Enantioselective synthesis of condensed and transannular ring skeletons containing pyrrolidine moiety

Article abstract of DOI:10.1016/j.tet.2009.12.013

A new approach toward condensed and transannular ring structures containing pyrrolidine unit has been developed, based on diastereoselective nucleophilic addition of lithium enolate of α-diazoacetoacetate to chiral N-sulfinyl imine and ring-closing metathesis.

Full text of DOI:10.1016/j.tet.2009.12.013

Tetrahedron 66 (2010) 1274–1279
Contents lists available at ScienceDirect
Tetrahedron
journal homepage: www.elsevier.com/locate/tet
Enantioselective synthesis of condensed and transannular ring skeletons
containing pyrrolidine moiety
,b,
Fanyang Mo a, Fei Li a, Di Qiu a, Jianbo Wang a
*
a Beijing National Laboratory of Molecular Sciences (BNLMS) and Key Laboratory of Bioorganic Chemistry and Molecular Engineering of Ministry of Education,
College of Chemistry, Peking University, Beijing 100871, China
b State Key Laboratory of Organometallic Chemistry, Chinese Academy of Sciences, Shanghai 200032, China
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 4 October 2009
Received in revised form 29 November 2009
Accepted 4 December 2009
Available online 26 December 2009
A new approach toward condensed and transannular ring structures containing pyrrolidine unit has been
developed, based on diastereoselective nucleophilic addition of lithium enolate of a-diazoacetoacetate to
chiral N-sulfinyl imine and ring-closing metathesis.
Ó 2009 Elsevier Ltd. All rights reserved.
Keywords:
Enantioselective synthesis
Diazo compounds
Nucleophilic addition
Pyrrolidine
Ring-closing olefin metathesis
1. Introduction
HO
H
OH
CH2OH
O
H
N
N
HO
The enantioselective construction of pyrrolidine skeletons,
a frequently observed structural unit in various alkaloid type nat-
ural products, pharmaceutical molecules, etc., is of current in-
terest.1,2 Among the various pyrrolidine-containing structures,
condensed and transannluar ring skeletons are important struc-
tural subunits present in many alkaloids and are common scaffolds
in biologically active and pharmaceutically significant compounds.3
For example, (þ)-harmicine was extracted from the Malaysian
plant Kopsia griffithii by Kam and Sim and showed strong anti-
Leishmania activity.4 Polyhydroxylated pyrrolizidines and
indolizidines (related to iminosugars) such as Swainsonine have
increasingly gained attention because of their ability to inhibit
glycosidases (Scheme 1).5
Besides the classical total synthesis approach to complex
structures, particularly attractive is the development of synthetic
methodologies that allow for the preparation of a large number of
structurally similar analogs from limited few common in-
termediates.6 As a part of our program for the development of novel
synthetic methodology based on diazo compounds, we have
recently developed a concise and efficient method to construct
N
N
H
H
Subulacine
(+)-Harmicine
Swainsonine
N
OH
N
N
O
H
TBDMSO
O
3-Butyllehmizidine
Methyllycaconitine
Securinine
Scheme 1.
5-substituted 2-oxo and 3-oxo pyrrolidines with high enantiomeric
purity.7 Here we report the further application of this methodology
to the enantioselective synthesis of condensed and transannular
ring skeletons containing pyrrolidine units.
This new approach to condensed and transannular ring skele-
tons is outlined in Scheme 2. With the reactions that have been
reported previously, we can easily prepare 2-oxo-5-vinyl-
pyrrolidine 1. Introducing the side chains that contain olefin moiety
to either N or C3 position affords key intermediates 2 and 3, re-
spectively. Ring-closing metathesis (RCM),8 which has emerged as
powerful tool to construct ring system through intramolecular C]C
bond formation, is applied to 2 and 3 to afford condensed and
transannular ring systems 4 and 5.9
* Corresponding author. Fax: þ86 10 6275 1708.
E-mail address: wangjb@pku.edu.cn (J. Wang).
0040-4020/$ – see front matter Ó 2009 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2009.12.013

F. Mo et al. / Tetrahedron 66 (2010) 1274–1279
1275
amount of DMAP, affording N-Boc protected diazo compound 9 in
95% yield. Irradiation of diazo compound 9 with high-pressure Hg
O
O
N
N
lamp (l>300 nm) in a Pyrex tube gave (5R)-2-oxo-3-allyloxy-
carbonyl-5-vinylpyrrolidine 10 in 60% isolated yield.7,13
4
2
With 10 in hand, we next proceeded to build the condensed
rings based on the strategy summarized in Scheme 2. The con-
densed alkaloid structure can be built from 10 through N-alkylation
and ring-closing metathesis. Thus, Pd(PPh3)4-catalyzed deal-
lyloxycarbonylation14 in the presence of morpholine afforded (5R)-
N-Boc-2-oxo-5-vinylpyrrolidine 11 in 88% yield. Removal of the
nitrogen protecting group with 5 equiv of TFA in CH2Cl2 gave (R)-2-
oxo-5-vinylpyrrolidine in nearly quantitative yield. (R)-2-Oxo-5-
vinylpyrrolidine was then reacted with allyl bromide, homoallyl
bromide, and pent-4-enyl 4-methylbenzenesulfonate, respectively,
in the presence of base to give the products 13, 14, and 15 as the
precursors for the next RCM reaction. Finally, the pyrrolidines 13,
14, and 15 were subjected to the RCM reaction by using second
generation Grubbs catalyst. The expected ring-closing products 16,
17, and 18 were obtained in nearly quantitative yields (Scheme 4).
Products 16, 17, and 18 are potentially valuable chiral building
blocks for enantioselective synthesis of polysubstituted pyrrolizi-
dines and indolizidines.15
O
N
PG
1
O
O
N
N
PG
3
PG
5
Scheme 2.
1.1. Results and discussions
The investigation began with the preparation of chiral pyrroli-
dine 10 (Scheme 3). First, diastereoselective addition of lithium
enolate of
ded -N-sulfinylamino
analysis showed compound 8 with 97% de. The absolute configu-
ration of the newly generated chiral center in -ketoester 8 was
a
-diazoacetoacetate 7 to chiral N-sulfinyl imine 6 affor-
d
a
-diazo -ketoester 8 in 70% yield. HPLC
b
b
established by X-ray analysis of its single crystal.10 The absolute
configuration is also confirmed by converting 8 into known com-
pounds (vide infra). When the chiral center of sulfur has S config-
uration, the newly formed chiral center has R configuration. This
stereochemical outcome is consistent with the previous reports of
the addition of enolates derived from esters or ketones to chiral
N-sulfinyl imines.11,12
O
O
Pd(PPh3)4 (5 mol%)
THF, rt
O
O
N
N
morpholine (1.5 eq.)
88%
Boc
11
Boc
10
O
O
O
LiHMDS
(2 eq.)
CH2Cl2, -78 o
20 min, 70%
S
1) TFA (5 eq.), CH2Cl2
rt, overnight
p-Tol
N
+
O
O
O
O
N
N
N
C
N2
H
2) K2CO3(1.2 eq.)
KOH (3 eq.)
Bu4NBr(0.2 eq.)
MeCN, reflux, 3h
6
7
14
15
75%
73%
13 78%
O
1) TFA/MeOH
S
,
p-Tol
NH
O
O
Br
0oC rt, 2h
2) Boc2O, Et3N
DMAP, THF
0oC, 2h
Br
or
TsO
O
N2
97% de
NH
8
Grubbs 2nd (10 mol%)
CH2Cl2, reflux
Boc
O
O
O
N
O
N
O
O
N
hv, 375 W
O
>98%
O
N2
95%
Benzene, 3h
60%
17
18
16
O
N
Boc
10
9
Scheme 4.
Next, we conceived the further application of pyrrolidine 10 in
the construction of transannular ring structures. As shown in
Scheme 2, by introducing an alkene moiety on C3 of pyrolidine ring,
the transannular ring structures could be built by the same RCM
strategy. First, the pyrrolidine 10 was subjected to Pd-catalyzed
decarboxylative allylic alkylation, with the expectation that C3
allylation might occur simultaneously. However, the desired
intramolecular allylic alkylation process did not occur when 10 was
catalyzed by Pd(PPh3)4 using THF as solvent (Eq. 1). Changing sol-
vent and Pd catalyst were attempted, but all efforts proved to be
fruitless.
X-ray structure of 8
Scheme 3.
O
Our previous study has shown that N-sulfinyl group is liable to
decompose in the Wolff rearrangement reaction, which is under
irradiation conditions. Thus, the N-sulfinyl group is replaced by
O
Pd(PPh3)4 (5 mol%)
THF, rt.
x
O
O
N
(1).
N
N-Boc group in two steps. First,
b-ketoester 8 was treated with
Boc
10
Boc
19
5 equiv of TFA in MeOH to remove the N-sulfinyl auxiliary, giving
the free amine as the trifluoroacetate salt. Being neutralized with
6 equiv of Et3N, the amine was treated with Boc2O and catalytic

1276
F. Mo et al. / Tetrahedron 66 (2010) 1274–1279
We then attempted a different approach, which was direct al-
2. Conclusions
lylic alkylation of 10 followed by deallyloxycarbonylation. As out-
lined in Scheme 5, treatment of 10 in acetone with allyl bromide
and K2CO3 at 60 ꢀC for 3 h furnished a pair of diastereoisomers 20 in
87% yield, which was subjected to the Pd-catalyzed deal-
lyloxycarbonylation to afford two products 19a and 19b in 1:1 ratio.
Compounds 19a and 19b could be separated with chromatography
column and their structure could be assigned by NOE experiments.
The cis isomer 19a was then subjected to RCM reaction with Grubbs
second catalyst, affording the ring-closing product (þ)-23 in nearly
quantitative yield.
In summary, we have developed versatile routes to condensed
and transannular ring structures containing pyrrolidine unit. These
products may be potential scaffolds for the synthesis of alkaloids of
biological and pharmaceutical interests. In addition, (R)-Pyrolam A
was synthesized enantioselectively, further exhibiting application
flexibility of this methodology. Efforts to apply this chemistry to the
synthesis of alkaloids of more structural complexity are underway
in our laboratory.
3. Experimental section
3.1. General
O
Br
( )n
O
( )n
O
K2CO3, acetone
Bu4NBr, 60oC
O
O
Caution: diazo compounds are generally toxic and potentially
explosive. They should be handled with care in a well-ventilated
fume hood.
O
N
Boc
N
Boc
n=1, 20, 87%
n=2, 21, 85%
10
3.1.1. (R)-Allyl
2-diazo-5-((S)-4-methylphenylsulfinamido)-3-oxo-
( )n
( )n
hept-6-enoate (8). To a solution of 618 (193 mg, 1 mmol) in CH2Cl2
(25 mL) was added LiHMDS (2 mmol,1.0 M in hexane) at ꢁ78 ꢀC and
then 7 (252 mg, 1.5 mmol) in CH2Cl2 (5 mL) was dropped in the so-
lution in 5 min. After stirring for another 10–15 min, the reactionwas
quenched with saturated aqueous NH4Cl at ꢁ78 ꢀC and thenwarmed
quickly to room temperature. The organic layer was separated and
the aqueous layer was extracted with CH2Cl2 (2ꢂ15 mL). The organic
layers were combined and dried over Na2SO4. Then the solvent was
removed under reduced pressure and the resulting crude product
was purified by column chromatography (petroleum ether/ethyl
acetate 3:1) to give the addition products 8 (252 mg, 70% yield). IR
(film) 3208, 2137, 1714, 1649, 1371, 1304, 1090, 1057, 1016, 923, 813,
Pd(PPh3)4 (5 mol%)
+
O
N
Boc
O
morpholine (1.5 eq.)
THF, rt, 2h
N
n=1, 19a+19b, 97%
n=2, 22a+22b, 82%
Boc
1 : 1
( )n
O
Grubbs 2nd (1 mol%)
( )n
N
O
CH2Cl2, reflux
N
n=1, (+)-23, >98%
n=2, (+)-24, >98%
Boc
Boc
19a, 22a
Scheme 5.
746 cmꢁ1; 1H NMR (300 MHz, CDCl3)
d
7.57 (d, J¼7.8 Hz, 2H), 7.28 (d,
J¼7.8 Hz, 2H), 6.02–5.87 (m, 2H), 5.37–5.21 (m, 4H), 4.82 (d, J¼7.2 Hz,
1H), 4.70–4.67 (m, 2H), 4.31 (qd, J¼6.1, 7.2 Hz, 1H), 3.19 (dd, J¼4.5,
16.5 Hz, 1H), 3.08 (dd, J¼7.1, 16.5 Hz, 1H), 2.40 (s, 3H); 13C NMR
Compound (ꢁ)-23 is a key intermediate in the total synthesis of
an anti-influenza neuramidase inhibitor Oseltamivir (Tamiflu)
reported by Corey and co-workers (Scheme 6).16
(75 MHz, CDCl3)
d 190.1, 160.6, 141.7, 141.1, 138.1, 131.1, 129.3, 125.4,
119.2, 116.6, 65.8, 53.1, 45.6, 21.2; EIMS (m/z, relative intensity): 361
(4), 243 (3), 222 (25), 194 (9), 171 (7), 155 (7), 139 (100), 123 (17), 108
(16), 91 (58), 77 (13), 65 (23), 41 (100), 27 (16). HRMS (EI) calcd for
O
20
C17H19N3O4S 361.1096, found 361.1095. [
a
]
þ127.0 (c 0.8, CHCl3).
D
Boc
O
AcHN
H3N
Corey's work
N
OEt
ref. 15
3.1.2. (R)-Allyl 5-(tert-butoxycarbonylamino)-2-diazo-3-oxo-hept-6-
enoate (9). The addition product 8 (1.083 g, 3 mmol) was treated
with TFA (1.710 g, 15 mmol, 5.0 equiv) in MeOH (20 mL) at 0 ꢀC. The
reaction was monitored by TLC and the sulfinyl group in 8 was
removed in about 2 h to give the corresponding trifluoroacetate
salt. The solution was concentrated, and then was dissolved in THF
(20 mL). The solution was treated with Boc2O (770 mg, 3.6 mmol,
1.2 equiv), Et3N (1.818 g, 18 mmol, 6 equiv) and a catalytic amount
of DMAP (18 mg, 0.15 mmol, 0.05 equiv) at 0 ꢀC. After stirred for
about 2 h at this temperature, the solution was concentrated and
purified by flash chromatography (petroleum ether/ethyl acetate
10:1) to give the N-Boc protected diazo product 9 (920 mg, yield
95%) as a yellow oil. IR (film) 3374, 2974, 2135, 1712, 1650, 1366,
O
Tamiflu
(-)-23
H2PO4
Scheme 6.
With the same approach, [4.2.1] bicyclic system (þ)-24 could be
synthesized by easily changing allyl bromide to homoallyl bromide
in the alkylation of 10 and then following the same subsequent
steps as for the synthesis of (þ)-23.
Finally, total synthesis of (R)-Pyrrolam A17 has been achieved
with this methodology (Scheme 7). RCM precursor (R)-25 was
obtained from 12 via simple reduction and acylation with a yield of
60% and then (R)-25 was subjected to RCM reaction catalyzed by
10 mol % of Grubbs second catalyst to give (R)-Pyrolam A 26 in 68%
isolated yield.
1308, 1169, 922, 743 cmꢁ1 1H NMR (300 MHz, CDCl3)
; d 6.01–5.81
(m, 2H), 5.39–5.29 (m, 2H), 5.23–5.09 (m, 3H), 4.73 (d, 2H,
J¼5.7 Hz), 4.60 (s, 1H), 3.21–3.14 (m, 2H), 1.43 (s, 9H); 13C NMR
(75 MHz, CDCl3) d 190.4, 160.8, 155.0, 137.6, 131.2, 119.2, 114.8, 79.3,
Grubbs 2nd
(10 mol%)
Toluene, 80 oC
overnight
65.9, 49.5, 44.3, 28.2; EIMS (m/z, relative intensity): 323 (1), 267
1) LAH, THF
60 oC 4h
(23), 250 (8), 154 (9), 136 (10), 100 (25), 57 (100), 41 (49), 29 (7).
N
N
O
20
N
H
2) CH2=CHC(O)Cl
K2CO3, EtOAc/H2O
HRMS (EI) calcd for C15H21N3O5 323.1481, found 323.1485. [a]
D
O
O
ꢁ36.4 (c 1.4, CHCl3).
0 o
C 5 min
12
(R)-25
two steps 60%
(R)-pyrrolam A
26, 68%
3.1.3. (R)-3-Allyl 1-tert-butyl 2-oxo-5-vinylpyrrolidine-1,3-dicarboxyl-
Scheme 7.
ate (10). A solution of 9 (920 mg, 2.85 mmol) in benzene (200 mL)

F. Mo et al. / Tetrahedron 66 (2010) 1274–1279
1277
in a Pyrex tube was irradiated with a 500 W high-pressure Hg lamp
with a water-cooled tube inserted into the solvent. The reaction
temperature was kept at about 35 ꢀC. The reaction was complete in
about 3 h (monitored by IR and TLC). The solution was concentrated
under reduced pressure to give the crude product, which was pu-
rified by flash chromatography (petroleum ether/ethyl acetate 8:1)
to give the diastereomeric mixture of the corresponding 3-allyl-
oxycarbonyl-2-oxo pyrrolidines 10 (504 mg, yield 60%) as a yellowy
oil. The diastereomeric mixture could not be separated by column
chromatography. IR (film) 2977, 1786, 1731, 1368, 1298, 1251, 1150,
d
5.82–5.61 (m, 2H), 5.30–5.01 (m, 4H), 4.09–4.02 (m, 1H), 3.71–
3.41 (m, 1H), 2.99–2.90 (m, 1H), 2.47–2.33 (m, 2H), 2.30–2.15 (m,
3H), 1.88–1.56 (m, 1H); 13C NMR (75 MHz, CDCl3)
174.8, 137.7,
ꢁ58.2 (c 0.85,
d
20
135.2, 117.7, 116.6, 61.2, 39.7, 31.7, 30.0, 25.4; [
CHCl3).
a]
D
3.1.9. (R)-1-(Pent-4-enyl)-2-oxo-5-vinylpyrrolidine (15)21. 1H NMR
(300 MHz, CDCl3) 5.86–5.74 (m, 1H), 5.72–5.60 (m, 1H), 5.27–5.19
d
(m, 2H), 5.05–4.94 (m, 2H), 4.08–4.00 (m, 1H), 3.59–3.49 (m, 1H),
2.95–2.86 (m, 1H), 2.48–2.34 (m, 2H), 2.30–2.16 (m, 1H), 2.036 (q,
J¼7.5 Hz, 2H), 1.80–1.69 (m, 1H), 1.67–1.46 (m, 2H); 13C NMR
970, 925 cmꢁ1 1H NMR (300 MHz, CDCl3)
; d 6.00–5.79 (m, 2H),
5.42–5.17 (m, 4H), 4.75–4.51 (m, 3H), 3.67–3.53 (m, 1H), 2.70–2.66
(75 MHz, CDCl3)
30.0, 26.3, 25.4; [
d
174.8, 137.8, 137.6, 117.7, 114.8, 61.3, 40.1, 30.9,
20
(m, 1H), 2.26–2.03 (m, 1H), 1.50 (s, 9H); 13C NMR (75 MHz, CDCl3)
a
]
ꢁ62.6 (c 0.95, CHCl3).
D
d
168.5, 168.2, 149.2, 137.5, 136.0, 131.3, 131.2, 118.9, 118.8, 116.5,
115.8, 83.4, 66.4, 66.3, 59.0, 57.6, 49.0, 48.3, 28.2, 27.8; EIMS (m/z,
relative intensity): 295 (3), 280 (5), 239 (40), 195 (20), 154 (100),
136 (95), 110 (98), 67 (46), 57 (52), 41 (66). HRMS (EI) calcd for
C15H21NO5 295.1420, found 295.1422.
3.2. General procedure for the RCM reaction
Compound 13, 14 or 15 (0.08 mmol) was dissolved in dry CH2Cl2
(100 mL) under nitrogen atmosphere. Second generation Grubbs
catalyst (24 mg, 10 mol %) was added. The resulting mixture was
heated at reflux temperature (monitored by TLC). After completion
of the reaction, the solvent was then evaporated, and the residual
oil was purified by flash chromatography on silica gel (petroleum
ether/ethyl acetate 5:1) to give the ring-closing product 16, 17 or 18
in nearly quantitative yields.
3.1.4. (R)-tert-Butyl 2-oxo-5-vinylpyrrolidine-1-carboxylate (11)
Compound 10 (183 mg, 0.62 mmol) wasdissolvedinTHF (10 mL), and
then morpholine (81 mg, 0.93 mmol, 1.5 equiv) and Pd(PPh3)4
(36 mg, 0.031 mmol, 5 mol %) were added in room temperature.
When the reaction was complete as monitored by TLC, the solution
was concentrated under reduced pressure and purified by flash col-
umn chromatography (petroleum ether/ethyl acetate 5:1) to give the
pyrrolidine derivative 11 (115 mg, yield 88%) as a yellow oil. IR (film)
3.2.1. (R)-5,7a-Dihydro-1H-pyrrolizin-3(2H)-one (16)21,22
(300 MHz, CDCl3) 5.92–5.86 (m, 2H), 4.71–4.63 (m, 1H), 4.43–4.36
(m, 1H), 3.71–3.64 (m, 1H), 2.79–2.67 (m, 1H), 2.46–2.30 (m, 2H),
1.89–1.75 (m, 1H); 13C NMR (75 MHz, CDCl3)
177.9, 130.5, 128.1,
.
1H NMR
d
2981, 1782, 1750, 1717, 1367, 1305, 1255, 1153, 1020, 850 cmꢁ1
;
1H
NMR (300 MHz, CDCl3) 5.91–5.80 (m, 1H), 5.20–5.15 (m, 2H), 4.67–
d
d
4.62 (m,1H), 2.64–2.52 (m,1H), 2.47–2.37 (m,1H), 2.30–2.17 (m,1H),
67.4, 49.6, 34.0, 29.5; IR (film) 3474, 2917, 1681, 1459, 1391, 1280,
1.86–1.77 (m,1H),1.50 (s, 9H);13C NMR (75 MHz, CDCl3)
d 174.2,149.5,
1190, 990, 769 cmꢁ1; EIMS (m/z, relative intensity): 123 (50), 122
20
136.4, 115.0, 82.6, 59.4, 30.8, 27.7, 24.0; [
a
]
þ27.7 (c 0.95, CHCl3).
D
(17), 94 (6), 80 (8), 67 (100), 55 (52), 39 (52), 32 (13), 27 (32); HRMS
20
(ESI) calcd for C7H9NONa(MþNa) 146.0576, found 146.0571. [
a]
D
3.1.5. (R)-2-Oxo-5-vinylpyrrolidine (12)19. TFA (684 mg, 6 mmol,
5 equiv) was added to a solution of 11 (252 mg, 1.2 mmol) in
CH2Cl2 (10 mL) at 0 ꢀC and then the reaction was allowed to
continue in room temperature overnight. When being completed
as monitored by TLC, the reaction was neutralized by saturated
NaHCO3 to pHz7. The organic layer was separated and the
aqueous layer was extracted with CH2Cl2 (2ꢂ15 mL). The organic
layers were then combined and dried over Na2SO4. The solution
was concentrated under reduced pressure and purified by flash
column chromatography (petroleum ether/ethyl acetate 1:1) to
give the title compound 12 (131 mg) in nearly quantitative yield as
ꢁ19.5 (c 0.5, CHCl3).
3.2.2. (R)-1,2,5,6-Tetrahydroindolizin-3(8aH)-one (17)21,23
(300 MHz, CDCl3) 5.28–5.67 (m, 2H), 4.24–4.15 (m, 2H), 2.90–2.81
(m, 1H), 2.55–2.39 (m, 2H), 2.30–2.20 (m, 2H), 2.11–2.02 (m, 1H),
1.67–1.53 (m, 1H); 13C NMR (75 MHz, CDCl3)
172.9, 128.1, 124.8,
54.8, 36.1, 31.5, 26.2, 24.4; IR (film) 2919, 1685, 1437, 1421, 1363,
.
1H NMR
d
d
20
1306, 1265, 841 cmꢁ1; [
a
]
þ94.0 (c 0.8, CHCl3).
D
3.2.3. (R)-5,6,7,9a-Tetrahydro-1H-pyrrolo[1,2-a]azepin-3(2H)-one
(18)21. 1H NMR (300 MHz, CDCl3)
5.80–5.72 (m, 1H), 5.49 (ddd,
a yellow oil. 1H NMR (300 MHz, CDCl3)
d 7.20 (s, 1H), 5.81 (ddd,
d
J¼1.8, 3.7, 11.4 Hz, 1H), 4.37–4.31 (m, 1H), 4.12–4.03 (m, 1H), 3.05–
J¼6.7, 10.1, 16.9 Hz, 1H), 5.26–5.10 (m, 2H), 4.23–4.17 (m, 1H), 2.45–
2.97 (m, 1H), 2.50–1.74 (m, 8H); 13C NMR (75 MHz, CDCl3)
d 174.6,
ꢁ7.9 (c 1.35,
2.27 (m, 3H), 1.90–1.78 (m, 1H); 13C NMR (75 MHz, CDCl3)
d 178.8,
20
20
131.8, 131.4, 58.3, 42.6, 29.9, 27.5, 26.7, 26.2; [
CHCl3).
a]
D
138.4, 115.4, 56.6, 29.8, 27.7; [
a]
ꢁ39.2 (c 1, CHCl3).
D
3.1.6. (R)-1-Substituted-5-vinylpyrrolidin-2-ones 13, 14, and 15. The
title compounds were obtained from 12 according to literature
procedure.20
3.2.4. (5R)-3-Allyl 1-tert-butyl 3-allyl-2-oxo-5-vinylpyrrolidine-1,3-
dicarboxylate (20). To a solution of 10 (118 mg, 0.4 mmol) in ac-
etone (9 mL) were successively added K2CO3 (66 mg, 0.48 mmol,
1.2 equiv), Bu4NBr (26 mg, 0.08 mmol, 0.2 equiv), and allyl bro-
mide (145 mg, 1.2 mmol, 3 equiv). The resulting mixture was
heated at 60 ꢀC for 3 h (monitored by TLC). After cooled to room
temperature, the mixture was concentrated under reduced
pressure. The residue was purified by flash column chromatog-
raphy (petroleum ether/ethyl acetate 7:1) to give the title com-
pound as a yellow oil (117 mg, 87%). 1H NMR (300 MHz, CDCl3)
3.1.7. (R)-1-Allyl-2-oxo-5-vinylpyrrolidine (13). IR (film) 2980,1687,
1643, 1406, 1278, 1253, 1189, 1128, 992, 923, 844, 726 cmꢁ1 1H
;
NMR (300 MHz, CDCl3) d 5.76–5.59 (m, 2H), 5.24–5.09 (m, 4H), 4.29
(ddt, J¼15.3, 4.8, 1.5 Hz, 1H), 4.05 (dt, J¼8.1, 5.4 Hz, 1H), 3.41(dq,
J¼7.5, 1.2 Hz, 1H), 2.52–2.32 (m, 2H), 2.30–2.18 (m, 1H), 1.83–1.72
(m, 1H); 13C NMR (75 MHz, CDCl3)
d 174.6, 137.4, 132.3, 117.9, 117.6,
60.6, 42.8, 29.8, 25.2; EIMS (m/z, relative intensity): 151 (37), 136
(31), 124 (55), 96 (19), 84 (11), 67 (41), 54 (28), 41 (100), 39 (60), 27
d
5.96–5.63 (m, 3H), 5.38–5.31 (m, 6H), 4.66–4.61 (m, 2H), 4.56–
4.49 (m, 1H), 2.88–2.51 (m, 2H), 2.39–2.25 (m, 1.5H), 1.80–1.70
(m, 0.5H), 1.50 (s, 9H); 13C NMR (75 MHz, CDCl3)
170.8, 170.2,
(35); HRMS (ESI) calcd for C9H13NONa(MþNa) 174.0889, found
20
174.0887. [
a]
ꢁ165.1 (c 1.3, CHCl3).
d
D
169.7, 138.3, 137.2, 132.3, 131.9, 131.2, 120.1, 119.9, 118.9, 118.6,
116.3, 115.9, 115.7, 83.5, 83.3, 76.5, 66.3, 66.3, 58.0, 57.3, 56.4, 56.1,
39.4, 38.3, 33.2, 32.6, 27.8; EIMS (m/z, relative intensity): 335 (5),
3.1.8. (R)-1-(But-3-enyl)-2-oxo-5-vinylpyrrolidine (14)21. IR (film)
2974, 1687, 1415, 1256, 993, 920 cmꢁ1 1H NMR (300 MHz, CDCl3)
;

1278
F. Mo et al. / Tetrahedron 66 (2010) 1274–1279
279 (18), 235 (12), 194 (55), 176 (25), 150 (100), 136 (45), 108
(20), 79 (25), 57 (35), 41 (44); HRMS (EI) calcd for C18H25NO5
335.1733, found 335.1735.
for about 2 h (monitored by TLC). After the reaction was complete,
the solution was concentrated under reduced pressure and purified
by flash column chromatography (petroleum ether/ethyl acetate
7:1) to give 22a (61 mg) and 22b (63 mg) both as a yellow oil.
Compound 22a: Rf¼0.6 (petroleum ether/EtOAc 3:1). 1H NMR
3.2.5. (5R)-tert-Butyl 3-allyl-2-oxo-5-vinylpyrrolidine-1-carboxyl-
ates (19a and 19b). Compound 20 (117 mg, 0.35 mmol) was dis-
solved in THF (8 mL), and then morpholine (46 mg, 0.524 mmol,
1.5 equiv) and Pd(PPh3)4 (20 mg, 0.0175 mmol, 5 mol %) were
added at room temperature. After the reaction was complete, the
solution was concentrated under reduced pressure and purified by
flash column chromatography (petroleum ether/ethyl acetate 7:1)
to give 19a (42 mg) and 19b (41 mg), both as a yellow oil. Compound
19a: Rf¼0.6 (petroleum ether/EtOAc 3:1). IR (film) 2954, 2924,
(300 MHz, CDCl3) d 5.85–5.72 (m, 2H), 5.31–5.13 (m, 3H), 5.07–4.98
(m, 2H), 4.43 (q, J¼7.3 Hz,1H), 2.54–2.33 (m, 2H), 2.24–1.97 (m, 3H),
1.50 (s, 9H), 1.47–1.40 (m, 1H); 13C NMR (75 MHz, CDCl3)
d
176.2,
149.9, 138.9, 137.4, 115.5, 115.4, 82.9, 58.7, 41.9, 31.2, 30.3, 27.8; IR
(film) 2980,1782, 1746, 1721, 1367,1299, 1256, 1152, 914 cmꢁ1; EIMS
(m/z, relative intensity): 209 (17), 192 (4), 165 (10), 155 (56), 111
(28), 84 (34), 67 (25), 57 (100), 49 (53), 41 (50), 29 (28). Anal. Calcd
for C15H23NO3: C, 67.90; H, 8.74; N, 5.28. Found: C, 67.81; H, 8.66; N,
20
2853, 1783, 1725, 1458, 1368, 1299, 1255, 1154, 916 cmꢁ1
;
1H NMR
5.06. [
a
]
þ0.7 (c 1.2, CHCl3). Compound 22b: Rf¼0.7 (petroleum
D
(300 MHz, CDCl3)
d
5.84–5.70 (m, 2H), 5.23–5.06 (m, 4H), 4.45 (dd,
ether/EtOAc 3:1). 1H NMR (300 MHz, CDCl3)
d 5.91–5.72 (m, 2H),
J¼9.0, 6.0 Hz, 1H), 2.69–2.53 (m, 2H), 2.39–2.29 (m, 1H), 2.24–2.14
5.19–5.13 (m, 2H), 5.07–4.97 (m, 2H), 4.62–4.57 (m, 1H), 2.62–2.51
(m, 1H), 2.21–1.99 (m, 4H), 1.91–1.80 (m, 1H), 1.50(d, 9H), 1.45–1.37
(m, 1H), 1.57–1.52 (m, 1H), 1.50 (s, 9H); 13C NMR (75 MHz, CDCl3)
d
175.6, 149.9, 138.9, 134.9, 117.2, 115.5, 82.9, 58.6, 42.2, 35.2, 30.2,
(m, 1H); 13C NMR (75 MHz, CDCl3)
d 175.7, 149.7, 137.5, 136.3, 115.3,
27.8; EIMS (m/z, relative intensity): 251 (28), 236 (4), 195 (100), 151
(92), 109 (95), 79 (83), 67 (92), 56 (85), 41 (84); HRMS (EI) calcd for
115.1, 82.6, 57.3, 40.4, 31.1, 31.0, 29.2, 27.8; IR (film) 2980, 1782,
1748,1718, 1306, 1199, 1152, 913 cmꢁ1; EIMS (m/z, relative in-
tensity): 209 (65),192 (11),165 (20),155 (100),137 (11),121 (11),111
(50), 94 (29), 67 (26), 57 (86), 41 (33), 29 (37); Anal. Calcd for
20
C14H21NO3 251.1521, found 251.1523. [
a
]
ꢁ17.1 (c 0.96, CHCl3).
D
Compound 19b: Rf¼0.7 (petroleum ether/EtOAc 3:1). IR (film) 2954,
2924, 2845, 1783, 1717, 1461, 1299, 1255, 1154, 912 cmꢁ1 1H NMR
(300 MHz, CDCl3) 5.91–5.69 (m, 2H), 5.19–5.05 (m, 4H), 4.62–4.57
(m, 1H), 2.72–2.60 (m, 2H), 2.23–2.12 (m, 1H), 2.01–1.86 (m, 2H),
1.50 (s, 9H); 13C NMR (75 MHz, CDCl3)
175.0, 149.7, 136.3, 134.8,
;
C15H23NO3: C, 67.90; H, 8.74; N, 5.28. Found: C, 67.83; H, 8.72; N,
20
d
5.38. [
a
]
þ17.6 (c 0.4, CHCl3).
D
d
3.2.9. (1R,6R)-tert-Butyl 8-oxo-7-azabicyclo[4.2.1]non-4-ene-7-carb-
oxylate (24). The title compound was obtained as a pale yellow oil
in nearly quantitative yield, following the method we employed for
the preparation of (þ)-23. Compound 24: IR (film) 2977, 2934, 1781,
117.2, 115.1, 82.7, 57.3, 40.7, 34.2, 30.4, 27.8; EIMS (m/z, relative in-
tensity): 251 (30), 236 (6), 195 (100), 151 (90), 109 (93), 79 (82), 67
(90), 56 (84), 41 (82); HRMS (EI) calcd for C14H21NO3 251.1521,
20
found 251.1523; [
a
]
þ33.5 (c 1.1, CHCl3).
1746, 1713, 1366, 1304, 1273, 1255, 1146, 1011, 840, 781 cmꢁ1 1H
;
D
NMR (400 MHz, CDCl3)
d
6.06 (ddd, J¼3.0, 6.5,11.0 Hz,1H), 5.87(ddd,
3.2.6. (1R,5R)-tert-Butyl 7-oxo-6-azabicyclo[3.2.1]oct-3-ene-6-carb-
oxylate ((þ)-23)16. Compound 19a (20 mg, 0.08 mmol) was dis-
solved in dry CH2Cl2 (40 mL) under nitrogen atmosphere. Second
generation Grubbs catalyst (1 mg, 1 mol %) was added. The resulting
mixture was heated at reflux temperature for 0.5 h (monitored by
TLC). The solvent was then evaporated, and the residual oil was pu-
rified by flash chromatography on silica gel (petroleum ether/ethyl
acetate 5:1) to give the ring-closing product (þ)-23 (18 mg, quant.) as
a pale yellow oil. IR (film) 2978, 2929, 1782, 1751, 1707, 1345, 1309,
J¼3.2, 8.4,11.3 Hz,1H), 4.52 (t, J¼7.1 Hz,1H), 2.93–2.89 (m,1H), 2.43–
2.16 (m, 4H), 1.86–1.78 (m, 1H), 1.74 (d, J¼12.1 Hz, 1H), 1.51 (s, 9H);
13C NMR (100 MHz, CDCl3)
d 177.2,149.7,133.2,132.5, 82.6, 56.1, 44.2,
33.2, 32.0, 28.0, 24.7; EIMS (m/z, relative intensity): 237 (7),181 (36),
164 (24), 137 (39), 121 (13), 109 (12), 93 (36), 79 (28), 57 (100), 41
(45), 29 (19), 27 (12). Anal. Calcd for C13H192N0 O3: C, 65.80; H, 8.07; N,
5.90. Found: C, 65.83; H, 8.02; N, 5.78. [
a
]
D
þ6.0 (c 1.0, CHCl3).
3.2.10. (R)-1-(2-Vinylpyrrolidin-1-yl)prop-2-en-1-one
((R)-25)24
1252, 1160, 1138, 911, 784, 676 cmꢁ1
;
1H NMR (300 MHz, CDCl3)
LiAlH4 (40 mg, 1.05 mmol, 1.2 equiv) was added to a stirred solution
of 12 (98 mg, 0.88 mmol) in THF (5 mL) at 0 ꢀC under a nitrogen
atmosphere. After 5 min the reaction mixture was allowed to reflux
for about 4 h (monitored by TLC). After cooling to room tempera-
ture, the reaction mixture was quenched with saturated aqueous
potassium sodium tartrate tetrahydrate and stirred for another 2 h.
Then the mixture was extracted with ethyl acetate (10 mLꢂ3). The
combined organic layers were dried (Na2SO4) and evaporated in
vacuo. The resulting residue was used in next step without further
purification. To this residue were added 2 mL EtOAc, 2 mL water,
and K2CO3 (242 mg, 1.76 mmol, 2 equiv) and then cooled to 0 ꢀC,
and then acryloyl chloride (119 mg, 1.32 mmol, 1.5 equiv) was
added dropwise to this mixture. This acylation reaction proceeded
very fast. After about 5 min the reaction mixture was extracted
with ethyl acetate (5 mLꢂ3) and combined organic layers were
dried over Na2SO4. Concentration in vacuo followed by flash
chromatography on a column of silica gel (petroleum ether/EtOAc
2:1), afforded the desired product 25 (80 mg, 60% yield) as a yellow
d
6.34–6.29 (m, 1H), 5.72–5.66 (m, 1H), 4.36–4.33 (m, 1H), 2.85–2.84
(m, 1H), 2.52–2.36 (m, 2H), 2.31–2.24 (m, 1H), 2.00 (dd, J¼9, 12 Hz,
1H,),1.52 (s, 9H); 13C NMR (75 MHz, CDCl3)
d 176.3,149.4,130.7,127.8,
20
82.5, 52.5, 41.5, 31.7, 28.6, 28.0; [
a
]
¼ 121.0 (c 0.92, CHCl3).
D
3.2.7. (R)-3-Allyl 1-tert-butyl 3-(but-3-enyl)-2-oxo-5-vinylpyrro-
lidine-1,3-dicarboxylate (21). The title compound was obtained as
a yellow oil (85%), following the method we employed for the
preparation of 20. IR (film) 2982, 1785, 1728, 1303, 1199, 1153,
918 cmꢁ1; 1H NMR (300 MHz, CDCl3)
d 5.96–5.70 (m, 3H), 5.37–5.12
(m, 4H), 5.06–4.95 (m, 2H), 4.66–4.52 (m, 3H), 2.75 (dd, J¼7.8,
13.5 Hz, 0.4H), 2.47 (dd, J¼2.7, 13.5 Hz, 0.6H), 2.32–1.96 (m, 3.5H),
1.92–1.78 (m, 1H), 1.72–1.65 (m, 0.5H), 1.50–1.49 (d, 9H); 13C NMR
(75 MHz, CDCl3)
d 171.1, 171.0, 170.3, 169.8, 149.4, 138.3, 137.1, 137.0,
136.9, 131.2, 118.9, 118.6, 116.3, 115.8, 115.8, 115.3, 83.4, 83.2, 76.4,
66.2, 66.2, 58.0, 57.2, 57.1, 56.6, 56.0, 34.6, 34.2, 33.6, 33.5, 28.8, 28.5,
27.8; EIMS (m/z, relative intensity): 293 (12), 276 (4), 249 (16), 239
(46), 208 (8), 195 (57), 57 (86), 41 (100), 28 (21). Anal. Calcd for
C19H27NO5: C, 65.31; H, 7.79; N, 4.01. Found: C, 65.19; H, 7.81; N, 4.03.
oil. 1H NMR (200 MHz, CDCl3)
1H), 5.67–5.58 (m, 1H), 5.20–5.03 (m, 2H), 4.51–4.44 (m, 1H), 3.71–
3.50 (m, 2H), 2.23–1.71 (m, 4H); 13C NMR (50 MHz, CDCl3)
165.0,
138.1, 136.9, 128.8, 128.6, 127.6, 127.1, 115.2, 114.1, 59.2, 58.5, 46.7,
d 6.57–6.26 (m, 2H), 5.90–5.70 (m,
d
3.2.8. (5R)-tert-Butyl
3-(but-3-enyl)-2-oxo-5-vinylpyrrolidine-1-
20
carboxylates (22a and 22b). Compound 21 (200 mg, 0.57 mmol)
was dissolved in THF (8 mL), and then morpholine (75 mg,
0.86 mmol, 1.5 equiv), Pd(PPh3)4 (33 mg, 0.0286 mmol, 5 mol %)
were added at room temperature. The resulting mixture was stirred
46.1, 32.3, 30.2, 23.5, 21.4; [
a]
þ23.2 (c 1.13, CHCl3).
D
3.2.11. (R)-Pyrrolam A (26)17. Second generation Grubbs catalyst
(24 mg, 10 mol %) was added to a solution of 25 (42 mg, 0.28 mmol)

F. Mo et al. / Tetrahedron 66 (2010) 1274–1279
1279
49, 2373–2376; (d) Wakamatsu, H.; Sato, Y.; Fujita, R. o; Mori, M. Adv. Synth.
Catal. 2007, 349, 1231–1246; (e) Sletten, E. M.; Liotta, L. J. J. Org. Chem. 2006, 71,
1335–1343; (f) Chang, M.-Y.; Hsu, R.-T.; Tseng, T.-W.; Sun, P.-P.; Chang, N.-C.
Tetrahedron 2004, 60, 5545–5550; (g) Ahn, J.-B.; Yun, C.-S.; Kim, K. H.; Ha, D.-C.
J. Org. Chem. 2000, 65, 9249–9251; (h) White, J. D.; Hrnciar, P. J. Org. Chem. 2000,
65, 9129–9142; (i) Overkleeft, H. S.; Burggeman, P.; Pandit, U. K. Tetrahedron
Lett. 1998, 39, 3869–3872; (j) Martin, S. F.; Chen, H.-J.; Courtney, A. K.; Liao, Y.;
Pa¨tzel, M.; Ramser, M. N.; Wagmzan, A. S. Tetrahedron 1996, 52, 7251–7264; (k)
Fu¨rstner, A.; Langemann, K. Synthesis 1997, 792–803.
9. Similar strategy for constructing 9-azabicyclo[4.2.1]nonane skeleton has been
reported by Martin and co-workers, see: (a) Washburn, D. G.; Heidebrecht, R.
W., Jr.; Martin, S. F. Org. Lett. 2003, 5, 3523–3525; (b) Brenneman, J. B.; Martin,
S. F. Org. Lett. 2004, 6, 1329–1331; (c) Brenneman, J. B.; Machauer, R.; Martin,
S. F. Tetrahedron 2004, 60, 7301–7314.
in dry toluene 100 mL under nitrogen atmosphere. The resulting
mixture was heated at 80 ꢀC for 12 h (monitored by TLC). The sol-
vent was then evaporated, and the residual oil was purified by flash
chromatography on silica gel (petroleum ether/ethyl acetate 1:1) to
give the ring-closing product 26 (23 mg, 68% yield) as a white solid.
1H NMR (200 MHz, CDCl3) 7.20 (dd, J¼1.7, 5.8 Hz, 1H), 6.04 (dd,
J¼1.5, 5.7 Hz, 1H), 4.30–4.22 (m, 1H), 3.55–3.41 (m, 1H), 3.33–3.20
(m, 1H), 2.37–2.24 (m, 2H), 2.20–2.04 (m, 1H), 1.23–0.96 (m, 1H);
13C NMR (50 MHz, CDCl3)
d175.6, 148.7, 128.4, 67.7, 41.8, 29.8, 28.9;
20
[
a]
ꢁ25.9 (c 0.7 in CHCl3).
D
10. CCDC-746178 contains the supplementary crystallographic data for this paper.
These data can be obtained free of charge from The Cambridge Crystallographic
Data Center via http://www.ccdc.cam.ac.uk/data_request/cif.
Acknowledgements
11. For reviews, see: (a) Ellman, J. A.; Owens, T. D.; Tang, T. P. Acc. Chem. Res.
2002, 35, 984–995; (b) Zhou, P.; Chen, B. C.; Davis, F. A. Tetrahedron 2004, 60,
8003–8030; (c) Morton, D.; Stockman, R. A. Tetrahedron 2006, 62, 8869–
8905; (d) Davis, F. A. J. Org. Chem. 2006, 71, 8993–9003.
12. (a) Davis, F. A.; Reddy, R. E.; Szewczyk, J. M. J. Org. Chem. 1995, 60, 7037–7039;
(b) Davis, F. A.; Yang, B. J. Am. Chem. Soc. 2005, 127, 8398–8407; (c) Davis, F. A.;
Ramachandar, T.; Chai, J.; Skucas, E. Tetrahedron Lett. 2006, 47, 2743–2746; (d)
Davis, F. A.; Zhang, Y.; Li, D. Tetrahedron Lett. 2007, 48, 7838–7840; (e) Davis, F.
A.; Ramachandar, T. Tetrahedron Lett. 2008, 49, 870–872.
The project is generously supported by NSFC (Grant No.
20832002, 20772003, 20821062), the Ministry of Education of
China, and National Basic Research Program of China (973 Program,
No. 2009CB825300).
Supplementary data
13. (a) Wang, J.; Hou, Y. J. Chem. Soc., Perkin Trans. 1 1998, 1919–1924; (b) Wang, J.;
Hou, Y.; Wu, P.; Qu, Z.; Chan, A. S. C. Tetrahedron: Asymmetry 1999, 10, 4553–
4561; (c) Lee, D. J.; Kim, K.; Park, Y. J. Org. Lett. 2002, 4, 873–876.
14. Pd catalyzed deallyloxycarbonylation examples: (a) Georgiades, S. N.; Clardy, J.
Bioorg. Med. Chem. Lett. 2008, 18, 3117–3121; (b) Tsuji, J.; Nisar, M.; Shimizu, I. J.
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Supplementary data associated with this article can be found in
the online version, at doi:10.1016/j.tet.2009.12.013.
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