Concise total synthesis of (±)-aloperine and 6-epi-aloperine

Article abstract of DOI:10.1021/ol0263144

(figure presented) Total synthesis of aloperine and 6-epj-aloperine is reported. The crucial steps of the synthetic strategy are an aza-annulation reaction and an intermolecular Diels-Alder reaction. The synthetic plan proceeds from commercially available

Full text of DOI:10.1021/ol0263144

ORGANIC
LETTERS
2002
Vol. 4, No. 17
2925-2928
Concise Total Synthesis of (±)-Aloperine
and 6-epi-Aloperine
Daniele Passarella,* Marco Angoli, Alessandra Giardini, Giordano Lesma,
Alessandra Silvani, and Bruno Danieli
Dipartimento di Chimica Organica e Industriale, UniVersita` degli Studi di Milano,
Via Venezian 21, 20133 Milano, Italy
Daniele.Passarella@unimi.it
Received June 6, 2002
ABSTRACT
Total synthesis of aloperine and 6-epi-aloperine is reported. The crucial steps of the synthetic strategy are an aza-annulation reaction and an
intermolecular Diels−Alder reaction. The synthetic plan proceeds from commercially available piperidine-2-ethanol.
Aloperine 1, a member of a small family of C15 lupinine
alkaloids,1 was first isolated in 1935 from the seeds and
leaves of Sophora alopecuroides,2 a shrub that grows in
China and Russia, and later from Leptorhabdos parViflor
Benth.2f The use of the plant in traditional chinese medicine3
and the results of the recent investigation concerning the
pharmacological activity (cardiovascular, antiinflammatory,
antiallergic) of the isolated alkaloid4 moved the Overman
group toward an intense synthetic interest, recently culminat-
ing in the first enantioselective total synthesis.5 The central
element of the Overman synthetic strategy is an intramo-
lecular Diels-Alder reaction in which the cycloaddendes are
temporarily tethered by a removable N-silylamine linkage.
We report here a synthesis of (()-aloperine and 6-epi-
aloperine using an efficient intermolecular Diels-Alder
reaction as crucial step where the required diene is prepared
following an aza-annulation reaction sequence.6
(1) Lupinine family includes also N-methyl (2) and N-allyl (3) derivatives.
(2) (a) Kuchkarov, S.; Kushmuradov, Yu. K. Khim. Prir. Soedin. 1979,
413; Chem. Abstr. 1979, 91(23), 189799k. (b) Kuchkarov, S.; Kushmuradov,
Yu. K.; Aslanov, Kh. A.; Sadykov, A. S. Khim. Prir. Soedin. 1978, 44;
Chem. Abstr. 1978, 93(17), 164311y. (c) Kuchkarov, S.; Kushmuradov,
Yu. K.; Begisheva, A. I.; Aslanov, Kh. A. Sb. Nauchn. Tr. Tashk. Un-t.
1976, 108; Chem. Abstr. 1976, 87(1): 2564g. (d) Monakhova, T. E.;
Tolkachev, O. N.; Kabanov, V. S.; Perel’son, M. E.; Proskurnina, N. F.
Khim. Prir. Soedin. 1974, 472; Chem. Abstr. 1974, 82(9), 54176y. (e)
Orechoff, A.; Proskurnina, N.; Konowalowa, R. Chem. Ber. 1935, 68, 431.
(f) Bocharnikova, A. V.; Massagetov, P. S. Zh. Obshch. Khim. 1964, 34,
1025. (g) For a brief review, see: Aslanov, K. A.; Kushmuradov, Y. K.;
Sadykov, A. S. Alkaloids (N.Y.) 1987, 31, 167.
Our retrosynthetic plan (Scheme 1) is based on the key
cleavage of the N-C10 bond that reveals the octahydro-
quinoline system of type A. This moiety is accessible by an
intermolecular Diels-Alder reaction of a 5-alkenyl-3,4-
dihydropyridin-2-one B with methyl acrylate. We planned
to build this N-acylaminodiene7 by aza-annulation reaction
(5) (a) Brosius, A. D.; Overman, L. E.; Schwink, L. J. Am. Chem. Soc.
1999, 121, 700. (b) Brosius, A. D.; Overman, L. E. J. Org. Chem. 1997,
62, 440. (c) Brosius, A. D.; Ziller, J. W.; Zhang, Q. M. Acta Crystallogr.
1997, C53, 1510.
(6) (a) Paulvannan, K.; Stille, J. R. J. Org. Chem. 1994, 59, 1613. (b)
Cook, G. R.; Beholz, L. G.; Stille, J. R. J. Org. Chem. 1994, 59, 3575. (c)
Barta, N. S.; Brode, A.; Stille, J. R. J. Am. Chem. Soc. 1994, 116, 6201.
(d) Beholz, L. G.; Benovsky, P.; Ward, D. L.; Barta, N. S.; Stille, J. R. J.
Org. Chem. 1997, 62, 1033. (e) Benovsky, P.; Stephensen, G. A.; Stille, J.
R. J. Am. Chem. Soc. 1998, 120, 1033.
(3) Long, D. W. Drugs Future 1999, 809.
(4) (a) Zhou, C.; Gao, H.; Sun, X.; Shi, H.; Liu, W.; Yuan, H.; Wang,
Z. Zhongguo Yaoli Xuebao 1989, 10, 360; Chem. Abstr. 1989, 111(13),
108662s. (b) Zhao, D.; Li, Z.; Yang, X.; Sheng, B. Zhongcaoyao 1986, 17,
170; Chem. Abstr. 1986, 105(1), 437j. (c) Li, X.; Wu, Y.; Liu, L.; He, L.
Zhongguo Yaolixue Yu Dulixue Zazhi 1988, 2, 72; Chem. Abstr. 1988,
108(17), 143225m. (d) Li, X.; Dai, S.; Li, W.; Zhou, Y.; Zhao, X.; Gao, L.
Zhongcaoyao 1987, 18, 214; Chem. Abstr. 1987, 107(15), 126695b.
10.1021/ol0263144 CCC: $22.00 © 2002 American Chemical Society
Published on Web 07/27/2002

Scheme 1. Retrosynthetic Analysis
Scheme 2a
using an acetylenic ketone of type C as a substrate. The
presence of the ketone functionality was necessary to induce
the aza-annulation reaction that proceeds by an initial
addition of the primary amine to the electrophilic triple
bond.
a Reagents and conditions: (a) CrO3, H2SO4 (65%); (b) (Boc)2O,
NaOH, t-BuOH (86%); (c) CH3NH(OCH3)‚HCl, DCC, DMPA
(71%); (d) LiCCSi(CH3)3, -78 °C, THF (42%); (e) TBAF (84%);
(f) (Boc)2O, AcOEt (95%); (g) Dess-Martin periodinane (89%);
(h) BrMgCCSiMe3, -78 °C (86%); (i) (COCl)2, DMSO, Et3N
(87%).
We were confident of the success of the crucial Diels-
Alder step considering our previous results in the diastereo-
selective synthesis of 3-oxo-14,15-dihydro-andranginine8
where we have demonstrated the successful use of 5-ethenyl-
N-alkyl-3,4-dihydropyridin-2-one in the regio- and stereo-
selective endo Diels-Alder reaction.
However, in our planned synthesis, presence of the
stereogenic carbon (C6) in diene B determines the like (lk)
and unlike (ul) facial selectivity problem9 that could not be
addressed a priori.
(71% yield). The introduction of the ethynyl fragment was
accomplished by reaction of 8 with the lithium derivative
of trimethylsilylacetylene12 in THF at -78 °C to give 9 that,
by desilylation with TBAF, gave 10 in 84% yield. The
unsatisfactory yield for the preparation of 8 and the use of
the Cr(VI) moved us toward the elaboration of a more
convenient preparation of 10.
The aminol 4 was first transformed into the corresponding
carbamate 6 (95% yield) by a conventional procedure13 and
subsequently oxidized to the aldehyde 11 by Dess-Martin
periodinane14 in 89% yield. Ethynylation of aldehyde 11 with
the Grignard reagent, prepared from trimethylsilyl acety-
lene,15 gave cleanly the diastereomeric alcohols 12 (1:1) in
86% yield. Swern oxidation to ketone and cleavage of the
C-Si bond with TBAF gave compound 10 (53% overall
yield from 4).
Compound 10 was reacted with benzylamine (Scheme 3)
in THF at 25 °C, and the intermediate enamine was directly
cyclized with acryloyl chloride in THF at 65 °C to give
dihydropyridinone 13 in 56% yield. Reduction of 13 with
NaBH4 gave a mixture of diastereoisomeric alcohols 14,
which by direct thermal treatment furnished exclusively the
desired E diene 15. Heating a solution of 15 in toluene with
methyl acrylate led to compounds 16 (56%) and 1716 (28%),
which were separated by column chromatography. In a more
10
The synthesis began with the CrO3 in H2SO4 oxidation
of the commercially available piperidine-2-ethanol 4 to the
corresponding carboxylic acid 5 in 65% yield (Scheme 2).
The protection of the nitrogen as carbamate11 (86% yield)
and the subsequent condensation reaction with N,O-dimeth-
ylhydroxylamine hydrochloride gave the Weinreb amide 8
(7) The usefulness of N-acylaminodienes was demonstrated through the
synthesis of several alkaloids: (a) Oppolzer, W.; Keller, K. J. Am. Chem.
Soc. 1971, 93, 3836. (b) Oppolzer, W.; Frostl, W. HelV. Chim. Acta 1975,
58, 583. (c) Overman, L. E.; Jessup, P. J. Am. Chem. Soc. 1978, 100, 5179.
(d) Overman, L. E.; Lesuisse, D.; Hashimoto, M. J. Am. Chem. Soc. 1983,
105, 5373. (e) Stork, G.; Morgans, D. J. J. Am. Chem. Soc. 1979, 101,
7110. (f) Rawal, V. H.; Michoud, C.; Monestel, R. F. J. Am. Chem. Soc.
1993, 115, 3030. (g) Kozmin, S. A.; Rawal, V. H. J. Am. Chem. Soc. 1998,
120, 13523. For other recent interesting applications of 1-aza-butadiene in
Diels-Alder reactions, see: (h) Huang, Y.; Iwama, T.; Rawal, V. H. J.
Am. Chem. Soc. 2000, 122, 7843. (i) Kozmin, S. A.; Janey, J. M.; Rawal,
V. H. J Org. Chem. 1999, 64, 3039. (j) Neushutz, K.; Simone, J.-M.;
Thyrann, T.; Neier, R. HelV. Chim. Acta 2000, 83, 2712. (k) Kozmin, S.
A.; Green, M. T.; Rawal, V. H. J. Org. Chem. 1999, 64, 8045. (l) Kozmin,
S. A.; Rawal, V. H. J. Am. Chem. Soc. 1997, 119, 7165. (m) Kozmin, S.
A.; Rawal, V. H. J. Org. Chem. 1997, 62, 5252. (n) Kozmin, S. A.; Rawal,
V. H. J. Am. Chem. Soc. 1999, 121, 9562.
(8) (a) Danieli B.; Lesma G.; Martinelli M.; Passarella D.; Silvani A. J.
Org. Chem. 1997, 62, 6519. (b) Danieli B.; Lesma G.; Luzzani, M.;
Passarella D.; Silvani A. Tetrahedron 1996, 52, 11291. (c) Bigogno, C.;
Danieli, B.; Lesma, G.; Passerella, D. Heterocycles 1995, 41, 973.
(9) Seebach, D.; Prelog, V. Angew. Chem., Int. Ed. Engl. 1982, 21, 654.
(10) Marshall, W. D.; Nguyen, T. T.; McLeand, D. B.; Spencer, I. D.
Can. J. Chem. 1975, 17, 41.
(12) Muller, M.; Mann, A.; Taddei, M. Tetrahedron Lett. 1993, 34, 3289.
(13) Iketa, M.; Kugo, Y.; Sato, T. J. Chem. Soc., Perkin Trans 1 1996,
1819.
(14) Dess, D. B.; Martin, J. C. J. Am. Chem. Soc. 1991, 113, 7277.
(15) Reed, P. E.; Karzenellenbogen, J. A. J. Org. Chem. 1991, 56, 2624.
(16) Reported structures represent a mixture of enantiomers.
(11) Morley, C.; Knight, D. W.; Share, A. C. J. Chem. Soc., Perkin Trans.
1994, 2903.
2926
Org. Lett., Vol. 4, No. 17, 2002

Scheme 3a
Scheme 4a
a Reagents and conditions: (a) TFA (quantitative); (b) LiAlH4
(94%); (c) CBr4-PPh3, CH2Cl2; (d) Et3N, 40 °C (22 45%, 23 42%);
(e) Li, NH2(CH2)2NH2 (1 80%, 24, 83%).
a Reagents and conditions: (a) BnNH2, CH2dCHCOCl, THF
(56%); (b) NaBH4; (c) ∆; (d) CH2dCHCOOCH3, PhCH3, 110 °C
(16 56%, 17 28%).
as a first step the LiAlH4 reduction to provide compounds
20 and 21. The reduction of both the ester and the amide
functions was possible by keeping the reaction at room
temperature for 4 days. The formation of the final N-C10
bond was accomplished by reaction with CBr4-PPh3 fol-
lowed by addition of triethylamine. Removal of the benzyl
group from N12 was rather problematic: the application of
the conventional procedure with sodium18 or lithium19 in
ammonia gave poor results. Fortunately, the application of
the protocol described by Angle et al.,20 which employs the
use of ethylenediamine (dry) and lithium, furnished aloperine
1 (80%, starting from 22) and the analogue 24 (83% starting
from 23), identified as 6-epi-aloperine.5b Synthetic aloperine
1 appeared identical to a commercially obtained sample. The
1H and 13C NMR spectra of diamine 24 were significantly
different from those of aloperine 1 different from quinolizi-
dine signals are concerned. In particular, the chemical shift
of C6 of compound 24 that appeared at δ 66.6 downfield
shifted (6.5 ppm) relative to the corresponding line of
aloperine 1 was structurally characteristic. This difference
is in agreement with the trans-fused21 quinolizidine ring
convenient protocol, alcohols 14 were directly dissolved in
toluene and heated at 110 °C in the presence of methyl
acrylate and a catalytic amount of PTSA to give compounds
16 and 17 in a two-step one-pot reaction.
Despite a detailed spectroscopic investigation, the similar-
ity of the 1H NMR spectra of compounds 16 and 17
prevented a definite relative stereochemical assignment. Our
previous results suggested that the obtained products derive
from the endo approach of the methyl acrylate to the two
diastereotopic faces of the diene 15.8a,b
That the two compounds 16 and 17 are epimers at C6 was
demonstrated by removal of t-Boc group to give 18 and 19,
respectively. Treatment of 18 with NCS gave the corre-
sponding N-chloride derivative that by direct elimination
reaction in the presence of DBU17 gave the N-C6 imine
derivative, which was reduced with NaBH3CN, to provide a
mixture of compounds 18 and 19. The same result was
obtained using 19 as starting material. The definite stereo-
chemical assignment could be ascertained only when the final
compounds 1 and 24 were obtained.
The conversion of compounds 18 and 19 to the tetracyclic
(18) Gurjar, M. K.; Pal, S.; Rama Rao, A. V.; Paria, R. J.; Chorgade, S.
Tetrahedron 1977, 53, 4769.
lupinine skeleton (Scheme 4) was separately obtained using
(19) Smith, H. Organic Reactions in Liquid Ammonia; Interscience: New
York, 1963; Vol. 2, Part 2.
(20) Angle, S. R.; Henry, R. M. J. Org. Chem. 1998, 63, 7490.
(17) Davis, B. G.; Maughan, M. A. T.; Chapman, T. M.; Villard, R.;
Courtney, S. Org. Lett. 2002, 4, 103.
Org. Lett., Vol. 4, No. 17, 2002
2927

system with respect to the cis-quinolizidine present in
aloperine 15 thus confirming the C6 stereochemistry depicted
in 24.
Acknowledgment. The authors express their gratitude to
Dr. Letizia Franco and Dr. Marisa Martinelli for their
precious collaboration in the collection of the preliminary
results. The authors express their gratitude to Ministero
dell’Istruzione dell’Universita` e della Ricerca for financial
support. The work was partially supported by DGICYT,
Spain (BQU2000-0651).
In conclusion, we have described a practical synthesis of
aloperine and 6-epi-aloperine that proceeds toward the final
products in 12 steps starting from the commercially available
piperidine-2-ethanol. This strategy can be applied to the
synthesis of differently N-substituted aloperine derivatives.
The aza-annulation reaction appears to be a useful crucial
step for the construction of skeletons containing the
1,2,3,4,6,7,8,8a-octahydroquinoline system.
Supporting Information Available: Experimental pro-
cedures and characterization for all new compounds and 1H
and 13C NMR spectra for compounds 8-10, 12, 13, 15-24,
and 1. This material is available free of charge via the Internet
at http://pubs.acs.org.
(21) (a) Hughes, D. W.; Spenser, I. D.; Wrobel, J. T. Magn. Reson. Chem.
2000, 38, 707. (b) LaLonde, R. T.; Donvito, T. N. Can. J. Chem. 1974, 52,
3778.
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