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

Article abstract of DOI:10.1039/b606338a

A sequential, organocatalysed asymmetric reaction to access chiral 1,2-oxazines from achiral ketone starting materials is reported, which proceeds in moderate to good yields and excellent enantioselectivity. The Royal Society of Chemistry 2006.

Full text of DOI:10.1039/b606338a

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A highly selective, organocatalytic route to chiral 1,2-oxazines from
ketones
Sirirat Kumarn, David M. Shaw and Steven V. Ley*
Received (in Cambridge, UK) 5th May 2006, Accepted 5th June 2006
First published as an Advance Article on the web 19th June 2006
DOI: 10.1039/b606338a
The use of pyrrolidinyl-tetrazole 1a as a catalyst for this process
was based on its improved properties when compared for example
to L-proline. As with other chemistries developed independently by
ourselves,9 Yamamoto10 and Arvidsson11 where 1a was an
especially effective catalyst,7f,g it also proved to be the compound
of choice in this work.
A sequential, organocatalysed asymmetric reaction to access
chiral 1,2-oxazines from achiral ketone starting materials is
reported, which proceeds in moderate to good yields and
excellent enantioselectivity.
One of the important goals in chemistry is to develop
stereoselective transformations which generate useful structural
components present in biologically active natural products.1
Similarly, finding efficient ways of selectively preparing certain
heterocyclic systems still provides a significant challenge in organic
chemistry. Enantiopure 1,2-oxazines are potentially useful target
heterocycles as they can be further derivatised into various useful
groups by straightforward chemistry.2
The initial conditions that we had developed previously for
aldehydes,6 however, were disappointingly ineffective when applied
to ketonic substrates. As this was a severe limitation, we have
devised a new protocol which is reported herein to solve this
problem.
Firstly, the conditions employed for the a-oxyamination step
were similar to those used by Yamamoto.7g These, crucially, use a
much smaller excess of ketone (3 eq) such that the subsequent steps
may be carried out in a single pot. Another benefit of these
conditions was the use of reduced catalyst loading (5 mol%). It is
also worth noting that slow addition of nitrosobenzene to a
mixture of ketone and the pyrrolidinyl-tetrazole catalyst was
necessary to minimise the formation of the homodimer of
nitrosobenzene. However, the sequential Wittig process became
problematic. The optimisation study was then centred on the
cyclisation step from the a-oxyamination intermediates of
cyclohexanone and butan-2-one (Table 1). After several bases,
Wittig reagents and solvent systems had been investigated, the
reaction from butan-2-one was found to be optimal by the use of
KH as a base. A mixed solvent system (1 : 1 THF/DMSO) also
noticeably increased the yield (Entry 15, Table 1). Moreover, these
conditions facilitate the tandem nature of the reaction as the
a-oxyamination step was carried out in DMSO. Remarkably, an
excess of KH did not cause racemisation of the stereogenic centre
generated during the a-oxyamination process (99% ee).
Previously, two routes to this class of molecule have been
predominant. They are the [4 + 2] cycloaddition between nitroso
compounds and dienes, and the ring closing metathesis of suitable
alkene precursors. However, the reaction of nitroso compounds
with dienes can suffer from poor regiocontrol and the products are
racemic without control induced by chiral substituents3 or chiral
auxiliaries.4 These asymmetric methods also have a very limited
substrate scope, generating only certain substitution patterns. Ring
closing metathesis is more general and supplies useful regio- and
stereocontrol. However, this must be imparted from particular
chiral starting materials.5
We have recently demonstrated an efficient new route to chiral
dihydro-1,2-oxazines from commercially available achiral alde-
hydes with excellent enantioselectivity using pyrrolidinyl-tetrazole
1a as an organocatalyst in a tandem reaction sequence (Scheme 1).6
The transformation involves an asymmetric organocatalytic
a-oxyamination7 with nitrosobenzene and the catalyst, using
conditions similar to those developed by Zhong,7a to afford an
intermediate which undergoes conjugate addition to a vinylpho-
sphonium salt. The resulting ylide cyclises to the dihydro-1,2-
oxazine via an intramolecular Wittig process8 (Scheme 2).
The absolute configuration of both the a-oxyaminated ketone
intermediates and oxazine products was determined by correlation
with the aD values found from the analogous reactions using
L-proline as catalyst.
Armed with this information, the scope of the ketone substrates
(7a–e) was then investigated using catalyst 1a (Table 2). We were
Scheme 1 Synthesis of dihydro-1,2-oxazines from aldehyde substrates.
Department of Chemistry, University of Cambridge, Lensfield Road,
Cambridge, UK CB2 1EW. E-mail: svl1000@cam.ac.uk;
Fax: +44 1223 336442; Tel: +44 1223 336398
Scheme 2 Projected synthesis of chiral 1,2-oxazines.
Chem. Commun., 2006, 3211–3213 | 3211
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Table 1 Optimisation reactions for the sequential Wittig step
Entry
2
Base
—
Solvent Temp. (uC)
3
Product Entry
2
Base
Solvent
Temp. (uC)
3
Product
112
2
3
4
2a
MeCN
THF
85
3a 5 (8%)a
9
10
11
12
13
14
15
2b 1.1 eq NaH THF
2b 1.1 eq NaH DMF
2b 1.8 eq NaH THF
2b 2.0 eq NaH THF
2b 2.0 eq NaH THF
0 A rt
0 A rt
0 A rt
0 A rt
0
3a
3a
—
—
2a 1.1 eq NaH
0 A rt
278
rt
3a 5b
2a 1.1 eq nBuLi THF
3a
3a
—
—
3a 4b (13)a
3a 4b (28)a
3a 4b (29)a
3a 4b (48)a
3a 4b (71)a
2a 1.1 eq NaH
2a 2.0 eq NaH
2a 1.3 eq NaH
2b
2b
DMF
THF
DMSO 0 A rt
MeCN
MeOH
5
0 A rt
3a 5b
613
712
814
a
3a
—
2b 3.0 eq KH
2b 3.0 eq KH
THF
THF/DMSO
0
0
—
—
85
20
3a 6ab
3b 6bb
Isolated yields of material after chromatography. Detected by crude 1H NMR.
b
Table 2 Synthesis of 1,2-oxazines catalysed by L-pyrrolidinyl-tetra-
zole
pleased to find that the reaction conditions developed were indeed
applicable to a range of ketones (3 eq) using just 5 mol% catalyst,
to give moderate to good yields of product and excellent ee’s
throughout.{ In only one case (Entry 5, Table 2), that of the linear
butan-2-one substrate, was it necessary to use a higher excess of
ketone (20 eq) and catalyst (20 mol%).
The use of more substituted vinylphosphonium bromide 3c in
this reaction gave the tetrasubstituted 1,2-oxazine 4f (Entry 6,
Table 2). It is also of note that the 1,2-oxazine 4g was generated
with complete diastereoselectivity15 and excellent enantioselectivity
(Entry 7, Table 2).
Entry
1
Ketone
3
1,2-Oxazine
Yielda (ee)b
60 (99)
%
The opposite enantiomer of the pyrrolidinyl-tetrazole catalyst,
1b was also applied to selected ketone examples to verify its use in
these transformations. This was successful in providing the
corresponding enantiomeric 1,2-oxazine products (Table 3).
3a
2
3
4
3a
3a
3a
33 (99)
51 (99)
50 (99)
Table 3 Synthesis of 1,2-oxazines catalysed by D-pyrrolidinyl-tetra-
zole
Entry
1
Ketone
1,2-Oxazine
Yielda (ee)b
57 (99)
%
5
6
7
3a
3c
3d
46c (99)
39 (99)
65 (99)
2
3
a
54 (99)
38 (99)
b
a
b
Isolated yields of material after chromatography. The ee values
c
were determined directly by chiral HPLC. Reaction of 20 eq of 7b
was conducted with 20 mol% of 1a.
Isolated yields of material after chromatography. The ee values
were determined directly by chiral HPLC.
3212 | Chem. Commun., 2006, 3211–3213
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and 3 N aqueous HCl (20 eq). The resulting suspension was stirred
vigorously at room temperature until the reaction was determined to be
complete by TLC. The reaction mixture was quenched (NaHCO3), diluted
(H2O) and extracted (3 6 EtOAc). The combined organic phase was dried
(MgSO4), filtered and concentrated in vacuo. The resulting residue was
purified by flash column chromatography to provide the desired
compound.
Table 4 Synthesis of cis-allylic alcohols through N–O bond cleavage
1 (a) H. Terano, S. Takase, J. Hosoda and M. Kohsaka, J. Antibiot.,
1989, 42, 145; (b) I. Uchida, S. Takase, H. Kayakiri, S. Kiyoto,
M. Hashimoto, T. Tada, S. Koda and Y. Morimoto, J. Am. Chem.
Soc., 1987, 109, 4108; (c) M. Iwami, S. Kiyoto, H. Terano, M. Kohsaka,
H. Aoki and H. Imanaka, J. Antibiot., 1987, 40, 589; (d) S. Kiyoto,
T. Shibata, M. Yamashita, T. Komori, M. Okuhara, H. Terano,
M. Kohsaka, H. Aoki and H. Imanaka, J. Antibiot., 1987, 40, 594; (e)
K. Shimomura, O. Hirai, T. Mizota, S. Matsumoto, J. Mori,
F. Shibayama and H. Kikuchi, J. Antibiot., 1987, 40, 600; (f) O. Hirai,
K. Shimomura, T. Mizota, S. Matsumoto, J. Mori and H. Kikuchi,
J. Antibiot., 1987, 40, 607; (g) Z. Hori, M. Yamauchi, T. Imanishi,
J. Parello, M. Hanaoka and S. Munavall, Tetrahedron Lett., 1972, 1877.
2 P. G. Tsoungas, Heterocycles, 2002, 57, 915.
Entry 1,2-Oxazine Time (h) Alcohol
Yielda (ee)b
83 (99)
%
1
2
3
a
48
18
36
quant. (99)
88 (99)
3 (a) P. F. Vogt and M. J. Miller, Tetrahedron, 1998, 54, 1317; (b) J. Streith
and A. Defoin, Synlett, 1996, 189; (c) S. E. Denmark and
A. Thorarensen, Chem. Rev., 1996, 96, 137.
4 X. Ding, Y. Ukaji, S. Fujinami and K. Inomata, Chem. Lett., 2003, 32,
582.
b
Isolated yields of material after chromatography. The ee values
were determined directly by chiral HPLC.
5 (a) A. Le Flohic, C. Meyer, J. Cossy and J. R. Desmurs, Tetrahedron
Lett., 2003, 44, 8577; (b) Y. K. Yang and J. Tae, Synlett, 2003, 2017; (c)
Y. K. Yang and J. Tae, Synlett, 2003, 1043; (d) K. Koide,
J. M. Finkelstein, Z. Ball and G. L. Verdine, J. Am. Chem. Soc.,
2001, 123, 398.
Cleavage of the N–O bond of selected examples liberated the
synthetically useful free cis-allylic alcohols in high yield using zinc
in methanolic HCl, with retention of enantiopurity (Table 4).{
In summary, we have described a sequential one-pot synthesis of
more substituted chiral 1,2-oxazines from commercially available
achiral ketone starting materials. The products undergo facile N–O
bond cleavage to provide cis-allylic alcohols, thus proving that
these substrates could be elaborated to more useful building
blocks. Further efforts to evaluate the use of these methods and
their application to natural product synthesis and related processes
are underway.
6 S. Kumarn, D. M. Shaw, D. A. Longbottom and S. V. Ley, Org. Lett.,
2005, 7, 4189.
7 For representative papers, see: (a) G. Zhong, Angew. Chem., Int. Ed.,
2003, 42, 4247; (b) S. P. Brown, M. P. Brochu, C. J. Sinz and D. W. C.
MacMillan, J. Am. Chem. Soc., 2003, 125, 10808; (c) A. Bogevig,
H. Sunden and A. Cordova, Angew. Chem., Int. Ed., 2004, 43, 1109; (d)
Y. Hayashi, J. Yamaguchi, T. Sumiya and M. Shoji, Angew. Chem., Int.
Ed., 2004, 43, 1112; (e) Y. Hayashi, J. Yamaguchi, K. Hibino and
M. Shoji, Tetrahedron Lett., 2003, 44, 8293; (f) Y. Yamamoto,
N. Momiyama and H. Yamamoto, J. Am. Chem. Soc., 2004, 126,
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Natl. Acad. Sci. U. S. A., 2004, 101, 5374; (h) W. Wang, J. Wang, H. Li
and L. Liao, Tetrahedron Lett., 2004, 45, 7235; (i) D. B. Ramachary and
C. F. Barbas, III, Org. Lett., 2005, 7, 1577.
We gratefully acknowledge the Royal Thai Government (to
S.K.), AstraZeneca (to D.M.S.) and Novartis for a research
fellowship (to S.V.L.) and Dr G. Sedelmeier and V. Aureggi for
the kind donation of D-pyrrolidinyl-tetrazole. We also thank Drs
Deborah A. Longbottom, Matthew Ball and Alejandro Dieguez
for useful discussions.
8 E. E. Schweizer, J. E. Hayes and E. M. Hanawalt, J. Org. Chem., 1985,
50, 2591.
9 (a) A. J. A. Cobb, D. M. Shaw and S. V. Ley, Synlett, 2004, 558; (b)
A. J. A. Cobb, D. A. Longbottom, D. M. Shaw and S. V. Ley, Chem.
Commun., 2004, 1808; (c) A. J. A. Cobb, D. M. Shaw,
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2005, 3, 84; (d) C. E. T. Mitchell, S. E. Brenner and S. V. Ley, Chem.
Commun., 2005, 5346; (e) K. R. Knudsen, C. E. T. Mitchell and
S. V. Ley, Chem. Commun., 2006, 66; (f) C. E. T. Mitchell, S. E. Brenner,
J. Garc´ıa-Fortanet and S. V. Ley, Org. Biomol. Chem., 2006, 4, 2039; (g)
Notes and references
{ Typical experimental procedure.
Synthesis of 1,2-oxazines. To a stirred solution of (2S)-5-pyrrolidin-2-yl-
1H-tetrazole (7 mg, 0.05 mmol, 5 mol%) and the appropriate ketone
(3.00 mmol) in DMSO (3 ml) was added a solution of nitrosobenzene
(0.11 g, 1.00 mmol) in DMSO (2 ml) dropwise via syringe over 1 h. The
reaction mixture was allowed to stir for a further 1 h, then vinyltriphe-
nylphosphonium bromide (0.57 g, 1.50 mmol) was added. The resulting
solution was added to a stirred suspension of KH (0.40 g, 30% in mineral
oil, washed with hexanes, 3.00 mmol) in THF (5 ml) at 0 uC. After 2 h of
vigorous stirring at 0 uC, the reaction mixture was quenched (NH4Cl aq),
extracted (3 6 Et2O) and washed (LiCl aq). The combined organic phase
was dried (MgSO4), filtered and concentrated in vacuo. The resulting
residue was purified by flash column chromatography to provide the
oxazine products.
ˇ
V. Franckevicius, K. R. Knudsen, M. Ladlow, D. A. Longbottom and
S. V. Ley, Synlett, 2006, 889.
10 H. Torii, M. Nakadai, K. Ishihara, S. Saito and H. Yamamoto, Angew.
Chem., Int. Ed., 2004, 43, 1983.
11 (a) A. Hartikka and P. I. Arvidsson, Tetrahedron: Asymmetry, 2004, 15,
1831; (b) A. Hartikka and P. I. Arvidsson, Eur. J. Org. Chem., 2005,
4287.
12 R. J. Linderman and A. I. Meyers, Tetrahedron Lett., 1983, 24, 3043.
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5497.
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M. M. Zaleska and J. A. Moyer, J. Med. Chem., 1998, 41, 236.
15 Assigned by 700 MHz NOESY spectrum.
{ Synthesis of cis-allylic alcohols via N–O bond cleavage. To a stirred
solution of the 1,2-oxazine (1 eq) in MeOH was added zinc powder (5 eq)
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Chem. Commun., 2006, 3211–3213 | 3213