Diastereoselective synthesis of highly functionalized β 2,2,3-substituted amino acids from 4-substituted-1,3-oxazinan-6-ones

Article abstract of DOI:10.1016/j.tet.2012.04.012

1,3-Oxazinan-6-ones were used to generate substituted β ^2,2,3-substituted amino acid derivatives. The enolates of 1,3-oxazinan-6-ones were trans-selectively intercepted with electrophiles. This alkylation was subsequently optimized for a one-pot dialkylation to form 5,5-disubstituted oxazinanones. The initial 5-monomethylated compounds could be enolized and then diastereoselectively intercepted with different electrophiles to form differentially 5,5-disubstituted products. The 5,5-dialkylated oxazinanones were then transformed to N-methyl β^2,2,3- substituted amino acids by reductive cleavage. Hydrolysis or solvolysis of the oxazinanones afforded β^2,2,3-substituted amino acids or esters, respectively. The chemistry thus provides access to a range of symmetrical and stereopure β^2,2,3-substituted amino acids and further establishes 1,3-oxazinan-6-ones as useful intermediates.

Full text of DOI:10.1016/j.tet.2012.04.012

Tetrahedron 68 (2012) 4745e4756
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Diastereoselective synthesis of highly functionalized
b
2,2,3-substituted amino
acids from 4-substituted-1,3-oxazinan-6-ones
,
,
Nghi H. Nguyen a, Brad E. Sleebs b c, Jonathan M. White d, Andrew B. Hughes a
*
a Department of Chemistry, La Trobe University, Victoria 3086, Australia
b The Walter and Eliza Hall Institute of Medical Research, Bundoora 3086, Australia
c Department of Medical Biology, The University of Melbourne, Parkville 3010, Australia
d Department of Chemistry and Bio-21 Institute, The University of Melbourne, Parkville 3010, Australia
a r t i c l e i n f o
a b s t r a c t
1,3-Oxazinan-6-ones were used to generate substituted b
2,2,3-substituted amino acid derivatives. The
Article history:
Received 13 January 2012
Received in revised form 14 March 2012
Accepted 2 April 2012
enolates of 1,3-oxazinan-6-ones were trans-selectively intercepted with electrophiles. This alkylation
was subsequently optimized for a one-pot dialkylation to form 5,5-disubstituted oxazinanones. The
initial 5-monomethylated compounds could be enolized and then diastereoselectively intercepted with
different electrophiles to form differentially 5,5-disubstituted products. The 5,5-dialkylated ox-
Available online 12 April 2012
azinanones were then transformed to N-methyl b
2,2,3-substituted amino acids by reductive cleavage.
Keywords:
Hydrolysis or solvolysis of the oxazinanones afforded
b
2,2,3-substituted amino acids or esters, re-
Beta-amino acids
Oxazinanones
Stereoselective
Enolate
spectively. The chemistry thus provides access to a range of symmetrical and stereopure b2,2,3
-
substituted amino acids and further establishes 1,3-oxazinan-6-ones as useful intermediates.
Crown Copyright Ó 2012 Published by Elsevier Ltd. All rights reserved.
N-Methyl amino acids
1. Introduction
described herein is to employ the oxazinanone to gain access to
b
2,2,3-substituted amino acid residues. This class of residue has risen
Previously we reported studies concerned with formation and
chemistry of 1,3-oxazolidin-5-ones including, importantly, their
to prominence in recent years through the
b-peptide conformation
work of Seebach and others.9e11 The 2,2,3-substituted amino acid
b
reductive cleavage to form N-methyl
sequently, an ArndteEistert homologation of numerous
acids allowed formation of novel 1,3-oxazinan-6-ones that were
a
-amino acids.1e5 Sub-
-amino
residues are of great interest in this work, because these residues
a
have been shown to induce a specific type of helical conformation in
b
-peptides, that less substituted
shown by Seebach and others that these
potential to be of therapeutic relevance.10e17
b
-residues cannot.9e11 It has been
similarly reductively cleaved to give N-methyl and N-alkyl
b
-amino
b-peptides have immense
acids.5e8
These oxazinanones are versatile intermediates and they have
potential to be manipulated in various ways that could provide
efficient access to a structurally diverse group of b-amino acid de-
rivatives for numerous applications. A key structural feature of the
oxazinanones is the 5-methylene group, which is a site for enoli-
zation. Indeed, we have reported the successful enolization of 1,3-
oxazinan-6-ones and the trans-selective formation of 5-methyl
and 5-hydroxy derivatives.7 The trans-selective methylation in
that study was conducted using methyl iodide exclusively as the
methyl source.
However, gaining access to stereopure b
2,2,3-substituted resi-
dues has been synthetically challenging.18 Herein we describe new
conditions for the enolization and alkylation and dialkylation of
oxazinanones,7 that leads to the successful stereoselective gener-
ation of this important class of the
And finally, access to -amino acids is achieved through reductive
b
2,2,3-substituted amino acid.
b
and hydrolytic cleavages.
To gain access to the
b
2,2,3-substituted amino acids, improve-
ments in yields on our previous work7 were required. This would
allow for a more facile transition to the work leading into the
To further demonstrate the utility of the oxazinanone to gain
access to highly substituted b-amino acids, the goal of the work
stereoselective alkylations to gain access to the
amino acids.
b
2,2,3-substituted
To improve alkylation yields of the 1,3-oxazinan-6-one it was
proposed to replace the iodide electrophile, used in previous
studies, with the more reactive methyl triflate. In earlier studies
(Scheme 1),7 it was demonstrated that the methylation product
* Corresponding author. E-mail address: andrew.hughes2@optusnet.com.au (A.B.
Hughes).
0040-4020/$ e see front matter Crown Copyright Ó 2012 Published by Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2012.04.012

4746
N.H. Nguyen et al. / Tetrahedron 68 (2012) 4745e4756
mixture consisted primarily of the monomethyl 2 (and 3 (minor))
and also small amounts of the dimethyl 4 adducts. It was postulated
that the reaction (Scheme 1) could be optimized for exclusive for-
mation of the dimethyl adduct 4, preferably in a one-pot reaction.
This methodology could then be extended to other disubstituted
adducts, such as those derived from allylation and benzylation.
In most examples (Table 1) the mixed toluene/DMPU solvent
gave better selectivity than toluene only for the trans-monomethyl
adducts 2, 6, 10, 14, 18. The exception is substrate 17 (entry 8),
which gave the trans-monomethyl adduct 18 exclusively (47%
yield) when toluene was the solvent. In comparison with the ear-
lier methyl iodide reactions, the methyl triflate reactions are better
according to several measures. Recovered starting material
(6e15%) is generally less than that recovered from reactions with
methyl iodide (18%).7 Overall conversions with methyl triflate are
generally higher, particularly when recovered starting material is
taken into account. Further, the amounts of dimethyl adducts 4, 8,
12, 16, 20 (av 5%) are less than the yields of those adducts using
methyl iodide (av 16%). However, the stereoselectivity of the
methyl triflate reactions is no better than the earlier iodide
reactions.
Scheme 1. 5-Alkylation of the 1,3-oxazinan-6-one. Reagents and conditions: (a) 1.
Base, THF, ꢀ78 ꢁC, 40 min; 2. MeI, 3 h at ꢀ78 ꢁC, then warmed to ꢀ15 ꢁC, satd aq NH4Cl
quench.
In a further extension of the work it was suggested adducts like
2 could be enolized a second time and then diastereoselectively
intercepted with different electrophiles to form optically pure 5,5-
disubstituted oxazinanones. And lastly, to demonstrate the utility
of these oxazinanone intermediates, reductive cleavages, hydrolysis
The results from this study prompted the use of alternate elec-
trophiles, in particular the use of allyl bromide, benzyl bromide and
ethyl triflate. The behavior of these electrophiles in oxazinanone
alkylations would give valuable insight for the penultimate goal of
this work, a study on the sequential stereoselective dialkylation of
oxazinanones.
and solvolysis would be performed to give novel N-methyl b2,2,3
-
-
substituted amino acids, b
2,2,3-substituted amino acids and b2,2,3
Ethylation of the oxazinanone 5 using ethyl triflate proceeded in
a similar manner to the methylation reactions. A 49% yield of the 5-
ethyl oxazinanone 25 was obtained (Table 2, entry 3) in comparison
to methylation on the same substrate 5 where a 61% yield of 6/7
was obtained (Table 1, entry 3).
substituted amino esters, respectively. Successful conduct of this
group of transformations would significantly increase the range of
b-amino acid compounds available for peptide and peptidomimetic
synthesis.
2. Results and discussion
Table 2
Previously, oxazinanones 1 were enolized with KHMDS (and
other amide bases) and then methylated with methyl iodide
(Scheme 1) in a mixture of THF and HMPA (or DMPU).7 We sought
to improve these yields by utilizing methyl triflate. Thus the first
series of reactions in the current work employed the oxazinanones
1, 5, 9, 13 and 17 to form the corresponding enolates with KHMDS
(Scheme 2). Under the new conditions, the enolates were stirred at
ꢀ78 ꢁC for 40 min before addition of 1.5 equiv of methyl triflate. It is
noteworthy that the solvent used in these studies was toluene, not
THF as used in previous studies. Toluene was used to abrogate the
reactivity of the triflate with THF.20 The results of these experi-
ments, aimed at forming the trans-monomethyl adducts 2, 6, 10, 14,
18, are summarized in Table 1.
5-Allylation, 5-benzylation and 5-ethylation of 1,3-oxazinan-6-ones
Entry
Substrate
Recovered
substrate (%)
trans mono
adduct (%)
5,5-Disubstituted
adduct (%)
1
2
3
4
5
6
7
1 R¼Me
1 R¼Me
5 R¼iPr
5 R¼iPr
5 R¼iPr
17 R¼Bn
13 R¼sBu
19
22
20
14
15
30
28
21 14
23 ta
22 32
24 33
26 ta
28 13
30 14
32 20
34 27
25 49
27 42
29 29
31 10
33 23
a
t¼trace.
The allylation and benzylation reactions were conducted in
a similar manner as the monoethylation. Scheme 3 and Table 2
show that the allylation and benzylation reactions are not well
controlled. There were three significant products in each reaction.
These products were recovered starting material, the desired trans-
mono adduct and the 5,5-diallyl or 5,5-dibenzyl adducts. The poor
alkylation control is attributed to the increased acidity of the alpha
H-5 proton of the mono benzylated or allyl adducts. This often led
to more of the dialkylated product rather than the desired trans-
mono adduct (Table 2).
Scheme 2. 5-Methylation of 1,3-oxazinan-6-ones. Reagents and conditions: (a) 1.
KHMDS, toluene or toluene/DMPU, ꢀ78 ꢁC, 40 min; 2. MeOTf, 3 h at ꢀ78 ꢁC, then
warmed to ꢀ40 ꢁC, satd aq NH4Cl quench.
Table 1
5-Methylation of 1,3-oxazinanones using methyl triflate
Entry
Substrate
Solvent
Substrate
recovered (%)
Monomethyl
yield (%) (trans/cis)
trans/cis
Dimethyl
adduct (%)
Monomethyl ratioa
1
2
3
4
5
6
7
8
1 R¼Me
1 R¼Me
5 R¼iPr
5 R¼iPr
9 R¼iBu
9 R¼iBu
13 R¼sBu
17 R¼Bn
PhMe
PhMe /DMPU 2:1
PhMe
PhMe /DMPU 2:1
PhMe
PhMe /DMPU 2:1
PhMe /DMPU 2:1
PhMe
6
14
8
6
11
9
2/3 (74)
2/3 (60)
6/7 (61)
6/7 (53)
10/11 (44)
10/11 (37)
14/15 (42)
18/19 (47)
1.7:1
4.7:1
4.8:1
>19:1
12.5:1
>19:1
>19:1
>19:1
4 (-)
4 (5)
8 (5)
8 (7)
12 (5)
12 (7)
16 (10)
20 (e)
15
8
a
trans/cis ratio was determined by examination of 1H NMR signal integrations.

N.H. Nguyen et al. / Tetrahedron 68 (2012) 4745e4756
4747
and cis-monomethyl adducts, but the efficiency of conversion to
the dimethyl adducts 1, 5 and 13 was higher than the sequential
reaction scheme.
The ability of the oxazinanones to form enolates in one-pot
dimethylation reactions invited the use of other electrophiles. Ac-
cordingly, Scheme 5 and Table 4 show use of allyl and benzyl re-
action partners in diallylation and dibenzylation reactions.
Scheme 3. 5-Allylation, 5-benzylation and 5-ethylation of 1,3-oxazinan-6-ones. Re-
agents and conditions: a) 1. KHMDS (1.1 equiv), toluene, ꢀ78 ꢁC, 40 min; 2. Allyl
bromide or BnBr or EtOTf (5 equiv), 3 h at ꢀ78 ꢁC, then warmed to ꢀ40 ꢁC, satd aq
NH4Cl quench.
The results of the monoalkylation study demonstrated that
dialkylation products were observed in nearly all cases (Tables 1and
2). This observation suggests that oxazinanones are indeed good
candidates for the penultimate goal of this work, a study on the
sequential stereoselective dialkylation of the oxazinanone. How-
ever, before commencing the stereoselective dialkylations, it was
proposed to perform several symmetrical dialkylations to give an
indication of what yields might be expected.
Scheme 5. One-pot diallylation and dibenzylation of 1,3-oxazinan-6-ones. Reagents
and conditions: (a) 1. KHMDS (1.1 equiv), toluene, ꢀ78 ꢁC, 40 min; 2. BnBr or allyl
bromide (1.5 equiv) at ꢀ78 ꢁC, then warmed to ꢀ15 ꢁC, 3. KHMDS (2.1 equiv), ꢀ78 ꢁC,
40 min; 4. BnBr or allyl bromide (3.0 equiv), then warmed to ꢀ15 ꢁC, satd aq NH4Cl
quench.
The symmetrical dialkylation was planned in two ways. The 5-
monoalkylated oxazinanone 1 could be enolized, followed by ad-
dition of the alkylating electrophile. Or alternatively, a one-pot
dialkylation method could be done, starting from the non-
substituted 5-oxazinanones 1, 5 or 13 (Scheme 4).
Table 4
One-pot diallylation and dibenzylation of 1,3-oxazinan-6-ones
Entry
Substrate
Dialkylated adduct
trans-Mono adduct (%)
1
2
3
4
1 R¼Me
5 R¼iPr
1 R¼Me
5 R¼iPr
22 (65)
24 (51)
28 (53)
30 (48)
21 (3)
23 (0)
27 (9)
29 (7)
The one-pot diallylation and dibenzylation reactions proceeded
smoothly, using both the alanine and valine derived oxazinanones,
1 and 5, as the starting substrates. Even given the hindered nature
of the second alkylation, in the one-pot process, very little mono
adduct formation was observed (Table 4), presumably due to the
increased acidity of the a-hydrogen once the mono-allylation and
benzylation has occurred. This hypothesis is reinforced by the
quantity of diallylated or dibenzylated product obtained in the
monoalkylation reactions described in Table 2. Further to this
theory was the observation that monoethylation of the oxazina-
none 5 only resulted in a trace amount of the diethyl adduct 26
(Table 2). The successful dibenzylation and diallylation of the
oxazinanones 1 and 5 was reassuring, and confirmed that the
hindered sequential stereoselective dialkylation of the oxazinanone
was feasible.
Scheme 4. Sequential and one-pot 5,5-dimethylation of 1,3-oxazinan-6-ones. Reagent
and conditions: (a) 1. KHMDS (1.1 equiv), toluene, ꢀ78 ꢁC, 40 min; 2. MeOTf (1.5 equiv),
3 h at ꢀ78 ꢁC, then warmed to ꢀ40 ꢁC, satd aq NH4Cl quench; (b) 1. KHMDS (1.1 equiv),
toluene, ꢀ78 ꢁC, 40 min; 2. MeOTf (1.5 equiv) at ꢀ78 ꢁC, then warmed to ꢀ15 ꢁC, 3.
KHMDS (2.1 equiv), ꢀ78 ꢁC, 40 min; 4. MeOTf (3.0 equiv), then warmed to ꢀ15 ꢁC, satd
aq NH4Cl quench.
All the previous alkylation reactions laid the foundation for the
last group of reactions in this study. In the last group, the formation
of a chiral center at the 5-position of the oxazinanones was
attempted using the monomethyl adducts 2/3, 6/7 and 10/11.
Enolates were formed from these substrates under the established
conditions and then they were quenched with a variety of elec-
trophiles (allyl bromide, benzyl bromide and ethyl iodide or tri-
flate). Scheme 6 and Table 5 show the results of these reactions.
Firstly, the 5-monomethyl adducts 2/3 were enolized, by addi-
tion of base, and then quenched with methyl triflate, affording the
dimethyl adduct 4 in 47% yield (Scheme 4). The overall yield from
substrate 1 to adduct 4 was 27%.
The one-pot version of the dimethylation was attempted next.
This reaction was conducted in the first part in the same way as for
the 5-monomethylation. Then, instead of quenching the reaction
(ꢀ15 ꢁC) for work-up, the reaction was cooled to ꢀ78 ꢁC and
a further 2.1 equiv of KHMDS and 3.0 equiv of methyl triflate
were added. Subsequent work-up in the usual manner, afforded the
dimethyl adducts 8, 12, 16 (45e60% yield) (Table 3) from the
starting materials 1, 5 and 13. It can be seen that the one-pot
dimethylation still generated significant amounts of the trans-
Table 3
One-pot dimethylation of 1,3-oxazinanones
Entry
Substrate
Dimethyl adduct (%)
cis/trans Monomethyl (%)
1
2
3
1 R¼Me
5 R¼iPr
8 (49)
12 (45)
16 (60)
2/3 (25)
6/7 (22)
14/15 (8)
Scheme 6. Stereoselective alkylations 5-methyl-1,3-oxazinan-6-ones. Reagents and
conditions: (a) 1. KHMDS (1.1 equiv), toluene, ꢀ78 ꢁCfor 40 min; 2. electrophile
(5 equiv), ꢀ78 ꢁCfor 3 h, then ꢀ15 ꢁC, satd aq NH4Cl quench.
13 R¼sBu

4748
N.H. Nguyen et al. / Tetrahedron 68 (2012) 4745e4756
Table 5
Stereoselective alkylations of 5-methyl-1,3-oxazinanones
Entry Substrate
Electrophile % Recovered Adduct ratio % Yield
substrate
trans/cisa
transþcis
1
2
3
4
5
6
7
8
2/3 R¼Me
2/3 R¼Me
2/3 R¼Me
6/7 R¼iPr
6/7 R¼iPr
6/7 R¼iPr
Allyl-Br
EtOTf
BnBr
12
9
35/36 13:1
37/38 13:1
39/40 10:1
41/42 >19:1 47
43/44 >19:1 45
45/46 >19:1 48
47/48 >19:1 47
49/50 >19:1 50
56
56
58
14
14
14
10
15
8
Allyl-Br
EtOTf
BnBr
10/11 R¼iBu Allyl-Br
10/11 R¼iBu BnBr
trans/cis ratio was determined by examination of 1H NMR signal integrations.
Fig. 2. Illustration of the angle of approach of the electrophile to the oxazinanone
enolate.19
a
sweeps across the face of the oxazinanone ring. As one face of the
ring is hindered by the substituent at C-4, preferential approach
occurs from the opposite face giving excellent anti selection as
shown in Fig. 2. The 5-methyl substituent is perpendicular to the
plane of the oxazinanone ring, and takes no part in the de-
termination of facial approach of the electrophile. When the 4-R
group is larger than a methyl, such as compounds 41, 43, 45, 47
and 49 exclusive facial selectivity is observed.
Given the exclusive trans selectivity at the 5-position, when the
4-R group is larger than a methyl, in the next set of reactions it was
decided to ascertain the effect on stereoselectivity, if the starting
substrates were the 5-mono-allyl 27, benzyl 29 and ethyl 25 oxa-
zinanones. In these instances the electrophile being used was
methyl triflate (Scheme 7). However, when these reactions were
conducted, in all instances poor selectivity was observed (Table 6).
trans Selectivity was preferred, as determined by a comparison of
the 1H NMR spectrum from previously formed compounds 41, 43
and 45. The lack of selectivity with this set of reactions was in direct
contrast to results obtained from the study shown in Scheme 6 and
Table 5.
The data for the preparation of the trans adducts was pleasing in
that the reactions were highly stereoselective. The yields of these
reactions were similar to those in previous reactions in the study. In
Table 5 entries 1e3 where the 4-R group controlling the facial se-
lectivity of the alkylations was a methyl group, the diaster-
eoselectivity was the lowest (10:1e13:1). Presumably the steric
bulk of the methyl is the least of all the examples trialled and so the
facial bias is not high leading to a few percent of the cis adducts 36,
38 and 40. The remaining entries 4e8 all showed >19:1 selectivity
for the trans adducts 41, 43, 45, 47 and 49 as assessed by NMR signal
integration.
In order to unambiguously assign the diastereoselectivity of the
alkylation reactions depicted in Scheme 6, an X-ray crystal struc-
ture was acquired on compound 49 (Fig. 1). The X-ray crystallog-
raphy study confirmed that the amino acid derived R group does
control facial selectivity and the trans product is therefore obtained
exclusively.
Scheme 7. Reverse alkylation sequence using methyl triflate. Reagents and conditions:
(a) 1. KHMDS (1.1 equiv), toluene, ꢀ78 ꢁCfor 40 min; 2. Methyl triflate (5 equiv),
ꢀ78 ꢁCfor 3 h, then ꢀ15 ꢁC, satd aq NH4Cl quench.
Table 6
Reverse alkylation sequence of 5-mono substituted oxazinanones using methyl
triflate
Entry
Substrate
% Recovered
substrate
Adduct ratio
trans/cis
% Yield
transþcis
1
2
3
25 R¼Et
8
11
10
43/44 1.8:1
41/42 1.3:1
45/46 1.1:1
61
60
57
27 R¼allyl
29 R¼Bn
Fig. 1. Thermal ellipsoid plot for 49. Ellipsoids are at the 20% probability level.
It is proposed that little selectivity is observed in these alkyl-
ations with methyl triflate (Scheme 7), due to the interplay of the 5-
substituent being forced onto the opposite face to the 4-R group by
steric repulsion. Hindrance is now observed at the trans face as well
as the cis face. This results in repulsion of the electrophile at the
trans and cis faces. The slight trans selectivity that was observed
was a result of the hindrance of the 4-R substituent (Fig. 3).
From the reactions performed on 5-mono-allyl 27, benzyl 29 and
ethyl 25 oxazinanones and using methyl triflate as an electrophile
(Scheme 7), it is now clear that in order to obtain the 5,5-
substituted oxazinanones in high stereoselectivity the route
depicted in Scheme 6 is preferred.
The selectivity obtained can be explained mechanistically, as
depicted by Fig. 2. The Houk trajectory suggests the electrophile
approaches the molecule at an angle of 106ꢁ, near perpendicular to
the enolate plane.19 This is due to the interaction of the highest
occupied molecular orbital (HOMO) of the enolate with the lowest
unoccupied molecular orbital (LUMO) of the electrophile. Further-
more, the electrophile is tilted at a right angle to the enolate plane,
due to the repulsive interaction between the electrophile LUMO
and the oxygen atom of the enolate. This also signifies the elec-
trophile starts its approach from the opposite side of the oxazina-
none ring to the carbonyl group. Essentially, the electrophile

N.H. Nguyen et al. / Tetrahedron 68 (2012) 4745e4756
4749
Fig. 3. Mechanistic rationale for the poor selectivity of alkylation, using methyl
triflate.19
Scheme 9. Reductive cleavage product and mechanistic rationale. Reagents and
conditions: (a) BF3$Et2O, Et3SiH, CH2Cl2, 25 ꢁC, 20 h, 65%; (b) BF3$Et2O, CH2Cl2, 25 ꢁC,
6 h, 77%.
The oxazinanone has previously been shown to be a useful
synthon for producing a variety of
-amino acid residues.1,5e8 To
cleavage circumstances the iminium ion 58 is intercepted by a nu-
cleophilic hydride source, such as triethylsilane, to form the N-
methyl residue 57. However, in this instance the more nucleophilic
alkene attacks the iminium ion to form a cationic aza nonyl species
59. The cation 59 is then intercepted by the carboxylic moiety to
form the oxa-3-azabicyclo[4.2.1]nonan-8-one 60. The facial pref-
erence of the cation exclusively affords the 1R,2S,6R-isomer 60 in
a 65% yield (Scheme 9). Only a trace amount of the N-methyl
product 57 was obtained. The mechanism leading to the bicycle 60
does not require triethylsilane. The reaction was repeated in the
absence of triethylsilane and afforded the bicycle 60 in 77% yield. A
study is now being undertaken to ascertain the full synthetic po-
tential of this cyclization and also the application of the lactone
adduct products.
b
further demonstrate these transformations can also be applied to
the highly substituted oxazinanones produced in this study, a small
variety of ring opening transformations were performed to dem-
onstrate access to
Hydrolysis of the oxazinanone 45 smoothly formed the desired
2,2,3-substituted amino acid 51 in good yield (71%). The b2,2,3
b
2,2,3-substituted amino acid derivatives.
b
-
substituted amino ethyl ester 52 was also obtained in good yield
(72%) by solvolysis of the oxazinanone 4 using sodium hydrogen
carbonate in ethanol at reflux (Scheme 8).
3. Conclusions
In conclusion, elaboration of previous oxazinanone enolization
work has allowed the synthesis of highly substituted b-amino acids.
The symmetrical 5,5-substituted analogues could be obtained via
either alkylation of the 5-methyl oxazinanone or the higher
yielding one-pot dialkylation of 5,5-unsubstituted oxazinanones.
Differential alkylation of the 5-methyl oxazinanone has allowed
exclusive formation of the trans diastereoisomer. The trans ste-
reochemistry was unambiguously confirmed by obtaining an X-ray
crystal structure. The symmetrical and unsymmetrical 5,5-
substituted analogues were then transformed into a variety of
Scheme 8. Transformations of the oxazinanone to generate the corresponding b2,2,3
-
b
2,2,3-substituted amino acid derivatives. The methodology de-
scribed here further establishes the 5-oxazinanone as a useful
synthon to gain access to functionalized -amino acids. Further-
more, the
2,2,3-substituted residues produced from this work, have
substituted amino acid derivatives. Reagents and conditions: (a) 4 N LiOH, H2O/THF,
20 ꢁC, 6 h; (b) NaHCO3, EtOH, reflux, 20 h; (c) BF3$Et2O, Et3SiH, CH2Cl2, 25 ꢁC, 6e20 h.
b
b
Previous experience has shown that reductive cleavage of the a-
application in the increasingly important field of therapeutic
b-
amino acid derived oxazolidinones can also be applied to the ho-
peptides.
mologous oxazinanones.1,5e8 However, in unpublished work,
studies have found that the reductive cleavage of an
substituted oxazolidinone does not proceed smoothly and negli-
gible yields of N-methyl -disubstituted -amino acid are
obtained. A mechanistic study is currently being undertaken to
determine why low yields occur in this circumstance. These results
will be reported elsewhere. Based upon this finding it was proposed
a,a-di-
4. Experimental section
4.1. General methods
a,
a
a
Unless otherwise stated, all reactions were carried out under an
argon atmosphere in oven-dried glassware. KHMDS was purchased
commercially and titrated before use. TLC was performed on kie-
selgel 60 F254 plates and visualized with a UV lamp or staining.
Optical rotations were measured at the stated temperatures in the
stated solvent using a polarimeter at the sodium d-line (589 nm);
that the reductive cleavage of the
a,a-disubstituted oxazinanone
would also be troublesome. However, this was not the case, the
reductive cleavage of the a,a-disubstituted compounds 39, 4, 8, and
16, proceeded smoothly, giving high yields of the N-methyl b2,2,3
residues 53e56 (76e83%) (Scheme 8).
-
However, when the
a
-substitution was an allyl group (35) the
[a]
D values are given in 10ꢀ1 deg cm2 gꢀ1. Elemental analyses were
reductive cleavage to the expected N-methyl residue 57 was not
observed. The major product isolated was an intriguing bicyclic
adduct 60. The unexpected formation of this bicyclic lactone 60 can
be explained mechanistically as shown in Scheme 9. The addition of
the Lewis acid boron trifluoride etherate commits the oxazinanone
35 to ring open and form the iminium ion 58. In usual reductive
performed by Chemical and Microanalytical Services, Melbourne
using a Carlo Erba NA1106 Elemental Analyser. Flash column
chromatography was carried out using silica gel 60 particle size
0.040e0.063 mm (230e400 mesh ASTM). NMR spectra were de-
termined in (D)-chloroform at 300 K unless otherwise stated on
a 300 MHz spectrometer. Data for 1H NMR are reported as follows:

4750
N.H. Nguyen et al. / Tetrahedron 68 (2012) 4745e4756
chemical shift (
d
in parts per million), multiplicity (s, singlet; br s,
cis) ratio (77.0 mg, 53%) and 5,5-disubstituted oxazinanone 8
(10.7 mg, 7%).
broad singlet; d, doublet; dd, doublet of doublets; t, triplet; q,
quartet; m, multiplet). Coupling constant (J) are reported in Hertz
(hertz). Infrared spectra were recorded on a Fourier transform IR
spectrometer using a thin film NaCl plate. Low-resolution mass
spectra were recorded on a mass spectrometer at 300 ꢁC and a scan
rate of 5500 m/z/second using either acetonitrile/formic acid (99:1)
or methanol/formic acid (99:1) mixtures as the mobile phase.
High-resolution electrospray ionization mass spectra were recor-
ded on a mass spectrometer with an ionization energy of 70 eV
using methanol-acetic acid (99:1) mixtures as the mobile phase.
High-resolution electron ionization mass spectra were recorded on
a Kratos Concept ISQ mass spectrometer using an ionization en-
ergy of 70 eV and 5.3 kV accelerating voltage with the sample
being introduced by direct insertion probe into the ion source and
spectra were scanned over the range m/z 35 to 800, with ion
source held at 200 ꢁC and probe tip heated to 300 ꢁC. Accurate
masses were obtained at a resolution of 8000 by ‘peak matching’
using perfluorokerosene. Parent ion peaks are reported as m/z
values.
4.2.1.1.3. (4S,5S)-N-Benzyloxycarbonyl-4-isobutyl-5-methyl-1,3-
oxazinan-6-one 10, (4S,5R)-N-benzyloxycarbonyl-4-isobutyl-5-
methyl-1,3-oxazinan-6-one 11 and (4S)-N-benzyloxycarbonyl-4-
isobutyl-5,5-dimethyl-1,3-oxazinan-6-one 12. The general pro-
cedure A was followed for the alkylation of oxazinanone 9 (146 mg,
0.50 mmol) to afford starting material 9 (16 mg, 11% recovery),
a mixture of diastereoisomers 10/11 as a colorless oil in a 12.5:1
(trans/cis) ratio (67.0 mg, 44%), and 5,5-disubstituted oxazinanone
12 (8.0 mg, 5%), with spectra identical to those of an authentic
sample.7
The general procedure A was followed for the alkylation of
oxazinanone 9 (146 mg, 0.50 mmol) with a toluene/DMPU mixture
(2:1, 4.0 mL) as the solvent to afford starting material 9 (13.0 mg, 9%
recovery), the oxazinanones 10/11 as a colorless oil in a >19:1
(trans/cis) ratio (56.0 mg, 37%) and 5,5-disubstituted oxazinanone
12 (11.2 mg, 7%).
4.2.1.1.4. (4S,5S)-N-Benzyloxycarbonyl-4-benzyl-5-methyl-1,3-
oxazinan-6-one 18. The general procedure A was followed for the
alkylation of oxazinanone 17 (163 mg, 0.50 mmol) to afford starting
material 17 (13.0 mg, 8% recovery) and the oxazinanones 18/19 as
a colorless oil in a >19:1 (trans/cis) ratio (8.0 mg, 47%), with spectra
identical to those of an authentic sample.7
4.2. Synthesis
4.2.1. Synthesis of 5-alkylated 1,3-oxazinan-6-ones
4.2.1.1.5. (4S,5S)-N-Benzyloxycarbonyl-(4R)-sec-butyl-5-methyl-
1,3-oxazinan-6-one 14 and (4S,5S)-N-benzyloxycarbonyl-(4R)-sec-
butyl-5,5-dimethyl-1,3-oxazinan-6-one 16. The general procedure A
was followed for the alkylation of oxazinanone 13 (146 mg,
0.50 mmol) with a toluene/DMPU mixture (2:1, 4.0 mL) as the
solvent to afford starting material 13 (22.0 mg, 15% recovery). The
oxazinanones 14/15 was isolated as a colorless oil in a >19:1 (trans/
cis) ratio (64.0 mg, 42%). m/z HRMS (EI): found [Mþ], 305.1625;
C17H23NO4 requires [Mþ], 305.1627; Rf (20% EtOAc/hexane) 0.39;
. 4.2.1.1. General procedure A. The oxazinanone (0.50 mmol) was
dissolved in freshly distilled dry toluene (4.0 mL) and the solution
was cooled to ꢀ78 ꢁC under an argon atmosphere. Then KHMDS
(1.1 equiv, 1.10 mL, 0.55 mmol of a 0.50 M solution in toluene) was
added dropwise and the solution was left to stir at ꢀ78 ꢁC for
40 min. Methyl triflate (0.184 mL, 1.5 equiv, 0.75 mmol) was added
dropwise, and stirring was continued for 3 h at ꢀ78 ꢁC. The solution
was then allowed to warm to ꢀ40 ꢁC, and the reaction was then
quenched with satd aq NH4Cl solution (5 mL). The solution was
diluted with ethyl acetate (20 mL) and washed with water (20 mL).
The organic layer was dried over MgSO4 and concentrated in vacuo
to give a yellow oily residue. The oil was subjected to column
chromatography, eluting with 5e20% ethyl acetate/hexane.
4.2.1.1.1. (4S,5S)-N-Benzyloxycarbonyl-4,5-dimethyl-1,3-oxazin-
an-6-one 2, (4S,5R)-N-benzyloxycarbonyl-4,5-dimethyl-1,3-
oxazinan-6-one 3 and (4S)-N-benzyloxycarbonyl-4,5,5-trimethyl-
1,3-oxazinan-6-one 4. General procedure A was followed for the
alkylation of oxazinanone 1 (125 mg, 0.50 mmol) to obtain
starting material 1 (7.5 mg, 6% recovery) and a mixture of di-
astereoisomers 2/3 as a colorless oil in a 1.7:1 (trans/cis) ratio
(97 mg, 74%), with spectra identical to those of an authentic
sample.7
½
a 2D6
ꢂ
þ67.5 (c 0.7, MeOH); nmax (NaCl)/cmꢀ1 2968, 2939, 1756, 1705,
1697, 1455, 1408, 1253, 1132, 1076, 1001, 920; 1H NMR (300 MHz,
CDCl3) (325 K): d 7.38 (5H, s), 5.86 (1H, br s), 5.14 (2H, s), 4.96 (1H, d,
J 10.6 Hz), 3.81 (1H, br s), 2.76 (1H, dd, J 6.8, 13.6 Hz), 1.78e1.65 (1H,
m), 1.52 (1H, br s), 1.31 (3H, d, J 6.7 Hz), 1.15e1.03 (1H, m), 0.99 (3H,
d, J 6.3 Hz), 0.89 (3H, t, J 6.7 Hz); 13C NMR (75 MHz, CDCl3) (325 K):
d
172.5, 154.8, 135.1, 128.2, 128.1, 127.8, 72.5, 67.9, 60.3, 38.0, 37.4,
24.1, 15.7, 15.2, 11.3.
The oxazinanone 16 was isolated as a colorless oil (16.0 mg,10%).
m/z HRMS (EI): found [Mþ], 319.1782; C18H25NO4 requires [Mþ],
319.1784; Rf (20% EtOAc/hexane) 0.49; ½a D25
þ13.0 (c 1.0, MeOH);
ꢂ
nmax (NaCl)/cmꢀ1 2967, 2934, 1748, 1709, 1454, 1418, 1331, 1244,
1099, 1013, 966, 908; 1H NMR (300 MHz, CDCl3) (325 K):
d 7.34 (5H,
s), 5.94 (1H, br s), 5.21e5.18 (3H, m), 4.05 (1H, br s), 1.75 (1H, br s),
1.57e1.45 (1H, m), 1.29 (6H, s), 1.15e1.03 (1H, m), 1.04 (3H, d, J
6.3 Hz), 0.89 (3H, t, J 7.5 Hz); 13C NMR (75 MHz, CDCl3) (325 K):
General procedure A was followed for the alkylation of oxazi-
nanone 1 (125 mg, 0.50 mmol) with a toluene/DMPU mixture (2:1,
4.0 mL) as the solvent to afford starting material 1 (17.5 mg, 14%
recovery), a mixture of diastereoisomers 3/4 as a colorless oil in
a 16.5:1 (trans/cis) ratio (8 mg, 62%) and 5,5-disubstituted oxazi-
nanone 4 (6.9 mg, 5%).
d
174.2, 154.4, 135.4, 128.2, 128.0, 127.7, 74.7, 67.8, 63.2, 42.5, 36.6,
27.9, 24.7, 21.3, 16.6, 12.3.
4.2.2. 5-Ethyl/benzyl/allylation of 1,3-oxazinan-6-ones.
4.2.1.1.2. (4S,5S)-N-Benzyloxycarbonyl-4-isopropyl-5-methyl-1,3-
oxazinan-6-one 6, (4S,5R)-N-benzyloxycarbonyl-4-isopropyl-5-
methyl-1,3-oxazinan-6-one 7 and (4S)-N-benzyloxycarbonyl-4-
isopropyl-5,5-dimethyl-1,3-oxazinan-6-one 8. General procedure A
was followed for the alkylation of oxazinanone 5 (139 mg,
0.50 mmol) to afford starting material 5 (11.0 mg, 8% recovery),
a mixture of diastereoisomers 6/7 as a colorless oil in a 4.7:1 (trans/
cis) ratio (89.0 mg, 61% yield), and disubstituted oxazinanone 8
(7.6 mg, 5%) with spectra identical to those of an authentic sample.7
The general procedure A was followed for the alkylation of
oxazinanone 5 (139 mg, 0.50 mmol) with a toluene/DMPU mixture
(2:1, 4.0 mL) as the solvent to afford starting material 5 (8.30 mg, 6%
recovery), the oxazinanone 6/7 as a colorless oil in a >19:1 (trans/
4.2.2.1. General procedure B. The oxazinanone (0.50 mmol) was
dissolved in dry toluene/DMPU mixture (2:1, 4.0 mL) and the so-
lution was cooled to ꢀ78 ꢁC under an argon atmosphere. Then
KHMDS (1.1 equiv, 1.10 mL, 0.55 mmol, a 0.50 M solution in toluene)
was added dropwise and the solution was left to stir at ꢀ78 ꢁC for
40 min. The alkylating agent (5 equiv, 2.50 mmol) was added
dropwise and stirring was continued for 3 h at ꢀ78 ꢁC. The solution
was then allowed to warm to ꢀ40 ꢁC, and the reaction was then
quenched with satd aq NH4Cl solution (5 mL). The solution was
diluted with ethyl acetate (20 mL) and washed with water (20 mL).
The organic layer was dried over MgSO4 and concentrated in vacuo
to give a yellow oily residue. The oil was subjected to column
chromatography, eluting with 5e20% ethyl acetate/hexane.

N.H. Nguyen et al. / Tetrahedron 68 (2012) 4745e4756
4751
4.2.2.1.1. (4S,5S)-N-Benzyloxycarbonyl-4-methyl-5-allyl-1,3-
with allyl bromide (216
mL, 2.50 mmol) as the electrophile to afford
oxazinan-6-one 21, and (4S)-N-benzyloxycarbonyl-4-methyl-5,5-
diallyl-1,3-oxazinan-6-one 22. The general procedure B was fol-
lowed for the alkylation of oxazinanone 1 (125 mg, 0.50 mmol)
starting material 5 (19.5 mg, 14% recovery). The oxazinanone 27
was isolated as a colorless oil (64.1 mg, 42% yield). m/z HRMS (EI):
found [Mþ], 317.1621; C18H23NO4 requires [Mþ], 317.1627; Rf (10%
with allyl bromide (216
m
L, 2.50 mmol) as the electrophile to afford
EtOAc/hexane) 0.22; ½a D25
ꢂ
þ157.3 (c 1.0, MeOH); nmax (NaCl)/cmꢀ1
starting material 1 (23.7 mg, 19% recovery). The oxazinanone 21
was isolated as a colorless oil (20.2 mg, 14% yield). m/z HRMS (ESI,
MeOH/AcOH): [MþH]þ, found 290.1387. C16H19NO4 requires
3068, 3034, 2966, 2934, 2878, 1756, 1717, 1695, 1404, 1316, 1251,
1156,1124,1026, 991, 922; 1H NMR (300 MHz, CDCl3) (325 K):
d 7.30
(5H, s), 5.92 (1H, d, J 10.2 Hz), 5.85e5.74 (1H, m), 5.17 (2H, s), 5.08
(2H, d, J 11.7 Hz), 4.95 (1H, d, J 10.2 Hz), 3.96 (1H, br s), 2.71 (1H, dd, J
5.7, 11.7 Hz), 2.44 (2H, dd, J 6.9,12.6 Hz),1.99e1.88 (1H, m),1.00 (3H,
d, J 6.6 Hz), 0.91 (3H, d, J 6.6 Hz); 13C NMR (75 MHz, CDCl3) (325 K):
290.1387; Rf (20% EtOAc/hexane) 0.24; ½a D25
þ144.0 (c 0.22, MeOH);
ꢂ
nmax (NaCl)/cmꢀ1 3077, 3034, 2977, 2917, 1761, 1717, 1699, 1415,
1334, 1253, 1130, 998, 916; 1H NMR (300 MHz, (CD3)2CO) (300 K):
d
7.41e7.31 (5H, m), 5.95e5.81 (1H, m), 5.75 (1H, d, J 10.9 Hz), 5.31
d 170.5, 154.6, 135.3, 134.1, 128.2, 128.0, 127.7, 117.9, 72.4, 67.9, 57.7,
(1H, d, J 11.1 Hz), 5.18 (2H, q, JAB 12.6 Hz), 5.06 (2H, dd, J 13.2,
10.2 Hz), 3.93 (1H, dt, J 6.0, 10.2 Hz), 2.85 (1H, dt, J 6.0, 10.2 Hz), 2.45
(2H, dd, J 6.0, 13.2 Hz), 1.37 (3H, d, J 6.0 Hz); 13C NMR (75 MHz,
43.4, 34.3, 30.3, 19.6, 17.2.
The oxazinanone 28 was isolated as a colorless oil (23.2 mg, 13%
yield). m/z HRMS (EI): found [Mþ], 357.1924; C21H27NO4 requires
CDCl3) (300 K):
d
170.9, 153.4, 135.2, 133.9, 128.3, 128.1, 127.8, 117.8,
[Mþ], 357.1940; Rf (10% EtOAc/hexane) 0.40; ½a 2D3
þ36.0 (c 0.5,
ꢂ
70.4, 67.7, 49.8, 46.0, 31.7, 15.3.
MeOH); nmax (NaCl)/cmꢀ1 3077, 3035, 2966, 1749, 1714, 1695, 1694,
The oxazinanone 22 was isolated as a colorless oil (52.7 mg, 32%
1416, 1315, 1269, 1245, 1153, 1102, 994, 918; 1H NMR (300 MHz,
yield). m/z HRMS (ESI, MeOH/AcOH): [MþH]þ, found 330.1700.
(CD3)2CO) (320 K):
d 7.39e7.31 (5H, m), 5.90e5.77 (2H, m),
C19H23NO4 requires 330.1700; Rf (20% EtOAc/hexane) 0.39; ½a D24
ꢂ
5.73e5.59 (1H, m), 5.40 (1H, d, J 9.9 Hz), 5.23e5.14 (4H, m), 5.03
(2H, d, J 13.8 Hz), 4.22 (1H, d, J 4.5 Hz), 2.69 (1H, dd, J 5.7, 15.0 Hz),
2.45 (1H, dd, J 7.2, 14.4 Hz), 2.40e2.22 (3H, m), 1.01 (3H, d, J 6.8 Hz),
þ63.5 (c 0.52, MeOH); nmax (NaCl)/cmꢀ1 3077, 3034, 2979, 2939
(CeH), 1750, 1717 (C]O), 1699, 1695 (C]C), 1417, 1329, 1275, 1250,
1146, 1107, 1057, 1001, 922; 1H NMR (300 MHz, CDCl3) (325 K):
0.97 (3H, d, J 6.8 Hz); 13C NMR (75 MHz, CDCl3) (320 K):
d 171.3,
d
7.34 (5H, s), 5.86 (1H, d, J 9.6 Hz), 5.79e5.60 (2H, m), 5.25e5.14
154.2, 135.3, 131.4, 131.3, 128.3, 128.1, 127.8, 119.8, 119.3, 75.2, 67.8,
59.8, 48.3, 39.1, 34.6, 28.9, 20.7, 17.9.
4.2.2.1.5. (4S,5S)-N-Benzyloxycarbonyl-4-isopropyl-5-benzyl-1,3-
oxazinan-6-one 29, and (4S)-N-benzyloxycarbonyl-4-isopropyl-5,5-
dibenzyl-1,3-oxazinan-6-one 30. The general procedure B was fol-
lowed for the alkylation of oxazinanone 5 (139 mg, 0.50 mmol)
(5H, m), 5.06 (2H, dd, J 10.8, 18.3 Hz), 4.34 (1H, d, J 6.3 Hz), 2.68 (1H,
dd, J 7.2, 15.0 Hz), 2.46e2.31 (2H, m), 2.23 (1H, dd, J 7.2, 15.0 Hz),
1.31 (3H, d, J 6.3 Hz); 13C NMR (75 MHz, CDCl3) (325 K):
d 171.0,
153.0, 135.4, 131.7, 131.1, 128.2, 128.1, 127.7, 119.5, 118.8, 72.3, 67.7,
51.5, 50.3, 38.7, 35.0, 14.8.
4.2.2.1.2. (4S)-N-Benzyloxycarbonyl-4-methyl-5,5-dibenzyl-1,3-
oxazinan-6-one 24. The general procedure B was followed for the
alkylation of oxazinanone 1 (125 mg, 0.50 mmol) with benzyl
with benzyl bromide (297 mL, 2.50 mmol) as the electrophile to
furnish starting material 5 (20.8 mg, 15% recovery). The oxazina-
none 29 was isolated as a colorless oil (53.3 mg, 29% yield). m/z
HRMS (EI): found [Mþ], 367.1776; C22H25NO4 requires [Mþ],
bromide (297 mL, 2/50 mmol) as the electrophile to afford starting
material 1 (27.5 mg, 22% recovery) and trace amount of the oxazi-
nanone 23. The oxazinanone 24 was isolated as a white solid
(70.9 mg, 33% yield). m/z HRMS (ESI, MeOH/AcOH): [MþH]þ, found
430.2013. C27H27NO4 requires 430.2013; mp 103e105 ꢁC; requires
430.2013; mp 103e105 ꢁC; Rf (20% EtOAc/hexane) 0.32 Rf (20%
367.1784; Rf (10% EtOAc/hexane) 0.20; ½a D25
þ128.0 (c 0.25, MeOH);
ꢂ
nmax (NaCl)/cmꢀ1 3030, 2964, 2930, 2877, 1749, 1706, 1404, 1311,
1250, 1151, 1123, 1020, 993; 1H NMR (300 MHz, CDCl3) (325 K):
d
7.39e7.08 (10H, m), 5.96 (1H, d, J 10.4 Hz), 5.18 (2H, s), 4.99 (1H, d,
J 10.4 Hz), 3.91 (1H, br s), 3.17 (1H, dd, J 4.8, 13.2 Hz), 2.92e2.77 (2H,
m), 1.94e1.83 (1H, m), 0.86 (3H, d, J 6.6 Hz), 0.81 (3H, d, J 6.6 Hz);
EtOAc/hexane) 0.32; ½a D25
ꢂ
þ83.5 (c 0.48, MeOH); nmax (NaCl)/cmꢀ1
3031, 2961, 2935, 1750, 1713, 1496, 1419, 1346, 1248, 1140, 1080,
13C NMR (75 MHz, CDCl3) (325 K):
d 170.6, 154.6, 137.9, 135.2,
1031, 1003, 913; 1H NMR (300 MHz, CDCl3) (300 K):
d
7.33e7.14
128.8, 128.2, 128.1, 128.0, 127.8, 126.3, 72.4, 68.1, 57.7, 45.8, 36.6,
29.7, 19.6, 17.2.
(15H, m), 5.65 (1H, br s), 5.28 (1H, d, J 10.2 Hz), 5.08 (1H, d, J
12.3 Hz), 5.06 (1H, d, J 12.3 Hz), 4.52 (1H, d, J 6.8 Hz), 3.26 (2H, dd, J
13.5, 14.4 Hz), 2.99 (1H, d, J 14.6 Hz), 2.78 (1H, d, J 14.6 Hz), 1.36 (3H,
The oxazinanone 30 was isolated as a colorless oil (32.0 mg, 14%
yield). m/z HRMS (EI): found [Mþ], 457.2223; C29H31NO4 requires
d, J 6.8 Hz); 13C NMR (75 MHz, CDCl3) (300 K):
d
171.1, 154.4, 135.8,
[Mþ], 457.2253; Rf (10% EtOAc/hexane) 0.26; ½a 2D5
þ64.7 (c 0.7,
ꢂ
135.2, 135.1, 130.1, 129.9, 128.3, 128.2, 127.9, 127.7, 126.9, 126.7, 73.1,
67.6, 52.5, 51.0, 41.3, 38.5, 15.3.
MeOH); nmax (NaCl)/cmꢀ1 3030, 2967, 2937, 1746, 1706, 1496, 1454,
1419, 1338, 1246, 1159, 1136, 1082, 995, 912; 1H NMR (300 MHz,
4.2.2.1.3. (4S,5S)-N-Benzyloxycarbonyl-4-isopropyl-5-ethyl-1,3-
oxazinan-6-one 25. The general procedure B was followed for the
alkylation of oxazinanone 5 (139 mg, 0.50 mmol) with EtOTf
(133 mg, 1.5 equiv) as the electrophile to afford starting material 5
(27.8 mg, 20% recovery) and a trace amount of oxazinanone 26.
The oxazinanone 25 was isolated as a colorless oil (74.8 mg, 49%
yield). m/z HRMS (ESI, MeOH/AcOH): [MþNa]þ found 328.1508.
CDCl3) (325 K): d 7.31e7.06 (15H, m), 5.58 (1H, br s), 5.21 (1H, d, J
9.6 Hz), 5.07e4.98 (2H, m), 4.46 (1H, br s), 3.35 (2H, dd, J 6.9,
14.4 Hz), 3.12 (1H, d, J 14.4 Hz), 2.70 (1H, d, J 14.4 Hz), 2.44e2.38
(1H, m), 1.07 (3H, d, J 6.8 Hz), 0.98 (3H, d, J 6.8 Hz); 13C NMR
(75 MHz, CDCl3) (325 K):
d 171.1, 154.0, 136.1, 135.3, 130.2, 130.1,
128.1, 128.0, 127.9, 127.6, 126.8, 126.5, 73.7, 67.6, 59.2, 52.4, 42.3,
38.7, 29.1, 21.4, 18.3.
4.2.2.1.6. (4S,5S)-N-Benzyloxycarbonyl-4-benzyl-5-allyl-1,3-
oxazinan-6-one 31 and (4S)-N-benzyloxycarbonyl-4-benzyl-5,5-
diallyl-1,3-oxazinan-6-one 32. General procedure B was followed
for the alkylation of oxazinanone 17 (289 mg, 0.89 mmol) with allyl
C17H23NO4 requires 328.1519; Rf (20% EtOAc/hexane) 0.36; ½a D25
ꢂ
þ116.1 (c 0.5, MeOH); nmax (NaCl)/cmꢀ1 2965, 2936, 2878, 1755,
1713, 1466, 1408, 1316, 1252, 1163, 1128, 1020, 993; 1H NMR
(300 MHz, CDCl3) (300 K):
d 7.39 (5H, s), 5.89 (1H, br s), 5.22e5.12
(2H, m), 4.96 (1H, d, J 10.5 Hz), 3.94 (1H, br s), 2.57 (1H, dd, J 6.0,
12.0 Hz), 1.96e1.89 (1H, m), 1.77e1.71 (2H, m), 0.94e0.86 (9H, m);
bromide (385 mL, 4.45 mmol) as the electrophile to afford starting
material 17 (86.9 mg, 30% recovery). The oxazinanone 31 was iso-
lated as a colorless oil (32.5 mg, 10% yield). m/z HRMS (EI): found
[Mþ], 365.1627; C22H23NO4 requires [Mþ], 365.1627; Rf (20% EtOAc/
13C NMR (75 MHz, CDCl3) (300 K):
d 171.4, 154.8, 135.3, 128.2, 128.1,
127.7, 72.3, 67.9, 58.2, 44.9, 30.3, 23.5, 19.6, 17.2, 11.3.
4.2.2.1.4. (4S,5S)-N-Benzyloxycarbonyl-4-isopropyl-5-allyl-1,3-
oxazinan-6-one 27, and (4S)-N-benzyloxycarbonyl-4-isopropyl-5,5-
diallyl-1,3-oxazinan-6-one 28. The general procedure B was fol-
lowed for the alkylation of oxazinanone 5 (139 mg, 0.50 mmol)
hexane) 0.43; ½a D25
ꢂ
þ140 (c 0.8, MeOH); nmax (NaCl)/cmꢀ1 3063,
3030, 2943, 2924, 1745, 1718, 1693, 1454, 1418, 1331, 1254, 1029,
999; 1H NMR (300 MHz, CDCl3) (325 K):
5.96e5.82 (1H, m), 5.68 (1H, d, J 9.6 Hz), 5.22e5.05 (4H, m), 4.34
d 7.38e7.07 (10H, m),

4752
N.H. Nguyen et al. / Tetrahedron 68 (2012) 4745e4756
(1H, d, J 10.8 Hz), 4.27e4.25 (1H, m), 3.19 (1H, dd, J 4.2,14.0 Hz), 2.88
(1H, dd, J 4.2, 14.1 Hz), 2.65e2.58 (1H, m), 2.54e2.42 (2H, m); 13C
4.2.3.1.1. (4S)-N-Benzyloxycarbonyl-4,5,5-trimethyl-1,3-oxazinan-
6-one 4 and (4S,5S/R)-N-benzyloxycarbonyl-4,5-dimethyl-1,3-
oxazinan-6-one 2/3. The general procedure C was followed for
the dimethylation of oxazinanone 1 (102 mg, 0.41 mmol) to af-
ford a mixture of diastereoisomers of 2/3 (27.0 mg, 25% yield),
and the dimethylated oxazinanone 4, isolated as a colorless oil
(55.7 mg, 49% yield) with spectra identical to those of an au-
thentic sample.7
4.2.3.1.2. (4S)-N-Benzyloxycarbonyl-4-isopropyl-5,5-dimethyl-
1,3-oxazinan-6-one 8 and (4S,5S/R)-N-benzyloxycarbonyl-4-
isopropyl-5-methyl-1,3-oxazinan-6-one 6/7. The general procedure
C was followed for the dimethylation of oxazinanone 5 (76.3 mg,
0.28 mmol) and afforded a mixture of diastereoisomers 6/7
(17.2 mg, 22% yield). The dimethylated oxazinanone 8 was isolated
as a colorless oil (37.7 mg, 45% yield) with spectra identical to those
of an authentic sample.7
4.2.3.1.3. (4S)-N-Benzyloxycarbonyl-(4R)-sec-butyl-5,5-dimethyl-
1,3-oxazinan-6-one 16 and (4S,5S/R)-N-benzyloxycarbonyl-(4R)-sec-
butyl-5-methyl-1,3-oxazinan-6-one 14/15. The general procedure C
was followed for the dimethylation of oxazinanone 13 (134 mg,
0.46 mmol) and afforded a mixture of diastereoisomers 14/15
(12.2 mg, 8% yield). The dimethylated oxazinanone 16 was isolated
as a colorless oil (88.2 mg, 60% yield) with spectra identical to that
reported above.
NMR (75 MHz, CDCl3) (325 K):
d 170.8, 153.7, 135.3, 135.1, 133.9,
129.6, 128.3, 128.0, 127.7, 127.5, 126.8, 117.8, 71.6, 67.8, 53.5, 42.2,
36.9, 31.8.
The oxazinanone 32 was isolated as a colorless oil (72.2 mg, 20%
yield). m/z HRMS (EI): found [Mþ], 405.1934; C25H27NO4 requires
[Mþ], 405.1940; Rf (20% EtOAc/hexane) 0.57; ½a 2D4
þ70.0 (c 1.0,
ꢂ
MeOH); nmax (NaCl)/cmꢀ1 3065, 3030, 2980, 2922, 1746, 1713, 1699,
1496, 1418, 1323, 1248, 1130, 1111, 1030, 988; 1H NMR (300 MHz,
(CD3)2CO) (320 K):
d 7.31e7.13 (10H, m), 6.03e5.92 (1H, m), 5.88
(1H, d, J 10.1 Hz), 5.77e5.63 (1H, m), 5.39 (1H, d, J 10.1 Hz), 5.26 (2H,
dd, J 17.1, 11.1 Hz), 5.11e4.85 (4H, m), 4.65 (1H, br s), 3.25 (1H, dd, J
3.9, 10.2 Hz), 2.92e2.76 (2H, m), 2.52e2.35 (3H, m); 13C NMR
(75 MHz, (CD3)2CO) (320 K): d 170.5, 153.4, 137.0, 136.1, 132.3, 131.8,
128.5, 128.1, 127.9, 127.5, 127.3, 126.1, 118.9, 118.2, 72.3, 66.8, 57.4,
50.1, 39.2, 34.7, 33.1.
4.2.2.1.7. (4S,5S)-N-Benzyloxycarbonyl-(4R)-sec-butyl-5-allyl-
1,3-oxazinan-6-one 33, and (4S)-N-benzyloxycarbonyl-(4R)-sec-bu-
tyl-5,5-diallyl-1,3-oxazinan-6-one 34. General procedure
followed for the alkylation of oxazinanone 13 (239 mg, 0.85 mmol)
with allyl bromide (368 L, 4.25 mmol) as the electrophile to afford
B was
m
starting material 13 (66.9 mg, 28% recovery). The oxazinanone 33
was isolated as a colorless oil (64.8 mg, 23% yield). m/z HRMS (ESI,
MeOH/AcOH): [MþH]þ found 332.1853. C19H25NO4 requires
332.1856; Rf (20% EtOAc/hexane) 0.46; ½a D26
ꢂ
þ121.9 (c 1.8, MeOH);
4.2.4. One-pot synthesis of 5,5-dibenzyl and allyl-
rivatives.
b-amino acid de-
nmax (NaCl)/cmꢀ1 3067, 3034, 2968, 2935, 2878, 1749, 1709, 1700,
1456, 1418, 1316, 1251, 1151, 1126, 1026, 993, 920; 1H NMR
4.2.4.1. General procedure D. A solution of oxazinanone (0.063 M in
freshly distilled dry toluene/DMPU mixture (2:1)) was cooled to
ꢀ78 ꢁC under an argon atmosphere. Then KHMDS (1.1 equiv of
a 0.50 M solution in toluene) was added dropwise and the solution
was left to stir at ꢀ78 ꢁC for 40 min. The alkylating agent
(5.00 equiv) was added dropwise, and stirring was continued for
1.5 h at ꢀ78 ꢁC. The solution was then allowed to warm to ꢀ15 ꢁC,
and the reaction was cooled to ꢀ78 ꢁC, and a second addition of
KHMDS (2.50 equiv) and alkylating agent (10.0 equiv) was carried
out in the same manner as the first. The solution was allowed to
warm to ꢀ15 ꢁC and then the reaction mixture was quenched with
satd aq NH4Cl solution (5 mL). The solution was diluted with ethyl
acetate (20 mL) and washed with water (20 mL). The organic layer
was dried over MgSO4 and concentrated in vacuo to give an oil. The
oil was subjected to column chromatography, eluting with 5e20%
ethyl acetate/hexane.
(300 MHz, CDCl3) (325 K):
d 7.33 (5H, s), 5.92 (1H, d, J 10.5 Hz),
5.85e5.72 (1H, m), 5.17 (2H, s), 5.08 (2H, d, J 11.4 Hz), 4.98 (1H, d, J
10.5 Hz), 4.01 (1H, br s), 2.74 (1H, dd, J 5.7, 11.4 Hz), 2.43 (2H, dd, J
6.6, 12.9 Hz), 1.73e1.64 (1H, m), 1.53e1.42 (1H, m), 1.14e1.02 (1H,
m), 0.97 (3H, d, J 6.9 Hz), 0.89 (3H, m); 13C NMR (75 MHz, CDCl3)
(325 K):
d 170.5, 154.4, 135.3, 133.9, 128.2, 128.0, 127.8, 117.9, 72.3,
67.9, 56.9, 43.4, 36.7, 34.7, 24.1, 15.5, 10.7.
The oxazinanone 34 was isolated as a colorless oil (85.2 mg, 27%
yield). m/z HRMS (ESI, MeOH/AcOH): [MþH]þ found 372.2166.
C22H29NO4 requires 372.2169; Rf (20% EtOAc/hexane) 0.59; ½a D26
ꢂ
þ42.7 (c 1.7, MeOH); nmax (NaCl)/cmꢀ1 3068, 3035, 2966, 2935,
2878,1746,1710,1700,1640,1454,1419,1336,1302,1251,1153, 1103,
1002, 920; 1H NMR (300 MHz, CDCl3) (325 K):
d 7.33 (5H, s), 5.93
(1H, d, J 6.8 Hz), 5.85e5.71 (1H, m), 5.69e5.57 (1H, m), 5.24e5.14
(5H, m), 5.05 (2H, dd, J 10.1, 17.8 Hz), 4.22 (1H, br s), 2.77 (1H, dd, J
6.9, 15.2 Hz), 2.45e2.38 (1H, m), 2.32e2.21 (2H, m), 1.92e1.81 (1H,
m), 1.59e1.50 and 1.15e1.02 (2H, m), 0.97e0.87 (6H, m); 13C
4.2.4.1.1. (4S)-N-Benzyloxycarbonyl-4-methyl-5,5-diallyl-1,3-
oxazinan-6-one 22. General procedure D was followed for the al-
kylation of oxazinanone 1 (53.5 mg, 0.22 mmol) with allyl bromide
NMR (75 MHz, CDCl3) (325 K):
d 171.4, 154.2, 135.4, 131.5, 128.2,
128.0, 127.7, 119.4, 118.9, 75.1, 67.8, 60.6, 48.4, 39.7, 36.4, 34.6, 24.6,
16.4, 12.5.
(first addition 92.9 mL, 1.07 mmol; second addition 184 mL,
2.14 mmol) as the electrophile to afford the diallyl oxazinanone 22
(45.1 mg, 65%) and the mono adduct 21 (2.1 mg, 3%).
4.2.3. Dimethylation of the oxazinanone in a one-pot reaction
. 4.2.3.1. General procedure C. A solution of oxazinanone (0.102 M
in freshly distilled dry toluene) was cooled to e78 ꢁC under an
argon atmosphere. Then KHMDS (1.1 equiv of a 0.50 M solution in
toluene) was added dropwise and the solution was left to stir at
ꢀ78 ꢁC for 40 min. Methyl triflate (1.5 equiv) was added dropwise,
and stirring was continued for 1.5 h at ꢀ78 ꢁC. The solution was
then allowed to warm to ꢀ15 ꢁC, and the reaction was cooled to
ꢀ78 ꢁC, and a second addition of KHMDS (2.1 equiv) and MeOTf
(3.0 equiv) was carried out in the same manner as the first. The
solution was allowed to warm to ꢀ15 ꢁC and then the reaction
mixture was quenched with satd aq NH4Cl solution (5 mL). The
solution was diluted with ethyl acetate (20 mL) and washed with
water (20 mL). The organic layer was dried over MgSO4 and con-
centrated in vacuo to give a yellow oily residue. The oil was sub-
jected to column chromatography, eluting with 5e20% ethyl
acetate/hexane.
4.2.4.1.2. (4S)-N-Benzyloxycarbonyl-4-methyl-5,5-dibenzyl-1,3-
oxazinan-6-one 24. General procedure D was followed for the al-
kylation of oxazinanone 1 (66.8 mg, 0.27 mmol) with benzyl bro-
mide (first addition 161 mL, 1.35 mmol; second addition 321 mL,
2.70 mmol) as the electrophile to afford the dibenzyl oxazinanone
24 (58.6 mg, 51%).
4.2.4.1.3. (4S)-N-Benzyloxycarbonyl-4-isopropyl-5,5-diallyl-1,3-
oxazinan-6-one 28. General procedure D was followed for the
alkylation of oxazinanone 5 (88.3 mg, 0.32 mmol) with allyl
bromide (first addition 136
mL, 1.59 mmol; second addition
276 L, 3.18 mmol) as the electrophile to afford the diallyl
m
oxazinanone 28 (60.3 mg, 53%) and the mono adduct 27
(9.1 mg, 9%).
4.2.4.1.4. (4S)-N-Benzyloxycarbonyl-4-isopropyl-5,5-dibenzyl-
1,3-oxazinan-6-one 30. General procedure D was followed for the
alkylation of oxazinanone 5 (53.5 mg, 0.19 mmol) with benzyl
bromide (first addition 115 mL, 0.97 mmol; second addition 230 mL,

N.H. Nguyen et al. / Tetrahedron 68 (2012) 4745e4756
4753
1.94 mmol) as the electrophile to afford the dibenzyl oxazinanone
the alkylation of
a-methyl-1,3-oxazinan-6-one 6/7 (109 mg,
30 (41.6 mg, 65%) and the mono adduct 29 (4.8 mg, 7%).
0.37 mmol) with allyl bromide (161 mL, 1.85 mmol) as the electro-
phile to afford starting material 6/7 (14.8 mg, 14% recovery). The
title compound 41 was isolated in a >19:1 (trans/cis) ratio (60.6 mg,
49% yield) as a colorless oil. m/z HRMS (EI): found: [Mþ], 331.1791;
C19H25NO4 requires [Mþ], 331.1784; Rf (20% EtOAc/hexane) 0.58;
4.2.5. Diastereoselective alkylation of the 5-methyl-1,3-oxazinan-6-
one.
4.2.5.1. General procedure E. A solution of 5-methyl oxazinanone
(0.125 M in dry freshly distilled toluene) was cooled to ꢀ78 ꢁC
under an argon atmosphere. Then KHMDS (1.1 equiv of a 0.50 M
solution in toluene) was added dropwise and the solution was left
to stir at ꢀ78 ꢁC for 40 min. The alkylating agent (5.00 equiv) was
then added dropwise and stirring was continued for 3 h at ꢀ78 ꢁC.
The solution was then allowed to warm to ꢀ15 ꢁC, and the reaction
was then quenched with satd aq NH4Cl solution (5 mL). The solu-
tion was diluted with ethyl acetate (20 mL) and washed with water
(20 mL). The organic layer was dried over MgSO4 and concentrated
in vacuo to give an oily residue. The oil was subjected to flash
column chromatography, eluting with 5e10% ethyl acetate/hexane.
4.2.5.1.1. (4S,5S)-N-Benzyloxycarbonyl-4,5-dimethyl-5-allyl-1,3-
oxazinan-6-one 35/36. General procedure E was followed for the
½
a 2D4
ꢂ
þ38.0 (c 0.5, MeOH); nmax (NaCl)/cmꢀ1 3075, 3034, 2965, 2941,
1746, 1712, 1700, 1695, 1416, 1316, 1244, 1101, 1011, 918; 1H NMR
(300 MHz, CDCl3) (325 K):
d 7.38 (5H, s), 5.91 (1H, d, J 9.0 Hz),
5.73e5.65 (1H, m), 5.28 (1H, d, J 9.0 Hz), 5.18 (2H, s), 5.11 (2H, dd, J
15.3, 17.1 Hz), 4.12 (1H, br s), 2.39e2.23 (2H, m), 2.12e2.00 (1H, m),
1.26 (3H, s), 1.02 (3H, d, J 6.5 Hz), 0.97 (3H, d, J 6.5 Hz); 13C NMR
(75 MHz, CDCl3) (325 K):
d 172.7, 153.1, 135.4, 131.5, 128.2, 128.1,
127.8, 119.4, 74.8, 67.7, 60.6, 46.3, 43.4, 29.7, 20.9, 19.1, 18.1.
4.2.5.1.5. (4S,5S)-N-Benzyloxycarbonyl-4-isopropyl-5-methyl-5-
ethyl-1,3-oxazinan-6-one 43. General procedure E was followed for
the alkylation of
a-methyl-1,3-oxazinan-6-one 6/7 (96.3 mg,
0.33 mmol) with EtOTf (90.8 mg, 1.50 equiv) as the electrophile to
afford starting material 6/7 (13.3 mg, 14% recovery). The title
compound 43 was isolated in a >19:1 (trans/cis) ratio (42.6 mg, 45%
yield) as a colorless oil. m/z HRMS (EI): found [Mþ], 319.1781;
C18H25NO4 requires [Mþ], 319.1784; Rf (20% EtOAc/hexane) 0.57;
alkylation of
0.47 mmol) with allyl bromide (205
a
-methyl-1,3-oxazinan-6-one 2/3 (125 mg,
L, 2.35 mmol) as the elec-
m
trophile to afford starting material 2/3 (14.7 mg, 12%). The title
compound 35/36 was isolated as a mixture of diastereoisomers in
a 13:1 (trans/cis) ratio (79.9 mg, 56% yield) as a colorless oil. m/z
HRMS (ESI, MeOH/AcOH): [MþH]þ found 304.1543. C17H21NO4 re-
quires 304.1543; Rf (20% EtOAc/hexane) 0.38; nmax (NaCl)/cmꢀ1
3066, 3033, 2983, 2935, 1756, 1705, 1697, 1422, 1328, 1246, 1111,
½
a 2D5
ꢂ
þ32.0 (c 1.0, MeOH); nmax (NaCl)/cmꢀ1 2968, 1748, 1705, 1456,
1420, 1314, 1267, 1246, 1099, 1010; 1H NMR (300 MHz, CDCl3)
(325 K): d 7.37 (5H, s), 5.84 (1H, br s), 5.21 (1H, d, J 9.6 Hz), 5.13 (2H,
s), 4.11 (1H, br s), 2.10e2.00 (1H, m), 1.66e1.55 (2H, m), 1.23 (3H, s),
1.02 (3H, d, J 6.3 Hz), 0.96 (3H, d, J 6.9 Hz), 0.86 (3H, t, J 6.9 Hz); 13C
1056, 1001, 919; 1H NMR (300 MHz, CDCl3) (325 K):
d
7.38 (5H, s),
NMR (75 MHz, CDCl3) (325 K): d 173.0, 154.2, 135.5, 128.2, 128.1,
5.87 (1H, d, J 9.9 Hz), 5.78e5.64 (1H, m), 5.23 (1H, d, J 9.9 Hz), 5.18
(2H, s), 5.10 (2H, dd, J 10.2, 17.4 Hz), 4.32e4.30 (1H, m), 2.39e2.25
(2H, m), 1.31 (3H, d, J 7.2 Hz), 1.17 (3H, s); 13C NMR (75 MHz, CDCl3)
127.8, 74.9, 67.7, 60.8, 46.3, 31.5, 29.3, 20.9, 18.3, 8.0.
4.2.5.1.6. (4S,5S)-N-Benzyloxycarbonyl-4-isopropyl-5-methyl-5-
benzyl-1,3-oxazinan-6-one 45. General procedure E was followed
(325 K):
67.7, 51.7, 47.4, 42.4, 18.9, 14.8.
d
172.7, 153.1, 135.4, 131.7, 128.2, 128.1, 127.8, 119.2, 72.2,
for the alkylation of
0.48 mmol) with benzyl bromide (154
a
-methyl-1,3-oxazinan-6-one 6/7 (138 mg,
L, 2.40 mmol) as the elec-
m
4.2.5.1.2. (4S,5S)-N-Benzyloxycarbonyl-4,5-dimethyl-5-ethyl-1,3-
oxazinan-6-one 37/38. General procedure E was followed for the
alkylation of a-methyl-1,3-oxazinan-6-one 2/3 (176 mg, 0.67 mmol)
trophile to afford starting material 6/7 (13.6 mg, 10% recovery). The
title compound 45 was isolated in a >19:1 (trans/cis) ratio (85.7 mg,
48% yield) as a white solid; found: C, 72.51; H, 7.19; N, 3.58;
C23H27NO4 requires C, 72.42; H, 7.13; N, 3.67; mp 105e107 ꢁC; Rf
with EtOTf (179 mg, 1.50 equiv) as the electrophile to afford starting
material 2/3 (15.7 mg, 9% recovery). The title compound 37/38 was
isolated as a mixture of diastereoisomers in a 13:1 (trans/cis) ratio
(114 mg, 56% yield) as a colorless oil. m/z HRMS (EI): found [Mþ],
291.1472; C16H21NO4 requires [Mþ], 291.1471; Rf (20% EtOAc/hex-
ane) 0.46; nmax (NaCl)/cmꢀ1 2978, 2939,1748,1712,1454,1418,1327,
(20% EtOAc/hexane) 0.53; ½a D25
þ11.3 (c 0.6, MeOH); nmax (NaCl)/
ꢂ
cmꢀ1 3031, 2965, 1750, 1738, 1495, 1409, 1250, 1140, 1090, 1013; 1H
NMR (300 MHz, CDCl3) (325 K): d 7.31e7.11 (10H, m), 5.86 (1H, br s),
5.35 (1H, d, J 9.6 Hz), 5.19 (2H, s), 4.18e4.10 (1H, m), 2.95 (2H, dd, J
13.5, 15.3 Hz), 2.05e1.97 (1H, m), 1.22 (3H, s), 0.99 (3H, d, J 6.8 Hz),
1277,1248,1005, 916, 860; 1H NMR (300 MHz, CDCl3) (320 K):
d
7.32
0.95 (3H, d, J 6.8 Hz); 13C NMR (75 MHz, CDCl3) (325 K):
d 172.6,
(5H, s), 5.82 (1H, d, J 9.6 Hz), 5.21 (1H, s), 5.18 (2H, s), 4.28 (1H, br s),
1.68e1.52 (2H, m), 1.26 (3H, d, J 6.9 Hz), 1.12 (3H, s), 0.86 (3H, t, J
154.0, 135.4, 135.1, 130.2, 128.2, 128.1, 127.8, 127.5, 126.7, 75.2, 67.8,
61.0, 47.3, 44.7, 29.7, 21.1, 19.5, 18.1.
4.2.5.1.7. (4S,5S)-N-Benzyloxycarbonyl-4-isobutyl-5-methyl-5-
allyl-1,3-oxazinan-6-one 47. General procedure E was followed for
7.2 Hz); 13C NMR (75 MHz, CDCl3) (320 K):
d
173.1, 153.2, 135.4,
128.2, 128.1, 127.8, 72.2, 67.6, 51.8, 47.8, 30.7, 18.3, 15.0, 8.0.
4.2.5.1.3. (4S,5S)-N-Benzyloxycarbonyl-4,5-dimethyl-5-benzyl-
1,3-oxazinan-6-one 39/40. General procedure E was followed for
the alkylation of
0.36 mmol) with allyl bromide (154
a
-methyl-1,3-oxazinan-6-one 10/11 (109 mg,
L, 1.80 mmol) as the electro-
m
the alkylation of
0.37 mmol) with benzyl bromide (220
a
-methyl-1,3-oxazinan-6-one 2/3 (97.4 mg,
L, 1.85 mmol) as the elec-
phile to afford starting material 10/11 (16.4 mg, 15% recovery). The
title compound 47 was isolated as a colorless oil in a >19:1 (trans/
cis) ratio (58.1 mg, 47% yield). m/z HRMS (EI): found [Mþ], 345.1941;
C20H27NO4 requires [Mþ], 345.1940; Rf (20% EtOAc/hexane) 0.57;
m
trophile to afford starting material 2/3 (13.2 mg, 14% recovery). The
title compound 39/40 was isolated as a mixture of diastereoisomers
in a 10:1 (trans/cis) ratio (75.6 mg, 58% yield) as a colorless oil. m/z
HRMS (ESI, MeOH/AcOH): [MþH]þ found 354.1699. C21H23NO4
requires 354.1700; Rf (20% EtOAc/hexane) 0.33; nmax (NaCl)/cmꢀ1
3030, 2986, 2978, 2933, 1748, 1712, 1496, 1454, 1417, 1328, 1277,
1249, 1136, 1090, 1057, 1002, 913; 1H NMR (300 MHz, CDCl3)
½
a 2D7
ꢂ
þ44.0 (c 1.0, MeOH); nmax (NaCl)/cmꢀ1 3074, 3034, 2957, 2871,
1746, 1705, 1699, 1423, 1250, 1101, 1007, 924; 1H NMR (300 MHz,
CDCl3) (325 K):
d 7.33 (5H, s), 5.98 (1H, d, J 8.7 Hz), 5.73e5.65 (1H,
m), 5.23 (1H, d, J 12.3 Hz), 5.20 (1H, d, J 12.3 Hz), 5.09e5.00 (3H, m),
4.28 (1H, br s), 2.36 (2H, dd, J 7.2, 15.0 Hz), 1.56e1.24 (3H, m), 1.13
(3H, s), 0.92e0.88 (6H, m); 13C NMR (75 MHz, CDCl3) (325 K):
(300 K):
d 7.33e7.13 (10H, m), 5.89 (1H, d, J 8.9 Hz), 5.31 (1H, d, J
8.9 Hz), 5.25 (1H, d, J 12.0 Hz), 5.21 (1H, d, J 12.0 Hz), 4.37 (1H, br s),
2.97 (2H, d, J 13.5 Hz), 2.92 (1H, d, J 13.5 Hz), 1.23 (3H, d, J 7.2 Hz),
d 172.9, 153.8, 135.2, 131.7, 128.2, 128.1, 127.9, 119.3, 72.3, 67.9, 54.3,
47.9, 42.7, 36.5, 24.1, 23.7, 20.7, 18.8.
4.2.5.1.8. (4S,5S)-N-Benzyloxycarbonyl-4-isobutyl-5-methyl-5-
benzyl-1,3-oxazinan-6-one 49. General procedure E was followed
1.11 (3H, s); 13C NMR (75 MHz, CDCl3) (300 K):
d
173.1, 153.0, 135.2,
135.1, 130.2, 128.3, 128.2, 128.0, 127.9, 126.7, 72.6, 67.8, 51.9, 48.4,
43.7, 19.2, 15.1.
4.2.5.1.4. (4S,5S)-N-Benzyloxycarbonyl-4-isopropyl-5-methyl-5-
allyl-1,3-oxazinan-6-one 41. General procedure E was followed for
for the alkylation of
0.20 mmol) with benzyl bromide (122
trophile to afford starting material 10/11 (5.1 mg, 8% recovery). The
a
-methyl-1,3-oxazinan-6-one 10/11 (62.5 mg,
mL, 1.02 mmol) as the elec-

4754
N.H. Nguyen et al. / Tetrahedron 68 (2012) 4745e4756
title compound 49 was isolated as a white solid in a >19:1 (trans/
cis) ratio (41.4 mg, 50% yield). m/z HRMS (ESI, MeOH/AcOH):
[MþH]þ found 396.2172. C24H29NO4 requires 396.2169; mp
m), 5.8.2e5.99 (2H, m), 5.19 (2H, s, minor), 5.14 (2H, s, major),
4.26e4.05 (2H, br s, minorþmajor), 3.34 (1H, d, J 14.0 Hz, major),
2.93 (3H, d, J 15.0 Hz, minorþmajor), 2.51e2.40 (1H, m, major),
2.05e1.99 (1H, m, minor),1.21 (3H, s, minor),1.16 (3H, s, major),1.12
(6H, s, major), 1.01 (3H, d, J 6.6 Hz, minor), 0.95 (3H, d, J 7.2 Hz,
117e119 ꢁC; Rf (20% EtOAc/hexane) 0.56; ½a 2D6
þ14.0 (c 1.0, MeOH);
ꢂ
nmax (NaCl)/cmꢀ1 2956, 1750, 1703, 1423, 1250, 1087, 1009; 1H NMR
(300 MHz, CDCl3) (325 K):
d
7.37e7.12 (10H, m), 6.02 (1H, br s), 5.22
minor); 13C NMR (75 MHz, CDCl3) (325 K):
d 172.6, 154.3, 154.0,
(1H, d, J 12.3 Hz), 5.18 (1H, d, J 12.3 Hz), 5.11 (1H, d, J 10.2 Hz), 4.38
(1H, br s), 2.96 (2H, dd, J 13.5, 7.2 Hz),1.65e1.32 (3H, m),1.06 (3H, s),
135.4,134.9,130.2, 130.1,128.2,128.1,128.0,127.9,127.8,127.5,126.7,
126.6, 75.2, 74.6, 67.8, 67.7, 62.3, 61.0, 47.3, 46.3, 44.7, 38.2, 29.7,
29.1, 23.2, 21.1, 19.5, 18.1, 17.7.
0.91e0.85 (6H, m); 13C NMR (75 MHz, CDCl3) (325 K):
d 172.8, 153.9,
135.5, 135.2, 130.2, 128.2, 127.9, 127.8, 127.7, 126.6, 72.5, 68.0, 55.1,
49.1, 44.2, 36.7, 24.3, 23.4, 20.8, 18.9.
4.2.7. Base hydrolysis of the dialkylated 1,3-oxazinan-6-one
. 4.2.7.1. (2R,3S)-N-Benzyloxycarbonyl-3-amino-2-methyl-2-benzyl-
4-methyl-pentanoic acid 51. The oxazinanone 45 (90.1 mg,
0.24 mmol) was dissolved in THF (2.8 mL) at 0 ꢁC, and a 4 N lithium
hydroxide solution (1.98 mL) was added. The mixture was stirred
for 6 h at 0 ꢁC (monitored by TLC), and the THF was removed under
reduced pressure. The aqueous solution was washed with ether
(5 mL), the aqueous layer was acidified with 1 M hydrochloric acid
solution, and then it was extracted with ethyl acetate (3ꢃ5 mL). The
combined organic extracts were dried (MgSO4) and concentrated
under reduced pressure. The yellow residue was subjected to silica
chromatography, eluting with 5e30% ethyl actate/hexane. The acid
51 was isolated as a white solid (62.3 mg, 71% yield); found: C,
71.61; H, 7.36; N, 3.80; C22H27NO4 requires C, 71.52; H, 7.37; N, 3.79;
4.2.6. Reverse alkylation of 5-substituted oxazinanones.
4.2.6.1. General procedure F. A solution of 5-substituted oxazina-
none (0.125 M in dry freshly distilled toluene) was cooled to
ꢀ78 ꢁC under an argon atmosphere. Then KHMDS (1.10 equiv of
a 0.50 M solution in toluene) was added dropwise and the solution
was left to stir at ꢀ78 ꢁC for 40 min. Methyl triflate (1.50 equiv)
was then added dropwise and stirring was continued for 3 h at
ꢀ78 ꢁC. The solution was then allowed to warm to ꢀ15 ꢁC, and the
reaction was then quenched with satd aq NH4Cl solution (5 mL).
The solution was diluted with ethyl acetate (20 mL) and washed
with water (20 mL). The organic layer was dried over MgSO4 and
concentrated in vacuo to give an oily residue. The oil was sub-
jected to flash column chromatography, eluting with 5e10% ethyl
acetate/hexane.
mp 151e152 ꢁC; ½a D25
ꢂ
ꢀ59.7 (c 2.0, MeOH); nmax (NaCl)/cmꢀ1 3431,
3321e2598, 3030, 2963, 2876, 1713, 1514, 1470, 1454, 1350, 1315,
4.2.6.1.1. (4S,5S)-N-Benzyloxycarbonyl-4,5-dimethyl-5-allyl-1,3-
oxazinan-6-one 41 and (4S,5R)-N-benzyloxycarbonyl-4,5-dimethyl-
5-allyl-1,3-oxazinan-6-one 42. General procedure F was followed
for the alkylation of 5-allyl-1,3-oxazinan-6-one 27 (61.1 mg,
1223, 1146, 1091, 1007, 974, 908; 1H NMR (300 MHz, CDCl3) (325 K):
d
10.01 (1H, br s), 7.41e7.09 (10H, m), 5.93 (1H, d, J 11.8 Hz), 5.22
(1H, d, JAB 11.7 Hz), 5.17 (1H, d, JAB 11.7 Hz), 3.81 (1H, d, J 10.5 Hz),
3.32 (1H, d, J 13.4 Hz), 2.66 (1H, d, J 13.4 Hz), 2.18e2.15 (1H, m), 1.13
(3H, s), 1.01 (3H, d, J 6.8 Hz), 0.82 (3H, d, J 6.8 Hz); 13C NMR (75 MHz,
0.19 mmol) with MeOTf (31.3
afford starting material 27 (6.8 mg, 11%). The 5,5-disubstituted-1,3-
oxazinan-6-one 41/42 was isolated as mixture of di-
astereoisomers in a 1.3:1.0 ratio (38.2 mg, 60% yield) as a colorless
oil. 1H NMR (300 MHz, CDCl3) (325 K):
7.38 (5H, s), 5.90e5.76 (2H,
mL, 0.29 mmol) as the electrophile to
CDCl3) (325 K):
d 181.7, 156.8, 136.4, 136.2, 129.9, 128.1, 127.8, 127.6,
a
126.4, 66.6, 62.1, 49.7, 43.6, 28.6, 22.2, 18.9, 15.5.
d
4.2.8. Base solvolysis of the dimethylated 1,3-oxazinan-6-one.
4.2.8.1. (3S)-Ethyl-N-benzyloxycarbonyl-3-amino-2-dimethyl-buta-
noate 52. The oxazinanone 4 (51.0 mg, 0.19 mmol) was dissolved in
dry ethanol (4.0 mL), and dry sodium hydrogen carbonate (42.1 mg,
2.5 mmol) was added under an argon atmosphere. The solution was
heated at reflux for 22 h. The solvent was removed in vacuo, the
residue was taken up in ethyl acetate (10 mL), and it was then
washed with water (10 mL). The organic layer was dried (MgSO4)
and concentrated under reduced pressure. The resulting residue
was purified by column chromatography, eluting with 5e10% ethyl
acetate/hexane. The ester 52 was isolated as a colorless oil (38.8 mg,
72% yield); m/z HRMS (ESI, MeOH/AcOH): [MþH]þ found 294.1699.
m), 5.32 (1H, d, J 9.6 Hz, major), 5.24 (1H, d, J 9.7 Hz, minor),
5.18e4.99 (5H, m), 4.10 (1H, br s), 2.77 (1H, dd, major), 2.39e2.56
(2H, m, majorþminor), 2.23e2.13 (1H, m, major), 2.07e2.03 (1H,
minor), 1.26 (3H, s, minor), 1.24 (3H, s, major), 1.01e0.94 (7H, m,
minorþmajor); 13C NMR (75 MHz, CDCl3) (325 K):
d 172.9, 172.7,
154.3, 154.1, 135.5, 131.8, 131.5, 128.2, 128.0, 127.8, 127.7, 127.6, 119.4,
119.2, 74.9, 74.8, 67.7, 61.6, 60.5, 46.3, 44.6, 43.2, 37.5, 29.3, 28.8,
23.3, 20.9, 20.7, 19.1, 18.1, 17.7.
4.2.6.1.2. (4S,5S)-N-Benzyloxycarbonyl-4,5-dimethyl-5-ethyl-1,3-
oxazinan-6-one 43 and (4S,5R)-N-benzyloxycarbonyl-4,5-dimethyl-
5-ethyl-1,3-oxazinan-6-one 44. General procedure F was followed
for the alkylation of 5-ethyl-1,3-oxazinan-6-one 25 (65.6 mg,
C16H23NO4 requires 294.1700; Rf (20% EtOAc/hexane) 0.56; ½a D25
ꢂ
0.21 mmol) with MeOTf (35.6
to afford starting material 25 (5.1 mg, 8%). The 5,5-disubstituted-
1,3-oxazinan-6-one 42/43 was isolated as mixture of di-
astereoisomers in a 1.8:1 ratio (41.2 mg, 61% yield) as a colorless
oil. 1H NMR (300 MHz, CDCl3) (320 K):
7.38 (5H, s), 5.85 (1H, br
m
L, 0.32 mmol) as the electrophile
þ24.0 (c 1.0, MeOH); nmax (NaCl)/cmꢀ1 3431, 3347, 2980, 2940,1728,
1531, 1504, 1454, 1261, 1238, 1170, 1143, 1101, 1053, 916, 860; 1H
a
NMR (300 MHz, CDCl3) (320 K): d 7.34e7.24 (5H, m), 5.29 (1H, br s),
5.09 (2H, s), 4.16 (2H, q, J 7.1 Hz), 3.86e3.81 (1H, m), 1.25 (3H, t, J
d
7.1 Hz), 1.18 (6H, s), 1.12 (3H, d, J 6.6 Hz); 13C NMR (75 MHz, CDCl3)
s), 5.30 (1H, d, J 9.6 Hz), 5.18 (2H, s), 4.08 (1H, br s), 2.12e1.94
(2H, m, minorþmajor), 1.71e1.57 (2H, m), 1.23 (3H, s), 1.02 (9H, s);
(rotamers): d 175.9, 155.7, 136.5, 128.0, 127.6, 66.2, 60.2, 53.1, 45.9,
22.6, 22.4, 16.8, 13.7.
13C NMR (75 MHz, CDCl3) (320 K):
d 173.3, 154.4, 135.5, 128.2,
128.1, 127.7, 74.6, 67.7, 61.5, 45.1, 31.5, 29.3, 28.8, 25.4, 22.4, 21.0,
18.1, 7.4.
4.2.6.1.3. (4S,5S)-N-Benzyloxycarbonyl-4,5-dimethyl-5-benzyl-
1,3-oxazinan-6-one 45 and (4S,5R)-N-benzyloxycarbonyl-4,5-
4.2.9. Reductive cleavage of the dialkylated oxazinanone.
4.2.9.1. General procedure G. To the 5,5-dialkyl oxazinanone in dry
dichloromethane (0.06 M solution) were added boron trifluoride
etherate (2.00 equiv) and triethylsilane (3.00 equiv). Then, the re-
action mixture was stirred for 6e20 h (monitored by TLC). The
solvent was evaporated under reduced pressure. The resulting
residue was subjected to silica chromatography, eluting with
10e30% ethyl acetate/hexane.
4.2.9.1.1. (2R,3S)-N-Benzyloxycarbonyl-3-methylamino-2-
methyl-2-benzylbutanoic acid 53. The oxazinanone 39 (46.1 mg,
0.13 mmol) was transformed according to General procedure G,
dimethyl-5-benzyl-1,3-oxazinan-6-one 46. General procedure
was followed for the alkylation of 5-benzyl-1,3-oxazinan-6-one 29
(37.1 mg, 0.10 mmol) with MeOTf (16.1 L, 0.14 mmol) as the
F
m
electrophile to afford starting material 29 (3.6 mg, 10%). The 5,5-
disubstituted-1,3-oxazinan-6-one 45/46 were isolated as a mix-
ture of diastereoisomers in a 1.1:1.0 ratio (21.9 mg, 57% yield) as
a white solid. 1H NMR (300 MHz, CDCl3) (325 K):
d 7.41e7.06 (10H,

N.H. Nguyen et al. / Tetrahedron 68 (2012) 4745e4756
4755
furnishing N-methyl acid 53 as a colorless oil (35.3 mg, 76% yield);
m/z HRMS (ESI, MeOH/AcOH): [MþH]þ found 356.1856. C21H25NO4
trifluoride etherate (29.2
m
L, 0.24 mmol, 2.00 equiv) Then, the re-
action mixture was stirred at rt for 6 h (monitored by TLC). The
mixture was concentrated under reduced pressure, and the residue
was taken up in ethyl acetate (15 mL). The organic phase was
washed with satd aq NaHCO3. The organic layer was dried over
MgSO4 and concentrated in vacuo to give an oily residue. The oil
was subjected to column chromatography, eluting with 5e20%
ethyl acetate/hexane to afford the bicyclic product 60 as a colorless
oil (26.8 mg, 77% yield), with spectra identical to that previously
obtained.
requires 356.1856; ½a D24
ꢂ
ꢀ83.2 (c 1.0, MeOH); nmax (NaCl)/cmꢀ1
3157e2583, 3063, 3030, 2984, 1728, 1694, 1495, 1454, 1327, 1169,
1080, 910, 731; 1H NMR (300 MHz, CDCl3) (320 K):
d 7.35e7.17 (10H,
m), 5.16 (1H, d, JAB 12.6 Hz), 5.14 (1H, d, JAB 12.6 Hz), 4.61 (1H, br s),
3.31 (1H, d, J 12.8 Hz), 2.93 (3H, s), 2.63 (1H, d, J 12.8 Hz),1.30 (3H, d,
J 7.2 Hz), 1.11 (3H, s); 13C NMR (75 MHz, CDCl3) (320 K):
d 180.3,
157.1, 137.1, 136.4, 130.1, 128.1, 127.7, 127.4, 126.2, 67.1, 57.4, 51.9, 41.2,
30.1, 19.1, 13.2.
4.2.9.1.2. (3S)-N-Benzyloxycarbonyl-3-methylamino-2-
dimethylbutanoic acid 54. The oxazinanone 4 (208 mg, 0.75 mmol)
was transformed according to General procedure G, affording N-
methyl acid 54 as a white solid (83% yield); found: C, 64.43; H, 7.42;
N, 5.11; C15H21NO4 requires C, 64.50; H, 7.58; N, 5.01; mp 68e70 ꢁC;
4.2.10. X-ray crystallography. Crystals of compound 49 were
mounted in low temperature oil then flash cooled to 130 K using
an Oxford low temperature device. Intensity data were collected at
130 K with an Oxford XCalibur X-ray diffractometer with CCD
½
a 2D7
ꢂ
ꢀ13.0 (c 2.0, MeOH); nmax (NaCl)/cmꢀ1 3165e2559, 3064,
detector using Cu-K
a
radiation (
l
¼1.54184 A). Data were reduced
ꢀ
2980, 1728, 1697, 1477, 1456, 1402, 1323, 1161, 1082, 1041, 910, 866,
and corrected for absorption.21 The Structures were solved by di-
rect methods and difference fourier synthesis using the SHELX
suite of programs22 as implemented within the WINGX23 soft-
ware. Thermal ellipsoid plots were generated using the program
ORTEP-3.
843; 1H NMR (300 MHz, CDCl3) (300 K):
(2H, s), 4.61e4.53 (1H, m), 2.81 (3H, s), 1.23e1.18 (9H, m); 13C NMR
(75 MHz, CDCl3) (rotamers): 182.1, 156.9, 156.5, 136.5, 136.2, 128.1,
d 7.33e7.28 (5H, m), 5.12
d
127.6, 127.3, 67.1, 66.9, 56.5, 55.9, 46.8, 30.1, 29.7, 23.7, 21.3, 20.9,
13.6, 13.2.
Crystallographic data for 49 have been deposited in the Cam-
bridge Crystallographic Data Centre (CCDC) as supplementary
publication number CCDC 840584. These data can be freely
obtained from the CCDC by sending an application by email to
deposit@ccdc.cam.ac.uk.
4.2.9.1.3. (3S)-N-Benzyloxycarbonyl-3-methylamino-2,2-
dimethyl-4-methyl-pentanoic acid 55. The oxazinanone 8 (128 mg,
0.24 mmol) was transformed according to general procedure G,
affording N-methyl acid 55 as a white solid (103 mg, 80% yield);
found: C, 66.52; H, 8.54; N, 4.49. C17H25NO4 requires C, 66.43; H,
Crystal data for compound 49: (C24H29NO4) (0.5 CHCl3),
8.20; N, 4.56; mp 147e148 ꢁC; ½a D27
ꢂ
þ28.0 (c 1.0, MeOH); nmax
M¼910.33, T¼130.0(2) K, ¼1.54180, Monoclinic, space group P21
3
ꢀ ꢀ
l
(NaCl)/cmꢀ1 3041e2639, 2969, 2980, 1728, 1694, 1476, 1455, 1339,
a¼6.1037(3) b¼20.0226(9), c¼18.9650(7) A, V¼2317.7(2) A , Z¼4,
1164,1135, 971, 871; 1H NMR (300 MHz, CDCl3) (300 K):
d
7.42e7.26
Dcalcd¼1.304 mg Mꢀ3
m
(Cu-K
a
) 2.239 mmꢀ1, F(000)¼964, crystal
(5H, m), 5.24e5.14 (2H, m), 4.62e4.53 (1H, m), 2.82 (3H, s),
size 0.46ꢃ0.07ꢃ0.07 mm. 16,609 reflections measured, 8751 in-
2.03e1.92 (1H, m), 1.26e1.14 (6H, m), 0.94e0.85 (6H, m); 13C NMR
dependent reflections (Rint¼0.0424), the final
R was 0.0420
(75 MHz, CDCl3) (rotamers):
d
183.8, 183.2, 157.0, 136.5, 128.1, 127.9,
[I>2s
(I)] and wR(F2) (all data) was 0.0986.
127.4, 127.2, 66.9, 64.4, 64.2, 45.7, 29.9, 29.7, 27.6, 25.7, 20.7, 20.6,
19.6, 19.1.
Acknowledgements
4.2.9.1.4. (3S)-N-Benzyloxycarbonyl-3-methylamino-2,2-
dimethyl-4-methyl-hexanoic acid 56. The oxazinanone 16 (75.5 mg,
0.24 mmol) was transformed according to general procedure G,
affording N-methyl acid 56 as a white solid (61.9 mg, 80% yield);
Found: C, 66.98; H, 8.54; N, 4.45. C18H27NO4 requires C, 67.26; H,
We thank La Trobe University for the provision of a postgraduate
scholarship awarded to N.H.N.
8.47 N, 4.36; mp 125e127 ꢁC; ½a D25
þ22.0 (c 1.0, MeOH); nmax (NaCl)/
ꢂ
Supplementary data
cmꢀ1 3163e2630, 2968, 2882, 1728, 1693, 1454, 1339, 1167, 1138,
993, 957; 1H NMR (300 MHz, CDCl3) (300 K):
d 7.42e7.28 (5H, m),
Supplementary data associated with this article can be found, in
the online version, at doi:10.1016/j.tet.2012.04.012.
5.25e5.11 (2H, m), 4.72e4.65 (1H, m), 2.82 (3H, s), 1.81e1.74 (1H,
m), 1.8e0.99 (8H, m), 0.89e0.78 (6H, m); 13C NMR (75 MHz, CDCl3)
(rotamers):
d 183.9, 183.7, 157.1, 136.6, 136.4, 128.1, 127.9, 127.5,
References and notes
127.4, 127.3, 127.2, 67.9, 66.8, 62.2, 62.1, 45.7, 33.3, 30.0, 29.8, 25.9,
25.8, 19.4, 19.0, 14.7, 14.5, 10.1, 9.8.
1. Sleebs, B. E.; Hughes, A. B. Aust. J. Chem. 2006, 58, 778e784.
2. Sleebs, B. E.; Hughes, A. B. Aust. J. Chem. 2008, 61, 131e137.
3. Aurelio, L.; Brownlee, R. T. C.; Hughes, A. B.; Sleebs, B. E. Aust. J. Chem. 2000, 53,
425e433.
4. Aurelio, L.; Box, J. S.; Brownlee, R. T. C.; Hughes, A. B.; Sleebs, M. M. J. Org. Chem.
2003, 68, 2652e2667.
4.2.9.1.5. (1R,2S,6R)-N-Benzyloxycarbonyl-1,2-dimethyl-7-oxa-3-
azabicyclo[4.2.1]nonan-8-one 60
Method 1. The oxazinanone 35 (121 mg, 0.40 mmol) was trans-
formed according to general procedure G, affording bicycle 60 as
a colorless oil (79.1 mg, 65% yield) and a trace amount of N-methyl
product. m/z HRMS (ESI, MeOH/AcOH): [MþH]þ found 304.1543.
5. Van Nguyen, T. T.; Brownlee, R. T. C.; Hughes, A. B. Synthesis 2009, 12,
1991e1998.
6. Sleebs, B. E.; Hughes, A. B. Helv. Chim. Acta 2006, 89, 2611e2637.
7. Sleebs, B. E.; Hughes, A. B. J. Org. Chem. 2007, 72, 3340e3352.
8. Sleebs, B. E.; Hughes, A. B. Synth. Commun. 2009, 39, 48e60.
9. Seebach, D.; Gardiner, J. Acc. Chem. Res. 2008, 41, 1366e1375.
10. Seebach, D.; Beck, A. K.; Bierbaum, D. J. Chem. Biodiversity 2004, 1, 1111e1239.
11. Wu, Y.-D.; Han, W.; Wang, D.-P.; Gao, Y.; Zhao, Y.-L. Acc. Chem. Res. 2008, 41,
1418e1427.
12. Akkarawongsa, R.; Potocky, T. B.; English, E. P.; Gellman, S. H.; Brandt, C. R.
Antimicrob. Agents Chemother. 2008, 52, 2120e2129.
13. Mowery, B. P.; Lee, S. E.; Kissounko, D. A.; Epand, R. F.; Epand, R. M.; Weisblum,
B.; Stahl, S. S.; Gellman, S. H. J. Am. Chem. Soc. 2007, 129, 15474e15476.
14. Murray, J. K.; Gellman, S. H. Biopolymers 2007, 88, 657e686.
15. Porter, E. A.; Weisblum, B.; Gellman, S. H. J. Am. Chem. Soc. 2002, 124,
7324e7330.
C17H21NO4 requires 304.1543; ½a D24
þ34.2 (c 0.82, MeOH); nmax
ꢂ
(NaCl)/cmꢀ1 2979, 1767, 1692, 1470, 1456, 1419, 1318, 1252, 1196,
1119,1052,1009, 961, 895; 1H NMR (300 MHz, CDCl3) (325 K):
d 7.32
(5H, s), 5.15 (2H, m), 4.68 (1H, br s), 4.37e4.16 (1H, m), 3.92e3.76
(1H, m), 2.85 (1H, dt, J 4.5 Hz, 11.1 Hz), 2.01e2.19 (2H, m) 1.90e1.74
(2H, m), 1.33 (3H, d, J 11.4 Hz), 1.23 (3H, d, J 7.1 Hz); 13C NMR
(75 MHz, CDCl3) (rotamers): d 179.2, 179.1, 155.5, 154.9, 136.2, 136.1,
128.2, 127.8, 127.5, 127.4, 74.5, 74.3, 67.1, 67.0, 57.0, 56.5, 45.2, 45.1,
39.2, 39.1, 35.6, 35.2, 32.6, 31.9, 23.9, 23.6, 13.4, 13.0.
Method 2.
To the 4,5-dimethyl-5-allyl-1,3-oxazinan-6-one 35 (35.0 mg,
0.12 mmol) in dry dichloromethane (2.0 mL) was added boron
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