Stereoselective rearrangement of β-hydroxy-N-acyloxazolidin-2-ones to afford N-2-hydroxyethyl-1,3-oxazinane-2,4-diones

Article abstract of DOI:10.1055/s-2005-865212

Zinc alkoxides of syn- or anti-β-hydroxy-N-acyloxazolidin-2-ones undergo stereoselective rearrangement to afford their corresponding syn- or anti-N-2-hydroxyethyl-1,3-oxazinane-2,4-diones in good yield.

Full text of DOI:10.1055/s-2005-865212

1090
LETTER
Stereoselective Rearrangement of b-Hydroxy-N-acyloxazolidin-2-ones to
Afford N-2-Hydroxyethyl-1,3-oxazinane-2,4-diones
S
tereoselectiv
r
e
R
earran
e
gement of
d
b
-
Hydroxy-
N
-acyl
J
oxazolidin
.
-2-ones P. Feuillet, D. Gangani Niyadurupola, Rachel Green, Matt Cheeseman, Steven D. Bull*
Department of Chemistry, University of Bath, BA2 7AY, UK
Fax +44(1225)386231; E-mail: s.d.bull@bath.ac.uk
Received 8 February 2005
O
Abstract: Zinc alkoxides of syn- or anti-b-hydroxy-N-acyloxazol-
idin-2-ones undergo stereoselective rearrangement to afford their
corresponding syn- or anti-N-2-hydroxyethyl-1,3-oxazinane-2,4-
diones in good yield.
O
O
HO
Me
Br
(i)
N
O
O
N
95%
Me
O
Ph
>99% de
Me
Me
Key words: aldol reaction, diastereoselective, intramolecular rear-
rangement, 1,3-oxazinane-2,4-dione, zinc alkoxide
1
2
O
O
O
HO
Benzo-1,3-oxazinane-2,4-diones have often been
screened for activity as potential drug candidates,1 and a
range of synthetic methods is available for their prepara-
tion.2 Synthetic routes towards other types of 1,3-oxazi-
nane-2,4-dione are less well established, however,3 and as
a consequence their biological activity is less well ex-
plored. We were interested in preparing new types of 1,3-
oxazinane-2,4-dione as potential synthetic intermediates,4
or as novel medicinal agents,5 and now report that zinc
alkoxides of b-hydroxy-N-acyloxazolidin-2-ones undergo
stereoselective rearrangement to afford their correspond-
ing N-2-hydroxyethyl-5,6-disubstituted-1,3-oxazinane-
2,4-diones in good yield.
Me
(ii)
N
O
O
N
63%
>90% de
OBn
O
Me
OBn
3
4
O
O
O
HO
HO
O
N
O
N
O
Me
(iii)
O
N
+
:
O
Ph
O
Ph
83%
Br
Me
Me
5
62
38
6
7
Scheme 1 Reagents and conditions: (i) SnCl2, LiAlH4, THF,
PhCHO, 20 °C; (ii) LDA, THF, –78 °C, Ti(Oi-Pr)3Cl (3.3 equiv),
trans-crotonaldehyde; (iii) Zn, THF, PhCHO, 0 °C.
Oxazolidin-2-ones have proven particularly useful as
chiral auxiliaries in asymmetric aldol reactions for the
preparation of chiral b-hydroxy acid derivatives.6 For ex-
ample, boron,7 titanium,8 and germanium enolates9 of
chiral N-acyloxazolidin-2-ones react with aldehydes to af-
ford ‘Evans’ or ‘non-Evans’ syn-aldol products in high de.
Alternatively, boron enolates of chiral N-acyloxazolidin-
2-ones in the presence of excess Et2AlCl,10 their chromi-
um enolates,11 or Evans’ recently published magnesium
halide-catalysed protocol,12 all result in anti-aldol prod-
ucts in high de. Whilst these procedures normally afford
their respective aldol products in good yield and high de,
a number of reports has described the formation of N-2-
hydroxyethyl-1,3-oxazinane-2,4-diones as unexpected
rearrangement products.13,14 For example, reaction of a tin
enolate derived from N-acyloxazolidin-2-one 1 with benz-
aldehyde resulted in formation of 1,3-oxazinane-2,4-di-
one 2 in >99% de,15 whilst reaction of the lithium enolate
of 3 with crotonaldehyde in the presence of Ti(Oi-Pr)3Cl
gave 1,3-oxazinane-2,4-dione 4 in >90% de.4 Alternative-
ly, Terashima et al. reported that reaction of a zinc enolate
derived from 5 with benzaldehyde at 0 °C afforded a
62:38 mixture of (rac)-anti-1,3-oxazinane-2,4-dione 6
and (rac)-syn-1,3-oxazinane-2,4-dione 7 in 83% yield
(Scheme 1).16
Whilst no N-acyloxazolidin-2-one aldol intermediates
were isolated in these rearrangement reactions, these re-
ports clearly implied that tin-, titanium- or zinc alkoxides
of b-hydroxy-N-acyloxazolidin-2-ones could rearrange to
their corresponding 1,3-oxazinane-2,4-diones in high de.
We therefore decided to investigate whether suitable
conditions could be identified which would enable the
stereoselective rearrangement of diastereoisomerically
pure b-hydroxy-N-acyloxazolidin-2-ones to occur, thus
affording the corresponding 1,3-oxazinane-2,4-diones in
good yield and in high de.
Therefore, a series of twelve racemic and enantiomerical-
ly pure N-acyloxazolidin-2-one-syn-aldols 9a–l was pre-
pared in high de via reaction of the boron enolates of N-
acyloxazolidin-2-ones 8a–d with a series of commercially
available aldehydes,17 according to well established liter-
ature precedent.18 Given the precedent of Terashima et
al.,16 we proposed that conversion of syn-aldols 9a–l into
their corresponding zinc alkoxides would result in clean
SYNLETT 2005, No. 7, pp 1090–1094
0
2.
0
5.
2
0
0
5
Advanced online publication: 14.04.2005
DOI: 10.1055/s-2005-865212; Art ID: D03905ST
© Georg Thieme Verlag Stuttgart · New York

LETTER
Stereoselective Rearrangement of b-Hydroxy-N-acyloxazolidin-2-ones
1091
LZnO
rearrangement to afford their corresponding syn-1,3-ox-
azinane-2,4-diones 10a–l in high de.19 Consequently, it
was found that treatment of syn-aldol 9a with a commer-
cially available solution of 10 mol% Et2Zn in CH2Cl2 at
room temperature resulted in a clean rearrangement reac-
tion to afford its corresponding syn-1,3-oxazinane-2,4-di-
one 10a in >95% de, and 58% isolated yield.20 The
structure of syn-1,3-oxazinane-2,4-dione 10a was con-
firmed by carrying out a HMBC 1H-13C NMR correlation
experiment which clearly revealed cross-peaks between
O
L
Zn
O
N
O
O
O
retro
aldol
O
O
N
Ar
O
Ar
L
R
R
Zn
11
12
O
O
+
R
H
Ar
N
LZnO
O
N
L
O
1
the 13C resonance of its C-2 carbonyl, and the H reso-
Zn
O
O
O
aldol
N
O
nances of its H-6, and N-CH2 protons (Figure 1). Zinc
alkoxides of seven further racemic and enantiomerically
pure syn-aldols 9b–h were then generated under identical
conditions, affording their corresponding syn-1,3-oxazi-
nane-2,4-diones 10b–h in >95% de and in 65–94% isolat-
ed yield after chromatographic purification (Scheme 2,
Table 1).21 The structure of each syn-1,3-oxazinane-2,4-
O
Ar
O
Ar
R
R
13
14
Figure 2 Reversible retro-aldol/aldol pathway to explain the for-
mation of anti-1,3-oxazinane-2,4-diones 14.
1
dione product was apparent from its H NMR spectrum
[J(5,6) = 3.0–4.5 Hz],22 which also revealed a large upfield
shift for their C-5 ring protons (<3.0 ppm), when com-
pared to the corresponding resonances of the C-2 protons
(>3.5 ppm) of their parent syn-aldols 9b–h, respectively.
zinc alkoxide 11 to afford the zinc alkoxide of its respec-
tive b-aryl-anti-aldol 13, which would then rearrange to
afford the zinc alkoxide of its corresponding anti-1,3-ox-
azinane-2,4-dione 14.
Whilst zinc alkoxides of syn-aldols 9a–h rearranged
cleanly to afford their corresponding syn-1,3-oxazinane-
2,4-diones 10a–h in >95% de, it was found that rearrange-
ment of b-aryl-syn-aldols 9i–l occurred with poorer
stereocontrol, affording their corresponding syn-1,3-ox-
azinane-2,4-diones 10i–l in only 70–90% de.
Further insight into the mechanism of this rearrangement
reaction was gained on investigation of the reactivity of
the zinc alkoxides of anti-b-aryl-aldol 15, and the enantio-
merically pure syn-aldols 17 and 19 (Scheme 3). Firstly,
treatment of anti-b-aryl-aldol 1525 with 10 mol% Et2Zn
resulted in clean rearrangement to afford anti-1,3-oxazi-
nane-2,4-dione 16 [J(5,6) = 11.5 Hz]22 as a single product
in >95% de.26 This clearly demonstrated that the zinc
alkoxide of anti-aldol 15 had rearranged to its respective
R
O
O
O
O
O
OH
3
HO
N
O
R1
2
i
ii
O
N
O
N
R2
6
5
O
R2
R1
Table 1 Yields for Rearrangement of N-Acyl-oxazolidin-2-one-syn-
aldols 9a–l to Afford syn-1,3-Oxazinane-2,4-diones 10a–l
R1
R
R
8a R = H, R1 = Me,
8b R = H, R1 = iPr,
8c R = Bn, R1= Me,
8d R = Bn, R1 = iPr
10a–l
9a–l
Entry 1,3-Oxazinane-R
2,4-dione
R1
R2
de
(%)
Yield
(%)a
1
2
10a
10b
10c
10d
10e
10f
10g
10h
10i
H
Me
Et
>95 58
>95 88
>95 90
Scheme 2 Reagents and conditions: (i) 9-BBN-OTf, i-Pr2NEt,
CH2Cl2, 0 °C to –78 °C, R2CHO, CH2Cl2; (ii) 10 mol% Et2Zn, THF,
toluene, r.t.
H
i-Pr Et
3
H
i-Pr Cyclohexyl
O
4
H
i-Pr (E)-MeCH=CH– >95 65
H
H
HO
C
N
C
2 O
5
Bn
Bn
Bn
Bn
H
Me
Me
Me
Et
>95 94
>95 92
>95 94
>95 90
6
H
5
O
6
i-Pr
Me
syn-10a
7
Cyclohexyl
8
i-Pr Et
Me Ph
Figure 1 Selected resonances from a HMBC 1H-13C NMR correla-
tion experiment on syn-10a.
9
90
80
80
70
82
52
61
51
10
11
12
10j
10k
10l
H
i-Pr Ph
In order to explain this partial loss in stereocontrol,23 it
was proposed that rearrangement of the zinc alkoxide of
b-aryl-syn-aldol 11 to afford syn-1,3-oxazinane-2,4-dione
alkoxide 12 was occurring in the presence of a competing
reversible retro-aldol/aldol reaction pathway (Figure 2).24
This pathway would enable partial equilibration of the
H
i-Pr p-MeOC6H4
i-Pr p-O2NC6H4
H
a Yields are for pure syn-1,3-oxazinane-2,4-diones 10a–l isolated after
chromatographic purification.
Synlett 2005, No. 7, 1090–1094 © Thieme Stuttgart · New York

1092
F. J. P. Feuillet et al.
LETTER
O
Acknowledgment
O
O
OH
HO
We would like to thank the University of Bath (FJPF), EPSRC (MC,
RG, DGN) and the Royal Society (SDB) for funding, and the Mass
Spectrometry Service at Swansea, University of Wales for their
assistance.
i
N
O
O
N
Ph
O
Ph
15
16
References
Ph
O
O
OH
O
(1) (a) Tubulin polymerisation inhibitors, see: Mu, F.; Lee, D.
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Tetrahedron Lett. 1987, 28, 2425. (d) Kemp, D. S.; Duclos,
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(g) Stenseth, R. E.; Baker, J. W.; Roman, D. P. J. Med.
Chem. 1963, 6, 212.
HO
O
N
Ph
i
N
O
8c
17
+
+
O
Ph
PhCHO
Ph
17
18
O
O
O
O
OH
O
i
O
N
O
N
Ph
+
H
Ph
Ph
Ph
Ph
Ph
20
19
Scheme 3 Reagents and conditions: (i) 10 mol% Et2Zn, THF, toluene,
r.t.
anti-1,3-oxazinane-2,4-dione 16 with no loss of stereo-
control. Secondly, treatment of b-aryl-syn-aldol 17 under
the same conditions resulted in a mixture of syn-1,3-ox-
azinane-2,4-dione 18 [>90% de, J(5,6) = 3.5 Hz], N-propi-
onyloxazolidin-2-one 8c, and recovered starting material
17. Therefore, it is proposed that formation of 8c and
benzaldehyde in this reaction arises from syn-aldol 17
undergoing a retro-aldol reaction. The existence of this
retro-aldol pathway was confirmed via treatment of a-
aryl-b-styryl-syn-aldol 19 with Et2Zn, which resulted in
formation of N-phenylacetyloxazolidin-2-one 20, and
cinnamaldehyde as the only products. Therefore, it ap-
pears that the added electronic stabilisation afforded by
the a-aryl-fragment of the zinc enolate of 20, coupled with
the conjugative stabilisation of cinnamaldehyde, is suffi-
cient to ensure that retro-aldol fragmentation dominates
the reactivity of the zinc alkoxide of syn-aldol 19. We
believe that these results, in conjunction with the observa-
tion that reaction of the zinc alkoxide of 5 with
benzaldehyde affords a mixture of anti-6 and syn-7
(Scheme 1),16 provide good evidence that the partial loss
of stereocontrol observed for the rearrangement of zinc
alkoxides of syn-b-aryl-aldols is a consequence of the
competing retro-aldol/aldol pathway described in
Figure 2.
(3) (a) Barton, D. H. R.; Liu, W. Chem. Commun. 1997, 571.
(b) Pintye, J.; Fülöp, F.; Bernáth, G.; Sohár, P. Monatsh.
Chem. 1985, 116, 857. (c) Sainsbury, M. In Comprehensive
Heterocyclic Chemistry, Vol. 3; Katritzky, A. R.; Rees, C.
W., Eds.; Pergamon Press: New York, 1984, 995–1038; and
references contained therein..
(4) For a demonstration of the synthetic potential of N-2-
hydroxyethyl-1,3-oxazinane-2,4-diones see: Kamino, T.;
Murata, Y.; Kawai, N.; Hosokawa, S.; Kobayashi, S.
Tetrahedron Lett. 2001, 42, 5249.
(5) For a patent on their usage as sedatives, hypnotics,
anticonvulsants and depressants see: Ozaki, S.; Koto, K. Jpn.
Tokkyo Koho, JP 19660502, 1969; Chem. Abstr. 1969, 72,
43701.
(6) For a review on the use of oxazolidin-2-ones as chiral
auxiliaries for asymmetric synthesis see: Ager, D. J.;
Prakash, I.; Schaad, D. R. Aldrichimica Acta 1997, 30, 3.
(7) (a) Evans, D. A.; Bartroli, J.; Shih, T. L. J. Am. Chem. Soc.
1981, 103, 2127. (b) Evans, D. A.; Nelson, J. V.; Taber, T.
Top. Stereochem. 1982, 13, 1. (c) Davies, S. G.; Nicholson,
R. L.; Smith, A. D. Org. Biomol. Chem. 2004, 2, 3385.
(8) (a) Nerz-Stormes, M.; Thornton, E. R. J. Org. Chem. 1991,
56, 2489. (b) Evans, D. A.; Rieger, D. L.; Bilodeau, M. T.;
Urpi, F. J. Am. Chem. Soc. 1991, 113, 1047. (c) Yan, T. H.;
Tan, C. H.; Lee, H. C.; Lo, H. C.; Huang, T. Y. J. Am. Chem.
Soc. 1993, 115, 2613. (d) Crimmins, M. T.; She, J. Synlett
2004, 1371.
In conclusion, we have demonstrated that zinc alkoxides
of readily prepared syn- or anti-b-hydroxy-N-acyloxazol-
idin-2-ones undergo stereoselective rearrangement to
afford a highly practical route to their corresponding syn-
or anti-1,3-oxazinane-2,4-diones in good de.
(9) Kagoshima, H.; Hashimoto, Y.; Ogura, D.; Saigo, K. J. Org.
Chem. 1998, 63, 691.
(10) Walker, M. A.; Heathcock, C. H. J. Org. Chem. 1991, 56,
5747.
(11) Gabriel, T.; Wessjohann, L. Tetrahedron Lett. 1997, 38,
4387.
Synlett 2005, No. 7, 1090–1094 © Thieme Stuttgart · New York

LETTER
Stereoselective Rearrangement of b-Hydroxy-N-acyloxazolidin-2-ones
1093
(12) Evans, D. A.; Tedrow, J. S.; Shaw, J. T.; Downey, C. W. J.
Am. Chem. Soc. 2002, 124, 392.
4.0 Hz, CHO). 13C NMR (100 MHz, CDCl3): d = 9.0, 18.8,
21.2, 22.3, 14.5, 43.1, 48.4, 59.8, 78.0, 151.6, 170.0. IR:
3436 (br, OH), 1749 (C=O), 1691 (C=O) cm–1.
(13) For previous reports where these type of 1,3-oxazinane-2,4-
diones were formed as unwanted products of other types of
synthetic transformation see: (a) Mickel, S. J.; Sedelmeier,
G. H.; Niederer, D.; Schuerch, F.; Koch, G.; Kuesters, E.;
Daeffler, R.; Osmani, A.; Seeger-Weibel, M.; Schmid, E.;
Hirni, A.; Schaer, K.; Gamboni, R.; Bach, A.; Chen, S.;
Chen, W.; Geng, P.; Jagoe, C. T.; Kinder, F. R. Jr.; Lee, G.
T.; McKenna, J.; Ramsey, T. M.; Repič, O.; Rogers, L.;
Shieh, W.-C.; Wang, R.-M.; Waykole, L. Org. Proc. Res.
Dev. 2004, 8, 107. (b) Keck, G. E.; Lundquist, G. D. J. Org.
Chem. 1999, 64, 4482. (c) Narasaka, K.; Yamamoto, I.
Tetrahedron 1992, 48, 5743.
(14) For a report where reaction of the boron enolate of a related
N-propionyl-1,3-oxazinan-2-one with benzaldehyde in the
presence of excess Bu2BOTf resulted in a rearranged 1,3-
oxazinane-2,4-dione product see: Abbas, T. R.; Cadogan, J.
I. G.; Doyle, A. A.; Gosney, I.; Hodgson, P. K. G.; Howells,
G. E.; Hulme, A. N.; Parsons, S.; Sadler, I. H. Tetrahedron
Lett. 1997, 38, 4917.
syn-3-(2-Hydroxyethyl)-5-isopropyl-6-[(E)-1-propenyl]-
1,3-oxazinane-2,4-dione (10d): 1H NMR (300 MHz,
CDCl3): d = 0.97 [3 H, d, J = 7.0, CH(CH3)2], 1.03 [3 H, d,
J = 7.0 Hz, CH(CH3)2], 1.71 (3 H, d, J = 7.0 Hz,
CH3CH=CH), 1.97 (1 H, t, J = 5.5 Hz, OH), 2.10 [1 H, m,
J = 7.0 Hz, CH(CH3)2], 2.55 (1 H, dd, J = 7.0, 4.5 Hz, CHi-
Pr), 3.74 (2 H, app dt, J = 5.5, 5.5 Hz, CH2OH), 3.94–3.98 (2
H, m, CH2N), 4.92 (1 H, app t, J = 7.0 Hz, CHO), 5.47 (1 H,
ddd, J = 15.0, 7.0, 1.5 Hz, CH3CH=CH), 5.91 (1 H, dq, J =
15.0, 7.0 Hz, CH3CH=CH). 13C NMR (75 MHz, CDCl3):
d = 17.0, 19.7, 20.3, 24.8, 43.2, 49.5, 60.1, 76.6, 122.1,
132.7, 151.3, 169.7. IR: 3430 (br, OH), 1755 (C=O), 1699
(C=O) cm–1.
(5S,6R)-3-[(S)-1-Benzyl-2-hydroxyethyl]-6-ethyl-5-
methyl-1,3-oxazinane-2,4-dione (10e): [a]D20 –6.4 (c 0.47,
CH2Cl2). 1H NMR (300 MHz, CDCl3): d = 0.82 (3 H, t, J =
7.5 Hz, CH2CH3), 0.99 (3 H, d, J = 7.5, CH3CH), 1.33 (2 H,
m, CH2CH3), 2.50 (1 H, qd, J = 7.5, 3.5 Hz, CHCH3), 2.99
(1 H, dd, J = 14.0, 7.0 Hz, PhCHACHB), 3.16 (1 H dd, J =
14.0, 10.5 Hz, PhCHACHB), 3.68 (2 H, obscured m, CHO),
3.82 (1 H, dd, J = 12.0, 4.0 Hz, CHAHBOH), 4.01 (1 H, dd,
J = 12.0, 7.0 Hz, CHAHBOH), 5.04 (1 H, app dtd, J = 10.5,
7.0, 4.0 Hz, CHN), 7.10–7.15 (5 H, m, Ph). 13C NMR (75
MHz, CDCl3): d = 9.2, 9.5, 22.6, 33.7, 39.2, 56.5, 63.3,
78.4, 126.6, 128.5, 129.1, 137.4, 151.8, 173.1. IR: 3462 (br,
OH), 1755 (C=O), 1700 (C=O) cm–1.
(5S,6R)-3-[(S)-1-Benzyl-2-hydroxyethyl]-6-ethyl-5-
isopropyl-1,3-oxazinane-2,4-dione (10h): [a]D20 –6.8 (c
0.59, CH2Cl2). 1H NMR (300 MHz, CDCl3): d = 0.84 (3 H,
t, J = 7.5 Hz, CH2CH3), 0.85 [3 H, d, J = 7.0 Hz, CH(CH3)2],
0.92 [3 H, d, J = 7.0 Hz, CH(CH3)2], 1.31–1.46 (1 H, dqd,
J = 14.0, 7.5, 5.0 Hz, CHAHBCH3), 1.45–1.61 (1 H, m,
CHAHBCH3), 1.94–2.05 [1 H, m, CH(CH3)2], 2.18 (1 H, app
t, J = 4.5 Hz, CHi-Pr), 2.53 (1 H, br s, OH), 2.99 (1 H, dd,
J = 14.0, 7.0 Hz, CHAHBPh), 3.13 (1 H, dd, J = 14.0, 10.5 Hz,
CHAHBPh), 3.64 (1 H, obscured m, CHO), 3.82 (1 H, dd, J =
12.0, 4.0 Hz, CHAHBOH), 4.02 (1 H, dd, J = 12.0, 7.0 Hz,
CHAHBOH), 5.04–5.14 (1 H, app dtd, J = 10.5, 7.0, 4.0 Hz,
CHN), 7.08–7.22 (5 H, m, Ph). 13C NMR (75 MHz, CDCl3):
d = 10.4, 20.2, 22.6, 23.4, 25.5, 34.3, 50.2, 56.5, 63.7, 79.4,
127.0, 128.9, 129.5, 135.0, 152.5, 171.4. IR: 3423 (br, OH),
1754 (C=O), 1691 (C=O) cm–1.
(15) Kende, A. S.; Kawamura, K.; DeVita, R. J. J. Am. Chem.
Soc. 1990, 112, 4070.
(16) Ito, Y.; Terashima, S. Tetrahedron 1991, 47, 2821.
(17) Representative Synthetic Protocol for syn-Aldol
Reactions.
A 0.5 M solution of 9-BBN·OTf in hexanes (1.2 equiv) was
added to a stirred solution of N-acyloxazolidin-2-one (1
equiv) in CH2Cl2 at 0 °C and allowed to stir for 5 min. N,N-
Diisopropylethylamine (1.4 equiv) was added, the reaction
stirred for 25 min at 0 °C and cooled to –78 °C. An aldehyde
(1.1 equiv) was then added, the reaction was stirred for 2 h
and the reaction then allowed to warm to 0 °C for 30 min.
Then, pH 7.0 phosphate buffer was added, followed by a 2:1
solution of MeOH–H2O2. The reaction was extracted with
CH2Cl2 (3 ×) and the combined organic extracts washed with
aq NaHCO3, brine, dried (MgSO4) and concentrated in
vacuo to afford the appropriate syn-aldol which was then
purified by chromatography.
(18) These conditions have been employed previously for
asymmetric syn-aldol reactions using imidazolidin-2-one
derived glycine enolates, see: Caddick, S.; Parr, N. J.;
Pritchard, M. C. Tetrahedron Lett. 2000, 41, 5963.
(19) We have reported previously on a single example of this
rearrangement see: Feuillet, F. J. P.; Robinson, D. E. J. E.;
Bull, S. D. Chem. Commun. 2003, 2184.
syn-3-(2-Hydroxyethyl)-5-methyl-6-phenyl-1,3-
(20) Representative Synthetic Protocol for Rearrangement
Reaction.
oxazinane-2,4-dione (10i): 1H NMR (300 MHz, CDCl3):
d = 1.01 (3 H, d, J = 7.5 Hz, CH3), 2.17 (1 H, s, OH), 2.99 (1
H, qd, J = 7.5, 3.5 Hz, CHCH3), 3.75–3.82 (2 H, m, CH2OH),
3.97 (1 H, app dt, J = 14.0, 5.5 Hz, CHAHBN), 4.05 (1 H, app
dt, J = 14.0, 5.5 Hz, CHAHBN), 5.62 (1 H, d, J = 3.5 Hz,
CHO), 7.24–7.38 (5 H, m, Ph-H). 13C NMR (75 MHz,
CDCl3): d = 10.4, 41.5, 44.6, 61.2, 78.1, 126.0, 129.2, 129.4,
134.4, 152.4, 173.2. IR: 3447 (br, OH), 1755 (C=O), 1703
(C=O) cm–1.
syn-3-(2-Hydroxyethyl)-5-isopropyl-6-(4-methoxy-
phenyl)-1,3-oxazinane-2,4-dione (10k): mp 79–81 °C. 1H
NMR (300 MHz, CDCl3): d = 0.87 [3 H, d, J = 7.0 Hz,
CH(CH3)2], 0.98 (3 H, d, J = 7.0 Hz, CH(CH3)2], 1.96 [1 H,
m, J = 7.0, 4.0 Hz, CH(CH3)2], 2.26 (1 H, br s, OH), 2.79 (1
H, t, J = 4.0 Hz, CHi-Pr), 3.83 (3 H, s, ArOCH3), 3.81–3.87
(2 H, m, CH2OH), 4.02 (1 H, app dt, J = 14.0, 5.5 Hz,
CHAHBN), 4.16 (1 H, app dt, J = 14.0, 5.5 Hz, CHAHBN),
5.71 (1 H, d, J = 4.0 Hz, CHO), 6.94 (2 H, d, J = 8.5 Hz, Ar-
H), 7.29 (2 H, d, J = 8.5 Hz, Ar-H). 13C NMR (75 MHz,
CDCl3): d = 19.8, 23.1, 26.0, 44.7, 52.0, 55.7, 61.3, 78.4,
114.6, 126.7, 127.1, 152.9, 160.1, 171.4. IR: 3353 (br, OH),
1740 (C=O), 1691 (C=O) cm–1.
A 1.0 M solution of Et2Zn in toluene (0.1 equiv) was added
dropwise to a stirred solution of the syn-aldol (1 equiv) in
CH2Cl2 at r.t. The reaction was stirred for 2 h. Then, sat. aq
NH4Cl was added and the reaction extracted with CH2Cl2
(3 ×). The combined organic extracts were washed with
brine, dried (MgSO4), and concentrated in vacuo to afford
the desired syn-1,3-oxazinane-2,4-dione which was then
purified by chromatography.
(21) All new compounds were fully characterised. Selected data
for new compounds:
syn-6-Ethyl-3-(2-hydroxyethyl)-5-isopropyl-1,3-
oxazinane-2,4-dione (10b): 1H NMR (300 MHz, CDCl3):
d = 0.97 [3 H, d, J = 7.0 Hz, CH(CH3)2], 1.00 (3 H, t, J = 7.5
Hz, CH2CH3), 1.02 [3 H, d, J = 7.0 Hz, CH(CH3)2], 1.60 (1
H, dqd, J = 14.0, 7.5, 5.0 Hz, CHAHBCH3), 1.80 (1 H, ddq,
J = 14.0, 9.0, 7.5 Hz, CHAHBCH3), 2.08–2.21 [1 H, m, J =
7.0, 5.0, CH(CH3)2], 2.25 (1 H, br s, OH), 2.52 (1 H, dd, J =
5.0, 4.0 Hz, CHi-Pr), 3.74 (2 H, app t, J = 5.5 Hz, CH2OH),
3.89 (1 H, app dt, J = 14.0, 5.5 Hz, CHAHBN), 4.01 (1 H, app
dt, J = 14.0, 5.5 Hz, CHAHBN), 4.39 (1 H, ddd, J = 9.0, 5.0,
Synlett 2005, No. 7, 1090–1094 © Thieme Stuttgart · New York

1094
F. J. P. Feuillet et al.
LETTER
(22) syn-1,3-Oxazinane-2,4-diones exhibit J(5,6) coupling
constants of <4.5 Hz, whilst anti-1,3-oxazinane-2,4-diones
exhibit J(5,6) coupling constants of >10.0 Hz; see ref. 13c, 14,
16.
(23) An alternative mechanism involving zinc alkoxide-catalysed
epimerisation of the a-stereocentres of syn-b-aryl-aldols 9i–
l (or syn-b-aryl-1,3-oxazinane-2,4-diones 10i–l) was
discounted because their acidities are similar to those of the
a-stereocentres of syn-b-alkyl-aldols 9a–k that had been
shown to rearrange with no loss of stereocontrol under these
conditions.
(24) A similar reversible retro-aldol/aldol mechanism has been
proposed to explain the diastereoselectivity observed for
reaction of metal enolates of N-acyl-oxazolidin-2-ones with
ketones, see:Bartroli, J.; Turmo, E.; Belloc, J.; Forn, J. J.
Org. Chem. 1995, 60, 3000.
(25) N-Acyl-oxazolidin-2-one-anti-aldol 15 was prepared using
Evans’ magnesium halide-catalysed protocol, see ref. 12.
(26) anti-3-(2-Hydroxyethyl)-5-methyl-6-phenyl-1,3-
oxazinane-2,4-dione (16). 1H NMR (300 MHz, CDCl3):
d = 1.02 (3 H, d, J = 7.0 Hz, CH3), 2.21 (1 H, br s, OH), 2.89
(1 H, dq, J = 11.5, 7.0 Hz, CHCH3), 3.77–3.80 (2 H, app t,
J = 5.5 Hz, CH2OH), 3.94 (1 H, dt, J = 14.0, 5.5 Hz,
CHAHBN), 4.06 (1 H, app dt, J = 14.0, 5.5 Hz, CHAHBN),
5.04 (1 H, d, J = 11.5 Hz, CHPh), 7.24–7.38 (5 H, m, Ph-H).
13C NMR (75 MHz, CDCl3): d = 10.1, 40.4, 43.5, 59.6, 80.5,
126.1, 127.9, 128.7, 134.2, 151.1, 170.5. IR: 3435 (br, OH),
1755 (C=O), 1694 (C=O) cm–1.
Synlett 2005, No. 7, 1090–1094 © Thieme Stuttgart · New York