Highly stereoselective [4 + 3] cycloadditions of nitrogen-stabilized oxyallyl cations with pyrroles. An approach to parvineostemonine

Article abstract of DOI:10.1021/ol070103n

Figure presented A highly stereoselective [4 + 3] cycloaddition of N-substituted pyrroles with allenamide-derived nitrogen-stabilized chiral oxyallyl cations is described here. This method provides an approach for constructing tropinone alkaloids.

Full text of DOI:10.1021/ol070103n

ORGANIC
LETTERS
2007
Vol. 9, No. 7
1275-1278
Highly Stereoselective [4
+ 3]
Cycloadditions of Nitrogen-Stabilized
Oxyallyl Cations with Pyrroles. An
Approach to Parvineostemonine†
Jennifer E. Antoline, Richard P. Hsung,* Jian Huang, Zhenlei Song, and Gang Li
DiVision of Pharmaceutical Sciences and Department of Chemistry,
UniVersity of Wisconsin, Madison, Rennebohm Hall, 777 Highland AVenue,
Madison, Wisconsin 53705
rhsung@wisc.edu
Received January 14, 2007
ABSTRACT
A highly stereoselective [4
+ 3] cycloaddition of N-substituted pyrroles with allenamide-derived nitrogen-stabilized chiral oxyallyl cations is
described here. This method provides an approach for constructing tropinone alkaloids.
Heteroatom-substituted oxyallyl cations have emerged as
the most effective 1,3-dipoles in [4 + 3] cycloadditions.1-5
In our active efforts to develop methods employing
allenamides,6-9 we have demonstrated that nitrogen-stabilized
chiral oxyallyl cations 2b derived from epoxidations of
allenamides 1 can undergo highly diastereoselective inter-10
and intramolecular11 [4 + 3] cycloadditions with dienes
(Scheme 1). Given that achieving highly stereoselective
† With deepest respect and appreciation, this paper is dedicated to
Professor Gilbert Stork on the special occasion of his 85th birthday.
(1) For excellent reviews on heteroatom-substituted oxyallyl cations,
see: (a) Harmata, M. AdV. Synth. Catal. 2006, 348, 2297. (b) Harmata, M.
Recent Res. DeV. Org. Chem. 1997, 1, 523.
(2) For general reviews, see: (a) Hartung, I. V.; Hoffmann, H. M. R.
Angew. Chem., Int. Ed. 2004, 43, 1934. (b) Harmata, M.; Rashatasakhon,
P. Tetrahedron 2003, 59, 2371. (c) Harmata, M. Acc. Chem. Res. 2001,
34, 595. Also see: (d) Davies, H. M. L. In AdVances in Cycloaddition;
Harmata, M., Ed.; JAI Press: Greenwich, 1998; Vol. 5, p 119. (e) West, F.
G. In AdVances in Cycloaddition; Lautens, M., Ed.; JAI: Greenwich, 1997;
Vol. 4, p 1. (f) Rigby, J. H.; Pigge, F. C. Org. React. 1997, 51, 351. (g)
Harmata, M. Tetrahedron 1997, 53, 6235.
(5) For some examples of other heteroaton-substituted oxyallyl cations,
see: (a) Harmata, M.; Wacharasindhu, S. Org. Lett. 2005, 7, 2563. (b) Sa´ez,
J. A.; Arno´, M.; Domingo, L. R. Tetrahedron 2005, 61, 7538. (c) Harmata,
M.; Kahraman, M.; Adenu, G.; Barnes, C. L. Heterocycles 2004, 62, 583.
(d) Sa´ez, J. A.; Arno´, M.; Domingo, L. R. Org. Lett. 2003, 5, 4117. (e)
Funk, R. L.; Aungst, R. A. Org. Lett. 2001, 3, 3553. (f) Harmata, M.;
Sharma, U. Org. Lett. 2000, 2, 2703. (g) Lee, K.; Cha, J. K. Org. Lett.
1999, 1, 523. (h) Masuya, K.; Domon, K.; Tanino, K.; Kuwajima, I. J. Am.
Chem. Soc. 1998, 120, 1724. (i) Harmata, M.; Elomari, S.; Barnes, C. J. J.
Am. Chem. Soc. 1996, 118, 2860 and references cited therein.
(3) For examples of nitrogen-stabilized oxyallyl cations in [4 + 3]
cycloadditions, see: (a) MaGee, D. I.; Godineau, E.; Thornton, P. D.;
Walters, M. A.; Sponholtz, D. J. Eur. J. Org. Chem. 2006, 3667. Also see:
(b) Walters, M. A.; Arcand, H. R.; Lawrie, D. J. Tetrahedron Lett. 1995,
36, 23. (c) Walters, M. A.; Arcand, H. R. J. Org. Chem. 1996, 61, 1478.
(4) Also see: (a) Myers, A. G.; Barbay, J. K. Org. Lett. 2001, 3, 425.
(b) Sung, M. J.; Lee, H. I.; Chong, Y.; Cha, J. K. Org. Lett. 1999, 1, 2017.
(c) Dennis, N.; Ibrahim, B.; Katritzky, A. R. J. Chem. Soc., Perkin Trans.
1 1976, 2307.
(6) For a compendium on the chemistry of allenes, see: Krause, N.;
Hashmi, A. S. K. Modern Allene Chemistry; Wiley-VCH Verlag GmbH &
Co. KGaA: Weinheim, Germany, 2004; Vols. 1 and 2.
(7) For reviews on the chemistry and synthesis of allenamides, see: (a)
Hsung, R. P.; Wei, L.-L.; Xiong, H. Acc. Chem. Res. 2003, 36, 773. (b)
Tracey, M. R.; Hsung, R. P.; Antoline, J.; Kurtz, K. C. M.; Shen, L.; Slafer,
B. W.; Zhang, Y. In Science of Synthesis, Houben-Weyl Methods of
Molecular Transformations; Weinreb, S. M., Ed.; Georg Thieme Verlag
KG: Stuttgart, 2005; Chapter 21.4.
10.1021/ol070103n CCC: $37.00
© 2007 American Chemical Society
Published on Web 03/03/2007

Scheme 1. [4 + 3] Cylcoadditions with Pyrroles
Table 1. Feasibility of the Pyrrole-[4 + 3] Cycloaddition
a Isolated yields or decompositions of the starting allenamide and
1
pyrroles. b Ratios determined by H and/or 13C NMR.
[4 + 3] cycloadditions represents a significant challenge, it
has continued to attract elegant synthetic efforts,1-2,12 and
nitrogen-substituted oxyallyl cations3,4,10,11 have proven to
be a unique design in this endeavor, as evident in the fact
that Harmata’s13 and our own14 offer to date the only
asymmetric variant of this powerful cycloaddition.12j
Despite our preliminary success, pyrroles remained pre-
carious as a suitable diene. Pyrroles in general behave as a
poor diene in cycloadditions due to competing retro-
cycloaddition to regain its aromaticity, and as a result, efforts
in this aspect of [4 + 3] cycloaddition have remained scarce
with a few elegant exceptions.15 Therefore, success in this
endeavor would constitute a highly stereoselective entry to
tropinone alkaloids (see 5). We report here a highly stereo-
selective [4 + 3] cycloaddition of nitrogen-stabilized chiral
oxyallyl cations with N-substituted pyrroles as an approach
to parvineostemonine.
in Table 1. The key elements to our ultimate success are the
following: (1) The pyrrole needs to be substituted with an
electron-withdrawing group such as Boc [entry 4] or Bz
[entry 5] to avoid unwanted oxidation by DMDO, (2) the
reaction proceeds better at -45 °C likely due to the fact
that it is the temperature at which the epoxidation of
allenamides occurs optimally,16 and (3) DMDO needs to be
added via a syringe pump to improve the chemoselectivity
of the epoxidation in favor of the allenamide over pyrrole.
Under these conditions, cycloadducts 7 and 817 were
isolated in 76% and 86% yields, respectively, with isomeric
ratios of 82:18 [entry 4] and 83:17 [entry 5]. However, we
recognized that in comparison with respective cycloadditions
using furan and cyclopentadiene,10 the observed diastereo-
meric ratio here was even lower than when using 2.0 equiv
of ZnCl2.10
To improve the diastereoselectivity, we examined a range
of chiral auxiliaries as shown in Figure 1. It appears that the
Evans type auxiliaries18 (see cycloadducts 9 and 11) and
Sibi’s auxiliary19 (see cycloadduct 10) provided modest to
poor ratios, whereas the Seebach’s auxiliary20 and the
(1R,2S)-(+)-2-amino 1,2-diphenylethanol derived oxazoli-
dinone auxiliary appeared to be the best, leading to cycload-
ducts 12 (also see 14 with the MeOCO N-substitution) and
We were able to establish the feasibility of [4 + 3]
cycloadditions of nitrogen-stabilized chiral oxyallyl cations
with pyrroles via employing chiral allenamide 6 as shown
(8) For our recent efforts, see: (a) Huang, J.; Ianni, J. C.; Antoline, J.
E.; Hsung, R. P.; Kozlowski, M. C. Org. Lett. 2006, 8, 1565. (b) Berry, C.
R.; Hsung, R. P.; Antoline, J. E.; Petersen, M. E.; Rameshkumar, C.;
Nielson, J. A. J. Org. Chem. 2005, 70, 4038. (c) Shen, L.; Hsung, R. P.;
Zhang, Y.; Antoline, J. E.; Zhang, X. Org. Lett. 2005, 7, 3081.
(9) For recent reports on the allenamide chemistry, see: (a) Parthasarathy,
K.; Jeganmohan, M.; Cheng, C.-H. Org. Lett. 2006, 8, 621. (b) Fena´ndez,
I.; Monterde, M. I.; Plumet, J. Tetrahedron Lett. 2005, 46, 6029. (c) de los
Rios, C.; Hegedus, L. S. J. Org. Chem. 2005, 70, 6541. (d) Alouane, N.;
Bernaud, F.; Marrot, J.; Vrancken, E.; Mangeney, P. Org. Lett. 2005, 7,
5797.
(10) Xiong, H.; Hsung, R. P.; Berry, C. R.; Rameshkumar, C. J. Am.
Chem. Soc. 2001, 123, 7174.
(11) (a) Xiong, H.; Huang, J.; Ghosh, S. K.; Hsung, R. P. J. Am. Chem.
Soc. 2003, 125, 12694. (b) Rameshkumar, C.; Hsung, R. P. Angew. Chem.,
Int. Ed. 2004, 43, 615.
(15) (a) For an elegant equivalent of pyrrole-[4 + 3] cycloaddition via
a tandem cyclopropanation/Cope rearrangement en rout to tropinones, see:
Davies, H. M. L.; Matasi, J. J.; Hodges, L. M.; Huby, N. J. S.; Thornley,
C.; Kong, N.; Houser, J. H. J. Org. Chem. 1997, 62, 1095. (b) For our
preliminary communication, see: Abstracts of Papers, 231st ACS National
Meeting of the American Chemical Society, Atlanta, GA, Spring 2006;
American Chemical Society: Washington, DC, 2006; Abstract No. ORGN-
192. During our efforts, MaGee and Walters reported one example of
pyrrole-[4 + 3] cycloaddition employing nitrogen-stabilized oxyallyl cations
derived from R-bromo-R-amido ketones, although the yield was low [see
ref 3a].
(16) Rameshkumar, C.; Xiong, H.; Tracey, M. R.; Berry, C. R.; Yao, L.
J.; Hsung, R. P. J. Org. Chem. 2002, 67, 1339.
(17) See the Supporting Information. Also although not specifically
described in the text, the oxazolidinone auxiliary could be removed by using
SmI2 [see the Supporting Information].
(12) For recent stereoselective attempts, see: (a) Davies, H. M. L.; Dai,
X. J. Am. Chem. Soc. 2004, 126, 2693. (b) Prie´, G.; Pre´vost, N.; Twin, H.;
Fernandes, S. A.; Hayes, J. F.; Shipman, M. Angew. Chem., Int. Ed. 2004,
43, 6517. (c) Grainger, R. S.; Owoare, R. B.; Tisselli, P.; Steed, J. W. J.
Org. Chem. 2003, 68, 7899. (d) Montana˜, A. M.; Grima, P. M. Tetrahedron
2002, 58, 4769. (e) Beck, H.; Stark, C. B. W.; Hoffman, H. M. R. Org.
Lett. 2000, 2, 883 and ref 11 cited therein. (f) Cho, S. Y.; Lee, J. C.; Cha,
J. K. J. Org. Chem. 1999, 64, 3394. (g) Harmata, M.; Jones, D. E.;
Kahraman, M.; Sharma, U.; Barnes, C. L. Tetrahedron Lett. 1999, 40, 1831.
(h) Kende, A. S.; Huang, H. Tetrahedron Lett. 1997, 38, 3353. (i) Harmata,
M.; Jones, D. E. J. Org. Chem. 1997, 62, 4885. For a recent account that
constitutes an enatioselective formal [4 + 3] cycloaddition, see: (j) Dai,
X.; Davies, H. M. L. AdV. Synth. Catal. 2006, 348, 2449.
(18) (a) Evans, D. A. Aldrichim. Acta 1982, 15, 23. (b) Heathcock, C.
H. Aldrichim. Acta 1990, 23, 99.
(19) For a leading reference, see: Sibi, M. P.; Porter, N. A. Acc. Chem.
Res. 1999, 32, 163.
(13) Harmata, M.; Ghosh, S. K.; Hong, X.; Wacharasindu, S.; Kirch-
hoefer, P. J. Am. Chem. Soc. 2003, 125, 2058.
(14) Huang, J.; Hsung, R. P. J. Am. Chem. Soc. 2005, 127, 50.
(20) For a leading reference, see: Hintermann, T.; Seebach, D. HelV.
Chim. Acta 1998, 81, 2093.
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Org. Lett., Vol. 9, No. 7, 2007

Scheme 2. Functionalization of the Pyrrole-[4 + 3]
Cycloadduct
Figure 1. Product chart.
group afforded allyl amine 21 as a highly crystalline material
that was suitable for X-ray analysis. Single-crystal X-ray
structure of 21 (Figure 2) confirmed stereochemically that
13, respectively, in good yields essentially as single diaster-
eomers. This is unexpected as all three types of auxiliaries
led to high diastereoselectivities in the cycloadditions of furan
especially when applying 2.0 equiv of ZnCl2.10 We are not
certain of the reason behind this difference between cycload-
ditions of pyrrole and furan.
Finally, although Close’s auxiliary21 led to lower yields
(likely due to stability of the respective allenamide), it also
provided high diastereoselectivity (Figure 1). In addition, we
were able to establish that both antipodes of the cycloadduct
15 could be attained through the usage of both enantiomers
of the auxiliary.
Establishing the stereochemical assignment for these
cycloadducts proved to be a real challenge. We had to
embark on a series of transformations to identify crystalline
materials suitable for X-ray analysis. For example, depro-
tonation of hydrogenated cycloadduct 13 with LDA followed
by additions of electrophilic reagents such as methyl
R-bromoacetate16a and methyl chloroformate16b led to ester
17 and â-ketoester 18 in good yields as single diastereomers
(Scheme 2). Unfortunately, neither was crystalline.
Consequently, a stereoselective DIBAL-H reduction of 13
provided alcohol 19 in 98% yield, and this in turn allowed
us to remove the Boc group en route to amine 20. Attempts
to remove the Boc group under various acidic conditions
without first reducing the ketone led to retro-Mannich
fragmentation.22 Finally, capping of amine 20 with an allyl
Figure 2. X-ray sturcture of allyl amine 21.
our pyrrole-[4 + 3] cycloadditions are endo-selective in favor
of the endo products as shown. Therefore, the mechanistic
origin of diastereoselectivity should be similar to that
proposed for cycloadditions of furan and cyclopentadiene
(see 3 f 4 in Scheme 1).10
Our efforts in trying to establish the stereochemical
assignment directed our focus to potential applications of
these new tropinones as chiral templates. Specifically, we
explored a synthetic sequence en route to the aza-tricyclic
core of a new stemona alkaloid parvineostemonine (Scheme
3), featuring a ring-closing metathesis.23 Parvineostemonine
was found by Ye and co-workers from Stemona parViflora
gathered in the Hainan Province of China and used as
traditional Chinese medicine for treatment of coughing and
also as insecticides.24 While parvineostemonine contains a
(21) Close, W. J. J. Org. Chem. 1950, 15, 1131.
(22) Acidic conditions used to remove the Boc group led to pyrrole ii
via a retro-Mannich fragmentation followed by re-aromatization of the
iminium intermediate i. This in essence represents an equivalent of the Type-
III cycloadduct or R-arylation of a methyl ketone. For a recent elegant
account related to this fragmentation, see: Cramer, N.; Juretschke, J.;
Laschat, S.; Baro, A.; Frey, W. Eur. J. Org. Chem. 2004, 1397.
(23) For recent reviews on RCM, see: (a) Trnka, T. M.; Grubbs, R. H.
Acc. Chem. Res. 2001, 34, 18. (b) Walters, M. A. In Prog. Heterocycl.
Chem. 2003, 15, 1. (c) Deiters, A.; Martin, S. F. Chem. Rev. 2004, 104,
2199. (d) McReynolds, M. D.; Dougherty, J. M.; Hanson, P. R. Chem. Rev.
2004, 104, 2239. (e) Wallace, D. J. Angew. Chem., Int. Ed. 2005, 44, 1912.
Org. Lett., Vol. 9, No. 7, 2007
1277

noteworthy that the acid-catalyzed retro-Mannich22 fragmen-
tation does not occur when the olefin is first hydrogenated.
A standard N-allylation gave allyl amine 23, and a subsequent
allylation of the lithium enolate generated from 23 led to
diene 24. Although this alkylation regiochemically compli-
ments our earlier work (see Scheme 2), we are not certain
as to the origin of this change of regioselectivity. Subjecting
diene 24 to ring-closing metathesis conditions employing
Grubbs’ Gen-I catalyst23 led to 25 containing the aza-tricyclic
core of parvineostemonine.
Scheme 3. A RCM Approach to Parvineostemonine
We have described here a highly stereoselective [4 + 3]
cycloaddition of N-substituted pyrroles with allenamide-
derived nitrogen-stabilized chiral oxyallyl cations and dem-
onstrated that this cycloaddition method could serve as an
approach toward parvineostemonine.
Acknowledgment. The authors thank NIH-NIGMS
[GM066055] and UW-Madison for financial support. The
authors also thank Dr. Vic Young’s [University of Min-
nesota] valiant efforts in obtaining and providing X-ray
structural information. Finally, the authors acknowledge
ChemMatCARS for attempts at obtaining a single-crystal
X-ray structure. ChemMatCARS Sector 15 is principally
supported by NSF/DOE under grant no. CHE0087817 and
by the Illinois board of higher education.
basic skeleton similar to other known stemona alkaloids,25,26
it is unique as the bridging nitrogen atom is part of the
7-membered B-ring.
Hydrogenation of cycloadduct 13 followed by Boc-
removal led to amine 22 in good yields (Scheme 3). It is
(24) Isolations: Ke, C. Q.; He, Z. S.; Yang, Y. P.; Ye, Y. Chin. Chem.
Lett. 2003, 14, 173.
(25) For an excellent review, see: Pilli, R. A.; Oliveria, M. C. F. Nat.
Prod. Rep. 2000, 17, 117.
Supporting Information Available: Experimental and
1H NMR spectra and characterizations for all new compounds
as well as X-ray structrural data. This material is available
free of charge via the Internet at http://pubs.acs.org.
(26) (a) Chen, C. Y.; Hart, D. J. J. Org. Chem. 1990, 55, 6236. (b) Wipf,
P.; Kim, Y.; Goldstein, D. M. J. Am. Chem. Soc. 1995, 117, 11106. (c)
Martin, S. F.; Barr, K. J.; Smith, D. W.; Bur, S. K. J. Am. Chem. Soc.
1999, 121, 6990. (d) Kende, A. S.; Martin Hernando, J. I.; Milbank, J. B.
J. Org. Lett. 2001, 3, 2505. (e) Ginn, J. D.; Padwa, A. Org. Lett. 2002, 4,
1515. (f) Olivo, H. F.; Tovar-Miranda, R.; Barragan, E. J. Org. Chem. 2006,
71, 3287.
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