As it was reported that a variety of C-nucleophiles
including Grignard reagents,11 methyl sulfinyl organolithium
anions,12 ester lithium enolates, and 1,3-lithio-dithianes13
reacted regioselectively with N-BOC protected ethyl pyro-
glutamate leading to open-chain products, it was of great
interest to investigate the reaction of some C-nucleophiles
with compounds 6. We have found that nonstabilized
carbanions such as organolithium reagents reacted with 6
leading to complex mixtures of products under different
reaction conditions. However, the reaction of Grignard
reagents with 6b-f resulted in a clean transformation leading
to the corresponding ketones in good yields.14
affording ketones in excellent yields likely by formation of
stable intermediates such as 10, similar to those described
for well-known acylating reagents such as Weinreb amides15
and related compounds16 (Scheme 2).
Scheme 2
Except for 6a, the reaction seems to be general since a
complete chemoselectivity is observed regardless of the
nature of the N-acyl group attached to the pyroglutamate
(Table 2). For 6a, the reaction with PhMgBr afforded
In light of the results with heteronucleophiles and those
previously reported in aldol condensation,5 it was of interest
to test the chemoselective reaction of 6 toward O-nucleo-
philes in an intramolecular fashion to achieve a diastereo-
selective and efficient preparation of â-hydroxy acids.
Scheme 3 illustrates the method, based upon the stereo-
Table 2. Reaction of 6 with Grignard Reagents
N-acyl
yield of
yield of
entry
derivative (6)
R1
7 (%)
3 (%)
1
2
3
4
5
6
7
8
9
6a
6b
6d
6e
6f
6f
6f
6f
6f
C6H5
C6H5
C6H5
C6H5
C6H5
C2H5
n-C3H7
CH2dCH
CH2dCHCH2
22
85
88
85
77
76
64
65
63
50
87
90
85
81
83
77
77
80
Scheme 3
complex mixtures from which the expected ketone could be
isolated in only 22% yield (Table 2, entry 1).
These results demonstrate not only the highly selective
removal of the chiral moiety in 6 with heteronucleophiles
and C-nucleophiles, but also the efficiency of the whole
process, allowing the conversion of the N-acyl groups into
a ketone functional group. In this context the N-acyl
pyroglutamates can be viewed as acylating compounds
(10) General procedure for heteronucleophiles: To a solution of 6 (0.15
mmol) in the appropriate solvent (THF for morpholine and the corresponding
alcohol for alkoxides) was added the heteronucleophile (0.165 mmol of
morpholine and 0.15 mmol of the alkoxide) and the reaction mixture was
refluxed for 24 h (morpholine) or stirred at room temperature for 1 h
(alkoxides). Then the solvent was evaporated and the residue treated with
CH2Cl2. The organic phase was washed with HCl (morpholine) or NaCl
(alkoxydes), the solvent was evaporated, and the residue was chomato-
graphed on silica gel with hexane/EtOAc as eluent (1:1 allowed isolation
of amides and 7:3 of esters). Pyroglutamate 3 was recovered with a 3:7
mixture of solvents.
(11) Ezquerra, J.; Pedregal, C.; Rubio, A.; Valenciano, J.; Garc´ıa Nav´ıo,
J. L.; Alvarez-Builla, J.; Vaquero, J. J. Tetrahedron Lett. 1993, 39, 6317.
(12) Ezquerra, J.; Rubio, C.; Pedregal, C.; Sanz, G.; Rodriguez, J. H.;
Garc´ıa Ruano, J. L. Tetrahedron Lett. 1993, 34, 4989.
(13) Ezquerra, J.; de Mendoza, J.; Pedregal, C.; Ramirez, C. Tetrahedron
Lett. 1992, 33, 5589.
(14) General procedure for C-nucleophiles: To a solution of 6 (0.15
mmol) in THF at -40 °C was added the Grignard reagent (0.15 mmol)
and the reaction mixture was stirred for 5 h, then treated with NH4Cl solution
and extracted with CH2Cl2. The residue obtained after evaporation of the
solvent was chomatographed on silica gel with hexane/EtOAc as eluent
(9:1) for isolation of ketones. Auxilar 3 was recovered as indicated in ref
10.
selective aldol reaction between 5 and aldehydes, followed
by intramolecular hydroxy group attack in the presence of
DBU. Formation of the â-hydroxy acids 11 involves removal
of DMPG and likely formation of the intermediate â-lactone
10, which could not be isolated under reaction conditions17
(Scheme 3). The acids, without isolation, were converted into
the benzyl esters 1218 for an accurate ee determination (chiral-
HPLC).
(15) Nahm, S.; Weinreb, S. M. Tetrahedron Lett. 1981, 56, 291
(16) (a) Evans, D. A.; Gauchet-Prunet, J. A. J. Org. Chem. 1993, 58,
2446. (b) Heras, M. A.; Molina, A.; Vaquero, J. J.; Garc´ıa, J. L.; Alvarez-
Builla, J. J. Org. Chem. 1993, 58, 5862. (c) Sibi, P. M.; Marvin, M.;
Sharma., R. J. Org. Chem. 1995, 60, 5016. (d) Sibi, M. P.; Christensen, J.
W.; Kim, S.-G.; Eggen, M. J.; Stessman, C.; Oien, L. Tetrahedron Lett.
1995, 36, 6209. (e) Williams, J. M.; Jobson, R. B.; Yasuda, N.; Marchesini,
G.; Dolling, U.-H.; Grabowski, J. J. Tetrahedron Lett. 1995, 36, 5461. (f)
Sawamura, M.; Hamashima, H.; Shinoto, H.; Ito, Y. Tetrahedron Lett. 1995,
36, 64479. (g) Davies, S. G.; McCarthy, T. D. Synlett 1995, 700. (h) Braslau,
R.; Naik, N.; Olmstead, M. M. J. Org. Chem. 1996, 61, 368.
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