A highly selective, organocatalytic route to chiral dihydro-1,2-oxazines

Article abstract of DOI:10.1021/ol051577u

(Chemical Equation Presented) The organocatalyzed asymmetric synthesis of chiral dihydro-1,2-oxazines from achiral starting materials proceeds in moderate to excellent yields and excellent enantioselectivity. This sequential reaction gives the desired pro

Full text of DOI:10.1021/ol051577u

ORGANIC
LETTERS
2005
Vol. 7, No. 19
4189-4191
A Highly Selective, Organocatalytic
Route to Chiral Dihydro-1,2-oxazines
Sirirat Kumarn, David M. Shaw, Deborah A. Longbottom, and Steven V. Ley*
Department of Chemistry, UniVersity of Cambridge, Lensfield Road,
Cambridge CB2 1EW, U.K.
sVl1000@cam.ac.uk
Received July 6, 2005
ABSTRACT
The organocatalyzed asymmetric synthesis of chiral dihydro-1,2-oxazines from achiral starting materials proceeds in moderate to excellent
yields and excellent enantioselectivity. This sequential reaction gives the desired products in a single pot.
The synthesis of enantiomerically pure 1,2-oxazines repre-
sents an interesting challenge because there is a scarcity of
methods for their preparation.1 This unit is present in
biologically active natural products2 (Figure 1) and is an
nitroso compounds with dienes can suffer from poor regio-
control and is inherently racemic without control induced
by chiral substituents4 or chiral auxiliaries.5 Ring-closing
metathesis is also useful in that regio- and stereocontrol can
be imparted from chiral starting materials, although it can
be somewhat protracted as a result.6 Elegant new methods
for the synthesis of tetrahydro-1,2-oxazine derivatives have
been achieved with either diastereoselective7 or enantio-
(2) (a) Terano, H.; Takase, S.; Hosoda, J.; Kohsaka, M. J. Antibiot. 1989,
42, 145. (b) Uchida, I.; Takase, S.; Kayakiri, H.; Kiyoto, S.; Hashimoto,
M.; Tada, T.; Koda, S.; Morimoto, Y. J. Am. Chem. Soc. 1987, 109, 4108.
(c) Iwami, M.; Kiyoto, S.; Terano, H.; Kohsaka, M.; Aoki, H.; Imanaka,
H. J. Antibiot. 1987, 40, 589. (d) Kiyoto, S.; Shibata, T.; Yamashita, M.;
Komori, T.; Okuhara, M.; Terano, H.; Kohsaka, M.; Aoki, H.; Imanaka,
H. J. Antibiot. 1987, 40, 594. (e) Shimomura, K.; Hirai, O.; Mizota, T.;
Matsumoto, S.; Mori, J.; Shibayama, F.; Kikuchi, H. J. Antibiot. 1987, 40,
600. (f) Hirai, O.; Shimomura, K.; Mizota, T.; Matsumoto, S.; Mori, J.;
Kikuchi, H. J. Antibiot. 1987, 40, 607. (g) Hori, Z.; Yamauchi, M.; Imanishi,
T.; Parello, J.; Hanaoka, M.; Munavall, S. Tetrahedron Lett. 1972, 1877.
(3) Tsoungas, P. G. Heterocycles 2002, 57, 915.
Figure 1. Natural products containing the 1,2-oxazine functionality.
(4) (a) Vogt, P. F.; Miller, M. J. Tetrahedron 1998, 54, 1317. (b) Streith,
J.; Defoin, A. Synlett 1996, 189. (c) Denmark, S. E.; Thorarensen, A. Chem.
ReV. 1996, 96, 137.
amino-heterocycle with potential as a medicinal scaffold, as
well as scope for further elaboration.3 Achieving an efficient
and selective method for the preparation of this group is
therefore a valuable goal. In general two routes to this class
of molecule are used. They are the [4 + 2] cycloaddition
between nitroso compounds and dienes and the ring-closing
metathesis of suitable precursors. However, the reaction of
(5) Ding, X.; Ukaji, Y.; Fujinami, S.; Inomata, K. Chem. Lett. 2003, 32,
582.
(6) (a) Le Flohic, A.; Meyer, C.; Cossy, J.; Desmurs, J. R. Tetrahedron
Lett. 2003, 44, 8577. (b) Yang, Y. K.; Tae, J. Synlett 2003, 2017. (c) Yang,
Y. K.; Tae, J. Synlett 2003, 1043. (d) Koide, K.; Finkelstein, J. M.; Ball,
Z.; Verdine, G. L. J. Am. Chem. Soc. 2001, 123, 398.
(7) (a) Young, I. S.; Williams, J. L.; Kerr, M. A. Org. Lett. 2005, 7,
953. (b) Ganton, M. D.; Kerr, M. A. J. Org. Chem. 2004, 69, 8554. (c)
Miyata, O.; Namba, M.; Ueda, M.; Naito, T. Org. Biomol. Chem. 2004, 2,
1274. (d) Young, I. S.; Kerr, M. A. Angew. Chem., Int. Ed. 2003, 42, 3023.
(1) Tsoungas, P. G. Heterocycles 2002, 57, 1149.
10.1021/ol051577u CCC: $30.25
© 2005 American Chemical Society
Published on Web 08/23/2005

selective control.8 Despite these notable examples, the
catalytic synthesis of chiral nonracemic 1,2-oxazines from
commercially available achiral starting materials is not
known. Here we describe such a process: a multicomponent
reaction sequence to produce dihydro-1,2-oxazines, which
proceeds with excellent enantio- and regioselectivity.
It was envisaged that R-oxyamination of an enamine
intermediate with nitrosobenzene9-12 could be followed by
nucleophilic attack on a vinyl phosphonium salt, which would
subsequently form a dihydro-1,2-oxazine through an in-
tramolecular Wittig process13 (Scheme 1).
Table 1. Synthesis of Dihydro-1,2-oxazines Catalyzed by
L-Pyrrolidinyl-tetrazole 2
Scheme 1. Projected Synthesis of Chiral Dihydro-1,2-oxazines
Initial work centered on conditions most appropriate for
the organocatalytic R-oxyamination reaction, while remaining
suitable to carry out the following steps in a single pot. We
therefore chose conditions similar to those first developed
by Zhong,10 as only a small excess of aldehyde partner was
required. Studies were carried out with isovaleraldehyde,
owing to the good yields achieved in R-oxyamination
reactions. Following R-oxyamination, attempts to effect
conjugate addition based upon thermally inducing the reac-
tion were unsuccessful, and addition through a base-mediated
reaction was subsequently investigated. Pleasingly, after
optimization, it was found that addition of 2 equivalents of
(8) Sibi, M. P.; Ma, Z. H.; Jasperse, C. P. J. Am. Chem. Soc. 2005, 127,
5764.
a Isolated yields of chromatographed material. b The ee values were
determined directly by chiral HPLC. c The ee was determined by chiral
HPLC following N-O bond cleavage. d The ee was determined directly
by chiral GC.
(9) (a) Hayashi, Y.; Yamaguchi, J.; Hibino, K.; Shoji, M. Tetrahedron
Lett. 2003, 44, 8293. (b) Brown, S. P.; Brochu, M. P.; Sinz, C. J.; MacMillan,
D. W. C. J. Am. Chem. Soc. 2003, 125, 10808. (c) Bogevig, A.; Sunden,
H.; Cordova, A. Angew. Chem., Int. Ed. 2004, 43, 1109. (d) Casas, J.;
Sunden, H.; Cordova, A. Tetrahedron Lett. 2004, 45, 6117. (e) Cheong, P.
H. Y.; Houk, K. N. J. Am. Chem. Soc. 2004, 126, 13912. (e) Cordova, A.;
Sunden, H.; Bogevig, A.; Johansson, M.; Himo, F. Chem. Eur. J. 2004,
10, 3673. (f) Hayashi, Y.; Yamaguchi, J.; Hibino, K.; Sumiya, T.; Urushima,
T.; Shoji, M.; Hashizume, D.; Koshino, H. AdV. Synth. Catal. 2004, 346,
1435. (g) Hayashi, Y.; Yamaguchi, J.; Sumiya, T.; Hibino, K.; Shoji, M. J.
Org. Chem. 2004, 69, 5966. (h) Hayashi, Y.; Yamaguchi, J.; Sumiya, T.;
Shoji, M. Angew. Chem., Int. Ed. 2004, 43, 1112. (i) Ibrahem, I.; Casas, J.;
Cordova, A. Angew. Chem., Int. Ed. 2004, 43, 6528. (j) Mathew, S. P.;
Iwamura, H.; Blackmond, D. G. Angew. Chem., Int. Ed. 2004, 43, 3317.
(k) Merino, P.; Tejero, T. Angew. Chem., Int. Ed. 2004, 43, 2995. (l) Wang,
W.; Wang, J.; Li, H.; Liao, L. X. Tetrahedron Lett. 2004, 45, 7235. (m)
Zhong, G.; Yu, Y. P. Org. Lett. 2004, 6, 1637. (n) Zhong, G. Chem.
Commun. 2004, 606. (o) Engqvist, M.; Casas, J.; Sunden, H.; Ibrahem, I.;
Cordova, A. Tetrahedron Lett. 2005, 46, 2053. (p) Ramachary, D. B.;
Barbas, C. F. Org. Lett. 2005, 7, 1577. (q) Sunden, H.; Dahlin, N.; Ibrahem,
I.; Adolfsson, H.; Cordova, A. Tetrahedron Lett. 2005, 46, 3385. (r) Janey,
J. M. Angew. Chem., Int. Ed. 2005, 44, 4292.
NaH gave excellent conversion (71% yield) and showed
excellent enantioselectivity (99% ee).
The absolute configuration was assigned by comparison
with the R-oxyamination of isovaleraldehyde with L-proline
by Zhong, where the absolute configuration was determined
unambiguosly.10 Pyrrolidinyl-tetrazole 2, developed inde-
pendently by our group,14 Yamamoto,12 and Arvidsson,15 was
found to be the optimum catalyst tested in this process.11,16
With this information in hand, the scope of this reaction was
(14) (a) Cobb, A. J. A.; Shaw, D. M.; Ley, S. V. Synlett 2004, 558. (b)
Cobb, A. J. A.; Longbottom, D. A.; Shaw, D. M.; Ley, S. V. Chem.
Commun. 2004, 1808. (c) Cobb, A. J. A.; Shaw, D. M.; Longbottom, D.
A.; Gold, J. B.; Ley, S. V. Org. Biomol. Chem. 2005, 3, 84.
(15) Hartikka, A.; Arvidsson, P. I. Tetrahedron: Asymmetry 2004, 15,
1831.
(10) Zhong, G. Angew. Chem., Int. Ed. 2003, 42, 4247.
(11) Momiyama, N.; Torii, H.; Saito, S.; Yamamoto, H. Proc. Natl. Acad.
Sci. U.S.A. 2004, 101, 5374.
(12) Torii, H.; Nakadai, M.; Ishihara, K.; Saito, S.; Yamamoto, H. Angew.
Chem., Int. Ed. 2004, 43, 1983.
(13) Schweizer, E. E.; Hayes, J. E.; Hanawalt, E. M. J. Org. Chem. 1985,
50, 2591.
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2004, 126, 5962.
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Org. Lett., Vol. 7, No. 19, 2005

then assessed using catalyst 2 and a range of aldehydes
(Table 1).
methanolic HCl (Table 3). Upon N-O cleavage, enantio-
purity and side chain geometry were retained (entries 2 and
Interestingly linear aldehydes gave yields lower than those
of branched derivatives. This is thought to be related to the
ease of homo-aldol coupling and potential side reactions of
the products. Increasing the number of equivalents of
aldehyde tended to reduce the overall yield, supporting the
hypothesis that aldol products may interfere with the reaction.
The increasing yields observed as substitution of the aldehyde
increases (39% for 4d, 71% for 4a, and 82% for 4h) may
also suggest homo-aldol processes are competitive, as greater
substitution should disfavor homo-aldol reactions.
The reaction was then extended to the synthesis of a more
substituted dihydro-1,2-oxazine. Phosphonium salt 3b was
reacted under standard conditions to give the desired dihydro-
1,2-oxazine 4i in 53% yield and 99% ee, proving that access
to trisubstituted allylic alcohols could be achieved following
N-O bond reduction.
3).
Table 3. Synthesis of cis-Allylic Alcohols through N-O
Cleavage
Finally, we investigated the matched/mismatched effects
by using citronellal as a chiral aldehyde to create dihydro-
1,2-oxazines with pendant chirality. Although yields are
similar, diastereoselectivity did differ with a diastereomeric
ratio of 11:1 observed for the mismatched case (entry 1,
Table 2). Interestingly, with L-proline as catalyst, only a trace
of 4k was observed using the matched coupling partner.
a Isolated yields of chromatographed material. b The ee values were
determined directly by chiral HPLC.
Table 2. Synthesis of Dihydro-1,2-oxazines from Citronellal
In summary, a new one-pot synthesis of chiral dihydro-
1,2-oxazines from achiral starting materials has been devel-
oped. The products undergo facile N-O reduction to give
cis-allylic alcohols. We are now investigating the extension
of this methodology to supply tetrasubstituted dihydro-1,2-
oxazines and further synthetic applications of these dihydro-
1,2-oxazines and allylic alcohols shall be reported in due
course.
Acknowledgment. We gratefully acknowledge the Royal
Thai Government (to S.K.), AstraZeneca (to D.M.S), Trinity
College and the EPSRC (to D.A.L.), and Novartis for a
research fellowship (to S.V.L.). We also thank Dr. Matthew
J. Gaunt for useful discussion.
a Isolated yields of chromatographed material. b The de values were
determined directly by crude H NMR.
Supporting Information Available: Detailed experi-
mental procedure and characterization of the products. This
material is available free of charge via the Internet at
http://pubs.acs.org.
1
Cleavage of the N-O bond to liberate the free allylic
alcohol was then accomplished in high yield using zinc in
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