Asymmetric Aza-[3 + 3] annulation in the synthesis of indolizidines: An unexpected reversal of regiochemistry

Article abstract of DOI:10.1021/ol2017438

An enantioselective and diastereoselective aza-[3 + 3] annulation of pyrrolidine-based exo-cyclic vinylogous amides and urethanes with chiral vinyl iminium salts is described. This asymmetric annulation manifold is possible because of an unexpected regiochemical reversal whereby head-to-tail annulations dominated over the predicted head-to-head. It should find prevalent synthetic applications in the enantioselective synthesis of indolizidines.

Full text of DOI:10.1021/ol2017438

ORGANIC
LETTERS
2011
Vol. 13, No. 16
4402–4405
Asymmetric Aza-[3 þ 3] Annulation in the
Synthesis of Indolizidines: An Unexpected
Reversal of Regiochemistry
Grant S. Buchanan, Huifang Dai,* Richard P. Hsung,* Aleksey I. Gerasyuto, and
Casi M. Scheinebeck
Division of Pharmaceutical Sciences and Department of Chemistry, University of
Wisconsin, Madison, Wisconsin 53705, United States
hdai5@wisc.edu; rhsung@wisc.edu
Received June 28, 2011
ABSTRACT
An enantioselective and diastereoselective aza-[3 þ 3] annulation of pyrrolidine-based exo-cyclic vinylogous amides and urethanes with chiral vinyl
iminium salts is described. This asymmetric annulation manifold is possible because of an unexpected regiochemical reversal whereby head-to-tail
annulations dominated over the predicted head-to-head. It should find prevalent synthetic applications in the enantioselective synthesis of indolizidines.
Aza-[3 þ 3] annulations1ꢀ6 have proven to be powerful
domino or iterative pathways.7 We have been developing
an aza-[3 þ 3] annulation that proceeds through a tandem
sequence of Knoevenagel condensation of vinylogous
amides 1 and vinyl iminium ions 2, followed by pericyclic
ring-closure of the resulting 1-azatrienes 3 [Scheme 1].8
This annulation constitutes a unified strategy that has been
employed in a number of complex alkaloid syntheses.4,9
However, while achieving highly diastereoselective annu-
lations through the use of chiral auxiliary [X*]10,11 or chiral
substituents [R*]12 allowed us to establish the first exam-
ples of highly torquoselective pericyclic ring-closure of
in the rapid construction of nitrogen heterocycles via
(1) For reviews on hetero-[3 þ 3] annulations, see: (a) Harrity,
J. P. A.; Provoost, O. Org. Biomol. Chem. 2005, 3, 1349. (b) Hsung,
R. P.; Kurdyumov, A. V.; Sydorenko, N. Eur. J. Org. Chem. 2005, 23.
(2) (a) Tang, Y.; Oppenheimer, J.; Song, Z.; You, L.; Zhang, X.;
Hsung, R. P. Tetrahedron 2006, 62, 10785. (b) Laschat, S.; Dickner, T.
Synthesis 2000, 1781.
(3) For a symposium-in-print devoted to aza-annulations, see: Harrity,
J. P. A. Tetrahedron 2008, 64, No. Symposium in Print No. 133.
(4) For some recent studies on aza-[3 þ 3] annulations, see: (a) Guo,
H.; Xu, Q.; Kwon, O. J. Am. Chem. Soc. 2009, 131, 6318. (b) Jeanne
Alladoum, J.; Toum, V.; Hebbe, S.; Kadouri-Puchot, C.; Dechoux, L.
Tetrahedron Lett. 2009, 50, 617. (c) Zhong, W.; Lin, F.; Chen, R.; Su, W.
Synthesis 2008, 2561. (d) Hayashi, Y.; Gotoh, H.; Masui, R.; Ishikawa,
H. Angew. Chem., Int. Ed. 2008, 47, 4012. (e) Mancey, N. C.; Butlin,
R. J.; Harrity, J. P. A. Synlett 2008, 2647. (f) Trost, B. M.; Dong, G. Org.
Lett. 2007, 9, 2357. (g) Provoost, O. Y.; Hazelwood, A. J.; Harrity,
J. P. A. Beil. J. Org. Chem. 2007, 3, 8.
(8) Hsung, R. P.; Wei, L.-L.; Sklenicka, H. M.; Douglas, C. J.;
McLaughlin, M. J.; Mulder, J. A.; Yao, L. J. Org. Lett. 1999, 1, 509.
(9) For our recent total syntheses, see: (a) Li, G.; Hsung, R. P. Org.
Lett. 2009, 11, 4616. (b) Li, G.; Sagamanova, I. K.; Carlson, L. J.;
Hsung, R. P.; Slafer, B. W.; Sklenicka, H. M.; Sydorenko, N.; Gilardi, C.
Synthesis 2009, 2905. (c) Zhang, Y.; Long, Q. A.; Gerasyuto, A. I.;
Hsung, R. P. Synlett 2009, 237. (d) Li, G.; Hsung, R. P.; Slafer, B. W.;
Sagamanova, I. K. Org. Lett. 2008, 10, 4991. (e) Gerasyuto, A. I.; Hsung,
R. P. J. Org. Chem. 2007, 72, 2476. (f) Swidorski, J. J.; Wang, J.; Hsung,
R. P. Org. Lett. 2006, 8, 777. (g) Gerasyuto, A. I.; Hsung, R. P. Org. Lett.
2006, 8, 4899.
(5) For recent reviews on applications of aza-[3 þ 3] annulation in
natural product synthesis, see: (a) Buchanan, G. S.; Feltenberger, J. B.;
Hsung, R. P. Curr. Org. Chem. 2010, 7, 363. (b) Gademann, K.;
Lawrence, A. K. Synthesis 2008, 331.
(6) Also see: Hsung, R. P.; Cole, K. P. In Strategies and Tactics in
Organic Synthesis; Harmata, M., Ed.; Elsevier Science/Pergamon Press:
Oxford, England, 2004; Vol. 4, pp 41ꢀ70.
(10) Sklenicka, H. M.; Hsung, R. P.; Wei, L.-L.; McLaughlin, M. J.;
Gerasyuto, A. I.; Degen, S. J.; Mulder, J. A. Org. Lett. 2000, 2, 1161.
(11) Sklenicka, H. M.; Hsung, R. P.; McLaughlin, M. J.; Wei, L.-L.;
Gerasyuto, A. I.; Brennessel, W. W. J. Am. Chem. Soc. 2002, 124, 10435.
(7) For leading reviews, see: (a) Tietze, L. F. Chem. Rev. 1996, 96, 115.
(b) Tietze, L. F.; Beifuss, U. Angew. Chem., Int. Ed. Engl. 1993, 32, 131.
(c) Tietze, L. F. J. Heterocycl. Chem. 1990, 27, 47.
r
10.1021/ol2017438
Published on Web 07/25/2011
2011 American Chemical Society

Scheme 1. Asymmetric Aza-[3 þ 3] Annulations
Scheme 2. Surprising Enantiomeric Inductionsa
1-azatrienes,13,14 developing a successful asymmetric var-
iant of this annulation had remained elusive.
a a All reactions were run in EtOAc [concn = 0.10 M] with 3.0 equiv
Na2SO4. b Isolated yields. c Determined by CSP-HPLC. d Time: 30 h. e
Time: 16 h.
In particular, the use of chiral amine salts15,16 has not
been effective because the Knoevenagel sequence mechan-
istically embodies a premature loss of the chiral amine
[HNR*2]; and thus, the stereochemical determining step
[the ring-closure of 3] is deprived of an asymmetric indu-
cing element in the absence of X* or R*. The intramole-
cular annulation [5f6] could be rendered asymmetric, as it
circumvents this predicament with the asymmetric induc-
tion likely occurring during an N-1,4-addition11,17 to chiral
vinyl iminium ion.18 To succeed in an asymmetric inter-
molecular annulation, we must develop either an N-1,
4-addition [7] or C-1,4-addition [8] pathway.
and CdN aligned]19 regiochemical orientation shown in
7 leading to 1,2-dihydropyridines 4, but the annulation
shown in 8 implies a reversal of regiochemistry in favor
of the rare head-to-tail orientation.20 We report herein
our success in developing an asymmetric intermolecular
aza-[3 þ 3] annulation due to an unexpected reversal of
regiochemistry.
Our keen interest in indolizidine, quinolizidine, and other
prevalent alkaloid scaffolds21,22 prompted the investigation
into both an intermolecular annulation using exo-cyclic
vinylogous amides and urethanes.23 We had found that
pyrrolidine-based exo-cyclic vinylogous amides and ur-
ethanes such as 1024 and 1125,26 underwent efficient aza-[3
þ 3] annulation promoted by amine salt 99c,11,18 to give the
reasonably presumed indolizidines 13 and 14, respectively
[Scheme 2]. Both 13 and 14 would represent a head-to-
head regiochemical orientation in the annulation.
The latter poses a challenge because our aza-annula-
tion has predominately given the head-to-head [CdO
(12) Sydorenko, N.; Hsung, R. P.; Vera, E. L. Org. Lett. 2006,
8, 2611.
(13) Forelegantworkinthisarea,see:(a)Tanaka,K.;Katsumura,S.J. Am.
Chem. Soc. 2002, 124, 9660. (b) Tanaka, K.; Mori, H.; Yamamoto, M.;
Katsumura, S. J. Org. Chem. 2001, 66, 3099. (c) Tanaka, K.; Kobayashi, T.;
Mori, H.; Katsumura, S. J. Org. Chem. 2004, 69, 5906.
(14) Okamura, W. H.; de Lera, A. R. In Comprehensive Organic
Synthesis; Trost, B. M., Fleming, I., Eds.; Paquette, L. A., Vol. Ed.; Pergamon
Press: New York, 1991; Vol. 5, pp 699ꢀ750.
(20) The Hickmott-Greenhill-Stille aza-annulation is exclusively
head-to-tail, see: (a) Hickmott, P. W.; Sheppard, G. J. Chem. Soc. C
1971, 2112. (b) Chaaban, J.; Greenhill, J. V.; Rauli, M. J. Chem. Soc.,
Perkin Trans. 1 1981, 3120. (c) Benovsky, P.; Stephenson, G. A.; Stille,
J. R. J. Am. Chem. Soc. 1998, 120, 2493. (c) Paulvannan, K.; Stille, J. R.
J. Org. Chem. 1992, 57, 5319.
(15) For seminal reviews, see: (a) Nielsen, M.; Worgull, D.; Zweifel,
T.; Gschwend, B.; Bertelsen, S.; Jørgensen, K. A. Chem. Commun. 2011,
47, 632. (b) Mukherjee, S.; Yang, J. W.; Hoffmann, S.; List, B. Chem.
€
Rev. 2007, 107, 5471. (c) Erkkila, A.; Majander, I.; Pihko, P. M. Chem.
(21) For leading reviews see: (a) Michael, J. P. Nat. Prod. Rep. 1999,
16, 675–697. (b) Michael, J. P. Nat. Prod. Rep. 2000, 17, 579. (c) Michael,
J. P. Nat. Prod. Rep. 2008, 25, 139 and references cited therein. (d) Jones,
T. H.; Gorman, J. S. T.; Snelling, R. R.; Delabie, J. H. C.; Blum, M. S.;
Garraffo, H. M.; Jain, P.; Daly, J. W.; Spande, T. F. J. Chem. Ecology
1999, 25, 1179.
(22) Also see: (a) Daly, J. W.; Garraffo, H. M.; Spande, T. F. The
Alkaloids: Amphibian Alkaloids; Cordell, G. A., Ed.; Academic Press: New
York, 1993; Vol. 43, p 185. (b) Ayer, W. A.; Trifonov, l. S. In Lycopodium
Alkaloids; Academic Press: San Diego, 1994. (c) Ma, X.; Gang, D. R. Nat.
Prod. Rep. 2004, 21, 752.
(23) Ghosh, S. K.; Buchanan, G. S.; Long, Q. A.; Wei, Y.; Al-Rashid,
Z. F.; Sklenicka, H. M.; Hsung, R. P. Tetrahedron 2008, 63, 883.
(24) (a) Pendrak, I.; Wittrock, R.; Kingsbury, W. D. J. Org. Chem.
1995, 60, 2912. (b) Cheng, Y.; Zhao, M.; Wang, M.-X.; Wang, L.-B.;
Huang, Z.-T. Synth. Commun. 1995, 25, 1339. (c) Park, K.-H.; Marshall,
W. J. J. Org. Chem. 2005, 70, 2075.
Rev. 2007, 107, 5416. For a review on proline-catalyzed asymmetric
reactions, see:(d) List, B. Tetrahedron 2002, 58, 5573. For a special
edition, see:(e) Acc. Chem. Res. 2004, 37, No. 8.
(16) For some seminal work, see: (a) Jen, W. S.; Wiener, J. J. M.;
MacMillan, D. W. C. J. Am. Chem. Soc. 2000, 122, 9874. (b) Ahrendt,
K. A.; Borths, C. J.; MacMillan, D. W. C. J. Am. Chem. Soc. 2000, 122,
4243. (c) Betancort, J. M.; Barbas, C. F., III Org. Lett. 2001, 3, 3737. (d)
List, B. J. Am. Chem. Soc. 2002, 124, 5656. (e) Alexakis, A.; Andrey, O.
Org. Lett. 2002, 4, 3611. (f) Melchiorre, P.; Jorgensen, K. A. J. Org.
Chem. 2003, 68, 4151. (g) Juhl, K.; Jørgensen, K. A. Angew. Chem., Int.
Ed. 2003, 42, 1498. (h) List, B.; Hoang, L.; Martin, H. J. Proc. Natl.
Acad. Sci. U.S.A. 2004, 101, 5839. (i) Yamamoto, Y.; Momiyama, N.;
Yamamoto, H. J. Am. Chem. Soc. 2004, 126, 5962. (j) Hayashi, Y.;
Yamaguchi, J.; Sumiya, T.; Shoji, M. Angew. Chem., Int. Ed. 2004, 43,
1112.
(17) Wei, L.-L.; Sklenicka, H. M.; Gerasyuto, A. I.; Hsung, R. P.
Angew. Chem., Int. Ed. 2001, 40, 1516.
(18) (a) Gerasyuto, A. I.; Hsung, R. P.; Sydorenko, N.; Slafer, B. W.
J. Org. Chem. 2005, 70, 4248. (b) Sydoreenko, N.; Zificsak, C. A.;
Gerasyuto, A. I.; Hsung, R. P. Org. Biomol. Chem. 2005, 3, 2140.
(19) For descriptions of head-to-head and head-to-tail regiochemis-
try, see: Sydorenko, N.; Hsung, R. P.; Darwish, O. S.; Hahn, J. M.; Liu,
J. J. Org. Chem. 2004, 69, 6732.
(25) (a) Lacroix, S.; Rixhon, V.; Marchand-Brynaert, J. Synthesis
2006, 2327–2334. (b) Shiosaki, K. The Eschenmoser Coupling Reaction,
Trost, B. M., Fleming, I., Eds.; Comprehensive Organic Synthesis;
Pergamon: Oxford, 1991; Vol. 2, p 865. (c) Pinnick, H. W.; Chang, Y.-
H. J. Org. Chem. 1978, 43, 4662.
(26) See Supporting Information.
Org. Lett., Vol. 13, No. 16, 2011
4403

Table 1. Optimization Employing Proline-Based Amine Saltsa
Scheme 3. Unexpected Reversal in Regiochemistry
entry amides: R = cat. [40 mol %]b product yield [%]c ee [%]d
1
2
3
4
5
6
7
8
9
11: R = OMe
11: R = OMe
10: R = Me
11: R = OMe
11: R = OMe
10: R = Me
10: R = Me
11: R = OMe
10: R = Me
20a
20b
20c
20d
20e
20e
20f
14
14
13
14
14
13
13
14
13
13
14
44
22
77
62
56
65
57
51
75
44
28
20
38
59
38
70
70
70
54
66
10
20
Subsequently, we pursued these annulations with a
number of chiral amines salts such as 15ꢀ16 in part to
examine the counteranion effect on the reaction rate. We
had found that these annulations proceed at ambient
temperature in good yields by employing trifluoroacetate
as the counteranion, instead of acetate or halides.18a
Serendipitously, it turned out that while the yields were
not particularly high, the products were found enantio-
merically enriched with reasonable ee when using Mac-
Millian’s chiral imidazolidinone salts 17 and 1815,16,27
[entries 3 and 4, Scheme 2]. We were very surprised by this
outcome, as we had believed that it was a head-to-head
regiochemical orientation as usual, and rationalized that
the low reaction temperature had preserved their optical
integrity.
Consequently, we attempted the racemization via a
sequence of ring-opening and ring-closure [Scheme 3],
which represents another major impediment to developing
asymmetric intermolecular aza-annulation, as 1,2-dihy-
dropyridines are prone to such ring-opening process even
at 50 °C.11 However, we found no racemization even after
heating 13 at 140 °C for 48 h! This outcome and later X-ray
assignment confirmed that 13 and 14 are in fact aza-[3 þ 3]
annulation products representing a rare head-to-tail regio-
chemical orientation.19
20g
20g
20h
20i
10 10: R = Me
11 11: R = OMe
a All reactions were run in EtOAc [concn = 0.10 M] with 1.4 equiv of
enal 12 and 3.0 equiv of Na2SO4. b The trifluoroacetate salts were all
generated in situ by addition of 40 mol % TFA to the reaction mixture.
c Isolated yields. d Determined by CSP-HPLC.
Table 1]. Overall, steric bulk of the R1 group on the
tertiary hydroxyl and of the aryl moiety appeared to be
critical for the asymmetric induction. Consequently,
catalysts 20e and 20g, asymmetric intermolecular
aza-[3 þ 3] annulations of exocyclic vinylogous amide
10, as well as urethanes 11 and 21 with a variety of enals
were examined [Table 2]. Most proceeded to give
indolizidines 27aꢀh in modest to good yields and
enantioselectivity.
To unambiguously determine both the regioselectivity
and stereochemistry of this annulation, we were left with
the only option of attaining an X-ray structure. To this
end, we synthesized chiral enal 28a from the acid of (S)-
naproxen and submitted it to our annulation conditions
with vinylogous amide 10 using either achiral catalyst 9
or chiral catalyst 20e. While the intent was to isolate
both diastereomers using 9 [56:44 see entry 1 in Table 3]
and separate them for submission to the crystallization
process, 29a and 29a00 were unfortunately very difficult
to separate.
Although chiral enals would give nonzero dr values,12,23
we observed a much enhanced diastereoselectivity of 11:1
for annulation product 29 when using chiral catalyst 20e
[Table 3, entry 2]; and that ratio was reversed when using
ent-20e [entry 3]. Another intriguing phenomenon was
seen from the annulations of chiral enals 28b [entries 4
and 5] and 28c [entries 6 and 7] in which the diastereose-
lective ratio was reversedwhenusing 9. While the high level
of amplification in the stereoselectivity of the annulation of
28a should be useful, the observed “matched” and “mis-
matched” cases suggest that the asymmetric induction is
dictated through the chiral amine.
Recognizing that this could prove to be an invaluable
entry to enantioselective synthesis of indolizidine alkaloids,21
we proceeded to examine various factors to optimize
this asymmetric reaction.28 We quickly found that
proline-based amines were more effective for asym-
metric annulation.18a Jørgensen’s catalysts15,16,29
20eꢀg with trifluoracetate as the counteranion pro-
vided the best enantiomeric excess [entries 5ꢀ7 in
(27) For some recent work, see: (a) Rendler, S.; MacMillan, D. W. C.
J. Am. Chem. Soc. 2010, 132, 5027. (b) Borths, C. J.; Carrera, D. E.;
MacMillan, D. W. C. Tetrahedron 2009, 65, 6746.
(28) Solvents have a noticeable effect on the enantioselectivity with
EtAOc being the best solvent. Reactions [concn = 0.10 M] were run with
10, 1.4 equiv of 12, 3.0 equiv of Na2SO4 and 40 mol % of amine catalyst
20e at RT for 3 h. Solvents were and the respective ee values evaluated
were: benzene [ee 58%]; EtOAc [ee 70%]; CH2Cl2 [ee 48%]; THF [ee
42%]; acetone [ee 26%]; EtOH [30].
(29) (a) Marigo, M.; Wabnitz, T. C.; Fielenbach, D.; Jørgensen,
ꢀ
K. A. Angew. Chem., Int. Ed. 2005, 44, 794. (b) Franzen, J.; Marigo,
M.; Fielenbach, D.; Wabnitz, T. C.; Kjærsgaard, A.; Jørgensen, K. A. J.
Am. Chem. Soc. 2005, 127, 18296. Also see:(c) Andersen, N. R.; Hansen,
S. G.; Bertelsen, S.; Jørgensen, K. A. Adv. Synth. Catal. 2009, 351, 3193.
The X-ray structure of 30 [hydrogenated 29a] allowed
us to unambiguously determine both the regioselectivity
4404
Org. Lett., Vol. 13, No. 16, 2011

Table 2. Scope of the Asymmetric Aza-Annulationa
Table 3. Amplified Diastereoselective Aza-[3 þ 3] Annulationa
a All reactions were run in EtOAc [concn = 0.10 M] with 1.4 equiv of
the respective chiral enal and 3 equiv of Na2SO4. b The TFA salt of 20e
was generated in situ by addition of 40 mol % TFA to the reaction
mixture. c The two diastereomers are inseparable. d Isolated yields.
e Ratios determined by crude 1H NMR. f Enal (2.8 equiv) was used.
a All reactions were run in EtOAc [concn = 0.10 M] with 1.4 equiv of
the respective enal, 3.0 equiv of Na2SO4 and 40 mol % of the amine
catalyst. The TFA salts were generated in situ by addition of 40 mol %
TFA to the reaction mixture. b Isolated yields. c Determined by CSP-
HPLC. d Observed in crude 1H NMR. e Not determined. f Inseparable by
CSP-HPLC.
and stereochemistry [Figure 1]. The matching of the
derivatives of 3026 with the major enantiomer of 27d led
to the assignment of its absolute configuration. Conse-
quently, a model for the asymmetric induction could be
reasonably proposed here, although a precise rationale
behind the stereoselectivity amplification when using chir-
al aldehydes remains unknown to us. In addition, while we
are not certain as to the reason for the regiochemical
divergence in the annulations of exo-cyclic versus endo-
cyclic vinylogous amides, exo-cyclic ones have behaved
precariously, leading to alternative and/or unexpected
reactions pathways.30 Nevertheless, we now finally pos-
sess a window for understanding how an asymmetric
intermolecular aza-[3 þ 3] annulation can be achieved.
We have described here the first successful enantioselective
aza-[3 þ 3] annulation of pyrrolidine-based exo-cyclic viny-
logous amides and urethanes with chiral vinyl iminium salts.
This asymmetric aza-annulation manifold is possible because
of an unexpected regiochemical reversal whereby head-to-tail
annulations dominated over the predicted head-to-head.
Further mechanistic understanding and applications in en-
antioselective synthesis of indolizidines are underway.
Figure 1. X-ray Structure of 30.
fellowship sponsored by Procter and Gamble Company.
H.D. thanks China Scholarship Council for a Visiting
Scholar Research Fellowship. We also thank Dr. Vic
Young of University of Minnesota for providing X-ray
structural data.
Acknowledgment. We thank the NIH [NS38049] for
financial support. G.S.B. thanks the AFPE for a
Supporting Information Available. Experimental pro-
cedures, X-ray data as well as NMR spectra and char-
acterizations. This material is available free of charge via
the Internet at http://pubs.acs.org.
(30) Piperidine-based exo-cyclic vinylogous amides and urethanes
surprisingly gave carbo-[3 þ 3] annulation products, leading to as
quinolines synthesis [see ref 23]. Azepane-based exo-cyclic vinylogous
amide gave 16% ee but very low yield in the annulation.
Org. Lett., Vol. 13, No. 16, 2011
4405