C O M M U N I C A T I O N S
Scheme 2 a
Scheme 4 a
a
Conditions: (a) i. ethyl propiolate, MeOH, rt, 12 h; ii. Dowtherm A,
250 °C, 30 min; (b) Ph3PBr2, CH3CN, microwave, 170 °C, 15 min.
a
Conditions: (a) ADmix-R, CH3SO2NH2, tBuOH, H2O, 0 °C, 86%;
(b) i. trimethylorthoacetate, PPTS (cat), CH2Cl2; ii. acetyl bromide, CH2Cl2;
iii. K2CO3, MeOH, 77%; (c) i. Et2AlCl, thioanisole, 0 °C to rt, then
microwave, 200 °C, 20 min, 74%.
Scheme 3 a
Acknowledgment. This paper is dedicated to the memory and
legacy of Prof. Satoru Masamune. The work was supported by the
NIH (GM-59316), by fellowship support to I.T.R. from the NSF,
and by a generous gift of a microwave reactor from Personal
Chemistry. We thank Prof. S. L. Buchwald and Dr. Shawn Walker
for helpful discussions and a gift of ligand 19.
Supporting Information Available: Complete experimental pro-
cedures and characterization data for products and all isolated inter-
mediates (PDF). This material is available free of charge via the Internet
a
Conditions: (k) Pd(OAc)2, 19 (2.5 mol %), K3PO4‚H2O, THF, 16 h,
rt, >20:1 E/Z, 89%; (l) ADmix-â, CH3SO2NH2, tBuOH, H2O, 0 °C, >96:4
dr, 88%; (m) i. trimethylorthoacetate, PPTS (cat), CH2Cl2; ii. acetyl bromide,
CH2Cl2; iii. K2CO3, MeOH, 81%; (n) Et2AlCl, thioanisole, 0 °C to rt, then
microwave, 200 °C, 20 min, 68%.
References
(1) (a) For reviews, see: Nicolaou, K. C.; Snyder, S. A. Classics in Total
Synthesis II: More Targets, Strategies, Methods; Wiley-VCH: Weinheim,
Germany, 2003; Ch. 15. (b) Turner, R. B.; Woodward, R. B. The
Chemistry of the Cinchona Alkaloids. In The Alkaloids; Manske, R. H.
F., Ed.; Academic Press: New York, 1953; Vol. 3, Ch. 16. (c) Grethe,
G.; Uskokovi, M. R. In The Chemistry of Heterocyclic Compounds;
Sexton, J. E., Ed.; Wiley-Interscience: New York, 1983; Vol. 23, Part 4,
p 279.
in 89% yield. Attempts to access 21 directly via established
asymmetric catalytic epoxidation methods13 led to unsatisfactory
results in model systems. In contrast, application of the Sharpless
dihydroxylation proved highly successful. Dihydroxylation of 20
with dihydroquinidine-based ADmix-â14 provided the (R,R) diol
in >96:4 dr, and afforded only trace amounts of the tetraol and
terminal vinyl dihydroxylation products. Sequential treatment of
the diol with trimethylorthoacetate, acetyl bromide, and K2CO3 in
one pot15 provided epoxide 21 in 81% yield (Scheme 3).
Removal of the benzyl carbamate was accomplished with Et2-
AlCl/thioanisole.16 Other deprotection strategies either led to no
reaction or resulted in decomposition to complex mixtures. The
long reaction times generally required to effect cyclization to the
quinuclidine core4,17 proved unnecessary as a result of a second
implementation of microwave technology; irradiation at 200 °C in
CH3CN for only 20 min provided a 68% isolated yield of synthetic
quinine.
(2) (a) Kacprzak, K.; Gawron´ski, J. Synthesis 2001, 961-998. (b) Yoon, T.
P.; Jacobsen, E. N. Science 2003, 299, 1691-1693.
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G. J. Am. Chem. Soc. 2001, 123, 3239-3242.
(4) Gutzwiller, J.; Uskokovic, M. J. Am. Chem. Soc. 1978, 100, 576-581,
and references therein.
(5) Taylor, M. S.; Jacobsen, E. N. J. Am. Chem. Soc. 2003, 125, 11204-
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(8) For a review, see: Ley, S. V.; Norman, J.; Griffith, W. P.; Marsden, S.
P. Synthesis 1994, 639-666.
(9) Takai, K.; Shinomiya, N.; Kaihara, H.; Yoshida, N.; Moriwake, T. Synlett
1995, 963-964.
(10) Nicolaou, K. C.; Gross, J. L.; Kerr, M. A. J. Heterocycl. Chem. 1996, 33,
735-746.
(11) Attempts to carry out the Suzuki cross coupling with Pd(PPh3)4,
Pd(MeCN)2Cl2, Pd(PPh3)2Cl2, Pd2dba3/AsPh3, and Pd2dba3/PPh3 with and
without CuI additives gave only trace amounts of product. To the best of
our knowledge, no accounts exist of cross couplings between vinyl
boronate esters and 4-halo/triflatoquinolines.
Quinidine, a natural product that serves as a pseudo-enantiomeric
ligand and catalyst relative to quinine, is in fact epimeric to quinine
at C8 and C9. Trans epoxide 22 (diastereomeric to 21) was accessed
with high selectivity using dihydroquinine-based ADmix-R. Depro-
tection and thermal cyclization afforded quinidine (Scheme 4). Both
synthetic products were found to match the spectroscopic and
(12) Walker, S.; Buchwald, S. L. Manuscript in preparation.
(13) (a) Chang, S.; Galvin, J. M.; Jacobsen, E. N. J. Am. Chem. Soc. 1994,
116, 6937-6938. (b) Wang, Z.; Tu, Y.; Frohn, M.; Zhang, J.; Shi, Y. J.
Am. Chem. Soc. 1997, 119, 11224-11235. (c) Aggarwal, V. K.; Alonso,
E.; Hynd, G.; Lydon, K. M.; Palmer, M. J.; Porcelloni, M.; Studley, J. R.
Angew. Chem., Int. Ed. 2001, 41, 1430-1433.
(14) Sharpless, K. B.; Amberg, W.; Bennani, Y. L.; Crispino, G. A.; Hartung,
J.; Jeong, K.; Kwong, H.; Morikawa, K.; Wang, Z.; Xu, D.; Zhang, X. J.
Org. Chem. 1992, 57, 2768-2771.
(15) Kolb, H. C.; Sharpless, K. B. Tetrahedron 1992, 48, 10515-10530.
(16) Murai, A.; Tsujimoto, T. Synlett 2002, 1283-1284.
(17) (a) Brown, R. T.; Curless, D. Tetrahedron Lett. 1986, 27, 6005-6008.
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2346.
1
physical properties of authentic samples (HRMS, H NMR, 13C
NMR).5,18
Asymmetric catalyst-based syntheses open the possibility of
accessing diastereomeric products by a common route by simply
varying the stereochemistry of the catalysts,19 as is illustrated
compellingly in these enantioselective syntheses of quinine and
quinidine. The fact that classical and challenging synthetic targets
such as the cinchona alkaloids can be accessed efficiently (16 steps
in the longest linear sequence, with overall yields of ca. 5%) stands
as testament to the ever-growing scope and utility of modern
asymmetric catalysis.
(18) See the Supporting Information.
(19) Masamune, S.; Choy, W.; Petersen, J. S.; Sita, L. R. Angew. Chem., Int.
Ed. Engl. 1985, 24, 1-30.
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