CYCLOPROPANATION PROCESS

This invention relates to a process of preparing cyclopropane carbinols from allylic alcoholates.

Cyclopropane carbinols are desirable compounds for some industries, for example, the fragrance and flavour industries. There is therefore an interest in their efficient production. One possible method is by the cyclopropanation of allylic alcohols. (In the following description, the term "allylic alcohol" includes homoallylic alcohols, and the term "cyclopropane carbinol" includes 2-cyclopropyl-ethanols).

Allylic alcohols have been cyclopropanated by a variety of methods, which are described in recent reviews, for example, those by A.B.Charette, A.Beauchemin, Organic Reactions 58, 1 - 416, 2001, and by M.Regitz, Carbenoids, Methoden der organischen Chemie, Houben-Weyl, (Georg Thieme Verlag Stuttgart - New York, Vol. E19b, pp 179 - 212, 1989). The reaction is believed to proceed via the formation of an allylic alcoholate and a carbenoide.

The most convenient and efficient of these methods are those using a metal or a metal mixture (Zn, Cu, Sm and Hg) or an organometallic reagent (ZnEt ₂ , AlEt ₃ or iPrMgCl), together with an iodinated carbenoide precursor (CH ₂ I ₂ or ClCH ₂ I). From these reagents, there are formed carbenoides, intermediates of the type X-M-CH ₂ -X (M = metal, X = halide). hi the presence of an allylic alcohol or allylic alcoholate, the CH ₂ -group of the carbenoide is directed intramolecularly on to the allylic double bond and effects cyclopropanation (a recent review describing this mechanism is one by A. H. Hoveyda, D. A. Evans, G. C. Fu Chem. Rev. 93, 1307 - 1370, 1993).

It would be more efficient to use dibromomethane rather than iodinated dihalomethanes because it is less expensive, more stable and avoids undesired iodine wastes. However, dibromomethane is less reactive than diiodomethane in this reaction. This can be overcome by activating with a zinc-copper couple, followed by cyclopropanation by means of ultrasound (E. C. Friedrich, J. M. Domek, R. Y. Pong, J. Org. Chem. 50, 4640 - 4642, 1985) or with additives

such as copper halides and acetyl halides (E. C. Friedrich, F. Niyati-Shirkhodaee, J. Org. Chem. 56, 2202 - 2205, 1991). However, both of these methods result in the generation of environmentally-unfriendly zinc- and copper-based wastes.

It has now been found that it is possible efficiently to cyclopropanate allylic alcoholates with dibromomethane under Grignard or Barbier conditions conveniently between 0 ⁰ C and 70°C. There is therefore provided a method for the preparation of a compound of the formula I:

comprising the generation of an alcoholate of the formula II and the subsequent cyclopropanation of this alcoholate with a reagent system selected from (A) magnesium metal and dibromomethane, and (B) dibromomethane and a tertiary Grignard reagent, the reaction being carried out in the presence of an ether solvent, C ^α , C , C ^Ύ and Q being selected according to the possibilities (a) and (b):

(a) C ^α , C' ³ , C ^Ύ represent carbon atoms that may be protonated or substituted with up to a total of 5 substituents for all three carbon atoms, the substituents being selected from the group consisting of alkyl, alkenyl, cycloalkyl and cycloalkenyl groups; and Q represents a moiety selected from (i) a saturated or unsaturated carbon chain having from 1-6 carbon atoms, preferably 1 carbon atom, which carbon atoms are protonated or substituted, the substituents being selected from any of those of C ^α , C ¹³ , C ^γ ; and

(ii) a single covalent bond joining C ^α and C^; and; (b) C ^α , C^, C ^γ and all or part of Q together form a cycloalkyl or cycloalkenyl ring; and

(c) M is an alkali metal, an alkaline earth metal, or an alkaline earth metal monohalide

Any substituents that may be present on C ^α , C , C ⁷ and Q may themselves be substituted with functional groups, such as (but not limited to) alcohols, ethers, amines, alkyl amines, alkenes, alkynes, cycloalkanes and cycloalkenes.

The alcoholate of Formula II may be prepared from many precursors and by many methods. The preparation of such alcoholates is well known to the art, and will not be further described in detail here, but the general scheme specific for allyl alcoholates shown below (with the substituents R, R ^α , R^, R ^γ and M = Na, Li or MgX (where X=halide) as hereinabove described) illustrates some of the possibilities. It is to be borne in mind that this scheme is for purposes of illustration only and is not to be construed to be in any way limiting on the scope of the method.

cyclopropyl carbinols

conjugated conjugated allylic alcohols acids and esters ketones

Without restricting the scope of the invention in any way, it is believed that, under the conditions hereinabove defined, carbenoides of the type X-Mg-CH ₂ -Br are formed from the reagent systems, and that the CH ₂ group of this carbenoide is delivered on to the double bond of the compound of Formula II, giving the cyclopropane carbinol. In this carbenoide, X is nearly always Cl.

This is surprising as carbenoides derived from dibromomethane and organomagnesium reagents have been reported as being unstable above -50 ⁰ C (J. Villieras, Comptes Rendues 261, 4137 - 4138, 1965), and only recently a low conversion (19%) of an allylic alcohol to the corresponding cyclopropane carbinol has been observed (C. BoIm, D. Pupowicz, Tetrahedron Lett. 38, 7349 — 7352, 1997) under such conditions (isopropyl magnesium chloride, dibromomethane, -70 ⁰ C, 3 days).

The reaction is carried out in the presence of an ether solvent. In a particular embodiment, the ether solvent (which may be a single solvent or a mixture of such solvents) is present from the beginning, but in a further embodiment, it is added at the same time as, or immediately prior to, the addition of the reagent system. The ether solvent may be any ether known to be useful as a solvent, particular examples including tetrahydrofuran (THF), diethyl ether and methyl if-butyl ether.

In a particular embodiment, the reagent system is used with allylic alcohols, including homoallylic alcohols, i.e, alcohols in which, in the Formula II above, Q is respectively a single bond and a single carbon atom. There is therefore also provided a method of preparation of a cyclopropyl carbinol, comprising the generation of an allylic alcoholate and the subsequent cyclopropanation of this allylic alcoholate with a reagent system selected from (A) magnesium metal and dibromomethane (hereinafter "System A"), and (B) dibromomethane and a tertiary Grignard reagent (hereinafter "System B"), the reaction being carried out in the presence of an ether solvent. The magnesium metal is usually in the form of turnings or powder.

In the embodiment of this process utilising System B, the tertiary Grignard reagent may be a commercially-available material or one prepared prior to its use in the process. The Grignard

reagent is of the formula R ₃ CMgX, the moieties R being selected from C1-C7 alkyl, such that the number of carbon atoms in R ₃ C is from 4-22. In addition, one or more of the moieties R may, with the C, form part of at least one ring system. In particular embodiments, R ₃ C is tert- butyl or tert-amyl, and the halide X is particularly Cl.

It should be noted that, while both Systems A and B work in all cases, there is a difference in efficacy, depending on the nature of the compound of Formula II. For example, in the case of Q having two or more carbon atoms (that is, not being an allylic or homoallylic alcoholate), System A is more efficient than System B in terms of conversion of double bonds to cyclopropane rings when this double bond is more than one carbon atom removed from the α- C atom of Formula II (i.e., when Q is at least 2).

In the case where Q represents a single bond, the allylic alcohols are preferably disubstituted in their α,γ- or β,γ-positions, trisubstituted in their α,β,γ-positions, tetrasubstituted in α,β,γ,γ- positions or pentasubstituted in their α,oc,β,γ,γ-positions. Fewer substituents and/or substituents in other positions are also possible but they give a lower percentage conversion (that is, more reagent is needed for complete conversion).

Particular examples of alcohols that undergo the cyclopropanation reaction using System A, including remote alkenes in the same molecule include those with the following structures:

HI IV V VI

In these cases, Q is a single carbon atom in Formula III and a single covalent bond in Formulae IV, V and VI. However, in the case of Foπnulae V and VI, each molecule has an additional double bond at a position which corresponds to Q being at least 2. hi this case, cyclopropanation of these more remote double bonds also takes place, but this

cyclopropanation is only partial. Complete conversion is possible, but only by repeating the process several times.

An example of such a remote cyclopropanation is the complete conversion of nor-Radjanol™ (Formula V) to Javanol™ and Geraniol (Formula VI) to its bis-cyclopropanated Geraniol analog in 3 cyclopropanation cycles and Barbier reaction conditions.

Javanol™

Examples of allylic alcohols (in which Q represents a single bond) that undergo the cyclopropanation reaction using System B include those with the following structures:

Examples of homoallylic alcohols (in which Q represents a single carbon atom) that undergo reaction with System B include those with the following structures:

When System B is used, particular examples of processes include:

- an allylic alcohol in 2 - 5 (particularly <3) equiv dibromomethane is cyclopropanated by slow addition of 2 - 5 (particularly <3) equiv of a tertiary (α-trisubstituted) Grignard reagent

R ₃ CMgX at 10 - 20 ⁰ C (X = Cl, Br) in ether solvents;

- 2 - 5 (particularly <3) equiv dibromomethane and 2 - 5 (particularly <3) equiv of a tertiary (α-trisubstituted) Grignard reagent R ₃ CMgX are added portionwise or continuously but separately to the allylic alcohol in ether solvents.

It is possible to show that these tertiary Grignard reagents give a much more effective cyclopropanation than secondary ones, e.g. isopropyl magnesium chloride (employed by C. BoIm, D. Pupowicz, Tetrahedron Lett. 38, 7349 - 7352, 1997).

10° - 2O ⁰ C

In this case, it is believed (without restricting the invention in any way) that the first equiv of Grignard reagent acts as deprotonation reagent, thus generating an allylic alcoholate of Formula II, and that the other 3 equiv effect cyclopropanation. Other reagents can be used for deprotonation, such as NaH, LiH, organolithium reagents and other Grignard reagents. Yields

and selectivities are, under the less drastic conditions of System B, generally higher than those obtained under Barbier conditions. For example, if an allylic alcoholate also comprises a remote alkene (i.e., there are more than 2 carbon atoms between the hydroxy group and the alkene), the allylic alcohol alkene will be cyclopropanated almost exclusively.

In another embodiment of this process, conjugated aldehydes, ketones, acids and esters as well as allylic esters, allylic carbonates and vinyloxiranes of the type shown in the scheme above may be alkylated and cyclopropanated in sequential (tandem) reactions, that is, in situ before work-up. Alkylation of all these substrates gives allylic alcoholates, which are further cyclopropanated according to the methods hereinabove described. This tandem cyclopropanation is also possible with allylic alcoholates generated from saturated aldehydes, ketones and esters via addition of alkenyl magnesium halides.

Sequential or tandem reactions, sometimes referred to as "one-pot" reactions, are chemical processes in which two or more consecutive molecular transformations may be carried out without the need to isolate intermediates. The reactions proceed in a consecutive fashion and new bonds and stereo centers are created in a second or subsequent step. Such reactions enhance the synthetic efficiency in the construction of complex molecules from simpler ones. (G. H. Posner, Chem. Rev. 86, 831, 1986. L. F. Tietze, U. Beifuss, Angew. Chem., Int. Ed. Engl. 32, 131, 1993. T.-L. Ho, Tandem Organic Reactions; Wiley: New York, 1992).

Conjugated aldehydes (i.e., aldehydes attached to an ethylenic double bond via a single bond) are first 1,2-alkylated (at the carbonyl group) with an appropriate organomagnesium (RMgX) or organolithium (RLi) reagent followed by (A) addition of magnesium and subsequent cyclopropanation with CH ₂ Br ₂ at reflux or (B) cyclopropanation with dibromomethane and tøt-butyl magnesium chloride (^BuMgCl) at 10°-20°C.

Examples of conjugated aldehydes that undergo this sequential reaction to the corresponding ■sy/2-configurated cyclopropane carbinols include those in the following transformations:

n-heptyl-MgBr, then cyclopropanation

Ph^^_ _u _ MeMgCI, then ph CHO >fc- cyclopropanation OH

MeMgCI, then cyclopropanation

Conjugated ketones are first 1,2-alkylated (at the carbonyl group) with ≥l equiv of an appropriate organomagnesium (RMgX) or preferably an organolithium (RLi) reagent under cooling followed by cyclopropanation with dibromomethane and tens-Butyl-MgCl at 0°-5°C. A similar tandem reaction, addition of MeLi to a conjugated ketone, followed by a Simmons- Smith cyclopropanation has been reported by T.Cohen et al., Organic Letters, 3, 2121, 2001. A

subsequent cyclopropanation of the allyloxylithium intermediate with dibromomethane under Grignard conditions, however, is new and more efficient.

Examples of conjugated ketones that undergo this sequential reaction to the corresponding cis- configurated cyclopropane carbinols, include those in the following transformations:

Conjugated esters are first alkylated with >2 equiv of an appropriate organomagnesium (RMgX) or preferably an organolithium (RLi) reagent under cooling followed by cyclopropanation with dibromomethane and tert-Butyl-MgCl at 0°-5°C.

Examples of conjugated esters that undergo this sequential reaction include those in the following transformations:

1-Alkenyl halides are first converted to the corresponding 1-alkenyl magnesium reagents by known procedures (as described by K.Nύtzel in Methoden der organischen Chemie, Houben- Weyl, (G.Thieme Verlag, Stuttgart), VoI 13/2a, pp 47 - 529, 1973) followed by addition of an

aldehyde or ketone, followed by (A) Mg / CH ₂ Br ₂ or (B) CH ₂ Br ₂ / tBuMgCl cyclopropanation of the allyloxy magnesium intermediate. Alternatively, alkenyl halides are converted to the corresponding alkenyllithium reagents by known processes (as described by U. Schδllkopf in Methoden der organischβn Chemie, Houben-Weyl, VoI 13/2a, pp 47 - 529, 1973) followed by addition of an aldehyde followed by (A) Mg / CH ₂ Br ₂ or (B) CH ₂ Br ₂ / tBuMgCl cyclopropanation of the thus-formed allyloxylithium intermediate. Alternatively, alkenyllithium reagents can be added to ketones followed by CH ₂ Br ₂ / tBuMgCl cyclopropanation of the thus-formed allyloxylithium intermediate.

Examples of alkenyl halides that undergo this sequential reaction to the corresponding cyclopropane carbinols, include the following transformation:

Allylic or homoallylic esters and allylic or homoallylic carbonates are cleaved with an appropriate amount of Grignard reagent (RMgX) or organolithium (RLi) reagent followed by (A) addition of magnesium and subsequent cyclopropanation with CH ₂ Br ₂ at reflux or (B) addition of dibromomethane and subsequent cyclopropanation with a tertiary Grignard reagent at 10-20°C. Examples of these sequential reactions are given by the following transformations:

2-3 eq MeMgBr, then

R - Ac cyclopropanation

R = CO ₂ Et

Vinyloxiranes are first alkylated with an appropriate organolithium (RLi) reagent, with or without an additional base to adjust selectivity, followed by (A) addition of magnesium and subsequent cyclopropanation with CH ₂ Br ₂ at reflux or (B) cyclopropanation with dibromomethane and tert-butyl-MgCl at 10°-20°C. The S _N 2' selective opening of isoprene

oxide with organolithium reagents (RLi) is described in Tetrahedron Lett. 22, 577, 1980. Examples of this sequential reaction are given by the following transformations:

⁰ iPrLi, then cyclopropanation

nBuLi, then cyclopropanation

The above embodiments of the cyclopropanation process have many uses, including the relatively easy and inexpensive manufacture of flavour and fragrance ingredients.

Some of the compounds prepared by this method are novel. There is therefore also disclosed the following compounds:

1 -(2-ethylcyclopropyl)propan-2-ol

l-(5,5-dimethylbicyclo[4.1.0]heptan-l-yl)ethanol

dispiro[4.0.4.1]undecan-4-ol

2,2,5a,7a-tetramethyldecahydro-lH-dicyclopropa[b,d]naphthale n-6a- yl)methanol

5-ethyl-l,2-dimethylbicyclo[3.1.0]hexan-2-ol

The invention is now further described with reference to the following non-limiting examples.

Example 1 : (l-methyl^-fαiS.SR.SRVljα-trimethvlbicvclora.l.Oihexan-S-y nmethvn- cyclopropyl)methanol (Javanol™)

System A: (E)-2-methyl-4-(2,2,3-trimethylcyclopent-3-enyl)but-2-en-l-o l (J. A. Bajgrowicz, I. Frank, G. Frater, M. Hennig, HeIv. Chim. Acta. 81, 1349 - 1358, 1998) (200 g, 1 mol) and lithium hydride (1O g, 1.24 mol) in tetrahydrofuran are heated under strong stirring and argon for 6 h at 65 ⁰ C until hydrogen evolution ceases. Magnesium turnings (100 g, 4.1 mol) and 1900 ml tetrahydrofuran are added at 25°C. After addition of dibromoethane (8.5 g, 50 mmol) the mixture is heated to 65°C, where dibromomethane (280 ml, 4 mol) is added over 7 h. After another hour at 65 °C the suspension is quenched with 2M HCl under cooling. Tert-Butyl methyl ether extraction, washing of the organic phase with H ₂ O until pH 7, drying over MgSO ₄ and concentration gives a crude (65 % corr.) mono- and biscyclopropane mixture (75 : 20), which is, after another two reaction cycles, giving 95g (43%) of pure Javanol after distillation (100°C/0.05 Torr), whose analytical data (NMR, MS, IR, odor) are consistent with the ones

described for this compound in the literature (J. A. Bajgrowicz, G.Frater, EP 801049, priority 9 A.1991 to Givaudan-Roure).

System B: (£)-2-methyl-4-((l S, 3S, 5R)- 1 ,2,2-trimethylbicyclo-[3.1.0]hexan-3-yl)but-2-en- 1 -ol (5 g, 24 mmol) (F. Schroder, WO 2006066436, priority 20.12.2005 to Givaudan) is added undercooling and stirring to methyl magnesium chloride 3M in tetrahydrofuran (8 ml, 24 mmol) under nitrogen. Dibromomethane and tert-butyl magnesium chloride are added at a temperature of 10°-20°C. The dibromomethane and tert-butyl magnesium chloride are each added in 3 portions, one portion of dibromomethane (4.2 g, 24 mmol) followed by a portion of tert-butyl-magnesium chloride (12 ml, 24 mmol). After the addition of each pair of portions (72 mmol) the mixture is stirred for an appropriate time at room temperature. When complete or nearly complete conversion is reached, as checked by GC, the mixture is quenched by addition of cone. NH ₄ Cl. Tert-Butyl methyl ether extraction, washing of the organic phase with H ₂ O until pH 7, drying over MgSO ₄ and concentration gives 16.6g of an an oily residue, which is bulb-to bulb-distilled at 120°C/0.07 Torr giving 4.7 g (89%) of Javanol (dr = 1:1), whose analytical data are consistent with the ones described for this compound in the literature (J. A. Bajgrowicz, G. Frater, EP 801049, priority 9.4.1997 to Givaudan-Roure).

Example 2: (trøn5V(l-methyl-2-(((i?)-2,2,3-trimethylcyclopent-3-enyl)m ethyl)cyclopropyI)- methanol.

Prepared as described in Example 1 (System B) from «σr-Radjanol (12.6 g, 65 mmol) (J. A. Bajgrowicz, I. Frank, G. Frater, M. Hennig, HeIv. ChIm. Acta 81, 1349 - 1358, 1998), methyl magnesium chloride 3M in tetrahydrofuran (22 ml, 65 mmol), dibromomethane (3 x 10 g, 0.17 mol) and tert-butyl magnesium chloride 2M in diethyl ether (3 x 28 ml, 0.17 mol). Work-up and bulb-to bulb-distillation at 110 ⁰ C/ 0.1 Torr gives 12.5g (93%) of a colorless oil (dr = 1:1), whose analytical data (NMR, MS, IR, odor) are consistent with the ones described for this compound in the literature (J. A. Bajgrowicz, I. Frank, G. Frater, M. Hennig, HeIv. CMm. Acta 81, 1349 - 1358, 1998).

Example 3: (syn, ft'««s ⁱ )-l-(2-ethyl-l-methylcyclopropyl)hexan-l-ol.

This compound was prepared using both Systems A and B of Example 1

System A: «-Butyl lithium (11 ml, 17 mmol) is added dropwise and under cooling to (E)-4- methyldec-3-en-5-ol (R. Kaiser, D. Lamparsky, EP 45453, Givaudan, 1980) (3 g, 17 mmol). Magnesium powder (2.6 g, 0.1 mol) is added and the Barbier reaction started with a few drops of dibromomethane (18 g, 0.1 mol), which is then added at 60 ⁰ C over 1 h. After 18h at 60 ⁰ C the mixture is worked-up as above. Bulb-to-bulb distillation at 55°C / 0.05 mbar gives 2.15g (68% corr.) of a colorless oil {synlanti = 97:3).

System B: (E)-4-methyldec-3-en-5-ol (R. Kaiser, D. Lamparsky, EP 45453, Givaudan 1980) (25 g, 0.15 mol) is added under cooling and stirring to methyl magnesium chloride 3M in tetrahydrofuran (49 ml, 0.15 mol) under nitrogen. Alternatively, the (iT)-dec-3-en-5-olate magnesium halide is prepared from (£)-2-methylpent-2-enal (12.6 g, 0.15 mol) and pentane- magnesium bromide 2 M in diethyl ether (75 ml, 0.15 mol). Dibromomethane (77 g, 0.44 mol) is added to the the Grignard product followed by dropwise addition of tert-hnty\ magnesium chloride 2M in diethyl ether (220 ml, 0.44 mol) at 10°-20°C. After 16 h at 25°C 2M HCl is added. Tert-Butyl methyl ether extraction, washing of the organic phase with cone. NaHCO ₃ , H ₂ O and cone. NaCl, drying over MgSO ₄ , filtration and concentration gives 30.3g of an oily residue, which is distilled at 45°C/ 0.03 Torr giving 24.4g (90%) product as colorless oil.

Odour: green, fresh, spicy, chocolate. ¹ H NMR (CDCl ₃ ): δ -0.05 (m, 1 H), 0.5 (2 H), 0.9 (t, 3 H), 0.99 (t, 3 H), 1.01 (s, 3 H), 1.25 - 1.35 and 1.35 - 1.6 (11 H), 2.7 (dd, 1 H) ppm. ¹³ C-NMR (CDCl ₃ ): δ 11.6 (q), 14.0 (q), 14.3 (q), 17.8 (t), 22.0 (t), 22.6 (t), 24.0 (d), 24.9 (s), 26.0 (t), 32.0 (t), 33.9 (t), 80.9 (d). ^-configuration confirmed by NMR-analysis of the ethyl ether. MS (EI): m/z (%) 166 ([M - 18] ⁺ , 3) , 141 (5), 128 (15), 113 (10), 99 (32), 84 (35), 72 (85), 71 (100), 69 (60), 55 (70), 43 (75).

Example 4: (c/5.5w)-l-(-2-ethvIcycIopropyl)propan-2-ol.

System A: Prepared as described in Example 3 from (Z)-hept-4-en-2-ol (S. C. Watson, D. B. Malpass, G. S. Yeargin, DE 2430287 , Texas Alkyls Inc.USA, 1975) (3 g, 26 mmol), R-butyl lithium (16.5 ml, 26 mmol), magnesium powder (3.8 g, 0.16 mol) and dibromomethane (27 g, 0.16 mol). After 18h at 6O ⁰ C work-up and bulb-to-bulb distillation at 55 ⁰ C / 0.05 mbar gives 2.1g (57% corr) of a colorless oil {synlanti - Th:21).

System B: Prepared as described in Example 7 but in 2 reaction cycles from (Z)-hept-4-en-2-ol (4 g, 35 mmol) and dibromomethane (2 x 18.2 g, 0.2 mol) in diethyl ether by dropwise addition of føt-butyl magnesium chloride 2M in diethyl ether (2 x 52 ml, 0.2 mol) at 10°-20°C. Workup after 18 h at 25°C gave 5.7g of a crude oil which was distilled at 45°C / 12 mbar, giving 2.5 g (55%) of a colorless oil (97% purity, synlanti = 83:17).

¹ H- NMR (CDCl ₃ ): δ -0.2 (m, 1 H), 0.6 - 0.8 (2 m, 2 H), 1.0 (t, 3H), 1.2 (d, 3 H), 1.2 - 1.4 (3 H), 1.6 (1 H), 2.3 (br, OH), 3.9 (m, 1 H) ppm. ¹³ C-NMR (^-isomer): 5 10.5 (t), 12.4 (d), 14.2 (q), 16.6 (d), 22.0 (t), 23.0 (q), 37.8 (t), 68.8 (d). ¹³ C-NMR (anti-isomer): δ 10.5 (t), 12.3 (d), 14.2 (q), 17.3 (d), 22.1 (t), 23.1 (q), 37.9 (t), 68.6 (d). ^-configuration confirmed by conversion to the camphanoyl ester and X-ray analysis. MS (EI): m/z (%) 110 ([M - 18] ⁺ , 3), 95 (12), 84 (11), 81 (20), 68 (23), 55 (50), 45 (100). Retention times: 5.82 (syή), 5.86 (anti). IR (film): 3340 (br), 2961 (s), 2929 (m), 2872 (m), 1456 (m), 1374 (m), 1308 (w), 1120 (m), 1084 (m), 1063 (m), 1022 (m), 994 (w), 940 (m), 927 (m), 855 (w), 815 (w), 739 (w).

Example 5 : (^fl/wV(2-methyl-2-(4-methylpent-3-envl)cyclopropyI)methanol .

Prepared according to Example 1 (System A) from (£)-Geraniol (50 g, 0.32 mol), lithium hydride (3.4 g, 0.4 mol) in tetrahydrofuran (350 ml), magnesium powder (31.5 g, 1.3 mol) and dibromomethane (225 g, 1.3 mol). Work-up after 4 h at 65°C and bulb-to-bulb distillation gave 36g (66%) of a colorless oil, whose analytical data are consistent with the ones described for this compound in the literature (G. A. Molander, L. S. Harring, J. Org. Chern. 54, 3525 — 3532, 1989).

Example 6: (^rø«s)-(2-(2-(2,2-dimethylcyclopropyl)ethyI)-2-methyIcycI opropyI)methanol.

The (2-methyl-2-(4-methylpent-3-enyl)cyclopropyl)methanol obtained in Example 5 was subjected to another 2 reaction cycles under the conditions of Example 1 (System A) using the same amount of reagents as in Example 24 giving after work-up and distillation 15g (25% from Geraniol) of a colorless oil, whose analytical data are consistent with the ones described for this compound in the literature (H. Sakauchi, H. Asao, T. Hasaba, S. Kuwahara, H. Kiyota, Chemistry & Biodiversity, 3, 544 - 552, 2006).

Example 7: rc/5)-{2-f2-f2.3-Dimethvl-tricvcIor2.2.1.0(2.6)1hept-3-vlVet hvn-l-methvl- cyclopropylj-methanol.

Prepared as described in Example 1 (System B) from (E)-2-methy\-4-((lS,3S,5R)-l,2,2- trimethylbicyclo[3.1.0]-hexan-3-yl)but-2-en-l-ol (M. Tamura, G. Suzukamo, Tetrahedron Lett. 22, 577, 1981) (5.3 g, 24 mmol), methyl magnesium chloride 3M in tetrahydrofuran (8 ml, 24 mmol), dibromomethane (2 x 6.3 g, 72 mmol) and tert-butyl magnesium chloride 2M in diethyl ether (2 x 18 ml, 72 mmol). Work-up after 18 h and bulb-to-bulb distillation gives 3.85 g of a

colorless oil (68%). Odour: woody, creamy, weak. ¹ H NMR (CDCl ₃ ): δ 0.08 (dd, 1 H), 0.45 (dd, 1 H), 0.6 (m, 1 H), 0.8 and 0.82 (2s, 3 H), 0.83 and 0.86 (2s, 3 H), 1.0 (s, 3 H), 1.05 (2 H), 1.1 - 1.45 (7 H), 1.5 - 1.6 (3 H), 3.5 - 3.6 (2d, 2 H) ppm. ¹³ C-NMR (CDCl ₃ ): δ 10.7 (2 q), 17.5 (2 t), 17.6 (2 q), 19.4 (2 d), 19.5 (2 d), 22.3 (s), 22.7 (2 q), 24.3 (2 t), 25.9 (2 d), 27.5 (2 s), 30.9 (2 t), 31.4 (2 t), 34.8 (2 t), 38.1 and 38.2 (2 d), 45.6 (2 q), 67.3 and 67.4 (2 t). MS (EI): m/z (%) 234 (M ⁺ , 3), 219 ([M - 15] ⁺ , 1), 203 ([M - IS] ⁺ , 2), 161 (7), 121 (82), 107 (20), 93 (100), 91 (40), 79 (32), 77 (25), 55 (25), 41 (40).

Example 8: (RS)-l-((lR5.6Si?V5,S-dimethvlbicyclor4.1.01heptan-l-vnethan ol.

Prepared as described in Example 1 (System B) from l-(3,3-dimethylcyclohex-l-enyl)ethanol (A. T. Levorse, US 5234902, priority 28.2.1992 to IFF) (3.7 g, 24 mmol), methyl magnesium chloride 3M in tetrahydrofuran (8 ml, 24 mmol), dibromomethane (2 x 6.3 g, 72 mmol) and tert-bntyl magnesium chloride 2M in diethyl ether (2 x 18 ml, 72 mmol). Work-up after 20 h at 25°C and bulb-to-bulb distillation gives 3.2 g (82%) product (syn/anti = 97:3). Odour: Agrestic, strong. ¹ H NMR (CDCl ₃ ): δ 0.18 (m, 1 H), 0.44 (m, 2 H), 0.85 - 1.5 (6 H), 0.95 (s, 3 H), 1.05 (s, 3 H), 1.19 (d, 3 H), 1.95 (1 H), 3.02 (m, 1 H). ¹³ C-NMR: (CDCl ₃ ): δ 15.8 (t), 18.9 (t), 19.4 (q), 23.2 (t), 26.1 (s), 27.8 (s), 28.4 (d), 30.9 (q), 30.5 (q), 35.2 (t), 76.4 (d). Relative configuration confirmed by NMR-analysis of the benzyl ether and X-ray analysis of the Camphanate. MS (EI): m/z (%) 168 (M ⁺ , 1), 150 ([M - 18] ⁺ , 20), 135 (30), 121 (25), 109 (50), 107 (65), 93 (50), 82 (50), 81 (55), 79 (56), 69 (65), 59 (65), 55 (55), 43 (100).

Example 9: (syn, ^rαns)-l-((jE)-2-methyl-2-(4-methylpent-3-enyl)cyclopropyl) ethanol.

This example shows the preparation of the abovementioned compound, using one of four initial stages (a)-(d) below:

a) (£)-4,8-dimethylnona-3,7-dien-2-ol (EP 0743297 to Givaudan) (3.6 g, 24 mmol) and methyl magnesium chloride 3M in tetrahydrofuran (8 ml, 24 mmol).

b) (£)-Citral (4 g, 24 mmol) and methyl magnesium chloride 3M in tetrahydrofuran (8 ml, 24 mmol).

c) 4,8-dimethylnona-3,7-dien-2-yl acetate (V. K. Agarwal, T. K. Thappa, S. Agarwal, M. S. Mehra, K. L. Dhar, C. K. Atal, Indian Perfumer 27, 112-118, 1983) (5 g, 24 mmol) and methyl magnesium chloride 3M in tetrahydrofuran (19 ml, 60 mmol).

d) 4,8-dimethylnona-3,7-dien-2-yl ethyl carbonate (J. -P. Barras, B. Bourdin, F. Schroder, Chimia 60, 574 - 579, 2006) (6 g, 24 mmol) and methyl magnesium chloride 3M in tetrahydrofuran (25 ml, 60 mmol).

In each case, subsequent cyclopropanation is carried out (according to Example 1, Method B) with dibromomethane (3 x 4.2 g, 72 mmol) and te/t-butyl magnesium chloride 2M in diethyl ether (3 x 12 ml, 72 mmol). Work-up after 16 h at 25°C and bulb-to-bulb distillation gives 3.7 g (86%) product. Odour: citrus, weak. Analytical data identical with the ones reported for this compound (G. A. Molander, L. S. Harring, J. Org. Chem. 54, 3525 - 3532, 1989). Syn- configuration confirmed by COSY, HSQC, NOESY in CDCl ₃ .

Example 10: (syn, *rαHs)-l-(2-tørf-butylcycIopropyl)ethanol.

Tert-butyl magnesium chloride 2M in diethyl ether (13 ml, 26 mmol) is added dropwise and at 10°-20°C to (£)-5,5-dimethylhex-3-en-2-ol (P. Jacob III, H. C. Brown, J. Org. Chem. 42, 579, 1977) (0.7 g, 5.3 mmol) in dibromomethane (4.6 g, 26 mmol). After 24 h at 25°C 2M HCl is added. Tert-Butyl methyl ether extraction, washing of the organic phase with cone. NaHCO ₃

and cone. NaCl, drying over MgSO ₄ , filtration and concentration gives 1.8g of an an oily residue, which is purified by flash chromatography over silicagel (hexane / tert-Butyl methyl ether gradient 95:5 to 80:20) giving 0.6g (80%) of a colorless liquid. ¹ H NMR (CDCl ₃ ): δ 0.3 (m, 1 H), 0.45 (ddd, 1 H), 0.53 (ddd, 1 H), 0.85 (s, 9 H), 1.27 (d, 3 H), 1.65 (br, OH), 3.07 (dq, 1 H) ppm. ¹³ C-NMR: δ 6.4 (t), 22.7 (q), 23.0 (d), 28.4 (3C, q), 28.6 (d), 29.1 (s), 73.1 (d). syn- confϊguration confirmed by HMBC, HMQC, COSY, NOESY in DMSO. MS (EI): m/z (%) 124 ([M- IS] ⁺ , 4), 109 (11), 87 (7), 85 (5), 83 (6), 70 (100), 57 (16), 55 (53), 43 (24), 41 (25).

Example 11 : (sj«)-dispiro[4.0.4.1]undecan-4-ol.

Prepared as described in Example 8 from 2-cyclopentylidene-cyclopentanol (A. Martin, EP 770671, priority 30.10.1996 to Quest International B.V.) (5 g, 32 mmol), dibromomethane (23 g, 0.13 mol) in tetrahydrofuran (20 ml) using tert-bvXy\ magnesium chloride 2M in diethyl ether (66 ml, 0.13 mol) at 10°-20°C. Work-up after 16 h at 25°C and flash chromatography over Silicagel (hexane/tert-butyl methyl ether 3:1) gives 3.4 g (64%) product as a colorless oil. Odour: animalic, agrestic, strong. ¹ HNMR (CDCl ₃ ): δ 0.34 (d, 1 H), 0.71 (d, 1 H), 1.4 - 1.9 (14 H), 3.8 (dd, 1 H) ppm. ' ³ C-NMR: δ 22.4 (t), 22.5 (t), 25.8 (t), 26.2 (t), 30.7 (t), 32.3 (s), 32.4 (t), 32.7 (t), 35.8 (s), 36.1 (t), 75.5 (d). ^-configuration confirmed by COSY, HRQC, HMBC, NOESY. MS (EI): m/z (%) 166 [M] ⁺ , 1), 148 ([M- 18] ⁺ , 1), 137 (3), 133 (5), 119 (14), 105 (10), 97 (50), 91 (25), 85 (60), 84 (35), 83 (36), 82 (55), 79 (38), 67 (100), 55 (32), 41 (35). IR (film): 3344 (br, OH), 2947 (s), 2863 (s), 1447 (m), 1327 (w), 1300 (w), 1168 (w), 1140 (w), 1074 (m), 1028 (m), 1008 (m), 964 (m), 893 (w), 851 (w), 656 (br,w).

Example 12: ((I lS,5α5,6αi?,7fli?,76S)-2,2,5a,7a-tetramethyldecahydro-lH- dicyclopropa[b,d]naphthalen-6a-yl)methanol.

Prepared as described in Example 1 (System B) from ((ll,S ^> ,5a5 ^r ,8a5)-2,2,5a,8-tetramethyl- l,2,3,4,5,5a,6,8a-octahydrocyclopropa[d]naphthalen-7-yl)meth anol (P. C. Traas, H. Boelens, Recueil des Travaux Chimiques des Pays-Bas 92, 985 - 995, 1973), (1 g, 4.4 mmol), dibromomethane (5 x 0.75 g, 21 mmol) and tert-b\xty\ magnesium chloride 2M in diethyl ether 5 (5 x 2.1 ml, 21 mmol). Work-up after 18 h and flash chromatography (hexane/tert-butyl methyl ether 9:1 → 1:1) over Silicagel gives 0.75 g (70%) white crystals. M.p. 93°C from hexane. ¹ H NMR (CDCl ₃ ): 6 -0.01 (dd, 1 H), 0.15 (2 m, 2 H), 0.3 (d, 1 H), 0.6 (s, 3 H), 1.0 (s, 3 H), 1.04 (s, 3 H), 1.1 - 1.2 (m, 2 H), 1.2 - 1.3 (m, 2 H), 1.33 (s, 3 H), 1.4 - 1.6 (4 H), 1.7 - 1.85 (m, 1 H), 3.33 (d, 1 H), 3.6 (d, 1 H) ppm. ¹³ C-NMR (CDCl ₃ ): δ 7.15 (t), 19.5 (t), 19.7 (s), 21.7 (s),

10 22.7 (q), 23.7 (t), 24.8 (d), 26.9 (q), 28.0 (q), 29.2 (q), 31.8 (s), 33.6 (s), 34.4 (s), 37.1 (t), 40.9 (t), 42.9 (t), 69.7 (t). Relative configuration confirmed by COSY, HSQC, HMBC, NOESY in C ₆ D ₆ . MS (EI): m/z (%) 248 [M] ⁺ , 6), 233 ([M - 15] ⁺ , 4), 217 (17), 178 (17), 177 (100), 161 (15), 159 (20), 147 (19), 145 (27), 123 (48), 121 (65), 119 (49), 109 (66), 107 (65), 105 (68), 95 (69), 93 (74), 91 (66), 69 (48), 67 (28), 55 (54), 41 (58). IR (film): 3310 (br, OH), 2900 (m),

15 1483 (w), 1454 (w), 1438 (w), 1371 (w), 1320 (w), 1104 (w), 1061 (w), 1015 (s), 969 (w), 907 (w), 728 (w).

Example 13 : (c/sV3-isopropvl-6-methyIbicycIo[4.1.01|heptan-3-ol.

0 Prepared as described in Example 10 from Terpinen-4-ol (2 g, 13 mmol) and dibromomethane (9.15 g, 52 mmol) in diethyl ether by dropwise addition of tert-bntyl magnesium chloride 2M in diethyl ether (26 ml, 52 mmol) at 10°-20°C. Work-up after 16 h at 25°C and bulb-to-bulb distillation gave 2.1 g (85%) of a colorless oil. Odour: Agrestic. ¹ H- NMR (CDCl ₃ ): δ 0.3 (dd, 1 H), 0.43 (dd, 1 H), 0.6 (dddd, IH), 0.89 (d, 3 H), 0.91 (d, 3 H), 1.03 (s, 3 H), 1.1 - 1.2 (m, 2 5 H), 1.2 - 1.3 (m, 1 H), 1.5 - 1.7 (2 m, 2 H), 1.75 - 1.9 (2 H), 2.2 (m, 2 H) ppm. ¹³ C-NMR: δ 14.4 (s), 16.2 (q), 16.4 (q), 17.7 (d), 19.9 (t), 27.2 (q), 28.1 (t), 31.6 (t), 31.9 (d), 35.7 (t), 72.8 (s). ^-configuration confirmed by COSY, HSQC, HMBC, NOESY in CDCl ₃ . MS (EI): m/z (%) 168 [M] ⁺ , 3), 150 ([M - 18] ⁺ , 8), 125 (32), 107 (65), 86 (38), 71 (80), 43 (100). IR (film):

3419 (br), 2936 (m), 2863 (m), 1458 (m), 1379 (w), 1302 (w), 1225 (w), 1133 (m), 1049 (w), 992 (s), 957 (w), 906 (w), 863 (w).

Example 14: (/rg^5,5y/?)-l-((l-methyl-2-((2.,2,3-trimethylcycIopent-3-en yl)methyl)- 5 cyclopropyl)ethanol.

Prepared as described in Example 1 (System B) from nor-Radj aldehyde (US 4052341 to Givaudan Corp.) (4.6 g, 24 mmol), methyl magnesium chloride 3M in tetrahydrofuran (8 ml, 24 mmol), dibromomethane (2 x 6.3 g, 72 mmol) and tert-butyl magnesium chloride 2M in

10 diethyl ether (2 x 18 ml, 72 mmol). Work-up after 5 h at 25°C and distillation gives 3.5g (65%) of a colorless oil (syn, dr = 1:1). Odour: sandalwood, green. ¹ H NMR (CDCl ₃ ): δ 0.07 and 0.05 (1 H), 0.55 (m, 2 H), 0.75 (2 s, 3 H), 1.0 (s, 3 H), 1.05 (s, 3 H), 1.2 (2 d, 3 H), 1.2 - 1.5 (3 H), 1.6 (s, 3 H), 1.7 - 2.0 (2 H), 2.35 (1 H), 3.0 (1 H), 5.25 (1 H) pρm. ¹³ C-NMR: δ 11.3 and 12.1 (q), 12.6 (q), 18.2 and 18.7 (t), 19.2 (q), 19.5 and 19.6 (q), 20.4 and 21.0 (d), 25.7 and

15 25.8 (q), 28.5 and 29.0 (t), 35.6 and 35.7 (t), 47.0 (d), 76.4 (d), 121.7 and 121.8 (d), 149.0 (s). ■yjw-confϊguration confirmed by NMR-analysis of the ethyl ether. MS (EI): m/z (%) 222 ([M] ⁺ , 1), 204 ([M - 18] ⁺ , 5), 189 (8) 153 (24), 135 (21), 134 (22), 133 (15), 121 (60), 109 (64), 108 (80), 107 (70), 95 (60), 94 (35), 93 (100), 91 (44), 81 (29), 79 (58), 77 (34).

Example 15: (synVl-rø-propvlcvclopropyDethanol.

Prepared as described in Example 1 (System B) from is-hex-2-enal (2.35 g, 24 mmol), methyl magnesium chloride 3M in tetrahydrofuran (8 ml, 24 mmol), dibromomethane (3 x 5.5 g, 96 mmol) and tert-butyl magnesium chloride 2M in diethyl ether (3 x 16 ml, 96 mmol). Work-up after 18 h at 25°C and bulb-to-bulb distillation gives 2.8g (90%) of a colorless oil (syn/αnti = 25 87:13). ¹ H NMR (CDCl ₃ ): δ 0.3 (m, 1 H), 0.45 (m, 1 H), 0.6 (m, 1 H), 0.65 (1 H), 0.9 (t, 3 H), 1.15 (m, 2 H), 1.25 (d, 3 H), 1.38 (m, 2 H), 1.7 (br, OH), 3.1 (m, 1 H) ppm. ¹³ C-NMR (syn- isomer): δ 10.3 (t), 13.9 (q), 16.4 (d), 22.55 (q), 22.6 (t), 27.0 (d), 35.8 (t), 72.5 (d). ¹³ C-NMR

(anti-isomer): δ 9.4 (t), 13.9 (q), 17.0 (d), 22.2 (q), 22.8 (t), 26.8 (d), 35.85 (t), 72.3 (d). Syn- configuration confirmed by COSY, HSQC, NOESY. MS (EI): mlz (%) 110 ([M - 18] ⁺ , 4), 95 (18) 81 (25), 71 (55), 58 (100), 57 (70), 56 (62), 55 (92), 45 (69), 43 (90).

Example 16: (sjw)~l~(2-methyl-cyclopropyl)-octan-l-ol.

Prepared as described in Example 3 (System B) from heptyl magnesium bromide (prepared from heptyl bromide (26 g, 0.14 mol) and magnesium (3.43 g, 0.14 mol) in tetrahydrofuran (68 ml) at 70 ⁰ C), E-crotonaldehyde (8.4 g, 0.12 mol), dibromomethane (62.5 g, 0.36 mol) and of tert-butyl magnesium chloride 2M in diethyl ether (3 x 60 ml, 0.36 mol) at 10°-20°C. Work-up and distillation at 6O ⁰ C/ 0.04 Torr gave 24.4g (86%) of the trans-isomcr as colorless oil.

This compound was also prepared by Grignard reaction of Octanal (18 g, 0.14 mol) with E/Z- 1-propenyl magnesium bromide (prepared from magnesium (3.8 g, 0.14 mol), 1-bromo- propene (17 g, 0.14 mol) in tetrahydrofuran (60 ml) at 60 ⁰ C) followed by tandem cyclopropanation and work-up as described in the first part of example 14 giving 23.5g (83%) product (cisltrans = 1:1)

Odour: green, earthy, substantive. ¹ H NMR (CDCl ₃ ) (trø/w-isomer): δ 0.25 (m, 1 H), 0.4 (m, 1 H), 0.6 (m, 1 H) ₅ 0.9 (t, 3 H), 1.05 (d, 3 H), 1.2 - 1.45 (10 H), 1.5 - 1.55 (3 H), 2.88 (m, 1 H) ppm. ¹³ C-NMR (CDCl ₃ ) (trans-isomev): δ 10.7 (t), 11.15 (d), 14.1 (q), 18.3 (q), 22.6 (t), 25.7 (t), 26.9 (d), 29.3 (t), 29.7 (t), 31.8 (t), 37.4 (t), 76.4 (d). confirmed by NMR-analysis of the ethyl ether. MS (EI): m/z (%) 166 ([M - 18] ⁺ , 2), 85 (100), 67 (32), 57 (50), 55 (30), 43 (42), 41 (45).

Example 17: (y;«,?rø/fcϊ)-cyclopentyl(2~isopropylcyclopropyl)methanol .

Prepared as described in Example 3 (System B) from cyclopentyl magnesium bromide 2M in diethyl ether (5 ml, 10 mmol), E-4-methyl-2-pentenal (1 g, 10 mmol), dibromomethane (5.2 g, 30 mmol) and tert-butyl magnesium chloride 2M in diethyl ether (15 ml, 30 mmol) at 0°- 10 ⁰ C. Work-up and bulb-to-bulb distillation at 0.05 mbar gave 1 g (50%) of a colorless oil (synlaπti = 99:1). ¹ H NMR (CDCl ₃ ): δ 0.3 (m, 1 H), 0.4 (m, 1 H), 0.5 (m, 1 H), 0.75 (m), 1.0 (2d, 6 H), 1.2-1.7 (8 H), 1.7 - 1.85 (2 H), 2.05 (m, 1 H), 2.75 (m, 1 H) ppm. ¹³ C-NMR (CDCl ₃ ): δ 9.6 (t), 21.9 (q), 22.2 (q), 24.2 (d), 25.55 (t), 25.6 (t), 25.8 (t), 28.2 (t), 29.1 (t), 32.5 (d), 46.3 (d), 79.7 (d). Sj/n-configuration assigned by COSY, HMBC, HSQC, NOESY in CDCl ₃ . MS (EI): m/z (%) 164 ([M- H ₂ O] ⁺ , 1), 121 (3), 113 (13), 95 (36), 81 (8), 71 (7), 69 (8), 67 (8), 57 (100), 55 (12).

Example 18: (syn.transVl-Q-phenyl-cycIopropylVethanol.

Prepared as described in Example 1 (System B) from E-cinnamon aldehyde (3.2 g, 24 mmol), methyl magnesium chloride 3M in tetrahydrofuran (8 ml, 24 mmol), dibromomethane (2 x 6.3 g, 72 mmol) and tert-butyl magnesium chloride 2M in diethyl ether (2 x 18 ml, 72 mmol). Work-up after 18 h at 25°C and bulb-to-bulb distillation gives 3.3g (83%) of a colorless oil (syn/anti = 82: 18), whose analytical data are identical to the ones described for this compound in the literature (Charette, A. B.; Lebel, H. J. Org. Chem. 60, 2966 - 2967, 1995).

Example 19: (RS)-l-((lRS.2SR)-2-((E)-hex-l-enyϊ)cycloγropyϊ)ethanol

Prepared as described in Example 1 (System B) from methyl magnesium chloride 3 M in tetrahydrofuran (7.3 ml, 21 mmol), (2E,4£)-nona-2,4-dienal (3 g, 21 mmol), dibromomethane (15 g, 87 mmol) and tert-butyl magnesium chloride 2M in diethyl ether (43 ml, 87 mmol) at 0°-10°C. Work-up after 18 h and bulb-to-bulb distillation at 80 ⁰ C / 0.05 mbar gave 3.1 g (77%) of a colorless oil (synfαnti = 83:17). Odour: fruity, pear, green. ¹ H NMR (CDCl ₃ ): δ ¹ H NMR (CDCl ₃ ): δ 0.5 (m, 1 H), 0.7 (m, 1 H), 0.8 - 1 (2 H), 0.9 (t, 3 H), 1.2 - 1.4 (6 H), 1.8 - 2.0 (3 H), 3.2 (m, 1 H), 5.0 (m, 1 H), 5.5 (m, 1 H) ppm. ¹³ C-NMR (CDCl ₃ ) syw-isomer: δ 11.5 (t), 13.9 (q), 18.8 (d), 22.2 (d), 22.5 (q), 28.1 (d), 31.7 (t), 32.1 (t), 71.5 (d), 128.9 (d), 131.7 (d). ¹³ C-NMR (CDCl ₃ ) αnti-isomer: δ 10.8 (t), 14.0 (q), 19.6 (d), 22.2 (d), 22.5 (q), 28.3 (d), 31.7 (t), 32.1 (t), 72.0 (d), 128.7 (d), 132.0 (d). sj/rc-configuration assigned by GC retention time. MS (EI): m/z (%) 168 ([M] ⁺ , 1), 150 ([M- H ₂ O] ⁺ , 7), 113 (48), 95 (47), 82 (33), 81 (80), 68 (72), 67 (100), 57 (43), 55 (45), 54 (80), 45 (75), 43 (56), 41 (64). IR (film): 3340 (br, OH), 2958 (m), 2925 (m), 2871 (m), 2858 (m), 1455 (m), 1414 (w), 1366 (m), 1290 (w), 1180 (w), 1103 (m), 1076 (m), 1029 (m), 959 (s), 897 (m).

Example 20: (cwVl-hexyl-l-methylbicyclop.l.O^hexaπ-l-ol.

Methyl lithium 1.6 M in diethyl ether (4 ml, 7 mmol) is added dropweise to 2-hexylcyclopent- 2-enone (Isojasmone Bl 1) (1 g, 6 mmol) in diethylether (4 ml) at -78°C. At 0° - 5°C dibromomethane (3 x 0.6 ml, 24 mmol) and tert-butyl magnesium chloride 2M in diethyl ether (3 x 4 ml, 24 mmol) are added. Work-up after 18 h at 25 ⁰ C (as described in example 1) and bulb-to-bulb distillation gives 0.7g (60%) of a colorless oil (cis/trαns = 93:7). ¹ H NMR (CDCl ₃ ): δ 0.3 (m, 1 H), 0.7 (m, 1 H), 0.9 (t, 3 H), 1.05 (m, 1 H), 1.2 - 2 (15 H), 1.3 (s, 3 H) ppm. ¹³ C-NMR (CDCl ₃ ): δ 11.0 (t), 14.0 (q), 22.6 (t), 23.4 (d), 24.7 (t), 25.15 (q), 27.5 (t), 29.9 (t), 31.2 (t), 31.8 (t), 34.3 (s), 37.9 (t), 81.05 (s). cw-configuration assigned by COSY, HMBC,

HSQC, NOESY in CDCl ₃ . MS (EI): m/z (%) 196 (M ⁺ , 2), 181 ([M - 15] ⁺ , 14), 155 (24), 138 (15), 135 (27), 125 (32), 110 (34), 107 (38), 93 (92), 79 (50), 57 (14), 43 (100).

Example 21: (m)-5-isopropyl-2-methylbicyclo [3.1.0] hexan-2-ol.

Prepared as described in Example 20 from 3-isopropylcyclopent-2-enone (V. Jurkauskas, J. P. Sadighi, S. L. Buchwald, Org. Lett. 5, 2417-2420, 2003), (0.5 g, 4 mmol), methyl lithium 1.6 M in diethyl ether (2.8 ml, 4.5 mmol), dibromomethane (2.8 g, 16 mmol) and tert-butyl- magnesium chloride 2M in diethyl ether (8 ml, 16 mmol) at 0°-10°C. Work-up after 6 h (as described in Example 1) and flash chromatography over silicagel (hexane / tert-butyl methyl ether 3 : 1) gave 0.23 g (45%) of a colorless oil. MS (EI): m/z (%) 196 (M ⁺ , 5), 139 ([M - 15] ⁺ , 14), 136 ([M - 18] ⁺ , 29), 121 (38), 107 (12), 93 (100), 71 (60), 55 (34), 43 (85). NMR- and IR data identical with the ones described for cώ-Sabinene Hydrate in the literature (D. Cheng, K. R. Knox, T. Cohen, J. Am. Chem. Soc. 122, 412 - 413, 2000).

Example 22: (c/^-S-ethyl-U-dimethylbicycloβ.l.Olhexan-I-ol

Prepared as described in Example 20 (System B) from 3-ethyl-2-methylcyclopent-2-enone (4 g, 32 mmol) (G. Berube, A. G. Fallix, Can.J.Chem. 69, 11 - 78, 1991), addition of methyl- lithium 1.6 M in diethyl ether (28 ml, 45 mmol) at -20 ⁰ C, dibromomethane (2 x 8.4 g, 97 mmol) and tert-butyl magnesium chloride 2M in diethyl ether (2 x 24 ml, 97 mmol). Work-up after 18 h at 25°C (as described in example 1) and bulb-to-bulb distillation gives 3g (60%) of a waxy yellowish solid. ¹ H NMR (CDCl ₃ ): δ -0.1 (d, 1 H), 0.75 (d, 1 H), 0.95 (t, 3 H), 1.1 (s, 3 H), 1.25 (s, 1 H), 1.2 - 1.3 (1 H), 1.3 - 1.4 (2 H), 1.5 - 1.6 (2 H), 1.7 (1 H) ppm. ¹³ C-NMR (CDCl ₃ ): δ 11.4 (q), 12.7 (q), 18.4 (t), 24.9 (q), 25.8 (t), 28.5 (t), 32.35 (s), 34.6 (s), 36.5 (t), 81.3 (s). Cώ-configuration determined by NMR-analysis in water-free DMSO. MS (EI): m/z

(%) 154 (M ⁺ , 1), 139 ([M - 15] ⁺ , 38), 136 ([M - 18] ⁺ , 67), 125 (37), 121 (27), 107 (86), 96 (59), 81 (100), 67 (30), 57 (42), 55 (36), 43 (86), 41 (40). IR (film): 3297 (br, OH), 2959 (s), 2859 (m), 1452 (s), 1365 (s), 1300 (m), 1199 (s), 1167 (m), 1115 (vs), 1062 (m), 970 (s), 938 (s), 926 (s). 5

Example 23: (E)- 2-(2-phenylcyclopropyl)propan-2-ol

Methyl lithium 1.6 M in diethyl ether (27.5 ml, 44 mmol) was added dropwise to (J5)-ethyl cinnamate (3 g, 19 mmol) in diethyl ether (15 ml) at -10 ⁰ C. At 0°-5°C dibromomethane (3 x

10 4.5 g, 75 mmol) and tert-butyl magnesium chloride 2M in diethyl ether (3 x 13 ml, 75 mmol) are added portionwise. Work-up after 18 h at 25 °C as described in Example 1 and bulb-to-bulb distillation under high vacuum gives 2.2g (65%) of a colorless oil, whose analytical data are consistent with the ones described for this compound in the literature (e.g. by A. Mordini et al., Tetrahedron 61, 3349, 2005).

15

Example 24: (^m»sV2-(2-hexyIcyclopropyl)propan-2-ol

Prepared as described in Example 23 from methyl lithium 1.6 M in diethyl ether (7.4 ml, 12 mmol) and (j-j)-methyl non-2-enoate (Neofolione) (1 g, 6 mmol) in diethyl ether (10 ml) at -

20 78°C, followed by dibromomethane (5 x 1 g, 30 mmol) and tert-butyl magnesium chloride 2M in diethyl ether (5 x 3 ml, 30 mmol) at 0°-5°C. Work-up after 18 h at 25°C and bulb-to-bulb distillation under high vacuum gives 0.8g (74%) of a colorless oil. ¹ H NMR (CDCl ₃ ): δ 0.15 (m, 1 H), 0.45 (m, 1 H), 0.7 (2 m, 2 H), 1.15 (s, 3 H), 1.2 (s, 3 H), 1.2 - 1.4 (7 H) ppm. ¹³ C- NMR (CDCl ₃ ): δ 8.1 (t), 14.1 (q), 15.1 (d), 22.6 (t), 28.4 (q), 28.9 (q), 29.2 (t), 29.4 (t), 30.3

25 (d), 31.9 (t), 34.1 (t), 69.7 (s). MS (EI): m/z (%) 169 ([M- 15] ⁺ , 19), 151 (3), 123 (4), 110 (11), 109 (12), 97 (14), 95 (37), 72 (88), 71 (89), 43 (100). IR (film): 3377 (br, OH), 2960 (m), 2922 (s), 2853 (m), 1464 (m), 1367 (m), 1229 (w), 1145 (m), 944 (m), 915 (m).

Example 25: ((c/sM-methyl^-pentylcyclopropyDmethanol.

2-Methyl-2-vinyl oxirane (1 g, 11 mmol) is added dropwise to « -butyl lithium 1.6 M in hexane (7 ml, 11 mmol) in diethyl ether (20 ml) at -78°C. After 1 h at -78°C the solution is slowly 5 warmed up to room temperature. Dibromomethane (7.7 g, 45 mmol) is added followed by dropwise addition of tert-butyl magnesium chloride (23 ml, 45 mmol) at 10°-20°C. After 24 h at 25 ⁰ C the mixture is poured upon 2M HCl. Extraction with tert-butyl methyl ether, washing of the organic phase with cone. NaHCO ₃ , cone. NaCl, drying over MgSO ₄ , filtration and evaporation of the solvents gives 2.3 g of a residue, which is purified by bulb-to-bulb

10 distillation at 5O ⁰ C / 0.06 mbar giving 1.45g (83%) of a colorless oil (cis/trans = 85:15). ¹ H NMR (CDCl ₃ ): δ 0.1 (m, 1 H), 0.45 (m, 1 H), 0.65 (m, 1 H), 0.9 (t, 3 H), 1.15 (s, 3 H), 1.2 - 1.5 (8 H), 3.5 - 3.6 (2 d, 2 H) ppm. ¹³ C-NMR (CDCl ₃ ) cw-isomer: 6 14.0 (q), 17.6 (t), 22.0 (s), 22.6 (t), 22.7 (q), 25.1 (d), 29.2 (t), 29.9 (t), 31.7 (t), 67.5 (t). m-configuration determined by 1 ³ C-NMR (CH ₂ O shift). ¹³ C-NMR (CDCl ₃ ) trans-isomer. δ 15.2 (q), 16.8 (t), 21.9 (s), 22.6 (t),

15 22.7 (q), 25.1 (d), 29.0 (t), 29.8 (t), 31.75 (t) 72.8 (t). MS (EI): m/z (%) 138 ([M- H ₂ O] ⁺ , 1), 125 (1), 123 (1), 99 (33), 83 (47), 71 (42), 69 (44), 58 (98), 57 (87), 56 (68), 55 (100), 43 (51), 41 (63). IR (film): 3331 (br, OH), 2655 (m), 2924 (s), 2857 (m), 1465 (m), 1378 (w), 1198 (w), 1097 (w), 1028 (s), 966 (w), 920 (w), 973 (w), 725 (w). 0 Example 26: ((cw)-2~isobutyl-l-methylcyclopropyl)methanol.

Prepared as described in Example 25 from 2-methyl-2-vinyl oxirane (1 g, 11 mmol), isopropyl -lithium 0.7 M in pentane (16 ml, 11 mmol), dibromomethane (7.7 g, 45 mmol) and tert-butyl magnesium chloride (23 ml, 45 mmol). Work-up and bulb-to-bulb distillation at 45 ⁰ C / 0.06 5 mbar gave 1.3 g (84%) of a colorless oil (cis/trans = 75:25). ¹ H NMR (CDCl ₃ ): δ 0.0 and 0.1 (2 m, 1 H), 0.45 and 0.55 (2 m, 1 H), 0.65 (1 H), 0.9 (2 d, 6 H), 1.05 - 1.15 (1 H), 1.13 and 1.18 (2 s, 3 H), 1.45 (1 H), 1.65 (1 H), 3.5 - 3.6 (2 d, 2 H) ppm. ¹³ C-NMR (CDCl ₃ ) cώ-isomer: δ 18.0 (t), 21.7 (s), 22.6 and 22.7 (2 q), 23.4 (d), 26.95 (q), 29.1 (d) 38.2 (t), 67.5 (t). cis-

configuration determined by ¹³ C-NMR (CH ₂ O shift). ¹³ C-NMR (CDCl ₃ ) frβαy-isomer: δ 16.9 (t), 21.8 (s), 22.5 and 22.7 (2 q), 23.4 (d), 29.0 (d), 29.4 (q), 38.0 (t), 72.8 (t). MS (EI): m/z (%) 124 ([M-H ₂ O] ⁺ , 3), 111 (7), 109 (19), 85 (39), 71 (30), 69 (90), 58 (100), 57 (97), 56 (65), 56 (68), 55 (99), 43 (100), 41 (93). IR (film): 3335 (br, OH), 2953 (s), 2928 (m), 2902 (m), 2869 (m), 1465 (m), 1382 (m), 1366 (m), 1029 (s), 970 (w), 877 (w).

Example 27: αSiUR£4&SMHPentvlspiror2.71decan-4-ol.

Prepared as described in Example 24 from l-vinyl-9-oxabicyclo[6.1.0]nonane (JP Kokai 10 S49-047345, Takasago Perfumery Co., Ltd.) (3 g, 18 mmol), w-butyl lithium 1.6 M in hexane (11 ml, 18 mmol), dibromomethane (12.5 g, 72 mmol) and tert-butyl magnesium chloride (36 ml, 72 mmol). Work-up and bulb-to-bulb distillation at 98°C / 0.05 mbar gave 2.6 g (65 %) of a colorless oil (dr - 93:7). ¹ H NMR (CDCl ₃ ): δ 0.3 (m, 1 H), 0.5 (m, 1 H), 0.8 (m, 1 H), 0.8 - 1.1 and 1.2 - 2.4 (22 H), 3.25 (1 H) ppm. ¹³ C-NMR (CDCl ₃ ): δ 14.1 (q), 20.7 (t), 22.7 (t), 23.3 15 (t), 23.5 (t), 24.3 (d), 26.5 (t), 26.8 (t), 28.9 (t), 29.4 (s), 29.7 (t), 30.4 (t), 31.2 (t), 31.7 (t), 73.7 (d). c/s-configuration assigned by COSY, HMBC, HSQC, NOESY in DMSO-D ₆ . MS (EI): m/z (%) 224 (M ⁺ , 1), 206 ([M- 18] ⁺ , 10), 178 (4), 163 (5), 149 (12), 135 (22), 126 (24), 109 (22), 107 (24), 98 (58), 97 (33), 96 (80), 95 (46), 93 (54), 69 (41), 68 (42), 67 (84), 55 (100), 41 (80). IR (film): 3362 (br, OH), 2919 (s), 2852 (m), 1456 (m), 1364 (w), 1106 (w), 1029 (m), 20 989 (m), 811 (w), 741 (w), 726 (w).