Scheme 3. Rearrangement of Lithiated Pyrrolidines
the yields of the products 11 were significantly improved
by the addition of the Lewis acid TMSOTf, which presum-
ably coordinates to the Boc group to aid rearrangement.10
The enantiomer ratios of the products 11 were determined
by chiral HPLC (Chiralcel OD column) after conversion to
the p-bromobenzoate derivatives. The enantiomer ratios of
the products 13 were determined directly by chiral HPLC
(Chiralcel OD column). The structure of the secondary
alcohol 13b (R ) Bu) was confirmed by X-ray structure
analysis (see the Supporting Information). To determine the
absolute configuration (which was not possible from the
X-ray of 13b), the alcohol 13a was converted to the
derivative 14 and X-ray crystal structure analysis was
performed (Figure 1) (see the Supporting Information). On
the basis of the refined absolute structure parameter,11 the
product has (S)-stereochemistry. As asymmetric deprotona-
tion of N-Boc-pyrrolidine and N-Boc-indoline occur to give
the (S)-enantiomer of the organolithiums,8,9,12 the fact that
the (S)-enantiomer of the product 13a (and by assumption
11a,b and 13b) is formed implies that the electrophilic
quench of these organolithiums occurs with retention of
configuration at the carbanion carbon to give the borates 15
and 16 (Figure 2). Reaction of N-Boc-2-lithiopyrrolidine and
N-Boc-2-lithioindoline with retention of configuration at the
Figure 1. X-ray crystal structure of compound 14.
carbanion center is in line with all other known electrophilic
quenches of these anions.1,2,13
Figure 2. Derivative 14 (Ar ) p-BrC6H4) and borate intermediates
n
15 (from 10) and 16 (from 12), R ) Et or Bu.
In summary, we have developed the electrophilic quench
of several chiral R-amino-organolithiums, followed by rear-
rangement of the intermediate borates. This gives a selection
of chiral secondary alcohols with high levels of enantiose-
lectivity. The N-linked carbamates are evidently poorer
leaving groups than O-linked carbamates, but 1,2-rearrange-
ment of the intermediate ate complexes (formed by electro-
philic quench with trialkylboranes) can be promoted by
Lewis acid activation.
(5) Matteson, D. S. Tetrahedron 1998, 54, 10555.
(6) This chemistry is only applicable to boranes and not boronate
esters: (a) Aggarwal, V. K.; Fang, G. Y.; Schmidt, A. T. J. Am. Chem.
Soc. 2005, 127, 1642. (b) Fang, G. Y.; Aggarwal, V. K. Angew. Chem.,
Int. Ed. 2007, 46, 359. (c) Fang, G. Y.; Wallner, O. A.; Blasio, N. D.;
Ginesta, X.; Harvey, J. N.; Aggarwal, V. K. J. Am. Chem. Soc. 2007, 129,
14632. For a discussion of leaving group ability of onium ions in this type
of reaction, see: (d) Aggarwal, V. K.; Harvey, J. N.; Robiette, R. Angew.
Chem., Int. Ed. 2005, 44, 5468.
Acknowledgment. We thank EPSRC, the University of
Sheffield, and AstraZeneca for support of this work. We are
grateful to the EPSRC X-ray crystallography service at the
University of Southampton for data collection for structure
14.
(7) (a) Park, Y. S.; Boys, M. L.; Beak, P. J. Am. Chem. Soc. 1996, 118,
3757. (b) Faibish, N. C.; Park, Y. S.; Lee, S.; Beak, P. J. Am. Chem. Soc.
1997, 119, 11561.
(8) Beak, P.; Kerrick, S. T.; Wu, S.; Chu, J. J. Am. Chem. Soc. 1994,
116, 3231.
(9) Bertini Gross, K. M.; Jun, Y. M.; Beak, P. J. Org. Chem. 1997, 62,
7679.
(10) In related reactions employing boronate esters [e.g., EtB(pin)] instead
of boranes, the use of TMSOTf was not sufficient to promote rearrangement.
It has been reported that the activation barrier for rearrangement of borate
complexes is significantly higher with oxygen substituents on boron
compared to carbon substituents. For example, the rearrangement shown
in Scheme 1 begins to occur at -40 °C, whereas the related reaction of
borate esters requires +40 °C and Lewis acid action (MgBr2). See ref 4a
and: (a) Stoddard, J. M.; Shea, K. J. Chem. Commun. 2004, 830. (b) Bottoni,
A.; Lombardo, M.; Neri, A.; Trombini, C. J. Org. Chem. 2003, 68, 3397.
(11) Flack, H. D. Acta Crystallogr. 1983, A39, 876.
Supporting Information Available: Experimental pro-
cedures; chiral chromatography traces for the alcohols 9, 11
(as p-bromobenzoate esters), and 13; crystallographic data
for compounds 13b and 14; spectroscopic data and NMR
spectra for the products 11 and 13. This material is available
OL702734U
(13) For electrophilic quench with borates, which occurs with retention
of configuration, see: Batsanov, A. S.; Grosjean, C.; Schutz, T.; Whiting,
A. J. Org. Chem. 2007, 72, 6276.
(12) Gawley, R. E.; Narayan, S.; Vicic, D. A. J. Org. Chem. 2005, 70, 328.
Org. Lett., Vol. 10, No. 1, 2008
143