ment of 3 with the Grignard reagent derived from 4-bro-
mobutene cleanly generated the hemiacetal 4 in 74% yield.
The diastereoselectivity of the process was moderate (5/1)
and the stereochemistry of the major diastereomer was not
determined. The hemiacetal in 4 was readily allylated (TiCl4,
allyltrimethylsilane, -40 °C) to provide the dialkylated
glycolamide derivative 5 (68%) as a single diastereomer (1H
NMR, Scheme 1).
Scheme 2
Scheme 1
in good yield (82%, Scheme 2) and 96% ee.10 Details of the
homobenzylic C-N bond cleavage in 6 are not known at
present. It is plausible that, at some stage in the reduction,
a benzylic carbanion is generated and it undergoes facile
â-elimination of the N-acyl moiety.11
The formal synthesis of (-)-quinic acid was achieved by
bromolactonization of 7. Treatment of 7 with N-bromosuc-
cinimide in moist THF at ambient temperature generated the
bromolactone 8 (54% (unoptimized), 96% ee, Scheme 3).
At this stage, the stereochemistry of the newly generated
stereocenter in 5 was assigned the “S” configuration on the
basis of a NOE experiment, which indicated a syn orientation
of the allyl group and the benzylic hydrogen in the mor-
pholinone ring.8 The overall conversion of the dione 3 to
the dialkyl glycolamide 5 constitutes an asymmetric dialkyla-
tion of a chiral oxalic acid derivative. This procedure is an
alternative to conventional approaches to chiral R,R-dialkyla-
ted glycolic acid derivatives that are based on sequential
dialkylation of glycolate anions.4f,9 The approach may be
beneficial when the reactivity of the electrophile is a
limitation.
Scheme 3
The diene 5 is an excellent substrate for a ring-closing
metathesis reaction. Thus, treatment of 5 with the Grubbs
(generation I) catalyst (7 mol %, CH2Cl2, room temperature)
cleanly generated the spiro-morpholinone 6 (96%), which
contains the key R-hydroxy acid functionality and the carbon
skeleton necessary for quinic acid (Scheme 2).
Spectroscopic data for lactone 8 were in agreement with those
reported earlier4f,12 and the optical rotation confirmed the “S”
configuration at the R-carbon in the lactone ([R]D -11.1, c
2, CH2Cl2; lit.4f [R]D -9.1°, c 1.36, CH2Cl2 for material with
82% ee). This also confirmed the absolute stereochemistry
of 5.
Dissolving metal reduction of 6 (Na/NH3, -78 °C)
removed the ephedrine portion to give the hydroxy amide 7
To the best of our knowledge, this is the shortest and most
efficient synthesis of enantiomerically enriched (-)-8. The
only other asymmetric synthesis4f of (-)-8 employs an
enantiomerically enriched dioxolanone (a chiral glycolate
derivative with 80% ee) as the starting material, which is
obtained by a multistep synthesis from D-mannitol, and the
key R,R-dialkylation of the dioxolanone proceeds with low
diastereoselectivity (2/1). The present method represents a
significant improvement since it requires fewer steps, and
the dialkylglyolamide derivative 5 is easily prepared with
high diastereoselectivity.
(5) (a) Gonza´lez, C.; Carballido, M.; Castedo, L. J. Org. Chem. 2003,
68, 2248. (b) Box, J. M.; Harwood, L. M.; Humphreys, J. L.; Morris, G.
A.; Redon, P. M.; Whitehead, R. C. Synlett 2002, 358. (c) An, M.;
Toochinda, T.; Bartlett, P. A. J. Org. Chem. 2001, 66, 1326. (d) Gonza´lez-
Bello, C.; Coggins, J. R.; Hawkins, A. R.; Abell, C. J. Chem. Soc., Perkin
Trans. 1 1999, 849.
(6) See refs 4a, 4b, and 4d.
(7) For a synthesis of ent-3 see: Rudchenko, V. F.; Shtamburg, V. G.;
Pleshkova, A. P.; Kostyanovskii, R. G. Bull Acad. Sci. USSR DiV. Chem.
Sci. (Engl. Transl.) 1981, 30, 825. For a preparation rac-3 see: Drefahl,
G.; Hartmann, M.; Skurk, A. Chem. Ber. 1963, 96, 1011.
(8) This result can be explained by a stereoelectronically controlled axial
allylation of the intermediate oxocarbenium ion in a boatlike transition state
assembly. Pansare, S. V.; Ravi, R. G.; Jain, R. P. J. Org. Chem. 1998, 63,
4120.
(10) Determined by HPLC analysis on a Chiralpak AD-H column; see
the Supporting Information for details.
(9) Ley, S. V.; Diez, E.; Dixon, D. J.; Guy, R. T.; Michel, P.; Natrass,
G.; Sheppard, T. D. Org. Biomol. Chem. 2004, 2, 3608 and references
therein.
(11) For examples of homobenzylic C-O bond cleavage in Na/NH3
reduction, see: Samizu, K.; Ogasawara, K. Tetrahedron Lett. 1994, 43,
7989.
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Org. Lett., Vol. 8, No. 10, 2006