C O M M U N I C A T I O N S
deprotection of the piperidine and quinoline rings and cyclization,22
but apparently oxidation of the quinoline ring was slow. However,
simply stirring the crude reaction mixture under an atmosphere of
O2 overnight effected oxidation and gave quinine in 73% yield over
four steps.
2003, 125, 10926. (i) Davoust, M.; Brie`re, J.-F.; Jaffre`s, P. A.; Metzner,
P. J. Org. Chem. 2005, 70, 4166. (j) Hansch, M.; Illa, O.; McGarrigle,
E. M.; Aggarwal, V. K. Chem. Asian J. 2008, 3, 1657. (k) Badine, D. M.;
Hebach, C.; Aggarwal, V. K. Chem. Asian J. 2006, 1, 438. (l) Gui, Y.; Li,
J.; Guo, C.-S.; Li, X.-L.; Lu, Z.-F.; Huang, Z.-Z. AdV. Synth. Catal. 2008,
350, 2483. (m) Sarabia, F.; Chammaa, S.; Garc´ıa-Castro, M.; Mart´ın-Ga´lvez,
F. Chem. Commun. 2009, 5763.
(5) (a) Weitkamp, A. W. J. Am. Chem. Soc. 1959, 81, 3430. (b) Weitkamp,
A. W. Chem. Abs. 1962, 57, 4706g (U.S. Patent 3,026,315, Mar 20, 1962).
(6) Although the original procedure by Weitkamp had been optimized and
operated on a >100 gallon scale, it still resulted in low yield and erosion
in er and required a difficult separation of the product isothiocineole from
various side products. By adding γ-terpinene a much improved synthesis
was achieved without erosion of er and with simple isolation. Full details
on its role will be reported in due course.
(7) (R)-Limonene is an extremely cheap chiral pool material, available in bulk
quantities. Sulfide (-)-1 costs <$1/g to synthesize based on Aldrich’s current
UK prices. (S)-Limonene is also available in bulk but is normally available
as a 90:10 mixture of enantiomers. In this case, two successive low
temperature (-50 °C) recrystallizations from pentane furnished enantiopure
(+)-isothiocineole.
Quinidine, which is an epimer of quinine at C8 and C9, was
easily made simply by using the opposite sulfide enantiomer ent-
1. In the key step, reaction of sulfonium salt ent-10 with aldehyde
6 gave epoxide 12 as an 84:16 mixture of trans/cis epoxides which,
again, were the only two isomers detected by NMR. Since both
epoxides 11 and 12 had been isolated and their differences identified
by NMR, it was clear that they had been formed exclusively in the
epoxidation step, showing that the sulfide is able to deliver perfect
enantiocontrol. As before, treatment with CsF in DMF under
microwave conditions initiated a reaction cascade which, after
stirring over O2, gave quinidine in 78% yield.
In conclusion, we have developed a facile synthesis of isothio-
cineole, a sulfide which has been found to be highly effective in
asymmetric epoxidation and aziridination reactions. The straight-
forward synthesis of the sulfide, broad scope of epoxidations and
aziridinations especially in the synthesis of synthetically useful 1,2-
arylalkyl and R,ꢀ-unsaturated epoxides and aziridines, and simple
reaction conditions now allow the asymmetric sulfur ylide mediated
transformations to be routinely employed for everyday use and
larger scale applications in synthesis. This has been demonstrated
in a convergent and stereoselective synthesis of each of the
diastereoisomers of the cinchona alkaloids, quinine and quinidine.
(8) We have scaled up the reaction uneventfully to an ∼1 mol scale. This
material is commercially available from TCI (T2578 and T2579).
(9) This was prepared by alkylation of the sulfide with BnBr and required
24 h at 20 °C. The alkylation of sulfides with flanking gem-dimethyl groups,
e.g. 1,4-oxathianes (see 4k) or 1,3-thioacetals [Solladie´-Cavallo, A.; Diep-
ˇ
Vohuule, A.; Sunjic¸, V.; Vinkovic, V. Tetrahedron: Asymmetry 1996, 7,
1783. ] is usually difficult. In the event, alkylation proved to be facile,
presumably because of the lack of heteroatoms within the ring which, in
the case of 1,4-oxathianes or 1,3-thioacetals, reduce the nucleophilicity of
the sulfide through inductive effects.
(10) See page S14 in the SI for a comparison with sulfide 2.
(11) For other notable examples using sulfur ylides see: ref 4c,g,h,k: Aggarwal,
V. K.; Bae, I.; Lee, H.-Y.; Richardson, J.; Williams, D. T. Angew. Chem.,
Int. Ed. 2003, 42, 3274. Zanardi, J.; Lamazure, D.; Minie`re, S.; Reboul,
V.; Metzner, P. J. Org. Chem. 2002, 67, 9083. For a review on vinyl
epoxides see ref 3b.
(12) For reviews see: (a) Mu¨ller, P.; Fruit, C. Chem. ReV. 2003, 103, 2905. (b)
Aggarwal, V. K.; Badine, D. M.; Moorthie, V. A. In Aziridines and
Epoxides in Asymmetric Synthesis; Yudin, A. K., Ed.; Wiley-VCH:
Weinheim, Germany 2006; Chapter 1. (c) Sweeney, J. B. ibid; Chapter 4.
For highly enantioselective sulfur ylide aziridinations: (d) Aggarwal, V. K.;
Alonso, E.; Fang, G.; Ferrara, M.; Hynd, G.; Porcelloni, M. Angew. Chem.,
Int. Ed. 2001, 40, 1433. (e) Saito, T.; Sakairi, M.; Akiba, D. Tetrahedron
Lett. 2001, 42, 5451. (f) Aggarwal, V. K.; Thompson, A.; Jones, R. V. H.;
Standen, M. C. H. J. Org. Chem. 1996, 61, 8368. (g) Li, A.-H.; Zhou,
Y.-G.; Dai, L.-X.; Hou, X.-L.; Xia, L.-J.; Lin, L. Angew. Chem., Int. Ed.
1997, 36, 1317. (h) Li, A.-H.; Zhou, Y.-G.; Dai, X.-L.; Hou, X.-L.; Xia,
L.-J.; Lin, L. J. Org. Chem. 1998, 63, 4338. (i) Li, A.-H.; Dai, L.-X.; Hou,
X.-L.; Chen, M.-B. J. Org. Chem. 1996, 61, 4641. (j) Solladie´-Cavallo,
Acknowledgment. O.I. thanks the Departament d’Educacio i
Universitats de la Generalitat de Catalunya for a Fellowship. M.A.
thanks the Higher Education Commission of Pakistan for a
studentship. A.R. thanks the EU for a Marie Curie Fellowship.
V.K.A. thanks the RS for a Wolfson Research Merit Award, the
EPSRC for a Senior Research Fellowship, and Merck for research
support.
ˇ
A.; Roje, M.; Welter, R.; Sunjic¸, V. J. Org. Chem. 2004, 69, 1409. (k)
Stipet´ı, I.; Roje, M.; Hamersˇak, Z. Synlett 2008, 3149.
(13) (a) Aggarwal, V. K.; Richardson, J. Chem. Commun. 2003, 2644. (b)
Aggarwal, V. K.; Harvey, J. N.; Richardson, J. J. Am. Chem. Soc. 2002,
124, 5747.
(14) For an excellent review see: Kaufmann, T. S.; Ru´veda, E. A. Angew. Chem.,
Int. Ed. 2005, 44, 854. For the first stereocontrolled synthesis see: (a) Stork,
G.; Niu, D.; Fujimoto, R. A.; Koft, E. R.; Balkovec, J. M.; Tata, J. R.;
Dake, G. R. J. Am. Chem. Soc. 2001, 123, 3239. For recent discussion
surrounding Woodward’s synthesis see: (b) Seeman, J. I. Angew. Chem.,
Int. Ed. 2007, 46, 1378. (c) Smith, A. C.; Williams, R. M. Angew. Chem.,
Int. Ed. 2008, 47, 1736.
(15) Gutzwiller, J.; Uskokovic, M. J. Am. Chem. Soc. 1978, 100, 576.
(16) (a) Raheem, I. T.; Goodman, S. N.; Jacobsen, E. N. J. Am. Chem. Soc.
2004, 126, 706. (b) Igarashi, J.; Katsukawa, M.; Wang, Y.-G.; Acharya,
H. P.; Kobayashi, Y. Tetrahedron Lett. 2004, 45, 3783. (c) Igarashi, J.;
Kobayashi, Y. Tetrahedron Lett. 2005, 46, 6381.
(17) Taylor, E. C.; Martin, S. F. J. Am. Chem. Soc. 1974, 96, 8095.
(18) Kobayashi used this protecting group on the piperidine ring in his synthesis
of quinine. Ref 16c.
Supporting Information Available: Synthesis and characterization
of all compounds. This material is available free of charge via the
References
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by a group not involved in the development of chiral sulfides: Morales-
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(21) Although aldehyde 6 has been prepared by total synthesis (ref 16c), we
obtained it more directly from quinine (5 steps) using procedures described
previously (see SI): Martinelli, M. J.; Peterson, B. C.; Khau, V. V.;
Hutchison, D. R.; Sullivan, K. A. Tetrahedron Lett. 1993, 34, 5413. Clark,
J. S.; Townsend, R. J.; Blake, A. J.; Teat, S. J.; Johns, A. Tetrahedron
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are relay syntheses.
(4) (a) Breau, L.; Durst, T. Tetrahedron: Asymmetry 1991, 2, 367. (b) Solladie´-
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Cavallo, A.; Roje, M.; Isarno, T.; Sunjic¸, V.; Vinkovic, V. Eur. J. Org.
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Chem. 2001, 66, 5620. (h) Aggarwal, V. K.; Alonso, E.; Bae, I.; Hynd, G.;
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