Stereoselective synthesis of a C1-C6 fragment of pinnatoxin A via a 1,4-addition/alkylation sequence

Article abstract of DOI:10.1016/j.tetasy.2008.04.013

A C1-C6 fragment of pinnatoxin A, (5S,6R)-5,6-dimethyl-3-methyleneoxepan-2-one, which features a γ,δ-trans-dimethyl-substituted α-methylene lactone, has been synthesized in an enantiomerically pure form from ethyl (E)-4-benzyloxy-2-butenoate through an auxiliary-based conjugate addition and alkylation reaction. The excellent diastereoselectivity (98:2) observed in the alkylation reaction is the result of stereocontrol from both the adjacent stereocenter and the chiral oxazolidinone.

Full text of DOI:10.1016/j.tetasy.2008.04.013

Available online at www.sciencedirect.com
Tetrahedron: Asymmetry 19 (2008) 1059–1067
Stereoselective synthesis of a C1–C6 fragment
of pinnatoxin A via a 1,4-addition/alkylation sequence
Seiichi Nakamura, Fumiaki Kikuchi and Shunichi Hashimoto*
Faculty of Pharmaceutical Sciences, Hokkaido University, Sapporo 060-0812, Japan
Received 1 March 2008; accepted 8 April 2008
Abstract—A C1–C6 fragment of pinnatoxin A, (5S,6R)-5,6-dimethyl-3-methyleneoxepan-2-one, which features a c,d-trans-dimethyl-
substituted a-methylene lactone, has been synthesized in an enantiomerically pure form from ethyl (E)-4-benzyloxy-2-butenoate through
an auxiliary-based conjugate addition and alkylation reaction. The excellent diastereoselectivity (98:2) observed in the alkylation reaction
is the result of stereocontrol from both the adjacent stereocenter and the chiral oxazolidinone.
Ó 2008 Elsevier Ltd. All rights reserved.
1. Introduction
struct the G ring portion of these molecules, a biomimetic
intramolecular Diels–Alder reaction appeared attractive
due to the concurrent formation of the 27-membered
carbocycle. Indeed, Kishi et al. accomplished total synthe-
ses by an intramolecular cycloaddition-based approach.5,7a
On the other hand, an intermolecular Diels–Alder
approach has the advantage of allowing convenient access
to simpler analogues for biological evaluation. The stereo-
chemical arrangement of the G ring of pinnatoxins/pteria-
toxins would require an exo-selective Diels–Alder reaction.
In this regard, Roush et al. demonstrated the striking pref-
erence of conformationally s-cis-restricted enone and eno-
ate dienophiles for exo cycloaddition.13,14 Based on these
precedents, we elected to take advantage of an intermolec-
ular reaction using a-methylene lactone 2 as the dienophile
for the synthesis of 1 and its congeners. Therefore, a
practical route to enantiomerically pure lactone 2 needed
to be developed. Herein, we report a stereoselective route
Pinnatoxins1 and pteriatoxins,2 isolated and characterized
by Uemura et al. in 1995 and 2001, respectively, are the
members of a class of marine toxins that are implicated
in shellfish poisoning.3 Structurally, these molecules feature
a 27-membered carbocyclic ring that comprises a [6,5,6]-
dispiroketal (BCD ring), a [5,6]-bicycloketal (EF ring),
and a [6,7]-spiroimine (AG ring). Not surprisingly, the
unprecedented molecular architecture and biological activ-
ity, in conjunction with the scarcity of the natural material,
have provided an impetus to develop a route to this class of
shellfish toxins.4 The first total synthesis of (ꢀ)-pinnatoxin
A was reported by Kishi et al. in 1998, leading to the abso-
lute configuration assignment for the natural product.5
They also established the complete stereochemistry of pin-
natoxins B and C6 and of pteriatoxins A–C7 by total syn-
theses. A formal total synthesis of pinnatoxin A was
documented by Hirama et al.,8 and synthetic approaches
have been pursued extensively in the laboratories of Ishiha-
ra and Murai,9 Kitching,10 and Zakarian.11
Me
Me
1
39
A
Me
Me
HN
As part of our own synthetic studies on these natural prod-
ucts, we have already reported a stereoselective construc-
tion of the [6,5,6]-dispiroketal ring system by exploiting a
tandem hemiketal formation/hetero-Michael reaction se-
quence through the agency of LiOMe as a base.12 To con-
G
6
10
CO2
OH
1
12
H
30
6
O
O
B
O
25
F
16
39
O
C
O
E
O
O
1D9
HO
C1—C6 Fragment 2
Me
Me
23
*
Corresponding author. Tel.: +81 11 706 3236; fax: +81 11 706 4981;
e-mail: hsmt@pharm.hokudai.ac.jp
Pinnatoxin A 1
0957-4166/$ - see front matter Ó 2008 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetasy.2008.04.013

1060
S. Nakamura et al. / Tetrahedron: Asymmetry 19 (2008) 1059–1067
O
to lactone 2, in which a chiral auxiliary, (R)-4-phenyl-
2-oxazolidinone, plays a pivotal role as the source of
asymmetry for the creation of both stereocenters at C2
and C3.
HN
Ph
O
O
O
O
O
b
8
1
1
BnO
BnO
BnO
a
OR
4
4
O
O
N
N
88% (2 steps)
6: R = Et
7: R = H
Ph
9
2. Results and discussion
O
Me
O
Me
O
The C1–C6 fragment 2 features a seven-membered a-meth-
ylene lactone containing branched methyl groups with a
1,2-trans-relationship. To construct the methyl-bearing ste-
reocenters at C2 and C3, we planned to take advantage of
asymmetric reactions using a common chiral oxazolidi-
none: 1,4-addition15 of a methylmagnesium reagent to a
chiral a,b-unsaturated 3-acyl-2-oxazolidinone 3 and subse-
quent alkylation with MeI (Scheme 1). However, to the
best of our knowledge, the chiral oxazolidinone-based
1,4-addition/alkylation sequence has not been employed
to install 1,2-dimethyl arrangements along acyclic back-
bones.16 With regard to the oxazolidinone-based 1,4-addi-
tion reaction, Hruby et al. demonstrated that a phenyl-
substituted auxiliary (R = Ph) is effective for asymmetric
induction at the b-carbon. The major concern with this
1,4-addition/alkylation sequence was the control of the
configuration at the a-carbon (C3) by alkylation, since
Evans et al. demonstrated that the phenyl group is a less
effective substituent to shield the diastereoface of the lith-
ium enolate in the alkylations of N-butyryl-2-oxazolidinon-
es with MeI at ꢀ30 °C than any other groups examined,
providing a 4.24:1 mixture of alkylation products.17
c
1
1
BnO
+
4
O
4
N
97%
(10:11 = 94:6)
Ph
Ph
10
11
d
dr = 98:2
O
Me
O
1
BnO
4
O
N
Me
Ph
12
83%
Scheme 2. Reagents and conditions: (a) LiOH, 5:1 THF/H2O, 72 h; (b)
PivCl, Et3N, THF, ꢀ20 °C, 2 h, then oxazolidinone 8, LiCl, rt, 3 h; (c)
MeMgBr, CuBrꢂSMe2, 24:8:1 THF/Me2S/CH2Cl2, ꢀ78 °C, 30 min, then
ꢀ30 °C, 30 min; (d) NaHMDS, THF, ꢀ78 °C, 30 min, then MeI, 6 h.
be removed by recrystallizations from 4:1 AcOEt/n-hexane,
providing diastereomerically pure carboximide 10, mp
68.5–69.0 °C, ½aꢁD ¼ ꢀ52:8 (c 2.08, CHCl3), as colorless
22
needles. Our effort was then directed toward the crucial
methylation reaction: the reaction of the sodium enolate
generated from 10 with MeI in THF at ꢀ78 °C exhibited
excellent diastereoselectivity (98:2) for the desired alkyl-
ation product 12 with 1,2-syn-dimethyl stereocenters.23
The excellent diastereoselection observed with 10 can be
attributed to the complementary influence on the facial
bias imposed on the sodium enolate by the b-stereocenter
as well as the chiral auxiliary.24 In this context, McGarvey
and Williams reported that a good level of 1,2-asymmetric
induction from the b-substituent was observed in the meth-
ylation of ester enolates bearing oxygen substitution at the
c-position.25 For example, treatment of the lithium enolate
derived from ester 13 with MeI in THF at ꢀ78 °C afforded
an 89:11 mixture of products favoring the syn-dimethyl-
substituted ester 15 in 85% combined yield (Eq. 1). They
The synthesis of lactone 2 was initiated by the N-acylation
of the D-phenylglycine-derived oxazolidinone 815 with the
known 4-benzyloxy-2-butenoic acid 7,18 obtained by the
hydrolysis of ethyl ester 619 with LiOH in aqueous THF,
under Merck conditions [PivCl, Et3N, LiCl, THF]20 to af-
26
ford carboximide 9, mp 115.5–116.5 °C, ½aꢁD ¼ ꢀ67:3 (c
2.07, CHCl3), in 88% yield in two steps (Scheme 2). Conju-
gate addition of MeMgBr to the a,b-unsaturated imide 9
was carried out according to Hruby conditions15 in the
presence of CuBrꢂSMe2 in THF/Me2S/CH2Cl2 (ꢀ78 to
ꢀ30 °C) to produce a mixture of 1,4-adducts, 10 and its
C2 epimer 11, in 97% yield in a ratio of 94:6 as determined
by 500 MHz 1H NMR.21 The minor diastereomer 11 could
MeMgBr
O
O
Me
O
O
2
1. 1,4-addition
2. alkylation
1
BnO
Me
BnO
3
1
3
2
4
O
4
O
N
N
CH2OTBS
Me
O
Me
LDA, THF
O Li
OEt
R
R
MeI
H
Me
TBSO
4
OEt
–78 °C
H
I
3
13
Me
Me
Me
6
14
ð1Þ
1
1
HO
CO2H
4
4
O
Me
6
O
Me
5
MeI
TBSO
39
OEt
+
anti-isomer
O
85%
(dr = 89:11)
Me
syn
C1—C6 Fragment 2
Scheme 1. Plan for the synthesis of C1–C6 fragment 2.
15

S. Nakamura et al. / Tetrahedron: Asymmetry 19 (2008) 1059–1067
1061
reasoned that the homoallylic oxygen in the enolate would
enhance the donor ability of the substituted carbon via lone
pair participation, leading to the transition state 14, where-
in the electron-donating CH2OTBS group is aligned anti to
the forming bond and the sterically unencumbered hydro-
gen atom occupies the inside position. Based on the
McGarvey precedent, the predominant formation of the
1,2-syn diastereomer 12 can be rationalized by the transi-
tion state A, wherein the benzyloxymethyl group at C2
and the phenyl group of the auxiliary act in concert to di-
rect the alkylation from the re-face of the enolate (Fig. 1).
periodinane27 in CH2Cl2 was followed by Horner–Wads-
worth–Emmons olefination with triethyl phosphonoacetate
to give enoate 18 as an 8:1 E/Z mixture of olefin isomers in
93% yield in two steps. Hydrogenation of the C4–C5 olefin
and hydrogenolytic cleavage of the C1 benzyl protecting
group were effected in a single operation by the treatment
of 18 with Pd(OH)2/C in AcOEt under a hydrogen atmo-
22
sphere to afford e-hydroxyester 19, ½aꢁD ¼ ꢀ10:6 (c 2.40,
CHCl3), in 97% yield. Saponification of 19 with KOH in
MeOH and subsequent TsOH-catalyzed lactonization at
high dilution (14 mM in benzene) provided the seven-mem-
21
bered lactone 20, ½aꢁD ¼ ꢀ43:1 (c 2.02, CHCl3), in 90%
After chromatographic separation of the desired carboxim-
yield in two steps.
20
ide 12, ½aꢁD ¼ ꢀ82:0 (c 2.01, CHCl3), reductive removal of
the chiral auxiliary with LiBH4 in aqueous THF26 afforded
With the seven-membered lactone 20 in hand, the remain-
ing operation necessary for the synthesis of the C1–C6
fragment 2 was the a-methylidenation of lactone 20. In this
regard, Takeda et al. successfully utilized the Paterson
procedure28 for the conversion of e-caprolactone to
a-methylene-e-caprolactone.14b Following this literature
precedent, lactone 20 was uneventfully converted to the
corresponding silyl ketene acetal, which, upon treatment
with a-chlorothioanisole in the presence of a catalytic
amount of ZnBr2 in CH2Cl2 afforded a-(phenylthio-
methyl)lactone 21 as a 1:1 mixture of diastereomers in
58% yield in two steps along with 13% recovery of lactone
20. Finally, the oxidation of sulfide 21 with NaIO4 in aque-
ous MeOH and subsequent elimination of the correspond-
21
the primary alcohol 16, ½aꢁD ¼ þ6:2 (c 2.00, CHCl3), in
73% yield along with 66% recovery of the auxiliary
(Scheme 3). Oxidation of alcohol 16 with Dess–Martin
BnO
Si-hindered
1
O
Me
O
O Na
1
BnO
Me
2
H
4
O
4
N
3
O
H
N
Me
Ph
O
Ph
12
H
Re-accessible
ing sulfoxide in refluxing toluene furnished the target
21
MeI
a-methylene lactone 2, ½aꢁD ¼ ꢀ6:7 (c 2.01, CHCl3), in
A
75% yield in two steps.
Figure 1. Stereochemical model for the predominant formation of syn-
isomer 12.
3. Conclusion
We have achieved the stereoselective synthesis of a C1–C6
fragment of pinnatoxin A in 14 steps with an overall yield
of 13.7%. The foregoing synthetic sequence demonstrated
the utility of phenyl-substituted oxazolidinone as a com-
mon chiral auxiliary to set the contiguous methyl-bearing
stereocenters in a syn-stereochemical relationship through
a 1,4-addition of MeMgBr and subsequent alkylation with
MeI, wherein the facial bias conferred on the enolate was
reinforced by the adjacent stereocenter created by the 1,4-
addition. This is the first example of a stereoselective con-
struction of a 1,2-syn-dimethyl array via the chiral oxazo-
lidinone-based 1,4-addition/alkylation sequence. Efforts
to complete the total synthesis of pinnatoxin A 1 using
an intermolecular Diels–Alder strategy are currently in
progress in our laboratory and will be reported in due
course.29
O
Me
Me
O
a
c
1
1
BnO
R
BnO
4
O
N
73%
99%
Me
Me
Ph
16: R = CH2OH
17: R = CHO
12
b
94%
Me
Me
6
6
d
e, f
1
1
BnO
Me
CO2Et
HO
CO2Et
97%
90%
Me
Me
18 (E:Z = 8:1)
19
Me
Me
Me
Me
Me
g, h
i, j
75%
1
1
1
6
O
6
6
O
SPh
O
58%
(dr = 1:1)
O
20
O
4. Experimental
4.1. General
O
2
21
Scheme 3. Reagents and conditions: (a) LiBH4, H2O, THF, 0 °C, 3 h, then
rt, 1.5 h; (b) Dess–Martin periodinane, CH2Cl2, 10 min; (c) (EtO)2-
P(O)CH2CO2Et, tBuOK, THF, ꢀ78 °C, 30 min, then 0 °C, 30 min; (d) H2,
20% Pd(OH)2/C, AcOEt, 5 h; (e) KOH, MeOH, 4 h; (f) TsOH, benzene
(14 mM), reflux, 1 h; (g) LDA, THF, ꢀ78 °C, 1 h, then TMSCl, ꢀ78 °C,
30 min and rt, 1 h; (h) PhSCH2Cl, ZnBr2, CH2Cl2, 12 h; (i) NaIO4, 9:1
MeOH/H2O, 24 h; (j) toluene, reflux, 3 h.
Melting points were determined on a Buchi 535 digital
¨
melting point apparatus and are uncorrected. Optical rota-
tions were measured on a JASCO P-1030 digital polari-
meter with
a sodium lamp. Infrared (IR) spectra
were recorded on JASCO FT/IR-5300 or FT/IR-4100

1062
S. Nakamura et al. / Tetrahedron: Asymmetry 19 (2008) 1059–1067
spectrometers and absorbance bands are reported in wave-
numbers (cmꢀ1). 1H NMR spectra were recorded on JEOL
JNM- ECA500 (500 MHz) or Bruker ARX500 (500 MHz)
spectrometers with tetramethylsilane (d 0.00) or C6H6 (d
7.20) as an internal standard. Coupling constants (J) are re-
ported in Hertz (Hz). Abbreviations of multiplicity are as
follows: s, singlet; d, doublet; t, triplet; q, quartet; m, mul-
tiplet; br, broad. Data are presented as follows: chemical
shift, multiplicity, coupling constants, integration, and
assignment. Pinnatoxin numbering is used for proton
assignments of all the compounds. 13C NMR spectra were
recorded on JEOL JNM-EX270 (67.8 MHz), JNM-AL400
(100.6 MHz) or JNM-ECX-400P (99.6 MHz) spectrome-
ters with CDCl3 (d 77.0) as an internal standard. Electron
impact (EI) and fast atom bombardment (FAB) mass spec-
tra were recorded on JEOL JMS-FABmate and JMS-
HX110 spectrometers, respectively, by the Center for
Instrumental Analysis, Hokkaido University.
washed with saturated aqueous NaHCO3 (150 mL) and
brine (2 ꢃ 100 mL), and dried over anhydrous Na2SO4.
Filtration and evaporation in vacuo furnished the crude
product (21.7 g, brown solid), which was recrystallized
from 1:1 n-hexane/AcOEt to give carboximide 9 (13.9 g,
74%) as colorless plates. Concentration of the mother
liquor followed by purification by column chromatography
(silica gel 110 g, 3:1 n-hexane/AcOEt) gave 9 (2.56 g,
14%) as a white solid: TLC Rf = 0.24 (3:1 n-hexane/
26
AcOEt); mp 115.5–116.5 °C; ½aꢁD ¼ ꢀ67:3 (c 2.07, CHCl3);
IR (nujol) 2924, 2855, 1796, 1767, 1682, 1644, 1462, 1379,
1366, 1333, 1209, 1138, 972, 718 cmꢀ1
;
1H NMR
(500 MHz, CDCl3) d 4.21 (dd, J = 2.0, 4.5 Hz, 2H, C1–
H2), 4.29 (dd, J = 3.9, 8.8 Hz, 1H, one of CH2O), 4.57 (s,
2H, PhCH2O), 4.71 (t, J = 8.8 Hz, 1H, one of CH2O),
5.49 (dd, J = 3.9, 8.8 Hz, 1H, PhCHN), 7.08 (dt, J =
15.4, 4.5 Hz, 1H, C2–H), 7.27–7.40 (m, 10H, ArH), 7.54
(dt, J = 15.4, 2.0 Hz, 1H, C3–H); 13C NMR (67.8 MHz,
CDCl3) d 56.7 (CH), 68.8 (CH2), 69.8 (CH2), 72.6 (CH2),
120.2 (CH), 125.8 (CH), 127.58 (CH), 127.63 (CH), 128.3
(CH), 128.5 (CH), 129.0 (CH), 137.6 (C), 138.8 (C), 146.4
(CH), 153.4 (C), 164.0 (C); FAB-HRMS m/z calcd for
C20H20NO4 (M+H)+ 338.1392, found 338.1400; Anal.
Calcd for C20H19NO4: C, 71.20; H, 5.68; N, 4.15. Found:
C, 71.27; H, 5.61; N, 4.26.
Column chromatography was carried out on Kanto Silica
Gel 60 N (63–210 lm). Analytical TLC was carried out
on Merck Kieselgel 60 F254 plates. Visualization was
accomplished with ultraviolet light and anisaldehyde or
phosphomolybdic acid stain, followed by heating.
Reagents and solvents were purified by standard means or
used as received unless otherwise noted. Dehydrated stabi-
lizer free THF was purchased from Kanto Chemical Co.,
Inc. Dichloromethane (CH2Cl2) was distilled from P2O5
and redistilled from calcium hydride prior to use. Diisopro-
pylamine (iPr2NH) and TMSCl were distilled from calcium
hydride prior to use.
4.3. [4R,3(3R)]-3-(4-Benzyloxy-3-methylbutanoyl)-4-phenyl-
2-oxazolidinone 10
MeMgBr in THF (0.93 M, 127 mL, 119 mmol) was added
to a suspension of CuBrꢂSMe2 (32.5 g, 158 mmol) in 3:2
THF/Me2S (400 mL) at ꢀ78 °C under an argon atmo-
sphere. After stirring at ꢀ78 °C for 20 min and at 0 °C
for 20 min, the yellow suspension was cooled to ꢀ78 °C,
and a solution of carboximide 9 (13.3 g, 39.4 mmol) in
6:1 THF/CH2Cl2 (140 mL) was added. After stirring at
ꢀ78 °C for 30 min, the mixture was warmed to ꢀ30 °C
over 30 min and stirred at this temperature for 30 min.
The reaction was quenched with saturated aqueous NH4Cl
(150 mL), and the mixture was extracted with AcOEt
(300 mL). The organic extract was successively washed
with saturated aqueous NH4Cl (2 ꢃ 150 mL), H2O
(80 mL) and brine (2 ꢃ 80 mL), and dried over anhydrous
Na2SO4. Filtration and evaporation in vacuo furnished the
30
CuBrꢂSMe2 and Dess–Martin periodinane31 were pre-
pared according to literature procedures.
4.2. [4R,3(2E)]-3-(4-Benzyloxy-2-butenoyl)-4-phenyl-2-
oxazolidinone 9
Lithium hydroxide monohydrate (4.67 g, 111 mmol) was
added to a solution of ethyl 4-benzyloxy-2-butenoate19
6
(12.3 g, 55.6 mmol) in 5:1 THF/H2O (240 mL). After stir-
ring for 72 h, THF was removed in vacuo, and the residue
was partitioned between Et2O (100 mL) and 2 M aqueous
NaHSO4 (150 mL). The aqueous layer was extracted with
AcOEt (300 mL). The combined organic extracts were
washed with brine (100 mL) and dried over anhydrous
Na2SO4. Filtration and evaporation in vacuo furnished
the crude product (11.0 g, slightly yellow solid), which
was used without further purification.
1
slightly yellow solid (14.4 g), whose H NMR [integration
of C3-H, desired isomer 10 (2.68 ppm), undesired isomer
11 (2.86 ppm)] revealed a 10/11 ratio of 94:6. Purification
of the crude product by column chromatography (silica
gel 300 g, 100:1 CH2Cl2/AcOEt) afforded a mixture of
1,4-adducts (13.6 g, 97%) as a white solid, which was
recrystallized twice from 4:1 AcOEt/n-hexane to afford
desired isomer 10 (7.06 g, 51%) as colorless needles. Con-
centration of the mother liquor followed by two recrystal-
lizations from 4:1 AcOEt/n-hexane gave 10 (2.03 g, 15%) as
colorless needles. This sequence was repeated again to pro-
vide another crop of carboximide 10 (877 mg, 6%), result-
Trimethylacetyl chloride (9.3 mL, 61.2 mmol) was added to
a solution of the crude carboxylic acid 7 (11.0 g) and Et3N
(24 mL, 167 mmol) in THF (200 mL) at ꢀ25 °C under an
argon atmosphere. After stirring at ꢀ20 °C for 2 h, LiCl
(3.5 g, 83.5 mmol) and 2-oxazolidinone 815 (10.0 g,
61.2 mmol) were added, and the mixture was allowed to
warm to room temperature. After stirring for 3 h, the reac-
tion mixture was poured into an ice-cooled, two-layer mix-
ture of Et2O (100 mL) and saturated aqueous NaHCO3
(150 mL), and the whole mixture was extracted with
AcOEt (300 mL). The organic extract was successively
ing in a combined yield of 72%: TLC Rf = 0.23 (4:1
22
n-hexane/AcOEt); mp 68.5–69.0 °C; ½aꢁD ¼ ꢀ52:8 (c 2.08,
CHCl3); IR (nujol) 2922, 2855, 1782, 1699, 1462, 1381,
1300, 1200, 1121, 1036, 762, 729, 698 cmꢀ1 1H NMR
;
(500 MHz, CDCl3) d 0.94 (d, J = 6.8 Hz, 3H, C2–CH3),
2.42 (m, 1H, C2–H), 2.68 (dd, J = 6.2, 16.1 Hz, 1H, one

S. Nakamura et al. / Tetrahedron: Asymmetry 19 (2008) 1059–1067
1063
of C3–H2), 3.25 (dd, J = 7.3, 16.1 Hz, 1H, one of C3–H2),
3.31 (dd, J = 7.6, 9.2 Hz, 1H, one of C1–H2), 3.39 (dd,
J = 5.6, 9.2 Hz, 1H, one of C1–H2), 4.14 (dd, J = 3.8,
8.8 Hz, 1H, one of CH2O), 4.36 (t, J = 8.8 Hz, 1H, one
of CH2O), 4.42 (d, J = 11.8 Hz, 1H, one of PhCH2O),
4.44 (d, J = 11.8 Hz, 1H, one of PhCH2O), 5.23 (dd,
J = 3.8, 8.8 Hz, 1H, PhCHN), 7.23–7.37 (m, 10H, ArH);
13C NMR (67.8 MHz, CDCl3) d 17.1 (CH3), 30.6 (CH),
39.2 (CH2), 57.4 (CH), 69.5 (CH2), 72.7 (CH2), 75.0
(CH2), 125.8 (CH), 127.36 (CH), 127.43 (CH), 128.2
(CH), 128.4 (CH), 129.0 (CH), 138.6 (C), 139.2 (C), 153.7
(C), 172.0 (C); FAB-HRMS m/z calcd for C21H24NO4
(M+H)+ 354.1705, found 354.1718; Anal. Calcd for
C21H23NO4: C, 71.37; H, 6.56; N, 3.96. Found: C, 71.30;
H, 6.62; N, 3.84.
aqueous NH4Cl (50 mL), and the mixture was extracted
with AcOEt (300 mL). The organic extract was successively
washed with saturated aqueous NH4Cl (2 ꢃ 80 mL) and
brine (100 mL), and dried over anhydrous Na2SO4. Filtra-
tion and evaporation in vacuo furnished the crude product
(15.0 g, yellow oil), whose diastereomeric ratio was deter-
1
mined to be 98:2 by H NMR [integration of the benzylic
proton at C4 of the oxazolidinone, desired syn-isomer 12
(4.91 ppm), undesired anti-isomer (5.45 ppm)]. Purification
of the crude product by column chromatography (silica gel
300 g, 6:1?4:1?2:1 n-hexane/AcOEt) afforded syn-isomer
12 (12.2 g, 83%) as a colorless oil, along with a 6.3:1 mix-
ture of 10 and anti-isomer (2.22 g) as a white solid: TLC
20
Rf = 0.36 (4:1 n-hexane/AcOEt); ½aꢁD ¼ ꢀ82:0 (c 2.01,
CHCl3); IR (film) 3032, 2969, 2932, 2878, 1779, 1705,
1454, 1383, 1319, 1204, 1098, 982, 741, 700 cmꢀ1 1H
;
4.4. [4S,3(3R)]-3-(4-Benzyloxy-3-methylbutanoyl)-4-phenyl-
2-oxazolidinone ent-11
NMR (500 MHz, CDCl3) d 0.92 (d, J = 7.0 Hz, 3H, C2–
CH3), 1.03 (d, J = 6.9 Hz, 3H, C3–CH3), 2.31 (m, 1H,
C2–H), 3.39 (t, J = 9.3 Hz, 1H, one of C1–H2), 3.47 (dd,
J = 5.2, 9.3 Hz, 1H, one of C1–H2), 3.83 (dq, J = 8.9,
6.9 Hz, 1H, C3–H), 3.92–3.99 (m, 2H, CH2O), 4.39 (d,
J = 11.4 Hz, 1H, one of PhCH2O), 4.46 (d, J = 11.4 Hz,
1H, one of PhCH2O), 4.91 (dd, J = 4.7, 8.4 Hz, 1H,
PhCHN), 7.15–7.18 (m, 2H, ArH), 7.25–7.39 (m, 8H,
ArH); 13C NMR (67.8 MHz, CDCl3) d 13.7 (CH3), 14.9
(CH3), 35.6 (CH), 40.0 (CH), 57.4 (CH), 69.1 (CH2), 72.7
(CH2), 75.4 (CH2), 125.4 (CH), 127.4 (CH), 127.5 (CH),
128.1 (CH), 128.2 (CH), 128.9 (CH), 138.6 (C), 139.5 (C),
153.6 (C), 176.5 (C); FAB-HRMS m/z calcd for
C22H26NO4 (M+H)+ 368.1862, found 368.1871; Anal.
Calcd for C22H25NO4: C, 71.91; H, 6.86; N, 3.81. Found:
Trimethylacetyl chloride (0.01 mL, 76.1 lmol) was added
to a solution of (R)-4-benzyloxy-3-methylbutanoic acid22
(12.0 mg, 57.6 lmol) and Et3N (0.03 mL, 0.215 mmol) in
THF (1 mL) at ꢀ25 °C under an argon atmosphere. After
stirring at ꢀ20 °C for 2 h, LiCl (3.7 mg, 87.3 lmol) and
oxazolidinone ent-8 (9.5 mg, 58.2 lmol) were added, and
the mixture was allowed to warm to room temperature.
After stirring for 3 h, the reaction was quenched with satu-
rated aqueous NaHCO3 (3 mL), and the mixture was ex-
tracted with AcOEt (15 mL). The organic extract was
successively washed with saturated aqueous NaHCO3
(2 ꢃ 5 mL) and brine (2 ꢃ 5 mL), and dried over anhy-
drous Na2SO4. Filtration and evaporation in vacuo fur-
C, 71.99; H, 6.94; N, 3.78. Data for [4R,3(2S,3R)]-isomer:
23
nished the crude product (21.7 mg, yellow oil), which was
purified by column chromatography (silica gel 4 g, 4:1 n-
TLC Rf = 0.23 (4:1 n-hexane/AcOEt); ½aꢁ ¼ ꢀ16:6 (c
1.28, CHCl3); IR (nujol) 2924, 2854, 1786D, 1701, 1457,
hexane/AcOEt) to give ent-11 (19.1 mg, 94%) as a colorless
1377, 1319, 1211, 1083, 749, 714 cmꢀ1 1H NMR
;
18
oil: TLC Rf = 0.23 (4:1 n-hexane/AcOEt); ½aꢁD ¼ þ43:5 (c
(500 MHz, CDCl3) d 0.89 (d, J = 6.9 Hz, 3H, C2–CH3),
1.08 (d, J = 6.9 Hz, 3H, C3–CH3), 2.16 (m, 1H, C2–H),
3.14–3.24 (m, 2H, C1–H2), 3.83 (quintet, J = 6.9 Hz, 1H,
C3–H), 4.22–4.33 (m, 3H, one of CH2O, PhCH2O), 4.68
(t, J = 9.2 Hz, 1H, one of CH2O), 5.45 (dd, J = 4.6,
9.2 Hz, 1H, PhCHN), 7.22–7.38 (m, 10H, ArH); 13C
NMR (99.6 MHz, CDCl3) d 13.0 (CH3), 15.9 (CH3), 36.4
(CH), 40.5 (CH), 57.8 (CH), 69.5 (CH2), 72.0 (CH2), 72.8
(CH2), 126.2 (CH), 127.36 (CH), 127.39 (CH), 128.3
(CH), 128.6 (CH), 129.0 (CH), 138.5 (C), 139.0 (C), 153.4
(C), 176.1 (C); FAB-HRMS m/z calcd for C22H26NO4
(M+H)+ 368.1862, found 368.1848.
1.08, CHCl3); IR (film) 3032, 2961, 2927, 2857, 1781, 1706,
1455, 1385, 1325, 1200, 1121, 1096, 758, 710 cmꢀ1 1H
;
NMR (500 MHz, CDCl3) d 0.94 (d, J = 6.9 Hz, 3H, C2–
CH3), 2.37 (m, 1H, C2–H), 2.86 (dd, J = 8.0, 16.6 Hz,
1H, one of C3–H2), 3.04 (dd, J = 5.7, 16.6 Hz, 1H, one
of C3–H2), 3.30 (dd, J = 6.9, 9.2 Hz, 1H, one of C1–H2),
3.35 (dd, J = 5.7, 9.2 Hz, 1H, one of C1–H2), 4.21 (dd,
J = 3.4, 8.6 Hz, 1H, one of CH2O), 4.42 (s, 2H, PhCH2O),
4.56 (t, J = 8.6 Hz, 1H, one of CH2O), 5.31 (dd, J = 3.4,
8.6 Hz, 1H, PhCHN), 7.20–7.40 (m, 10H, ArH); 13C
NMR (99.6 MHz, CDCl3) d 17.0 (CH3), 30.2 (CH), 39.8
(CH2), 57.6 (CH), 69.9 (CH2), 72.9 (CH2), 74.8 (CH2),
125.9 (CH), 127.5 (CH), 127.6 (CH), 128.3 (CH), 128.6
(CH), 129.1 (CH), 138.5 (C), 139.2 (C), 153.7 (C), 171.9
(C); FAB-HRMS m/z calcd for C21H24NO4 (M+H)+
354.1705, found 354.1715.
4.6. (2R,3R)-4-Benzyloxy-2,3-dimethyl-1-butanol 16
A 2.0 M solution of LiBH4 in THF (21.5 mL, 43.0 mmol)
was added to a solution of carboximide 12 (12.7 g,
34.6 mmol) in THF (120 mL) and H2O (0.78 mL,
43.2 mmol) at 0 °C. After stirring for 3 h, the reaction mix-
ture was allowed to warm to room temperature and stirred
for 1.5 h. The mixture was poured into an ice-cooled, two-
layer mixture of Et2O (10 mL) and saturated aqueous
NH4Cl (60 mL), and the whole mixture was extracted with
AcOEt (150 mL). The organic extract was successively
washed with saturated aqueous NH4Cl (80 mL) and brine
(2 ꢃ 80 mL), and dried over anhydrous Na2SO4. Filtration
and evaporation in vacuo furnished the crude product
4.5. [4R,3(2R,3R)]-3-(4-Benzyloxy-2,3-dimethylbutanoyl)-4-
phenyl-2-oxazolidinone 12
A solution of carboximide 10 (14.1 g, 40.0 mmol) in THF
(50 mL plus 2 ꢃ 4 mL rinse) was added to a 0.5 M solution
of NaHMDS in THF (104 mL, 52.0 mmol) at ꢀ78 °C un-
der an argon atmosphere. After stirring for 30 min, MeI
(12.5 mL, 199 mmol) was added, and the mixture was stir-
red for 6 h. The reaction was quenched with saturated

1064
S. Nakamura et al. / Tetrahedron: Asymmetry 19 (2008) 1059–1067
(13.5 g, white solid), which was purified by column chro-
matography (silica gel 250 g, 8:1 n-hexane/AcOEt?4:1
CH2Cl2/AcOEt) to give alcohol 16 (5.22 g, 73%) as a color-
30 min, the reaction mixture was allowed to warm to
0 °C and stirred for 30 min. The reaction was quenched
with saturated aqueous NH4Cl (30 mL), and the whole
mixture was extracted with AcOEt (150 mL). The organic
extract was successively washed with saturated aqueous
NH4Cl (40 mL) and brine (40 mL), and dried over anhy-
drous Na2SO4. Filtration and evaporation in vacuo fur-
nished the crude product (5.30 g, slightly yellow oil),
which was purified by column chromatography (silica gel
150 g, 20:1 n-hexane/AcOEt) to give a,b-unsaturated esters
(E)-18 (3.02 g, 89%) and (Z)-18 (368 mg, 11%) as colorless
less oil, along with recovered oxazolidinone 8 (3.7 g) as a
21
white solid: TLC Rf = 0.31 (3:1 n-hexane/AcOEt); ½aꢁD
¼
þ6:2 (c 2.00, CHCl3); IR (film) 3387 (br), 3030, 2876,
1454, 1364, 1094, 737, 698 cmꢀ1 1H NMR (500 MHz,
;
CDCl3) d 0.90 (d, J = 7.0 Hz, 6H, C2–CH3, C3–CH3),
1.70 (m, 1H, C3–H), 1.87 (m, 1H, C2–H), 2.20 (br s, 1H,
OH), 3.38 (dd, J = 7.2, 9.3 Hz, 1H, one of C1–H2), 3.42
(dd, J = 4.8, 9.3 Hz, 1H, one of C1–H2), 3.48 (dd, J =
5.8, 11.1 Hz, 1H, one of C4–H2), 3.60 (dd, J = 5.0,
11.1 Hz, 1H, one of C4–H2), 4.51 (d, J = 11.9 Hz, 1H,
one of PhCH2O), 4.53 (d, J = 11.9 Hz, 1H, one of
PhCH2O), 7.25–7.38 (m, 5H, ArH); 13C NMR
(67.8 MHz, CDCl3) d 12.8 (CH3), 13.1 (CH3), 34.4 (CH),
37.4 (CH), 65.7 (CH2), 72.9 (CH2), 73.9 (CH2), 127.36
(CH), 127.42 (CH), 128.1 (CH), 138.0 (C); EI-HRMS
m/z calcd for C13H20O2 (M)+ 208.1463, found 208.1465;
Anal. Calcd for C13H20O2: C, 74.96; H, 9.68. Found: C,
74.84; H, 9.71.
oils. Data for (2E,4S,5R)-isomer (E)-18: TLC Rf = 0.29
22
(10:1 n-hexane/AcOEt); ½aꢁD ¼ ꢀ46:2 (c 2.09, CHCl3); IR
(film) 2969, 2876, 1719, 1651, 1454, 1368, 1265, 1184,
737, 698 cmꢀ1 1H NMR (500 MHz, CDCl3) d 0.90 (d,
;
J = 6.9 Hz, 3H, C2–CH3), 1.00 (d, J = 6.8 Hz, 3H, C3–
CH3), 1.29 (t, J = 7.1 Hz, 3H, OCH2CH3), 1.89 (m, 1H,
C2–H), 2.49 (m, 1H, C3–H), 3.29 (dd, J = 6.3, 9.3 Hz,
1H, one of C1–H2), 3.37 (dd, J = 6.4, 9.3 Hz, 1H, one of
C1–H2), 4.19 (q, J = 7.1 Hz, 2H, OCH2CH3), 4.48 (s, 2H,
PhCH2O), 5.78 (dd, J = 0.9, 15.7 Hz, 1H, C5–H), 6.93
(dd, J = 7.6, 15.7 Hz, 1H, C4–H), 7.25–7.36 (m, 5H,
ArH). 13C NMR (100.6 MHz, CDCl3) d 13.5 (CH3), 14.2
(CH3), 14.6 (CH3), 37.6 (CH), 37.9 (CH), 60.0 (CH2),
72.9 (CH2), 73.3 (CH2), 120.1 (CH), 127.31 (CH), 127.34
(CH), 128.1 (CH), 138.3 (C), 153.3 (CH), 166.6 (C); EI-
HRMS m/z calcd for C17H24O3 (M)+ 276.1725, found
276.1741; Anal. Calcd for C17H24O3: C, 73.88; H, 8.75.
4.7. (2R,3R)-4-Benzyloxy-2,3-dimethylbutanal 17
A solution of alcohol 16 (2.77 g, 13.3 mmol) in CH2Cl2
(9 mL) was added to a solution of Dess–Martin period-
inane (6.80 g, 16.0 mmol) in CH2Cl2 (40 mL) at 0 °C under
an argon atmosphere. After stirring at room temperature
for 10 min, the reaction was quenched with a mixture of
1 M aqueous Na2S2O3 (100 mL) and saturated aqueous
NaHCO3 (100 mL), and the whole mixture was extracted
with AcOEt (600 mL). The organic extract was successively
washed with saturated aqueous NaHCO3 (4 ꢃ 100 mL)
and brine (100 mL), and dried over anhydrous Na2SO4.
Filtration and evaporation in vacuo furnished the crude
product (2.90 g, colorless oil), which was purified by col-
umn chromatography (silica gel 40 g, 10:1 n-hexane/
Found: C, 73.78; H, 8.68. Data for (2Z,4S,5R)-isomer
24
(Z)-18: TLC Rf = 0.35 (10:1 n-hexane/AcOEt); ½aꢁD
¼
þ22:6 (c 1.99, CHCl3); IR (film) 2976, 2874, 1721, 1644,
1454, 1416, 1182, 1098, 1032, 737, 698 cmꢀ1 1H NMR
;
(500 MHz, CDCl3) d 0.91 (d, J = 6.3 Hz, 3H, C2–CH3),
1.00 (d, J = 6.3 Hz, 3H, C3–CH3), 1.27 (t, J = 7.1 Hz,
3H, OCH2CH3), 1.74 (m, 1H, C2–H), 3.24 (dd, J = 7.7,
9.2 Hz, 1H, one of C1–H2), 3.43 (dd, J = 5.0, 9.2 Hz, 1H,
one of C1–H2), 3.46 (m, 1H, C3–H), 4.15 (q, J = 7.1 Hz,
2H, OCH2CH3), 4.46 (d, J = 12.0 Hz, 1H, one of
PhCH2O), 4.47 (d, J = 12.0 Hz, 1H, one of PhCH2O),
5.71 (d, J = 11.5 Hz, 1H, C5–H), 6.09 (t, J = 11.5 Hz,
1H, C4–H), 7.24–7.35 (m, 5H, ArH); 13C NMR
(100.6 MHz, CDCl3) d 14.2 (CH3), 14.5 (CH3), 17.1
(CH3), 35.1 (CH), 38.6 (CH), 59.7 (CH2), 72.8 (CH2),
74.1 (CH2), 118.3 (CH), 127.2 (CH), 127.3 (CH), 128.1
(CH), 138.5 (C), 154.4 (CH), 166.1 (C); EI-HRMS m/z
calcd for C17H24O3 (M)+ 276.1725, found 276.1713.
AcOEt) to give aldehyde 17 (2.57 g, 94%) as a colorless
21
oil: TLC Rf = 0.32 (10:1 n-hexane/AcOEt); ½aꢁ ¼ ꢀ39:8
(c 2.16, CHCl3); IR (film) 2967, 2876, 1723, 1D454, 1364,
1
1100, 737, 698 cmꢀ1; H NMR (500 MHz, CDCl3) d 0.87
(d, J = 6.9 Hz, 3H, C2–CH3), 1.00 (d, J = 7.0 Hz, 3H,
C3–CH3), 2.34 (m, 1H, C2–H), 2.53 (m, 1H, C3–H), 3.31
(dd, J = 8.2, 9.3 Hz, 1H, one of C1–H2), 3.43 (dd, J =
5.2, 9.3 Hz, 1H, one of C1–H2), 4.48 (d, J = 12.1 Hz, 1H,
one of PhCH2O), 4.49 (d, J = 12.1 Hz, 1H, one of
PhCH2O), 7.25–7.38 (m, 5H, ArH), 9.65 (d, J = 1.7 Hz,
1H, C4–H); 13C NMR (67.8 MHz, CDCl3) d 8.6 (CH3),
12.8 (CH3), 33.5 (CH), 48.1 (CH), 72.8 (CH2), 127.3
(CH), 128.1 (CH), 138.0 (C), 204.5 (CH); EI-HRMS m/z
calcd for C13H18O2 (M)+ 206.1307, found 206.1315; Anal.
Calcd for C13H18O2: C, 75.69; H, 8.80. Found: C, 75.49; H,
8.79.
4.9. Ethyl (4S,5R)-6-hydroxy-4,5-dimethylhexanoate 19
Pd(OH)2 on carbon (20%, 123 mg) was added to a solution
of enoate 18 (3.29 g, 11.9 mmol) in AcOEt (30 mL) under
an argon atmosphere, and the mixture was vigorously
stirred for 5 h under 1 atm of hydrogen. The catalyst was
filtered through a Celite pad, and the filtrate was evapo-
rated in vacuo. Purification of the crude product (2.29 g,
slightly yellow oil) by column chromatography (silica gel
65 g, 4:1 n-hexane/AcOEt) afforded hydroxyester 19
4.8. Ethyl (4S,5R)-6-benzyloxy-4,5-dimethyl-2-hexenoate 18
Triethyl phosphonoacetate (3.8 mL, 18.6 mmol) was added
t
to a suspension of BuOK (2.08 g, 18.5 mmol) in THF
(2.19 g, 97%) as a colorless oil: TLC Rf = 0.13 (4:1 n-hex-
22
(50 mL) at 0 °C under an argon atmosphere. After stirring
at room temperature for 30 min, the solution was cooled to
ꢀ78 °C, and a solution of aldehyde 17 (2.54 g, 12.3 mmol)
in THF (8 mL plus 2 ꢃ 1 mL rinse) was added. After
ane/AcOEt); ½aꢁD ¼ ꢀ10:6 (c 2.40, CHCl3); IR (film)
1
3428 (br), 2961, 2928, 1736, 1181, 1036 cmꢀ1; H NMR
(500 MHz, CDCl3) d 0.82 (d, J = 6.7 Hz, 3H, C3–CH3),
0.84 (d, J = 6.8 Hz, 3H, C2–CH3), 1.26 (t, J = 7.2 Hz,

S. Nakamura et al. / Tetrahedron: Asymmetry 19 (2008) 1059–1067
1065
3H, OCH2CH3), 1.50 (m, 1H, one of C4–H2), 1.55–1.75 (m,
3H, C2–H, C3–H, one of C4–H2), 2.24–2.40 (m, 2H, C5–
H2), 3.48–3.57 (m, 2H, C1–H2), 4.13 (q, J = 7.2 Hz, 2H,
OCH2CH3); 13C NMR (67.8 MHz, CDCl3) d 11.3 (CH3),
13.9 (CH3), 14.0 (CH3), 29.7 (CH2), 32.3 (CH2), 32.7
(CH), 39.2 (CH), 60.1 (CH2), 66.0 (CH2), 174.0 (C);
FAB-HRMS m/z calcd for C10H21O3 (M+H)+ 189.1491,
found 189.1504; Anal. Calcd for C10H20O3: C, 63.80; H,
10.71. Found: C, 63.71; H, 10.71.
was suspended in pentane (60 mL) and filtered through a
plug of Celite. Evaporation of the filtrate in vacuo fur-
nished the crude product (2.91 g), which was used without
further purification.
ZnBr2 (20.3 mg, 90.1 lmol) was added to a solution of the
crude silyl ketene acetal and a-chlorothioanisole (1.8 mL,
13.4 mmol) in CH2Cl2 (30 mL) under an argon atmo-
sphere. After stirring for 12 h, the volatile elements were re-
moved in vacuo, and the residue (5.21 g, orange oil) was
purified by column chromatography (silica gel 90 g, 8:1 n-
hexane/AcOEt) to give sulfide 21 (1.37 g, 58%) as a color-
4.10. (5S,6R)-5,6-Dimethyloxepan-2-one 20
KOH (85%, 2.18 g, 33.0 mmol) was added to a solution of
hydroxyester 19 (2.07 g, 11.0 mmol) in MeOH (20 mL) at
0 °C. After stirring at room temperature for 4 h, the solvent
was removed in vacuo, and the residue was partitioned
between AcOEt (150 mL) and 2 M aqueous NaHSO4
(35 mL). The organic extract was washed with brine
(30 mL) and dried over anhydrous Na2SO4. Filtration
and evaporation in vacuo furnished the crude product
(1.96 g), which was used without further purification.
less oil, along with recovered lactone 20 (168 mg, 13%) as a
23
white solid: TLC Rf = 0.39 (4:1 n-hexane/AcOEt); ½aꢁD
¼
ꢀ1:2 (c 2.01, CHCl3); IR (film) 2963, 2930, 1732, 1584,
1480, 1381, 1262, 1179, 1154, 1094, 741, 693 cmꢀ1 1H
;
NMR (500 MHz, C6D6) d 0.34 (d, J = 6.9 Hz, 1.5H, C2–
CH3), 0.55–0.65 (m, 3H, C3–CH3), 0.73 (m, 0.5H, C3–
H), 0.77 (d, J = 6.9 Hz, 1.5H, C2–CH3), 0.84 (m, 0.5H,
C2–H), 0.93–1.09 (m, 1H, C2–H, one of C4–H2), 1.27
(m, 0.5H, C3–H), 1.41–1.53 (m, 1H, C4–H2), 1.79 (dd,
J = 3.4, 14.3 Hz, 0.5H, one of C4–H2), 2.50–2.60 (m, 1H,
C5–H), 2.76–2.87 (m, 1H, one of CH2SPh), 3.23 (dd,
J = 9.7, 13.2 Hz, 0.5H, one of C1–H2), 3.28 (dd, J = 3.4,
13.2 Hz, 0.5H, one of C1–H2), 3.41 (dd, J = 1.7, 13.2 Hz,
0.5H, one of C1–H2), 3.605 (d, J = 13.2 Hz, 0.5H, one
of C1–H2), 3.609 (dd, J = 4.6, 13.7 Hz, 0.5H, one of
CH2SPh), 3.65 (dd, J = 4.6, 13.7 Hz, 0.5H, one of
CH2SPh), 6.95 (t, J = 7.4 Hz, 1H, ArH), 7.03 (t, J =
7.4 Hz, 1H, ArH), 7.04 (t, J = 7.4 Hz, 1H, ArH), 7.28 (d,
J = 7.4 Hz, 1H, ArH), 7.31 (d, J = 7.4 Hz, 1H, ArH); 13C
NMR (67.8 MHz, CDCl3) d 16.3 (CH3), 16.4 (CH3), 19.0
(CH3), 20.6 (CH3), 30.8 (CH2), 34.0 (CH), 36.0
(2 ꢃ CH2), 36.9 (CH), 37.3 (CH), 37.4 (CH2), 39.7 (CH),
40.8 (CH), 41.2 (CH), 67.8 (CH2), 73.3 (CH2), 126.27
(CH), 126.32 (CH), 128.9 (CH), 129.5 (CH), 129.6 (CH),
135.5 (C), 135.6 (C), 175.90 (C), 175.93 (C); EI-HRMS
m/z calcd for C15H20O2S (M)+ 264.1184, found 264.1177;
Anal. Calcd for C15H20O2S: C, 68.14; H, 7.63; S, 12.13.
Found: C, 68.02; H, 7.55; S, 12.15.
TsOH (41.9 mg, 0.22 mmol) was added to a solution of the
crude hydroxycarboxylic acid 5 (1.96 g) in benzene
(800 mL), and the mixture was refluxed for 1 h. After the
solvent was removed by distillation at atmospheric pres-
sure, the residue was partitioned between AcOEt
(300 mL) and saturated aqueous NaHCO3 (60 mL). The
organic extract was successively washed with saturated
aqueous NaHCO3 (60 mL) and brine (80 mL), and dried
over anhydrous Na2SO4. Filtration and concentration by
atmospheric fractional distillation furnished the crude
product (1.89 g), which was purified by column chromatog-
raphy (silica gel 40 g, 5:2 n-hexane/Et2O) to give lactone 20
(1.41 g, 90%) as a white solid: TLC Rf = 0.28 (3:1 n-hex-
21
ane/AcOEt); mp 41.0–42.0 °C; ½aꢁD ¼ ꢀ43:1 (c 2.02,
CHCl3); IR (nujol) 2922, 1750, 1458, 1377, 1277, 1074,
903 cmꢀ1
;
1H NMR (500 MHz, CDCl3) d 0.98 (d,
J = 6.9 Hz, 3H, C2–CH3), 1.04 (d, J = 6.2 Hz, 3H, C3–
CH3), 1.38–1.51 (m, 2H, C3–H, one of C4–H2), 1.57 (m,
1H, C2–H), 1.89 (m, 1H, one of C4–H2), 2.60–2.69 (m,
2H, C5–H2), 4.03 (dd, J = 8.4, 12.9 Hz, 1H, one of C1–
H2), 4.07 (dd, J = 2.1, 12.9 Hz, 1H, one of C1–H2); 13C
NMR (67.8 MHz, CDCl3) d 16.5 (CH3), 20.4 (CH3), 30.2
(CH2), 32.4 (CH2), 39.8 (CH), 40.0 (CH), 72.9 (CH2),
175.8 (C); EI-HRMS m/z calcd for C8H14O2 (M)+
142.0994, found 142.0997; Anal. Calcd for C8H14O2: C,
67.58; H, 9.92. Found: C, 67.68; H, 9.73.
4.12. (5S,6R)-5,6-Dimethyl-3-methyleneoxepan-2-one 2
A solution of sodium periodate (1.17 g, 5.47 mmol) in H2O
(4 mL) was added to a solution of sulfide 21 (1.31 g,
4.96 mmol) in MeOH (36 mL). After stirring for 24 h, the
mixture was filtrated through a Celite pad, and the filtrate
was evaporated in vacuo. The residue was partitioned
between AcOEt (50 mL) and H2O (20 mL), and the aque-
ous layer was extracted with AcOEt (50 mL). The com-
bined organic extracts were washed with brine (20 mL)
and dried over anhydrous Na2SO4. Filtration and evapora-
tion in vacuo furnished the crude product (1.50 g), which
was purified by column chromatography (silica gel 45 g,
1:2 n-hexane/AcOEt) to give sulfoxide (1.23 g, 89%) as a
white wax.
4.11. (5S,6R)-5,6-Dimethyl-3-(phenylthiomethyl)oxepan-2-
one 21
BuLi in n-hexane (1.56 M, 11.6 mL, 18.1 mmol) was added
i
to a solution of Pr2NH (2.6 mL, 18.6 mmol) in THF
(20 mL) at ꢀ30 °C under an argon atmosphere. After stir-
ring for 30 min, the solution was cooled to ꢀ78 °C, and a
solution of lactone 20 (12.8 g, 9.00 mmol) in THF
(10 mL) was added. After 1 h, TMSCl (2.3 mL, 18.1 mmol)
was added, and the resulting mixture was stirred for
30 min. The reaction mixture was allowed to warm to room
temperature and stirred at this temperature for 1 h. After
the volatile elements were removed in vacuo, the residue
A solution of the sulfoxide (1.23 g, 4.39 mmol) in toluene
(10 mL) was refluxed for 3 h. The solvent was evaporated
in vacuo, and the residue (1.22 g) was purified by column
chromatography (silica gel 35 g, 6:1 n-hexane/Et2O) to give
a-methylene lactone 2 (572 mg, 84%) as a white solid: TLC

1066
S. Nakamura et al. / Tetrahedron: Asymmetry 19 (2008) 1059–1067
Sakamoto, S.; Kamada, K.; Nitta, A.; Noda, T.; Oguri, H.;
Hirama, M. Synlett 2003, 891–893.
Rf = 0.34 (4:1 n-hexane/AcOEt); mp 30.0–31.0 °C;
21
½aꢁD ¼ ꢀ6:7 (c 2.01, CHCl3); IR (nujol) 2963, 2930, 1732,
1462, 1308, 1181, 1140, 1032, 934, 802 cmꢀ1 1H NMR
;
9. (a) Sugimoto, T.; Ishihara, J.; Murai, A. Tetrahedron Lett.
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awa, A.; Murai, A. Chem. Commun. 2001, 1392–1393; (e)
Ishihara, J.; Horie, M.; Shimada, Y.; Tojo, S.; Murai, A.
Synlett 2002, 403–406.
(500 MHz, CDCl3) d 1.02 (d, J = 6.9 Hz, 3H, C2–CH3),
1.04 (d, J = 6.4 Hz, 3H, C3–CH3), 1.46–1.62 (m, 2H, C2–
H, C3–H), 2.17 (dd, J = 10.7, 14.6 Hz, 1H, one of C4–
H2), 2.50 (dd, J = 3.2, 14.6 Hz, 1H, one of C4–H2), 3.94
(dd, J = 6.7, 12.6 Hz, 1H, one of C1–H2), 4.15 (dd,
J = 2.1, 12.6 Hz, 1H, one of C1–H2), 5.43 (s, 1H, one of
C5@CH2), 5.75 (s, 1H, one of C5@CH2); 13C NMR
(67.8 MHz, CDCl3) d 16.2 (CH3), 19.9 (CH3), 38.2 (CH2),
38.2 (CH), 39.3 (CH), 72.4 (CH2), 123.5 (CH2), 141.0
(C), 172.4 (C); EI-HRMS m/z calcd for C9H14O2 (M)+
154.0994, found 154.0999; Anal. Calcd for C9H14O2: C,
70.10; H, 9.15. Found: C, 69.92; H, 9.19.
10. Suthers, B. D.; Jacobs, M. F.; Kitching, W. Tetrahedron Lett.
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Acknowledgments
This research was supported in part by a Grant-in-Aid for
Scientific Research on Priority Areas (A) ‘Exploitation of
Multi-Element Cyclic Molecules’ and Priority Areas
18032002 from the Ministry of Education, Culture, Sports,
Science and Technology (MEXT) and by the Akiyama
Foundation. We thank Ms. H. Matsumoto, A. Maeda, S.
Oka, M. Kiuchi, and Mr. T. Hirose of the Center for
Instrumental Analysis, Hokkaido University for technical
assistance in mass and elemental analyses.
14. For the use of a-methylene lactones in Diels–Alder reactions
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Tetrahedron Lett. 1990, 31, 4863–4866; (b) Takeda, K.;
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