Davies et al.
JOCArticle
hydride reducing agents, which is often ascribed to the
stabilization of the tetrahedral intermediate through chela-
tion; this property of Weinreb amides allows for a very
convenient and efficient synthesis of aldehydes and ketones.
Within this area, we have recently reported that N-acyl
derivatives of N-1-(10-naphthyl)ethyl-O-tert-butylhydroxyl-
amine 1 are able to act as chiral Weinreb amide equiva-
lents.3,4 Treatment of enantiopure N-acyl derivatives 2 with
KHMDS followed by an alkyl halide proceeds with high
levels of diastereoselectivity (>95:5 dr) to give the corres-
ponding R-substituted derivatives 3 in good yield and as
single diastereoisomers (>99:1 dr) after purification. Treat-
ment of 3 with LiAlH4 gives direct access to the correspond-
ing R-stereogenic aldehyde 4 while treatment with MeLi
gives the corresponding R-stereogenic ketone 5 in very high
enantiopurity (>95:5 er), indicating that the cleavage reac-
tion is accompanied by little competing epimerization or
racemization of the R-stereocenter (Figure 1). This sequence
of transformations allows for a convenient preparation of
R-stereogenic aldehydes and ketones in a single reductive
operation and as such is superior to many of the chiral
auxiliary based approaches to these compounds using, for
instance, Oppolzer’s sultam5 and Evans’s oxazolidinones,6
cleavage of which to generate aldehydes requires at least two
synthetic steps.7,8
FIGURE 1. Alkylation of chiral Weinreb amide equivalents 2,
derived from N-1-(10-naphthyl)ethyl-O-tert-butylhydroxylamine 1,
and cleavage to give homochiral aldehydes 4 and ketones 5.
Results and Discussion
Auxiliary Design Concept. A survey of the known solid-
state conformations of Weinreb amides 6 within the CCDC
revealed some common structural preferences. The N-O bond
and carbonyl group generally prefer to adopt an anti-periplanar
conformation (OdC;N;O dihedral angle ∼180°), with the
nitrogen atom being pyramidalized. The N-lone pair generally
prefers to lie syn-periplanar to the O-methyl group, which is
presumably due to a desire to minimize lone pair-lone pair
repulsion between the heteroatoms;9 the O-methyl group is
therefore located approximately perpendicular to the plane
containing the N-O bond and the carbonyl group (OC-N-
O-CH3 dihedral angle ∼90°). Applying Ockham’s razor10 to
these observations led to the proposal of the “chiral Weinreb
amide” 7, resulting from the incorporation of an R-arylethyl
group on the nitrogen atom (R1 and R2=Me and Ar). Minimi-
zation of A1,3 strain was expected to place the R-hydrogen atom
syn-pentane to the carbonyl oxygen, with subsequent minimi-
zation of steric interactions between the N- and O-alkyl groups
placing the O-tert-butyl group preferentially over one of the
diastereotopic faces of the carbonyl group (a chiral relay
effect).11 This preference was expected to result in the N-lone
Herein we delineate the design concept of auxiliary 1, and
describe the synthesis and subsequent alkylation of a series
of analogues of 2, incorporating variation in the structure
of the chiral auxiliary 1, that enable the design concept to be
validated and the origin of the high alkylation diastereo-
selectivities to be probed.
(3) Chernega, A. N.; Davies, S. G.; Goodwin, C. J.; Hepworth, D.;
Kurosawa, W.; Roberts, P. M.; Thomson, J. E. Org. Lett. 2009, 11, 3254.
(4) Masamune has also reported a benzopyranoisoxazolidine auxiliary
that is capable of acting as a chiral Weinreb amide equivalent; see: Abiko, A.;
Moriya, O.; Filla, S. A.; Masamune, S. Angew. Chem., Int. Ed. Engl. 1995, 34,
793. Abiko, A.; Masamune, S. Tetrahedron Lett. 1996, 37, 1081.
(5) Oppolzer, W.; Chapuis, C.; Bemardiielli, G. Helv. Chim. Acta 1984,
67, 1397. For reviews, see: Oppolzer, W. Tetrahedron 1987, 43, 1969.
Oppolzer, W. Pure Appl. Chem. 1990, 62, 1241.
(6) Evans, D. A.; Bartroli, J.; Shih, T. L. J. Am. Chem. Soc. 1981, 103,
2127. For reviews, see: Evans, D. A. Aldrichim. Acta 1982, 15, 23. Arya, P.;
Quin, H. Tetrahedron 2000, 56, 917.
(9) This conformational preference is in accord with hydroxylamine itself,
for which the lowest energy conformation has bonds and lone pairs eclipsed;
the interconversion of conformers by N-O bond rotation is also considered
to be a high-energy process; see: Ali, S. A.; Hassan, A.; Wazeer, M. I. M.
J. Chem. Soc., Perkin Trans. 2 1996, 1479.
(10) Ockham’s razor (also spelled Occam’s razor) is a principle attributed
to the 14th Century English logician and Franciscan friar William of
Ockham. The principle states that the explanation of any phenomenon
should make as few assumptions as possible.
(11) Bull, S. D.; Davies, S. G.; Fox, D. J.; Garner, A. C.; Sellers, T. G. R.
Pure Appl. Chem. 1998, 70, 1501. Bull, S. D.; Davies, S. G.; Fox, D. J.; Sellers,
T. G. R. Tetrahedron: Asymmetry 1998, 9, 1483. Bull, S. D.; Davies, S. G.;
Epstein, S. W.; Ouzman, J. V. A. Chem. Commun. 1998, 659. Bull, S. D.;
Davies, S. G.; Epstein, S. W.; Leech, M. A.; Ouzman, J. V. A. J. Chem. Soc.,
Perkin Trans. 1 1998, 2321. Bull, S. D.; Davies, S. G.; Garner, A. C.;
Mujtaba, N. Synlett 2001, 781. Bull, S. D.; Davies, S. G.; Garner, A. C.;
O’Shea, M. D. J. Chem. Soc., Perkin Trans. 1 2001, 3281. Sibi, M. P.;
Venkatraman, L.; Liu, M.; Jasperse, C. P. J. Am. Chem. Soc. 2001, 123, 8444.
Quaranta, L.; Corminboeuf, O.; Renaud, P. Org. Lett. 2002, 4, 39. Corminboeuf,
O.; Quaranta, L.; Renaud, P.; Liu, M.; Jasperse, C. P.; Sibi, M. P. Chem.;
Eur. J. 2003, 9, 29. Malkov, A. V.; Hand, J. B.; Kocovsky, P. Chem. Commun.
2003, 1948. Hitchcock, S. R.; Casper, D. M.; Vaughn, J. F.; Finefield, J. M.;
Ferrence, G. M.; Esken, J. M. J. Org. Chem. 2004, 69, 714. Sibi, M. P.;Stanley,
L. M. Tetrahedron: Asymmetry 2004, 15, 3353. Sibi, M. P.; Prabagaran, N.
Synlett 2004, 2421. Clayden, J.; Vassiliou, N. Org. Biomol. Chem. 2006, 4,
2667. Parrott, R. W. II; Hitchcock, S. R. Tetrahedron: Asymmetry 2007, 18,
377. Bull, S. D.; Davies, S. G.; Epstein, S. W.; Garner, A. C.; Mujtaba, N.;
Roberts, P. M.; Savory, E. D.; Smith, A. D.; Tamayo, J. A.; Watkin, D. J.
Tetrahedron 2006, 62, 7911. Bull, S. D.; Davies, S. G.; Garner, A. C.; Parkes,
A. L.; Roberts, P. M.; Sellers, T. G. R.; Smith, A. D.; Tamayo, J. A.;
Thomson, J. E.; Vickers, R. J. New J. Chem. 2007, 31, 486.
(7) For instance, see: Evans, D. A.; Weber, A. E. J. Am. Chem. Soc. 1986,
108, 6757. Evans, D. A.; Polniaszek, R. P.; DeVries, K. M.; Guinn, D. E.;
Mathre, D. J. J. Am. Chem. Soc. 1991, 113, 7613. Evans, D. A.; Miller, S. J.;
Ennis, M. D. J. Org. Chem. 1993, 58, 471. Taylor, R. E.; Chen, Y. Org. Lett.
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Suzuki, T.; Nakada, M. Tetrahedron Lett. 2002, 43, 3263.
(8) Perhaps the most useful auxiliaries for the direct (one step) prepara-
tion of R-chiral aldehydes are Davies’s SuperQuat, the ephedrine/pseudoe-
phedrine approach of Larcheveque and Myers, respectively, and Enders’s
SAMP/RAMP hydrazone method. For leading references, see: Larcheveque,
M.; Ignatova, E.; Cuvigny, I. Tetrahedron Lett. 1978, 19, 3961. Larcheveque,
M.; Ignatova, E.; Cuvigny, I. J. Organomet. Chem. 1979, 177, 5. Myers, A. G.;
Yang, B. H.; Chen, H.; Gleason, J. L. J. Am. Chem. Soc. 1994, 116, 9361. Myers,
A. G.; Yang, B. H.; Chen, H.; McKinstry, L.; Kopecky, D. J.; Gleason, J. L.
J. Am. Chem. Soc. 1997, 119, 6496. Enders, D.; Eichenauer, H. Angew. Chem.,
Int. Ed. Engl. 1976, 15, 549. Enders, D.; Eichenauer, H. Tetrahedron Lett. 1977,
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H. Angew. Chem., Int. Ed. Engl. 1979, 18, 397. Enders, D.; Eichenauer, H.; Baus,
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S. G.; Jones, S.; Polywka, M. E. C.; Prasad, R. S.; Sanganee, H. J. Synlett 1998,
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