Enantioselective synthesis of (-)-stemoamide

Article abstract of DOI:10.1055/s-0032-1317499

An enantioselective synthesis of (-)-stemoamide is presented. Noyoris ruthenium complex catalyzed asymmetric transfer hydrogenation of an alkynone delivered the (S)-C8 stereogenic center in 97.7% ee. An iron(III) chloride promoted and bioinspired N-iminium ion cyclization afforded a 3:1 ratio of two diastereomers in favor of the cis-isomer. The diastereomeric ratio was enriched to 50:1 by a silver-catalyzed cycloisomerization. The subsequent dynamic ruthenium-catalyzed CO-insertion reaction secured an enantioselective total synthesis of (-)-stemoamide in 18% overall yield with high optical purity.

Full text of DOI:10.1055/s-0032-1317499

3432▌
FEATURE ARTICLE
fEeanturae nartticiloe selective Synthesis of (–)-Stemoamide
Enantioselective Synthesis of (–)-Stemoamide
Xianwei Mi,1,a,b Yan Wang,1,a Lili Zhu,a Renxiao Wang,b Ran Hong*a
a
Key Laboratory of Synthetic Chemistry of Natural Substances, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences,
Shanghai 200032, P. R. of China
E-mail: rhong@sioc.ac.cn
b
State Key Laboratory of Bioorganic and Natural Products Chemistry, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences,
Shanghai 200032, P. R. of China
Received: 13.08.2012; Accepted after revision: 02.10.2012
Dedicated to Professor Guo-Qiang Lin on the occasion of his 70th birthday
2
Abstract: An enantioselective synthesis of (–)-stemoamide is pre-
sented. Noyori’s ruthenium complex catalyzed asymmetric transfer
hydrogenation of an alkynone delivered the (S)-C8 stereogenic cen-
ter in 97.7% ee. An iron(III) chloride promoted and bioinspired N-
iminium ion cyclization afforded a 3:1 ratio of two diastereomers in
favor of the cis-isomer. The diastereomeric ratio was enriched to
50:1 by a silver-catalyzed cycloisomerization. The subsequent dy-
namic ruthenium-catalyzed CO-insertion reaction secured an enan-
tioselective total synthesis of (–)-stemoamide in 18% overall yield
with high optical purity.
H
9a
O
11
N
O
H
8
O
H
H
H
stemoamide (1)
N
O
O
H
O
N
H
O
H
stemonine (2)
OMe
H
Key words: carbonylation, biomimetic synthesis, asymmetric
transfer hydrogenation, iminium ion cyclization, stemoamide
O
pyrrolo[1,2-a]
azapine
N
H
O
O
O
H
protostemonamide (3)
Introduction
OMe
H
H
n-Bu
Traditional Chinese medicine (TCM) has offered tremen-
dous opportunities for the treatment of diseases since an-
cient times, and now it has become a rich source of
chemical diversity and lead structures for modern drug
discovery.2 The investigation of ingredients discloses
many intriguing skeletons as well as bioactive compounds
that show potent insecticidal, antibacterial, and anticancer
activity. Stemona alkaloids are known from the monocot-
yledonous family of Stemonaceae, which is mainly dis-
tributed in southeast Asia.3 The characteristic pyrrolo[1,2-
a]azapine nucleus usually associated with a carbon chain
at C4 and C8–C9 1–4 (Figure 1). A protostemonine-type
skeleton, as classified in the seminal review by Greger,4
represents a structurally interesting subclass of stemona
alkaloids and includes several of the most active ingredi-
ents in this family indentified so far.
N
O
O
O
O
stemofoline (4)
Figure 1 Representative stemona alkaloids with a lactone-fused pyr-
rolo[1,2-a]azapine motif
by Jacobi and co-workers stands as a milestone among
them.7c The development of concise synthetic access to
stemoamide is still of great interest in the synthetic com-
munity today.8,9 The pyrrolo[1,2-a]azapine ring system
represents a classic architecture and serves as a potential
precursor for other more complex stemona alkaloids. The
recent comprehensive investigation by Aubé and co-
workers on structure derivatization inspired from stemona
alkaloids led to the discovery of potent chemotype sigma
ligands.10 Stemona alkaloids continue to be of great inter-
est to the synthetic community and an invaluable resource
for the discovery of lead compounds of pharmaceutical
use.5c,11
The complex architecture and intriguing bioactivity of
stemona alkaloids has stimulated many synthetic groups
to undertake total synthesis, structure derivatization, and
biological evaluation.5 Stemoamide (1), a bowl-shaped
lactone-fused pyrrolo[1,2-a]azapine structure, was first
characterized by Xu and co-workers in 1992 from Stemo-
na tuberosa Lour and related stemona species.6 Since the
first enantioselective total synthesis of (–)-stemoamide
accomplished by Williams and co-workers, more than a
dozen synthetic routes have been reported.7 The synthesis
Besides synthetic efforts, a biosynthesis proposal ap-
peared to interpret the structural relationship among sev-
eral subclasses of stemona alkaloids. Inspired by the
biosynthesis of pyrrolizidine alkaloids, Seger, Greger and
co-workers suggested a biosynthesis stemming from a
spermidine precursor coupled with an isoprene unit, fol-
lowed by a stereochemistry-defined step of enzymatic im-
inium ion cyclization, which establishes the carbon
framework12 (Scheme 1). With the consideration of struc-
SYNTHESIS 2012, 44, 3432–3440
Advanced online publication: 25.10.2012
0
0
3
9
-
7
8
8
1
1
4
3
7
-
2
1
0
X
DOI: 10.1055/s-0032-1317499; Art ID: SS-2012-Z0663-FA
© Georg Thieme Verlag Stuttgart · New York

FEATURE ARTICLE
Enantioselective Synthesis of (–)-Stemoamide
3433
turally related pandanus alkaloids in Stemonaceae,13 formation between C9 and C9a may require an enzymatic
Greger further modified the original proposal and pointed iminium ion cyclization. The formation of an iminium ion
out that an asymmetric 1,6-aza-Michael addition would can be derived from the reaction of a free amine with an
constitute a C4-lactone unit, which was originally sug- aldehyde in the first proposal or from the oxidation of a
gested from the isoprene motif. Although these two bio- tertiary amine in the second.
synthesis proposals need to be verified, the key bond
Biographical sketches█
Xianwei Mi was born in versity in 2009, and then the biomimetic synthesis of
1986 in Sichuan province, joined the Shanghai Insti- natural products and medic-
China. He received his tute of Organic Chemistry inal chemistry under the su-
bachelor degree from the and has been conducting re- pervision of Prof. Renxiao
China Pharmaceutical Uni- search on a joint program in Wang and Prof. Ran Hong.
Yan Wang was born in chuan University in 2008, her Ph.D. research on the
1985 in Sichuan province, she then joined the Hong biomimetic synthesis of nat-
China. After obtained her group at the Shanghai Insti- ural products and method
bachelor degree from the tute of Organic Chemistry development in the Hong
College of Chemistry at Si- and is currently conducting group.
Lili Zhu was born in 1985 the Zhejiang Normal Uni- and has been working on the
in Zhejiang province, Chi- versity in 2007. She then biomimetic synthesis of ter-
na. She received her bache- joined the Shanghai Insti- penoids during her Ph.D. re-
lor degree in chemistry from tute of Organic Chemistry search in the Hong group.
Prof. Renxiao Wang re- University of Michigan organic molecules regulate
ceived both his B.Sc. (1994) Medical School as a re- their biological targets
and Ph.D. (1999) in physical search investigator (2001– through molecular model-
chemistry from Peking Uni- 2005). In 2005, he joined ing approaches. He received
versity. After postdoctoral the faculty of Shanghai In- the Corwin Hansch Award
training at the University of stitute of Organic Chemistry issued by the Cheminfor-
California Los Angeles as a ‘One-Hundred Talents’ matics & QSAR Society in
(1999–2000) and George- professor. Prof. Wang’s re- 2012 for his outstanding
town University (2000– search interest focuses on contributions to this field.
2001), he then worked at the understanding how small
Prof. Ran Hong majored After conducting postdoc- tute of Organic Chemistry in
in physical chemistry at toral research in the labora- March 2007; his interests
Sichuan University (B.Sc., tories of the late Prof. Jay K. focus on exploring the bio-
1996) and Ph.D. (2001) Kochi at the University of mimetic approach in meth-
from the Shanghai Institute Houston and Prof. Li Deng od development and natural
of Organic Chemistry (advi- at Brandeis University, he product synthesis.
sor, Prof. Guo-Qiang Lin). returned the Shanghai Insti-
© Georg Thieme Verlag Stuttgart · New York
Synthesis 2012, 44, 3432–3440

3434
X. Mi et al.
FEATURE ARTICLE
Seger and Greger (2004)
H2N
radical generated a nucleophilic carbon center at C1,
which was proposed to be the electrophilic reaction center
in Greger’s biogenesis landscape.12 We envisioned that
the nucleophilicity of C9 can be pre-installed in the form
of an allylsilane (Scheme 1). The Speckamp and Hiemstra
groups have a long interest in this field and established nu-
merous methods to realize the addition of an iminium ion
with allylsilane in both an intermolecular and intramolec-
ular manner.15 Encouraged by these literature precedents,
we thus embedded a key reaction reminiscent of enzymat-
ic iminium ion cyclization in the synthesis of ste-
moamide,8c where the chirality at C8 would command the
stereochemical outcome during the subsequent cationic
cyclization to give the desired stereochemistry at C9 and
C9a. Directed by the hydroxyl group at C8, a transition-
metal-catalyzed carbonylation will then readily construct
the complete structure of stemoamide. With the successful
completion of a concise and bioinspired synthesis of (±)-
stemoamide, herein we disclose its enantioselective total
synthesis.
enzymatic
iminium ion
cyclization
C5 unit
H2N
N
HN
N
spermidine
oxidation
key feature for biomimetic approach:
O
H
N
simulating the proposed enzymatic
iminium ion cyclization as a
stereochemistry-defined step
O
H
H
O
our biomimetic approach
CO insertion
H
biomimetic
iminium ion
cyclization
TMS
RO
TMS
RO
RO
H
H
N
H
N
O
LG
H
O
Scheme 1 Biosynthesis proposal and biomimetic approach to ste-
moamide
Evolution of the Synthetic Route
From a synthetic point of view, taking steps from the bio-
synthesis or the biosynthesis proposal is conceptually in-
spirational. Although numerous synthetic strategies have
been evaluated for the total synthesis of stemoamide, none
of the synthetic designs followed this line. Only three
groups underlined the formation of the azapine ring
through the radical coupling of C9 with C9a at a later
stage of the synthesis by the Narasaka, Khim, and Cossy
groups,9b,14 respectively. However, the polarity-inversed
Preparation of the Chiral Propargylic Alcohol
During our racemic synthesis of stemoamide, a dynamic
ruthenium-catalyzed CO-insertion convergently trans-
formed two isomers of I to a single stereoisomer trans-V
(Scheme 2). Since the unexpected isomer cis-I dominated
in the iminium ion cyclization,8c it implies that the abso-
lute configuration of C8 should be pre-installed in the S-
O
O
9a
Ru3(CO)12
9a
N
•
N
H
H
O
8
8
O
HO
H
cis-I
trans-V
R*-C(8)
"Ru(CO)X"
S*-C(8)
reductive
elimination
•
H
O
H
9a
8
O
8
•
N
9a
8
N
H
H
[Ru]
9a
H
N
H
[Ru]
O
H rebound
[Ru]
H
O
O
O
H
O
II
cis-II
IV
H rebound
H
[Ru]
O
reduction
(H addition)
•
H
O
8
CO
insertion
9a
•
N
9a
[Ru]
N
H
H
H
8
O
O
H
O
III
trans-II
Scheme 2 Dynamic ruthenium-catalyzed CO-insertion and epimerization of the alcohol at C8
Synthesis 2012, 44, 3432–3440
© Georg Thieme Verlag Stuttgart · New York

FEATURE ARTICLE
Enantioselective Synthesis of (–)-Stemoamide
3435
configuration, which will be subsequently epimerized to end, the trimethylsilylmethyl group was replaced by tri-
the designed R-stereochemistry for C8 in (–)-stemoamide. methylsilyl (route c). Gratifyingly, compound 5c is stable
Therefore, S-configured alcohol 6a was used for the enan- and can easily be prepared in large quantities (>7 g). Ap-
tioselective total synthesis of stemoamide. Our original plying Corey’s protocol,17 the optical active propargylic
direct addition of 4-bromobutylaldehyde with lithiated alcohol 6c can be prepared with moderate enantioselectiv-
propargyltrimethylsilane successfully delivered racemic ity (70% ee). In the synthesis of a similar chiral propargyl
6a. A straightforward design for the installation of the C8- alcohol, the Noyori catalyst always offered excellent en-
stereogenic center would be asymmetric addition antioselectivity.19 Therefore, alkynone 5c was subjected
(Scheme 3, route a). However, earlier reported catalyst to asymmetric transfer hydrogenation giving 6c in high
systems did not provide a promising result for this partic- enantiomeric excess (95% ee) albeit using three portions
ular aldehyde.16
of ruthenium complex (overall 30 mol% of catalyst was
used) to reach a high conversion.
route a
O
OH
Asymmetric Transfer Hydrogenation
Br
Br
H
The asymmetric hydrogenation of alkynone 5c required
an overall 30 mol% catalyst loading of Noyori’s rutheni-
um complex (Table 1, entry 1). This clearly is not feasible
at an early stage of the total synthesis. When 6-chlorinated
alkynone 7 was subjected to asymmetric transfer hydroge-
nation, high enantioselectivity was maintained while
complete conversion can be achieved within six hours ap-
plying a lower catalyst loading (10 mol%, entry 2). When
the catalyst loading was further decreased to 5 mol%, the
efficiency of ruthenium complex was still maintained and
no deterioration in the enantiomeric excess was observed.
However, lowering the catalyst loading further was not
possible since full conversion of 7 was not observed, de-
+
TMS
TMS
6a
route b
Ph
Ph
H
N
O
O
OH
B
Br
X
Me
TMS
TMS
B2H6-Me2S
30–45%
50–56% ee
5a (X = Br) unstable
5b (X = Cl) unstable
6a (X = Br)
6b (X = Cl)
Ph
Ph
H
O
route c
O
N
B
OH
Table 1 Optimization of the Asymmetric Transfer Hydrogenation
Me
catecholborane
70% ee
Reaction Conditionsa
Br
Br
Ts
TMS
TMS
Ph
N
5c
6c
Ru
N
Ph
H
Scheme 3 Initial attempts at the synthesis of the chiral alcohol
OH
O
Noyori catalyst
Cl
Cl
i-PrOH, 27 h, r.t.
TMS
An alternative approach would be feasible as indicated in
route b (Scheme 3) based on asymmetric reduction of al-
kynones 5a and 5b. Corey’s chiral borane reagent17 con-
verted the alkynone 5a into the desired propargylic
alcohol in 56% ee and 45% yield, however, the readily de-
composition of the corresponding alkynone 5a (X = Br)
(t1/2 = 4–5 h at 25 °C) indicates that it is necessary to find
an alternative substrate use in the synthesis. We noticed
that during the preparation of racemic 6a a serious side
product was isolated due to the fragile ring-closure reac-
tion which followed after the addition of the alkyne to the
aldehyde in the presence of a strong base.8c We suspected
the existence of bromine in 5a might lead to similar side
reactions. The introduction of chlorine, as in 5b, again
failed to give a high yield of 6b and serious decomposition
of 5b was found. It was concluded that the motif of the
(trimethylsilyl)propargyl ketone results in the inherent in-
stability of 5a and 5b. Therefore, substrate 5c was synthe-
sized from commercially available 4-bromobutanoyl
chloride with bis(trimethylsilyl)acetylene in the presence
of aluminum(III) chloride in quantitative yield.18 To this
TMS
8
7
Entry
Catalyst loading Concn of substrate Conv.
ee
(mol%)
(M)
(%)
(%)b
1c
2d
3e
4
30
10
5
0.1
0.1
0.1
0.1
1.0
0.5
95
>98
>98
41f
95
98
97.7
98.9
97.9
97.8
3
5
5
10f
6
5
50
a Unless otherwise noted, the reaction scale was 0.25 mmol–1.25
mmol of alkynone 7.
b The ee value was determined by chiral HPLC (OD-H).
c Compound 5c was used for the reduction.
d The reaction was run for 6 h.
e The reaction was run for 10 h and the substrate scale was 34.5 mmol.
f The conversion was determined by 1H NMR.
© Georg Thieme Verlag Stuttgart · New York
Synthesis 2012, 44, 3432–3440

3436
X. Mi et al.
FEATURE ARTICLE
spite product 8 being obtained with excellent enantiomer-
ic excess (98.9% ee) (entry 4). Increasing the
concentration of 7 (entries 5 and 6) did not improve the ef-
ficiency of the catalyst. The reason for the higher turnover
obtained for chlorinated alkynone 7 compared to 5c was
not clear. Further mechanistic study is currently ongoing.
The optimized conditions were thus identified as: 5 mol%
of ruthenium complex catalyst and 0.1 M concentration of
substrate to cumulate in the key starting material chiral al-
cohol (S)-8.19d
OH
OTBS
c
Cl
a, b
Cl
TMS
9
8
TMS
OTBS
d
Cl
O
N
TBSO
TMS
O
10
11
Scheme 4 Reagents and conditions: (a) TBSCl (1.4 equiv), DBU
(1.4 equiv), r.t., 1 h; (b) K2CO3, MeOH, 0 °C, 1 h, 94% (2 steps); (c)
LDA (2 equiv), ICH2TMS (2 equiv), THF, –78 °C to 60 °C, 80%; (d)
succinimide (2 equiv), K2CO3 (2 equiv), DMF, 50 °C, 94%.
Synthesis of (–)-Stemoamide
Subsequently, the asymmetric transfer hydrogenation of 7
was run on a seven-gram scale to obtain the requisite
propargylic alcohol 8 in 98% ee and 96% isolated yield.
The absolute configuration was confirmed to be S by
Mosher’s method and this was also consistent with the
general prediction from using the Noyori catalyst on a
similar system.19 The protection of the alcohol with a TBS
group, and the removal of the TMS group under mild ba-
sic conditions yielded 9 in 94% for two steps (Scheme 4).
The nature of the base used proved to be crucial during the
alkylation of the chlorinated derivative 9 with in situ gen-
erated (trimethylsilyl)methyl iodide. Butyllithium is com-
monly used for the alkylation of terminal alkynes,15b,20
however under these conditions serious side reactions
were observed with 9. A less nucleophilic base, lithium
diisopropylamide, gave an excellent yield of 10 after flash
chromatography. The installation of the succinimide
group with potassium carbonate in N,N-dimethylform-
amide at elevated temperatures generated the same inter-
mediate in 94% yield as in our previous report.
Furthermore, the value of 97% ee of compound 11 con-
firmed the reliability of the current procedure.
The subsequent mono-reduction of 11 with sodium boro-
hydride and the well-established iron(III) chloride pro-
moted N-acyl imnium ion cyclization8c,21 delivered the
two inseparable stereoisomers of azapine 12 in a ratio of
3:1 in favor of cis-12a, in which the absolute configura-
tion of C9a was expected to be S and its enantiomeric pu-
rity was further confirmed by HPLC (98.6% ee for 12a
and 99.5% ee for 12b) (Scheme 5). A series of experi-
ments designed to improve the stereoselectivity of the cy-
clization, such as different Lewis acids, protecting groups,
and solvent screening, were unfortunately unsuccessful.
The fact that the two isomers of azepine 12 have the same
polarity led us to seek the separation of the isomers by
subsequent deprotection of the TBS group, however, the
corresponding two isomers of free allenic alcohols 13
were still inseparable. In the racemic synthesis, although
the epimerization during the carbonylation inverted the
chirality at C8 and would deliver (–)-stemoamide from
13a. The inseparable 13b may eventually give its antipode
and diminish the enantiomeric purity of the final com-
pound (–)-stemoamide. Therefore, depletion of 13b at a
certain stage becomes critical in terms of the efficiency of
the current synthesis.
O
O
O
O
9a N
9a
C
N
C
N
C
N
C
e, f
g
+
H
+
H
11
H
H
TBSO
8
TBSO
HO
8
HO
12a
12b
13a
13b
h
O
O
O
O
H
9a
9a
N
9a N
9a
8
N
j
i
C
N
H
H
H
+
O
O
8
8
H
O
O
O
HO
H
H
H
(–)-stemoamide
13a
14a,b
15
Scheme 5 Synthesis of (–)-stemoamide. Reagents and conditions: (e) NaBH4 (5 equiv), EtOH, 0 °C; (f) FeCl3 (1 equiv), toluene, 0 °C, 86% for
2 steps; (g) TBAF (2 equiv), THF, r.t., 96%; (h) AgNO3, CaCO3, acetone–H2O, r.t., 36 h; (i) Ru3(CO)12 (3 mol%), CO (10 atm), Et3N, 100 °C,
6 h, 45% (2 steps); (j) NiCl2·6H2O (0.3 equiv), NaBH4, MeOH, –30 °C, 2 h, 74% (recryst.).
Synthesis 2012, 44, 3432–3440
© Georg Thieme Verlag Stuttgart · New York

FEATURE ARTICLE
Enantioselective Synthesis of (–)-Stemoamide
3437
um-complex-catalyzed
asymmetric
transfer
O
H
O
H
hydrogenation of alkynone 7 delivered the desired C8-ste-
reogenic center in 98% ee. After the installation of the (tri-
methylsilyl)methyl group at the terminal alkyne, the
subsequent bioinspired iron(III) chloride promoted N-im-
inium ion cyclization afforded a 3:1 ratio of two diastereo-
mers in favor of the cis-isomer. The ratio was further
enriched to 50:1 by a novel silver-catalyzed cycloisomer-
ization. The subsequent dynamic ruthenium-catalyzed
CO-insertion reaction secured the total synthesis of (–)-
stemoamide. The current synthesis offers an approach to
construct pyrrolo[1,2-a]azapines in a practical manner for
future synthetic design leading to more complex stemona
alkaloids.
O
H
8
N
cycl.
AgNO3
CaCO3
N
HO
HO
N
H
O
H
fast
C
H
9a
C
Ag
13b
I
14
Ag
C
H
C
H
AgNO3
H
N
H
N
CaCO3
O
OH
13a
OH
O
II
Unless otherwise noted, all reactions were performed under a N2 at-
mosphere. All solvents used in the reactions were dried and distilled
according to standard procedure. All commercial available reagents
were used as received without further purification. 1H and 13C NMR
were recorded on a Varian mercury 400 MHz spectrometers or a
Bruker AM–400 MHz spectrometers in CDCl3 [reference δ = 7.26
(1H) or 77.16 (13C)]. IR spectra were recorded on a Perkin–Elmer
983, Digital FT-IR spectrophotometer or Bruker–Tensor 27; only
selected absorbance are reported; HRMS were determined on an
Agilent technologies 6224 TOF–LC/MS or Bruker Daltonics, Inc.
APEXIII 7.0 TESLA FTMS (ESI) mass spectrometers.
H
Ag
9a
III
O
H
N
C
cycl.
H
8
slow
HO
O
N
H
9a-epi-14
O
unfavorable
Scheme 6 Conformation analysis of the cycloisomerization of 13a
and 13b
With the conformational analysis based on the X-ray
structure of cis-isomer 13a in our previous synthesis and
the known structure of rac-13b in Bates’ elegant synthesis
of stemoamide,8b the pseudo-equatorial hydroxyl group in
13b is assumed to be favorable for the cycloisomerization
under Marshall’s condition22 since there is a proximity ef-
fect between the activated distal alkene and the hydroxyl
group (Scheme 6).8c Clearly, stereoisomer 13a must over-
come a high energy barrier to reach a conformationally
accessible transition state III, which eventually leads to
another cyclized product 9a-epi-14. In other words, ste-
reoisomer 13b can be depleted and 13a can be recovered
in a good yield. Indeed, when the mixture of 13a and 13b
was exposed to the silver-catalyzed reaction, an excellent
ratio of 50:1 (13a/13b) resulted from the initial 3:1 ratio
after the reaction was performed at room temperature for
36 hours. Although the resulting 13a, 14a, and 14b23
could be separated based on TLC results, we used
the mixture in the subsequent carbonylation under
Takahashi’s conditions.24 As expected, compound 14 re-
6-Chloro-1-(trimethylsilyl)hex-1-yn-3-one (7)
To a soln of 4-chlorobutanoyl chloride (4.4 mL, 40 mmol) and
bis(trimethylsilyl)acetylene (10 mL, 44 mmol, 1.1 equiv) in CH2Cl2
(200 mL) was added anhyd AlCl3 (6.4 g, 48 mmol, 1.2 equiv) at 0
°C in one portion. The resulting mixture was stirred at 0 °C for 30
min. The mixture was stirred for an additional 3 h at r.t. The result-
ing brown mixture was then cooled to 0 °C, and aq 1 M HCl was
added until the initially generated white solid disappeared. The or-
ganic layer was separated, and the aqueous layer was extracted with
CH2Cl2. The combined organic layers were washed with brine and
dried (anhyd Na2SO4). Purification by flash chromatography pro-
vided alkynone 7 (8.00 g, quant.) as a light yellow oil; Rf = 0.80
(PE–EtOAc, 10:1).
FT-IR (thin film, KBr): 2963, 2902, 2150, 1679, 1252, 1111, 847,
762 cm–1.
1H NMR (400 MHz, CDCl3): δ = 3.57–3.60 (t, J = 2.4 Hz, 2 H),
2.76–2.80 (t, J = 7.2 Hz, 2 H), 2.08–2.15 (m, 2 H), 0.25 (s, 9 H).
13C NMR (100 MHz, CDCl3): δ = 186.31, 101.85, 98.57, 44.02,
42.27, 26.54, –0.68.
HRMS (ESI): m/z [M + H]+ calcd for C9H16ClSiO: 203.0659; found:
203.0651.
mained in the reaction mixture and the ruthenium-cata- (S)-6-Chloro-1-(trimethylsilyl)hex-1-yn-3-ol (8)
To a soln of alkynone 7 (7.00 g, 34.74 mmol) in i-PrOH (345 mL),
lyzed CO-insertion of 13a with complete inversion of the
chirality at C8 smoothly delivered a single diastereomer
of butenolide trans-15 in 45% isolated yield for two steps.
Using the known reduction conditions,14a (–)-stemoamide
was obtained in 74% yield. The synthetic sample is com-
pletely identical with the reported literature data.6,7
Noyori catalyst (1.03 g, 1.7 mmol) was added in CH2Cl2 (5 mL). Af-
ter 12 h, the mixture was then concentrated under reduced pressure.
The resulting brown residue was subjected to purification by flash
chromatography to yield S-configured alcohol 8 (7.07 g, 96%) as a
clear oil; Rf = 0.29 (PE–EtOAc, 10:1); 97.7% ee [chiral HPLC (Chi-
ralcel OD-H, i-PrOH–n-hexane, 2:98, flow rate = 0.5 mL/min, T =
25 °C, λ = 214 nm): tR = 11.64 (minor), 12.71 min (major)].
[α]D25 –5.87 (c 1.08, CHCl3).
Conclusion
FT-IR (thin film, KBr): 3360, 2960, 2922, 2895, 2850, 2172, 1251,
1069, 844, 761 cm–1.
1H NMR (400 MHz, CDCl3): δ = 4.37–4.40 (t, J = 6 Hz, 1 H), 3.55–
The enantioselective synthesis of (–)-stemoamide was ac-
complished in an overall 18% yield. The Noyori rutheni- 3.59 (t, J = 6 Hz, 2 H), 2.35 (brs, 1 H), 1.91–1.95 (m, 2 H), 1.23–
1.84 (m, 2 H), 0.15 (s, 9 H).
© Georg Thieme Verlag Stuttgart · New York
Synthesis 2012, 44, 3432–3440

3438
X. Mi et al.
FEATURE ARTICLE
13C NMR (100 MHz, CDCl3): δ = 106.27, 89.99, 62.09, 44.77,
34.84, 28.34, –0.08.
HRMS (ESI): m/z [M – H2 + H]+ calcd for C16H32ClOSi2: 333.1680;
found: 331.16747.
HRMS (ESI): m/z [M + Na]+ calcd for C9H17ClNaOSi: 227.0635;
found: 227.0629.
(S)-1-[4-(tert-Butyldimethylsiloxy)-7-(trimethylsilyl)hept-5-yn-
1-yl]pyrrolidine-2,5-dione (11)
To a soln of 10 (1.00 g, 3 mmol) in DMF (30 mL) were added
K2CO3 (0.83 g, 2 equiv) and succinimide (0.59 g, 2 equiv). The mix-
ture was stirred at 50 °C for 24 h. After cooled to r.t., the mixture
was diluted by EtOAc and quenched with H2O. The organic layer
was separated and the aqueous layer was extracted with EtOAc. The
combined extracts were washed with H2O and brine and dried (an-
hyd Na2SO4), After removal of solvent under reduced pressure, the
residue was subjected to purification by flash chromatography (sil-
ica gel, PE–EtOAc, 7:1) to give the product 11 (1.12 g, 94%) as a
yellow oil. The spectra data of 11 is identical with reported data;8c
96.8% ee [chiral HPLC (Chiralcel AD-H, i-PrOH–n-hexane, 2:98,
flow rate = 0.4 mL/min, T = 25 °C, λ = 214 nm): tR = 12.42 (minor),
13.30 min (major).
Preparation of the Noyori Catalyst
A dried 100-mL round-bottom flask was charged with a pre-catalyst
dichloro(p-cymene)ruthenium(II) dimer (551.0 mg, 0.9 mmol),
powdered KOH (745.9 mg, 7.4 equiv), and (1S,2S)-(+)-N-p-tosyl-
1,2-diphenylethylenediamine (658.8 mg, 1.8 mmol).; CH2Cl2 (32
mL) was added. The resulting orange mixture was stirred for 5 min,
and H2O (32 mL) was added in one portion. The corresponding mix-
ture was stirred for a further 10 min till the organic layer turned dark
purple. The mixture was diluted with H2O (50 mL) and the organic
layer was separated and the aqueous phase was extracted with
CH2Cl2 (2 × 50 mL). The combined organic layers were dried
(CaH2). Filtration and concentration furnished the catalyst (1.034 g,
94%) as dark purple solid.
[α]D25 –34.71 (c 0.85, CHCl3).
(S)-tert-Butyl[(6-chlorohex-1-yn-3-yl)oxy]dimethylsilane (9)
To a soln of 8 (1.14 g, 5.6 mmol) in CH2Cl2 (14 mL) was added
TBSCl (2.27 g, 1.4 equiv) at 0 °C. The soln was warmed to r.t., and
DBU (1.92 mL, 1.4 equiv) was added. The resulting mixture was
stirred for 1 h and quenched with aq 1 M HCl. The organic layer was
separated and the aqueous phase was extracted with CH2Cl2. The
combined organic layers were washed with H2O and brine and dried
(anhyd Na2SO4). The solvent was removed, the dark yellow residue
was dissolved in anhyd MeOH (23 mL), and K2CO3 (0.93 g, 1.2
equiv) was added at 0 °C. The mixture was stirred for a further 1 h.
K2CO3 was removed by filtration through a short pad of Celite.
Concentration and purification on flash chromatography (silica gel,
PE) provided alkyne 9 (1.30 g, 94%) as a colorless oil.
1H NMR (400 MHz, CDCl3): δ = 4.34–4.36 (m, 1 H), 3.51–3.55 (m,
2 H), 2.69 (s, 4 H), 1.68–1.74 (m, 2 H), 1.59–1.63 (m, 2 H), 1.45–
1.46 (d, J = 2.4 Hz, 2 H), 0.88 (s, 9 H), 0.08–0.11 (m, 15 H).
(8S)-8-(tert-Butyldimethylsiloxy)-9-vinylidenehexahydro-1H-
pyrrolo[1,2-a]azepin-3(2H)-one (12)
Compound 11 (458 mg, 1.16 mmol) was dissolved in anhyd EtOH
(7.5 mL) and cooled to 0 °C, then NaBH4 (220 mg, 5.8 mmol) was
added in one portion. The resulting mixture was stirred at the same
temperature and an ethanolic solution of sulfuric acid (1 M, 0.12
mL) was added every 15 min. After 1 h, the reaction mixture was
diluted with Et2O (10 mL) and poured into ice-cold water (10 mL).
The aqueous layer was extracted with Et2O (3 × 20 mL). The com-
bined organic layers were washed with H2O and brine, respectively.
The solution was dried over anhyd Na2SO4, and concentrated under
vacuum. The cyclization precursor was obtained after purification
by silica gel chromatography (PE–EtOAc, 2:1) as a yellow oil (460
mg, quant.).
FT-IR (thin film, KBr): 3308, 2957, 2886, 2858, 2360, 2116, 1472,
1254, 1099, 839, 799, 656 cm–1.
1H NMR (400 MHz, CDCl3): δ = 4.38–4.42 (m, 1 H), 3.54–3.58 (t,
J = 6.8 Hz, 2 H), 2.38–2.39 (d, J = 2.4 Hz, 1 H), 1.90–1.96 (m, 2 H),
1.78–1.83 (m, 2 H), 0.89 (s, 9 H), 0.13 (s, 3 H), 0.10 (s, 3 H).
A soln of the above cyclization precursor (460 mg, 1.16 mmol) in
toluene (28 mL) was cooled to 0 °C, and then anhyd FeCl3 (188 mg,
1.16 mmol) was added in one portion. After completion (TLC mon-
itoring), the reaction was quenched with aq sat. sodium potassium
tartrate soln (15 mL) with vigorous stirring. The organic layer was
separated and the aqueous layer was extracted with EtOAc (3 × 30
mL). The combined organic layers were washed with H2O and
brine, respectively. The soln was dried (anhyd Na2SO4) and concen-
trated under reduced pressure. The residue was subjected to purifi-
cation by flash chromatography (silica gel, PE–EtOAc, 5:1) to
provide the product 12 (311 mg, 87%, cis/trans 3:1) as a yellow oil.
The spectral data of 12a and 12b are identical with the reported da-
ta;8c ratio cis-isomer 12a/trans-isomer 12b, 3:1.
13C NMR (100 MHz, CDCl3): δ = 85.03, 72.65, 62.19, 62.17, 44.87,
35.79, 28.35, 25.87, 18.29, 18.27 –4.46, –5.00.
HRMS (ESI): m/z [M – H2 + H]+ calcd for C12H22ClOSi: 245.1128;
found: 245.1117.
(S)-tert-Butyl[(7-chloro-1-(trimethylsilyl)hept-2-yn-4-yl)oxy]di-
methylsilane (10)
To a soln of i-Pr2NH (0.13 mL, 0.90 mmol, 2 equiv) in THF (1 mL),
BuLi (0.38 mL, 0.90 mmol, 2 equiv) was added at –30 °C. The mix-
ture was stirred for 15 min at 0 °C, and the resulting LDA soln was
cooled to –78 °C. To the LDA soln, a soln of 9 (0.11 g, 0.45 mmol)
in THF (1.3 mL) was added via a syringe over 5 min. The resulting
mixture was stirred for 30 min and then ICH2TMS (0.14 mL, 0.19
g, 2 equiv) was added in one portion. The mixture was warmed up
and stirred at 60 °C for an additional 12 h. The mixture was cooled
to r.t. and quenched by addition of sat. NH4Cl soln. The organic lay-
er was separated and the aqueous layer was extracted with Et2O.
The combined organic layers were washed with brine and dried (an-
hyd Na2SO4). Concentration and purification flash chromatography
(silica gel, PE) provided compound 10 (0.12 g, 80%) as a colorless
oil.
cis-Isomer 12a
98.6% ee [chiral HPLC (Chiralcel ID–H, i-PrOH–n-hexane, 2:98,
flow rate = 0.5 mL/min, T = 25 °C, λ = 214 nm): tR = 38.51 (minor),
40.93 min (major)].
trans-Isomer 12b
99.5% ee [HPLC (ID-H, i-PrOH–n-hexane, 2:98, flow rate = 0.5
mL/min, T = 25 °C, λ = 214 nm): tR = 34.63 (major), 36.71 min (mi-
nor)].
FT-IR (thin film, KBr): 2929, 2885, 2857, 2359, 2342, 2220, 1250,
1089, 840, 777 cm–1.
1H NMR (400 MHz, CDCl3): δ = 4.38–4.41 (m, 1 H), 3.57–3.59 (t,
J = 6.4 Hz, 2 H), 1.89–1.97 (m, 2 H), 1.73–1.79 (m, 2 H), 1.47 (d,
J = 2 Hz, 2 H), 0.89 (s, 9 H), 0.09–0.14 (m, 15 H).
13C NMR (100 MHz, CDCl3): δ = 82.77, 80.20, 62.88, 45.20, 36.61,
28.76, 25.98, 18.37, 7.18, –1.85, –4.33, –4.91.
(8S)-8-Hydroxy-9-vinylidenehexahydro-1H-pyrrolo[1,2-a]aze-
pin-3(2H)-one (13)
The TBS-protected allenic alcohols 12 (cis-isomer 12a/trans-iso-
mer 12b, 3:1, 310 mg, 1.0 mmol) were dissolved in anhyd THF (10
mL). 1 M TBAF in THF (2.0 mL, 2.0 mmol) was added in dropwise
via a syringe. The mixture was stirred at r.t. for 3 h and then
quenched with H2O (10 mL). The organic layer was separated and
the aqueous layer was extracted with EtOAc (3 × 45 mL).The com-
bined organic layers were dried (anhyd Na2SO4), and concentrated
Synthesis 2012, 44, 3432–3440
© Georg Thieme Verlag Stuttgart · New York

FEATURE ARTICLE
Enantioselective Synthesis of (–)-Stemoamide
3439
in vacuo. The residue was subjected to purification by chromatog-
raphy (silica gel, EtOAc) to provide the product 13 (186 mg, 96%,
ratio cis/trans, 3:1) as a white solid. The spectra data of 13 is iden-
tical with reported data.8c
1H NMR (400 MHz, CDCl3): δ = 4.12–4.22 (m, 2 H), 3.95–4.01 (m,
1 H), 2.54–2.67 (m, 2 H), 2.36–2.43 (m, 4 H), 2.00–2.07 (m, 1 H),
1.83–1.86 (m, 1 H), 1.67–1.76 (m, 1 H), 1.48–1.54 (m, 2 H), 1.28
(d, J = 6.8 Hz, 3 H).
(3aS,10aR)-2,3a,4,5,6,9,10,10a-Octahydro-8H-furo[3,2-c]pyr-
rolo[1,2-a]azepin-8-one (14)25 and (3aR,10aS)-1-Methyl-
3a,4,5,6,10,10a-hexahydro-2H-furo[3,2-c]pyrrolo[1,2-a]aze-
pine-2,8(9H)-dione (15)25
Acknowledgment
Financial support for this work is generously provided by the Natio-
nal Natural Science Foundation of China (21172236), Chinese Aca-
demy of Sciences, and the National Basic Research Program of
China (2010CB833200). We thank Dr. Rob Hoen (GP Pharm,
Spain) for helpful discussions.
To a soln of the allenic alcohol (mixture of cis- and trans-13, ratio
3:1) (160 mg, 0.83 mmol) in acetone (10.4 mL) and H2O (6.9 mL),
AgNO3 (128 mg, 0.75 mmol) and CaCO3 (75 mg, 0.75 mmol) were
added under exclusion of light. The resulting mixture was stirred at
r.t. for 36 h. The reaction was quenched with H2O (10 mL) and the
organic layer was separated. The aqueous layer was extracted with
EtOAc (3 × 30 mL). The combined organic layers were washed
with brine and dried (anhyd Na2SO4). The soln was filtered through
diatomite and the filter was concentrated under reduced pressure to
give a mixture of allenic alcohol 13a (cis/trans, 50:1) and two dihy-
drofuran derivatives 14 and 9a-epi-14 (conversion: 42%, the com-
bined yield of 13a, 14, and 9a-epi-14: quant.). The mixture was used
in next step without further purification.
Supporting Information for this article is available online at
http://www.thieme-connect.com/ejournals/toc/synthesis.SnoIufproi
m
tgioSrantnugIifoop
r
itmnatr
References
(1) These authors (X. Mi and Y. Wang) contributed equally to
this work.
The above mixture of α-allenic alcohol 13a (cis/trans, 50:1) and di-
hydrofuran derivatives 14 and 9a-epi-14 (100 mg, 0.52 mmol),
Ru3(CO)12 (15.0 mg, 0.023 mmol), and Et3N (20 mL) were added to
a 100-mL stainless autoclave. The resulting mixture was flushed
with CO (30 atm) (3 ×), and pressurized to 10 atm of CO. Then, the
mixture was stirred at 100 °C for 6 h, and cooled to r.t. by a H2O
bath. The CO gas was released and the mixture was transferred into
a 100-mL round-bottom flask. The mixture was filtered through a
short pad of Celite to remove the catalyst and the filtrate was con-
centrated under reduce pressure. The residue was crystallized
(EtOAc–Et2O, 4 mL:10 mL) to give the butenolide 15 (52.1 mg,
45% for 2 steps) as a colorless solid. The spectra data of 15 is iden-
tical with reported data;8c mp 168–170 °C (Lit.7b 127–129 °C, Lit.7c
166–167 °C).
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27
24
[α]D –261.14 (c 0.33, MeOH) (Lit.7b [α]D –246.3 (c 0.63,
MeOH), Lit.7c [α]D24 –261.05 (c 1.33, MeOH).
1H NMR (400 MHz, CDCl3): δ = 4.84–4.87 (d, J = 11.6 Hz, 1 H),
4.70–4.74 (t, J = 7.2 Hz, 1 H), 4.23–4.26 (d, J = 14 Hz, 1 H), 2.41–
2.56 (m, 5 H), 1.85 (s, 3 H), 1.61–1.79 (m, 3 H), 1.25–1.36 (m, 1 H).
(–)-Stemoamide (1)
Butenolide 15 (33 mg, 0.15 mmol) was dissolved in anhyd MeOH
(2.3 mL), and then cooled to –30 °C. NiCl2·6H2O (8.9 mg, 0.04
mmol) and NaBH4 (23 mg, 0.60 mmol) were added, both in one por-
tion under N2. The resulting mixture turned black immediately, and
was stirred vigorously at the same temperature for 2 h. The reaction
was quenched with aq 1 M HCl (4 mL). The organic layer was sep-
arated and the aqueous layer was extracted with CH2Cl2 (3 × 10
mL). The combined organic layers were washed with sat. aq
NaHCO3 and brine, respectively. The soln was dried (anhyd
Na2SO4) and concentrated under reduced pressure. The residue was
crystallized (CH2Cl2–Et2O, 1 mL:2 mL) to give (–)-stemoamide (1)
(13.6 mg, 0.06 mmol) as a colorless solid. The mother liquid was
concentrated and further purified by flash chromatography (silica
gel, CH2Cl2–MeOH, 20:1) to provide an additional 11.1 mg of a col-
orless solid. The combined yield of (–)-stemoamide (1) was 74%.
The spectra data of 1 is identical with reported data;8c mp 181–183
°C (Lit.7a 190–191 °C, Lit.7b 187–188 °C, Lit.7c 186–187 °C, Lit.7e
185–186 °C, Lit.7f 185–186 °C, Lit.7g 182–183 °C, Lit.7h 184–185
°C).
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[α]D27 –151.58 (c 0.46, MeOH) [Lit.7a [α]D26 –141 (c 0.19, MeOH),
26
30
Lit.7a [α]D –181 (c 0.89, MeOH), Lit.7b [α]D –219.3 (c 0.50,
MeOH), Lit.7c [α]D25 –183.5 (c 1.36, MeOH), Lit.7e [α]D25 –191.6 (c
0.5, MeOH), Lit.7f [α]D25 –187 (c 0.5, MeOH), Lit.7g [α]D20 –141 (c
0.3, MeOH), Lit.7h [α]D20 –138 (c 0.2, MeOH).
© Georg Thieme Verlag Stuttgart · New York
Synthesis 2012, 44, 3432–3440

3440
X. Mi et al.
FEATURE ARTICLE
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(25) Correct nomenclature for cyclized products 14 and 15. A
consistent numbering scheme is used for convenience in
Figure 1, Scheme 5, and the text.
Synthesis 2012, 44, 3432–3440
© Georg Thieme Verlag Stuttgart · New York