Allyl silane additions to highly electrophilic 5, 6-Dihydro-2H-1, 4-oxazinones

Article abstract of DOI:10.2174/157017809787893046

Allylsilane addition to the dihydro-2H-1, 4-oxazinones, 1, proceeded in moderate to good yields with transdiastereoselectivity.The yield of addition reactions of 5-phenyl-5, 6-dihydro-2H-1, 4-oxazin-2-one with allylsilanes is improved over the correspondi

Full text of DOI:10.2174/157017809787893046

2
24
Letters in Organic Chemistry, 2009, 6, 224-228
Allyl Silane Additions to Highly Electrophilic 5,6-Dihydro-2H-1,4-
oxazinones
§
,c
a
,a,b,c
Cynthia M. Shafer , Julie Pigza and Tadeusz F. Molinski*
a
b
Department of Chemistry and Biochemistry; Skaggs School of Pharmacy and Pharmaceutical Sciences University of
c
California, San Diego, 9500 Gilman Drive, CA 92093, USA and Department of Chemistry, University of California,
One Shields Avenue, Davis, CA 95616, USA
Received January 13, 2009: Revised January 23, 2009: Accepted January 25, 2009
Abstract: Allylsilane addition to the dihydro-2H-1,4-oxazinones, 1, proceeded in moderate to good yields with trans-
diastereoselectivity. The yield of addition reactions of 5-phenyl-5,6-dihydro-2H-1,4-oxazin-2-one with allylsilanes is im-
proved over the corresponding additions of Grignard reagents to 1 and illustrates a simple path to protected ꢀ,ꢀ-
disubstituted ꢁ-amino acids.
Keywords: Imine, amino acid, oxazinone, morpholinone.
1
. INTRODUCTION
non-proteinogenic ꢀ,ꢀ-disubstituted ꢁ-amino acids is not
feasible by these methods.
Earlier, we reported preparation and characterization of
highly-reactive 3-unsubstituted dihydro-2H-1,4-oxazinones
1, Scheme 1, referred hereafter as 'oxazinones') [1], by a
O
O
(
O
N
3
SeO2
O
O
novel oxidative rearrangement of 2-oxazolines. The electron-
deficient imine bond in 1 is exceedingly electrophilic. For
example, 1b reacts with nucleophiles such as MeOH [1a]
and Grignard reagents [2] to give 3-substituted-2-
morpholinones [2]. Conventional preparation of oxazinones
from glycine and the corresponding phenylglycinols require
several steps, but we have shown oxazinones 1a and 1b (R =
Ph) can be readily prepared by one-pot oxidation of the cor-
dioxane
100 ˚C
N
N
R
5
R
Ph
R = H, alkyl, aryl
1
1
a R = Ph (5R)
b R = Ph (5S)
1c R = i-Pr (5S)
1d (Ref. [9])
O
O
2
responding oxazolines with SeO followed by non-aqueous
t-Bu
t-Bu
O
workup (Scheme (1)) [1]. Substituted 2-morpholinones have
been used for preparation of ꢁ-amino acids [2,3], including
non-proteinogenic amino acids found in marine natural
product peptides [4]. Further, 3-unsubstituted oxazinones 1a-
c have potential as electrophilic glycine equivalents for ꢁ-
amino acid synthesis that complements existing methodolo-
gies [3].
O
O
N
HN
OH
NH2
Ph
2
Ph
3
4
Scheme 1.
Methods for asymmetric synthesis of ꢁ-amino acid syn-
theses based on alkylation of chiral nucleophilic glycine
equivalents have been reported [5]. For example, excellent
diastereoselectivities have been obtained by C2 alkylation of
benzophenone Schiff base glycinates under phase transfer
catalysis conditions using cinchonidinium quaternary am-
monium salts to give ꢀ-monosubstituted alanines in high
yields and enantiomeric ratios (%ee 92-99.5 [5i]). Unfortu-
Harwood [2] and others [1,3] showed that preformed 3-
alkyl- and 3-aryl-oxazinones are easily converted into ꢁ-
amino acids by a two-step solvolysis-hydrogenolysis. For
example, we demonstrated that oxazinone 2, obtained by
oxidative-rearrangement of the corresponding 2-neo-
pentyloxazoline, could be hydrogenated to give 3 (dr ~15:1).
Compound 3, in turn, was converted in two-steps to (S)-tert-
leucine (4, 75% two-steps, ee >99%). We have also prepared
(S)-N,N-ꢀ,ꢀ-tetramethyltryptophan using a modification of
this method, and employed this amino acid to complete the
total synthesis of the cytotoxic peptide, milnamide D [6].
Nevertheless, there are some advantages to preparation of the
requisite 3-substituted 2-morpholinones by C-C bond con-
struction upon 3-unsubstituted oxazinones 1. Here, we report
comparative diastereoselective, one-step nucleophilic addi-
tions of three different allylsilanes to the C=N bond of 3-
unsubstituted oxazinones, 1a-c, to give 3-alkenyl-2-
morpholinones, including 3-tert-alkenyl derivatives, which
N
nately, the scope is limited to S 2 alkylations at the ꢁ-carbon
of the glycinate ester by primary alkyl halides; the reaction is
not applicable to preparation of ꢀ-branched amino acids be-
cause of competitive elimination with the required secondary
and tertiary alkyl halides. Consequently, the synthesis of
*
Address correspondence to this author at the Department of Chemistry and
Biochemistry, UC San Diego, 9500 Gilman Drive, La Jolla, CA 92093,
USA; Tel: +1 858 534-7115; E-mail: tmolinski@ucsd.edu
§
Present Address: Novartis Institutes for Biomedical Research, 4560 Horton
Street, Emeryville, CA 94608, USA.
1
570-1786/09 $55.00+.00
© 2009 Bentham Science Publishers Ltd.

Allylsilane-Oxazinone Addition
Letters in Organic Chemistry, 2009, Vol. 6, No. 3
225
a
Table 1. Allyl Silane Additions to Oxazinones 1a-c
O
O
BF •Et O
O
O
3
2
1
c
HN
HN
CH Cl ,
2
2
–
78˚ C
5
c
6c
i-Pr
i-Pr
O
O
R
R
R
R
BF •Et O
O
O
3
2
1
a
HN
HN
CH Cl ,
2
2
–78˚ C
7
a R = H Ph
a R = Me
8a R = H Ph
10a R = Me
O
9
O
BF •Et O
3
2
O
O
1b
CH Cl ,
HN
HN
2
2
–
78˚ C
11b
12b
Ph
Ph
R
SiMe3
SiMe3
SiMe3
i
ii
iii R = H
iv R = Cl
#
Oxazinone
Nucleophile
Yield
dr,
Products
Major Product
Ref
b
1
(5S)-1c
(5R)-1a
(5R)-1a
(5S)-1b
1c
i
78%
58%
25%
60%
57%
34%
8.2:1
8:1
5:1
2:1
1:1
–
5c:6c
(3S,5S)
(3R,5R)
(3R,5R)
(3S,5S)
–
e
e
c
2
i
ii
7a:8a
c
3
9a:10a
e
4
iii
11b:12b
e
d
5
6
PhMgBr
MeMgBr
13
f,g
g
h
1a
14
(3S,5S)
a
3 2
Addition of BF •Et O (2.0 equiv) to a mixture of allyl silane (1.3 eq) and oxazinone 1 was carried out at –78 ˚C and the mixture stirred for 30 min before addition of satd. aq. Na-
HCO and usual workup. Yields are for combined diastereomers after purification by silica chromatography. Diastereomeric ratios, dr, were determined from integrals of the corre-
3
1 b c 13 d e f g h
sponding H NMR spectra. yield from NMR ds determined from C NMR spectrum. mixture of epimers (1:1). this work. Reference 1 Reference 2. reported as single di-
astereomer.
are useful intermediates in the synthesis of ꢀ,ꢀ-dimethyl-
substituted ꢁ-amino acids.
(0.1789 g). The crude material was purified by column chro-
matography (2.5 ꢂ 17 cm; 3:7 EtOAc:hexane to EtOAc to
1
7
:9 MeOH:CHCl
3
) to give 5c and 6c as a mixture (0.0659 g,
–1
8% based on NMR). IR (NaCl, neat) 3345 (NH), 1741 cm
1
2
. EXPERIMENTAL
(
C=O); H NMR (300 MHz, CDCl
3
) ꢃ 0.87 (d, 3 H, J = 6.8
Hz), 0.91 (d, 3 H, J = 6.8 Hz), 1.61 (dq, 1 H, J = 6.8 Hz),
General procedures can be found elsewhere [1].
1
6
.81 (bs, 1 H, NH), 2.50 (m, 2 H), 2.76 (ddd, 1 H, J = 10.1,
.8, 4.0 Hz), 3.61 (dd, 1 H, J = 8.5, 4.3 Hz), 4.10 (dd, 1 H, J
General Procedure for Allylsilane Additions
=
11.0, 10.1 Hz), 4.30 (dd, 1 H, J = 11.0, 4.0 Hz), 5.12 (m, 2
13
H), 5.82 (m, 1 H); C NMR (CDCl
3
) ꢃ 18.7 (CH
), 54.1 (CH), 54.2 (CH), 71.2
), 133.9 (CH), 171.4 (C); HREIMS found
+
3
), 19.0
Preparation of (3S,5S)-5-Isopropyl-3-(prop-2-enyl)-3,4,5,6-
tetrahydro-1,4-oxazin-2-one (5c)
(
(
CH
CH
3
), 29.8 (CH), 36.1 (CH
), 119.2 (CH
2
2
2
Allyltrimethylsilane (0.085 mL, 0.54 mmol) was added
m/z 183.1263 [M] , calcd. 183.1259 for C10
3R,5R)-5-Phenyl-3-(prop-2-enyl)-3,4,5,6-tetrahydro-1,4-
oxazin-2-one (7a)
IR (NaCl, neat) ꢄ 3335 (NH), 1743 cm (C=O); H NMR
CDCl ) ꢃ 2.74 (m, 2 H), 3.93 (dd, 1 H, J = 8.1, 4.8 Hz, H3),
.42 (m, 3 H, H5, H6), 5.25 (m, 2 H), 5.94 (m, 1 H), 7.40 (m,
2
H17NO .
to a solution of 1c (0.0565 g, 0.40 mmol) in CH
at -78˚C. After 15 minutes, BF •OEt (0.1 mL, 0.813 mmol)
was added. After 30 minutes, the reaction was quenched
with satd. aqu. NaHCO (0.5 mL). The aqueous layer was
extracted with EtOAc (2 x 50 mL), and the organic layer was
dried through MgSO and reduced in vacuo to a brown oil
2 2
Cl (3 mL)
(
3
2
-
1
1
3
(
4
3
4

2
26 Letters in Organic Chemistry, 2009, Vol. 6, No. 3
Shafer et al.
1
3
5
(
1
H); C NMR (CDCl
3
) ꢀ 36.1 (CH ), 52.9 (CH), 54.3
improvement over additions to the C=N double bond with
Grignard reagents (33-57%) [2]. The relative configuration
of the disubstituted 7a was established by nOe measure-
2
CH), 72.8 (CH ), 119.2 (CH ), 126.8 (2ꢁCH), 128.1 (CH),
28.7 (2 ꢁ CH), 133.5 (CH), 138.3 (C), 170.8 (C); HREIMS
found m/z 217.1103 [M] , Calcd. 217.1103 for C13
2
2
+
1
H
15NO
2
.
ments. Irradiation of the H-3 signal in the H NMR spectrum
gave rise to a 10% nOe of the ortho-phenyl proton signals as
shown in Fig. (1). Thus, allyltrimethylsilane (i) adds to the
less hindered face of the oxazinone C=N double bond, on the
side opposite the C5 substituent. Addition of methallyl-
trimethylsilane (iii, entry 4) to 1b gave the corresponding 2-
morpholinones 11b:12b, albeit with lower diastereoselectiv-
ity (dr 2:1). FInally addition of 3,3,-dimethylallyltrimethyl-
silane (ii, entry 3) to 1a gave exclusively addition to the
more substituted terminus and generated a mixture of 9a:10a
(25% unoptimized yield) with lower diastereoselectivity (dr
5:1).
3
1
-(1,1-Dimethylprop-2-enyl)-5-Phenyl-3,4,5,6-tetrahydro-
,4-oxazin-2-one Major isomer (3R,5R)-9a
-
1 1
oil. IR (NaCl, neat) ꢂ 3342 (NH), 1741 (C=O) cm ; H
NMR (CDCl ) ꢀ 1.35 (s, 6 H), 3.62 (s, 1 H, H3), 4.48 (m, 1
H), 4.61 (m, 2 H), 5.20 (m, 2 H), 5.39 (bs, 1H), 6.06 (dd, 1
3
1
3
H, J = 17.4, 10.5 Hz), 7.40 (m, 5 H); C NMR (CDCl
3
) 24.3
), 40.8 (C), 53.9 (CH), 61.7 (CH), 70.3
), 127.1 (2 ꢁ CH), 128.7 (CH), 129.1 (2 ꢁ
(
(
CH
CH
3
), 24.9 (CH
), 115.3 (CH
3
2
2
CH), 136.0 (CH), 142.8 (C), 167.6 (C). Minor isomer (3S,
R)-10a: ꢀ 22.6 (CH ), 42.0 (C), 56.6 (CH), 66.2 (CH), 74.1
CH ), 113.8 (CH ), 126.5 (CH), 128.7 (CH), 128.9 (CH),
37.7 (CH), 144.5 (C), 168.0 (C); HRESIMS found m/z
5
(
3
2
2
The stereochemical outcome of the reaction (Table 1, en-
try 2) can be rationalized by an electrocyclic reaction and the
transition state model a shown in Fig. (1). BF •Et O activa-
3 2
1
2
+
46.1502 [M+H] , calcd. 246.1494 for C15
3S,5S)-3-(2-Methylallyl)-5-phenyl-3,4,5,6-tetrahydro-1,4-
oxazin-2-one (11b)
IR (neat, ATR) ꢀ 3322 (NH), 1740 (C=O) cm ; H NMR
500 MHz, CDCl ) ꢁ 1.76 (br s, 3H), 2.00 (br s, 1H), 2.97-
.61 (m, 2H), 3.96 (dd, 1H, J = 8.9, 6.0 Hz, 1H), 4.39-4.28
m, 3H), 4.79 (br s, 1H), 4.91 (br s, 1H), 7.43-7.32 (m, 5H);
2
H19NO .
(
tion of the imine bond of 1a is followed by nucleophilic ad-
dition of the allylsilane and transfer of the silyl group to N
(the silyl group is lost by protodesilylation upon aqueous
workup). Transition state b is disfavored by non-bonded
interactions between the coordinated Lewis acid and the
phenyl group. The conformation of the product 7a (con-
firmed by nOe) more closely resembles the transition state a
upon activation of the imine by coordination of the Lewis
-
1 1
(
2
3
(
1
3
C NMR (125 MHz, CDCl
CH), 53.7 (CH), 74.0 (CH
28.7 (CH), 129.0 (CH), 138.1 (C), 141.1 (C), 171.1 (C);
3
) 21.6 (CH
3
), 40.4 (CH
2
), 52.4
(
1
2
), 115.3 (CH
2
), 127.2 (CH),
3 2
acid (BF •Et O) but non-bonded steric interactions in the
+
product forces the C5 Phe group into a pseudo-axial orienta-
tion [7]. Presumably, the C3 epimer, 8a, adopts the alternate
all-equatorial conformation (Fig. (1)).
HRESIMS found m/z 232.1333 [M+H] , calcd. 232.1338 for
C H17NO .
14 2
Coordination of the catalyst to the nitrogen atom in the
reactive intermediate imposes a sterically-induced conforma-
tional preference upon the C5 substituent. We predict that
varying the structure of the Lewis acid catalyst will affect the
diastereoselectivity of allyl silane additions to oxazinone 1
[8]. Further constraints may be imposed by the orientation of
the silyl group which must align parallel to the polarized ꢃ
3
. RESULTS AND DISCUSSION
Oxazinones 1a-d were prepared as previously described
[
1]. Addition of allyltrimethylsilane i to a mixture of 1 and
BF •Et O (1.0 equiv, -78 ˚C, CH Cl , 30 min) gave predomi-
nantly trans tetrahydrooxazinones (2-morpholinones, Table
3
2
2
2
1
, trans:cis; 7a:8a dr 8:1, 58%; 5c:6c, dr 8.2:1, 78%), an
SiMe3
O
O
O
O
N
N
BF3
BF
3
a
SiMe3
b
1a•BF3
favored
disfavored
ꢀ-
ꢀ+
O
nOe 10%
O
H
H
N
H
O
H
H
NH
O
8a
7
a
Fig. (1). Proposed transition state for allylsilane-oxazinone additions.

Allylsilane-Oxazinone Addition
Letters in Organic Chemistry, 2009, Vol. 6, No. 3
227
bond of the allyl group in order to gain p-orbital overlap and
stabilization of the dipolar transition state. The somewhat
lower diastereoselectivity obtained in the reactions with
more bulky silanes (Table 1, entries 3 and 4) may be amelio-
rated by an additional substituent at C6 on the oxazinone
ring which would enhance from the ꢀ-face [1b, 9].
terium- and tritium-labeled S and R leucine, respectively, by
homogeneous catalytic hydrogenation of the disubstituted
2
3
2 2
vinyl group with H and H followed by liberation of the
free amino acid by hydrogenolysis-solvolysis.
Other C-C bond forming reactions 1 have been investi-
gated. Chiral glycine equivalent 1a has been used in hetero-
Diels-Alder cycloadditions, albeit with poor yields [12],
while the homolog 1d undergoes highly diastereoselective
Mannich reactions with electron rich phenols to generate
phenylglycine equivalents [9]. Nevertheless, considerable
scope remains for exploration of 1a-c in diastereoselective
C-C bond forming reactions for example, tandem alkylation-
allylsilane addition using bi-functional allylsilanes such as
the chloromethyl analog, iv.
The important role of imine activation played by the
Lewis acid catalyst is revealed by comparison with Grignard
reagent additions. In previous work [1], we showed reaction
of 1c with PhMgBr, in the absence of Lewis acid (entry 5)
gave only C2 addition to give the product oxazolidine 13 as
a mixture of epimers in 41% combined yield (Fig. (2)). This
contrasts with the report of Harwood and co-workers that
describes addition of MeMgBr to oxazinone 1b in the pres-
ence of BF
tion as the only identifiable product, albeit in poor yield
34%) [2]. The formation of 9a:10a demonstrates a signifi-
3 2
•Et O which gave 14 (e.g. entry 6) from C3 addi-
CONCLUSIONS
(
cant advantage of allylsilane additions to 1 over Grignard
additions: formation of a quaternary carbon center next to C3
and potential for synthesis of ꢁ,ꢁ-disubstituted-ꢀ-amino ac-
ids (see below).
Additions of allyltrimethylsilane and related substituted
allylsilanes to dihydroxazinones were shown to be effective
in the synthesis of trans-3-substituted 2-morpholinone in-
termediates that are valuable for the preparation of highly
branched ꢁ,ꢁ-disubstituted ꢀ-amino acids.
O
O
H
Ph
O
O
O
ACKNOWLEDGEMENTS
HN
HN
OH
We thank J. Hubbs for preparation of starting materials.
This work was funded, in part, by NIH (AI31660,
AI039987). Part-funding of NMR spectrometers at UC Davis
NH2
Ph
14
13
15
(
(
400 MHz) and UCSD (500 MHz) was provided by NSF
CHE-9808183, CHE-0741968, respectively).
Fig. (2). Products of carbon-centered nucleophilic additions to 1
13, from C=O addition of 1c; 14, from C=N addition to 1a], and D-
[
neopentylglycine (15), the predicted hydrogenolysis product of 9a.
REFERENCES AND NOTES
The yields of allylsilane addition to oxazinones (up to
[1]
(a) Shafer, C.M.; Molinski, T.F. J. Org. Chem., 1996, 61, 2044-
2050. (b) Shafer, C.M. PhD Thesis, 1998, University of California,
Davis, 1998.
Harwood, L.M.; Tyler, S.N.G.; Anslow, A.S.; MacGilp, I.D.;
Drew, M.G.B. Tetrahedron Asymmetry, 1997, 8, 4007.
7
(
8%) are significantly higher than those of Grignard reagents
33-57%) [2]. Comparison of BF •Et O promoted addition of
-catalyzed addition of i to 3-bromo-5,6-
3
2
[2]
i to 1 with ZnCl
2
diphenylmorpholinones [3a,b] reveals substantial diastereo-
selectivity in both, even in the absence of coordinating tran-
sition metals, as a consequence of the exceptionally high
electrophilicity of the reactive partners 3-unsubstituted oxaz-
inones [9]. Unlike common usage of oxazinones as auxillar-
ies for ꢀ-amino acid synthesis that rely on diastereofacial
hydrogenation of the imine double bond of 3-substituted
oxazinones (e.g. 3) [2,3], allylsilane addition to 1 sets the
configuration of the ꢀ-centers of 5-12 by C-C bond forma-
tion. Since we have demonstrated preparations of ꢁ,ꢁ-
disubstituted amino acids from 3-substituted oxazinones
[3]
3-Bromo-5,6-diphenyl-5,6-dihydrooxazinones have been used as
chiral electrophilic glycine equivalents (see also preceding refer-
ence) in additions of organozincs, cuprates, silylketene acetals,
enolsilanes, allylsilane and other nucleophiles. (a) Williams, R.M.;
Sinclair, P.J.; Zhai, D.; Chen, D. J. Am. Chem. Soc., 1988, 110,
1
547. (b) Sinclair, P.J.; Zhai, D.; Reibenspies, J.; Williams, R.M. J.
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was never isolated.
(a) Andersen, R.J.; Coleman, J.E.; Piers, E.P.; Wallace, D.J. Tetra-
hedron Lett., 1997, 38, 317-320. (b) Hamada, T.; Sugawara, T.;
Matsunaga, S.; Fusetani, N. Tetrahedron Lett., 1994, 35, 719. (c)
Hamada, T.; Matsunaga, S.; Yano, G.; Fusetani, N. J. Am. Chem.
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(a) Chu, K.S.; Negrete, G.R.; Konopelski, J.P.; Lakner, F.J.; Woo,
N.-T.; Olmstead, M.M. J. Am. Chem. Soc., 1992, 114, 1800. (b)
Chu, K.S.; Negrete, G.R.; Konopelski, J.P. J. Org. Chem., 1991,
56, 5196. (c) Schöellkopf, U.; Neubauer, H. J. Synthesis, 1982, 10,
[
4]
5]
[
1,6], the present work establishes proof of principle for use
[
of allylsilane additions to 1 for asymmetric amino acid syn-
thesis. 2-Methyloxazolines - the precursors of 1 - are readily
available from simple carboxylic acids by various methods
8
3
61. (d) Dellaria, J.F.; Santarsiero, B.D. J. Org. Chem., 1989, 54,
916. (e) Groth, U.; Halfbrodt, W.; Schöellkopf, U. Liebigs Ann.
[
10]. Therefore, the three-step sequence, carboxylic acid -
oxazoline - oxazinone - 3-alkenyl-2-morpholinone, consti-
tutes a facile entry to precursors for complex non-
proteinogenic ꢁ-disubstituted-ꢀ-amino acids. For example,
hydrogenolysis-solvolysis of 9a would provide the rare
amino acid (R)-2-amino-3,3-dimethylpentanoic acid (D-
neopentylglycine, 15 [11]) which occurs in the highly cyto-
toxic marine peptides polytheonamides A and B (IC50 2 pM)
Chem., 1992, 4, 351. (f) O'Donnell, M.J. Aldrichimica Acta, 2001,
4, 3. (g) O’Donnell, M.J.; Boniece, J.M.; Earp, S.E. Tetrahedron
3
Lett., 1978, 19, 2641. (h) Lygo, B.; Wainwright, P.G. Tetrahedron
Lett., 1997, 38, 8595. (i) Corey, E.J.; Xu, F.; Noe, M.C. J. Am.
Chem. Soc., 1997, 119, 12414. (j) Corey, E.J.; Noe, M.C.; Xu, F.
Tetrahedron Lett., 1998, 39, 5347. (k) Williams, R.M. Synthesis of
Optically Active ꢀ-Amino Acids, Pergamon: Oxford, 1989. (l) Cur-
rie, G.S.; Drew, M.G.B.; Harwood, L.M.; Hughes, D.J.; Luke,
R.W.A.; Vickers, R.J. J. Chem. Soc. Perkin Trans. I, 2000, 2982
[
5b,c]. In addition, 11b and 12b can be used to prepare deu-

2
28 Letters in Organic Chemistry, 2009, Vol. 6, No. 3
Shafer et al.
[
6]
Liu, C.; Masuno, M.N.; MacMillan, J.B.; Molinski, T.F. Angew.
Chem. Int. Ed. Engl, 2004, 43, 5951.
Molecular modeling (Chem3D, MM2 level) of 1a•BF indicates
3
hma, S.; Rikimaru, K.; Endo, A.; Shimamoto, K.; Kan, T.; Fuku-
yama, T. Synthesis 2004, 909. Oxazinone 1d undergoes addition
with i in the presence of TFA to give the corresponding 3-allyl-2-
morpholinone single diastereomer in 88% yield.
(a) Meyers, A.I.; Knaus, G.; Kamata, K.; Ford, M.E. J. Am. Chem.
Soc., 1976, 98, 567. (b) Allen, Jr., Paul; Ginos, J. J. Org. Chem.,
[7]
that two minimized conformations, of almost equal steric energy,
exist in non-polar solvent (low dielectric). Structure i (E = 10.6
[10]
-
1
kcal.mol ) exists as a flattened chair except for O–C6–C5–Ph tor-
sional angle of ꢀ = -73˚. This places the C5-Ph bond essentially
perpendicular to the averaged plane of the oxazinone ring. The sec-
1
963, 28, 2759. (c) Gorunova, O.N.; Keuseman, K.J.; Goebel,
B.M.; Kataeva, N.A.; Churakov, A.V.; Kuz’mina, L.G.; Dunina,
V.V.; Smoliakova, I.P. J. Organomet. Chem., 2004, 689, 2382. (d)
Gossage, R.A.; Sadowy, A.L. Lett. Org. Chem., 2005, 2, 25. (e)
Sakakura, A.; Kondo, R.; Ishihara, K. Org. Lett., 2005, 7, 1971. (f)
Sakakura, A.; Kondo, R.; Umemura, S.; Ishihara, K. Tetrahedron,
2009, in press.
ent-15 (L-neopentylglycine) can be prepared by asymmetric two-
enzyme-coupled catalyzed reductive amination on an industrial
scale (~30 kg, Krix, G.; Bommarius, A.S.; Drauz, K.; Kottenhahn,
M.; Schwarm, M.; Kula, M.-R. J. Biotech., 1997, 53, 29), however,
no convenient synthesis of D-15 has been reported.
-
1
3
ond conformation for 1a•BF (E = 10.5 kcal.mol ) places the
phenyl group pseudo-equatorial (ꢀ = -175˚) and presents a pseudo-
axial hydrogen at C5 which is not expected to bias the facial selec-
tivity significantly. Models of the 1c•BF analog show a greater
3
-1
preference for a C5-pseudo axial substituent (ꢀE = 2.4 kcal.mol ).
Interestingly, the solid state conformations of 2 (R = Et, Bn) in the
[
11]
12]
2
absence of Lewis acid (X-ray) shows only pseudo-equatorial C5
phenyl groups but ‘heterogeneity’ of oxazinone ring conformations
[2].
[
8]
9]
It is more difficult to predict the effect of the more bulky allyl
silanes ii and iii upon facial selectivity towards 1a. The erosion in
diastereoselectivity seen in entries 3 and 4 may be reflect perturba-
tion of this simple internally coordinated transition state model by
the more hindered silane or an alternate mechanism involving an
[
Ager, D.; Cooper, N.; Cox, G.G.; Garro-Hélion, F.; Harwood, L.M.
Tetrahedron Asymmetry, 1996, 7, 2563.
‘
open transition’ state.
A recent report by Fukuyama and coworkers highlight the utility of
d (Scheme (1)), a 6,6-gem-dimethylsubstituted homolog of 1b that
was prepared from (S)-phenylglycine methyl ester in six steps. To-
[
1