Total synthesis of (-)-amathaspiramide F

Article abstract of DOI:10.1016/j.tet.2009.10.051

The stereoselective total synthesis of the marine alkaloid, (-)-amathaspiramide F (1), was achieved from the α-hydroxy-α-ethynylsilane 2. The key steps involved in the synthesis were (1) the enolate Claisen rearrangement of the α-acyloxy-α-alkenylsilane f

Full text of DOI:10.1016/j.tet.2009.10.051

Tetrahedron 65 (2009) 10355–10364
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Tetrahedron
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Total synthesis of (ꢀ)-amathaspiramide F
*
Kazuhiko Sakaguchi , Miki Ayabe, Yusuke Watanabe, Takuya Okada, Kazushige Kawamura,
*
Tetsuro Shinada, Yasufumi Ohfune
Graduate School of Science, Department of Material Science, Osaka City University, Sugimoto, Sumiyoshi, Osaka 558-8585, Japan
a r t i c l e i n f o
a b s t r a c t
Article history:
The stereoselective total synthesis of the marine alkaloid, (ꢀ)-amathaspiramide F (1), was achieved from
Received 15 September 2009
Received in revised form 14 October 2009
Accepted 14 October 2009
Available online 31 October 2009
the
rearrangement of the
C5 and C9 chiral centers of 1 (erythro configuration), (2) the construction of aza-spirohemiaminal 28, and
(3) dibromination during the final stage of the total synthesis. The reaction of the (Z)- -acyloxy-
a-hydroxy-a-ethynylsilane 2. The key steps involved in the synthesis were (1) the enolate Claisen
a
-acyloxy-a-alkenylsilane for the stereoselective construction of the consecutive
a
a-
alkenylsilane 22 possessing the Boc-homoallylglycine ester as the acyloxy group underwent stereo-
selective enolate Claisen rearrangement to give the desired erythro product 23. On the other hand, the
reaction of the a-acyloxy-a-alkenylsilane (Z)-5 having Boc-proline gave the unexpected threo product 6.
Keywords:
Amathaspiramide F
Enolate Claisen rearrangement
Oxidative cleavage of the vinylsilane group of 23 followed by treatment with heptamethyldisilazane as
the methylamine equivalent gave aza-spirohemiaminal 28. The problematic regioselective dibromination
to 28 was achieved using n-Bu4NBrCl2.
a
-Acyloxysilane
Heptamethyldisilazane
Tetrabutylammonium dichlorobromate
Ó 2009 Elsevier Ltd. All rights reserved.
1. Introduction
a hemiaminal structure exhibit an important biological activity,2
amathaspiramides have attracted interest from medicinal chem-
Amathaspiramides A–F were isolated from a New Zealand
collection of the marine bryozoan Amathia wilsoni by Prinsep and
Morris in 1999 (Fig. 1).1 The structural features common to these
istry. However, only preliminary biological tests regarding their
antimicrobial, antiviral, and cytotoxic activities have been per-
formed for amathaspiramides A–C and E. Amathaspiramide
E exhibited a potent antiviral activity (4þ, 40
Poliovirus Type-I. Amathaspiramides A and E exhibited moderate
cytotoxicity (1þ, 40 g/well) to the BSC-1 cells in addition to
a weak antimicrobial activity (1 mm inhibition zone, 60 g/disk)
mg/well) against
Me
Me
Me
2
1
O
O
O
Me
8
O
R
R
H
N
N
N
N
N
N
N
N
m
O
O H
O H
O H
O H
5
m
9
Br
Br
Br
Br
against the Gram-positive bacterium Bacillus subtilis and fungus
Trichophyton mentagrophytes. Amathaspiramides B and D were
inactive against these viruses, cells, bacteria, and fungi. On the
other hand, the biological activities of the other congeners have
not yet been reported probably due to only minute quantities
available from the marine sources. Only two examples for the
total synthesis of amathaspiramide F (1) have been reported by
Trauner and Hughes3 and our group.4 Their unique structures
together with the unanswered questions surrounding their
biological activity prompted us to synthesize these alkaloids. In
this report, we describe (1) the stereoselective construction of the
consecutive C5 and C9 chiral centers of 1 by the enolate Claisen
11
OMe
OMe
OMe
OMe
13
Br
E
Br
Br
Br
A: R1 = Me
B: R2 = Me
F (1)
D: R2 = H
C: R1 = H
Figure 1. Amathaspiramides.
alkaloids are characterized by a novel aza-spirobicyclic frame-
work that consists of three contiguous chiral centers in which one
of the amino groups is attached to the quaternary carbon center,
a cyclic hemiaminal moiety, and 11,13-dibrominated aromatic
ring (amathaspiramide numbering). Their structures and absolute
configurations were determined by the X-ray diffraction analysis
of amathaspiramide F (1) and extensive NMR studies. Since sev-
rearrangement of the a-acyloxy-a-alkenylsilane and (2) the total
synthesis of (ꢀ)-1 using this method as the key step.
eral natural products containing
a cyclic spirolactam or
2. Results and discussion
The optically active
nificant attention because of its chirality as well as functional group
a-acyloxy-a-alkenylsilane has received sig-
* Corresponding authors. Tel.: þ81 6 6605 2571; fax: þ81 6 6605 2522.
E-mail address: sakaguch@sci.osaka-cu.ac.jp (K. Sakaguchi).
0040-4020/$ – see front matter Ó 2009 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2009.10.051

10356
K. Sakaguchi et al. / Tetrahedron 65 (2009) 10355–10364
transferring properties from the
a
- to
g
-position through a metal-
has been well documented (Eq. 1).6a–c We considered that route b,
which included the pyrrolidine formation from (2S,3R)-E, would
complementarily cover the uncertainties of route a. Both
catalyzed cationic rearrangement5 or an electrocyclic rearrange-
ment with the enolate derived from its acyloxy group.6 In particular,
the ZnCl2-assisted ester-enolate Claisen rearrangement7 of the
intermediates C and D would be prepared from the (S)-
a
-hydroxy-
-hydroxy-
a
-acyloxy-
acids as the acyloxy group produced the vinylsilane-containing
-substituted -amino acids with the complete transfer of the orig-
inal chirality. Theseresults werereportedbyour previous studies, i.e.,
(1) the reaction of the (S,E)- and (S,Z)- -acyloxy- -alkenylsilanes
a
-alkenylsilanes having various N-protected
a
-amino
a-alkynylsilane F, which could be synthesized from the
a
a-ethynylsilane 2 by the arylation of its alkyne terminus and
a
a
subsequent oxidation of the hydroxyl group followed by the
enantioselective reduction of the resulting ketone.10 Since the
natural 1 possesses a methoxy group at its meta position on
the aromatic ring, an electrophilic bromination would occur at its
40 and 60 positions based on electronic reasons. Therefore, the
methoxy substituted aryl group was employed during the initial
stage of these synthetic studies.
a
a
having an N-Boc-acyclic amino acid produced the (2S,3R)- and
(2S,3S)-vinylsilanes, respectively (Eq. 1)6a–c and (2) the reaction was
also applicable to the (S)-a-alkenylsilane having an N-Boc-proline to
give the optically pure (S)-
a
-substituted proline (Eq. 2).6d
O
NHBoc
2.1. Synthetic approaches along the line of route a
HO2C
NHBoc
R
O
R
2S
3R
The synthesis began with the preparation of (Z)-a-acyloxy-a-
S
Si
Si
alkenylsilane 5 from the readily available
a-hydroxy-
a
-ethynylsi-
E
Si = TBS
R = H, Me, Bn
enolate Claisen
rearrangement
lane 210 (Scheme 2).
(1)
O
NHBoc
R
HO2C
NHBoc
R
O
2S
3S
1) n-Bu3SnH
PdCl2(PPh3)2
THF, rt, 1 h
Ar-I
PdCl2(PPh3)2
Et3N, CuI
OH
OH
Ar
Si
S
Si
Si
OH
Z
Si
2) AcOH, MeOH
Si
THF, rt, 1 h
67%
60 oC, 16 h
(Z)-4
Ar
2
3
93% (2 steps)
Boc
N
O
Boc
N
enolate Claisen
rearrangement
O
Boc
N
Boc-L-Pro
OMe
HO2C
EDCI, DMAP
O
Si = TBS
Ar =
O
Si = TBS
(2)
Si
Ar
CH2Cl2, rt, 2 h
97%
Si
S
Si S
(Z)-5
Scheme 2. Synthesis of (Z)-5.
>95% ee
Our plan for the synthesis of 1 was to adopt these methods for
the stereoselective construction of the consecutive C5 and C9
chiral centers of 1 as shown in Scheme 1. We chose the (2S,3R)-
erythro vinylsilane B as the key platform whose oxidative cleavage
of the vinylsilane moiety followed by treatment with methylamine
would furnish the aza-spirohemiaminal A, while the dibromina-
tion of A leading to a natural product remained uncertain at the
planning stage. According to our previous studies in Eqs. 1 and 2,
This compound was prepared in a racemic form for the pre-
liminary examination of the enolate Claisen rearrangement of the
disubstituted olefin with N-Boc-proline as the acyloxy group. The
palladium-catalyzed Sonogashira coupling of 2 with m-iodoanisole
under standard conditions11 afforded the desired coupling product
3 in 67% yield. Hydrogenation of 3 to the (Z)-olefin 4 using the
Lindlar catalyst in several solvents (AcOEt, MeOH, or n-hexane)
even at high pressure (5 atm) was unsuccessful, resulting in the
complete recovery of 3. The use of Pd/C produced the corre-
sponding alkane. Finally, the conversion of 3 to (Z)-4 was success-
fully performed by the Pd-catalyzed hydrostanylation followed by
treatment with AcOH to give the (Z)-olefin 4 (93%, two steps).12 The
the enolate Claisen rearrangement of the (S,Z)-a-acyloxy-a-alke-
nylsilane C or D would proceed through a chair-like transition
state to afford B with the requisite (2S,3R)-configuration. Thus, we
planned two routes (route a via (S,Z)-C and route b via (S,Z)-D) for
the synthesis of B. Route a can minimize the synthetic sequence
although the enolate Claisen rearrangement of the disubstituted
esterification of 4 with Boc-L-proline was effected by EDCI in the
presence of the catalytic DMAP to give the rearrangement pre-
cursor (Z)-5 in 97% yield. The enolate Claisen rearrangement of (Z)-
5 under the conditions employed in our previous studies in Eq. 2
olefin-containing a-acyloxysilane C with an N-protected proline is
unprecedented.8,9 On the other hand, the stereochemical outcome
of the rearrangement of the N-protected acyclic amino acid ester D
P
N
Ar
O
P
N
O
oxidative
route a
O
cleavage
Me
O
P
N
P
N
O
N
Ar
Si
S
OH
OH
Si
5S
RO2C
Z
OH
9R
6'
C
2S
3R
S
Si
Si
(-)-1
enolate Claisen rearrangement
Ar
B
Ar
Si
bromination
F
2
erythro
OR'
Zn
Ar
NP
R' = H or Me
O
4'
A
O
NHP
NHP
Ar
RO2C
2S
3R
O
route b
Si = TBS
P = protecting
group
O
Si
Ar
Si
S
Si
Z
erythro
E
OMe
or
OMOM
D
Ar =
Scheme 1. Synthetic plan.

K. Sakaguchi et al. / Tetrahedron 65 (2009) 10355–10364
10357
Boc
N
HN
HN
Boc
N
Boc
N
O
MeO2C
MeO2C
TsOH.H2O
threo-6
+
erythro-6
1) LHMDS (3 equiv)
-78 °C to rt, THF
MeO2C
MeO2C
O
+
OMe
OMe
+
CH3CH2CN
100 °C, 14 h
Ar
2) CH2N2, Et2O
Si
Si
Ar
Si
Ar
erythro-6
threo-10
68%
erythro-10
19%
(dr 3.5:1)
(Z)-5
Si = TBS Ar =
threo-6
TFA
OMe
32%, threo:erythro = >20:1 (with 20% HMPA)
88%, threo:erythro = 16:1 (without HMPA)
N
O3, MeOH,
-78 °C, 1 min
MeO2C
(CF3CO)2O
threo-10
(major isomer)
Scheme 3. Enolate Claisen rearrangement of (Z)-5.
OMe
OMe
pyridine, rt, 1.5 h
91%
then Me2S
quant
threo-11
6d
TFA
N
(3 equiv LHMDS in HMPA/THF (1:4) at ꢀ78 ꢁC to rt)
gave the
H
O
TFA
O
NaBH4
N
O
5
rearranged product 6 in 32% yield (Scheme 3). Although the yield
was moderate, the diastereoselectivity of this rearrangement was
>20:1 (by 1H NMR). The major product either the threo or erythro
isomer was determined by the conversion of 6 to a spirolactone
(vide infra, Scheme 5), which revealed that the major isomer was
the undesired threo-6. Without HMPA, the yield increased to 88%,
however, the undesired threo-6 was the major product (dr 16:1).
These results suggested that the Claisen rearrangement of (Z)-5 did
not proceed through the conventional chair-like transition state as
shown in Scheme 1. To gain an insight into the enolate Claisen
rearrangement of the proline-containing disubstituted olefin, our
next attempt was the reaction using an E-isomer.
MeO2C
O
MeOH, 0 °C
9
N
O
OMe
43%
H
H
TFA
OMe
TFA
N
5
threo-13
threo-12
TFA
N
O
O
31% (3 steps)
O
9
O
erythro-10
(minor isomer)
H
NOE
OMe
H
O
OMe
erythro-13
TFA =
F3C
Scheme 5. Determination of relative configuration of threo-6 and erythro-6.
The (E)-olefin 5 was prepared from m-anisaldehyde (7) by the
following sequence of reactions (Scheme 4): (1) Horner–Wads-
worth–Emmons olefination of 7 with (
(2) Luche reduction of the resulting (E)-silyl ketone 9,14 and (3)
esterification of the resulting alcohol (E)-4 with Boc- -Pro (86%,
three steps from 7). However, the enolate Claisen rearrangement of
(E)-5 {LHMDS (3 equiv), HMPA/THF (1:4), ꢀ78 ꢁC to rt} resulted in
the predominant formation of threo-6 in 36% yield (dr >20:1). The
threo selectivity was decreased to 3.5:1 (91% yield) without HMPA.
The 3.5:1 mixture 6, inseparable by preparative TLC, was converted
to the spirolactone 13 for the determination of the relative ste-
reochemistry of 6 (Scheme 5).
a
-phosphonoacyl)silane 8,13
results suggested that the reaction of (E)-5 proceeded via the
conventional chair-like transition state.
In a previous report, we proposed that the enolate Claisen
rearrangement of the proline ester with a monosubstituted olefin
in the presence of HMPA proceeded through a chair-like transition
state with the Z-enolate (Z/E, >98:2) to give the rearrangement
product with complete transfer of the original chirality (Eq. 2).8
However, it was found that the reaction of the disubstituted (Z)-
olefin 5 produced the undesired isomer threo-6, suggesting that the
reaction did not proceed via the conventional chair-like transition
state. To account for the same threo selectivity (>20:1) in the
enolate Claisen rearrangement of both (Z)-5 and (E)-5 possessing
L
an Ar group at C3, we examined the B3LPY/6-31G
calculations16 to
*
OMe
O
OH
8, NaH
NaBH4, CeCl3-7H2O
MeOH, 0 °C, 5 min
92%
estimate the activation energy of the enolate Claisen rearrange-
ment using the model enolates (Z)-14 and (E)-14, where the TBS,
N-Boc, and Ar groups of 5 were replaced with the H3Si, N-Ac, and Ph
groups, respectively (Scheme 6). The calculations were carried out
for both the enolates (Z)-14 and (E)-14 with a boat and chair-like
transition state (G, H, K, and L from (Z)-14 and I, J, M, and N from
(E)-14), respectively, while the preferential formation of the mon-
oanionic Z-enolate (Z/E, >98:2) in the presence of HMPA was pro-
posed in our previous studies.8 According to the calculation of the
Z-enolate transition state derived from (Z)-14, the boat-like tran-
sition state G was found to be more stable (2.0 kcal/mol) than the
chair-like H probably due to the severe steric repulsion between the
Ph group and the N-Ac group. Both E-enolates with the chair and
boat-like transition state structures, K and L, respectively, showed
higher activation energy than that of G. These calculations support
that (Z)-5 would undergo the enolate Claisen rearrangement via the
boat-like G to give threo-6 as the major product,17 which is in good
agreement with the experimental result of the high threo selectivity
(dr >20:1) observed during the conversion of (Z)-5 to threo-6.
The calculations of the transition state derived from (E)-14
revealed that the chair-like I was the most stable transition state
form among the other forms, J, M, and N, which agrees with the
high threo selectivity for the rearrangement of (E)-5 to threo-6 (dr
>20:1).18 These results clearly indicated that the enolate Claisen
rearrangement of both the (Z)- and the (E)-proline-containing
Si
Ar
Si
Ar
THF, rt, 15 h
quant
OHC
9
(E)-4
7
Boc
N
O
1) LHMDS (3 equiv)
-78 °C to rt, THF
Boc-L-Pro
threo-6
+
O
EDCI, DMAP
CH2Cl2, rt, 2.5 h
94%
2) CH2N2, Et2O
erythro-6
Si
Ar
(E)-5
36%, threo:erythro = >20:1
(with 20% HMPA)
O
O
P
Si = TBS
91%, threo:erythro = 3.5:1
(without HMPA)
OMe
OMe
8
Si
Scheme 4. Enolate Claisen rearrangement of (E)-5.
To avoid the troublesome oxidative cleavage of the vinylsilane,15
the silyl group of 6 was removed using TsOH to give a mixture of the
cyclic amine 10. Fortunately, the mixture was separable by silica gel
column chromatography to give the major isomer-10 (68%) and the
minor isomer-10 (19%). Each major-10 and minor-10 was converted
to the corresponding spirolactones major-13 and minor-13, by the
following sequence of reactions: (1) protection of the amino group
by a trifluoroacetyl (TFA) group, (2) ozonolysis of the olefin 11, and
(3) the reduction of the resulting aldehyde 12 followed by lacto-
nization. The NOE experiments of each spirolactone clearly in-
dicated that the major-13 possessed the threo configuration and the
minor-13 possessed the erythro configuration at C5 and C9. These
a
-acyloxy-
a-alkenylsilanes 5 gave the undesired threo-6 for the
construction of the C5 and C9 stereogenic centers of 1 (route a).

10358
K. Sakaguchi et al. / Tetrahedron 65 (2009) 10355–10364
O
Ph
NHBoc
Ar
O
Boc-homoallylglycine
OH
Ph
O
O
EDCI, DMAP
CH2Cl2, rt, 4 h
97%
N
Ar
Ac
Si
threo
Si
O
Si
N
K
(Z)-4
G
Si
15
O
Ac
Z-enolate, boat
E-enolate, chair
33.3 kcal/mol
1) OsO4, NMO
1,4-dioxane-H2O (3:1), rt, 2.5 h
NHBoc
31.9 kcal/mol
MeO2C
LDA, ZnCl2
(Z)-14
AcN
Ph
Ph
THF, -78 °C to rt, 1.5 h
then CH2N2
2) NaIO4
t-BuOH-pH 6.86 buffer (3:2), rt, 3 h
3) NaBH3CN, AcOH, 70 °C, 45 min
69% (3 steps)
O
Si
Ar
16 (dr 4.2:1)
Ac
O
N
erythro
64%
Si
L
O
Si
O
Boc
H
E-enolate, boat
35.3 kcal/mol
Zn
Ar
NBoc
Si = TBS
Ar =
N
Z-enolate, chair
O
MeO2C
33.9 kcal/mol
OMe
Si = H3Si
Si
Ar
Ac
O
O
AcN
O
O
N
Si
homoallyl
erythro-6 (dr 4.5:1)
Ph
threo
Scheme 7. Synthesis of erythro-6 from (Z)-4.
O
Si
Ph
M
Si
O
I
Z-enolate, chair
E-enolate, boat
amounts of methylamine in MeOH gave the aza-spirohemiaminal
1719 as the exclusive diastereomer in 36% yield. The electrophilic
bromination of 17 with NBS (2 equiv) in DMF (rt, 18 h) gave only
monobrominated product 18 in 84% yield. However, none of the
40,60-dibrominated product was detected even at elevated tem-
perature.20 The reaction with Br2 (2 equiv) in CH2Cl2 also gave 18
(30%). Numerous attempts for the electrophilic bromination by the
addition of TsOH, AcOH or SiO2 were unsuccessful.21 These results
suggested that the highly reactive phenol is necessary to accom-
plish the dibromination reaction on the aromatic ring instead of the
methoxybenzene moiety of 17.
25.3 kcal/mol
29.5 kcal/mol
(E)-14
O
O
O
N
Ph
erythro
Ac
J
Si
Ph
N
Si
N
O
Ac
Z-enolate, boat
27.9 kcal/mol
E-enolate, chair
29.7 kcal/mol
Ac
O
Ac
O
N
O
N
O
To generate the phenol moiety during the late stage of the total
synthesis, the methoxymethyl (MOM) group was chosen for its
protecting group because this group can be readily removed under
Ph
H3Si
Ph
H3Si
(Z)-14
(E)-14
Scheme 6. Activation energies of the enolate Claisen rearrangement of (Z)-14 and
TFA
N
(E)-14 by B3LYP/6-31G calculation.
*
Scheme 5
MeO2C
O
MeNH2 (80 equiv)
OMe MeOH, rt, 13 h
36%
erythro-6
(dr 4.5:1)
2.2. Synthetic approaches via route b
86% (3 steps)
Next, we turned our attention to route b. We envisioned that the
(S,Z)-
a
-acyloxy-
a
-alkenylsilane having the homoallylglycine
D
erythro-12
TFA
TFA
would undergo the enolate Claisen rearrangement via the chair-like
transition state with a dianionic Z-enolate to give the (2S,3R)-
erythro-E (Scheme 1).6a–c The rearrangement precursor 15 was
prepared by the coupling of (Z)-4 with Boc-homoallylglycine (97%)
(Scheme 7). The dianionic enolate Claisen rearrangement of 15 was
examined under the established conditions.6a–c The treatment of 15
with LDA (3 equiv) and ZnCl2 (1.2 equiv) in THF under ꢀ78 ꢁC to rt
followed by esterification with CH2N2 gave the rearranged product
16 in 64% yield as an inseparable mixture of its diastereomer (dr
4.2:1, by 1H NMR). The mixture was converted to the desired
erythro-6 (dr 4.5:1) by the following sequence of reactions: (1)
chemoselective dihydroxylation of the terminal olefin with OsO4,
(2) oxidative cleavage of the resulting diol with NaIO4, and (3)
reductive amination with NaBH3CN in AcOH (67%, three steps from
16). The 1H NMR of the resulting erythro-6 was in good agreement
with that of the minor isomer 6 synthesized in route a (Scheme 3).
Thus, the desired erythro-6 was selectively obtained via route b,
which indicated that the ZnCl2-assisted dianionic enolate Claisen
rearrangement of 15 preferentially proceeded via the chair-like
transition state O.
O
N
O
N
NBS (2.3 equiv)
DMF, rt, 18 h
Me
N
Me
N
OMe
OMe
O H
Br
O H
4'
6'
4'
84%
17
18
Scheme 8. Synthesis of 18 from erythro-6.
mild acidic conditions. Toward the enantioselective synthesis of 1
via route b, we synthesized the enolate Claisen precursor (S,Z)-22 in
an optically active form (Scheme 9). The a-hydroxysilane 19 was
prepared by the Sonogashira coupling of 2 with MOM-protected
3-iodophenol (73%). The oxidation of 19 using Jones reagent or
other chromium reagents was accompanied by a significant loss of
the TBS group to give the silyl ketone 20 in moderate yields. On the
other hand, Mukaiyama’s oxidation (NCS and catalytic PhSNH-t-Bu)
afforded 20 in 81% yield without any loss of the TBS group.22 The
enantioselective reduction of 20 by (þ)-DIP-Cl23 gave the optically
Toward the total synthesis of 1, the unexploited aza-spiro-
hemiaminal formation and the dibromination of the aromatic
group remained to be solved. The preliminary attempts for these
transformations are summarized in Scheme 8. The treatment of the
diastereomerically pure erythro-12, prepared from erythro-6 in
a manner similar to those of the threo-12 (Scheme 5), with excess
pure (S)-a-hydroxy-a-alkynylsilane 19 (87%, >95% ee). The (S,Z)-
olefin 21 was prepared by the Pd-catalyzed hydrostanylation of
(S)-19 followed by the acidic treatment (66%, two steps). The
esterification of 21 with racemic Boc-homoallylglycine was effected
a-acyloxysilane 22 in 90% yield.
The enolate Claisen rearrangement of (S,Z)-22 {LDA (4 equiv),
by EDCI and DMAP to give the (S,Z)-

K. Sakaguchi et al. / Tetrahedron 65 (2009) 10355–10364
10359
would prevent the undesired
b
-elimination reaction. In fact, the
Ar-I
PhSNH-t-Bu
PdCl2(PPh3)2
Et3N, CuI
O
OH
OH
treatment of 27 with excess heptamethyldisilazane gave 28 in 50%
yield and was reproducible (Scheme 12). The lactam 31 was the
only byproduct (12%) isolated from the reaction mixture. The
relative stereochemistry of 28 including the hydroxy group at C8
was assigned as shown in Scheme 12 based on its NOE experiments.
NCS, K2CO3
Si
Si
Si
THF, rt, 1 h
73%
MS4A, CH2Cl2
0 °C, 3 h
81%
Ar
Ar
2
20
19
1) PdCl2(PPh3)2
OH
n-Bu3SnH
OH
(+)-DIP-Cl
THF, rt, 1 h
TFA
N
Ar
TFA
N
Si
Si
O
O
2) AcOH, MeOH
60 °C, 16 h
THF, -40 °C, 17 h
87%
Ar
(S)-19
21
>95% ee
O
O
Me
N
+
66% (2 steps)
TFA
N
TFA
N
Ar
Ar
OMOM
MeO
29 (18%)
TFA
HN
MeO2C
O
NHBoc
HO
28 (24%)
MeNH2
Ar =
Si = TBS
Boc-homoallylglycine
EDCI, DMAP
MeO2C
O
(5 equiv)
O
BCl
Ar
Ar
MeOH
rt, 2 h
(+)-DIP-Cl =
CH2Cl2, rt, 4 h
Si
S
Ar
O
H
2
22
90%
27
+
X
N
Me
Scheme 9. Synthesis of 22.
H
Ar
H
OH
MeHN
Ar =
ZnCl2 (1.2 equiv), THF, ꢀ78 ꢁC to rt, 3 h, then CH2N2} smoothly
proceeded to give the desired (2S,3R)-isomer 23 as an inseparable
mixture of its diastereomer24 (83%, dr 7:1) (Scheme 10).25 The
30: X = O (22%)
31: X = NMe (12%)
Scheme 11. Construction of aza-spirohemiaminal by MeNH2.
mixture was converted to the a-substituted proline 24 in a manner
similar to the preparation of erythro-6 as shown in Scheme 7 (67%,
three steps). The treatment of 24 with TsOH gave the protection-
free phenol derivative 25 in 88% yield. Re-protection of the
resulting amino group with a TFA group gave 26 (91%), which, upon
ozonolysis, afforded the aldehyde 27. The minor diastereomer was
separated at this stage by flash silica gel chromatography to give the
diastereomerically pure (2S,3R)-27 (73%).
TFA
N
O
TFA
N
Me
H
N
8S
MeN(TMS)2
(100 equiv)
MeO2C
O
28
HO
H
H
MeOH, rt, 15 h
50%
OH
H
H
OH
NOESY
27
Scheme 12. Construction of aza-spirohemiaminal by MeN(TMS)2.
Boc
N
LDA (4 equiv)
NHBoc
Ar
Scheme 7
MeO2C
MeO2C
Prior to the dibromination of 28, we attempted the dibromina-
tion using 26 as a model substrate. However, the 1H NMR of the
reaction mixture indicated that the bromination of 26 with NBS
(2 equiv) in DMF at 0 ꢁC afforded a mixture of the 60-mono- and
20,40,60-tribrominated products as the major products. Only a de-
tectable amount of the desired 40,60-dibrominated product was
produced (Scheme 13). Increasing amounts of NBS (3 equiv) affor-
ded the 20,40,60-tribrominated product as the exclusive product.
Using Br2 and changing the solvent and temperature, the reaction
gave the same products as that of NBS.28
ZnCl2 (1.2 equiv)
2S
3R
22
THF, -78 °C to rt, 3 h
then CH2N2
67%
Si
Si
Ar
(3 steps)
24 (dr 7:1)
23 (dr 7:1)
83%
TFA
N
HN
MeO2C
MeO2C
TsOH.H2O
(CF3CO)2O
pyridine, rt, 1.5 h
OH
OH
CH3CH2CN
100 °C, 14 h
91%
25 (dr 7:1)
88%
26 (dr 7:1)
TFA
N
Br
O3, MeOH,
MeO2C
2'
-78 °C, 1 min
R
R
R
R
OH
Br
OH
Br
OH
OH
NBS (2 equiv)
2S
3R
OMOM
+
+
Si = TBS
Ar =
O
then Me2S
73%
OH
4'
6'
DMF, 0 °C
20 min
Br
Br
Br
6'-monobromo 4',6'-dibromo
2',4',6'-tribromo
26 (dr 7:1)
27
TFA
N
(20 : 1 : 36, by 1H NMR)
Scheme 10. Synthesis of 27 from 22.
MeO2C
R =
The final approach to amathaspiramide F was the construction
of the aza-spirohemiaminal and the dibromination. The aldehyde
27 was subjected to an excess amount of methylamine in MeOH to
give the desired spirohemiaminal 28 as the exclusive diastereomer.
However, the yield was moderate (32%) as observed in the prepa-
ration of 17 (Scheme 8). Thus, we examined the control experi-
ments of this transformation as follows: the treatment with 5 equiv
of methylamine gave a mixture of products consisting of the de-
sired 28 (24%), spirolactone 2926 (18%), butenolide 30 (22%), and
lactam 31 (12%) (Scheme 11).27 Further treatment of each product
under the same reaction conditions remained unchanged. Pre-
sumably, the side products 30 and 31 were produced by the retro-
Michael reaction in which methylamine attacked the proton
Scheme 13. Bromination of 26 using NBS.
Upon careful survey of the literature regarding electrophilic
bromination, Negoro et al. reported that tetrabutylammonium
dichlorobromate (n-Bu4NBrCl2) is an effective reagent for the
electrophilic o,p-dibromination of phenols as a mild source of
bromonium chloride (Scheme 14).29 Thus, we examined the
Br
n-Bu4NBrCl2
OH
Br
OH
Br
OH
OH
(2 equiv)
+
+
CH2Cl2, 0 °C
Br
Br
Br
11%
86%
3%
attached to the
a-position (Scheme 11). We considered that the
Scheme 14. Dibromination of 3-methylphenol using n-Bu4NBrCl2.
sterically bulky heptamethyldisilazane instead of methylamine

10360
K. Sakaguchi et al. / Tetrahedron 65 (2009) 10355–10364
dibromination using Negoro’s conditions. The reaction of 28 with
n-Bu4NBrCl2 (2.5 equiv) in CH2Cl2 smoothly proceeded to give the
desired 40,60-dibrominated product 32 in 59% yield (Scheme 15)
accompanied by a trace amount of the 60-monobrominated prod-
uct. Finally, etherification of the phenol moiety of 32 (MeI, K2CO3,
acetone, rt, 48 h) afforded the N-TFA protected amathaspiramide F
(33) (84%), which was Trauner’s synthetic intermediate.3 The TFA
group was removed by LiBH4 to give the (ꢀ)-amathaspiramide F (1)
(53%). The spectroscopic data of the synthetic (ꢀ)-1 were in good
agreement with those of the natural product.30
parts per million (ppm,
d
) relative to CHCl3
(
d
¼7.26) in CDCl3. 13
C
NMR spectra were recorded on either JOEL JNM-LA 300 (75 MHz),
JOEL JNM-LA 400 (100 MHz), or Bruker AVANCE 600 (150 MHz)
spectrometer. Chemical shifts of 13C NMR were reported in ppm (
d)
relative to CHCl3
(
d¼77.0) in CDCl3. Low resolution mass spectral
(LRMS) analysis and high resolution mass spectral (HRMS) analysis
were measured on either JEOL JMS-D300 or JEOL JMS-AX500
spectrometer by means of electron ionization (EI), chemical ioni-
zation (CI), or fast atom bombardment ionization (FAB). All re-
actions were monitored by thin layer chromatography (TLC), which
was performed with glass-support precoated plates (Merck Kie-
selgel 60 F254, 0.25 mm). TLC visualization was accompanied using
UV lamp (254 nm) or a charring solution (ethanolic p-anisaldehyde,
ethanolic phosphomolybdic acid, aqueous potassium permanga-
nate, and butanolic ninhydrin). All products were purified by flash
column chromatography on silica gel (Daisogel IR-60 1002 W, 40/
TFA
N
TFA
N
O
O
n-Bu4NBrCl2
(2.5 equiv)
Me
N
Me
N
2'
8
CH2Cl2, 0 oC, 3 h
OH
Br
OH
O H
Br
O H
63
(AcOEt) unless otherwise indicated. The activation energy for the
enolate Claisen rearrangement was estimated by the B3LYP/6-31G
mm) eluting with a solvent mixture of hexane and ethyl acetate
59%
4'
6'
32
28
*
TFA
single-point energy calculations, based on the optimized transition
state structure from Hartree–Fock 3-21G calculations.
Full experimental details and characterization data of erythro-11,
erythro-12, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32,
33, and (ꢀ)-1 were reported.4
O
N
MeI (1.4 equiv)
K2CO3 (1 equiv)
LiBH4 (4 equiv)
Me
N
(-)-1
OMe
Br
acetone, rt, 48 h
84%
THF, rt, 1.5 h
53%
O H
Br
33
3.1.1. 1-(tert-Butyldimethylsilyl)-3-(3-methoxyphenyl)prop-2-yn-1-
ol (3). To a solution of PdCl2(PPh3)2 (1.72 g, 2.45 mmol), CuI
(467 mg, 2.45 mmol), Et3N (3.4 mL, 36.77 mmol), and iodoanisole
(3.7 mL, 31.86 mmol) in THF (44 mL) was added dropwise 2 (4.17 g,
24.51 mmol) in THF (18 mL) at rt, and the reaction mixture was
stirred at rt for 1 h. The reaction mixture was exposed to saturated
NH4Cl and was extracted with ether. The organic layer was washed
with brine and dried over anhydrous MgSO4. The solvent was
evaporated in vacuo to give a crude residue, which was purified by
flash column chromatography on silica gel (n-hexane/AcOEt¼30:1)
to give 3 (4.56 g, 67%) as yellow oil: FTIR (neat) 3446, 2216, 2171,
1604, 1576, 1489, 1481, 1464, 1429, 1391, 1363, 1316, 1289, 1249,
1206, 1175, 1165, 1082, 1048, 1014 cmꢀ1; 1H NMR (300 MHz, CDCl3)
Scheme 15. Synthesis of (ꢀ)-1.
In conclusion, we achieved the stereoselective total synthesis of
-hydroxy- -ethynylsilane 2
(ꢀ)-amathaspiramide F (1) from the
a
a
in 17 steps (1.3% overall yield). The key features of the present
synthesis are as follows: (1) stereoselective construction of the
contiguous C5 and C9 stereogenic centers by the ester-enolate
Claisen rearrangement of the a-acyloxy-a-alkenylsilane 22 having
an N-Boc-homoallylglycine as the acyloxy group, (2) efficient dia-
stereoselective construction of the aza-spirohemiaminal 28 by the
use of the sterically bulky heptamethyldisilazane to avoid the un-
desired b
-elimination, and (3) electrophilic 40,60-dibromination of
d
7.21 (t, J¼8.0 Hz, 1H), 6.99 (d, J¼8.0 Hz, 1H), 6.93 (m, 1H), 6.85 (dd,
J¼8.0, 2.6 Hz, 1H), 4.44 (s, 1H), 3.80 (s, 3H), 1.51 (br s, 1H), 1.02 (s,
9H), 0.17 (s, 3H), 0.15 (s, 3H); 13C NMR (75 MHz, CDCl3)
159.2,
the 30-substituted phenol 28 with n-Bu4NBrCl2. During the con-
struction of the consecutive C5 and C9 chiral centers, a high threo
selectivity was observed in the ester-enolate Claisen rearrange-
d
129.3, 124.4, 123.8, 116.3,114.3, 90.4, 87.9, 55.2, 55.0, 26.9, 17.0, ꢀ7.8,
ꢀ8.4; HRMS (EI) m/z calcd C16H24O2Si for (M)þ 276.1546, found
276.1547.
ment of both the (E)- and the (Z)-a-acyloxy-a-alkenylsilanes 5
having N-Boc-proline as the acyloxy group. The synthesis of other
congeners of amathaspiramide (A–E) as well as the biological
evaluation of 1 is currently in progress in our laboratories.
3.1.2. (Z)-1-(tert-Butyldimethylsilyl)-3-(3-methoxyphenyl)prop-2-
en-1-ol {(Z)-4}. To a solution of PdCl2(PPh3)2 (117 mg, 0.167 mmol)
and 5 (4.6 g, 16.7 mmol) in THF (30 mL) was added dropwise tribu-
tyltin hydride (5.4 mL, 19.9 mmol) in THF (20 mL), and the reaction
mixturewas stirred at rt for 1 h. The solvent was evaporated in vacuo
to give a crude residue, which was purified by flash column chro-
matography on silica gel (n-hexane/AcOEt¼90:1) to give (E)-1-(tert-
butyldimethylsilyl)-3-(tributylstannyl)-3-(3-methoxyphenyl)prop-
2-en-1-ol (9.5 g) with a small amount of impure material. To the
resulting (E)-1-(tert-butyldimethylsilyl)-3-(tributylstannyl)-3-(3-
methoxyphenyl)prop-2-en-1-ol were added AcOH (40 mL) and
MeOH (80 mL), and the reaction mixture was stirred at 60 ꢁC for
16 h. The reaction mixture was exposed to saturated NaHCO3 and
was extracted with ethyl acetate. The organic layer was washed with
brine and dried over anhydrous MgSO4. The solvent was evaporated
in vacuo to give a crude residue, which was purified by flash column
chromatography on silica gel (n-hexane/AcOEt¼50:1) to give 4
(4.3 g, 93%) as yellow oil: FTIR (neat) 3446, 1597, 1577, 1490, 1464,
1433, 1362, 1255, 1147, 1081, 1049 cmꢀ1; 1H NMR (300 MHz, CDCl3)
3. Experimental section
3.1. General methods
All reagents and solvents were purchased from either Aldrich
Chemical Company, Inc., Merck & Co., Inc., Nacalai Tesque Company,
Ltd, Peptide Institute, Tokyo Kasei Kogyo Co. Ltd, or Wako Pure
Chemical Industries, Ltd, and used without further purification
unless otherwise indicated. Dichloromethane (CH2Cl2) was distilled
from diphosphorus pentaoxide (P2O5). Tetrahydrofuran (THF),
diethyl ether (Et2O), acetonitrile (CH3CN), and dimethylformamide
(DMF) of anhydrous grade were used. Ozone was generated by
Japan Ozone ON-3-2. Specific optical rotation ([a]D) was taken on
a Perkin Elmer 241 polarimeter or JASCO P-1030 polarimeter with
a sodium lamp (D line). FTIR spectra were measured on a Jasco FT-IR
420 infrared spectrophotometer. 1H and 13C NMR spectra were
recorded on either JEOL JNM-LA 300 (300 MHz), JEOL JNM-LA 400
(400 MHz) or Bruker AVANCE 600 (600 MHz) spectrometer at
ambient temperature. Chemical shifts of 1H NMR were reported in
d
7.24 (t, J¼7.6 Hz,1H), 6.84–6.78 (3H), 6.41 (d, J¼11.4 Hz,1H), 5.83 (t,
J¼11.4 Hz,1H), 4.81 (d, J¼11.4 Hz,1H), 3.81 (s, 3H),1.37 (br s,1H), 0.96

K. Sakaguchi et al. / Tetrahedron 65 (2009) 10355–10364
10361
(s, 9H), 0.09 (s, 3H), ꢀ0.01 (s, 3H); 13C NMR (100 MHz, CDCl3)
d
159.5,
3.1.5. (E)-1-(tert-Butyldimethylsilyl)-3-(3-methoxyphenyl)prop-2-
en-1-one (9). To a suspension of NaH (13.2 mg, 0.552 mmol) in THF
(1.9 mL) was added the Horner–Emmons reagent 8 (200 mg,
0.752 mmol) at 0 ꢁC under an argon atmosphere. After the reaction
mixture was stirred at rt for 5 min, to the mixture was added
138.4,133.9,129.1,128.0,121.2,114.2,112.5, 62.3, 55.2, 27.0,17.1, ꢀ7.1,
ꢀ8.7; HRMS (FAB) m/z calcd for C16H25O2Si (MꢀH)þ 277.1624, found
277.1624.
3.1.3. tert-Butyl (Z)-1-(tert-butyldimethylsilyl)-3-(3-methoxyphenyl)-
m-anisaldehyde (7, 30 mL, 0.251 mmol). The reaction mixture was
allyl pyrrolidine-1,2-dicarboxylate {(Z)-5}. To
(404 mg,1.46 mmol) in CH2Cl2 (4.4 mL) were added N-Boc-
a
solution of
4
stirred at rt for 15 h, and then quenched by saturated NH4Cl. The
mixture was extracted with AcOEt, and organic layer was washed
with brine and dried over anhydrous MgSO4. The solvent was
evaporated in vacuo. The residue was purified by flash column
chromatography on silica gel (n-hexane/AcOEt¼10:1) to give 9
(72 mg, quant) as pale red oil: FTIR (neat) 1697, 1638, 1624, 1578,
1562, 1488, 1464, 1434, 1392, 1363, 1290, 1274, 1251, 1193, 1159,
L-proline
(631 mg, 2.93 mmol), 1-ethyl-3-(3-dimethylaminopropyl)-carbo-
diimide (EDCI, 560 mg, 2.93 mmol), and 4-N,N-dimethylaminopyr-
idine (DMAP, 18 mg, 0.15 mmol) and the mixture was stirred at rt
for 2 h. The reaction mixture was exposed to saturated NH4Cl and
was extracted with ethyl acetate. The organic layer was washed
with brine and dried over anhydrous MgSO4. The solvent was
evaporated in vacuo to give a crude residue, which was purified by
flash column chromatography on silica gel (n-hexane/AcOEt¼20:1)
to give (Z)-5 (673 mg, 97%, a mixture of diastereomers, dr¼1:1) as
colorless oil: FTIR (neat) 1733, 1699, 1598, 1576, 1489, 1471, 1464,
1048, 1007 cmꢀ1 1H NMR (400 MHz, CHCl3)
; d 7.35–7.29 (2H), 7.15
(d, J¼7.8 Hz, 1H), 7.07 (m, 1H), 6.99 (d, J¼16.4 Hz, 1H), 6.94 (dd,
J¼7.8, 2.4 Hz, 1H), 3.83 (s, 3H), 0.97 (s, 9H), 0.30 (s, 6H); 13C NMR
(75 MHz, CDCl3) d 235.3,159.9,140.6,136.3,131.3,129.9,121.0,116.0,
113.3, 55.3, 26.6, 16.8, ꢀ6.1; HRMS (FAB) m/z calcd for C16H25O2Si
1393, 1365, 1257, 1160, 1121, 1087, 1039 cmꢀ1
;
1H NMR (400 MHz,
(MþH)þ 277.1624, found 277.1617.
CDCl3) 7.26–7.20 (1H), 7.11–6.99 (2H), 6.79–6.75 (1H), 6.37–6.33
d
(1H), 6.03–5.96 (1H), 5.63–5.56 (1H), 4.37 (dd, J¼8.6, 3.2 Hz, 1/3H),
4.29 (dd, J¼8.8, 3.7 Hz, 2/3H), 3.82–3.81 (3H), 3.56–3.48 (5/3H),
3.41–3.35 (1/3H), 2.29–2.12 (1H), 2.04–1.97 (1H), 1.93–1.86 (2H),
1.46 (s, 9/3H),1.42 (s, 18/3H), 0.85 (s, 9/3H), 0.84 (s, 18/3H), ꢀ0.00 (s,
3.1.6. (E)-1-(tert-Butyldimethylsilyl)-3-(3-methoxyphenyl)prop-2-
en-1-ol {(E)-4}. To a solution of 9 (67 mg, 0.243 mmol) and cerium
chloride$7H2O (135 mg, 0.365 mmol) in MeOH (1.2 mL) was added
sodium borohydride (11 mg, 0.291 mmol) at 0 ꢁC, and the reaction
mixture was stirred for 5 min at 0 ꢁC. The reaction mixture was
exposed to saturated NH4Cl and was extracted with ethyl acetate.
The organic layer was washed with brine and dried over anhy-
drous MgSO4. The solvent was evaporated in vacuo to give a crude
residue, which was purified by flash column chromatography on
silica gel (n-hexane/AcOEt¼30:1) to give (E)-4 (62 mg, 92%) as pale
yellow oil: FTIR (neat) 3459, 3001, 2954, 2928, 2884, 2856, 1692,
1640, 1599, 1579, 1489, 1464, 1433, 1391, 1362, 1317, 1287, 1252,
3H), ꢀ0.08 (s, 3H); 13C NMR (100 MHz, CDCl3)
d 172.8, 172.7, 159.59,
159.52, 154.2, 153.8, 138.5, 138.3, 129.4, 129.3, 129.27, 129.25, 128.6,
128.3, 120.97, 120.94, 113.6, 113.3, 113.1, 112.9, 79.9, 79.4, 66.94,
66.88, 59.4, 59.2, 55.2, 46.4, 46.3, 30.8, 29.8, 28.41, 28.37, 26.73,
26.70, 24.3, 23.4, 17.00, 16.97, ꢀ7.37, ꢀ7.40, ꢀ8.02, ꢀ8.04; HRMS
(FAB) m/z calcd for C26H41NO5Si (M)þ 475.2754, found 475.2754. A
complex 1H NMR was observed because of a mixture of di-
astereomers and rotamers.
1193, 1156, 1047, 1007 cmꢀ1 1H NMR (300 MHz, CDCl3)
; d 7.23 (t,
3.1.4. (R
*
)-1-tert-Butyl 2-methyl 2-{(R
*
,E)-3-(tert-butyldimethylsilyl)-
J¼7.9 Hz, 1H), 6.95 (d, J¼7.9 Hz, 1H), 6.89 (m, 1H), 6.76 (m, 1H),
1-(3-methoxyphenyl)allyl}pyrrolidine-1,2-dicarboxylate (threo-6). To
a solution of hexamethyl disilazane (1.0 mL, 4.96 mmol) in degassed
THF (7 mL) was added n-BuLi in n-hexane (4.26 mmol) at ꢀ78 ꢁC
and the reaction mixture was stirred at ꢀ78 ꢁC for 20 min. To the
solution was added a solution of (Z)-5 (674 mg, 1.42 mmol) in THF
(8 mL). After removing the cooling bath, the reaction mixture was
stirred at rt for 1.5 h. The pH of the reaction mixture was adjusted to
1 with 1 N HCl, and the mixture was extracted with ethyl acetate.
The organic layer was washed with brine and dried over anhydrous
MgSO4. The solvent was evaporated in vacuo to give a crude residue.
To a solution of crude residue in diethyl ether was added dropwise
a solution of diazomethane in diethyl ether at 0 ꢁC for 1 h. The sol-
vent was evaporated in vacuo to give a crude residue, which was
purified by flash column chromatography on silica gel (n-hexane/
AcOEt¼20:1) to give threo-6 (612 mg, 88%, dr¼16:1) as colorless oil:
FTIR (neat) 1748, 1697, 1599, 1454, 1434, 1396, 1248, 1160, 1052,
6.45–6.44 (2H), 4.36 (m, 1H), 3.82 (s, 3H), 1.44 (br s, 1H), 0.99 (s,
9H), 0.06 (s, 3H), 0.01 (s, 3H); 13C NMR (75 MHz, CDCl3)
d 159.8,
139.1, 133.1, 129.5, 125.2, 118.6, 112.2, 111.6, 67.3, 55.1, 26.9, 17.1,
ꢀ7.5, ꢀ8.9; HRMS (FAB) m/z calcd for C16H25O2Si (MꢀH)þ
277.1624, found 277.1636.
3.1.7. tert-Butyl (E)-1-(tert-butyldimethylsilyl)-3-(3-methoxyphenyl)-
allyl pyrrolidine-1,2-dicarboxylate {(E)-5}. To a solution of (E)-4
(1.09 g, 3.92 mmol) in CH2Cl2 (19 mL) were added N-Boc-L-proline
(1.71 g, 7.84 mmol), 1-ethyl-3-(3-dimethylaminopropyl)carbodii-
mide (EDCI, 1.51 mg, 7.84 mmol), and 4-N,N-dimethylaminopyr-
idine (DMAP, 47 mg, 0.39 mmol) and the mixture was stirred at rt
for 2.5 h. The reaction mixture was exposed to saturated NH4Cl and
was extracted with ethyl acetate. The organic layer was washed
with brine and dried over anhydrous MgSO4. The solvent was
evaporated in vacuo to give a crude residue, which was purified by
flash column chromatography on silica gel (n-hexane/AcOEt¼30:1)
to give (E)-5 (1.75 g, 94%, a mixture of diastereomers, dr¼1:1) as
colorless oil: FTIR (neat) 1745, 1699, 1599, 1579, 1470, 1397, 1365,
1005 cmꢀ1; 1H NMR (400 MHz, CDCl3)
d 7.13 (m, 1H), 6.83–6.74 (3H),
6.46–6.38 (1H), 5.72 (d, J¼20.5 Hz, 1/2H), 5.66 (d, J¼20.5 Hz, 1/2H),
4.76 (d, J¼6.2 Hz, 1/2H), 4.55 (d, J¼6.0 Hz, 1/2H), 3.76 (s, 3H), 3.71 (s,
3H), 3.61 (m, 1/2H), 3.43 (m, 1/2H), 2.58–2.35 (2H), 2.18 (m, 1H), 1.86
(m, 1H), 1.53 (m, 1H), 1.46 (9/2H), 1.40 (9/2H), 0.81 (9H), 0.00 (6H);
1252, 1159, 1087, 1045 cmꢀ1; 1H NMR (300 MHz, CDCl3)
d 7.26–7.18
(1H), 6.95–6.84 (2H), 6.78–6.73 (1H), 6.47–6.34 (1H), 6.26–6.17
(1H), 5.55–5.46 (1H), 4.45 (m, 38/100H), 4.33 (dd, J¼8.6, 3.3 Hz, 62/
100H), 3.80 (3H), 3.54–3.39 (2H), 2.30–2.14 (1H), 2.10–1.86 (3H),
1.47–1.33 (9H), 0.95 (s, 9H), 0.07 (s, 3H), 0.05 (s, 3H); 13C NMR
13C NMR (75 MHz, CDCl3)
d 174.5, 174.3, 159.1, 159.0, 153.8, 153.0,
147.0, 146.8, 142.3, 141.7, 130.1, 130.0, 128.6, 128.3, 122.4, 122.3, 116.2,
116.1, 111.9, 80.4, 79.4, 70.4, 69.9, 55.12, 55.08, 54.1, 52.8, 52.0, 47.91,
47.88, 34.8, 33.1, 28.4, 28.3, 26.42, 26.40, 23.3, 22.7, 16.7, 16.6, ꢀ6.0,
ꢀ6.2, ꢀ6.3; HRMS (FAB) m/z calcd for C27H44NO5Si (MþH)þ
490.2989, found 490.2977. A complex 1H NMR was observed because
of a mixture of rotamers.
According to the procedure described above, (E)-5 (220 mg,
0.46 mmol) was used instead of (Z)-5 to give threo-6 (206 mg, 91%,
an inseparable mixture of diastereomers, threo/erythro¼3.5:1) as
colorless oil.
(75 MHz, CDCl3)
d 172.7, 172.6, 172.5, 172.3, 159.70, 159.67, 154.22,
154.17, 153.9, 138.9, 138.40, 138.36, 129.8, 129.42, 129.41, 129.32,
129.29, 128.49, 128.45, 127.7, 127.6, 127.4, 127.1, 127.0, 118.8, 118.7,
112.7, 112.54, 112.48, 111.7, 111.62, 111.55, 79.91, 79.86, 79.6, 79.4,
69.6, 69.5, 69.41, 69.37, 69.3, 59.3, 59.2, 59.1, 55.1, 46.5, 46.4, 46.23,
46.20, 30.8, 30.0, 29.9, 29.6, 28.4, 28.3, 28.2, 26.84, 26.81, 24.3, 24.2,
23.5, 23.3, 16.99, 16.96, 16.94, ꢀ7.4, ꢀ7.85, ꢀ7.88, ꢀ7.95; HRMS
(FAB) m/z calcd for C26H41NO5Si (M)þ 475.2754, found 475.2758. A

10362
K. Sakaguchi et al. / Tetrahedron 65 (2009) 10355–10364
complex 1H NMR was observed because of a mixture of di-
astereomers and rotamers.
12 (20 mg, 0.054 mmol) in MeOH (0.5 mL) was added sodium
borohydride (2.4 mg, 0.064 mmol) at 0 ꢁC, and the reaction mixture
was stirred at rt for 1 h. The reaction mixture was exposed to sat-
urated NH4Cl and was extracted with ethyl acetate. The organic
layer was washed with brine and dried over anhydrous MgSO4. The
solvent was evaporated in vacuo to give a crude residue, which was
purified by flash column chromatography on silica gel (n-hexane/
AcOEt¼15:1) to give threo-13 (8 mg, 43%) as colorless oil: FTIR
(neat) 1787, 1691, 1653, 1494, 1456, 1217, 1148, 1021 cmꢀ1; 1H NMR
3.1.8. (R
*
)-Methyl 2-{(R
*
)-1-(3-methoxyphenyl)allyl}pyrrolidine-2-
solution of threo-6 (50 mg,
carboxylate (threo-10). To
a
0.099 mmol, dr>20:1) in propionitrile (0.2 mL) was added p-tol-
uenesulfonic acid monohydrate (170 mg, 0.89 mmol), and the re-
action mixture was stirred at 100 ꢁC for 21 h. To the reaction
mixture was added saturated NaHCO3, and the mixture was
extracted with ethyl acetate. The organic layer was washed with
brine and dried over anhydrous MgSO4. The solvent was evaporated
in vacuo to give a crude residue, which was purified by flash column
chromatography on silica gel (n-hexane/AcOEt¼10:1) to give threo-
10 (24 mg, 88%) as colorless oil: FTIR (neat) 3352, 1732, 1599, 1490,
(600 MHz, CDCl3)
d
7.31 (t, J¼8.0 Hz, 1H), 6.90 (dd, J¼8.0, 2.0 Hz,
1H), 6.72 (d, J¼8.0 Hz, 1H), 6.64 (d, J¼2.0 Hz, 1H), 4.71 (t, J¼8.4 Hz,
1H), 4.62 (dd, J¼10.9, 8.4 Hz,1H), 4.50 (dd, J¼10.9, 8.4 Hz,1H), 3.80–
3.76 (4H), 3.63 (m, 1H), 2.08 (ddd, J¼12.5, 6.6, 5.1 Hz, 1H), 1.96 (ddd,
J¼12.5, 9.1, 7.0 Hz, 1H), 1.85 (m, 1H), 1.18 (m, 1H); 13C NMR
1455, 1435, 1316, 1260, 1193, 1135, 1046 cmꢀ1
CDCl3)
;
1H NMR (400 MHz,
(100 MHz, CDCl3)
d
174.4, 160.3, 155.9 (q, J¼37.8 Hz), 135.4, 130.4,
d
7.15 (t, J¼8.1 Hz, 1H), 6.84–6.82 (2H), 6.73 (m, 1H), 6.30 (dt,
120.3, 116.0 (q, J¼287.1 Hz), 114.4, 113.5, 70.9, 67.7, 55.2, 48.3 (q,
J¼4.0 Hz), 44.1, 30.2, 23.5; HRMS (FAB) m/z calcd for C16H17NO4F3
(MþH)þ 344.1109, found 344.1102.
J¼19.3, 9.5 Hz, 1H), 5.19–5.10 (2H), 3.77 (s, 3H), 3.63 (d, J¼9.5 Hz,
1H), 3.56 (s, 3H), 2.96–2.93 (2H), 2.30 (br s, 1H), 2.14–2.01 (2H), 1.73
(m, 1H), 1.60 (m, 1H); 13C NMR (75 MHz, CDCl3)
d 177.0, 159.3, 142.8,
137.5, 129.0, 120.6, 117.5, 114.0, 112.0, 72.8, 56.8, 55.0, 51.9, 47.1, 34.3,
25.1; HRMS (CI) m/z calcd for C16H22NO3 (MþH)þ 276.1599, found
276.1597.
3.1.12. (S
*
)-Methyl 2-{(R )-1-(3-methoxyphenyl)allyl}pyrrolidine-2-
*
carboxylate (erythro-10). To a solution of 6 (190 mg, 0.39 mmol,
threo/erythro¼3.5:1) in propionitrile (0.5 mL) was added p-tolue-
nesulfonic acid monohydrate (664 mg, 3.50 mmol), and the re-
action mixture was stirred at 100 ꢁC for 21 h. To the reaction
mixture was added saturated NaHCO3, and the mixture was
extracted with ethyl acetate. The organic layer was washed with
brine and dried over anhydrous MgSO4. The solvent was evaporated
in vacuo to give a crude residue, which was purified by flash column
chromatography on silica gel (n-hexane/AcOEt¼30:1) to give threo-
10 (73 mg, 68%) and erythro-10 (20 mg, 19%) as colorless oil: FTIR
(neat) 3353, 1729, 1636, 1598, 1583, 1490, 1454, 1435, 1314, 1265,
3.1.9. (R
*
)-Methyl 1-(2,2,2-trifluoroacetyl)-2-{(R )-1-(3-methoxy-
*
phenyl)allyl}pyrrolidine-2-carboxylate (threo-11). To a solution of
threo-10 (13.2 mg, 0.048 mmol) in CH2Cl2 (0.5 mL) were added
pyridine (5.8
mL, 0.072 mmol) and trifluoroacetic anhydride
(TFAA, 8.1
m
L, 0.057 mmol) at 0 ꢁC, and the reaction mixture was
stirred at rt for 10 min. The reaction mixture was exposed to
saturated NaHCO3 and was extracted with ethyl acetate. The or-
ganic layer was washed with brine and dried over anhydrous
MgSO4. The solvent was evaporated in vacuo to give a crude
residue, which was purified by flash column chromatography on
silica gel (n-hexane/AcOEt¼10:1) to give threo-11 (16.2 mg, 91%)
as colorless oil: FTIR (neat) 1750, 1691, 1599, 1584, 1492, 1454,
1178, 1122, 1102,1047 cmꢀ1 1H NMR (300 MHz, CDCl3)
; d 7.19 (t,
J¼7.8 Hz, 1H), 6.99 (m, 1H), 6.94 (d, J¼7.8 Hz, 1H), 6.77 (dd, J¼7.8,
2.6 Hz, 1H), 6.22 (dt, J¼15.0, 9.0 Hz, 1H), 5.07 (s, 1H), 5.01 (m, 1H),
3.79 (s, 3H), 3.69 (s, 3H), 3.63 (d, J¼9.2 Hz, 1H), 2.91 (dt, J¼9.7,
7.1 Hz, 1H), 2.78 (dt, J¼9.7, 6.6 Hz, 1H), 2.25 (br s, 1H), 2.04 (ddd,
J¼13.2, 7.9, 5.7 Hz, 1H), 1.77 (dt, d, J¼13.2, 7.7 Hz, 1H), 1.55–1.31
1351, 1299, 1266, 1226, 1199, 1152, 1118, 1048 cmꢀ1
(400 MHz, CDCl3)
(ddd, J¼17.1, 10.5, 6.6 Hz, 1H), 5.26–5.15 (2H), 4.75 (d, J¼6.6 Hz,
1H), 3.76 (s, 3H), 3.74 (s, 3H), 3.70 (m, 1H), 2.67–2.51 (2H), 2.22
(m, 1H), 2.06 (m, 1H), 1.84 (m, 1H); 13C NMR (75 MHz, CDCl3)
;
1H NMR
d
7.18 (t, J¼7.8 Hz, 1H), 6.80–6.73 (m, 3H), 6.27
(2H); 13C NMR (75 MHz, CDCl3)
d 177.1, 159.2, 141.9, 138.4, 128.8,
122.0, 116.4, 115.2, 112.2, 73.5, 57.3, 55.2, 52.2, 46.6, 33.8, 24.9;
HRMS (FAB) m/z calcd for C16H22NO3 (MþH)þ 276.1599, found
276.1607.
d
172.4, 159.3, 155.3, (q, J¼36.6 Hz), 140.5, 136.6, 129.0, 121.5,
118.6, 115.8 (q, J¼283.6 Hz), 115.2, 113.0, 72.5, 55.1, 52.6, 49.6, 48.5
(q, J¼3.5 Hz), 32.1, 24.2; HRMS (FAB) m/z calcd for C18H21NO4F3
(MþH)þ 372.1422, found 372.1426.
3.1.13. (5S
*
,9S
*
)-9-(3-Methoxyphenyl)-1-(2,2,2-trifluoroacetyl)-1-
solution of
aza-7-oxa-6-oxospiro[4,4]nonane (erythro-13). To
a
erythro-12 (15.3 mg, 0.041 mmol) in CH2Cl2 (0.5 mL) was added
sodium borohydride (5.1 mg, 0.135 mmol) at 0 ꢁC, and the reaction
mixture was stirred at rt for 1 h. The reaction mixture was exposed
to saturated NH4Cl and was extracted with ethyl acetate. The or-
ganic layer was washed with brine and dried over anhydrous
MgSO4. The solvent was evaporated in vacuo to give a crude resi-
due, which was purified by flash column chromatography on silica
gel (n-hexane/AcOEt¼15:1) to give erythro-13 (5.0 mg, 34%) as
colorless oil: FTIR (neat) 1778, 1690, 1602, 1493, 1456, 1216, 1146,
3.1.10. (R
*
)-Methyl 1-(2,2,2-trifluoroacetyl)-2-{(R )-formyl(3-methoxy-
*
phenyl)methyl}pyrrolidine-2-carboxylate (threo-12). Ozone was bub-
bled into a solution of threo-11 (16 mg, 0.043 mmol) in MeOH
(3.5 mL) at ꢀ78 ꢁC for 1 min (flow rate of O2: 150 NL/h, which
corresponded to 3 g/h of O3). To the mixture was added dimethyl
sulfide (4.8 mL, 0.065 mmol). The mixture was warmed to rt and
concentrated under reduced pressure. The residue was purified by
flash column chromatography on silica gel (n-hexane/AcOEt¼10:1)
to give threo-12 (16 mg, quant) as colorless oil: FTIR (neat) 1744,
1690, 1600, 1489, 1455, 1313, 1265, 1233, 1215, 1153, 1042 cmꢀ1; 1H
1038 cmꢀ1; 1H NMR (600 MHz, CDCl3)
d
7.27 (t, J¼8.0 Hz, 1H), 6.88
(dd, J¼8.0, 2.2 Hz, 1H), 6.81 (d, J¼8.0 Hz, 1H), 6.77 (m, 1H), 4.84 (dd,
J¼10.7, 9.1 Hz, 1H), 4.59 (t, J¼9.1 Hz, 1H), 3.78 (s, 3H), 3.71–3.66
(2H), 3.04 (m, 1H), 2.61 (m, 1H), 2.22 (dt, J¼12.2, 5.7 Hz, 1H), 2.10
NMR (300 MHz, CDCl3)
d
9.90 (d, J¼1.6 Hz, 1H), 7.26 (t, J¼8.3 Hz,
1H), 6.89 (dd, J¼8.3, 1.7 Hz, 1H), 6.73–6.68 (2H), 5.14 (d, J¼1.6 Hz,
1H), 3.77 (s, 3H), 3.76 (s, 3H), 3.66 (m, 1H), 2.74–2.54 (2H), 2.47
(ddd, J¼14.1, 7.5, 3.8 Hz, 1H), 1.98 (m, 1H), 1.62 (m, 1H); 13C NMR
(m, 1H), 1.92 (m, 1H); 13C NMR (150 MHz, CDCl3)
d 174.3, 159.9,
156.5 (q, J¼37.5 Hz), 135.1, 129.9, 121.0, 115.8 (q, J¼285.0 Hz), 114.2,
114.1, 71.1, 69.1, 55.2, 53.5, 48.2 (q, J¼4.0 Hz), 39.4, 24.3; HRMS (EI)
m/z calcd for C16H16O4NF3 (M)þ 343.1031, found 343.1030.
(75 MHz, CDCl3)
d
197.0, 172.0, 160.0, 155.8 (q, J¼37.2 Hz), 132.0,
129.8, 122.8, 116.0, 115.8 (q, J¼285.7 Hz), 114.5, 72.0, 56.0, 55.2, 53.2,
48.0 (q, J¼3.6 Hz), 32.2, 24.4; HRMS (FAB) m/z calcd for
C17H19O5NF3 (MþH)þ 374.1245, found 374.1196.
3.1.14. tert-Butyl 1-(((Z)-3-(3-methoxyphenyl)-1-(tert-butyldimethylsi-
lyl)allyloxy)-carbonyl)pent-4-enylcarbamate (15). To
a solution of
3.1.11. (5R
*
,9S
*
)-9-(3-Methoxyphenyl)-1-(2,2,2-trifluoroacetyl)-1-
(Z)-4 (1.01 g, 3.68 mmol) in CH2Cl2 (11 mL) were added N-Boc-
aza-7-oxa-6-oxospiro[4,4]nonane (threo-13). To a solution of threo-
homoallylglycine (racemic, 1.29 g, 5.63 mmol), 1-ethyl-3-(3-

K. Sakaguchi et al. / Tetrahedron 65 (2009) 10355–10364
10363
dimethylaminopropyl)-carbodiimide (EDCI, 1.08 g, 5.63 mmol), and
4-N,N-dimethylaminopyridine (DMAP, 45 mg, 0.37 mmol) and the
mixture was stirred at rt for 3 h. The reaction mixture was exposed
to saturated NH4Cl and was extracted with ethyl acetate. The or-
ganic layer was washed with brine and dried over anhydrous
MgSO4. The solvent was evaporated in vacuo to give a crude resi-
due, which was purified by flash column chromatography on silica
gel (n-hexane/AcOEt¼20:1) to give 15 (1.75 g, 97%, a mixture of
diastereomers, dr¼1:1) as colorless oil: FTIR (neat) 3360,1715,1641,
1599, 1579, 1492, 1464, 1435, 1392, 1366, 1254, 1165, 1049 cmꢀ1; 1H
buffer (3 mL, 3:2) was added NaIO4 (127 mg, 0.612 mmol) at 0 ꢁC,
and the reaction mixture was stirred at rt for 3 h. The reaction
mixture was exposed to aqueous NaHSO3 and was extracted with
ethyl acetate. The organic layer was washed with brine and dried
over anhydrous MgSO4. The solvent was evaporated in vacuo to
give a crude residue. To a solution of the residue in AcOH (3 mL)
was added NaBH3CN (38 mg, 0.612 mmol) at rt. The reaction mix-
ture was stirred at 70 ꢁC for 45 min, and the solvent was evaporated
in vacuo to give a crude residue. The excess hydride was quenched
with aqueous NaHCO3 and the mixture was extracted with ethyl
acetate. The organic layer was washed with brine and dried over
anhydrous MgSO4. The solvent was evaporated in vacuo to give
a crude residue, which was purified by flash column chromatog-
raphy on silica gel (n-hexane/AcOEt¼30:1) to give erythro-6
(103 mg, 69%, an inseparable mixture of diastereomers, dr¼4.5:1)
as colorless oil: FTIR (neat) 1748, 1701, 1600, 1366, 1255, 1162,
NMR (300 MHz, CDCl3)
d
7.24 (t, J¼7.9 Hz, 1H), 7.05 (m, 1H), 6.98 (d,
J¼7.9 Hz, 1H), 6.77 (dd, J¼7.9, 2.4 Hz, 1H), 6.37 (d, J¼11.9 Hz, 1H),
6.04 (d, J¼11.3 Hz, 1/2H), 5.98 (d, J¼10.8 Hz, 1/2H), 5.79 (m, 1H),
5.60 (dt, J¼11.3, 8.8 Hz, 1H), 5.08–4.93 (3H), 4.34 (m, 1H), 3.81 (s,
3H), 2.20–2.02 (2H), 1.92 (m, 1H), 1.71 (m, 1H), 1.43 (s, 9H), 0.85 (s,
9H), 0.03 (s, 3/2H), 0.01 (s, 3/2H), ꢀ0.05 (s, 3/2H), ꢀ0.07 (s, 3/2H);
13C NMR (75 MHz, CDCl3)
d
172.6, 172.5, 159.5, 155.1, 138.2, 138.1,
1050 cmꢀ1; 1H NMR (400 MHz, CDCl3)
d 7.18 (m, 1H), 6.97–6.94 (3/
137.0, 136.9, 129.24, 129.23, 129.0, 128.9, 128.7, 128.6, 120.8, 115.5,
115.4, 113.5,112.9, 112.8, 79.5, 67.5, 67.2, 55.1, 53.3, 53.11, 53.10, 53.0,
32.0, 29.3, 29.2, 28.2, 26.6, 16.87, 16.85, ꢀ7.4, ꢀ7.5, ꢀ8.0, ꢀ8.3;
HRMS (FAB) m/z calcd for C27H43NO5Si (M)þ 489.2911, found
489.2925.
2H), 6.83–6.73 (3/2H), 6.40–6.30 (1H), 5.75–5.63 (1H), 4.76 (d,
J¼6.2 Hz, 1/10H), 4.62 (d, J¼8.0 Hz, 4/10H), 4.55 (d, J¼6.0 Hz, 1/
10H), 4.45 (d, J¼8.0 Hz, 4/10H), 3.78–3.71 (3H), 3.63 (s, 3/2H), 3.61
(s, 3/2H), 3.36–3.21 (1H), 2.58–2.29 (2H), 2.18–1.80 (5/2H), 1.66–
1.1.56 (1/2H), 1.46 (9/2H), 1.41 (9/2H), 0.81 (9H), 0.00 (6H); 13C NMR
(100 MHz, CDCl3)
d 174.5, 174.3, 173.5, 173.3, 158.9, 153.7, 153.1,
3.1.15. tert-Butyl
(E,3R
*
,4S
*
)-4-(methoxycarbonyl)-3-(3-methoxy-
152.9, 147.0,146.8,146.5, 145.7, 142.7, 142.6, 142.3,141.7, 130.7, 130.0,
129.6, 128.4, 128.3, 122.7, 122.5, 122.4, 122.3, 116.4, 116.1, 111.9, 111.7,
111.3, 80.3, 80.1, 79.4, 71.2, 70.4, 69.9, 56.1, 55.1, 55.0, 54.1, 52.8, 51.9,
51.7, 48.9, 48.6, 47.9, 35.6, 34.8, 34.6, 33.1, 28.3, 26.4, 23.3, 23.2, 22.8,
22.6, 16.5, ꢀ5.9, ꢀ6.2, ꢀ6.3; HRMS (FAB) m/z calcd for C27H44NO5Si
(M)þ 489.2911, found 489.2893. A complex 1H NMR (400 MHz,
CDCl3) spectrum was observed because of a mixture of di-
astereomers and rotamers.
phenyl)-1-(tert-butyldimethylsilyl)octa-1,7-dien-4-ylcarbamate
(16). To a solution of diisopropyl amine (0.41 mL, 3.0 mmol) in
degassed THF (1.5 mL) was added n-BuLi in n-hexane (1.75 mL,
2.73 mmol) at ꢀ78 ꢁC and the reaction mixture was stirred at
ꢀ78 ꢁC for 20 min. To the solution was added a solution of 15
(487 mg, 1.00 mmol, dr¼1:1) in degassed THF (2.5 mL) and ZnCl2 in
Et2O (1.50 mL, 1.50 mmol) at ꢀ78 ꢁC and the reaction mixture was
stirred at ꢀ78 ꢁC for 30 min. After removing a cooling bath, the
reaction mixture was stirred at rt for 1.5 h. The pH of the reaction
mixture was adjusted to 1 with 1 N HCl, and the mixture was
extracted with ether. The organic layer was washed with brine and
dried over anhydrous MgSO4. The solvent was evaporated in vacuo
to give a crude residue. To a solution of the crude residue in diethyl
ether was added dropwise a solution of diazomethane in diethyl
ether at 0 ꢁC for 1 h. The solvent was evaporated in vacuo to give
a crude residue, which was purified by flash column chromatog-
raphy on silica gel (n-hexane/AcOEt¼30:1) to give 16 (322 mg, 64%
yield, an inseparable mixture of diastereomers, dr¼4.2:1) as yellow
oil: FTIR (neat) 3426, 1716, 1641, 1600, 1493, 1391, 1365, 1285, 1258,
Acknowledgements
This study was financially supported by
a Grant-in-Aid
(16201045, 19201045, and 16073214) for Scientific Research from
the Japan Society of the Promotion of Science (JSPS) and the Min-
istry of Education, Culture, Sports, Science and Technology, Japan.
Supplementary data
The characterization data of the new compounds 3, (Z)-4, (Z)-5,
threo-6, 9, (E)-4, (E)-5, threo-10, threo-11, threo-12, threo-13,
erythro-10, erythro-13, 15, 16, and erythro-6 are available. Supple-
mentary data associated with this article can be found in online
version, at doi:10.1016/j.tet.2009.10.051.
1167, 1085, 1051, 1023 cmꢀ1; 1H NMR (400 MHz, CDCl3)
d 7.21–7.15
(1H), 6.77–6.60 (3H), 6.51 (dd, J¼18.6, 9.5 Hz, 4/5H), 6.39 (dd,
J¼18.3, 9.3 Hz, 1/5H), 5.88 (d, J¼18.6 Hz, 4/5H), 5.80–5.69 (6/5H),
5.46 (m, 1H), 4.98–4.90 (2H), 4.31 (d, J¼9.3 Hz, 4/5H), 3.93 (d,
J¼8.8 Hz, 1/5H), 3.78–3.75 (27/5H), 3.66 (s, 3/5H), 2.59 (m, 1H),
2.12–2.04 (2H), 1.73 (m, 1H), 1.45 (s, 9H), 0.87 (s, 9H), 0.05 (s, 3H),
References and notes
0.00 (s, 3H); 13C NMR (75 MHz, CDCl3)
d
172.7, 172.6, 159.3, 159.2,
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731–735; (e) Pseurotin A: Komagata, D.; Fujita, S.; Yamashita, N.; Saito, S.;
Morino, T. J. Antibiot. 1996, 49, 958–959; (f) Synerazol: Ando, O.; Satake, H.;
Nakajima, M.; Sato, A.; Nakamura, T.; Kinoshita, T.; Furuya, K.; Haneishi, T.
J. Antibiot. 1991, 44, 382–389.
3. Hughes, C. C.; Trauner, D. Angew. Chem., Int. Ed. 2002, 41, 4556–4559.
4. Sakaguchi, K.; Ayabe, M.; Watanabe, Y.; Okada, T.; Kawamura, K.; Shinada, T.;
Ohfune, Y. Org. Lett. 2008, 10, 5449–5452.
5. (a) Sakaguchi, K.; Higashino, M.; Ohfune, Y. Tetrahedron 2003, 59, 6647–6658;
(b) Sakaguchi, K.; Yamada, T.; Ohfune, Y. Tetrahedron Lett. 2005, 46, 5009–5012;
(c) Sakaguchi, K.; Okada, T.; Yamada, T.; Ohfune, Y. Tetrahedron Lett. 2007, 48,
3925–3928.
153.9, 153.6, 145.2, 144.8, 141.5, 140.8, 137.9, 137.6, 131.9, 129.0,
128.9, 121.5, 120.6, 115.0, 114.8, 114.64, 114.55, 112.2, 112.1, 79.1, 66.9,
60.3, 59.6, 57.8, 55.1, 55.0, 52.4, 52.1, 33.3, 31.7, 28.8, 28.4, 28.3, 26.5,
26.4, 21.0, 16.6, 16.6, 14.2, ꢀ6.0, ꢀ6.1, ꢀ6.27, ꢀ6.33; HRMS (FAB) m/z
calcd for C28H46NO5Si (MþH)þ 504.3145, found 504.3135.
3.1.16. (S
*
)-1-tert-Butyl 2-methyl 2-{(R ,E)-3-(tert-butyldimethylsilyl)-
*
1-(3-methoxyphenyl)allyl}pyrrolidine-1,2-diarboxylate(erythro-6). To
a solution of 16 (160 mg, 0.317 mmol, dr¼4.2:1) in 1,4-dioxane/H2O
(3 mL, 3:1) were added OsO4 in t-BuOH (0.015 mL, 0.096 mmol) and
4-methylmorpholine N-oxide (NMO, 74.3 mg, 0.634 mmol) at 0 ꢁC,
and the reaction mixture was stirred at rt for 2.5 h. The reaction
mixture was exposed to aqueous NaHSO3 and was extracted with
ethyl acetate. The organic layer was washed with brine and dried
over anhydrous MgSO4. The solvent was evaporated in vacuo to
give a crude residue. To a solution of the residue in t-BuOH/pH 6.86
6. (a) Sakaguchi, K.; Suzuki, H.; Ohfune, Y. Chirality 2001, 13, 357–365; (b) Mor-
imoto, Y.; Takanishi, M.; Kinoshita, T.; Sakaguchi, K.; Shibata, K. Chem. Commun.

10364
K. Sakaguchi et al. / Tetrahedron 65 (2009) 10355–10364
2002, 42–43; (c) Sakaguchi, K.; Yamamoto, M.; Kawamoto, T.; Yamada, T.;
19. The relative configuration of the hemiaminal moiety in 17 was assigned as
shown in Scheme 8 since this compound was identical with the compound
derived from the phenol derivative 28 (MeI (1 equiv), K2CO3 (1 equiv), acetone,
rt, 15 h, 30%).
Shinada, T.; Shimamoto, K.; Ohfune, Y. Tetrahedron Lett. 2004, 45, 5869–5872;
(d) Sakaguchi, K.; Yamamoto, M.; Watanabe, Y.; Ohfune, Y. Tetrahedron Lett.
2007, 48, 4821–4824.
7. The ZnCl2-assisted dianionic enolate Claisen rearrangement of the N-protected
20. At elevated temperature (NBS (2.2 equiv), DMF, 100 ꢁC), a trace amount of the
dehydrated 34 was observed by the 1H NMR analysis of the reaction mixture.
a
-amino acid allyl ester was originally developed by Kazmaier: Kazmaier, U.
Angew. Chem., Int. Ed. Engl. 1994, 33, 998–999.
8. The enolate Claisen rearrangement of (S)- -acyloxy-a-vinylsilane having Boc-
TFA
a
proline as the acyloxy group (>95% ee) (LHMDS (3 equiv), HMPA/THF (1:4),
O
N
ꢀ78 ꢁC to rt) gave the
a-substituted proline with (S)-configuration (>95% ee),
see Ref. 6d.
Me
N
9. (a) The chelation-controlled stereoselective enolate Claisen rearrangement of
(E)-crotyl pyroglutamate using chiral ligands: Kazmaier, U.; Mues, H.; Krabs, A.
Eur. J. Chem. 2002, 8, 1850–1855; (b) The diastereoselective enolate Claisen
rearrangement of the 5-substituted-Boc-proline (E)-allylic ester: Lee, M.; Lee,
T.; Kim, E.-Y.; Ko, H.; Kim, D.; Kim, S. Org. Lett. 2006, 8, 745–748.
10. Sakaguchi, K.; Fujita, M.; Suzuki, H.; Higashino, M.; Ohfune, Y. Tetrahedron Lett.
2000, 41, 6589–6592.
11. Sonogashira, K. In Metal-catalyzed Cross-coupling Reactions; Diederrich, F.,
Stang, P. L., Eds.; Wiley-VCH: Weinheim, 1998; Chapter 5.
12. Liron, F.; Garrev, P. L.; Alami, M. Synlett 1999, 246–248.
OMe
34
21. The reaction of 17 with Br2 (2.2 equiv) in the presence of AcOH or SiO2
(CH2Cl2, rt, 10 min) also gave the monobrominated product 18 in moderate
yield (22–30%). The reaction of 17 with NBS (2 equiv) and TsOH (0.22 equiv) in
DMF (rt, 18 h) afforded a trace amount of 18.
13. Nowick, J. S.; Danheiser, R. L. J. Org. Chem. 1989, 54, 2798–2802.
14. Luche, J. L. J. Am. Chem. Soc. 1978, 100, 2226–2227.
22. Matsuo, J.; Iida, D.; Yamanaka, H.; Mukaiyama, T. Tetrahedron 2003, 59,
6739–6750.
15. It has been reported that the ozonolysis of the vinylsilane does not give the
corresponding aldehyde, see: (a) Bu¨chi, G.; Wu¨ est, H. J. Am. Chem. Soc. 1978, 100,
294–295; (b) Murakami, M.; Sakita, K.; Igawa, K.; Tomooka, K. Org. Lett. 2006, 8,
4023–4026.
23. (a) Sonderquist, E. J.; Anderson, C. L.; Miranda, E. I.; Rivera, I. Tetrahedron Lett.
1990, 31, 4677–4680; (b) Dahr, R. K. Aldrichimica Acta 1994, 27, 43–51.
24. The absolute configuration of the minor isomer was not determined.
25. The reaction without ZnCl2 resulted in the decreased yield of 23 (28%).
26. The spirolactone 29 was obtained as a single diastereomer. The relative ste-
reochemistry of 29 was not determined.
16. The calculation was performed by Spartan ’04.
17. For examples of the [3,3] sigmatropic rearrangement that proceeded via the
boat-like transition state, see: (a) Waetzig, S. R.; Tunge, J. A. J. Am. Chem. Soc.
2007, 129, 4138–4139; (b) Lindstroem, U. M.; Somfai, P. Eur. J. Chem. 2001, 7, 94–
98; (c) Wipf, P. In Comprehensive Organic Synthesis; Trost, B. M., Fleming, I., Eds.;
Pergamon: Oxford, 1991; Vol. 5, p 827.
27. Lower amounts of methylamine (2 equiv) resulted in the decreased yield of 28
(<20%).
28. For the electrophilic 4,6-dibromination of 3-substituted phenol, see: (a) Osuna,
M. R.; Agurrie, G.; Somanathan, R.; Molins, E. Tetrahedron: Asymmetry 2002, 13,
2261–2266; (b) Hashimoto, A.; Jacobson, A. E.; Rothman, R. B.; Dersch, C. M.;
George, C.; F-Anderson, J. L.; Rice, K. C. Bioorg. Med. Chem. 2002, 10, 3319–3329.
29. Negoro, T.; Wada, M.; Someya, M. Bull. Fac. Edu. Wakayama Univ. Natur. Sci.
18. The reaction of
a-acyloxy-a-vinylsilane having Boc-proline as the acyloxy group
(>95% ee, Eq. 2) gave the rearranged product (71% ee) under the conditions in
the absence of HMPA, suggesting the contamination of the monoanionic E-
enolate.6d According to the energy calculation results (Scheme 6), the E-enolate
derived from (E)-5 would undergo the enolate Claisen rearrangement via both
the transition states M and N to give the threo and erythro-6, respectively.
Therefore, the moderate threo selectivity (dr 3.5:1) would be observed in the
reaction of (E)-5 without HMPA.
1998, 48, 1–7.
28
30. The optical rotation of the synthetic (ꢀ)-1 was [
a
]
ꢀ39.0 (c 0.30, MeOH),
D
which is in good agreement with that of the synthetic 1 reported by Trauner
{[a
]
ꢀ41.0 (c 0.50, MeOH)},3 while the natural sample was recorded as [
a]
25
D
D
ꢀ10.0 (c 0.0023, MeOH).1