Azacyclopentenyl Carbinyl Radical Isomerizations
A R T I C L E S
by lysine 2,3-aminomutase (Frey)10 and potentially others.11 In
these pyridoxal phosphate (PLP) dependent isomerizations, a
sequence of Schiff base formation from lysine and PLP,
γ-hydrogen atom abstraction, azacyclopropyl carbinyl radical
isomerization, hydrogen atom quench at the R-carbon, and
hydrolysis results in the amino group isomerization necessary
to metabolize lysine. An elegant and convincing chemical model
was reported by Frey and Han in 1990 (eq 2),10a and has since
Table 1. Steric and Concentration Dependence of
Azacyclopentenyl Carbinyl Radical Isomerization (eq 5)a
%eeb
% ee loss
c
entry
[5] (M)
5
6
5 f 6
yield (%)
1
2
3
4
0.01
0.05
0.1
96
96
96
96
63
80
96
89
33
16
0
85
74
70
e
0.01d
7
-
a All reactions used 2.2 equiv of nBu3SnH. See Supporting Information
for complete details. b Measured by HPLC using a Chiralcel AD column.
c Isolated yield. d (PhSe)2 used as additive (20 mol %). e Not determined.
been the object of computational attention.12 It is also apparent
that Nature uses radical-mediated isomerizations of this kind
for a variety of biochemical purposes.13
independently to gate, or modulate, the isomerization process.
An example is also provided in which equilibrium control is
exerted over the isomerization by effecting a 1,4-amino group
transfer reaction as part of an aryl amination.
Three-membered-ring carbinyl radical isomerizations are
normally easily detected since they often favor the chain form.
The opposite is true for five-membered-ring carbinyl radical
isomerizations.14-16 Additionally, some members of the three-
membered-ring carbinyl radical isomerizations differ mecha-
nistically from their higher homologues by the availability of a
radical cation pathway. The R-acyloxy radical rearrangement
(eq 1, X ) OC(O)R) is an example of a 1,2-shift that accesses
a radical cation pair intermediate not available to a homologous
rearrangement.17 Hence, caution should be exercised when
making a direct mechanistic comparison between 1,2-atom (or
group) shifts and their 1,n-homologues.
Results
Carbinyl radical 3 was accessed by free radical-mediated aryl
amination in which an aryl radical adds to the nitrogen of an
azomethine π-bond. o-Bromophenethyl benzophenone imine
precursors were conveniently synthesized as previously de-
scribed.18 In the experiments described here, the degree of
enantiomeric excess (ee) retention from 5 to 6 was used to
identify and measure the extent of ring fragmentation.
We report here the identification of a new member of the
carbinyl radical isomerizations, the azacyclopentenyl carbinyl
radical isomerization (ACCRI) (eqs 3 and 4). We also demon-
The effect of stannane concentration on the reaction was first
determined (Table 1, entries 1-3). Importantly, it was unneces-
sary to add the stannane slowly in any of the transformations
n
described; only when 8 equiv of Bu3SnH and a concentration
of 0.1 M were used did the product of direct aryl radical
reduction (ArH) become significant (∼10%). In the case of 5a,
a steady erosion of enantiopurity was observed at lower
concentrations of ketimine, but no racemization was observable
at 0.1 M in 5a. It was also possible to use the Crich protocol
(Table 1, entry 4) in which in situ generated benzene selenol
serves as a more effective hydrogen atom transfer agent to curtail
isomerization at concentrations that otherwise produced 6a of
diminished ee.19
A key experiment in which the conditions in entry 1 were
implemented but the reaction stopped at 50% conversion
removed from consideration the possibility that either 5a or 6a
was racemized by the reaction conditions. In this experiment,
5a and 6a were recovered in 96% and 63% ee, respectively,
indicating that isomerization must occur after aryl radical
formation yet prior to chain-propagating hydrogen atom transfer
from stannane. The possibility that 6a was epimerized by
nBu3SnBr formed during the reaction was further eliminated by
appropriate control experiments.20
strate the use of steric and electronic (polarization) effects
(10) (a) Han, O.; Frey, P. A. J. Am. Chem. Soc. 1990, 112, 8982-8983. (b)
Frey, P. A.; Reed, G. H. Arch. Biochem. Biophys. 2000, 382, 6-14. (c)
Cosper, N. J.; Booker, S. J.; Ruzicka, F.; Frey, P. A.; Scott, R. A.
Biochemistry 2000, 39, 15668-15673. (d) Frey, P. A.; Booker, S. AdV.
Free Rad. Chem. 1999, 2, 1-43.
(11) He, X. M.; Liu, H. Annu. ReV. Biochem. 2002, 71, 701-54.
(12) Wetmore, S. D.; Smith, D. M.; Radom, L. J. Am. Chem. Soc. 2001, 123,
8678-8689.
(13) For leading references, see: (a) Choi, S.-C.; Dowd, P. J. Am. Chem. Soc.
1989, 111, 2313-2314. (b) Dowd, P.; Choi, S.-C.; Duah, F.; Kaufman, C.
Tetrahedron 1988, 44, 2137-2148. (c) Wollowitz, S.; Halpern, J. J. Am.
Chem. Soc. 1988, 110, 3112-3120.
(14) Beckwith, A. L. J. Tetrahedron 1981, 37, 3073-3100.
(15) Cyclopropyl carbinyl radical isomerizations (5-hexenyl radical cycliza-
tions): (a) Beckwith, A. L. J. Chem. Soc. ReV. 1993, 143. (b) RajanBabu,
T. V. Acc. Chem. Res. 1991, 24, 139. (c) Beckwith, A. L. Tetrahedron
1981, 37, 3073. (d) Giese, B. Angew. Chem., Int. Ed. Engl. 1983, 22, 753.
(e) Julia, M. Acc. Chem. Res. 1971, 4, 386.
(16) Cyclopentyloxy radical fragmentations, although not carbinyl radicals, are
similar and favor the chain form: ref 2.
(17) Crich, D. In Radicals in Organic Synthesis; Renaud, P., Sibi, M., Eds.;
Wiley-VCH: Weinheim, 2001; Vol. 2, pp 188-206.
(18) (a) Johnston, J. N.; Plotkin, M. A.; Viswanathan, R.; Prabhakaran, E. N.
Org. Lett. 2001, 3, 1009-1011. (b) Viswanathan, R.; Plotkin, M. A.;
Prabhakaran, E. N.; Johnston, J. N. J. Am. Chem. Soc. 2003, 125, 163-
168. (c) Prabhakaran, E. N.; Cox, A. L.; Nugent, B. M.; Nailor, K. E.;
Johnston, J. N. Org. Lett. 2002, 4, 4197-4200.
(19) Crich, D.; Mo, X.-S. J. Org. Chem. 1997, 62, 8624.
(20) Evidence of the Lewis acidity of stannyl halides is somewhat contradictory.
For example: (a) Yoder, C. H.; Otter, J. C.; Grushow, A.; Ganunis, T. F.;
Enders, B. G.; Zafar, A. I.; Spencer, J. N. J. Organomet. Chem. 1990,
385, 33-37. (b) Sibi, M. P.; Ji, J. J. Am. Chem. Soc. 1996, 118, 3063 and
references therein.
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