coordination of the Lewis acid cis to the amide moiety15
which is followed by formation of structure 3,16 resulting in
an efficient transfer of chirality from the R-carbon to the
nitrogen nucleus. Subsequent deprotonation of 3 with Et3N
provides ylide 4, which suffers a homolytic cleavage of the
C-N bond (see structure 5) and then a radical recombination
to form complex 6. Although the bicyclic structure in 5 is
achiral, efficient NfC chirality transfer is secured by
selective migration of the benzyl radical on the R-face.
Finally, hydrolysis of 6 gives 2a, the absolute stereochemistry
of which is identical to the starting material 1a.17 To define
the scope and limitation of the rearrangement, proline
derivatives 1b-h were prepared and subjected to the
optimized reaction conditions. Substrates 1b-d, having
different electronic properties, smoothly provided the enan-
tioenriched amides 2b-d in excellent yields (entries 2-4).
Increasing the steric hindrance in the ortho position, as in
derivative 1e, provided the corresponding product 2e in
excellent yield and selectivity (entry 5). When employing
1-naphthyl derivative 1f, prolonged reaction time was
necessary to achieve full conversion to 2f (entry 6). The more
sterically demanding 1g, having a 9-anthracenyl moiety,
provided the corresponding quaternary amino acid derivative
2g, although in a somewhat lower isolated yield (entry 7).
This, then, should provide an efficient entry to novel
fluorescent amino acid derivatives, compounds of current
interest.18 Interestingly, employing thiophene derivative 1h
provides the novel amino acid derivative 2h in good isolated
yield, illustrating the generality of the presented methodology
(entry 8).19
subsequently treated with propylene oxide.20 After standard
purification (S)-R-benzylproline (7) was isolated in 67% yield
and >98:2 er (Scheme 3), which also confirmed the absolute
configuration of 2a.21
Scheme 3. Hydrolysis of 2a
In conclusion, the first example of asymmetric Lewis acid
mediated [1,2]-Stevens rearrangement was developed. This
reaction serves as an efficient method for the preparation of
proline derivatives having a quaternary stereocenter. The
transformation is operationally simple and proceeds in good
to excellent yields and with retention of the stereochemical
purity of the starting material. In one case, it has been shown
that the rearrangement product can be easily hydrolyzed into
the corresponding amino acid.
Acknowledgment. This work was financially supported
by the Royal Institute of Technology, the Swedish Research
Council, and the Knut and Alice Wallenberg foundation.
Supporting Information Available: Experimental pro-
cedures and spectroscopic characterization data. This material
Finally, hydrolysis of amides 2 to the corresponding amino
acids was briefly investigated. Subjecting 2a to 6 M HCl
gave the corresponding hydrochloride salt, which was
OL8028803
(18) For fluorescent anthracene-based amino acid derivatives, see: Kohta,
S.; Shah, V. R.; Mishra, P. P.; Datta, A. Amino Acids 2007, 35, 169-173.
For a study on efficient incorporation of fluorescent nonnatural amino acids,
see: (a) Doi, Y.; Ohtsuki, T.; Shimizu, Y.; Ueda, T.; Sisido, M. J. Am.
Chem. Soc. 2007, 129, 14458–14462. (b) Hohsaka, T.; Kajihara, D.;
Ashizuka, Y.; Murakami, H.; Sisido, M. J. Am. Chem. Soc. 1999, 121, 34.
(19) Only one example of [1,2]-Stevens rearrangement of an ammonium
salt containing a thienylmethyl moiety has been reported. See: Kocharyan,
S. T.; Karapetyan, V. E.; Churkina, N. P. Russ. J. Gen. Chem. 2000, 70,
1094–1097.
(13) Compound 1a was prepared from commercially available N,N-
dimethyl L-prolineamide.
(14) Similar rearrangement at 60 °C gave 2a in 82% yield and 90:10
er.
(15) This is believed to arise from a preferential N pyramidal form, in
which the substituent on nitrogen and the C-2 substituent are trans disposed.
See: Vedejs, E.; Arco, M. J.; Powell, D. W.; Renga, J. M.; Singer, S. P. J.
Org. Chem. 1978, 43, 4831–4837.
(16) Blid, J.; Brandt, P.; Somfai, P. J. Org. Chem. 2004, 69, 3043–
3049. For the case with chiral Lewis acid, see: (a) Blid, J.; Panknin, O.;
Tuzina, P.; Somfai, P. J. Org. Chem. 2007, 72, 1294. (b) Blid, J.; Panknin,
O.; Somfai, P. J. Am. Chem. Soc. 2005, 127, 9352.
(17) The enantiomeric ratio of 2a was determined by HPLC using a
Chiracel OD-H column.
(20) MacQuarrie-Hunter, S.; Carlier, P. R. Org. Lett. 2005, 7, 5305–
5308.
(21) The assignment was confirmed by comparison of the sign of 7 [R]23
D
-21.2 (c 0.27, H2O) with that of the known (S)-7 ([R]20 -18.1 (c 0.27,
D
H2O)). See: Genin, M. J.; Baures, P. W.; Johnson, R. L. Tetrahedron Lett.
1994, 35, 4967–4968.
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