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Title:
PROCESS FOR PREPARING HYDROCINNAMIC ALDEHYDES IN ENANTIOPURE OR ENANTIOMERICALLY ENRICHED FORM
Document Type and Number:
WIPO Patent Application WO/2010/131274
Kind Code:
A1
Abstract:
A process is described for preparing hydrocinnamic aldehydes in enantiopure or enantiomerically enriched form of Formula I, in which R is isopropyl or tert-butyl and R' is hydrogen, or R and R' when taken together are a methylenedioxolyl group, comprising the following steps: a) reacting the hydrocinnamic aldehyde of Formula I with the alcohol of Formula Il in enantiopure or enantiomerically enriched form to give the crystallized hemiacetal of Formula III, in which R, R' have the same meaning as Formula I and (*) indicates a stereogenic centre in the absence of a solvent or in one or more aprotic solvents or mixtures thereof with apolar solvents; b) recovering the hydrocinnamic aldehyde of Formula I in enantiopure or enantiomerically enriched form from the crystallized hemiacetal of Formula III and the aldehyde of opposite configuration in enantiopure or enantiomerically enriched form from the hemiacetal crystallization mother liquors. The invention also concerns a process for preparing the alcohol of Formula Il to be introduced into step a).

Inventors:
CAPPARELLA, Elisa (Via Dradi31, Ravenna, I-48100, IT)
CARLONI, Silvia (Largo Fanfulla 39, Traversetolo, I-43029, IT)
Application Number:
IT2009/000212
Publication Date:
November 18, 2010
Filing Date:
May 14, 2009
Export Citation:
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Assignee:
ENDURA S.P.A (Viale Pietramellara 5, Bologna, I-40121, IT)
CAPPARELLA, Elisa (Via Dradi31, Ravenna, I-48100, IT)
CARLONI, Silvia (Largo Fanfulla 39, Traversetolo, I-43029, IT)
International Classes:
C07C41/56; C07C209/88; C07C211/27; C07D317/54; C07D317/58; C07D317/60
Other References:
LIGHTFOOT A ET AL: "Enantioselective hydrogenation of olefins with Iridium- Phosphanodihydrooxazole catalysts" ANGEWANDTE CHEMIE. INTERNATIONAL EDITION, WILEY VCH VERLAG, WEINHEIM, vol. 37, no. 20, 2 November 1998 (1998-11-02), pages 2897-2899, XP002381775 ISSN: 1433-7851 cited in the application
LI ET AL: "Enantioselective hydrogenation of olefins with axial chiral iridium QUINAP complex" TETRAHEDRON LETTERS, ELSEVIER, AMSTERDAM, NL, vol. 48, no. 22, 3 May 2007 (2007-05-03), pages 3915-3917, XP022059009 ISSN: 0040-4039 cited in the application
ENDERS D ET AL: "First asymmetric synthesis of both enantiomers of Tropional<(>R) and their olfactory evaluation" TETRAHEDRON ASYMMETRY, PERGAMON PRESS LTD, OXFORD, GB, vol. 15, no. 11, 7 June 2004 (2004-06-07), pages 1813-1817, XP004512332 ISSN: 0957-4166 cited in the application
ROJE M ET AL: "Stereoselective cyclopropanation and ring-opening: Application to the synthesis of pure (S)-2-methyl-3-arylpropylamines" TETRAHEDRON, ELSEVIER SCIENCE PUBLISHERS, AMSTERDAM, NL, vol. 54, no. 31, 30 July 1998 (1998-07-30), pages 9123-9128, XP004495537 ISSN: 0040-4020
Attorney, Agent or Firm:
CATTANEO Elisabetta @ (Notarbartolo & Gervasi S.P.A, Corso di Porta Vittoria 9, Milan, 20122, IT)
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Claims:
CLAIMS

1. Process for preparing hydrocinnamic aldehydes in enantiopure or enantiomerically enriched form of Formula I

Formula I in which R is isopropyl or tert-butyl and R' is hydrogen, or R and R' when bound together are a methylenedioxolyl group, comprising the following steps: a) reacting the racemic hydrocinnamic aldehyde of Formula I with the alcohol of Formula Il in enantiopure or enantiomerically enriched form

Formula Il to give the crystallized hemiacetal of Formula III

Formula III in which R, R' have the same meaning as Formula I and (*) indicates a stereogenic centre in the absence of a solvent or in one or more aprotic solvents or mixtures thereof with apolar solvents; b) recovering the hydrocinnamic aldehyde of Formula I in enantiopure or enantiomerically enriched form from the crystallized hemiacetal of Formula III, and the aldehyde of opposite configuration in enantiopure or enantiomerically enriched form from the crystallization mother liquor of the hemiacetal. 2. Process according to claim 1 wherein R and R' in the compound of Formula Il are bound together to form a methylenedioxolyl group.

3. Process according to claim 1 or 2 wherein R and R' in the compound of Formula I are bound together to form a methylenedioxolyl group.

4. Process according to any one of claims 1 to 3 wherein the alcohol of Formula Il and the racemic aldehyde of Formula I are reacted in a molar ratio within the range from 1.0 to 0.4, preferably within the range from 0.8 to 0.5 and even more preferably of about 0.6.

5. Process according to any one of claims 1 to 4 wherein step a) takes place in the presence of one or more aprotic solvents chosen from the group consisting of diisopropyl ether, methyl tert-butyl ether, toluene, ethyl acetate, dichloromethane, mixtures thereof and mixtures with apolar solvents such as cyclohexane or methylcyclohexane.

6. Process according to any one of claims 1 to 5 wherein the temperature of step a) is within the range from -20 0C to 20 0C, preferably from -10 O to 10 0C, and even more preferably from -5 0C to 5 0C.

7. Process according to any one of claims 1 to 6 wherein in step b) recovery of the hydrocinnamic aldehyde and the alcohol of Formula Il from the hemiacetal takes place by heating to a temperature within the range from 40 0C to 60 0C in an aprotic solvent. 8. Process according to claim 7 wherein said aprotic solvent is preferably diisopropyl ether.

9. Process according to any one of claims 7 to 8 wherein separation of the hydrocinnamic aldehyde from the alcohol in the aprotic solvent solution occurs by formation of a hydrocinnamic aldehyde bisulphite adduct by treating the mixture with an aqueous 40% solution of sodium bisulphite in a quantity such as to obtain a sodium bisulphite/hydrocinnamic aldehyde molar ratio of 1.5.

10. Process according to any one of claims 7 to 9 wherein in step b) recovery of the hydrocinnamic aldehyde in the opposite configuration to that recovered from the crystallized hemiacetal and the alcohol present in the crystallization mother liquor occurs by formation of a hydrocinnamic aldehyde bisulphite adduct in the crystallization mother liquor by treating the crystallization mother liquor with an aqueous 40% solution of sodium bisulphite in a quantity such as to obtain a sodium bisulphite/hydrocinnamic aldehyde molar ratio of 1.5.

11. Process according to any one of claims 1 to 10 wherein the optically active alcohol of Formula Il recovered from the hemiacetal and that recovered from the crystallization mother liquor is re-introduced, with no further purification, into step a) of the process of the invention to resolve the racemic hydrocinnamic aldehyde.

12. Process according to any one of claims 1 to 11 wherein the hydrocinnamic aldehyde obtained in step b), whether derived from the hemiacetal or that obtained from the crystallization mother liquor, can be purified or enantiomerically enriched by crystallization from one or more solvents.

13. Process according to any one of claims 1 to 12 wherein the alcohol of Formula Il is in the enantiopure or enantiomerically enriched (S) form, which forms the crystallized hemiacetal of Formula III in the (RS) form in step a) as follows:

and in step b) the hydrocinnamic aldehyde in the (R) configuration is recovered from the crystallized hemiacetal and the aldehyde in (S) form from the crystallization mother liquor.

14. Process according to any one of claims 1 to 12 wherein the alcohol of Formula Il is in the enantiopure or enantiomerically enriched (R) form which forms the crystallized hemiacetal of Formula III in the (SR) form in step a) as follows:

and in step b) the hydrocinnamic aldehyde in the (S) configuration is recovered from the crystallized hemiacetal and the aldehyde in (R) form from the crystallization mother liquor. 15. Crystallized hemiacetal compound of Formula III in which R is isopropyl or tert-butyl and R' is hydrogen, or R and R' when bound together are a methylenedioxolyl group and (*) indicates a stereogenic centre.

16. Compound of claim 15 wherein said R and R' are bound together to form a methylenedioxolyl group.

17. Process for preparing the alcohol in enantiopure or enantiomerically enriched form of Formula Il

Formula Il in which (*) indicates a stereogenic centre which comprises the following steps: c) oxidizing the aldehyde of formula I

Formula I to give the acid of Formula IV

Formula IV in which R is isopropyl or tert-butyl and R' is hydrogen, or R and R' when bound together are a methylenedioxolyl group; and d) reacting the acid of formula IV with an optically active amine of formula V

NH2

Formula V in which (*) indicates a stereogenic centre and where R1 and R2, being the same or different, are hydrogen, CrC4 alkyl, CrC4 alkoxy, or R1 and R2 when taken together with the aromatic ring form a group of Formula Vl

Formula Vl R3 is chosen from CrC4 alkyl, CrC4 hydroxyalkyl, phenyl, benzyl, benzyl substituted by CrC4 alkyl and CrC4 alkoxy, or R3 is a group of Formula VII:

Formula VII in an alcohol or hydroalcohol solvent to form a diastereoisomeric salt of an optically active compound of Formula IV and of the optically active amine of Formula V, e) recovering the acid of Formula IV in enantiopure or enantiomerically enriched form from the crystallized diastereoisomeric salt and the acid of Formula IV of opposite configuration in enantiopure or enantiomerically enriched form from the crystallization mother liquor of the diastereoisomeric salt, f) reducing the enantiopure or enantiomerically enriched acid to alcohol.

18. Process according to claim 17 wherein the oxidation step c) is conducted in the presence of hydrogen peroxide.

19. Process according to claim 17 or 18 wherein the pH values at which to carry out said oxidation are within the range from 7 to 9 and at a temperature within the range from 40 QC to 80 5C.

20. Process according to any one of claims 17 to 19 wherein step d) takes place in the presence of alcohol or hydroalcohol solvents chosen from the group consisting of methanol, ethanol, n-propanol, isopropanol, n-butanol, isobutanol, tert-butanol, mixtures thereof and mixtures thereof with water. 21. Process according to any one of claims 17 to 20 wherein in the amines of Formula V of step d), R1 is chosen from hydrogen, CrC2 alkyl, Ci-C2 alkoxy, R2 is hydrogen, or R1 and R2 when taken together with the aromatic ring form a group of Formula Vl, and R3 is chosen from CrC2 alkyl, phenyl, benzyl, 4-methylbenzyl or a group of Formula VII.

22. Process according to claim 21 wherein in the amines of Formula V in step d), R1 is chosen from hydrogen, methyl, methoxy;

R2 is hydrogen, or R1 and R2 when taken together with the aromatic ring form a group of Formula Vl; R3 is chosen from the group consisting of methyl, benzyl, 4-methylbenzyl and a group of formula VII.

23. Process according to any one of claims 17 to 22 wherein, following the recovery step e) but before the reduction step f), a sub-step e1 ) occurs of enriching the acid in the enantiomeric form most present in the mother liquors of said crystallization by crystallization from suitable solvents and separation of the racemic acid.

24. Process according to any one of claims 17 to 23 wherein the reduction step f) occurs by means of reducing agents chosen from the group consisting of lithium aluminium hydride; sodium aluminium hydride; sodium bis(2-methoxyethoxy) aluminium hydride; derivatives of lithium aluminium hydride, sodium aluminium hydride, sodium bis(2-methoxyethoxy) aluminium hydride; and borane, as such or dissolved in suitable apolar solvents.

25. Process according to any one of claims 17 to 24 wherein the alcohol of Formula Il presents R and R' bound together in a methylenedioxolyl group. 26. Process according to any one of claims 1 to 16 wherein the alcohol of Formula Il of step a) is obtained by means of the process according to any one of claims 17 to 25.

27. Diastereoisomeric salt of an optically active compound of Formula IV

Formula IV in which R is isopropyl or tert-butyl and R' is hydrogen, or R and R' when taken together are a methylenedioxolyl group; and of the optically active amine of Formula V

Formula V in which (*) indicates a stereogenic centre and where R1 and R2, being the same or different, are chosen from hydrogen, CrC4 alkyl, CrC4 alkoxy, or R1 and R2 when taken together with the aromatic ring form a group of Formula Vl

Formula Vl

R3 is chosen from CrC4 alkyl, CrC4 hydroxyalkyl, phenyl, benzyl, benzyl substituted by CrC4 alkyl and CrC4 alkoxy, or R3 is a group of Formula VII:

Formula VII

28. Diasteroisomeric salt of claim 27 in which the acid of Formula IV is the compound in which R and R' together form a methylenedioxolyl group.

29. Diasteroisomeric salt of claim 27 or 28 comprising the amine of Formula V in which R1 is chosen from hydrogen, CrC2 alkyl, CrC2 alkoxy, R2 is hydrogen, or R1 and R2 when taken together with the aromatic ring form a group of Formula Vl, R3 is a CrC2 alkyl, phenyl, benzyl, 4-methylbenzyl or a group of Formula VII.

30. Diastereoisomeric salt according to any one of claims 27 to 29 wherein R1 is chosen from hydrogen, methyl, methoxy, R2 is hydrogen, or R1 and R2 when taken together with the aromatic ring form a group of Formula Vl, R3 is chosen from the group consisting of methyl, benzyl, 4-methylbenzyl and a group of Formula VII.

31. (S)-1-phenyl-2-(benzo[1 ,3]dioxol-5-yl) ethylamine.

32. (R)-1 -phenyl-2-(benzo[1 ,3]dioxol-5-yl) ethylamine.

33. Process for preparing hydrocinnamic aldehydes in enantiopure or enantiomerically enriched form according to any one of claims 1 to 14 wherein the alcohol in enantiopure or enantiomerically enriched form of Formula Il in step a) is obtained by reduction of the recovered hydrocinnamic aldehyde of step b).

34. Process according to claim 33 wherein the reduction takes place with sodium borohydride at ambient temperature in dichloromethane and methanol.

Description:
PROCESS FOR PREPARING HYDROCINNAMIC ALDEHYDES IN ENANTIOPURE OR ENANTIOMERICALLY ENRICHED FORM

FIELD OF THE INVENTION The present invention relates to a process for preparing hydrocinnamic aldehydes in enantiopure or enantiomerically enriched form of Formula I

Formula I in which R is isopropyl or tert-butyl and R' is hydrogen, or R and R' when bound together are a methylenedioxolyl group. The invention in particular concerns a process for preparing the compound 3-(benzo[1 ,3]dioxol-5-yl)-2-methylpropanal, also known as Helional, in either the enantiomerically pure or the enantiomerically enriched form. STATE OF THE ART The variously substituted hydrocinnamic aldehydes of Formula I are commonly used compounds in the fragrance field.

The first published data on the olfactory differences between the two enantiomers of an odorant substance appeared in 1961 , when Ohloff described the properties of β-citronellol; the (+)-β-citronellol exhibits a typical citronella aroma, whereas the odour of (-)-β-citronellol is reminiscent of geranium (R. Rienacker, G. Ohloff; Angew. Chem., 1961 , 73, 240).

Since then a number of studies were carried out on the synthesis and separation of the enantiomers of substances used in the aroma and fragrance field and their various olfactory properties have been evaluated (E. Brenna, C. Fuganti, S. Serra; Tetrahedron: Asymmetry, 2003, 14, 1-42). Indeed, the two enantiomers of the same substance can differ in relation to both quality of the perceived odour and its olfactory intensity.

With regard to the hydrocinnamic aldehydes class, different methods are known for preparing products in enantiopure or enantiomerically enriched form. Japanese patent JP55036459 describes the preparation of 3-(4-tert-butylphenyl)- 2-methylpropanal, also known as lilial, in the optically active form, by resolution of the salt between the corresponding acid and a chiral amine by diastereoselective crystallization in an alcohol solvent. In 1990 Enders (D. Enders, H. Dyker; Liebigs Ann. Chem., 1990, 1107-1110) instead reported the synthesis and olfactory properties of the two lilial enantiomers, obtained by formation of the chiral hydrazone and subsequent diastereoselective methylation. Despite both products presenting a lily of the valley odour, the (R) enantiomer of lilial (e.e. 95%) is described as being more potent and aggressive than the racemic form, with a slightly more marine odour. The (S) enantiomer (e.e. 93%) on the other hand is fainter and less expressive than its raceme.

In 1998 the preparation of lilial, enantiomerically enriched at 94%, was reported by Pflatz (A. Lightfoot, P. Schnider, A. Pfaltz; Angew. Chenr Int. Ed., 1998, 37, 2897-2899J through enantioselective hydrogenation of the corresponding cinnamic alcohol, catalyzed by an optically active Ir-phosphanodihydro-oxazole complex. The first asymmetric synthesis of both enantiomers of Helional and an evaluation of their olfactory properties was reported by said Enders (D. Enders, M. Backes; Tetrahedron: Asymmetry, 2004, 15, 1813-1817). The four-step preparation is based on the diastereoselective nucleophilic substitution of a chiral hydrazone on 5-bromomethyl-1 ,3-benzodioxol. Said reaction is carried with lithium diisopropylamide (LDA) at -100 e C, to obtain, after a series of steps, Helional in the two optically active forms with an enantiomeric excess of 90%. Olfactory evaluation of Helional obtained in this manner demonstrates that the two isomers exhibit different notes: the (S) form exhibits a greener floral odour, with marine, ozone and cumin notes, whereas the (R) form demonstrates a floral perfume reminiscent of cyclamen and lily of the valley, with aldehyde and citrus- like notes. Furthermore the (S) enantiomer is found to be about five times more intense than the (R) enantiomer. (R)-3-(benzo[1 ,3]dioxol-5-yl)-2-methylpropanol (e.e/ 95%) which can be easily oxidized to Helional by common oxidative methods, was synthesized by Li et. al (X. Li, L Kong, Y. Gao, X. Wang; Tetrahedron Letters, 2007, 48, 3915-3917) by enantioselective hydrogenation of the corresponding cinnamic alcohol with an optically pure iridium-based organometallic catalyst ((S)-Ir-QUINAP complex). These methods, however, due to the reaction conditions or the catalyst used, are not advantageous from the industrial viewpoint. The object of the present invention is therefore to provide the hydrocinnamic aldehydes of formula I, in particular the Helional compound in enantiopure or enantiomerically enriched form by means of an industrial scale process which simultaneously enables good enantiomer yields to be achieved in both resolved enantiomers. SUMMARY OF THE INVENTION

The aforementioned object has been achieved by a process for preparing hydrocinnamic aldehydes in enantiopure or enantiomerically enriched form of Formula I

Formula I in which R is isopropyl or tert-butyl and R' is hydrogen, or R and R' when bound together are a methylenedioxolyl group, comprising the following steps: a) reacting the racemic hydrocinnamic aldehyde of Formula I with the alcohol of Formula Il in enantiopure or enantiomerically enriched form

Formula Il to give the crystallized hemiacetal of Formula

Formula III in which R, R' have the same meanings as Formula I and ( * ) indicates a stereogenic centre in the absence of a solvent or in one or more aprotic solvents or mixtures thereof with apolar solvents; b) recovering the hydrocinnamic aldehyde of Formula I in enantiopure or enantiomerically enriched form from the crystallized hemiacetal of Formula III and the aldehyde of opposite configuration in enantiopure or enantiomerically enriched form from the crystallization water of the hemiacetal.

In a first embodiment of the invention, the alcohol of Formula Il is the enantiopure or enantiomerically enriched (S) form which forms the crystallized hemiacetal of Formula III in the (RS) form as follows:

and the hydrocinnamic aldehyde in the (R) configuration is recovered from the crystallized hemiacetal and the aldehyde in the (S) configuration is recovered from the crystallization water.

In a second embodiment of the invention the alcohol of Formula Il is the enantiopure or enantiomerically enriched (R) form which forms the crystallized hemiacetal of Formula III in the (SR) form as follows:

and the hydrocinnamic aldehyde in the (S) configuration is recovered from the crystallized hemiacetal and the aldehyde in the (R) configuration is recovered from the crystallization water.

Advantageously, the invention provides for the alcohol of Formula Il from step b) to be recovered from both the crystallized hemiacetal of Formula III and the crystallization water and to be introduced into step a).

Another aspect of the invention relates to a process for preparing the alcohol in enantiopure or enantiomerically enriched form of Formula Il

Formula Il in which ( * ) indicates a stereogenic centre which comprises the following steps: c) oxidizing the aldehyde of formula I

Formula I to give the acid of Formula IV

Formula IV in which R is isopropyl or tert-butyl and R' is hydrogen, or R and R' when bound together are a methylenedioxolyl group; and d) reacting the acid of formula IV with an optically active amine of formula V

Formula V in which ( * ) indicates a stereogenic centre and where R1 and R2, being the same or different, are hydrogen, CrC 4 alkyl, CrC 4 alkoxy, or R1 and R2 when taken together with the aromatic ring form a group of Formula Vl

Formula Vl

R3 is chosen from CrC 4 alkyl, CrC 4 hydroxyalkyl, phenyl, benzyl, benzyl substituted by CrC 4 alkyl and CrC 4 alkoxy, or R3 is a group of Formula VII

Formula VII in an alcohol or hydroalcohol solvent to form and crystallize a diastereoisomeric salt of an optically active compound of Formula IV and the optically active amine of Formula V, e) recovering from the crystallized diastereoisomeric salt the acid of Formula IV in enantiopure or enantiomerically enriched form and the acid of opposite configuration in enantiomerically pure or enriched form from the crystallization mother liquors of the diastereoisomeric salt, f) reducing the enantiomerically pure or enriched acid to alcohol.

In a preferred embodiment the invention advantageously relates to the resolution of Helional in the enantiomerically pure or enriched form and to the preparation of the respective alcohol in enantiomerically pure or enriched form. Surprisingly the inventors of the present invention have discovered that, in the absence of a solvent or with an aprotic solvent or mixtures thereof with apolar solvents, from mixtures of the hydrocinnamic aldehydes of Formula I, such as Helional, and the respective alcohol in different ratios and both as racemes, the corresponding diastereomerically pure hemiacetal (in an enantiomer pair) is separated by crystallization. This one, when removed from the reaction mixture, proves to be stable up to a maximum temperature of 60 Q C. Subsequently the inventors observed that, under the same conditions, from mixtures of the hydrocinnamic aldehydes such as racemic Helional and the respective enantioenriched alcohol (with e.e. > 80%) in different ratios, the corresponding enantiomerically pure hemiacetal is separated by crystallization ; this one , when removed from the reaction mixture, proves to be stable up to a temperature of about 70-73 S C. The present invention therefore concerns a process for obtaining hydrocinnamic aldehydes in the two enantiomerically pure or enriched forms by the synthesis and diastereoselective crystallization of hemiacetals obtained from mixtures of hydrocinnamic aldehydes in racemic form and the respective alcohol (in the case of Helional, the alcohol is 3-(benzo[1 ,3]dioxol-5-yl)-2-methylpropanol) in optically active form. Advantageously the optically active alcohol of step a) needed for the synthesis of the hemiacetals of Formula III is also obtained as the final product of the invention process and can be recycled within said process. DETAILED DESCRIPTION OF THE INVENTION The invention therefore relates to a process for preparing hydrocinnamic aldehydes in enantiopure or enantiomerically enriched form, of Formula I

Formula I in which R is isopropyl or tert-butyl and R' is hydrogen, or R and R' when bound together are a methylenedioxolyl group, comprising the following steps: a) reacting the hydrocinnamic aldehyde of Formula I with the alcohol of Formula Il in enantiopure or enantiomerically enriched form

Formula Il to give the crystallized hemiacetal of Formula

Formula III in which R, R' have the same meaning as Formula I and ( * ) indicates a stereogenic centre in the absence of a solvent or in one or more aprotic solvents or mixtures thereof with apolar solvents; b) recovering the hydrocinnamic aldehyde of Formula I in enantiopure or enantiomerically enriched form from the crystallized hemiacetal of Formula III and the aldehyde of opposite configuration in enantiopure or enantiomerically enriched form from the crystallization water of the hemiacetal.

Step a) of the process of the invention comprises the synthesis of the hemiacetal of Formula III by reaction of the hydrocinnamic aldehyde of Formula I with the optically active alcohol of Formula II. Preferably the alcohol of Formula Il and the racemic aldehyde of Formula I are reacted in a molar ratio within the range from 1.0 to 0.4, more preferably within the range from 0.8 to 0.5 and even more preferably of about 0.6. Said reaction takes place in the absence of a solvent or in one or more aprotic solvents or mixtures thereof with apolar solvents. Said aprotic solvent is preferably chosen from the group consisting of diisopropyl ether, methyltertbutyl ether, toluene, ethyl acetate, dichloromethane, mixtures thereof and mixtures with apolar solvents such as cyclohexane or methylcyclohexane. The temperature of said reaction is advantageously within the range from -20 5 C to 20 6 C, preferably from -10 9 C to 10 9 C and even more preferably from -5 9 C to 5 9 C.

Another aspect of the invention relates to the crystallized hemiacetal of Formula III

Formula III in which R is isopropyl or tert-butyl and R' is hydrogen, or R and R' when bound together are a methylenedioxolyl group and ( * ) indicates a stereogenic centre. Said crystallized compound is stable. Preferably R and R 1 are bound together to form a methylenedioxolyl group.

Preferably in a first embodiment, the crystallized hemiacetal is formed from the alcohol of Formula Il in the enantiopure or enantiomerically enriched (S) form and has Formula III in the (2R, 2 1 S) form as follows:

More preferably, R and R' are bound together to form a methyienedioxolyl group and the crystallized (2R, 2'S) hemiacetal proves to be very stable and has a melting point of about 70-71 9 C.

Preferably in a second embodiment, the crystallized hemiacetal is formed from the alcohol of Formula Il in the enantiopure or enantiomerically enriched (R) form and has Formula III in the following (2S, 2'R) form:

More preferably, R and R' are bound together to form a methylenedioxolyl group and the crystallized (2R,2'S) hemiacetal proves to be very stable and has a melting point of about 72-73 Q C.

In step b) of the process of the invention the hydrocinnamic aldehyde of Formula I in enantiopure or enantiomerically enriched form is obtained from the crystallized hemiacetal of Formula III and the other aldehyde of opposite configuration in enantiopure or enantiomerically enriched form is obtained from the crystallization mother liquors .

In one embodiment an aldehyde in enantiopure or enantiomerically enriched form is obtained by diastereoselective crystallization of Formula III in the (RS) or (SR) form from the aforesaid reaction mixture at a temperature preferably within a range from -20 9 C to 20 9 C, more preferably from -10 9 C to 10 5 C and even more preferably from -5 9 C to 5 9 C.

Recovery of the aldehyde in step b) and the alcohol of Formula Il from the crystallized hemiacetal can take place by heating, preferably at a temperature within the range from 40 9 C to 60 9 C, in an aprotic solvent. Said aprotic solvent is preferably diisopropyl ether. The separation of said aldehyde from the alcohol, in the aprotic solvent solution, can therefore advantageously be achieved by formation of a hydrocinnamic aldehyde bisulphite adduct by preferably treating the mixture with an aqueous 40% (% by weight) solution of sodium bisulphite, more preferably in a quantity such as to obtain a sodium bisulphite/hydrocinnamic aldehyde molar ratio of 1.5.

Then in step b) the recovery takes place of the other enantiopure or enantiomerically enriched hydrocinnamic aldehyde of opposite configuration and of the alcohol with the same configuration as the hydrocinnamic aldehyde. Said recovery step preferably takes place by formation of a hydrocinnamic aldehyde bisulphite adduct in the crystallization mother liquors by analogous treatment of the hemiacetal solution with an aqueous 40% (% by weight) sodium bisulphite solution, more preferably in a quantity such as to obtain a sodium bisulphite/hydrocinnamic aldehyde molar ratio of 1.5 Advantageously the alcohol of Formula Il recovered from the crystallized hemiacetal and that recovered from the crystallization mother liquors can hence be reintroduced, without further purification, into step a) of the process of the invention for resolving the racemic hydrocinnamic aldehyde. The hydrocinnamic aldehyde obtained from step b), whether derived from the crystallized hemiacetal or that obtained from the crystallization mother liquors, can be enantiomerically purified or enriched by crystallization from suitable solvents, such as diisopropyl ether.

In a first embodiment of the invention the alcohol of Formula Il is the enantiopure or enantiomerically enriched (S) form, which forms the crystallized hemiacetal of Formula III in the (2R,2'S) form as follows:

and the (R) configuration hydrocinnamic aldehyde is recovered from the crystallized hemiacetal and the (S) configuration aldehyde is recovered from the crystallization mother liquors.

In a second embodiment of the invention, the alcohol of Formula Il is the enantiopure or enantiomerically enriched (R) form, which forms the crystallized hemiacetal of Formula III in the (2S,2'R) form as follows:

and the hydrocinnamic aldehyde in the (S) configuration is recovered from the crystallized hemiacetal and the aldehyde in the (R) configuration from the crystallization mother liquors.

Preferably the process for preparing enantiopure or enantiomerically enriched hydrocinnamic aldehydes employs as reagent in step a) the alcohol of Formula Il in which R and R' are bound together to form a methylenedioxolyl group and in which the stereogenic atom is a carbon atom in the (S) configuration. The crystallized hemiacetal of Formula III will therefore be a (2R,2'S) hemiacetal from which the (R) form of the hydrocinnamic aldehyde is recovered in step b). Hence in an advantageous form thereof, an aspect of the present invention is the process for preparing Helional in the two enantiomerically pure or enriched R or S forms by synthesis and diastereoselective crystallization of the 3- (benzo[1 ,3]dioxol-5-yl-1 -(3'-benzo[1 ',3']-dioxol-5'-yl-2'-methyl-propoxy)-2-metil- propan-1-ol hemiacetals formed using the corresponding alcohol derivative in optically active form.

The process which leads to the preparation of Helional in the R and S forms and uses in step a) the alcohol of Helional in the (S) form is given in the following scheme I:

Crystallized product Mother liquors

Scheme I: Preparation of (R) and (S) Helional from racemic Helional

A further aspect of the present invention is the process for preparing the enantiomerically pure or enriched alcohol used in the aforesaid hemiacetal synthesis process, by resolution of the corresponding acid. The invention therefore concerns a process for preparing the alcohol of Formula Il

Formula in which ( * ) indicates a stereogenic centre which comprises the following steps: c) oxidizing the aldehyde of Formula I

Formula I to give the acid of Formula IV

Formula IV in which R is isopropyl or tert-butyl and R' is hydrogen, or R and R' when bound together are a methylenedioxolyl group; and d) reacting the acid of formula IV with an optically active amine of formula V

Formula V in which ( * ) indicates a stereogenic centre and where R1 and R2, being the same or different, are hydrogen, CrC 4 alkyl, CrC 4 alkoxy or R1 and R2, when taken together with the aromatic ring form a group of Formula Vl

Formula Vl

R3 is chosen from CrC 4 alkyl, CrC 4 hydroxyalkyl, phenyl, benzyl, benzyl substituted by CrC 4 alkyl and CrC 4 alkoxy, or R3 is a group of Formula VII:

Formula VII in an alcohol or hydroalcohol solvent to form a diastereoisomeric salt of an optically active compound of Formula IV and the optically active amine of Formula V, e) recovering the acid of Formula IV from the diastereoisomeric salt in enantiopure or enantiomerically enriched form and the acid of Formula IV of opposite configuration in enantiomerically pure or enriched form from the crystallization mother liquors of the diastereoisomeric salt, f) reducing the acid, in enantiopure or enantiomerically enriched form, to alcohol. The process for preparing the enantiomerically pure or enriched alcohol of Formula Il comprises, in step c), synthesis of the racemic acid by oxidizing the hydrocinnamic aldehyde of Formula II. Preferably said step c) is carried in the presence of oxidizing agents such as hydrogen peroxide, preferably at concentrations between 30% and 60%, more preferably using 35% (% by weight) aqueous hydrogen peroxide. Advantageously the pH values at which to perform the oxidation are within the range from 7.0 to 9.0 at a temperature within the range from 40 Q C to 80 S C, but more preferably from 65 Q C to 75 5 C. In step d) the resolution of said acid takes place by formation and diastereoselective crystallization of diastereoisomeric salts with suitable optically active amines. Said diastereoisomeric salt crystallization step takes place in the presence of alcohol or hydroalcohol solvents, preferably chosen from the group consisting of methanol, ethanol, n-propanol, isopropanol, n-butanol, isobutanol, tert-butanol, mixtures thereof and mixtures thereof with water. The optically active amines of step d) are primary amines of Formula V

Formula V in which ( * ) indicates a stereogenic centre and where R1 and R1 , being the same or different, are chosen from hydrogen, CrC 4 alkyl, CrC 4 alkoxy, or R1 and R2 when taken together with the aromatic ring, form a group of Formula Vl

Formula Vl

R3 is chosen from CrC 4 alkyl, CrC 4 hydroxyalkyl, phenyl, benzyl, benzyl substituted by CrC 4 alkyl or CrC 4 alkoxy, or R3 is a group of Formula VII

Formula VII

Preferably R1 is chosen from hydrogen, CrC 2 alkyl, CrC 2 alkoxy, R2 is hydrogen, or R1 and R2 when taken together with the aromatic ring form a group of Formula Vl; R3 is a d-C 2 alkyl, phenyl, benzyl, 4-methylbenzyl or a group of Formula VII.

Even more preferably R1 is chosen from hydrogen, methyl, methoxy; R2 is hydrogen, or R1 and R2 when taken together with the aromatic ring form a group of Formula Vl; R3 is chosen from the group consisting of methyl, benzyl, 4- methylbenzyl and a group of Formula VII. Of the primary amines used in step d), the inventors of the present invention have prepared the optically active 1-phenyl-2-(benzo[1 ,3]dioxol-5-yl) ethylamine of formula VIII.

Therefore another aspect of the invention relates to the optically active compound

1 -phenyl-2-(benzo[1 ,3]dioxol-5-yl) ethylamine:

Formula VIII

In a preferred form said active amine is (S) 1 -phenyl-2-(benzo[1 ,3]dioxol-5-yl) ethylamine of formula:

The absolute configuration of said amine was determined by 1 H-NMR analysis after derivatization with (R)-mandelic acid (B. M. Trost, R.C. Bunt, S. R. Shon, R.

Pulley; J. Org. Chem., 1994, 59 (15), 4202-4205).

In a second preferred form said active amine is (R)-1-phenyl-2-(benzo[1 ,3]dioxol-

5-yl) ethylamine.

In step d) of the process of the invention the diastereoisomeric salt is formed of an optically active compound of Formula IV and of the optically active amine of

Formula V. Said diastereoisomeric salts or complexes form a further aspect of the invention and are characterized by a high stability which allows separation of the racemic acid into its two enantiomers.

A further aspect of the invention hence comprises a diastereoisomeric salt of an optically active compound of Formula IV

Formula IV in which R is isopropyl or tert-butyl and R' is hydrogen, or R and R' bound together are a methylenedioxolyl group; and of the optically active amine of Formula V

Formula V in which ( * ) indicates a stereogenic centre and where R1 and R2, being the same or different, are chosen from hydrogen, CrC 4 alkyl, CrC 4 alkoxy, or R1 and R2 when taken together with the aromatic ring form a group of Formula Vl

Formula Vl

R3 is chosen from d-C 4 alkyl, CrC 4 hydroxyalkyl, phenyl, benzyl, benzyl substituted by CrC 4 alkyl and CrC 4 alkoxy, or R3 is a group of Formula VII:

Formula VII

Preferably said diastereoisomeric salt comprises the acid of the Helional of Formula

in which R and R1 bound together form a methylenedioxolyl group and an optically active amine of Formula V in which R1 is hydrogen, C 1 -C 2 alkyl, CrC 2 alkoxy, R2 is hydrogen, or R1 and R2 when taken together with the aromatic ring form a group of Formula Vl, R3 is CrC 2 alkyl, phenyl, benzyl, 4-methylbenzyl or a group of Formula VII. Even more preferably said diastereoisomeric salt comprises the acid of Helional of formula in which R and R' form a methylenedioxolyl group and an optically active amine of Formula V in which R1 is chosen from the group consisting of hydrogen, methyl, methoxy; R2 is hydrogen, or R1 and R2 when taken together with the aromatic ring form a group of Formula Vl; R3 is chosen from the group consisting of methyl, benzyl, 4-methylbenzyl and a group of Formula VII.

In step a) the acid of Formula IV in enantiopure or enantiomerically enriched form is recovered from the crystallized diastereoisomeric salt and the acid of opposite configuration in enantiopure or enantiomerically enriched form from the crystallization mother liquors of the diastereoisomeric salt. Preferably the process comprises a sub-step e1 ) following the recovery step e) but before the reduction step f) which consists of a further enrichment, to enantiomeric excesses exceeding 95%, of the acid in the enantiomeric form most present in the mother liquors of said crystallization, by crystallization from suitable solvents and separation of the racemic acid.

Step f) is reduction of the enantiopure or enantioenriched acid to the respective alcohol. Said reduction step can preferably take place by means of reducing agents chosen from the group consisting of lithium aluminium hydride; sodium aluminium hydride; sodium bis(2-methoxyethoxy) aluminium hydride; derivatives of lithium aluminium hydride, sodium aluminium hydride, sodium bis(2- methoxyethoxy) aluminium hydride; and borane, as such or dissolved in suitable apolar solvents. More preferably said reduction step takes place at temperatures within the range from 0 5 C to 70 5 C, more preferably from 25 e C to 60 Q C, and even more preferably from 40 9 C to 55 5 C. In a preferred embodiment of the invention the alcohol to be obtained by the process of the invention is the alcohol of Helional.

The process hence comprises a step of oxidizing the racemic Helional to acid, which can be advantageously resolved by an amine of Formula V. In step d) if the amine used is (S)-1 -phenyl-2-(p-tolyl)ethylamine, then the acid of Helional in the (S) form will form the diastereoisomeric salt in solid form and the acid in (R) form will be found in the crystallization mother liquors.

An example of the process of the invention for synthesizing the alcohol of Helional in the (S) and (R) form is given in the following scheme 2:

product

From the mother liquors

Scheme 2 : process for preparing the alcohol of Helional in (S) and (R) form. Advantageously, in the process for preparing hydrocinnamic aldehydes in enantiopure or enantiomerically enriched form, the alcohol in enantiopure or enantiomerically enriched form of Formula Il in step a) is obtained by reduction of the hydrocinnamic aldehyde recovered from step b). In this manner the resolving agent is advantageously regenerated. Preferably the reduction takes place with sodium borohydride at ambient temperature in dichloromethane and methanol. The process of the invention which allows the two enantiomers of the hydrocinnamic aldehydes of Formula I 1 in particular Helional, to be prepared from the respective racemes, is industrially reproducible, and enables good yields to be obtained of the enantiomer of interest as will become evident from the following experimental part given by way of non-limiting examples of the invention. Without being tied to any theory, the inventors of the present invention maintain that they have succeeded in obtaining excellent resolution of the hydrocinnamic aldehydes of Formula I by virtue of identifying the resolving compound of Formula Il used in the process of the invention. Advantageously the alcohol of Formula Il has been found to be the key compound which has enabled the aims of the invention to be reached. Experimental part Example 1

Synthesis of 3-(benzoH ,31dioxol-5-yl)-2-methylpropionic acid 250 g of water were heated to 70 0 C. 196.1 g (1.00 mol) of Helional (98.0% w/w) were added and, while maintaining the temperature between 70° and 75 0 C, 490 g (4.97 mol) of 35% H 2 O 2 were added under stirring in 7 portions of 70 g , each 20 minutes, adjusting the pH if it fell below 8 by adding a 2M aqueous Na 2 Cθ3 solution, for a total of 365 ml (0.73 mol). After the final addition, the mixture was kept under stirring at 70 0 C for a further 3 hours. The mixture was cooled to ambient temperature and washed with diisopropyl ether (150 ml + 100 ml). The aqueous phase was cooled to 10 0 C, then 164 g (1.66 mol) of 37% (% by weight) HCI were slowly added until pH 2. A white solid precipitated from the solution which was filtered off, washed with H 2 O (3 x 50 ml) and dried under reduced pressure at 50 0 C, to provide 172.2 g (0.83 mol) of acid, whose mass and NMR spectra were found to conform to the expected structure. M.p. = 81.4-82.9 0 C. Example 2

Resolution of 1-phenyl-2-(benzoH .3|dioxol-5-yl)-ethylamine: synthesis of the L- asparate salt of (S)-1-phenyl-2-(benzof1 ,31dioxol-5-yl)-ethylammonium 500 ml of a 3/1 v/v water/methanol mixture were added to 98.07 g (0.404 mol) of distilled 1 -phenyl-2-(benzo[1 ,3]dioxol-5-yl)-ethylamine (99.3% w/w) and heated to 60 0 C under agitation. 54.30 g (0.404 mol) of L-aspartic acid were then added and the mixture brought to reflux (78 0 C) until complete dissolution of the solid. The solution was cooled to 60 0 C, the temperature at which formation of a solid was observed, then kept under stirring at 70 0 C for 1.5 hours to achieve dissolution of most of the solid. The solution was then cooled to 25 0 C over 2 hours and maintained at this temperature for a further hour. The solid was filtered off and washed with 3/1 v/v water/methanol (3 x 40 ml), to obtain 107.47 g (0.287 mol) of salt (d.e. = 33.8% (S)amine). Mother liquors d.e. = 67.8% ( R)amine. 107.47 g (0.287 mol) of the obtained salt were dissolved at reflux, under stirring, in 600 ml of a 3/1 v/v water/methanol mixture. The solution was then cooled to 60 0 C until the appearance of a crystallized product; the suspension was kept under stirring at 70 0 C for one hour. It was then cooled over 2 hours at 25 0 C, kept at this temperature for a further hour and filtered. After washing with 3/1 v/v water/methanol (3 x 40 ml), 63.07 g (0.168 mol) of salt (d.e. = 100% (S)amine) were obtained. Mother liquors d.e. = 63.0% (R)amine. M.p. 221.6 0 C Example 3 Synthesis of (S)-1 -phenyl-2-(benzoH ,31dioxol-5-yl) ethylamine 150 ml of toluene, 150 ml of H 2 O and 21.25 g (0.170 mol) of NaOH were added to 60.10 g (0.160 mol) of the crystallized salt from example 2 (d.e. = 100% (S)amine) until pH 10. The mixture was heated to 40 0 C then kept under stirring for 20 minutes, until complete dissolution of the solid. The solution was then cooled to 25 °C and the phases were separated. The aqueous phase was extracted with toluene (2 x 40 ml) and the collected organic phases were washed with H 2 O (2 x 40 ml). The organic phase was evaporated under reduced pressure to provide 40.58 g (0.155 mol) of the (S) amine with a concentration of 92.4% and e.e. of 100%.

40.58 g (0.155 mol) of the (S) amine thus obtained, distilled at 0.05 mbar (T = 126 0 C - 130 0 C) have provided 35.29 g (0.144 mol) of the (S) amine with a concentration of 98.2% and e.e. of 100%. [OC]D 20 = +20.8 [c = 1.0 in CHCI 3 ]

1 H-NMR (CDCI 3 , 400MHz): δ, ppm = 1.64 (bs, 2H 1 NH 2 ); 2.69 (dd, 1 H, J=13.55 Hz, J=8.70 Hz 1 -CH 2 -CAr); 2.87 (dd, 1 H, J=13.55 Hz, J=5.10 Hz, -CIH 2 -CAr); 4.06 (dd, 1 H, J=8.70 Hz, J=5.10 Hz, CH); 5.81 (s, 2H, 0-CH 2 -O); 6.57 (dd, 1 H, J=7.98 Hz, J=1.57 Hz, CH BD ); 6.62 (d, 1 H, J=1.57 Hz, CH BD ); 6.67 (d, 1 H, J=7.98 Hz, CH BD ); 7.17-7.24 (m, 1 H, CH Ph ); 7.25-7.33 (m, 1 H, CH Ph ).

13 C-NMR (CDCI 3 , 300MHz): δ, ppm = 45.81 ((CH 2 -CBD); 57.31 (CH); 100.50 (O- CH 2 -O); 107.85, 109.27, 121.99 (3C, C BD H); 126.13 (2C, o-C Ph H); 126.78 (p- Cp h H); 128.10 (2C, m-C Ph H); 132.51 (C_ BD CH 2 ); 145.27 (C Ph CH); 145.76, 147.31 (2C, CBDO). IR (neat) 3373, 3343, 3027, 2894, 1606, 1489, 1442, 1360, 1248, 1189, 1039, 930, 771 , 753, 701 cm 1

MS (El) m/z (%) = 242 (47) [M + H] + , 225 (35), 135 (10), 106 (100), 79 (12) Example 4 (R)-1 -phenyl-2-(benzo[1 ,31dioxol-5-yl) ethylamine: recovery from mother liquors The mother liquors from the first and second crystallizations of example 2 (containing 0.236 theoretical moles of salt) were concentrated to a weight of 620 g. 250 ml of toluene and 31.25 g (0.5 mol) of 32 % (% by weight) NaOH were added until pH 10. The mixture was kept under stirring for 20 minutes, then the phases were separated. The aqueous phase was extracted with toluene (2 x 40 ml) and the collected organic phases washed with H 2 O (2 x 40 ml). The organic phase was evaporated under reduced pressure to provide 63.17 g (0.227 mol) of the (R) amine with a concentration of 86.5% and e.e. of 71.0% (R). The aqueous phase was combined with the aqueous phase of example 3 and acidified with 55.5 g (0.563 mol) of 37% (% by weight) HCI to pH 3; precipitation of a solid was observed. The mixture was kept under stirring at 4 5 C for 2 hours, then filtered and the solid washed with H 2 O (3 x 30 ml). After drying under reduced pressure at 50 Q C, 46.82 g (0.352 mol) of L-aspartic acid were recovered. Example 5

Resolution of 1 -phenyl-2-(benzof1 ,3ldioxol-5-yl)-ethylamine: synthesis of the D- aspartate salt of (R)-1 -phenyl-2-(benzoM .31dioxol-5-yl)-ethylammonium 640 ml of a 3/1 v/v water/methanol mixture were added to 61.65 g (0.221 mol) of the enantiomerically enriched 1-phenyl-2-(benzo[1 ,3]dioxol-5-yl)-ethylamine of example 4 (86.5% w/w; e.e. = 71.0% ( R) ) and heated to 60 Q C under stirring. 29.71 g (0.221 mol) of D-aspartic acid were then added and the mixture brought to reflux (78 0 C) until complete dissolution of the solid. The solution was cooled to 55 0 C until a precipitate appeared and was kept under stirring at 70 0 C for 1 hour, achieving dissolution of most of the solid. The suspension was then cooled to 20 0 C over 2 hours and kept at that temperature for a further hour. The solid was filtered off, washed with 3/1 v/v water/methanol (3 x 40 ml) and with acetone (3 x 30 ml), obtaining 63.86 g (0.171 mol) of salt (d.e. = 100% (R ) amine). Mother liquors d.e. = 15.6 % (S) amine. M.p. = 220.2 0 C Example 6

Synthesis of (R)-1 -phenyl-2-(benzof1 ,3ldioxol-5-yl) ethylamine 150 ml of toluene, 150 ml of H 2 O and 21.65 g (0.173 mol) of NaOH were added to 61.00 g (0.163 mol) of the crystallized salt from example 5 (d.e. = 100% (R ) amine) until pH 10. The mixture was placed under stirring at 23 0 C for 30 minutes, until complete dissolution of the solid; the phases were then separated. The aqueous phase was extracted with toluene (2 x 40 ml) and the collected organic phases were washed with H 2 O (2 x 40 ml). After solvent removal under reduced pressure, 40.70 g of the ( R) amine were obtained from the organic phase. The 40.70 g of the (R ) amine thus obtained, distilled at 0.08 mbar (T = 147 0 C - 150 0 C) have provided 36.70 g (0.150 mol) of the (R) amine with a concentration of 98.9% and e.e. of 100%, whose mass, IR and 1 H NMR spectra were found to conform to the expected structure. [OC]D 20 = -22.1 [C = 1 .0 in CHCI 3 ] Example 7

Resolution of 3-(benzoH ,31dioxol-5-yl)-2-methylpropionic acid: synthesis of the (S)-3-(benzoM .31dioxol-5-vD-2-propionate salt of (S)-1-phenyl-2-(p- tolvDethylammonium

660 ml of a 2/1 v/v isopropanol/methanol mixture and 46.5 g (0.22 mol) of (S)-1- phenyl-2-(p-tolyl)ethylamine were added to 83.3 g (0.40 mol) of the racemic 3- (benzo[1 ,3]dioxol-5-yl)-2-methylpropionic acid of example 1 , heating to 70 5 C under stirring until complete dissolution of all of the solid. The solution was cooled to 60 g C and seeded with 10 mg of the (S)-3-benzodioxolyl-2-methyl propionate salt of (S)-1-phenyl-2-(p-tolyl)ethylammonium; crystallization of the salt was observed. The suspension was heated to 70 Q C until dissolution of most of the solid was achieved then kept under stirring at this temperature for 1 hour. The mixture was then cooled to 20 Q C over a period of 2.5 hours and kept at this temperature for another hour. The crystallized product was filtered off and washed with 2/1 v/v isopropanol/methanol (2 x 30 ml), to obtain 69.5 g (0.166 mol) of salt (d.e. = 80.8% (S) acid). Mother liquors d.e. = 59.2 % (R) acid. 69.5 g (0.166 mol) of the obtained salt were dissolved at reflux (75 0 C) in 810 ml of 2/1 v/v isopropanol/methanol. The solution was cooled to 70 0 C, seeded with 10 mg of the (S)-3-benzodioxolyl-2-methyl propionate salt of (S)-1 -phenyl-2-(p- tolyl)ethylammonium and kept under stirring at 67 0 C for one hour. The mixture was cooled to 23 0 C over 3 hours, kept for a further hour at this temperature and filtered. After washing the solid with 2/1 v/v isopropanol/methanol (3 x 20 ml), 59.9 g (0.143 mol) of salt (d.e. = 96.4% (S) acid) were obtained. Mother liquors d.e. = 16.4% (R) acid.

59.9 g (0.143 mol) of the obtained salt were dissolved at reflux (75 0 C) in 720 ml of 2/1 v/v isopropanol/methanol. The solid was then made to crystallize by following the aforegiven procedure. After filtering off the crystallized product and washing with 2/1 v/v isopropanol/methanol (3 x 20 ml), 53.9 g (0.128 mol) of salt (d.e. = 99.2% (S ) acid) were obtained. Mother liquors d.e. = 68.2% (S) acid. [CC]D 20 = +22.4 [c = 1.0 in CHCI 3 ] M.p. = 146.0 °C

IR (KBr) 2919, 2195, 1631 , 1573, 1499, 1247, 1188, 1035, 923, 864, 813, 755, 698, 631 , 563 cm "1 Example 8 Resolution of 3-(benzo[1 ,31dioxol-5-yl)-2-methylpropionic acid: synthesis of the (S)-3-(benzo[1.3]dioxol-5-yl)-2-propionate salt of (SH-phenylethylammonium 100 ml of isopropanol and 5.00 g (0.041 mol) of (S)-i-phenylethylamine were added to 15.62 g (0.075 mol) of the racemic 3-(benzo[1 ,3]dioxol-5-yl)-2- methylpropionic acid of example 1. The mixture was brought to reflux until complete dissolution of the solid then cooled to 50 6 C, the temperature at which formation of a crystallized product was observed. The mixture was then kept at 63 5 C for 1 hour, then cooled to 23 Q C over 1 hour and kept at this temperature for a further hour. The crystallized product was filtered off and washed with isopropanol (3 x 5 ml), to obtain 10.36 g (0.0315 mol) of salt (d.e. = 35.8% (S) acid). Mother liquors d.e. = 28.4% (R ) acid.

From successive recrystallizations of the obtained salt, conducted according to the reported procedure, a salt with d.e. = 92.3% ((S) acid) was obtained. M.p. = 138.8 9 C. Example 9 Resolution of 3-(benzoπ ,31dioxol-5-vh-2-methylpropionic acid: synthesis of the

(S)-3-(benzoH .31dioxol-5-vπ-2-proDionate salt of (RV1-phenyl-2-( benzoπ ,31dioxol-5-yl)ethylammonium

60 ml of a 3/1 v/v isopropanol/methanol mixture and 5.20 g (0.022 mol) of the (R)-

1 -phenyl-2-(benzo[1 ,3]dioxol-5-yl)ethylamine of example 6 (98.9% e.e. = 100%) were added to 8.36 g (0.040 mol) of the racemic 3-(benzo[1 ,3]dioxol-5-yl)-2- methylpropionic acid of example 1. The mixture was brought to reflux (76 °C) until complete dissolution of the solid then cooled to 50 0 C, the temperature at which crystallization initiated. The mixture was then brought to 60 0 C, until dissolution of most of the solid was achieved, and the mixture was kept under stirring at this temperature for 1 hour. The mixture was then cooled to 25 0 C over 1 hour, 10 ml of a 3/1 v/v isopropanol/methanol mixture were added and the mixture was kept at this temperature for a further hour. The crystallized product was filtered off and washed with the 3/1 v/v isopropanol/methanol mixture (3 x 5 ml), to obtain 7.63 g (0. 017 mol) of salt (d.e. = 36.2% (S) acid). Mother liquors d.e. = 26.0% (R) acid. From successive recrystallizations of the salt obtained, conducted according to the reported procedure, a salt with d.e. = 91 .4% ((S) acid) was obtained. M.p. = 135.8 0 C Example 10

Resolution of 3-(benzo[1 ,31dioxol-5-yl)-2-methylpropionic acid: synthesis of the (R)-3-(benzoπ .31dioxol-5-vn-2-propionate salt of (S)-1 -phenyl-2-(benzoπ .3ldioxol- 5-yl)-ethylammonium 60 ml of isopropanol and 5.35 g (0.022 mol) of the (S)-1 -phenyl-2- (benzo[1 ,3]dioxol-5-yl)-ethylamine of example 3 (98.2% e.e. = 100%) were added to 8.36 g (0.040 mol) of the racemic 3-(benzo[1 ,3]dioxol-5-yl)-2-methylpropionic acid of example 1. The mixture was brought to reflux (82 0 C) until complete dissolution of the solid then cooled to 65 0 C, the temperature at which crystallization initiated. The mixture was then brought to 75 9 C until dissolution of most of the solid was achieved, and kept under stirring at this temperature for 1 hour. The mixture was then cooled to 23 Q C over 1 hour, 20 ml of isopropanol were added and maintained at this temperature for a further hour. The crystallized product was filtered off and washed with isopropanol (3 x 5 ml), to obtain 9.03 g (0.020 mol) of salt (d.e. = 24.6%(R) acid). Mother liquors d.e. = 41 .0% (S) acid. Example 11

Synthesis of (S)-3-(benzo[1 .31dioxol-5-yl)-2-methylpropionic acid: recovery from the crystallized product 18 g of 32% (% by weight) NaOH were slowly added under agitation to a mixture of 54.04 g (0.124 mol) of the salt of example 7 (d.e. 99.2%), 120 ml of toluene and 120 ml of water, to bring pH to 12.

The mixture was kept under stirring at 25 9 C for 30 minutes, after which the phases were separated. The aqueous phase was extracted with toluene (3 x 10 ml) and the collected organic phases were washed with water (3 x 10 ml). After evaporation of the solvent under reduced pressure, 26.24 g (0.123 mol) of (S)-1- phenyl-2-(p-tolyl)-ethylamine at 99.3% a/a were recovered. 50 ml of toluene were added to the pooled aqueous phases, then 15 g of 37% (% by weight) HCI were added under agitation to bring pH to 2. The mixture was then kept under stirring at 25 0 C for 30 minutes, after which the phases were separated. The aqueous phase was extracted with toluene (3 x 15 ml) and the collected organic phases were washed with water (3 x 10 ml). After evaporation of the solvent under reduced pressure, 24.33 g (0.1 12 mol) of (S)-3- (benzo[1 ,3]dioxol-5-yl)-2-methylpropionic acid at 95.8% w/w (e.e. = 99.3%) were obtained from the organic phase. [α] D 20 = +21 .5 [C = 1 .0 in CHCI 3 ] 1H-NMR (CDCI 3 , 400MHz): δ, ppm = 1 .15 (d, 3H, J=7.00 Hz, CH 3 ); 2.58 (dd, 1 H 1 J=13.35 Hz, J=7.85 Hz, -CIH 2 -C Ar ); 2.69 (m, 1 H, CH); 2.97 (dd, 1 H 1 J=13.35 Hz 1 J=7.90 Hz 1 -CM 2 -C Ar ); 5.88 (s, 2H 1 0-CH 2 -O); 6.61 (dd, 1 H, J=8.00 Hz 1 J=1.50 Hz 1 Ar); 6.66 (d, 1 H, J=1 .50 Hz 1 Ar); 6.71 (d, 1 H 1 J=8.00 Hz 1 Ar); 1 1.9 (bs, 1 H, COOH). 13 C-NMR [CDCI 3 , 300MHz): δ, ppm = 16.26 (CH 3 ); 38.89 (CH 2 -C Ar ); 41 .39 (CH); 100.74 (0-CH 2 -O); 108.05, 109.20, 121 .84 (3C, C Ar H); 132.63 (C A rCH 2 ); 145.99, 147.50 (2C, C Ar O); 182.65 (COOH).

LC-MS (AP-ESK+)) m/z (%) = 455 (59) [2M + K] + , 439 (16) [2M + Na] + , 247 (9) [M + K] + , 231 (8) [M + Na] + , 228 (16), 191 (100), 163 (68), 135 (77), 105 (19), 79 (22) IR (neat) 2976, 1708, 1491 , 1443, 1415, 1292, 1244, 1 190, 1099, 1040, 932, 813 cm "1 Example 12

Synthesis of (R)-3-(benzo[1 .31dioxol-5-yl)-2-methylpropionic acid: recovery from mother liquors

The mother liquors of the first crystallization, obtained by combining two tests conducted as reported in example 7 and containing 3-(benzo[1 ,3]dioxol-5-yl)-2- methylpropionic acid enriched in the (R) enantiomer (e.e. = 62.9%, 0.258 theoretical moles) and (S)-1 -phenyl-2-(p-tolyl)-ethylamine (0.060 theoretical moles), were concentrated under reduced pressure to remove the solvent. 150 ml of toluene and 250 ml of water were added followed by 18 g of 32% (% by weight) NaOH, under agitation, to bring the pH to12. The mixture was kept under stirring at 25 °C for 20 minutes, then the phases were separated and the organic phase washed with water (3 x 30ml). After evaporation of the solvent under reduced pressure, 13.2 g of (S)-1 -phenyl-2-(p-tolyl)- ethylamine at 96.3% a/a were recovered from the organic phase. 100 ml of toluene were added to the combined aqueous phases and 15 g of 37% were added under agitation to bring pH to 2. The mixture was kept under stirring at 25 S C for 20 minutes, after which the phases were separated. The aqueous phase was extracted with toluene (3 x 30 ml) and the pooled organic phases were washed with water (3 x 30 ml). After evaporation of the solvent under reduced pressure 53.15 g (0.242 mol) of (R)-3-(benzo[1 ,3]dioxol-5-yl)-2-methylpropionic acid at 94.7% w/w (e.e = 62.5%) were obtained from the organic phase. Example 13 Resolution of 3-(benzo[1.31dioxol-5-yl)-2-methylpropionic acid: synthesis of the (R)-3-(benzo[1 ,31dioxol-5-yl)-2-propionate salt of (RH -phenylethylammonium 450 ml of isopropanol and 25.45 g (0.21 mol) of (R)-i-phenylethylamine were added to 53.31 g (0.242 mol) of the acid enantiomerically enriched in (R) of example 12 (94.7% w/w, e.e. = 62.6%). The mixture was brought to reflux (82 0 C) until complete dissolution of the solid then cooled to 70 °C, at which point crystallization started. The suspension was then brought to 75 0 C, until dissolution of most of the solid was achieved, and kept under stirring at this temperature for 1 hour. It was then cooled to 0 0 C over 3 hours and kept at this temperature for 1.5 hours. The crystallized product was filtered off and washed with isopropanol (3 x 15 ml) to obtain 64.36 g (0.195 mol) of salt (d.e. = 78.2% (R) acid). Mother liquors = 2.4% (S) acid.

64.36 g (0.195 mol) of the previous crystallized product were dissolved at reflux in 360 ml of isopropanol. The solution was cooled to 75 0 C, the temperature at which crystallization initiated, kept at 80 9 C for 1 hour, cooled to 0 5 C over 2 hours and kept at this temperature for a further hour. The crystallized product was filtered off and washed with isopropanol (3 x 15 ml), to obtain 60.37 g (0.183 mol) of salt (d.e. = 83.4% (R) acid). Mother liquors d.e. = 10.2% (S) acid.

60.37 g (0.183 mol) of the previous crystallized product were dissolved at reflux in 340 ml of isopropanol and recrystallized as reported above. 57.5 g (0.175 mol) of salt (d.e. = 88.0% (R) acid) were obtained. Mother liquors d.e. = 8.6% (S) acid. 57.5 g (0.175 mol) of the previous crystallized product were dissolved at reflux in 330 ml of isopropanol and recrystallized as reported above. 54.83 g (0.166 mol) of salt (d.e. = 91.6% (R) acid) were obtained. Mother liquors d.e. = 20.0% (R) acid. 54.83 g (0.166 mol) of the previous crystallized product were dissolved at reflux in 330 ml of isopropanol and recrystallized as reported above. 52.21 g (0.159 mol) of salt (d.e. = 93.2% (R) acid) were obtained. Mother liquors d.e. = 47.4%( R) acid. 52.21 g (0.159 mol) of the previous crystallized product were dissolved at reflux in 330 ml of isopropanol and recrystallized as reported above. 49.51 g (0.150 mol) of salt (d.e. = 95.6% (R) acid) were obtained. Mother liquors d.e. = 58.6% (R) acid. 49.51 g (0.150 mol) of the previous crystallized product were dissolved at reflux in 330 ml of isopropanol and recrystallized as reported above. 47.47 g (0.144 mol) of salt (d.e. = 97.0% (R) acid) were obtained. Mother liquors d.e. = 68.2% (R) acid. 47.47 g (0.144 mol) of the previous crystallized product were dissolved at reflux in 320 ml of isopropanol and recrystallized as reported above. 45.74 g (0.139 mol) of salt (d.e. = 97.8% (R) acid) were obtained. Mother liquors d.e. = 78.2%( R) acid. 45.74 g (0.139 mol) of the previous crystallized product were dissolved at reflux in 350 ml of isopropanol and recrystallized as reported above. 43.70 g (0.133 mol) of salt (d.e. = 98.6% (R) acid) were obtained. Mother liquors d.e. = 85.4% (R) acid. 43.70 g (0.133 mol) of the previous crystallized product were dissolved at reflux in 350 ml of isopropanol and recrystallized as reported above. 41.73 g (0.127 mol) of salt (d.e. = 98.8% (R) acid) were obtained. Mother liquors d.e. = 89.6% (R) acid. [α] D 20 = -5.2 [c = 1.0 in CHCI 3 ] M.p. = 144.9 0 C Example 14

Synthesis of (R)-3-(benzof1.31dioxol-5-yl)-2-methylpropionic acid: recovery from the crystallized product To a mixture of 41.15 g (0.125 mol) of the salt of example 13 (d.e. 98.8%), 80 ml of toluene and 80 ml of water, there were slowly added 11 ml of 37% (% by weight) HCI under agitation until the pH = 2.

The mixture was kept under stirring at 25 9 C for 20 minutes, after which the phases were separated. The aqueous phase was extracted with toluene (3 x 15 ml) and the collected organic phases washed with water (3 x 20 ml). After evaporating the solvent under reduced pressure, 25.32 g (0.109 mol) of (R)-3- (benzo[1 ,3]dioxol-5-yl)-2-methylpropionic acid at 89.9% w/w (e.e = 99.0%) were recovered from the organic phase.

40 ml of toluene were added to the collected aqueous phases and 15 ml of 32% (% by weight) NaOH were added under agitation to bring pH to 2. The mixture was held under agitation at 25 Q C for 20 minutes, then the phases were separated. The aqueous phase was extracted with toluene (3 x 15 ml) and the collected organic phases were washed with water (3 x 15 ml). After evaporating the solvent under reduced pressure, 10.24 g (0.085 mol) of (R)-i -phenyl-ethylamine at 100% a/a were obtained from the organic phase. Example 15 Purification of (R)-3-(benzo[1 ,31dioxol-5-yl)-2-methylpropionic acid

30.0 g of diisopropyl ether were added to 51.71g (0.215 mol) of (R)-enriched acid (86.5%, e.e. = 57.8%) recovered from the crystallization mother liquors, according to the procedure of example 12. The mixture was heated under stirring to 60 0 C to dissolve the solid, then cooled to 35 0 C, the temperature at which crystallization of a solid initiated, and was kept under stirring for 1 hour at 4O 0 C. The suspension was then cooled to 20 0 C over a period of one hour and kept for a further hour at this temperature, then the solid was filtered off and washed with diisopropyl ether (3 x 10 ml). After drying the crystallized product under vacuum at 40 0 C, 21.14 g of acid with e.e. = 20.4% (R) were obtained. Mother liquors e.e. = 85.8% (R) acid. The mother liquors were concentrated under reduced pressure to a weight of 40.0g, heated under stirring to 60 0 C then cooled slowly to 25 0 C, to obtain the precipitation of a solid. The suspension was kept at 30 0 C for 1 hour, then cooled to 10 8 C over 1 hour and kept at this temperature for a further hour. The solid was then filtered off and washed with diisopropyl ether at 10 0 C (3 x 10 g). From the crystallized product dried under vacuum at 40 °C, 3.52 g of acid with e.e. = 23.0% (R) were obtained, and from the concentrated mother liquors 24.7 g of acid (concentration = 89.7% 0.106 mol) with e.e. = 95.6% (R) were obtained, whose mass and 1 H NMR spectra were found to be identical to those of the racemic acid. 110.5 g of isopropanol and 11.36 g (0.106 mol) of benzylamine were added to 24.7 g (0.106 mol) of the acid enantiomerically enriched in (R) (89.7% w/w, e.e. = 95.6%). The mixture was heated at reflux under stirring to achieve complete dissolution of the solid then cooled to 68 0 C, the temperature at which crystallization of a solid initiated. The suspension was kept at 72 0 C for 1 hour, then cooled to 25 5 C over 1 hour and kept at this temperature for a further hour. The solid was then filtered off and washed with isopropanol (3 x 10 ml), to obtain 29.54 g (0.094 mol) of salt. 60 ml of toluene, 60 ml of H 2 O and 10 g (0.101 mol) of 37% (% by weight) HCI were added to 29.54 g of the obtained salt. The solution was kept under stirring for 15 minutes, after which the phases were separated. The aqueous phase was washed with toluene (2 x 10 ml) and the collected organic phases washed with H 2 O (2 x 10 ml). On removal of the solvent under reduced pressure, 19.49 g (0.091 mol) of (R) acid with e.e. = 99.0% (concentration = 97.3%) were obtained from the organic phase, whose mass, IR and 1 H NMR spectra were found to conform to the expected structure. [α] D 20 = -23.2 [c = 1 .0 in CHCI 3 ] Example 16 Synthesis of (S)-3-(benzo[1 ,3ldioxol-5-yl)-2-methylpropanol)

A solution of 20.0 g (0.092 mol) of the (S) acid of example 1 1 (95.8% w/w, e.e. = 99.3%) and 120.0 ml of toluene, under N 2 atmosphere, was brought to reflux for 1 hour, distilling off 60 ml of azeotrope to dry the system. This was followed by cooling to 15 0 C, after which 4.0 ml of THF were added and 3.0 g (0.075 mol) of 95% LiAIH 4 were added in pellet form over 30 minutes, maintaining the temperature between 20 0 C and 25 0 C. At the end of the addition the suspension was kept under stirring at 45 0 C for 4 hours. It was then cooled to 5 0 C and 5 ml of H 2 O and 50 ml (0.30 mol ) of 6 M HCI were slowly added, until pH 2 of the aqueous phase The phases were separated, the aqueous phase was washed with toluene (2 x 10 ml) and the organic phases washed again with a saturated solution of Na 2 CO 3 (10 ml) then with H 2 O (2x1 OmI). From the organic phase, concentrated under reduced pressure, 18.17 g (0.0876 mol) of the (S) alcohol were obtained with e.e. = 98.2% (concentration = 93.6%). 18.17 g (0.0876 mol) of the (S) alcohol thus obtained, distilled at 0.3 mbar (T = 1 17 0 C - 120 0 C), have provided 13.42 g (0.068 mol) of the (S) alcohol with 99.8% concentration and e.e. of 98.2%, whose mass and 1 H NMR were found to conform to the expected structure. [α] D 20 = -14.1 [c = 1.0 in CHCI 3 ] [lit: D. Enders, M. Backes; Tetrahedron: Asymmetry, 2004, 15, 1813-1817, [α] D 22 = -11.0 (c = 1.0 in CHCI 3 )] IR (neat) 3350, 2918, 1506, 1490, 1441 , 1248, 1190, 1039, 935, 811 cm "1 Example 17 Synthesis of hemiacetal using (R)-3-(benzof1.31dioxol-5-yl)-2-methylpropanol

A mixture of 20.0 g (0.102 mol) of racemic Helional (98.8%), 15.0 g (0.064 mol), of (R)-3-(benzo[1 ,3]dioxol-5-yl)-2-methylpropanol (82.8% w/w, e.e. = 86.0%), 10 g of diisopropyl ether and 10 g of methylcyclohexane was cooled over 30 minutes to 0 9 C, under moderate stirring (100 rpm). The solution was seeded with 5 mg of enantiopure hemiacetal and kept at 0 Q C under stirring for 7 hours. The solid was filtered off, washed with the 1/1 diisopropyl ether/methylcyclohexane mixture (3 x 6 ml) and dried under reduced pressure. 14.5 g (0.0375 mol) of the hemiacetal were obtained, and found to be composed of Helional with e.e. = 56.5% (S) and the alcohol with e.e. = 90.4% (R). (The enantiomeric excesses of Helional were calculated on the NaBH 4 -treated hemiacetal, by subtracting the quantity corresponding to each enantiomer of the alcohol, determined by gas chromatography before the reduction).

Helional with e.e. = 38.6 % (R) and the alcohol with e.e. = 74.8% (R) were present in the mother liquors. (The enantiomeric excesses of Helional were calculated on the NaBH 4 -treated hemiacetal, by subtracting the quantity corresponding to each enantiomer of the alcohol, determined by gas chromatography before the reduction). Example 18 Synthesis of hemiacetal using (S)-3-(benzoM ,3ldioxol-5-yl)-2-methylpropanol A mixture of 20.0 g (0.102 mol) of racemic Helional (97.8% w/w), 15.68 g (0.063 mol) of (S)-3-(benzo[1 ,3]dioxol-5-yl)-2-methylpropanol (77.9% w/w, e.e. = 86.6%), 10 g of diisopropyl ether and 10 g of methylcyclohexane was cooled over 30 minutes to 0 9 C, under moderate stirring (100 rpm). The solution was seeded with 5 mg of enantiopure hemiacetal and kept at 0 Q C under agitation for 7 hours. The solid was filtered off, washed with the 1/1 diisopropyl ether/methylcyclohexane mixture (3 x 6 ml) and dried under reduced pressure. 12.7 g (0.033 mol) of hemiacetal were obtained, and found to be composed of Helional with e.e. = 96.6% (R) and the alcohol with e.e. = 97.8% (S). (The enantiomeric excesses of Helional were calculated on the NaBH 4 -treated hemiacetal, by subtracting the quantity corresponding to each enantiomer of the alcohol, determined by gas chromatography before the reduction). Helional with e.e. = 48.1% (S) and the alcohol with e.e. = 75.8% (S) were present in the mother liquors. (The enantiomeric excesses of Helional were calculated on the NaBH 4 -treated hemiacetal, by subtracting the quantity corresponding to each enantiomer of the alcohol, determined by gas chromatography before the reduction). [α] D 20 = -9.4 [c = 1.0 in acetonitrile] M.p. = 70-71 0 C

1 H-NMR {CDCN, 400MHz): δ, ppm = 0.65 (d, 3H, J=6.95 Hz, CH 3 ); 0.70 (d, 3H, J=6.95 Hz, CH 3 ); 1.71 -1.78 (m, 2H, 2CH-CH 3 ) 2.10 (dd, 1 H, J=13.54 Hz, J=9.34 Hz, CH 2 -CAr); 2.16 (dd, 1 H, J=13.54 Hz, J=7.69 Hz, CH 2 -CAr) 2.47 (dd, 1 H, J=13.54 Hz, J=6.41 Hz, CjH 2 -CAr) 2.62 (dd, 1 H, J=13.54 Hz, J=4.97 Hz, CH 2 -CAr); 2.91 (dd, 1 H, J=9.45 Hz, J=6.22 Hz, CH 2 -O); 3.35 (dd, 1 H, J=9.45 Hz, J=5.68 Hz, CH 2 -O); 3.53 (d, 1 H, J=7.69, OH); 4.14 (dd, 1 H, J=7.69 Hz, J=4.76 Hz, -CH-OH), 5.71 (s, 4H, 20-CH 2 -O); 6.45 (d, 2H, J=8.05 Hz, CH B D); 6.52 (dd, 2H, J=2.50, J=1.46 Hz, CH BD ); 6.56 (dd, 2H, J=7.89, J=2.50 Hz, CH BD ). 1 3 C-NMR (CDCN, 400MHz): δ, ppm = 16.62, 16.86 (2C 1 CH 3 ); 36.19 (CH-CH 3 ); 38.17 (CH 2 -C Ar ); 39.73 (CH 2 -C Ar );42.19 (CH-CH 3 ); 71.86 (CH 2 -O); 100.07(CH-OH); 101.49 (0-CH 2 -O); 108.28, 109.28, 122.51 (6C, C Ar H); 135.41 , 135.57 (2C, C Ar CH 2 ); 146.13, 148.03 (4C, C Ar O). IR (KBr) 3306, 3218, 2958, 2911 , 1607, 1501 , 1488, 1439, 1361 , 1248, 1190, 1090, 1038, 932, 805, 724 cm "1 Example 19

Synthesis of hemiacetal using (S)-3-(benzoM ,3ldioxol-5-yl)-2-methylpropanol A mixture of 28.5 g (0.1485 mol) of racemic Helional, 12.24 g (0.063 mol) of (S)-3- (benzo[1 ,3]dioxol-5-yl)-2-methylpropanol (e.e. = 88.6%), 10 g of diisopropyl ether and 10 g of methylcyclohexane was cooled over 30 minutes to 0 Q C, under moderate stirring (100 rpm). The solution was seeded with 5 mg of enantiopure hemiacetal and kept at 0 Q C under stirring for 7 hours. The solid was filtered off, washed with the 1/1 diisopropyl ether/methylcyclohexane mixture (4 x 5 ml) and dried under reduced pressure. 14.55 g (0.038 mol) of h ' emiacetal were obtained which, when analyzed as reported in example 18, was found to be composed of Helional with e.e. = 93.6% (R) and the alcohol with e.e. = 97.6% (S). Helional with e.e. = 35.4% (S) and the alcohol with e.e. = 56.0% (S) were present in the mother liquors analyzed as reported in example 18. Example 20

Synthesis of hemiacetal using (S)-3-(benzoM ,31dioxol-5-yl)-2-methylpropanol A mixture of 98.26 g (0.467 mol) of racemic Helional (91.4% w/w), 58.0 g (0.300 mol) of (S)-3-(benzo[1 ,3]dioxol-5-yl)-2-methylpropanol (99.4% w/w, e.e. = 98.4%), 50 g of diisopropyl ether and 50 g of methylcyclohexane was cooled over 20 minutes to 0 Q C, under moderate stirring (100 rpm). The solution was seeded with 5 mg of enantiopure hemiacetal and kept at 0 Q C under stirring for 7 hours. The suspension was then further cooled to -10 9 C and kept at this temperature for 30 minutes. The solid was filtered off, washed with the 1/1 diisopropyl ether/methylcyclohexane mixture (4 x 20 ml) and dried under reduced pressure. 72.32 g (0.187 mol) of hemiacetal were obtained which, when analyzed as reported in example 18, was found to be composed of Helional with e.e. = 83.6% (R) and the alcohol with e.e. = 96.2% (S). Helional with e.e. = 56.7% (S) and the alcohol with e.e. = 87.0% (S) were present in the mother liquors analyzed as reported in example 18. Example 21

Synthesis of hemiacetal using (S)-3-(benzof 1 ,31dioxol-5-yl)-2-methylpropanol 40 g of diisopropyl ether and 40 g of methylcyclohexane were added to a mixture containing 89.76 g (0.467 mol) of racemic Helional and 58.27 g (0.300 mol) of (S)- 3-(benzo[1 ,3]dioxol-5-yl)-2-methylpropanol (e.e. = 98.4%), obtained by combining the crystallized product and mother liquors derived from example 20 and after successive re-crystallizations. The solution was cooled over 40 minutes to 0 9 C, under moderate stirring (100 rpm). The solution was seeded with 5 mg of enantiopure hemiacetal and kept at 0 9 C under stirring for 6 hours. The suspension was then further cooled to -10 9 C and kept at this temperature for 1 hour. The solid was filtered off, washed with the 1/1 diisopropyl ether/methylcyclohexane mixture (4 x 20 ml) and dried under reduced pressure. 68.32 g (0.177 mol) of hemiacetal were obtained which, when analyzed as reported in example 18, was found to be composed of Helional with e.e. = 90.1% (R) and the alcohol with e.e. = 96.4% (S). Helional with e.e. = 55.9% (S) and the alcohol with e.e. = 85.4% (S) were present in the mother liquors analyzed as reported in example 18. Example 22

Recovery of (R) Helional and (S)-3-(benzo[1.3]dioxol-5-yl)-2-methylpropanol from crystallized hemiacetal A mixture of 68.32 g (0.177 mol) of the crystallized hemiacetal obtained from example 21 and 100 g of diisopropyl ether was heated at 60 9 C to dissolve the solid. The solution obtained was then cooled to 25 9 C to which was added a freshly prepared solution of 25.20 g (0.133 mol) of Na 2 S 2 O 5 in 38 g of H 2 O. The solution was kept under stirring and after a few minutes, the formation of a white precipitate was observed. The mixture was then kept under stirring at 20-25 8 C for 3 hours, then the solid was filtered off and washed with diisopropyl ether (3 x 30 ml) to provide 91.8 g of a bisulphite adduct.

The filtered organic phase was washed with water (3 x 15 ml), dried with 5 g of Na 2 SO 4 then concentrated under reduced pressure at ambient temperature to provide 34.7 g (0.167 mol) of the (S) alcohol with concentration = 93.6% w/w and e.e. = 99.6%.

60 g of diisopropyl ether, a previously prepared solution of 36.76 g (0.266 mol) of K 2 CO 3 in 105 g of H 2 O and the aqueous phase (45 g) used for washing the previous crystallization mother liquors were added to 91.8 g of the obtained solid. The reaction mixture was heated to 40 5 C and kept under stirring for 30 minutes until complete dissolution of the solid. The solution was then cooled to 25 5 C, the phases separated and the aqueous phase washed with diisopropyl ether (2 x 25 ml). The collected organic phases were washed with H 2 O (3x25 ml) and subsequently concentrated under reduced pressure. 35.17 g (0.174 mol) of (R ) Helional with concentration = 95.0% w/w and e.e. = 88.0% were obtained. Example 23 Recovery of (S) Helional and (S)-3-(benzoF1 ,31dioxol-5-yl)-2-methylpropanol from the hemiacetal crystallization mother liquors

The crystallization mother liquors of example 21 were concentrated under reduced pressure to a weight of 310 g, to which was added a freshly prepared solution of 46.05 g (0.242 mol) of Na 2 S 2 O 5 in 70 g of H 2 O. The solution was maintained under agitation at 25 9 C and after a few minutes the formation of a white precipitate was observed. The mixture was kept under stirring at 25 -C for 4 hours, then the solid was filtered off and washed with diisopropyl ether (4 x 20 ml) to provide 148.6 g of a bisulphite adduct. The filtered organic phase was washed with water (3 x 20 ml) then concentrated under reduced pressure at ambient temperature to provide 34.15 g (0.122 mol) of the (S) alcohol with concentration = 63.5% w/w and e.e. = 85.4%. 150 g of diisopropyl ether, a previously prepared solution obtained from 80.2 g (0.58 mol) of K 2 CO 3 in 285 g of H 2 O and the aqueous phase (90 g) used for washing the previous crystallization mother liquors, were added to 148.6 g of the solid obtained. The reaction mixture was heated to 35-40 9 C and kept under stirring for 1 hour until complete dissolution of the solid. The solution was then cooled to 30 9 C, the phases separated and the aqueous phase washed with diisopropyl ether (2 x 40 ml). The collected organic phases were washed with H 2 O (3x40 ml) and subsequently concentrated under reduced pressure. 56.82 g (0.272 mol) of (S) Helional with concentration = 91.9% w/w and e.e. = 57.2% were obtained. Example 24

Second synthesis cycle of hemiacetal: use of recovered (S)-3-(benzoH ,31dioxol-5- yl)-2-methylpropanol To a mixture of 98.26 g (0.467 mol) of racemic Helional (91.4%), 45 g of diisopropyl ether and 45 g of methylcyclohexane there was added (S)-3- (benzo[1 ,3]dioxol-5-yl)-2-methylpropanol obtained in the following manner: 34.23 g (0.165 mol) recovered from the crystallized product obtained from example 22 (concentration = 93.6%, e.e. = 98.4%), 33.54 g (0.110 mol) recovered from the mother liquors obtained from example 23 (concentration = 63.5%, e.e. = 85.4%), 4.95 g (0.025 mol) of fresh product obtained as in example 16 (concentration = 99.4%, e.e. = 98.4%). The solution was cooled to 0 9 C over 30 minutes, under moderate stirring (100 rpm) and, following the procedure of example 21 , 68.70 g (0.178 mol) of hemiacetal were obtained, which, when analyzed as reported in example 18, was found to be composed of Helional with e.e. = 90.3% (R) and alcohol with e.e. = 94.2% (S). Helional with e.e. = 56.3% (S) and the alcohol with e.e. = 76.8% (S) were present in the mother liquors, analyzed as reported in example 18. Example 25

Second cycle: recovery of (R) Helional and (S)-3-(benzo[1 ,3ldioxol-5-yl)-2- methylpropanol) from the crystallized hemiacetal 103 g of diisopropyl ether were added to 68.70 g (0.178 mol) of the crystallized hemiacetal obtained from example 24. Following the procedure reported in example 22 and by treatment with a freshly prepared solution of 26.16 g (0.134 mol) of Na 2 S 2 O 5 in 40 g of H 2 O, there were obtained 35.66 g (0.162 mol) of the (S) alcohol (concentration = 88.4% w/w and e.e. 99.4%) and 34.89 g (0.174 mol) of (R) Helional (concentration = 95.6% w/w and e.e = 90.1%). Example 26

Second cycle: recovery of (S) Helional and (S)-3-(benzo[1 ,3ldioxol-5-yl)-2- methylpropanol from the crystallization mother liquors of the hemiacetal The crystallization mother liquors of example 24 were concentrated under reduced pressure to a weight of 205 g. Following the procedure reported in example 23 and by treatment with a freshly prepared solution of 47.30 g (0.242 mol) of Na 2 S 2 O 5 in 70 g of H 2 O, there were obtained 43.74 g (0.108 mol) of the (S) alcohol (concentration = 47.9% w/w and e.e. 78.4%) and 55.95 g (0.270 mol) of (S) Helional (concentration = 92.8% w/w and e.e = 57.7%). Example 27

Purification of (R) Helional obtained from crystallized hemiacetal 40 g of diisopropyl ether were added to 85.0 g (0.398 mol) of (R) Helional (90.1% concentration, e.e. = 90.0%), obtained by combining the products derived from the crystallized hemiacetal from examples 22 and 25 and a further resolution cycle conducted in a similar manner. Under stirring (150 rpm), the solution was cooled to -15 5 C and seeded by adding 10 mg of (R) Helional in solid form. When a crystallized product started to form, the mixture was maintained under agitation for 1 hour at -5 6 C then cooled to -15 Q C over 30 minutes and adding, over the same time period, a further 40 g of diisopropyl ether. After 7 hours the crystallized product was filtered off through a jacketed filter maintained at -15 e C and washed with cold diisopropyl ether (4 x 10 ml). From the mother liquors, concentrated under reduced pressure, 24.5 g (0.107 mol) of oil were obtained (Helional concentration = 83.7% w/w; e.e = 75.1% (R)). From the crystallized product, dissolved at ambient temperature and concentrated under reduced pressure, 60.0 g (0.279 mol) of oil were obtained (Helional concentration = 89.5% w/w; e.e = 94.2% (R)), whose mass and 1 HNMR spectra were found to conform to the expected structure. Example 28

Purification of (R) Helional obtained from crystallized hemiacetal 100 g of diisopropyl ether were added to a mixture of 135.0 g (0.651 mol) of (R) Helional (92.7% concentration, e.e. = 87.2%), obtained by combining the products derived from the crystallized hemiacetal of six resolution cycles conducted as in examples 21 and 22, then cooled to 0 9 C under stirring at 150 rpm. The solution was seeded by the addition of 10 mg of (R) Helional in solid form. When a crystallized product started to form, the mixture was kept under stirring for 1 hour at 5 S C then cooled to -15 5 C over 1.5 hours and adding, over the same time period, a further 90 g of diisopropyl ether. After 4 hours the crystallized product was filtered off through a jacketed filter maintained at -15 Q C and washed with cold diisopropyl ether (4 x 20 ml).

From the mother liquors, concentrated under reduced pressure, 38.2 g (0.172 mol) of oil were obtained (Helional concentration = 92.3% a/a; e.e = 55.4% (R)). From the crystallized product, dissolved at ambient temperature and concentrated under reduced pressure, 93.0 g (0.479 mol) of oil (Helional concentration = 98.9% w/w; e.e = 96.4% (R)) were obtained. Example 29 Purification of (S) Helional obtained from the mother liquors First crystallization: 80 g of diisopropyl ether were added to 286.8 g (1.314 mol) of (S) Helional (88.1 %, e.e = 54.0%), derived from the hemiacetal crystallization mother liquors, obtained from examples 23 and 26 and subsequent resolution cycles conducted as in examples 24 to 26, then placed under stirring (100 rpm).

The solution was cooled to -10 9 C then seeded by addition of 10 mg of (S) Helional in solid form. When a crystallized product started to form, the mixture was kept under stirring at 0 5 C for 1 hour then cooled to -15 Q C over 1.5 hours and adding, over the same time period, a further 120 g of diisopropyl ether. After 4 hours the crystallized product was filtered off at -15 9 C and washed with cold diisopropyl ether (4 x 20 ml).

From the mother liquors, concentrated under reduced pressure, 181.6 g (0.801 mol) of oil were obtained (Helional concentration = 94.9% a/a; e.e = 31.8% (S)). From the crystallized product, dissolved at ambient temperature and concentrated under reduced pressure, 103.0 g (0.513 mol) of oil (Helional concentration =

95.7% w/w; e.e = 88.3% (R)) were obtained.

Second crystallization: 70 g of diisopropyl ether were added to 103.0 g (0.513 mol) of (S) Helional (95.7% e.e. = 88.3%), obtained from the previous crystallization, and placed under stirring. The solution was cooled to 0 Q C and seeded by the addition of 10 mg of (S) Helional in solid form. After about 1 hour a crystallized product began to form, the mixture was brought to 5 Q C and kept at this temperature for 1 hour, then adding a further 60 g of diisopropyl ether. The suspension was cooled to -15 Q C over 1.5 hours, adding a further 30 g of solvent over the same amount of time, and was kept at this temperature for a further 3.5 hours. The crystallized product was filtered off at -15 Q C, and washed with cold diisopropyl ether (4 x 20 ml).

From the mother liquors, concentrated under reduced pressure, 28.7 g (0.100 mol) of oil were obtained (Helional concentration = 98.0% a/a; e.e = 67.2% (S)). From the crystallized product, dissolved at ambient temperature and concentrated under reduced pressure, 83.4 g (0.413 mol) of oil (Helional concentration = 95.1% w/w; e.e = 97.4% (S)) were obtained, whose mass and 1 HNMR spectra were found to conform to the expected structure.

Example 30 Synthesis of (R)-3-(benzoM .31dioxol-5-yl)-2-methylpropanol by reduction of R

Helional

107 g of dichloromethane and 10.7 g of methanol were added to 60.0 g (0.279 mol) of the (R) Helional (concentration 89.5% e.e. = 94.2%) of example 27 and placed under agitation at 20 °C. NaBH 4 was added in 1.O g portions every 15 minutes, for a total of 4 additions (4.0 g; 0.104 mol), keeping the temperature at around 30 ° - 35 0 C. One hour after the final NaBH 4 addition, 50 ml of 3M HCI were added slowly until pH 2. The mixture was kept under stirring for 10 minutes, then the phases were separated. The aqueous phase was extracted with dichloromethane (3 x 50 ml) and the collected organic phases were washed with dichloromethane (3 x 50 ml). After solvent evaporation under reduced pressure, from the organic phase 55.55 g (0.276 mol) of (R)-3-(benzo[1 ,3]dioxol-5-y)-2-methylpropanol (concentration = 96.6% w/w, e.e. = 90.6%) were obtained whose mass, IR and 1 H NMR spectra were found to conform to the expected structure.

[α] D 20 = -10.1 [c = 1.0 in CHCI 3 ] [lit: D. Enders, M. Backes; Tetrahedron: Asymmetry, 2004, 15, 1813-1817, [α] D 22 = +11.1 (c = 1.0 in CHCI 3 )] Example 31

Synthesis of hemiacetal using (R)-3-(benzoF1 ,31dioxol-5-yl)-2-methylpropanol A mixture of 74.78 g (0.384 mol) of racemic Helional (98.8%), 49.86 g (0.248 mol) of (R)-3-(benzo[1 ,3]dioxol-5-yl)-2-methylpropanol (concentration = 96.6% w/w, e.e. = 90.6%) from example 30, 37 g of diisopropyl ether and 37 g of methylcyclohexane was cooled to 0 0 C over 30 minutes under moderate stirring (100 rpm), and seeded with 5 mg of enantiopure hemiacetal. The suspension was kept at 0 0 C for 1 hour then cooled over 5 hours to -10 0 C and kept d at this temperature for a further hour. The solid was filtered off, washed with the 1/1 diisopropyl ether/methylcyclohexane mixture (3 x 10 ml) and dried under reduced pressure. 49.77 g (0.129 mol) of hemiacetal were obtained which, after treatment with NaBH 4 provided alcohol with e.e. = 4% (R). Example 32

Recovery of (S) Helional and (R)-3-(benzoH .31dioxol-5-vh-2-methylpropanol from crystallized hemiacetal 74 g of diisopropyl ether were added to 49.67 g (0.128 mol) of the crystallized hemiacetal obtained from example 31 and heated to 50 0 C to dissolve the solid. By following the procedure given in example 22, and by treatment with a freshly prepared solution of 18.32 g (0.096 mol) of Na 2 S 2 O 5 in 28 g of H 2 O, there were obtained 29.49 g (0.123 mol) of the (R) alcohol (concentration = 81.0% w/w, e.e = 97.8%) and 25.79 g (0.121 mol) of (S) Helional (concentration = 90.4% w/w, e.e = 86.1%). Example 33

Recovery of (R) Helional and (R)-3-(benzof 1.31dioxol-5-yl)-2-methylpropanol from the hemiacetal crystallization mother liquors

By following the procedure given in example 23, the crystallization mother liquors of example 31 were reacted with a freshly prepared solution of 36.36 g (0.191 mol) of Na 2 S 2 O 5 in 55.9 g of H 2 O. 35.37 g (0.109 mol) of the (R) alcohol (concentration = 56.9% w/w, e.e = 82.4%) and 53.58 g (0.247 mol) of (R) Helional (concentration = 88.8% w/w, e.e = 42.9%) were obtained. Example 34 Second hemiacetal synthesis cycle: use of recovered (R)-3-(benzoH ,31dioxol-5- yl)-2-methylpropanol

By following the procedure given in example 31 , a mixture of 76.4 g (0.393 mol) of racemic Helional (98.8%) in 38 g of methylcyclohexane and 38 g of diisopropyl ether was reacted with (R)-3-(benzo[1 ,3]dioxol-5-yl)-2-methylpropanol obtained in the following manner: 29.49 g (0.123 mol) recovered from the crystallized product obtained from example 32 (concentration = 81.0% w/w, e.e = 97.8%), 35.37 g (0,109 mol) recovered from the mother liquors obtained from example 33 (concentration = 56.9% w/w, e.e = 82.4%), 4.05 g (0.020 mol) of fresh product obtained from example 18 (concentration = 96.6% w/w, e.e. = 90.6%). 58.86 g (0.152 mol) of hemiacetal were obtained which, on NaBH 4 treatment, provided an alcohol with e.e. = 0% whose 1 H NMR and IR spectra were found to conform to the expected structure. [α] D 20 = +9.4 [c = 1.0 in acetonitrile] M.p. = 72-73 0 C Example 35 Second cycle: recovery of (S) Helional and (R)-3-(benzo[1.3ldioxol-5-yl)-2- methylpropanol from crystallized hemiacetal 87 g of diisopropyl ether were added to the 58.86 g (0.152 mol) of the crystallized hemiacetal obtained from example 34 then, following the procedure reported in example 22, treated with a freshly prepared solution of 21.67 g (0.114 mol) of Na 2 S 2 O 5 in 33 g of H 2 O. 39.29 g (0.127 mol) of the (R) alcohol (concentration = 62.8% w/w and e.e = 98.4%) and 29.88 g (0.139 mol) of (S) Helional (concentration = 89.8% w/w and e.e = 90.8%) were obtained. Example 36

Second cycle: recovery of (R) Helional and (R)-3-(benzo[1 ,3ldioxol-5-yl)-2- methylpropanol from the hemiacetal crystallization mother liquors By following the procedure reported in example 23, the crystallization mother liquors of example 34 were treated with a freshly prepared solution of 34.36 g (0.181 mol) of Na 2 S 2 O 5 in 53.5 g of H 2 O. 35.69 g (0.033 mol) of the (R) alcohol (concentration = 18.0% w/w and e.e = 78.0%) and 44.96 g (0.201 mol) of ( R) Helional (concentration = 85.9% w/w and e.e = 57.5%) were obtained. Example 37 Purification of (S) Helional obtained from the crystallized hemiacetal

70 g of diisopropyl ether were added to a mixture of 107.5 g (0.505 mol) of the (S) Helional (concentration 90.4%, e.e. = 88.9%) obtained by combining the products derived from the crystallized hemiacetal of examples 32 and 35 and from the crystallized hemiacetal of two successive resolution cycles conducted as in examples 34 to 36, followed by cooling to 0 0 C under stirring at 150 rpm. Proceeding with the crystallization as in example 28, and adding 120 g of diisopropyl ether to the mixture, 37.3 g (0.165 mol) of oil (Helional concentration = 97.1% a/a; e.e. = 59% (S)) were obtained from the concentrated mother liquors. 67.4 g (0.340 mol) of oil (Helional concentration = 97.1 %; e.e. = 97.2% (S)) were obtained from the crystallized product whose mass and 1 H NMR spectra were found to conform to the expected structure. M.p. = 17-19 "C

[α] D 20 = -2.8 [c = 1.0 in CHCI 3 ] [lit: D. Enders, M. Backes; Tetrahedron: Asymmetry, 2004, 15, 1813-1817, [α] D 24 = -2.8 (c = 1.0 in CHCI 3 )] IR (neat) 2898, 2610, 1724, 1606, 1490, 1443, 1247, 1190, 1039, 931 , 813 cm "1 Example 38 Purification of (R )Helional obtained from mother liquors First crystallization: 290.5 g (1.34 mol) of (R) Helional (concentration 88.8%, e.e. = 51.2%) were obtained by mixing the Helional recovered from the hemiacetal crystallization mother liquors of examples 33 to 36, and the Helional recovered from the mother liquors of two successive resolution cycles conducted as in examples 34 and 36 and also the Helional from the crystallization mother liquors of example 28. 100 g of diisopropyl ether were added to this mixture which was then placed under stirring. The solution was seeded at -5 0 C and the crystallization was conducted as in example 15, adding to the mixture a further 80 g of diisopropyl ether. From the mother liquors concentrated under reduced pressure 168.8 g (0.745 mol) of oil (Helional concentration = 93.7% a/a; e.e. = 23,6% (R)) were obtained. From the crystallized product, 115.2 g (0.595 mol) of oil (Helional concentration = 99.4%; e.e. = 88.4% (R)) were obtained.

Second crystallization: 100 g of diisopropyl ether were added to 115.2 g (0.595 mol) of the (R) Helional (concentration 99.4%, e.e. = 88.4%) obtained from the previous crystallization, and placed under stirring. By conducting the crystallization as given in example 29 and adding 30 g + 30 g of diisopropyl ether, 29.7 g (0.154 mol) of oil (Helional concentration = 99.5% a/a; e.e. = 61.8% (R)) were obtained from the mother liquors concentrated under reduced pressure. From the crystallized product 86.4 g (0.438 mol) of oil (Helional concentration = 98.6%; e.e. = 96.8% (R)) were obtained, whose mass, IR and 1 H NMR spectra were found to conform to the expected structure. M.p. = 16-18 0 C

[α] D 20 = +3.9 [c = 1.0 in CHCI 3 ] [lit: D. Enders, M. Backes; Tetrahedron: Asymmetry, 2004, 15, 1813-1817, [α] D 24 = +3.3 (c = 1.0 in CHCI 3 )]