Enantioselective construction of quaternary stereocenters: Rearrangements of O-acylated azlactones catalyzed by a planar-chiral derivative of 4-(pyrrolidino)pyridine [12]

Full text of DOI:10.1021/ja982890c

11532
J. Am. Chem. Soc. 1998, 120, 11532-11533
Table 1. Dependence of Enantioselectivity on the 2-Substituent of
the O-Acylated Azlactone
Enantioselective Construction of Quaternary
Stereocenters: Rearrangements of O-Acylated
Azlactones Catalyzed by a Planar-Chiral Derivative
of 4-(Pyrrolidino)pyridine
J. Craig Ruble and Gregory C. Fu*
Department of Chemistry
Massachusetts Institute of Technology
Cambridge, Massachusetts 02139
ReceiVed August 12, 1998
The development of catalytic enantioselective carbon-carbon
bond-forming reactions, particularly those that produce quaternary
stereocenters, is one of the most difficult challenges in stereo-
selective organic synthesis.1,2 In 1970, Steglich reported that
4-(dimethylamino)pyridine (DMAP) and 4-(pyrrolidino)pyridine
(PPY) catalyze the rearrangement of O-acylated azlactones to their
C-acylated isomers, thereby generating both a new carbon-carbon
bond and a new quaternary stereocenter (eq 1).3,4 The products
achieving enantioselectiVe rearrangements with planar-chiral
derivatives of 4-(dialkylamino)pyridines. In this communication,
we report the realization of this objective through the use of a
new catalyst, PPY* (eq 2).
of this rearrangement process represent useful building blocks
for synthetic organic chemistry, since nucleophiles react prefer-
entially at the azlactone carbonyl group to provide protected
R-alkylated R-amino acids.5-8 To the best of our knowledge,
there have been no reports of either diastereoselective or enan-
tioselective variants of this nucleophile-catalyzed rearrangement
reaction.
Our initial investigation into asymmetric Steglich rearrange-
ments focused on the use of previously reported DMAP* as the
chiral catalyst.9,12 In the meantime, however, we developed a
related new catalyst, PPY*,13 which we have discovered affords
a greater reaction rate and higher enantioselectivity in this
rearrangement as compared with DMAP* (eq 3).14,15
Several years ago, we initiated a research program directed at
the development of planar-chiral derivatives of DMAP (e.g., 1a,b)
as enantioselective nucleophilic catalysts. To date, we have
An optimization study exploring the dependence of enantiose-
lectivity on the 2-substituent of the O-acylated azlactone reveals
(8) For an approach to the synthesis of enantiopure R-alkylated R-amino
acids that relies upon ring-opening of racemic azlactones with 1 equiv of an
enantiomerically pure amine, followed by separation of the resulting diaster-
eomers, see: Obrecht, D.; Bohdal, U.; Broger, C.; Bur, D.; Lehmann, C.;
Ruffieux, R.; Scho¨nholzer, P.; Spiegler, C.; Mu¨ller, K. HelV. Chim. Acta 1995,
78, 563-580.
described the effectiveness of these complexes in the kinetic
resolution of secondary alcohols9 and in the deracemization/ring-
opening of azlactones.10,11 In view of Steglich’s discovery that
the rearrangement of O-acylated azlactones is subject to catalysis
by 4-(dialkylamino)pyridines (eq 1), we set our sights on
(9) (a) Ruble, J. C.; Latham, H. A.; Fu, G. C. J. Am. Chem. Soc. 1997,
119, 1492-1493. (b) Ruble, J. C.; Tweddell, J.; Fu, G. C. J. Org. Chem.
1998, 63, 2794-2795.
(1) For a recent review, see: Corey, E. J.; Guzman-Perez, A. Angew. Chem.
Int. Ed. 1998, 37, 388-401. See also: Fuji, K. Chem. ReV. 1993, 93, 2037-
2066.
(2) Dosa, P. I.; Fu, G. C. J. Am. Chem. Soc. 1998, 120, 445-446.
(3) Steglich, W.; Ho¨fle, G. Tetrahedron Lett. 1970, 4727-4730.
(4) For reviews of the chemistry of 4-(dialkylamino)pyridines, see: (a)
Ho¨fle, G.; Steglich, W.; Vorbru¨ggen, H. Angew. Chem., Int. Ed. Engl. 1978,
17, 569-583. (b) Hassner, A.; Krepski, L. R.; Alexanian, V. Tetrahedron
1978, 34, 2069-2076. (c) Scriven, E. F. V. Chem. Soc. ReV. 1983, 12, 129-
161.
(5) For a review of the chemistry of azlactones, see: Rao, Y. S.; Filler, R.
In Oxazoles; Turchi, I. J., Ed.; Wiley: New York, 1986; Chapter 3.
(6) For a brief overview of the synthesis and the significance of R-alkylated
R-amino acids, see: Wirth, T. Angew. Chem., Int. Ed. Engl. 1997, 36, 225-
227 and references therein.
(7) To the best of our knowledge, only one catalytic enantioselective method
for the synthesis of R-alkylated R-amino acids has been reported (palladium-
catalyzed allylic alkylation): Trost, B. M.; Ariza, X. Angew. Chem., Int. Ed.
Engl. 1997, 36, 2635-2637.
(10) Liang, J.; Ruble, J. C.; Fu, G. C. J. Org. Chem. 1998, 63, 3154-
3155.
(11) For recent work by others on chiral derivatives of 4-(dialkylamino)-
pyridines, see: (a) Kawabata, T.; Nagato, M.; Takasu, K.; Fuji, K. J. Am.
Chem. Soc. 1997, 119, 3169-3170. (b) Vedejs, E.; Chen, X. J. Am. Chem.
Soc. 1997, 119, 2584-2585; 1996, 118, 1809-1810.
(12) Ruble, J. C.; Fu, G. C. J. Org. Chem. 1996, 61, 7230-7231.
(13) For the preparation of enantiopure PPY*, see the Supporting Informa-
tion.
(14) (a) At room temperature, the corresponding reactions catalyzed by
(-)-PPY* and (-)-DMAP* provide the rearranged product in 76% and 71%
ee, respectively. (b) The use of solvents other than tert-amyl alcohol (e.g.,
CH2Cl2, THF, toluene, and Et2O) leads to lower enantioselectivity. (c) The
rate of rearrangement with PPY* as the catalyst is ∼4-5 times greater than
that with DMAP*. (d) Catalyst 1b is inferior to PPY* and to DMAP* in
terms of both rate and enantioselectivity.
(15) Parallel observations regarding relative reactivity have been reported
for the achiral parent compounds (i.e., PPY displays greater activity than
DMAP in the rearrangement of O-acylated azlactones). See ref 4a.
10.1021/ja982890c CCC: $15.00 © 1998 American Chemical Society
Published on Web 10/27/1998

Communications to the Editor
J. Am. Chem. Soc., Vol. 120, No. 44, 1998 11533
Table 2. Enantioselective Rearrangements of O-Acylated
Azlactones Catalyzed by (-)-PPY*
Scheme 1
Preliminary studies indicate that, under the typical reaction
conditions, the rate of rearrangement is zero-order in substrate
and independent of concentration. This observation is consistent
with the pathway outlined in Scheme 1, wherein the resting state
of the system is ion pair 3. The crossover experiment illustrated
in eq 7 suggests that reaction of the O-acylated azlactone with
PPY* (Scheme 1, step A) is reversible (thereby forming scrambled
“starting materials” 4 and 5) and that the counterions of the ion
pair can exchange (thereby forming 4-7). Our demonstration
that the rearranged products are configurationally stable under
the reaction conditions provides evidence that step B of Scheme
1 is irreversible.
that alkyl (Table 1, entries 1 and 2) and heteroaryl (entry 3) groups
provide lower selectivity than do aryl substituents (entries 4-6).
Although the stereoselection appears to be relatively insensitive
to substitution on the aromatic ring (entries 4-6), the reaction
rate is affected more significantly, with use of the 4-methoxy
group leading to the most rapid rearrangement.16
Further improvement in enantioselectivity can be gained
through appropriate choice of the migrating acyl group (eq 4).
Although little variation in ee is observed for a range of simple
aliphatic substituents, use of the benzyl derivative leads to
appreciably enhanced stereoselection.
Under these optimized conditions, (-)-PPY* catalyzes the
rearrangement of an array of O-acylated azlactones with high
enantioselectivity and in excellent yield (2% catalyst; tert-amyl
alcohol, 0 °C, 2-6 h; Table 2).17,18 The utility of these
rearrangement products is illustrated by their conversion to
dipeptide and R-methylserine derivatives (eqs 5 and 6).6,19,20
In summary, we have described synthetic and mechanistic
studies of a new method for the enantioselective construction of
quaternary stereocenters, the nucleophile-catalyzed rearrangement
of O-acylated azlactones. Using a new planar-chiral catalyst,
PPY*, we can effect this carbon-carbon bond-forming reaction,
which furnishes protected R-alkylated R-amino acids, with high
levels of enantioselectivity. Further investigations of the scope
and the mechanism of this process are underway.
(16) This electronic effect is consistent with carbon-carbon bond formation
being the turnover-limiting step (vide infra).
(17) General procedure: A pink, 0 °C solution of (-)-PPY* (3.8 mg, 0.010
mmol) in tert-amyl alcohol (4.0 mL) is added by cannula to a 0 °C solution
of the O-acylated azlactone (0.50 mmol) in tert-amyl alcohol (6.0 mL),
resulting in a deep-blue or purple solution. After the pink color of the catalyst
has returned (2-6 h), the reaction mixture is passed through a plug of silica
(EtOAc as the eluant) to remove the catalyst (the catalyst can be recovered
by then flushing the silica with 10% NEt3/90% EtOAc). The solvents are
evaporated, and the product is purified by flash chromatography.
(18) The absolute configuration of the rearranged product for R ) CH2Ph
(Table 2) was determined through an X-ray crystallographic study of an amide
derived from ring-opening of the rearranged product with an enantiopure amine
(see Supporting Information for details). The absolute configurations of the
other reactions products were assigned by analogy.
Acknowledgment. We thank the Buchwald group (MIT) for gener-
ously sharing their GC and HPLC equipment and Michael M.-C. Lo for
solving X-ray crystal structures. Support has been provided by the Alfred
P. Sloan Foundation, the American Cancer Society, Bristol-Myers Squibb,
the Camille and Henry Dreyfus Foundation, Eli Lilly, Glaxo Wellcome,
the National Institutes of Health (National Institute of General Medical
Sciences, R01-GM57034), the National Science Foundation (predoctoral
fellowship to J.C.R.; Young Investigator Award to G.C.F., with funding
from Merck, Pharmacia & Upjohn, DuPont, Bayer, and Novartis), Pfizer,
Procter & Gamble, and the Research Corp.
(19) For a discussion of the synthesis and the significance of R-methylserine,
see: Moon, S.-H.; Ohfune, Y. J. Am. Chem. Soc. 1994, 116, 7405-7406.
(20) The absolute configuration of the R-methylserine derivative illustrated
in eq 6 was correlated with a literature compound (Leplawy, M. T.; Olma, A.
Polish J. Chem. 1979, 53, 353-367); see Supporting Information for details.
See also ref 18.
Supporting Information Available: Experimental procedures and
compound characterization data (67 pages). See any current masthead
page for ordering information and Web access instructions.
JA982890C