Enantioselective synthesis of β-hydroxy-α-methyl-α-methylthio esters as precursors of anti-vic-hydroxymethyl units

Article abstract of DOI:10.1016/S0040-4039(01)01238-2

A new method for the synthesis of optically active anti-vic-hydroxymethyl units that correspond to anti-aldol derivatives is developed by way of successive enantioselective aldol and diastereoselective desulfurization reactions.

Full text of DOI:10.1016/S0040-4039(01)01238-2

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 42 (2001) 6303–6306
Enantioselective synthesis of b-hydroxy-a-methyl-a-methylthio
esters as precursors of anti-vic-hydroxymethyl units
Isamu Shiina* and Ryoutarou Ibuka
Department of Applied Chemistry, Faculty of Science, Science University of Tokyo, Kagurazaka, Shinjuku-ku,
Tokyo 162-8601, Japan
Received 23 May 2001; revised 13 June 2001; accepted 6 July 2001
Abstract—A new method for the synthesis of optically active anti-vic-hydroxymethyl units that correspond to anti-aldol
derivatives is developed by way of successive enantioselective aldol and diastereoselective desulfurization reactions. © 2001
Elsevier Science Ltd. All rights reserved.
Stereoselective aldol reactions are frequently employed
for the syntheses of complicated natural and unnatural
oxygenated products since syn-vic-hydroxymethyl units
that correspond to syn-aldol derivatives are now pre-
pared easily by Mukaiyama–Evans type aldol reactions
via chiral boron enolates.1 Chiral diamine-coordinated
tin(II) enolates2 and other metal enolates having chiral
auxiliaries3 were also successfully utilized for the enan-
tioselective synthesis of aldol units. Then, chiral Lewis
acid-mediated aldol reactions of enol silyl ethers or
ketene silyl acetals with aldehydes were developed as
powerful tools for the synthesis of optically active aldol
units.4 In the above synthesis, the corresponding syn-
aldol units were obtained in good yields with high
diastereo- and enantioselectivities when the reactions of
silyl nucleophiles prepared from propanoic acid deriva-
tives with aldehydes were carried out in the presence of
chiral Lewis acids including such metals as tin(II),5
boron and titanium(IV), etc.4
anti-aldol units possessing chiral quaternary centers at
the C2-position were obtained in high yields with high
diastereo- and enantioselectivities.7 These methods were
successfully applied to the stereoselective syntheses of
natural and unnatural polyoxy compounds such as
monosaccharides,8 leinamycin,9 paclitaxel (Taxol®),10
cephalosporolide D11 and khafrefungin.12
The construction of several optically active synthetic
intermediates by asymmetric aldol reaction was thus
realized. However, there have not been many reports
that practically provided anti-aldol units and methods
for stereoselective synthesis of anti-vic-hydroxymethyl
units that correspond to anti-aldol derivatives still
needed to be improved. The following are some exam-
ples that provided anti-aldol derivatives. Masamune et
al. obtained anti-aldols preferentially by using ketene
silyl acetals, achiral aldehydes and a catalytic amount
of chiral boron Lewis acid in 1992.13 Then in 1997,
Masamune and Abiko et al. further developed
diastereoselective asymmetric aldol reaction by utilizing
boron enolate derived from (2S,1R)-1-phenyl-2-
{benzyl[(2,4,6 - trimethylphenyl)sulfonyl]amino}propyl
propanoate.14 Kobayashi et al. recently reported anti-
selective catalytic asymmetric aldol reaction of ketene
silyl acetal with achiral aldehydes by using a chiral
zirconium(IV) complex prepared from Zr(OtBu)4 and
(R)-3,3%-diiodo-1,1%-bi-2-naphthol in situ.15
A unique method for the preparation of syn- or anti-
1,2-diol units by asymmetric aldol reaction of enol silyl
ethers derived from S-ethyl (t-butyldimethyl-
siloxy)ethanethioate and S-ethyl benzyloxyethane-
thioate with achiral aldehydes using chiral tin(II) Lewis
acids was reported from our laboratory in 1991.6 In
1992, this method was further developed into the reac-
tion of silyl nucleophiles derived from alkyl 2-benzyl-
oxypropanoate and S-ethyl 2-benzyloxypropanethioate
with achiral aldehydes, and the corresponding syn- or
Ketene silyl acetals derived from S-ethyl t-
butylthioethanethioate16 and ethyl 1,3-dithiolane-2-
carboxylate17 are useful nucleophiles since alkylthio
groups are easily converted to other functionalities. A
* Corresponding author. Fax: (+81)-3-3260-5553; e-mail: shiina@
ch.kagu.sut.ac.jp
0040-4039/01/$ - see front matter © 2001 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(01)01238-2

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I. Shiina, R. Ibuka / Tetrahedron Letters 42 (2001) 6303–6306
planned as our strategy for stereoselective syntheses of
Diamine
(1.3 eq.)
Sn(OTf)2
(1.1 eq.)
aldol units having chiral quaternary centers at the
C2-position by using tin(II) Lewis acids.7 It was
assumed that anti-aldol units would be produced more
efficiently if enantio- and diastereoselective aldol and
diastereoselective desulfurization reactions were succes-
sively performed. Here, we would like to describe a
sequential methodology for the stereoselective synthesis
of anti-vic-hydroxymethyl units that correspond to
anti-aldol derivatives by combining enantioselective
aldol and diastereoselective desulfurization reactions.
OTMS
OEt
OH
O
OH O
MeS
+
+
RCHO
R
OEt
R
OEt
Additive
(1.2 eq.)
CH2Cl2
Me SMe
Me SMe
Me
(1.0 eq.)
syn
anti
1
(Z / E = 88 / 12)
-78 ˚C, 1 h
(1.1 eq.)
N
N
N
N
H
Me
Me
First, a regioisomeric mixture of 118 (Z/E=88/12) was
prepared from ethyl 2-methylthiopropanoate by treat-
ing it with LDA and chlorotrimethylsilane. Asymmetric
aldol reaction of the mixed ketene silyl acetal 1 with
benzaldehyde in the presence of tri-n-butyltin fluoride
(4) and tin(II) trifluoromethanesulfonate coordinated
with chiral diamine 2 at −78°C gave the corresponding
syn-aldol adduct with high diastereo- and enantioselec-
tivities (see Scheme 1, Table 1, entry 1). The use of
di-n-butyltin diacetate (5) as an additive increased the
yield to 83% and stereoselectivities were slightly higher
than those using 4 (entries 1 and 2). The combination
of 5 and chiral diamine 3 was not found suitable for the
present method as shown in entries 3 and 6. When
3-phenylpropanal, an aliphatic aldehyde, was used as a
substrate, the desired syn-aldol was obtained in good
yield with high stereoselectivities by the promotion of
tin(II) trifluoromethanesulfonate coordinated with chi-
ral diamine 2 in the coexistence of 4 (entry 4).
Diamine 2
nBu3SnF (4)
Diamine 3
nBu2Sn(OAc)2 (5)
Scheme 1. Asymmetric aldol reaction using chiral tin(II)
Lewis acid.
method for the synthesis of optically active syn- and
anti-aldol units was then introduced in 1998 by Kiyo-
oka et al. by way of successive asymmetric aldol and
desulfurization reactions.18 In this protocol, syn- or
anti-aldols that possessed methylthio groups at the
C2-position were prepared by the asymmetric aldol
reaction of 1-ethoxy-1-trimethylsiloxy-2-methylthio-1-
propene (1) with achiral aldehydes by promoting a
chiral boron Lewis acid. Further, both syn- and anti-
desulfurizated aldol units were obtained from the above
aldols in high enantiopurity.
On the other hand, preparation of optically active
2-alkylthio-substituted aldols by using ketene silyl
acetals derived from 2-alkylthiopropanoic acid was also
Examples of the optically active syn-aldols prepared by
the present protocol are listed in Table 2. The reaction
Table 1. Reaction conditions and stereoselectivities of the asymmetric aldol reaction
Entry
RCHO
Diamine
Additive
Yield (%)
syn/anti
Ee (%)a
1
2
3
4
5
6
PhCHO
PhCHO
PhCHO
Ph(CH2)2CHO
Ph(CH2)2CHO
Ph(CH2)2CHO
2
2
3
2
2
3
4
5
5
4
5
5
68
83
38
55
66
Trace
95/5
97/3
80/20
92/8
90/10
–
92
95
44
92
65
–
a Ee of syn-aldol.
Table 2. Stereoselective synthesis of aldols that possess asymmetric quaternary centers at the C2-position
Entry
RCHO
Additive
Yield (%)
syn/anti
Ee (%)a
1
2
3
4
PhCHO
5
5
5
5
5
5
4
4
4
83
83
86
87
74
85
55
52
65
97/3
99/1
99/1
97/3
96/4
95/5
92/8
91/9
91/9
95
92
91
90
95
90
92
92
95
4-MeOC6H4CHO
4-MeC6H4CHO
4-ClC6H4CHO
(E)-CH3CHꢀCHCHO
(E)-PhCHꢀCHCHO
PhCH2CH2CHO
CH3(CH2)6CHO
c-C6H11CHO
5
6b
7
8c
9c
a Ee of syn-aldol.
b 1.2 equiv. of 1, 1.4 equiv. of diamine 2, 1.2 equiv. of Sn(OTf)2 and 1.3 equiv. of additive 5 were used.
c 1.5 equiv. of 1, 1.7 equiv. of diamine 2, 1.5 equiv. of Sn(OTf)2 and 1.6 equiv. of additive 4 were used.

I. Shiina, R. Ibuka / Tetrahedron Letters 42 (2001) 6303–6306
6305
of 1 with aromatic aldehydes (entries 1–4) and a,b-
unsaturated aldehydes (entries 5 and 6) proceeded
smoothly at −78°C in the presence of chiral tin(II)
Lewis acid to give the corresponding aldols in good
yields with high stereoselectivities. In the cases of using
aliphatic aldehydes, the chemical yields were generally
moderate. However, syn-aldols here were obtained with
high diastereo- and enantioselectivities, as shown in
entries 7–9.
stable ts-A and unstable ts-B is ca. 0.9 kcal/mol in
UHF/6-31G**//UHF/3-21G level.19
Furthermore, it was found that the desulfurization of
4-methoxybenzylidene derivatives, i.e. cis-9 prepared
from aromatic syn-aldols, gave desirable trans-10 pre-
dominantly by treating it with Raney nickel (W5) as
illustrated in Scheme 3.
As shown in Scheme 4, aliphatic anti-aldol units are
also available from the optically active aldol adducts
containing methylthio groups at the C2-position. Com-
pound trans-12 was produced in good yield with com-
plete stereoselectivity by ways of successive reduction of
A typical experimental procedure is described for the
synthesis of ethyl (2S,3R)-3-hydroxy-2-methyl-2-
methylthio-3-phenylpropanoate (syn-6);18 to tin(II) tri-
fluoromethanesulfonate (101 mg, 0.242 mmol) were
added a solution of chiral diamine 2 (69.1 mg, 0.288
mmol) in dichloromethane (0.5 mL) and a solution of 5
(91.5 mg, 0.261 mmol) in dichloromethane (0.5 mL) at
room temperature. After the reaction mixture was
stirred for 5 min at the same temperature, a solution of
the mixed ketene silyl acetal 1 (Z/E=88/12, 52.6 mg,
0.239 mmol) in dichloromethane (0.5 mL) and a solu-
tion of benzaldehyde (22.5 mg, 0.212 mmol) in
dichloromethane (0.5 mL) were successively added to
the clear solution at −78°C. The reaction mixture was
stirred for 1 h at −78°C and saturated aqueous sodium
hydrogencarbonate was added. Then, the mixture was
Ph
Ph
OH
O
O
O
O
O
a
b
Ph
OEt
Ph
Ph
Me SMe
Me SMe
Me
syn-6
cis-7
8
Scheme 2. Transformation of the aldols to cyclic compounds.
(a) (1) LiBH4, CH2Cl2, rt, quant. (from syn-6), 89% (from
anti-6); (2) PhCH(OMe)2, CSA, CH2Cl2, rt, quant. (for cis-7),
84% (for trans-7); (b) Raney Ni (W5), EtOH, reflux, 67%,
cis-8/trans-8=11/89 (from cis-7), trace (from trans-7).
filtered through
a
short pad of Celite with
dichloromethane and the filtrate was extracted with
dichloromethane. The organic layer was washed with
brine and dried over sodium sulfate. After filtration of
the mixture and evaporation of the solvent, the crude
product was purified by thin layer chromatography
(hexane/AcOEt=5/1) to afford syn-6 (43.0 mg, 80%)
and anti-6 (1.5 mg, 2.8%) as colorless oils. syn-6:
[h]2D4=+38.0° (c 1.05, CHCl3); HPLC (CHIRALCEL
AD, i-PrOH/hexane=1/19, flow rate=1.0 mL/min):
tR=8.8 min (2.6%), tR=9.9 min (97.4%).
H
H
Ph
Ph
O
O
Ph
Ph
Me
Me
O
O
Ph
ts-A
trans-8
O
O
Ph
Me
Me
Me
Ph
Ph
4
O
O
O
5
Ph
Ph
H
O
H
ts-B
cis-8
Next, stereoselective desulfurization of the derivatives
of aldol adducts to give anti-aldol units was studied.
Although several attempted reductions of syn- and
anti-aldols 6 and their linear derivatives gave poor
stereoselectivities, desulfurization of cis-stereoisomer of
benzylideneacetal 7 with Raney nickel (W5) afforded
trans-8 with good diastereoselectivity (cis/trans=11/89)
in which the desired anti-vic-hydroxymethyl unit was
contained (Scheme 2). On the other hand, reduction of
trans-7, which was prepared from anti-6, scarcely took
place under the same conditions. Therefore, asymmetric
aldol reaction of 1 with aldehydes to give syn-aldols
preferentially was proved appropriate for the produc-
tion of anti-aldol units according to this sequential
aldol-desulfurization methodology.
Figure 1. Assumed pathway to give desulfurizated com-
pounds.
PMP
O
PMP
O
Raney Ni
(W5)
Ar = Ph; 51%
O
O
= 4-MeOC6H4; 78%
= 4-MeC6H4; 77%
= 4-ClC6H4; 64%
EtOH
reflux
Ar
Ar
Me SMe
Me
cis-9
trans-10
Scheme 3. Stereoselective desulfurization of 4-methoxyben-
zylidene derivatives.
PMP
OH
O
O
O
OPMB
Me
The stereoselectivity in hydrogenation step was
assumed to be determined by the direction of hydrogen
approach to the six-membered free radical intermediate
generated by desulfurization with Raney nickel in the
transition state (Fig. 1). The transition state giving
trans-8 which corresponds to the anti-aldol unit seems
more stable than that of giving cis-8 because of the
repulsion between functionalities at the C4- and C5-
positions of cis-8. Calculated energy difference between
a
b
Ph
OEt
Me SMe
syn-11
Ph
Ph
OH
Me
trans-12
anti-13
Scheme 4. Stereoselective synthesis of anti-vic-hydroxymethyl
units. (a) (1) LiBH4, CH2Cl2, rt, 94%; (2) PMPCH(OMe)2,
CSA, CH2Cl2, rt, 89%; (3) Raney Ni (W5), EtOH, reflux,
73%, cis/trans=0/100; (b) DIBAL, CH2Cl2, rt, 80%.

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I. Shiina, R. Ibuka / Tetrahedron Letters 42 (2001) 6303–6306
syn-11, formation of 4-methoxybenzylidene acetal, and
successful desulfurization. Thus obtained trans-12 can
easily be transformed to the desired anti-vic-hydroxy-
methyl unit 13 which corresponds to the anti-aldol
derivative by the known reductive cleavage.
Bull. Chem. Soc. Jpn. 1994, 67, 1708–1716; See also: (d)
Kobayashi, S.; Kawasuji, T. Tetrahedron Lett. 1994, 35,
3329–3332; (e) Kobayashi, S.; Horibe, M. Chem. Eur. J.
1997, 3, 1472–1481.
7. (a) Kobayashi, S.; Shiina, I.; Izumi, J.; Mukaiyama, T.
Chem. Lett. 1992, 373–376; (b) Mukaiyama, T.; Shiina,
I.; Izumi, J.; Kobayashi, S. Heterocycles 1993, 35, 719–
724.
8. (a) Mukaiyama, T.; Shiina, I.; Kobayashi, S. Chem. Lett.
1990, 2201–2204; (b) Mukaiyama, T.; Anan, H.; Shiina,
I.; Kobayashi, S. Bull. Soc. Chim. Fr. 1993, 130, 388–394;
See also: (c) Kobayashi, S.; Onozawa, S.; Mukaiyama, T.
Chem. Lett. 1992, 2419–2422; (d) Kobayashi, S.; Kawa-
suji, T. Synlett 1993, 911–913.
9. (a) Kanda, Y.; Fukuyama, T. J. Am. Chem. Soc. 1993,
115, 8451–8452; (b) Fukuyama, T.; Kanda, Y. J. Synth.
Org. Chem. Jpn. 1994, 52, 888–899.
10. (a) Mukaiyama, T.; Shiina, I.; Sakata, K.; Emura, T.;
Seto, K.; Saitoh, M. Chem. Lett. 1995, 179–180; (b)
Mukaiyama, T.; Shiina, I.; Iwadare, H.; Saitoh, M.;
Nishimura, T.; Ohkawa, N.; Sakoh, H.; Nishimura, K.;
Tani, Y.; Hasegawa, M.; Yamada, K.; Saitoh, K. Chem.
Eur. J. 1999, 5, 121–161.
The distinctive features of this synthetic protocol are to
construct optically active syn-aldol adducts having
asymmetric quaternary centers at the C2-position first,
and then to produce anti-vic-hydroxymethyl units by
successive desulfurization of the derivatives of aldol
adducts. The present method is expected to be quite
useful for the preparation of anti-aldol units which are
otherwise not easily obtained from propanoic acid
derivatives. It could also be employed for the stereose-
lective syntheses of polyketides having these functional-
ities. Our programs for applying these utilities to the
total syntheses of natural products are now in progress.
Acknowledgements
This work was partially supported by a Grant-in-Aid
for Scientific Research from the Ministry of Education,
Science, Sports and Culture, Japan.
11. (a) Shiina, I.; Fukuda, Y.; Ishii, T.; Fujisawa, H.;
Mukaiyama, T. Chem. Lett. 1998, 831–832; (b) Shiina, I.;
Fujisawa, H.; Ishii, T.; Fukuda, Y. Heterocycles 2000, 52,
1105–1123.
12. Wakabayashi, T.; Mori, K.; Kobayashi, S. J. Am. Chem.
Soc. 2001, 123, 1372–1375.
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19. There are the imaginary frequencies of ts-A at −2157
cm−1 and of ts-B at −2126 cm−1. In ROHF/cc-pVTZ//
ROHF/3-21G level, the difference is ca. 1.2 kcal/mol
(−3211 and −3151 cm−1). All calculations were performed
with the program package SPARTAN 5.0.3 of Wavefunc-
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