Enantioselective aldol reaction of tetrasubstituted ketene silyl acetals with achiral aldehydes for the construction of asymmetric tertiary alcohols: An application for the divergent total syntheses of buergerinins F and G

Article abstract of DOI:10.1055/s-0029-1216922

The asymmetric aldol reaction of heteroatom-substituted ketene silyl acetals with achiral aldehydes has been developed by the promotion of tin(II) triflate coordinated with a chiral diamine to afford the corresponding aldols having chiral tertiary alcohol

Full text of DOI:10.1055/s-0029-1216922

PAPER
2915
Enantioselective Aldol Reaction of Tetrasubstituted Ketene Silyl Acetals with
Achiral Aldehydes for the Construction of Asymmetric Tertiary Alcohols:
An Application for the Divergent Total Syntheses of Buergerinins F and G
E
nantios
s
elective
A
a
ldol Reacti
m
ons u Shiina,* Takashi Iizumi, Yu-suke Yamai, Yo-ichi Kawakita, Kazutoshi Yokoyama, Yo-ko Yamada
Contribution from the Department of Applied Chemistry, Faculty of Science, Tokyo University of Science, Kagurazaka, Shinjuku-ku,
Tokyo 162-8601, Japan
Fax +81(3)32605609; E-mail: shiina@rs.kagu.tus.ac.jp
Received 30 May 2009
dibutyltin diacetate. The reaction of KSA 3 possessing a
Abstract: The asymmetric aldol reaction of heteroatom-substituted
tert-butyldimethylsiloxy group at C2 with achiral alde-
hydes smoothly proceeds to give the corresponding syn-
ketene silyl acetals with achiral aldehydes has been developed by
the promotion of tin(II) triflate coordinated with a chiral diamine to
afford the corresponding aldols having chiral tertiary alcohols at the
a,b-dihydroxy thioester derivatives in high yields with
a-positions. This reaction has been successfully applied to the con- good stereoselectivities (Scheme 2).3 It then becomes pos-
struction of the basic skeletons of buergerinins F and G starting
from achiral materials. (+)-Buergerinin G, a potentially antiphlogis-
sible to control the enantiofacial selectivity of the KSAs
generated from a-hydroxy thioester derivatives just by
tic and febrifuge agent having a unique trioxatricyclo[5.3.1.01,5]un-
choosing the appropriate protective groups for the hy-
decane skeleton, is stereoselectively prepared by means of the
droxy groups of the KSAs, and the two diastereomers of
enantioselective aldol reactions via ten linear steps from crotonalde-
the optically active a,b-dihydroxy thioesters can be easily
synthesized.
hyde in 18% overall yield including an effective intramolecular
Wacker-type ketalization of the dihydroxy-g-lactone as a key step.
In addition to the former establishment for the synthesis of (+)-buer-
gerinin F, effective divergent methods for the preparation of buer-
gerinins F and G were developed through a unified optically active
aldol-type intermediate, which was generated from the tetrasubsti-
tuted ketene silyl acetal with crotonaldehyde by the asymmetric
Mukaiyama aldol reaction.
N
Me
N
N
Me
N
Sn
H
Sn
TfO OTf
TfO OTf
Key words: Aldol reaction, tin–chiral amine catalyst, enantioselec-
1a
1b
tive, tertiary alcohol, ketene silyl acetal
N
Et
N
N
N
Pr
Sn
Sn
Enantioselective aldol addition is one of the most power-
ful tools for the construction of new C–C bonds with con-
trol of the absolute configuration of the new chiral centers,
and the utility of this reaction has been demonstrated by a
number of applications for the synthesis of natural prod-
ucts, such as carbohydrates and macrolide and polyether
antibiotics, etc.1
TfO OTf
TfO OTf
1c
1d
Figure 1
OTMS
SEt
OH
O
Sn(II) complex
1b or 1c
O
+
For example, various optically active anti-a,b-dihydroxy
thioester derivatives are obtained in good yields from
achiral aldehydes and ketene silyl acetal (KSA) 2 derived
from a-(benzyloxy)acetic acid with excellent diastereo-
and enantioselectivities when the chiral diamine–tin(II)
complex 1b or 1c and dibutyltin diacetate are employed
together (Figure 1, Scheme 1).2 According to the present
aldol methodology, two hydroxy groups can be stereose-
lectively introduced at the 1,2-positions during the new
C–C bond formation.
R
SEt
Bu2Sn(OAc)2
CH2Cl2, –78 °C
59–88%
R
H
OBn
OBn
2
syn/anti = 2:98 to 1:99
95–98% ee (anti)
Scheme 1
OTMS
SEt
OH
O
Sn(II) complex
1d
O
+
R
SEt
R
H
Bu2Sn(OAc)2
CH2Cl2, –78 °C
46–93%
OTBS
OTBS
On the other hand, several syn-aldol adducts are also ob-
tained under similar reaction conditions, namely, in the
presence of the chiral diamine–tin(II) complex 1d and
3
syn/anti = 88:12 to 97:3
82–94% ee (syn)
Scheme 2
SYNTHESIS 2009, No. 17, pp 2915–2926
Advanced online publication: 30.07.2009
DOI: 10.1055/s-0029-1216922; Art ID: C02109SS
© Georg Thieme Verlag Stuttgart · New York
x
x.
x
x
.
2
0
0
9
The successful method for producing the chiral syn- and
anti-diol units can also be applied to the construction of an
asymmetric quaternary carbon, which is included in the

2916
I. Shiina et al.
PAPER
aldol structure. In the presence of the chiral diamine– proceeded to afford the corresponding KSAs in excellent
tin(II) complex 1a, the desired optically active carboxylic yields.
esters possessing asymmetric quaternary carbons at the a-
Next, examination of the aldol reaction of the KSAs 4–6
positions could be synthesized in good yields with high
with achiral aldehydes was carried out as shown in
stereoselectivities (Scheme 3).4 In this synthetic strategy,
Table 1 and a variety of chiral molecules, which include
asymmetric quaternary carbons at the a-positions, were
successfully produced. For instance, in the presence of the
a variety of nucleophiles, such as tetrasubstituted KSAs
derived from propanoic acid equivalents having a-alkoxy,
a-(alkylthio), and a-(alkylseleno) groups, were easily uti-
chiral tin(II) Lewis acid 1a, the desired optically active
lized to produce the corresponding optically active com-
syn-a-(benzyloxy)-b-hydroxy-a-methyl esters 7a–d were
synthesized in good yields with high stereoselectivities
pounds with high enantioselectivities.
from 2-(benzyloxy)-1-isopropoxy-1-(trimethylsiloxy)-
OH
O
OTMS
YR3
propene (4) derived from isopropyl 2-(benzyloxy)pro-
panoate. As shown in entries 1–4, a variety of electro-
philes, such as aromatic, a,b-unsaturated, and aliphatic
aldehydes could be applied in the present protocol and
high enantioselectivities are generally attained in all cas-
es. The catalytic reaction also produced the optically ac-
tive aldol 7a with excellent enantiomeric excess (96% ee)
in high diastereoselectivity (syn/anti 90:10) starting from
KSA 4 with benzaldehyde when using 20 mol% of the
chiral tin(II) complex 2a. These successful results
prompted us to develop an enantioselective method for the
construction of the basic skeleton of buergerinins F and G,
which possess asymmetric tertiary alcohols at C5 (vide
infra).
Sn(II) complex
1a
O
R2X
R1
YR3
+
R1
H
additive
CH2Cl2, –78 °C
Me XR2
Me
syn or anti
high ee
XR2 = OBn, OMe, SMe, SeMe
YR3 = OMe, OEt, OPh, SEt
Scheme 3
In this paper, we fully describe the results of the system-
atic studies for the preparation of aldol-type molecules in-
cluding asymmetric quaternary carbons at the a-positions
and disclose the extended applications of this novel strat-
egy to prepare useful molecules. We also report a new
method for the synthesis of (+)-buergerinin G to demon-
strate the efficiency of the present protocol for providing
chiral compounds starting from both achiral tetrasubsti-
tuted KSA and aldehyde using the enantioselective Mu-
kaiyama aldol reaction.
Furthermore, the asymmetric aldol reaction of 1-ethoxy-
2-(methylthio)-1-(trimethylsiloxy)propene (5), a tetrasub-
stituted KSA derived from ethyl 2-(methylthio)pro-
panoate, with achiral aldehydes was examined as shown
in entries 5–8. The reaction of KSA 5 with benzaldehyde
(entry 5) and a,b-unsaturated aldehydes (entries 6 and 7)
smoothly proceeded at –78 °C in the presence of the chiral
diamine–tin(II) complex 1a with dibutyltin diacetate (A)
as an additive to give the desired syn-aldols 8a–c in good
yields with high stereoselectivities. On the other hand,
better stereoselectivities were observed for the reaction of
aliphatic aldehydes, such as cyclohexanecarbaldehyde, by
promotion of the combined use of the chiral diamine–
tin(II) complex 1a with tributyltin fluoride (B) as an effec-
tive co-reagent (entry 8 for producing 8d).
Synthesis of Diol Units Including Asymmetric Qua-
ternary Carbons via Enantioselective Aldol Reac-
tions
We first prepared several kinds of tetrasubstituted KSAs
4–6, which function as nucleophiles in the asymmetric al-
dol reaction (Scheme 4). In every reaction, conventional
enolate formation using lithium diisopropylamide and
successive transmetalation of lithium to silicon smoothly
OLi
O
OTMS
TMSCl
LDA
Me
Me
Me
Oi-Pr
Oi-Pr
Oi-Pr
THF, –78 °C
THF, r.t.
quant.
OBn
OBn
OBn
4
OTMS
OEt
O
OLi
OEt
LDA
TMSCl
MeS
MeS
MeS
OEt
THF, –78 °C
THF, r.t.
quant.
Me
Me
Me
5
O
OLi
OMe
OTMS
OMe
TMSCl
LDA
MeSe
MeSe
MeSe
OMe
THF, r.t.
quant.
THF, –78 °C
Me
Me
Me
6
Scheme 4
Synthesis 2009, No. 17, 2915–2926 © Thieme Stuttgart · New York

PAPER
Enantioselective Aldol Reactions
2917
Examples of the preparation of the optically active syn-al- 9f, which were used as key synthetic intermediates of the
dols 9a–f by the present protocol using 1-methoxy-2- anti-b-hydroxy-a-methyl units for the total synthesis of
(methylseleno)-1-(trimethylsiloxy)propene (6), which (–)-octalactins A and B.5
contains an alkylseleno group at C2, were demonstrated
as listed in entries 9–14. In the presence of the chiral di-
amine–tin(II) complex 1a with additive A, KSA 6 reacted
Additionally, this reaction was successfully applied to
produce the precursors of the optically active b-hydroxy-
a-methylene esters, equivalent compounds to the Morita–
with achiral aldehydes, such as benzaldehyde and a,b-un-
Baylis–Hillman adducts.4d For example, when the syn-al-
saturated aldehydes, to produce the corresponding opti-
dol 9a, derived from KSA 6 with benzaldehyde, was treat-
ed with hydrogen peroxide in tetrahydrofuran at 0 °C, the
desired deselenization rapidly proceeded to regioselec-
tively afford the eliminated compound 10 with a high
cally active syn-a-(alkylseleno)-b-hydroxy-a-methyl
esters 9a–c, which possess quaternary carbons at the a-po-
sitions (entries 9–11). The use of additive B also gave fair-
ly good yields and stereoselectivities for the reaction of
enantioselectivity (93% ee) (Scheme 5).
the aliphatic aldehydes (entries 12–14), as well as had
This protocol was successfully used for the preparation of
multi-oxygenated b-hydroxy-a-methylene ester 11, which
could be converted into the cyclic ether moiety of the de-
rivatives of the naturally occurring complex molecules
been found that additive B was a suitable co-reagent for
the reaction of KSA 5 with aliphatic aldehydes (cf., entry
8). The reaction of KSA 6 with 2-(triisopropylsiloxy)pro-
panal and 3-(triisopropylsiloxy)butanal preferentially
(Scheme 6).
produced the corresponding syn-aldol compounds 9e and
Table 1 Asymmetric Aldol Reaction of Tetrasubstituted KSAs 4–6 Using a Stoichiometric Amount of Tin(II) Complex 1a
1a
N
N
Me
H
Sn
OTMS
OR3
O
TfO OTf
OH
O
R2X
+
R1
H
n-Bu2Sn(OAc)2 (A)
or
n-Bu3SnF (B)
R1
OR3
Me
Me XR2
7a–d
8a–d
9a–f
4; R2X = BnO, R3 = i-Pr
5; R2X = MeS, R3 = Et
6; R2X = MeSe, R3 = Me
Entry
1
R1
KSA
4a
Additive
Yieldd (%)
Ratioe syn/anti eef (%)
syn-Product
Ph
A
A
A
A
A
A
A
B
A
A
A
B
B
B
89
79
85
52
83
74
85
65
86
85
66
66
64
57
96:4
96:4
97:3
97:3
97:3
96:4
95:5
91:9
92:8
94:6
95:5
89:11
80:20
75:25
83
88
87
97
95
95
90
95
93
94
94
90
90
95
7a
7b
7c
7d
8a
8b
8c
8d
9a
9b
9c
9d
9e
9f
2
(E)-CH=CHMe
(E)-CH=CHPh
Cy
4a
3
4a
4
4a
5
Ph
5b
5b
5b
5b
6c
6
(E)-CH=CHMe
(E)-CH=CHPh
Cy
7
8
9
Ph
10
11
12
13
14
(E)-CH=CHMe
(E)-CH=CHPh
(CH2)6Me
CH2OTIPS
(CH2)2OTIPS
6c
6c
6c
6c
6c
a 4; ratio E/Z 71:29.
b 5; ratio E/Z 12:88.
c 6; ratio E/Z 10:90.
d Combined yield of syn- and anti-aldols.
e Determined after isolation of syn- and anti-aldols.
f ee of syn-product.
Synthesis 2009, No. 17, 2915–2926 © Thieme Stuttgart · New York

2918
I. Shiina et al.
PAPER
O
complex 1a
Bu2Sn(OAc)2
Ph
H
OH
O
OH
O
30% H2O2
+
Ph
OMe
Ph
OMe
THF, 0 °C
94% yield
CH2Cl2, –78 °C
86% yield
syn/anti = 92:8
93% ee (syn)
Me SeMe
OTMS
OMe
MeSe
10 (93% ee)
9a
Me
6
Scheme 5
TBSO
OH
O
TBSO
O
OTMS
complex 1a
Bu3SnF
CH2Cl2, –78 °C
75% yield
Me
Me
MeSe
+
OMe
Me SeMe
H
OMe
TBSO Me
TBSO
TBSO
Me
Me
6
OH
O
30% H2O2
Me
OMe
THF, 0 °C
85% yield
TBSO
Me
11
Scheme 6
The present method provides another way for producing cluding the primary, secondary, and tertiary hydroxy
chiral Morita–Baylis–Hillman adducts with high enantio- groups, carboxylic acid, and methyl ketone parts
meric excesses, and the substrate generality of this reac- (Figure 2). An optically active multi-oxygenated com-
tion could be applied to the synthesis of many kinds of b- pound 15 might be used as a precursor for the construction
hydroxy-a-methylene esters having aromatic, alkenyl, of the framework 14 by one-carbon extension (Scheme 7).
and aliphatic substituents at the b-positions.
Compound 15 has an aldol-type structure, including the
asymmetric quaternary carbon at the C2 position, and we
postulated that it could be synthesized by enantioselective
aldol reaction between the tetrasubstituted KSA 16 and
crotonaldehyde.
Total Synthesis of (+)-Buergerinin G
Buergerinin G (13, Figure 2) was isolated in 2000 from
the roots of Scrophularia buergeriana Miq. together with
a related tricyclic triether, buergerinin F (12).6 A series of
Scrophularia species has been used as an ingredient of
Asian herbal medicine, hence, determination of the bioac-
tive assay of buergerinins F and G is an interesting topic
in the field of bioorganic chemistry. The absolute config-
uration of 12 and 13 were clarified in 2003 through the to-
tal synthesis of natural compounds starting from
thymidine by Lowary et al.7 In Lowary’s total synthesis,
12 was elegantly converted into 13 by ruthenium(IV) ox-
ide oxidation with the acceleration of pyridine.
O
HO
OH
C1 elongation
OTBS
2
OH
MeO
O
OBn
O
H
H
O
HO
H
equivalent oxo trihydroxy
carboxylic acid (14)
15
asymmetric
aldol
reaction
OH
O
OTMS
TBSO
2
OMe
OMe
Buergerinin G (13) consists of a unique tricyclic ring
framework; the equivalent unfolded component 14 shows
the highly oxidized compact structure of the molecule in-
OBn
O
OBn
16
TBSO
15
H
Scheme 7 Retrosynthetic analysis of buergerinin equivalent 14 via
aldol 15
HO
OH
O
O
O
O
O
OH
O
O
O
O
H
H
H
H
O
Although the enantioselective aldol reactions of tetrasub-
stituted KSAs 4–6 prepared from propanoic acid deriva-
tives with achiral aldehydes had already been established
as shown in the former section (Table 1), there has not yet
been an example of using tetrasubstituted KSA generated
equivalent oxo trihydroxy
carboxylic acid (14)
buergerinin F (12)
buergerinin G (13)
Figure 2 Structures of buergerinin F (12), buergerinin G (13), and
the unfolded component equivalent to the latter 14
Synthesis 2009, No. 17, 2915–2926 © Thieme Stuttgart · New York

PAPER
Enantioselective Aldol Reactions
2919
from butanoic acid derivatives for the synthesis of asym-
metric quaternary carbons next to the ethyl group at the a-
position in the aldol structure. Therefore, we newly pre-
pared KSA 17 from methyl 2-(benzyloxy)butanoate under
standard reaction conditions and further examined the
reaction of 17 with an achiral aldehyde to produce the
desired aldol product (Scheme 8). Fortunately, we deter-
mined that the nucleophilic addition of 17 to benzalde-
hyde smoothly proceeded at –78 °C in the presence of the
tin(II) Lewis acid 1a to afford the corresponding aldol 18
possessing the asymmetric quaternary center at the a-po-
sition with a high enantioselectivity (95% ee).
OTMS
R
TBSO
N
N
OMe
15
Me
H
Sn
H
OBn
O
TfO OTf
*LSn
Sn(II) complex 1a
R = (E)-MeCH=CH
*LSn
Scheme 10 Assumed transition state to give aldol 15 starting from
KSA 16 with crotonaldehyde
right-ring
formation
left-ring
formation
O
O
O
O
O
OH
O
OTMS
HO
Sn(II) complex
1a
O
O
H
H
+
Ph
OMe
OTBS
OMe
buergerinin F (12)
Ph
H
Bu2Sn(OAc)2
CH2Cl2, –78 °C
57% yield
syn/anti = 87:13
95% ee (syn)
19
MeO
Et OBn
OBn
OBn
17
HO
H
18
15
OH
Scheme 8
O
OH
O
O
O
right-ring
formation
O
O
left-ring
formation
H
H
The above successful result prompted us to use more ad-
vanced materials for the enantioselective aldol reaction in
order to produce the key intermediate 15, which might be
easily converted into buergerinins F (12) and G (13) in
short steps. Indeed, the coupling reaction of tetrasubstitut-
ed KSA 16 with crotonaldehyde (Scheme 9) was effec-
tively promoted by chiral tin(II) complex 1a to give the
desired aldol adduct 15 (94% ee) including all the func-
tionalities required for the transformation into 14, the
equivalent molecule of the basic structure of 13.
buergerinin G (13)
20
Scheme 11 Divergent synthetic pathways for buergerinins F (12)
and G (13)
decided to develop an alternative method to prepare 13,
not from 12 via oxygenation, but directly from the precur-
sory dihydroxy-g-lactone 20 using the intramolecular
Wacker-type ketalization (Scheme 11; left → right-hand-
ed ring formation).
The high stereoselectivities attained in this aldol reaction
can be explained by assuming the open-chained transition
state as depicted in Scheme 10. In the reaction of KSA 16
with crotonaldehyde, the chiral tin(II) complex has a rigid
structure in which the conformation is highly controlled
by the coordination of nitrogens in the chiral diamine and
oxygen in the benzyloxy group of KSA 16 onto the central
tin(II) metal. The re-face of the activated aldehyde is al-
most completely shielded during the nucleophilic addition
process and KSA 16 attacks from the si-face via forming
a five-membered ring to give the syn-aldol adduct in high
enantio- and diastereoselectivities.
A new way for producing the trioxatricyclo[5.3.1.01,5]un-
decane skeleton was planned by the intramolecular ketal-
ization of the key intermediate dihydroxy-g-lactone 20
according to the retrosynthetic analysis described below
(Scheme 12). The g-lactone moiety in 20 might be con-
structed by facile ring formation via the oxidative treat-
ment of the corresponding dithioacetal 21, which could be
obtained by the one-carbon elongation of the epoxide 22
generated from the corresponding triol 23. It is postulated
that the reduction of the multifunctionalized aldol 15
would easily produce the desired triol 23, therefore, the
unified intermediate 15 derived from the KSA 16 and cro-
tonaldehyde was chosen as the starting material for the
synthesis of buergerinin G (13).
Based on the above strategy, we synthesized buergerinin
F (12) starting from 15 using the Wacker-type cyclization
to produce hydroxyketal 19 followed by iodine-mediated
five-membered ether ring closure (Scheme 11; right →
left-handed ring formation).8 However, oxidative conver-
sion of 12 into 13 was not successfully carried out by us
due to the significant volatile feature of 12. Therefore, we
First, the ester function in the optically active aldol 158
was reduced by Red-Al and the corresponding diol 24 was
obtained in high yield (Scheme 13). The benzyl protective
group on the tertiary hydroxy was cleaved using lithium
OH
O
OTMS
Sn(II) complex
1a
O
+
TBSO
OMe
OMe
H
Bu2Sn(OAc)2
EtCN, –78 °C
74% yield
OBn
OBn
TBSO
syn/anti > 99:1
94% ee (syn)
16
15
Scheme 9
Synthesis 2009, No. 17, 2915–2926 © Thieme Stuttgart · New York

2920
I. Shiina et al.
PAPER
lactone
formation
Wacker
ketalization
S
OTBS
OH
O
O
O
OH
O
OH
S
O
O
O
H
H
H
H
buergerinin G (13)
20
21
C1
elongation
O
O
H
triol
formation
epoxide
formation
OTBS
OTBS
OTBS
MeO
HO
HO
OBn
OH
HO
HO
H
H
15
23
22
Scheme 12 Retrosynthetic analysis of buergerinin G (13) from aldol 15
4,4¢-di-tert-butylbiphenylide (LDBB) to afford the de- hand, treatment of 25 with DBU also produced 22 in high
sired triol 23 in a reasonable yield. The attempted trans- yield (95%). Coupling of lithiated 1,3-dithiane with 22 af-
formation of the primary hydroxy into the leaving group forded the epoxy-opening product 21, which was further
by treatment with tosyl chloride in pyridine produced the converted into lactone 27 in good yield by the successive
corresponding tosylate 25 in 69% yield accompanied by deprotection of the dithioacetal moiety and the oxidation
the formation of the epoxide 22 in 8% yield. It was found of the hemiacetal part in 26. Deprotection of the tert-
that the tosylate 25 spontaneously cyclized to form the de- butyldimethylsilyl (TBS) group on the primary hydroxy
sired epoxide 22 during development of the preparative in 27 produced the desired g-lactone 20. The intramolec-
TLC plate in the purification stage, therefore, we attempt- ular Wacker-type ketalization of 20 using a catalytic
ed further conversion of 25 into 22 by treatment with sili- amount of palladium dichloride was finally carried out
ca gel. Actually, after stirring the isolated 25 on silica gel and the corresponding bicyclic ketal, the target molecule
1
without solvent at room temperature, we succeeded in ob- 13, was produced in good yield. The H and 13C NMR
taining the epoxide 22 in 71% yield and 23% of the unre- spectra of the obtained 13 showed that the synthetic sam-
acted tosylate 25 was additionally recovered. On the other ple has the same relative stereochemistry as naturally oc-
O
OTBS
OTBS
1'
OTBS
HO
HO
2
HO
HO
2'
Red-Al®
1
LDBB
MeO
OH
OBn
OBn
3
toluene
–45 to 0 °C
99%
THF
–78 °C
quant.
5
HO
H
H
6
4
H
15
24
23
TsCl
py, r.t.
69% of 25
8% of 22
S
Li
a) silica gel
r.t.
71% of 22
23% of 25
O
S
S
OTBS
OTBS
OTBS
TsO
HO
OH
OH
S
or
O
H
THF
–19 °C
80%
HO
b) DBU
CH2Cl2,
r.t.
H
H
H
21
22
25
95%
MeI, CaCO3
MeCN, H2O
r.t.
6
1) PDC
CH2Cl2, r.t.
60% (2 steps)
7
4
5
OTBS
OR
PdCl2
CuCl
O
1
O
O
HO
OH
O
OH
3
2) TBAF
O
O2
DME, r.t.
86%
O
O
8
9
AcOH
THF, r.t.
83%
10
H
H
H
26
(+)-buergerinin G (13)
27; R = TBS
20; R = H
Scheme 13 Total synthesis of buergerinin G (13)
Synthesis 2009, No. 17, 2915–2926 © Thieme Stuttgart · New York

PAPER
Enantioselective Aldol Reactions
2921
Isopropyl (2S,3R)-2-(Benzyloxy)-3-hydroxy-2-methyl-3-phe-
nylpropanoate (7a); Typical Procedure for the Catalytic Reac-
tion
curring buergerinin G. Other properties of the synthetic
(1R,5R,8S)-13 including its optical rotation were identical
to those of buergerinin G isolated by Zhu et al.6 and pro-
duced by Lowary et al.7
To Sn(OTf)2 (23.8 mg, 57.1 mmol) at r.t. was added a soln of (S)-1-
methyl-2-[(1-naphthylamino)methyl]pyrrolidine (16.5 mg, 68.6
mmol) in EtCN (1.0 mL). The mixture was stirred at r.t. for 5 min
and then a mixture of KSA 4 (84.1 mg, 0.286 mmol) and benzalde-
hyde (30.4 mg, 0.286 mmol) in EtCN (1.5 mL) was slowly added at
–78 °C with a mechanically driven syringe over a 4 h period. The
mixture was further stirred at –78 °C for 2 h and then sat. aq
NaHCO3 was added. The mixture was extracted with Et2O, and the
organic layer was washed with H2O and brine and dried (Na2SO4).
Filtration of the mixture and evaporation of the solvent gave crude
product that was purified by TLC to afford the aldol-type adducts as
their trimethylsilyl ethers. The trimethylsilyl ethers were treated
with a mixture of THF–1.0 M HCl (20:1) at 0 °C to give the corre-
sponding aldol 7a (50.8 mg, 54%, 90% ee) and its anti-isomer (5.6
mg, 6%, 51% ee) as colorless oils.
Thus, an efficient method for the synthesis of (+)-buerger-
inin G (13) was established via the enantioselective aldol
reaction of tetrasubstituted KSA 16 with a simple achiral
aldehyde, one-carbon extension using dithiane coupling,
and then the Wacker-type ketalization. The synthesis of
13 proceeds in ten steps and ca. 18% overall yield from
crotonaldehyde with an achiral nucleophile. The absolute
stereochemistry of 13 including the asymmetric quaterna-
ry carbon was additionally confirmed by the enantioselec-
tive synthesis. Based on the present studies, our chiral
induction technology, a systematic protocol to produce
the optically active aldols including asymmetric tertiary
alcohols at the a-positions, was successfully applied for
the preparation of an optically active linear precursor of
(+)-buergerinin G. In addition to the former establishment
for the alternative synthesis of (+)-buergerinin F,8 effec-
tive methods for the preparation of buergerinins F (12)
and G (13) were developed starting from the unified opti-
cally active aldol-type intermediate. These divergent syn-
thetic methods would be widely applicable to the creation
of various derivatives of highly functionalized naturally
occurring molecules.
Isopropyl (2S,3R)-2-(Benzyloxy)-3-hydroxy-2-methyl-3-phe-
nylpropanoate (7a)
HPLC (Chiralcel OD, hexane–i-PrOH, 9:1, flow rate = 1.0 mL/
min): tR = 5.3 (95.0%), 8.4 min (5.0%).
IR (neat): 3498, 1727 cm–1.
1H NMR (CDCl3): d = 7.39–7.30 (m, 10 H, Ph), 5.10 (qq, J = 6.2,
6.2 Hz, 1 H, i-Pr), 4.97 (s, 1 H, H3), 4.59 (d, J = 10.8 Hz, 1 H, Bn),
4.50 (d, J = 10.8 Hz, 1 H, Bn), 3.15 (br s, 1 H, OH), 1.34 (s, 3 H, 2-
Me), 1.31 (d, J = 6.2 Hz, 3 H, i-Pr), 1.26 (d, J = 6.2 Hz, 3 H, i-Pr).
13C NMR (CDCl3): d = 172.3 (1), 138.6 (Ph), 138.2 (Ph), 128.3
(Ph), 128.0 (Ph), 127.8 (Ph), 127.8 (Ph), 127.8 (Ph), 127.7 (Ph),
83.6 (2), 78.6 (3), 69.1 (Bn), 67.1 (i-Pr), 21.9 (i-Pr), 21.7 (i-Pr), 16.2
(2-Me).
All reactions were carried out under argon atmosphere in dried
glassware otherwise noted. CH2Cl2 was distilled from P2O5, then
CaH2, and dried over MS 4 Å, toluene was distilled from P2O5 and
dried over MS 4 Å, and THF and Et2O were distilled from Na/ben-
zophenone immediately prior to use. TLC was performed on Wako-
HRMS: m/z [M + Na]+ calcd for C20H24O4Na: 351.1567; found:
351.1576.
1
gel B5F. All melting points are uncorrected. H and 13C NMR
Isopropyl (2S,3R,4E)-2-(Benzyloxy)-3-hydroxy-2-methylhex-4-
enoate (7b)
HPLC (Chiralpak AD, hexane–i-PrOH, 50:1, flow rate = 1.0 mL/
min): tR = 13.6 (93.9%), 16.2 min (6.1%).
spectra were recorded with CHCl3 (in CDCl3) or benzene (in ben-
zene-d6) as internal standard. All reagents were purchased from To-
kyo Kasei Kogyo Co., Ltd., Kanto Chemical Co., Inc., or Aldrich
Chemical Co., Inc. and used without further purification unless oth-
IR (neat): 3411, 1732 cm–1.
1
erwise noted. Carbon atoms in parentheses of H and 13C NMR
1H NMR (CDCl3): d = 7.41–7.25 (m, 5 H, Ph), 5.77 (dq, J = 15.5,
6.3 Hz, 1 H, H5), 5.55 (ddq, J = 15.5, 7.6, 1.5 Hz, 1 H, H4), 5.10
(qq, J = 6.3, 6.3 Hz, 1 H, i-Pr), 4.58 (d, J = 10.9 Hz, 1 H, Bn), 4.51
(d, J = 10.9 Hz, 1 H, Bn), 4.28 (d, J = 7.6 Hz, 1 H, H3), 2.61 (br s,
1 H, OH), 1.71 (dd, J = 6.3, 1.5 Hz, 3 H, H6), 1.42 (s, 3 H, 2-Me),
1.27 (d, J = 6.3 Hz, 3 H, i-Pr), 1.27 (d, J = 6.3 Hz, 3 H, i-Pr).
13C NMR (CDCl3): d = 172.3 (1), 138.4 (Ph), 130.4 (4), 128.3 (Ph),
127.7 (Ph), 127.6 (5), 127.5 (Ph), 83.1 (2), 77.6 (3), 68.8 (Bn), 66.9
(i-Pr), 21.8 (i-Pr), 21.7 (i-Pr), 17.9 (6), 16.4 (2-Me).
spectra data of 15 and 20–27 are numbered according to the nomen-
clature of the basic skeleton of aldol 15 throughout.
Asymmetric Aldol Reaction
Methyl (2S,3R)-3-Hydroxy-2-methyl-2-(methylselanyl)-3-phe-
nylpropanoate (9a); Typical Procedure
To Sn(OTf)2 (217.4 mg, 0.516 mmol) at r.t. were successively add-
ed a soln of (S)-1-methyl-2-[(1-naphthylamino)methyl]pyrrolidine
(143.1 mg, 0.615 mmol) in CH2Cl2 (1.1 mL) and a soln of
Bu2Sn(OAc)2 (197.2 mg, 0.556 mmol) in CH2Cl2 (1.1 mL). The
mixture was stirred at r.t. for 5 min and to this were added at –78 °C
a soln of KSA 6 (123.5 mg, 0.511 mmol) in CH2Cl2 (1.1 mL) and a
soln of benzaldehyde (48.0 mg, 0.452 mmol) in CH2Cl2 (1.27 mL).
The mixture was stirred at –78 °C for 1 h and then sat. aq NaHCO3
was added. The mixture was filtered through a short pad of Celite
and the filtrate was extracted with CH2Cl2. The organic layer was
washed with H2O and brine and dried (Na2SO4). Filtration of the
mixture and evaporation of the solvent gave the crude product,
which was purified by TLC to afford aldol 9a (102.8 mg, 79%, 93%
ee) and its anti-isomer (9.0 mg, 7%, 59% ee) as colorless oils.
MS (ESI): m/z [M + Na]+ calcd for C17H24O4Na: 315.1567; found:
315.1557.
Isopropyl (2S,3R,4E)-2-(Benzyloxy)-3-hydroxy-2-methyl-5-
phenylpent-4-enoate (7c)
HPLC (Chiralpak AS, hexane–i-PrOH, 9:1, flow rate = 0.8 mL/
min): tR = 6.6 (6.4%), 7.5 min (93.6%).
IR (neat): 3498, 1729 cm–1.
1H NMR (CDCl3): d = 7.43–7.20 (m, 10 H, Ph), 6.67 (d, J = 15.8
Hz, 1 H, H5), 6.23 (dd, J = 15.8, 6.9 Hz, 1 H, H4), 5.12 (qq, J = 6.3,
6.3 Hz, 1 H, i-Pr), 4.64 (d, J = 10.9 Hz, 1 H, Bn), 4.54 (d, J = 10.9
Hz, 1 H, Bn), 4.51 (d, J = 6.9 Hz, 1 H, H3), 2.77 (br s, 1 H, OH),
1.48 (s, 3 H, 2-Me), 1.27 (d, J = 6.3 Hz, 3 H, i-Pr), 1.27 (d, J = 6.3
Hz, 3 H, i-Pr).
Synthesis 2009, No. 17, 2915–2926 © Thieme Stuttgart · New York

2922
I. Shiina et al.
PAPER
13C NMR (CDCl3): d = 172.2 (1), 138.3 (Ph), 136.5 (Ph), 133.3 (5),
128.5 (Ph), 128.3 (Ph), 127.7 (Ph), 127.6 (Ph), 126.9 (Ph), 126.5
(Ph), 126.0 (4), 83.1 (2), 77.4 (3), 69.0 (Bn), 67.0 (i-Pr), 21.8 (i-Pr),
21.7 (i-Pr), 16.8 (2-Me).
13C NMR (CDCl3): d = 171.8 (1), 136.5 (Ph), 133.4 (4), 128.5 (Ph),
128.0 (5), 126.6 (Ph), 125.8 (Ph), 72.2 (3), 61.3 (OEt), 55.6 (2), 16.8
(OEt), 14.1 (2-Me), 12.5 (SMe).
HRMS: m/z [M + Na]+ calcd for C15H20O3SNa: 303.1025; found:
303.1038.
MS (ESI): m/z [M + Na]+ calcd for C22H26O4Na: 377.1723; found:
377.1723.
Ethyl (2S,3R)-3-Cyclohexyl-3-hydroxy-2-methyl-2-(methyl-
thio)propanoate (8d)
HPLC (Chiralcel OD, hexane–i-PrOH, 100:1, flow rate = 1.0 mL/
min): tR = 5.7 (2.6%), 6.4 min (97.4%).
Isopropyl (2S,3R)-2-(Benzyloxy)-3-cyclohexyl-3-hydroxy-2-
methylpropanoate (7d)
HPLC (Chiralpak AD, hexane–i-PrOH, 100:1, flow rate = 1.0 mL/
min): tR = 11.1 (98.4%), 13.0 min (1.6%).
IR (neat): 3483, 1716 cm–1.
IR (neat): 3564, 1728 cm–1.
1H NMR (CDCl3): d = 4.24–4.12 (m, 2 H, OEt), 3.67 (d, J = 7.3 Hz,
1 H, H3), 2.77 (s, 1 H, OH), 2.13–2.06 (m, 1 H, H4), 2.08 (s, 3 H,
SMe), 1.77–1.61 (m, 3 H, c-Hex), 1.44–0.95 (m, 7 H, c-Hex), 1.33
(s, 3 H, 2-Me), 1.28 (t, J = 7.1 Hz, 3 H, OEt).
13C NMR (CDCl3): d = 171.7 (1), 73.0 (3), 61.1 (OEt), 55.5 (2), 41.1
(c-Hex), 30.4 (c-Hex), 26.6 (c-Hex), 26.4 (c-Hex), 26.2 (c-Hex),
26.1 (c-Hex), 15.6 (OEt), 14.0 (2-Me), 12.2 (SMe).
1H NMR (CDCl3): d = 7.28–7.17 (m, 5 H, Ph),5.04 (qq, J = 6.4, 6.4
Hz, 1 H, i-Pr), 4.42 (s, 2 H, Bn), 3.57 (d, J = 4.4 Hz, 1 H, H3), 2.48
(br s, 1 H, OH), 1.87–1.01 (m, 11 H, c-Hex), 1.40 (s, 3 H, 2-Me),
1.20 (d, J = 6.4 Hz, 3 H, i-Pr), 1.19 (d, J = 6.4 Hz, 3 H, i-Pr).
13C NMR (CDCl3): d = 172.8 (1), 138.4 (Ph), 128.3 (Ph), 127.6
(Ph), 127.5 (Ph), 83.0 (2), 79.5 (3), 68.8 (Bn), 66.5 (i-Pr), 39.3 (c-
Hex), 31.1 (c-Hex), 27.7 (c-Hex), 26.6 (c-Hex), 26.3 (c-Hex), 26.1
(c-Hex), 21.8 (i-Pr), 21.7 (i-Pr), 16.3 (2-Me).
HRMS: m/z [M + Na]+ calcd for C13H24O3SNa: 283.1338; found:
283.1339.
MS (ESI): m/z [M + Na]+ calcd for C20H30O4Na: 357.2036; found:
357.2023.
Methyl (2S,3R)-3-Hydroxy-2-methyl-2-(methylselanyl)-3-phe-
nylpropanoate (9a)
Ethyl (2S,3R)-3-Hydroxy-2-methyl-2-(methylthio)-3-phenyl-
propanoate (8a)
HPLC (Chiralpak AS, hexane–i-PrOH, 9:1, flow rate = 1.0 mL/
min): tR = 6.1 (3.4%), 7.0 min (96.6%).
HPLC (Chiralpak AD, hexane–i-PrOH, 19:1, flow rate = 1.0 mL/
min): tR = 8.8 (2.6%), 9.9 min (97.4%).
IR (neat): 3480, 1715 cm–1.
1H NMR (500 MHz, CDCl3): d = 7.41–7.26 (m, 5 H, Ph), 5.20 (d,
J = 1.5 Hz, 1 H, H3), 4.19–4.15 (m, 2 H, OEt), 3.26 (d, J = 1.5 Hz,
1 H, OH), 2.24 (s, 3 H, SMe), 1.27 (s, 3 H, 2-Me), 1.25 (t, J = 7.5
Hz, 3 H, OEt).
IR (neat): 3479, 1716 cm–1.
1H NMR (CDCl3): d = 7.40–7.23 (m, 5 H, Ph), 5.16 (s, 1 H, H3),
3.70 (s, 3 H, OMe), 3.28 (br s, 1 H, OH), 2.16 (s, 3 H, SeMe), 1.32
(s, 3 H, 2-Me).
13C NMR (CDCl3): d = 172.9, 137.8, 127.9, 127.9, 127.7, 73.2, 52.5,
52.2, 16.4, 4.6.
HRMS: m/z [M + Na]+ calcd for C12H16O3SeNa: 311.0163; found:
311.0160.
13C NMR (CDCl3, 126 MHz): d = 171.5, 138.1, 127.9, 127.9, 127.8,
72.4, 61.3, 56.5, 16.4, 14.0, 12.7.
HRMS: m/z [M + Na]+ calcd for C13H18O3SNa: 277.0869; found:
277.0863.
Methyl (2S,3R,4E)-3-Hydroxy-2-methyl-2-(methylseleno)hex-
4-enoate (9b)
HPLC (Chiralpak AS, hexane–i-PrOH, 19:1, flow rate = 0.5 mL/
min): tR = 12.3 (2.9%), 13.5 min (97.1%).
IR (neat): 3457, 1716 cm–1.
1H NMR (CDCl3): d = 5.81 (dqd, J = 15.3, 6.5, 1.0 Hz, 1 H, H5),
5.51 (ddq, J = 15.3, 6.9, 1.5 Hz, 1 H, H4), 4.41 (dd, J = 6.9, 1.0 Hz,
1 H, H3), 3.74 (s, 3 H, OMe), 3.00 (br s, 1 H, OH), 2.08 (s, 3 H,
SeMe), 1.71 (dd, J = 6.5, 1.5 Hz, 3 H, H6), 1.44 (s, 3 H, 2-Me).
13C NMR (CDCl3): d = 173.4, 130.4, 127.3, 73.4, 52.1, 50.8, 17.9,
17.0, 4.0.
HRMS: m/z [M + Na]+ calcd for C9H16O3SeNa: 275.0163; found:
275.0166.
Ethyl (2S,3R,4E)-3-Hydroxy-2-methyl-2-(methylthio)hex-4-
enoate (8b)
HPLC (Chiralcel OD, hexane–i-PrOH, 50:1, flow rate = 0.5 mL/
min): tR = 17.1 (2.5%), 19.2 min (97.5%).
IR (neat): 3474, 1716 cm–1.
1H NMR (CDCl3): d = 5.80 (dq, J = 15.2, 6.5 Hz, 1 H, H5), 5.46 (dd,
J = 15.2, 6.8 Hz, 1 H, H4), 4.43 (d, J = 6.8 Hz, 1 H, H3), 4.19 (q,
J = 7.1 Hz, 2 H, OEt), 2.82 (br, 1 H, OH), 2.13 (s, 3 H, SMe), 1.69
(d, J = 6.5 Hz, 3 H, H6), 1.34 (s, 3 H, 2-Me), 1.27 (t, J = 7.1 Hz, 3
H, OEt).
13C NMR (CDCl3): d = 172.1 (1), 130.5 (4), 127.3 (5), 72.5 (3), 61.2
(OEt), 55.3 (2), 17.9 (6), 17.0 (OEt), 14.1 (2-Me), 12.4 (SMe).
HRMS: m/z [M + Na]+ calcd for C10H18O3SNa: 241.0869; found:
Methyl (2S,3R,4E)-3-Hydroxy-2-methyl-2-(methylseleno)-5-
phenylpent-4-enoate (9c)
241.0859.
HPLC (Chiralpak AS, hexane–i-PrOH, 9:1, flow rate = 0.5 mL/
min): tR = 14.3 (2.9%), 16.9 min (97.1%).
Ethyl (2S,3R,4E)-3-Hydroxy-2-methyl-2-(methylthio)-5-phe-
nylpent-4-enoate (8c)
HPLC (Chiralcel OD, hexane–i-PrOH, 50:1, flow rate = 1.0 mL/
min): tR = 21.9 (4.8%), 13.3 min (95.2%).
IR (neat): 3483, 1716 cm–1.
1H NMR (CDCl3): d = 7.40–7.21 (m, 5 H, Ph), 6.72 (d, J = 15.8 Hz,
1 H, H5), 6.21 (dd, J = 15.8, 6.4 Hz, 1 H, H4), 4.65 (d, J = 6.4 Hz,
1 H, H3), 3.75 (s, 3 H, OMe), 3.12 (br s, 1 H, OH), 2.11 (s, 3 H,
SeMe), 1.50 (s, 3 H, 2-Me).
13C NMR (CDCl3): d = 173.3, 136.4, 133.5, 128.5, 127.8, 126.6,
125.6, 73.2, 52.3, 51.1, 17.0, 4.3.
IR (neat): 3486, 1716 cm–1.
1H NMR (CDCl3): d = 7.35–7.16 (m, 5 H, Ph), 6.68 (dd, J = 15.9,
1.2 Hz, 1 H, H5), 6.13 (dd, J = 15.9, 6.3 Hz, 1 H, H4), 4.64 (dd,
J = 6.3, 1.2 Hz, 1 H, H3), 4.23–4.11 (m, 2 H, OEt), 2.96 (br, 1 H,
OH), 2.12 (s, 3 H, SMe), 1.36 (s, 3 H, 2-Me), 1.24 (t, J = 7.1 Hz, 3
H, OEt).
HRMS: m/z [M + Na]+ calcd for C14H18O3SeNa: 337.0319; found:
337.0322.
Synthesis 2009, No. 17, 2915–2926 © Thieme Stuttgart · New York

PAPER
Enantioselective Aldol Reactions
2923
Methyl (2S,3R)-3-Hydroxy-2-methyl-2-(methylseleno)decan-
oate (9d)
Methyl (2S,3R,4E)-2-(Benzyloxy)-2-[2-(tert-butyldimethylsil-
oxy)ethyl]-3-hydroxyhex-4-enoate (15)
HPLC (Chiralcel OD-H*2, hexane–i-PrOH, 1000:1, flow rate = 0.5
mL/min): tR = 43.4 (5.0%), 52.4 min (95.0%).
IR (neat): 3508, 1716 cm–1.
1H NMR (CDCl3): d = 3.86 (dd, J = 9.4, 1.5 Hz, 1 H, H3), 3.72 (s,
3 H, OMe), 2.71 (br s, 1 H, OH), 2.02 (s, 3 H, SeMe), 1.64–1.16 (m,
12 H, H4, H5, H6, H7, H8, H9), 1.40 (s, 3 H, 2-Me), 0.86–0.82 (m,
3 H, H10).
13C NMR (CDCl3): d = 173.4, 71.3, 52.2, 52.0, 31.7, 31.5, 29.4,
29.2, 27.0, 22.6, 16.0, 14.0, 3.9.
HRMS: m/z [M + Na]+ calcd for C13H26O3SeNa: 333.0945; found:
333.0946.
To Sn(OTf)2 (3.55 g, 8.52 mmol) at r.t. was added successively a
soln of (S)-1-methyl-2-[(1-naphthylamino)methyl]pyrrolidine (2.32
g, 9.65 mmol) in EtCN (20 mL) and a soln of Bu2Sn(OAc)2 (3.19 g,
9.09 mmol) in EtCN (20 mL). The mixture was stirred at r.t. for 5
min and then a soln of KSA 16 (3.50 g, 8.52 mmol) in EtCN (10
mL) and a soln of crotonaldehyde (398 mg, 5.68 mmol) in EtCN (10
mL) were added at –78 °C. The mixture was stirred at –78 °C for 41
h and then sat. aq NaHCO3 was added. The mixture was filtered
through a short pad of Celite and the filtrate was extracted with
Et2O. The organic layer was washed with H2O and brine and dried
(Na2SO4). After filtration of the mixture and evaporation of the sol-
vent, the crude product was purified by column chromatography
(hexane–EtOAc, 10:1) to afford aldol 15 (1.72 g, 74%, 94% ee).
[a]D25 +25.1 (c 0.913, benzene).
Methyl (2S,3R)-3-Hydroxy-2-methyl-2-(methylseleno)-4-(tri-
isopropylsiloxy)butanoate (9e)
HPLC (Chiralcel IA, hexane–i-PrOH, 1000:1, flow rate = 1.0 mL/
min): tR = 14.5 (5.0%), 15.7 min (95.0%).
HPLC (Chiralcel OD, hexane–i-PrOH, 50:1, flow rate = 0.7 mL/
min): tR = 11.5 (3.2%), 14.2 min (96.8%).
IR (neat): 3480, 1739 cm–1.
IR (neat): 3487, 1720 cm–1.
1H NMR (CDCl3): d = 7.42–7.27 (m, 5 H, Ph), 5.83 (ddq, J = 15.3,
0.8, 6.1 Hz, 1 H, H5), 5.64 (ddq, J = 15.3, 6.5, 1.4 Hz, 1 H, H4), 4.73
(d, J = 11.2 Hz, 1 H, Bn), 4.63 (d, J = 11.2 Hz, 1 H, Bn), 4.41 (dd,
J = 6.5, 0.8 Hz, 1 H, H3), 3.86 (ddd, J = 10.5, 7.3, 3.2 Hz, 1 H, H2¢),
3.75 (s, 3 H, OMe), 3.72 (ddd, J = 10.5, 8.4, 5.9 Hz, 1 H, H2¢), 2.22
(ddd, J = 15.7, 8.4, 7.3 Hz, 1 H, H1¢), 2.13 (ddd, J = 15.7, 5.9, 3.2
Hz, 1 H, H1¢), 1.72 (dd, J = 6.1, 1.4 Hz, 3 H, H6), 0.89 (s, 9 H,
TBS), 0.06 (s, 6 H, TBS).
13C NMR (CDCl3): d = 172.8 (1), 138.6 (Ph), 129.4 (4), 129.4 (Ph),
128.2 (5), 128.2 (Ph), 127.4 (Ph), 84.2 (2), 75.8 (3), 67.4 (Bn), 58.4
(2¢), 51.9 (OMe), 35.2 (1¢), 25.9 (TBS), 18.3 (TBS), 17.9 (6), –5.47
(TBS), –5.49 (TBS).
1H NMR (CDCl3): d = 4.13 (dd, J = 6.3, 5.4 Hz, 1 H, H3), 3.76 (dd,
J = 10.0, 6.3 Hz, 1 H, H4), 3.71 (dd, J = 10.0, 5.4 Hz, 1 H, H4), 3.72
(s, 3 H, OMe), 2.92 (br s, 1 H, OH), 2.06 (s, 3 H, SeMe), 1.50 (s, 3
H, 2-Me), 1.17–0.94 (m, 21 H, TIPS).
13C NMR (CDCl3): d = 172.9 (1), 72.1 (3), 63.6 (4), 52.1 (OMe),
48.8 (2), 17.8 (TIPS), 16.8 (2-Me), 11.8 (TIPS), 4.2 (SeMe).
HRMS: m/z [M + H]+ calcd for C16H35O4SeSi: 399.1470; found:
399.1463.
Methyl (2S,3R)-3-Hydroxy-2-methyl-2-(methylseleno)-5-(tri-
isopropylsiloxy)pentanoate (9f)
HRMS: m/z [M + Na]+ calcd for C22H36O5SiNa: 431.2224; found:
431.2233.
HPLC (Chiralpak AD-H, hexane–i-PrOH, 1000:1, flow rate = 0.5
mL/min): tR = 25.3 (97.7%), 37.4 min (2.3%).
IR (neat): 3504, 1720 cm–1.
1H NMR (CDCl3): d = 4.22 (ddd, J = 9.9, 1.3, 0.9 Hz, 1 H, H3),
3.99–3.86 (m, 2 H, H5), 3.72 (s, 3 H, OMe), 3.48 (br s, 1 H, OH),
2.06 (s, 3 H, SeMe), 1.84–1.69 (m, 1 H, H4), 1.57–1.46 (m, 1 H,
H4), 1.48 (s, 3 H, 2-Me), 1.14–1.02 (m, 21 H, TIPS).
13C NMR (CDCl3): d = 173.5 (1), 71.0 (3), 62.3 (5), 52.1 (OMe),
50.7 (2), 34.3 (4), 17.9 (TIPS), 16.5 (2-Me), 11.8 (TIPS), 4.0
(SeMe).
(2R,3R,4E)-2-(Benzyloxy)-2-[2-(tert-butyldimethylsiloxy)eth-
yl]hex-4-ene-1,3-diol (24)
To a soln of aldol 15 (4.47 g, 10.9 mmol) in toluene (186 mL) at
–45 °C was added Red-Al in toluene (65%, 32.8 mL, 109 mmol).
The mixture was stirred at –45 °C for 20 min and at 0 °C for 1 h and
then MeOH was added. The mixture was allowed to warm to r.t. and
then sat. aq potassium sodium tartrate was added. The mixture was
extracted with EtOAc and the organic layer was washed with H2O
and brine and dried (Na2SO4). After filtration of the mixture and
evaporation of the solvent, the crude product was purified by col-
umn chromatography (hexane–EtOAc, 5:1) to afford diol 12 (4.12
g, 99%) as a pale yellow oil.
HRMS: m/z [M + H]+ calcd for C17H37O4SeSi: 413.1626; found:
413.1631.
Methyl (2S)-2-(Benzyloxy)-2-[(R)-hydroxy(phenyl)methyl]bu-
tanoate (18)
[a]D24 +32.8 (c 1.10, benzene).
HPLC (Chiralpak AD-H, hexane–i-PrOH, 9:1, flow rate = 0.5 mL/
min): tR = 12.2 (97.7%), 15.2 min (2.3%).
IR (neat): 3448, 1736 cm–1.
IR (neat): 3448 cm–1.
1H NMR (CDCl3): d = 7.29–7.16 (m, 5 H, Ph), 5.72 (ddq, J = 15.3,
0.8, 6.4 Hz, 1 H, H5), 5.52 (ddq, J = 15.3, 6.8, 1.4 Hz, 1 H, H4), 4.56
(d, J = 11.0 Hz, 1 H, Bn), 4.51 (d, J = 11.0 Hz, 1 H, Bn), 4.19 (ddd,
J = 6.8, 4.8, 0.8 Hz, 1 H, H3), 3.83–3.60 (m, 4 H, H1, H2¢), 3.50 (dd,
J = 7.3, 5.9 Hz, 1 H, 1-OH), 3.18 (d, J = 4.8 Hz, 1 H, 3-OH), 1.97
(ddd, J = 13.5, 6.5, 3.5 Hz, 1 H, H1¢), 1.81 (ddd, J = 13.5, 7.6, 3.8
Hz, 1 H, H1¢), 1.66 (dd, J = 6.4, 1.4 Hz, 3 H, H6), 0.92 (s, 9 H,
TBS), 0.11 (s, 6 H, TBS).
13C NMR (CDCl3): d = 138.8 (Ph), 129.0 (4), 128.9 (Ph), 128.3 (5),
128.3 (Ph), 127.4 (Ph), 79.8 (2), 74.5 (3), 64.2 (Bn), 64.1 (1), 58.6
(2¢), 33.9 (1¢), 25.8 (TBS), 18.2 (TBS), 18.0 (6), –5.57 (TBS), –5.60
(TBS).
1H NMR (CDCl3): d = 7.47–7.29 (m, 10 H, Ph), 5.04 (s, 1 H, H1¢),
4.60 (d, J = 10.8 Hz, 1 H, Bn), 4.56 (d, J = 10.8 Hz, 1 H, Bn), 3.61
(s, 3 H, OMe), 3.49 (br s, 1 H, OH), 2.02 (dq, J = 15.2, 7.6 Hz, 1 H,
H3), 2.00 (dq, J = 15.2, 7.6 Hz, 1 H, H3), 1.12 (t, J = 7.6 Hz, 3 H,
H4).
13C NMR (CDCl3): d = 171.6 (1), 138.7 (Ph), 137.8 (Ph), 128.4
(Ph), 128.0 (Ph), 127.8 (Ph), 127.7 (Ph), 127.2 (Ph), 127.2 (Ph),
86.0 (2), 75.9 (1¢), 66.7 (Bn), 51.5 (OMe), 23.4 (3), 7.8 (4).
MS (ESI): m/z [M + Na]+ calcd for C19H22O4Na: 337.1410; found:
337.1409.
HRMS: m/z [M + H]+ calcd for C21H37O4Si: 381.2461; found:
381.2463.
Synthesis 2009, No. 17, 2915–2926 © Thieme Stuttgart · New York

2924
I. Shiina et al.
PAPER
(2R,3R,4E)-2-[2-(tert-Butyldimethylsiloxy)ethyl]hex-4-ene-
1,2,3-triol (23)
(1R,2E)-1-{(2R)-2-[2-(tert-Butyldimethylsiloxy)ethyl]oxiran-2-
yl}but-3-en-1-ol (22)
To a soln of 4,4¢-di-tert-butylbiphenyl (26.6 g, 100 mmol) in THF
(200 mL) at 0 °C was added Li (694 mg, 100 mmol). The mixture
was stirred at r.t. for 9 h. The thus prepared soln of LDBB in THF
(0.50 M) was instantly used in the following reaction.
Method a: To a soln of tosylate 25 (14.2 mg, 32.0 mmol) in CH2Cl2
(0.5 mL) at r.t. was added silica gel (28.5 mg). The mixture was con-
centrated by evaporation of the solvent under atmospheric pressure.
The residue was stirred at r.t. for 51 h without solvent and then
EtOAc was added to the mixture. After filtration of the mixture and
evaporation of the solvent, the crude product was purified by TLC
to afford epoxide 22 (6.2 mg, 71%) and the recovered tosylate 25
(3.3 mg, 23%) as colorless oils.
To a soln of diol 24 (2.22 g, 5.84 mmol) in THF (30 mL) at –78 °C
was added 0.5 M LDBB in THF (164 mL, 81.8 mmol). The mixture
was stirred at –78 °C for 9 h and then sat. aq NH4Cl was added. The
mixture was extracted with EtOAc and the organic layer was
washed with H2O and brine and dried (Na2SO4). After filtration of
the mixture and evaporation of the solvent, the crude product was
purified by column chromatography (hexane–EtOAc, 2:1) to afford
triol 23 (1.69 g, quant.) as a colorless oil.
Method b: To a soln of tosylate 25 (75.2 mg, 0.169 mmol) in
CH2Cl2 (2.3 mL) at 0 °C was added DBU (0.101 mL, 0.677 mmol).
The mixture was stirred at r.t. for 40 min and then sat. aq NH4Cl was
added at 0 °C. The mixture was extracted with CH2Cl2 and the or-
ganic layer was washed with brine and dried (Na2SO4). After filtra-
tion of the mixture and evaporation of the solvent, the crude product
was purified by TLC to afford epoxide 22 (43.6 mg, 95%) as a col-
orless oil.
[a]D23 +21.6 (c 0.70, benzene).
IR (neat): 3410 cm–1.
1H NMR (CDCl3): d = 5.78 (ddq, J = 15.4, 0.8, 6.5 Hz, 1 H, H5),
5.54 (ddq, J = 15.4, 6.8, 1.3 Hz, 1 H, H4), 4.06 (ddd, J = 6.8, 4.9,
0.8 Hz, 1 H, H3), 3.91 (dd, J = 12.7, 6.5 Hz, 1 H, H1), 3.85 (dd,
J = 12.7, 6.2 Hz, 1 H, H1), 3.77 (s, 1 H, 2-OH), 3.62–3.47 (m, 2 H,
H2¢), 3.05 (br d, J = 4.9 Hz, 1 H, 3-OH), 2.88 (br dd, J = 6.5, 6.2 Hz,
1 H, 1-OH), 1.89 (ddd, J = 14.8, 6.2, 4.9 Hz, 1 H, H1¢), 1.73 (dd,
J = 6.5, 1.3 Hz, 3 H, H6), 1.61 (ddd, J = 14.8, 5.1, 4.1 Hz, 1 H, H1¢),
0.91 (s, 9 H, TBS), 0.10 (s, 6 H, TBS).
13C NMR (CDCl3): d = 129.9 (4), 128.8 (5), 76.3 (2), 75.5 (3), 66.2
(1), 59.5 (2¢), 34.6 (1¢), 25.8 (TBS), 18.1 (TBS), 18.0 (6), –5.6
(TBS), –5.6 (TBS).
HRMS: m/z [M + H]+ calcd for C14H31O4Si: 291.1991; found:
291.1991.
[a]D23 +8.9 (c 0.96, benzene).
IR (neat): 3436 cm–1.
1H NMR (C6D6): d = 5.75 (ddq, J = 15.3, 1.2, 6.3 Hz, 1 H, H5), 5.52
(ddq, J = 15.3, 6.0, 1.5 Hz, 1 H, H4), 3.98 (dddd, J = 6.0, 6.0, 1.2,
1.2 Hz, 1 H, H3), 3.71 (ddd, J = 10.2, 7.5, 5.1 Hz, 1 H, H2¢), 3.58
(ddd, J = 10.2, 6.3, 5.4 Hz, 1 H, H2¢), 2.74 (d, J = 6.0 Hz, 1 H, OH),
2.65 (d, J = 5.0 Hz, 1 H, H1), 2.48 (d, J = 5.0 Hz, 1 H, H1), 1.98
(ddd, J = 12.9, 7.5, 5.4 Hz, 1 H, H1¢), 1.77 (ddd, J = 12.9, 6.3, 5.1
Hz, 1 H, H1¢), 1.58 (ddd, J = 6.3, 1.5, 1.2 Hz, 3 H, H6), 0.98 (s, 9 H,
TBS), 0.05 (s, 6 H, TBS).
13C NMR (C6D6): d = 130.6 (4), 128.7 (5), 74.9 (3), 60.1 (2), 59.6
(1), 50.5 (2¢), 34.1 (1¢), 26.0 (TBS), 18.3 (TBS), 17.8 (6), –5.4
(TBS), –5.5 (TBS).
(2R,3R,4E)-2-[2-(tert-Butyldimethylsiloxy)ethyl]-1-(tosyl-
oxy)hex-4-ene-2,3-diol (25)
HRMS: m/z [M + Na]+ calcd for C14H28O3SiNa: 295.1700; found:
To a soln of triol 23 (30.0 mg, 0.103 mmol) in pyridine (1.0 mL) at
0 °C was added TsCl (59.0 mg, 0.309 mmol). The mixture was
stirred at r.t. for 16 h and then sat. aq NaHCO3 was added at 0 °C.
The mixture was extracted with Et2O and the organic layer was
washed with sat. aq CuSO4, sat. aq NaHCO3, H2O, and brine and
dried (Na2SO4). After filtration of the mixture and evaporation of
the solvent, the crude product was purified by column chromatog-
raphy to afford tosylate 25 (31.6 mg, 69%), epoxide 22 (2.2 mg,
8%), and the recovered triol 23 (3.1 mg, 10%) as colorless oils.
Above prepared tosylate 25 was instantly used in the following re-
action as soon as possible.
295.1700.
(3R,4R,5E)-1-[2-(tert-Butyldimethylsiloxy)ethyl]-3-(1,3-
dithian-2-ylmethyl)hept-5-ene-3,4-diol (21)
To a soln of 1,3-dithiane (74.4 mg, 0.618 mmol) in THF (1.2 mL)
at –78 °C was added 1.50 M BuLi in hexane (0.40 mL, 0.61 mmol).
The mixture was stirred at –78 °C for 10 min and at –30 °C for 2 h
and then a soln of epoxide 22 (16.5 mg, 60.6 mmol) in THF (1.2 mL)
was added at –30 °C. The mixture was stirred at –19 °C for 3 h and
then sat. aq. NH4Cl was added. The mixture was extracted with
Et2O, and the organic layer was washed with H2O and brine and
dried (Na2SO4). After filtration of the mixture and evaporation of
the solvent, the crude product was purified by column chromatog-
raphy to afford dithioacetal 21 (19.0 mg, 80%) and the recovered
epoxide 22 (2.5 mg, 15%) as colorless oils.
[a]D23 +17.0 (c 1.10, benzene).
IR (neat): 3443 cm–1.
1H NMR (C6D6): d = 7.83 (d, J = 8.5 Hz, 2 H, Ts), 6.72 (d, J = 8.5
Hz, 2 H, Ts), 5.70–5.55 (m, 2 H, H4, H5), 4.43 (d, J = 10.0 Hz, 1 H,
H1), 4.24 (d, J = 10.0 Hz, 1 H, H1), 4.13 (dd, J = 6.5, 5.0 Hz, 1 H,
H3), 3.92 (s, 1 H, 2-OH), 3.84 (ddd, J = 10.5, 9.5, 3.5 Hz, 1 H, H2¢),
3.62 (ddd, J = 10.5, 5.0, 4.5 Hz, 1 H, H2¢), 2.38 (d, J = 6.5 Hz, 1 H,
3-OH), 1.89 (ddd, J = 15.0, 9.5, 4.5 Hz, 1 H, H1¢), 1.85 (s, 3 H, Me),
1.62 (ddd, J = 15.0, 5.0, 3.5 Hz, 1 H, H1¢), 1.51 (dd, J = 6.0, 1.0 Hz,
3 H, H6), 0.89 (s, 9 H, TBS), 0.00 (s, 3 H, TBS); –0.03 (s, 3 H,
TBS).
13C NMR (C6D6): d = 144.3 (Ph), 133.8 (4), 129.9 (Ph), 129.2 (5),
129.2 (Ph), 128.2 (Ph), 75.2 (3), 75.2 (2), 71.6 (1), 59.9 (2′), 34.1
(1′), 26.0 (TBS), 25.9 (TBS), 21.1 (Me), 18.1 (TBS), 17.8 (6), –5.7
(TBS), –5.7 (TBS).
[a]D22 +29.7 (c 0.99, benzene).
IR (neat): 3446 cm–1.
1H NMR (C6D6): d = 5.91 (ddq, J = 15.5, 1.0, 6.5 Hz, 1 H, H5), 5.74
(ddq, J = 15.5, 6.0, 1.5 Hz, 1 H, H4), 4.51 (dd, J = 6.0, 5.5 Hz, 1 H,
H3), 4.38 (dd, J = 6.5, 5.0 Hz, 1 H, l¢¢-H), 3.99 (s, 1 H, 2-OH), 3.89
(ddd, J = 10.5, 9.0, 4.0 Hz, 1 H, H2¢), 3.75 (ddd, J = 10.5, 5.0, 4.5
Hz, 1 H, H2¢), 3.08 (d, J = 5.5 Hz, 1 H, 3-OH), 2.53–2.30 (m, 4 H,
SCH2), 2.25 (dd, J = 15.0, 5.0 Hz, 1 H, H1), 2.16 (dd, J = 15.0, 6.5
Hz, 1 H, H1), 2.09 (ddd, J = 15.0, 9.0, 4.5 Hz, 1 H, H1¢), 1.74 (ddd,
J = 15.0, 5.0, 4.0 Hz, 1 H, H1¢), 1.60 (dd, J = 6.5, 1.5 Hz, 3 H, H6),
1.59–1.55 (m, 1 H, SCH2CH2), 1.44–1.38 (m, 1 H, SCH2CH2), 0.95
(s, 9 H, TBS), 0.05 (s, 3 H, TBS), 0.03 (s, 3 H, TBS).
13C NMR (C6D6): d = 129.9 (4), 128.6 (5), 76.8 (3), 76.4 (2), 60.2
(2¢), 43.1 (1), 42.6 (1¢¢), 37.2 (1¢), 30.9 (SCH2), 30.8 (SCH2), 26.0
(TBS), 25.4 (SCH2CH2), 18.2 (TBS), 18.0 (6), –5.5 (TBS), –5.5
(TBS).
HRMS: m/z [M + Na]+ calcd for C21H36O6SSiNa: 467.1894; found:
467.1892.
Synthesis 2009, No. 17, 2915–2926 © Thieme Stuttgart · New York

PAPER
Enantioselective Aldol Reactions
IR (neat): 3417, 1769 cm–1.
2925
HRMS: m/z [M + Na]+ calcd for C18H36O3S2SiNa: 415.1767; found:
415.1754.
1H NMR (C6D6): d = 5.70–5.58 (m, 2 H, H4, H5), 4.03 (d, J = 7.5
Hz, 1 H, H3), 3.32 (ddd, J = 10.5, 6.3, 4.5 Hz, 1 H, H2′), 3.24 (ddd,
J = 10.5, 7.7, 4.0 Hz, 1 H, H2′), 2.50 (d, J = 17.0 Hz, 1 H, H1), 2.08
(d, J = 17.0 Hz, 1 H, H1), 1,51 (d, J = 6.0 Hz, 3 H, H6), 1.36 (ddd,
J = 14.3, 7.7, 4.5 Hz, 1 H, H1′), 1.04 (ddd, J = 14.3, 6.3, 4.0 Hz, 1
H, H1′).
13C NMR (C6D6): d = 174.4 (1′′), 132.9 (4), 124.4 (5), 88.0 (3), 78.2
(2), 59.3 (2′), 42.9 (1), 37.6 (1′), 17.8 (6).
HRMS: m/z [M + Na]+ calcd for C9H14O4Na: 209.0784; found:
(2RS,4R,5R)-4-[2-(tert-Butyldimethylsiloxy)ethyl]-5-[(E)-prop-
2-enyl]tetrahydrofuran-2,4-diol (26)
To a soln of dithioacetal 21 (7.2 mg, 18.4 mmol) in MeCN–H2O
(4:1, 0.7 mL) at r.t. was added CaCO3 (9.2 mg, 91.8 mmol) and MeI
51.0 mL, 0.826 mmol). The mixture was stirred at r.t. for 40 h and
then it was diluted with CH2Cl2. The mixture was filtered through a
short pad of alumina gel (CHCl3–MeOH, 9:1) and the filtrate was
evaporated under reduced pressure. The crude product was instantly
used in the following reaction without further purification. It was
observed that there exists equilibrium between lactol 26 and its
open-chain structure (ca. 2:1 in C6D6) by 1H NMR.
209.0778.
(+)-Buergerinin G (13)
IR (neat): 3419 cm–1.
To a suspension of PdCl2 (0.87 mg, 4.92 mmol) and CuCl (4.87 mg,
49.2 mmol) in DME (0.22 mL) at r.t. under an O2 atmosphere was
added a soln of lactone 20 (2.3 mg, 12.3 mmol) in DME (1.8 mL).
The mixture was stirred at r.t. for 11 h and at –78 °C for 12 h and
then the mixture was diluted with Et2O. The mixture was filtered
through a short pad of Florisil and the solvent was evaporated and
then the crude product was purified by TLC (hexane–EtOAc, 3:2)
to afford (+)-buergerinin G (13) (1.9 mg, 86%) as a white solid; mp
148–149 °C.
1H NMR (C6D6): d = 5.91 (ddq, J = 15.3, 7.2, 1.5 Hz, 1 H, H4), 5.77
(ddq, J = 15.3, 0.9, 6.3 Hz, 1 H, H5), 5.45 (dd, J = 9.5, 5.1 Hz, 1 H,
H1¢¢), 4.00 (br d, J = 9.5 Hz, 1 H, 1¢¢-OH), 3.95 (dd, J = 7.2, 0.9 Hz,
1 H, H3), 3.77 (s, 1 H, 2-OH), 3.75–3.56 (m, 2 H, H2¢), 2.12 (d,
J = 12.9 Hz, 1 H, H1), 1.74 (ddd, J = 14.1, 6.9, 5.1 Hz, 1 H, H1¢),
1.65 (dd, J = 12.9, 5.1 Hz, 1 H, H1), 1.60 (dd, J = 6.3, 1.5 Hz, 1 H,
H6), 1.37 (ddd, J = 14.1, 6.6, 5.1 Hz, 1 H, H1¢), 0.93 (s, 9 H, TBS),
0.01 (s, 3 H, TBS), 0.00 (s, 3 H, TBS).
28
[a]D +31.9 (c 0.56, CHCl3) {Lit.6 [a]D18 +47.7 (c 0.509, CHCl3);
13C NMR (C6D6): d = 129.5 (4), 129.0 (5), 98.6 (1¢¢), 88.5 (3), 75.5
(2), 60.7 (2¢), 46.3 (1), 38.2 (1¢), 25.9 (TBS), 18.1 (6), 18.0 (TBS),
–5.5 (TBS), –5.6 (TBS).
Lit.7 [a]D +33.2 (c 1.0, CHCl3)}.
IR (KBr): 1766 cm–1.
1H NMR (CDCl3): d = 4.87 (dd, J = 6.8, 2.2 Hz, 1 H, H1), 4.04 (dd,
J = 12.1, 6.2 Hz, 1 H, H7), 3.72 (ddd, J = 12.4, 12.1, 3.8 Hz, 1 H,
H7), 2.79 (d, J = 17.8 Hz, 1 H, H4), 2.56 (d, J = 17.8 Hz, 1 H, H4),
2.53 (dd, J = 14.9, 6.8 Hz, 1 H, H9), 2.30 (ddd, J = 12.7, 12.4, 6.2
Hz, 1 H, H6), 2.24 (dd, J = 14.9, 2.2 Hz, 1 H, H9), 1.58 (s, 3 H,
H10), 1.50 (dd, J = 12.7, 3.8 Hz, 1 H, H6).
13C NMR (CDCl3): d = 174.6 (3), 107.8 (8), 85.9 (5), 84.2 (1), 60.0
(7), 42.7 (9), 39.3 (4), 29.8 (6), 23.9 (10).
HRMS: m/z [M + H]+ calcd for C9H13O4: 185.0814; found:
185.0811.
HRMS: m/z [M + Na]+ calcd for C15H30O4SiNa: 325.1806; found:
325.1799.
(3R,4R,5E)-3-[2-(tert-Butyldimethylsiloxy)ethyl]-3-hydroxy-
hept-5-en-4-olide (27)
To a soln of the crude lactol 26 in CH2Cl2 (0.7 mL) at r.t. was added
PDC (25.4 mg, 67.5 mmol). The mixture was stirred at r.t. for 16.5
h and then it was diluted with Et2O. The mixture was filtered
through a short pad of celite and the solvent was evaporated. The
crude product was purified by TLC to afford lactone 27 (3.3 mg,
60% from 21) as a colorless oil.
[a]D25 +30.9 (c 1.31, benzene).
IR (neat): 3458, 1779 cm–1.
1H NMR (C6D6): d = 5.76 (ddq, J = 15.0, 7.5, 1.5 Hz, 1 H, H4), 5.63
(dq, J = 15.0, 6.5 Hz, 1 H, H5), 4.08 (d, J = 7.5 Hz, 1 H, H3), 3.46
Supporting Information for this article is available online at
http://www.thieme-connect.com/ejournals/toc/synthesis.
(ddd, J = 10.5, 6.5, 5.0 Hz, 1 H, H2¢), 3.36 (ddd, J = 10.5, 7.5, 4.0 Acknowledgment
Hz, 1 H, H2¢), 2.55 (d, J = 17.0 Hz, 1 H, H1), 2.12 (d, J = 17.0 Hz,
The author thanks the Shin-Etsu Chemical Co., Ltd. (Japan) for
1 H, H1), 1.51 (dd, J = 6.5, 1.5 Hz, 3 H, H6), 1.39 (ddd, J = 14.5,
7.5, 5.0 Hz, 1 H, H1¢), 1.16 (ddd, J = 14.5, 6.5, 4.0 Hz, 1 H, H1¢),
0.87 (s, 9 H, TBS), –0.06 (s, 3 H, TBS), –0.07 (s, 3 H, TBS).
13C NMR (C6D6): d = 173.8 (1¢¢), 132.4 (4), 125.1 (5), 87.8 (3), 78.0
(2), 60.3 (2¢), 43.0 (1), 37.8 (1¢), 25.8 (TBS), 18.0 (6), 17.9 (TBS),
–5.7 (TBS), –5.8 (TBS).
kindly providing TBSCl as a bulk sample. The authors also thank
the Central Glass Co., Ltd. (Japan) for kindly providing TfOH as a
bulk sample. This study was partially supported by a Research
Grant from the Center for Green Photo-Science and Technology,
and Grants-in-Aid for Scientific Research from the Ministry of Edu-
cation, Science, Sports and Culture, Japan.
HRMS: m/z [M + Na]+ calcd for C15H28O4SiNa: 323.1649; found:
323.1653.
References
(3R,4R,5E)-3-Hydroxy-3-(2-hydroxyethyl)hept-5-en-4-olide
(20)
(1) Schetter, B.; Mahrwald, R. Angew. Chem. Int. Ed. 2006, 45,
7506.
To a soln of lactone 27 (7.8 mg, 26.0 mmol) in THF (0.5 mL) at 0
°C was added a mixture of AcOH–1.0 M TBAF (1:1, 0.5 mL). The
mixture was stirred at r.t. for 1.5 h and then phosphate buffer (pH 7)
was added at 0 °C. The mixture was extracted with EtOAc, and the
organic layer was washed with H2O and brine and dried (Na2SO4).
The mixture was filtered and the solvent was evaporated. The crude
product was purified by TLC to afford lactone 20 (4.0 mg, 83%) as
a colorless oil.
(2) (a) Shiina, I. In Modern Aldol Reactions, Vol. 2; Mahrwald,
R., Ed.; Wiley-VCH: Weinheim, 2004, 105–165.
(b) Mukaiyama, T.; Uchiro, H.; Shiina, I.; Kobayashi, S.
Chem. Lett. 1990, 1019. (c) Mukaiyama, T.; Shiina, I.;
Uchiro, H.; Kobayashi, S. Bull. Chem. Soc. Jpn. 1994, 67,
1708.
(3) Mukaiyama, T.; Shiina, I.; Kobayashi, S. Chem. Lett. 1991,
1901.
[a]D25 +13.9 (c 1.16, benzene).
Synthesis 2009, No. 17, 2915–2926 © Thieme Stuttgart · New York

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I. Shiina et al.
PAPER
(4) (a) Kobayashi, S.; Shiina, I.; Izumi, J.; Mukaiyama, T.
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