These findings can be rationalized by arguments that
extend from our earlier studies of the enolization of R,R-
dialkyl pseudoephenamine and pseudoephedrine amide
enolates, summarized in Figure 1.5 Briefly, both matched
Scheme 2. Optimized Synthesis of R-Allyl Quaternary Amide 6
Scheme 1. Synthesis of Cyclic Amino Acid Derivativesa
(eq 2), and R,R0-dibromo-o-xylene (eq 3). Due to their
chromatographic instability (believed to be a consequence
of facile NfO acyl transfer), products from the latter two
alkylations were directly subjected to transacylation with
lithium benzyloxide, a useful transformation we discuss in
greater detail below.
As a concluding alkylation result, in Scheme 2 above we
summarize a successful R-allylation of the matched sub-
strate 1, which required development of an alternative
workup method (using hydroxylamine in lieu of acid to
cleave the tert-butyl imine function of the alkylated
product). Interestingly, hydrolysis of the imine function
of the allylated product under the usual conditions (1 N
HCl) led to a significant byproduct (Scheme 3, aminal 7,
accompanied by an unidentified minor diastereomeric
aminal byproduct in a 7:1 ratio, respectively). Crystal-
lization afforded a single crystal of pure 7 suitable for
X-ray analysis (see Supporting Information). As depicted
in Scheme 3, byproduct 7 presumably arises from an aza-
Cope rearrangement followed by cyclization.7
An exceptional and highly useful feature of the present
study was the finding that R-quaternary R-amino amides
of pseudoephenamine undergo hydrolysis to afford R-
amino acids simply upon refluxing in aqueous dioxane
(salt-free conditions, Table 3), whereas treatment with
lithium alkoxides affords R-amino esters (Table 4 and
Scheme 1). In the former case, the pseudoephenamine
auxiliary can be easily recovered in high yield by a simple
extractive isolation procedure, whereas in the latter it can
be isolated chromatographically.
a Diastereomeric ratios were determined by 1H NMR analysis of the
crude alkylation reaction mixtures.
and mismatched substrates are proposed to form the same
E-enolate intermediate (with the enoxy and R-imino
groups in trans disposition), which then undergoes alkyla-
tion predominantly or exclusively in the usual sense.6
Enolization of the mismatched substrate is believed to be
less E-selective, however, because E-enolization requires
approach of the base along a trajectory impeded by the
auxiliary. Interestingly, if we are correct in this proposal,
then formation of the Z-enolate from the mismatched
substrate must remain a higher energy pathway in spite
of the fact that it would arise from deprotonation along a
more favorable trajectory. We speculate that an imporant
factor may be a developing repulsive electronic interaction
between the enolate oxygen atom and the R-imino lone
pair in the transition state for formation of the Z-enolate.
As depicted in Scheme 1, it proved possible to assemble
cyclic R-amino acid derivatives containing an R-quatern-
ary center in a single operation using bis-electrophiles such
as 3-bromopropyl trifluoromethanesulfonate (eq 1),
(R)-3-chloro-2-methylpropyl trifluoromethanesulfonate
Prior auxiliary-based methods for R-alkylation of ala-
nine derivatives have generally achieved stereochemical
control of both the enolate geometry and the nascent
quaternary carbon center by incorporating the alanine
(7) This interesting transformation suggests a possible new approach
to transfer aminoallylation. See, for example: Sugiura, M.; Mori, C.;
Kobayashi, S. J. Am. Chem. Soc. 2006, 128, 11038–11039.
(8) For selected references describing chiral auxiliary-based methods
for the asymmetric synthesis of quaternary R-methyl R-amino acids, see:
€
(a) Schollkopf, U.; Hausberg, H. H.; Hoppe, I.; Segal, M.; Reiter, U.
Angew. Chem., Int. Ed. Engl. 1978, 17, 117–119. (b) Seebach, D.; Aebi,
J. D.; Naef, R.; Weber, T. Helv. Chim. Acta 1985, 68, 144–154. (c)
Williams, R. M.; Im, J. J. Am. Chem. Soc. 1991, 113, 9276–9286. (d)
Berkowitz, D. B.; Smith, M. K. J. Org. Chem. 1995, 60, 1233–1238. (e)
Alonso, F.; Davies, S. G.; Elend, A. S.; Haggitt, J. L. J. Chem. Soc.,
ꢀ
Perkin Trans. 1 1998, 257–264. (f) Chinchilla, R.; Galindo, N.; Najera,
C. Synthesis 1999, 704–717. (g) Lu, T.; Lin, C. J. Org. Chem. 2011, 76,
1621–1633.
(5) Kummer, D. A.; Chain, W. J.; Morales, M. R.; Quiroga, O.;
Myers, A. G. J. Am. Chem. Soc. 2008, 130, 13231–13233.
(6) The E-enolate obtained from the matched diastereomer could be
trapped in the form of a cyclic siloxane whose stereochemistry was
determined by NOE experiments. See Supporting Information for
details.
(9) For leading references, see: (a) Kano, T.; Sakamoto, R.; Mii, H.;
Wang, Y.; Maruoka, K. Tetrahedron 2010, 66, 4900–4904. (b) Jew, S.;
Jeong, B.; Lee, J.; Yoo, M.; Lee, Y.; Park, B.; Kim, M. G.; Park, H.
J. Org. Chem. 2003, 68, 4514–4516. (c) Ooi, T.; Takeuchi, M.; Kameda,
M.; Maruoka, K. J. Am. Chem. Soc. 2000, 122, 5228–5229.
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