Oxygenated stereotriads with definite absolute configuration by lipase-mediated kinetic resolution: De novo synthesis of imino sugars and 6-deoxy- C-glycosides

Article abstract of DOI:10.1002/ejoc.201000558

The lipase-mediated kinetic resolution of compound 1 was investigated, to prepare chiral synthons showing oxygenated stereotriads in a definite configurational arrangement. These key intermediates were embedded in biologically relevant structures, such as hydroxylated pyrrolidine 3 and C-phenyl glycosides by classical organic reactions.

Full text of DOI:10.1002/ejoc.201000558

FULL PAPER
DOI: 10.1002/ejoc.201000558
Oxygenated Stereotriads with Definite Absolute Configuration by Lipase-
Mediated Kinetic Resolution: De Novo Synthesis of Imino Sugars and
6-Deoxy-C-glycosides
Daniela Acetti,[a] Elisabetta Brenna,*[a] and Francesco G. Gatti[a]
Keywords: Iminosugars / Enzymes / Kinetic resolution / Chirality / C-glycosides
The lipase-mediated kinetic resolution of compound 1 was
investigated to prepare chiral synthons showing oxygenated
stereotriads in a definite configurational arrangement. These
key intermediates were embedded in biologically relevant
structures, such as hydroxylated pyrrolidine 3 and C-phenyl
glycosides by classical organic reactions.
Imino sugars II and III have been widely investigated due
to their potential as glycosidase inhibitors.[2] Both natural
and non-natural hydroxylated pyrrolidines and piperidines
were prepared to investigate the influence of substituents
and configurational and conformational changes on inhibi-
tion.[3] 2,6-Dideoxypyranosides IV are essential compo-
nents of steroidal glycosides, antibiotics and antitumour
compounds.[4] They are scarcely available from microbial
sources, and their preparation is still the object of intense
investigation,[5]even according to de novo approaches.[6] C-
Glycosides V, particularly those showing Y = aryl, have
been found to possess antibacterial, antitumour and anti-
fungal activities.[7] These characteristics, in addition to their
limited availability from natural sources, makes them intri-
guing and timely targets for total synthesis.
Introduction
The single enantiomers of configurationally defined
stereotriads are very precious building blocks of modern
organic chemistry:[1] if they show adequate functionalis-
ation, such as those of type I (Scheme 1), they can be incor-
porated into chiral molecules with multiple stereogenic
centres, such as glycosidase inhibitors II and III or deoxy-
sugar derivatives IV and V.
In the aim of synthesising useful oxygenated synthons
showing stereochemical differentiation, we investigated the
kinetic resolution of substrate 1 (Scheme 2) mediated by li-
pase PS. Single stereoisomers of acetates 2 were obtained,
their absolute configurations were established, and they
were converted into imino sugar 3 and deoxysugar deriva-
tives 4 to show the structural differentiation that these build-
ing blocks can afford.
Scheme 1. X, Y, Z = suitable functional groups, or alkyl or aryl
substituents.
The common strategies to synthons I usually start from
carbohydrates available from the chirality pool, and they are
thus finalised to the synthesis of a single configurational
isomer, the one allowed by the stereochemistry of the start-
ing natural building block. Sometimes stereodiversity has
to be achieved, either to investigate the biological activity
of all the different stereoisomers of a certain molecule or
to obtain configurations that are complementary to those
available from natural sources.
[a] Politecnico di Milano, Dipartimento di Chimica, Materiali,
Ingegneria Chimica,
Via Mancinelli 7, 20131 Milano, Italy
Fax: +39-02-23993180
E-mail: elisabetta.brenna@polimi.it
Supporting information for this article is available on the
WWW under http://dx.doi.org/10.1002/ejoc.201000558.
Scheme 2.
4468
© 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2010, 4468–4475

Oxygenated Stereotriads with Definite Absolute Configuration
(R,4S,5S)-2a (99%ee, HPLC of the corresponding alcohol
on a chiral column) was obtained after 48 h at room tem-
perature (Scheme 4). The unreacted alcohols consisted of
three stereoisomers, which were submitted again to lipase-
mediated kinetic resolution under the same conditions to
afford, after 96 h at room temperature, acetate (R,4R,5R)-
2b (99%ee, HPLC of the corresponding alcohol on a chiral
column) and a 1:1 mixture of alcohols (S,4R,5R)-1a and
(S,4S,5S)-1b.
Acetate (+)-2b was submitted to ozonolysis followed by
NaBH4 quenching to obtain, after saponification
(Scheme 4), the O3,O4-isopropylidene derivative of 1-deoxy-
-lyxitol (–)-7b of known absolute configuration.[9] Thus,
the relative anti stereochemistry of C-4 and C-5 was estab-
lished and (R) configuration was assigned to the stereogenic
carbon atom bearing the OH group acetylated by lipase PS
in (+)-2b, and by analogy in (–)-2a. This attribution was
also confirmed by the transformation of (–)-2a into the cor-
responding known pyrrolidine (2S,3S,4S)-(+)-3.
Results and Discussion
Kinetic Resolution of Substrates 1a–d
Aldolic condensation of cinnamaldehyde and hy-
droxyacetone in methanol solution promoted by 40%
NaOH (Scheme 3) afforded a 1:0.8 mixture of the two race-
mic diastereoisomers of dihydroxy ketone 5. After aceto-
nide protection, diastereoisomers 6a and 6b could be sepa-
rated by column chromatography and submitted separately
to NaBH4 reduction to give a 1:1 mixture of alcohols 1a/
1b and 1c/1d, respectively. The relative configuration of the
two acetonide derivatives was first tentatively assigned: a
1
crude mixture showing the H NMR signals of 5-deoxy-
2,3-O-isopropylidene-β-ribofuranose[8] was recovered from
the ozonolysis and dimethyl sulfide quenching of a mixture
of 1c and 1d. This attribution was then confirmed by the
outcome of the sequence that was developed starting from
these substrates.
Interestingly, when rac-1c and rac-1d (Scheme 5) were
treated with lipase PS under the same transesterification
conditions, enantiopure acetates (R,4R,5S)-2c (99%ee,
HPLC of the corresponding alcohol on a chiral column)
and (R,4S,5R)-2d (99%ee, HPLC of the corresponding
alcohol on a chiral column) were simultaneously obtained
and separated by column chromatography. A mixture of
(S,4S,5R)-1c and (S,4R,5S)-1d was left unreacted after the
enzyme-mediated kinetic resolution.
Acetate (+)-2d was submitted to ozonolysis followed by
NaBH4 quenching to obtain, after deprotection and acety-
lation, the tetracetyl derivative of 1-deoxy--arabitol (+)-8
of known absolute configuration.[10] Thus, the (R) configu-
ration was established for the stereogenic carbon atom bear-
ing the OH group acetylated by lipase PS in (+)-2d, and by
analogy in (–)-2c. The relative configurations of the ste-
reocentres in the 4- and 5-positions of starting acetonide 1d
were also confirmed.
Scheme 3. Reagents and conditions: (i) Hydroxyacetone, NaOH
40%, MeOH; (ii) 2,2-dimethoxypropane, PPTS, acetone, column
chromatography; (iii) NaBH4, CH2Cl2, MeOH.
When the 1:1 mixture of rac-1a and rac-1b (four stereo-
isomers) was treated with lipase PS in methyl tert-butyl
This latter information was also supported by isolation
ether solution in the presence of vinyl acetate, acetate of derivative 9, then converted into the O3,O4-isopropylid-
Scheme 4. Reagents and conditions: (i) Lipase PS, vinyl acetate, methyl tert-butyl ether, column chromatography; (ii) O3, MeOH/CH2Cl2,
then NaBH4; (iii) KOH, MeOH.
Eur. J. Org. Chem. 2010, 4468–4475
© 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
4469

D. Acetti, E. Brenna, F. G. Gatti
FULL PAPER
described to be obtained[16] also from the corresponding N-
oxide, prepared from -ribose by unsaturated hydroxyl-
amine, employing the nitrone addition and the Cope–House
cyclisation. The employment of stereoselective hetero-
Diels–Alder reactions either with chiral N-dienylpyro-
glutamates or with chiral p-tolylsulfinyl-1,3-pentadiene with
nitrosoformates, followed by osmylation and suitable
chemical transformations, afforded (2S,3R,4S)-[17] and
(2S,3S,4R)-3,[18] and a derivative of the latter.[19] Com-
pound (2S,3R,4S)-3 was also obtained[20] as a hydrochloric
acid salt from 1-hydroxymethyl-4-sulfonylbutadiene, em-
ploying a Sharpless epoxidation. In 2002,[21] (2S,3S,4S)-3
was prepared by MeMgBr addition to the succinimide de-
rived from -tartaric acid, followed by stereocontrolled tri-
Scheme 5. Reagents and conditions: (i) Lipase PS, vinyl acetate,
methyl tert-butyl ether, column chromatography; (ii) O3, MeOH/ ethylsilane-promoted reduction of the resulting cyclic
CH2Cl2, then NaBH4; (iii) KOH, MeOH; (iv) HCl, AcOH, THF/
amidol. In 2007, the same enantiomer was prepared by Chi-
H2O; (v) Ac2O, pyridine.
Huey Wong[22] by -fructose-6-phosphate aldolase cata-
lysed reaction of azido acetaldehyde and hydroxyacetone,
followed by hydrogenation in the presence of Pd(OH)2/C.
ene derivative of 1-deoxy--ribitol (+)-7c of known absolute
configuration,[11] besides the monoacetate of 1-deoxyarabit-
ol 10, from the mixture of 1c and 1d recovered unreacted
from lipase PS treatment (Scheme 6). After acetylation with
Ac2O and pyridine, the mixture of 1c and 1d was treated
with O3 followed by reductive quenching to afford
monoacetates 9 and 10. The migration of the acetyl group
occurred only in one stereoisomer, and thus we could sepa-
rate them by column chromatography. Compound 9 gave
(+)-7c upon saponification.
Scheme 7. Isomers of pyrrolidine 3 known in the literature.
We envisaged the possibility to synthesise pyrrolidine 3
by means of our chiral synthons: enantiopure acetate
(R,4S,5S)-2a was employed as a model starting material to
investigate the synthetic procedure reported in Scheme 8
and to prepare the single stereoisomer (2S,3S,4S)-3. The
key steps were the conversion of aldehyde 12 into nitrile 13
by reaction with iodine and ammonium hydroxide in THF,
and the final ring closure to pyrrolidine 3 by intramolecular
nucleophilic substitution of the amino function on the mes-
ylate group in derivative 15.
Scheme 6. Reagents and conditions: (i) Ac2O, pyridine; (ii) O3,
MeOH/CH2Cl2; then NaBH4, column chromatography; (iii) KOH,
MeOH.
Stereoselective Synthesis of Pyrrolidine 3
Scheme 8. Reagents and conditions: (i) KOH/MeOH; (ii) O3,
–78 °C, then (CH3)2S; (iii) I2, NH3 30%, THF, room temp.;
(iv) MsCl/Py, 0 °C; (v) Boc2O, NiCl2·6H2O, then NaBH4 at 0 °C;
(vi) HCl/MeOH; (vii) K2CO3/acetone.
Much interest has been devoted recently to the chemistry
and the biological activity of polyhydroxylated pyrrolidines
3,[12] because they have been shown to selectively inhibit the
oligosaccharide processing enzyme called glycosidases.[13]
Thus, they are potentially useful as antiviral, antiadhesive,
antimetastatic and antibacterial agents.[14]
Acetate (R,4S,5S)-2a was submitted to saponification,
followed by ozonolysis and dimethyl sulfide quenching. Al-
Stereoisomer (2R,3R,4S)-3 (Scheme 7) was prepared in dehyde (4R,5S,R)-12 was recovered and reacted with NH3
1995 by Chi-Huey Wong[15] starting from -ribose, and by and I2 to afford nitrile (4S,5S,R)-13, which was treated with
selectively converting the OH at C-4 into an amino func- mesyl chloride in pyridine to afford derivative (R,4R,5S)-
tionality. The hydrobromic acid salt of this enantiomer was 14.[23] Reduction of the nitrile moiety with concomitant
4470
www.eurjoc.org
© 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2010, 4468–4475

Oxygenated Stereotriads with Definite Absolute Configuration
protection of the resulting amine gave derivative (R,4R,5S)- products of ketal migration to the syn OH groups in the
15.[24] Treatment with hydrochloric acid promoted the re- ring closed derivatives obtained from the epoxidation of the
moval of the Boc protecting group and the acetonide moi- Re–Re face of 1a and the Si–Si face of 1b, respectively; a
ety: subsequent reaction with potassium carbonate in ace- 1:1 mixture of triols 21a and 21b, obtained from deprotec-
tone allowed us to obtain the enantiopure five-membered tion of the C-glycosides derived from the epoxidation of the
ring amino sugar (2S,3S,4S)-3.
Si–Si face and the Re–Re face of 1a and 1b, respectively.
Stereoselective Synthesis of 6-Deoxy-C-phenylglycosides
C-Aryl glycosides[25] are characterised by the presence of
a carbohydrate moiety that is directly attached to an aro-
matic ring through a C–C bond rather than a C–O bond.
This type of connectivity makes them quite stable to both
enzymatic and acid hydrolysis: they are indeed potent en-
zyme inhibitors and substrates for carbohydrate-binding
proteins.[26] Most of the existing strategies that lead to sim-
ple C-aryl glycosides are based on the formation of the key
C–C bond between the carbohydrate and the aromatic com-
ponents.[27] A few have involved the construction of the
sugar fragment from nonsaccharide precursors.[28] The
chemical structure of the chiral synthons prepared in this
work allowed the de novo preparation of C-glycosides ac-
cording to this second approach by epoxidation of the
double bond conjugated with the aromatic ring.
Treatment of compound (R,4R,5S)-1c, obtained upon
saponification of acetate (R,4R,5S)-2c (Scheme 5), with m-
chloroperbenzoic acid followed by column chromatography
separation allowed the isolation of two fractions
(Scheme 9). The first one consisted of a 1:1 mixture of the
two ring-closed acetonide derivatives 16 and 17, and the
second one was found to be C-phenyl-β--alloside 18. In-
tramolecular ring closure occurred during the reaction and
its workup, with either migration or loss of the acetonide
Scheme 10. Reagents and conditions: (i) m-chloroperbenzoic acid,
CH2Cl2, 0 °C; (ii) workup, then column chromatography.
The ratio of these epoxidation products was calculated
protection. Acetonides 16 and 17 were converted into deriv- from the weight of the isolated products: 20a/20b/mixture
ative 18 by acid hydrolysis. The epoxidation reaction was 21a,21b = 1.4:1.0:6.8. Diastereoselectivity was not complete
totally stereoselective on the Si–Si face of the double bond, as observed in the case of substrate 1c, but it was found to
affording only β--alloside 18, whose relative configuration be in favour of the conformationally most stable glycosides
1
was assigned by analysis of the H NMR spectra of the for both 1a (48%) and 1b (54%). Compounds 20a and 20b
corresponding triacetate derivative 19.
were characterised as acetyl derivatives, then submitted to
When a 1:1 mixture of unreacted alcohols (S,4R,5R)-1a acid hydrolysis and extensive acetylation to afford the tri-
(99%ee, HPLC) and (S,4S,5S)-1b (99%ee) was treated with acetates of β--guloside 22 and α--mannoside 23
m-chloroperbenzoic acid (Scheme 10), the following prod- (Scheme 11). The relative configuration of compound 22
ucts in order of elution could be isolated by column was confirmed by NOE experiments. When the hydrogen
chromatography: acetonides 20a and 20b, which are the atom at C-2 was irradiated, NOE effects were observed on
Scheme 9. Reagents and conditions: (i) m-chloroperbenzoic acid, CH2Cl2, 0 °C; then column chromatography; (ii) 37% HCl, AcOH in
THF/H2O; (iii) Ac2O, pyridine.
Eur. J. Org. Chem. 2010, 4468–4475
© 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
4471

D. Acetti, E. Brenna, F. G. Gatti
FULL PAPER
tion of the solvents. Column chromatography of this residue gave
acetate (R,4S,5S)-2a (1.5 g, 18.5 %). The starting material (5 g,
0.020 mol) was submitted again to lipase PS reaction, and after
96 h, acetate (R,4R,5R)-2b was recovered (1 g, 17 %). Data for
(R,4S,5S)-2a: 1H NMR (400 MHz, CDCl3): δ = 7.23–7.41 (m, 5 H,
Ar), 6.67 (d, J = 15.9 Hz, 1 H, Ar-CH), 6.14 (dd, J = 7.5, 15.9 Hz,
1 H, ArCH=CH), 5.08 (dq, J = 6.5, 4.5 Hz, 1 H, CH-OAc), 4.38
(t, J = 7.9 Hz, =CH-CH-O), 3.84 (dd, J = 4.5, 8.1 Hz, 1 H, CH-
O), 2.08 (s, 3 H, OAc), 1.48 (s, 3 H, CCH3), 1.46 (s, 3 H, CCH3),
1.30 (d, J = 6.7 Hz, 3 H, CHCH3) ppm. 13C NMR (100.6 MHz,
CDCl3): δ = 16.7, 21.1, 26.6, 27.1, 68.6, 78.3, 82.4, 109.4, 126.1,
H–C-3 (10%) and H–C-6 (13%). The 1:1 mixture of 21a
and 21b was acetylated to give the corresponding acetyl de-
rivatives of α--idoside 24 and β--glucoside 25
(Scheme 11).
Scheme 11.
126.6, 128.0, 128.5, 134.1, 136.1, 170.2 ppm. GC–MS: tR
=
23.45 min. GC–MS: m/z (%) = 275 (6) [M – 15], 230 (25), 172 (100),
159 (35), 145 (82). [α]2D0 = –16.4 (c = 1.17, CHCl3). Data for
(R,4R,5R)-2b: 1H NMR (400 MHz, CDCl3): δ = 7.22–7.42 (m, 5
H, Ar), 6.67 (d, J = 15.7 Hz, 1 H, ArCH), 6.16 (dd, J = 7.7,
15.7 Hz, 1 H, ArCH=CH), 5.10 (m, 1 H, CH-OAc), 4.45 (t, J =
8.0 Hz, =CH-CHO), 3.83 (dd, J = 5.5, 8.0 Hz, 1 H, CH-O), 1.98
(s, 3 H, OAc), 1.47 (s, 3 H, CCH3), 1.45 (s, 3 H, CCH3), 1.31 (d, J
= 6.7 Hz, 3 H, CHCH3) ppm. 13C NMR (100.6 MHz, CDCl3): δ
= 16.2, 20.6, 26.7, 26.5, 69.5, 79.5, 81.9, 108.9, 126.3, 127.7, 128.2,
133.4, 135.9, 169.4 ppm. GC–MS: tR = 23.24 min. GC–MS: m/z
(%) = 275 (4) [M – 15], 232 (17), 172 (100), 159 (39), 145 (87).
[α]2D0 = +33 (c = 1.2, CHCl3).
Conclusions
The structural optimisation of certain biologically rel-
evant molecular skeletons can be achieved by investigating
the effect of absolute configuration on their specific activity.
Methods to obtain these molecules in all the possible ste-
reochemical arrangements are thus required to perform this
screening. Lipase-mediated kinetic resolution of hydroxy
derivatives has been employed as a useful and versatile
method to obtain stereochemical differentiation and prepare
chiral synthons showing controlled absolute configuration.
The known preference of lipase PS for the reaction with R
stereogenic carbon atoms was confirmed also in these ki-
netic resolutions.[29] Classical organic chemistry transfor-
mations allowed the structural differentiation necessary to
embed these suitably functionalised building blocks into
biologically active molecules, such as hydroxylated pyrrol-
idines and C-phenyl glycosides.
(R)-1-{(4R,5S)-2,2-Dimethyl-5-[(E)-styryl]-1,3-dioxolan-4-yl}ethyl
Acetate [(R,4R,5S)-2c] and (R)-1-{(4S,5R)-2,2-Dimethyl-5-[(E)-styr-
yl]-1,3-dioxolan-4-yl}ethyl Acetate [(R,4S,5R)-2d]: The mixture of
racemic (RS,4RS,5SR)-1c and (SR,4RS,5SR)-1d (6 g, 0.024 mol)
was submitted to lipase PS in vinyl acetate/methyl tert-butyl ether
(1:4, 200 mL) at room temperature for 96 h. Then the enzyme was
removed, and the solvents were evaporated. Column chromatog-
raphy (hexane Ǟhexane/ethyl acetate) gave the enantiomerically
pure diastereoisomers acetate (R,4R,5S)-2c (1.3 g, 18.7%) and acet-
ate (R,4S,5R)-2d (1.2 g, 17%). Data for (R,4R,5S)-2c: 1H NMR
(400 MHz, CDCl3): δ = 7.15–7.42 (m, 5 H, Ar), 6.63 (d, J =
15.9 Hz, 1 H, ArCH), 6.12 (dd, J = 7.6, 15.9 Hz, 1 H, ArCH=CH),
4.96 (m, 1 H, CH-OAc), 4.79 (t, J = 7.0 Hz, =CHCHO), 4.13 (t, J
= 7.0 Hz, 1 H, CH-O), 1.77 (s, 3 H, OAc), 1.51 (s, 3 H, CCH3),
1.39 (s, 3 H, CCH3), 1.29 (d, J = 6.4 Hz, 3 H, CHOAcCH3) ppm.
13C NMR (100.6 MHz, CDCl3): δ = 16.9, 20.7, 25.0, 27.4, 68.6,
78.4, 79.5, 108.6, 124.1, 126.3, 127.7, 128.3, 133.0, 136.1,
169.4 ppm. GC–MS: tR = 23.01 min. GC–MS: m/z (%) = 290 (1)
[M]+, 275 (2), 230 (10), 174 (100), 159 (43), 145 (79). [α]2D0 = –4.8
(c = 1.3, CHCl3). Data for (R,4S,5R)-2d: 1H NMR (400 MHz,
CDCl3): δ = 7.20–7.40 (m, 5 H, Ar), 6.64 (d, J = 15.9 Hz, 1 H,
ArCH), 6.13 (dd, J = 7.9, 15.9 Hz, 1 H, ArCH=CH), 4.99 (q, J =
6.5 Hz, 1 H, CH-OAc), 4.74 (t, J = 7.2 Hz, =CH-CH-O), 4.14 (t,
J = 6.5 Hz, 1 H, CH-O), 2.02 (s, 3 H, OAc), 1.56 (s, 3 H, CCH3),
1.41 (s, 3 H, CCH3), 1.22 (d, J = 6.4 Hz, 3 H, CHCH3) ppm. 13C
NMR (100.6 MHz, CDCl3): δ = 16.9, 21.1, 25.5, 27.4, 68.4, 78.4,
80.3, 109.0, 124.2, 126.5, 127.9, 128.5, 133.9, 136.1, 169.9 ppm.
GC–MS: tR = 23.31 min. GC–MS: m/z (%) = 290 (1) [M]+, 275 (3),
230 (12), 174 (100), 159 (46), 145 (91). [α]2D0 = +19.17 (c = 1.1,
CHCl3).
Experimental Section
General Methods: Lipase PS “ Amano” SD from Burkholderia ce-
pacia (Amano Enzyme Inc. Japan) was employed in this work. GC–
MS analyses were performed by using
(30 mϫ0.25 mmϫ0.25 µm). The following temperature program
was employed:
60 °C (1 min)/6 °Cmin–1/150 °C (1 min)/
a HP-5MS column
12 °Cmin–1/280 °C (5 min). 1H and 13C NMR spectra were re-
corded with a 400 MHz spectrometer. The chemical shift scale was
based on internal tetramethylsilane. Optical rotations were mea-
sured with a Dr. Kernchen Propol digital automatic polarimeter at
589 nm. TLC analyses were performed on Merck Kieselgel 60 F254
plates. All the chromatographic separations were carried out on
silica gel columns. The enantiomeric excess values were determined
by HPLC analysis by using a ChiralCel OD column, installed on
a Merck–Hitachi 1-7100 instrument with a Merck–Hitachi L-4250
UV/Vis detector: 0.6 mLmin–1, 210 nm, hexane/isopropanol (98:2):
(R,4S,5S)-1a, tR = 40.453 min; (R,4R,5R)-1b, tR = 26.8 min;
(S,4R,5R)-1a and (S,4S,5S)-1b, tR
= 18.92 and 27.03 min;
(S,4S,5R)-1c, tR = 30.39 min; (R,4R,5S)-1c, tR = 34.97 min;
(R,4S,5R)-1d, tR = 21.21 min; (S,4R,5S)-1d, tR = 22.76 min.
(R,4S,5S)-1a and (R,4R,5S)-1c: Saponification of acetate deriva-
tives (R,4S,5S)-2a (1.5 g, 5 mmol) and (R,4R,5S)-2c (1.3 g, 4 mmol)
with KOH (0.43 g, 7.6 mmol and 0.38 g, 6.7 mmol) in methanol
(30 mL for each reaction) gave (R,4S,5S)-1a (1.25 g, 97 %) and
(R,4R,5S)-1c (1.1 g, 98 %), respectively. Data for (R,4S,5S)-1a:
[α]2D0 = –1.78 (c = 1.27, CHCl3). Data for (R,4R,5S)-1c: [α]2D0 = +1.7
(c = 0.95, CHCl3).
(R)-1-{(4S,5S)-2,2-Dimethyl-5-[(E)-styryl]-1,3-dioxolan-4-yl}ethyl
Acetate [(R,4S,5S)-2a] and (R)-1-{(4R,5R)-2,2-Dimethyl-5-[(E)-styr-
yl]-1,3-dioxolan-4-yl}ethyl Acetate [(R,4R,5R)-2b]: The mixture
diastereoisomers (SR,4RS,5RS)-1a and (RS,4RS,5RS)-1b (7 g,
0.028 mol) was submitted to lipase PS in vinyl acetate/methyl tert-
butyl ether (1:4, 200 mL) at room temperature. After 36 h, the en-
zyme was filtered, and an oily residue was obtained after evapora-
(4R,5S)-5-[(R)-1-Hydroxyethyl]-2,2-dimethyl-1,3-dioxolane-4-carb-
aldehyde [(4R,5S,R)-12]: Ozonised oxygen was bubbled into a solu-
4472
www.eurjoc.org
© 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2010, 4468–4475

Oxygenated Stereotriads with Definite Absolute Configuration
tion of (R,4S,5S)-2a (1.2 g, 4.8 mmol) in CH2Cl2/MeOH (2:1) at
–78 °C until the appearance of a blue colour. Dimethyl sulfide
(0.45 g, 7.3 mmol) was added dropwise at the same temperature.
After standing 1 h at room temperature, the reaction mixture was
concentrated, and the residue was chromatographed on SiO2 (ethyl
acetate/hexane) to yield (4R,5S,R)-12 (0.6 g, 72 %). 1H NMR
(400 MHz, CDCl3): δ = 9.78 (s, 1 H, CHO), 3.8–4.1 (m, 3 H, CH-
OH, 2 CH-O), 1.51 (s, 3 H, CCH3), 1.41 (s, 3 H, CCH3), 1.26 (d,
J = 6.6 Hz, 3 H, CHCH3) ppm. 13C NMR (100.6 MHz, CDCl3): δ
= 18.6, 26.3, 26.6, 67.1, 80.5, 81.1, 110.9, 200.98 ppm. GC–MS: tR
= 8.75 min. GC–MS: m/z (%) = 159 (20) [M – 15], 145 (59), 129
(24), 101 (17), 85 (39), 59 (100). [α]2D0 = –8.04 (c = 0.9, CHCl3).
85.0 ppm. [α]2D0 = +12.9 (c = 1.04, MeOH) {ref.[22] for (2R,3R,4R)-
3: [α]2D0 = –13.3 (c = 0.71, H2O)}.
(3aR,4R,6S,7S,7aS)-2,2,4-Trimethyl-6-phenyltetrahydro-3aH-[1,3]-
dioxolo[4,5-c]pyran-7-ol (16), (3aS,4S,6R,7R,7aR)-2,2,6-Trimethyl-
4-phenyltetrahydro-3aH-[1,3]dioxolo[4,5-c]pyran-7-ol (17),
(2R,3S,4R,5R,6S)-2-Methyl-6-phenyltetrahydro-2H-pyran-3,4,5-
triol (18) and (2R,3R,4R,5S,6S)-2-Methyl-6-phenyltetrahydro-2H-
pyran-3,4,5-triyl Triacetate (19): Acetate (R,4R,5S)-2c (1.2 g,
4.1 mmol) was hydrolysed in MeOH (20 mL) with KOH (0.35 g,
6.2 mmol), and the corresponding alcohol (R,4R,5S)-1c (0.9 g,
89%) was submitted to epoxidation with m-chloroperbenzoic acid
(30% water; 0.85 g, 5.4 mmol) in CH2Cl2 (20 mL) at 0 °C. After
2 h at room temperature, the reaction mixture was poured into
water, washed with a 10% solution of sodium pyrosulfite and a
saturated solution of NaHCO3 and extracted with CH2Cl2. The
organic phase was dried (Na2SO4) and concentrated under reduced
pressure to give a residue, which was chromatographed (hexane Ǟ
hexane/ethyl acetate) to afford in order of elution first a 1:1 mixture
of derivatives 16 and 17 (0.53 g, 43%) and at the end derivative 18
(0.25 g, 27 %). Data for 16 and 17 (1:1 mixture): 1H NMR
(400 MHz, CDCl3): δ = 7.42 –7.24 (m, Ar), 4.55 (t, J = 4.4 Hz, 1
H, Heq), 4.52 (t, J = 4.4 Hz, 1 H, Heq), 4.43 (d, J = 9.6 Hz, 1 H,
CHPh), 4.35 (d, J = 9.0 Hz, CHPh), 4.08 (dd, J = 9.1, 4.6 Hz, 1
H), 3.86 (dd, J = 9.0, 4.5 Hz, 1 H), 3.82 (dd, J = 9.6, 4.4 Hz, 1 H),
3.70 (dq, J = 9.5, 6.1 Hz, 1 H, CHCH3), 3.61 (dq, J = 9.1, 6.2 Hz,
1 H, CHCH3), 3.59 (dd, J = 9.5, 4.0 Hz, 1 H), 1.64 (s, 3 H, CCH3),
1.58 (s, 3 H, CCH3), 1.43 (s, 3 H, CCH3), 1.40 (s, 3 H, CCH3), 1.38
(4S,5S)-5-[(R)-1-Hydroxyethyl]-2,2-dimethyl-1,3-dioxolane-4-carbo-
nitrile [(4S,5S,R)-13]: To a stirred solution of aldehyde 12 (0.6 g,
3.4 mmol) in THF was added 30% NH3 (20 mL) and I2 (0.9 g,
3.4 mmol) at room temperature. The initially dark coloured solu-
tion became colourless at the end of reaction (after 1 h). The mix-
ture was then poured into water, extracted with ethyl acetate (3ϫ)
and the solvent was then evaporated to give nitrile (4S,5S,R)-13
(0.5 g, 86%). 1H NMR (400 MHz, CDCl3): δ = 4.58 (d, J = 6.4 Hz,
1 H, O-CH-CN), 4.29 (dd, J = 4.2, 6.4 Hz, 1 H, CH-O), 3.84 (dq,
J = 4.2, 6.4 Hz, 1 H, CH-OH), 1.53 (s, 3 H, CCH3), 1.48 (s, 3 H,
CCH3), 1.30 (d, J = 6.4 Hz, 3 H, CHCH3) ppm. 13C NMR
(100.6 MHz, CDCl3): δ = 19.2, 24.7, 26.3, 64.5, 66.4, 83.7, 113.1,
117.9 ppm. GC–MS: tR = 9.89 min. GC–MS: m/z (%) = 156 (65)
[M – 15], 126 (39), 97 (23), 59 (33), 43 (100). [α]2D0 = –6.74 (c =
0.95, CHCl3).
(d, J = 6.2 Hz, 3 H, CHCH3), 1.30 (d, J = 6.2 Hz, 3 H, CHCH3).
1
(R)-1-[(4R,5S)-5-Cyano-2,2-dimethyl-1,3-dioxolan-4-yl]ethyl Meth- Data for (2R,3S,4R,5R,6S)-18: H NMR (400 MHz, CDCl3): δ =
anesulfonate [(R,4R,5S)-14]: Nitrile (4S,5S,R)-13 (0.5 g, 2.9 mmol)
was dissolved in pyridine (5 mL) and methanesulfonyl chloride
(0.33 g, 2.9 mmol) was added dropwise at 0 °C. After stirring for
2 h at room temperature, the reaction mixture was poured into
water and extracted with ethyl acetate. The organic phase was
washed with 1% HCl and dried with Na2SO4 to afford a residue
(0.65 g, 90%) that was submitted without any further purification
to the following reaction step.
7.37 (m, 5 H, Ar), 4.43 (d, J = 9.5 Hz, 1 H, H–C-6), 4.23 (m, 1 H,
H–C-4), 3.73 (dq, J = 9.5, 6.0 Hz, 1 H, H–C-2), 3.57 (dd, J = 9.5,
2.5 Hz, 1 H, H–C-5 or H–C-3), 3.35 (dd, J = 9.5, 2.8 Hz, 1 H, H–
C-3 or H–C-5),1.31 (d, J = 6.3 Hz, 3 H, CHCH3) ppm. 13C NMR
(100.6 MHz, CDCl3): δ = 16.9, 70.2, 73.8, 76.4, 77.7, 93.3, 126.0,
128.1, 128.6, 139.1 ppm. The compound had to be purified by con-
verting it into the corresponding triacetate by reaction with acetic
anhydride (3 mL) in pyridine (3 mL) to afford compound
1
(2R,3S,4R,5R,6S)-19 (0.36 g, 93%): H NMR (400 MHz, CDCl3):
(R)-1-{(4R,5S)-5-[(tert-Butoxycarbonylamino)methyl]-2,2-dimeth-
yl-1,3-dioxolan-4-yl}ethyl Methanesulfonate [(R,4R,5S)-15]: To a
stirred solution of (R,4R,5S)-14 (0.6 g, 2.4 mmol) in MeOH
(30 mL) was added Boc2O (1.05 g, 4.8 mmol) and a catalytic
amount of NiCl2·6H2O; then, at 0 °C, NaBH4 (0.64 g, 16.8 mmol)
was added portionwise over 30 min. The reaction mixture was
stirred for 24 h. After the usual workup, column chromatography
(hexane Ǟ hexane/ethyl acetate) gave (R,4R,5S)-15 (0.6 g, 70%).
1H NMR (400 MHz, CDCl3): δ = 4.78 (m, 1 H, CHOMs), 3.98
(ddd, J = 3.6, 5.1, 7.9 Hz, 1 H, CH2CHO), 3.77 (dd, J = 5.3,
7.9 Hz, 1 H, CH-O), 3.20–3.40 (m, 2 H, CH2NH), 3.1 (s, 3 H,
SO2CH3), 1.35–1.49 (m, 18 H) ppm. 13C NMR (100.6 MHz,
CDCl3): δ = 17.4, 27.0, 28.0, 38.2, 41.8, 76.1, 77.8, 79.4, 84.7, 109.3,
146.4, 155.7 ppm. GC–MS: tR = 24.35 min. GC–MS: m/z (%) =
282 (15) [M – 71], 223 (23), 165 (35), 127 (49), 57 (100).
δ = 7.33 (m, 5 H, Ar), 5.66 [m, 1 H, H-C(4)], 5.01 (dd, J = 10.0,
2.9 Hz, 1 H, H–C-3 or H–C5), 4.81 (dd, J = 10.0, 2.5 Hz, H–C5
or H–C-3), 4.66 (d, J = 10.0 Hz, 1 H, H–C-6), 4.03 (dq, J = 10.0,
6.0 Hz, 1 H, H–C-2), 1.23 (d, J = 6.0 Hz, 3 H, CHCH3) ppm. 13C
NMR (100.6 MHz, CDCl3): δ = 17.6, 20.3, 20.6, 20.7, 68.5, 70.4,
70.5, 75.3, 88.9, 126.0, 128.2, 128.8, 139.8, 168.7, 169.3, 169.9 ppm.
GC–MS: tR = 24.60 min. GC–MS: m/z (%) = 290 (1) [M – 60], 247
(2), 230 (100), 215 (69), 188 (24), 173 (52). [α]D = +13.9 (c = 0.95,
CHCl3). Derivatives 16 and 17 were treated with AcOH (0.5 mL)
and a few drops of 37% HCl in THF solution (5 mL) for 12 h at
room temperature. After the usual workup, the residue was acety-
lated with Ac2O (3 mL) in pyridine (3 mL) to afford triacetate
(2R,3S,4R,5R,6S)-19.
(3aR,4R,6S,7R,7aS)-2,2,6-Trimethyl-4-phenyltetrahydro-3aH-[1,3]-
dioxolo[4,5-c]pyran-7-ol (20a), (3aS,4S,6S,7S,7aR)-2,2,6-Trimethyl-
4-phenyltetrahydro-3aH-[1,3]dioxolo[4,5-c]pyran-7-ol (20b),
(2S,3S,4S,5R,6S)-2-Methyl-6-phenyltetrahydro-2H-pyran-3,4,5-triol
(21a) and (2S,3R,4R,5S,6R)-2-Methyl-6-phenyltetrahydro-2H-
pyran-3,4,5-triol (21b): A 1:1 mixture of (S,4R,5R)-1a (99%ee) and
(2S,3S,4S)-2-Methylpyrrolidine-3,4-diol [(2S,3S,4S)-3]: Compound
(R,4R,5S)-15 (0.6 g, 1.7 mmol) was treated with 37% HCl at room
temperature for 24 h in methanol solution. Then, the solvent was
removed, and the residue was treated with K2CO3 (0.25 g,
2.5 mmol) in acetone (15 mL) to obtain (2S,3S,4S)-3 (0.15, 75%): (S,4S,5S)-1b (99%ee) (2.0 g, 8.0 mmol) was submitted to epoxid-
1H NMR (400 MHz, CD3OD): δ = 4.04 (m, 1 H, CH2CHOH),
ation with m-chloroperbenzoic acid (30% water; 1.7 g, 10.8 mmol)
3.59 (dd, J = 3.2, 4.9 Hz, 1 H, CH3CHCHOH), 3.11 (dd, J = 5.3, in CH2Cl2 (20 mL) at 0 °C. After 2 h at room temperature, the reac-
12.4 Hz, 1 H, CHHNH), 2.93 (m, 1 H, CHCH3), 2.88 (dd, J = 2.1,
12.4 Hz, 1 H, CHHNH), 1.29 (d, J = 6.7 Hz, 3 H, CHCH3) ppm.
13C NMR (100.6 MHz, CD3OD): δ = 18.3, 52.9, 62.2, 79.2,
tion mixture was poured into water, washed with a 10% solution
of sodium pyrosulfite and a saturated solution of NaHCO3 and
extracted with CH2Cl2. The organic phase was dried (Na2SO4) and
Eur. J. Org. Chem. 2010, 4468–4475
© 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
4473

D. Acetti, E. Brenna, F. G. Gatti
FULL PAPER
concentrated under reduced pressure to give a residue, which was
chromatographed (hexane Ǟ hexane/ethyl acetate) to afford in or-
der of elution derivatives 20a (0.23 g, 11%), 20b (0.17 g, 8%) and
a 1:1 mixture of triols 21a and 21b (0.96 g, 54%). Compounds 20a,
20b, 21a and 21b were characterised as acetates derivatives, after
acetylation with acetic anhydride in pyridine. Data for the acetate
of (3aR,4R,6S,7R,7aS)-20a: 1H NMR (400 MHz, CDCl3): δ = 7.48
–7.28 (m, 5 H, Ar), 5.21 (t, J = 1.9 Hz, 1 H, H–C-7–OAc), 4.36 (d,
J = 9.2 Hz, 1 H, H–C-4–Ph), 4.20 (dd, J = 5.0, 2.2 Hz, H–C-7a),
4.10 (dd, J = 9.2, 5.0 Hz, 1 H, H–C-3a), 4.06 (dq, J = 1.6, 6.5 Hz,
1 H, H–C-6–CH3), 2.16 (s, 3 H, OAc), 1.62 (s, 3 H, CCH3), 1.37
(s, 3 H, CCH3), 1.24 (d, J = 6.5 Hz, 3 H, CHCH3) ppm. 13C NMR
(100.6 MHz, CDCl3): δ = 15.9, 20.5, 26.1, 28.1, 69.6, 70.9, 74.4,
75.2, 79.4, 109.3, 126.3, 127.5, 128.1, 139.9, 169.9 ppm. [α]D = +21
(c = 1.50, CHCl3). Data for the acetate of (3aS,4S,6S,7S,7aR)-20b:
1H NMR (400 MHz, CDCl3): δ = 7.45 –7.25 (m, 5 H, Ar), 5.09 (t,
J = 6.5 Hz, 1 H, H–C-7–OAc), 4.86 (d, J = 6.0 Hz, 1 H, H–C-4–
Ph), 4.44 (t, J = 6.0 Hz, H–C-7a or H–C-3a), 4.27 (t, J = 6.0 Hz,
H–C-3a or H–C-7a), 3.79 (quint., J = 6.5 Hz, 1 H, H–C-6–CH3),
2.09 (s, 3 H, OAc), 1.60 (s, 3 H, CCH3), 1.37 (s, 3 H, CCH3), 1.30
(d, J = 6.5 Hz, 3 H, CHCH3) ppm. 13C NMR (100.6 MHz, CDCl3):
δ = 16.7, 20.8, 25.8, 27.6, 69.1, 72.8, 73.3, 75.5, 76.2, 109.3, 126.6,
128.3, 129.9, 139.0, 169.7 ppm. [α]D = –10.1 (c = 1.1, CHCl3).
H, H–C-3–OAc), 5.12 (dd, J = 9.2, 3.0 Hz, H–C-4–OAc), 5.05 (d,
J = 2.4 Hz, 1 H, H–C-6–Ph), 3.64 (dq, J = 8.2, 6.2 Hz, 1 H, H–C-
2–CH3), 2.16, 2.05 and 2.01 (3 s, 9 H, 3 OAc), 1.29 (d, J = 6.4 Hz,
3 H, CHCH3) ppm. 13C NMR (100.6 MHz, CDCl3): δ = 17.3, 20.5,
20.6, 20.8, 68.9, 69.5, 69.8 71.3, 75.5, 126.2, 128.0, 128.8, 135.8,
168.9, 169.7, 170.2 ppm. GC–MS: tR = 24.56 min. GC–MS: m/z
(%) = 290 (1) [M – 60], 230 (61), 215 (50), 188 (17), 173 (100).
Supporting Information (see footnote on the first page of this arti-
cle): Experimental procedures and spectroscopic data.
[1] S. Shang, H. Iwadare, D. E. Macks, L. Ambrosini, D. Tan, Org.
Lett. 2007, 9, 1895–1898; K. A. Parker, Q. Z. Me, Org. Lett.
2008, 10, 1349–1352; K. A. Parker, H. Y. Kao, Org. Lett. 2006,
8, 3541–3544; S. R. Chemler, W. R. Roush, J. Org. Chem. 2003,
68, 1319–1333.
[2] P. Compain, O. R. Martin, Iminosugars: From Synthesis to
Therapeutic Applications, Wiley, Chichester, 2007; A. E. Stütz,
Iminosugars as Glycosidase Inhibitors: Nojirimycin and Beyond,
Wiley-VCH, Weinheim, 1999.
[3] T. D. Heightman, A. T. Vasella, Angew. Chem. Int. Ed. 1999,
38, 750–770; D. L. Zechel, S. G. Withers, Acc. Chem. Res. 2000,
33, 11–18; V. H. Lillelund, H. H. Jensen, X. Liang, M. Bols,
Chem. Rev. 2002, 102, 515–554; G. Danoun, J. Ceccon, A. E.
Greene, J.-F. Poisson, Eur. J. Org. Chem. 2009, 4221–4224; E.
Moreno-Clavijo, A. T. Carmona, Y. Vera-Ayoso, A. J. Moreno-
Vargas, C. Bello, P. Vogel, I. Robina, Org. Biomol. Chem. 2009,
7, 1192–1202.
[4] J. F. Kennedy, C. A. White, Bioactive Carbohydrates in Chemis-
try, Biochemistry and Biology, Ellis Horwood Publishers,
Chichester, 1983; A. Kirschning, A. F. W. Bechthold, J. Rohr,
Top. Curr. Chem. 1997, 188, 1–84; X. M. He, H. W. Liu, Curr.
Opin. Chem. Biol. 2002, 6, 590–597.
[5] M. T. Crimmins, A. Long, Org. Lett. 2005, 7, 4157–4160; M.
Handa, W. J. Smith, W. R. Roush, J. Org. Chem. 2008, 73,
1036–1039; H. Wehlan, M. Dauber, M. T. M. Fernaud, J.
Schuppan, S. Keiper, R. Mahrwald, M.-E. J. Garcia, U. Koert,
Chem. Eur. J. 2006, 12, 7378–7397; E. Fan, W. Shi, T. L.
Lowary, J. Org. Chem. 2007, 72, 2917–2928; D. Hou, T. L.
Lowary, J. Org. Chem. 2009, 74, 2278–2289.
[6] S. Hanessian, Total Synthesis of Natural Products: The “Chi-
ron” Approach, Pergamon Press, Oxford, 1983; F. M. Hauser,
S. R. Ellenberger, Chem. Rev. 1986, 86, 35–67; A. Kirschning,
M. Jesberger, K.-U. Schöning, Synthesis 2001, 507–540; M.
Brasholz, H.-U. Reißig, Eur. J. Org. Chem. 2009, 3595–3504.
[7] M. R. Hansen, L. H. Hurley, Acc. Chem. Res. 1996, 29, 249–
258; J. A. Moral, S.-J. Moon, S. Rodriguez-Torres, T. G. Mine-
han, Org. Lett. 2009, 11, 3734–3737.
(2S,3R,4S,5S,6S)-24 and (2S,3S,4R,5R,6R)-25: 1H NMR
(400 MHz, CDCl3): δ = 7.40–7.20 (m, Ar), 5.46 (t, J = 9.5 Hz, 1
H, H–C-4 or H–C-5 of 24), 5.30 (t, J = 9.4 Hz, 1 H, H–C-3 or H–
C-4 or H–C-5 of 25), 5.21 (dd, J = 9.9, 6.5 Hz, 1 H, H–C-3 of 24),
5.12 (t, J = 9.5 Hz, 1 H, H–C-3 or H–C-4 or H–C-5 of 25), 5.07
(t, J = 9.6 Hz, 1 H, H–C-4 or H–C-5 of 24), 4.98 (t, J = 9.6 Hz, 1
H, H–C-3 or H–C-4 or H–C-5 of 25), 4.64 (d, J = 9.7 Hz, 1 H, H–
C-6 of 24), 4.57 (quint., J = 6.5 Hz, 1 H, H–C-2–CH3 of 24), 4.37
(d, J = 9.8 Hz, 1 H, H–C-6 of 25), 3.72 (dq, J = 9.8, 6.2 Hz, 1 H,
H–C-2–CH3 of 25), 2.07, 2.00, 1.81 (3 s, 3 OAc of 24), 2.06, 1.99,
1.78 (3 s, 3 OAc of 25), 1.40 (d, J = 6.5 Hz, 3 H, CHCH3); 1.27 (d,
J = 6.1 Hz, 3 H, CHCH3) ppm. GC–MS: tR = 24.62 min. GC–MS:
m/z (%) =290 (1) [M – 60], 230 (100), 215 (70), 188 (21), 173 (100).
GC–MS: tR = 24.99 min. GC–MS: m/z (%) = 290 (1) [M – 60], 230
(100), 215 (75), 188 (21), 173 (91).
(2S,3R,4S,5R,6R)-2-Methyl-6-phenyltetrahydro-2H-pyran-3,4,5-
triyl Triacetate (22): The acetate derivative of (3aR,4R,6S,7R,7aS)-
20a (0.240 g, 0.82 mmol) was treated with AcOH (0.5 mL) and a
few drops of 37% HCl in THF solution (5 mL) for 12 h at room
temperature. After the usual workup, the residue was acetylated
with Ac2O (3 mL) in pyridine (3 mL) to afford triacetate 22 (0.21 g,
[8] M. A. Glomb, D. Rösch, R. H. Nagaraj, J. Agric. Food Chem.
2001, 49, 366–372.
1
74%). H NMR (400 MHz, CDCl3): δ = 7.40–7.20 (m, 5 H, Ar),
[9] M. A. Bukhari, A. B. Foster, J. Lehmann, J. M. Webber, J.
Chem. Soc. 1963, 2287–2290.
5.39 (t, J = 3.4 Hz, 1 H, H–C-4–OAc), 5.19 (dd, J = 10.2, 3.2 Hz,
1 H, H–C-5–OAc), 4.96 (dd, J = 3.6, 1.3 Hz, H–C-3), 4.68 (d, J =
10.2 Hz, 1 H, H–C-6–Ph), 4.20 [dq, J = 1.3, 6.5 Hz, 1 H, H–C-2–
CH3), 2.22, 2.21 and 1.79 (3 s, 9 H, 3 OAc), 1.21 (d, J = 6.5 Hz, 3
H, CHCH3) ppm. 13C NMR (100.6 MHz, CDCl3): δ = 16.1, 20.3,
20.7, 20.8, 67.4, 69.2, 70.4, 70.9, 76.0, 127.3, 128.2, 128.3, 137.8,
168.6, 169.2, 169.9 ppm. GC–MS: tR = 24.45 min. GC–MS: m/z
(%) = 290 (0.1) [M – 60], 247 (1), 230 (100), 215 (65), 188 (22), 173
(65).
[10] J. C. Sowden, D. R. Strobach, J. Am. Chem. Soc. 1960, 82,
3707–3709.
[11] P. Munier, A. Krusinski, D. Picq, D. Anker, Tetrahedron 1995,
51, 1229–1244.
[12] B. L. Stocker, E. M. Dangerfield, A. L. Win-Mason, G. W.
Haslett, M. S. M. Timmer, Eur. J. Org. Chem. 2010, 1615–1637.
[13] G. Legler, Adv. Carbohydr. Chem. Biochem. 1990, 48, 319–384;
N. Asano, R. J. Nash, R. J. Molyneux, G. W. J. Fleet, Tetrahe-
dron: Asymmetry 2000, 11, 1645–1680; M. E. Sinnott, Chem.
Rev. 1990, 90, 1171–1202; D. L. Zechel, St. G. Withers, Acc.
Chem. Res. 2000, 33, 11–18.
[14] G. C. Look, C. H. Fotsch, C.-H. Wong, Acc. Chem. Res. 1993,
26, 182; Y. Nishimura, Stud. Nat. Prod. Chem. 1992, 10, 495;
Y. L. Merrer, L. Poitout, J. D. Depezay, I. Dosbaa, S. Geoffroy,
M. J. Foglietti, Bioorg. Med. Chem. 1997, 5, 519–533.
[15] C.-H. Wong, L. Provencher, J. A. Porco Jr., S.-H. Jung, Y.-F.
Wang, L. Chen, R. Wang, D. H. Steensma, J. Org. Chem. 1995,
60, 1492–1501.
(2S,3S,4R,5S,6S)-2-Methyl-6-phenyltetrahydro-2H-pyran-3,4,5-triyl
Triacetate (23): The acetate derivative of (3aS,4S,6S,7S,7aR)-20b
(0.16 g, 0.52 mmol) was treated with AcOH (0.5 mL) and a few
drops of 37% HCl in THF solution (5 mL) for 12 h at room tem-
perature. After the usual workup, the residue was acetylated with
Ac2O (3 mL) in pyridine (3 mL) to afford triacetate 23 (0.13 g,
70%): 1H NMR (400 MHz, CDCl3):[30] δ = 7.40–7.20 (m, 5 H, Ar),
6.01 (t, J = 2.9 Hz, 1 H, H–C-5–OAc), 5.18 (dd, J = 9.2, 8.5 Hz, 1
4474
www.eurjoc.org
© 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2010, 4468–4475

Oxygenated Stereotriads with Definite Absolute Configuration
[16]
[17]
[27] K. A. Parker, Y. H. Koh, J. Am. Chem. Soc. 1994, 116, 11149–
11150; T. Hosoya, E. Takashiro, T. Matsumoto, K. Suzuki, J.
Am. Chem. Soc. 1994, 116, 1004–1015; K. Toshima, G. Matsuo,
T. Ishizuka, Y. Ushiki, M. Nakata, S. Matsumura, J. Org.
Chem. 1998, 63, 2307–2313; K. A. Parker, A. T. Georges, Org.
Lett. 2000, 2, 497–499; F. M. Hauser, X. Hu, Org. Lett. 2002,
4, 977–978; S. Vijayasaradhi, I. S. Aidhen, Org. Lett. 2002, 4,
1739–1742; C. Rousseau, O. R. Martin, Org. Lett. 2003, 5,
3763–3766; E. Brenna, C. Fuganti, P. Grasselli, S. Serra, S.
Zambotti, Chem. Eur. J. 2002, 8, 1872–1878.
[28] S. J. Danishefsky, B. J. Uang, G. Quallich, J. Am. Chem. Soc.
1985, 107, 1285–1293; B. Schmidt, Org. Lett. 2000, 2, 791–794;
B. Schmidt, J. Chem. Soc. Perkin Trans. 1 1999, 2627–2637;
F. M. Hauser, X. Hu, Org. Lett. 2002, 4, 977–97; S. Bernd, W.
Holger, Eur. J. Org. Chem. 2000, 3145–3163; B. Schmidt, H.
Wildemann, Synlett 1999, 1591–1593; B. Koo, F. E. McDon-
ald, Org. Lett. 2005, 7, 3621–3624; K. B. Bahnck, S. D. Rych-
novsky, Chem. Commun. 2006, 2388 2390.
A. M. Palmer, V. Jäger, Eur. J. Org. Chem. 2001, 2547–2558.
M. Joubert, A. Defoin, C. Tarnus, J. Streith, Synlett 2000,
1366–1368.
J.-B. Behr, C. Chevrier, A. Defoin, C. Tarnus, J. Streith, Tetra-
hedron 2003, 59, 543–553.
C. Arribas, M. C. Carreño, J. L. Garcia-Ruano, J. F. Rodriguez,
M. Santos, M. A. Sanz-Tejedor, Org. Lett. 2000, 2, 3165–3168.
D. Diez, M. T. Beneitez, I. S. Marcos, N. M. Garrido, P. Bas-
abe, J. C. Urones, Synlett 2001, 655–657; D. Diez, M. T. Benei-
tez, I. S. Marcos, N. M. Garrido, P. Basabe, J. C. Urones, Tetra-
hedron: Asymmetry 2002, 13, 639–646.
[18]
[19]
[20]
[21] H. J. Jeong, J. M. Lee, M. K. Kim, S.-G. Lee, J. Heterocycl.
Chem. 2002, 39, 1019–1024.
[22] M. Sugiyama, Z. Hong, P.-H. Liang, S. M. Dean, L. J. Whalen,
W. A. Greenberg, C.-H. Wong, J. Am. Chem. Soc. 2007, 128,
14811–14817.
[23] J. J. Shie, J. M. Fang, J. Org. Chem. 2003, 68, 1158–1160.
[24] S. Caddick, D. B. Judd, A. K. de K. Lewis, M. T. Reich,
M. R. V. Williams, Tetrahedron 2003, 59, 5417–5423.
[25] C. Jaramillo, S. Knapp, Synthesis 1994, 1.
[29] R. V. Muralidhar, R. R. Chirumamilla, R. Marchant, V. N. Ra-
machandran, O. P. Ward, P. Nigam, World J. Microbiol. Bi-
otechnol. 2002, 18, 81–97.
[26] G. D. Daves Jr., Acc. Chem. Res. 1990, 23, 201; H. Togo, W.
He, Y. Waki, M. Yokoyama, Synlett 1998, 700; M. Isobe, R.
Nishizawa, S. Hosokawa, T. Nishikawa, Chem. Commun. 1998,
2665; L. Somsák, Chem. Rev. 2001, 101, 81; C. Taillefumier, Y.
Chapleur, Chem. Rev. 2004, 104, 263.
[30] Vicinal coupling constants for derivative 23 were reported by
P. M. Collins, A. S. Travis, J. Chem. Soc. Perkin Trans. 1 1980,
779–786.
Received: April 22, 2010
Published Online: June 29, 2010
Eur. J. Org. Chem. 2010, 4468–4475
© 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
4475