Reductive aldol cyclizations of unsaturated thioester derivatives of 1,3-cyclopentanedione catalyzed by chiral copper hydrides

Article abstract of DOI:10.1016/j.tet.2011.07.057

The first study on the asymmetric reductive aldol reactions of enethioate derivatives of 1,3-cyclopentanedione showed that 5 mol % of TANIAPHOS (SL-T001-1), and Cu(OAc)₂·H₂O, together with phenylsilane as the stoichiometric reductant

Full text of DOI:10.1016/j.tet.2011.07.057

Tetrahedron 68 (2012) 3450e3456
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Reductive aldol cyclizations of unsaturated thioester derivatives of 1,
3-cyclopentanedione catalyzed by chiral copper hydrides
*
Jun Ou, Wing-Tak Wong, Pauline Chiu
Department of Chemistry, The University of Hong Kong, Pokfulam Road, Hong Kong, PR China
a r t i c l e i n f o
a b s t r a c t
Article history:
The first study on the asymmetric reductive aldol reactions of enethioate derivatives of 1,3-
cyclopentanedione showed that 5 mol % of TANIAPHOS (SL-T001-1), and Cu(OAc)2$H2O, together with
phenylsilane as the stoichiometric reductant, generated the best yields and enantioselectivities of b-
hydroxythioester products. With S-benzyl keto-enethioate as substrate, the bicyclo[4.3.0] hydrox-
ythioester product was obtained only as the all-cis diastereomer, in good yield (84%) and enantiose-
lectivity (up to 90% ee). With the related indanedione enethioate derivatives, the reductive aldol
cyclization could attain up to 96% ee. These results demonstrate that enethioates have a significantly
different reactivity and selectivity profile compared to enoate derivatives in the copper-catalyzed re-
ductive aldol cyclization.
Received 16 March 2011
Received in revised form 8 July 2011
Accepted 21 July 2011
Available online 26 July 2011
Keywords:
Aldol reaction
Reduction
Cyclization
Copper
Ó 2011 Elsevier Ltd. All rights reserved.
Enantioselective catalysis
1. Introduction
We began our investigations in enantioselective reductive aldol
cyclizations by desymmetrization in the context of enone de-
Asymmetric domino reactions are powerful tools to construct
optically enriched cyclic and polycyclic compounds.1 The in-
corporation of domino reactions can confer tremendous efficiency
and economy to a synthetic plan, which are particularly significant
in order to simplify the synthesis of complex natural products.2 The
ability to execute asymmetric domino reactions in a catalytic
manner further augments the utility and application of these
reactions.3
rivatives of 1,3-diketones, such as 1 (Fig. 1).8 However, after a series
of screenings with various chiral ligands, the enantiomeric excesses
obtained in the aldol reaction were rather dismal.
We have had a long standing interest in reductive aldol re-
actions mediated by copper hydrides.4 Especially in the context of
intramolecular aldol reactions, the generation of enolates by con-
jugate reduction differentiates the roles of multiple carbonyl
groups in the precursor, and obviates the need to synthesize pre-
formed enolates by a separate step. This copper hydride-induced
reductive aldol cyclization has already found application in
a number of total syntheses of natural products, where conven-
tional aldol reactions produced inferior results.5
In recent years, these domino reductive aldol cyclizations have
been developed to achieve asymmetric induction.6 Usefully, the
intramolecular versions of these reactions can construct mono- and
polycyclic compounds with several contiguous stereogenic centers
and functional groups.7
Fig. 1. Substrates for copper hydride catalyzed reductions.
Recently we have investigated the conjugate reduction of un-
saturated thioesters.9 Thioesters are versatile synthetic substrates
and intermediates. They enolize more readily to react as nucleo-
philes,10 and are also more activated for acylation;11 under catalysis
by palladium they can be reduced to aldehydes12 or alkylated to
yield ketones.13 Compared with oxoesters, conjugate addition to
the unsaturated thioester is also more facile.14
Therefore we were surprised that a,b-unsaturated thioesters 2
were initially rather resistant to copper-catalyzed conjugate re-
duction (Fig. 1). Finally, the use of ligands, such as bis(diphenyl-
phosphino)ferrocene (dppf) and bis(diphenylphosphino)benzene
(BDP) produced copper hydrides, which were significantly more
reactive, and catalyzed the conjugate reduction effectively in the
presence of PMHS as the stoichiometric reductant. Under similar
* Corresponding author. Tel.: þ852 2859 8949; fax: þ852 2857 1586; e-mail
address: pchiu@hku.hk (P. Chiu).
0040-4020/$ e see front matter Ó 2011 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2011.07.057

J. Ou et al. / Tetrahedron 68 (2012) 3450e3456
3451
conditions, reductive aldol cyclization of keto-enethioates, such as
3 (n¼0, 1; Fig. 1) could also be effected.9
overnight. Many other products appeared to have been generated
under these reaction conditions.
Encouraged by these results, we proceeded to investigate the
catalytic enantioselective reductive aldol reactions of thioester
derivatives. Herein we report the first examples of desymmetrizing
reductive aldol cyclizations of keto-enethioates to produce bicyclic
hydroxythioesters in good yield and diastereoselectivity, and with
up to 96% ee.
Table 1
Screening of ligands for reductive aldol cyclization of 6a
2. Results and discussion
2.1. Preparation of substrates 6
Entry
Ligand
BDPc
(R)-BINAP
(R)-p-toleBINAP
(R)-MeOeBIPHEP
(R)-BINAPHANE
JosiPhos (SL-J001-1)
TaniaPhos (SL-T001-1)
MandyPhos (SL-M001-1)
WalPhos (SL-W001-1)
t (h)
Isolated yield
dr
64:36
93:7
88:12
75:25
92:8
98:2
>98:2
98:2
% eea
1b
2
3
4
5
6
7
8
9
12
12
12
12
72
48
72
72
72
16%
43%
26%
16%
22%
43%
72%
51%
60%
d
18
26
4
To investigate the desymmetrizing reductive aldol cyclization,
a family of meso unsaturated thioester substrates 6 were synthe-
sized. Reaction of 2-methyl-1,3-cyclopentanedione with acrolein
yielded aldehyde 4a, which was subjected to Wittig reactions with
each of 5aee15 to yield a series of thioesters 6aee for the in-
vestigations. Similarly, the Wittig reaction of indanediones 4bec
yielded enethioates 6feg (Scheme 1).
2
17
79
24
56
>98:2
a
The unsaturated thioesters
6 were generally obtained as
Enantiomeric excesses were determined by HPLC using a Chiralcel AD-3 chiral
column.
a 7e10:1 mixture of E:Z isomers, except for 6b, which was a 2.7:1 E/
Z mixture, and 6feg, which were found exclusively in the (E)-form.
In the cases where E/Z isomeric mixtures of 6 were obtained, the
isomers were unfortunately inseparable by flash chromatography.
An attempt to obtain pure (E)-isomer by treatment of the mixture
of 6a isomers with a catalytic amount of DMAP resulted in only
a 34% yield of pure (E)-6a.14 It appeared that, in addition to pro-
moting the equilibration of (Z)-6a to (E)-6a, DMAP also induced
other side reactions. Therefore this first study on reductive aldol
cyclizations were carried out in some cases with isomeric mixtures
of 6, predominantly in the (E)-form (Scheme 1).
b
c
Cu(OAc)2$H2O (10 mol %) was used.
BDP (10 mol %) was used.
Biphenyl or binapthyl chiral ligands, such as (R)-p-toleBINAP,
(R)-MeOeBIPHEP, and (R)-BINAPHANE produced copper hydrides
that mediated the reductive aldol reaction without any significant
increase in yields, although the diastereoselectivity was improved
(Table 1, entries 3e5). Of these, (R)-BINAP was the most effective,
and the yield and dr improved to 43% and 93:7, respectively. The
enantioselectivity, however, was low (Table 1, entry 2). Bisphos-
Scheme 1. Synthesis of enethioates 6aeg.
2.2. Enantioselective reductive aldol cyclization of 6a
phine ligands based on the ferrocene skeleton, such as JosiPhos,
TaniaPhos, MandyPhos, and WalPhos were also screened. All of
these ligands formed copper hydrides that induced the reductive
aldol reaction with better yields and greatly improved diaster-
eoselectivity. In particular, the use of TaniaPhos (SL-T001-1) gen-
erated 7a bearing three functional groups and three contiguous
stereocenters, as the only diastereomer observed. The highest yield
and enantioselectivity attained so far was 72% yield and 79% ee,
respectively (Table 1, entry 7).
The reductive aldol cyclization catalyzed by copper hydrides
was first investigated using 6a as substrate (Table 1). Using 10 mol %
of each of Cu(OAc)2$H2O and BDP, 5 hydride equivalents of PMHS,
which are the conditions that had been used for the copper-
catalyzed reductive aldol reactions of 3,9 the reaction of 6a disap-
pointingly yielded a 64:36 diastereomeric mixture of aldol prod-
ucts, in only 16% yield after reaction at room temperature

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J. Ou et al. / Tetrahedron 68 (2012) 3450e3456
2.3. Structure determination of 7a
The structure of the major product is assigned as 7a, in which
the methyl, hydroxyl, and thioester groups are all in cis relative to
each other. The stereochemistry of 7a was deduced based on 2D-
NMR (H-H NOESY, COSY) spectral analysis, as shown in Fig. 2.16 The
relative stereochemistry was suggested by the NOE correlations of
H4 (whose coupling constant J¼11.9 Hz indicated that it was axial)
to H6a, and H2a.The absence of any NOE between the methyl group
and H4, and the NOE correlation of the methyl moiety with both the
axial and equatorial protons of C7 were indicative of the methyl
group adopting an equatorial position.
Scheme 2. Reductive cyclization of enoate 8.7a
derived, on the selectivity of the reductive aldol reaction. As shown
in Scheme 3, unsaturated thioesters 6bee were subjected to re-
action under the optimized conditions in the presence of 5 mol % of
copper and the TaniaPhos ligand. In all cases, the all-cis di-
astereomers 7bed were the only aldol products observed. The re-
ductive cyclization yields were moderate to good. When R1¼t-Bu,
the increase in steric hindrance did not improve the enantiose-
lectivity and rather resulted in a loss of ee. Similarly, the thioester
(6e) derived from thiophenol also reacted to generate 7e with
lower enantioselectivity. However, the thioester 6d in which R1¼Bn
resulted in an improvement in the reductive cyclization to give 7d
in 85% ee and 62% yield.
Fig. 2. Structure elucidation of 7a by 2D-NOE correlations.
The related reductive aldol product (ꢀ)-7c (vide infra) is
a crystalline compound, and its relative stereochemistry was also
determined by X-ray crystallography (Fig. 3).17 The stereochemistry
was found to be the same as that of 7a.
Scheme 3. Optimizations of R1 in enethioates 7.
2.5. Optimizations of the reductant
With the optimized thioester in hand, the effect of the reductant
on the reaction was investigated. The most used stoichiometric
reducing agents in copper-mediated reductions are silanes, to take
advantage of the strong SieO bond formation that concomitantly
promotes copper hydride regeneration. The results are summarized
in Table 2. The identity of the silane did not have any significant
effect on the dr or the ee of the reaction. However, the activity of the
silane affected the yields and the time required for complete re-
action. The most effective silane was PhSiH3, which generated the
highest yield of product and in the shortest reaction time of 4 h
(Table 2, entry 1), while PhMe2SiH did not seem to be able to
promote copper hydride regeneration at all (Table 2, entry 3). We
also examined pinacolborane as a reductant, and while the re-
ductive aldol reaction proceeded, both the yield and the ee of 7d
were inferior to the those obtained using phenylsilane. The use of
Fig. 3. ORTEP of (ꢀ)-7c.
Notably, and in contrast, the relative stereochemistry of the
major product 9 obtained from the enantioselective reduction of
the analogous enoate derivative 8 possessed the alternative relative
stereochemistry of a trans-relationship between the hydroxyl
group and the oxoester (Scheme 2).7a
2.4. Optimizations of the enethioate substrate 6
With the optimized ligand in hand, we further explored the
effect of the particular mercaptan (R1) from which the thioester is

J. Ou et al. / Tetrahedron 68 (2012) 3450e3456
3453
Table 2
Screening of reductants
These results (Scheme 4) stand in contrast with the copper-
catalyzed reductive cyclization of oxoester derivative 8 (Scheme
2).7a Although the optimized conditions for enantioselective re-
ductive aldol reaction of 6 and 8 have been found to be rather
similar, enoate 8 was much more reactive, requiring only 2 h for
complete reaction at ꢁ50 ꢂC, and achieved a higher enantiose-
lectivity (Scheme 2). On the other hand,
a higher diaster-
eoselectivity was observed in the reduction of enethioate 6d;
moreover, the major aldol product was of a different relative
stereochemistry.
We have also applied the optimized reductive conditions to the
aldol reactions of indanediones 6f and 6g, which resulted in in-
complete reaction after 120 h, but achieved higher enantiose-
lectivities (96% ee and 95% ee, respectively) in the polycyclic
products 7f and 7g (Scheme 4).
Entry
Reductant
t (h)
Isolated Yield of 7d
dr
ee (%)a
1
2
3
4
PhSiH3
Ph2SiH2
PhMe2SiH
(EtO)2MeSiH
Pinacolborane
PhSiH3
4
16
48
48
16
4
83%
82%
nr
71%
74%
74%
>98:2
>98:2
d
84
83
d
>98:2
>98:2
>98:2
84
75
86
3. Conclusions
5
6b
a
In this study, the reductive adol cyclizations of keto-enethioate
derivatives of 1,3-cyclopentanedione and the related 1,3-
indanedione have been examined for the first time. Copper catal-
ysis with TaniaPhos (SL-T001-1) as ligand induced the reductive
aldol cyclization of 6d to produce cis-fused perhydroindane 7d as
a single diastereomer, in good yield and in up to 90% ee. The re-
ductive aldol cyclization of 6f produced 7f also as a single di-
astereomer, with an even higher 96% ee. The reaction potential and
versatility afforded by thioester group could allow ready access to
other related, optically active intermediates from 7d or 7f. The
differences in the reactivity and selectivity of this system compared
to its enoate counterpart merits additional investigation. The sub-
strate scope of this methodology and further optimizations of this
reaction type are currently under way.
Determined by HPLC on CHIRACEL AY-3 column.
CuF(PPh3)3 (5 mol %) was used.
b
an alternative, air-stable copper (I) source, tris(triphenylphosphine)
copper fluoride with phenylsilane was also an effective combina-
tion, in which the ee of 7d was similar, but the yield was reduced by
about 10%.
2.6. Optimization of temperature
Due to the significant decrease of reaction time employing
phenylsilane as reductant, we could then investigate the outcome
of the reductive aldol reaction at lower temperatures, which was
expected to increase the reaction time, but should result in im-
proved enantioselectivity. When the reduction of 6d was conducted
at ꢁ5 toꢁ10 ꢂC with 5 mol % of TaniaPhos and Cu(OAc)2$H2O in the
presence of phenylsilane, bicyclic 7d was obtained in 84% yield and
90% ee after reaction for 40 h (Scheme 4).
4. Experimental
4.1. General methods
All 1H and 13C NMR spectra were recorded in deuteriochloroform
(CDCl3), with tetramethylsilane (TMS) as an internal standard at
ambient temperature on a Bruker DPX 400, or 500 MHz Fourier
Transform Spectrometer operating at 400 MHz, or 500 MHz for 1H,
and at 100 MHz, or 125 MHz, respectively for 13C. All the spectra were
calibrated at d d
7.26 ppm for 1H and 77.03 ppm for 13C. Spectral fea-
tures are designated as follows: s¼singlet, d¼doublet, t¼triplet,
q¼quartet, m¼mutiplet, and br¼broad. IR absorption spectra were
recorded as a solution in CH2Cl2 on a Bio-Rad FT 165 Spectropho-
tometer from 4000 cmꢁ1 to 400 cmꢁ1. Mass spectrawere obtained on
a Finnigan MAT 95 mass spectrometer or API QSTAR PULSAR LC/MS/
TOFSystemforbothlow resolutionand highresolution, withaccurate
mass reported for the molecular ion (Mþ) or the next largest fragment
thereof. Analytical HPLC was carried out on Waters HPLC systems
equipped with a 1525 Binary HPLC Pump, Waters 2707 autosampler
and a Waters 2489 variable wavelength UVevis detector or Waters
2998 PDA detector, operated using Breeze2 software. Optical rota-
tions were obtained with a PerkineElmer polarimeter operating at
589 nm, using CH2Cl2 as solvent. X-ray crystallographic data was
collected on a Bruker Apex II CCD detector with graphite mono-
chromated Mo Ka radiation.
HPLC grade CH2Cl2 was used as received. PhMe was distilled
from CaH2 under argon.
4.2. General procedure for the preparation of keto-
enethioates 6aeg
Phosphoranes 5a (R1¼Et), 5b (R1¼C12H25), 5c (R1¼t-Bu), 5d
(R1¼Bn), 5e (R1¼Ph), were prepared from the corresponding S-
Scheme 4. Reductive cyclization of 6d,f,g at ꢁ10 ꢂC.

3454
J. Ou et al. / Tetrahedron 68 (2012) 3450e3456
alkyl 2-bromoethanethioates and triphenylphosphine, according to
literature procedures.18
(Mþ, 7), 193.1 (MþꢁSC7H7, 23), 165.1 (MþꢁCOSC7H7, 12); HRMS (EI,
20 eV): calcd for C18H20O3S (Mþ), 316.1128, found 316.1128.
To a solution of aldehyde 4 (1.0 equiv) in CH2Cl2 was added the
corresponding phosphorane 5aee (1.2 equiv). The reaction mixture
was stirred at room temperature for 12 h. The solvent was removed
by rotoevaporation, and the residue was subjected to flash chro-
matography on silica gel to give the corresponding enethioates
6aeg as mixture of (E)- and (Z)-isomers.
4.2.5. Synthesis of 6e. According to the general procedure in Sec-
tion 4.2, aldehyde 4a19 (0.95 g, 5.6 mmol) was treated with 5e
(2.8 g, 6.8 mmol) in CH2Cl2 (40 mL). After purification by chroma-
tography, 6e (0.31 g, 18% yield, E/Z¼10:1) was obtained as yellow
solid: Rf (25% EtOAc in hexane): 0.32; mp¼49e51 ꢂC; IR (CH2Cl2):
3051, 2927, 2856, 2360, 2337, 1722 (C]O, ketone), 1668 (C]O,
thioester), 1633 (C]C) cmꢁ1; (E)-6e: 1H NMR (400 MHz, CDCl3):
7.44e7.40 (m, 5H), 6.80 (dt, J¼15.4, 6.9 Hz, 1H), 6.12 (d, J¼15.5 Hz,
1H), 2.87e2.71 (m, 4H), 2.15e2.12 (m, 2H), 1.86e1.82 (m, 2H), 1.15
(s, 3H); 13C NMR (75 MHz, CDCl3): 215.7, 187.7, 146.0, 144.4, 134.6,
134.5, 133.2, 129.4, 129.2, 128.6, 127.3, 126.1, 56.1, 35.1, 35.0, 33.8,
32.5, 32.0, 27.3, 25.4, 20.1, 19.9 ppm; LRMS (EI, 20 eV): m/z 302.1
(Mþ, 0.8), 193.1 (MþꢁSC6H5, 35),165.1 (MþꢁCOSC6H5, 5); HRMS (EI,
20 eV): calcd for C17H18O3S (Mþ), 302.0971, found 302.0972.
4.2.1. Synthesis of 6a. According to the general procedure in Sec-
tion 4.2, aldehyde 4a19 (1.66 g, 9.87 mmol) was treated with
phosphorane 5a (4.30 g, 12.0 mmol) in CH2Cl2 (30 mL). After pu-
rification by chromatography, 6a (2.52 g, 98% yield, E/Z¼10:1) was
obtained as a yellow oil: Rf (25% EtOAc in hexane): 0.22; IR (CH2Cl2):
3053, 1724 (C]O, cyclopentanone), 1670 (unsaturated C]O, thio-
ester), 1635 (C]C) cmꢁ1; (E)-6a, 1H NMR (400 MHz, CDCl3):
d 6.69
(dt, J¼15.6, 8.3 Hz, 1H), 6.03 (d, J¼15.6 Hz, 1H), 2.92 (q, J¼7.3 Hz,
2H), 2.85e2.62 (m, 4H), 2.11e2.08 (m, 2H), 1.84e1.80 (m, 2H), 1.27
(t, J¼7.8 Hz, 1H), 1.15 (s, 3H) ppm; 13C NMR (100 MHz, CDCl3):
4.2.6. Synthesis of 6f. According to the general procedure in Section
4.2, aldehyde 4b20 (0.24 g, 1.5 mmol) was treated with 5d (1.0 g,
2.3 mmol) in CH2Cl2 (40 mL). After purification by chromatography,
6f (0.11 g, 20% yield, E/Z¼100:0) was obtained as an orange oil: Rf
(25% EtOAc in hexane): 0.40; IR (CH2Cl2): 3055, 2932, 2870, 1705
(C]O, ketone), 1674 (C]O, unsaturated thioester), 1628 (C]C),
1597 cmꢁ1; (E)-6f: 1H NMR (400 MHz, CDCl3): 7.96e7.94 (m, 2H),
7.84e7.81 (m, 2H), 7.29e7.22 (m, 5H), 6.71 (dt, J¼15.5, 6.4 Hz, 1H),
5.88 (dt, J¼15.5, 1.5 Hz, 1H), 4.13 (s, 2H), 2.06e1.97 (m, 4H), 1.29 (s,
3H); 13C NMR (75 MHz, CDCl3): 203.8, 188.8, 143.6, 141.1, 137.6,
135.9, 135.8, 128.8, 128.5, 127.2, 123.4, 53.3, 33.1, 32.8, 27.7, 25.6,
19.9 ppm; LRMS (ESI, 3 kV): m/z 365 (MþHþ); HRMS (ESI, 3 kV):
calcd for C22H20O3S (MþHþ) 365.1206, found 365.1200.
d
215.9,189.8, 144.1, 129.5, 56.1, 35.2, 32.6, 27.3, 23.2, 20.2, 14.8 ppm.
LRMS (EI, 20 eV): m/z 254.1 (Mþ, 1), 193.1 (MþꢁSC2H5, 26), 165.1
(MþꢁCOSC2H5, 4); HRMS (EI, 20 eV): calcd for C13H18O3S (Mþ),
254.0971, found 254.0964.
4.2.2. Synthesis of 6b. According to the general procedure in Sec-
tion 4.2, aldehyde 4a19 (0.95 g, 5.6 mmol) was treated with phos-
phorane 5b (3.5 g, 6.9 mmol) in CH2Cl2 (40 mL). After purification
by chromatography, 6b (0.51 g, 23% yield, E/Z¼2.7:1) was obtained
as yellow oil: Rf (25% EtOAc in hexane): 0.30; IR (CH2Cl2): 3051,1724
(C]O, ketone),1683 (C]O, thioester),1635 (C]C) cmꢁ1; (E)-6b: 1H
NMR (400 MHz, CDCl3): 6.70 (dt, J¼15.4, 6.9 Hz, 1H), 6.03 (d,
J¼15.5 Hz, 1H), 2.94e2.74 (m, 6H), 2.11e2.09 (m, 2H), 1.85e1.80 (m,
2H), 1.58e1.55 (m, 3H), 1.32e1.25 (m, 18H), 1.15 (s, 3H), 0.88 (t,
4.2.7. Synthesis of 6g. According to the general procedure in Sec-
tion 4.2, aldehyde 4c (2.42 g, 10.0 mmol) was treated with 5d
(4.60 g, 11.0 mmol) in CH2Cl2 (40 mL). After purification by chro-
matography, 6g (1 g, 26% yield, E/Z¼100:0) was obtained as yellow
oil: Rf (25% EtOAc in hexane): 0.45; IR (CH2Cl2): 3063, 2994, 2090,
1735 (C]O, ketone), 1712 (C]O, unsaturated thioester),
1566 cmꢁ1; (E)-6g: 1H NMR (400 MHz, CDCl3): 7.95e7.93 (m, 2H),
7.82e7.80 (m, 2H), 7.29e7.26 (m, 5H), 6.71e6.67 (m, 1H), 5.86 (d,
J¼15.5 Hz, 1H), 6.12 (d, J¼15.5 Hz, 1H), 5.45 (ddt, J¼17.4, 10.1, 7.5 Hz,
1H), 5.03 (dd, J¼16.9, 1.5 Hz, 1H), 4.90 (dd, J¼10.2, 1.6 Hz, 1H), 4.13
(s, 2H), 2.52 (d, J¼7.5 Hz, 2H), 2.01e1.98 (m, 4H); 13C NMR (75 MHz,
CDCl3): 203.3, 188.8, 143.5, 142.1, 137.6, 135.9, 131.1, 128.9, 128.6,
127.2, 123.1, 119.8, 57.7, 39.5, 32.9, 32.3, 27.6 ppm; LRMS (EI, 20 eV):
m/z 390.1 (Mþ, 0.9), 268.1 (MþꢁSC7H7, 3.5), 239.1 (MþꢁCOSC7H7,
5); HRMS (EI, 20 eV): calcd for C24H22O3S (Mþ), 390.1290, found
390.1284.
J¼6.6 Hz, 3H); 13C NMR (100 MHz, CDCl3):
d 217.8, 205.2, 77.8, 56.3,
53.7, 34.5, 31.9, 30.8, 29.6, 29.5, 29.4, 29.3, 29.2, 29.2, 29.0, 28.8,
28.3, 26.0, 22.7, 22.5, 19.1, 14.1 ppm; LRMS (EI, 20 eV): m/z 394.2
(Mþ, 5), 193.1 (MþꢁSC12H25, 24), 165.1 (MþꢁCOSC12H25, 25); HRMS
(EI, 20 eV): calcd for C23H38O3S (Mþ), 394.2536, found 394.2534.
4.2.3. Synthesis of 6c. According to the general procedure in Sec-
tion 4.2, aldehyde 4a19 (0.95 g, 5.6 mmol) was treated with reagent
5c (2.79 g, 7.1 mmol) in CH2Cl2 (35 mL). After purification by
chromatography, 6c (1.16 g, 73% yield, E/Z¼7:1) was obtained as
white solid. Melting point 66e70 ꢂC Rf (25% EtOAc in hexane): 0.25;
IR (CH2Cl2): 3051, 2968, 1722 (C]O, ketone), 1652 (C]O, un-
saturated thioester), 1627 (C]C) cmꢁ1; (E)-6c: 1H NMR (400 MHz,
CDCl3): 6.62 (dt, J¼15.5, 6.9 Hz, 1H), 5.92 (d, J¼15.5 Hz, 1H),
2.85e2.69 (m, 4H), 2.07e2.03 (m, 2H), 1.83e1.79 (m, 2H), 1.48 (s,
9H), 1.14 (s, 3H); 13C NMR (100 MHz, CDCl3):
d 215.9, 190.4, 141.7,
130.2, 56.1, 48.1, 35.0, 34.9, 32.8, 29.9, 27.2, 20.0 ppm; LRMS (EI,
20 eV): m/z 282.1 (Mþ, 1), 193.1 (MþꢁSC4H9, 26), 165.1
(MþꢁCOSC4H9, 3); HRMS (EI, 20 eV): calcd for C15H22O3S (Mþ),
282.1284, found 282.1283.
4.3. General procedure for asymmetric reductive aldol
cyclization of 6aeg
Cu(OAc)2$H2O (1.5 mg, 0.0075 mmol), TaniaPhos (SL-T001-1,
5.0 mg, 0.0075 mmol) were transferred into an oven-dried 5 mL
round-bottomed flask, to which anhydrous PhMe (1.0 mL) and si-
lane (0.75 mmol) were added under argon. The reaction mixture
was stirred at room temperature until a characteristic greenish-
yellow color was observed. The reaction mixture was cooled to
the target reaction temperature. Substrate 6 (0.15 mmol) in PhMe
(1.0 mL) was added to the reaction mixture via cannula. The
progress of the reaction was monitored by TLC. The reaction was
quenched by the addition of 1 M HCl (1.0 mL). The organic layer was
separated, and the aqueous layer was back-extracted with EtOAc
(3ꢃ5 mL). The combined organics were dried over anhydrous
MgSO4 and concentrated in vacuo. Flash chromatography of the
4.2.4. Synthesis of 6d. According to the general procedure in Sec-
tion 4.2, aldehyde 4a19 (1.71 g, 10.2 mmol) was treated with
phosphorane 5d (5.20 g, 6.2 mmol) in CH2Cl2 (35 mL). After puri-
fication by chromatography, 6d (2.33 g, 72% yield, E/Z¼10:1) was
obtained as yellow solid: Rf (25% EtOAc in hexane): 0.24;
mp¼58e61 ꢂC; IR (CH2Cl2): 3053, 2976, 1722 (C]O, ketone), 1668
(C]O, unsaturated thioester), 1633 (C]C) cmꢁ1; (E)-6d: 1H NMR
(400 MHz, CDCl3): 7.30e7.22 (m, 5H), 6.74 (dt, J¼15.5, 6.9 Hz, 1H),
6.04 (d, J¼15.5 Hz, 1H), 4.17 (s, 2H), 2.84e2.67 (m, 4H), 2.10e2.06
(m, 2H), 1.83e1.59 (m, 2H), 1.14 (s, 1H) ppm; 13C NMR (100 MHz,
CDCl3):
d 215.8, 188.9, 143.6, 137.5, 129.0, 128.9, 128.6, 127.3, 56.1,
35.2, 34.9, 32.9, 32.5, 27.3, 20.1 ppm; LRMS (EI, 20 eV): m/z 316.2

J. Ou et al. / Tetrahedron 68 (2012) 3450e3456
3455
residue on silica gel using 5%e20% EtOAc in hexane afforded aldol
product 7.
1H), 1.63e1.52 (m, 1H), 1.48 (s, 9H), 1.36 (ddd, J¼13.6, 13.5, 4.6 Hz,
1H), 1.14 (dtt, 13.3, 13.2, 3.8 Hz, 1H), 1.00 (s, 3H) ppm; 13C NMR
The corresponding reductive aldol reactions to obtain racemic
products were similarly executed, but using either BDP or dppf as
achiral ligands.
(125 MHz, CDCl3): d 217.9, 206.2, 78.0, 56.0, 49.2, 34.6, 30.8, 29.6,
28.3, 25.8, 22.6, 19.1 ppm. LRMS (EI, 20 eV): m/z 284.1 (Mþ, 3),
195.1 (MþꢁSC4H9, 59), 167.1 (MþꢁCOSC4H9, 98); HRMS (EI, 20 eV):
calcd for C15H24O3S (Mþ), 284.1441, found 284.1438.
4.3.1. Asymmetric reductive aldol cyclization of 6a. According to the
general procedure in Section 4.3, TaniaPhos (10 mg, 0.015 mmol),
4.3.4. Asymmetric reductive aldol cyclization of 6d. According to the
Cu(OAc)2$H2O (3.0 mg, 0.015 mmol), and PMHS (95
mL,1.5 mmol) in
general procedure in Section 4.3, Taniaphos (5.0 mg, 0.0075 mmol),
2.3 mL PhMe was treated with 6a (77 mg, 0.30 mmol) dissolved in
PhMe (2ꢃ0.3 mL) at room temperature for 72 h. After workup and
chromatographic purification, 7a was obtained as a colorless oil
Cu(OAc)2$H2O (1.5 mg, 0.0075 mmol), and PhSiH3 (38 mL, 0.3 mmol)
in 1.0 mL PhMe at ꢁ10 ꢂC was treated with 6d (47.4 mg, 0.15 mmol)
in PhMe (2ꢃ0.3 mL) and stirred at ꢁ10 ꢂC for 72 h. After workup
and chromatographic purification, 7d was obtained as a colorless
(55 mg, 72% yield, 79% ee). Compound 7a: ½a D20
ꢁ71.2 (c 1); DAICEL
ꢄ
CHIRALCEL AD-3, n-hexane/2-propanol¼96/4, flow rate¼0.5 mL/
oil (40.1 mg, 84% yield, 90% ee); ½a D20
ꢁ58.7 (c 1); DAICEL CHIR-
ꢄ
min,
l
¼254 nm, retention time: 18.44 min (minor), 19.104 min
ALCEL AY-3, n-hexane/2-propanol¼96/4, flow rate¼0.5 mL/min,
(major); Rf (25% EtOAc in hexane): 0.50; IR (CH2Cl2): 3053, 2974,
2939, 2932, 1739 (C]O, cyclopentanone), 1652 (C]O, thioester)
l
¼254 nm, retention time: 30.890 min (major), 38.272 min (mi-
nor); Rf (25% EtOAc in hexane): 0.40; IR (CH2Cl2): 3053, 1739 (C]O,
cmꢁ1
;
1H NMR (500 MHz, CDCl3):
d
4.36 (s, 1H), 2.91 (q, J¼7.4 Hz,
cyclopentanone), 1652 (C]O, thioester) cmꢁ1; 1H NMR (500 MHz,
2H), 2.56 (ddd, J¼19.6, 10.4, 2.1 Hz, 1H), 2.37 (dd, J¼11.9, 3.4 Hz, 1H),
2.25 (ddd, J¼19.7, 9.6, 9.5 Hz, 1H), 2.13 (dt, J¼13.1, 10.5 Hz, 1H), 2.03
(ddd, J¼11.7, 9.5, 1.9 Hz, 1H), 1.89 (dm, J¼13.9 Hz, 1H), 1.82 (dtd,
J¼12.7, 12.5, 3.3 Hz, 1H), 1.71 (dm, J¼12.4 Hz, 1H), 1.64e1.61 (m, 1H),
1.37 (ddd, J¼13.7, 13.3, 4.5 Hz, 1H), 1.32 (t, J¼7.3 Hz, 3H), 1.21 (dtt,
J¼13.2, 13.1, 3.7 Hz, 1H), 1.02 (s, 3H) ppm; 13C NMR (100 MHz,
CDCl3):
d
7.33e7.24 (m, 5H), 4.27 (br s, 1H), 4.18 (d, J¼13.9 Hz, 1H),
4.14 (d, J¼13.9 Hz, 1H), 2.55 (ddd, J¼19.7, 10.3, 2.4 Hz, 1H), 2.39 (dd,
J¼11.9, 3.4 Hz, 1H), 2.23 (ddd, J¼19.2, 10.0, 9.6 Hz, 1H), 2.11 (dt,
J¼13.5, 10.1 Hz, 1H), 2.00 (ddd, J¼13.2, 9.3, 1.9 Hz, 1H), 1.90 (dm,
J¼13.9 Hz, 1H), 1.83 (dtd, J¼12.7, 12.5, 3.4 Hz, 1H), 1.72 (dm,
J¼13.0 Hz,1H),1.71e1.60 (m,1H),1.37 (ddd, J¼13.6,13.3, 4.5 Hz,1H),
1.19 (dtt, J¼13.3, 13.0, 3.8 Hz, 1H), 1.02 (s, 3H) ppm; 13C NMR
CDCl3):
d 217.8, 205.2, 77.9, 56.8, 53.7, 34.5, 30.8, 28.3, 25.9, 23.6,
22.5, 19.1, 14.5 ppm; LRMS (EI, 20 eV): m/z 256.1 (Mþ, 7), 195.1
(MþꢁSC2H5, 17), 167.1 (MþꢁCOSC2H5, 72); HRMS (EI, 20 eV): calcd
for C13H20O3S (Mþ), 256.1128; found 256.1126.
(125 MHz, CDCl3): d 217.7, 204.2,136.6, 128.8,128.7, 127.6, 77.9, 56.2,
53.8, 34.5, 33.5, 30.9, 28.3, 26.0, 22.5,19.1 ppm; LRMS (EI, 20 eV): m/
z 318.2 (Mþ, 3), 195.1 (MþꢁSC7H7, 5), 167.1 (MþꢁCOSC7H7, 18);
HRMS (EI, 20 eV): calcd for C18H22O3S (Mþ), 318.1284, found
318.1285.
4.3.2. Asymmetric reductive aldol cyclization of 6b. According to the
general procedure in Section 4.3, TaniaPhos (5.0 mg, 0.0075 mmol),
Cu(OAc)2$H2O (1.5 mg, 0.0075 mmol), and PMHS (50
mL, 0.75 mmol)
4.3.5. Asymmetric reductive aldol cyclization of 6e. According to the
in 1 mL PhMe was treated with 6b (60 mg, 0.15 mmol) dissolved in
PhMe (2ꢃ0.3 mL) at room temperature for 60 h. After workup and
chromatographic purification, 7b was obtained as a colorless oil
general procedure in Section 4.3, Taniaphos (5.0 mg, 0.0075 mmol),
Cu(OAc)2eH2O (1.5 mg, 0.0075 mmol), and PMHS (30 mL, 0.75 mmol)
in 1.0 mL PhMe was treated with 6e (48.0 mg, 0.16 mmol) in PhMe
(2ꢃ0.3 mL) at room temperature for 40 h. After workup and
chromatographic purification, 7e was obtained as a colorless oil
(30 mg, 50% yield, 81% ee). Compound 7b: ½a D20
ꢁ37.5 (c 1); DAICEL
ꢄ
CHIRALCEL AS-3, n-hexane/2-propanol¼96/4, flow rate¼0.5 mL/
min,
(major); Rf (25% EtOAc in hexane): 0.47; IR (CH2Cl2): 3053, 2927,
2852, 1733 (C]O, ketone), 1652 (C]O, thioester) cmꢁ1 1H NMR
(400 MHz, CDCl3):
4.37 (br s, 1H), 2.91 (td, J¼7.2, 2.0 Hz, 2H), 2.56
l¼254 nm, retention time: 9.41 min (minor), 15.44 min
(29.3 mg, 60% yield, 67% ee); ½a D20
ꢁ74.3 (c 0.67); DAICEL CHIR-
ꢄ
ALCEL AY-3, n-hexane/2-propanol¼96/4, flow rate¼0.5 mL/min,
;
l
¼254 nm, retention time: 35.436 min (major), 41.772 min (mi-
nor); Rf (25% EtOAc in hexane): 0.42; IR (CH2Cl2): 3159, 2252, 1739
(C]O, cyclopentanone), 1670 (C]O, thioester) cmꢁ1 1H NMR
(500 MHz, CDCl3): 7.48e7.40 (m, 5H), 4.15 (br s, 1H), 2.61 (ddd,
d
(ddd, J¼19.7, 10.4, 2.1 Hz, 1H), 2.37 (dd, J¼11.9, 3.4 Hz, 1H), 2.25
(ddd, J¼19.4, 9.6, 9.5 Hz, 1H), 2.13 (dt, J¼13.1, 10.1 Hz, 1H), 2.01
(ddd, J¼15.0, 9.5, 1.9 Hz, 1H),1.90 (dm, J¼13.9 Hz, 1H), 1.81 (dtd,
J¼12.5, 12.4, 3.2 Hz, 1H), 1.70 (dm, J¼13.0 Hz, 1H), 1.70e1.61 (m,
4H), 1.59e1.14 (m, 23H), 1.02 (s, 3H), 0.88 (t, J¼6.8 Hz, 3H) ppm; 13C
;
d
J¼19.7, 10.0, 3.0 Hz, 1H), 2.52 (dd, J¼9.5, 5.3 Hz, 1H), 2.31 (ddd,
J¼19.6, 9.6, 9.5 Hz, 1H), 2.20e2.04 (m, 2H), 1.91 (dm, J¼13.2 Hz,
1H), 1.88e1.855 (m, 2H), 1.71e1.65 (m, 1H), 1.38 (ddd, J¼13.6, 13.1,
4.4 Hz, 1H), 1.28e1.20 (m, 1H), 1.03 (s, 3H) ppm; 13C NMR
NMR (100 MHz, CDCl3):
d 217.8, 205.2, 77.9, 56.3, 53.7, 34.5, 31.9,
30.8, 29.6, 29.5, 29.4, 29.3, 29.3, 29.2, 29.0, 28.8, 28.3, 26.0, 22.7,
22.6, 19.1, 14.1 ppm; LRMS (EI, 20 eV): m/z 396.2 (Mþ, 7), 195.1
(MþꢁSC12H25, 16), 167.1 (MþꢁCOSC12H25, 100); HRMS (EI, 20 eV):
calcd for C23H40O3S (Mþ), 396.2693, found 396.2709.
(125 MHz, CDCl3): d 217.7, 203.5, 134.4, 130.0, 129.5, 126.5, 78.0,
56.0, 53.8, 34.5, 31.0, 28.3, 26.1, 22.54, 19.1 ppm; LRMS (EI, 20 eV):
m/z 304.1 (Mþ, 0.5), 195.1 (MþꢁSC6H5, 7), 167.1 (MþꢁCOSC6H5, 41);
HRMS (EI, 20 eV): calcd for C17H20O3S (Mþ), 304.1128, found
304.1125.
4.3.3. Asymmetric reductive aldol cyclization of 6c. According to the
general procedure in Section 4.3, TaniaPhos (5.0 mg, 0.0075 mmol),
4.3.6. Asymmetric reductive aldol cyclization of 6f. According to the
Cu(OAc)2$H2O (1.5 mg, 0.0075 mmol), and PMHS (50
mL, 0.75 mmol)
general procedure in Section 4.3, Taniaphos (6.5 mg, 0.0095 mmol),
in 1.0 mL PhMe was treated with 6c (42.4 mg, 0.15 mmol) dis-
solved in PhMe (2ꢃ0.3 mL) at room temperature for 44 h. After
workup and chromatographic purification, 7c (27.9 mg, 66% yield,
Cu(OAc)2$H2O (1.9 mg, 0.095 mmol), and PhSiH3 (48.0 mL,
0.38 mmol) in 1.5 mL PhMe was treated with 6g (69 mg, 0.19 mmol)
in PhMe (2ꢃ0.25 mL) at ꢁ10 ꢂC for 120 h. After workup and
chromatographic purification, 7f was obtained as a white solid
(49 mg, 71% yield, 96% ee) along with recovered 6g (9.0 mg, 13%
60% ee) was obtained as a white solid; mp¼69e71 ꢂC; ½a D20
ꢁ33.5
ꢄ
(c 0.27); DAICEL CHIRALCEL AD-3, n-hexane/2-propanol¼96/4,
flow rate¼0.5 mL/min,
(minor), 13.232 min (major); Rf (25% EtOAc in hexane): 0.45; IR
(CH2Cl2): 3053, 1733 (C]O, ketone), 1652 (C]O, thioester) cmꢁ1
1H NMR (500 MHz, CDCl3):
l¼254 nm, retention time: 11.723 min
yield). Compound 7f: ½a D20
ꢁ112.4 (c 1); DAICEL CHIRALCEL AD-3, n-
ꢄ
hexane/2-propanol¼96/4, flow rate¼0.5 mL/min, ¼254 nm, re-
l
;
tention time: 36.4 min (minor), 43.7 min (major); Rf (25% EtOAc in
hexane): 0.65; mp¼100e102 ꢂC; IR (CH2Cl2): 3457 (OH), 3055,
d
4.48 (s, 1H), 2.55 (ddd, J¼19.7, 10.2,
2.2 Hz, 1H), 2.28e2.20 (m, 2H), 2.16e2.03 (m, 2H), 1.89 (dm,
J¼13.8 Hz, 1H), 1.79 (dtd, J¼12.6, 12.5, 3.3 Hz, 1H), 1.69e1.64 (m,
2940, 2338, 1720 (C]O, ketone), 1658 (C]O, thioester), 1605 cmꢁ1
;
1H NMR (500 MHz, CDCl3): 7.73e7.72 (m, 1H), 7.41e7.19 (m, 8H),

3456
J. Ou et al. / Tetrahedron 68 (2012) 3450e3456
4. (a) Chiu, P.; Chen, B.; Cheng, K. F. Tetrahedron Lett. 1998, 39, 9229e9232; (b)
Chiu, P.; Szeto, C. P.; Geng, Z.; Cheng, K. F. Org. Lett. 2001, 3, 1901e1903; (c) Chiu,
P.; Leung, S. K. Chem. Commun. 2004, 2308e2309; (d) Chung, W. K.; Chiu, P.
Synlett 2005, 55e58; (e) Leung, L. T.; Leung, S. K.; Chiu, P. Org. Lett. 2005, 7,
5249e5252; (f) Miao, R.; Li, S.; Chiu, P. Tetrahedron 2007, 63, 6737e6740.
5. (a) Chiu, P.; Szeto, C. P.; Geng, Z.; Cheng, K. F. Tetrahedron Lett. 2001, 42,
4091e4093; (b) Mukherjee, H.; McDougal, N. T.; Virgil, S. C.; Stoltz, B. M. Org.
Lett. 2011, 13, 825e827; (c) Schwartz, K. D.; White, J. D. Org. Lett. 2011, 13,
248e251.
5.23 (s, 1H), 4.16 (d, J¼13.9 Hz, 1H), 4.01 (d, J¼13.9 Hz, 1H),
2.29e2.23 (m, 2H), 1.90e1.73 (m, 3H), 1.62e1.55 (m, 1H), 1.33e1.25
(m, 1H), 1.05 (s, 3H); 13C NMR (125 MHz, CDCl3): 205.6, 204.8, 155.9,
136.8, 134.1, 128.7, 127.5, 123.9, 123.7, 78.7, 62.1, 56.7, 33.4, 28.5,
25.9, 24.1, 22.7; LRMS (ESI, 3 kV): m/z 389 (MþNaþ); HRMS (ESI,
3 kV): calcd for C22H22O3S (MþNaþ) 389.1182, found 389.1179.
6. (a) Zhao, D.; Oisaki, K.; Kanai, M.; Shibasaki, M. Tetrahedron Lett. 2006, 47,
1403e1407; (b) Kato, M.; Oki, H.; Ogata, K.; Fukuzawa, S. Synlett 2009,
1299e1302; (c) Welle, A.; Díez-Gonzalez, S.; Tinant, B.; Nolan, S. P.; Riant, O.
4.3.7. Asymmetric reductive aldol cyclization of 6g. According to the
general procedure in Section 4.3, Taniaphos (5.0 mg, 0.0075 mmol),
ꢀ
Cu(OAc)2$H2O (1.50 mg, 0.0075 mmol), and PhSiH3 (38.0
mL,
Org. Lett. 2006, 26, 6059e6062; (d) Chuzel, O.; Deschamp, J.; Chausteur, C.;
Riant, O. Org. Lett. 2006, 26, 5943e5946; (e) Zhao, D.; Oisaki, K.; Kanai, M.;
Shibasaki, M. J. Am. Chem. Soc. 2006, 128, 14440e14441; (f) Bee, C.; Han, S. B.;
Hassan, A.; Iida, H.; Krische, M. J. J. Am. Chem. Soc. 2008, 130, 2746e2747; (g)
Jung, C. K.; Krische, M. J. J. Am. Chem. Soc. 2006, 128, 17051e17056; (h) Han, S.
B.; Krische, M. J. Org. Lett. 2006, 8, 5657e5660; (i) Jung, C. K.; Garner, S. A.;
Krische, M. J. Org. Lett. 2006, 8, 519e522; (j) Huddleston, R. R.; Krische, M. J.
Org. Lett. 2003, 5, 1143e1146; (k) Jang, H. Y.; Huddleston, R. R.; Krische, M. J. J.
Am. Chem. Soc. 2002, 124, 15156e15157.
7. (a) Deschamp, J.; Riant, O. Org. Lett. 2009, 11, 1217e1220; (b) Lam, H. W.;
Murray, G. J.; Firth, J. D. Org. Lett. 2005, 7, 5743e5746; (c) Lam, H. W.; Joensuu, P.
M. Org. Lett. 2005, 7, 4225e4228; (d) Lipshutz, B. H.; Amorelli, B.; Unger, J. B. J.
Am. Chem. Soc. 2008, 130, 14378e14379.
0.300 mmol) in 1.0 mL PhMe was treated with 6g (58.6 mg,
0.150 mmol) in PhMe (2ꢃ0.30 mL) at ꢁ10 ꢂC for 120 h. After
workup and chromatographic purification, 7g was obtained as
a yellow oil (32 mg, 54% yield, 95% ee), along with recovered 6g
(10.7 mg, 18% yield). Compound 7g: ½a D20
ꢁ137.8 (c 1); DAICEL
ꢄ
CHIRALCEL AS-3, n-hexane/2-propanol¼96/4, flow rate¼1 mL/min,
l
¼254 nm, retention time: 9.29 min (major), 28.43 min (minor); Rf
(25% EtOAc in hexane): 0.55; IR (CH2Cl2): 3456 (OH), 2939, 2862,
1712 (C]O, ketone), 1651 (C]O, thioester), 1604 cmꢁ1 1H NMR
(500 MHz, CDCl3): 7.71e7.70 (m, 1H), 7.39e7.23 (m, 8H), 5.55
;
d
8. Fung, C. M. K. Ph.D. Dissertation, University of Hong Kong, 2005.
9. Li, N.; Ou, J.; Miesch, M.; Chiu, P. Org. Biomol. Chem. 2011, 9, 6134.
(dddd, J¼23.4, 15.0, 8.4, 6.5 Hz, 1H), 5.3 (s, 1H), 4.90 (dd, J¼10.1,
0.78 Hz, 1H), 4.85 (dd, J¼16.9, 1.4 Hz, 1H), 4.15 (d, J¼13.9 Hz, 1H),
4.00 (d, J¼13.9 Hz,1H), 2.42 (dd, J¼14.2, 8.5 Hz,1H), 2.29 (dt, J¼14.2,
3.1 Hz, 1H), 2.21 (dd, J¼12.3, 3.3 Hz, 1H), 1.88e1.73 (m, 3H), 1.53 (td,
J¼14.1, 4.5 Hz, 1H), 1.30e1.21 (m, 1H) ppm; 13C NMR (125 MHz,
10. (a) Yost, J. M.; Alfie, R. J.; Tarsis, E. M.; Chong, I.; Coltart, D. M. Chem. Commun.
2011, 571e572; (b) Sauer, S. J.; Garnsey, M. R.; Coltart, D. M. J. Am. Chem. Soc.
2010, 132, 13997e13999; (c) Kohler, M. C.; Yost, J. M.; Garnsey, M. R.; Coltart, D.
M. Org. Lett. 2010, 12, 3376e3379; (d) Tarsis, E.; Gromova, A.; Lim, D.; Zhou, G.;
Coltart, D. M. Org. Lett. 2008, 10, 4819e4822; (e) Zhou, G.; Lim, D.; Coltart, D. M.
Org. Lett. 2008, 10, 3809e3812; (f) Zhou, G.; Yost, J. M.; Sauer, S. J.; Coltart, D. M.
Org. Lett. 2007, 9, 4663e4665; (g) Lim, D.; Fang, F.; Zhou, G.; Coltart, D. M. Org.
Lett. 2007, 9, 4139e4142; (h) Zhou, G.; Yost, J. M.; Coltart, D. M. Synthesis 2007,
478e482; (i) Yost, J. M.; Zhou, G.; Coltart, D. M. Org. Lett. 2006, 8, 1503e1506.
11. (a) Masamune, S.; Kamata, S.; Schilling, W. J. Am. Chem. Soc. 1975, 97,
3515e3516; (b) Masamune, S.; Hayase, Y.; Schilling, W.; Chan, W. K.; Bates, G. S.
J. Am. Chem. Soc. 1977, 99, 6756e6758; (c) Kim, S.; Lee, J. I. J. Org. Chem. 1984, 49,
1712e1716; (d) Matsuo, K.; Shindo, M. Org. Lett. 2010, 12, 5346e5349; (e) In-
genito, R.; Wenschuh, H. Org. Lett. 2003, 5, 4587e4590.
CDCl3):
d 204.8, 203.8, 155.9, 136.7, 134.1, 133.9, 133.4, 128.8, 128.7,
128.6, 127.5, 123.7, 123.5, 117.7, 78.7, 62.5, 60.2, 41.9, 33.4, 30.9, 26.7,
25.9, 22.7 ppm; LRMS (EI, 20 eV): m/z 396.2 (Mþ, 0.6), 268.1
(MþꢁSC7H7, 2.59); HRMS (EI, 20 eV): calcd for C24H24O3S (Mþ),
392.1446, found 392.1441.
Acknowledgements
12. For comprehensive review see: (a) Fukuyama, T.; Tokuyama, H. Aldrichimica
Acta 2004, 37, 87e96; (b) Fukuyama, T.; Lin, S. C.; Li, L. J. Am. Chem. Soc. 1990,
112, 7050; (c) Tokuyama, H.; Yokoshima, S.; Lin, S. C.; Li, L.; Fukuyama, T.
Synthesis 2002, 1121.
We thank Solvias for the gift of chiral ligands. Mr. Peter Lam Shu
Wai and Dr. Lap Szeto are thanked for technical assistance. This
work was supported by the University of Hong Kong and the Re-
search Grant Council of Hong Kong SAR, P.R. China (GRF HKU 7017/
09P, HKU1/CRF/08).
13. (a) Moria, Y.; Sekia, M. Adv. Synth. Catal. 2007, 349, 2027e2038; (b) Ikeda, Z.;
Hirayama, T.; Matsubara, S. Angew. Chem., Int. Ed. 2006, 45, 8200e8203; (c)
Fausett, B. W.; Liebeskind, L. S. J. Org. Chem. 2005, 70, 4851e4853; (d) Wit-
tenberg, R.; Srogl, J.; Egi, M.; Liebeskind, L. S. Org. Lett. 2003, 5, 3033e3035;
(e) Li, H.; Yang, H.; Liebeskind, L. S. Org. Lett. 2008, 10, 4375e4378; (f) Pro-
kopcov, H.; Kappe, C. O. Angew. Chem., Int. Ed. 2008, 47, 3674e3676; (g)
Liebeskind, L. S.; Srogl, J. J. Am. Chem. Soc. 2000, 122, 11260e11261; (h) Yang,
H.; Li, H.; Wittenberg, R.; Egi, M.; Huang, W.; Liebeskind, L. S. J. Am. Chem.
Soc. 2007, 129, 1132e1140; (i) Savarin, C.; Srogl, J.; Liebeskind, L. S. Org. Lett.
Supplementary data
The 1H and 13C NMR spectra of 6aeg and 7aeg, and chiral HPLC
analyses are available. Supplementary data associated with this
article can be found, in the online version, at doi:10.1016/
j.tet.2011.07.057.
ꢀ
2000, 2, 3229e3231; (j) Prokopcova, H.; Pisani, L.; Kappe, C. O. Synlett 2007,
43e46.
14. Keck, G. E.; Boden, E. P.; Mabury, S. A. J. Org. Chem. 1985, 50, 709e710.
15. Keck, G. E.; Welch, D. S. Org. Lett. 2002, I, 3687e3690.
16. The absolute stereochemistry of 7 was not determined.
17. Crystal data for (ꢀ)-7c. C15H24O3S, MW¼280.40, Monoclinic, space group P 21/c,
ꢁ
ꢁ
ꢁ
a¼11.2783(3) A, b¼11.7656(3) A, c¼11.9180(3) A,
b
¼97.498(2)ꢂ, V¼1567.
References and notes
3
ꢁ
ꢁ3
95(4) A , Z¼4, Dx¼1.205 Mg m
, m
(Mo Ka
)¼0.21 mmꢁ1, F(000)¼616, T¼296 K;
crystal dimensions: 0.10ꢃ0.24ꢃ0.28 mm. All 2980 independent reflections
(Rint¼0.0403, 2231 reflections with I>2(I)) from a total 18,655 reflections par-
ticipated in the full-matrix least-square refinement against F2. In the final stage
of least-squares refinement, all non-hydrogen atoms were refined anisotropi-
1. (a) Fogg, D. E.; dos Santos, E. N. Coord. Chem. Rev. 2004, 248, 2365e2379; (b)
Tietze, L. F. Chem. Rev. 1996, 96, 115e136; (c) Pellissier, H. Tetrahedron 2006, 62,
1619e1665; (d) Tietze, L. F.; Brasche, G.; Gericke, K. M. Domino Reactions in
Organic Synthesis; Wiley VCH: Weinheim, Germany, 2006.
cally. Convergence (D/s)max<0.001 by full-matrix least-squares refinement on
2. (a) Nicolaou, K. C.; Edmonds, D. J.; Bulger, P. G. Angew. Chem., Int. Ed. 2006, 45,
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F2 reaches to R1¼0.035 and wR2¼0.097 with a goodness-of-fit of 1.030. Crys-
tallographic data for (ꢀ)-7c have been deposited at the Cambridge Crystallo-
graphic Data Center, CCDC 832860.
ꢀ
Poulin, J.; Grise-Bard, C. M.; Barriault, L. Chem. Soc. Rev. 2009, 38, 3092e3101;
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3. (a) Enders, D.; Grondal, C.; Huettl, M. R. Angew. Chem., Int. Ed. 2007, 46,
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