ORGANIC
LETTERS
2
005
Vol. 7, No. 10
051-2053
Reductive Spiroannulation of Nitriles
with Secondary Electrophiles
2
Matthew D. Morin and Scott D. Rychnovsky*
Department of Chemistry, 516 Rowland Hall, UniVersity of California, IrVine,
IrVine, California 92697-2025
srychnoV@uci.edu
Received March 15, 2005
ABSTRACT
The scope of reductive decyanation and spiroannulation reactions has been expanded to include secondary electrophiles for potentially
useful transformations. Secondary phosphates and chlorides, as well as terminal epoxides, cyclize in a stereospecific fashion. Both endo and
exo modes of cyclization were observed with terminal epoxides.
The stereoselective formation of novel spirocycles provides
an interesting challenge for organic chemists. Cyclization
of alkyllithium reagents is an annulation strategy that has
tions. Is the cyclization of a hindered tertiary organolithium
onto a secondary electrophile possible under the reaction
conditions? What is the stereochemistry of the two newly
formed vicinal stereocenters? Will the lithium-bearing cen-
ter react with retention or inversion of configuration? For
cases of epimeric stereochemistry at the electrophilic cen-
ter, will both diastereomers react? Will various electrophiles
be compatible with conditions required for reductive decya-
nation?
1
potential in the formation of spirocycles. In exploration of
the scope of reductive decyanation and cyclization reactions
using Freeman’s reagent (lithium-di-tert-butylbiphenylide,
2
LiDBB), recent efforts have shown that R-alkoxylithium
intermediates cyclize onto tethered olefins and allylic meth-
oxy ethers to give spirocyclic THP systems in a highly
3
diastereoselective fashion. Furthermore, spiroannulation with
To address these and other questions, optically pure cy-
clization precursors were constructed as shown in Table 1.4
Cyclic nitriles such as 1 may be alkylated with use of an
appropriate base to produce functionalized tertiary nitriles.5
Such reactions are known to be highly stereoselective for
six membered rings. Deprotonation of 1 with LDA in the
presence of DMPU and the bis-electrophiles 2a-h furnished
the equatorial alkylated products 3a-h as the only detect-
able stereoisomers (Table 1). For the chloride and diethyl
phosphate side chains, this product serves as the cyclization
precursor. For the epoxide substrates, further transformations
were necessary. For example, dioxolane 3e was deprotected
tethered primary chloride and phosphate electrophiles affords
3
five-, six-, and, in some cases, seven-membered rings. To
further extend the utility of these transformations, spiroan-
nulations with precursors bearing secondary electrophilic
centers on the side chains were explored, and the results are
reported herein.
Secondary electrophiles introduce a new stereocenter into
the cyclization, which raises important stereochemical ques-
(1) Alkenyllithium cyclizations: (a) Bailey, W. F.; Patricia, J. J.;
DelGobbo, V. C. J. Org. Chem. 1985, 50, 1999-2000. (b) Bailey, W. F.;
Nurmi, T. T.; Patricia, J. J.; Wang, W. J. Am. Chem. Soc. 1987, 109, 2442-
2
1
448. (c) Broka, C. A.; Lee, W. J.; Shen, T. J. Org. Chem. 1988, 53, 1336-
6
with PPTS in methanol to give diol 4, which was then
338. (d) Chamberlin, A. R.; Bloom, S. H.; Cervini, L. A.; Fotsch, C. H.
J. Am. Chem. Soc. 1988, 110, 4788-4796. (e) Broka, C. A.; Shen, T. J.
Am. Chem. Soc. 1989, 111, 2981-2984.
(4) Procedures for the preparation of 2-cyano-THP 1 and iodides 2a-h
may be found in Supporting Information.
(
2) Freeman, P. K.; Hutchinson, L. L. J. Org. Chem. 1980, 22, 1924-
1
930.
(5) Sinz, C. J.; Rychnovsky, S. D. Top. Curr. Chem. 2001, 216, 52-92.
Alkylation of metalated cyanohydrin acetonides: Swenson, S. S.; Rych-
novsky, S. D. J. Org. Chem. 1997, 62, 1333-1340.
(6) Mori, K.; Maemoto, S. Liebigs Ann. Chem. 1987, 863. Greene, T.
W.; Wuts, P. G. M. ProtectiVe Groups in Organic Synthesis, 2nd ed.;
Wiley: New York, 1991; p 126.
(
3) (a) Takaoka, L. R.; Rychnovsky, S. D. Angew. Chem., Int. Ed. 2003,
4
2, 818-820. (b) Rychnovsky, S. D.; Hata, T.; Kim, A. I.; Buckmelter,
A. J. Org. Lett. 2001, 3, 807-810. (c) Takaoka, L. R.; Buckmelter,
A. J.; LaCruz, T. E.; Rychnovsky, S. D. J. Am. Chem. Soc. 2005, 127,
5
28-529.
1
0.1021/ol050567q CCC: $30.25
© 2005 American Chemical Society
Published on Web 04/13/2005