Palladium-catalysed cyclisation of α-hydroxy allylic acetates: A formal synthesis of (±)-swainsonine

Article abstract of DOI:10.1055/s-0030-1260952

A hydroxy group in the allylic position directed the stereochemistry of cyclisation of allylic acetates to form nitrogen heterocycles, giving the trans isomer for the piperidine and the cis isomer for the pyrrolidine. A formal synthesis of (±)-swainsonine

Full text of DOI:10.1055/s-0030-1260952

LETTER
2053
Palladium-Catalysed Cyclisation of a-Hydroxy Allylic Acetates: A Formal
Synthesis of ( )-Swainsonine
P
alladium-Cataly
o
sed Cyclisat
d
ion of
a
-Hyd
e
roxy
A
llyli
r
c
A
cetate
i
s
ck W. Bates,* Mark R. Dewey, Chi H. Tang, Shahidah bte Safii, Yanhan Hong, Jolyn Ke Hui Hsieh,
Pei Shan Siah
Division of Chemistry and Biological Chemistry, School of Physical and Mathematical Sciences, Nanyang Technological University,
637371 Singapore, Singapore
Fax +6567911961; E-mail: roderick@ntu.edu.sg
Received 26 April 2011
For the study of six-membered-ring formation, readily
Abstract: A hydroxy group in the allylic position directed the ste-
available 4-azidobutanal (6)1 was treated with vinylmag-
reochemistry of cyclisation of allylic acetates to form nitrogen het-
nesium bromide to give allylic alcohol 7 (82%;
Scheme 2). Reduction of the azide group was followed by
o-nosylation6 without isolation of the polar amine. Palla-
dium chemistry is often tolerant of unprotected alcohol
groups and, therefore, cross metathesis was carried out di-
rectly by gradual addition of a solution of the Grubbs sec-
ond-generation catalyst (5 mol%) to a refluxing solution
of alkene 8 in dichloromethane, to give the cyclisation
substrate 9 (60%). Cyclisation proceeded readily on treat-
ment of the allylic acetate 9 with tetrakis(triphenylphos-
phine)palladium(0) (5 mol%) and tetramethylguanidine in
THF at room temperature. The cyclised product 107 was
obtained in 85% yield as an inseparable 8:1 mixture of ste-
reoisomers.8 The stereochemical identity of the major iso-
erocycles, giving the trans isomer for the piperidine and the cis
isomer for the pyrrolidine. A formal synthesis of ( )-swainsonine
was achieved.
Key words: piperidine, palladium, pyrrolidine, alkaloid, cyclisa-
tion
We recently reported a gold-catalysed cyclisation reaction
of the carbamates of allenic amines 1 leading to 2-vinylpi-
peridines 2 with the stereochemistry controlled by a silyl-
oxy group a to the allene (Scheme 1). The products were
employed in a formal synthesis of swainsonine (4)1 via the
unsaturated indolizidine 3 (R = TBS) and a synthesis of 2-
epi-fagomine.2 We reasoned that an alternative route to
such compounds could be via a palladium-catalysed cycli-
sation (Tsuji–Trost reaction)3 of allylic acetate 5 and lead
to a variant upon our swainsonine formal synthesis.4 The
required substituted allylic acetate cyclisation precursor
was expected to be available by cross metathesis of the di-
acetate of cis-2-butene-1,4-diol.5 It was of interest to in-
vestigate whether an oxygen substituent in the allylic
position would exert a stereochemical directing effect in a
similar way to the allene series.
1
mer was not apparent by inspection of the H NMR
spectrum. Pyne has shown that swainsonine can be pre-
pared by installation of the diol stereoselectively using di-
hydroxylation of unsaturated indolizidines.9 This same
concept has been exploited by Blechert10 and by Carrete-
ro.11 Pyne and Lindsay employed the benzyl protecting
group on the third hydroxyl group.9 Therefore, the mix-
ture from the cyclisation was O-benzylated. Dudley’s re-
agent, 2-benzyloxy-1-methylpyridinium triflate,12 proved
to be the best for this task, giving the benzyl ether 11, with
the minor isomer chromatographically removed, in 70%
yield. Benzyl ether 11 proved to be crystalline. X-ray
analysis13 showed that the oxygen and vinyl substituents
were trans-diaxial (Figure 1). Such an axial disposition of
the 2-substituent of N-sulfonyl and, especially, N-acyl pi-
peridines is now well-documented.14 With benzyl ether 11
in hand, the nitrogen was deprotected with potassium
ethane thiolate and allylated with allyl bromide. Cyclisa-
tion of diene 13 could then be achieved using Grubbs first-
generation catalyst (5 mol%) in the presence of tosic acid
(1 equiv). It may be noted that both allylation and RCM
proceed in a more facile manner with the benzyl protect-
ing group compared to a TBS group. In the latter case, al-
lylation had to be achieved indirectly and RCM required
the Grubbs second-generation catalyst.1 The RCM prod-
uct 3a proved to be identical to that reported by Pyne,9
thus completing a formal synthesis of ( )-swainsonine.
R1O
•
Au(III)
R1O
R1O
H
NHR2
N
1 R2 = t-Boc
R2
N
2
3
R1O
Pd(0)
OAc
ref. 9–11
HO
OH
OH
H
NHR2
N
5
4
Scheme 1 Synthetic routes to swainsonine
SYNLETT 2011, No. 14, pp 2053–2055
x
x
.x
x
.2
0
1
1
Advanced online publication: 14.07.2011
DOI: 10.1055/s-0030-1260952; Art ID: D12711ST
© Georg Thieme Verlag Stuttgart · New York

2054
R. W. Bates et al.
LETTER
for the trans isomers, which range form 0 to 2.5 Hz.15 The
coupling constants observed in our case were 7.5 Hz for
the major isomer and 3.5 Hz for the minor isomer. Mind-
ful that overreliance on such data is unwise, a definitive
demonstration of stereochemical identity was sought. The
isomers could be separated after formation of the 3,5-dini-
trobenzoate, and suitable crystals of the derivative of the
major isomer were obtained. X-ray analysis16 confirmed
the indication given by the coupling constant analysis of
cis stereochemistry (Figure 2).
MgBr
O
THF
N3
N3
82%
6
7
OH
1. Zn, AcOH
2. o-NsCl, Na2CO3
AcO
OAc
Grubbs II, CH2Cl2
o-NsHN
57%
60%
8
OH
HO
Pd(PPh3)4
TMG, THF
o-NsHN
OAc
85%
9
N
OH
o-Ns
10 (8:1)
1. o-NsCl, Et3N
2. IBX, DMSO
O
o-NsHN
H2N
OH
BnO
55%
11 R = o-Ns
12 R = H
Dudley's reagent
EtSH, K2CO3
MgO, ClCH2CH2Cl
DMF
75%
Br
MgBr
THF
AcO
OAc
70%
o-NsHN
N
R
Grubbs II, CH2Cl2
62%
14
NaOH
75%
36%
13 R = allyl
OH
BnO
H
Grubbs I
HO
TsOH, CH2Cl2
Pd(PPh3)4
TMG, THF
o-NsHN
OAc
56%
N
15
25%
N
OH
3a
o-Ns
16 (8:1)
Scheme 2 Formal synthesis of ( )-swainsonine
Scheme 3 Synthesis of cis-pyrrolidine 16
Figure 1 X-ray structure of piperidine 11
The same chemistry with the lower homologue gave a
contrasting result (Scheme 3). The substrate was prepared
from 3-aminopropan-1-ol by N-protection, oxidation, and
Grignard addition. Cross metathesis, with gradual addi-
tion of the Grubbs second-generation catalyst (3 mol%) to
the alkene 14, gave the allylic acetate 14 in only moderate
yield, as, surprisingly, did the palladium-catalysed cycli-
sation of allylic acetate 15. The pyrrolidine product 16
was obtained in just 25% yield as an 8:1 mixture of dia-
stereomers. More surprisingly, the major diastereomer
from the cyclisation was the cis isomer. The stereochem-
istry was initially assigned by inspection of the coupling
constants and comparison with reported coupling con-
stants of related compounds. Coupling constants of the cis
isomers range from 4.5 to 6.5 Hz and are larger than those
Figure 2 X-ray structure of the 3,5-dinitrobenzoyl derivative of
pyrrolidine 16
The hydroxy group in the allylic position is capable of di-
recting the stereochemical outcome of the palladium-
catalysed cyclisation. The process is particularly efficient
in the six-membered ring series, leading to a formal syn-
thesis of ( )-swainsonine. Surprisingly, the stereochemi-
cal outcome is opposite in the five-membered-ring
system, giving the cis isomer as the major product.
Synlett 2011, No. 14, 2053–2055 © Thieme Stuttgart · New York

LETTER
Palladium-Catalysed Cyclisation of a-Hydroxy Allylic Acetates
2055
(1 H, m), 7.71–7.62 (3 H, m), 5.75 (1 H, ddd, J = 17, 11, 5
Hz), 5.24 (1 H, ddd, J = 11, 2, 1 Hz), 5.23 (1 H, ddd, J = 17,
2, 1 Hz), 4.51 (1 H, m), 3.95 (1 H, m), 3.83 (1 H, br d, J = 13
Hz), 3.24 (1 H, dt, J = 13, 3 Hz), 1.98–1.85 (1 H, m), 1.78–
1.63 (2 H, m), 1.49 (1 H, m). 13C NMR (100 MHz, CDCl3):
d = 148.0, 133.7, 133.4, 132.0, 131.8, 131.1, 124.3, 124.1,
118.9, 67.5, 61.6, 41.9, 25.6, 19.0.
Acknowledgment
We thank Nanyang Technological University and the Singapore
Ministry of Education Academic Research Fund Tier 1 (RG33/05)
and Tier 2 (grant T206B1220RS) for support of this work.
References and Notes
(8) The corresponding t-Boc and aloc-protected substrates
failed to cyclise under these conditions.
(9) Lindsay, K. B.; Pyne, S. G. J. Org. Chem. 2002, 67, 7774.
(10) Buschmann, N.; Rückert, A.; Blechert, S. J. Org. Chem.
2002, 67, 4325.
(1) Bates, R. W.; Dewey, M. R. Org. Lett. 2009, 11, 3706.
(2) Bates, R. W.; Ng, P. S. Tetrahedron Lett. 2011, 52, 2696.
(3) Hyland, C. Tetrahedron 2005, 61, 3457.
(4) For reviews of swainsonine synthesis, see: (a) El Nemr, A.
Tetrahedron 2000, 56, 8579. (b) Pyne, S. G. Curr. Org.
Synth. 2005, 2, 39. For a recent synthesis, see: (c) Kwon, H.
Y.; Park, C. M.; Lee, S. B.; Youn, J. H.; Kang, S. H. Chem.
Eur. J. 2008, 14, 1023.
(11) De Vicente, J.; Arrayas, R. G.; Canada, J.; Carretero, J. C.
Synlett 2000, 53.
(12) Poon, K. W. C.; Dudley, G. J. Org. Chem. 2006, 71, 3923.
(13) Details have been deposited with the Cambridge
Crystallographic Database, CCDC 819544, and may be
obtained at http://www.ccdc.cam.ac.uk.
(14) Bates, R. W.; Lu, Y. Org. Lett. 2010, 12, 3938; and
references therein.
(5) Washenfelder, A.; Bussmann, D. A.; Grubbs, R. H. J. Am.
Chem. Soc. 2000, 122, 58.
(6) Fukuyama, T.; Jow, C.-K.; Cheung, M. Tetrahedron Lett.
1995, 36, 6373.
(15) (a) Bates, R. W.; Satcharoen, V. Synlett 2005, 532.
(b) Thaning, M.; Wistrand, L. G. J. Org. Chem. 1990, 55,
1406. (c) Carretero, J. C.; Arrayás, R. G.; de Cracia, I. S.
Tetrahedron Lett. 1996, 37, 3379.
(16) Details have been deposited with the Cambridge
Crystallographic Database, CCDC 819546, and may be
obtained at http://www.ccdc.cam.ac.uk.
(7) A solution of allylic acetate 9 (389 mg, 1.05 mmol),
tetrakis(triphenylphosphine)palladium(0) (60 mg, 5 mol%),
and tetramethyl guanidine (131 mL, 1.05 mmol) in THF (5
mL) under nitrogen was stirred at r.t. for 4 h. The mixture
was then concentrated in vacuo, and the residue was purified
by flash chromatography (silica gel, 30% EtOAc–hexane) to
give piperidine 10 (mixture of isomers) as a colourless oil.
Major isomer: 1H NMR (400 MHz, CDCl3): d = 8.12–8.05
Synlett 2011, No. 14, 2053–2055 © Thieme Stuttgart · New York

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