol type reactions provide an extremely valuable tool for generating chiral compounds with a high degree of stereospecificity. The adducts formed from the compound of the general formula I and a simple optically inactive molecule, for example benzaldehyde, could exist in any of four diastereoisomeric forms. In fact, one diastereoisomer is, in general, formed preferentially. This molecule can be cleaved to produce a new optically active molecule derived from the optically inactive molecule. A particular advantage of the compounds of the formula I is that the adducts are often highly crystalline compounds, making their handling relatively simple.

Compounds of formula I in which Q represents a sulphur atom are chiral derivatising agents of improved UV sensitivity for chromatographic monitoring.

Compounds of the general formula I can be supported on solid supports such as graphite. Alternatively, a compound containing free

hydroxy groups can be bound to a suitable support, for example a silica support. These materials may then be used for chromatographic separations.

Compounds of formula I could also be used as a basis for ligands for complexing to metals as optically active catalysts or reagents. The following Examples illustrate the invention.

Example 1

Preparation of 1.2:3,4-di-0-isopropylidene-D-galactopyranose A mixture consisting of anhydrous D-(+)-galactose (10 g, 0.056 mol), acetone (150 ml), powdered fused zinc chloride (12 g,

0.184 mol) and concentrated sulphuric acid (0.4 ml), was stirred for

4h at room temperature.

The reaction mixture was treated with a solution of sodium carbonate (10 g, 0.189 mol) in water (35 ml) and vigorously stirred until the supernatent became zinc free (1 hour). The precipitated salts (ZnCθ3) were filtered off and washed with acetone. The filtrate, consisting of two liquid phases, was completely freed of acetone under vacuo and the crude di-isopropylidene galactose, separating as a light yellow upper layer, was then taken up in diethyl ether, washed with water, dried (MgSθ ) and evaporated to yield the crude product as a thick, viscous, pale yellow oil (13.63 g ; 94%).

Physical Data boiling point 117 ^# C/0.015 mmH _g [oC] ²⁰ _D -52.6* (c=3, CHC1 ₃ )

¹ H NMR (200 MHz, CDC1 ₃ )£5.32 (1H, d, J-_5Hz, CH) , 4.39 (1H, dd, J-=8, 2Hz, CH), 4.12-4.04 (2H, m, 2CH) , 3.64-3.48 (3H, m, CH ₂ , CH), 1.31

(3H, s, CH3), 1.21 (3H, s, CH ₃ ), 1.11 (6H, s, 2CH ₃ ), ppm.

¹³ C NMR (50.3 MHz, CDCI3) S 108.61 (quat. C), 107.96 (quat. C), 95.61

(CH), 70.54 (CH), 70.03 (CH), 69.95 (CH), 67.97 (CH) , 60.90 (CH ₂ ),

25.28 (2CH ₃ ), 24.28 (CH3), 23.71 (CH3) ppm. IR (thin film)>>max 3460 (b,0H) cm ^*"1 .

Example 2

Preparation of 6-chloroformyl-1,2:3,4-di-O-isopropylidene-D-

Kalactopyranose

A solution of di-isopropylidene-galactopyranose prepared as in Example 1 (7.88 g, 0.0307 mol) and pyridine (2.43 g, 0.0307 mol) in

dry diethyl ether (100 ml), was added dropwise to a rapidly stirred solution of phosgene (45.6 ml of 20Z solution in toluene, 0.0921 mol), at O'C, under argon.

The reaction mixture was stirred at room temperature overnight (14h) and then filtered. The precipitate was washed thoroughly with dry diethyl ether and the combined filtrate and washings were evaporated to yield the chloroformate as a yellow viscous oil (9.28g, 95Z).

The chloroformate was used immediately to make the azidoformate (see Example 3). Physical data

^X H NMR (200 MHz, CDCI3) S 5.45 (IH, d, J-5Hz, CH), 4.57 (IH, dd, J-8, 3Hz, CH), 4.38 (IH, s, CHO), 4.35 (IH, s, CH0), 4.29-4.25 (IH, m, CH), 4.16 (IH, dd, J-8, 2Hz, CH), 4.05-4.01 (IH, m, CH), 1.45 (3H, s, CH3), 1.37(3H, s, CH3), 1.26 (6H, s, 2CH3) ppm.

¹³ C NMR (50.3 MHz, CDCI3) S 150.44 (C-0), 109.63 (quat. C), 108.70 (quat. C), 95.95 (CH), 70.46 (CH), 70.10 (CH), 70.03 (CH ₂ ), 65.22 (CH), 25.73 (2CH ₃ ), 24.64 (CH3), 24.21 (CH ₃ ) ppm. IR (Thin Film) "5 max 1775 (C-0) cm ^-1 . Example 3

Preparation of 6-azidoformyl-l.2:3.4-di-0-isopropylidene-D- galactopyranose

To a rapidly stirred solution of the chloroformate prepared as in Example 2 (9.88 g, 0.0307 mol) in methylene chloride (100 ml) was added, in one, a solution of sodium azide (3.98 g, 0.0612 mol) and tetra-butyl ammonium bromide (0.5 g) in water (100 ml).

The reaction mixture was rapidly stirred overnight (14h), separated, and the aqueous layer extracted with methylene chloride (3 x 30 ml). The combined extracts were washed with water (10 ml), dried (MgSO.,.) and evaporated to yield a pink solid. The solid was extracted into hot hexane to yield the azidoformate as a clean, colourless solid (8.77 g, 871). Physical data m.p. 102-103°C [e*] ²⁰ _I ^■ -60.5 ^,, (c=5, CH ₂ C1 ₂ ) NMR (200 MHz, CDCI3) S 5.50 (IH, d, J=5Hz, CH), 4.60 (IH, dd, J-8,

3Hz, CH), 4.34-4.27 (3H, m, CH ₂ , CH), 4.2 (IH, dd, J=8, 2Hz),

4.07-4.00 (IH, m, CH), 1.49 (3H, s, CH ₃ ), 1.42 (3H, s, CH ₃ ), 1.31 (6H, s, 2CH3) ppm.

¹³ C NMR (50.3 MHz, CDCI3) S 157.24 (C-0), 109.62 (quat. C), 108.70

(quat. C), 96.04 (CH), 70.60 (CH), 70.49 (CH), 70.20 (CH), 66.88

(CH ₂ ), 65.44 (CH), 25.82 (CH3), 25.78 (CH3), 24.74 (CH3), 24.29 (CH3) ppm.

IR (Nujol) **> max 2200, 2140 (both -N3), 1720 (S, C-0) cm ^-1 .

Example 4

Preparation of 5S-2.6-dioxa-4-aza-7S.8S:9R.10S-di-0-isopropylidene- spiro[4,5ldecan-3-one

A solution of the azidoformate prepared as in Example 3 (5 g, 0.015 mol) in tetrachloroethane (500 ml) was heated under reflux (147*C) for 4h under argon.

The reaction mixture was cooled then evaporated to yield a thick viscous brown oil. This brown oil was subjected to column chromatography using gradient elution (100Z petroleum ether to 100% ethyl acetate) to give, after recrystallisation from ethyl acetate, the oxazolidinone as a colourless solid (2.92 g; 60Z). Physical Data m.pt 169-170'C; \ρt] ^2Z _* = -88.4* (C=5, CHCI3)

^X H N.M.R. (200 MHz, CDCI3) £ 6.35 (br.s, IH, NH), 5.47 (d, J=4.2 Hz, IH, C ₇ -H), 4.69 (d of d, J-5.7, 1.6 Hz, IH, C ₉ -H), 4.44 (d, J=10.08 Hz, IH, Ci-H), 4.33 (d, J=7.2 Hz, IH, C ₁₀ -H), 4.26 (d, J=10.08 Hz, IH, Cx-H , 4.20 (d of d, J=2.59, 1.63 Hz, C ₈ -H), 1.60 (s, 3H, CH3), 1.40 (s, 3H, CH ₃ ), 1.33 (s, 3H, CH3), 1.32 (s, 3H, CH3) ppm.

¹³ C N.M.R. (50.3 MHz, CDC1 ₃ ) £ 156.68 (C-0), 109.86 (quat C), 109.78 (quat C), 94.50 (CH), 84.87 (quat C), 73.91 (CH ₂ ), 73.72 (CH), 71.40 (CH), 69.84 (CH), 26.00 (CH ₃ ), 25.82 (CH ₃ ), 24.75 (CH3), 24.00 (CH ₃ ) ppm. IR (Nujol)Omax 3370 (s, NH), 1790 (b, C=0) cm ^-1 . Example 5

Preparation of N-propionyl-5S-2.6-dioxa-4-aza-7S,8S:9R, 10S-di-O- isopropylidene-spirof4.5ldecan-3-one

To a stirred solution of the product of Example 4 (0.5 g, 1.56 x 10 ^-3 mol) at -78*C and under argon was added n-BuLi (1.1 ml of 1.6 M solution, 1.76 x 10~ ³ mol) via syringe. The reaction mixture was stirred for 30 minutes at -78"C, then freshly distilled propionyl chloride (0.28g, 3.03 x 10~ ³ mol) in dry tetrahydrofuran (10 ml) was added, dropwise, via syringe. The reaction mixture was warmed to room temperature and allowed to stir overnight (16 hrs).

Excess acid chloride was hydrolysed by addition of 1M K2CO3 solution (50 ml) followed by vigorous stirring for 30 minutes at room temperature. Volatiles were removed in vacuo and the product was extracted into methylene chloride (3 x 30 ml). The combined organic extracts were washed with water (10 ml), dried (MgSO^.) and evaporated to give a pale yellow solid (0.61 g). Recrystallisation of this yellow solid from ethyl acetate gave the product as a colourless crystalline solid (0.48 g, 84Z). Physical Data Mpt - 186-187-C [θt] ²² _. - + 15.7* (c-2, CH ₂ C1 ₂ )

^X H NMR (200 MHz, CDCI3) $ 5.33 (IH, d, J = 2.6 Hz, CH), 4.9 (IH, d, J = 5.4 Hz, CH), 4.62 (IH, d, J = 5.4 Hz, CH), 4.52 (IH, d, J = 10.4 Hz, CH), 4.27 (IH, d, J = 10.4 Hz, CH), 3.98 (IH, dd, J = 2.4, 0, Hz, CH), 2.98-2.80 (2H, m, CH ₂ ), 1.40 (3H, s, CH ₃ ), 1.39 (3H, s, CH ₃ ), 1.35 (3H, s, CH3), 1.32 (3H, s, CH ₃ ), 1.09 (3H, t, J = 7.3 Hz) ppm.

¹³ C NMR (50.3 MHz, CDCI3) ξ, 173.56 (C = 0), 153.02 (C = 0), 111.50 (quat C), 108.69 (quat C), 94.26 (CH), 88.92 (quat C), 78.68 (CH), 75.98 (CH), 73.41 (CH), 69.01 (CH ₂ ), 29.89 (CH ₂ ), 27.41 (CH3), 26.92 (CH3), 25.72 (CH ₃ ), 25.46 (CH3), 7.96 (CH ₃ ) ppm. IR (Nujol) ^* )max 1780 (C = 0), 1720 (C = 0) cm ^"1 .

Example 6

Preparation of N-(3-hvdroxy-3-phenyl-2-methyl-propionyl)-5S-2,6-dioxa-

4-aza-7S.8S:9R.10S-di-0-isopropylidene-spiro[4,5ldecan-3- one

To a solution of diisopropylamine (0.115g, 1.13x 10 ^-3 mol) in dry tetrahydrofuran (10 ml) at 0*C and under argon, was added a solution of n-BuLi (1.0 ml of 1.6 M, 1.60 x 10~ ³ mol). After 30 minutes, the solution was cooled to -78*C and the imide of Example 5 (0.27 g, 7.56 x 10""* mol) in tetrahydrofuran (10 ml) was added dropwise via syringe. The reaction mixture was stirred at -78*C for 1 hour and then to the resulting lithium enolate was added, rapidly, freshly distilled benzaldehyde (0.088 g, 8.30 x 10" ⁴ mol) in tetrahydrofuran (2 ml). After 15 minutes, the reaction was quenched with saturated ammonium chloride solution (2 ml), diluted with water (20 ml) and then extracted with diethyl ether ( 3 x 20 ml). The combined ether extracts were dried (MgSO^.) and evaporated to yield an off-white solid (0.35 g). N.M.R. of the crude product showed the presence of only two of the four possible diastereomers, these two being in the ratio of 16:1. Example 7 Reductive cleavage of aldol adduct of Example 6

To an ice-cooled solution of the aldol adduct (0.70 g, 1.51 x 10 ^~3 mol) of Example 6 in dry tetrahydrofuran (20 ml), under argon, was added water (30 1, 1.66 x 10~ ³ mol) and solid lithium borohydride (0.036 g, 1.66 x 10~ ³ mol). The reaction mixture was stirred at 0*C for 1% hours (thin layer chromatography showed no more starting material).

The reaction was quenched by dropwise addition of water (10 ml) followed by stirring until it went clear (about 15 minutes). The solution was poured onto ether/water and separated. The aqueous layer was extracted with diethyl ether (3 x 20 ml). The combined ether extracts were washed with water (10 ml), dried (MgSOj/,.) and evaporated to yield a clear, viscous oil (1.02 g).

The oil was subjected to column chromatography using stepwise gradient elution (from 100% petroleum ether to 100% diethyl ether). The first fraction to be eluted was (IS, 2R)-l-phenyl-2-methylpropane-

1,3-diol (0.20 g, 83%). The second fraction eluted was the oxazolidinone of Example 4 (0.29 g, 64%).

Physical Data for (IS,2R)-l-phenyl-2-methylpropane-l,3-diol

Ph

^X H NMR (200 MHz, CDC1 ₃ ) S 7.37-7.23 (5H, m, Ph), 4.87 (IH, d, J-4Hz, CH-0), 3.60 (2H, d, J__5Hz, CH ₂ -0), 3.40 (IH, bs, OH), 2.95 (IH, bs,

OH), 2.12-1.95 (IH, m, CH), 0.80 (3H, d, J=7Hz, CH3) ppm.

¹³ C NMR (50.3 MHz, CDCI3) S 142.52 (quat C), 127.94 (ArCH) 126.99

(ArCH), 125.97 (ArCH), 76.14 (CH), 65.98 (CH ₂ ), 41.21 (CH), 10.54

(CH3) ppm. [e] ²⁵ _D —62.5* (c-0.48, CHCI3) M.p. 74-75'C (from diethyl ether/hexane).

Example 8 (Comparative)

Examples 5 to 7 show the generation of a chiral molecule, lS,2R-l-phenyl-2-methylpropane-l,3-diol, using a compound of the general formula I. This Example repeats the general method of

Examples 5 to 7 using known chiral reagents. The known materials used were:

S0 ₂ Oppolzer et al, J. Am.Chem.Soc. , 1990, 112 2767; and

Evans et al, J. Am.Chem.Soc. , 1981, 103 2127.

When using reagent (a), a mixture of all four possible diastereomers were obtained in a ratio 10.0:75.7:9.1:5.2, giving a diastereomeric excess of 51%, compared with that of 88% obtained according to the invention.

When using reagent (b), a mixture of three of the four possible diastereomers were obtained in a ratio 24.1:10.3:65.5, giving a diastereomeric excess of 31%. Example 9 Preparation of acryloyl derivative

To a stirred solution of the oxazolidinone of example 4 (0.5 g, 1.66 x 10" ³ mol) in dry tetrahydrofuran (THF) (20 ml), at -78*C, under argon, was added dropwise n-butyl lithium (1.2 ml, 1.6 M, 1.83 x 10" ³ mol). After stirring at -78*C for 30 minutes, freshly distilled acryloyl chloride (0.30 g, 3.32 x 10 ^""3 mol, 2 eq) in THF

(5 ml) was added dropwise. The reaction mixture was stirred at -78*C for 15 minutes, then warmed to room temperature and stirred at this temperature for 30 minutes.

The reaction was quenched with saturated sodium carbonate solution (5 ml). The resulting solution was poured onto ether/water (1:1) and separated. The aqueous layer was extracted with ether (3 x 20 ml). The combined ether extracts were washed with water (10 ml), dried (MgSO^.) and then evaporated to yield a thick gum.

The crude product was subjected to column chromatography (about 50 g Silica), using hexane/ether 2:1 elution. This gave the product as a white solid (0.513 g, 87%).

The above general procedure was repeated with crotonoyl chloride and cinnamoyl chloride. N-(Acryloyl)-5S-2,6-dioxa-4-aza-7S,8S:9R,10S-di-0-isopropyli dene-spiro [4,5]decan-3-one. The yield was 87% and the melting point 155-156 ^C C. The [optical activity] was [«_*-] ²⁶ _D -- +21.1 ^* (c = 1.96, CH ₂ C1 ₂ ). ^X H NMR (200 MHz, CDC1 ₃ ) $ 7.34 (dd, J-16.9, 10.3Hz, IH, CH( _A )=), 6.46 (dd, J-16.9, 1.9Hz, IH, CH( _C )«), 5.82 (dd, J-10.3, 1.9Hz, IH, CH( _B )=), 5.32 (d, J-2.7HZ, IH, C ₇ H, 4.93 (d, J=5.5Hz, IH, C ₈ H), 4.63 (d, J-5.6Hz, IH, C ₉ H), 4.26 (d, J-10.4Hz, IH, CiH), 4.53 (d, J=10.5Hz,

IH, C H) , 3 . 97 (dd , J-2. 7, 0. 7Hz , IH, C ₁₀ H) , 1 . 37 ( S , 6H, 2CH ₃ ) , 1 . 32 (S , 3H, CH ₃ ) , 1 . 29 (S , 3H, CH ₃ ) ppm.

¹³ C NMR (50.3 MHz CDC1 ₃ ) S 164.28 (C-0), 152.77 (C-0) 132.17 (CH ₂ -_), 127.76 (CH-), 111.44 (quat c), 108.68 (quat c), 94.20 (CH), 89.00 (quat c), 78.55 (CH), 75.87 (CH), 73.16 (CH), 69.20 (CH ₂ ), 27.37 (CH3), 26.85 (CH3), 25.66 (CH3, 25.37 (CH3) ppm.

IR (Nujol) max 1780 (oxazolidinone C-O), 1720 (C-0), 1640 (C-C) cm ^-1 . Accurate Mass (FAB-MS) (M+H) Requires 356.13453 Found 356.13452

N-(Crotonoyl)-5S-2,6-dioxa-4-aza-7S,8S:9R,10S-di-0-isopro pylidene- spiro[4,5]decan-3-one. The yield was 60% and the melting point 102-103*C (from diisopropylether) and the [optical activity] was [β ] 8 _D _ + 15.6- (c-1.90, CH ₂ C1 ₂ ). *H NMR (200 MHz, CDCI3) S 7.15-7.08 (m, 2H, CH-CH), 5.33 (d, J-2.53Hz, IH, C ₇ H), 4.94 (d, J-5.4HZ, IH, C ₈ H), 4.62 (d, J-5.4HZ, IH, C ₉ H), 4.51 (d, J-10.4HZ, IH, CxH), 4.27 (d, J-10.4Hz, IH, CiH , 3.95 (d, J-2.6Hz, IH, C ₁₀ H), 1.39 (S, 3H, CH3), 1.37 (S, 3H, CH3), 1.34 (S, 3H, CH3), 1.30 (S, 3H, CH ₃ ), 1.07 (d, J-6.1Hz, 3H, CH3-CH-). ¹³ C NMR (50.3 MHz CDCI3) S 164.22 (C-0), 152.90 (C-0), 147.45 (CH-), 122.11 (CH-), 111.40 (quat c), 108.53 (quat c), 94.13 (CH), 88.97 (quat c), 78.70 (CH), 75.92 (CH), 73.37 (CH), 69.01 (CH ₂ ), 27.37 (CH3), 26.87 (CH3), 25.64 (CH) ₃ , 25.37 (CH3), 18.36 (CH ₃ ) ppm. IR (Nujol)Vmax 1780 (oxazolidinone C-0), 1690 (C-0), 1630 (C-C) cm ^-1 . Accurate Mass (FAB)

(M+H) Requires 370.15018 Found 370.15017 N-(Cinnamoyl)-5S-2,6-dioxa-4-aza-7S,8S:9R,10S-di-0-isopropyl idene- spiro[4,5]decan-3-one. The yield was 80% and the melting point 254-255'C.

^ NMR (200 MHz, CDCI3) £ 7.90 (d, J=15.7Hz, IH, CH=), 7.72 (d, J=15.7Hz, IH, CH-), 7.61-7.56 (m, 2H, ortho Ph), 7.42-7.35 (m, 3H, meta+para Ph), 5.40 (d, J=2.6Hz, IH, C ₇ H), 5.06 (d, J=5.40Hz, IH, C _β H , 4.72 (d, J=5.4Hz, IH, C ₉ H), 4.59 (d, J=10.4Hz, IH, CiH), 4.35 (d, J=10.4Hz, IH, CiH), 4.04 (d, J=2.6Hz, IH, C ₁₀ H), 1.46 (S, 3H,

CH ₃ ) , 1 .43 ( S , 3H, CH ₃ ) , 1 . 39 ( S , 3H, CH ₃ ) , 1 . 36 ( S , 3H, CH ₃ ) ppm.

¹³ C NMR (50.3 MHz CDC1 ₃ ) S 164.27 (C-O), 153.10 (C-O), 147.03 (CH=),

134.20 (quat c), 130.73 (CH), 128.76 (CH), 128.55 (CH), 117.14 (CH),

111.57 (quat c), 108.68 (quat c), 94.27 (CH), 89.17 (quat c), 78.82 (CH), 76.03 (CH), 73.56 (CH), 69.29 (CH ₂ ), 27.53 (CH ₃ ), 27.02 (CH3)

25.74 (CH3), 25.49 (CH3) ppm.

IR (Nujol)Omax 1780 (oxazolidinone C-O), 1710 (C-0), 1630 (C-C) cm ^*"1 .

Accurate Mass (FAB)

(M+H) Requires 432.16583 Found 432.16585

Example 10

Asymmetric Diels-Alder reaction

To a solution of the acrylate of example 9 (0.2 g, 5.63 x 10 ^* "4 mol) in dry methylene chloride (10 ml), at -78*C under argon, was added freshly cracked cyclopentadiene (0.37 g, 5.63 x 10~ ³ mol,

10 eq), followed by diethyl aluminium chloride (0.44 ml, 1.8 M,

7.89 x 10" mol, 1.4 eq). A transient yellow colour was observed. The reaction mixture was stirred at -78*C for 15 minutes, then quenched with saturated ammonium chloride solution (5 ml). The solution was allowed to warm up to room temperature and then poured onto methylene chloride/water 1:1. The aqueous layer was extracted with methylene chloride (3 x 20 ml). The combined organic layers were washed with water (10 ml), dried (MgSθ ) then evaporated to yield a thick gum. The crude product was subjected to column chromatography (about

50 g Silica) using hexane/ether 5:1 elution. This gave the product as an oil which crystallised on standing.

The above general procedure was repeated with the crontonate and the cinnamate. In the case of the cinnamate, the temperature had to be raised to -20*C and the reaction mixture stirred at this temperature for 30 minutes.

N-[(3 ^I S,4 ^, S,6 ^I R)-Bicyclo[2.2.1]heptene-4'-carbonylJ-5S-2,6-dioxa-

4-aza-7S,8S:9R,10S-di-0-isopropylidene 9-spiro[4,5]decan-3-one.

^X H NMR (200 MHz, CDCI3) 86.16 (dd, J=5.6, 3.1Hz, IH, CH-), 5.79 (dd, J-5.6, 2.8Hz, IH, CH-=), 5.30 (d, J=2.6Hz, IH C ₇ H), 4.85 (d, J=5.4Hz,

IH, C ₈ H), 4.50 (d, J=10.4Hz, IH, C H), 4.45 (d, J=5.4Hz, IH, C ₉ H) , 4.25 (d, J=10.4Hz, IH, CiH), 4.01-3.93 (m, 2H, CHC-0 + C ₁₀ H), 3.22 (brs, IH, CH) 2.87 (brs, IH, CH), 2.22-2.13 (m, IH, CH ₂ CHC=0) , 1.89-1.77 (m, IH, CH ₂ CHC=0),1.38 (S, 3H, CH ₃ ), 1.35 (S, 3H, CH ₃ ), 1.32 (S, 3H, CH ₃ ), 1.30 (S, 3H, CH ₃ ), 1.25-0.81 (m, 2H, bridgehead H) . IR (Nujol) Λ) max 1800 (doublet, oxazolidinone C=0, 1700 (C-O)cm ^""1 . N-[(3 ^• S,4 ^■ S,5'R,6 ^• R)-5' ethylbicyclo[2.2.1]heptene-4 ^« -carbonyl] -5S-2,6-dioxa-4-aza-7S,8S:9R,10S-di-0-isopropylidene-spiro [4,5]decan-3-one. The yield was 80% and the melting point 110-111°C (from hexane), diastereoisomeric excess de >90%; [o ] °r_ = -142° (CH ₂ C1 ₂ ). ^HNMR (200 MHz, CDCI3) & 6.33 (dd, J=5.6, 3.1HZ, IH, CH=), 5.72 (dd, J-5.6, 2.8Hz, IH, CH-), 5.33 (d, J=2.6Hz, IH, C ₇ H), 4.87 (d, J=5.4Hz, C ₈ H), 4.50 (d, J=10.4Hz, IH, CiH), 4.41 (d, J=5.4Hz, IH, C ₉ H), 4.26 (d, J=10.4Hz, IH, C ₁₀ H), 3.49 (t, J=4.1Hz, IH, CHC=0), 3.22 (brs, IH, CH), 2.48 (brd, IH, CH), 2.14-2.08 (m, IH, CHCH3), 1.66 (brd, IH, bridghead H), 1.43 (d, J-1.82Hz, IH, bridgehead H), 1.39 (S, 6H, 2CH ₃ ), 1.34 (S, 3H, CH3), 1.32 (S, 3H, CH3), 1.04 (d, J=7.1Hz, 3H, CH ₃ ). ¹³ C NMR (50.3MHz, CDCI3) S 173.42 (C=0), 152.91 (C-O), 140.19 (CH=1), 130.09 (CH=), 111.51 (quat c), 108.66 (quat c), 94.16 (CH), 89.38 (quat c), 78.61 (CH), 76.04 (CH), 73.19 (CH), 68.30 (CH ₂ ), 52.53 (CH), 49.21 (CH), 47.39 (CH), 46.91 (CH ₂ ), 35.40 (CH) 27.36 (CH3), 26.89 (CH ₃ ), 25.77 (CH3), 25.50 (CH3), 20.12 (CH ₃ ). IR (Nujol) λ? max 1790 (oxazolidinone C=0), 1720 (C-0)cm" ^"1

N-[(3'S, 4'S, 5'R, 6'R)-5'-Phenylbicyclo[2.2.1]heptene-4 ^l -carbonyl]- 5S-2,6-dioxa-4-aza-7S,8S:9R, 10S-di-0-isopropylidene-spiro[4,5] decan-3-one. The yield was 92% and the melting point 197-198 ^β C (from ethanol), diastereoisomeric excess de >95% and the [optical activity] was [o ] ²⁶ _D = -130° (c=l, CH ₂ C1 ₂ ). iHNMR (200 MHz, CDCI3) $ 7.28-7.14 (m, 5H, Ph), 6.51 (dd, J-5.3, 3.2Hz, IH, CH=), 5.91 (dd, J-5.4, 2.6Hz, IH, CH-), 5.35 (d, J=2.6Hz, IH, C ₇ H), 4.95 (d, J=5.2Hz, IH, C ₈ H), 4.55 (d, J=10.5Hz, IH, C H), 4.47 (d, J=5.4Hz, IH, C ₉ H) , 4.30 (d, J=10.5Hz, IH, CiH), 4.16 (dd, J=5.1, 3.4Hz, IH, CHC=0), 4.01 (d, J=2.5Hz, IH, C ₁₀ H) , 3.42-3.39 (m,

2H, CHPh + CH), 3.06 (brs, IH, CH), 1.93 (brd, IH, bridgehead H) ,

1.61-1.56 (m, IH, bridgehead H), 1.423 (S, 3H, CH ₃ ), 1.393 (S, 3H,

CH ₃ ), 1.367 (S, 3H, CH ₃ ), 1.364 (S, 3H, CH ₃ ).

¹³ CNMR (50.3 MHz, CDC1 ₃ ) £ 173.17 (C=0) , 152.79 (C-O), 143.47 (quat c), 140.58 (CH), 131.53 (CH) , 128.25 (CH), 127.28 (CH) , 125.86

(CH), 111.64 (quat c), 108.76 (quat c), 94.18 (CH), 89.40 (quat c),

78.72 (CH), 76.18 (CH), 73.34 (CH), 68.34 (CH ₂ ), 52.09 (CH), 48.68

(CH), 48.07 (CH ₂ ), 47.48 (CH), 45.58 (CH), 27.44 (CH3), 26.94 (CH3),

25.78 (CH3), 25.57 (CH3). IR (Nujol) \ max 1770 (oxazolidinone C-O), 1700 (C-O), 800-700

(aromatic).

Accurate mass (FAB)

(M+H) Requires 498.21277 Found 498.21274 Example 11

Cleavage of Diels-Alder adduct

To benzyl alcohol (0.10 g, 9.20 x 10~ ⁴ mol, 2 eq) in dry THF

(2 ml), at -78*C under argon, was added dropwise n-butyl lithium

(0.32 ml, 1.6 M, 5.06 x 10 ^~ 4 mol). After stirring for 15 minutes, the crotonate Diels-Alder adduct of example 10 (0.20 g, 4.60 x 10 ^~ 4 mol) in THF (5 ml) was added dropwise. The solution was stirred at -78 ^β C for 10 minutes, then warmed to room temperature.

The reaction was quenched after 15 minutes with saturated ammonium chloride (5 ml). The resulting solution was poured onto ether/water 1:1 and separated. The aqueous layer was extracted with ether (3 x 20 ml). The combined ether extracts were washed with water

(10 ml), dried (MgSO,.) and then evaporated.

The crude product was subjected to column chromatography (about

30 g Silica). Elution with hexane/ether 5:1 gave the benzyl ester fragment as a clear viscous oil (0.110 g, 99%). Further elution with ether gave the starting unsubstituted oxazolidinone (see example 4)

(0.069 g, 50%).

Phenylmethyl-(3S,4S,5R,6R)-5-Methylbicyclo[2.2.1]heptene- 4- carboxylate. The [optical activity] was [Crt] ²⁶ -- = -127° (c=1.0, CH ₂ C1 ₂ ).

¹ HNMR (200 MHz, CDC1 ₃ ) 5 7.43-7.31 (m, 5H, Ph), 6.28 (dd, J-5.7, 3.2Hz, IH, CH=), 5.98 (dd, J=5.7, 2.8Hz, IH, CH=), 5.09 (d, J=2.5Hz, 2H, OCH ₂ Ph), 3.16 (brs, IH, CH), 2.50-2.43 (M, 2H, CHC--0 + CH), 1.94-1.87 (Symm m, IH, CHCH3), 1.59-1.41 (m, 2H, bridgehead CH ₂ ), 1.21 (d, J=7.0Hz, 3H, CH3) ppm.

^N R (50.3 MHz, CDCI3) S 174.33 (C=0), 138.58 (CH), 136.25 (quat c), 133.08 (CH), 128.34 (CH), 127.85 (CH), 127.75 (CH), 65.73 (CH ₂ ), 52.39 (CH), 48.70 (CH), 45.84 (CH ₂ ), 37.71 (CH), 20.83 (CH) ppm. IR (thin film)"?max 1730 (C-O), 1610-1570 (triplet, weak, C-C). Example 12

Asymmetric acylation reaction

To diisopropylamine (0.093 g, 9.24 x 10 ^~4 mol, 1.1 eq) in dry THF (2 ml) at 0*C under argon, was added dropwise n-butyl lithium (0.53 ml, 1.6 M, 9.24 x 10 ^*"4 mol, 1.1 eq). After stirring at O'C for 15 minutes, the solution was cooled to -78*C and the propionyl imide of example 5 (0.3 g, 8.40 x 10~ ⁴ mol, 1.0 eq) in THF (5 ml) was added dropwise. The reaction mixture was stirred at -78*C for 30 minutes and then to the resulting enolate was added freshly distilled acetyl chloride (0.132 g, 1.68 x 10 ^-3 mol, 2 eq) in THF (1 ml). The reaction was quenched after 2 minutes with saturated ammonium chloride solution (5 ml). The resulting solution was allowed to warm up to room temperature and then poured onto ether/water 1:1 and separated. The aqueous layer was extracted with ether (3 x 20 ml). The combined ether extracts were washed with water (1 x 10 ml), dried (MgS0 ) then evaporated to yield an optically active white solid.

The above general procedure was repeated with propionyl chloride. N-K2 ^I S)-2'-Methyl-3-carbonylbutanoyl]-5S-2,6-dioxa-4-aza-7S ,8S:9R, 10S-di-0-isopropylidene-spiro[4,5]decan-3-one. The yield was 98% and the melting point 169-170 ^β C (from ethanol), diastereoisomeric excess >95% (*HNMR). The [optical activity] was [CX] ²⁶ _D = +9.35" (c=2, CH ₂ C1 ₂ ) .

¹ HbMR (200 MHz, CDCI3) fc 5.65 (q, J=7.1Hz, IH, CHCH3), 5.38 (d, J=2.8Hz, C ₇ H), 4.67 (d, J=6.3Hz, IH, C ₈ H), 4.60 (d, J=6.4Hz, IH, C ₉ H), 4.47 (d, J=9.8Hz, IH, CiH=, 4.32 (d, J=9.8Hz, IH, CiH , 4.15 (dd, J=2.8, 0.7Hz, IH, CI _Q H) , 2.15 (S, 3H, CH ₃ C-_0), 1.61 (d, J=7.1Hz, 3H,

CH3CH), 1.50 (S, 3H, CH ₃ ), 1.47 (S, 3H, CH3), 1.36 (S, 6H, 2CH ₃ ) ppm. V_?NMR (50.3 MHz, CDCI3) £> 167.26 (C=0), 154.61 (C=0), 133.40 (C=0), 117.22 (CH), 111.10 (quat c), 109.17 (quat c), 94.46 (CH), 90.92 (quat c), 75.99 (CH), 74,64 (CH), 69.91 (CH), 66.62 (CH ₂ ), 27.07 (CH3), 25.94 (CH ₃ ), 25.58 (CH3), 24.91 (CH ₃ ), 20.43 (CH3), 11.35 (CH ₃ ) ppm.

IR (Nujol max 1785 (oxazolidinone C-O), 1760 (C-O), 1690 (C-0) cm ^-1 . Accurate Mass (FAB) (M+H) Requires 399.15289 Found 399.15287

N-[(2 ^" S)-2'-Methyl-3-carbonylρentanoyl]-5S-2,6-dioxa-4-aza- 7S,8S:9R, 10S-di-0-isopropylidene-spiro[4,5]decan-3-one. The yield was 94% and the melting point 147-148*C (from ethanol), diastereoisomeric excess >95% (^-HNMR). The [optical activity] was [o<] ²⁶ _D = +6.6" (c=2, CH ₂ C1 ₂ ) .

^X HNMR (200 MHz, CDCI3) g 5.61 (q, J=7.1Hz, IH, CHCH3), 5.38 (d, J-2.8HZ, IH, C ₇ H), 4.66 (d, J-6.3Hz, IH, C ₈ H), 4.58 (d, J-6.3Hz, IH, C ₉ H), 4.45 (d, J-9.8HZ, IH, CiH), 4.30 (d, J-9.9Hz, IH, CiH), 4.13 (dd, J-2.8, 0.6Hz, IH, C ₁₀ H), 2.43 (q, J=7.6Hz, 2H, CH ₂ CH ₃ ), 1.58 (d, J=7.1Hz, 3H, CH3CH), 1.48 (S, 3H, CH ₃ ), 1.45 (S, 3H, CH3), 1.35 (S, 6H, 2CH ₃ ), 1.15 (t, J=7.5Hz, 3H, CH ₃ CH ₂ ) ppm.

¹³ CNMR (50.3 MHz, CDC1 ₃ ) 6 170.75 (C-O), 154.57 (C-O), 133.49 (C=0) , 116.91 (CH), 111.09 (quat c), 109.14 (quat c), 94.50 (CH), 90.84 (quat c), 76.15 (CH), 74.69 (CH), 70.06 (CH), 66.74 (CH ₂ ), 27.15 (CH3), 27.03 (CH ₂ ), 25.97 (CH ₃ ), 25.59 (CH3), 24.92 (CH ₃ ), 11.32 (CH3), 8.71 (CH3) ppm.

IR (Nujol)^raax 1790 (oxazolidinone C-0), 1755 (C-O), 1690 (C-O) cm ^*"1 . Accurate Mass (FAB) (M+H) Requires 414.17639 Found 414.17641 Example 13 Asymmetric bromination reaction

To diisopropylamine (0.062 g, 6.16 x 10" ⁴ mol, 1.1 eg) in dry THF (2 ml), at 0°C, under argon, was added dropwise n-butyl lithium (0.39 ml, 1.6M, 6.16 x 10 ^~4 mol, 1.1 eq). After stirring for 10

minutes the solution was cooled to -78"C and the propionyl imide of example 5 (0.2 g, 5.60 x 10 ^~4 mol) in THF (5 ml) was added dropwise. The reaction mixture was stirred at -78 ^β C for 30 minutes then to the resulting enolate was added N-bromosuccinimide (0.20 g, 1.12 x 10 ^~3 mol) in THF (5 ml).

The reaction was quenched after 10 minutes with saturated ammonium chloride solution (5 ml). The resulting solution was allowed to warm up to room temperature then poured onto ether/water 1:1 and separated. The aqueous layer was extracted with ether (3 x 20 ml). The combined ether layers were washed with water (10 ml), dried (MgSU ) then evaporated to yield a yellow solid.

Analysis of the 200 MHz -^HNMR spectrum, showed the presence of only one diastereomer, giving a diastereomeric excess, de of >95%. N-[(2'R)-2'-Bromopropionyl]-5S-2,6-dioxa-4-aza-7S,8S:9R, 10S-di-0-isoρropylidene-spiro[4,5]decan-3-one. The yield was 95% and the melting point 131-132*C (from hexane), diastereoisomeric excess de >95% ^HNMR). The [optical activity] was [ ] ²² _D - +50* (c-1, CHC1 ₃ ). iHN R (200 MHz, CDCI3) ξ> 5.71 (q, J-6.7Hz, IH, BrCHCH ₃ ), 5.35 (d, J=2.5Hz, IH, C ₇ H), 4.93 (d, J=5.3Hz, IH, C ₈ H), 4.57 (d, J=10.5Hz, IH, CiH , 4.49 (d, J=5.3Hz, IH, C ₉ H), 4.32 (d, J=10.5Hz, IH, CiH), 3.99 (d, J=2.6Hz, IH, C ₁₀ H), 1.77 (d, J=6.7Hz, 3H, CH ₂ CHBr), 1.40 (S, 6H, 2CH ₃ ), 1.36 (S, 3H, CH3), 1.34 (S, 3H, CH3). (50.3 MHz, CDCI3) S 169.22 (C=0), 151.98 (C-O), 111.56 (quat c), 108.82 (quat c), 94.19 (CH), 89.08 (quat c), 78.82 (CH), 76.09 (CH), 72.99 (CH), 69.20 (CH ₂ ), 39.09 (CH), 27.43 (CH ₃ ), 26.96 (CH3), 25.67 (CH ₃ ), 25.52 (CH3), 20.12 (CH3) ppm.

IR (Nujol) ^* -* max 1790 (oxazolidinone C=0), 1720 (C=0) cm ^-1 . Accurate Mass (FAB) (M+H) Requires 436.06074 Found 436.06072 Example 14 Resolution of racemic acid halides

To a solution of the oxazolidinone of example 4 (0.5 g, 1.66 x 10 ^"3 mol) in dry THF (20 ml), at -78°C, under argon, was added

dropwise n-butyl lithium (1.2 ml, 1.6 M, 1.83 x 10"" ³ mol, 1.1 eq). After stirring at -78 ^β C for 30 minutes, freshly distilled (±)- 2-bromopropionyl bromide (0.72 g, 3.32 x 10 ^"3 mol, 2 eq) in THF (5 ml) was added dropwise. The reaction mixture was stirred at -78*C for 15 minutes then warmed to room temperature and stirred at this temperature for 30 minutes.

The reaction was quenched with saturated sodium carbonate solution (5 ml). The resulting solution was poured onto ether/water 1:1 and separated. The aqueous layer was extracted with ether (3 x 20 ml). The combined ether extracts were washed with water, dried, (MgSθ ) and then evaporated to yield a thick, brown gum.

HPLC analysis of the crude product mixture gave a separability factor, , for the two diastereomers of 2.8 (spherisorb S5W, Hexane/ether 6:1 elution, flow rate 3.0 ml/min). The above general procedure was repeated using (±)-

2-chloropropionyl chloride. This gave a separability factor, Oi , of 2.7 (spherisorb S5W, Hexane/ether 6:1 elution, flow rate 3.0 ml/min).