Efficient entry to polysubstituted pyrrolizidines, indolizidines and quinolizidines via a sequential reaction process

Article abstract of DOI:10.1055/s-2006-932488

A sequential S_N2-Michael addition-Michael addition reaction process between ω-iodo-α,β-alkynoates and δ- or γ-amino α,β-unsaturated esters is developed, which affords polysubstituted pyrrolizidines, indolizidines or quinolizidines in good yield

Full text of DOI:10.1055/s-2006-932488

LETTER
1181
Efficient Entry to Polysubstituted Pyrrolizidines, Indolizidines and
Quinolizidines via a Sequential Reaction Process
E
fficient Entr
y
to
a
w
ted Pyrrolizidine
s
e
,
Indolizidi
i
nes and Quin
M
olizidines a,* Wei Zhu
State Key Laboratory of Bioorganic and Natural Products Chemistry, Shanghai Institute of Organic Chemistry, Chinese Academy of
Sciences, 354 Fenglin Lu, Shanghai 200032, P. R. of China
Fax +86(21)64166128; E-mail: madw@mail.sioc.ac.cn
Received 29 November 2005
ment with HCl as represented by preparation of 2b–f
Abstract: A sequential SN2–Michael addition–Michael addition
(Scheme 2). From diol 8, a reduction product of Boc-pro-
tected L-aspartic acid dimethyl ester, two a,b-unsaturated
reaction process between w-iodo-a,b-alkynoates and d- or g-amino
a,b-unsaturated esters is developed, which affords polysubstituted
esters were elaborated (Scheme 3). Swern oxidation of 8
followed by a Wittig reaction provided diene 9 in 45%
yield, which was treated with a gaseous hydrogen chloride
saturated ethyl acetate solution to afford g-amino a,b-un-
saturated ester 2g. In a parallel procedure, protection of 8
with DMP produced monoalcohol 10, which was subject-
ed to Swern oxidation and Wittig olefination to give 11.
Treatment of 11 with TFA and subsequent benzyl ether
formation provided 12, which was exposed on HCl in eth-
yl acetate to result in d-amino a,b-unsaturated ester 2h.
pyrrolizidines, indolizidines or quinolizidines in good yields.
Key words: cascade reactions, pyrrolizidines, indolizidines, quino-
lizidines
Recently, we have reported several cascade processes
using w-iodo-a,b-alkynoates 1 as bisfunctional building
blocks.1–3 When they reacted with other bisfunctional
compounds such as b-amino esters,1 d-chloropropyl-
amines,2 or 2-aryl aziridines,3 a variety of quinolizidi-
nones, indolizidinones, indolizidines or quinolizidines
were obtained. As a continuing effort of this project, we
report here a new cascade process employing d- or g-ami-
no a,b-unsaturated esters 2 as bisfunctional agents. As de-
picted in Scheme 1, reaction of 1 and 2 might undergo an
SN2 reaction between the amino group in 2 and the iodide
moiety in 1, and subsequent Michael addition between the
resultant secondary amine and the electron-deficient C–C
triple bond to provide monocyclic intermediates A. The
vinylogous anion thus formed would attack another
electronic deficient C–C double bond to furnish bicyclic
products 3.
+
NH3Cl–
NHBoc
CHO
NHBoc
ref. 4
HCl
R
CO2Et
R
R
CO2Et
~100%
4a: R = i-Pr
4b: R = Bn
2a: R = i-Pr
2b: R = Bn
4c: R = CH2CO2Et
2c: R = CH2CO2Et
+
NHBoc
NH3Cl–
HCl
BnO
BnO
CO2Et
CO2Et
~100%
5
2d
+
CO2Et
CO2Et
BocHN
Cl
–ClH3N
HCl
Cl
~100%
CO2Et
EtO2C
CO2Et
R'
CO2Et
2e
6
K2CO3, MeCN
reflux
I
Cl
Cl
+
+
Cl–H3N
+
N
NH3Cl–
R'
()n
NHBoc
()n
HCl
R
2
Ph
CO2Et
Ph
CO2Et
R
1a: n = 0
1b: n = 1
3
~100%
OBn
OBn
Michael addition
CO2Et
CO2Et
2f
7
SN2 and Michael
addition
–
Scheme 2
+
N
R
H
R'
A
Elaboration of the other two enantiopure d-amino a,b-un-
saturated esters 2i and 2j is demonstrated in Scheme 4.
After hydrogenolysis of b-amino ester 131 accompanying
with in situ Boc-protection to afford ester 14, reduction of
ester moiety and Swern oxidation were carried out to give
an aldehyde, which was reacted with a Wittig reagent to
provide olefin 15. Exposure of 15 on HCl in ethyl acetate
furnished 2i. Similarly, 2j was obtained from an L-ala-
nine-derived b-amino ester through olefin 16.
Scheme 1
The requisite d- or g-amino a,b-unsaturated esters 2 were
generally assembled via a Wittig reaction of the corre-
sponding N-Boc amino aldehyde4 and subsequent treat-
SYNLETT 2006, No. 8, pp 1181–1184
Advanced online publication: 10.03.2006
1
5.
0
5.
2
0
0
6
DOI: 10.1055/s-2006-932488; Art ID: W31805ST
© Georg Thieme Verlag Stuttgart · New York

1182
D. Ma, W. Zhu
LETTER
CO2Et
1. Swern oxidation
OH
EtO2C
Ph
N
Ph
2. Ph3P=CHCO2Et
45%
OH NHBoc
NHBoc
CO2Me
NHBoc
CO2Me
8
9
Pd/C, H2
HCl
+
NH3Cl–
(Boc)2O, MeOH
100%
MeO
MeO
CO2Et
EtO2C
OMe
DMP
90%
OMe
EtO2C
2g
13
14
1, NaBH4, LiCl
2. Swern oxidation
3. Ph3P=CHCO2Et
77%
BocN
BocN
1. Swern oxidation
O
O
HO
2. Ph3P=CHCO2Et
85%
+
11
10
NH3Cl–
NHBoc
CO2Et
1. TFA, CH2Cl2
2. BnBr, Ag2O
90%
CO2Et
HCl
+
MeO
MeO
NH3Cl–
OBn
NHBoc
OBn
OMe
OMe
HCl
EtO2C
15
2i
EtO2C
2h
12
+
NHBoc
NH3Cl–
HCl
Scheme 3
CO2Et
CO2Et
16
2j
Scheme 4
With the above d- or g-amino a,b-unsaturated esters in
hand, we next tried their reaction with w-iodo-a,b-
alkynoates. As summarized in Table 1, heating a mixture
of L-valine derived g-amino a,b-unsaturated ester 2a,
iodide 1b and K2CO3 in MeCN afforded 1,2,3-trisubstitut-
ed indolizidine 3a5,6 in 80% yield (entry 1). Its stereo-
chemistry was 1,2-trans as determined by NOESY, which
might result from the strong 1,2-induction during the last
Michael addition step. Similarly, indolizidines 3b–d were
obtained from the corresponding L-phenylalanine, L-as-
partic acid or L-serine-derived g-amino a,b-unsaturated
ester substrate (entries 2–4). Noteworthy is that we ob-
tained 8-substituted, 5,8-disubstituted and 5,6,8-trisubsti-
tuted indolizidines via sequential SN2–Michael addition–
SN2–SN2 reaction process.2 A combination of these two
processes would therefore be able to construct more
diverse substituted indolizidines.
due to incomplete conversion in the last step (entries 5 and
6). In the cases of d-branched g-amino a,b-unsaturated
esters as substrates, reaction with 1b produced 1,2,3-
trisubstituted quinolizidine 3g (entry 7), or even 1,2,3,4-
tetrasubstituted quinolizidine 3h5,7 (entry 8). Their stereo-
chemistry was still 1,2-trans, which was the same as that
of g-amino a,b-unsaturated ester derived products due
to a similar mechanism. However, when d-unbranched
g-amino a,b-unsaturated esters were employed, a mixture
of two isomers in favor of 1,2-cis-isomer formed (entries
9–11). We reasoned that this stereochemistry might be
contributed by a chair-like transition state at the intramo-
lecular Michael addition step, in which 1,3-substituents
preferred a cis relationship in the reactive conformer.
When methyl 7-iodo-2-hexynoate (1a) was used, this pro-
cess allowed the formation of 1,2,3-trisubstituted pyr-
rolizidines 3e and 3f although the yields were moderate
Table 1 Reaction of Iodides 1 and Amines 2a
Entry
1
Iodide
Amine
Product
Yield (%)b
80
1b
2a
CO2Et
EtO2C
R
N
3a: R = i-Pr
3b: R = Bn
2
3
1b
1b
2b
2c
76
65
3c: R = CH2CO2Et
Synlett 2006, No. 8, 1181–1184 © Thieme Stuttgart · New York

LETTER
Efficient Entry to Polysubstituted Pyrrolizidines, Indolizidines and Quinolizidines
1183
Table 1 Reaction of Iodides 1 and Amines 2a (continued)
Entry
4
Iodide
Amine
Product
Yield (%)b
64
1b
2d
CO2Et
OBn
EtO2C
N
3d
5
6
7
1a
1a
1b
2a
2d
2e
51c
49c
85
CO2Et
EtO2C
N
N
3e
CO2Et
OBn
EtO2C
3f
CO2Et
EtO2C
Cl
Cl
N
3g
8
9
1b
1b
1b
2f
2j
2h
74
CO2Et
OBn
EtO2C
N
N
N
Bn
3h
90d
CO2Et
EtO2C
3i
10
71d
CO2Et
EtO2C
R
3j: R = CH2OBn
11
12
1b
1b
2i
3k: R = 3,4-(MeO)2C6H3
85d
65
2g
CO2Et
EtO2C
CO2Et
N
3m
a Reaction conditions: 1 (0.2 mmol), 2 (0.2 mmol), K2CO3 (0.7 mmol), 4 Å MS (40 mg) in 3 mL of MeCN, refluxed for 5–24 h.
b Isolated yield.
c Monocyclic product was isolated in about 30% yield.
d Ratio for cis and trans was about 1.5:1.
Synlett 2006, No. 8, 1181–1184 © Thieme Stuttgart · New York

1184
D. Ma, W. Zhu
LETTER
0.88 (d, J = 8.7 Hz, 3 H), 0.77 (d, J = 6.9 Hz, 3 H). 13C NMR
(75 MHz, CDCl3): d = 172.6, 166.7, 162.4, 161.2, 95.5, 73.2,
60.1, 58.1, 44.9, 40.7, 38.0, 24.8, 23.4, 20.0, 17.3, 15.8, 14.8,
14.4. MS: m/z = 323 [M+]. ESI-HRMS: m/z calcd for
C18H29NO4Na: 346.1979 [M + Na]+; found: 346.1989.
(7) Selected data for 3h: [a]D14 +53.6 (c 0.95, CHCl3). IR (film):
2934, 1730, 1675, 1552 cm–1. 1H NMR (300 MHz, CDCl3):
d = 7.31–7.21 (m, 8 H), 7.12–7.10 (m, 2 H), 4.74 (d, J = 12.6
Hz, 1 H), 4.56 (d, J = 12.6 Hz, 1 H), 4.18–4.09 (m, 4 H),
3.74–3.73 (m, 1 H), 3.48 (d, J = 9.6 Hz, 1 H), 3.41–3.36 (m,
1 H), 3.28 (dt, J = 17.0, 5.0 Hz, 1 H), 3.07–2.99 (m, 1 H),
2.83–2.74 (m, 3 H), 2.61 (dd, J = 13.2, 4.7 Hz, 1 H), 2.52 (dt,
J = 11.9, 5.0 Hz, 1 H), 2.38 (dd, J = 16.4, 11.0 Hz, 1 H),
1.69–1.64 (m, 1 H), 1.56–1.47 (m, 3 H), 1.29–1.19 (m, 6 H).
13C NMR (75 MHz, CDCl3): d = 173.0, 169.2, 154.7, 139.0,
138.9, 129.0 (2 C), 128.5 (2 C), 128.3 (2 C), 127.4 (2 C),
127.3, 126.5, 93.0, 75.9, 70.1, 66.2, 60.2, 58.8, 52.6, 38.1,
36.9, 33.8, 27.8, 23.3, 20.5, 14.6, 14.3. MS (EI): m/z = 491
[M+]. ESI-HRMS: m/z calcd for C30H37NO5Na: 514.2586 [M
+ Na]+; found: 514.2564.
Notably, there was marked difference in yield between
formation of 3a and 3e (compare entries 1 and 5), or 3d
and 3f (compare entries 4 and 6). These results indicated
that the second intramolecular Michael addition should be
more difficult after formation of a five-membered ring
than that of a six-membered ring. However, it seemed that
a five-membered ring was easier to generate than a six-
membered ring for the intramolecular Michael addition
step because when 1b reacted with 2g, an amine bearing
two a,b-unsaturated ester units, only indolizidine 3m5,8
was isolated (entry 12).
In conclusion, we have developed a novel cascade reac-
tion process between w-iodo-a,b-alkynoates and d- or g-
amino a,b-unsaturated esters, which allowed the assem-
bly of polysubstituted indolizidines, quinolizidines, and
pyrrolizidines with a great diversity in a very efficient
manner.9 This method may find further application in the
total synthesis of natural products and designed molecules
for biological evaluation.
(8) Selected data for 3m: [a]D18 –12.3 (c 0.5, CHCl3). IR (film):
2930, 1728, 1665, 1574 cm–1. 1H NMR (300 MHz, CDCl3):
d = 6.88 (q, J = 7.5 Hz, 1 H), 5.90 (d, J = 15.5 Hz, 1 H),
4.22–4.03 (m, 6 H), 3.47 (q, J = 3.9 Hz, 1 H), 3.22–3.16 (m,
1 H), 3.09–2.96 (m, 2 H), 2.86–2.74 (m, 3 H), 2.52–2.47 (m,
2 H), 2.29 (dd, J = 15.6, 9.9 Hz, 1 H), 1.79–1.74 (m, 2 H),
1.65–1.59 (m, 2 H), 1.31–1.19 (m, 9 H). MS (EI): m/z = 393
[M+]. ESI-HRMS: m/z calcd for C21H32NO6: 394.2252 [M +
H]+; found: 394.2224.
Acknowledgment
The authors are grateful to the Chinese Academy of Sciences,
National Natural Science Foundation of China (grant 20132030),
and Science and Technology Commission of Shanghai Munici-
pality (grant 02JC14032) for their financial support.
(9) For some recent references for elaborating these molecules,
see: (a) Epperson, M. T.; Gin, D. Y. Angew. Chem. Int. Ed.
2002, 41, 1778. (b) Toyooka, N.; Fukutome, A.; Nemoto,
H.; Daly, J. W.; Spande, T. F.; Garraffo, H. M.; Kaneko, T.
Org. Lett. 2002, 4, 1715. (c) Barluenga, J.; Mateos, C.;
Aznar, F.; Valdés, C. Org. Lett. 2002, 4, 1971. (d) Lindsay,
K. B.; Pyne, S. G. J. Org. Chem. 2002, 67, 7774. (e) Amos,
D. T.; Renslo, A. R.; Danheiser, R. L. J. Am. Chem. Soc.
2003, 125, 4970. (f) Molander, G. A.; Pack, S. K. J. Org.
Chem. 2003, 68, 9214. (g) Randl, S.; Blechert, S. J. Org.
Chem. 2003, 68, 8879. (h) Gracias, V.; Zeng, Y.; Desai, P.;
Aubé, J. Org. Lett. 2003, 5, 4999. (i) Huang, H.; Spande, T.
F.; Panek, J. S. J. Am. Chem. Soc. 2003, 125, 626. (j) Back,
T. G.; Parvez, M.; Zhai, H. J. Org. Chem. 2003, 68, 9389.
(k) Alcaide, B.; Almendros, P.; Alonso, J. M.; Aly, M. F.
Chem. Eur. J. 2003, 9, 3415. (l) Davis, F. A.; Yang, B. Org.
Lett. 2003, 5, 5011. (m) Pu, X.; Ma, D. J. Org. Chem. 2003,
68, 4400. (n) Cassidy, M. P.; Padwa, A. Org. Lett. 2004, 6,
4029. (o) Poupon, E.; Francois, D.; Kunesch, N.; Husson, H.
P. J. Org. Chem. 2004, 69, 3836. (p) Zech, G.; Kunz, H.
Chem. Eur. J. 2004, 10, 4136. (q) Kuethe, J. T.; Comins, D.
L. J. Org. Chem. 2004, 69, 5219. (r) Singh, O. V.; Han, H.
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References and Notes
(1) Ma, D.; Zhu, W. Org. Lett. 2001, 3, 3927.
(2) Zhu, W.; Dong, D.; Pu, X.; Ma, D. Org. Lett. 2005, 7, 705.
(3) Zhu, W.; Cai, G.; Ma, D. Org. Lett. 2005, 7, 5545.
(4) Jurczak, J.; Golebiowski, A. Chem. Rev. 1989, 89, 149; and
references cited therein.
(5) General Procedure for Reaction of Iodides 1 with d- or g-
Amino a,b-Unsaturated Esters 2:
A mixture of 1 (0.22 mmol), 2 (0.23 mmol), anhyd K2CO3
(95 mg), and 4 Å MS (40 mg) in 3 mL of MeCN was
refluxed until the starting materials disappeared as
monitored by TLC. The cooled solution was concentrated
and partitioned between brine and Et2O. The organic phase
was dried over MgSO4 and concentrated. The residue was
purified via chromatography to give 3.
(6) Selected data for 3a: [a]D18 +138.0 (c 0.75, CHCl3). IR
(film): 1734, 1664, 1573 cm–1. 1H NMR (300 MHz, CDCl3):
d = 4.18–4.02 (m, 4 H), 3.28 (t, J = 3.6 Hz, 1 H), 3.22–3.18
(m, 1 H), 3.12–3.10 (m, 1 H), 3.03–2.99 (m, 1 H), 2.81 (dt,
J = 18.0, 6.5 Hz, 1 H), 2.64 (dd, J = 14.0, 3.4 Hz, 1 H), 2.36
(dd, J = 14.0, 8.8 Hz, 1 H), 2.02–1.96 (m, 1 H), 1.82–1.61
(m, 5 H), 1.25 (t, J = 7.1 Hz, 3 H), 1.24 (t, J = 7.1 Hz, 3 H),
Synlett 2006, No. 8, 1181–1184 © Thieme Stuttgart · New York