Enantioselective synthesis of either enantiomer of α-alkyl-α- hydroxy-α-phenylacetic acids using chiral auxiliaries

Article abstract of DOI:10.1016/j.tetasy.2005.03.032

The enantioselective synthesis of either enantiomer of α-alkyl- α-hydroxy-α-phenylacetic acids was achieved by using 2-acyloxathianes 1a-c and the mixed acyl-S,O-acetals 7 and 8 as chiral auxiliaries, which can straightforwardly be prepared from (1R)-(-)-myrtenal. This procedure allowed the preparation of the title compounds in >95% enantiomeric excess (ee).

Full text of DOI:10.1016/j.tetasy.2005.03.032

Tetrahedron:
Asymmetry
Tetrahedron: Asymmetry 16 (2005) 1837–1843
Enantioselective synthesis of either enantiomer of
a-alkyl-a-hydroxy-a-phenylacetic acids using chiral auxiliaries
a
Salvador Perez-Estrada, Selene Lagunas-Rivera, Marıa Elena Vargas-Dıaz,
a
a
´
´
Pedro Velazquez-Ponce, Pedro Joseph-Nathan and L. Gerardo Zepeda
´
a
b
a,
*
´
a
´ ´
Departamento de Quımica Organica, Escuela Nacional de Ciencias Biologicas, Instituto Politecnico Nacional,
Prol. de Carpio y Plan de Ayala, Mexico, D.F. 11340, Mexico
´
´
´
Departamento de Quımica, Centro de Investigacion y de Estudios Avanzados del Instituto Politecnico Nacional,
b
´
´
Apartado 14-740, Mexico, D.F. 07000, Mexico
´
´
Received 2 March 2005; accepted 30 March 2005
Abstract—The enantioselective synthesis of either enantiomer of a-alkyl-a-hydroxy-a-phenylacetic acids was achieved by using
2-acyloxathianes 1a–c and the mixed acyl-S,O-acetals 7 and 8 as chiral auxiliaries, which can straightforwardly be prepared
from (1R)-(ꢀ)-myrtenal. This procedure allowed the preparation of the title compounds in >95% enantiomeric excess (ee).
ꢀ 2005 Published by Elsevier Ltd.
1. Introduction
8,10 we herein report their use to synthesize either anti-
pode of some representative chiral a-alkyl-a-hydroxy-
a-phenylacetic acids. A comparative analysis concerning
the advantage of the use of acyloxathianes 1 and acyl-
S,O-acetals 7 and 8 is also described.
a-Hydroxy acids represent a useful arrangement of func-
tional groups widely used as building blocks for the syn-
thesis of molecules with synthetic1 or biological2,3
interest. Most enantioselective syntheses of the title
compounds involve the reduction of ketoesters by bio-
mimetic4 or by borane-mediated asymmetric reduc-
tions,5 ring-opening of epoxyacids with metalated
reagents,6 asymmetric hydrogenation of enol acetates,7
enzymatic protocols,8 and through dynamic kinetic res-
olution,9 although such procedures usually lead to only
one enantiomer. As an extension of our research on the
enantioselective preparation of chiral 1,2-diols using
(1R)-(ꢀ)-myrtenal-derived chiral auxiliaries 1, 7, and
2. Results and discussion
The preparation of both enantiomers of a-hydroxyalde-
hydes can be achieved by diastereoselective nucleophilic
additions to acylaminals11 and acyloxathianes12 used as
chiral auxiliaries, in which the inclusion order of the two
groups into the chiral auxiliary, either as the acyl group
or as the nucleophilic reagent, determines the absolute
12
OR
5
7
i
9
R1
R1
R1
SH
OH
ii
+
S
S
RO
O
O
1
3
R2 OH
O
O
2
1a R1 = Ph
1b R1 = Me
1c R1 = Et
4a R1 = Ph; R2 = Me
4b R1 = Ph; R2 = Et
4c R1 = Me; R2 = Ph
4d R1 = Et; R2 = Ph
3a R = Et; R1 = Ph
3b R = Me; R1 = Me
3c R = Me; R1 = Et
Scheme 1. Preparation of acyloxathianes 1a–c and their treatment with Grignard reagents. (i) C6H6, p-TsOH, reflux; (ii) R2MgBr, THF, ꢀ78 ꢁC.
*
Corresponding author. Tel.: +52 55 5729 6300x62412; fax: +52 55 5396 3503; e-mail: lzepeda@woodward.encb.ipn.mx
0957-4166/$ - see front matter ꢀ 2005 Published by Elsevier Ltd.
doi:10.1016/j.tetasy.2005.03.032

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S. Perez-Estrada et al. / Tetrahedron: Asymmetry 16 (2005) 1837–1843
1838
configuration of the new stereogenic center. In this con-
text, and based on the excellent capabilities of acyloxa-
thianes10a,b and mixed S,O-acetals10c as chiral
auxiliaries, the use of both protocols to selectively pre-
pare either desired enantiomer of the title compounds
is described.
of diastereoisomerically pure S,O-acetals 5 and 6,
respectively, with TBSCl in CH2Cl2 in the presence of
DMAP (Scheme 2).10c Once separated, S,O-acetals 7
and 8 were submitted to nucleophilic addition using
MeMgBr or EtMgBr, to give the derived diastereoiso-
meric carbinols 9–12 in good yields (>95%) and excel-
lent diastereoselective ratios (>99:1).
According to the first protocol, to achieve a representa-
tive synthesis of each antipode pair of two a-alkyl-a-
phenylacetic acids, we choose to prepare the three acyl-
oxathianes 1a–c, having a benzoyl, acetyl or propionyl
substituent as the acyl group, respectively, whose prepa-
ration (Scheme 1) was done as described.10a,b Thus,
hydroxythiol 2 was treated with the corresponding a-
ketoacetals 3a and 3b to yield the 2-acyloxathianes 1a
and b, respectively. Similarly, the new oxathiane 1c
was prepared in 32% isolated yield by condensing a-
ketoacetal13 3c with hydroxythiol 2. As was previously
done for oxathianes 1a and b,10a,b the stereochemistry
at C-5 of propionyloxathiane 1c was confirmed by an
NOE experiment, giving 5% and 8% enhancements in
the NMR signals of H-3 axial and H-7, respectively,
upon irradiation of H-5.
The oxidative hydrolyses of adducts 4a–d and 9–12 were
achieved using AgNO3 and NCS in acetonitrile (Scheme
3), giving the corresponding aldehydes and the chiral
auxiliary as sultine10a,b 13 (50–72% yield) or dimer 14
(91% yield), respectively. Aldehydes (S)-15 and (S)-16
were obtained from adducts 4a and b in 58% and 63%
yield, respectively, while hydrolysis of adducts 4c and
d gave aldehydes (R)-15 and (R)-16 in 67% and 72%
yield, respectively.
Purification of aldehydes (S)-15 and (R)-15 through col-
umn chromatography failed since they showed a faster
tendency to decompose than aldehydes (S)-16 and (R)-
16. The former aldehydes, even upon standing at room
temperature, decomposed to yield acetophenone. To
overcome this, oxidation of aldehydes (S)-15 and (R)-
15 should be done as soon as they have been prepared.
The oxidation process using Ag2O, to afford carboxylic
acids (S)-17 and (R)-17, is in agreement with the forma-
tion of acetophenone as a side product.12,15 At this
stage, carboxylic acids (S)-17 and (R)-17 were purified
by crystallization in CHCl3. In turn, aldehydes (S)-16
and (R)-16 were also oxidized using the same reaction
conditions to give carboxylic acids (S)-18 and (R)-18.
Spectroscopic data and specific rotations (see Experi-
mental) of the above hydroxyacids are in agreement
with those reported.11b,12,16,17
The nucleophilic addition of Grignard reagents on acyl-
oxathianes 1a–c were carried out as previously describ-
ed.10a,b Accordingly, the addition of MeMgBr and
EtMgBr on benzoyloxathiane 1a gave adducts 4a
(R1 = Ph; R2 = Me) and 4b (R1 = Ph; R2 = Et), respec-
tively, while addition of PhMgBr on oxathianes 1b and
c gave adducts 4c (R1 = Me; R2 = Ph) and 4d (R1 = Et;
R2 = Ph), respectively. The chemical yields of adducts
4a–d range from 85% to 95% isolated yield, while the
diastereomeric ratios (dr) were >99:1. The stereochemi-
cal outcome is consistent with the Cram chelated mod-
el,10,12,14 while diastereomeric ratios were calculated by
integrating the H-5 signals of each diastereoisomer in
the NMR spectra.
A comparison of the above two experimental protocols
is of interest in order to attain a specific structural or
stereochemical objective. The number of synthetic steps
required from hydroxythiol 2 to the addition products
4a–d, or 9–12, are two or three, respectively. Both pro-
tocols hold identical procedures before and after these
stages. However, in order to obtain two enantiomeric
pairs of a-hydroxyacids 17 and 18, it was necessary in
the first protocol to carry out three separate reactions
to prepare three different acyloxathianes 1a–c, while in
the second protocol, only one synthetic operation is
required to obtain the diastereoisomeric acyl-S,O-
acetals 5 and 6. This fact would clearly favor the acyl-
S,O-acetals protocol when the synthesis of a series of
compounds bearing a common substituent, such as a
For the second protocol, the synthesis of a mixture of
S,O-acetals 5 and 6 (Scheme 2) was achieved in 83%
yield in a 4:1 ratio.10c To increase the amount of S,O-
acetal 6, the above mixture was equilibrated to ca. 1:1
ratio after treatment with potassium carbonate in THF
at room temperature for 24 h. The separation of this
mixture can efficiently be done at this stage through col-
umn chromatography (silica gel 230–400; hexane:ethyl
acetate 4:1), or after its conversion to the corresponding
silyl derivatives 7 and 8 (silica gel 230–400, hexane:ethyl
acetate 49:1). Preparation of the two later compounds
proceeded without epimerization in 95%, by treatment
R4
S
R3
R4
S
R3
O
Ph
R2
Ph
i
iii
R = CH OTBS
SH
OH
R
R
2
R1
2
9 R1 = Me; R2 = OH; R3 = OEt; R4 = H
5 R = CH2OH; R3 = OEt; R4 = H
6 R = CH2OH; R3 = H; R4 = OEt
7 R = CH2OTBS; R3 = OEt; R4 = H
8 R = CH2OTBS; R3 = H; R4 = OEt
10 R1 = OH; R2 = Me; R3 = H; R4 = OEt
11 R1 = Et; R2 = OH; R3 = OEt; R4 = H
12 R1 = OH; R2 = Et; R3 = H; R4 = OEt
ii
Scheme 2. Preparation of acyl-S,O-acetals 7 and 8 and their treatment with Grignard reagents. (i) Compound 3a, CH2Cl2, p-TsOH, rt; (ii) TBSCl,
CH2Cl2, DMAP, rt; (iii) MeMgBr or EtMgBr, THF, ꢀ78 ꢁC.

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S. Perez-Estrada et al. / Tetrahedron: Asymmetry 16 (2005) 1837–1843
1839
O
13
S
O
i
S
O
R2
R1
4a R1 = OH; R2 = Me
4b R1 = Me; R2 = OH
4c R1 = OH; R2 = Et
4d R1 = Et; R2 = OH
O
O
ii
H
HO
R1 R2
R1 R2
14
)
S
(S)-(+)-17 R1 = Me; R2 = OH
(R)-(-)-17 R1 = OH; R2 = Me
(S)-(+)-18 R1 = Et; R2 = OH
(R)-(-)-18 R1 = OH; R2 = Et
(S)-15 R1 = Me; R2 = OH
(R)-15 R1 = OH; R2 = Me
(S)-16 R1 = Et; R2 = OH
(R)-16 R1 = OH; R2 = Et
2
R
R4
S
R3
i
R
R2
R1
9 R1 = OH; R2 = Me; R3 = OEt; R4 = H
10 R1 = Me; R2 = OH; R3 = H; R4 = OEt
11 R1 = OH; R2 = Et; R3 = OEt; R4 = H
12 R1 = Et; R2 = OH; R3 = H; R4 = OEt
Scheme 3. Oxidative hydrolysis of carbinols 4a–d and 9–12 and preparation of the respective a-hydroxyacids. (i) AgNO3, NCS, CH3CNÆH2O (1:1),
0 ꢁC; (ii) Ag2O, THFÆH2O (1:1), 0 ꢁC.
phenyl group, is the objective. This advantage of the
acyl-S,O-acetals protocol, over the acyloxathiane proto-
col, is due to the diastereoisomeric relationship at the
S,O-acetalic carbon in 7 and 8, which is equivalent of
having enantiomeric acyloxathianes, or to control the
nature of the nucleophilic reagent and the acyl group
at the oxathiane ring.
straightforward process, a situation that is strongly de-
sired in the field of asymmetric synthesis.
4. Experimental
4.1. General
On the other hand, recovery of the chiral auxiliary is effi-
ciently done in both protocols. Thus, the oxidative
hydrolysis of carbinols 4a–d yield the respective a-
hydroxyaldehydes and sultine 13, while hydrolysis of
S,O-acetals 9–12 provides the expected a-hydroxyalde-
hydes and dimer 14. Both sultine 13 and dimer 14 were
reconverted to hydroxythiol 2 in 72 and 91% yield,
respectively, with LiAlH4. From there, hydroxythiol 2
leads directly to acyloxathianes 4, while for the prepara-
tion of acyl-S,O-acetals 7 and 8, two reaction steps and a
separation are necessary. However, the additional reac-
tion steps can well be compensated, since acyl-S,O-ace-
tals can be obtained in higher yields than acyloxathianes.
Melting points were determined on an electrothermal
capillary melting point apparatus and are uncorrected.
Optical rotations were measured at 589 nm using a
1 dm cell on a JASCO DIP-370 polarimeter. Infrared
spectra were recorded on a Perkin–Elmer Spectrum
2000 spectrophotometer. 1H and 13C NMR spectra were
obtained on a Varian Mercury spectrometer at 300 and
75.4 MHz, or in a Bruker DMX at 500 and 125 MHz, as
specified, using CDCl3 as solvent and TMS as the inter-
nal standard. The low resolution mass spectra (LRMS)
were recorded on a Varian Saturn 2000 GC/Selective
Mass Detector, either using EI (70 eV) or CI, as speci-
fied. The high resolution electron impact mass spectra
(HREIMS) were recorded on a VG 7070 high resolution
mass spectrometer at the UCR Mass Spectrometry
Facility, University of California, Riverside, CA. Ele-
mental analyses were determined by A-M-W laborato-
ries, Phoenix, AZ. Thin-layer chromatograms were
done on precoated TLC sheets of silica gel 60 F254 (E.
Merck). Flash chromatography was carried out using
Merck silica gel (230–400 mesh). THF used in the nucle-
ophilic additions was distilled from Na immediately
prior to use, and all other reagents were used without
further purification.
3. Conclusion
In summary, when using acyloxathianes, the desired
absolute configuration at the new stereogenic center
can be determined by controlling both the nature of
the acyl group attached to the chiral auxiliary and the
incoming nucleophilic moiety of a Grignard reagent,
while the same goal can be achieved by using either
thioacetal 7 or 8 (Scheme 2), thus it being unnecessary
to switch between the nucleophile and the acyl groups.
Despite the existence of several enantioselective and dia-
stereoselective methods to obtain optically active
compounds, these methods normally give only one
enantiomer of a given pair. In this context, our thio-
acetal protocol allows us to obtain any configuration
of a given a-hydroxycarbonyl derivative in a more
4.2. (1S,2R,5R,7S,9R)-5-Propionyl-10,10-dimethyl-4-
oxa-6-thiatricyclo[7.1.1.02,7]undecane 1c
A solution containing 200 mg (1.07 mmol) of hydroxy-
thiol10a 2 and 184 mg (1.39 mmol) of ketoacetal 3c in
40 mL of benzene was refluxed for 1.5 h. The reaction

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S. Perez-Estrada et al. / Tetrahedron: Asymmetry 16 (2005) 1837–1843
1840
mixture was poured into a cold saturated solution of
NaHCO3, extracted with ethyl ether, washed with a sat-
urated solution of NaHCO3 (2 · 20 mL), dried over
anhydrous Na2SO4 and evaporated to dryness. The oily
residue was flash chromatographed using a mixture of
hexane:EtOAc (9:1) as the eluent, giving 94 mg (34%
(C-o), 128.6 (C-m), 85.0 (C-20), 66.0 (C-10), 64.2
(OCH2), 52.7 (C-2), 43.4 (C-5), 42.3 (C-1), 39.3 (C-4),
38.4 (C-6), 36.4 (C-3), 33.5 (C-7), 27.6 (Me-9), 23.6
(Me-8), 14.9 (CH2CH3). IR (CH2Cl2) mmax: 3477, 3059,
2980, 2921, 2869, 1681, 1596, 1578, 1091, 1044, 689,
734 cmꢀ1. EIMS (70 eV) m/z (rel. int): 348 (M+), 243
(73), 135 (48), 105 (52), 91 (40), 79 (100), 55 (16). EA
calcd for C20H28SO3: C, 68.96; H, 8.04; S, 9.19. Found:
C, 68.72; H, 7.86; S, 8.92.
yield) of propionyloxathiane 1c as a colorless syrup
25
D
(Rf 0.43, hexane:EtOAc 9:1). ½aꢁ = ꢀ5.2 (c 0.11,
1
CHCl3). H NMR (CDCl3) d 5.49 (s, 1H, H-5), 4.11
(dd, 1H, J = 10.7, 3.1 Hz, H-3eq), 3.82 (dt, 1H,
J = 8.5, 10.2 Hz, H-7), 3.65 (t, 1H, J = 11.3 Hz, H-
3ax), 2.66 (q, 2H, J = 7.4 Hz, H-20), 2.62 (m, 1H, H-
11eq), 2.48 (ddd, 1H, J = 11.3, 10.2, 3.1 Hz, H-2), 2.38
(m, 1H, H-8eq), 2.14 (bq, 1H, J = 6.1 Hz, H-9), 1.84
(bt, 1H, J = 5.9 Hz, H-1), 1.76 (m, 1H, H-8ax), 1.27 (s,
3H, Me-13), 1.16 (s, 3H, Me-12), 1.08 (t, 3H,
J = 7.3 Hz, Me-30), 1.02 (d, 1H, J = 9.6 Hz, H-11ax).
13C NMR (CDCl3) d 204.9 (C-10), 88.6 (C-5), 76.0 (C-
3), 51.1 (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), 31.4 (C-20), 29.5 (C-
13), 24.5 (C-12), 7.3 (C-30). IR (KBr) mmax: 2917, 1722,
1458, 1129, 1058 cmꢀ1. EIMS m/z (rel. int): 255
(M++1, 4), 197 (100), 135 (20), 107 (37), 93 (28), 79
(21). HREIMS calcd for C14H22O2S: 254.1341. Found:
254.1349.
4.3.2. (1S,2R,3S,5R,20S)-6,6-Dimethyl-3-(20-ethoxy-10-
phenyl-10-oxo-20-ethylsulfanyl)-20-hydroxymethyl-bicyclo-
[3.1.1]heptane 6. Colorless syrup (Rf 0.16, hexane:
24
D
EtOAc 4:1). ½aꢁ = +81.9 (c 0.71, EtOH). 1H NMR
(CDCl3) d 8.05 (dd, 2H, J = 6.8, 1.3 Hz, H-o), 7.56
(dd, 1H, J = 7.4, 1.3 Hz, H-p), 7.46 (ddd, 2H, J = 7.4,
6.8, 1.5 Hz, H-m), 5.76 (s, 1H, H-20), 3.97 (dq, 1H,
J = 9.2, 7.0 Hz, OCHa), 3.79 (dd, 1H, J = 10.9 y 6.4,
H-10a), 3.62 (m, 1H, OCHb), 3.62 (m, 1H, H-10b),
3.26 (ddd, 1H, J = 10.1, 7.5, 5.7 Hz, H-3), 2.46 (m,
1H, H-4eq), 2.34 (m, 1H, H-7eq), 2.14 (m, 1H, H-2),
2.06 (m, 1H, H-5), 1.85 (m, 1H, H-4ax), 1.85 (m, 1H,
H-1), 1.32 (t, 3H, J = 7.0 Hz, CH2CH3), 1.17 (s, 3H,
Me-9), 0.97 (d, 1H, J = 8.4, H-7ax), 0.96 (s, 3H, Me-
13
8). C NMR (CDCl3) d 191.5 (C-10), 134.4 (C-i),
133.3 (C-p), 128.9 (C-o), 128.5 (C-m), 84.6 (C-20), 66.4
(C-10), 64.5 (OCH2), 53.9 (C-2), 43.8 (C-5), 41.9 (C-1),
38.3 (C-4), 38.0 (C-6), 35.9 (C-3), 33.1 (C-7), 27.4 (Me-
4.3. Preparation of acyl-S,O-acetals 5 and 6
A solution containing 5.2 g (28 mmol) of hydroxythiol
2, 8.7 g (42 mmol) of 2,2-diethoxyacetophenone 3a and
0.53 g (3.1 mmol) of p-TsOH in 30 mL of CH2Cl2 was
stirred at room temperature for 5 h. After the addition
of 150 mL of CH2Cl2, the reaction mixture was washed
with a saturated solution of NaHCO3 (4 · 50 mL), the
organic layer dried over anhydrous Na2SO4 and concen-
trated to dryness, to give 12.5 g of a syrup. This mixture
was filtered through a short chromatography column
(5 cm diam. · 15 cm large of silica gel 230–400; hex-
ane:EtOAc 4:1) to give a mixture of 8.1 g (83% yield)
of S,O-acetals 5 and 6 in a ca. 4:1 ratio. Two gram of
this mixture was then treated with 0.2 g of K2CO3 in
50 mL of THF at room temperature for 24 h to give a
mixture of 5 and 6 in a ca. 1:1 ratio, whose separation
was achieved through column chromatography (3 cm
diam. · 40 cm large, silica gel mesh 230–400) using hex-
ane:EtOAc 4:1 as eluent, giving 0.8 g of compound 5
and 0.6 g of compound 6.
9), 23.5 (Me-8), 14.8 (CH2CH3). IR (CH2Cl2) mmax:
3453, 3058, 2981, 2920, 2869, 1682, 1596, 1578, 1093,
1044, 734, 686 cmꢀ1. EA calcd for C20H28SO3: C,
68.96; H, 8.04; S, 9.19. Found: C, 68.78; H, 7.93; S, 8.98.
4.4. Preparation of acyl S,O-acetals 7 and 8
A solution of 6.63 g (19.0 mmol) of S,O-acetals 5 and 6,
8.06 g (53.5 mmol) of TBSCl, 4.44 g (43.9 mmol) of tri-
ethylamine and 0.65 g (6.1 mmol) of DMAP in 40 mL
of CH2Cl2 was stirred at room temperature under an
N2 atmosphere for 22 h, at which point were added
150 mL of CH2Cl2 and the reaction mixture washed
(2 · 100 mL) with an HCl solution (0.5%). The organic
layer was dried over anhydrous Na2SO4 and concen-
trated to dryness, to give 11.2 g of the crude reaction
mixture, which was flash chromatographed (5 cm
diam. · 20 cm large, silica gel 230–400 mesh) using hex-
ane:EtOAc (30:1), giving 8.36 g (95% yield) of S,O-ace-
tals 7 and 8. A portion of 584 mg of 7 and 8 was
efficiently separated through column chromatography
(5 cm diam.) packed with silica gel mesh 230–400
(90 cm) and eluted with a mixture of hexane:EtOAc
(49:1), giving 252 mg of compound 7 and 236 mg of
compound 8.
4.3.1. (1S,2R,3S,5R,20R)-6,6-Dimethyl-3-(20-ethoxy-10-
phenyl-10-oxo-20-ethylsulfanyl)-2-hydroxymethyl-bicyclo-
[3.1.1]heptane 5. Colorless syrup (Rf 0.25, hexane:
28
D
EtOAc 4:1). ½aꢁ = +8.2 (c 0.529, EtOH). 1H NMR
(CDCl3) d 8.04 (dd, 2H, J = 7.1, 1.4 Hz, H-o), 7.57
(dd, 1H, J = 7.1, 1.4 Hz, H-p), 7.46 (dd, 2H, J = 7.3,
1.4 Hz, H-m), 5.86 (s, 1H, H-20), 3.99 (dq, 1H, J = 9.3,
7.0 Hz, OCHa), 3.63 (dq, 1H, J = 9.3, 7.0 Hz, OCHb),
3.45 (d, 2H, J = 6.0 Hz, H-10), 3.09 (ddd, 1H, J = 9.8,
8.1, 5.8 Hz, H-3), 2.66 (m, 1H, H-4eq), 2.41 (m, 1H,
H-7eq), 2.15 (m, 1H, H-4eq), 2.08 (m, 1H, H-5), 2.01
(m, 1H, H-2), 1.95 (m, 1H, H-1), 1.30 (t, 3H,
J = 7.0 Hz, CH2CH3), 1.19 (s, 3H, Me-9), 1.02 (d, 1H,
J = 9.9 Hz, H-7ax), 0.98 (s, 3H, Me-8). 13C NMR
(CDCl3) d 191.6 (C-10), 134.4 (C-i), 133.4 (C-p), 128.9
4.4.1. (1S,2R,3S,5R,20R)-6,6-Dimethyl-3-(20-ethoxy-10-
phenyl-10-oxo-20-ethylsulfanyl)-2-(O-t-butyl-dimethylsilyl-
hydroxymethyl)-bicyclo[3.1.1]heptane 7. Obtained in
96% yield as a colorless syrup (Rf 0.79, hexane:EtOAc
28
D
1
9:1). ½aꢁ = ꢀ4.4 (c 0.40, CHCl3). H NMR (CDCl3) d
8.02 (dd, 2H, J = 7.2, 1.6 Hz, H-o), 7.55 (dd, 1H,
J = 7.9, 1.6 Hz, H-p), 7.44 (dd, 2H, J = 7.2, 7.9 H-m),
5.84 (s, 1H, H-20), 4.01 (dq, 1H, J = 9.2, 7.2 Hz, OCHa),
3.60 (dq, 1H, J = 9.2, 7.2 Hz, OCHb), 3.38 (t, 1H,

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S. Perez-Estrada et al. / Tetrahedron: Asymmetry 16 (2005) 1837–1843
1841
J = 10.0 Hz, H-10a), 3.20 (dd, 1H, J = 10.0, 4.2 Hz, H-
10b), 2.85 (m, 1H, H-3), 2.77 (m, 1H, H-4eq), 2.38 (m,
1H, H-7eq), 2.18 (m, 1H, H-5), 2.11 (ddd, 1H,
J = 13.8, 5.9, 2.4 Hz, H-4ax), 1.91 (m, 1H, H-1), 1.86
(m, 1H, H-2), 1.29 (t, 3H, J = 7.2 Hz, CH2CH3), 1.17
(s, 3H, Me-9), 0.98 (s, 3H, Me-8), 0.94 (d, 1H,
J = 10.0 Hz, H-7ax), 0.77 (s, 9H, t-Bu), ꢀ0.12 (s, 3H,
Me-Si), ꢀ0.14 (s, 3H, Me-Si). 13C NMR (CDCl3) d
190.8 (C-10), 134.4 (C-i), 133.2 (C-p), 128.8 (C-o),
128.5 (C-m), 84.3 (C-20), 64.5 (C-10), 63.8 (OCH2),
52.1 (C-2), 42.3 (C-1), 41.9 (C-5), 39.7 (C-4), 38.4 (C-
6), 35.2 (C-3), 33.7 (C-7), 27.7 (Me-9), 25.9 (t-Bu), 23.4
(Me-8), 18.3 (CSi), 14.8 (CH2 CH3), ꢀ5.40 (Si–Me2).
IR (CH2Cl2) mmax: 3059, 2926, 2857, 1686, 1597, 1579,
1250, 1087, 836, 776 cmꢀ1. EIMS (70 eV) m/z (rel. int):
357 (M+ꢀ105, 8), 135 (100), 133 (16), 105 (44), 79
(93), 41 (19), 29 (18). EA calcd for C26H42O3SSi:
C, 67.51; H, 9.09; S, 6.92. Found: C, 67.69; H, 8.83; S,
7,20.
the remaining emulsion extracted with ethyl ether. The
organic layer was washed with a saturated solution of
ammonium chloride, dried over anhydrous Na2SO4
and evaporated to dryness, to give the corresponding
pure carbinols as colorless oils. Spectroscopic data for
compounds 4a–c are described.10c
4.5.1.
propyl)-10,10-dimethyl-4-oxa-6-thia-tricyclo[7.1.1.02,7]-
undecane 4d. Obtained in 78% yield as a colorless syr-
(1S,2R,5R,7S,10R)-5-(10-Hydroxy-10-phenyl-10-
20
D
up (Rf 0.39, hexane:EtOAc 9:1). ½aꢁ = ꢀ46.7 (c 0.28,
1
CHCl3). H NMR (CDCl3) d 7.51–7.21 (m, 5H, Ar),
5.09 (s, 1H, H-5), 4.00 (dd, 1H, J = 11.0, 3.1 Hz, H-
3eq), 3.65 (bq, 1H, J = 10.1 Hz, H-7), 3.57 (t, 1H,
J = 11.0 Hz, H-3ax), 2.91 (bs, 1H, OH), 2.57 (m, 1H,
H-11eq), 2.46–2.23 (m, 2H, H-2, H-8eq), 2.09 (bq, 1H,
J = 5.4 Hz, H-9), 2.02 (q, 2H, J 7.3 Hz, H-20), 1.78 (t,
1H, J = 5.6 Hz, H-1), 1.72 (m, 1H, H-8ax), 1.24 (s,
3H, Me-13), 1.10 (s, 3H, Me-12), 0.99 (d, 1H,
J = 9.6 Hz, H-11ax), 0.75 (t, 3H, J = 7.3 Hz, Me-30).
13C NMR (CDCl3) d 142.5 (C-i), 127.8 (C-m), 127.0
(C-p), 116.2 (C-o), 93.9 (C-5), 78.3 (C-10), 76.5 (C-3),
51.5 (C-2), 45.5 (C-1), 43.2 (C-9), 41.1 (C-7), 39.3 (C-
11), 39.0 (C-10), 33.4 (C-8), 29.8 (C-20), 29.5 (C-13),
24.4 (C-12), 7.5 (C-30). IR (film) mmax: 3501, 2921,
1448, 1368, 1258, 1063 cmꢀ1. EIMS (70 eV) m/z (rel.
int): 314 (M+ꢀ18, 1), 197 (100), 135 (30), 107 (32), 93
(30), 79 (22). HREIMS calcd for C20H28O2S+H:
333.1888. Found: 333.1902.
4.4.2. (1S,2R,3S,5R,20S)-6,6-Dimethyl-3-(20-ethoxy-10-
phenyl-10-oxo-20-ethylsulfanyl)-2-(O-t-butyl-dimethylsilyl-
hydroxymethyl)-bicyclo[3.1.1]heptane 8. Obtained in
95% yield as a colorless syrup (Rf 0.84, hexane:EtOAc
25
1
9:1). ½aꢁ = +75.3 (c 0.51, EtOH). H NMR (500 MHz,
D
CDCl3) d 8.01 (dd, 2H, J = 8.0, 1.2 Hz, H-o), 7.52 (dd,
1H, J = 7.5, 1.2 Hz, H-p), 7.41 (ddd, 2H, J = 8.0, 7.5,
1.2 Hz, H-m), 5.64 (s, 1H, H-20), 3.98 (dq, 1H, J = 9.5,
7.0 Hz, OCHa), 3.63 (dd, 1H, J = 10.0, 4.5 Hz, H-10a),
3.57 (dq, 1H, J = 9.5, 7.0 Hz, OCHb), 3.56 (t, 1H,
J = 10.0 Hz, H-10b), 3.01 (ddd, 1H, J = 10.0, 8.5,
6.0 Hz, H-3), 2.42 (ddd, 1H, J = 14.0, 10.0, 2.0 Hz, H-
4eq), 2.31 (m, 1H, H-7eq), 2.19 (td, 1H, J = 6.0,
2.0 Hz, H-5), 1.98 (m, 1H, H-2), 1.84 (ddd, 1H,
J = 14.0, 6.0, 3.0 Hz, H-4ax), 1.74 (ddd, 1H, J = 8.6,
6.0, 3.0 Hz, H-1), 1.29 (t, 3H, J = 7.0 Hz, CH2CH3),
1.13 (s, 3H, Me-9), 0.93 (s, 3H, Me-8), 0.87 (d, 1H,
J = 10.0 Hz, H-7ax), 0.84 (s, 9H, t-Bu), 0.004 (Si–Me),
0.003 (Si–Me). 13C NMR (125 MHz, CDCl3) d 192.5
(C-10), 134.4 (C-i), 133.2 (C-p), 128.9 (C-o), 128.4 (C-
m), 84.2 (C-20), 64.7 (C-10), 64.1 (OCH2), 53.2 (C-2),
42.1 (C-1), 41.9 (C-5), 38.5 (C-4), 38.1 (C-6), 34.5 (C-
3), 33.3 (C-7), 27.5 (Me-9), 25.9 (t-Bu), 23.4 (Me-8),
18.3 (CSi), 14.8 (CH2CH3), ꢀ5.29 (Si–Me2). IR
(CH2Cl2) mmax: 3058, 2926, 2855, 1689, 1597, 1578,
1250, 1079, 836, 776 cmꢀ1. EIMS (70 eV) m/z (rel. int):
462 (M+), 357 (21), 135 (99), 105 (49), 79 (100), 59
(16). EA calcd for C26H42O3SSi: C, 67.51; H, 9.09; S,
6.92. Found: C, 67.72; H, 8.80; S, 7.24.
4.5.2. (1S,2R,3S,5R,10R,20S)-6,6-Dimethyl-3-(10-ethoxy-
20-phenyl-20-hydroxy-10-propylsulfanyl)-2-(O-t-butyl-di-
methylsilyl-hydroxymethyl)-bicyclo[3.1.1]heptane
Obtained in 96% yield as a colorless syrup (Rf 0.79,
9.
24
D
hexane:EtOAc 4:1). ½aꢁ = +25.6 (c 0.90, CHCl3). 1H
NMR (CDCl3) d 7.60–7.20 (m, 5H, Ar), 4.62 (s,
1H, H-10), 3.90 (dq, 1H, J = 9.0, 7.0 Hz, OCHa),
3.64 (dd, 1H, J = 10.0, 5.0 Hz, H-10a), 3.59 (t, 1H,
J = 10.0 Hz, H-10b), 3.25 (dq, 1H, J = 9.0, 7.0 Hz,
OCHb), 2.90 (m, 1H, H-3), 2.40 (m, 2H, H-4eq, H-
7eq), 2.21 (t, 1H, J = 7.0 Hz, H-1), 2.15–1.95 (m,
3H, H-2, H-4ax, H-5) 1.62 (s, 3H, Me-30), 1.20 (s,
3H, Me-9), 1.18 (t, 3H, J = 7.0 Hz, CH2CH3), 0.95
(d, 1H, J = 10.0 Hz, H-7ax), 0.93 (s, 3H, Me-8), 0.80
(s, 9H, t-Bu), 0.02 (Si–Me2). 13C NMR (CDCl3) d
144.7 (C-i), 127.6 (C-m), 127.0 (C-p), 126.0 (C-o),
95.6 (C-10), 75.8 (C-20), 65.7 (C-10), 65.5 (OCH2), 53.0
(C-2), 42.3 (C-1), 42.1 (C-5), 38.8 (C-4), 38.2 (C-6),
37.1 (C-3) 33.2 (C-7), 27.7 (C-9), 25.9 (t-Bu), 25.3
(C-30), 23.4 (C-8), 18.5 (SiC), 14.8 (CH2CH3), ꢀ5.2,
ꢀ5.3 (Me2Si). IR (film) mmax: 3467, 2928, 2857, 1447,
1079, 699, 620 cmꢀ1. EIMS (70 eV) m/z (rel. int): 433
(4), 357 (73), 135 (100), 105 (58). HREIMS calcd for
C27H46O3SSi+Na: 501.2835. Found: 501.3725.
4.5. General procedure for the addition of Grignard
reagents to acyloxathianes 1a–c and S,O-acetals 9–12
To a solution of acyloxathianes 1a,10b 1b,10a 1c, and
S,O-acetals 7 and 8 (1 equiv) in anhydrous THF was
added the Grignard reagent (1.5–2 equiv) at ꢀ78 ꢁC un-
der an N2 atmosphere. After stirring for 2 h at the same
temperature, the reaction mixture was allowed to warm
up to room temperature and further stirred for 1 h. The
reaction mixture was quenched with 10 mL of a satu-
rated solution of ammonium chloride; the THF was
eliminated by evaporation under reduced pressure and
4.5.3. (1S,2R,3S,5R,10S,20R)-6,6-Dimethyl-3-(10-ethoxy-
20-phenyl-20-hydroxy-10-propylsulfanyl)-2-(O-t-butyl-di-
methylsilyl-hydroxymethyl)-bicyclo[3.1.1]heptane 10.
Obtained in 98% yield as a colorless syrup (Rf 0.77, hex-
25
ane:EtOAc 4:1). ½aꢁ = ꢀ122.4 (c 0.59, CHCl3). 1H
D
NMR (CDCl3) d 7.56 (d, 2H, J = 7.0 Hz, H-o), 7.33 (t,
2H, J = 7.0 Hz, H-m), 7.24 (t, 1H, J = 7.0 Hz, H-p),

´
S. Perez-Estrada et al. / Tetrahedron: Asymmetry 16 (2005) 1837–1843
1842
4.54 (s, 1H, H-10), 3.96 (dq, 1H, J = 9.9, 7.0 Hz, OCHa),
3.39 (dd, 1H, J = 5.0, 9.7 Hz, H-10a), 3.33 (dq, 1H,
J = 9.9, 7.0 Hz, OCHb), 3.28 (s, 1H, OH), 3.22 (t, 1H,
J = 9.7 Hz, H-10b), 2.44 (m, 1H, H-4eq), 2.36 (ddd,
1H, J = 9.7, 6.0, 6.0 Hz, H-7eq), 2.24 (ddd, 1H, J =
9.7, 9.7, 7.0 Hz, H-3), 2.14 (m, 1H, H-4ax), 2.14 (t,
1H, J = 6.0 Hz, H-1), 1.90 (m, 1H, H-2), 1.90 (m, 1H,
H-5), 1.62 (s, 3H, H-30), 1.20 (t, 3H, J = 7.0 Hz,
CH2CH3), 1.16 (s, 3H, H-9), 1.00 (d, 1H, J = 9.7 Hz,
H-7ax), 0.88 (s, 9H, t-Bu), 0.72 (s, 3H, H-8), 0.06 (s,
6H, SiMe2). 13C NMR (CDCl3) d 145.4 (C-i), 128.1
(C-m), 127.1 (C-p), 125.9 (C-o), 94.8 (C-10), 76.7 (C-
20), 65.9 (C-10), 65.4 (OCH2), 52.4 (C-2), 42.4 (C-1),
42.4 (C-5), 38.9 (C-6), 38.4 (C-4), 37.3 (C-3), 33.2
(C-7), 27.8 (C-8), 26.3 (t-Bu), 25.3 (C-30), 23.4 (C-8),
18.6 (C-Si), 14.9 (CH2CH3), ꢀ4.8 (SiMe), ꢀ4.9 (SiMe).
IR (film) mmax: 3467, 3058, 2928, 2857, 1471, 1447,
1380, 1367, 1254, 1079, 837, 776, 699 cmꢀ1. EIMS
(70 eV) m/z (rel. int): 460 (M+ꢀ18), 433 (3), 357 (57),
179 (10), 121 (18), 105 (58). HREIMS calcd for
C27H46O3SSi+Na: 501.2835. Found: 501.2827.
(d, 1H, J = 10.0 Hz, H-7ax), 0.88 (s, 9H, t-Bu), 0.71 (t,
3H, J = 9.1 Hz, H-40), 0.69 (s, 3H, H-8), 0.4 (s, 6H,
SiMe2). 13C NMR (CDCl3) d 142.8 (C-i), 127.6 (C-m),
126.5 (C-p), 126.1 (C-o), 94.2 (C-10), 79.2 (C-20), 65.3
(C.10), 64.9 (OCH2), 51.8 (C-2), 41.9 (C-1), 41.7 (C-5),
38.4 (C-6), 38.0 (C-4), 36.5 (C-3), 32.8 (C-7), 29.6 (C-
30), 27.4 (C-9), 25.9 (t-Bu), 22.9 (C-8), 18.2 (CSi), 14.5
(CH2CH3), 7.4 (C-40), ꢀ5.2 (SiMe), ꢀ5.3 (SiMe). IR
(film) mmax: 3467, 3059, 2928, 2857, 1470, 1448, 1385,
1367, 1254, 1079, 837, 775, 701 cmꢀ1. EIMS (70 eV)
m/z (rel. int): 447 (M+ꢀ45), 135 (100), 357 (53), 107
(39), 193 (5). HREIMS calcd for C28H48O3SSi+Na:
515.2991. Found: 515.3009.
4.6. General procedure for the hydrolysis of carbinols 4a–
d, and 9–12
Following the procedure previously described,10a–c
1 equiv of carbinols 4a–d and 9–12 in 5 mL of CH3CN
was treated with 2 equiv of NCS and AgNO3 in 35 mL
of CH3CN–H2O (4:1) at 0–4 ꢁC for 1–5 min. The
work-up was carried out by successively adding solu-
tions of NaCl, Na2SO3 and NaHCO3 (1 mL, each).
The white precipitate was filtered, and the filtrate ex-
tracted with a mixture of hexane:CH2Cl2 (1:1). The or-
ganic layer was dried with anhydrous Na2SO4, filtered,
and concentrated to dryness, to give a crude yellowish
4.5.4. (1S,2R,3S,5R,10R,20S)-6,6-Dimethyl-3-(10-ethoxy-
20-phenyl-20-hydroxy-10-butylsulfanyl)-2-(O-t-butyl-di-
methylsilyl-hydroxymethyl)-bicyclo[3.1.1]heptane
Obtained in 98% yield as a colorless syrup (Rf 0.66, hex-
11.
25
ane:EtOAc 9:1). ½aꢁ = +46.2 (c 0.80, CHCl3). 1H NMR
D
1
(CDCl3) d 7.60–7.20 (m, 5H, Ar), 4.60 (s, 1H, H-10), 3.90
(dq, 1H, J = 9.0, 7.0 Hz, OCHa), 3.59 (dd, 1H, J = 10.0,
5.0 Hz, H-10a), 3.59 (t, 1H, J = 10.0 Hz, H-10b), 3.30
(dq, 1H, J = 9.0, 7.0 Hz, OCHb), 2.82 (m, 1H, H-3),
2.40 (m, 2H, H-4eq, H-7eq), 2.20–1.80 (m, 4H, H-1,
H-2, H-5, H-4ax), 2.04 (q, 2H, J = 7.1 Hz, H-30), 1.20
(t, 6H, J = 7.2 Hz, CH2CH3, Me-9), 0.91 (d, 1H,
J = 10.0 Hz, H-7ax), 0.86 (s, 3H, Me-8), 0.80 (s, 9H, t-
Bu), 0.72 (t, 3H, J = 7.1 Hz, Me-40), 0.04 (Si–Me). 13C
NMR (CDCl3) d 142.3 (C-i), 127.6 (C-m), 126.7 (C-p),
126.4 (C-o), 95.6 (C-10), 78.5 (C-20), 65.5 (C-10), 65.3
(OCH2), 53.2 (C-2), 42.2 (C-1), 42.1 (C-5), 38.8 (C-4),
38.3 (C-6), 37.0 (C-3) 33.2 (C-7) 30.2 (C-30), 27.6 (C-
9), 26.0 (Ct-Bu), 23.4 (C-8), 18.3 (CSi), 14.8 (CH2CH3),
oil, whose H NMR spectrum showed the presence of
the respective aldehydes (S)-15, (S)-16, (R)-15, and
(R)-16. Aldehydes (S)-16 and (R)-16 were purified by
column chromatography using a mixture of hex-
ane:EtOAc (19:1). All spectroscopic data of aldehydes
(S)-15, (S)-16, (R)-15, and (R)-16 were fully consistent
with those described.11a,b,12,17–19
4.6.1. 2-Hydroxy-2-phenylbutanal (S)-(ꢀ)-16. Obtained
23
D
in 63% yield and >95% ee as a colorless liquid ½aꢁ
=
ꢀ13.1 (c 0.23, EtOH), lit.12 ½aꢁ23 = ꢀ13.4 (c 18.8, EtOH).
D
4.6.2. 2-Hydroxy-2-phenylbutanal (R)-(+)-16. Obtained
=
23
D
in 72% yield and >95% ee as a colorless liquid ½aꢁ
7.5 (C-40), ꢀ5.2 (SiMe), ꢀ5.3 (SiMe). IR (film) mmax
:
+13.3 (c 0.23, EtOH).
3467, 2928, 2857, 1448, 1079, 701, 665 cmꢀ1. EIMS
(70 eV) m/z (rel. int): 447 (2), 357 (53), 135 (100), 107
(39). HREIMS calcd for C28H48O3SSi+Na: 515.2991.
Found: 515.3092.
4.6.3. Bis-[(1S,2R,3S,5R)-2-(tert-butyl-dimethyl-silanyl-
oxymethyl)-6,6-dimethyl-bicyclo[3.1.1]heptane-3-thiol] 14.
Obtained in 70% yield as a colorless syrup (Rf 0.87, hex-
25
D
ane:EtOAc 19:1). ½aꢁ = +119.5 (c 0.48, CHCl3). 1H
4.5.5. (1S,2R,3S,5R,10S,20R)-6,6-Dimethyl-3-(10-ethoxy-
20-phenyl-20-hydroxy-10-butylsulfanyl)-20-(O-t-butyl-di-
NMR (CDCl3) d 3.77 (dd, 1H, J = 9.8, 4.8 Hz, H-
10eq), 3.60 (t, 1H, J = 9.8 Hz, H-10ax), 3.00 (ddd, 1H,
J = 9.8, 7.4, 5.9 Hz, H-3), 2.51 (1H, ddd, J = 13.0,
10.0, 2.7 Hz, H-4eq), 2.38 (m, 1H, H-7eq), 2.22 (dd,
1H, J=6.3, 6.0 Hz, H-1), 2.17 (m, 1H, H-2), 2.12 (m,
1H, H-4ax), 1.96 (m, 1H, H-5), 1.21 (s, 3H, Me-9),
1.11 (d, 1H, J = 9.7 Hz, H-7ax), 0.96 (s, 3H, Me-8),
0.89 (s, 9H, t-BuSi), 0.05 (s, 6H, Me2Si). 13C NMR
(CDCl3) d 65.6 (C-10), 52.6 (C-2), 43.1 (C-3), 42.1 (C-
1), 41.9 (C-5), 38.6 (C-6), 36.6 (C-4), 32.5 (C-7), 27.5
(Me-9), 26.0 (t-Bu), 23.3 (Me-8), 18.4 (CSi), ꢀ5.2
(Me2Si). IR (film) mmax: 2928, 2857, 1470, 1448, 1385,
1363, 1255, 1112, 837 cmꢀ1. EIMS (70 eV) m/z (rel.
int): 598 (1), 299 (3), 267 (16). HREIMS calcd for
C32H62O2S2Si2: 598.3730. Found: 598.3754.
methylsilyl-hydroxymethyl)-bicyclo[3.1.1]heptane
Obtained in 96% yield as a colorless syrup (Rf 0.63, hex-
12.
25
D
ane:EtOAc 9:1). ½aꢁ = +67.8 (c 0.64, CHCl3). 1H NMR
(CDCl3): d 7.5 (d, 2H, J = 7.0 Hz, H-o), 7.32 (t, 2H,
J = 7.0 Hz, H-m), 7.23 (t, 1H, J = 7.0 Hz, H-p), 4.56 (s,
1H, H-10), 3.98 (dq, 1H, J = 9.5, 7.0 Hz, OCHa), 3.37
(dq, 1H, J = 9.5, 7.0 Hz, OCHb), 3.28 (dd, 1H,
J = 9.9, 5.2 Hz, H-10a), 3.12 (t, 1H, J = 10.0 Hz, H-
10b), 3.02 (s, 1H, OH), 2.40 (m, 1H, H-4eq), 2.33
(ddd, 1H, J = 10.0, 6.0, 6.0 Hz, H-7eq), 2.06 (m, 1H,
H-4ax), 2.06 (m, 1H, H-5), 1.98 (m, 1H, H-3), 1.98 (m,
2H, H-30), 1.86 (m, 1H, H-1), 1.86 (m, 1H, H-2), 1.20
(t, 3H, J = 7.0 Hz, CH2CH3), 1.13 (s, 3H, H-9), 0.98

´
S. Perez-Estrada et al. / Tetrahedron: Asymmetry 16 (2005) 1837–1843
1843
US3789 19910605, 1991; Chem. Abstr. 1992, 116, 174137;
(c) Campbell, C. L. WO Patent 9322299 A1 19931111,
1993; Chem. Abstr. 1994, 120, 245069; (d) Nakajima, Y.;
Takeyama, T.; Furusato, T.; Ooya, H.; Nakayama, M.;
Sasabe, S. JP Patent 06220049 A2 19940809, 1994; Chem.
Abstr. 1995, 122, 133170.
4.7. General procedure for the preparation of a-hydroxy-
acids (S)-(+)-17, (R)-(ꢀ)-17, (S)-(+)-18, and (R)-(ꢀ)-18
Silver(I) oxide was freshly prepared as a brown dark
semisolid according to the procedure described by Cam-
paigne and LeSuer.20 To the above resulting suspension
containing 4 equiv of Ag2O, cooled at ꢀ5 ꢁC, were
added 1 equiv of aldehydes (S)-15, (S)-16, (R)-15, and
(R)-16, and the mixture was stirred during 15 min. The
reaction outcome was filtered and the filtrate was
washed with water and extracted with ethyl ether. The
aqueous layer was treated with aq 10% HCl until
pH = 4, and extracted with ethyl ether. The organic
layer was dried over anhydrous Na2SO4 and evaporated
to dryness to afford 40–58% yield of the corresponding
a-hydroxyacids in 95–98% ee.
3. (a) Nogle, L. M.; Gerwick, W. H. J. Nat. Prod. 2002, 65,
21; (b) Williams, P. G.; Yoshida, W. Y.; Moore, R. E.;
Paul, V. J. J. Nat. Prod. 2002, 65, 29; (c) Williams, P. G.;
Yoshida, W. Y.; Quon, M. K.; Moore, R. E.; Paul, V. J.
J. Nat. Prod. 2003, 66, 651; (d) Davies-Coleman, M. T.;
Dzeha, T. M.; Gray, C. A.; Hess, S.; Pannell, L. K.;
Hendricks, D. T.; Arendse, C. E. J. Nat. Prod. 2003, 66,
712; (e) Umezawa, K.; Nakazawa, K.; Ikeda, Y.; Naga-
nawa, H.; Kondo, S. J. Org. Chem. 1999, 64, 3034; (f)
Horgen, F. D.; Yoshida, W. Y.; Scheuer, P. J. J. Nat.
Prod. 2000, 63, 461; (g) Kimura, J.; Takada, Y.; Inayoshi,
T.; Nakao, Y.; Goetz, G.; Yoshida, W. Y.; Scheuer, P. J.
J. Org. Chem. 2002, 67, 1760; (h) Tan, L. T.; Sitachitta,
N.; Gerwick, W. H. J. Nat. Prod. 2003, 66, 764; (i)
Vervoort, H.; Fenical, W.; Epifanio, R. de A. J. Org.
Chem. 2000, 65, 782.
4.7.1. 2-Hydroxy-2-phenylpropanoic acid (S)-(+)-
17. Obtained in 46% yield and >95% ee as a white solid
22
D
mp 114–116 ꢁC, ½aꢁ = +37.1 (c 0.50, EtOH); lit.12 mp
114–116 ꢁC, [a]23 = +35.5 (c 3.464, EtOH, ee 96%);
lit.16 mp 116–117 ꢁC, [a]15 = +37.7 (c 3.5, EtOH).
4. (a) Burgess, V. A.; Davies, S. G.; Skerlj, R. T. Tetrahe-
dron: Asymmetry 1991, 2, 299; (b) Burgess, V. A.; Davies,
S. G.; Skerlj, R.; Whittaker, M. Tetrahedron: Asymmetry
1992, 3, 871; (c) Combret, Y.; Duflos, J.; Dupas, G.;
4.7.2. 2-Hydroxy-2-phenylpropanoic acid (R)-(ꢀ)-
22
´
Bourguignon, J.; Queguiner, G. Tetrahedron 1993, 49,
5237.
17. Obtained in 40% yield and >95% ee as a white solid
mp 114–116 ꢁC, ½aꢁ = ꢀ36.8 (c 0.40, EtOH).
D
5. (a) Yatagai, M.; Ohnuky, T. J. Chem. Soc., Perkin Trans.
1 1990, 1826; (b) Midland, M. M. Chem. Rev. 1989, 89,
1553.
4.7.3.
2-Hydroxy-2-phenylbutanoic
acid
18. Obtained in 53% yield and >95% ee as a white solid
(S)-(+)-
´
6. (a) Larcheveque, M.; Petit, Y. Tetrahedron Lett. 1987, 28,
24
D
mp 126–128 ꢁC, ½aꢁ = +31.5 (c 0.6; EtOH); lit.12 mp
1993; (b) Sharpless, K. B.; Chong, J. M. Tetrahedron Lett.
1985, 26, 4683.
7. Burk, M. J.; Kalberg, C. S.; Pizzano, A. J. Am. Chem. Soc.
1998, 125, 4345.
127.5–128 ꢁC, [a]24 = +31.53 (c 3.7, EtOH, 97% ee); lit.16,17
mp 128–129 ꢁC, [a]20 = +32.7 (c 4.0, EtOH).
8. (a) Zhang, W.; Wang, P. G. J. Org. Chem. 2000, 65, 4732;
(b) Huerta, F. F.; Laxmi, Y. R. S.; Ba¨ckvall, J.-E. Org.
Lett. 2000, 2, 1037; (c) Persson, B. A.; Larsson, L. E.; Ray,
M. L.; Ba¨ckvall, J.-E. J. Am. Chem. Soc. 1999, 121, 1645;
(d) Adam, W.; Lazarus, M.; Boss, B.; Saha-Mo¨ller, C. R.;
Humpf, H. U.; Schreier, P. J. Org. Chem. 1997, 62, 7841.
9. Tang, L.; Deng, L. J. Am. Chem. Soc. 2002, 124, 2870.
4.7.4. 2-Hydroxy-2-phenylbutanoic acid (R)-(ꢀ)-18.
Obtained in 58% yield and >95% ee as a white solid mp
127–129 ꢁC, [a]24 = ꢀ31.4 (c 0.40, EtOH); lit.12 mp
128–129 ꢁC), [a]23 = ꢀ30.9 (c 3.680, EtOH, 94% ee).
Acknowledgements
´
10. (a) Martınez-Ramos, F.; Vargas-Dıaz, M. E.; Chacon-
Garcıa, L.; Tamariz, J.; Joseph-Nathan, P.; Zepeda, L. G.
´
´
´
´
Tetrahedron: Asymmetry 2001, 12, 3095; (b) Vargas-Dıaz,
M. E.; Chacon-Garcıa, L.; Velazquez, P.; Tamariz, J.;
L.G.Z. acknowledges CGPI/IPN (grant 20020683,
20030702, and 20040199) and CONACyT-Mexico
(35013E, 44157-Q). M.E.V.D. and S.L.R. thank
CONACyT-Mexico (92069 and 125225, respectively)
and CGPI/IPN (PIFI) postgraduate fellowships. S.P.E.
and P.V.P. thank Institutional Fellowship (CGPI/IPN).
´
´
´
Joseph-Nathan, P.; Zepeda, L. G. Tetrahedron: Asymme-
´
´
try 2003, 14, 3225; (c) Chacon-Garcıa, L.; Lagunas-
´
´
Rivera, S.; Perez-Estrada, S.; Vargas-Dıaz, M. E.;
Joseph-Nathan, P.; Tamariz, J.; Zepeda, L. G. Tetra-
hedron Lett. 2004, 45, 2141.
11. (a) Mukaiyama, T.; Sakito, Y.; Asami, M. Chem. Lett.
1979, 6, 705; (b) Mukaiyama, T.; Sakito, Y.; Asami, M.
Chem. Lett. 1978, 11, 1253.
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