One-pot reductive coupling of N-acylcarbamates with activated alkenes: Application to the asymmetric synthesis of pyrrolo[1,2-a]azepin-5-one ring system and (-)-xenovenine

Article abstract of DOI:10.1039/c1ob06697h

The one-pot reductive coupling of N-acylcarbamates with activated alkenes is described. The method is based on partial reduction of N-acylcarbamates with DIBAL-H, followed by N-acyliminium ion formation and SmI₂-mediated radical coupling with activated alkenes. Both acyclic and cyclic N-acylcarbamates can be used as stable substrates, and a range of activated alkenes serve as effective radical receptors. The reductive coupling of l-N-acylcarbamates 12/13 gave 2,5-disubstituted pyrrolidine derivatives in high trans-diastereoselectivities. The reductive coupling with penta-2,4-dienoate proceeded exclusively in a 1,6-addition fashion, producing a single non-conjugated E-isomer. On the basis of this method, a three-step construction of pyrrolo[1,2-a]azepin-5-one 16, the skeleton of many stemona alkaloids and lehmizidine alkaloids, and a seven-step synthesis of (-)-xenovenine (pyrrolizidine cis-223H, ent-6), the unnatural enantiomer of the frog/ant venom alkaloid possessing potent inhibitory activity towards nAChR channel, were achieved starting from l-12. The Royal Society of Chemistry 2012.

Full text of DOI:10.1039/c1ob06697h

View Article Online / Journal Homepage / Table of Contents for this issue
Organic &
Biomolecular
Chemistry
Dynamic Article Links
Cite this: Org. Biomol. Chem., 2012, 10, 1275
www.rsc.org/obc
PAPER
One-pot reductive coupling of N-acylcarbamates with activated alkenes:
application to the asymmetric synthesis of pyrrolo[1,2-a]azepin-5-one ring
system and (-)-xenovenine†
Xue-Kui Liu,a Xiao Zheng,a Yuan-Ping Ruan,a Jie Maa and Pei-Qiang Huang*a,b
Received 6th October 2011, Accepted 3rd November 2011
DOI: 10.1039/c1ob06697h
The one-pot reductive coupling of N-acylcarbamates with activated alkenes is described. The method is
based on partial reduction of N-acylcarbamates with DIBAL-H, followed by N-acyliminium ion
formation and SmI2-mediated radical coupling with activated alkenes. Both acyclic and cyclic
N-acylcarbamates can be used as stable substrates, and a range of activated alkenes serve as effective
radical receptors. The reductive coupling of L-N-acylcarbamates 12/13 gave 2,5-disubstituted
pyrrolidine derivatives in high trans-diastereoselectivities. The reductive coupling with
penta-2,4-dienoate proceeded exclusively in a 1,6-addition fashion, producing a single non-conjugated
E-isomer. On the basis of this method, a three-step construction of pyrrolo[1,2-a]azepin-5-one 16, the
skeleton of many stemona alkaloids and lehmizidine alkaloids, and a seven-step synthesis of
(-)-xenovenine (pyrrolizidine cis-223H, ent-6), the unnatural enantiomer of the frog/ant venom
alkaloid possessing potent inhibitory activity towards nAChR channel, were achieved starting from
L-12.
Introduction
Efficiency is an important goal in organic synthesis.1 Step-
economic organic transformations,2 such as one-pot and tandem
reactions that combine at least two reactions in one pot,3 constitute
a valuable approach to that aim. In this context, methods based
on the DIBAL-H reduction in tandem with other reactions in one
pot have attracted much attention.4–7 Among the reported one-pot
DIBAL-H reduction/C–C bond formation methods, carboxylic
acid esters4 and nitriles5 are mostly involved as substrates. To the
best of our knowledge, no one-pot DIBAL-H reduction/radical-
based C–C bond formation method has been reported so far.
In connection with our interest in the development of efficient
a-amino C–C bond formation methods for the synthesis of
alkaloids,8 we recently reported a SmI2-mediated cross-coupling
Scheme 1 Stepwise (path a) versus one-pot (path b) reductive coupling of
N-acylcarbamate 1 with activated alkenes.
of N,O- and N,S-acetals and cyclic hemiaminals with activated
alkenes (Scheme 1, path a).9 A drawback in that method is
associated with the lability of the tertiary acyclic hemiaminals
substrates (e.g. 2a),6c which are prepared by partial reduction
of the corresponding acyclic N-acylcarbamates and can only be
used after protection of the hydroxyl group (e.g. as O-TMS N,O-
acetal 2b).6,7 In addition, the coupling reaction of less reactive
a,b-unsaturated compounds, such as acrylamides, gave low yields
(vide infra). To develop a more efficient coupling method allowing
the use of diverse and readily available substrates, a one-pot
method consisting of partial reduction of N-acylcarbamates10 and
in situ SmI2-mediated radical coupling with activated alkenes was
envisioned (Scheme 1, path b). The establishment of such a method
would pave the way for the synthesis of stemona11 alkaloids, such
as stemonine (4),12 and ant venom/frog alkaloids, such as 5–
813–17 (Figure 1). We now report the results of this investigation,
which include direct reductive coupling of N-acylcarbamates with
aDepartment of Chemistry and The Key Laboratory for Chemical Bi-
ology of Fujian Province, College of Chemistry and Chemical En-
gineering, Xiamen University, Xiamen, Fujian, 361005, P. R. China.
E-mail: pqhuang@xmu.edu.cn; Fax: 86-592-2186400
bThe State Key Laboratory of Elemento-Organic Chemistry, Nankai Uni-
versity, Tianjin, 300071, P. R. China
† Electronic supplementary information (ESI) available: 1H and 13C NMR
spectra of all new compounds; NOESY and 1D GOESY spectra of
compound 16. See DOI: 10.1039/c1ob06697h
This journal is
The Royal Society of Chemistry 2012
Org. Biomol. Chem., 2012, 10, 1275–1284 | 1275
©

View Article Online
Scheme 2 A plausible mechanism for the one-pot reductive coupling
reaction.
reduction of N-acylcarbamate 1 with DIBAL-H in THF at -78 ◦C,
4 equiv. of t-BuOH was added. The mixture was then treated
successively with methyl acrylate (2.0 equiv.), BF3·OEt2 (2.0 equiv.)
and a freshly prepared t-BuOH-containing SmI2 solution (4.0
equiv.) in THF at -40 ◦C. The desired reductive coupling product
3a was obtained in 60% yield, along with the reduced product 9
in 12% yield (Table 1, entry 2). A similar yield was obtained when
running the reaction along at -40 ◦C (Table 1, entry 3). To further
improve the yield, EtOH and MeOH were also investigated as
additives (Table 1, entries 4–6). To our delight, when 1.6 equiv.
of MeOH and 1.5 equiv. of DIBAL-H were used, the yield was
improved to 86% and only a trace of the reduced product 9 was
observed (Table 1, entry 6). Although theoretically only 2 equiv.
of SmI2 are needed for the reaction, as in the stepwise protocol,9 if
less than 4.0 equiv. of SmI2 was used, the reaction was incomplete
and the yield dropped. This may due to the high dilution of
the reaction mediate (in our case, initial concentration: 0.047 M,
final concentration: 0.016 M). In addition, activated alkenes may
consume some SmI2 as well.23 As such, 2.0 equiv. of activated
alkenes and 4.0 equiv. of SmI2 were used.
A plausible mechanism for the one-pot reductive cross-coupling
of N-acylcarbamates with activated alkenes is depicted in Scheme
2. Partial reduction of N-acylcarbamate 1 with DIBAL-H formed
the aluminum alkoxide of hemiaminal intermediate A, which
was quenched with MeOH to give the hemiaminal B. In the
presence of a Lewis acid, such as BF3·OEt2, the N-acyliminium
ion21 C was generated, which was reduced by SmI2 to give the a-
acylaminoalkyl radical intermediate D. The radical intermediate D
was trapped by an activated alkene to give another radical species
that received an electron from a second SmI2. Finally, quenching
the samarium(III) salt with t-BuOH yielded the cross-coupling
product 3a.
Fig. 1 Structures of stemonine and some ant venom/poison frog
alkaloids.
activated alkenes and the application of this method to the
construction of the pyrrolo[1,2-a]azepin-5-one core, skeleton of
stemona and lehmizidine alkaloids [e.g. frog alkaloid 275A (5)],
as well as to the asymmetric synthesis of the 3,5-disubstituted
pyrrolizidine alkaloid (-)-xenovenine (pyrrolizidine cis-223H,
ent-6).
Results and discussion
To test the feasibility of the envisioned idea, the reductive coupling
of N-acylcarbamate 16c with methyl acrylate was first investigated.
N-Acylcarbamate 1 was treated with DIBAL-H (1.5 equiv.) in
THF at -78 ◦C for 30 minutes. The resulting mixture was
warmed to -40 ◦C and then treated successively with methyl
acrylate (2.0 equiv.), BF3·OEt2 (2.0 equiv.) and a freshly prepared
t-BuOH-containing (4.0 equiv.) SmI2 solution in THF.18–20 To
our disappointment, neither the desired product 3a, nor the
reduction product 9 was obtained (Table 1, entry 1). The result
was attributed to the failure in formation of the N-acyliminium
ion intermediate21 from the stable aluminum alkoxide of the
hemiaminal intermediate (cf. Scheme 2). To tackle this problem,
the use of alcohols as useful additives for the SmI2-mediated
coupling reactions22 to decompose the complexes formed in
the DIBAL-H reduction was envisaged. Because t-BuOH is
a beneficial additive in SmI2-mediated coupling reactions,22c it
was chosen to quench the DIBAL-H reduction. Thus, after the
Table 1 Optimization of the conditions for the one-pot reductive cou-
pling of N-acylcarbamate 1 with methyl acrylate
With the optimal conditions for the direct reductive coupling
of N-acylcarbamate 1 with methyl acrylate defined, the reactions
with other activated alkenes were investigated. As can be seen
from Table 2, the one-pot reductive coupling reactions of acyclic
N-acylcarbamate 1 with a variety of activated alkenes underwent
smoothly to afford the desired coupling products 3b–3f. Compared
with the stepwise method (path a in Scheme 1),9b the yield of the
coupling reaction with t-butyl acrylate increased from 62% to 83%
(Table 2, entry 2). Notably, the reductive coupling reactions of N-
acylcarbamate 1 with less reactive acrylamides gave the desired
coupling products 3c and 3d in excellent yields (Table 2, entries
3 and 4, both in 95% yield), while only 23% and 26% yields,
respectively, were obtained from the coupling of N,O-acetal 2b
with acrylamides (cf. Scheme 1, path a).
Entry ROH (equiv.)
T (◦C)
% yielda of 3a
% yielda of 9
b
b
1
2
3
4
5
6
—
-78 to - 40
-78 to - 40
- 40
—
—
t-BuOH (4.0)
t-BuOH (4.0)
EtOH (4.0)
MeOH (4.0)
MeOH (1.6)
60
62
65
70
86
12
10
16
25
- 40
- 40
- 40
trace
a Isolated yield. b No product isolated.
1276 | Org. Biomol. Chem., 2012, 10, 1275–1284
This journal is
The Royal Society of Chemistry 2012
©

View Article Online
Table 2 One-pot reductive coupling of acyclic N-acylcarbamate 1 with
activated alkenes
Table 3 One-pot reductive coupling reactions of cyclic N-acylcarbamate
10 with activated alkenes
Entry
1
Activated alkenes
Coupling product (% yield)a
Entry
1
Activated alkenes
Coupling product (% yield)a
11a (78)
3a (85)
3b (83) (62)b
2
11b (64) (40)b
2
3c (95) (23)c
3d (95) (26)c
3
4
11c (69)
11d (91)
3
4
5
6
5
a Isolated yield; b Yield obtained by the stepwise method from 1 (cf. ref. 9b);
c Yield obtained by coupling with 2b. d E-geometry determined by variable
temperature NMR.
For the coupling with methyl penta-2,4-dienoate, the regioselec-
tivity was a major concern. Although the 1,4-addition (Michael
addition) of nucleophiles to electron-deficient olefins is popular
in organic chemistry, the corresponding 1,6-addition to electron-
deficient dienes has been less explored24 and has recently attracted
much attention.25 In our case, it was found that when an E-
and Z- stereoisomeric mixture of methyl penta-2,4-dienoate was
subjected to the one-pot coupling conditions, the desired 1,6-
addition product 3e was obtained in 73% yield as a single non-
conjugated E-isomer (Table 2, entry 5). The geometry of the olefin
was established on the basis of the observed J value (15.4 Hz) in the
1H NMR spectrum recorded at 70 ◦C. This kind of b,g-unsaturated
compounds can be exploited in further synthetic transformations,
such as Michael addition,26 Diels–Alder27 reaction and so on.28
We next investigated the one-pot reductive coupling reaction
of cyclic N-acylcarbamate 10,10a and the results are compiled
in Table 3. As can be seen from Table 3, the one-pot coupling
of cyclic N-acylcarbamate 10 with activated alkenes gave similar
results to those for the acyclic N-acylcarbamate 1 (Table 2). When
ethyl propiolate was used,29 the desired coupling product 11e was
obtained as a separable geometric mixture with a Z/E ratio of
42 : 58 (entry 5).
It is worth noting that compared with the stepwise method,9b
which requires using the hemiaminal of N-acylcarbamate 10 as
the substrate, the present method is not only more efficient, but
also broader in scope. A reliable method for the preparation
of the hemiaminal of N-acylcarbamate 10 was by oxidation of
N-benzyloxycarbonyl-L-proline,30 and that by partial reduction
of the corresponding cyclic N-acylcarbamate may suffer from
dehydration.31 The direct use of N-acylcarbamates as the sub-
strates overcome those limitations.
a Isolated yield; b Yield obtained by the stepwise method from N-
benzyloxycarbonyl-L-proline (cf. ref. 9b); c Determined by chromato-
graphic separation; d E-geometry assumed by analogy with compound
3e.
cyclic N-acylcarbamates 1232 and 1333 (Table 4) were investigated.
As can be seen from Table 4, compared with the stepwise method,9b
the one-pot method afforded higher yields (entry 3, 15a: 81% vs
68% and entry 4, 15b: 92% vs 49%), while maintaining the same
level of trans-diastereoselectivity.9b
Synthesis of pyrrolo[1,2-a]azepin-5-one 16
To demonstrate the synthetic value of the method, we undertook
the synthesis of pyrrolo[1,2-a]azepin-5-one 16,34 the basic skele-
ton of many stemona alkaloids,11 such as stemonine12 (4) and
lehmizidine 275A (5). The latter is an alkaloid isolated from skin
extracts of the Colombian poison frog Dendrobates lehmanni.14
Thus, compound 14b was subjected to catalytic hydrogenation
conditions to give the saturated and concomitantly N-deprotected
product, which, without further purification, was heated with
triethylamine in toluene at reflux to produce the desired lactam
16 in 70% yield over two steps (Scheme 3). The stereochemistry of
16 was confirmed by combined 1H-1H COSY, 2D NOESY and 1D
GOESY experiments. From the NOESY spectrum, it was difficult
to determine the stereochemistry of the lactam 16. But from the
1D GOESY spectrum, it is easy to observe the NOE correlations
of H9a with H10 and H10¢. No correlation between H9a and H3 was
observed. Thus the stereochemistry of 16 was established as trans
(3S,9aR).
To further extend the scope of the method, the reductive
coupling reactions of the known L-pyroglutamic acid-derived
This journal is
The Royal Society of Chemistry 2012
Org. Biomol. Chem., 2012, 10, 1275–1284 | 1277
©

View Article Online
Table 4 One-pot reductive coupling of cyclic N-acylcarbamates 12/13
with activated alkenes
Scheme 3 The synthesis of pyrrolo[1,2-a]azepin-5-one 16.
from ants and frog skins are believed to have the same absolute
configuration as 3R,5S,8S.15b,c,36 To date, both enantiomers of
xenovenine have been synthesized for several times.37,38 Using
the stepwise reduction-coupling method, we have previously
developed a total synthesis of (+)-xenovenine (6) starting from
L-pyroglutamic acid.9b In view of the high inhibitory activity
towards nicotinic acetylcholine receptor (nAChR) channel of
torpedo californica (IC50 0.05 mM) exhibited by the unnatural enan-
tiomer (-)-xenovenine (ent-6),38a we sought to develop a divergent
enantioselective synthesis of (-)-xenovenine (ent-6) starting from
N-L-acylcarbamate 12, which was also readily available from L-
pyroglutamic acid.
N-Acylcarbamate/
activated alkenes
Entry
1
Coupling producta (% yield)b (trans:cis)
14a (86) (85 : 15)c
2
As shown in Table 4, the one-pot reductive coupling of N-
L-acylcarbamate 12 with methyl acrylate gave diastereomeric
mixture 14a, which was treated with TBAF to give two sepa-
rable desilylated products, cis-17 and trans-18 in 15% and 85%
yield, respectively (Scheme 4). The major diastereomer 18 was
subjected successively to Parikh-Doering oxidation39 and Wittig
reaction37c,40 to produce olefin 19 in an overall yield of 45%.
Compound 19 was converted to methyl ketone derivative 21 via
Weinreb amide 20.41 Finally, in the presence of 20% Pd(OH)2/C
and under an atmosphere of H2, pyrrolidine 21 was converted to
(-)-xenovenine (ent-6) as the only observable diastereomer in 80%
3
4
15a (81) (90 : 10)c (68) (91 : 9)d
15b (92) (93 : 7)c (49) (92 : 8)d
5
6
15c (74) (>99 : 1)c
15d (84) (90 : 10)c
20
26
yield. The physical {[a]D -10.5 (c 1.4, CHCl3);38a [a]D -10.93 (c
1.45, CHCl3)} and spectral data of the synthetic compound (ent-6)
match those reported.38
7
8
a Only the major diastereomer is shown; b Isolated yield; c Determined by
HPLC analysis; d Results of the stepwise method from 12/13 (cf. ref. 9b);
e Determined by HPLC analysis after hydrogenation of the diastereomeric
mixture. f Determined by 1H NMR analysis; g E-geometry assumed by
analogy with compound 3e.
Asymmetric synthesis of (-)-xenovenine (pyrrolizidine cis-223H,
ent-6)
(5Z,8E)-3-Heptyl-5-methylpyrrolizidine (xenovenine, 6) is the first
3,5-disubstituted pyrrolizidine alkaloid isolated from the cryptic
thief ant Solenopsis sp. near tenneseensis.35 This compound was
later identified in anuran skin of a bufonid (Melanophryniscus)
toad by J. W. Daly and named as cis-223H.17 The alkaloids
Scheme
cis-223H, ent-6).
4
Asymmetric synthesis of (-)-xenovenine (pyrrolizidine
1278 | Org. Biomol. Chem., 2012, 10, 1275–1284
This journal is
The Royal Society of Chemistry 2012
©

View Article Online
t-Butyl 4-[benzyl(t-butoxycarbonyl)amino]pentanoate (3b)
Conclusions
Following the general procedure, the one-pot reaction of N-
acylcarbamate 1 with t-butyl acrylate afforded 3b9b (83%) as a
colorless oil. The physical and spectral data are in agreement with
those reported in ref. 9b.
In summary, we developed a one-pot method for the direct
reductive coupling of N-acylcarbamates with activated alkenes,
which was based on the partial reduction with DIBAL-H, followed
by N-acyliminium ion formation and SmI2-mediated radical cross-
coupling with activated alkenes. Compared with the stepwise
approach that we developed previously, the one-pot method shows
several advantages: (1) the scope of the method is greatly extended
due to the direct use of both acyclic and cyclic N-acylcarbamates,
which are both stable and readily available; (2) the overall efficiency
is significantly improved compared with the stepwise one; (3) the
one-pot method allows reaction with less reactive a,b-unsaturated
compounds, such as acrylamides; (4) the coupling of pyroglutamic
acid derived N-acylcarbamates 12/13 afforded high 2,5-trans-
diastereoselectivities and that with E/Z stereomeric mixture of
methyl penta-2,4-dienoate produced exclusively the 1,6-addition
product as a non-conjugated E-isomer. The application of this
method to 12 led to a three-step synthesis of pyrrolo[1,2-a]azepin-
5-one 16, the skeleton of many stemona alkaloids and lehmizidine
alkaloids, in an overall yield of 54%. In addition, (-)-xenovenine
(pyrrolizidine cis-223H, ent-6) was synthesized in seven steps with
an overall yield of 18.9% from 12.
t-Butyl benzyl(5-(benzylamino)-5-oxopentan-2-yl)carbamate (3c)
Following the general procedure, the one-pot reaction of N-
acylcarbamate 1 with N-benzylacrylamide afforded 3c (95%) as
a colorless oil. umax/cm-1 (film): 3304, 3063, 2973, 2919, 1687,
1650, 1453, 1365, 1164, 1029; dH (500 MHz, CDCl3) 1.12 (3H, d, J
6.9, Me), 1.34 and 1.48 (9H, 2 s, br, t-Bu), 1.68–1.92 (2H, m), 1.98–
2.22 (2H, m), 3.78–4.62 (5H, m, NCH NCH2Ph and OCH2Ph),
6.46–6.64 (1H, br, NH), 7.08–7.52 (10H, m, Ph). dC (125 MHz,
CDCl3) 19.1, 28.2, 31.0, 33.6, 43.4, 46.0 and 47.3, 50.7 and 53.5,
79.9, 126.6, 127.2, 127.7, 128.2, 128.5, 138.4, 139.9, 156.3, 172.6.
HRMS [M + K+] calculated for C19H30N2O3K, 373.1888; found:
373.1891.
t-Butyl benzyl(5-(dimethylamino)-5-oxopentan-2-yl)carbamate
(3d)
Following the general procedure, the one-pot reaction of N-
acylcarbamate 1 with N,N -dimethylacrylamide afforded 3d (95%)
as a colorless oil. umax/cm-1 (film): 3032, 2974, 2931, 1686, 1650,
1407, 1365, 1166; dH (500 MHz, CDCl3) 1.11 (3H, d, J 6.8, Me),
1.36 and 1.49 (9H, 2 s br, t-Bu), 1.70–1.82 (1H, m), 1.82–1.98 (1H,
m), 2.02–2.28 (2H, m), 2.78–2.98 (6H, m, NMe2), 3.72–4.62 (3H,
m, NCH and OCH2Ph), 7.12–7.38 (5H, m, Ph). dC (125 MHz,
CDCl3) 19.1, 28.2, 29.9, 30.1, 35.2, 36.9, 46.5 and 47.9, 51.5 and
52.7, 79.5, 126.7, 127.6, 128.1, 140.0, 155.7, 172.3. HRMS [M +
Na+] calculated for C24H32N2O3Na, 419.2305; found: 419.2309.
Experimental section
General procedure for the one-pot reductive coupling of
N-acylcarbamates with activated alkenes
To a solution of a N-acylcarbamate (0.5 mmol) in anhydride
THF (10 mL) was added dropwise a solution of DIBAL-H (1
M in hexane, 0.75 mL, 0.75 mmol) at -40 ◦C. The reaction
was stirred for 30 min and MeOH (32.4 mL, 0.8 mmol) was
added. The resulting mixture was stirred for another 30 min, then
an alkene substrate (1.0 mmol), BF3·Et2O (123 mL, 1.0 mmol)
and a freshly prepared t-BuOH-containing SmI2 (0.1 M in
THF, 20 mL, 2.0 mmol)9 were added successively. After being
stirred at -40 ◦C for 10 min, the reaction was quenched with
a saturated aqueous solution of NH4Cl (10 mL). The mixture
was extracted with diethyl ether (15 mL ¥ 3). The combined
organic layers were washed with brine, dried over anhydrous
Na2SO4, filtered and concentrated under reduced pressure. The
residue was purified by flash chromatography on a silica gel
(eluent: EtOAc/petroleum ether) to afford the desired coupling
product.
Methyl (E)-6-[benzyl(t-butoxycarbonyl)amino]hept-3-enoate (3e)
Following the general procedure, the one-pot reaction of N-
acylcarbamate 1 with methyl penta-2,4-dienoate afforded 3e (73%)
as a colorless oil. umax/cm-1 (film): 3063, 3030, 2973, 2921, 1738,
1688, 1593, 1407, 1365, 1164, 1029; dH (500 MHz, CDCl3) 1.05–
1.16 (3H, m, Me), 1.36 and 1.49 (9H, 2 s br, t-Bu), 2.05–2.46 (2H,
m), 2.80–3.10 (2H, m), 3.61–3.86 (4H, m, NCH and OMe), 4.18–
4.46 (2H, m, OCH2Ph), 5.30–5.65 (2H, m, HC CH), 7.12–7.38
(5H, m, Ph). dH (500 MHz, DMSO-d6 at 343K) 1.06 (3H, d, J
6.8, Me), 1.38 (9H, s, t-Bu), 2.10–2.18 (1H, m), 2.24–2.34 (1H, m),
3.00 (2H, d, J 6.2, COCHC CH), 3.61 (3H, s, Me), 3.88–4.02
(1H, m, NCH), 4.29 (1H, d, J 16.0, OCH2Ph), 4.33 (1H, d, J 16.0,
OCH2Ph), 5.42 (1H, td, J 6.2, 15.4, HC CH), 5.47 (1H, td, J 6.2,
15.4, HC CH), 7.12–7.38 (5H, m, Ph). dC (125 MHz, CDCl3)
18.4, 28.4, 37.8, 38.0, 44.5, 51.4, 51.6, 79.5, 121.5, 122.8, 123.9,
126.6, 127.0, 127.2, 127.4, 128.1, 128.5, 129.6, 131.4, 149.0, 166.8,
172.2 and 172.6. HRMS [M + Na+] calculated for C20H29NO4Na,
370.1989; found: 370.1988.
Methyl 4-[benzyl(t-butoxycarbonyl)amino]pentanoate (3a)
Following the general procedure, the one-pot reaction of N-
acylcarbamate 1 with methyl acrylate afforded 3a42 (85%) as a
colorless oil. umax/cm-1 (film): 3029, 2975, 2921, 1739, 1689, 1453,
1165; dH (500 MHz, CDCl3) 1.09 (3H, d, J 6.9, Me), 1.36 and 1.49
(9H, 2 s br, t-Bu), 1.66–1.80 (1H, m), 1.82–1.94 (1H, m), 2.08–
2.38 (2H, m), 3.63 and 3.65 (3H, 2 s br, OMe), 3.76–4.45 (3H, m,
NCH and OCH2Ph), 7.16–7.34 (5H, m, Ph). dC (125 MHz, CDCl3)
18.9 and 19.3, 28.2, 29.8, 30.9, 46.6 and 47.7, 51.0 and 52.1, 51.3,
79.6, 126.6, 127.4, 128.1, 139.7, 156.0, 173.5. HRMS [M + Na+]
calculated for C18H27NO4Na, 344.1832; found: 344.1837.
Benzyl 2-(3-methoxy-3-oxopropyl)pyrrolidine-1-carboxylate (11a)
Following the general procedure, the one-pot reaction of N-
acylcarbamate 10 with methyl acrylate afforded 11a (78%) as
a colorless oil. umax/cm-1 (film): 3030, 2953, 1738, 1698, 1587,
1410, 1357, 1097, 1028; dH (500 MHz, CDCl3) 1.62–1.78 (2H, m),
This journal is
The Royal Society of Chemistry 2012
Org. Biomol. Chem., 2012, 10, 1275–1284 | 1279
©

View Article Online
1.80–2.14 (4H, m), 2.24–2.46 (2H, m, COCH2), 3.32–3.55 (2H, m,
NCH2), 3.60 and 3.68 (3H, 2 s, OMe), 3.86–3.98 (1H, m, NCH),
5.02–5.24 (2H, m, OCH2Ph), 7.22–7.35 (5H, m, Ph). dC (125 MHz,
CDCl3) 23.0 and 23.7, 29.5 and 29.8, 30.0 and 30.7, 30.9 and
31.1, 46.3 and 46.6, 51.5, 56.5 and 57.2, 66.6 and 66.8, 127.8,
127.9, 128.4, 137.1, 155.2, 173.9. HRMS [M + Na+] calculated for
C16H21NO4Na, 314.1363; found: 314.1361.
(2H, m, COCH2), 3.32–3.54 (2H, m, NCH2), 3.66 (3H, s, OMe),
3.82–3.95 (1H, m, NCH), 5.06–5.24 (2H, m, OCH2Ph), 5.38–5.64
(2H, m, CH CH), 7.22–7.48 (5H, m, Ph). dC (125 MHz, CDCl3)
d 22.8 and 23.6, 29.1 and 23.0, 36.5, 37.5 and 37.8, 46.4 and
46.8, 51.6, 56.7 and 57.2, 66.4 and 66.6, 124.4, 127.7, 128.4, 130.5
and 130.6, 137.1, 154.7, 172.2. HRMS [M + Na+] calculated for
C18H23NO4Na, 340.1519; found: 340.1514.
Benzyl 2-(3-t-butoxy-3-oxopropyl)pyrrolidine-1-carboxylate (11b)
(2S,5S/R)-1-(Benzyloxycarbonyl)-2-[(t-butyldiphenylsilyloxy)
methyl]-5-[2-(methyloxycarbonyl)ethyl]pyrrolidine (14a)
Following the general procedure, the one-pot reaction of N-
acylcarbamate 10 with t-butyl acrylate afforded 11b9b (64%) as
a colorless oil. The physical and spectral data are in agreement
with those reported in ref. 9b.
Following the general procedure, the one-pot reaction of N-
acylcarbamate 12 with methyl acrylate afforded 14a (86%) as a
colorless oil, dr = 85 : 15, determined by HPLC: Shim-pack VP-
ODS (150 ¥ 4.6), CH3CN/H2O 75 : 25, 1.5 mL min-1, l = 220 nm,
t1 = 23.6 min (15.0%), t2 = 24.9 min (85.0%). umax/cm-1 (film):
3066, 2949, 2854, 1736, 1697, 1406; dH (500 MHz, CDCl3) 1.02
and 1.04 (9H, 2 s br, t-Bu), 1.52–1.74 (2H, m), 1.91–2.42 (6H, m),
3.48 (0.5H, m, NCH), 3.60 and 3.65 (3H, 2 s, OMe), 3.72 (0.5H,
m, NCH), 3.74–4.06 (3H, m, NCH and OCH2), 4.89–5.15 (2H, m,
OCH2Ph), 7.07–7.15 (1H, m, Ph), 7.16–7.43 (10H, m, Ph), 7.58–
7.68 (4H, m, Ph); dC (125 MHz, CDCl3) 19.1 and 19.2, 25.7, 26.3,
26.7 and 26.8, 28.1, 29.4, 31.3 and 31.4, 51.4 and 51.5, 57.5, 58.1,
58.5, 59.0, 63.3, 64.0, 66.5 and 66.6 and 66.7, 127.5 and 127.6 and
127.7 and 127.8 and 127.8 and 127.9 and 128.0, 128.3 and 128.4,
129.5 and 129.6, 133.4 and 133.5 and 133.6, 135.4 and 135.5, 136.0
and 136.8, 154.1, 173.4 and 173.6. HRMS [M + H+] calculated for
C33H42NO5Si, 560.2832; found: 560.2843.
Benzyl 2-(3-(benzylamino)-3-oxopropyl)pyrrolidine-1-carboxylate
(11c)
Following the general procedure, the one-pot reaction of N-
acylcarbamate 10 with N-benzylacrylamide afforded 11c (69%)
as a white solid. mp 99–101 ◦C. umax/cm-1 (film): 3291, 3030, 2968,
1650, 1588, 1413, 1095, 1029; dH (500 MHz, CDCl3) 1.62–2.02
(6H, m), 2.08–2.48 (2H, m, COCH2), 3.32–3.62 (2H, m, NCH2),
3.82–4.02 (1H, m, NCH), 4.22–4.58 (2H, m, NCH2Ph), 4.93–5.23
(2H, m, OCH2Ph), 5.50 (1H, br, NH), 7.22–7.42 (10H, m, Ph). dC
(125 MHz, CDCl3) 23.6, 30.6, 31.0, 33.3 and 33.6, 43.5, 46.2, 57.1,
66.8, 127.2, 127.5, 127.8, 127.9, 128.2, 128.4, 128.5, 136.8, 138.6,
155.8, 172.7. HRMS [M + Na+] calculated for C22H26N2O3Na,
389.1836; found: 389.1840.
(2S,5S/R)-1-(Benzyloxycarbonyl)-2-[(t-butyldiphenylsilyloxy)
methyl]-5-[(E)-5-(methyloxycarbonyl) pent-2-enyl]pyrrolidine
(14b)
Benzyl 2-(3-(dimethylamino)-3-oxopropyl)pyrrolidine-1-
carboxylate (11d)
Following the general procedure, the one-pot reaction of N-
acylcarbamate 10 with N,N -dimethylacrylamide afforded 11d
(91%) as a colorless oil. umax/cm-1 (film): 3030, 2962, 2916, 1695,
1644, 1410, 1261, 1095, 1019; dH (500 MHz, CDCl3) 1.64–2.02 (6H,
m), 2.16–2.46 (2H, m, COCH2), 2.64–3.02 (6H, m, NMe2), 3.32–
3.58 (2H, m, NCH2), 3.86–4.02 (1H, m, NCH), 5.02–5.20 (2H, m,
OCH2Ph), 7.24–7.42 (5H, m, Ph). dC (125 MHz, CDCl3) 22.9 and
23.7, 30.0 and 30.3, 30.6 and 31.0, 35.3, 36.9, 37.2, 46.2 and 46.6,
56.9 and 57.5, 66.4 and 66.8, 127.6 and 127.8, 128.0, 128.4, 137.1,
155.2, 172.7. HRMS [M + Na+] calculated for C17H24N2O3Na,
327.1679; found: 327.1671.
Following the general procedure, the one-pot reaction of N-
acylcarbamate 12 with methyl penta-2,4-dienoate afforded 14b
(77%) as a colorless oil, dr > 99 : 1, determined by HPLC: Shim-
pack VP-ODS (150 ¥ 4.6), CH3CN/H2O 75 : 25, 1.5 mL min-1,
l = 220 nm, t1 = 10.9 min (99.7%), t2 = 16.7 min (0.3%). umax/cm-1
(film): 3029, 2917, 2856, 1740 1691, 1590, 1385, 1111, 1029; dH
(500 MHz, CDCl3) 0.92–1.14 (9H, m, t-Bu), 1.60–1.74 (1H, m),
1.82–2.20 (4H, m), 2.36–2.68 (1H, m), 2.84–3.12 (2H, m, COCH2),
3.42–4.12 (7H, m, NCH NCH OCH2 and OMe), 4.88–5.24 (2H,
m, OCH2Ph), 5.34–5.64 (2H, m, CH CH), 7.08–7.48 (11H, m,
Ph), 7.54–7.72 (4H, m, Ph). dC (125 MHz, CDCl3) 19.2 and 19.3,
25.5, 26.2 and 26.5, 26.8 and 26.9, 27.8, 29.7, 35.6, 37.9 and 38.0,
51.8, 57.7 and 58.1, 58.0 and 59.3, 63.4 and 64.1, 66.5, 124.4,
124.5, 127.6, 127.68, 127.73, 127.8, 127.9, 128.0, 128.4, 128.5,
129.6, 129.7, 130.9, 131.0, 133.4, 133.6, 135.5, 135.6, 136.8, 154.1,
172.3. HRMS [M + Na+] calculated for C35H43NO5SiNa, 608.2803;
found: 608.2806.
Benzyl 2-(3-ethoxy-3-oxoprop-1-enyl)pyrrolidine-1-carboxylate
(11e)
Following the general procedure, the one-pot reaction of N-
acylcarbamate 10 with ethyl propiolate afforded 11e9b in 74%
(Z/E = 42/58) yield as a colorless oil. The physical and spectral
data are in agreement with those reported in ref. 9b.
(2S,5S/R)-1-(t-Butyloxycarbonyl)-2-[(t-butyldiphenylsilyl)
(E)-1-(Benzyloxycarbonyl)-2-[4-(methyloxycarbonyl)but-2-
oxymethyl]-5-[2-(methyloxycarbonyl)ethyl]pyrrolidine (15a)
enyl]pyrrolidine (11f)
Following the general procedure, the one-pot reaction of N-
acylcarbamate 13 with methyl acrylate afforded 15a9b in 81% yield
as a colorless oil, dr = 90 : 10, determined by HPLC: Shim-pack
VP-ODS (150 ¥ 4.6), CH3CN/H2O 75 : 25, 1.5 mL min-1, l =
220 nm, t1 = 31.1 min (10.0%), t2 = 33.5 min (90.0%). The physical
and spectral data are in agreement with those reported in ref. 9b.
Following the general procedure, the one-pot reaction of N-
acylcarbamate 10 with methyl penta-2,4-dienoate afforded 11f
(73%) as a colorless oil. umax/cm-1 (film): 3030, 2951, 2921, 1738,
1698, 1587, 1410, 1356, 1099, 1029; dH (500 MHz, CDCl3) 1.64–
1.98 (4H, m), 2.04–2.24 (1H, m), 2.32–2.64 (1H, m), 2.94–3.10
1280 | Org. Biomol. Chem., 2012, 10, 1275–1284
This journal is
The Royal Society of Chemistry 2012
©

View Article Online
(2S,5S/R)-1-(t-Butyloxycarbonyl)-2-[2-(t-butyloxycarbonyl)
ethyl]-5-[(t-butyldiphenylsilyl)oxymethyl]-pyrrolidine (15b)
58.6, 59.8, 60.1, 63.56, 63.64, 63.88, 79.2, 79.4, 79.6, 117.9, 118.6,
120.1, 127.5, 127.6, 129.5, 129.6, 133.16, 133.29, 133.39, 133.46,
135.4, 147.9, 148.6, 152.5, 153.3, 153.5, 153.8, 154.1, 154.3, 165.6,
166.3. HRMS [M + Na+] calculated for C31H43NO5SiNa, 560.2803;
found: 560.2811.
Following the general procedure, the one-pot reaction of N-
acylcarbamate 13 with t-butyl acrylate afforded 15b9b in 92% yield
as a colorless oil, dr = 93 : 7, determined by HPLC: Shim-pack
VP-ODS (150 ¥ 4.6), CH3CN/H2O 75 : 25, 1.5 mL min-1, l =
220 nm, t1 = 80.3 min (6.8%), t2 = 89.9 min (93.2%). The physical
and spectral data are in agreement with those reported in ref. 9b.
(2S,5S/R)-1-(t-Butyloxycarbonyl)-2-[(t-butyldiphenylsilyl)
oxymethyl]-5-[(E)-5-(methyloxycarbonyl)pent-2-enyl] pyrrolidine
(15f)
(2S,5S/R)-1-(t-Butyloxycarbonyl)-2-[(t-butyldiphenylsilyl)
oxymethyl]-5-[2-(benzylaminocarbonyl)ethyl]pyrrolidine (15c)
Following the general procedure, the one-pot reaction of N-
acylcarbamate 13 with methyl penta-2,4-dienoate afforded 15f
(86%) as a colorless oil, dr = 91 : 9, determined by HPLC: Shim-
pack VP-ODS (150 ¥ 4.6), CH3CN/H2O 75 : 25, 2.0 mL min-1, l =
220 nm, t1 = 34.0 min (8.95%), t2 = 69.3 min (91.1%). umax/cm-1
(film): 3030, 2917, 2856, 1740, 1691, 1590, 1385, 1259, 1166, 1030;
dH (500 MHz, CDCl3) 1.06 and 1.08 (9H, 2 s, t-Bu), 1.24–1.48 (9H,
m, t-Bu), 1.60–1.76 (1H, m), 1.90–2.20 (4H, m), 2.40–2.65 (1H, m),
2.80–3.15 (2H, m, COCH2), 3.60–4.05 (7H, m, NCH, NCH, OCH2
and OMe), 5.40–5.80 (2H, m, HC CH), 7.35–7.55 (6H, m, Ph),
7.60–7.75 (4H, m, Ph). dC (125 MHz, CDCl3) 19.15, 19.21, 25.9,
26.3, 28.3, 28.5, 35.7, 37.2, 37.8, 37.9, 38.0, 51.4, 51.6, 57.5, 57.7,
58.7, 63.6, 63.9, 78.97, 79.03, 124.0, 124.1, 127.55, 127.60, 127.64,
129.4, 129.6, 131.2, 133.4, 133.6, 133.7, 135.43, 135.46, 153.6,
153.7, 172.2. HRMS [M + Na+] calculated for C32H45NO5SiNa,
574.2959; found: 574.2959.
Following the general procedure, the one-pot reaction of N-
acylcarbamate 13 with N-benzylacrylamide afforded 15c (74%) as
a colorless oil, dr > 99 : 1, determined by HPLC: Shim-pack VP-
ODS (150 ¥ 4.6), CH3CN/H2O 75: 25, 1.5 mL min-1, l = 220 nm,
t1 = 64.4 min (0.3%), t2 = 69.3 min (99.7%). umax/cm-1 (film): 3305,
3030, 2917, 1643, 1384, 1260, 1111, 1030; dH (500 MHz, CDCl3) d
1.08 (9H, s, t-Bu), 1.28 (9H, s, t-Bu), 1.44–1.62 (2H, m), 2.03–2.40
(4H, m), 3.44–3.87 (4H, m, NCH NCH and OCH2), 4.39–4.56
(2H, m, OCH2Ph), 7.25–7.47 (11H, m, Ph), 7.64–7.67 (4H, m,
Ph). dC (125 MHz, CDCl3) 19.2, 26.0, 26.9, 28.3, 28.6, 28.9, 33.6,
43.6, 57.5, 58.5, 63.7, 79.7, 127.1, 127.7, 127.8, 128.1, 128.5, 128.7,
129.6, 129.7, 133.4, 135.5, 135.5, 138.7, 154.2, 172.2. HRMS [M +
Na+] calculated for C36H48N2O4SiNa, 623.3276; found: 623.3283.
(2S,5S/R)-1-(t-Butyloxycarbonyl)-2-[(t-butyldiphenylsilyl)
oxymethyl]-5-[2-(dimethylaminocarbonyl)ethyl]pyrrolidine (15d)
(3S,9aR)-3-[(t-Butyldiphenylsilyloxy)methyl]hexahydro-1H-
pyrrolo[1,2-a]azepin-5(6H)-one (16)
Following the general procedure, the one-pot reaction of N-
acylcarbamate 13 with N,N -dimethylacrylamide afforded 15d
(84%) as a colorless oil, dr = 90 : 10, determined by HPLC: Shim-
pack VP-ODS (150 ¥ 4.6), CH3CN/H2O 60 : 40, 2.0 mL min-1, l =
220 nm, t1 = 34.6 min (10.2%), t2 = 69.3 min (89.8%). umax/cm-1
(film): 3030, 2916, 2850, 1650, 1384, 1090, 1031; dH (500 MHz,
CDCl3) 1.06 (9H, s, t-Bu), 1.30 and 1.47 (9H, 2 s br, t-Bu), 1.75–
1.77 (2H, m), 2.00–2.43 (6H, m), 2.94–3.03 (6H, 2d, NMe2), 3.44–
3.97 (4H, m, NCH NCH and OCH2), 7.37–7.43 (6H, m, Ph),
7.64–7.66 (4H, m, Ph). dC (125 MHz, CDCl3) 19.2, 19.3, 26.0,
26.2, 26.8, 27.2, 28.3, 28.6, 29.0, 29.8, 30.8, 30.9, 31.1, 35.3, 35.4,
35.6, 37.3, 57.8, 58.4, 58.6, 63.6, 63.9, 79.1, 79.2, 127.4, 127.6,
127.7, 127.7, 127.8, 129.5, 129.6, 133.4, 133.6, 133.7, 135.5, 135.5,
153.8, 172.4, 172.8. HRMS [M + H+] calculated for C31H47N2O4Si,
539.3300; found: 539.3292.
A suspension of compound 14b (40 mg, 0.07 mmol), 20%
Pd(OH)2/C (4 mg) in MeOH (2 mL) was stirred at rt under 1 atm
of hydrogen for 20 h. The reaction mixture was filtered through
Celite and washed with MeOH. The combined filtrates were
concentrated under reduced pressure. The residue was dissolved
in toluene (40 mL) and NEt3 (0.06 mL) was added. The solution
was heated at reflux for 16 h. Then, the resulting mixture was
concentrated under reduced pressure and the crude product was
purified by flash column chromatography on silica gel (eluent:
EtOAc: hexanes 1 : 2) to furnish 16 (20 mg, 70%) as a pale yellow
20
oil. [a]D -29.4 (c 0.9 in CHCl3); umax/cm-1 (film): 3029, 2917,
2856, 1740, 1691, 1371, 1353, 1130, 1103; dH (500 MHz, CDCl3)
1.06 (9H, s, t-Bu), 1.48–1.70 (5H, m), 1.76–1.85 (1H, m), 1.96–2.05
(3H, m) 2.25–2.46 (3H, m), 3.64 (1H, dd, J 6.8, 9.8, H10), 3.76 (1H,
app. t, J 9.2, H9a), 3.76 (1H, dd, J = 3.3, 9.8, H10¢), 4.25–4.35 (1H,
m, H3), 7.31–7.45 (6H, m, Ph), 7.60–7.70 (4H, m, Ph); dC (125
MHz, CDCl3) d 19.2, 23.3, 25.4, 26.9, 29.7 32.6, 36.0, 38.4, 59.5,
59.6, 63.2, 127.58, 127.61, 129.5 129.6, 133.7, 133.8, 135.6, 174.0.
HRMS [M + H+] calculated for C26H36NO2Si, 422.2510; found:
422.2515.
(2S,5S/R)-1-(t-Butyloxycarbonyl)-2-[(t-butyldiphenylsilyl)
oxymethyl]-5-[2-(ethyloxycarbonyl)ethenyl]pyrrolidine (15e)
Following the general procedure, the one-pot reaction of N-
acylcarbamate 13 with ethyl propiolate afforded 15e (91%) as
a colorless oil. For 2,5-trans-15e Z/E = 35/65, determined
by 1H NMR, dr = 92 : 8, determined by HPLC analysis after
hydrogenation of the diastereomeric mixture. umax/cm-1 (film):
3030, 2917, 1693, 1591, 1384, 1260, 1110, 1030; dH (500 MHz,
CDCl3) 1.10 (9H, s, t-Bu), 1.26–1.48 (12H, m, 12H), 1.61–1.76
(m, 1H), 1.95–2.21 (m, 2H), 2.25–2.36 (m, 1H), 3.40–4.65 (m,
6H), 5.62–6.45 (m, 1H), 6.80–7.25 (m, 1H), 7.33–7.51 (6H, m,
Ph), 7.63–7.76 (4H, m, Ph). dC (125 MHz, CDCl3) 14.1, 19.08,
19.13, 26.7, 28.18, 28.24, 28.30, 29.7, 31.3, 31.4, 55.9, 56.6, 58.1,
Benzyl 2-(hydroxymethyl)-5-(3-methoxy-3-oxopropyl)
pyrrolidine-1-carboxylate (2S,5R-17) and (2S,5S-18)
To a solution of compound 14a (150 mg, 0.27 mmol) in THF
(5 mL) was added a 1 M THF solution of n-Bu4NF (0.4 mL,
0.4 mmol) at 0 ◦C, and the resulting solution was stirred at room
temperature for 3 h. After removing the solvent under reduced
pressure, the residue was purified by flash chromatography on
This journal is
The Royal Society of Chemistry 2012
Org. Biomol. Chem., 2012, 10, 1275–1284 | 1281
©

View Article Online
silica gel (eluent: EtOAc/petroleum ether 1 : 1) to afford (2S,5R)-
17 (13 mg, 15%) and (2S,5S)-18 (74 mg, 85%).
(2S,5R)-1-(t-Butyloxylcarbonyl)-2-(hept-1-enyl)-5-[2-(N-methyl-
N-methyloxylaminecarbonyl)ethyl]pyrrolidine (20)
(2S,5R)-17 (more polar diastereomer): yield: 15% Colorless oil:
To a suspension of N,O-dimethylhydroxylamine hydrochloride
salt (80 mg, 0.82 mmol) in CH2Cl2 (2 mL) at 0 C was dropwise
[a]D -11.9 (c 1.1 in CHCl3). umax/cm-1 (film): 3408, 3030, 2973,
20
◦
2921, 1745, 1680, 1407, 1365, 1164, 1029; dH (500 MHz, CDCl3)
1.50–2.16 (m, 6H), 2.20–2.58 (2H, m, COCH2), 3.46–3.66 (4H,
m, OCH and OMe), 3.70–3.84 (1H, m, NCH), 3.88–4.06 (2H, m,
NCH and OCH), 4.28–4.48 (1H, s br, OH), 5.00–5.22 (2H, m,
OCH2Ph), 7.22–7.42 (5H, m, Ph). dC (125 MHz, CDCl3) 26.3,
29.5, 30.1, 31.0, 51.5, 58.4, 61.7, 66.9, 67.3, 127.9, 128.0, 128.4,
136.2, 157.3, 173.6. HRMS [M + H+] calculated for C17H24NO5,
322.1648, found: 322.1643.
added AlMe3 (0.82 mL of a 1 M solution in toluene, 0.82 mmol).
After being stirred for 30 min, a solution of ester 19 (63 mg,
0.16 mmol) in CH2Cl2 (1 mL) was added. The mixture was stirred
for 3 h at rt, then quenched with a saturate aqueous solution of
KHSO4 and filtered through Celite. The filtrate was extracted with
EtOAc (5 mL ¥ 3), dried over with anhydrous Na2SO4, filtered and
concentrated under reduced pressure. The residue was purified by
flash chromatography on a silica gel (eluent: EtOAc/petroleum
ether 1 : 2) to afford compound 20 (53 mg, 78%) as a colorless oil
and recovered 19 (6 mg, 10%). umax/cm-1 (film): 3063, 3030, 2973,
2921, 1745, 1686, 1596, 1384, 1361, 1164, 1029; dH (500 MHz,
CDCl3) 0.80–0.96 (3H, m, Me), 1.15–1.35 (6H, m), 1.55–1.78 (3H,
m, NMe), 1.80–2.25 (m, 5H), 2.30–2.60 (m, 2H), 3.08 and 3.15 (2
s br, 3H), 3.55 and 3.68 (3H, 2 s, OMe), 3.82–4.02 (1H, m, NCH),
4.51–4.70 (1H, m, NCH), 5.00–5.15 (2H, m, OCH2Ph), 5.20–5.50
(2H, m, CH CH), 7.20–7.42 (5H, m, Ph). dC (125 MHz, CDCl3)
d 14.2, 22.6, 27.4, 27.8, 28.5 and 28.8, 29.3, 29.6, 30.6, 31.5 and
31.7, 32.4, 54.8 and 55.2, 57.42 and 57.43 and 58.01, 61.4, 66.7,
127.8, 128.0, 128.4, 128.6, 130.2, 130.7, 131.2, 131.3, 137.2, 154.4
and 154.9, 174.3. HRMS [M + Na+] calculated for C24H36N2O4Na,
439.2567, found: 439.2570.
(2S,5S)-18 (less polar diastereomer): yield: 85%. Colorless oil:
[a]D -41.5 (c 1.0 in CHCl3). umax/cm-1 (film): 3435, 3030, 2973,
20
2921, 1738, 1688, 1593, 1365, 1029; dH (500 MHz, CDCl3) 1.50–
1.75 (m, 3H), 1.85–2.10 (m, 3H), 2.12–2.50 (2H, m, COCH2),
3.35–3.80 (5H, m, NCH OCH2 and OMe), 3.80–3.90 (1H, s br,
OH), 3.92–4.05 (1H, m, NCH), 5.02–5.22 (2H, m, OCH2Ph), 7.25–
7.50 (5H, m, Ph). dC (125 MHz, CDCl3) 26.5 and 27.0, 28.0 and
28.1, 29.0, 31.2 and 31.4, 51.6, 58.0 and 58.8, 60.4, 66.1, 66.8 and
67.2, 128.03, 128.07, 128.5, 136.4, 156.1, 173.3. HRMS [M + H+]
calculated for C17H24NO5, 322.1648; found: 322.1650.
(2S,5S)-1-(t-Butyloxycarbonyl)-2-(hept-1-enyl)-5-[2-(methyl
oxycarbonyl)ethyl]pyrrolidine (19)
A
solution of sulfur trioxide–pyridine complex (594 mg,
(2S,5R)-1-(t-Butyloxylcarbonyl)-2-(hept-1-enyl)-5-(3-oxobutyl)-
3.74 mmol) in DMSO (3 mL) was added to a cooled solution
(0 to 5 ◦C) of (2S,5S)-18 (200 mg, 0.623 mmol) and triethylamine
(0.26 mL, 1.87 mmol) in DMSO (2 mL). The mixture was stirred
at rt for 30 min and then diluted with diethyl ether (10 mL).
A 10% citric acid solution was added to the mixture to adjust
the acidity to pH 4. The organic phase was separated, and the
aqueous phase was extracted with diethyl ether (5 mL ¥ 3). The
combined organic layers were washed with brine, dried over with
anhydrous Na2SO4, filtered and concentrated to give a colorless
oil. To a solution of hexyltriphenylphosphonium bromide (533
mg, 1.25 mmol) in THF (10 mL) was added n-BuLi (2.5 M in
hexane, 0.5 mL, 1.25 mmol) at -78 ◦C. After being stirred for
15 min at -78 ◦C and 15 min at rt, a solution of the above
mentioned crude product in THF (4 mL) was added at -78 ◦C
and the resulting mixture was stirred at -78 ◦C for 2 h. The
reaction mixture was allowed to warm to rt and quenched with a
saturated aqueous solution of NH4Cl (3 mL). The organic layer
was separated, and the aqueous phase extracted with diethyl ether
(5 mL ¥ 3). The combined organic layers were washed with brine,
dried over anhydrous Na2SO4, filtered, and concentrated under
reduced pressure. The residue was chromatographed on silica gel
(eluent: EtOAc/petroleum ether 1 : 5) to afford compound 19 (110
mg, 45%) as a colorless oil. umax/cm-1 (film): 3063, 3030, 1738,
1688, 1593, 1407, 1365, 1164; dH (500 MHz, CDCl3) 0.80–0.96
(3H, m, Me), 1.05–1.50 (6H, m), 1.55–1.72 (3H, m), 1.77–2.45
(7H, m), 3.56 and 3.65 (3H, 2 s, OMe), 3.85–4.00 (1H, m, NCH),
4.55–4.70 (1H, m, NCH), 5.00–5.25 (2H, m, OCH2Ph), 5.23–5.51
(2H, m, CH CH), 7.24–7.38 (5H, m, Ph). dC (125 MHz, CDCl3)
14.0, 22.5, 27.2, 27.5, 28.2, 28.8, 29.1 and 29.3, 30.4, 31.4 and 31.5,
51.6, 54.7, 57.5, 66.6, 127.7, 128.0, 128.2, 128.4, 130.1, 131.0, 136.9,
154.8, 173.7. HRMS [M + Na+] calculated for C23H33NO4Na,
410.2301; found: 410.2299.
pyrrolidine (21)
To a solution of 44 mg (0.11 mmol) of amide 20 in 2 mL of
THF at -78 ◦C was added 0.46 mL (0.74 mmol) of a 1.6 M
solution of MeLi in diethyl ether. After being stirred at -78 ◦C
for 30 min, the reaction was quenched with 2 mL of saturated
aqueous NH4C1 and diluted with 25 mL of diethyl ether. The
layers were separated and the aqueous phase extracted with
diethyl ether (10 mL ¥ 3). The combined organic layers were
washed with brine, dried over with anhydrous Na2SO4, filtered
and concentrated under reduced pressure. The residue was purified
by flash chromatography on silica gel (eluent: EtOAc/petroleum
ether 1 : 2) to afford compound 21 (36 mg, 92%) as a colorless
oil. umax/cm-1 (film): 3063, 3030, 2921, 2854, 1738, 1697, 1407,
1365, 1164, 1029; dH (500 MHz, CDCl3) 0.81–0.94 (3H, m, Me),
1.15–1.34 (6H, m), 1.55–1.66 (3H, m), 1.80–2.22 (8H, m), 2.26–
2.56 (2H, m, COCH2), 3.80–3.95 (1H, m, NCH), 4.50–4.70 (1H,
m, NCH), 5.00–5.55 (4H, m, OCH2PH and CH CH), 7.20–7.40
(5H, m, Ph). dC (125 MHz, CDCl3) 14.2, 22.6, 27.4 and 27.6, 27.9
and 28.1, 28.6, 29.3 and 29.6, 29.9, 30.5, 31.5 and 31.7, 41.2, 54.9
and 55.2, 57.1 and 57.6, 66.8, 127.9, 128.1, 128.4, 128.6, 130.3,
130.5, 131.2, 137.1, 155.0, 208.8. HRMS [M + Na+] calculated for
C23H33NO3Na 394.2353; found: 394.2358.
(-)-Xenovenine (ent-6)
A suspension of compound 21 (40 mg, 0.11 mmol), 20%
Pd(OH)2/C (7 mg) in MeOH (2 mL) was stirred at rt under
1 atm of hydrogen for 20 h. The reaction mixture was filtered
through Celite and washed with CH2Cl2. The combined organic
solvents were concentrated under reduced pressure. The residue
was purified by column chromatography on basic alumina (eluent:
1282 | Org. Biomol. Chem., 2012, 10, 1275–1284
This journal is
The Royal Society of Chemistry 2012
©

View Article Online
n-hexane: Et2O = 7 : 1) to give (-)-xenovenine (ent-6) (19 mg, 80%)
C. Johnstone and J. P. A. Harrity, Tetrahedron, 2004, 60, 8869–8880;
(f) R. A. Wybrow, N. G. Stevenson and J. P. A. Harrity, Synlett, 2004,
140–142; (g) D.-Y. Shin, J.-K. Jung, S.-Y. Seo, Y.-S. Lee, S.-M. Paek, Y.
K. Chung, D. M. Shin and Y.-G. Suh, Org. Lett., 2003, 5, 3635–3638;
(h) Y. G. Suh, D. Y. Shin, J. K. Jung and S. H. Kim, Chem. Commun.,
2002, 1064–1065; (i) Y.-G. Suh, S.-H. Kim, J.-K. Jung and D.-Y. Shin,
Tetrahedron Lett., 2002, 43, 3165–3167; (j) M. P. DeNinno, C. Eller and
J. B. Etienne, J. Org. Chem., 2001, 66, 6988–6993.
7 For one-pot methods for the preparation of N,O and O,O-acetals, see:
(a) F. Szemes Jr., A. Fousse, R. B. Othman, T. Bousquet, M. Othman
and V. Dalla, Synthesis, 2006, 875–879; (b) Y. Zhang and T. Rovis, Org.
Lett., 2004, 6, 1877–1879; (c) D. J. Kopecky and S. D. Rychnovsky,
J. Org. Chem., 2000, 65, 191–198; (d) V. H. Dahanukar and S. D.
Rychnovsky, J. Org. Chem., 1996, 61, 8317–8320; (e) D. Sames, Y. Liu,
L. DeYoung and R. Polt, J. Org. Chem., 1995, 60, 2153–2159; (f) S.
Kiyooka, M. Shirouchi and Y. Kaneko, Tetrahedron Lett., 1993, 34,
1491–1494.
20
38a
26
as a colorless oil. [a]D -10.5 (c 1.4 in CHCl3) { [a]D -10.93
(c 1.45 in CHCl3);38c [a]D -11.4 (c 1.37 in CHCl3)}; umax/cm-1
23
(film): 2955, 2925, 2855, 1461, 1371, 1353, 1130, 1103; dH (500
MHz, CDCl3) 0.86 (3H, t, J 7.1, Me), 1.09 (3H, d, J 6.0, Me),
1.26–1.60 (m, 17H), 1.87–2.05 (m, 3H) 2.57–2.62 (1H, m, NCH),
2.71–2.78 (1H, m, NCH), 3.59 (1H, m, NCH); dC (125 MHz,
CDCl3) d 14.0, 21.9, 22.6, 27.2, 29.3 29.9, 31.7, 31.8, 32.1, 32.4,
34.5, 37.1, 61.7, 65.0, 66.6. MS (ESI, m/z): 224 (M + H+). HRMS
[M + H+] calculated for C17H24NO5, 224.2373; found: 224.2379.
Acknowledgements
The authors are grateful to the National Basic Research Program
(973 Program) of China (Grant No. 2010CB833200), the NSF
of China (20402012; 20832005), the Natural Science Foundation
of Fujian Province of China (2010J01050) and the Fundamental
Research Funds for the Central Universities of China (Grant No.
201112G001) for financial support.
8 For an account, see: (a) P.-Q. Huang, Synlett, 2006, 1133–1149. For
recent examples, see: (b) S.-T. Ruan, J.-M. Luo, Y. Du and P.-Q.
Huang, Org. Lett., 2011, 13, 4938–4941; (c) G.-J. Lin, X. Zheng and
P.-Q. Huang, Chem. Commun., 2011, 47, 1545–1547; (d) K.-J. Xiao,
Y. Wang, K.-Y. Ye and P.-Q. Huang, Chem.–Eur. J., 2010, 16, 12792–
12796; (e) K.-J. Xiao, J.-M. Luo, K.-Y. Ye, Y. Wang and P.-Q. Huang,
Angew. Chem., Int. Ed., 2010, 49, 3037–3040; (f) S.-F. Wu, Y.-P. Ruan,
X. Zheng and P.-Q. Huang, Tetrahedron, 2010, 66, 1653–1660; (g) S.-
F. Wu, X. Zheng, Y.-P. Ruan and P.-Q. Huang, Org. Biomol. Chem.,
2009, 7, 2967–2975; (h) X. Zheng, C.-G. Feng and P.-Q. Huang, Org.
Lett., 2005, 7, 553–556; (i) P.-Q. Huang and J. Deng, Synlett, 2004,
247–250; (j) P.-Q. Huang, T.-J. Wu and Y.-P. Ruan, Org. Lett., 2003, 5,
4341–4344.
Notes and references
1 C. J. Li and B. M. Trost, Proc. Natl. Acad. Sci. U. S. A., 2008, 105,
13197–13202.
9 (a) X.-K. Liu, S. Qiu, Y.-G. Xiang, Y.-P. Ruan, X. Zheng and P.-Q.
Huang, J. Org. Chem., 2011, 76, 4952–4963; (b) Y.-G. Xiang, X.-W.
Wang, X. Zheng, Y.-P. Ruan and P.-Q. Huang, Chem. Commun., 2009,
7045–7047.
2 For an account, see: (a) P. A. Wender, V. A. Verma, T. J. Paxton and
T. H. Pillow, Acc. Chem. Res., 2008, 41, 40–49. For selected examples,
see: (b) T. J. Harrison, S. Ho and J. L. Leighton, J. Am. Chem. Soc.,
2011, 133, 7308–7311; (c) J. M. Richter, Y. Ishihara, T. Masuda, B. W.
Whitefield, T. Llamas, A. Pohjakallio and P. S. Baran, J. Am. Chem.
Soc., 2008, 130, 17938–17954; (d) P. A. Wender, M. P. Croatt and B.
Witulski, Tetrahedron, 2006, 62, 7505–7511.
3 For recent books and reviews on tandem reactions, see: (a) L. F. Tietze,
G. Brasche and K. Gericke, Domino Reactions in Organic Synthesis,
Wiley-VCH, Weinheim, Germany, 2006; (b) T. L. Ho, Tandem Reactions
in Organic Synthesis, New York, Wiley–Interscience, 1992; (c) D.
Enders, C. Grondal and M. R. M. Hu¨ttl, Angew. Chem., Int. Ed.,
2007, 46, 1570–1581; (d) K. C. Nicolaou, D. J. Edmons and P. G.
Bulger, Angew. Chem., Int. Ed., 2006, 45, 7134–7186; (e) H. Pellissier,
Tetrahedron, 2006, 62, 1619–1665 (Part A); (f) H. Pellissier, Tetrahedron,
2006, 62, 2143–2173 (Part B); (g) H.-C. Guo and J.-A. Ma, Angew.
Chem., Int. Ed., 2006, 45, 354–366; (h) J. C. Wasilke, S. J. Obrey, R. T.
Baker and G. C. Bazan, Chem. Rev., 2005, 105, 1001–1020.
4 (a) T. Tomioka, Y. Yabe, T. Takahashi and T. K. Simmons, J. Org.
Chem., 2011, 76, 4669–4674; (b) M. J. Chae, A. R. Jeon, J. K. Park and
D. K. An, Tetrahedron Lett., 2011, 52, 1718–1720; (c) L. R. Reddy, S.
G. Das, Y. Liu and M. Prashad, J. Org. Chem., 2010, 75, 2236–2246;
(d) C. Kuhakarn, N. Panyachariwat and S. Ruchirawat, Tetrahedron
Lett., 2007, 48, 8182–8184; (e) T. R. Hoye, L. C. Kopel and T. D.
Ryba, Synthesis, 2006, 1572–1574; (f) H. Razavi and R. Polt, J. Org.
Chem., 2000, 65, 5693–5706; (g) H. Razavi and R. Polt, Tetrahedron
Lett., 1998, 39, 3371–3374; (h) D. Sames and R. Polt, Synlett, 1995,
552–554; (i) D. Sames and R. Polt, J. Org. Chem., 1994, 59, 4596–4601;
(j) P. L. McGrane and T. Livinghouse, J. Am. Chem. Soc., 1993, 115,
11485–11489; (k) S.-i. Kiyooka, K. Suzuki, M. Shirouchi, Y. Kaneko
and S. Tanimori, Tetrahedron Lett., 1993, 34, 5729–5732; (l) R. Polt,
M. A. Peterson and L. DeYoung, J. Org. Chem., 1992, 57, 5469–5480;
(m) S.-i. Kiyooka and M. Shirouchi, J. Org. Chem., 1992, 57, 1–2; (n) R.
Polt and M. A. Peterson, Tetrahedron Lett., 1990, 31, 4985–4986.
5 (a) G. Cainelli, E. Mezzina and M. Panunzio, Tetrahedron Lett., 1990,
31, 3481–3484; (b) H. L. Goering and C. C. Tseng, J. Org. Chem., 1981,
46, 5250–5252.
6 For stepwise DIBAL-H reduction/C-C bond formation reactions (a-
amidoalkylations), see: (a) R.-C. Liu, W. Huang, J.-Y. Ma, B.-G. Wei
and G.-Q. Lin, Tetrahedron Lett., 2009, 50, 4046–4049; (b) H.-Y. Kang,
Y.-G. Suh and J.-K. Jung, Bull. Korean Chem. Soc., 2007, 28, 1401–1404;
(c) C. Kuhakarn, N. Panyachariwat and S. Ruchirawat, Tetrahedron
Lett., 2007, 48, 8182–8184; (d) J.-W. Jung, D.-Y. Shin, S.-Y. Seo, S.-H.
Kim, S.-M. Paek, J.-K. Jung and Y.-G. Suh, Tetrahedron Lett., 2005, 46,
573–575; (e) R. A. Wybrow, A. S. Edward, N. G. Stevenson, H. Adams,
10 For the preparation of N-acylcarbamates, see: (a) K.-I. Lee, J. H. Kim,
K.-Y. Ko and W.-J. Kim, Synthesis, 1991, 935–936; (b) A. Giovannini,
D. Savoia and A. Umani-Ronchi, J. Org. Chem., 1989, 54, 228–234.
11 For recent reviews on stemona alkaloids, see: (a) R. A. Pilli, G. B.
Rossoa and M. C. F. de Oliveira, Nat. Prod. Rep., 2010, 27, 1908–1937;
(b) R. Alibe´s and M. Figueredo, Eur. J. Org. Chem., 2009, 2421–2435;
(c) H. Greger, Planta Med., 2006, 72, 99–113. For a recent contribution
from our laboratory in this field, see: (d) S.-C. Tuo, J.-L. Ye, A.-E. Wang,
S.-Y. Huang and P.-Q. Huang, Org. Lett., 2011, 13, 5270–5273.
12 For isolation of stemonine, see: (a) H. Koyama and K. Oda, J. Chem.
Soc. B, 1970, 1330–1333; (b) K. Suzuki, J. Pharm. Soc. Jpn., 1931, 51,
419; (c) K. Suzuki, J. Pharm. Soc. Jpn., 1929, 49, 457. For the first total
synthesis of (-)-stemonine, see: (d) D. R. Williams, K. Shamim, J. P.
Reddy, G. S. Amato and S. M. Shaw, Org. Lett., 2003, 5, 3361–3364.
13 For a recent review on poison frog alkaloids, see: J. W. Daly, T. F.
Spande and H. M. Garraffo, J. Nat. Prod., 2005, 68, 1556–1575.
14 For isolation of 275A, see: (a) H. M. Garraffo, P. Jain, T. F. Spande
and J. W. Daly, J. Nat. Prod., 2001, 64, 421–427; (b) C. W. Myers and
J. W. Daly, Bull. Am. Mus. Nat. Hist., 1976, 157, 173–262. For a recent
synthesis, see: (c) G. Lesma, A. Sacchetti and A. Silvani, Tetrahedron:
Asymmetry, 2010, 21, 2329–2333.
15 For isolation of alkaloid cis-223H, see: (a) H. M. Garraffo, J. Caceres,
J. W. Daly and T. F. Spande, J. Nat. Prod., 1993, 56, 1016–1038. For
the absolute configuration, see: (b) ref. 13 (c) N. Toyooka, D.-J. Zhou,
H. Nemoto, Y. Tezuka, S. Kadota, N. R. Andriamaharavo, H. M.
Garraffo, T. F. Spande and J. W. Daly, J. Org. Chem., 2009, 74, 6784–
6791 and references cited therein.
16 For identification of 195F, see: V. C. Clark, C. J. Raxworthy, V.
Rakotomalala, P. Sierwald and B. L Fisher, Proc. Natl. Acad. Sci.
U. S. A., 2005, 102, 11617–11622.
17 For identification of 223B, see: H. M. Garraffo, T. F. Spande, J. W.
Daly, A. Baldessari and E. G. Gros, J. Nat. Prod., 1993, 56, 357–373.
18 For a recent book on the application of SmI2 in organic synthesis, see:
(a) D. J. Procter, R. A. Flowers and T. Skrydstrup, Organic Synthesis
Using Samarium Diiodide: A Practical Guide, Cambridge, Royal Society
of Chemistry, 2010. For reviews on the chemistry of SmI2, see: (b) K. C.
Nicolaou, S. P. Ellery and J. S. Chen, Angew. Chem., Int. Ed., 2009, 48,
7140–7165; (c) G.-Q. Lin, M.-H. Xu, Y.-W. Zhong and X.-W. Sun, Acc.
Chem. Res., 2008, 41, 831–840; (d) K. Gopalaiah and H. B. Kagan,
New J. Chem., 2008, 32, 607–637; (e) D. J. Edmonds, D. Johnston
and D. J. Procter, Chem. Rev., 2004, 104, 3371–3403; (f) H. B. Kagan,
This journal is
The Royal Society of Chemistry 2012
Org. Biomol. Chem., 2012, 10, 1275–1284 | 1283
©

View Article Online
Tetrahedron, 2003, 59, 10351–10372; (g) A. Krief and A. M. Laval,
Chem. Rev., 1999, 99, 745–777; (h) G. A. Molander and C. R. Harris,
Tetrahedron, 1998, 54, 3321–3354; (i) G. A. Molander and C. R. Harris,
Chem. Rev., 1996, 96, 307–338. For selected recent applications, see:
(j) M. Szostak and D. J. Procter, Angew. Chem., Int. Ed., 2011, 50, 7737–
7739; (k) D. Parmar, K. Price, M. Spain, H. Matsubara, P. A. Bradley
and D. J. Procter, J. Am. Chem. Soc., 2011, 133, 2418–2420; (l) D.
Parmar, L. A. Duffy, D. V. Sadasivam, H. Matsubara, P. A. Bradley, R.
A. Flowers II and D. J. Procter, J. Am. Chem. Soc., 2009, 131, 15467–
15473; (m) G. Guazzelli, S. de Grazia, K. D. Collins, H. Matsubara, M.
Spain and D. J. Procter, J. Am. Chem. Soc., 2009, 131, 7214–7215; (n) L.
A. Duffy, H. Matsubara and D. J. Procter, J. Am. Chem. Soc., 2008,
130, 1136–1137.
2005, 7, 5629–5632; (j) T. Hayashi, S. Yamamoto and N. Tokunaga,
Angew. Chem., Int. Ed., 2005, 44, 4224–4227; (k) K. Kukuhara and H.
Urabe, Tetrahedron Lett., 2005, 46, 603–606; (l) M. Uerdingen and N.
Krause, Tetrahedron, 2000, 56, 2799–2804.
26 (a) R. D. Little, M. R. Masjedizadeh, O. Wallquist and J. I. Mcloughlin,
2004. The Intramolecular Michael Reaction. Organic Reactions, 315-
552; (b) C. Han, S. Rangarajan, A. C. Voukides, A. B. Beeler, R.
Johnson, J. A. Porco and Jr, Org. Lett., 2009, 11, 413–416; (c) ref.
24c; (d) ref. 24e; (e) ref. 24g.
27 (a) S. Luo, P. Dai and S. E. Schaus, J. Org. Chem., 2007, 72, 9998–10008;
(b) A. Padwa and J. D. Ginn, J. Org. Chem., 2005, 70, 5197–5206; (c) J.
D. Ginn and A. Padwa, Org. Lett., 2002, 4, 1515–1517.
28 S. Kesavan, J. S. Panek, J. A. Porco and Jr, Org. Lett., 2007, 9, 3229–
19 For recent methods on the SmI2-mediated a-amino C-C bond for-
mation, see: (a) J. M. Aurrecoechea, F. Bustos, B. Lo´pez, C. Saornil
and R. Suero, Arkivoc, 2009, part xi, 94–104 at www.arkat-usa.org
and references cited therein; (b) Y.-W. Zhong, Y.-Z. Dong, K. Fang,
K. Izumi, M.-H. Xu and G.-Q. Lin, J. Am. Chem. Soc., 2005, 127,
11956–11957; (c) Y.-W. Zhong, M.-H. Xu and G.-Q. Lin, Org. Lett.,
2004, 6, 3953–3956; (d) P. Blakskjær, A. Gavrila, L. Andersen and T.
Skrydstrup, Tetrahedron Lett., 2004, 45, 9091–9094; (e) G. Masson, P.
Cividino, S. Py and Y. Valle´e, Angew. Chem., Int. Ed., 2003, 42, 2265–
2268; (f) G. Masson, S. Py and Y. Valle´e, Angew. Chem., Int. Ed., 2002,
41, 1772–1775; (g) A. R. Katritzky, Z.-S. Luo, Y.-F. Fang, D. M. Feng
and I. Ghiviga, J. Chem. Soc., Perkin Trans. 2, 2000, 1375–1380.
20 For the preparation of SmI2, see: (a) J. L. Namy, P. Girard and H. B.
Kagan, New J. Chem., 1977, 1, 5–7; (b) P. Girard, J. L. Namy and H. B.
Kagan, J. Am. Chem. Soc., 1980, 102, 2693–2698; (c) T. Imamoto and
M. Ono, Chem. Lett., 1987, 501–502.
3231.
29 For a stereoselective SmI2-mediated couplings of ketones with ethyl
propiolate, see: D. W. Kwon, M. S. Cho and Y. H. Kim, Synlett, 2001,
627–628.
30 (a) H. Fujioka, H. Hirose, Y. Ohba, K. Murai, K. Nakahara and Y.
Kita, Tetrahedron, 2007, 63, 625–637; (b) ref. 9b.
31 (a) D. F. Oliveira, P. C. M. L. Miranda and C. R. D. Correia, J. Org.
Chem., 1999, 64, 6646–6652; (b) R. K. Dieter and R. R. Sharma, J.
Org. Chem., 1999, 64, 4180–4184; (c) W. Marais and C. W. Holzapfel,
Synth. Commun., 1998, 28, 3681–3691.
32 J. E. Kitulagoda, A. Palmelund and V. K. Aggarwal, Tetrahedron, 2010,
66, 6293–6299.
33 (a) J. M. Humphrey, Y. Liao, A. Ali, T. Rein, Y.-L. H.-J. Wong, Chen, A.
K. Courtney and S. F. Martin, J. Am. Chem. Soc., 2002, 124, 8584–8592;
(b) L. Bunch, P.-O. Norrby, K. Frydenvang, P. Krogsgaard-Larsen and
U. Madsen, Org. Lett., 2001, 3, 433–435.
21 For recent reviews on N-acyliminium based C–C bond formation
methods, see: (a) A. Yazici and S. G. Pyne, Synthesis, 2009, 513–541;
(b) A. Yazici and S. G. Pyne, Synthesis, 2009, 339–368; (c) J. Royer,
Chem. Rev., 2004, 104, 2311–2352; (d) B. E. Maryanoff, H.-C. Zhang,
J. H. Cohen, I. J. Turchi and C. A. Maryanoff, Chem. Rev., 2004, 104,
1431–1628; (e) C. M. Marson, Arkivoc, 2001, part 1, 1–16; (f) S. K. Bur
and S. F. Martin, Tetrahedron, 2001, 57, 3221–3242; (g) W. N. Speckamp
and M. J. Moolenaar, Tetrahedron, 2000, 56, 3817–3856.
22 For an account of the additives for SmI2, see: (a) R. A. Flowers II.
Synlett, 2008, 1427-1439. For selected application, see: (b) M. Amiel-
Levy and S. Hoz, J. Am. Chem. Soc., 2009, 131, 8280–8284; (c) T.
K. Hutton, K. W. Muir and D. J. Procter, Org. Lett., 2003, 5, 4811–
4814; (d) S. -i. Fukuzawa, A. Nakanishi, T. Fujinami and S. Sakai, J.
Chem. Soc., Chem. Commun., 1986, 624–625.
23 (a) A. M. Hansen, K. B. Lindsay, P. K. S. Antharjanam, J. Karaffa,
K. Daasbjerg, R. A. Flowers II and T. Skrydstrup, J. Am. Chem. Soc.,
2006, 128, 9616–9617; (b) M. Sono, S.-i. Hanamura, M. Furumaki, H.
Murai and M. Tori, Org. Lett., 2011, 13, 5720–5723.
24 The following reviews partially deal with 1,6-addition reactions: (a) M.
A. Fredrick and M. Hulce, Tetrahedron, 1997, 53, 10197–10227; (b) N.
Krause and A. Gerold, Angew. Chem., Int. Ed., 1997, 36, 186–204. See,
also: (c) J. W. Ralls, Chem. Rev., 1959, 59, 329–344.
25 (a) T. Nishimura, H. Makino, M. Nagaosa and T. Hayashi, J. Am.
Chem. Soc., 2010, 132, 12865–12867; (b) T. Gallagher, I. Derrick, P.
M. Durkin, C. A. Haseler, C. Hirschha¨user and P. Magrone, J. Org.
Chem., 2010, 75, 3766–3774; (c) T. Nishimura, Y. Yasuhara, T. Sawano
and T. Hayashi, J. Am. Chem. Soc., 2010, 132, 7872–7873; (d) J. Wencel-
Delord, A. Alexakis, C. Cre´visy and M. Mauduit, Org. Lett., 2010, 12,
4335–4337; (e) T. Hartog, D. J. Dijken, A. J. Minnaard and B. L.
Feringa, Tetrahedron: Asymmetry, 2010, 21, 1574–1584; (f) H. Gong,
R. S. Andrew, J. L. Zuccarello, S. J. Lee and M. R. Gagne´, Org. Lett.,
2009, 11, 879–882; (g) L. Bernard, J. Lo´pez-Cantarero, B. Niess and
K. Jørgensen, A., J. Am. Chem. Soc., 2007, 129, 5772–5778; (h) T.
Nishimura, Y. Yasuhara and T. Hayashi, Angew. Chem., Int. Ed., 2006,
45, 5164–5166; (i) G. I. Herra´n, C. Murcia and A. G. Csa´ky¨, Org. Lett.,
34 For selected asymmetric synthesis of pyrrolo[1,2-a]azepine lactam, see:
(a) F. Sa´nchez-Izquierdo, P. Blanco, F. Busque´, R. Alibe´s, P. March,
M. Figueredo, J. Font and T. Parella, Org. Lett., 2007, 9, 1769–1772;
(b) R. Alibe´s, P. Blanco, M. Closa, P. March, M. Figueredo, J. Font, E.
´
´
Sanfeliu and A. Alvarez-Larena, J. Org. Chem., 2005, 70, 3157–3167;
(c) G. M. Weeresakare, Z. Liu and J. D. Rainier, Org. Lett., 2004, 6,
1625–1627.
35 T. H. Jones, M. S. Blum, H. M. Fales and C. R. Thompson, J. Org.
Chem., 1980, 45, 4778–4780.
36 R. A. Saporito, H. M. Garraffo, A. F. Donnelly, A. L. Edwards, J.
T. Longino and J. W. Daly, Proc. Natl. Acad. Sci., 2004, 101, 8045–
8050.
37 For selected asymmetric synthesis of (+)-xenovenine, see: (a) V. M.
Arredondo, S. Tian, F. E. McDonald and T. J. Marks, J. Am. Chem.
Soc., 1999, 121, 3633–3639; (b) H. Dhimane, C. Vanucci-Bacque, L.
Hamon and G. Lhommet, Eur. J. Org. Chem., 1998, 1955–1963; (c) H.
Takahata, H. Bandoh and T. Momose, J. Org. Chem., 1992, 57, 4401–
4404; (d) O. Provot, J. P. Ce´le´rier, H. Petit and G. Lhommet, J. Org.
Chem., 1992, 57, 2163–2166; (e) S. Arseniyadis, P.-Q. Huang and H.-P.
Husson, Tetrahedron Lett., 1988, 29, 1391–1394.
38 For the asymmetric synthesis of (-)-xenovenine, see: (a) Y. Saito, S.
Takahashi, N. Azer, A. T. Eldefrawi, M. E. Eldefrawi and H. Takahata,
Heterocycles, 2009, 79, 1043–1060; (b) H. Takahata, S. Takahashi,
N. Azer, A. T. Eldefrawi and M. E. Eldefrawi, Bioorg. Med. Chem.
Lett., 2000, 10, 1293–1295; (c) H. Dhimanea, C. Vanucci-Bacquea´, L.
Hamonb and G. Lhommet, Eur. J. Org. Chem., 1998, 1955–1963; (d) C.
G. Oppolzer, E. Bochet and E. Merifield, Tetrahedron Lett., 1994, 35,
7015–7018; (e) ref. 37c.
39 (a) Y. Hamada, M. Shibata, T. Sugiura, S. Kato and T. Shioiri, J. Org.
Chem., 1987, 52, 1252–1255; (b) J. R. Parikh and W. von E. Doering, J.
Am. Chem. Soc., 1967, 89, 5505–5507.
40 C. Beier and E. Schaumann, Synthesis, 1997, 1296–1300.
41 S. Nahm and S. M. Weinreb, Tetrahedron Lett., 1981, 22, 3815–3818.
42 D. Crich and K. Ranganathan, J. Am. Chem. Soc., 2005, 127, 9924–
9929.
1284 | Org. Biomol. Chem., 2012, 10, 1275–1284
This journal is
The Royal Society of Chemistry 2012
©