"REMOTE" DIANIONS 5. SYNTHESIS OF δ-CONICEINE

Article abstract of DOI:10.1016/S0040-4039(00)93425-7

A total synthesis of (+/-) δ-coniceine from 1,4-butanediol is herein reported.A pivotal transformation of the synthesis involves the addition of the dianion of 4-(phenylsulphonyl)butanoic acid to an activated imine followed by subsequent cyclization to form a substituted piperidone intermediate.

Full text of DOI:10.1016/S0040-4039(00)93425-7

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Tetrahedron Letters, Vol.32, No.38, pp 5051-5054, 1991
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"REMOTE" DIANIONS 5. SYNTIIESIS OF ~-CONICEINE
Diana L.C. Green and Charles M. Thompson"
Department of Chemistry, Loyola University of Chicago, Chicago, Illinois 60626
Abstract: A total synthesis of (+/-) t%coniceine from 1,4-butanediol is herein reported. A pivotal
transformation of the synthesis involves the addition of the dianion of 4-(phenylsulfonyl)butanoic acid to an
activated imine followed by subsequent cyclization to form a substituted piperidone intermediate.
Indolizidine alkaloids are found in nature in a variety of plant sources. Many of these natural products
exhibit potent enzyme inhibition properties and, as a result, have been the focus of much recent study.t Some
noteworthy synthetic targets among this compound class include castanospermine 1 and swainsonine 2, the
former having been implicated as a potential anti-viral therapeutic.2 Among the least complex of this class of
compounds is tS-coniceine 3, the indolizidine skeleton itself.
QH
OH
O
~
H
, , o H
ttO
1: (+) castanospermine
2: (-) swainsonine
3: delta-coniceine
The previous syntheses of 3 were reviewed in 1986,3 and since that time eleven additional syntheses of
6-coniceine have appeared', indicating current widespread interest in this molecule. With limited functional
groups, the &coniceine skeletal structure provides an ideal model system for investigating a general synthetic
strategy for the construction of more complex indolizidine alkaloids such as 1 and 2.
We previously utilized the dianion of 4-(phenylsulfonyl)butanoic acid (4-PSBA) 5 in the preparation of
heterocycles, for example 6-1actones from carbonyls5 and 2-piperidones 6 from imines6 (Scheme I).
5051

5052
SO2Ph
e
SO2Ph
N ~
R 1 y R2
I NI
BF3.OEt2
Scheme I
+
v
R2
R3
R l
O
O
4
5
6
Our initial approach to the synthesis of indolizidines was extension of the latter method to an appropriately
substituted cyclic imine that would permit direct construction of the indolizidine bicyclic system (Scheme II).
Unfortunately, addition of the dianion of 4-PSBA to select cyclic imines led only to very poor conversion to the
corresponding bicyclie system. Most likely drawbacks to this approach were the inability to cleanly prepare
and suitably activate the precursor cyclic imines.
SO2Ph
Rl
~ O2Ph
BF3"OEt2
+
Scheme II
o e
O
O
Alternatively, an acyclic imine suitably substituted at the terminus would permit indolizidine ring
construction if a cyclization step could be effectively incorporated in the sequence. An obvious point to
consider in this extension was potential failure of the imine addition step due to competing coordination of the
activating agent (BF3-etherate) by the protected terminal functional group.
Thus, preparation of the __N,O-dibenzylimine 10 was accomplished in three steps from 1,4-butanediol via
mono-benzylation (excess diol, PhCH2Br, KOH, RT, 95%), PCC oxidation to the aldehyde7 (70%, Swern and
Collins oxidations did not significantly improve the yield) and final imine formation (PhCH2NHx, PhCH3,
-H20, 95%) (Scheme III).
H
o
~
O
H
PhCH2Br~
KOH
~
O
C
H
2
P
h
H
O
7
8
Scheme III
PCC
O
H
~
P h C H 2 N H 2
O
'
~
C
H 2Ph
PhCH2 ~
N
~
~
,
~
O
B
n
-
PhCH3
10
-H20

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Boron trifluoride etherate (1.25 eq.) activation of 10 (-78 °C, THF) followed by addition to 58 yielded
the desired lactams lla as a diastereomerie pair in good yield (76%) (Scheme IV). This transformation was
very sensitive to the Lewis acid and required the use of freshly distilled boron trifluoride etherate. Flash
chromatographic separation of these diastereomers led to a cis:trans mixture approximating 70:30fl Selective
catalytic hydrogenolysis (10-20 psi H2, Pd-C 10%, TFA) of the diastereomers afforded hydroxy lactarns llbt°
in 82% yield. The amides were reduced to the corresponding piperidines 12a (BH3*THF, 89%), which were
mesylated (CH3SO2CI, TEA, RT, 2 h) resulting in formation of the bicyclic quaternary salts. These products
were subjected to hydrogenolysis (Pearlman's catalyst, 10-20 psi Hz)H without purification to provide the 8-
phenylsulfonylindolizidines 13 (46-73%). Reductive cleavage of the phenylsuifone moiety (6% Na/Hg, MeOH,
2 h, 71%) provided (+/-) ~-coniceine 3.~2
S 0 2 P h
SO2Ph
5+10 BF3"OEt2 .~ ~ ~ ~ / " ~ O R B2H6v
~ , ~ I ~N ~c H 2 ph
12a: R=H
12b: R=Ms
O
11a: R=CH2Ph
11b: R=H
[2
d(OH) 2
Scheme IV
1~
H
~O2Ph
3
13
In summary, ~5-coniceine was prepared in seven steps from readily available starting materials utilizing
the "remote dianion" approach. The success of the dianion addition to a functionalized imine, ring
manipulations and removal of the phenylsulfonyl group are noteworthy transformations. Extension of this
synthetic strategy to the preparation of more complex indolizidine alkaloids as well as a stereospecific route are
currently under investigation.
Acknowledgements: The author wishes to thank Loyola University Chicago for the purchase of the Varian
VXR-300 MHz NMR used in this study, a fellowship to D.L.C.G. and supporting research funds through the

5054
Biomedical Research Support Grant. The authors also wish to thank Dr. G.D. Green for useful discussions.
This work was supported in part by the National Institute of Environmental Health Sciences (ESO-4434).
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9. Cis and trans assignments were made through MMX modeling (Serena Software) and ~H NMR coupling
constant (Karplus correlation) analyses.
10. llh Isolated as white crystals from methylene chloride/hexane, mp = 136-137 °C. Anal calcd, for
C21HzsNO4S: C, 65.09; H, 6.50; N, 3.61. Found: C, 64.85; H, 6.39; N, 3.55. IR; 3400 (br), 1640 cm~. ~H
NMR (CDCI~): ~ 1.09 (m, 1H), 1.24 (m, 1H), 1.56 (m, 1H), 1.73 (m, 1H), 1.93 (s, 1H), 2.26 (m, 3H), 2.75
(m, 1H), 3.21 (dt, 1H, J=2.6, 9.4 Hz), 3.35 (m, 2H), 3.67 (dt, 1H, J = 2.6, 9.4 Hz), 3.98 (d, 1H, J = 14.7
Hz), 5.25 (d, 1H, J = 14.7 Hz), 7.42 (m, 10H). ~3C NMR (CDCI3): 19.7, 27.8, 28.8, 30.1, 48.1, 53.3,
60.7(CH), 61.3(CH), 127.7, 128.7, 128.7, 129.1, 129.3, 133.9, 136.6, 169.6.
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12. Spectral and chemical properties were consistent with literature values, see 4b.
(Received in USA 22 April 1991; accepted 30 May 1991)