SmI2-mediated hetero-coupling reaction of lactams with aldehydes; synthesis of indolizidine alkaloids, (-)-δ-coniceine, (+)-5-epiindolizidine 167B and (+)-lentiginosine

Article abstract of DOI:10.1016/S0040-4039(01)00214-3

Treatment of alicyclic and aromatic lactams with several aldehydes in the presence of samarium(II) diiodide was found to undergo a novel nitrogen-carbon (hetero) coupling reaction to generate N-α-hydroxyalkylated lactams in high yield. The chiral lactams with an aldehyde-side chain incorporating the L-pyroglutamic acid- or L-tartaric acid-derived skeleton also reacted intramolecularly under the same conditions to afford the corresponding bicyclic coupling products, which were further applied to the convenient syntheses of (-)-δ-coniceine, (+)-5-epiindolizidine 167B and (+)-lentiginosine, respectively.

Full text of DOI:10.1016/S0040-4039(01)00214-3

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 42 (2001) 2509–2512
SmI2-mediated hetero-coupling reaction of lactams with
aldehydes; synthesis of indolizidine alkaloids, (−)-d-coniceine,
(+)-5-epiindolizidine 167B and (+)-lentiginosine
Hidemi Yoda,* Hideaki Katoh, Yasuaki Ujihara and Kunihiko Takabe
Department of Molecular Science, Faculty of Engineering, Shizuoka University, Hamamatsu 432-8561, Japan
Received 27 December 2000; revised 22 January 2001; accepted 2 February 2001
Abstract—Treatment of alicyclic and aromatic lactams with several aldehydes in the presence of samarium(II) diiodide was found
to undergo a novel nitrogen–carbon (hetero) coupling reaction to generate N-a-hydroxyalkylated lactams in high yield. The chiral
lactams with an aldehyde-side chain incorporating the
L-pyroglutamic acid- or L-tartaric acid-derived skeleton also reacted
intramolecularly under the same conditions to afford the corresponding bicyclic coupling products, which were further applied to
the convenient syntheses of (−)-d-coniceine, (+)-5-epiindolizidine 167B and (+)-lentiginosine, respectively. © 2001 Elsevier Science
Ltd. All rights reserved.
between lactams and aldehydes mediated by SmI2 to
provide N-a-hydroxyalkylated lactams and its applica-
tion to the short synthesis of biologically active
indolizidine alkaloids, (−)-d-coniceine, (+)-5-epiin-
dolizidine 167B and (+)-lentiginosine.
Samarium(II) diiodide has been extensively investigated
as a powerful electron donor able to promote a wide
range of reductions and coupling reactions.1 Its use in
synthesis has been especially advantageous for ring
closure reactions and CꢀC bond formation such as
hydroxyl-directed conjugate addition and stereocon-
trolled intramolecular pinacol reactions involving a
variety of carbonyl compounds.2 The reactions of acid
chlorides and acid anhydrides with this reagent have
also been researched3 in addition to intramolecular and
intermolecular Grignard-type reactions.4
Initial experiments have been performed on a cross-
coupling reaction mediated by SmI2 (2 equiv.) between
N-alkoxycarbonyl lactams (1a–1c) and heptanal as
shown in Table 1 (entries 1–3), which gave unexpect-
edly the decarboxylated nitrogen–carbon (hetero) cou-
pling product 2a in low yields instead of the desired
pinacolic-type adduct. Enhancement of the yield was
not observed even in the case of employing simple
2-pyrrolidinone (1d), however, the use of excess SmI2 (3
equiv.) remarkably brought about 2a in 90% isolated
yield (entry 5).9 Although it became apparent that this
procedure was not applicable for the reaction of N-H
lactams with ketones, the beneficial results was again
obtained in intramolecular reactions (entries 8 and 9)10
and in reactions employing an aromatic N-H lactam
(1g) (entries 10–12). It is reasonable to assume that the
reaction may proceed by a radical mechanism since the
reaction with Bu3SnH (1.5 equiv.) and cat. AIBN in
toluene at 90°C afforded the same coupling product 2a
in 75% yield. However, the ionic simple acetalization
involving a samarium(III) chelated six-membered ring
structure of 2 obtained from nucleophilic attack of the
lactam-anion to the aldehyde should be also consid-
ered. Additional studies on the precise mechanistic
aspect are in progress.
Towards the carbonyl group of imides, on the other
hand, two reactions, i.e. an intramolecular Barbier-type
reaction of some N-iodoalkyl cyclic imides5 and a
coupling reaction of acyclic imides such as N-acyllac-
tams with carbonyl compounds6 are known. In this
connection we have also recently reported the first
pinacolic cross-coupling reaction between phthalimides
and carbonyl compounds and its application to the
complete stereoselective deoxygenation.7 However, the
lack of studies concerning the reactivity of samar-
ium(II) compounds towards simple amides is surprising
except in some special cases.8 This should be attributed
to their low reactivity. Herein we wish to describe the
first nitrogen–carbon (hetero) coupling reaction
Keywords: coupling reaction; samarium(II) diiodide; lactam;
indolizidine alkaloid; lentiginosine.
* Corresponding author. Tel.: +81-53-478-1150; fax: +81-53-478-1150;
e-mail: yoda@mat.eng.shizuoka.ac.jp
0040-4039/01/$ - see front matter © 2001 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(01)00214-3

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H. Yoda et al. / Tetrahedron Letters 42 (2001) 2509–2512
Table 1. Hetero-coupling reaction of lactams (1) with aldehydes mediated by SmI2
In light of the above outcome, we turned our attention
to the short and convenient synthesis of some biologi-
cally active indolizidine alkaloids, such as (−)-d-coni-
ceine, (+)-5-epiindolizidine 167B and (+)-lentiginosine.
To begin with, treatment of 2d obtained from the
intramolecular hetero-coupling reaction with Et3SiH in
the presence of BF3·OEt2 easily afforded the deox-
genated compound 3 in high yield, which was in turn
reduced with LiAlH4 to give the known product, (−)-d-
coniceine (4) ([h]D23.5 −4.02° (c 2.12, EtOH)).12 On the
other hand, 2d was effected by BF3·OEt2-induced
allylation13 with allyltrimethylsilane and hydrogenation
followed by reduction under the same conditions as
noted above, leading to the alkaloid, 5-epiindolizidine
167B (6), [h]D23.8 +9.59° (c 0.75, CH2Cl2)14 as a single
stereoisomer15 (determined by 13C NMR and HPLC
analysis) in 62% overall yield from 2d (Scheme 1).
These two compounds have properties identical to
those reported in the literature, respectively.
The same approach was also applicable to the short
synthesis of the least hydroxylated indolizidine alkaloid,
(+)-lentiginosine (11), which was found to be ca. twice
as potent as castanospermine known to inhibit replica-
tion of human immunodeficiency virus (HIV), as fol-
lows; the trans-substituted homochiral lactam 7 (>99%
d.e.) obtained from
L-tartaric acid based on our
reported method17 was cleavaged via dihydroxylation
after exchange of TIPS-protecting groups to ben-
zylethers, providing the aldehyde 9 in high yield. This
was subjected to the SmI2-mediated coupling reaction
followed by deoxgenation with Et3SiH to lead to the
indolizidine lactam 10 in 78% 2 steps yield. Deprotec-
tion and reduction of 10 finally accomplished the total
synthesis of (+)-11 (Scheme 2), [h]2D5 +3.20° (c 0.60,
MeOH) (lit.18a [h]D27 +3.20° (c 1.07, MeOH)), whose
spectral data were completely identical to those of the
natural19 and previously synthesized product in this
laboratory.18
Scheme 1. Reagents and conditions: (a) Et3SiH, BF3·OEt2, CH2Cl2, −20°C; quant.; (b) LiAlH4, ether, rt; quant.; (c) 1,
allyltrimethylsilane, BF3·OEt2, CH2Cl2, −78 to −50°C; 69%; 2, H2, Pd/C, EtOH; 90%; (d) LiAlH4, ether, rt; quant.

H. Yoda et al. / Tetrahedron Letters 42 (2001) 2509–2512
2511
Scheme 2. Reagents and conditions: (a) 1, Bu4NF, THF; quant.; 2, BnBr, Ag2O, CH3COOEt; 63%; (b) 1, CAN, CH3CN–H2O
(9:1); 75%; 2, OsO4, NMO, acetone–H2O (1:1); 95%; 3, NaIO4, H2O–Et2O (1:); quant.; (c) 1, SmI2 (3 equiv.), THF; 85%; 2,
Et3SiH, BF3·OEt, CH2Cl, −20°C; 92%; (d) 1, Pd(black), 4.4% HCOOH–MeOH; 90%; 2, LiAlH4, THF, reflux; quant.
In summary we have disclosed herein the first example
of SmI2-mediated N-C (hetero) coupling reaction
between N-unsubstituted lactams and aldehydes. This
procedure found application in the shortest synthesis of
three types of biologically important indolizidine alka-
loids and will be widely applicable to the synthesis of
other fused alkaloidal natural products.
4. (a) Molander, G. A.; McKie, J. A. J. Org. Chem. 1993,
58, 7216; (b) Mochrouhi, F.; Namy, J.-L.; Kagan, H. B.
Synlett 1996, 633.
5. Ha, D.-C.; Yun, C.-S.; Yu, E. Tetrahedron Lett. 1996, 37,
2577.
6. Farcas, S.; Namy, J.-L. Tetrahedron Lett. 2000, 41, 7299.
7. Yoda, H.; Matsuda, K.; Nomura, H.; Takabe, K. Tetra-
hedron Lett. 2000, 41, 1775.
8. (a) Ogawa, A.; Takami, N.; Nanke, T.; Ohya, S.; Hirao,
T. Tetrahedron 1997, 53, 12895; (b) Kikukawa, T.;
Hanamoto, T.; Inanaga, J. Tetrahedron Lett. 1999, 40,
7497; (c) Molander, G. A.; Etter, J. B.; Zinke, P. W. J.
Am. Chem. Soc. 1987, 109, 453.
9. Typical experimental conditions: To a deep-blue THF (3
mL) solution prepared from samarium metal powder
(0.54 g, 3.60 mmol) and diiodomethane (0.95 g, 3.53
mmol) under Ar was added a solution of 2-pyrrolidine
(0.10 g, 1.18 mmol) and heptanal (0.40 g, 3.56 mmol) in
THF (3 mL) at 0°C. After the mixture was stirred for 3
h at room temperature, it was poured into a dilute HCl
and extracted with ethyl acetate. The product was chro-
matographed (eluted with ethyl acetate) to give 2a (0.21
g, 1.06 mmol) in 90% yield.
Acknowledgements
This work was supported in part by a Grant-in-Aid for
Scientific Research from Japan Society for the Promo-
tion of Science.
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.