Torquoselective 6π-electron electrocyclic ring closure of 1-azatrienes containing acyclic chirality at the C-terminus

Article abstract of DOI:10.1021/ol060932t

Torquoselective pericyclic ring closures of 1-azatrienes that contain acyclic chirality at the C-terminus are described herein.

Full text of DOI:10.1021/ol060932t

ORGANIC
LETTERS
2006
Vol. 8, No. 12
2611-2614
Torquoselective 6π-Electron
Electrocyclic Ring Closure of
1-Azatrienes Containing Acyclic Chirality
at the C-Terminus
Nadiya Sydorenko, Richard P. Hsung,* and Eymi L. Vera
DiVision of Pharmaceutical Sciencies and Department of Chemistry, Rennebohm Hall,
777 Highland AVenue, UniVersity of Wisconsin, Madison, Wisconsin 53705-2222
rhsung@wisc.edu
Received April 17, 2006
ABSTRACT
Torquoselective pericyclic ring closures of 1-azatrienes that contain acyclic chirality at the C-terminus are described herein.
Pericyclic processes represent an important venue in organic
synthesis.We have been developing an aza-[3 + 3] annulation
reaction1-5 involving a Knoevenagel-type condensation of
the in situ generated iminium ions 1 with vinylogous amides
2 followed by a 6π-electron electrocyclic ring closure of
1-azatrienes 36,7 en route to 1,2-dihydropyridines 4 (Scheme
1). While this annulation has become an attractive strategy1,2
(1) For reviews, 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. (c) Coverdale, H. A.; Hsung, R. P. ChemTracts
2003, 16, 238.
Scheme 1
(2) For a review on vinylogous amide chemistry, see: Kucklander, U.
Enaminones as Synthons. In The Chemistry of Functional Groups: The
Chemistry of Enamines Part I; Rappoport, Z., Ed.; John Wiley & Sons:
New York, 1994; p 523.
(3) For recent studies in this area, see: (a) Shintani, R.; Hayashi, T. J.
Am. Chem. Soc. 2006, 128, ASAP. (b) Goodenough, K. M.; Raubo, P.;
Harrity, J. P. A. Org. Lett. 2005, 7, 2993. (c) Goodenough, K. M.; Moran,
W. J.; Raubo, P.; Harrity, J. P. A. J. Org. Chem. 2005, 70, 207. (d) Agami,
C.; Dechoux, L.; Hebbe, S.; Me´nard, C. Tetrahedron 2004, 60, 5433. (e)
Ji, S.-J.; Jiang, Z.-Q.; Lu, J.; Loh, T.-P. Synlett 2004, 831. (f) Zolfigol, M.
A.; Safaiee, M. Synlett 2004, 827. (g) Hedley, S. J.; Moran, W. J.; Price,
D. A.; Harrity, J. P. A. J. Org. Chem. 2003, 68, 4286. For interesting related
studies, see: (h) Hong, B.-C.; Gupta, A. K.; Wu, M.-F.; Liao, J.-H.; Lee,
G.-H. Org. Lett. 2003, 5, 1689 and references therein. (i) Hong, B. C.; Wu,
M. F.; Tseng, H. C.; Liao, J. H. Org. Lett. 2006, 8, ASAP.
(4) For our work on intermolecular aza-[3 + 3], see: (a) Sydorenko,
N.; Hsung R. P.; Darwish, O. S.; Hahn, J. M.; Liu, J. J. Org. Chem. 2004,
69, 6732. (b) McLaughlin, M. J.; Hsung, R. P.; Cole, K. C.; Hahn, J. M.;
Wang, J. Org. Lett. 2002, 4, 2017. (c) 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.
for constructing various nitrogen heterocycles, it provides a
unique opportunity to develop approaches toward a stereo-
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selective pericyclic ring closure of 1-azatrienes, leading to
chiral 1,2-dihydropyrindes. Such efforts have been largely
overlooked with the elegant exception of Tanaka and
Katsumura’s electrocyclic ring closure using chiral amines8
and our own report of a torquoselective ring closure of
1-azatrienes 5 employing a chiral auxiliary on the nitrogen
atom en route to 1-azadecalins 6.9 A more general and
practical approach remains elusive.10 We report here a
torquoselective11 pericyclic ring-closure of 1-azatrienes
containing acyclic chirality at the C-terminus.
To establish an initial level of torquoselectivity, we
prepared chiral R,â-unsaturated aldehydes 7-1112-15 and
employed them as precursors for generating 1-azatrienes
bearing chirality at the C-terminus through the aza-[3 + 3]
annulation reaction with N-benzyltetronamide 12 under
standard reaction conditions.4,9 The feasibility and stereose-
lectivity for their respective annulation reactions are sum-
marized in Table 1.16
ring closures of 1-azatrienes and diminish the annulation
yield.4b,9a
On the other hand, the annulation yields are good when
employing enal 7 and 10,17 and their stereoselectivities are
comparable with the respective dihydropyridines 13 and 16
possessing ratios of 76:24 and 75:25 (entries 1 and 4). The
reaction with the more bulky diphenyl acetonide enal 8 (entry
2) showed a notable decrease in selectivity for 14 (62:38)
relative to 13. Dihydropyridine 17 obtained from the reaction
with enal 11 was also formed with low diastereoselectivity.
In this case, the chirality in enal 11 is likely too remote from
the newly formed stereogenic center of 17 to be significant
for asymmetric induction, although it is still surprising to
still see any stereoinduction.
To unambiguously determine the stereochemical assign-
ment, dihydropyridine 13a was successfully dihydroxylated
to give diol 18 as a single diastereomer (Scheme 2).
Scheme 2
Table 1. Aza-[3 + 3] Annulations with N-Benzyltetronamide
Unfortunately, all attempts to grow a single crystal from 18
or its acetonide derivatives failed. Fortuitously, monohydro-
genation of the major isomer of 16 provided 19 that allowed
(5) For intramolecular aza-[3 + 3], see: (a) Swidorski, J. J.; Wang, J.;
Hsung R. P. Org. Lett. 2006, 8, 777. (b) Gerasyuto, A. I.; Hsung, R. P.;
Sydorenko, N.; Slafer, B. W. J. Org. Chem. 2005, 70, 4248. (c) Sydorenko,
N.; Zificsak, C. A.; Gerasyuto, A. I.; Hsung, R. P. Organic Biomol. Chem.
2005, 3, 2140. (d) Luo, S.; Zificsak, C. Z.; Hsung, R. P. Org. Lett. 2003,
5, 4709. (e) Wei, L.-L.; Sklenicka, H. M.; Gerasyuto, A. I.; Hsung, R. P.
Angew. Chem., Int. Ed. 2001, 40, 1516.
(6) For leading references on electrocyclic ring-closures involving
1-azatrienes, see: (a) Maynard, D. F.; Okamura, W. H. J. Org. Chem 1995,
60, 1763. (b) de Lera, A. R.; Reischl, W.; Okamura, W. H. J. Am. Chem.
Soc. 1989, 111, 4051. For an earlier account, see: (c) Oppolzer, V. W.
Angew. Chem. 1972, 22, 1108.
(7) For some recent studies of the ring-closure of azatrienes, see: (a)
Meketa, M. L.; Weinreb, S. M. Org. Lett. 2006, 8, 1443. (b) Alajar´ın, M.;
Ort´ın, M.-M.; Sa´nchez-Andrada, P.; Vidal, A.; Bautista, D. Org. Lett. 2005,
7, 5281.
a The iminium salt was generated using 1 equiv of piperidine and 1 equiv
of Ac2O at 85 °C for 1 h. b All reactions were carried out in EtOAc/toluene
(2:3) in a sealed tube for 24-72 h. c Isolated yields only. d Ratios determined
by 1H NMR. e Two diastereomers are inseparable. f Stereochemistry is
confirmed through the X-ray analysis of the corresponding derivative (see
Scheme 2).
(8) For recent elegant accounts on stereoselective ring-closure of
1-azatrienes, 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.
(9) a) 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.
(d) Wei, L.-L.; Hsung, R. P.; Xiong, H.; Mulder, J. A.; Nkansah, N. T.
Org. Lett. 1999, 1, 2145.
It was found that most of the diastereoselectivities are
modest with the best dr being 83:17 while employing chiral
enal 9 (entry 3). However, the yield for the annulation
product 15 was poor, and this is likely due to the steric
encumbrance of the N-Boc group. It is consistent with our
earlier finding that bulky â-substituents of enals can hinder
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Org. Lett., Vol. 8, No. 12, 2006

us to obtain X-ray quality crystals. The X-ray structure of
19 reveals the assignment for the major isomer of 16 to be
S for the new stereocenter. The absolute stereochemistry of
cycloadducts 13-15, 17, and 23-29 were assigned by
comparison to 16.
Other examples of such a stereoselective approach to
pericyclic ring closure of 1-azatrienes are shown in Table
2.18 It was found that the best stereoselectivity was obtained
Similarly, annulations of amides 20-22 with the iminium
salt derived from enal 11 proceeded in a rather stereorandom
manner (entries 3, 5, and 7).
While these ratios are modest, it provides an opportunity
to examine this ring closure more closely from a mechanistic
perspective. It is not obvious that one should expect any
diastereomeric induction during the ring-closure step of the
aza-[3 + 3] annulation given the high degree of conforma-
tional freedom of the chirality at the C-terminus of these
1-azatrienes. Toward this end, we proposed a model based
on a potential rotational preference to rationalize observed
torquoselectivity.
Table 2. Variations in the Amides
As shown in Scheme 3, there are two predominant con-
formations, 30A and 30B, with both minimizing allyl strains
Scheme 3
by placing the largest RL group at the allylic position in the
plane of the C-terminus vinyl strand. While both can undergo
ring-closure, simple molecular modeling reveals that 1-aza-
triene 30A could have an advantage over 30B given the
remote steric interaction (in green) between the N-Bn group
and the C-terminus allylic substituent. With 1-azatriene 30A
as the preferred conformation, a disrotatory ring closure in
the direction a (in red) should be favored to give the observed
major isomer because the direction b (in blue) would bring
the RL group (dotted arrow in blue) into closer contact with
the N-Bn group.
a The iminium salt was generated using 1 equiv of piperidine and 1 equiv
of Ac2O at 85 °C for 1 h. b The iminium salt was generated using 1 equiv
of piperidine trifluoroacetate salt at 85 °C for 1 h. c All reactions were carried
out in EtOAc/toluene (2:3) in a sealed tube for 24-72 h. d Isolated yields
only. e Ratios determined by 1H NMR. f The two diastereomers are insepa-
rable.
With this model in mind, we should note that 6π-electron
electrocyclic ring-closure can be reversible,19,20 especially
at high temperatures, leading to ratios reflecting thermody-
namic stabilities of the two diastereomeric isomers. We did
from the reactions of the iminium salt derived from enal 10,
which gave dihydropyridines 24, 26, and 28 with ratios of
77:23, 69:31, and 83:17, respectively (entries 2, 4, and 6).
(10) For a review on rotational preferences leading to diastereomeric
induction during a 6π-electron electrocyclic ring closure, see: Okamura,
W. H.; de Lera, A. R. ComprehensiVe Organic Synthesis; Trost, B. M.,
Fleming, I., Eds.; Paquette, L. A., Vol. Ed.; Pergamon Press: New York,
1991; Vol. 5, pp 699-750.
(11) For some examples of torquoselective processes, see: (a) Harmata,
M.; Lee, D. R.; Barnes, C. L. Org. Lett. 2005, 7, 1881. (b) Harmata, M.;
Schreiner, P. R.; Lee, D. R.; Kirchhoefer, P. L. J. Am. Chem. Soc. 2004,
126, 10954. (c) Murakami, M.; Hasegawa, M.; Igawa, H. J. Org. Chem.
2004, 69, 587. (d) Murakami, M.; Miyamoto, Y.; Ito, Y. Angew. Chem.,
Int. Ed. 2001, 40, 189. (e) Murakami, M.; Miyamoto, Y.; Ito, Y. J. Am.
Chem. Soc. 2001, 123, 6441. (f) Giese, S.; Kastrup, L.; Stiens, D.; West, F.
G. Angew. Chem., Int. Ed. Engl. 2000, 39, 1970.
(12) (a) Earle, M. J.; Abdur-Rashid, A.; Priestley, N. J. Org. Chem. 1996,
61, 5697. (b) Brown, J. M.; Leppard, S. J.; Oakes, J.; Thornthwaite, D.
Chirality 2000, 12, 496.
(13) (a) Campbell, A. D.; Raynham, T. M., Taylor, R. J. K Synthesis
1998, 12, 1707. (b) Zhang, X.; Ni, W.; van der Donk, W. A. J. Org. Chem.
2005, 70, 6685.
(14) Gonzales, F.; Lesage, S.; Perlin, A. S. Carbohydr. Res. 1975, 42,
267.
(15) Castaldi, G.; Cavicchioli, S.; Giordano, C.; Uggeri, F. J. Org. Chem.
1987, 52, 3018.
(16) See the Supporting Information.
(17) For a study employing enal 10 in oxa-[3 + 3] annulations with
4-hydroxy-2-pyrones, see: Sagar, R.; Singh, P.; Kumar, R.; Maulik, P. R.;
Shaw, A. K. Carbohydr. Res. 2005, 340, 1287.
(18) Despite our efforts, we were not able to render the reaction of 7 to
proceed feasibly with either aminopyrone 21 or amide 22.
(19) For a review on rotational preferences leading to diastereomeric
induction during a 6π-electron electrocyclic ring closure, see: 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 699-750.
(20) For a recent computational study, see: Cabaleiro-Lago, E. M.;
Rodr´ıguez-Otero, J.; Santiago M. Varela-Varela, S. M.; Pena˜-Gallego, A.;
Hermida-Ramon, J. M. J. Org. Chem. 2005, 70, 3921.
Org. Lett., Vol. 8, No. 12, 2006
2613

carry out relevant equilibration experiments employing 13
or 16 with a starting ratio of 1:1 and found that the respective
ratios reported in Table 1 (entries 1 and 4) could be reached
ultimately but at temperatures higher than (∼250 °C) the
reaction temperature.21 This suggests that equilibration under
the reaction conditions can play a role in the selectivity but
it is likely not the only factor. Thus, the aforementioned
rotational preference in the proposed model remains a
possible rationale.
The second assertion is already consistent with the fact
that amide 22 provided a higher dr in 28 (entry 6 of Table
2) than N-benzyltetronamide 12 that gave 16 (entry 4 of
Table 1). The larger internal angle of the six-membered ring
shown in 1-azatriene 36B (see Scheme 5) should lead to an
Scheme 5
By examining our model more closely, it reveals two
interesting factors. First, the size of the nitrogen substituent
should influence the rotational preference with the larger
substituent providing higher dr. Second, a greater A1,3-strain
interaction (see 30B: in red) may also enhance the selectivity
because it can push the nitrogen substituent closer toward
the C-terminus allylic fragment, thereby further favoring both
the conformation 30A and a disrotatory ring-closure in the
direction a. Based on these two assertions, we pursued the
following studies to further support our proposed model.
As shown in Scheme 4, tetronamides 32 and 3422 were
prepared and reacted with the chiral iminium salt 31
enhanced allylic strain (in red) relative to 30B (in Scheme
3) and an enhanced interaction between the N-Bn group and
allylic fragment (in green). As suggested above, these
enhancements collectively can further favor a disrotatory ring
closure in the direction a through the conformation 36A (not
shown but respective to 36B), thereby giving 28 in higher
dr than 16.
Scheme 4
With this analysis, to put it altogether, an N-diphenyl-
methyl group as shown in 37 should provide an even
higher torquoselectivity via ring-closure in the direction a
through the conformation 37A (Scheme 5). This predic-
tion was confirmed with the reaction of amide 38, which
provided dihydropyridine 39 with the highest torquoselec-
tivity (92:8).
We have described here a torquoselective ring closure of
1-azatrienes containing acyclic chirality at the C-terminus,
which represents an unexplored venue for stereochemical
control of this pericyclic process.
(generated from 10). As predicted above, with a much bulkier
N-diphenylmethyl group (in green), tetronamide 32 provided
the cycloadducts 33a and 33b with an improved ratio of 87:
13 from that of 16, although the yield was lower. At the
same time, with a smaller N-methyl group (in green), tetron-
amide 34 gave the corresponding annulation products 35a
and 35b at much higher yield (82%) but with a noticeable
loss of stereoselectivity (63:37). These two experiments are
in agreement with the first suggested assertion.
Acknowledgment. We thank the NIH (N.S.38049) and
the School of Pharmacy and The Comprehensive Cancer
Center at UWsMadison for funding and Mr. Benjiman E.
Kucera and Dr. Vic Young from the University of Minnesota
for providing X-ray structural analysis. E.L.V. thanks UMN
for a Heisig Fellowship. This work was carried out in part
at University of Minnesota.
Supporting Information Available: Experimental de-
tails, NMR spectral characterization data for all new com-
pounds, as well as X-ray structrural data. This material is
available free of charge via the Internet at http://pubs.acs.org.
(21) Theoretical calculations using SPARTAN-′02 at B3LYP/6-31G*
level were neither conclusive nor consistent as to which diastereomeric
isomer is more stable energetically.
(22) (a) Greenhill, J. V.; Tomassini, T. Tetrahedron Lett. 1974, 31, 2683.
(b) Shandala, M. Y.; Ayoub, M. T.; Mohammad, M. J. J. Heterocycl. Chem.
1984, 21, 1753.
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