ORGANIC
LETTERS
2012
Vol. 14, No. 14
3592–3595
3,4-Dihydroxypyrrolidines via Modified
Tandem Aza-Payne/Hydroamination Pathway
Aman Kulshrestha, Nastaran Salehi Marzijarani, Kumar Dilip Ashtekar,
Richard Staples, and Babak Borhan*
Department of Chemistry, Michigan State University, East Lansing, Michigan 48824,
United States
Received May 2, 2012
ABSTRACT
The outcome of a tandem aza-Payne/hydroamination reaction is modified via the use of a latent nucleophile. The latter initially serves as an
electrophile to intercept the aziridine alkoxide and afterward turns into a nucleophile thereby performing the aziridine ring opening, out competing
the intramolecular aza-Payne pathway. Subsequent hydroamination in the same pot provides N-Ts enamide carbonates, which can be easily
converted into biologically significant 3,4-dihydroxylactams.
Polyhydroxylated alkaloids constitute the skeletal frame-
work of several important iminosugars and a number of
natural products.1 They mimic the structures of monosac-
charides, and their exceptional biological activity as gly-
cosidase inhibitors makes them one of the most attractive
classes of carbohydrate mimics reported so far.2
Motivated by both their biological significance and our
synthetic interest, we have focused on the diastereoselec-
tive assembly and functionalization of heterocycles that
possess the latter structural motif.3 A tandem aza-Payne/
hydroamination methodology was recently reported that
yields densely decorated pyrrolidines.3b The protocol in-
volves the deprotonation of a stereodefined aziridine
alcohol 1a (syn-aziridinols are obtained efficiently and in
high stereoselectivity)4 followed by an aza-Payne rearran-
gement of the resulting alkoxide intermediate 2a yielding
an epoxy N-Ts amide intermediate 3a (Figure 1a). The
latter readily undergoes a 5-exo-dig ring closure to yield the
tetrasubstituted pyrrolidine 4a.3b Synthetic elaborations
on the latter toward complex and advanced level inter-
mediates are currently underway. Nonetheless, our interest
in further exploiting the aza-Payne/hydroamination path-
way in a manner to increase diversity in structure, particularly
in light of our interest to gain access to polyhydroxylated
motifs, led us to explore the reaction manifold.1,5
We began our investigation with a plan of intercepting
the aza-Payne intermediate 2a with a latent nucleophile to
alter the outcome of the subsequent hydroamination reac-
tion. Aziridine ring opening with a modified nucleophile
would then lead to enamide compounds embellished with
functionalities of different natures. Figure 1a illustrates
our proposal that relies on the use of CO2 as a latent
nucleophile. We anticipated that CO2 would initially serve
as an electrophile to affect the carboxylation of the alk-
oxide intermediate, thereby introducing instead a carbo-
nate nucleophile to carry out the aziridine ring opening.
Ensuing 5-exo-ring closure would then deliver the functio-
nalized enamide carbonate product containing the masked
dihydroxylated unit 6a.6
(1) Ferla, B. L.; Cipolla, L.; Nicotra, F. General Strategies for the
Synthesis of Iminosugars and New Approaches Towards Iminosugar
Libraries; John Wiley & Sons, Ltd.: 2008.
(2) (a) Asano, N.; Nash, R. J.; Molyneux, R. J.; Fleet, G. W. J.
Tetrahedron: Asymmetry 2000, 11, 1645. (b) Lee, R. E.; Smith, M. D.;
Nash, R. J.; Griffiths, R. C.; McNeil, M.; Grewal, R. K.; Yan, W.; Besra,
G. S.; Brennan, P. J.; Fleet, G. W. J. Tetrahedron Lett. 1997, 38, 6733.
(c) Compain, P.; Martin, O. R. Iminosugars: Past, Present and Future;
John Wiley & Sons, Ltd.: 2008.
(3) (a) Schomaker, J. M.; Bhattacharjee, S.; Yan, J.; Borhan, B.
J. Am. Chem. Soc. 2007, 129, 1996. (b) Schomaker, J. M.; Geiser, A. R.;
Huang, R.; Borhan, B. J. Am. Chem. Soc. 2007, 129, 3794.
(4) Kulshrestha, A.; Schomaker, J. M.; Holmes, D.; Staples, R. J.;
Jackson, J. E.; Borhan, B. Chem.;Eur. J. 2011, 17, 12326.
The aza-Payne process is an efficient intramolecular
pathway and therefore makes the attempt to interject an
(5) (a) Wu, C.-Y.; Chang, C.-F.; Chen, J. S.-Y.; Wong, C.-H.; Lin,
C.-H. Angew. Chem., Int. Ed. 2003, 42, 4661. (b) La Ferla, B.; Bugada,
P.; Cipolla, L.; Peri, F.; Nicotra, F. Eur. J. Org. Chem. 2004, 2004, 2451.
(c) Paulsen, H.; von Deyn, W. Liebigs Ann. Chem. 1987, 1987, 125. (d)
Boglio, C. C.; Stahlke, S.; Thorimbert, S.; Malacria, M. Org. Lett. 2005,
7, 4851. (e) Cong, X.; Liu, K.-G.; Liao, Q.-J.; Yao, Z.-J. Tetrahedron
Lett. 2005, 46, 8567.
(6) Myers, A. G.; Widdowson, K. L. Tetrahedron Lett. 1988, 29, 6389.
r
10.1021/ol301204w
Published on Web 06/28/2012
2012 American Chemical Society