Highly diastereoselective nucleophilic additions using a novel myrtenal-derived oxathiane as a chiral auxiliary

Article abstract of DOI:10.1016/S0957-4166(01)00545-6

The synthesis of novel oxathiane 3 and its acetyl derivative 12, from commercially available (-)-myrtenal 4, is described. The addition of several nucleophilic reagents to 12 furnished the corresponding tertiary carbinols in highly diastereomeric excess. The hydrolysis of 11a, b yielded the expected α-hydroxycarbonyl compounds in excellent enantiomeric excess.

Full text of DOI:10.1016/S0957-4166(01)00545-6

TETRAHEDRON:
ASYMMETRY
Pergamon
Tetrahedron: Asymmetry 12 (2001) 3095–3103
Highly diastereoselective nucleophilic additions using a novel
myrtenal-derived oxathiane as a chiral auxiliary
Federico Mart´ınez-Ramos,a Mar´ıa Elena Vargas-D´ıaz,a Luis Chaco´n-Garc´ıa,a Joaqu´ın Tamariz,a
Pedro Joseph-Nathanb and L. Gerardo Zepedaa,*
aDepartamento de Qu´ımica Orga´nica, Escuela Nacional de Ciencias Biolo´gicas, IPN, Prol. de Carpio y Plan de Ayala, Me´xico,
DF 11340, Mexico
bDepartamento de Qu´ımica del Centro de Investigacio´n y de Estudios Avanzados, Instituto Polite´cnico Nacional,
Apartado 14-740, Me´xico, DF 07000, Mexico
Received 20 September 2001; accepted 20 November 2001
Abstract—The synthesis of novel oxathiane 3 and its acetyl derivative 12, from commercially available (−)-myrtenal 4, is described.
The addition of several nucleophilic reagents to 12 furnished the corresponding tertiary carbinols in highly diastereomeric excess.
The hydrolysis of 11a, b yielded the expected a-hydroxycarbonyl compounds in excellent enantiomeric excess. © 2002 Elsevier
Science Ltd. All rights reserved.
1. Introduction
Chiral 1,3-oxathiane derivatives have been widely used
in the synthesis of chiral a-hydroxycarbonyl
compounds1a,b,c,d with high enantiomeric excess (e.e.).
Particularly, 1,3-oxathiane 1, which was prepared2a,b
from (R)-(+)-pulegone 2, has proven to be a good chiral
auxiliary for the enantioselective preparation of a-
hydroxycarbonyl compounds3a,b,c,d,e,f and a useful chro-
matographic auxiliary in the synthesis of a prostaglandin
precursor.4 In addition, it has been used in the resolution
of a-alkylcyclopentanones5,6 and in the enantioselective
synthesis of b-lactams7 and b-amino alcohols.8 Recently,
a similar camphor-derived 1,3-oxathiane has been used
in the enantioselective preparation of epoxides.9 Inter-
ested in the potential of the 1,3-oxathiane ring to induce
asymmetric nucleophilic additions, we decided to prepare
benzylmercaptane and 10% aqueous NaOH in THF at
oxathiane 3, a structural analogue of compound 1,
room temperature gave adduct 5 (92% yield and 96%
starting from commercially available (−)-myrtenal 4.
d.e.) after 18 h. Both hydrogenolysis of the benzylmer-
captan and reduction of the carbonyl group to the
corresponding mercaptoalcohol were initially attempted
under Birch conditions with Na and liquid ammonia in
2. Results and discussion
anhydrous THF. While the carbonyl group was indeed
reduced, 1,2-elimination of benzylmercaptan took place,
The synthesis of oxathiane 3 was explored using a
procedure similar to that described for the synthesis of
giving myrtenol 6. To overcome this problem, the alde-
oxathiane 1.2b Thus, treatment of (−)-myrtenal 4 with
hyde group in 5 was reduced to the corresponding
alcohol with LiAlH4 in ethyl ether, giving 7 in 96% yield,
which, in turn, was hydrogenolyzed to mercaptoalcohol
8 under Birch reduction conditions (Scheme 1).
* Corresponding author. Fax: (52-55) 5396 3503; e-mail: lzepeda@
woodward.encb.ipn.mx
0957-4166/01/$ - see front matter © 2002 Elsevier Science Ltd. All rights reserved.
PII: S0957-4166(01)00545-6

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F. Mart´ınez-Ramos et al. / Tetrahedron: Asymmetry 12 (2001) 3095–3103
Hydroxythiol 8 was treated with paraformaldehyde in
the presence of p-toluenesulfonic acid, to give oxathi-
ane 3 and compound 10 in 35 and 6% yields, respec-
tively. The latter was formed by condensation of two
molecules of formaldehyde with hydroxythiol 8. In
order to verify the stereochemistry of the new stereo-
genic centers in oxathiane 3, the vicinal coupling con-
stant between H-2 and H-7 (J=10.2 Hz) clearly reveals
their relative anti relationship. In addition, a nOe differ-
ence experiment irradiating Me-12, produced enhance-
ments of 10.5 and 2.5% for the H-7 and H-3ax signals,
respectively, while H-2 remained unchanged. These
data confirm that the absolute configuration is (R) at
C(2) and (S) at C(7).
Scheme 1. (i) BnSH, THF, 10% aq. NaOH; (ii) NH3, Na; (iii)
LiAlH4, Et2O, −10°C; (iv) CH3COSH, Py, 8°C, 10 h.
In some instances the hydrogenolysis reaction did not
give satisfactory results, since small differences in reac-
tion conditions drastically changed the course of the
reaction, sometimes affording a complex mixture of
uncharacterized compounds. In order to develop repro-
ducible reaction conditions, thiolacetic acid was used as
the nucleophile in the 1,4-addition to (−)-myrtenal 4 to
give adduct 9 in 98% yield with >99% d.e. Compound
9 was subsequently treated with LiAlH4 affording the
hydroxythiol 8 in 95% yield. This procedure allowed us
to carry out the reduction of the thioester group to the
corresponding thiol using a one-pot procedure (instead
of the complex C–S cleavage of the thiobenzyl group
via hydrogenolysis) and the conversion of the aldehyde
to the primary alcohol (Scheme 2).
The condensation of acetaldehyde with the carbanion
generated from oxathiane 3, employing similar reaction
conditions as described for oxathiane 1,2a was
attempted for the preparation of adduct 11g and/or
13g. This procedure failed, and all attempts to obtain
deuterium exchange in the oxathiane methylene of 3 by
quenching the expected carbanion with D2O, gave a
mixture of isotopically unexchanged starting material 3
and traces of decomposition products.
Since the preparation of 11g and 13g failed, a new
synthetic strategy, starting from hydroxythiol 8, was
designed to obtain acetyloxathiane 12. Thus, treatment
of 8 with a,a-dimethoxyacetone gave oxathiane 12 in
32% yield, which was crystallized from chloroform–hex-
ane yielding adequate crystals (mp 67–69°C) for X-ray
crystallography.10 The ORTEP drawing of oxathiane 3
(Fig. 1), clearly shows the anti-oriented relationship
between H-2 and H-7 (H-2 and H-3 in Fig. 1) as a
consequence of the endo approach of thiolacetic acid on
myrtenal 4 because of the steric effect of Me-12 (Me-9
in Fig. 1). Another important structural feature in the
solid state is the equatorial disposition of the acetyl
group and the preferred quasi-coplanar conformation
of the carbonyl group with sulfur atom, as revealed by
the torsion angle S(1)–C(11)–C(12)–O(2)=14.5(6)°
(Fig. 1). The chair-like conformation of the oxathiane
ring is also of note. In solution, the (R)-configuration
at C(5) (C11 in Fig. 1) can also be determined by means
Scheme 2. (i) (HCHO)n, p-TsOH, C6H6; (ii) 1. n-BuLi, THF,
2. CH3CHO; (iii) CH3COCH(OMe)2, p-TsOH, C6H6.
Figure 1. ORTEP drawing of acetyloxathiane 12. The crystallographic numbering shown differs from the systematic numbering.

F. Mart´ınez-Ramos et al. / Tetrahedron: Asymmetry 12 (2001) 3095–3103
Table 1. Diastereoselective nucleophilic additions on acetyloxathiane 12
3097
Reagent
5
5
+
S
S
S
O
O
O
R OH
R
O
HO
11
12
13
Entry
Reagent
Comp. (%)
Ratio 11:13a
1
2
3
4
5
6
7
8
9
PhMgBr
EtMgBr
i-PrMgBr
PhCH2MgBr
n-BuLi
sec-BuLi
PhLi
LAH
11a (92)
11b (97)
11c (93)
11d (95)
11e (60)
11f (53)
11a (89)
11g (70)
11g (76)
11g (82)
\99:B1
\99:B1
96:4
95:5
\99:B1
\99:B1
\99:B1
71:29
80:20
\99:B1
DIBAL
LS-Selectride
10
a Determined by 1H NMR integration of H-5, on the crude reaction mixture.
of a nOe difference experiment, since irradiation of H-5
gave signal enhancements of H-7 (6.4%) and H-3ax
(3.6%).
1,2-Additions to acetyloxathiane 12 in THF with a
number of nucleophiles, provided mainly oxathiane-
carbinols 11 mixed with small amounts of 13. The results,
summarized in Table 1, show that in six of the ten cases11
diastereoisomers 11 were formed almost exclusively.
As can be seen, the addition of PhMgBr and PhLi gave
the same diastereoisomer 11a in alike d.r., and reduction
with LS-Selectride produced the major diastereoisomer
11g in higher d.r. than reactions using DIBAL-H and
LAH. The major product obtained from the three hydride
donors can be easily distinguished from the minor adduct
bytakingadvantageofthecoupling constant betweenH-5
and H-1% (it being 3.3 and 6.9 Hz, respectively, in
agreement with the predicted values derived from
PCMODEL calculations).12 The minimum energy found
for both compounds is also in agreement with the
corresponding hydrogen-bridged epimers, whose confor-
mational analysis13a,b through H5-H1% dihedral angles
showed that the major compound is formed by hydride
addition to the Re face of the carbonyl group.
Scheme3. (i)AgNO3, NCS, CH3CN:H2O4:1;(ii)LiAlH4, Et2O.
lithium reagents proceed by attacking the Re face of the
carbonyl group of acetyl oxathiane 12. From these results,
it could be concluded that the addition of Grignard
reagents, and the reduction using LS-Selectride, can be
rationalized in terms of the Cram chelation model, in a
similar way as was explained for nucleophilic additions
to oxathiane 1.14,15 It is assumed that the carbonyl–sulfur
coplanarity observed in solid state (Fig. 1) is lost in
solution in order to form the Cram chelated model when
Grignard reagents and LS-Selectride are used. The major
compounds obtained with the less chelating DIBAL,
LAH and alkyllithium reagents, could in turn be ratio-
nalized via the anti Felkin-Anh model (L=O).16 It is
worth mentioning that the 2-acetyl derivative of 1
provides reversal in stereoselectivity by using DIBAL as
compared with LS-Selectride and LAH, while in our case
the three hydride donors gave the same stereoinduction.
Small differences in steric requirements between the two
chiral auxiliaries may account for these changes.17
In order to gain information about the approaching
preference of the nucleophile to the carbonyl faces,
cleavage of adducts 11a and 11d was undertaken to afford
aldehydes 14a and 14d (R=Ph, C6H5CH2, respectively),
and presumably sultine 15, since 1H NMR spectra of the
corresponding crude reaction mixture showed the alde-
hyde mixed with another compound displaying the
characteristic spectral data expected for 15 (see Section
3). Because of the instability of the above aldehydes, the
crude reaction mixtures were individually reduced with
LiAlH4 giving, after column chromatography, the corre-
sponding diols (R)-(−)-16a (83%, >99% e.e.) and (R)-(−)-
16d (74%, >99% e.e.), and unracemized hydroythiol 8
(63–72%) (Scheme 3).
The absolute configuration of diols 16a and 16d indicates
that the nucleophilic additions of Grignard and alkyl-

3098
F. Mart´ınez-Ramos et al. / Tetrahedron: Asymmetry 12 (2001) 3095–3103
3. Experimental
3.3. (1S,2R,3S)-2-Hydroxymethyl-6,6-dimethyl-3-thio-
benzyl-bicyclo[3.1.1]heptane 7
3.1. General
To a well-stirred suspension of LiAlH4 (1.0 g, 26.3
mmol) in dry ethyl ether (15 mL) were added dropwise
5 (5 g, 18.2 mmol) in dry ethyl ether (25 mL) and the
mixture stirred under reflux under an N2 atmosphere
for 40 min. The reaction mixture was cooled (0°C),
diluted with ethyl ether (100 mL), quenched by careful
addition of ethanol, ice and 10% aq. HCl, and stirred
until formation of a white precipitate. After filtration,
the organic layer was washed with brine (3×40 mL),
dried over anhydrous Na2SO4 and evaporated to dry-
ness. The residue was flash chromatographed using a
mixture of hexane–EtOAc (19:1), giving 7 as a colorless
Melting points were determined on an Electrothermal
capillary melting points apparatus and are uncorrected.
Infrared spectra were recorded on a Perkin–Elmer 599B
spectrometer. H and 13C NMR spectra were obtained
1
on Varian Gemini and Mercury spectrometers at 300
and 75.4 MHz, respectively, using CDCl3 as solvent
and TMS as internal standard. H and 13C NMR data
1
were assigned according to the numbering of com-
pounds 5 (bicyclic series) and 11g (tricyclic series) in
Schemes 1 and 2, respectively. The mass spectra (MS)
were recorded on a Hewlett–Packard 5971A GC/Selec-
tive Mass Detector at 70 eV. Microanalyses were per-
formed by the M-H-W Laboratories, Phoenix, AZ,
USA. Thin-layer chromatograms were carried out using
precoated TLC sheets of silica gel 60 F254 (E. Merck).
Flash chromatography was carried out using Merck
silica gel (230–400 mesh). The purification of the
oxathianecarbinols 11a–g was performed on a Biotage
Flash 40 apparatus using Flash 40S 4.0×7.0 cm
prepacked cartridges. THF used in the nucleophilic
additions was distilled from Na immediately prior to
use and all other reagents were used without further
purification. Optical rotations were measured at 589 nm
using a 1 dm cell on a Jasco DIP–370 polarimeter.
X-Ray data were collected on a Bruker AXS D8-APEX
difractometer equipped with CCD. Molecular Model-
ing Calculations: minimum energy structures were gen-
erated using the MMX force-field as implemented in
the PCMODEL molecular modeling program V6 (Ser-
ena Software, Box 3076, Bloomington, IN 47402-3076).
1
oil (4.82 g, 96%). H NMR (CDCl3): l 7.36–7.17 (m,
5H, Ar), 3.77 and 3.74 (AB system, J=13 Hz, 2H,
CH2-Ph), 3.58 (dd, 1H, J=9.1, 7.8 Hz, H-10a), 3.46 (t,
1H, J=9.1 Hz, H-10b), 2.78 (ddd, 1H, J=9.4, 7.6, 5.7
Hz, H-3), 2.45 (m, 1H, H-4eq), 2.41 (m, 1H, H-7eq),
2.25 (s, 1H, OH), 2.12 (m, 1H, H-4ax), 2.07 (m, 1H,
H-1), 2.04 (m, 1H, H-2), 1.95 (m, 1H, H-5), 1.18 (s, 3H,
Me-9), 1.09 (d, 1H, J=9.9 Hz, H-7ax), 0.85 (s, 3H,
Me-8). 13C NMR (CDCl3): l 139.2 (C-1%), 128.7(C-2%
and C-6%), 128.5 (C-3% and C-5%), 127.0 (C-4%), 66.7
(C-10), 52.0 (C-2), 43.2 (C-1), 42.0 (C-5), 38.4 (C-6),
37.7 (C-4), 36.3 (C-3), 35.8 (C6 H2-Ph), 33.0 (C-7), 27.5
(C-9), 23.3 (C-8). EM m/z (rel. int.): 276 (M+, 8), 245
(1), 207 (7), 185 (14), 143 (8) 135 (9), 121 (7), 91 (100),
79 (20), 65 (20), 55(6).
3.4. (1S,2R,3S)-2-Hydroxymethyl-6,6-dimethyl-3-mer-
capto-bicyclo[3.1.1]heptane 8
Compound 8 was prepared by the following two
procedures.
3.2. (1S,2R,3S)-2-Formyl-6,6-dimethyl-3-thiobenzyl-
bicyclo[3.1.1]heptane 5
A mixture containing (−)-myrtenal 4 (4.96 g, 33 mmol),
benzylmercaptan (8.6 mL, 8.18 g, 66 mmol) and 10%
aq. NaOH (5 mL) in THF (5 mL), was stirred at room
temperature under an N2 atmosphere for 20 h. The
reaction was extracted with cold EtOAc, washed suc-
cessively with 15% aq. NaOH (5×40 mL) and water
(3×40 mL), dried over anhydrous Na2SO4, and concen-
trated to dryness. The residue was subjected to frac-
tional distillation on a Kugelrohr apparatus and the
portion collected at 130–132°C/5 Torr gave 5 as a
colorless oil (9.0 g, 92% yield, 96% d.e.). 1H NMR
(CDCl3): l 9.60 (s, 1H, H-10), 7.38–7.22 (m, 5H, Ar),
3.78 and 3.74 (AB system, 2H, J=13 Hz, H11a and
H11b), 3.70 (ddd, 1H, J=10.1, 5.7, 5.4 Hz, H-3), 2.81
(dd, 1H, J=5.4, 2.8 Hz, H-2), 2.55 (m, 1H, H-1), 2.47
(m, 1H, H-4eq), 2.42 (m, 1H, H-7eq), 1.98 (m, 1H,
H-4ax), 1.95 (m, 1H, H-5), 1.42 (d, 1H, J=10 Hz,
H-7ax), 1.20 (s, 3H, Me-9), 0.65 (s, 3H, Me-8). 13C
NMR (CDCl3): l 203.0 (C-10), 138.1 (C-1%), 128.5 (C-6%
and C-2%), 128.5 (C-5% and C-3%), 127.0 (C-4%), 62.0
Method (a): A solution of 9 (23.6 g, 0.104 mol) in
anhydrous ethyl ether (20 mL) was added dropwise to a
well-stirred cooled (−5°C) suspension of LiAlH4 (7.92 g,
0.208 mol) in dry ethyl ether (100 mL), and the result-
ing mixture was stirred for 1.5 h under an N2 atmo-
sphere. After dropwise addition of EtOH (2 mL), the
reaction mixture was stirred for a further 20 min at the
above temperature, then stirred in the presence of ice (5
g) and 7% aq. HCl (50 mL) at 5°C until formation of a
white emulsion. The organic layer was separated,
washed with water until pH 7, dried over anhydrous
Na2SO4 and evaporated to dryness, yielding hydroxy-
thiol 8 as white needles mp 46°C (18.5 g, 95%).
Method (b): According to the procedure described by
Eliel et al.,1c a solution of 7 (1 g, 3.62 mmol) in
anhydrous ethyl ether (4 mL) was treated with a solu-
tion of Na (260 mg, 11.39 mmol) and liquid NH3 (7
mL). The oily residue obtained after workup was flash
chromatographed using a mixture of hexane–EtOAc
(19:1) as the eluent, giving 8 (490 mg, 72%) mp 46°C.
(C-2), 42.4 (C-1), 41.1 (C-5), 38.3 (C-6), 36.6 (C6 H2Ar),
35.5 (C-4), 30.8 (C-3), 30.1 (C-7), 26.5 (C-9), 23.0 (C-8).
IR (CHCl3) 3040, 2850, 1710, 1435, 1270, 840, 810
cm−1.
1
[h]23=+76.5 (c=0.5, EtOH). H NMR (CDCl3): l 3.75
(dd, 1H, J=10.6, 7.1 Hz, H-10a), 3.60 (dd, 1H, J=

F. Mart´ınez-Ramos et al. / Tetrahedron: Asymmetry 12 (2001) 3095–3103
3099
10.6, 7.8 Hz, H-10b), 3.20 (dq, 1H, J=8.4, 7.3 Hz,
H-3), 2.65 (br s, 1H, OH), 2.61 (m, 1H, H-4eq), 2.45
(m, 1H, H-7eq), 2.27 (dddd, 1H, J=7.8, 7.3, 7.1, 1.9
Hz, H-2), 2.25 (d, 1H, J=7.1 Hz, SH), 2.08 (td, 1H,
J=5.9, 1.9 Hz, H-1), 1.96 (m, 1H, H-5), 1.93 (m, 1H,
H-4ax), 1.22 (s, 3H, Me-9), 1.12 (d, 1H, J=10.3 Hz,
H-7ax), 0.97 (s, 3H, Me-8). 13C NMR (CDCl3): l 66.3
(C-10), 57.1 (C-2), 43.7 (C-1), 42.3 (C-5), 40.4 (C-4),
38.0 (C-6), 33.8 (C-7), 32.1 (C-3), 27.6 (C-9), 23.4 (C-8).
IR (CHCl3) 3486, 2922, 2574, 1074 cm−1. MS m/z (rel.
int.) 186 (M+, 0.5), 171 (6), 155 (9), 145 (13), 121 (18),
99 (20), 85 (25), 82 (100), 67 (25), 55 (27). Anal. calcd
for C10H18OS: C, 64.47; H, 9.74; S, 17.21. Found: C,
64.55; H, 9.49; S, 17.38%.
(d, 1H, J=9.7 Hz, H-11ax). 13C NMR (CDCl3): l 76.6
(C-3), 74.0 (C-5), 52.5 (C-2), 46.2 (C-9), 43.5 (C-1), 42.1
(C-7), 39.6 (C-11), 39.1 (C-10), 33.6 (C-8), 29.6 (C-13),
24.5 (C-12). IR (CHCl3): 2920, 1457, 1064, 835 cm−1.
MS m/z (rel. int.): 198 (M+, 25), 183 (1), 168 (7), 142
(13), 129 (39), 111 (23), 99 (66), 91 (100), 79 (93), 67
(90), 53 (49).
3.7. (1S,2R,7S)-12,12-Dimethyl-4,6-dioxa-8-thia-tricy-
clo[9.1.1.02,9]tridecane 10
The latter fractions of the chromatography of the above
product gave 10 (77 mg, 6%) as a colorless oil. 1H
NMR (CDCl3): l 5.16 (d, 1H, J=11.8 Hz, OCHaS),
4.81 (d, 1H, J=6.5 Hz, OCHaO), 4.80 (d, 1H, J=11.8
Hz, OCHbS), 4.68 (d, 1H, J=6.5 Hz, OCHbO), 3.77 (t,
1H, J=12.3 Hz, H-3eq), 3.70 (dt, 1H, J=10.5, 5.5 Hz,
H-7), 3.44 (dd, 1H, J=12.3, 6.7 Hz, H-3ax), 3.12
(dddd, 1H, J=12.3, 6.7, 5.5, 2.2 Hz, H-2), 2.54 (m, 1H,
H-8eq), 2.34 (m, 1H, H-11eq), 1.95 (m, 1H, H-9), 1.74
(m, 1H, H-1), 1.70 (m, 1H, H-8ax), 1.20 (s, 3H, Me-13),
1.18 (d, 1H, J=11.0 Hz, H-11ax), 1.01 (s, 3H, Me-12).
3.5. (1S,2R,3S)-2-Formyl-6,6-dimethyl-3-thioacetyl-
bicyclo[3.1.1]heptane 9
A cold (−5°C) solution of (−)-myrtenal 4 (15.7 g, 0.1
mol) in thiolacetic acid (15.9 g, 0.21 mol) and pyridine
(1 mL) was stirred for 5 h. The reaction mixture was
diluted with CH2Cl2 (650 mL), washed successively with
saturated aqueous NaHCO3 (3×250 mL), 10% aq. HCl
(3×250 mL) and brine (2×250 mL). The organic layer
was dried over anhydrous Na2SO4 and evaporated
under reduced pressure to leave pure 9 as a yellowish
syrup (23.58 g, 98% yield, 99% d.e.). [h]23=−4.4 (c=
13C NMR (CDCl3): l 96.0 (O-C
(O-CH2-S), 53.4 (C-2), 41.5 (C-9), 38.5 (C-11), 36.2
6 H2-O), 73.9 (C-3), 71.4
6
(C-10), 34.5 (C-6), 31.9 (C-8), 27.3 (C-13), 23.3 (C-12).
MS m/z: 228 (M+, 2), 198 (0.5), 183 (1), 168 (2), 152
(3), 134 (5), 129 (14), 113 (11), 99 (55), 82 (100), 67 (79),
53 (43).
1
0.52, EtOH). H NMR (CDCl3): l 9.83 (s, 1H, H-10%),
4.43 (ddd, 1H, J=10.3, 5.3, 4.1 Hz, H-3), 2.80 (dd, 1H,
J=5.3, 2.9 Hz, H-2), 2.70 (m, 1H, H-4eq), 2.56 (m, 1H,
H-5), 2.45 (m, 1H, H-7eq), 2.31 (s, 3H, COCH3), 1.98
(m, 1H, H-1), 1.95 (m, 1H, H-4ax), 1.28 (d, 1H, J=10.3
Hz, H-7ax), 1.22 (s, 3H, Me-9), 0.79 (s, 3H, Me-8). 13C
NMR (CDCl3): l 203.0 (C-10), 195.5 (C-11), 60.7 (C-2),
43.2 (C-5), 40.7 (C-1), 38.0 (C-6), 35.1 (C-4), 30.8 (C-3),
30.0 (C-7), 30.0 (C-12), 26.2 (C-9), 23.8 (C-8). IR
(CHCl3): 2938, 1723, 1683, 1457 cm−1. MS m/z: 226
(M+), 183, 151, 107, 95, 53. Anal. calcd for C12H18O2S:
C, 63.68; H, 8.02; S, 14.17. Found: C, 63.82; H, 7.92; S;
13.98%.
3.8. (1S,2R,5R,7S)-5-Acetyl-10,10-dimethyl-4-oxa-6-
thia-tricyclo[7.1.1.02,7]undecane 12
A solution of 8 (6.1 g, 32.8 mmol), a,a-dimethoxyace-
tone (4.1 g, 34.7 mmol) and p-TsOH 0.614 g, 3.22
mmol) in benzene (75 mL) was stirred at room temper-
ature for 45 min. The reaction mixture was poured into
cold saturated aqueous NaHCO3, extracted with ethyl
ether, washed with saturated aqueous NaHCO3 (2×50
mL), dried over anhydrous Na2SO4 and evaporated to
dryness. The residue was dissolved in toluene (100 mL)
and p-TsOH (300 mg) were added. After heating the
mixture under reflux for 10 min, the reaction mixture
was cooled, diluted with ethyl ether (500 mL) and
saturated aqueous NaHCO3 (50 mL) were added. The
organic layer was washed with a saturated soln of
NaHCO3 (2×200 mL), dried over anhydrous Na2SO4
and evaporated to dryness. The oily residue was
purified through a Chromatoflash system using a mix-
ture of hexane:EtOAc (10:1) as the eluent, obtaining the
acetyloxathiane 12 as a white solid (2.5 g, 31%) (mp
3.6. (1S,2R,7S)-10,10-Dimethyl-4-oxa-6-thia-tricyclo-
[7.1.1.02,7]undecane 3
A
solution containing
8
(1.0 g, 5.3 mmol),
paraformaldehyde (186 mg, 6.2 mmol) and p-TsOH
(6.5 mg, 0.0377 mmol) in toluene (2 mL) was heated
under reflux under an N2 atmosphere for 4 h in a round
bottom flask equipped with a Dean–Stark trap. The
solvent was eliminated under reduced pressure, the
residue was diluted with hexane, washed with brine,
dried over anhydrous Na2SO4 and evaporated to dry-
ness. The residue was flash chromatographed using a
mixture of hexane–EtOAc (19:1), giving initially 3 as a
1
41°C). [h]22=+52.3 (c=0.2, EtOH). H NMR (CDCl3):
l 5.49 (1H, s, H-5), 4.11 (dd, 1H, J=12.0, 3.1 Hz,
H-3eq), 3.81 (q, 1H, J=11.6 Hz, H-7), 3.65 (t, 1H,
J=12.0 Hz, H-3ax), 2.52 (m, 1H, H-11eq), 2. 48 (m,
1H, H-2), 2.33 (m, 1H, H-8eq), 2.28 (s, 3H, Me-2%), 2.14
(m, 1H, H-9), 1.85 (t, 1H, J=6.0 Hz, H-1), 1.77 (ddd,
1H, J=11.6, 2.7, 1.2 Hz, H-8ax), 1.28 (s, 3H, Me-13),
1.16 (s, 3H, Me-12), 1.02 (d, 1H, J=9.5 Hz, H-11ax).
13C NMR (CDCl3): l 202.1 (C-1%), 88.7 (C-5), 76.0
(C-3), 51.0 (C-2), 45.6 (C-1), 43.3 (C-9), 41.9 (C-7), 39.5
(C-11), 39.0 (C-10), 33.4 (C-8), 29.5 (C-13), 25.7 (C-2%),
24.5 (C-12). IR (CHCl3) 2993, 2922, 1722, 1455, 1357,
1226 cm−1. MS m/z (rel. int.) 240 (M+, 4), 197 (100),
1
colorless oil (373 mg, 35%) H NMR (CDCl3): l 4.96
and 4.94 (AB system, J=12 Hz, 2H, H-5a and H-5b),
3.96 (dd, 1H, J=11.0, 3.2 Hz, H-3eq), 3.73 (dt, 1H,
J=10.2, 8.8 Hz, H-7), 3.60 (t, 1H, J=11.0 Hz, H-3ax),
2.60 (m, 1H, H-11eq), 2.51 (ddd, 1H, J=11.0, 10.2, 3.1
Hz, H-2), 2.36 (dddd, 1H, J=13.3, 8.8, 4.6, 2.0 Hz,
H-8eq), 2.11 (qd, 1H, J=6.0, 1.5 Hz, H-9), 1.78 (t, 1H,
J=6.0 Hz, H-1), 1.73 (ddd, 1H, J=13.3, 10.2, 1.5 Hz,
H-8ax), 1.27 (s, 3H, Me-13), 1.17 (s, 3H, Me-12), 1.03

3100
F. Mart´ınez-Ramos et al. / Tetrahedron: Asymmetry 12 (2001) 3095–3103
3.10. (1S,2R,5R,7S)-5-[(R)-2%-Hydroxy-2%-butyl)]-10,10-
135 (20), 107 (40), 93 (65), 79 (65), 69 (30), 55 (15).
Anal. calcd for C13H20O2S: C, 64.96; H, 8.39. Found:
C, 64.96; H, 8.35%.
dimethyl-4-oxa-6-thiatricyclo[7.1.1.02,7]undecane 11b
Following the procedure (a) for the preparation of
11a, compound 12 (169 mg, 0.7 mmol) in anhydrous
THF (5 mL) was treated with ethylmagnesium bro-
mide (187.7 mg, 1.4 mmol) in ethyl ether (0.47 mL).
After workup pure 11b was obtained as a single
diastereoisomer (colorless oil; 184.4 mg, 97%). [h]23=
3.9. (1S,2R,5R,7S)-5-[(R)-1%-Hydroxy-1%-phenyl-1%-
ethyl)]-10,10-dimethyl-4-oxa-6-thia-tricyclo[7.1.1.02,7]-
undecane 11a
This compound was obtained using the following two
procedures.
1
−12.6 (c=0.45, EtOH). H NMR (CDCl3): l 4.82 (s,
1H, H-5), 4.06 (dd, 1H, J=10.9, 3.2 Hz, H-3eq), 3.70
(td, 1H, J=10.4, 8.6 Hz, H-7), 3.62 (t, 1H, J=10.9
Hz, H-3ax), 2.58 (dddd, 1H, J=9.6, 8.0, 6.2, 1.8 Hz,
H-11eq), 2.40 (br s, 1H, OH), 2.39 (dddd, 1H, J=
10.9, 10.4, 8.1, 3.2 Hz, H-2), 2.35 (dddd, 1H J=10.5,
9.2, 8.6, 1.8 Hz, H-8eq), 2.12 (ddd, 1H, J=10.5, 6.2,
1.4 Hz, H-9), 1.82 (t, 1H, J=8.0 Hz, H-1), 1.75 (ddd,
1H, J=10.4, 9.2, 1.4 Hz, H-8ax), 1.60 (m, 2H, CH2-
3%), 1.27 (s, 3H, Me-13), 1.23 (s, 3H, Me-1%), 1.15 (s,
3H, Me-12), 1.02 (d, 1H, J=9.6 Hz, H-11ax), 0.95 (t,
3H, J=7.5 Hz, Me-4%). 13C NMR (CDCl3): l 92.7
(C-5), 76.4 (C-3), 74.3 (C-2%), 51.7 (C-2), 45.7 (C-1),
43.3 (C-9), 41.1 (C-7), 39.5 (C-11), 39.0 (C-10), 33.6
(C-8), 31.3 (C-3%), 29.6 (C-13), 24.5 (C-12), 22.6 (C-
1%), 7.7 (C-4%). IR (CH2Cl2): 3467, 2911, 1456, 1063,
1045, 733 cm−1. MS m/z (rel. int.): 270 (M+, 5), 255
(8), 241 (10), 197 (100), 135 (30), 107 (42), 93 (65), 79
(62), 69 (20), 55 (15). Anal. calcd for C15H26O2S: C,
66.62; H, 9.69; S, 11.86. Found: C, 66.64; H, 9.54; S,
11.53%.
Method (a): To a well-stirred cooled (−78°C) solution
of 12 (158.3 mg, 0.65 mmol) in anhydrous THF (10
mL) under an N2 atmosphere, a solution of phenyl-
magnesium bromide (239.2 mg, 1.31 mmol) in diethyl
ether (0.43 mL) was added dropwise. After stirring
for 4 h at the same temperature, the reaction mixture
was allowed to warm to room temperature and the
mixture stirred for a further 1 h. The reaction mixture
was quenched with saturated aqueous ammonium
chloride (10 mL), the THF was evaporated and the
remaining emulsion was extracted with ethyl ether.
The organic layer was washed with saturated aqueous
ammonium chloride, dried over anhydrous Na2SO4
and concentrated to dryness giving pure diastereoiso-
mer 11a as a colorless oil (193.5 mg, 92%).
Method (b): A well-stirred cooled (−78°C) solution of
acetyloxathiane 12 (24 mg, 0.1 mmol) in anhydrous
THF (2 mL) was treated with PhLi in cyclohexane
(0.15 mmol) and stirred under an N2 atmosphere for
2 h. The mixture was quenched with saturated soln of
ammonium chloride (1 mL) and allowed to warm to
room temperature. THF was evaporated and the
residue extracted with ethyl ether (50 mL). The
organic layer was washed with 5% aq. HCl (3×30
mL) and brine (1×30 mL), dried over anhydrous
Na2SO4 and evaporated to dryness. The crude reac-
tion outcome was purified through a Chromatotron
system using a mixture of hexane:EtOAc (19:1) as the
eluent to give 11a as a colorless oil (28 mg, 89%).
[h]21=−58.9 (c=0.34, EtOH). 1H NMR (CDCl3): l
7.48–7.21 (m, 5H, Ar-H), 5.01 (s, 1H, H-5), 3.98 (dd,
1H, J=10.6, 2.8 Hz, H-3eq), 3.57 (q, 1H, J=11.0 Hz,
H-7), 3.55 (t, 1H, J=10.6 Hz, H-3ax), 3.04 (br s, 1H,
OH), 2.53 (m, 1H, H-11eq), 2.36 (td, 1H, J=10.6, 3.4
Hz, H-2), 2.22 (m, 1H, H-8eq), 2.05 (dd, 1H, J=7.5,
1.5 Hz, H-9), 1.77 (t, 1H, J=5.9 Hz, H-1), 1.62 (m,
1H, H-8ax), 1.61 (s, 3H, Me-2%), 1.21 (s, 3H, Me-13),
1.08 (s, 3H, Me-12), 0.99 (d, 1H, J=9.7 Hz, H-11ax).
13C NMR (CDCl3): l 144.2 (C-ipso), 128.0 (2 C-orto),
127.4 (C-para), 125.7 (2 C-meta), 93.7 (C-5), 77.2 (C-
1%), 75.9 (C-3), 51.4 (C-2), 45.6 (C-1), 43.4 (C-9), 41.1
(C-7), 39.4 (C-11), 39.0 (C-10), 33.4 (C-8), 29.6 (C-
13), 24.7 (C-12), 24.4 (C-2%). IR (CHCl3) 3953, 2921,
1449, 1369, 1057, 760, 699 cm−1. MS m/z (rel. int.)
318 (M+, 6), 303 (12), 241 (22), 197 (100), 135 (20),
107 (40), 93 (65), 79 (65), 69 (30), 55 (15). Anal. calcd
for C19H26O2S: C, 71.66; H, 8.23; S, 10.05. Found: C,
71.59; H, 7.95; S, 9.93%.
3.11. (1S,2R,5R,7S)-5-[(R)-2%-Hydroxy-3%-methyl-2%-
butyl)]-10,10-dimethyl-4-oxa-6-thia-tricyclo[7.1.1.02,7]-
undecane 11c
Following procedure (a) for the preparation of 11a,
compound 12 (109 mg (0.45 mmol) in anhydrous
THF (4 mL) was treated with iso-propylmagnesium
chloride (93.6 mg, 0.91 mmol) in ethyl ether (0.53
mL). After workup pure 11c were obtained as a single
diastereoisomer (colorless oil; 120 mg, 93%). [h]23=
1
−29.1 (c=0.13, EtOH). H NMR (CDCl3): l 4.93 (s,
1H, H-5). 4.06 (dd, 1H, J=10.6, 2.8 Hz, H-3eq), 3.57
(dd, 1H, J=10.6, 8.6 Hz, H-7), 3.55 (t, 1H, J=10.6
Hz, H-3ax), 2.60 (m, 1H, H-11eq), 2.36 (td, 1H, J=
10.6, 3.4 Hz, H-2), 2.18 (s, 1H, OH), 2.13 (m, 1H,
H-9), 1.93 (hep, 1H, J=6.9 Hz, H-3%), 1.81 (t, 1H,
J=5.8 Hz, H-1), 1.75 (m, 1H, H-8ax), 1.27 (s, 3H,
Me-13), 1.17 (s, 3H, Me-1%), 1.15 (s, 3H, Me-12), 1.02
(d, 1H, J=9.7 Hz, H-11ax), 0.98 (d, 3H, J=6.9 Hz,
Me-4%), 0.93 (d, 3H, J=6.9 Hz, Me-5%). 13C NMR
(CDCl3): l 92.2 (C-5), 77.2 (C-3), 76.2 (C-2%), 51.9
(C-2), 45.9 (C-1) 43.5 (C-9), 41.1 (C-7), 39.5 (C-11),
39.1 (C-10), 33.9 (C-3%), 33.7 (C-8), 29.7 (C-13), 24.6
(C-1%), 19.6 (C-12), 17.5 and 16.7 (i-Pr Me’s). IR
(CH2Cl2) 3515, 2918, 1486, 1419, 1356, 1233, 1135,
1064, 735 cm−1. MS m/z (rel. int.): 284 (M+, 13), 269
(8), 241 (10), 197 (100), 135 (25), 93 (40), 79 (35), 55
(9). Anal. calcd for C16H28O2S: C, 67.56; H, 9.92; S,
11.27. Found: C, 67.29; H, 9.94; S, 11.43.

F. Mart´ınez-Ramos et al. / Tetrahedron: Asymmetry 12 (2001) 3095–3103
3101
3.12. (1S,2R,5R,7S)-5-[(R)-2%-Hydroxy-1%-phenyl-2%-
propyl]-10,10-dimethyl-4-oxa-6-thia-tricyclo-
[7.1.1.02,7]undecane 11d
3.14. (1S,2R,5R,7S)-5-[(2%R,3%S*)-2%-Hydroxy-3%-
methyl-2%-pentyl)]-10,10-dimethyl-4-oxa-6-thia-tricyclo-
[7.1.1.02,7]undecane 11f
Following procedure (a) for the preparation of 11a,
acetyloxathiane 12 (124 mg, 0.5 mmol) in THF (5 mL)
was treated with benzylmagnesium chloride (233 mg,
1.5 mmol) in ethyl ether (1.54 mL). After usual workup
and separation through a Chromatoflash system using a
mixture of hexane:EtOAc (10:1) as the eluent were
obtained 11d (165 mg, 95%) and 13d (9 mg, 5%) as
colorless oils. Compound 11d shows: [h]23=−46.5 (c=
Carbinol 11f was obtained similarly as 11a following
procedure (b) by addition of sec-BuLi (53 mg, 0.82
mmol) in hexane (0.41 mL) to 12 (99 mg, 0.412 mmol)
in anhydrous THF (5 mL). After separation by flash
chromatography using hexane:EtOAc (19:1), 11e was
obtained as a colorless oil (66 mg, 53%). 1H NMR
(CDCl3): l 4.82 (s, 1H, H-5), 4.76 (s, 1H, H-5 epimer),
4.05 (dd, 2H, J=10.9, 3.2 Hz, H-3eq), 3.73 (td, 1H,
J=10.4, 8.6 Hz, H-7), 3.65 (t, 1H, J=10.9 Hz, H-3ax),
2.62 (dddd, 1H, J=9.6, 8.0, 6.2, 1.8 Hz, H-11eq), 2.44
(dddd, 1H, J=10.9, 10.4, 8.1, 3.2 Hz, H-2), 2.36 (dddd,
1H J=10.5, 9.2, 8.6, 1.8 Hz, H-8eq), 2.14 (ddd, 1H,
J=10.5, 6.2, 1.4 Hz, H-9), 1.82 (t, 1H, J=8.1 Hz, H-1),
1.78 (ddd, 1H, J=10.4, 9.2, 1.4 Hz, H-8ax), 1.51 (m,
1H, H-3%), 1.39 (m, 2H, CH2-4%), 1.27 (s, 3H, Me-1%),
1.24 (s, 3H, Me-13), 1.22 (s, 3H, Me-12), 1.09 (d, 1H,
1
0.6, EtOH). H NMR (CDCl3): l 7.25 (m, 5-H, Ar),
4.87 (s, 1H, H-5), 3.95 (dd, 1H, J=10.6, 3.5 Hz,
H-3eq), 3.61 (dd, 1H, J=10.5, 8.6 Hz, H-7), 3.59 (t,
1H, J=10.6 Hz, H-3ax), 3.11 (s, 1H, OH), 2.91 and
2.85 (AB system, J=13.5 Hz, 2H, CH2-1%), 2.6 (m, 1H,
H-11eq), 2.4 (tdd, 1H, J=10.6, 5.9, 3.5 Hz, H-2), 2.29
(m, 1H, H-8eq), 2.01 (dd, 1H, J=7.5, 3.4 Hz, H-9),
1.78 (t, 1H, J=5.9 Hz, H-1), 1.66 (m, 1H, H-8ax), 1.59
(s, 3H, Me-3%), 1.26 (s, 3H, Me-13), 1.05 (s, 3H, Me-12),
0.95 (d, 1H, J=9.5 Hz, H-11ax). 13C NMR (CDCl3): l
137.5 (C-ipso), 130.8 (C-meta), 128.0 (C-para), 126.3
(C-orto), 92.9 (C-5), 76.8 (C-3), 75.9 (C-2%), 51.4 (C-2),
45.6 (C-1), 43.4 (C-9), 41.1 (C-7), 39.4 (C-11), 39.1
(C-1%), 39.0 (C-10), 33.4 (C-8), 29.6 (C-13), 24.7 (C-12),
24.4 (C-3%). IR (CH2Cl2) 3952, 2920, 1648, 1449, 1369,
1056, 759, 699 cm−1. MS m/z (rel. int.): 332 (M+, 8), 317
(8), 241 (11), 197 (100), 135 (24), 115 (8), 93 (42), 79
(40), 55 (12). Anal. calcd for C20H28O2S: C, 72.28; H,
8.43; S, 9.66. Found: C, 72.43; H, 8.49; S, 9.63%.
J=9.6 Hz, H-11ax), 0.93 (m, 6H, Me-5% and Me-6%). 13
C
NMR: l 92.7 (C-5), 91.6 (C-5 epimer), 76.3 (C-3), 74.5
(C-2%), 51.7 (C-2), 45.7 (C-1), 43.3 (C-9), 41.1 (C-7),
39.5 (C-11), 39.1 (C-10), 33.6 (C-3%), 31.3 (C-8), 29.6
(Me-13), 24.5 (Me-12), 23.2 and 23.1 (C-5% and C-4%)
22.6 (Me-1%), 7.7 (Me-6%). MS m/z (rel. int.): 283 (M+−
15, 3), 241 (15), 197 (100), 169 (30), 135 (22), 115 (30),
93 (68), 79 (70), 55 (18). Anal. calcd for C17H30O2S: C,
68.41; H, 10.13; S, 10.74. Found: C, 68.57; H, 9.95; S,
10.66.
3.15. (1S,2R,5R,7S)-5-[(S)-1%-Hydroxyethyl)]-10,10-
3.13. (1S,2R,5R,7S)-5-[(R)-2%-Hydroxy-3%-methyl-2%-
pentyl)]-10,10-dimethyl-4-oxa-6-thia-tricyclo-
[7.1.1.02,7]undecane 11e
dimethyl-4-oxa-6-thia-tricyclo-[7.1.1.02,7]undecane 11g
Three procedures were followed to obtain this
compound.
Carbinol 11e was obtained similarly as 11a, following
procedure (b) by addition of n-BuLi (66 mg, 1.02
mmol) in hexane to 12 (124 mg, 0.52 mmol) in anhy-
drous THF (5 mL). After separation by flash chro-
matography using hexane:EtOAc (99:5), 11e was
obtained as a colorless oil (92 mg, 60%). [h]23=−4.8
(c=0.45, EtOH). 1H NMR (CDCl3): l 4.82 (s, 1H,
H-5), 4.05 (dd, 1H, J=10.9, 3.2 Hz, H-3eq), 3.69 (td,
1H, J=10.4, 8.6 Hz, H-7), 3.62 (t, 1H, J=10.9 Hz,
H-3ax), 2.59 (dddd, 1H, J=9.6, 8.0, 6.2, 1.8 Hz, H-
11eq), 2.40 (dddd, 1H, J=10.9, 10.4, 8.1, 3.2 Hz, H-2),
2.34 (dddd, 1H, J=10.5, 9.2, 8.6, 1.8 Hz, H-8eq), 2.11
(ddd, 1H, J=10.5, 6.2, 1.4 Hz, H-9), 1.76 (t, 1H, J=8.1
Hz, H-1), 1.75 (ddd, 1H, J=10.4, 9.2, 1.4 Hz, H-8ax),
1.55 (m, 2H, CH2-5%), 1.32 (m, 4H, CH2’s 3% and 4%), 127
(s, 3H, Me-1%), 1.24 (s, 3H, Me-13), 1.15 (s, 3H, Me-12),
1.02 (d, 1H, J=9.6 Hz, H-11ax), 0.95 (t, 3H, J=7.5
Hz, Me-6%). 13C NMR (CDCl3): l 92.7 (C-5), 76.3
(C-3), 74.5 (C-2%), 51.7 (C-2), 45.7 (C-1), 43.3 (C-9),
41.1 (C-7), 39.5 (C-9), 39.1 (C-10), 33.6 (C-3%), 31.3
(C-8), 29.6 (C-13), 24.5 (C-12), 23.1 and 23.1 (C-4% and
C-5%) 22.6 (Me-10), 7.7 (Me-6%). MS m/z (rel. int.): 283
(M+-15, 2), 241 (8), 197 (100), 135 (24), 115 (8), 93 (42),
79 (40), 69 (18), 55 (12). Anal. calcd for C17H30O2S: C,
68.41; H, 10.13; S, 10.74. Found: C, 68.57; H, 9.95; S,
10.66.
Method (a): A solution of 12 (99 mg, 0.41 mmol) in dry
ethyl ether (5 mL) was added to a stirred and cooled
(−78°C) suspension of LiAlH4 (31 mg, 0.82 mmol). The
mixture was further stirred for 4 h and ethyl ether (50
mL) was added. The reaction was quenched by the slow
successive addition of EtOH (0.1 mL) and cold water
(0.2 g). The formed white precipitate was filtered and
the organic layer was washed with brine (2×25 mL),
dried over Na2SO4 and evaporated to dryness, yielding
a mixture of 11g and 13g in a 71:29 ratio, respectively.
The abundant diastereoisomer 11g was obtained as a
colorless oil (70 mg, 70%) after separation on a Chro-
matoflash system using hexane:EtOAc (19:1) as the
eluent.
Method (b): A cold (−78°C) solution of 12 (24 mg, 0.1
mmol) in toluene (2 mL) was treated dropwise with
DIBAL (24 mg, 0.17 mmol) in THF and stirred under
an N2 atmosphere for 2 h. The reaction mixture was
quenched with saturated aqueous NH4Cl (0.5 mL) at
−78°C and allowed to warm to room temperature.
Ethyl ether (15 mL) was added and the organic layer
was washed with brine (2×5 mL), dried over anhydrous
Na2SO4 and evaporated to dryness. The residue was
flash chromatographed using
a mixture of hex-

3102
F. Mart´ınez-Ramos et al. / Tetrahedron: Asymmetry 12 (2001) 3095–3103
3.17. (R)-(+)-2-Phenyl-1,2-propanediol 16a
ane:EtOAc (19:1) as the eluent, giving 11g as a color-
less oil (18.4 mg, 76%).
The above crude reaction mixture was treated with
LiAlH4 (42 mg 0.1 mmol) in ethyl ether (15 mL) at
room temperature for 1 h the mixture was then
treated successively with EtOH (1 mL), water (2 mL)
and ethyl ether (15 mL). The organic layer was
washed with brine (3×8 mL), dried over anhydrous
Na2SO4, evaporated to dryness and the residue was
purified through flash chromatography using hexane–
EtOAc (4:1) as the eluent to give diol 16a (102 mg,
83%) as a colorless oil. [h]23=+5.9 (c=4.5, EtOH)
Method (c): To a cold (−78°C) solution containing 12
(24 mg, 0.1 mmol) in toluene (2 mL) was added
dropwise LS-Selectride (40 mg, 0.17 mmol) in THF
(0.17 mL) and the mixture stirred under an N2 atmo-
sphere for 4 h. The reaction mixture was allowed to
warm to room temperature and stirred overnight,
cooled at −78°C and quenched with a saturated
aqueous NH4Cl. After reaching room temperature,
the organic layer was dried over Na2SO4 and evapo-
rated to dryness. The residue was treated with cold
hexane (5 mL) and the formed white precipitate was
filtered. The solvent was evaporated to dryness and
the residue was flash chromatographed using a mix-
ture of hexane–EtOAc (19:1) to give 11g as a color-
less oil (20 mg, 82%). Only adduct 11g was fully
1
(lit.18 +5.4). H NMR (CDCl3): l 7.51–7.23 (5H, Ar),
3.80 (d, 1H, J=11 Hz, OCHa), 3.62 (d, 1H, J=11
Hz, OCHb), 2.70–2.30 (br s, 2H, 2 HO), 1.53 (s, 3H,
CH3-3). 13C NMR l 145 (C-1%), 128.4 (C-3%), 127.4
(C-4%), 125.0 (C-2%), 74.8 (C-2), 71.1 (C-1), 22.1 (C-3).
These data are in agreement with those reported2a at
100 (1H) and 25 (13C) MHz.
1
characterized. [h]23=−49.1 (c=0.23, EtOH). H NMR
(CDCl3): l 4.95 (s, 1H, J=3.3 Hz, H-5), 4.04 (dd,
1H, J=11.3, 3.1 Hz, H-3eq), 3.99 (m, 1H, H-1%), 3.73
(dd, 1H, J=12.2, 8.7 Hz, H-7), 3.65 (t, 1H, J=11.3
Hz, H-3ax), 2.51 (m, 1H, H-11eq), 2.42 (dddd, 1H,
J=11.3, 8.7, 5.8, 3.1 Hz, H-2) 2.36 (m, 1H, H-8eq),
2.22 (br s, 1H, OH), 2.10 (dd, 1H, J=5.8, 3.3 Hz,
H-9), 1.81 (t, 1H, J=5.8 Hz, H-1) 1.79 (ddd, 1H,
J=12.2, 10.9, 1.3 Hz, H-8ax), 1.27 (s, 3H, Me-13),
1.26 (d, 3H, J=5.5 Hz, Me-2%), 1.14 (s, 3H, Me-12),
1.02 (d, 1H, J=9.7 Hz, H-11ax). 13C NMR (CDCl3):
l 90.7 (C-5), 76.1 (C-3), 69.6 (C-1%), 51.7 (C-2), 45.8
C-1), 43.5 (C-5), 41.1 (C-7), 39.5 (C-11), 39.1 (C-10),
33.6 (C-8), 29.6 (C-13), 24.5 (C-12), 18.6 (C-2%). IR
(CHCl3) 3470, 2929, 1467, 1254, 1115, 1081, 839, 776
cm−1. MS m/z (rel. int.): 242 (M+, 12), 197 (100), 135
(20), 107 (25), 93 (42), 79 (45), 55 (8). Anal. calcd for
C13H22O2S: C, 64.42; H, 9.15; S, 13, 23. Found: C,
64.65; H, 9.45; S, 12.96.
3.18. (R)-(+)-2-Methyl-3-phenyl-1,2-propanediol 16d
The crude reaction mixture obtained from the hydroly-
sis of adduct 11d was treated with LiAlH4 as
described in Section 3.17. After column chromatogra-
phy hydroxythiol 8 (72%) and diol 16d (82%) were
obtained. [h]23=+10.6 (c=1.8, CDCl3), lit.19a [h]23=
−24.0 (c=1.0, H2O and lit.19c [h]D=−7.2 (c=2.5,
CH2Cl2)) for the (S)-enantiomer. 1H NMR (CDCl3):
l 7.19–7.26 (5H, Ar), 3.80 (d, 1H, J=11 Hz, OCHa),
3.62 (d, 1H, J=12 Hz, OCHb), 2.70–2.30 (br s, 2H, 2
HO), 1.16 (s, 3H, CH3-3). 13C NMR l 145 (C-1%),
128.4 (C-3%), 127.4 (C-4%), 125.0 (C-2%), 74.8 (C-2),
71.1 (C-1), 22.1 (C-3). These data are in agreement
with those reported19b at 100 (1H) and 25 (13C) MHz.
Acknowledgements
3.16. (S)-2-Hydroxy-2-phenylpropanaldehyde 14a and
(1S,2R,6S)-9,9-dimethyl-4-oxa-5-thia-tricyclo-
[6.1.1.02,6]decane 5-oxide 15
The authors wish to thank IQ Fernando Labarrios
for MS measurements, and Gabriela Vargas-Diaz and
Herbert Ho¨pfl (CIQ, Universidad Auto´noma del
Estado de Morelos) for providing us the X-ray struc-
ture of compound 12. L.G.Z. acknowledges DEPI/
IPN (grant 933503) and CONACyT (grants 1569P
and 35013E). L.C.-G. and M.E.V.-D. thank CONA-
CyT (grants 92069 and 125225, respectively) and
DEPI/IPN (PIFI) postgraduate fellowships.
Following the procedure described by Eliel et al.,2a
carbinol 11a (256 mg, 0.806 mmol) in CH3CN (5 mL)
were treated with NCS (274 mg, 1.61 mmol) and
AgNO3 (215 mg, 1.61 mmol) in CH3CN–H2O (4:1, 35
mL). After usual workup a yellowish oil was obtained
1
(258 mg), whose H NMR spectrum showed the pres-
ence of 15 and aldehyde 14a (Scheme 3). Compound
14a: 1H NMR (CDCl3): l 9.47 (s, 1H, H-1), 7.48–
7.26 (5H, Ar), 2.60 (br s, 1H, OH), 1.72 (s, 3H,
CH3-3). 13C NMR (CDCl3): l 186.3 (C-1), 138.7 (C-
1%), 129.0 (C-3%, C-5%), 128.3 (C-4%), 126.8 (C-2%, C-6%),
60.8 (C-2), 23.2 (C-3). Compound 13: 1H NMR
(CDCl3): l 3.65–3.51 (m, 3H, H-3ax, H-3eq and H-6),
2.58 (m, 1H, H-10eq), 2.43 (m, 1H, H-2), 2.45–1.86
(3H, H-4eq, H-5 and H-1), 1.68 (m, 1H, H-7ax, 1.20
(s, 3H, CH3-12), 1.03 (d, J=9.70 Hz, H-10ax), 0.92
(s, 3H, Me-11). 13C NMR (CDCl3): l 65.3 (C-3), 53.1
(C-2), 42.9 (C-1), 42.2 (C-8), 41.5 (C-10), 38.9 (C-9),
36.0 (C-6), 33.2(C-7), 27.3 (C-12), 22.6 (C-11).
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