Enzymatic approach to enantiomerically pure 5-alken-2,4-diols and 4-hydroxy-5-alken-2-ones: Application to the synthesis of chiral synthons

Article abstract of DOI:10.1021/jo060581w

Enantiomerically pure 1,3-diols 1-3 were obtained by a chemoenzymatic approach (lipase PS from Burkholderia cepacia). These diols were converted into useful chiral synthons, which could be considered homologues of glyceraldehyde and glyceric acid acetonid

Full text of DOI:10.1021/jo060581w

Enzymatic Approach to Enantiomerically Pure 5-Alken-2,4-diols
and 4-Hydroxy-5-alken-2-ones: Application to the Synthesis of
Chiral Synthons
Agnese Abate, Elisabetta Brenna,* Alessia Costantini, Claudio Fuganti, Francesco G. Gatti,
Luciana Malpezzi, and Stefano Serra
Dipartimento di Chimica, Materiali ed Ingegneria Chimica del Politecnico, CNR - Istituto del
Riconoscimento Molecolare, Via Mancinelli 7, I-20131 Milano, Italy
elisabetta.brenna@polimi.it
ReceiVed March 16, 2006
Enantiomerically pure 1,3-diols 1-3 were obtained by a chemoenzymatic approach (lipase PS from
Burkholderia cepacia). These diols were converted into useful chiral synthons, which could be considered
homologues of glyceraldehyde and glyceric acid acetonides. Applications of these synthons to the de
novo synthesis of sugars and preparation of conagenin carboxylic moiety were shown. Hydroxy ketone
4 was chosen as a model system for another synthetic evolution: it was obtained in enantiomerically
pure form by enzymatic resolution and converted into chiral tetrahydropyranes, such as the stereoisomers
of the commercial fragrance Gyrane.
Introduction
We now report on the enzyme-mediated preparation of
enantiomerically enriched stereoisomers of diols 1-3, obtained
by reduction of the corresponding aldol derivatives 4-6. We
will show that diols 1-3 are useful chiral synthons: a carbonyl
functionality can be generated by ozonolysis of the double bond
to afford the protected chiral dihydroxy carbonyl derivatives
7-9. Interesting applications of these chirons to the de novo
synthesis of deoxy sugars and preparation of conagenin car-
boxylic moiety will be described.
We chose hydroxy ketone 4 as a model compound to show
another synthetic development: (R)-4, obtained in enantiopure
form by lipase-catalyzed resolution, can be employed to prepare
chiral tetrahydropyrane stereoisomers 10.
According to the annual survey on chiral chemistry published
in Chemical and Engineering News in 20041 the global sales
of single-enantiomer compounds are expected to reach $14.94
billion by the end of 2009, growing annually by 11.4%. By
2009, the share of the market realized through traditional
technology would drop to 41%, the share of chemocatalysis
would reach 36%, and the share of biocatalysis would reach
22%. Demand for enantiomerically pure chiral compounds is
progressively rising, primarily for use in pharmaceuticals but
also in three other sectors: flavor and fragrance chemicals,
agricultural chemicals, and specialty materials.
One strategy employed to speed up the process of “chiral
switch”, from both an economical and a chemical point of view,
is to optimize enantiomerically pure chiral synthons in order to
kill two birds with one stone. For example, C3 chirons showing
a stereocenter in position 2, such as protected glycerol, gly-
ceraldehydes, and glyceric acid derivatives, are well-known
versatile intermediates amenable for a variety of synthetic
transformations.
Results and Discussion
A. Lipase-Catalyzed Resolution of Diols 1-3. The 1,3-diol
moiety occurs frequently in natural compounds.2 The synthetic
(2) 1,3-Diols: (a) Rychnovsky, S. D. Chem. ReV. 1995, 95, 2021. (b)
Schneider, C. Angew. Chem., Int. Ed. Engl. 1998, 37, 1375. (c) Oishi, T.;
Nakata, T. Synthesis 1990, 635.
(1) Rouhi, A. M. Chem. Eng. News 2004, 82 (June 14), 47.
10.1021/jo060581w CCC: $33.50 © 2006 American Chemical Society
Published on Web 06/13/2006
5228
J. Org. Chem. 2006, 71, 5228-5240

Application to the Synthesis of Chiral Synthons
CHART 1
SCHEME 1a
SCHEME 2a
a Redrawn from ref 7.
strategies to syn- and anti-1,3-diols include the following: (a)
reduction of â-hydroxy ketones (diastereoselection can be
obtained by suitable choice of the reducing agent),3 (b)
Tishchenko reaction,4 and (c) stereoselective reduction of 1,3-
diketone.5 The latest developments in this field have been
summarized by Mu¨ller et al. in a recent review.6
Study of the enzyme-mediated transesterification of 1,3-diols
is a challenge in synthetic organic chemistry. While our work
was in progress an interesting paper by Ba¨ckwall appeared in
PNAS. Ba¨ckwall reported7 on the one-pot synthesis of enan-
tiomerically pure syn-1,3-diacetates from racemic syn/anti
mixtures of 1,3-diols by dynamic kinetic asymmetric transfor-
mation (Scheme 1). Lipase-mediated acetylation of unsym-
metrical 1,3-diols I, with a large and small group, combined
with a ruthenium epimerization catalyst would give a mixture
of R-monoacetates II and III.
a (i) Lipase PS, tert-butyl methyl ether, vinyl acetate; column chroma-
tography.
to give enantiomerically pure diacetate V. According to this
procedure several differently substituted unsymmetrical, acyclic
syn-1,3-diacetates were obtained in yields up to 73% (yields
determined by GC or HPLC) with excellent enantioselectivities
(>99%) and good diastereomeric ratios (>90% syn).
We prepared diols 1-3 by NaBH4 reduction of the corre-
sponding hydroxy ketones 4-6, prepared by classical aldol
condensation. Interestingly enough, high regioselectivity (95%)
was obtained in the reaction of cinnamaldehyde with methyl
ethyl ketone using 10% NaOH in methanol solution.
We performed a preliminary investigation of the lipase PS-
mediated acetylation of the 1:1 syn/anti mixture of diol 1 in
tert-butyl methyl ether in the presence of vinyl acetate (Scheme
2). By assuming that lipase PS promotes the acetylation of
stereogenic centers of well-defined configuration, the syn
diastereoisomer was expected to give a diacetate and diol of
opposite configuration while the anti diastereoisomer should give
two regioisomeric monoacetates of opposite configuration.
After 7 days the following products could be isolated (Scheme
2): (2R,4R)-syn-11 (de > 99%, ee ) 96% of the corresponding
diol), (2S,4S)-syn-1 (de > 99%, ee ) 97%), anti-12 (impure,
7% of syn-12 and 10% of syn-13), anti-13 (impure, 10% of
syn-13). Neither diacetate anti-11 nor diol anti-1 could be
isolated. The absolute stereochemistry of syn-11 and syn-1 was
tentatively assigned on the basis of a known preference of lipase
PS for (R) stereocenters. The two regioisomeric anti monoac-
etates could not be isolated as pure compounds; thus, no
conclusion could be drawn on their optical purity and absolute
configuration. We chose lipase PS as a catalyst because we had
experienced its efficiency in the transesterification of allylic
alcohols.8a,b
According to Ba¨ckwall, monoacetate II can undergo fast syn-
acyl migration to give IV, whereas the corresponding anti-acyl
migration from III is slow. Because of the ruthenium-catalyzed
epimerization of III to II, almost all of the monoacetate will
be converted into IV via the syn-acyl transfer. The released
R-alcohol in IV will finally undergo fast enzymatic acylation
(3) Syn-reduction, see for example: (a) Narasaka, K.; Pai, F. C.
Tetrahedron 1984, 40, 2233. (b) Kathawala, F. G.; Prager, B.; Prasad, K.;
Repic, O.; Shapiro, M. S.; Stabler, R. S.; Widler, L. HelV. Chim. Acta 1986,
69, 803. (c) Hoveyda, A. H.; Evans, D. A. J. Org. Chem. 1990, 55, 5190.
Anti-reduction, see for example: (a) Umekawa, Y.; Sakaguchi, S.; Nish-
iyama, Y.; Ishii, Y. J. Org. Chem. 1997, 62, 3409. (b) Hoveyda, A. H.;
Evans, D. A. J. Am. Chem. Soc. 1990, 112, 6447. (c) Anwar, S.; Davis, A.
P. Tetrahedron 1988, 44, 3761.
(4) (a) Bodnar, P. M.; Shaw, J. T.; Woerpel, K. A. J. Org. Chem. 1997,
62, 5674. (b) Umekawa, Y.; Sakaguchi, S.; Nishiyama, Y.; Ishii, Y. J. Org.
Chem. 1997, 62, 3409. (c) Marwald, R.; Cortisella, B. Synthesis 1996, 1087.
(d) Evans, D. A.; Hoveyda, H. A. J. Am. Chem. Soc. 1990, 112, 6447.
(5) Reduction of diketones. By catalytic hydrogenation: (a) Chan, A. S.
C. Tetrahedron: Asymmetry 1997, 8, 4041. (b) Brunner, H.; Terfort, A.
Tetrahedron: Asymmetry 1995, 6, 919. By enzymatic methods: (c) Ikeda,
H.; Sato, E.; Sugai, T.; Ohta, H. Tetrahedron 1996, 52, 8113. (d) Takeshita,
M.; Miura, M.; Unuma, Y. J. Chem. Soc., Perkin Trans. 1 1993, 2901. (e)
Chenevert, R.; Thiboutot, S. Can. J. Chem. 1986, 64, 1599. With metallic
hydrides: for example, see: (f) Bonini, C.; Righi, G.; Rossi, L. Tetrahedron
1992, 48, 9801. (g) Barluenga, J.; Resa, J.; Olano, B. J. Org. Chem. 1987,
52, 1425. (h) Yamada, F.; Horie, T.; Kawai, M.; Yamamura, H. Araki, S.
Tetrahedron 1997, 53, 15685. (i) Bartoli, G.; Bosco, M.; Bellocci, M. C.;
Dal pozzo, R.; Marcantoni, E.; Sambri, L. Org. Lett. 2000, 2, 45-47.
(6) Bode, S. E.; Wolberg, M.; Mu¨ller, M. Synthesis 2006, 557-588.
(7) Edin, M.; Steinreiber, J.; Ba¨ckwall, J. E. Proc. Natl. Acad. Sci. U.S.A.
2004, 101, 5761-5766.
We then decided to exploit the lipase PS acetylation of the
parent hydroxy ketone 4, which we had already experimented8c,d
within a work devoted to the chemistry of fragrances. The data
(8) (a) Brenna, E.; Fuganti, C.; Fronza, G.; Malpezzi, L.; Righetti, A.;
Serra, S. HelV. Chim. Acta 1999, 82, 2246-2259. (b) Brenna, E.; Fuganti,
C.; Grasselli, P.; Serra, S. Eur. J. Org. Chem. 2001, 1349-1357. (c) Abate
A.; Brenna, E.; Fuganti, C.; Serra, S. FlaVour Fragrance J. 2004, 19, 382-
393. (d) Abate, A.; Brenna, E.; Fronza, G.; Fuganti, C.; Gatti, F. G.; Serra,
S. Zardoni, E. HelV. Chim. Acta 2004, 87, 765-780.
J. Org. Chem, Vol. 71, No. 14, 2006 5229

Abate et al.
SCHEME 3a
SCHEME 4a
a (i) Lipase PS, tert-butyl methyl ether, vinyl acetate; column chroma-
tography.
a (i) Lipase PS, tert-butyl methyl ether, vinyl acetate; column chroma-
tography.
SCHEME 5a
of the transesterification was also confirmed by the work of
Joly and Nair.9 These authors determined the enantiomeric purity
by HPLC analysis and assigned the absolute stereochemistry
to hydroxy ketone 4 by means of chemical correlation.9 Lipase
PS transesterification of hydroxy ketone 4 was rather slow but
afforded the corresponding acetate derivative (R)-14 with high
enantiomeric excess (ee > 96%) (Scheme 3).
a (i) CBr4, PPh3, CH2Cl2. (ii) Redal in Toluene. (iii) O3, CH2Cl2/MeOH
2/1, then PPh3.
Reduction and saponification of (R)-14 gave a 1:1 mixture
of the two diastereoisomeric diols (2R,4R)-syn-1 and (2S,4R)-
anti-1, which was submitted to lipase PS-mediated acetylation
in tert-butyl methyl ether, in the presence of vinyl acetate
(Scheme 3). After 7 days we could recover the syn stereoisomer
as a diacetate, (2R,4R)-syn-11 (de > 99%, ee ) 96% of the
corresponding diol), and the anti stereoisomer as a monoacetate,
(3R,5S)-anti-11 (de > 99%, ee ) 96% of the corresponding
diol). (The numbering seems to be deceptive but it is that
obtained by applying IUPAC rules of nomenclature.) No
unreacted diol was recovered. We could not discriminate
whether formation of the syn diacetate did or did not involve
an intermediate acyl migration. Anyway, the result was a
complete diastereoselectivity in the formation of (2R,4R)-syn-
11. As for the anti stereoisomer, no anti diacetate could be found,
only trace amounts of monoacetate (2S,4R)-anti-13, probably
generated by an acyl migration of (3R,5S)-anti-12. The con-
figuration of 4 was known,9 and the relative configuration of
diols 1 was established by comparison with the proton spectra
of the same diols reported in the literature10 and confirmed by
the 1H NMR spectra of the corresponding acetonides (see
Experimental Section).
A great preference for the acetylation of R stereogenic centers
was confirmed. We could verify that if the anti diol was not
epimerized, it did not interfere in the acetylation of the syn
diastereoisomer and both of them could be recovered as single
enantiomers with de > 99%.
According to our approach, starting from (R)-4 it is possible
to recover enantiomerically pure (2R,4R)-syn- and (2S,4R)-anti-1
as single diastereoisomers, while both enantiomers of syn-1 can
be obtained using a racemic mixture of syn- and anti-1 as a
substrate for lipase-catalyzed acetylation.
the corresponding diol) and diol (2S,4S)-syn-2 (ee > 99% by
HPLC) (Scheme 4).
Biocatalyzed acetylation of (()-anti-2 afforded, after a 7 day
reaction time, two regioisomeric monoacetates, (2R,4S)-anti-
16 and (3R,5S)-anti-17, which could be separated by column
chromatography. When (2R,4S)-anti-16 and (3R,5S)-anti-17
were hydrolyzed, two enantiomeric diols were obtained, show-
ing, respectively [R]D ) -32.8 (c ) 0.86, CHCl3) and +30.6
(c ) 0.96, CHCl3).
The relative configuration of the derivatives of this series
was assigned on the basis of the 1H NMR spectra of the
corresponding acetonides (see Experimental Section) by com-
parison with those derived from syn- and anti-1.
The absolute configuration of the anti monoacetates and their
enantiomeric purity were established by chemical correlation
according to the sequence reported in Scheme 5. (3R,5S)-anti-
17 was treated with CBr4 and PPh3 in CH2Cl2. The crude
reaction product 18 was reduced to alcohol (-)-19 by reaction
with Redal in toluene solution. Alcohol (-)-19 was converted
into hydroxy ketone (R)-(-)-2011 (optical purity ) 92%) by
treatment with ozone followed by PPh3 quenching.
The absolute stereochemistry of syn diacetate and unreacted
syn diol was tentatively assigned by analogy. All four stereo-
isomers of diol 2 were obtained in enantiomerically pure form.
As for diol 3, we had in our hands a hydroxy ketone precursor
6 which was obtained as a 1:2 mixture of syn and anti
stereoisomers by aldol condensation of cinnamaldehyde and
ethyl methyl ketone. Less than 5% (NMR) of the regioisomer
5-hydroxy-7-phenylhept-6-en-3-one was detected. Reduction and
column chromatography afforded the following products: (a)
a 1:1 mixture of (()-syn,syn-3 and (()-syn,anti-3; (b) (()-anti,-
syn-3 (de > 99%); (c) (()-anti,anti-3 (de > 99%). The relative
configuration of anti,anti-3 was established by X-ray diffraction.
Diol (()-anti,anti-3 was submitted to lipase PS acetylation
(Scheme 6) in the usual conditions to afford diacetate (2R,3R,4S)-
As for diol 2, the two racemic diastereoisomers could be
separated by column chromatography, and they were submitted
separately to lipase PS transesterification. After 7 days (()-
syn-2 gave diacetate (2R,4R)-syn-15 (ee > 99%, by HPLC of
(9) Joly, S.; Nair, M. S. J. Mol. Catal. B: Enzym. 2003, 22, 151.
(10) For anti-1: Keck, G. E.; Wager, C. A.; Sell, T.; Wager, T. T. J.
Org. Chem. 1999, 64, 2172-2173. For syn- and anti-1: Aprile, C.;
Gruttadauria, M.; Lo Meo, P.; Noto, R. Heterocycles 2001, 57, 293-305.
(11) Schro¨der, F.; Fettko¨ther, R.; Noldt, U.; Dettner, K.; Ko¨nig, W. A.;
Franche, W. Liebigs Ann. Chem. 1994, 1211-1218.
5230 J. Org. Chem., Vol. 71, No. 14, 2006

Application to the Synthesis of Chiral Synthons
SCHEME 6a
(O1-H1O ‚‚‚O2-C4-C3-C2) showing a distorted chair
conformation.
B. Glyceraldehyde Homologues. Once having reached the
stereochemical control on the 1,3-diol stereocenters, we submit-
ted the double bond to oxidative cleavage to create the
carbonylic function as anticipated in Chart 1. A recent report
by Trost et al.12 presenting S,O-acetals as novel “chiral
aldehyde” equivalents showed the importance of gaining access
to chiral functionalized carbonyl derivatives.
Enantiomerically pure diols (2R,4R)-syn-1, (2S,4R)-anti-1,
(2R,4R)-syn-2, (2R,4S)-anti-2, (2S,3S,4R)-anti,anti-3, and
(2R,3S,4R)-anti,syn-3 were treated with dimethoxypropane in
acetone in the presence of a catalytic amount of pyridinium
p-toluenesulfonate to afford the corresponding acetonides (Chart
2).
The acetonides 25-27 were treated with ozone in methylene
chloride/methanol 2:1 solution followed by PPh3 quenching.
Column chromatography allowed us to isolate carbonyl deriva-
tives 7-9 (Chart 3). Ozonization of (4S,6R)-anti-25 was rather
troublesome. We performed it in methylene chloride/methanol
2/1 solution and quenched it with either PPh3 or (CH3)2S. We
obtained invariably the same result: when the temperature of
the ozonolysis mixture was allowed to rise to room temperature
aldehyde anti-7 gave a rearrangement to the methyl deoxy
glycoside 28 with loss of the acetonide protection.
Carbonyl compounds 7-9 can be considered homologues of
glyceraldehyde acetonides 29 and of protected aldehydes 30,13
representing a complete series from C3 to C6 chirons with fixed
configuration of the stereogenic centers (Chart 3).
C. De Novo Synthesis of Deoxy Sugars. The rapid develop-
ment of glycobiology and carbohydrate-based pharmaceuticals
has prompted research in the field of natural and nonnatural
carbohydrate synthesis.14 The approach based on the de novo
synthesis of carbohydrates is of great relevance.15
Recently, synthetic sequences based on aldol condensation
have been reported. MacMillan et al.16 disclosed a ‘two-step’
synthesis of aldohexoses consisting of a proline-catalyzed aldol
reaction between R-oxygenated aldehydes followed by a Mu-
kaiyama-aldol reaction to generate the carbohydrate. Cordova
et al.17 and Enders et al.18 proposed their own independent routes
based on the proline-catalyzed aldol reaction of suitable
dihydroxyacetone derivatives with several aldehydes.
Another recent approach is based on dihydroxylation of
double bonds. Galacto sugars and deoxy sugars have been
obtained via iterative dihydroxylation of dienoates.19 Racemic
mono- and dihydroxylated furanoses, pyranoses, and oxepanose
a (i) Lipase PS, tert-butyl methyl ether, vinyl acetate; column chroma-
tography.
anti,anti-21 (ee ) 97%, HPLC of the corresponding diol) and
(2S,3S,4R)-anti,anti-3 (ee ) 97%, HPLC).
Lipase PS treatment of diol (()-anti,syn-3 led to isolate the
following products by column chromatography: monoacetate
(2R,3R,4R)-anti,syn-22 (ee ) 95%, HPLC of the corresponding
diol) and (2S,3R,4S)-anti,syn-3 (ee ) 96%, HPLC). A tiny
amount (3%) of regioisomeric monoacetate anti,syn-23, which
was found to be racemic by HPLC of the corresponding diol,
was obtained, probably by acyl migration. The relative config-
uration of (2R,3R,4R)-anti,syn-22 was established by X-ray
diffraction analysis.
When the 1:1 mixture of (()-syn,syn-3 and (()-syn,anti-3
was submitted to enzyme-mediated transesterification, it was
possible to obtain a 1:1 mixture of monoacetates syn,syn-22 and
syn,anti-22 and 1:1 mixture of regioisomers syn,syn-23 and syn,-
anti-23 by column chromatography. Formation of both regio-
isomeric monoacetates of syn,anti-3 was probably due to acetyl
shift.
We also experimented a strategy starting from resolution of
hydroxy ketone 4. The 2:1 mixture of hydroxy ketones anti-
and syn-6 was treated with lipase PS in the usual conditions.
After 7 days column chromatography afforded as the first eluted
fraction a 4:1 mixture of (3S,4S)-anti-24 and (3S,4R)-syn-24.
From this mixture acetoxy ketone (3S,4S)-anti-24 separated as
a white solid by treatment with hexane. The relative configu-
ration of anti-24 was established by X-ray diffraction analysis,
and the absolute stereochemistry was assigned by analogy. Upon
NaBH4 reduction and saponification compound (3S,4S)-anti-
24 afforded a 1:1 mixture of (2R,3R,4S)-syn,syn-3 and (2R,3R,4S)-
syn,syn-3, which could be separated by column chromatography.
Our chemoenzymatic approach allowed us to prepare both
enantiomers of diols anti,anti-3 and diol anti,syn-3 and selec-
tively obtain their (4S)-stereoisomers by lipase-mediated acetyl-
ation of the corresponding hydroxy ketone.
(12) Trost, B. M.; Crawley, M. L.; Lee, C. B. Chem. Eur. J. 2006, 12,
2171-2187.
(13) Servi, S. J. Org. Chem. 1985, 50, 5865.
(14) In Glycochemistry: Principles, Synthesis, and Applications; Wang,
P., Bertozzi, C., Eds.; Marcel Dekker: New York, 2001.
(15) (a) Ogawa, T. Chem. Soc. ReV. 1994, 23, 397-407. (b) Danishefsky,
S. J.; Bilodeau, M. T. Angew. Chem., Int. Ed. 1996, 35, 1380-1520. (c)
Hanessian, S. PreparatiVe Carbohydrate Chemistry; Marcel Dekker: New
York, 1997. (d) Hudlicky, T.; Entwistle, D. A.; Pitzer, K. K.; Thorpe, A. J.
Chem. ReV.1996, 96, 1195-1220.
(16) (a) Northrup, A. B.; Mangion, I. K.; Hettche, F.; MacMillan, D.
W. C. Angew. Chem., Int. Ed. 2004, 43, 2152-2154. (b) Northrup, A. B.;
MacMillan, D. W. C. Science 2004, 305, 1752-1755.
(17) Casas, J.; Engqvist, M.; Ibrahem, I.; Kaynak, B.; Cordova, A. Angew.
Chem., Int. Ed. 2005, 44, 1343-1345. Ibrahem, I.; Zou, W.; Xu, Y.;
Cordova A. AdV. Synth. Catal. 2006, 348, 211-222.
(18) Enders, D.; Grondal, C. Angew. Chem. Int. Ed. 2005, 44, 1210-
1212. Grondal, C.; Enders, D. Tetrahedron 2006, 62, 329-337.
(19) Ahmed, M. M.; Berry, B. P.; Hunter, T. J.; Tomcik, D. J.;
O’Doherty, G. A. Org. Lett. 2005, 7, 745-748.
The X-ray structures of (()-anti,anti-3 (A), (2R,3R,4R)-anti,-
syn-22 (B), and (3S,4S)-anti-24 (C) are reported in Figure 1.
The configurations of the stereogenic centers are well defined
by the torsion angles reported in Table 1, while some aspects
of molecular geometries are illustrated by the dihedral angles
reported in Table 2.
The crystal structure of (()-anti,anti-3 reveals the presence
of an intramolecular hydrogen bonding between the two OH
groups (O1‚‚‚O2 ) 2.592(6) Å, H1O‚‚‚O2 ) 1.87(4) Å, O1-
H1O‚‚‚O2 ) 146.(2)°) that yields a six-membered pseudo ring
J. Org. Chem, Vol. 71, No. 14, 2006 5231

Abate et al.
FIGURE 1. X-ray structures of anti,anti-3 (A), anti,syn-22 (B), and anti-24 (C).
TABLE 1. Selected Torsion Angles
CHART 2
torsion angles (deg)
anti,anti-3
anti,syn-22
anti-24
O1-C2-C3-C13
C1-C2-C3-C13
C13-C3-C4-O2
C13-C3-C4-C5
C1-C2-C3-C4
C2-C3-C4-C5
C3-C4-C5-C6
C4-C5-C6-C7
175.9(4)
49.2(6)
54.9(4)
-64.9(4)
-56.4(3)
57.1(3)
104.1(4)
-73.9(5)
174.5(3)
-65.0(4)
50.4(5)
171.4(3)
121.3(3)
-177.6(3)
-174.6(4)
-51.3(5)
177.6(4)
179.6(4)
111.5(5)
-177.0(4)
170.3(3)
-176.5(3)
-115.8(4)
-176.1(3)
TABLE 2. Dihedral Angles (deg) between Least-Squares Planes
plane-plane
anti,anti-3
anti,syn-22
anti-24
Π(C4/C7)-Π(C6/C12)
Π(C1/C5)-Π(C4/C7)
Π(C1/C5)-Π(C6/C12)
4.9
69.2
64.3
6.6
60.2
54.3
8.9
38.6
29.9
to be eventually employed in the preparation of natural product
analogue libraries have been recently prepared involving dihy-
droxylation as a key step.20
CHART 3
Our synthetic approach led to the preparation of single
enantiomers of carbonyl derivatives 7-9 which are themselves
deoxy sugars, namely 7 and 9 are protected dideoxyaldopentoses
and 8 are protected trideoxyketohexoses. Furthermore, to show
the synthetic potentiality of these compounds as chiral synthons,
we prepared a trideoxyaldohexose and dideoxyaldohexose
starting from (4R,6R)-syn-7.
(4R,6R)-syn-7 was reduced with NaBH4 to give alcohol
(4R,6R)-syn-31 (Scheme 8), which was converted into nitrile
(4R,6R)-syn-32 via tosylate and cyanide displacement.
The nitrile moiety was reduced with diisobutylaluminum
hydride at -10 °C, and aldehyde (4R,6R)-syn-33 was recovered
at the end of the sequence. This aldehyde had been used as an
intermediate in the synthesis of (-)-endo-dimethyl-1,3-dioxa-
2,9-bicyclo[3.3.1]nonane,21 a biologically active substance
(20) Yu, X. M.; Han, H.; Blagg, B. S. J. J. Org. Chem. 2005, 70, 5599-
5605.
(21) Masoni, C.; Deschenaux, P. F.; Kallimopoulos, T.; Jacot-Guillarmod,
A. HelV. Chim. Acta 1989, 72, 1285.
5232 J. Org. Chem., Vol. 71, No. 14, 2006

Application to the Synthesis of Chiral Synthons
SCHEME 7a
SCHEME 9a
a (i) Lipase PS, tert-butyl methyl ether, vinyl acetate; column chroma-
tography. (ii) NaBH4, CH2Cl2/MeOH 2/1. (iii) KOH, MeOH. (iv) Column
chromatography.
a (i) Vinyl magnesium bromide in THF. (ii) O3, CH2Cl2-MeOH, then
DMS; MeOH, HCl Cat.; Ac2O in pyridine. (iii) Column chromatography.
(iv) MeONa cat. in MeOH.
SCHEME 8a
polar fraction contained 4,6-dideoxy-R-D,L-arabinohexopirano-
side and methyl 4,6-dideoxy-â-D,L-ribohexopiranoside. In the
more polar fraction we could detect signals of 4,6-dideoxy-â-
D,L-arabinohexopiranoside,26 the NMR spectrum of which has
not been reported.
D. Synthesis of the Carboxylic Fragment of Conagenin.
We envisaged the possibility of employing syn,syn-3 to obtain
the carboxylic fragment of natural (+)-conagenin (40). (+)-
Conagenin was originally isolated from fermentation broths of
Streptomyces roseosporus.27 It was found to stimulate activated
T cells by producing lymphokines as a low molecular weight
immunomodulator.28 Improvement of the efficacy of antitumor
agents, such as mitomycin C and adriamycin, by (+)-conagenin
was also reported.29 A few syntheses of (+)-conagenin have
appeared in the literature.30
As we have previously shown, isolation of (2R,3S,4S)-syn,-
syn-3 was rather troublesome; thus, we focused our attention
on a synthetic analogue of diol syn,syn-3, the furane-substituted
diol 41. It is well known that the furane ring can be cleaved by
ozonolysis to give a carboxylic moiety (Scheme 10).
Aldol condensation of furfural with ethyl methyl ketone gave
a 2:1 mixture of anti- and syn-42 with high regioselectivity
(>95%). The mixture of four stereoisomers of diol 41, obtained
upon NaBH4 reduction, was treated with lipase PS in the usual
conditions to afford a mixture of the four stereoisomers of
monoacetate 43 and the unreacted diol 41. The monoacetate
a (i) NaBH4 in CH2Cl2-MeOH. (ii) p-Toluensulfonyl chloride in
pyridine; NaCN in DMSO. (iii) DIBAl, toluene. (iv) THF-H2O, AcOH,
HCl conc. cat.
isolated from Norway spruce infested by Trypodendron lineatum
Oliv.,22 and (-)-tarchonanthuslactone,23 a natural product
isolated from a compositae, Tarchonanthus trilobus. In the first
case it was prepared starting from (R)-methyl 3-hydroxybu-
tanoate; in the second case chiral sulfoxides were employed to
obtain enantioselectivity. Our chemoenzymatic approach af-
forded both enantiomers of syn-33 in high ee and de.
Deprotection of (4R,6R)-33 with acetic acid in aqueous
tetrahydrofuran in the presence of a catalytic amount of
concentrated HCl afforded 2,4,6-trideoxy-D-erithrohexopyranose
(R,R-34). This kind of deoxy sugars can be prepared by aldol
reactions catalyzed by 2-deoxyribose-5-phosphate aldolase
(DERA).24 (R,R)-34, in particular, was obtained by tandem aldol
condensation of 3 mol of acetaldehyde catalyzed by DERA.
Our route to deoxy sugars through the key intermediate (R,R)-
syn-7 could be easily expanded. We also investigated the
possibility of introducing a new stereogenic center bearing a
hydroxylic group (Scheme 9).
We treated racemic syn-7 with vinylmagnesium bromide in
THF to obtain a mixture of the two possible diastereoisomers
35. Ozonolysis combined with DMS quenching, followed first
by treatment with methanol and catalytic HCl(g) and then with
acetic anhydride in pyridine, afforded a mixture (two spots by
TLC) of two pairs of acetylated methyl glycoside anomers.
Column chromatography allowed us to isolate from the first
eluted fractions a mixture of two acetylated methyl glycosides
36 and 37. These latter derivatives were deacetylated with
sodium methoxide in methanol to establish their configuration.
Analysis of NMR spectra25 allowed us to establish that the less
(25) (a) Kefurt, K.; Kefurtova, Z.; Jary, J. Collect. Czech. Chem.
Commun. 1975, 40, 164-173. (b) Monneret, C.; Florent, J.-C.; Gladieux,
N.; Khoung-Huu, Q. Carbohydr. Res. 1976, 50, 35-44. (c) Kefurt, K.;
Kefurtova, Z.; Jary, J. Collect. Czech. Chem. Commun. 1984, 49, 2130-
2140. (d) Hanessian, S.; Roy, R. Can. J. Chem. 1985, 63, 163. (e) Keck,
G. E.; Boden, E. P.; Wiley, M. R. J. Org. Chem. 1988, 54, 896-906. (f)
Bauer, T. Tetrahedron 1997, 53, 4763-4768.
(26) Banaszek, Z. Rocz. Chem. 1971, 45, 391-398.
(27) Yamashita, T.; Iijima, M.; Nakamura, H.; Isshiki, K.; Naganawa,
H.; Hattori, S.; Hamada, M.; Ishizuka, M.; Takeuchi, T.; Iitaka, Y. J.
Antibiot. 1991, 44, 557-559.
(28) Kawatsu, M.; Yamashita, T.; Osono, M.; Ishizuka, M.; Takeuchi,
T. J. Antibiot. 1993, 46, 1687-1691. Kawatsu, M.; Yamashita, T.; Osono,
M.; Masuda, T.; Ishizuka, M.; Takeuchi, T. J. Antibiot. 1993, 46, 1692-
1698. Kawatsu, M.; Yamashita, T.; Ishizuka, M.; Takeuchi, T. J. Antibiot.
1994, 47, 1123-1129.
(29) Kawatsu, M.; Yamashita, T.; Ishizuka, M.; Takeuchi, T. J. Antibiot.
1995, 48, 222-225.
(30) (a) Kovacs-Kulyassa, A.; Herczegh, P.; Sztaricskai, F. J. Tetrahedron
Lett. 1996, 37, 2499-2502. (b) Hatakeyama, S.; Fukuyama, H.; Mukugi,
Y.; Irie, H. Tetrahedron Lett. 1996, 37, 4047-4050. (c) Enders, D.; Bartsch,
M.; Runsink, J. Synthesis 1999, 243-248. (d) Sano, S.; Miwa, T.; Hayashi,
K.; Nozaki, K.; Ozaki, Y.; Nagao, Y. Tetrahedron Lett. 2001, 42, 4029-
4031. (e) Rodrigues, J. A. R.; Moran, P. J. S.; Milagre, C. D. F.; Ursini, C.
V. Tetrahedron Lett. 2004, 45, 3579-3582. (f) Matsukawa, Y.; Isobe, M.;
Kotsuki, H.; Ichikawa, Y. J. Org. Chem. 2005, 70, 5339-5341.
(22) Heemann, V.; Franche, W. Naturwissenschaften 1976, 63, 344.
(23) Solladie´, G.; Gressot-Kempf, L. Tetrahedron: Asymmetry 1996, 7,
2371.
(24) (a) Gijsen, H. J. M.; Wong, C. H. J. Am. Chem. Soc. 1994, 116,
8422. (b) Wong, C. H.; Garcia-Junceda, E.; Chen, L.; Blanco, O.; Gijsen,
H. J. M.; Steensma, D. H. J. Am. Chem. Soc. 1995, 117, 3333. (c) Gijsen,
H. J. M.; Wong, C. H. J. Am. Chem. Soc. 1995, 117, 7585.
J. Org. Chem, Vol. 71, No. 14, 2006 5233

Abate et al.
SCHEME 10a
SCHEME 12a
a (i) TosCl, pyridine; CH3CH2CH2MgBr, THF, Li2CuCl4. (ii) POCl3,
pyridine.
a (i) NaBH4, CH2Cl2/MeOH 2/1. (ii) Lipase PS, tert-butyl methyl ether,
vinyl acetate; column chromatography. (iii) CH3CHO, pyridium p-toluen-
sulfonate. (iv) O3, CH2Cl2/MeOH 2/1; NaBH4. (v) NaOH 10%; HCl 10%.
of adduct 49, which was treated with Hg(OAc)2 and NaBH4 to
give a 1:1 mixture of (2R,4R,6R)-cis-50 and (2R,4S,6R)-cis-
50, which could be separated by column chromatography. The
ring closure was unexpectedly highly stereoselective, and only
derivatives showing cis arrangement of the substituent at C2
and C6 were obtained. This high stereoselectivity can be
attributed to formation of a cyclic mercurinium ion intermediate
(Scheme 11), which undergoes ring opening by nucleophilic
attack in a chairlike transition state. This hypothesis is in
accordance with one of the mechanisms which have been
postulated to describe the oxymercuration of olefins.31 Diaster-
eoisomers (2R,4R,6R)-cis-50 and (2R,4S,6R)-cis-50 were acetyl-
ated to give cis-(2R,4R,6R)-cis-51 and (2R,4S,6R)-cis-51, re-
spectively.
SCHEME 11a
Ozonolysis of the latter acetylated compounds followed by
NaBH4 quenching afforded alcohols (2R,4R,6R)-cis-52 and
(2R,4S,6R)-cis-52.
From this step onward the synthetic sequence was to
experiment on the two racemic diastereoisomers of alcohol cis-
52 (Scheme 12). We wished to investigate the course of the
critical dehydration reaction (necessary to convert 47 into 48)
before starting the complete synthesis. The work devoted to
preparation of all the enantiomerically pure isomers of Gyrane
will be the subject of another publication.
a (i) CHdCHCH2MgCl, THF. (ii) Hg(OAc)2, NaBH4. (iii) AcONa, Ac2O.
(iv) O3, then NaBH4.
fraction was submitted to saponification and converted into the
corresponding acetaldehyde acetal 44. We found that column
chromatography of the mixture of the four acetals allowed the
isolation of (4R,5S,6R)-44 as a pure compound. This latter was
submitted to ozonolysis: the reaction mixture was treated with
NaBH4 and hydrolyzed with NaOH solution. We decided to
not isolate the carboxylic acid 45 but to convert it into lactone
(3R,4R,5R)-46 by treatment with HCl 10% at room temperature
for 1 h and extraction. The absolute stereochemistry of lactone
46, precursor of the carboxylic moiety of conagenin, was
known.30e
E. Synthesis of Substituted Tetrahydropyranes. We envis-
aged the possibility of employing hydroxy ketones 4-6 as
precursors in the synthesis of substituted chiral tetrahydropyr-
anes, as shown in Chart 1.
In particular, we were interested in the stereoisomers of
compound 47, potential precursors of Gyrane (48); so (R)-
hydroxybutanone 4 was chosen as a model compound. Gyrane
is a commercial fragrance showing radiant green floral and
spicy geranium notes, which is formally a mixture of three
regioisomers of two possible diastereoisomers (Scheme 11).
Addition of allylmagnesium chloride to hydroxy butanone
(R)-4 gave a 1:1 mixture of the two possible diastereoisomers
Schlosser reaction performed on the two racemic diastereo-
isomers of compound cis-52 afforded the two cis stereoisomers
of 47. Compounds cis-47a and cis-47b were dehydrated with
POCl3 in pyridine to afford, respectively, a 3:3:1 mixture of
the three regioisomers 48a, 48b, and 48c and a 1:1:3.5 mixture
of 48a, 48b, and 48c. The configuration of the carbon atom in
position 4 was tentatively attributed on the basis of these
considerations. POCl3 dehydration is known to occur via a
phosphoric ester which undergoes an anti elimination promoted
by pyridine. When the OH group is axial, endo products are
favored: their formation occurs via anti elimination of the axial
hydrogens at C3 and C5. When the OH is equatorial, a hydrogen
of the methyl group can meet the steric requirement for anti
elimination so that the exo product is favored. The configuration
of the C(4) in cis-47a and cis-47b was thus assigned on the
basis of the outcome of the dehydration process.
(31) Pasto, D. J.; Gontarz, J. A. J. Am. Chem. Soc. 1971, 93, 6902-
6908. Kozikowski, A. P.; Lee, J. J. Org. Chem. 1990, 55, 863-870.
5234 J. Org. Chem., Vol. 71, No. 14, 2006

Application to the Synthesis of Chiral Synthons
1H, J ) 15.9, 6.1 Hz), 4.76 (dq, 1H, J ) 1.2, 6.1 Hz), 2.76 (d, 2H,
J ) 6.1 Hz), 2.22 (s, 3H); 13C NMR9 (62.90 MHz, CDCl3) δ 208.7,
136.4, 130.3, 128.4, 127.7, 127.3, 126.4, 68.3, 49.4, 30.8. Anal.
Calcd for C12H14O2: C, 75.76; H, 7.42. Found: C, 75.65; H, 7.53.
We submitted the two mixtures of Gyrane isomers to a
preliminary evaluation (Givaudan perfumers) with the following
results.
Mixture A (48a/48b/48c 3/3/1): Green, fruity, metallic
vegetable note with the grapefruit-onion-like bitterness of
Oxane and the herbal aspects of Buccoxime, stronger than
mixture B both in top and dry down. Dry down linear, same
just weaker but still stronger than Mixture B.
Mixture B (48a/48b/48c 1/1/3.5): Green, fruity, metallic
vegetable note with the grapefruit-onion-like bitterness of
Oxane and the herbal aspects of Buccoxime, very similar to
mixture A but weaker in top and dry down. Dry down linear,
green, metallic.
The preliminary results on odor evaluations are encouraging;
the mixture enriched in the endo isomers seems to be more
potent than that containing mainly the exo derivative. We plan
to perform the synthesis of all single stereoisomers of Gyrane.
(2R,4R,5E)-6-Phenylhex-5-ene-2,4-diyl Diacetate ((2R,4R)-syn-
11), (2S,4R,5E)-4-Hydroxy-6-phenylhex-5-en-2-yl Acetate ((2S,4R)-
anti-13), and (3R,5S,1E)-5-Hydroxy-1-phenylhex-1-en-3-yl Ac-
etate ((3R,5S)-anti-12). The 1:1 mixture of the two (2RS,4R)-1
diastereoisomers (13.5 g, 0.070 mol) was treated with lipase PS
(10 g) in tert-butylmethyl ether solution (250 mL) in the presence
of vinyl acetate (25 mL). After 7 days the reaction mixture was
filtered and separated by column chromatography on silica gel
(hexane/ethyl acetate 9/1) to give, according to the elution order,
(2R,4R)-syn-11 (7.70 g, 40%), (2S,4R)-anti-13 (0.98 g, 6%), and
(3R,5S)-anti-12 (5.10 g, 31%).
1
Data of (2R,4R)-syn-11: [R]D ) +68.5 (c ) 1.62, CHCl3); H
NMR (250 MHz, CDCl3) δ 7.40-7.20 (m, 5H), 6.70 (d, 1H, J )
15.9 Hz), 6.10 (dd, 1H, J ) 15.9, 7.3 Hz), 5.48 (q, 1H, J ) 7.3
Hz), 4.98 (m, 1H), 2.20-2.00 (m + 2s at 2.08 and 2.02, 7H), 1.85
(m, 1H), 1.28 (d, 3H, J ) 6.2 Hz); 13C NMR (62.90 MHz, CDCl3)
170.4, 170.2, 136.2, 132.9, 128.6, 128.1, 126.9, 126.6; 71.8, 67.8,
40.6, 21.3, 20.2; GC/MS tR 22.59 min, m/z 233 (M+ - 43, 3), 216
(8), 174 (72), 156 (40), 145 (66), 131 (100). Anal. Calcd for
C16H20O4: C, 69.55; H, 7.30. Found: C, 69.62; H, 7.21.
Conclusions
Lipase PS-mediated acetylation of 5-alken-2,4-diols 1-3 is
a satisfactory approach to obtain these compounds in enantio-
merically pure form. High stereochemical control on the
configuration of the stereogenic centers can be achieved. The
double bond can be cleaved by reaction with ozone to generate
a useful carbonyl functionality and finally afford the enantio-
merically pure chiral synthons 7-9. The synthetic versatility
of these derivatives has been shown by employing them as key
intermediates in a new de novo approach to deoxy sugars.
Combination of lipase-mediated acetylation and ozonolysis has
been employed to obtain lactone 46, precursor of the carboxylic
moiety of conagenin.
Nucleophilic addition to the carbonyl group of hydroxy ketone
4, followed by oxymercuration and double bond cleavage,
represents a new path to chiral cis-tetrahydropyranes. Many
chiral fragrances, not yet evaluated as single enantiomers, belong
to this structural class, and this method can be easily extended
to prepare them.
1
Data of (2S,4R)-anti-13 containing 25% of (3R,5S)-anti-12: H
NMR (250 MHz, CDCl3) δ 7.40-7.20 (m, 5H), 6.65 (dd, 1H, J )
15.9, 1.0 Hz), 6.25 (dd, 1H, J ) 15.9, 6.1 Hz), 5.23 (m, 1H), 4.32
(m, 1H), 2.11 (s, 3H), 1.85 (m, 2H), 1.34 (d, 3H, J ) 6.3 Hz);
GC/MS tR 21.75 min, m/z 234 (M+, 1), 191 (5), 174 (64), 131
(60), 115 (60), 104 (100). Anal. Calcd for C14H18O3: C, 71.77; H,
7.74. Found: C, 71.65; H, 7.58.
1
Data of (3R,5S)-anti-12: [R]D ) +99.0 (c ) 2.27, CHCl3); H
NMR (250 MHz, CDCl3) δ 7.40-7.20 (m, 5H), 6.63 (d, 1H, J )
15.9 Hz), 6.18 (dd, 1H, J ) 15.9, 6.9 Hz), 5.67 (m, 1H), 3.81 (m,
1H), 2.13 (s, 3H), 1.78 (m, 2H), 1.23 (d, 3H, J ) 6.4 Hz); 13C
NMR (62.90 MHz, CDCl3) 171.4, 136.2, 132.2, 128.6, 128.1, 127.4,
126.6, 72.2, 63.7, 44.6, 23.2, 21.3; GC/MS tR 21.46 min, m/z 234
(M+, 3), 191 (62), 174 (65), 131 (100), 115 (60), 104 (60). Anal.
Calcd for C14H18O3: C, 71.77; H, 7.74. Found: C, 71.84; H, 7.82.
(2R,4R,5E)-6-Phenylhex-5-ene-2,4-diol ((2R,4R)-syn-1). Sa-
ponification of (2R,4R)-syn-11 (7.5 g, 0.027 mol) with KOH (2.34
g, 0.042 mol) in MeOH (150 mL) after the usual workup gave
(2R,4R)-syn-1 (4.41 g, 85%): mp 60-63 °C; [R]D ) +15.7 (c )
1.66, CHCl3); 1H NMR (250 MHz, CDCl3) δ 7.40-7.20 (m, 5H),
6.60 (d, 1H, J ) 15.9 Hz), 6.20 (dd, 1H, J ) 15.9, 6.5 Hz), 4.55
(q, 1H, J ) 6.5 Hz), 4.11 (m, 1H), 1.71 (m, 2H), 1.23 (d, 3H, J )
6.2 Hz); 13C NMR (62.90 MHz, CDCl3) 136.7, 132.0, 130.0, 128.6,
127.9, 126.5, 73.4, 68.4, 45.1, 24.1; GC/MS tR 20.59 min, m/z 192
(M+, 14), 174 (19), 133 (48), 115 (48), 104 (100). Anal. Calcd for
C12H16O2: C, 74.97; H, 8.39. Found: C, 74.82; H, 8.27.
(2S,4R,5E)-6-Phenylhex-5-ene-2,4-diol ((2S,4R)-anti-1). Sa-
ponification of (3R,5S)-anti-12 (5.0 g, 0.021 mol) with KOH (1.76
g, 0.031 mol) in MeOH (150 mL) after the usual workup gave
(2S,4R)-anti-1 (3.61 g, 88%): mp 50-52 °C, [R]D ) +40.5 (c )
1.13, CHCl3); 1H NMR (250 MHz, CDCl3) δ 7.50-7.20 (m, 5H),
6.65 (dd, 1H, J ) 15.9, 1.0 Hz), 6.30 (dd, 1H, J ) 15.9, 5.9 Hz),
4.66 (qd, 1H, J ) 5.9, 1.0 Hz), 4.21 (m, 1H), 1.81 (m, 2H), 1.27
(d, 3H, J ) 6.4 Hz); 13C NMR (62.90 MHz, CDCl3) 136.8, 132.0,
130.0, 128.6, 127.6, 126.5, 70.4, 65.4, 44.4, 23.7; GC/MS tR 20.56
min, m/z 192 (M+, 10), 174 (20), 129 (50), 115 (50), 104 (100).
Anal. Calcd for C12H16O2: C, 74.97; H, 8.39. Found: C, 75.06; H,
8.49.
Experimental Section
(S,E)-4-Hydroxy-6-phenylhex-5-en-2-one ((S)-4) and (R,E)-
5-Oxo-1-phenylhex-1-en-3-yl Acetate ((R)-14). Racemic 4 (60.0
g, 0.32 mol) was treated with lipase PS (20 g) in tert-butylmethyl
ether solution (500 mL) in the presence of vinyl acetate (50 mL).
After 7 days the reaction mixture was filtered and separated by
column chromatography on silica gel (hexane/ethyl acetate 9/1) to
give (R,E)-(+)-14 (21.5 g, 29%) and (S,E)-(-)-4 (27.3 g, 45%)
(Enantiomeric ratio32 E ) 83).
Data of (R,E)-(+)-14: [R]D ) +67.5 (c ) 1.18, CHCl3) [lit.9
[R]D ) +65.3 (c ) 0.52, CHCl3), ee >96%]; 1H NMR9 (250 MHz,
CDCl3) δ 7.40-7.20 (m, 5H), 6.64 (d, 1H, J ) 15.9 Hz), 6.14 (dd,
1H, J ) 15.9, 7.1 Hz), 5.81 (m, 1H), 2.95 (dd, 1H, J ) 16.4, 7.6
Hz), 2.76 (dd, 1H, J ) 16.4, 5.5 Hz), 2.19 (s, 3H), 2.06 (s, 3H);
13C NMR9 (62.90 MHz, CDCl3) δ 204.4, 169.7, 135.9, 132.5, 128.4,
128.2, 126.6, 126.0, 70.3, 48.4, 30.4, 21.3. Anal. Calcd for
C14H16O3: C, 72.39; H, 6.94. Found: C, 72.45; H, 6.87.
Data of (S,E)-(-)-4: [R]D ) -14.7 (c ) 1.26, CHCl3) [lit.9 [R]D
) -10.1 (c ) 0.96, CHCl3), ee ) 53%; lit.33 [R]D ) +15.5 (c )
0.96, CHCl3), ee ) 53% for (R)-4]; 1H NMR9 (250 MHz, CDCl3)
δ 7.40-7.20 (m, 5H), 6.64 (dd, 1H, J ) 15.9, 1.1 Hz), 6.20 (dd,
(2R,4R,E)-5-Methyl-6-phenylhex-5-ene-2,4-diyl Diacetate
((2R,4R)-syn-15) and (2S,4S,E)-5-Methyl-6-phenylhex-5-ene-2,4-
diol ((2S,4S)-syn-2). Racemic syn-2 (21.0 g, 0.10 mol) was treated
with lipase PS (20 g) in tert-butylmethyl ether solution (500 mL)
in the presence of vinyl acetate (50 mL). After 7 days the reaction
mixture was filtered and separated by column chromatography on
(32) Chen, C. S.; Fujimoto, Y.; Girdaukas, G.; Sih, C. J. Am. Chem.
Soc. 1982, 104, 7294-7299.
(33) Yanagisawa, A.; Matsumoto, Y.; Nakashima, H.; Asakawa, K.;
Yamamoto, H. J. Am. Chem. Soc. 1997, 119, 9319.
J. Org. Chem, Vol. 71, No. 14, 2006 5235

Abate et al.
silica gel (hexane/ethyl acetate 9/1) to give diacetate (2R,4R)-syn-
15 (12.1 g, 41%) and diol (2S,4S)-syn-2 (7.2 g, 35%) (E ) 1057).
Data of (2R,4R)-syn-15: [R]D ) +7.5 (c ) 0.94, CHCl3), ee >
99% (HPLC of the corresponding diol); 1H NMR δ 7.40-7.10 (m,
5H), 6.49 (br s, 1H), 5.38 (t, J ) 6.5 Hz, 1H), 4.94 (m,1H), 2.16-
2.08 (m, 1H), 2.08 (s, 3H), 2.02 (s, 3H), 1.90-1.80 (m, 1H), 1.84
(d, J ) 1.7 Hz, 3H), 1.28 (d, J ) 6.5 Hz); 13C NMR (62.90 MHz,
CDCl3) δ 170.5, 137.1, 135.3, 129.1, 128.4, 128.3, 126.9, 76.5,
68.2, 39.0, 21.4, 21.5, 20.3, 13.7; GC/MS tR 23.77 min, m/z 247
(M+ - 43, 7), 230 (15), 188 (43), 170 (67), 155 (100). Anal. Calcd
for C17H22O4: C, 70.32; H, 7.64. Found: C, 70.55; H, 7.51.
Data of (2S,4S)-syn-2: [R]D ) +21.4 (c ) 1.0, CHCl3), ee >
acetate 9/1) to give diacetate (2R,3R,4S)-anti,anti-21 (5.35 g, 38%)
and diol (2S,3S,4R)-anti,anti-3 (3.50 g, 35%) (E ) 525).
Data of (2R,3R,4S)-anti,anti-21: [R]D ) +51.7 (c ) 1.31,
1
CHCl3), ee ) 98% (HPLC of the corresponding diol); H NMR
(250 MHz, CDCl3) δ 7.40-7.20 (m, 5H), 6.57 (d, J ) 16.0 Hz,
1H), 6.08 (dd, J ) 16.0, 7.1 Hz, 1H), 5.43 (t, J ) 7.1 Hz, 1H),
4.95 (quintuplet, J ) 6.3 Hz, 1H), 2.17 (m, 1H), 2.09 (s, 3H), 2.04
(s, 3H), 1.19 (d, J ) 6.3 Hz, 3H), 0.95 (d, J ) 6.9 Hz, 3H); 13C
NMR (62.90 MHz, CDCl3) 169.9, 166.1, 135.9, 133.4, 128.2, 127.7,
126.3, 124.2, 74.9, 70.6, 40.8, 21.7, 20.9, 15.9, 10.3; GC/MS tR
23.12 min, m/z 290 (M+, 2), 230 (12), 188 (50), 133 (100). Anal.
Calcd for C17H22O4: C, 70.32; H, 7.64. Found: C, 70.56; H, 7.49.
Data of (2S,3S,4R)-anti,anti-3: mp 71 °C, [R]D ) +16.5 (c )
1
99% (HPLC); H NMR (250 MHz, CDCl3) δ 7.35-7.00 (m,5H),
1
6.54 (br s, 1H), 4.41 (m, 1H), 4.09 (m, 1H), 1.89 (d, J ) 1.5 Hz,
3H), (1.85-1.60, m, 2H), 1.20 (d, J ) 6.2 Hz, 3H); 13C NMR (62.90
MHz, CDCl3) δ 142.3, 139.7, 131.1, 130.2, 128.6, 127.4, 80.7, 70.9,
45.4, 26.2, 15.8; GC/MS tR 22.38 min, m/z 206 (M+, 10), 188 (12),
147 (58), 129 (100). Anal. Calcd for C13H18O2: C, 75.69; H, 8.80.
Found: C, 75.80; H, 8.69.
1.31, CHCl3), ee > 99% (HPLC); H NMR (250 MHz, CDCl3) δ
7.40-7.20 (m, 5H), 6.58 (d, J ) 16.0 Hz, 1H), 6.21 (dd, J ) 16.0,
8.0 Hz, 1H), 4.23 (t, J ) 8.0 Hz, 1H), 3.85 (dq, J ) 8.0, 6.2 Hz,
1H), 1.68 (m, 1H), 1.24 (d, J ) 6.2 Hz, 3H), 0.82 (d, J ) 6.9 Hz,
3H); 13C NMR (62.90 MHz, CDCl3) δ 136.6, 131.9, 131.0, 128.5,
127.6, 126.5, 78.6, 72.6, 45.5, 21.6, 13.2. Anal. Calcd for
C13H18O2: C, 75.69; H, 8.80. Found: C, 75.81; H, 8.77.
Saponification of (2R,4R)-syn-15 (11.90 g, 0.041 mol) with KOH
(2.75 g, 0.049 mol) in MeOH (50 mL) gave (2R,4R)-syn-2 (7.85
g, 93%): [R]D ) -20.8 (c ) 0.94, CHCl3), ee > 99% (HPLC).
(2R,4S,E)-4-Hydroxy-5-methyl-6-phenylhex-5-en-2-yl Acetate
((2R,4S)-anti-16) and (3R,5S,E)-5-Hydroxy-2-methyl-1-phenyl-
hex-1-en-3-yl Acetate ((3R,5S)-anti-17). Racemic anti-2 (21.0 g,
0.10 mol) was treated with lipase PS (20 g) in tert-butylmethyl
ether solution (500 mL) in the presence of vinyl acetate (50 mL).
After 7 days the reaction mixture was filtered and separated by
column chromatography on silica gel (hexane/ethyl acetate 9/1) to
give monoacetate (2R,4S)-anti-16 (8.43 g, 34%) and the other
regioisomer (3R,5S)-anti-17 (7.44 g, 30%).
(2R,3R,4R,E)-4-Hydroxy-3-methyl-6-phenylhex-5-en-2-yl Ac-
etate ((2R,3R,4R)-anti,syn-22) and (2S,3R,4S,E)-3-Methyl-6-
phenylhex-5-ene-2,4-diol ((2S,3R,4S)-anti,syn-3). Racemic anti,-
syn-3 (10.0 g, 0.05 mol) was treated with lipase PS (10 g) in tert-
butylmethyl ether solution (250 mL) in the presence of vinyl acetate
(256 mL). After 7 days the reaction mixture was filtered and
separated by column chromatography on silica gel (hexane/ethyl
acetate 9/1) to give monoacetate (2R,3R,4R)-anti,syn-22 (4.83 g,
39%) and diol (2S,3R,4S)-anti,syn-3 (3.21 g, 32%) (E ) 164).
Data of (2R,3R,4R)-anti,syn-22: mp 78°C, [R]D ) +44.2 (c )
1
0.92, CHCl3), ee ) 95% (HPLC of the corresponding diol); H
1
NMR (250 MHz, CDCl3) δ 7.45-7.20 (m, 5H), 6.59 (d, J ) 16.0
Hz, 1H), 6.18 (dd, J ) 16.0, 7.0 Hz, 1H), 5.37 (dq, J ) 2.4, 6.5
Hz, 1H), 3.96 (t, J ) 7.0 Hz, 1H), 2.05 (s, 3H), 1.72 (dquintuplet,
J ) 2.4, 7.0 Hz, 1H), 1.28 (d, J ) 6.5 Hz, 3H), 0.93 (d, J ) 7.0
Hz, 3H); 13C NMR (62.90 MHz, CDCl3) δ 171.6, 137.0, 132.2,
130.6, 128.7, 127.9, 126.7, 74.6, 70.5, 44.4, 21.4, 18.2, 10.1. Anal.
Calcd for C15H20O3: C, 72.55; H, 8.12. Found: C, 72.43; H, 8.31.
Data of (2S,3R,4S)-anti,syn-3: mp 75 °C, [R]D ) +7.36 (c )
Data of (2R,4S)-anti-16: [R]D ) +19.8 (c ) 0.87, CHCl3); H
NMR δ 7.40-7.15 (m, 5H), 6.53 (br s, 1H), 5.16 (ddq, J ) 9.1,
3.6, 6.2 Hz, 1H), 4.15 (dd, J ) 9.1, 3.3, 1H), 2.05 (s, 3H), 1.91-
1.83 (m, 1H), 1.87 (d, J ) 1.1 Hz, 3H), 1.79 (ddd, J ) 14.3, 9.1,
3.6, 1H), 1.30 (d, J ) 6.2 Hz); 13C NMR (62.90 MHz, CDCl3) δ
171.3, 139.7, 137.5, 128.9, 128.0, 126.4, 125.4, 73.9, 68.5, 42.1,
21.2, 20.6, 13.6; GC/MS tR 23.34 min, m/z 248 (M+, 2), 230 (5),
188 (50), 129 (100). Anal. Calcd for C15H20O3: C, 72.55; H, 8.12.
Found: C, 72.39; H, 8.05.
1
0.92, CHCl3), ee ) 97% (HPLC of the corresponding diol); H
1
NMR (250 MHz, CDCl3) δ 7.60-7.20 (m, 5H), 6.63 (d, J ) 16.0
Hz, 1H), 6.25 (dd, J ) 16.0, 6.6 Hz, 1H), 4.32 (t, J ) 6.6 Hz, 1H),
4.17 (dq, J ) 2.3, 6.5 Hz, 1H), 1.78 (dquintuplet, J ) 2.3, 6.6 Hz,
1H), 1.23 (d, J ) 6.5 Hz, 3H), 0.96 (d, J ) 6.6 Hz, 3H); 13C NMR
(62.90 MHz, CDCl3) δ 136.7, 131.5, 131.1, 128.6, 127.6, 126.5,
76.5, 69.2, 43.4, 19.6, 11.5. Anal. Calcd for C13H18O2: C, 75.69;
H, 8.80. Found: C, 75.82; H, 8.72.
Data of (3R,5S)-anti-17: [R]D ) +50.6 (c ) 0.90, CHCl3); H
NMR δ 7.35-7.15 (m, 5H), 6.55 (br s, 1H), 5.53 (dd, J ) 10.3,
3.3 Hz, 1H), 3.79 (ddq, J ) 9.6, 2.9, 6.2, 1H), 2.12 (s, 3H), 1.89
(d, J ) 1.1 Hz, 3H), 1.90-1.80 (m, 1H), 1.74 (ddd, J ) 14.3, 9.6,
3.3, 1H), 1.23 (d, J ) 6.2 Hz); 13C NMR (62.90 MHz, CDCl3) δ
171.3, 137.0, 136.1, 128.9, 128.1, 127.2, 126.7, 76.6, 63.8, 43.1,
23.2, 21.9, 14.0; GC/MS tR 22.82 min, m/z 188 (M+ - 60.8), 170
(23), 155 (50), 129 (100). Anal. Calcd for C15H20O3: C, 72.55; H,
8.12. Found: C, 72.71; H, 8.24.
Saponification of (2R,3R,4R)-anti,syn-22 (4.50 g, 0.018 mol) with
KOH (1.24 g, 0.022 mol) in MeOH (50 mL) gave (2R,3S,4R)-anti,-
syn-3 (3.48 g, 94%): [R]D ) -6.98 (c ) 0.92, CHCl3), ee ) 95%
(HPLC).
(2R,4S,E)- and (2S,4R,E)-5-Methyl-6-phenylhex-5-ene-2,4-diol
((2R,4S,E)-anti-2 and (2S,4R,E)-anti-2). Saponification of (2R,4S)-
anti-16 (8.2 g, 0.033 mol) and (3R,5S)-anti-17 (6.9 g, 0.029 mol)
with KOH in methanol gave, respectively, (2R,4S,E)-anti-2 (6.45
g, 95%, [R]D ) -32.8 (c ) 0.86, CHCl3)) and (2S,4R,E)-anti-2
(5.38 g, 94%, [R]D ) +30.6 (c ) 0.96, CHCl3)): 1H NMR (250
MHz, CDCl3) δ 7.40-7.00 (m, 5H), 6.61 (br s, 1H), 4.47 (dd, J )
7.3, 3.8 Hz, 1H), 4.14 (m,1H), 1.86 (d, J ) 1.2 Hz, 3H), 1.90-
1.60 (m, 2H), 1.27 (d, J ) 6.6 Hz, 3H); 13C NMR (62.90 MHz,
CDCl3) δ 142.2, 139.7, 131.1, 130.2, 128.5, 126.7, 76.8, 67.6, 44.5,
25.7, 16.5; GC/MS tR 22.33 min, m/z 206 (M+, 9), 188 (12), 147
(60), 129 (100). Anal. Calcd for C13H18O2: C, 75.69; H, 8.80.
Found: C, 75.52; H, 8.95.
(2R,3R,4S,E)-3-Methyl-6-phenylhex-5-ene-2,4-diyl Diacetate
((2R,3R,4S)-anti,anti-21) and (2S,3S,4R,E)-3-Methyl-6-phenyl-
hex-5-ene-2,4-diol ((2S,3S,4R)-anti,anti-3). Racemic anti,anti-3
(10.0 g, 0.05 mol) was treated with lipase PS (10 g) in tert-
butylmethyl ether solution (250 mL) in the presence of vinyl acetate
(25 mL). After 7 days the reaction mixture was filtered and
separated by column chromatography on silica gel (hexane/ethyl
(3S,4S,E)-4-Methyl-5-oxo-1-phenylhex-1-en-3-yl Acetate ((3S,
4S)-anti-24). A 2:1 mixture of anti-6 and syn-6 (5.1 g, 0.025 mol)
was treated with lipase PS (2.0 g) in tert-butylmethyl ether solution
(50 mL) in the presence of vinyl acetate (5 mL). After 7 days the
reaction mixture was filtered and separated by column chromatog-
raphy on silica gel (hexane/ethyl acetate 9/1) to give, after
crystallization form hexane, (3S,4S)-anti-24 (1.48 g, 24%): mp 80
°C, [R]D ) +61.1 (c ) 1.14, CHCl3); 1H NMR (250 MHz, CDCl3)
δ 7.45-7.20 (m, 5H), 6.69 (d, 1H, J ) 16.0 Hz), 6.03 (dd, 1H, J
) 16.0, 7.6 Hz), 5.58 (t, 1H, J ) 7.6 Hz), 2.93 (m, 1H), 2.21 (s,
3H), 2.03 (s, 3H); 13C NMR (62.90 MHz, CDCl3) δ 208.9, 169.5,
135.8, 134.7, 128.4, 128.1, 126.5, 124.5, 75.6, 50.6, 28.8, 20.9,
12.7. GC/MS tR 21.69 min, m/z 186 (M+ - 60, 100), 171 (65), 128
(100). Anal. Calcd for C15H18O3: C, 73.15; H, 7.37. Found: C,
73.45; H, 7.49.
(2S,3R,4S,E)-3-Methyl-6-phenylhex-5-ene-2,4-diol ((2S,3R,4S)-
anti,syn-3) and (2R,3R,4S,E)-3-Methyl-6-phenylhex-5-ene-2,4-
diol ((2R,3R,4S)-anti,anti-3). Compound (3S,4S)-anti-24 (1.30 g,
5236 J. Org. Chem., Vol. 71, No. 14, 2006

Application to the Synthesis of Chiral Synthons
5.3 mmol) was treated with NaBH4 (0.100 g, 2.7 mmol) in CH2-
Cl2/MeOH (2/1) (20 mL). After the usual workup the crude
reduction mixture was treated with KOH (0.356 g, 6.4 mmol) in
MeOH (20 mL). After the usual work up column chromatography
(hexanes/ethyl acetate 8/2) afforded (2S,3R,4S)-(+)-anti,syn-3 (ee
> 99%, HPLC) (0.207 g, 19%) and (2R,3R,4S)-(-)-anti,anti-3 (ee
> 99%, HPLC) (0.262 g, 24%).
(68), 104 (100). Anal. Calcd for C16H22O2: C, 78.01; H, 9.00.
Found: C, 78.19; H, 9.15.
(f) (4R,5S,6R,E)-2,2,4,5-Tetramethyl-6-styryl-1,3-dioxane ((4R,5S,
6R)-anti,syn-27). Treatment of (2R,3S,4R)-anti,syn-3 (3.30 g, 0.016
mol) gave (4R,5S,6R)-anti,syn-27 (3.66 g, 93%): [R]D ) -51.5 (c
1
) 0.80, CHCl3); H NMR (250 MHz, CDCl3) δ 7.40-7.10 (m,
5H), 6.58 (d, 1H, J ) 16.1 Hz), 6.22 (dd, 1H, J ) 16.1, 7.2 Hz),
4.17 (quintuplet, 1H, J ) 6.5 Hz), 3.93 (t, J 7.5 Hz, 1H), 1.83 (m,
1H), 1.42 (s, 6H), 1.13 (d, J ) 6.5 Hz, 3H), 0.90 (d, 1H, J ) 6.8
Hz); 13C NMR (62.90 MHz, CDCl3) 136.7, 131.0, 128.9, 128.3,
127.4, 126.4, 100.4, 75.8, 64.8, 40.1, 24.9, 24.4, 16.6, 11.1; GC/
MS tR 20.32 min, m/z 246 (M+, 1), 188 (35), 133 (100), 104 (73).
Anal. Calcd for C16H22O2: C, 78.01; H, 9.00. Found: C, 77.81; H,
8.89.
Preparation of Acetonides. Treatment of the suitable diol (0.022
mol) with dimethoxypropane (10 mL) and acetone (100 mL) in
the presence of a catalytic amount of pyridinium p-toluenesulfonate
gave, after the usual workup, the corresponding acetonide.
(a) (4R,6R,E)-2,2,4-Trimethyl-6-styryl-1,3-dioxane ((4R,6R)-syn-
25). (2R,4R)-syn-1 (4.30 g, 0.022 mol) gave (4R,6R)-syn-25 (4.93
1
g, 95%): mp 53-55 °C; [R]D ) +41.4 (c ) 1.51, CHCl3); H
NMR (250 MHz, CDCl3) δ 7.50-7.10 (m, 5H), 6.59 (d, 1H, J )
15.9, 1.0 Hz), 6.17 (dd, 1H, J ) 15.9, 6.2 Hz), 4.53 (ddd, 1H, J )
2.5, 6.2, 11.4 Hz), 4.21 (ddq, 1H, J ) 2.5, 11.4, 6.1 Hz), 1.62 (dt,
1H, J ) 13.0, 2.6 Hz), 1.52 (s, 3H), 1.47 (s, 3H), 1.36 (m, 1H),
1.20 (d, 3H, J ) 6.1 Hz);13C NMR (62.90 MHz, CDCl3) 136.8,
130.6, 130.1, 128.5, 127.6, 126.6, 98.8, 70.1, 65.0, 38.9, 30.4, 22.2,
19.9; GC/MS tR 20.37 min, m/z 232 (M+, 1), 174 (17), 157 (28),
104 (100). Anal. Calcd for C15H20O2: C, 77.55; H, 8.68. Found:
C, 77.41; H, 8.79.
Ozonolysis of Acetonides. A solution of the suitable acetonide
(0.021 mol) in CH2Cl2-MeOH (2:1) (300 mL) was treated with
ozone. The reaction mixture was quenched with triphenylphosphine
and chromatographed on a silica gel column (hexane/ethyl acetate
8/2) to afford the corresponding carbonyl compound.
(a) (4R,6R)-2,2,6-Trimethyl-1,3-dioxane-4-carbaldehyde ((4R,6R)-
syn-7). Acetonide (4R,6R)-syn-25 (4.80 g, 0.021 mol) afforded
(4R,6R)-syn-7 (2.49 g, 75%); [R]D ) +72.5 (c ) 1.18, CHCl3); 1H
NMR (250 MHz, CDCl3) δ 9.59 (s, 1H), 4.30 (dd, 1H, J ) 12.2,
2.9 Hz), 4.05 (m, 1H), 1.74 (dt, 1H, J ) 12.8, 2.9 Hz), 1.48 (s,
6H), 1.30 (m), 1.22 (d, 1H, J ) 6.4 Hz);13C NMR (62.90 MHz,
CDCl3) 201.3, 99.1, 74.0, 64.5, 32.6, 29.8, 22.1, 19.5; GC/MS tR
(b) (4S,6R,E)-2,2,4-Trimethyl-6-styryl-1,3-dioxane ((4S,6R)-anti-
25). Treatment of (2S,4R)-anti-1 (3.50 g, 0.018 mol) gave (4S,6R)-
anti-25 (3.97 g, 94%) containing 10% of the starting diol: [R]D )
1
+71.2 (c ) 1.02, CHCl3); H NMR (250 MHz, CDCl3) δ 7.40-
-
5.97 min, m/z 143 (M+ 15, 21), 129 (23), 59 (100), 43 (92).
7.15 (m, 5H), 6.55 (d, 1H, J ) 16 Hz), 6.22 (dd, 1H, J ) 16.0, 6.3
Hz), 4.52 (dt, J ) 8.8, 6.5 Hz, 1H), 4.06 (dquintuplet, 1H, J ) 8.8,
6.5 Hz), 1.90 (ddd, J ) 12.8, 8.8, 6.5 Hz, 2H), 1.73 (ddd, J )
Anal. Calcd for C8H14O3: C, 60.74; H, 8.92. Found: C, 60.65; H,
8.86.
(b) Methyl 3,5-Dideoxy-L-threopentofuranoside) (L-28). Ac-
etonide (4S,6R)-anti-25 (3.80 g, 0.016 mol) afforded L-28 as a 3:1
mixture of two anomers (0.802 g, 38%): 1H NMR (250 MHz,
CDCl3) 4.85 (s, major anomer), 4.70 (d, J ) 4.5 Hz, minor anomer),
4.30-4.13 (m, both anomers), 3.53 (s, minor anomer), 3.38 (s,
major anomer), 2.56-2.32 (m, both anomers), 1.49 (m, both
anomers), 1.39 (d, J ) 6.1 Hz, major anomer), 1.34 (d, J ) 6.3
Hz, minor anomer); GC/MS tR 4.38 min major anomer, m/z 101
(M+ - 31, 9), 72 (48), 57 (100), 43 (42), tR 5.27 min minor anomer,
m/z 117 (M+ - 15, 3), 101 (10), 72 (42), 57 (100), 43 (47). Anal.
Calcd for C6H12O3: C, 54.53; H, 9.15. Found: C, 54.64; H, 9.27.
(c) 1-((4R,6R)-2,2,6-Trimethyl-1,3-dioxan-4-yl)ethanone ((4R,6R)-
syn-8). Acetonide (4R,6R)-syn-26 (7.80 g, 0.032 mol) afforded
(4R,6R)-syn-8 (3.76 g, 69%): [R]D ) +77.8 (c ) 0.78, CHCl3);
1H NMR (250 MHz, CDCl3) 4.26 (dd, 1H, J ) 12.1, 2.6 Hz), 4.04
(ddq, 1H, J ) 11.6, 2.6, 6.4 Hz), 2.21 (s, 3H), 1.76 (dt, 1H, J )
13.0, 2.6 Hz), 1.46 (s, 6H)), 1.27 (m, 1H), 1.20 (d, 3H, J ) 6.4
Hz); 13C NMR (62.90 MHz, CDCl3) 209.2, 99.0, 75.1, 65.0, 34.3,
30.2, 25.4, 22.2, 19.6; GC/MS tR 8.88 min, m/z 157(M+ - 15, 12),
129 (50), 59 (100). Anal. Calcd for C9H16O3: C, 62.77; H, 9.36.
Found: C, 62.61; H, 9.18.
12.8, 8.8, 6.5 Hz, 2H), 1.42 (s, 6H), 1.23 (d, 1H, J ) 6.5 Hz); 13
C
NMR (62.90 MHz, CDCl3) 136.7, 131.9, 130.0, 128.6, 127.6, 126.5,
96.0, 69.5, 64.1, 42.2, 37.4, 22.2, 20.9; GC/MS tR 19.98 min, m/z
232 (M+, 1), 174 (12), 157 (14), 104 (100). Anal. Calcd for
C15H20O2: C, 77.55; H, 8.68. Found: C, 77.63; H, 8.53.
(c) (4R,6R,E)-2,2,4-Trimethyl-6-(1-phenylprop-1-en-2-yl)-1,3-
dioxane ((4R,6R)-syn-26). Treatment of (2R,4R)-syn-2 (7.60 g, 0.037
mol) gave (4R,6R)-syn-26 (8.10 g, 89%): [R]D ) -10.6 (c ) 1.04,
1
CHCl3); H NMR (250 MHz, CDCl3) δ 7.50-7.10 (m, 5H), 6.55
(br s, 1H), 4.37 (dd, 1H, J ) 11.1, 2.4 Hz), 4.07 (ddq, 1H, J )
11.1, 2.4, 6.4 Hz), 1.87 (d, J ) 1.1 Hz, 3H), 1.62 (dt, 1H, J )
13.0, 2.4 Hz), 1.53 (s, 3H), 1.47 (s, 3H), 1.41 (dt, J ) 13.0, 11.1
Hz, 1H), 1.21 (d, 3H, J ) 6.4 Hz); 13C NMR (62.90 MHz, CDCl3)
138.4, 137.9, 129.2, 128.1, 126.5, 125.6, 98.9, 74.5, 65.3, 37.8,
30.5, 22.4, 20.1, 14.2; GC/MS tR 21.58 min, m/z 246 (M+, 5), 188
(36), 171 (30), 118 (100). Anal. Calcd for C16H22O2: C, 78.01; H,
9.00. Found: C, 78.14; H, 9.12.
(d) (4R,6S,E)-2,2,4-Trimethyl-6-(1-phenylprop-1-en-2-yl)-1,3-
dioxane ((4R,6S)-anti-26). Treatment of (2R,4S)-anti-2 (6.30 g,
0.030 mol) gave (4R,6S)-anti-26 (6.77 g, 90%): [R]D ) -13.8 (c
1
) 0.73, CHCl3); H NMR (250 MHz, CDCl3) δ 7.40-7.10 (m,
(d) 1-((4S,6R)-2,2,6-Trimethyl-1,3-dioxan-4-yl)ethanone ((4S,6R)-
anti-8). Acetonide (4R,6S)-anti-26 (6.50 g, 0.026 mol) afforded
(4S,6R)-anti-8 (2.95 g, 65%): [R]D ) -61.8 (c ) 1.10, CHCl3);
1H NMR (250 MHz, CDCl3) 4.23 (t, J ) 7.6 Hz, 1H), 3.96
(dquintuplet, 1H, J ) 9.9, 6.2 Hz), 2.22 (s, 3H), 2.01 (ddd, J )
13.0, 7.6, 6.2, 1H), 1.71 (ddd, J ) 13.0, 9.9, 7.6, 1H), 1.40 (s,
6H), 1.21 (d, 1H, J ) 6.2 Hz); 13C NMR (62.90 MHz, CDCl3)
209.0, 100.6, 73.2, 62.8, 34.5, 26.2, 24.5, 21.8; GC/MS tR 7.09
5H), 6.52 (br s, 1H, CHdC), 4.37 (dd, J ) 9.2, 6.5 Hz, 1H), 4.03
(dquintuplet, 1H, J ) 9.2, 6.5 Hz), 1.94 (ddd, J ) 13.0, 9.2, 6.5,
1H), 1.87 (d, J ) 1.1 Hz, 3H), 1.69 (ddd, J ) 13.0, 9.2, 6.5, 1H),
1.44 (s, 3H), 1.43 (s, 3H), 1.24 (d, 1H, J ) 6.5 Hz); 13C NMR
(62.90 MHz, CDCl3) 138.3, 138.0, 129.2, 128.2, 126.5, 125.1,
100.6, 71.7, 63.3, 38.7, 31.8, 25.3, 22.8, 14.3; GC/MS tR 21.21
min, m/z 246 (M+, 2), 188 (35), 118 (100). Anal. Calcd for
C16H22O2: C, 78.01; H, 9.00. Found: C, 77.86; H, 8.78.
(e) (4S,5S,6R,E)-2,2,4,5-Tetramethyl-6-styryl-1,3-dioxane ((4S,5S,
6R)-anti,anti-27). Treatment of (2S,3S,4R)-anti,anti-3 (3.30 g, 0.016
mol) gave (4S,5S,6R)-anti,anti-27 (3.58 g, 91%): [R]D ) -23.1
(c ) 1.04, CHCl3); 1H NMR (250 MHz, CDCl3) δ 7.50-7.10 (m,
5H), 6.59 (d, 1H, J ) 15.9 Hz), 6.11 (dd, 1H, J ) 15.9, 7.5 Hz),
4.06 (dd, 1H, J ) 10.0, 7.5 Hz), 3.68 (dq, 1H, J ) 10.0, 6.1 Hz),
1.52 (s, 3H), 1.45 (s, 3H), 1.34 (m, 1H), 1.21 (d, 3H, J ) 6.1 Hz),
0.81 (d, J ) 6.5 Hz, 3H); 13C NMR (62.90 MHz, CDCl3) 136.9,
133.3, 128.8, 128.6, 127.9, 126.8, 98.3, 76.9, 70.9, 41.0, 30.4, 20.1,
20.0, 12.8; GC/MS tR 20.44 min, m/z 246 (M+, 5), 188 (51), 171
-
min, m/z 157 (M+ 15, 8), 129 (58), 59 (100). Anal. Calcd for
C9H16O3: C, 62.77; H, 9.36. Found: C, 62.96; H, 9.49.
(e) (4S,5S,6S)-2,2,5,6-Tetramethyl-1,3-dioxane-4-carbaldehyde
((4S,5S,6S)-anti,anti-9). Acetonide (4S,5S,6R)-anti,anti-27 (3.30 g,
0.013 mol) afforded (4S,5S,6S)-anti,anti-9 (1.54 g, 67%): [R]D )
1
-136.8 (c ) 0.70, CHCl3); H NMR (250 MHz, CDCl3) δ 9.51
(d, J ) 2 Hz), 3.82 (dd, 1H, J ) 11.0, 2 Hz), 3.66 (dq, 1H, J )
10.0, 5.8 Hz), 1.53-1.39 (m + 2s, 7H), 1.21 (d, 3H, J ) 5.8 Hz),
0.88 (d, J ) 6.5 Hz, 3H); 13C NMR (62.90 MHz, CDCl3) 200.3,
98.4, 78.9, 70.3, 35.3, 29.9, 19.8, 19.7, 11.7; GC/MS tR 8.24 min,
J. Org. Chem, Vol. 71, No. 14, 2006 5237

Abate et al.
-
m/z 157 (M+
15, 20), 143 (40), 59 (100). Anal. Calcd for
(d, 1H); 13C NMR (62.90 MHz, CDCl3) 116.8, 99.2, 65.2, 64.6,
37.7, 29.9, 24.9, 21.9, 19.7; GC/MS tR 10.26 min, m/z 154 (M+ -
15, 31), 94 (46), 59 (54), 43 (100). Anal. Calcd for C9H15NO2: C,
63.88; H, 8.93; N, 8.28. Found: C, 63.75; H, 8.81; N, 8.14.
2-((4R,6R)-2,2,6-Trimethyl-1,3-dioxan-4-yl)acetaldehyde ((4R,
6R)-syn-33). Nitrile (4R,6R)-32 (1.10 g, 6.50 mmol) was reduced
with DIBALH (1.2 M solution in toluene, 6.5 mL) in toluene (20
mL) at -10 °C. After the usual workup the crude reaction product
was chromatographed on a silica gel column (hexane/ethyl acetate
C9H16O3: C, 62.77; H, 9.36. Found: C, 62.63; H, 9.48.
(f) (4S,5S,6R)-2,2,5,6-Tetramethyl-1,3-dioxane-4-carbaldehyde
((4S,5S,6R)-anti,syn-9). Acetonide (4R,5S,6R)-anti,syn-27 (3.40 g,
0.014 mol) afforded (4S,5S,6R)-anti,syn-9 (1.52 g, 64%): [R]D
)
-35.1 (c ) 0.90, CHCl3); 1H NMR (250 MHz, CDCl3) 4.03
(quintuplet, 1H, J ) 6.5, Hz), 3.80 (d, J ) 6.5 Hz, 1H), 2.06 (m,
1H), 1.41 (s, 3H), 1.40 (s, 3H), 1.11 (d, J ) 6.5 Hz, 3H), 1.03 (d,
1H, J ) 6.8 Hz); 13C NMR (62.90 MHz, CDCl3) 201.9, 100.8,
80.8, 64.8, 34.2, 29.8, 24.2, 17.2, 11.7; GC/MS tR 6.52 min, m/z
172 (M+, 0.5), 157 (7) 143 (23), 59 (100). Anal. Calcd for
C9H16O3: C, 62.77; H, 9.36. Found: C, 62.87; H, 9.52.
8:2) to afford aldehyde (4R,6R)-syn-33 (0.772 g, 69%): [R]D
)
1
-10.5 (c ) 1.14, CHCl3); H NMR (250 MHz, CDCl3) δ 9.78 (t,
1H, J ) 2 Hz), 4.38 (m, 1H), 4.00 (m, 1H), 2.51 (m, 2H, CH2-
CHO), 1.57 (dt, 1H, J ) 12.7, 2.5 Hz), 1.40 (s, 3H), 1.38 (s, 3H),
1.17 (d + m, 4H, J ) 6.0 Hz); 13C NMR (62.90 MHz, CDCl3)
200.1, 98.9, 64.8, 64.6, 49.5, 38.4, 30.1, 22.0, 19.7; GC/MS tR 10.06
min, m/z 157 (M+ - 15, 54), 97 (38), 69 (46), 59 (100), 43 (100).
Anal. Calcd for C9H16O3: C, 62.77; H, 9.36. Found: C, 62.65; H,
9.48.
(4R,5S,6R)-4-(Furan-2-yl)-2,5,6-trimethyl-1,3-dioxane ((4R,5S,
6R)-44). The mixture of diastereoisomeric diols (3R)-41 (3.99 g,
0.023 mol), obtained by hydrolysis of acetates (2R)-43 (6.0 g, 0.028
mol), was treated with acetaldehyde (3.10 g, 0.071 mol) in CH2Cl2
(25 mL) in the presence of pyridium p-toluenesulfonate (10 mg).
The reaction mixture was concentrated under reduced pressure and
chromatographed on a silica gel column to afford as the first eluted
product acetal (4R,5S,6R)-44 (0.460 g, 10%): [R]D ) -6.1 (c )
(4R,6R)-6-Methyl-tetrahydro-2H-pyran-2,4-diol (or 2,4,6-
Trideoxy-D-erithrohexopyranose) ((R,R)-34). Aldehyde (4R,6R)-
syn-33 (0.700 g, 4.10 mmol) was dissolved in THF (20 mL), and
water was added till turbidity appeared. Acetic acid (1 mL) and
one drop of HCl 37% were then added. The reaction mixture was
stirred at room temperature for 12 h. The reaction mixture was
neutralized and concentrated under reduced pressure to give (R,R)-
34 (0.276 g, 51%): 1H NMR24a (250 MHz, CDCl3) δ 5.32 (d, 1H,
J ) 4.8 Hz, R), 5.16 (br d, 1H, J ) 10.0 Hz, â), 4.42 (ddq, 1H, J
) 11.6, 2.2, 6.3 Hz, R), 4.32 (dq, 1H, J ) 2.6, 5.4, â), 4.22 (m,
1H, R), 4.07 (ddq, 1H, J ) 11.4, 6.3, 2.2 Hz, â), 1.40-2.00 (m,
4H, R +â), 1.23 (d, 3H, J ) 6.3 Hz, â), 1.21 (d, 3H, J ) 6.3 Hz,
R); 13C NMR (62.90 MHz, CDCl3) R anomer δ 92.2, 65.0, 59.1,
39.7, 34.5, 21.4, â anomer δ 92.9, 66.5, 65.6, 39.6, 39.4, 21.3.
Anal. Calcd for C6H12O3: C, 54.53; H, 9.15. Found: C, 54.64; H,
9.27.
Methyl 4,6-Dideoxy-R-D,L-arabinohexopiranoside (R-38) and
Methyl 4,6-Dideoxy-â-D,L-ribohexopiranoside (â-39). The 1:1
mixture of (1RS)-35 (1.50 g, 8.06 mmol) was treated with O3 in
CH2Cl2-MeOH solution (25 mL) at -78 °C. The reaction mixture
was quenched with dimethyl sulfide. The solution was concentrated
under reduced pressure. The residue was dissolved in methanol
containing a catalytic amount of HCl(g). The mixture was concen-
trated and treated with acetic anhydride in pyridine. After the usual
workup the residue (two spots by TLC, 0.987 g) was found to
contain four acetylated methyl glycosides by GC/MS: 1st tR 15.07
min (15%, GC/MS), 2nd tR 15.61 min (32%, GC/MS), 3rd tR 15.98
min (31%, GC/MS), 4th tR 16.42 min (22%, GC/MS).
1
0.80, CHCl3); H NMR (250 MHz, CDCl3) δ 7.42 (m, 1H), 6.38
(m, 1H), 6.27 (m, 1H), 4.95 (q, 1H, J ) 5.1 Hz), 4.84 (br s, 1H),
4.15 (dq, J ) 2.4, 6.5 Hz, 1H), 1.98 (m, 1H), 1.32 (d, J ) 5.1 Hz,
3H), 1.26 (d, J ) 6.5 Hz, 3H), 1.18 (d, 1H, J ) 6.5 Hz); 13C NMR
(62.90 MHz, CDCl3) 153.8, 142.2, 110.4, 108.3, 94.1, 75.6, 71.2,
33.6, 21.3, 18.8, 12.4; GC/MS tR 13.02 min, m/z 196 (M+ , 10),
152 (15), 97 (100). Anal. Calcd for C11H16O3: C, 67.32; H, 8.22.
Found: C, 67.48; H, 8.43.
(3R,4R,5R)-3-Hydroxy-4,5-dimethyl-dihydrofuran-2(3H)-
one ((3R,4R,5R)-46). A solution of acetal (4R,5S,6R)-44 (0.400 g,
2.04 mmol) in CH2Cl2-MeOH (2:1) (30 mL) was treated with
ozone. The reaction mixture was quenched with NaBH4 (0.077 g,
2.04 mmol) and then hydrolyzed with NaOH 10%. The water phase
was acidified with HCl 10% and extracted with ethyl acetate. The
organic phase was dried (Na2SO4) and concentrated under reduced
pressure. The residue was chromatographed on a silica gel column
(hexane/ethyl acetate 8/2) to afford lactone (3R,4R,5R)-46 (0.180
g, 68%): [R]D ) +57 (c ) 0.80, CHCl3), p.o. ) 95%, lit.30e [R]D
1
) +60 (c ) 0.80, CHCl3); H NMR (250 MHz, CDCl3) δ 4.71
(quintuplet, J ) 6.8 Hz, 1H), 4.06 (d, J ) 10.9 Hz, 1H), 2.56 (m,
1H), 1.29 (d, J ) 6.8 Hz, 3H), 1.18 (d, J ) 6.8 Hz, 3H); 13C NMR
(62.90 MHz, CDCl3); GC/MS tR 7.32 min, m/z 112 (M+ - 18 , 2),
87 (8), 71 (100). Anal. Calcd for C6H10O3: C, 77.55; H, 8.68.
Found: C, 77.39; H, 8.54.
(4R,6R)-2,2,6-Trimethyl-1,3-dioxan-4-yl)methanol ((4R,6R)-
syn-31). Reduction of (4R,6R)-7 (2.35 g, 0.015%) with NaBH4
(0.280 g, 7.0 mmol) in CH2Cl2-MeOH (2:1, 40 mL) at 0 °C
afforded (4R,6R)-31 (2.07 g, 87%): [R]D ) -13.3 (c ) 1.41,
Column chromatography on a silica gel column (hexane/ethyl
acetate 8/2) gave a first eluted fraction, which was a mixture of
two acetylated methyl glycosides (0.235 g, 12%): R-36 tR 15.61
min (67%, GC/MS), â-37 tR 15.98 min (33%, GC/MS). Anal. Calcd
for C11H18O6: C, 53.65; H, 7.37. Found: C, 53.74; H, 7.45.
Data of R-36:25b 1H NMR (250 MHz, CDCl3) δ 4.91 (q, 1H, J
) 3.0 Hz), 4.75 (m, 1H), 4.60 (br s, 1H), 4.01 (m, 1H), 3.38 (s,
3H), 2.09 (s, 3H), 2.07 (s, 3H), 1.90 -1.40 (m, 2H)), 1.22 (d, J )
1
CHCl3); H NMR (250 MHz, CDCl3) δ 3.99 (m, 2H), 3.53 (m,
2H), 1.47 (s, 3H), 1.41 (s + m, 4H), 1.26 (m, 1H), 1.18 (d, 1H, J
) 6.2 Hz); 13C NMR (62.90 MHz, CDCl3) 99.8, 69.8, 66.0, 64.7,
34.1, 30.1, 22.2, 19.9; GC/MS tR 7.37 min, m/z 145 (M+ - 15, 33),
129 (12), 59 (100), 43 (75). Anal. Calcd for C8H16O3: C, 59.98;
H, 10.07. Found: C, 59.87; H, 10.18.
-
6.3 Hz, 3H); GC/MS tR 15.98 min, m/z (M+ 60, 2), 144 (32),
2-((4S,6R)-2,2,6-Trimethyl-1,3-dioxan-4-yl)acetonitrile ((4R,6R)-
syn-32). Alcohol (4R,6R)-31 (1.90 g, 0.012 mol) was treated with
p-toluenesulfonyl chloride (3.42 g, 0.018 mol) in pyridine solution
(20 mL) at 0 °C. The reaction mixture was stirred at room
temperature for 1 h. After the usual work up the crude reaction
product was employed without any further purification. It was
dissolved in DMSO (20 mL), and NaCN was added (0.882 g, 0.018
mol). The reaction was heated at 60 °C for 2 h. The reaction mixture
was poured into water and extracted with ethyl acetate. The organic
phase was dried (Na2SO4), concentrated under reduced pressure,
and purified on a silica gel column (hexane/ethyl acetate 95/5) to
afford (4R,6R)-32 (1.25 g, 62%) containing 5% of the intermediate
126 (37), 102 (57), 84 (50), 43 (100).
Data of â-37: 1H NMR (250 MHz, CDCl3) δ 5.44 (q, 1H, J )
3.0 Hz), 4.70 (dd, 1H, J ) 3, 8.1 Hz), 4.66 (d, 1H, J ) 8.1 Hz),
4.14 (m, 1H), 3.50 (s, 3H), 2.10 (s, 3H), 2.03 (s, 3H), 1.90-1.40
(m, 2H), 1.25 (d, J ) 6.3 Hz); GC/MS tR 15.98 min, m/z (M+ -
60, 2), 144 (33), 126 (30), 102 (67), 84 (67), 43 (100).
This mixture R-36-â-37 was treated with a catalytic amount of
sodium methoxide in methanol to give a 2:1 mixture of compounds
R-38 and â-39. Anal. Calcd for C7H14O4: C, 51.84; H, 8.70.
Found: C, 51.95; H, 8.61.
Data of R-38: 1H NMR25f (250 MHz, CDCl3) δ 4.68 (br s, 1H),
4.11 (m, 1H), 3.87 (q, 1H, J ) 3 Hz), 3.62 (m, 1H), 3.43 (s, 3H),
1.85-1.65 (m, 2H), 1.24 (d, J ) 6.2 Hz); GC/MS tR 10.02 min,
m/z 131 (M+ - 31, 4), 105 (5), 74 (12), 60 (100).
1
tosylate: [R]D ) +8.69 (c ) 1.22, CHCl3); H NMR (250 MHz,
CDCl3) δ 4.25-3.85 (m, 2H), 2.51 (m, 2H, CH2CN), 1.67 (dt, 1H,
J ) 12.9, 2.3 Hz), 1.46 (s, 3H), 1.41 (s, 3H), 1.31 (m, 1H), 1.20
5238 J. Org. Chem., Vol. 71, No. 14, 2006

Application to the Synthesis of Chiral Synthons
Data of â-39: 1H NMR25c (250 MHz, CDCl3) δ 4.51 (d, 1H, J
) 8 Hz), 4.16 (q, 1H, J ) 3 Hz), 4.01 (ddq, 1H, J ) 11.5, 1.8, 6.1
Hz), 3.54 (s, 3H), 3.38 (dd, 1H, J ) 3.2, 8 Hz), 1.88 (dt, J ) 14.5,
2 Hz), 1.51 (ddd, J ) 14.5, 3, 11.5 Hz), 1.23 (d, J ) 6.3 Hz);
GC/MS tR 24.24 min m/z 214 (M+ - 60, 100), 199 (75), 131 (38).
Anal. Calcd for C17H22O3: C, 74.42; H, 8.08. Found: C, 74.36; H,
7.97.
(2R,4S,6R)-2,4-Dimethyl-6-((E)-styryl)-tetrahydro-2H-pyran-
4-yl Acetate ((2R,4S,6R)-cis-51). A mixture of compound
(2R,4S,6R)-cis-50 (5.40 g, 0.023 mol) and sodium acetate (2.30 g,
0.028 mol) in acetic anhydride (25 mL) was refluxed for 2 h. The
reaction mixture was poured into ice and extracted with ethyl
acetate. The organic phase was dried (Na2SO4) and concentrated
under reduced pressure to give compound (2R,4S,6R)-cis-51 (5.35
-
GC/MS tR 8.67 min, m/z 131 (M+ 31, 4), 105 (6), 74 (15), 60
(100).
Treatment of the mixture of four acetylated methyl glycosides
with catalytic sodium methoxide gave a mixture of methyl
glycosides in which we could detect the signals of â-38; not yet
reported in the literature: 1H NMR (250 MHz, CDCl3) δ 4.68 (d,
1H, J ) 1.7 Hz), 4.10 (q, 1H, J ) 3.5 Hz), 4.00 (m, 1H), 3.54 (m,
1H), 3.53 (s, 3H), 2.00-1.40 (m, 2H), 1.26 (d, J ) 6.1 Hz); GC/
MS tR 10.65 min, m/z (M+ - 31, 3), 105 (5), 74 (10), 60 (100).
(2R,4R,6R,E)-2,4-Dimethyl-6-styryl-tetrahydro-2H-pyran-4-
ol ((2R,4R,6R)-cis-50) and (2R,4S,6R,E)-2,4-Dimethyl-6-styryl-
tetrahydro-2H-pyran-4-ol ((2R,4S,6R)-cis-50). (R)-4 (15.0 g,
0.079 mol) was treated with allylmagnesium chloride (prepared
from 0.174 mol of allyl chloride and 0.208 mol of Mg in THF
solution) at -10 °C in THF solution (350 mL). The reaction mixture
was quenched with NH4Cl and extracted with ethyl acetate. The
organic phase was dried (Na2SO4) and concentrated under reduced
pressure to give a 1:1 mixture of the two possible diastereoisomers
of 49 (15.0 g, 82%), which was used for the subsequent step without
further purification.
A solution of 49 (two stereoisomers, 15.0 g, 0.065 mol) was
added to a mixture of mercuric acetate (20.7 g, 0.065 mol) in THF
(100 mL) and water (25 mL). The reaction mixture was stirred
overnight at room temperature. NaBH4 (2.45 g, 0.065 mol) was
added, and the mercury was allowed to settle. The reaction mixture
was diluted with water and filtered on a Celite pad. The filtrate
was extracted with ethyl acetate, dried (Na2SO4), and concentrated
under reduced pressure. The residue was chromatographed on a
silica gel column (hexane:ethyl acetate 95/5) to give, in order of
elution, (2R,4R,6R)-cis-50 (4.82 g, 32%) and (2R,4S,6R)-cis-50
(5.58 g, 37%).
1
g, 85%): [R]D ) +8.48 (c ) 0.78, CHCl3); H NMR (250 MHz,
CDCl3) δ 7.40-7.15 (m, 5H), 6.61 (d, 1H, J ) 16.0 Hz), 6.19 (dd,
1H, J ) 16.0, 6.0 Hz), 4.09 (ddd, 1H, J ) 11.5, 6.0, 2.4 Hz), 3.64
(ddq, 1H, J ) 11.5, 2.1, 6.1 Hz), 2.26 (dt, 1H, J ) 12.9, 2.1 Hz),
2.16 (dt, 1H, J ) 12.9, 2.1 Hz), 1.99 (s, 3H), 1.71 (t, 1H, J ) 12.3
Hz), 1.69 (s, 3H), 1.57 (t, 1H, J ) 12.3 Hz), 1.26 (d, J ) 6.2, 3H);
13C NMR (62.90 MHz, CDCl3) δ 170.3, 136.7, 130.8, 129.4, 128.4,
127.6, 126.4, 80.1, 74.7, 70.3, 44.5, 42.8, 22.4, 22.2, 21.8; GC/MS
tR 24.79 min, m/z 214 (M+ - 60, 100), 199 (27), 131 (20). Anal.
Calcd for C17H22O3: C, 74.42; H, 8.08. Found: C, 74.51; H, 8.14.
(2R,4R,6R)-2-(Hydroxymethyl)-4,6-dimethyl-tetrahydro-2H-
pyran-4-yl Acetate ((2R,4R,6R)-cis-52). Compound (2R,4R,6R)-
cis-51 (4.80 g, 0.017 mol) was ozonized in methylene chloride/
methanol 2:1 solution (70 mL) at -78 °C. The reaction mixture
was quenched with sodium boron hydride. After column chroma-
tography (hexane/ethyl acetate 8:2) compound (2R,4R,6R)-cis-52
was recovered (2.40 g, 70%): [R]D ) -6.05 (c ) 0.89, CHCl3);
1H NMR δ 3.71 (m, 2H), 3.63 (dd, 1H, J ) 11.5, 3.0 Hz), 3.49
(dd, 1H, J ) 11.5, 6.7 Hz), 2.27 (dt, 1H, J ) 14.1, 2.2 Hz), 2.14
(dt, 1H, J ) 14.1, 2.2 Hz), 2.01 (s, 3H), 1.52 (s, 3H), 1.27 (dd, 1H,
J ) 14.0, 11.5 Hz), 1.18 (d, J ) 6.3, 3H), 1.16 (dd, 1H, J ) 14.0,
11.5 Hz); 13C NMR (62.90 MHz, CDCl3) δ 170.3, 79.5, 73.1, 68.7,
65.8, 43.2, 37.1, 26.1, 22.3, 21.3; GC/MS tR 14.58 min, m/z 171
(M+ - 31, 1), 124 (5), 111 (100), 43 (55). Anal. Calcd for
C10H18O4: C, 59.39; H, 8.97. Found: C, 59.47; H, 8.84.
(2R,4S,6R)-2-(Hydroxymethyl)-4,6-dimethyl-tetrahydro-2H-
pyran-4-yl Acetate ((2R,4S,6R)-cis-52). (2R,4S,6R)-cis-51 (5.20
g, 0.019 mol) was ozonized in methylene chloride/methanol 2:1
solution (70 mL) at -78 °C. The reaction mixture was quenched
with sodium boron hydride. After column chromatography (hexane/
ethyl acetate 8:2) compound (2R,4S,6R)-cis-52 was recovered (2.61
Data of (2R,4R,6R)-cis-50: [R]D ) +8.63 (c ) 0.90 CHCl3);
1H NMR (250 MHz, CDCl3) δ 7.43-7.15 (m, 5H), 6.61 (d, 1H, J
) 15.9 Hz), 6.2 (dd, 1H, J ) 15.9, 6.2 Hz), 4.40 (ddd, 1H, J )
11.5, 6.2, 2.2 Hz), 3.94 (ddq, 1H, J ) 11.5, 2.2, 6.2 Hz), 1.68 (dt,
1H, J ) 13.6, 2.2 Hz), 1.59 (dt, 1H, J ) 13.6, 2.2 Hz), 1.48 (dd,
1H, J ) 13.5, 11.6 Hz), 1.34 (dd, 1H, J ) 13.5, 11.6 Hz), 1.29 (s,
3H), 1.24 (d, 3H, J ) 6.3 Hz); 13C NMR (62.90 MHz, CDCl3) δ
137.0, 130.5, 130.4, 128.5, 127.5, 126.5, 73.6, 69.0, 68.6, 45.8,
44.2, 31.7, 21.7; GC/MS tR 23.23 min, m/z 232 (M+, 58), 214 (25),
199 (33), 148 (23), 131 (50), 104 (100). Anal. Calcd for C15H20O2:
C, 77.55; H, 8.68. Found: C, 77.64; H, 8.59.
1
g, 68%): [R]D ) -10.11 (c ) 1.05, CHCl3); H NMR δ 3.67-
3.47 (m, 4H), 2.13 (dt, 1H, J ) 12.9, 2.1 Hz), 2.03 (dt, 1H, J )
12.9, 2.1 Hz), 1.97 (s, 3H), 1.63 (s, 3H), 1.58 (t, 1H, J ) 12.3 Hz),
1.51 (t, 1H, J ) 12.3 Hz), 1.21 (d, J ) 6.3, 3H); 13C NMR (62.90
MHz, CDCl3) δ 170.2, 80.1, 74.6, 70.2, 66.0, 44.7, 38.5, 22.4, 22.2,
21.7; GC/MS tR 15.78 min, m/z 171 (M+ - 31, 2), 111 (100), 43
(55). Anal. Calcd for C10H18O4: C, 59.39; H, 8.97. Found: C, 59.30;
H, 9.05.
Data of (2R,4S,6R)-cis-50: [R]D ) +14.3 (c ) 0.95, CHCl3);1H
NMR (250 MHz, CDCl3) δ 7.45-7.15 (m, 5H), 6.60 (d, 1H, J )
15.9 Hz), 6.2 (dd, 1H, J ) 15.9, 5.9 Hz), 4.04 (ddd, 1H, J ) 11.0,
5.9, 2.0 Hz), 3.60 (m, 1H), 1.80-1.40 (m, 4H), 1.37 (s, 3H), 1.26
(d, 3H, J ) 6.3 Hz); 13C NMR (62.90 MHz, CDCl3) δ 136.8, 130.7,
129.8, 128.5, 127.6, 126.5, 75.6, 71.2, 69.3, 47.8, 46.1, 26.90, 21.9;
GC/MS tR 23.40 min, m/z 232 (M+, 24), 214 (27), 199 (24), 148
(38), 131 (45), 104 (100). Anal. Calcd for C15H20O2: C, 77.55; H,
8.68. Found: C, 77.42; H, 8.76.
(2SR,4RS,6RS)-2-Butyl-4,6-dimethyl-tetrahydro-2H-pyran-4-
ol (cis-47a). Compound (2RS,4RS,6RS)-cis-52 (2.30 g, 0.011 mol)
was treated with p-toluenesulfonyl chloride (2.51 g, 0.013 mol) in
pyridine. After the usual workup the tosylate derivative was
34
dissolved in THF (50 mL), and Li2CuCl4 (1.3 mmol, prepared
from 1.3 mmol of CuCl2 and 2.6 mmol of LiCl) was added.
Propylmagnesium bromide (prepared from 0.0132 mol of propyl
bromide and 0.016 mol of magnesium) was added at -10 °C. The
reaction mixture was stirred at 0 °C for 1 h and then poured into
ice and quenched with a saturated solution of ammonium chloride.
The mixture was extracted with ethyl acetate; the organic phase
was dried (Na2SO4) and concentrated under reduced pressure.
Column chromatography (hexane/ethyl acetate 95/5) afforded cis-
47a (1.31 g, 64%): 1H NMR δ 3.77 (ddq, 1H, J ) 11.5, 1.6, 6.2
Hz), 3.62 (m, 1H), 1.58-1.18 (m, 10H), 1.24 (s, 3H), 1.17 (d, J )
6.2, 3H), 0.89 (t, 3H, J ) 6.8 Hz); 13C NMR (62.90 MHz, CDCl3)
72.9, 68.8, 68.7, 46.3, 44.3, 35.9, 31.72, 27.8, 22.8, 21.7, 14.0;
(2R,4R,6R)-2,4-Dimethyl-6-((E)-styryl)-tetrahydro-2H-pyran-
4-yl Acetate ((2R,4R,6R)-cis-51). A mixture of compound
(2R,4R,6R)-cis-51 (4.70 g, 0.020 mol) and sodium acetate (1.99 g,
0.024 mol) in acetic anhydride (25 mL) was refluxed for 2 h. The
reaction mixture was poured into ice and extracted with ethyl
acetate. The organic phase was dried (Na2SO4) and concentrated
under reduced pressure to give compound (2R,4R,6R)-cis-51 (4.93
1
g, 90%): [R]D ) -11.7 (c ) 1.10, CHCl3); H NMR (250 MHz,
CDCl3) δ 7.5-7.1 (m, 5H), 6.65 (d, 1H, J ) 16.0 Hz), 6.19 (dd,
1H, J ) 16.0, 6.0 Hz), 4.26 (ddd, 1H, J ) 11.5, 6.0, 2.4 Hz), 3.79
(ddq, 1H, J ) 11.5, 1.9, 6.2 Hz), 2.34 (m, 2H), 2.06 (s, 3H), 1.54
(s, 3H), 1.37 (dd, 1H, J ) 13.8, 11.5 Hz), 1.24 (m + d, J ) 6.3,
4H); 13C NMR (62.90 MHz, CDCl3) δ 170.4, 136.8, 130.6, 129.7,
128.4, 127.6, 126.4, 79.7, 73.2., 68.6, 42.9, 41.7, 26.1, 22.4, 21.6;
(34) Raederstorff, D.; Shu, A. Y. L.; Thompson, J. E.; Djerassi, C. J.
Org. Chem. 1987, 52, 2337-2346.
J. Org. Chem, Vol. 71, No. 14, 2006 5239

Abate et al.
GC/MS tR 11.45 min, m/z 168 (M+ - 18, 27), 153 (18), 129 (73),
87 (95), 58 (100), 43 (91). Anal. Calcd for C11H22O2: C, 70.92; H,
11.90. Found: C, 70.85; H, 11.82.
reaction product was chromatographed on a silica gel column
(hexane/ethyl acetate 98/2) to afford a 1:1:3.5 mixture of the three
regioisomers 48a, 48b, and 48c (0.715 g, 55%). Anal. Calcd for
C11H20O: C, 78.51; H, 11.98. Found: C, 78.60; H, 11.89.
Data of 48a and 48b: 1H NMR δ (main signals) 5.32 and 5.29
(m), 4.12 and 4.00 (m), 3.62 and 3.46 (m), 1.66 (s), 1.22 and 1.18
(d, J ) 6.2 Hz), 0.90 (t, J ) 6.8 Hz); GC/MS first peak tR 8.65
(2SR,4SR,6RS)-2-Butyl-4,6-dimethyl-tetrahydro-2H-pyran-4-
ol (cis-47b). Compound (2RS,4SR,6RS)-cis-52 (2.50 g, 0.012 mol)
was treated with p-toluenesulfonyl chloride (2.82 g, 0.015 mol) in
pyridine (30 mL). After the usual workup the tosylate derivative
was dissolved in THF. Propylmagnesium bromide (prepared from
0.0132 mol of propyl bromide and 0.016 mol of magnesium) was
added at -10 °C. The reaction mixture was stirred and then poured
into ice and quenched with a saturated solution of ammonium
chloride. The mixture was extracted with ethyl acetate; the organic
phase was dried (Na2SO4) and concentrated under reduced pressure.
Column chromatography (hexane/ethyl acetate 95/5) afforded cis-
47b (1.36 g, 61%): 1H NMR δ 3.45 (ddq, 1H, J ) 11.5, 1.5, 6.1
Hz), 3.30 (m, 1H), 1.67-1.22 (m, 10H), 1.30 (s, 3H), 1.20 (d, J )
6.2, 3H), 0.90 (t, 3H, J ) 6.8 Hz); 13C NMR (62.90 MHz, CDCl3)
75.1, 70.9, 69.4, 48.2, 46.2, 36.1, 27.8, 26.1, 22.7, 21.9, 14.0; GC/
MS tR 11.82 min, m/z 168 (M+ - 18, 6), 153 (3), 129 (71), 87
(94), 58 (88), 43 (100). Anal. Calcd for C11H22O2: C, 70.92; H,
11.90. Found: C, 71.01; H, 11.98.
(2RS,6SR)-6-Butyl-2,4-dimethyl-3,6-dihydro-2H-pyran (48a
or 48b), (2SR,6RS)-2-Butyl-4,6-dimethyl-3,6-dihydro-2H-pyran
(48b or 48a), and (2SR,6RS)-2-Butyl-6-methyl-4-methylene-
tetrahydro-2H-pyran (48c). (a) Dehydration of cis-47a. To a
solution of cis-47a (1.20 g, 6.45 mmol) in pyridine (10 mL) at 0
°C phosphorus oxychloride (1.18 g, 7.74 mmol) was added. The
reaction mixture was stirred at room temperature for 1 h. After the
usual workup the crude reaction product was chromatographed on
a silica gel column (hexane/ethyl acetate 98/2) to afford a 3:3:1
mixture of the three regioisomers 48a, 48b, and 48c (0.754 g, 58%).
(b) Dehydration of cis-47b. To a solution of cis-47b (1.20 g,
6.45 mmol) in pyridine (10 mL) at 0 °C phosphorus oxychloride
(1.18 g, 7.74 mmol) was added. The reaction mixture was stirred
at room temperature for 1 h. After the usual workup the crude
-
min, m/z 153 (M+ 15, 8), 126 (29), 111 (100), second peak tR
8.78 min, m/z 168 (M+, 54), 153 (61), 110 (77), 43 (100).
Data of 48c: 1H NMR δ (main signals) 4.68 (t, 1H, J ) 1.8
Hz), 3.37 (ddq, 1H, J ) 11.2, 2.2, 6.1 Hz), 3.22 (m, 1H), 2.18 (m),
1.22 (d, 3H, J ) 6.1 Hz), 0.90 (t, J ) 6.8 Hz); GC/MS tR 8.15
min, m/z 168 (M+, 17), 124 (8), 111 (42), 67 (100).
Acknowledgment. The authors thank Dr. Philip Kraft
(Givaudan Schweiz AG, Fragrance Research, Switzerland) for
the odor descriptions. COFIN-Murst is acknowledged for
financial support.
Supporting Information Available: Experimental details are
given for the preparation of (E)-4-hydroxy-5-methyl-6-phenylhex-
5-en-2-one (5), (3RS,4RS,5E)-4-hydroxy-3-methyl-6-phenylhex-5-
en-2-one (anti-6), (3RS,4SR,5E)-4-hydroxy-3-methyl-6-phenylhex-
5-en-2-one (syn-6), (3RS,4RS)-4-(furan-2-yl)-4-hydroxy-3-methylbu-
tan-2-one (syn-42), and (3RS,4SR)-4-(furan-2-yl)-4-hydroxy-3-
methylbutan-2-one (anti-42), reduction of hydroxy ketones 4-6
and 42 to diols 1-3 and 41, configurational assignment of
monoacetate (+)-anti-17 by chemical correlation to (R)-(-)-20,
lipase PS-mediated acetylation of 41 (four stereoisomers), prepara-
tion of (2RS,4R,5E)-6-phenylhex-5-ene-2,4-diol ((2RS,4R)-3) and
(1RS)-1-((4RS,6RS)-2,2,6-trimethyl-1,3-dioxan-4-yl)prop-2-en-1-
ol ((1RS)-syn-35), and X-ray analysis of anti,anti-3, anti,syn-22,
and anti-24. This material is available free of charge via the Internet
at http://pubs.acs.org.
JO060581W
5240 J. Org. Chem., Vol. 71, No. 14, 2006