Conjugate addition of lithium N-tert-butyldimethylsilyloxy-N-(α-methylbenzyl)amide: asymmetric synthesis of β2,2,3-trisubstituted amino acids

Article abstract of DOI:10.1016/j.tet.2010.04.027

Conjugate addition of the homochiral ammonia equivalent lithium N-tert-butyldimethylsilyloxy-N-(α-methylbenzyl)amide to a range of α,β-unsaturated esters gives the corresponding β-amino esters in moderate to good levels of diastereoselectivity. O-Desilylation and cyclisation furnishes homochiral isoxazolidin-5-ones in >99:1 dr after purification. Sequential alkylation of these templates proceeds to give the corresponding 3,4-anti-disubstituted and 3,4,4-trisubstituted derivatives as single diastereoisomers after purification. The first alkylation occurs with high levels of diastereoselectivity on the face of the enolate anti to the C(3)-substituent, whereas the facial selectivity of the second alkylation is governed by a chiral relay effect, which depends upon the relative steric bulk of both the C(3)- and C(4)-substituents. Subsequent hydrogenolysis promotes cleavage of both the N-α-methylbenzyl group and the N-O bond within the isoxazolidin-5-one ring in one pot to give the corresponding β^2,2,3-trisubstituted amino acids directly.

Full text of DOI:10.1016/j.tet.2010.04.027

Tetrahedron 66 (2010) 4604e4620
Contents lists available at ScienceDirect
Tetrahedron
journal homepage: www.elsevier.com/locate/tet
Conjugate addition of lithium N-tert-butyldimethylsilyloxy-N-(a-methylbenzyl)-
amide: asymmetric synthesis of b
2,2,3-trisubstituted amino acids
*
Scott A. Bentley, Stephen G. Davies , James A. Lee, Paul M. Roberts, Angela J. Russell,
James E. Thomson, Steven M. Toms
Department of Chemistry, Chemistry Research Laboratory, University of Oxford, Mansfield Road, Oxford OX1 3TA, UK
a r t i c l e i n f o
a b s t r a c t
Article history:
Conjugate addition of the homochiral ammonia equivalent lithium N-tert-butyldimethylsilyloxy-N-
(a-methylbenzyl)amide to a range of a,b-unsaturated esters gives the corresponding b-amino esters in
Received 18 January 2010
Received in revised form 17 March 2010
Accepted 6 April 2010
moderate to good levels of diastereoselectivity. O-Desilylation and cyclisation furnishes homochiral
isoxazolidin-5-ones in >99:1 dr after purification. Sequential alkylation of these templates proceeds to
give the corresponding 3,4-anti-disubstituted and 3,4,4-trisubstituted derivatives as single di-
astereoisomers after purification. The first alkylation occurs with high levels of diastereoselectivity on
the face of the enolate anti to the C(3)-substituent, whereas the facial selectivity of the second alkylation
is governed by a chiral relay effect, which depends upon the relative steric bulk of both the C(3)- and
Available online 10 April 2010
Keywords:
Conjugate addition
Homochiral ammonia equivalent
Isoxazolidin-5-ones
C(4)-substituents. Subsequent hydrogenolysis promotes cleavage of both the N-a-methylbenzyl group
and the NeO bond within the isoxazolidin-5-one ring in one pot to give the corresponding b
2,2,3-tri-
b
2,2,3-Trisubstituted amino acids
substituted amino acids directly.
Ó 2010 Elsevier Ltd. All rights reserved.
1. Introduction
Isoxazolidin-5-ones are popular synthetic targets due to their
desirable biological activity1 and their utility as homochiral building
blocks,2 for instance in the synthesis of
g
b
-amino acids and
-lactams.3 Several methods for the synthesis of isoxazolidin-5-ones
have been reported, with 1,3-dipolar cycloaddition of a nitrone,3,4 and
b- and
conjugate addition of a hydroxylamine to an a,b-unsaturated ester
followed by cyclisation5 representing the most common synthetic
strategies. For instance, Sibi et al. employed a chiral Lewis-acid
mediated amine conjugate addition protocol for the synthesis of
a range of isoxazolidin-5-ones,5c whilst Saito et al. utilised the doubly
diastereoselective ‘thermal’ addition of homochiral N-
benzylhydroxylamine 1 to homochiral esters 2 and 3 (derived from
-tartaric acid) to facilitate the synthesis of isoxazolidin-5-ones 6 and
a-methyl-
L
7.5a The elaboration of these templates to the C(4)-mono- and C(4)-
disubstituted derivatives 8e10 through sequential enolate alkylation
reactions was also disclosed, although these reactions failed to pro-
ceed to conversion and the reported 59e79% yields ‘were corrected
for recovered starting material’. The relative stereochemistries within
8e10 wereassignedontheassumptionthatthealkylationreactionsof
the intermediate enolates occur on the face anti to the C(3)-stereo-
directing group in all cases5a (Fig. 1).
Figure 1. Preparation of isoxazolidin-5-ones 6e10 employing the doubly diaster-
eoselective ‘thermal’ addition of homochiral N-
homochiral esters 2 and 3.
a-methylbenzylhydroxylamine 1 to
Previous investigations from this laboratory have demonstrated
that the conjugate addition of homochiral secondary lithium am-
ides (derived from
represents a general and efficient synthetic protocol for the syn-
thesis of
-amino esters and their derivatives.6 This methodology
a-methylbenzylamine) to a,b-unsaturated esters
b
has found numerous applications, including the total synthesis of
* Corresponding author. E-mail address: steve.davies@chem.ox.ac.uk (S.G. Davies).
natural products,7 molecular recognition phenomena8 and
0040-4020/$ e see front matter Ó 2010 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2010.04.027

S.A. Bentley et al. / Tetrahedron 66 (2010) 4604e4620
4605
resolution protocols,9 and has been reviewed.10 Although the con-
jugate addition of lithium dialkylamides to
a,b-unsaturated car-
bonyl compounds has been investigated extensively,10 there is only
one report into the analogous reaction employing a lithium N-
alkoxy-N-(
a-methylbenzyl)amide: Bew et al. investigated the
conjugate addition of lithium (S)-N-(tert-butoxycarbonyloxy)-N-(
a
-
methylbenzyl)amide to tert-butyl acrylate but did not observe any
products of conjugate addition.11 We wished to extend further our
conjugate addition methodology to encompass lithium N-alkoxy-
N-(a-methylbenzyl)amides 12 as we envisaged that the resultant
b
-N-alkoxyamino products 13 would be amenable to selective
cleavage of the OeX bond with concomitant cyclisation to generate
a range of isoxazolidin-5-ones 14, which could then be exploited for
highly diastereoselective, tandem alkylation reactions, giving 3,4,4-
trisubstituted derivatives 15 (Fig. 2). We anticipated that the use of
a robust O-protecting group would suppress any potential O- to
N-rearrangement, thus promoting the conjugate addition reaction,
and we delineate herein our investigations within this area.
i
Scheme 1. Reagents and conditions: (i) BrCH2CN, Pr2NEt, MeCN, rt, 16 h; (ii) mCPBA,
CH2Cl2, 0 ꢁC, 45 min, then rt, 15 min; (iii) NH2OH, MeOH, 60 ꢁC, 2 h; (iv) TBDMSCl,
imidazole, DMF, rt, 16 h.
resolution into sharp distinct sets of peaks and therefore the origin
of the broadness (restricted rotation about the NeO bond or slow
inversion at nitrogen) in this system could not be determined. The
absolute (3R,
reference to our transition state mnemonic16 to rationalize the high
facial selectivity exerted by lithium N-benzyl-N-( -methylbenzyl)
amide 2310 and lithium N-allyl-N-( -methylbenzyl)amide 2417 in
their conjugate addition reactions. In confirmation of this assign-
ment, treatment of 22 with Zn in AcOH gave the known N-
aS)-configuration within 22 was initially assigned by
a
a
a
-
methylbenzyl protected
(Scheme 2).
b
-amino ester 2518 in 88% yield and 95:5 dr
Figure 2. Synthesis and alkylation of isoxazolidin-5-ones 14 utilising conjugate ad-
dition of a homochiral lithium N-alkoxy-N-(
group.
a
-methylbenzyl)amide 12. X¼Protecting
2. Results and discussion
The conjugate addition of O-tert-butyl protected hydroxylamine
1612 to both tert-butyl and methyl cinnamate was initially in-
vestigated but returned only starting material under a range of
conditions. O-Silyl protected hydroxylamine 20 was prepared from
(S)-a-methylbenzylamine 17 in four steps following literature
procedures.12a,13 Alkylation of 17 with bromoacetonitrile gave 18,
which was oxidised with mCPBA to give nitrone 19. Hydrox-
Scheme 2. Reagents and conditions: (i) lithium (S)-N-tert-butyldimethylsilyloxy-N-(
methylbenzyl)amide 36 (0.1 M in THF), ꢀ78 ꢁC, 10 h; (iii) Zn, AcOH, ꢂ))), rt, 60 h.
a-
ylaminolysis afforded (S)-N-(a-methylbenzyl)hydroxylamine 1 in
44% overall yield. Treatment of 1 with TBDMSCl furnished 20 in 85%
In order to explore the generality of this methodology, the
conjugate addition of lithium (S)-N-tert-butyldimethylsilyloxy-N-
yield and >99:1 er14 (Scheme 1).
Treatment of 20 with BuLi in THF at ꢀ78 ꢁC followed by addition
of tert-butyl cinnamate returned only starting material under
a range of conditions, although reaction with methyl cinnamate 21
(a
-methylbenzyl)amide 36 to a range of
26e30 was investigated, and proceeded with modest to good levels
of diastereoselectivity. -(N-Silyloxy)amino esters 31e35 proved
a,b-unsaturated esters
b
under optimized conditions gave
b
-N-silyloxyamino ester 22 as the
somewhat unstable to purification on alumina and were isolated in
modest yields. In each case, the absolute configuration within the
major diastereoisomeric product of the conjugate addition reaction
was assigned by reference to the transition state mnemonic for this
class of lithium amides16 (Scheme 3).
With a range of N-silyloxyamino esters 22 and 31e35 in hand,
their conversion to the corresponding isoxazolidin-5-ones was in-
vestigated. Initial studies employing excess TBAF at rt to promote
the desilylation and concomitant cyclisation of 22 proved un-
successful, affording a complex mixture of products, with no
starting material or isoxazolidin-5-one observed by 1H NMR
sole product in 95:5 dr. Attempted purification of the crude re-
action mixture on silica led to substantial mass loss, giving 22 in
only 40% isolated yield; chromatography on basic alumina, how-
ever, allowed the isolation of 22 in 65% yield and 95:5 dr. The 1H
NMR spectrum of 22 exhibited line broadening when the spectrum
was recorded in a range of solvents. A range of hydroxylamines
have been shown to exhibit this behaviour, which is attributable to
either slow rotation about the NeO bond, or slow inversion at the
nitrogen atom.15 Heating the sample to 373 K in PhMe-d8 provided
a much sharper spectrum, although cooling to 213 K failed to effect

4606
S.A. Bentley et al. / Tetrahedron 66 (2010) 4604e4620
Scheme 3. Reagents and conditions: (i) lithium (S)-N-tert-butyldimethylsilyloxy-N-(a-
methylbenzyl)amide 36 (0.1 M in THF), ꢀ78 ꢁC, 10 h. [aDiastereoisomeric ratio refers to
both crude reaction mixture and isolated product].
Scheme 5. Reagents and conditions: (i) lithium (S)-N-tert-butyldimethylsilyloxy-N-(a-
methylbenzyl)amide 36 (0.1 M in THF), ꢀ78 ꢁC, 10 h ; (ii) HF$pyridine, THF, 0 ꢁC,
spectroscopic analysis. Upon treatment of 22 with 1.1 equiv of TBAF,
however, 80% conversion to isoxazolidin-5-one 6 (95:5 dr) was
observed. Purification allowed the isolation of 6 in 70% yield and
95:5 dr (Scheme 4).
20 min; (iii) LiHMDS, THF, ꢀ78 ꢁC, 30 min.
(>99:1 dr). Purification via flash column chromatography gave 8
and 43e46 in good isolated yield and >99:1 dr in each case.
A further series of alkylations applied to isoxazolidin-5-one 7 gave
alkylated products 9 and 47e49 in modest to good diaster-
eoselectivity (Scheme 6). The relative configuration within 9 was
unambiguously established via single crystal X-ray analysis, with
the absolute (S,S,S)-configuration being assigned from the known
configuration of the (S)-stereocentre within the
a-methylbenzyl
Scheme 4. Reagents and conditions: (i) TBAF, THF, rt, 12 h.
fragment (Fig. 3). This stereochemical outcome is consistent with
the alkylation proceeding on the face of the enolate opposite to the
C(3)-stereodirecting group. The relative and absolute configura-
tions within 8 and 43e49 were assigned by analogy to that
unambiguously proven for 9 (Scheme 6).
In order to obviate the difficulties associated with the purification
of
product was next investigated. Unfortunately, conjugate addition of
lithium (S)-N-tert-butyldimethylsilyloxy-N-( -methylbenzyl)amide
b-N-silyloxyamino ester 22, direct cyclisation of the crude reaction
a
36 to methyl cinnamate 21 followed by treatment of the crude re-
action product with TBAF (1.1 equiv) gave a complex mixture of
products. Inlightof thisresult, arangeofconditionswerescreened for
their efficacy in promoting the desilylation/cyclisation reaction se-
quence and although treatment with TBAF/AcOH,19 TMSOTf,20 LiCl/
H2O/DMF21 and PPTS/EtOH22 gave no trace of the desired iso-
xazolidin-5-one 6 in each case,23 it was found that treatment of the
crude reaction product 22 with HF$pyridine followed by LiHMDS
afforded isoxazolidin-5-one 6 in 95:5 dr, and in 78% yield (over three
steps from 21) and >99:1 dr after chromatographic purification. Ap-
plication of this sequential conjugate addition and cyclisation re-
O
(i)
Ph
N
O
Ph
N
O
O
R
R
R1
8, 9, 43-49
dr a
yield %
6, R = Ph
7, R = Me
product
R
R1X
Ph MeI
8
>99:1
>99:1
>99:1
>99:1
>99:1
70:30
>99:1
92:8
71
75
82
75
81
71
70
64
6
Ph BnBr
43
44
45
6
6
6
6
7
7
7
7
Ph allyl iodide
Ph EtI
Ph BrCH2CO2tBu 46
Me MeI
47
9
Me BnBr
Me allyl iodide
Me EtI
action sequence to
a,b-unsaturated esters 26, 28 and 29
48
49
69:31 60
(as representative examples) gave the corresponding isoxazolidin-5-
ones 41, 7 and 42 in modest yields over the three steps, and in >99:1
dr after purification, except for 42, which was isolated as a 78:22 di-
astereoisomeric mixture (Scheme 5).
O
Ph
N
O
Studies were next directed towards the investigation of the al-
kylation reactions of isoxazolidin-5-ones 6 and 7. Saito et al. have
previously shown that treatment of diastereoisomerically pure
isoxazolidin-5-one 6 with LiHMDS followed by MeI affords exclu-
sively the anti-product 8 in 59% yield.5a Application of this protocol
to ethylation of 6 gave predominantly the desired anti-product 45,
but was accompanied by the formation of w10% of the dialkylated
product 50, which presumably arises through deprotonation of the
product isoxazolidin-5-one by the excess base followed by further
alkylation. In order to suppress this side reaction, use of the hin-
dered base LiTMP was investigated.24 Under these conditions, ex-
clusive mono-alkylation of 6 was observed upon treatment with
a range of electrophiles, giving the corresponding C(4)-substituted
Ph
Et
Et
50
Scheme 6. Reagents and conditions: (i) LiTMP (1.2 equiv), THF, ꢀ78 ꢁC, 30 min, then
R1X (3 equiv), ꢀ78 ꢁC to rt, 12 h. [aDiastereoisomeric ratio refers to both crude reaction
mixture and isolated product].
The preparation of 3,4,4-trisubstituted-isoxazolidin-5-ones was
next investigated. Deprotonation of 3-phenyl-4-methyl-iso-
xazolidin-5-one 8 with LiHMDS followed by quenching with benzyl
bromide gave 53 in >99:1 dr, and in 76% isolated yield after chro-
matography (Scheme 7). The relative configuration within 53 was
unambiguously established by single crystal X-ray analysis, with
isoxazolidin-5-ones
8 and 43e46 as single diastereoisomers

S.A. Bentley et al. / Tetrahedron 66 (2010) 4604e4620
4607
Figure 3. Chem3D representation of the single crystal X-ray structure of 9 (some H
atoms omitted for clarity).
R2
X
O
(i)
Ph
N
H
OLi
O
Figure 4. Chem3D representation of the single crystal X-ray structure of 53 (some H
atoms omitted for clarity).
O
N
R*
R
N
Me
Me
R
8, R = Ph, >99:1 dr
47, R = Me, 70:30 dr
a stereoselective rather than stereospecific process, as expected. In
each case (with the exception of 54 and 61, resulting from alkyl-
ation with CD3I) purification of the crude reaction mixtures gave
diastereoisomerically pure (>99:1 dr) samples of the major di-
astereoisomers from the alkylation reactions (Scheme 7). The rel-
ative configuration within 57 was unambiguously established by
single crystal X-ray analysis, with the absolute (S,S,S)-configuration
being assigned from the known configuration of the (S)-stereo-
O
O
Ph
N
Ph
+
O
O
R
R
R2
Me
Me
51-57
R2
-
58 64
products
yield (dr) %b
R
R2X
dr a
centre within the a-methylbenzyl fragment (Fig. 5). The C(3)eC(4)
:58
48 (68:32)
74 (>99:1)
76 (>99:1)
Ph CD3I
51
68:32
8
8
8
relative configurations within 55 and 56 were assigned by analogy
to that proven for 57; in each case this assignment was supported
by 1H NMR NOE analysis. These results are again consistent with
the alkylation reaction occurring preferentially on the face of the
intermediate enolate opposite to the C(3)-methyl group, albeit with
reduced levels of diastereoselectivity as compared to the analogous
alkylation reactions of 8, bearing a C(3)-phenyl group (Scheme 7).
Ph allyl iodide
Ph BnBr
52:59
53:60
>99:1
>99:1
:61
57 (62:38)
39 (>99:1)
56 (>99:1)
88 (>99:1)
Me CD3I
54
62:38
69:31
97:3
47
47
47
47
Me allyl iodide
55:62
56:63
Me H2C=C(Me)CH2Br
Me BnBr
57:64 >99:1
Scheme 7. Reagents and conditions: (i) LiHMDS (1.2 equiv), THF, ꢀ78 ꢁC, 1 h, then R2X
(3 equiv), ꢀ78 ꢁC to rt, 12 h. [R
*
¼(S)-
a
-methylbenzyl; acrude; bisolated].
the absolute (S,S,S)-configuration being assigned from the known
configuration of the (S)-stereocentre within the -methylbenzyl
a
fragment (Fig. 4). Allylation of 8 proceeded with similarly excellent
levels of diastereoselectivity, furnishing 52 in 74% isolated yield and
>99:1 dr. Meanwhile, alkylation with CD3I gave a 68:32 mixture of
the diastereoisomeric isoxazolidin-5-ones 51 and 58, respectively,
which were inseparable by chromatography. The configurations
within 51 and 52 were assigned by analogy to that unambiguously
proven for 53, and in the case of 52 this assignment was supported
by 1H NMR NOE analysis.25 These results are consistent with ben-
zylation and allylation of the intermediate lithium enolate occur-
ring exclusively on the sterically more accessible face, anti to the
C(3)-phenyl group. In the case of alkylation with CD3I, steric in-
teractions between the C(3)-phenyl group and the electrophile are
smaller, which is manifest in a concomitant decrease in the dia-
stereoselectivity of the reaction. In order to probe this phenomenon
further, alkylation of 47 (bearing a relatively small C(3)-methyl
group) was investigated. Here, a trend towards increasing alkyl-
ation diastereoselectivity with increasing steric demand of the
electrophile was noted, with benzylation of 47 (a 70:30 mixture of
C(4)-epimers) resulting in the production of
a single di-
Figure 5. Chem3D representation of the single crystal X-ray structure of 57 (some H
astereoisomer 57, thus confirming that the alkylation reaction is
atoms omitted for clarity).

4608
S.A. Bentley et al. / Tetrahedron 66 (2010) 4604e4620
Saito et al. have previously reported that alkylation of the lithium
anion of isoxazolidin-5-one 9 with methyl iodide gives (3S,4R, S)-10
exclusively. However, all the data reported for (3S,4R, S)-10 matches
a
a
that obtained by us for (S,S,S)-57, suggesting that the stereochemical
assignment of Saito et al. is in error.5a Furthermore, these observa-
tions imply that the facial selectivity of alkylation of the C(4)-benzyl
substituted isoxazolidin-5-one 9 may not be ascribed simply to
preferential reaction of the intermediate enolate on the face anti to
the C(3)-stereodirecting group. In order to investigate this apparent
discrepancy, the alkylations of 4-benzyl-isoxazolidin-5-ones 9 and 43
were examined. Methylation of 3-phenyl-4-benzyl-isoxazolidin-5-
one 43 gave 53:60 in 97:3 dr, i.e., the same major diastereoisomeric
product as benzylation of 3-phenyl-4-methyl-isoxazolidin-5-one 8:
in the former reaction methylation of 43 occurs preferentially syn to
the C(3)-phenyl group, whereas in the latter reaction benzylation of 8
occurs preferentially on the face anti to the C(3)-phenyl group. A
further series of alkylation reactions applied to both 9 and 43 gave the
dialkylated products 57 and 64e74, thus establishing that with in-
creasing steric demand of the electrophile, the diastereoselectivity of
the alkylation reaction decreased (Scheme 8). The relative configu-
ration within 65 was unambiguously established via single crystal
X-ray analysis, with the absolute (S,S,S)-configuration being assigned
Figure 6. Chem3D representation of the single crystal X-ray structure of 65 (some H
atoms omitted for clarity).
Conformation A
Conformation B
Favoured
Disfavoured
Minimization of A1,3 strain places one of the C(4)-benzylic hydrogen
atoms syn-pentane to the enolate oxygen atom. The phenyl ring of
the C(4)-benzyl group may then occupy one of two possible sites,
with conformation A being expected to be favoured over conforma-
tion B due to minimization of steric repulsions with the C(3)-sub-
stituent. During alkylation of the lithium enolate derived from C(3)-
methyl substituted 9, the steric bulk of the phenyl ring of the C(4)-
benzyl group is clearly dominant over that of the C(3)-methyl group,
and therefore in all cases alkylation occurs preferentially through
conformation A, on the face syn to the pseudo-equatorial C(3)-methyl
group, although a decrease in diastereoselectivity with increased
bulk of the electrophile is noted. In the case of alkylation of the
lithium enolate derived from C(3)-phenyl substituted 43, the steric
bulk of the phenyl ring of the C(4)-benzyl group dominates over that
of the C(3)-phenyl group, potentially due to the location of the latter
in a pseudo-equatorial position somewhat remote from the site of
alkylation. Enolate alkylation then occurs preferentially through
conformation A on the face syn to the C(3)-phenyl group although
a more pronounced decrease in selectivity with increased bulk of the
electrophile is observed relative to the C(3)-methyl series. In the case
of alkylation of the C(4)-methyl substituted isoxazolidin-5-ones 8
and 47, the methyl group is unable to protrude over either face of the
enolate and therefore the reaction diastereoselectivity is controlled
by the relative steric bulk of the C(3)-substituent (vide supra).
A further series of alkylation reactions using isoxazolidin-5-one
templates 44, 45, 48 and 49 were also conducted, which gave
mixtures of the corresponding diastereoisomeric products. In each
case the C(3)eC(4) relative stereochemistry of the major di-
astereoisomer was established by 1H NMR NOE analysis. These
results again illustrate that the diastereoselectivity observed in the
second alkylation reaction is a function of the relative steric bulk of
both the C(3)- and C(4)-substituents (Schemes 9 and 10).
H
Ph
H
O
H
OLi
H
OLi
H
(i)
O
O
Ph
N
R*
R*
O
N
N
R
R
R
Ph
H
Bn
43, R = Ph, >99:1 dr
R2
X
9, R = Me, >99:1 dr
O
O
Ph
N
Ph
N
+
O
O
R
R
R2
Bn
R2
53, 57, 65-69
Bn
60, 64, 70-74
products
yield (dr) %b
R
R2X
dr %a
Ph MeI
53:60
65:70
66:71
67:72
97:3
73:27
56:44
54:46
72 (>99:1)
54 (>99:1)
30 (>99:1)
65 (54:46)
43
43
43
43
Ph allyl iodide
Ph H2C=C(Me)CH2Br
Ph ArCH2Br
Me MeI
57:64 >99:1
83 (>99:1)
78 (>99:1)
18 (61:39)
9
9
9
Me allyl iodide
Me ArCH2Br
68
:73
90:10
61:39
69:74
Scheme 8. Reagents and conditions: (i) LiHMDS (1.2 equiv), THF, ꢀ78 ꢁC, 1 h, then R2X
(3 equiv), ꢀ78 ꢁC to rt, 12 h. [Ar¼p-bromophenyl.
R
*
¼(S)-
a
-methylbenzyl; acrude;
bisolated].
from the known configuration of the (S)-stereocentre within the
-methylbenzyl fragment, confirming that the alkylation reaction
a
occurs preferentially on the face syn to the C(4)-phenyl group (Fig. 6).
The stereochemical outcome resulting from the remaining alkylation
reactions were assigned via 1H NMR NOE analysis. Notably,
methylation of 9 gave 57 as the only product, i.e., the same major
diastereoisomeric product as benzylation of 3,4-dimethyl-iso-
xazolidin-5-one 47. As predicted, therefore, these results clearly
demonstrate that the selectivity of alkylation of the C(4)-benzyl
substituted isoxazolidin-5-ones 9 and 43 is not simply a result of
preferential reaction of the intermediate enolate on the face anti to
the C(3)-substituent, but is dependent on the steric bulk of both the
C(3)- and C(4)-substituents (Scheme 8). A similar phenomenon has
been noted during the alkylation reactions of some lactone eno-
lates,26 and these observations may be rationalized by invoking
a chiral relay effect.27 In this scenario, it is expected that the lithium
enolates derived from isoxazolidin-5-ones 9 and 43 adopt an enve-
lope conformation within which the C(3)-substituent and the
Having prepared a range of 3,4,4-trisubstituted-isoxazolidin-5-
ones, their conversion to the corresponding
amino acids was investigated. Attempted hydrogenolysis of 53
using Pearlman’s catalyst in EtOH gave a 59:41 mixture of -amino
acid 87 and -amino ester 88, indicating that competitive ring-
b
2,2,3-trisubstituted
b
b
opening of the isoxazolidin-5-one ring by the solvent, followed by
hydrogenolysis, had occurred (Scheme 11). It was envisaged that
replacing EtOH with a kinetically less nucleophilic alcohol as the
solvent would prevent the formation of this unwanted side-
N-a
-methylbenzyl
group
occupy pseudo-equatorial
sites.

S.A. Bentley et al. / Tetrahedron 66 (2010) 4604e4620
4609
b-amino esters in moderate to excellent levels of diastereoselectivity.
O-Desilylation and subsequent cyclisation furnishes homochiral iso-
xazolidin-5-ones in >99:1 dr after purification. Alkylation of these
isoxazolidin-5-one templates proceeds to give the corresponding 3,4-
anti-disubstituted and 3,4,4-trisubstituted derivatives as single di-
astereoisomers after purification. The first alkylation occurs with high
levels of diastereoselectivity on the face of the enolate anti to the C(3)-
substituent, whereas the facial selectivity of the second alkylation is
governed by a chiral relay effect, which depends upon the relative
steric bulk of both the C(3)- and C(4)-substituents. Subsequent
hydrogenolysis promotes cleavage of both the N-a-methylbenzyl
groupand the NeO bond within the isoxazolidin-5-one ring in one pot
to give the corresponding
b
2,2,3-trisubstituted amino acids directly.
Scheme 9. Reagents and conditions: (i) LiHMDS (1.2 equiv), THF, ꢀ78 ꢁC, 1 h, then R2X
(3 equiv), ꢀ78 ꢁC to rt, 12 h. [acrude; bisolated].
4. Experimental
4.1. General experimental
O
O
O
(i)
Ph
N
Ph
N
Ph
N
+
O
O
O
All reactions involving organometallic or other moisture-sensi-
tive reagents were carried out under a nitrogen or argon atmo-
sphere using standard vacuum line techniques and glassware that
was flame dried and cooled under nitrogen before use. Solvents
were dried according to the procedure outlined by Grubbs et al.28
Other solvents and reagents were used as supplied (analytical or
HPLC grade) without prior purification. Organic layers were dried
over MgSO4. Thin layer chromatography was performed on alu-
minium plates coated with 60 F254 silica. Plates were visualised
using UV light (254 nm), iodine, 1% aq KMnO4, or 10% ethanolic
phosphomolybdic acid. Flash column chromatography was per-
formed on Kieselgel 60 silica on a glass column, or on a Biotage SP4
automated flash column chromatography platform.
R
R
R
Et
R2
R2
75-80
Et
81-86
Et
45, R = Ph, >99:1 dr
49, R = Me, 69:31 dr
yield (dr) %b
R
R2X
products
dr %a
42:58c 25 (>99:1)
45 Ph MeI
45
75:81
Ph allyl iodide 76:82
22:78
21:79
67 (93:7)
45
55 (>99:1)
Ph BnBr
Me MeI
77
:83
49
49
49
78:84
38 (>99:1)
40 (92:8)
64:36
69:31
Me allyl iodide 79:85
Me BnBr
80:86
90:10 53 (90:10)
Scheme 10. Reagents and conditions: (i) LiHMDS (1.2 equiv), THF, ꢀ78 ꢁC, 1 h, then R2X
(3 equiv), ꢀ78 ꢁC to rt, 12 h. [acrude; bisolated; creaction proceeded to 77% conversion].
Elemental analyses were recorded by the microanalysis service of
the Inorganic Chemistry Laboratory, University of Oxford, UK. Melt-
ing points were recorded on a Gallenkamp Hot Stage apparatus and
are uncorrected. Optical rotations were recorded on a PerkineElmer
241 polarimeter with a water-jacketed 10 cm cell. Specific rotations
are reported in 10ꢀ1 deg cm2 gꢀ1 and concentrations in g/100 mL. IR
spectra were recorded on a Bruker Tensor 27 FT-IR spectrometer as
either a thin film on NaCl plates (film) or a KBr disc (KBr), as stated.
Selected characteristic peaks are reported in cmꢀ1. NMR spectra were
recorded on Bruker Avance spectrometers in the deuterated solvent
stated. Spectra were recorded at rt unless otherwise stated. The field
was locked by external referencing to the relevant deuteron reso-
nance. Low-resolution mass spectra were recorded on either a VG
MassLab 20-250 or a Micromass Platform 1 spectrometer. Accurate
mass measurements were run on either a Bruker MicroTOF internally
calibrated with polyalanine, or a Micromass GCT instrument fitted
with a Scientific Glass Instruments BPX5 column (15 mꢃ0.25 mm)
using amyl acetate as a lock mass.
NH2
NH2
O
(i)
Ph
N
CO2H
CO2Et
+
O
Ph
Ph
87:88
Ph
59:41
Me Bn
Me Bn
Bn
Me
53
87
88
Scheme 11. Reagents and conditions: (i) H2, Pd(OH)2/C, EtOH, rt, 48 h.
t
product. Indeed, when the reaction was run in BuOH, clean for-
mation of 87 was noted. Ion-exchange chromatography gave 87 in
90% yield. Application to isoxazolidin-5-ones 52, 57, 65 and 67 gave
the corresponding b
2,2,3-trisubstituted amino acids 89e92 in good
yield and in >99:1 dr in all cases (Scheme 12).
NH2
O
(i)
Ph
N
CO2H
R3 R4
O
R
R
R2
R1
52, 53, 57, 65, 67
87, 89-92
4.2. General experimental procedures
R
R1 R2 product R3
R4 yield %
4.2.1. General procedure 1: lithium amide conjugate addition. BuLi
(solution in hexanes, 2 equiv) was added dropwise to a stirred solu-
87
89
90
Me
Bn
90
96
78
Ph Me
Bn
53
65
52
Ph allyl Bn
Ph Me allyl
C3H7 Bn
Me
Me
C3H7
Bn
tion of N-tert-butyldimethylsilyloxy-N-(a-methylbenzyl)amine 20
Me Me Bn
Me allyl Bn
91
92
90
86
57
67
(2 equiv) in dry THF at ꢀ78 ꢁC under N2. After stirring for 30 min
C3H7 Bn
a solution of a,b-unsaturated ester (1 equiv) was added in dry THF via
Scheme 12. Reagents and conditions: (i) H2, Pd(OH)2/C, tBuOH, 70 ꢁC, 20 h. [All
compounds were isolated diastereoisomerically pure (>99:1 dr)].
cannula. After stirring fora further 10 h atꢀ78 ꢁC thereaction mixture
wasquenched with satdaq NH4Cl. After warming to rtover15 minthe
mixture was extracted three times with Et2O, then the organic phases
were combined and washed with satd aq NaCl, before being dried and
concentrated in vacuo to give the crude reaction mixture.
3. Conclusion
In conclusion, the conjugate addition of the homochiral ammonia
equivalent lithium N-tert-butyldimethylsilyloxy-N-(a-methylbenzyl)
4.2.2. General procedure 2: isoxazolidin-5-one alkylation using
amide to a range of -unsaturated esters gives the corresponding
a
,
b
LiTMP. Preparation of LiTMP: BuLi (solution in hexanes, 1 equiv) was

4610
S.A. Bentley et al. / Tetrahedron 66 (2010) 4604e4620
added to
a
stirred solution of 2,2,6,6-tetramethylpiperidine
Zinc (500 mg, 7.5 mmol), was added to a stirred solution of 22
(1.1 equiv) in THF at ꢀ78 ꢁC and left for 1 h.
(50 mg, 0.12 mmol, 95:5 dr) in AcOH (2 mL) and the resultant
mixture was sonicated for 60 h. The mixture was filtered and the
remaining zinc was sonicated with EtOAc (3 mL) for a further
15 min before being filtered. The combined filtrates were washed
with aq NaOH (2.0 M, 10 mL) and the aqueous layer was extracted
with EtOAc (2ꢃ10 mL). The combined organic phases were washed
with NaOH (2.0 M, 20 mL), dried and concentrated in vacuo to give
Alkylation procedure: LiTMP (1.1 equiv) was added to a stirred
solution of the requisite isoxazolidin-5-one (1 equiv) in THF at
ꢀ78 ꢁC and stirred for 2 h. The requisite alkyl halide (3 equiv) was
then added and the reaction mixture allowed to slowly warm to rt
over 16 h, after which time satd aq NH4Cl was added and the two
phases separated. The aqueous phase was then extracted three
times with Et2O, and the organic phases combined, washed with
satd aq NaCl, dried and concentrated in vacuo to give the crude
reaction mixture.
25 as a clear oil (30 mg, 88%, 95:5 dr);18
[a
]
20 ꢀ16.3 (c 1.0 in CHCl3);
D
{lit.18
6.5, C(
[
a]
2D1ꢀ14.9 (c 1.0 in CHCl3)}; dH (400 MHz, CDCl3) 1.40 (3H, d, J
a)Me), 1.95 (1H, br s, NH), 2.72 (1H, dd, J 15.4, 6.1, C(2)HA),
2.80 (1H, dd, J 15.4, 7.5, C(2)HB), 3.68 (3H, s, OMe), 3.72 (1H, q, J 6.5,
C( )H), 4.26 (1H, m, C(3)H), 7.25e7.39 (10H, m, Ph).
4.2.3. General procedure 3: isoxazolidin-5-one alkylation using
LiHMDS. LiHMDS (1.2 equiv) was added to a stirred solution of the
requisite isoxazolidin-5-one in THF at ꢀ78 ꢁC and stirred for 2 h.
The requisite alkyl halide (3 equiv) was then added and the reaction
mixture allowed to slowly warm to rt over 16 h, after which time
satd aq NH4Cl was added and the two phases separated. The
aqueous phase was then extracted three times with Et2O, and the
organic phases combined, washed with satd aq NaCl, dried and
concentrated in vacuo to give the crude reaction mixture.
a
4.5. Methyl (3R,
aS)-3-[N-tert-butyldimethylsilyloxy-N-
(a
-methylbenzyl)amino]-3-(p-methoxyphenyl)propanoate 31
4.2.4. General procedure 4: hydrogenolysis of isoxazolidin-5-ones.
Pearlman’s catalyst (50% by weight) was added to a stirred, degassed
solution of the requisite isoxazolidin-5-one in tert-butanol. The re-
action mixture was then put under 1 atm of hydrogen, heated to
70 ꢁC and stirred for 20 h. Water was added to the solution before
filtering through Celite. The Celite was washed with warm water
(w40 ꢁC), then the combined water phases were washed with Et2O,
Following general procedure 1, BuLi (1.41 M in hexanes,
0.42 mL, 0.60 mmol), 20 (150 mg, 0.60 mmol) and 26 (58 mg,
0.30 mmol) in dry THF (8 mL) at ꢀ78 ꢁC gave 31 in 86:14 dr. Purifi-
cation via flash column chromatography (basic alumina, gradient
elution, 30e40 ꢁC petrol/Et2O, 50:1; increased to 30e40 ꢁC petrol/
Et2O, 20:1) gave 31 as a colourless oil (60 mg, 45%, 86:14 dr); nmax
(film) 1750 (C]O); dH (500 MHz, CDCl3) ꢀ0.29 (3H, s, SiMe), ꢀ0.08
before being concentrated in vacuo to give the
b-amino acid.
(3H, s, SiMe), 0.92 (9H, s, SiCMe3),1.29 (3H, d, J 6.5, C(
(1H, m C(2)HA), 2.94e3.03 (1H, m, C(2)HB), 3.50 (3H, s, OMe), 3.81
(3H, s, OMe), 3.94 (1H, q, J 6.5, C( )H), 4.40e4.48 (1H, m, C(3)H), 6.85
(2H, d, J 8.8, Ar), 7.13e7.34 (7H, m, Ar, Ph); dC (62.5 MHz, PhMe-d8)
ꢀ4.3 (SiMe), ꢀ4.2 (SiMe), ꢀ3.4 (SiCMe3),18.4 (C( )Me), 26.4 (SiCMe3),
37.2 (C(2)), 51.4 (OMe), 55.2 (OMe), 62.7 (C( )), 64.4 (C(3)),113.5,127.1,
a)Me), 2.45e2.65
4.3. Methyl (3R, S)-3-[N-tert-butyldimethylsilyloxy-
a
N-(a
-methylbenzyl)amino]-3-phenylpropanoate 22
a
a
a
128.0, 128.5, 129.7 (o-, m-, p-Ph, Ar), 143.3, 146.8 (i-Ph, Ar),172.5 (C(1));
m/z (ESIþ) 444 ([MþH]þ, 100%); HRMS (ESIþ) C25H37NNaO4Siþ
([MþNa]þ) requires 466.2384; found 466.2392.
4.6. Methyl (3R,
aS)-3-[N-tert-butyldimethylsilyloxy-
Following general procedure 1, BuLi (1.6 M in hexanes,
N-( -methylbenzyl)amino]-3-(p-cyanophenyl)propanoate 32
a
0.72 mL, 1.16 mmol), 20 (300 mg, 1.2 mmol) and 21 (121 mg,
0.75 mmol) in dry THF (15 mL) at ꢀ78 ꢁC gave 22 in 95:5 dr. Puri-
fication via flash column chromatography (basic alumina, eluent
30e40 ꢁC petrol/Et2O, 80:1) gave 22 as a colourless oil (200 mg,
65%, 95:5 dr); [
a]
23 ꢀ9.1 (c 1.0 in CHCl3); nmax (film) 1745 (C]O); dH
D
(500 MHz, PhMe-d8, 373 K) ꢀ0.01 (3H, s, SiMe), 0.02 (3H, s, SiMe),
0.99 (9H, s, SiCMe3), 1.28 (3H, d, J 6.8, C(
9.5, C(2)HA) 3.06 (1H, dd, J 15.4, 4.4, C(2)HB), 3.26 (3H, s, OMe), 4.04
(1H, q, J 6.8, C( )H), 4.72 (1H, dd, J 9.5, 4.4, C(3)H), 7.00e7.10 (4H, m,
Ph), 7.15e7.18 (3H, m, Ph), 7.35e7.46 (3H, m, Ph); dC (125 MHz,
PhMe-d8) ꢀ4.1 (2ꢃSiMe), 1.4 (SiCMe3), 18.7 (C( )Me), 26.7 (SiCMe3),
36.0 (C(2)), 50.9 (OMe), 63.6 (C( )), 65.7 (C(3)), 127.5, 127.8, 128.3,
a)Me), 2.67 (1H, dd, J 15.4,
a
Following general procedure 1, BuLi (2.5 M in hexanes, 0.08 mL,
0.20 mmol), 20 (50 mg, 0.20 mmol) and 27 (18.7 mg, 0.10 mmol) in
dry THF (3 mL) at ꢀ78 ꢁC gave 32 in 88:12 dr. Purification via flash
column chromatography (basic alumina, gradient elution, 30e40 ꢁC
petrol/Et2O, 100:1; increased to 30e40 ꢁC petrol/Et2O, 40:1) gave 32
as a colourless oil (20 mg, 46%, 88:12 dr); nmax (film) 2955 (CeH),
2230 (C^N), 1740 (C]O); dH (250 MHz, PhMe-d8, 363 K) ꢀ0.16 (3H,
a
a
128.4, 129.2, 137.3 (o-, m-, p-Ph), 141.1, 143.7 (i-Ph), 171.7 (C(1)); m/z
(ESIþ) 414 ([MþH]þ, 100%), 310 (80%); HRMS (ESIþ)
C24H35NNaO3Siþ ([MþNa]þ) requires 436.2278; found 436.2281.
s, SiMe), 0.00 (3H, s, SiMe), 0.93 (9H, s, SiCMe3), 1.18 (3H, d, J 6.7, C(a)
4.4. Methyl (3R,aS)-3-(N-a-methylbenzylamino)-3-
Me), 2.48 (1H, dd, J 15.9, 9.5, C(2)HA), 2.90 (1H, dd, J 15.9, 4.5, C(2)HB),
3.23 (3H, s, OMe), 3.89 (1H, q, J 6.7, C( )H), 4.54 (1H, dd, J 9.5, 4.5, C(3)
H), 6.97e7.26 (9H, m, Ph); dC (62.5 MHz, PhMe-d8) ꢀ4.1 (SiMe), ꢀ4.0
(SiMe), 1.2 (SiCMe3), 18.0 (C( )Me), 26.5 (SiCMe3), 36.0 (C(2)), 50.8
(OMe), 64.9 (C(3), C(
phenylpropanoate 25
a
a
a
)),118.2 (CN),127.8,128.5,128.6,129.5,131.7 (o-,
m-, p-Ph, Ar), 142.8, 146.0 (i-Ph, Ar), 171.0 (C(1)); m/z (ESIþ) 439
([MþH]þ ,100%); HRMS (ESIþ) C25H34N2NaO3Siþ ([MþNa]þ) requires
461.2231; found 461.2231.

S.A. Bentley et al. / Tetrahedron 66 (2010) 4604e4620
4611
23
4.7. Methyl (S,S)-3-[N-tert-butoxydimethylsilyloxy-
Et2O, 40:1) gave 35 as a colourless oil (63 mg, 33%, >95:5 dr); [
a
]
D
N-(a
-methylbenzyl)amino]butanoate 33
ꢀ8.4 (c 1.0 in CHCl3); nmax (film) 2957 (CeH), 1738 (C]O); dH
(250 MHz, PhMe-d8, 363 K) 0.07 (3H, s, SiMe), 0.12 (3H, s, SiMe), 0.75
(3H, d, J 6.6, C(4)MeA), 0.85 (3H, d, J 6.6, C(4)MeB), 0.94 (9H, s,
SiCMe3), 1.42 (3H, d, J 6.8, C(
(1H, dd, J 16.6, 7.0, C(2)HA), 3.07 (1H, dd, J 16.6, 3.8, C(2)HB),
3.27e3.34 (1H, m, C(3)H), 3.42 (3H, s, OMe), 4.06 (1H, q, J 6.8, C( )H),
6.97e7.36 (5H, m, Ph); dC (62.5 MHz, PhMe-d8, 363 K) ꢀ3.9 (SiMe),
ꢀ3.8 (SiMe), 1.2 (SiCMe3), 17.6 (C( )Me), 18.6 (C(4)MeA), 19.0 (C(4)
MeB), 26.5 (SiCMe3), 31.8 (C(4)), 33.7 (C(2)), 50.7 (OMe), 63.9 (C( )),
65.8 (C(3)), 127.4, 128.1, 129.0 (o-, m-, p-Ph), 143.8 (i-Ph), 173.5 (C(1));
m/z (ESIþ) 402 ([MþNa]þ, 42%), 380 ([MþH]þ, 100%); HRMS (ESIþ)
C21H37NNaO3Siþ ([MþNa]þ) requires 402.2435; found 402.2435.
a)Me), 1.50e1.62 (1H, m, C(4)H), 2.24
a
a
a
Following general procedure 1, BuLi (2.5 M in hexanes, 0.16 mL,
0.40 mmol), 20 (100 mg, 0.40 mmol) and 28 (20 mg, 0.20 mmol) in
dry THF (5 mL) at ꢀ78 ꢁC gave 33 in 75:25 dr. Purification via flash
column chromatography (silica, gradient elution, 30e40 ꢁC petrol/
Et2O, 100:1; increased to 30e40 ꢁC petrol/Et2O, 40:1) gave 33 as
a colourless oil (30 mg, 43%, 75:25 dr); nmax (film) 2955 (CeH), 1739
(C]O); dH (250 MHz, PhMe-d8, 363 K) 0.11 (3H, s, SiMe), 0.14 (3H, s,
SiMe), 0.89 (3H, d, J 6.7, C(4)H3), 0.97 (9H, s, SiCMe3),1.36 (3H, d, J 6.7, C
4.10. (3R,aS)-N(2)-a-Methylbenzyl-3-phenylisoxazolidin-
5-one 6
(
a
)Me), 2.19 (1H, dd, J 14.8, 8.2, C(2)HA), 2.78 (1H, dd, J 14.8, 5.5, C(2)
HB), 3.37 (3H, s, OMe), 3.50e3.66 (1H, m, C(3)H), 3.92e4.02 (1H, m, C
)H), 6.98e7.30 (5H, m, Ph); dC (62.5 MHz, PhMe-d8, 363 K) ꢀ3.7
(SiMe2), 1.2 (SiCMe3), 18.6 (C( )Me), 19.3 (C(4)), 26.6 (SiCMe3), 39.1 (C
(a
a
(2)), 50.5 (OMe), 57.4 (C(3)), 64.8 (C(a)), 127.3, 128.5 (o-, m-, p-Ph),
144.2 (i-Ph),171.9 (C(1)); m/z (ESIþ) 352 ([MþH]þ,100%); HRMS (ESIþ)
BuLi (2.5 M in hexanes, 0.40 mmol, 0.16 mL) was added to
a stirred solution of 20 (100 mg, 0.40 mmol) in THF (4 mL) at ꢀ78 ꢁC.
After 30 min a solution of 21 (32 mg, 0.20 mmol) in THF (1 mL) was
added and the reaction was stirred at ꢀ78 ꢁC for a further 10 h. Satd
aq NH4Cl (5 mL) was added, the two phases were separated and the
aqueous phase extracted with Et2O (3ꢃ5 mL). The organic phases
were combined and washed with satd aq NaCl (15 mL) before being
dried and concentrated in vacuo to give 22 as an orange oil (130 mg,
C19H33NNaO3Siþ ([MþNa]þ) requires 374.2122; found 374.2122.
4.8. Methyl (S,S)-3-[N-tert-butoxydimethylsilyloxy-
N-(a
-methylbenzyl)amino]decanoate 34
95:5 dr). Hydrogen fluorideepyridine complex (10 mL, 0.48 mmol)
was added to a stirred solution of 22 (125 mg, 0.40 mmol) in dry THF
(4 mL) at 0 ꢁC. After stirring for 20 min the reaction mixture was
diluted with Et2O (25 mL) then quenched with satd aq NaHCO3
(20 mL). The phases were then separated and the aqueous phase
extracted with Et2O (3ꢃ20 mL). The organic phases were combined,
dried and concentrated in vacuo to give 37 (74 mg). This residue was
dissolved in THF (3 mL) and cooled to ꢀ78 ꢁC. LiHMDS (1.0 M in THF,
0.6 mmol, 0.6 mL) was added and the resultant mixture was left to
stir for 30 min. The reaction was then quenched with satd aq NH4Cl
(2 mL) and the phases were separated. The aqueous phase was
extracted with Et2O (3ꢃ2 mL), then the organic phases were com-
bined and washed with satd aq NaCl, before being dried and con-
centrated in vacuo. Purification via flash column chromatography
(silica, eluent 40e60 ꢁC petrol/Et2O, 20:1) gave 6 as a pale yellow
solid (37 mg, 78% over three steps, >99:1 dr);5a mp 101e102 ꢁC
Following general procedure 1, BuLi (2.5 M in hexanes, 0.16 mL,
0.40 mmol), 20 (100 mg, 0.40 mmol) and 29 (33 mg, 0.20 mmol) in
dry THF (5 mL) at ꢀ78 ꢁC gave 34 in 78:22 dr. Purification via flash
column chromatography (silica, gradient elution, 30e40 ꢁC petrol/
Et2O, 100:1; increased to 30e40 ꢁC petrol/Et2O, 50:1) gave 34 as
a colourless oil (25 mg, 29%, 78:22 dr); nmax (film) 2960 (CeH), 1741
(C]O); dH (250 MHz, PhMe-d8, 363 K) 0.02 (3H, s, SiMe), 0.10 (3H, s,
SiMe), 0.83e0.89 (3H, m, C(10)H3), 0.94 (9H, s, SiCMe3), 1.16e1.26
(12H, m, C(4)H2eC(9)H2), 1.39 (3H, d, J 6.7, C(
15.2, 7.6, C(2)HA), 2.92 (1H, dd, J 15.2, 4.9, C(2)HB), 3.46 (3H, s, OMe),
3.90e3.97 (1H, m, C(3)H), 4.02e4.08 (1H, m, C( )H), 6.85e7.17 (5H, m,
Ph); dC (62.5 MHz, PhMe-d8, 363 K) ꢀ5.2 (SiMe), ꢀ5.0 (SiMe), 1.5
(SiCMe3) 14.4 (C(10)), 23.2, 26.7, 28.4, 29.6 (C(4)eC(9)),18.3 (C( )Me),
)), 127.7,
a)Me), 2.26 (1H, dd, J
a
a
23
22
(EtOH); [
a
]
þ120 (c 1.0 in CHCl3); {lit.5a
[
a
]
þ154 (c 2.05 in
D
D
6.5 (SiCMe3), 32.4 (C(2)), 50.8 (OMe), 58.2 (C(3)), 62.6 (C(
a
CHCl3)}; dH (400 MHz, CDCl3) 1.60 (3H, d, J 6.5, C(
a)Me), 2.91 (1H, dd,
127.9, 128.5 (o-, m-, p-Ph), 142.4 (i-Ph), 173.1 (C(1)); m/z (ESIþ) 436
([MþH]þ, 100%); HRMS (ESIþ) C25H45NNaO3Siþ ([MþNa]þ) requires
458.3061; found 458.3062.
J 17.4, 8.9, C(4)HA), 3.11 (1H, dd, J 17.4, 7.9, C(4)HB), 4.19 (1H, d, J 6.5, C
)H), 4.48e4.50 (1H, m, C(3)H), 7.24e7.31 (10H, m, Ph).
(a
4.11. (S,S)-N(2)-a-Methylbenzyl-3-methylisoxazolidin-5-one 7
4.9. Methyl (3R,aS)-3-[N-tert-butoxydimethylsilyloxy-
N-(a
-methylbenzyl)amino]-4-methylbutanoate 35
BuLi (1.41 M, 0.60 mmol, 0.43 mL) was added to a stirred so-
lution of 20 (150 mg, 0.60 mmol) in THF (6 mL) at ꢀ78 ꢁC. After
30 min a solution of 28 (30 mg, 0.30 mmol) in THF (2 mL) was added
andthereactionwasstirredatꢀ78 ꢁC fora further10 h. Satd aqNH4Cl
(8 mL) was added, the two phases were separated and the aqueous
phase was extracted with Et2O (3ꢃ8 mL). The organic phases were
Following general procedure 1, BuLi (1.6 M in hexanes, 0.63 mL,
1.00 mmol), 20 (250 mg, 1.00 mmol) and 30 (64 mg, 0.50 mmol) in
dry THF (15 mL) at ꢀ78 ꢁC gave 35 in >95:5 dr. Purification via flash
column chromatography (basic alumina, eluent 30e40 ꢁC petrol/

4612
S.A. Bentley et al. / Tetrahedron 66 (2010) 4604e4620
combined and washed with satd aq NaCl (20 mL) before being dried
and concentrated in vacuo to give 33 as an orange oil (180 mg, 75:25
dr). Hydrogen fluorideepyridine complex (30 mL, 0.72 mmol) was
140.4,159.4 (i-Ph, Ar),173.9 (C(5)); m/z (ESIþ) 617 ([2MþNa]þ,100%),
320 ([MþNa]þ, 78%), 298 ([MþH]þ, 52%); HRMS (ESIþ) C18H19NNaOþ3
([MþNa]þ) requires 320.1257; found 320.1256.
added to a stirred solution of 33 (180 mg, 0.60 mmol) in dry THF
(6 mL) at 0 ꢁC. After stirring for 20 min the reaction mixture was di-
luted with Et2O (35 mL) then quenched with satd aq NaHCO3 (30 mL).
The layers were then separated and the aqueous phase was extracted
with Et2O (3ꢃ30 mL). The organic phases were combined, dried and
concentrated in vacuo to give 39 (114 mg). This residue was dissolved
in THF (4 mL) and cooled to ꢀ78 ꢁC. LiHMDS (1.0 M, 0.90 mmol,
0.9 mL) was added and the mixture was left to stir for 30 min. The
reactionwasthenquenchedwithsatdaqNH4Cl(4 mL)andthephases
were separated. The aqueous phase was extracted with Et2O
(3ꢃ4 mL), then the organic phases were combined and washed with
satd aq NaCl, before being dried and concentrated in vacuo. Purifi-
cation via flash column chromatography (silica, gradient elution,
4.13. (S,S)-N(2)-a-Methylbenzyl-3-heptylisoxazolidin-
5-one 42
BuLi (1.22 M, 0.33 mmol, 0.27 ml) was added to a stirred
solution of 20 (83 mg, 0.33 mmol) in THF (3 mL) at ꢀ78 ꢁC. After
30 min a solution of 29 (30 mg, 0.16 mmol) in THF (1 mL) was
added and the reaction was stirred at ꢀ78 ꢁC for a further 10 h. Satd
aq NH4Cl (4 mL) was added, the two phases were separated and the
aqueous phase was extracted with Et2O (3ꢃ4 mL). The organic
phases were combined and washed with satd aq NaCl (10 mL) be-
fore being dried and concentrated in vacuo to give 34 as an orange
40e60 ꢁC petrol/Et2O, 20:1; increased to 40e60 ꢁC petrol/Et2O, 5:1)
23
gave 7 as a yellow oil (26 mg, 43% over three steps, >99:1 dr);5a
[a]
D
þ76.3 (c 1.0 in CHCl3); {lit.5a
[a]
19 þ84.3 (c 2.9 in CHCl3); dH (400 MHz,
D
CDCl3) 1.00 (3H, d, J 6.1C(3)Me),1.55 (3H, d, J 6.5, C(a)Me), 2.38(1H, dd,
J 17.4, 6.5, C(4)HA), 2.84(1H, dd, J 17.4, 7.5, C(4)HB), 3.40e3.60(1H, m, C
(3)H), 4.02 (1H, q, J 6.5, C( )H), 7.30e7.36 (5H, m, Ph).
oil (105 mg, 78:22 dr). Hydrogen fluorideepyridine complex (10 mL,
a
0.40 mmol) was added to a stirred solution of 34 (105 mg,
0.33 mmol) in dry THF (5 mL) at 0 ꢁC. After stirring for 20 min the
reaction mixture was diluted with Et2O (35 mL) then quenched
with satd aq NaHCO3 (25 mL). The phases were then separated and
the aqueous phase was extracted with Et2O (3ꢃ25 mL). The organic
phases were combined, dried and concentrated in vacuo to give 40
(75 mg). This residue was dissolved in THF (2 mL) and cooled to
ꢀ78 ꢁC. LiHMDS (1.0 M, 0.50 mmol, 0.50 mL) was added and the
mixture was left to stir for 30 min. The reaction was then quenched
with satd aq NH4Cl (3 mL) and the phases were separated. The
aqueous phase was extracted with Et2O (3ꢃ3 mL), then the organic
phases were combined and washed with satd aq NaCl (10 mL),
before being dried, filtered, and concentrated in vacuo. Purification
via flash column chromatography (silica, eluent 40e60 ꢁC petrol/
Et2O, 30:1) gave 42 as a yellow oil (41 mg, 30% over three steps,
78:22 dr); nmax (film) 1770 (C]O); dH (400 MHz, CDCl3) 0.85e0.91
(3H, m, C(3)(CH2)6CH3), 1.25e1.31 (12H, m, C(3)(CH2)6CH3), 1.64
4.12. (3R,aS)-N(2)-a-Methylbenzyl-3-(p-methoxyphenyl)
isoxazolidin-5-one 41
BuLi (1.41 M, 0.60 mmol, 0.42 ml) was added to a stirred so-
lution of 20 (150 mg, 0.60 mmol) in THF (6 mL) at ꢀ78 ꢁC. After
30 min a solution of 26 (58 mg, 0.3 mmol) in THF (2 mL) was added
and the reaction was stirred at ꢀ78 ꢁC for a further 10 h. Satd aq
NH4Cl (8 mL) was added, the two phases were separated and the
aqueous phase extracted with Et2O (3ꢃ8 mL). The organic phases
were combined and washed with satd aq NaCl (20 mL) before being
dried and concentrated in vacuo to give 31 as an orange oil (190 mg,
(3H, d, J 6.9, C(
7.7, C(4)HB), 3.26 (1H, dd, J 7.7, 5.8, C(3)H), 4.08 (1H, q, J 6.9, C(
7.32e7.39 (5H, m, Ph); dC (100 MHz, CDCl3) 12.0 (C(3)(CH2)6CH3),
20.4 (C( )Me), 22.6, 25.5, 25.8, 29.0, 29.1, 29.4 (C(3)(CH2)6CH3), 35.8
(C(4)), 60.9 (C(3)), 61.6 (C(
a
)Me), 2.33e2.35 (1H, m, C(4)HA), 2.86 (1H, dd, j 17.4,
a
)H),
a
a
)),126.0, 128.4, 129.2 (o-, m-, p-Ph), 136.5
(i-Ph), 175.0 (C(5)); m/z (ESIþ) 601 ([2MþNa]þ, 100%), 312
([MþNa]þ, 62%), 290 ([MþH]þ, 34%); HRMS (ESIþ) C18H27NNaOþ2
([MþNa]þ) requires 312.1934; found 312.1945.
86:14 dr). Hydrogen fluorideepyridine complex (2 mL, 0.72 mmol)
was added to a stirred solution of 31 (190 mg, 0.60 mmol) in dry THF
(6 mL) at 0 ꢁC. After stirring for 20 min the reaction mixture was
diluted with Et2O (40 mL) then quenched with satd aq NaHCO3
(30 mL). The phases were then separated and the aqueous phasewas
extracted with Et2O (3ꢃ30 mL). The organic phases were combined,
dried and concentrated in vacuo to give 38 (110 mg). This residue
was dissolved in THF (3 mL) and cooled to ꢀ78 ꢁC. LiHMDS (1.0 M,
0.90 mmol, 0.9 mL) was added and the mixture was left to stir for
30 min. The reaction was then quenched with satd aq NH4Cl (3 mL)
and the phases were separated. The aqueous phase was extracted
with Et2O (3ꢃ3 mL), then the organic phases were combined and
washed with satd aq NaCl (10 mL), before being dried and concen-
trated in vacuo. Purification via flash column chromatography (sil-
ica, eluent 40e60 ꢁC petrol/Et2O, 20:1) gave 41 as a yellow oil
4.14. (3R,4S,aS)-N(2)-a-Methylbenzyl-3-phenyl-
4-methylisoxazolidin-5-one 8
Following general procedure 2, LiTMP (0.2 M in THF, 0.55 mL,
0.11 mmol), 6 (26 mg, 0.10 mmol), MeI (20 mL, 0.30 mmol) and THF
(41 mg, 46% over three steps, >99:1 dr); [
nmax (film) 1778 (C]O); dH (400 MHz, CDCl3) 1.54 (3H, d, J 6.6, C(a)
a
]
23 þ78.0 (c 1.0 in CHCl3);
D
(1 mL) gave 8 in >99:1 dr. Purification via flash column chromatog-
raphy (silica, gradient elution, 40e60 ꢁC petrol/Et2O, 20:1; increased
to 40e60 ꢁC petrol/Et2O, 5:1) gave 8 as a colourless oil (20 mg, 71%,
Me), 2.85 (1H, dd, J 17.3, 9.1, C(4)HA), 3.00 (1H, dd, J 17.3, 7.6, C(4)HB),
3.79 (1H, s, OMe), 4.13 (1H, q, J 6.6, C( )H), 4.41e4.44 (1H, m, C(3)H),
6.79 (2H, d, J 8.7, Ar), 7.16 (2H, d, J 8.7, Ar), 7.20e7.25 (5H, m, Ph); dC
(100 MHz, CDCl3) 18.1 (C( )Me), 39.2 (C(4)), 55.3 (OMe), 65.7 (C( )),
65.9 (C(3)), 114.1, 127.8, 127.9, 128.3, 128.4 (o-, m-, p-Ph, Ar) 130.3,
23
25
>99:1 dr);5a
[a]
þ102 (c 1.0 in CHCl3); {lit.5a
[a]
þ128 (c 1.3 in
a
D
D
CHCl3)}; dH (400 MHz, CDCl3) 1.20 (3H, d, J 6.8, C(4)Me), 1.58 (3H, d, J
a
a
6.6, C(a)Me), 2.98e3.02 (1H, m, C(4)H), 3.95 (1H, d, J 12.3, C(3)H), 4.11
(1H, q, J 6.6, C(a)H), 7.16e7.32 (10H, m, Ph).

S.A. Bentley et al. / Tetrahedron 66 (2010) 4604e4620
4613
4.15. (3R,4S,
4-benzylisoxazolidin-5-one 43
a
S)-N(2)-
a
-Methylbenzyl-3-phenyl-
(3ꢃ2 mL), and the organic phases were combined, washed with satd
aq NaCl (5 mL), dried and concentrated in vacuo to give a 89:11
mixture of 45:50. Purification via flash column chromatography (sil-
ica, eluent 30e40 ꢁC petrol/Et2O, 20:1) gave 45 as a colourless oil
(68 mg, 63%, >99:1 dr); [
a
]
24 þ49.3 (c 1.0 in CHCl3); nmax (film) 1773
D
(C]O); dH (400 MHz, CDCl3) 0.91 (3H, t, J 7.3, C(4)CH2CH3),1.53 (3H, d,
J 6.5, C(
H), 4.03e4.08 (2H, m, C(3)H, C(
(100 MHz, CDCl3) 10.8 (C(4)CH2CH3), 17.2 (C(
52.2 (C(4)), 65.8 (C(
a
)Me), 1.64e1.71 (2H, m, C(4)CH2), 2.92 (1H, dt, J 12.0, 6.0, C(4)
)H), 7.12e7.31 (10H, m, Ph); dC
)Me), 20.0 (C(4)CH2),
)), 73.0 (C(3)),127.7,127.8,127.8,128.1,128.2,128.6
a
a
a
Following general procedure 2, LiTMP (0.2 M in THF, 1.45 mL,
0.29 mmol), 6 (70 mg, 0.26 mmol), BnBr (50 mL, 0.78 mmol) and THF
(o-, m-, p-Ph), 137.9, 139.9 (i-Ph), 174.6 (C(5)); m/z (ESIþ) 613
([2MþNa]þ, 78%), 591 ([2MþH]þ, 88%), 318 ([MþNa]þ, 18%), 296
([MþH]þ, 100%); HRMS (ESIþ) C19H21NNaOþ2 ([MþNa]þ) requires
318.1470; found 318.1458. Further elution gave 50 as a colourless oil
(2 mL) gave 43 in >99:1 dr. Purification via flash column chroma-
tography (silica, 40e60 ꢁC petrol/Et2O, 20:1; increased to 40e60 ꢁC
petrol/Et2O, 5:1) gave 43 as a colourless oil (70 mg, 75%, >99:1 dr);
(8 mg, 7%, >99:1 dr); [
O); dH (400 MHz, CDCl3) 0.80 (3H, t, J 7.5, C(4)CH2CH3),1.04 (3H, t, J 7.5,
a
]
24 þ54.9 (c 1.0 in CHCl3); nmax (film) 1770 (C]
D
[a]
23 þ69.9 (c 1.0 in CHCl3); nmax (film) 3031 (CeH), 1773 (C]O); dH
D
(400 MHz, CDCl3) 1.41 (3H, d, J 6.6, C(a)Me), 2.87 (1H, dd, J 14.5, 5.9, C
C(4)CH2CH3), 1.33e1.43 (1H, m, C(4)CHAHBCH3), 1.48 (3H, d, J 6.8, C(
Me), 1.61e1.70 (1H, m, C(4)CHAHBCH3), 1.82e1.98 (2H, m, C(4)
CH2CH3), 4.15 (1H, q, J 6.8, C( )H), 4.63 (1H, s, C(3)H), 7.21e7.36 (10H,
m, Ph); dC (100 MHz, CDCl3) 7.9 (C(4)CH2CH3), 8.9 (C(4)CH2CH3), 14.0
(C( )Me), 23.9 (C(4)CH2), 25.1 (C(4)CH2), 53.3 (C(4)), 62.8 (C( )), 71.3 (C
a)
(4)CHA), 3.10 (1H, dd, J 14.5, 4.9, C(4)CHB), 3.31e3.38 (1H, m, C(4)H),
3.89 (1H, q, J 6.6, C( )H), 4.03 (1H, d, J 11.6, C(3)H), 7.10e7.32 (15H, m,
Ph); dC (100 MHz, CDCl3) 17.5 (C( )Me), 32.8 (C(4)CH2), 52.8 (C(4)),
66.2 (C( )), 71.9 (C(3)), 127.3, 128.1, 128.3, 128.4, 128.7, 128.8, 128.9,
a
a
a
a
a
a
129.8, 130.0 (o-, m-, p-Ph), 137.3, 137.9, 140.2 (i-Ph), 174.7 (C(5)); m/z
(ESIþ) 358 ([MþH]þ, 90%), 254 (100%); HRMS (ESIþ) C24H24NOþ2
([MþH]þ) requires 358.1802; found 358.1802.
(3)), 127.4, 127.8, 128.0, 128.2, 128.4 (o-, m-, p-Ph), 134.6, 141.1 (i-Ph),
176.2 (C(5)); m/z (ESIþ) 669 ([2MþNa]þ, 100 %), 346 ([MþNa]þ, 90%),
324 ([MþH]þ, 55%); HRMS (ESIþ) C21H25NNaOþ2 ([MþNa]þ) requires
346.1778; found 346.1786.
Method B: following general procedure 2, LiTMP (0.2 M in THF,
2.05 mL, 0.41 mmol), 6 (100 mg, 0.37 mmol), ethyl iodide (90 mL,
4.16. (3R,4S,aS)-N(2)-a-Methylbenzyl-3-phenyl-
4-allylisoxazolidin-5-one 44
1.12 mmol) and THF (3 mL) gave 45 in >99:1 dr. Purification via
flash column chromatography (silica, eluent 30e40 ꢁC petrol/Et2O,
20:1) gave 45 as a colourless oil (82 mg, 75%, >99:1 dr).
4.18. (3R,4S,aS)-N(2)-a-Methylbenzyl-3-phenyl-4-
(tert-butoxycarbonylmethyl)isoxazolidin-5-one 46
Following general procedure 2, LiTMP (0.2 M in THF, 1.45 mL,
0.29 mmol),6(70 mg,0.26 mmol), allyliodide(70 mL,0.80 mmol)and
THF (2 mL) gave 44 in >99:1 dr. Purification via flash column chro-
matography (silica, 40e60 ꢁC petrol/Et2O, 40:1; increased to
40e60 ꢁC petrol/Et2O, 20:1) gave 44 as a colourless oil (66 mg, 82%,
>99:1 dr); [
a
]
23 þ100 (c 1.0 in CHCl3); nmax (film) 3032 (CeH), 1774
D
Following general procedure 2, LiTMP (0.23 M in THF, 2.00 mL,
(C]O); dH (400 MHz, CDCl3) 1.53 (3H, d, J 6.6, C(a)Me), 2.26e2.31 (1H,
0.45 mmol),
6 (100 mg, 0.37 mmol), tert-butyl bromoacetate
m, C(4)CHA), 2.47e2.53 (1H, m, C(4)CHB), 3.05e3.11 (1H, m, C(4)H),
4.07 (1H, q, J 6.6, C( )H), 4.16 (1H, d, J 11.9, C(3)H), 5.07e5.11 (2H, m, C
(4)CH2CH]CH2), 5.64e5.74 (1H, m, C(4)CH2CH]CH2), 7.13e7.24
(10H, m, Ph);dC (100 MHz, CDCl3) 17.5(C( )Me), 31.0(C(4)CH2), 51.2 (C
(4)), 66.3 (C( )), 72.4 (C(3)), 100.0 (C(4)CH2CH]CH2), 119.2 (C(4)
CH2CH]CH2), 128.1, 128.3, 128.5, 128.6, 129.0, 133.6, (o-, m-, p-Ph),
137.9, 140.2 (i-Ph),174.3 (C(5)); m/z (ESIþ) 308 ([MþH]þ, 40%) ; HRMS
(ESIþ) C20H22NO2þ ([MþH]þ) requires 308.1645; found 308.1645.
(0.16 mL,1.11 mmol) and THF (2 mL) gave 46 in >99:1 dr. Purification
a
via flash column chromatography (silica, eluent 30e40 ꢁC petrol/
24
Et2O, 20:1) gave 46 as a colourless oil (116 mg, 81%, >99:1 dr); [
a
]
D
a
þ69.2 (c 1.0 in CHCl3); nmax (film) 2979 (CeH),1778 (C]O),1730 (C]
O); dH (400 MHz, CDCl3) 1.35 (9H, s, CMe3), 1.56 (3H, d, J 6.6, C( )Me),
2.53 (2H, d, J 5.6, C(4)CH2), 3.31 (1H, ddd, J 11.9, 5.8, 5.6, C(4)H), 4.10
(1H, q, J 6.6, C( )H), 4.26 (1H, d, J 11.9, C(3)H), 7.10e7.32 (10H, m, Ph);
dC (100 MHz, CDCl3) 17.2 (C( )Me), 27.9 (CMe3), 32.3 (C(4)CH2), 48.3 (C
(4)), 65.9 (C( )), 73.1 (C(3)), 81.6 (CMe3), 127.7, 127.8, 128.1, 128.2,
a
a
a
a
a
4.17. (3R,4S,aS)-N(2)-a-Methylbenzyl-3-phenyl-
4-ethylisoxazolidin-5-one 45
128.4, 128.7 (o-, m-, p-Ph), 137.0, 139.9 (i-Ph), 169.2 (C(5)), 169.2
(CO2 Bu); m/z (ESIþ) 404 ([MþNa]þ, 75%), 382 ([MþH]þ,100%); HRMS
t
(ESIþ) C23H27NNaO4þ ([MþNa]þ) requires 404.1833; found 404.1817.
4.19. (S,S,S)-N(2)-a-Methylbenzyl-3,4-dimethylisoxazolidin-5-
one 47
MethodA: LiHMDS (1 M inTHF, 0.41 mL, 0.41 mmol) was added
to a stirred solution 6 (100 mg, 0.37 mmol) in THF (2 mL) at ꢀ78 ꢁC
and left for 2 h. Ethyl iodide (90 mL, 1.12 mmol) was then added and
the reaction mixture allowed to slowly warm to rt over 16 h, after
which time satd aq NH4Cl (0.5 mL) was added and the two phases
were separated. The aqueous phase was then extracted with Et2O

4614
S.A. Bentley et al. / Tetrahedron 66 (2010) 4604e4620
Following general procedure 2, LiTMP (0.23 M in THF, 3.20 mL,
0.73 mmol), (125 mg, 0.61 mmol), methyl iodide (0.11 mL,
1.83 mmol) and THF (3 mL) gave 47 in 70:30 dr. Purification via flash
column chromatography (silica, eluent 30e40 ꢁC petrol/Et2O, 20:1)
gave 47 as a white solid (80 mg, 71%, 70:30 dr); mp 155e157 ꢁC
(dec); nmax (film) 1768 (C]O); dH (400 MHz, CDCl3) 0.75 (3H, d, J 5.8,
Following general procedure 2, LiTMP (0.43 M in THF, 5 mL,
7
2.15 mmol), 7 (400 mg,1.95 mmol), allyl iodide (0.54 mL, 5.85 mmol)
and dry THF (10 mL) gave 48 in 92:8 dr. Purification via flash column
chromatography (silica, gradient elution, 30e40 ꢁC petrol/Et2O,
20:1; increased to 30e40 ꢁC petrol/Et2O, 5:1) gave 48 as a colourless
18
oil, (307 mg, 64%, 92:8 dr); [
a
]
þ42.2 (c 1.0 in CHCl3); nmax (film)
D
C(3)Me), 1.20 (3H, d, J 6.8, C(4)Me), 1.58 (3H, d, J 6.4, C(
2.51e2.59 (1H, m, C(4)H), 2.97e3.08 (1H, m, C(3)H), 3.97 (1H, q, J 6.4,
C( )H), 7.31e7.39 (5H, m, Ph); dC (100 MHz, CDCl3) 11.7 (C(4)Me),17.8
(C(3)Me), 19.3 (C(
a)Me),
2935 (CeH), 1771 (C]O); dH (400 MHz, CDCl3) 0.80 (3H, d, J 5.9, C(3)
Me), 1.57 (3H, d, J 6.5, C( )Me), 2.44 (2H, app t, J 6.3, C(4)CH2), 2.63
(1H, app dt, J 11.4, 5.7, C(4)H), 3.19 (1H, dq, J 11.4, 5.9, C(3)H), 3.98 (1H,
q, J 6.5, C( )H), 5.11e5.15 (2H, m, C(4)CHCH]CH2), 5.73e5.83 (1H, m,
C(4)CHCH]CH2), 7.30e7.39 (5H, m, Ph); dC (100 MHz, CDCl3) 18.4 (C
(3)Me), 19.3 (C( )Me), 31.6 (C(4)CH2), 48.8 (C(4)), 64.7 (C(3)), 67.3 (C
a
a
a
)Me), 44.4 (C(4)), 67.4 (C(
a)), 68.1 (C(3)), 127.1,
a
127.9, 128.6 (o-, m-, p-Ph), 140.6 (i-Ph), 175.7 (C(5)); m/z (ESIþ) 461
([2MþNa]þ, 100%), 242 ([MþNa]þ, 68%), 220 ([MþH]þ, 27%); HRMS
(ESIþ) C13H17NNaO2þ ([MþNa]þ) requires 242.1151; found 242.1162.
a
(a)), 118.4, 133.6, 134.5 (o-, m-, p-Ph), 140.8 (i-Ph), 174.8 (C(5)); m/z
(ESIþ) 246 ([MþH]þ, 100%); HRMS (ESIþ) C15H19NNaOþ2 ([MþNa])þ
requires 268.1308; found 268.1303.
4.20. (S,S,S)-N(2)-a-Methylbenzyl-3-methyl-
4-benzylisoxazolidin-5-one 9
4.22. (S,S,S)-N(2)-a-Methylbenzyl-3-methyl-
4-ethylisoxazolidin-5-one 49
Following general procedure 2, LiTMP (0.36 M in THF, 14.9 mL,
5.37 mmol),
7 (1.00 g, 4.88 mmol), benzyl bromide (1.74 mL,
14.6 mmol) and THF (20 mL) gave 9 in >99:1 dr. Purification via flash
column chromatography (silica, gradient elution, 30e40 ꢁC petrol/
Et2O, 20:1; increased to 30e40 ꢁC petrol/Et2O, 5:1) gave 9 as a white
Following general procedure 2, LiTMP (0.25 M in THF, 9.40 mL,
2.34 mmol), 7 (400 mg,1.95 mmol), ethyl iodide(0.47 mL, 5.85 mmol)
and THF (6 mL) gave 49 in 69:31 dr. Purification via flash column
chromatography (silica, gradient elution, 30e40 ꢁC petrol/Et2O, 20:1;
increased to 30e40 ꢁC petrol/Et2O, 5:1) gave 49 as a colourless oil
(273 mg, 60%, 69:31 dr); nmax (film) 1762 (C]O); dH (400 MHz, CDCl3)
0.80 (3H, d, J 6.0, C(3)Me), 1.03 (3H, t, J 7.6, C(4)CH2CH3), 1.57 (3H, d, J
solid (1.01 g, 70%, >99:1 dr);5a mp 79e81 ꢁC (EtOH); [
a]
D
24 þ85.3 (c
1.0 in CHCl3); {lit.5a þ89.6 (c 2.4 in CHCl3)}; dH (400 MHz, CDCl3) 0.67
(3H, d, J 5.6, C(3)Me), 1.48 (3H, d, J 6.5, C(a)Me), 2.83e2.88 (1H, m, C
(4)H), 2.94e2.99 (1H, m, C(4)CHA), 3.09e3.16 (2H, m, C(3)H, C(4)
CHB), 3.85 (1H, q, J 6.5, C( )H), 7.19e7.36 (10H, m, Ph).
a
6.6, C(
3.13e3.20 (1H, m, C(3)H), 3.98 (1H, q, J 6.6, C(
Ph); dC (100 MHz, CDCl3) 10.9 (C(4)CH2CH3), 18.7 (C(3)Me), 19.5 (C(
a
)Me),1.65e1.73 (2H, m, C(4)CH2), 2.47 (1H, dt, J 11.2, 6.0, C(4)H),
4.20.1. X-ray crystal structure determination for 9. Data were col-
lected using an EnrafeNonius -CCD diffractometer with graphite
monochromated Mo K radiation using standard procedures at
150 K. The structure was solved by direct methods (SIR92); all non-
hydrogen atoms were refined with anisotropic thermal parameters.
Hydrogen atoms were added at idealised positions. The structure
was refined using CRYSTALS.29
a)H), 7.28e7.39 (5H, m,
k
a)
a
Me), 20.5 (C(4)CH2), 50.3 (C(4)), 64.8 (C(3)), 67.5 (C(a)), 128.0, 128.2,
128.7 (o-, m-, p-Ph), 140.8 (i-Ph), 175.5 (C(5)); m/z (ESIþ) 489
([2MþNa]þ, 100%), 256 ([MþNa]þ, 74%); HRMS (ESIþ) C14H19NNaOþ2
([MþNa]þ) requires 256.1308; found 256.1306.
X-ray crystal structure data for 9 [C19H21NO2]: M¼295.38, or-
4.23. (3S,4R,aS)- and (S,S,S)-N(2)-a-Methylbenzyl-3-phenyl-
4-methyl-4-trideuteriomethylisoxazolidin-5-one 51 and 58
thorhombic, space group P 21 21 21, a¼5.8643(2) Å, b¼9.9505(4) Å,
c¼27.5990(12) Å, V¼1610.48(11) Å3, Z¼4,
m
¼0.079 mmꢀ1, colour-
less plate, crystal dimensions¼0.10ꢃ0.10ꢃ0.20 mm3. A total of
2106 unique reflections were measured for 5<q<27 and 1210 re-
flections were used in the refinement. The final parameters were
(I)].
wR2¼0.058 and R1¼0.087 [I>1.0
s
Crystallographic data (excluding structure factors) has been de-
posited with the Cambridge Crystallographic Data Centre as sup-
plementary publication number CCDC 747489. Copies of the data can
be obtained, free of charge, on application to CCDC, 12 Union Road,
Cambridge CB2 1EZ, UK [fax: þ44(0)-1223-336033 or e-mail:
deposit@ccdc.cam.ac.uk].
Following general procedure 3, LiHMDS (1.0 M in THF,
0.21 mL, 0.21 mmol), 8 (50 mg, 0.18 mmol), trideuteriomethyl io-
dide (30 mL, 0.54 mmol) and THF (1 mL) gave a 68:32 mixture of
51:58. Purification via flash column chromatography (silica, gradi-
ent elution, 40e60 ꢁC petrol/Et2O, 20:1; increased to 40e60 ꢁC
petrol/Et2O, 5:1) gave 51:58 in 68:32 dr as a colourless oil (26 mg,
48%); nmax (film) 1774 (C]O); m/z (ESIþ) 619 ([2MþNa]þ,100%), 321
([MþNa]þ, 32%), 299 ([MþH]þ, 20%); HRMS (ESIþ) C19H18D3NNaOþ2
([MþNa]þ) requires 321.1653; found 321.1645.
4.21. (S,S,S)-N(2)-
4-allylisoxazolidin-5-one 48
a-Methylbenzyl-3-methyl-
Data for major diastereoisomer: dH (400 MHz, CDCl3) 0.99 (3H, s,
C(4)Me), 1.50 (3H, d, J 6.8, C(
(1H, s, C(3)H), 7.21e7.34 (10H, m, Ph); dC (125 MHz, CDCl3) 14.2 (C
)Me), 19.8 (C(4)CH3), 46.1 (C(4)), 63.1 (C( )), 76.3 (C(3)), 127.5,
a)Me), 4.14 (1H, q, J 6.8, C(a)H), 4.23
(a
a
127.9, 128.2, 128.3, 128.3, 128.4 (o-, m-, p-Ph), 134.2, 141.0 (i-Ph)
178.5 (C(5)).

S.A. Bentley et al. / Tetrahedron 66 (2010) 4604e4620
4615
Data for minor diastereoisomer: dH (400 MHz, CDCl3) 1.23 (3H, s,
C(4)CH3), 1.50 (3H, d, J 6.8, C( )Me), 4.14 (1H, q, J 6.8, C( )H), 4.23
(1H, s, C(3)H), 7.21e7.34 (10H, m, Ph).
(0.17 mL, 2.76 mmol) and THF (10 mL) gave 53:60 in 97:3 dr. Purifi-
cation via flash column chromatography (silica, gradient elution,
40e60 ꢁC petrol/Et2O, 20:1; increased to 40e60 ꢁC petrol/Et2O, 5:1)
gave 53 as a white solid (206 mg, 72%, >99:1 dr).
a
a
4.24. (S,S,S)-N(2)-
4-methylisoxazolidin-5-one 52
a-Methylbenzyl-3-phenyl-4-allyl-
4.25.1. X-ray crystal structure determination for 53. Data were col-
lected using an EnrafeNonius
k-CCD diffractometer with graphite
monochromated Mo K radiation using standard procedures at
a
150 K. The structure was solved by direct methods (SIR92); all non-
hydrogen atoms were refined with anisotropic thermal parameters.
Hydrogen atoms were added at idealised positions. The structure
was refined using CRYSTALS.29
X-ray crystal structure data for 53 [C25H25NO2]: M¼371.48, or-
thorhombic, space group P 21 21 21, a¼7.43100(10) Å, b¼12.1146(2)
Å, c¼22.5635(4) Å, V¼2031.25(6) Å3, Z¼4,
m
¼0.076 mmꢀ1, colour-
Method A: following general procedure 3, LiHMDS (1.0 M in
THF, 0.16 mL, 0.16 mmol), 8 (30 mg, 0.11 mmol), allyl iodide (20 L,
less plate, crystal dimensions¼0.05ꢃ0.05ꢃ0.20 mm3. A total of
m
0.22 mmol) and THF (1 mL) gave 52:59 in >99:1 dr. Purification via
flash column chromatography (silica, gradient elution, 40e60 ꢁC
petrol/Et2O, 50:1; increased to 40e60 ꢁC petrol/Et2O, 10:1) gave 52
2639 unique reflections were measured for 5<q<27 and 2639 re-
flections were used in the refinement. The final parameters were
(I)].
wR2¼0.100 and R1¼0.058 [I>ꢀ3.0
s
as a colourless oil (26 mg, 74%, >99:1 dr); [
nmax (film) 2927 (CeH), 1773 (C]O); dH (400 MHz, CDCl3) 1.01 (3H, s,
a
]
24 þ50.3 (c 1.0 in CHCl3);
Crystallographic data (excluding structure factors) has been de-
posited with the Cambridge Crystallographic Data Centre as sup-
plementary publication number CCDC 747490. Copies of the data can
be obtained, free of charge, on application to CCDC, 12 Union Road,
Cambridge CB2 1EZ, UK [fax: þ44(0)-1223-336033 or e-mail:
deposit@ccdc.cam.ac.uk].
D
C(4)Me), 1.47 (3H, d, J 6.7, C(
2.52 (1H, dd, J 14.3, 5.1, C(4)CHB), 4.13 (1H, q, J 6.7, C(
C(3)H), 5.22e5.27 (2H, m, C(4)CH2CH]CH2), 5.77e5.87 (1H, m, C(4)
CH2CH]CH2), 7.20e7.34 (10H, m, Ph); dC (100 MHz, CDCl3) 17.1 (C(
Me),19.8 (C(4)Me), 39.4 (C(4)CH2), 49.8 (C(4)), 63.4 (C( )), 71.3 (C(3)),
a)Me), 2.12 (1H, dd, J 14.3, 9.5, C(4)CHA),
a)H), 4.55 (1H, s,
a)
a
119.9 (C(4)CH2CH]CH2), 127.6, 127.9, 128.2, 128.3, 128.4, 128.5 (o-,
m-, p-Ph), 133.2 (C(4)CH2CH]CH2), 134.6, 140.9 (i-Ph), 177.3 (C(5));
m/z (ESIþ) 643 ([2MþH]þ, 17%), 344 ([MþNa]þ, 38%), 322 ([MþH]þ,
100%); HRMS (ESIþ) C21H23NNaOþ2 ([MþNa]þ) requires 344.1621;
found 344.1621.
4.26. (3S,4R,aS)- and (S,S,S)-N(2)-a-Methylbenzyl-3,4-
dimethyl-4-trideuteriomethylisoxazolidin-5-one 54 and 61
Method B: following general procedure 3, LiHMDS (1.0 M in THF,
0.35 mL, 0.35 mmol), 44 (90 mg, 0.29 mmol), methyl iodide
(0.06 mL, 0.87 mmol) and THF (2 mL) gave 52:59 in a 60:40 dr. Pu-
rification via flash column chromatography (silica, gradient elution,
40e60 ꢁC petrol/Et2O, 50:1; increased to 40e60 ꢁC petrol/Et2O,10:1)
gave 52 as a colourless oil (35 mg, 38%, >99:1 dr).
Following general procedure 3, LiHMDS (1.0 M in THF, 0.21 mL,
0.21 mmol), 47 (50 mg, 0.23 mmol), trideuteriomethyl iodide (30 mL,
0.68 mmol) and THF (1 mL) gave 54:61 in 62:38 dr. Purification via
flash column chromatography (silica, gradient elution, 40e60 ꢁC
petrol/Et2O, 20:1; increased to 40e60 ꢁC petrol/Et2O, 5:1) gave 54:61
in 62:38 dr as a colourless oil (28 mg, 57%); nmax (film) 1772 (C]O);
m/z (ESIþ) 259 ([MþNa]þ, 100%), 237 ([MþH]þ, 58%); HRMS (ESIþ)
C14H16D3NNaOþ2 ([MþNa]þ) requires 259.1496; found 259.1500.
Data for major diastereoisomer: dH (400 MHz, CDCl3) 0.62 (3H, d, J
4.25. (S,S,S)-N(2)-a-Methylbenzyl-3-phenyl-4-benzyl-
4-methylisoxazolidin-5-one 53
6.3, C(3)Me), 1.15 (3H, s, C(4)Me), 1.58 (3H, d, J 6.6, C(
q, J 6.3, C(3)H), 3.97 (1H, q, J 6.6, C( )H), 7.30e7.39 (5H, m, Ph); dC
(125 MHz, CDCl3) 13.0 (C(3)Me), 17.2 (quin, J 20.0, C(3)CD3) 19.3 (C(
a)Me), 3.07 (1H,
a
a)
Me), 21.3 (C(4)CH3), 45.3 (C(4)), 67.0 (C(3)) 69.7 (C(a)), 127.8, 128.0,
Method A: following general procedure 3, LiHMDS (1.0 M inTHF,
128.5 (o-, m-, p-Ph), 141.4 (i-Ph), 179.0 (C(5)).
0.13 mL, 0.13 mmol), 8 (30 mg, 0.11 mmol), benzyl bromide (40
m
L,
Data for minor diastereoisomer: dH (400 MHz, CDCl3) 0.62 (3H, d,
J 6.3, C(3)Me),1.17 (3H, s, C(4)Me),1.58 (3H, d, J 6.6, C( )Me), 3.07 (1H,
q, J 6.3, C(3)H), 3.97 (1H, q, J 6.6, C( )H), 7.30e7.39 (5H, m, Ph).
0.39 mmol) and THF (1 mL) gave 53:60 in >99:1 dr. Purification via
flash column chromatography (silica, gradient elution, 40e60 ꢁC
petrol/Et2O, 20:1; increased to 40e60 ꢁC petrol/Et2O, 5:1) gave 53 as
a
a
a white solid (31 mg, 76%, >99:1 dr); mp 145e147 ꢁC; [
a]
D
20 þ27.0 (c
4.27. (S,S,S)-N(2)-a-Methylbenzyl-3,4-dimethyl-
4-allylisoxazolidin-5-one 55
0.4 in CHCl3); nmax (film) 3033 (CꢀH), 1762 (C]O); dH (400 MHz,
CDCl3) 1.11 (3H, s, C(4)Me),1.15 (3H, d, J 6.6, C(
C(4)CHA), 3.35 (1H, d, J 14.3, C(4)CHB), 3.82 (1H, q, J 6.6, C(
(1H, s, C(3)H), 7.18e7.41 (15H, m, Ph); dC (100 MHz, CDCl3) 14.2 (C(
Me), 21.5 (C(4)Me), 41.2 (C(4)CH2), 51.8 (C(4)), 63.6 (C( )), 69.9 (C(3)),
a)Me), 2.53 (1H, d, J 14.3,
a)H), 4.41
a
)
a
127.2, 127.5, 127.8, 128.1, 128.2, 128.4, 128.6, 128.8, 130.5 (o-, m-, p-Ph),
135.2, 136.6, 140.9 (i-Ph), 177.9 (C(5)); m/z (ESIþ) 430 ([Mþ59]þ,
100%); HRMS (ESIþ) C25H25NNaOþ2 ([MþNa]þ) requires 394.1778;
found 394.1763.
Method B: following general procedure 3, LiHMDS (1.0 M in THF,
0.92 mL, 0.92 mmol), 43 (275 mg, 0.77 mmol), methyl iodide
Method A: following general procedure 3, LiHMDS (1.0 M in
THF, 0.27 mL, 0.27 mmol), 47 (50 mg, 0.23 mmol), allyl iodide
(0.06 mL, 0.69 mmol) and THF (1 mL) gave a 69:31 mixture of 55:62.
Purification via flash column chromatography (silica, gradient

4616
S.A. Bentley et al. / Tetrahedron 66 (2010) 4604e4620
elution, 40e60 ꢁC petrol/Et2O, 20:1; increased to 40e60 ꢁC petrol/
dH (400 MHz, CDCl3) 0.62 (3H, d, J 6.5, C(3)Me), 1.29 (3H, s, C(4)
Me), 1.35 (3H, d, J 6.5, C( )Me), 2.59 (1H, d, J 14.0, C(4)CHA),
3.13e3.18 (1H, m, C(3)H), 3.20 (1H, d, J 14.0, C(4)CHB), 3.73 (1H, q,
J 6.5, C( )H), 7.15e7.32 (10H, m, Ph); dC (100 MHz, CDCl3) 13.0 (C
(3)Me), 18.3 (C( )Me), 29.7 (C(4)Me), 40.9 (C(4)CH2), 50.4 (C(4)),
64.5 (C(3)), 66.2 (C( )), 127.0, 127.8, 127.9, 128.5, 129.1, 130.2
22
Et2O, 5:1) gave 55 as a colourless oil (23 mg, 39%, >99:1 dr); [
a
]
a
D
þ49.3 (c 1.0 in CHCl3); nmax (film) 2937 (CeH), 1770 (C]O); dH
(400 MHz, CDCl3) 0.65 (3H, d, J 6.0, C(3)Me), 1.19 (3H, s, C(4)Me), 1.54
a
(3H, d, J 6.6, C(a)Me), 2.13 (1H, dd, J 14.2, 8.5, C(4)CHA), 2.45 (1H, dd, J
a
14.2, 6.1, C(4)CHB), 3.31 (1H, q, J 6.0, C(3)H), 3.97 (1H, q, J 6.6, C(
a)H),
a
5.08e5.16 (2H, m, C(4)CH2CH]CH2), 5.71e5.82 (1H, m, C(4)CH2CH]
CH2), 7.28e7.38 (5H, m, Ph); dC (100 MHz, CDCl3) 13.0 (C(3)Me), 17.3
(o-, m-, p-Ph), 136.3, 141.4 (i-Ph), 178.1 (C(5)); m/z (ESIþ) 641
([2MþNa]þ, 100%), 332 ([MþNa]þ, 78%), 310 ([MþH]þ, 23%);
HRMS (ESIþ) C20H23NNaOþ2 ([MþNa]þ) requires 332.1621; found
332.1621.
(C(4)Me), 19.0 (C(a)Me), 39.4 (C(4)CH2), 48.7 (C(4)), 65.7 (C(3)), 66.6
(C( )), 119.4 (C(4)CH2CH]CH2), 127.8, 127.9, 128.5 (o-, m-, p-Ph),
a
132.7 (C(4)CH2CH]CH2), 141.4 (i-Ph), 177.9 (C(5)); m/z (ESIþ) 541
([2MþNa]þ, 100%), 282 ([MþNa]þ, 29%), 260 ([MþH]þ, 16%); HRMS
(ESIþ) C16H21NNaO2þ ([MþNa]þ) requires 282.1465; found 282.1459.
Method B: following general procedure 3, LiHMDS (1.0 M in THF,
0.2 mL, 0.2 mmol), 48 (40 mg, 0.16 mmol), methyl iodide (0.03 mL,
0.48 mmol) and THF (1 mL) gave 55:62 in >99:1 dr. Purification via
flash column chromatography (silica, gradient elution, 40e60 ꢁC
petrol/Et2O, 20:1; increased to 40e60 ꢁC petrol/Et2O, 5:1) gave 55
as a colourless oil (37 mg, 89%, >99:1 dr).
Method B: following general procedure 3, LiHMDS (1.0 M in THF,
0.40 mL, 0.40 mmol), 9 (100 mg, 0.34 mmol), methyl iodide (60 mL,
1.02 mmol) and THF (2.5 mL) gave 57:64 in >99:1 dr. Purification
via flash column chromatography (silica, gradient elution,
40e60 ꢁC petrol/Et2O, 20:1; increased to 40e60 ꢁC petrol/Et2O, 5:1)
gave 57 as a colourless oil (87 mg, 83%, >99:1 dr).
4.29.1. X-ray crystal structure determination for 57. Data were col-
lected using an EnrafeNonius
k-CCD diffractometer with graphite
monochromated Mo K radiation using standard procedures at
a
150 K. The structure was solved by direct methods (SIR92); all non-
hydrogen atoms were refined with anisotropic thermal parameters.
Hydrogen atoms were added at idealised positions. The structure
was refined using CRYSTALS.29
4.28. (S,S,S)-N(2)-a-Methylbenzyl-3,4-dimethyl-
4-methallylisoxazolidin-5-one 56
X-ray crystal structure data for 57 [C20H23NO2]: M¼309.41, or-
thorhombic, space group P 21 21 21, a¼10.6697(2) Å, b¼7.2058(2) Å,
c¼22.4278(5) Å, V¼1724.33(7) Å3, Z¼4,
m
¼0.076 mmꢀ1, colourless
plate, crystal dimensions¼0.09ꢃ0.13ꢃ0.26 mm3. A total of 2256
unique reflections were measured for 5<q<27 and 1853 reflections
were used in the refinement. The final parameters were wR2¼0.074
Following general procedure 3, LiHMDS (1.0 M in THF, 0.2 mL,
0.22 mmol), 47 (36 mg, 0.17 mmol), methallyl bromide (67 mg,
0.5 mmol) and THF (1 mL) gave 56:63 in 97:3 dr. Purification via flash
column chromatography (silica, gradient elution, 40e60 ꢁC petrol/
Et2O, 25:1; increased to 40e60 ꢁC petrol/Et2O, 15:1) gave 56 as
and R1¼0.042 [I>ꢀ3.0
s(I)].
Crystallographic data (excluding structure factors) has been de-
posited with the Cambridge Crystallographic Data Centre as sup-
plementary publication number CCDC 753400. Copies of the data
can be obtained, free of charge, on application to CCDC, 12 Union
Road, Cambridge CB2 1EZ, UK [fax: þ44(0)-1223-336033 or e-mail:
deposit@ccdc.cam.ac.uk].
a colourless oil (25 mg, 56%, >99:1 dr); [
a
]
23 þ71.0 (c 1.0 in CHCl3);
D
nmax (film) 2975 (CeH),1769 (C]O); dH (400 MHz, CDCl3) 0.66 (3H, d,
J 5.9, C(3)Me),1.20 (3H, s, C(4)Me),1.55 (3H, d, J 6.7, C(
C(20)Me), 2.04 (1H, d, J 14.2, C(10)HA), 2.60 (1H, d, J 14.2, C(10)HB), 3.31
(1H, q, J 5.9, C(3)H), 3.99 (1H, q, J 6.7, C(
)H), 4.72 (1H, app s, C(30)HA),
4.88 (1H, app s, C(30)HB), 7.30e7.39 (5H, m, Ph); dC (100 MHz, CDCl3)
a)Me),1.7 (3H, s,
4.30. (S,S,S)-N(2)-a-Methylbenzyl-3-phenyl-4-allyl-
4-benzylisoxazolidin-5-one 65
a
13.0 (C(3)Me), 18.7 (C(
a
)Me), 19.4 (C(4)Me), 23.5 (C(20)Me), 42.7 (C
(10)), 48.3 (C(4)), 64.3 (C(3)), 66.4 (C(
a
)), 115.9 (C(30)), 127.9, 127.þ9,
128.5 (o-, m-, p-Ph), 141.2, 141.4 (C(20), i-Ph), 178.4 (C(5)); m/z (ESI )
569 ([2MþNa]þ, 100%), 296 ([MþNa]þ, 28%), 274 ([MþH]þ, 18%);
HRMS (ESIþ) C17H23NNaOþ2 ([MþNa]þ) requires 296.1621; found
296.1616.
4.29. (S,S,S)-N(2)-a-Methylbenzyl-3,4-dimethyl-
4-benzylisoxazolidin-5-one 57
Method A: following general procedure 3, LiHMDS (1.0 M in
THF, 0.18 mL, 0.18 mmol), 44 (50 mg, 0.16 mmol), benzyl bromide
(50 mL, 0.42 mmol) and THF (1.5 mL) gave 65:70 in 89:11 dr. Puri-
fication via flash column chromatography (silica, gradient elution,
40e60 ꢁC petrol/Et2O, 50:1; increased to 40e60 ꢁC petrol/Et2O,
10:1) gave 65 as a white solid (47 mg, 71%, >99:1 dr); C27H27NO2
requires C, 81.6; H, 6.85; N, 3.5%; found C, 81.5; H, 6.7; N, 3.5%; mp
Method A: following general procedure 3, LiHMDS (1.0 M in
THF, 0.16 mL, 0.16 mmol), 47 (30 mg, 0.14 mmol), benzyl bromide
84e86 ꢁC; [
a
]
D
24 þ73.6 (c 1.0 in CHCl3); nmax (film) 2921 (CeH) 1771
(C]O); dH (400 MHz, CDCl3) 1.12 (3H, d, J 6.8, C(a)Me), 1.88 (1H, dd,
(20
m
L, 0.42 mmol) and THF (1 mL) gave 57:64 in >99:1 dr. Puri-
J 14.2, 8.5, C(4)CHAHBCH]CH2), 2.44 (1H, d, J 14.4, C(4)CHAHBPh),
2.64 (1H, dd, J 14.2, 6.1, C(4)CHAHBCH]CH2), 3.47 (1H, d, J 14.4, C(4)
CHAHBPh), 3.83 (1H, q, J 6.8, C(a)H), 4.52 (1H, s, C(3)H), 5.00 (1H,
app d, J 17.0, C(4)CH2CH]CHAHB), 5.10 (1H, app d, J 10.1, C(4)
CH2CH]CHAHB), 5.69e5.77 (1H, m, C(4)CH2CH]CH2), 7.17e7.42
(15H, m, Ph); dC (100 MHz, CDCl3) 13.5 (C(a)Me), 38.7 (C(4)CH2CH]
fication via flash column chromatography (silica, gradient elution,
40e60 ꢁC petrol/Et2O, 20:1; increased to 40e60 ꢁC petrol/Et2O,
5:1) gave 57 as a colourless oil (38 mg, 88%, >99:1 dr). Recrys-
tallisation of an aliquot (EtOH/hexane) gave an analytical sample;
mp 71e73 ꢁC; [
a
]
25 þ58.0 (c 1.0 in CHCl3); nmax (film) 1768 (C]O);
D

S.A. Bentley et al. / Tetrahedron 66 (2010) 4604e4620
4617
CH2), 38.7 (C(4)CH2Ph), 54.6 (C(4)), 63.1 (C(
a
)), 69.5 (C(3)), 119.3 (C
4.32. (3S,4R,
aS)- and (S,S,S)-N(2)-a-Methylbenzyl-3-phenyl-
(4)CH2CH]CH2), 127.2, 127.5, 127.7, 128.2, 128.4, 128.6, 128.6, 128.9,
130.6 (o-, m-, p-Ph), 132.2 (C(4)CH2CH]CH2), 134.6, 136.9, 141.1 (i-
Ph), 173.9 (C(5)); m/z (ESIþ) 420 ([MþNa]þ, 50%), 398 ([MþH]þ,
100%); HRMS (ESIþ) C27H27NNaOþ2 ([MþNa]þ) requires 420.1934;
found 420.1922.
4-benzyl-4-(p-bromobenzyl)isoxazolidin-5-one 67 and 72
Method B: following general procedure 3, LiHMDS (1.0 M in
THF, 0.20 mL, 0.20 mmol), 43 (60 mg, 0.17 mmol), allyl iodide
(47 mL, 0.51 mmol) and THF (1 mL) gave 65:70 in 73:27 dr. Pu-
rification via flash column chromatography (silica, gradient
elution, 40e60 ꢁC petrol/Et2O, 50:1; increased to 40e60 ꢁC
petrol/Et2O, 10:1) gave 65 as
>99:1 dr).
a white solid (36 mg, 54%,
Following general procedure 3, LiHMDS (1.0 M in THF, 0.18 mL,
0.18 mmol), 43 (50 mg, 0.14 mmol), p-bromobenzyl bromide (80 mg,
0.42 mmol) and THF (2 mL) gave 67:72 in 54:46 dr. Purification via
flash column chromatography (silica, gradient elution, 40e60 ꢁC
petrol/Et2O, 20:1; increased to 40e60 ꢁC petrol/Et2O, 5:1) gave 67:72
in 54:46 dr as a colourless oil (48 mg, 65%); nmax (film) 1770 (C]O);
dC (125 MHz, CDCl3) 13.4, 14.1, 37.4, 38.2, 39.7, 40.3, 54.8, 54.9, 63.0,
63.2, 69.8, 69.9, 121.1, 121.2, 127.1, 127.2, 127.5, 127.6, 127.8, 127.9,
128.0, 128.2, 128.6, 128.6, 128.6, 128.7, 129.0, 130.5, 130.9, 131.0, 131.8,
132.2, 132.6, 134.1, 134.1, 134.3, 134.9, 135.7, 136.4, 140.2, 141.0, 174.8,
175.0; m/z (ESIþ) 548 ([MþNa]þ, 79Br, 100%); HRMS (ESIþ)
C31H2879BrNNaOþ2 ([MþNa]þ) requires 548.1196; found 548.1175.
Data for major diastereoisomer: dH (400 MHz, CDCl3) 1.13 (3H, d,
4.30.1. X-ray crystal structure determination for 65. Data were col-
lected using an EnrafeNonius -CCD diffractometer with graphite
monochromated Mo K radiation using standard procedures at
k
a
150 K. The structure was solved by direct methods (SIR92); all non-
hydrogen atoms were refined with anisotropic thermal parameters.
Hydrogen atoms were added at idealised positions. The structure
was refined using CRYSTALS.29
X-ray crystal structure data for 65 [C27H27NO2]: M¼795.03, or-
thorhombic, space group P 21 21 21, a¼9.98060(10) Å, b¼12.3492(2)
Å, c¼35.5508(6) Å, V¼4381.72(11) Å3, Z¼8,
m
¼0.075 mmꢀ1, col-
ourless plate, crystal dimensions¼0.20ꢃ0.20ꢃ0.40 mm3. A total of
5516 unique reflections were measured for 5<q<27 and 3517 re-
J 6.6, C(
a
)Me), 2.19e2.26 (2H, m, 2ꢃC(4)CHA), 3.19e3.30 (2H, m,
flections were used in the refinement. The final parameters were
(I)].
2ꢃC(4)CHB), 3.86 (1H, q, J 6.6, C(
a)H), 4.60 (1H, s, C(3)H), 6.90e7.44
wR2¼0.055 and R1¼0.060 [I>1.5
s
(19H, m, Ph).
Crystallographic data (excluding structure factors) has been de-
posited with the Cambridge Crystallographic Data Centre as sup-
plementary publication number CCDC 747491. Copies of the data can
be obtained, free of charge, on application to CCDC, 12 Union Road,
Cambridge CB2 1EZ, UK [fax: þ44(0)-1223-336033 or e-mail:
deposit@ccdc.cam.ac.uk].
Data for minor diastereoisomer: dH (400 MHz, CDCl3) [selected
peaks] 1.17 (3H, d, J 6.7, C(
a
)Me), 2.42e2.47 (2H, m, 2ꢃC(4)CHA),
3.30e3.38 (2H, m, 2ꢃC(4)CHB), 4.02 (1H, q, J 6.7, C(
a)H), 4.46 (1H, s, C
(3)H).
4.33. (S,S,S)-N(2)-a-Methylbenzyl-3-methyl-4-allyl-
4-benzylisoxazolidin-5-one 68
4.31. (S,S,S)-N(2)-a-Methylbenzyl-3-phenyl-4-benzyl-
4-methallylisoxazolidin-5-one 66
Method A: following general procedure 3, LiHMDS (1.0 M in
THF, 0.81 mL, 0.81 mmol), 9 (200 mg, 0.68 mmol), allyl iodide
(0.19 mL, 2.04 mmol) and THF (5 mL) gave 68:73 in 90:10 dr. Puri-
fication via flash column chromatography (silica, gradient elution,
40e60 ꢁC petrol/Et2O, 20:1; increased to 40e60 ꢁC petrol/Et2O, 5:1)
Following general procedure 3, LiHMDS (1.0 M in THF,
0.41 mL, 0.41 mmol), 43 (100 mg, 0.34 mmol), methallyl bromide
(136 mg, 1.01 mmol) and THF (3 mL) gave 66:71 in 56:44 dr. Pu-
rification via flash column chromatography (silica, gradient elu-
gave 68 as a colourless oil (178 mg, 78%, >99:1 dr); [
a
]
18 þ96.9 (c 1.0
D
in CHCl3); nmax (film) 2979 (CeH), 1767 (C]O); dH (400 MHz, CDCl3)
0.68 (3H, d, J 6.1, C(3)Me), 1.33 (3H, d, J 6.5, C(a)Me), 2.27 (1H, dd, J
14.1, 8.6, C(4)CHAHBCH]CH2), 2.53 (1H, d, J 14.3, C(4)CHAHBPh), 2.72
(1H, dd, J 14.1, 6.1, C(4)CHAHBCH]CH2), 3.21 (1H, q, J 6.1, C(3)H), 3.28
tion, 40e60 ꢁC petrol/Et2O, 25:1; increased to 40e60 ꢁC petrol/
23
Et2O, 15:1) gave 66 as a colourless oil (42 mg, 30%, >99:1); [
a
]
D
þ88.9 (c 1.0 in CHCl3); nmax (film) 1771 (C]O); dH (400 MHz,
CDCl3) 1.10 (3H, d, J 6.8, C(
a
)Me), 1.72 (1H, d, J 13.7, C(10)HA), 1.78
(1H, d, J 14.3, C(4)CHAHBPh), 3.72 (1H, q, J 6.5, C(
m, C(4)CH2CH]CH2), 5.95e6.06 (1H, m, C(4)CH2CH]CH2),
7.26e7.31 (10H, m, Ph); dC (100 MHz, CDCl3) 12.5 (C(3)Me), 18.1 (C(
Me), 36.5 (C(4)CH2), 38.6 (C(4)CH2Ph), 53.5 (C(4)), 64.5 (C(3)), 66.1 (C
)), 107.8 (C(4)CH2CH]CH2), 120.0 (C(4)CH2CH]CH2), 127.6, 127.7,
a)H), 5.18e5.23 (2H,
(3H, s, C(20)Me), 2.44 (1H, d, J 14.2, C(4)CHAHBPh), 2.70 (1H, d, J
13.7, C(10)HB), 3.65 (1H, d, J 14.2, C(4)CHAHBPh), 3.84 (1H, q, J 6.8, C
a)
(a
)H), 4.51 (1H, s, C(3)H), 4.68 (1H, app s, C(30)HA), 4.95 (1H, app s,
C(30)HB), 7.19e7.39 (15H, m, Ph); dC (125 MHz, CDCl3) 14.0 (C(
Me), 23.0 (C(20)Me), 40.0 (C(10)), 40.7 (C(4)CH2Ph), 51.8 (C(4)), 62.9
(C(
)), 70.2 (C(3)), 117.2 (C(30)), 127.0, 127.6, 127.7, 128.1, 128.3,
a
)
(a
128.4, 128.5, 130.1, 132.6 (o-, m-, p-Ph), 136.3, 141.4 (i-Ph), 176.0 (C
(5)); m/z (ESIþ) 394 ([Mþ59]þ, 100%); HRMS (ESIþ) C22H25NNaOþ2
([MþNa]þ) requires 358.1778; found 358.1773.
a
128.5, 128.6, 128.9, 130.8 (o-, m-, p-Ph), 135.0 (C(20)), 140.8, 141.2,
142.3 (i-Ph) 175.0 (C(5)); m/z (ESIþ) 434 ([MþNa]þ, 100%), 412
([MþH]þ, 23%); HRMS (ESIþ) C28H29NNaOþ2 ([MþNa]þ) requires
434.2091; found 434.2098.
Method B: following general procedure 3, LiHMDS (1.0 M in THF,
0.2 mL, 0.2 mmol), 48 (40 mg, 0.16 mmol), benzyl bromide (0.06 mL,
0.48 mmol) and THF (1 mL) gave 68:73 in 67:33 dr. Purification via

4618
S.A. Bentley et al. / Tetrahedron 66 (2010) 4604e4620
flash column chromatography on silica gel (silica, gradient elution,
40e60 ꢁC petrol/Et2O, 20:1; increased to 40e60 ꢁC petrol/Et2O, 5:1)
gave 68 as a colourless oil (25 mg, 47%, >99:1 dr).
4.36. (3S,4R,aS)-N(2)-a-Methylbenzyl-3-methyl-4-allyl-
4-ethylisoxazolidin-5-one 79
4.34. (3S,4R,aS)- and (S,S,S)-N(2)-a-Methylbenzyl-3-methyl-
4-benzyl-4-(p-bromobenzyl)isoxazolidin-5-one 69 and 74
Following general procedure 3, LiHMDS (1.0 M in THF, 0.13 mL,
0.13 mmol), 49 (23 mg, 0.11 mmol), allyl iodide (0.03 mL, 0.33 mmol)
and THF (0.5 mL) gave 79:85 in 69:31 dr. Purification via flash column
chromatography (silica, gradient elution, 40e60 ꢁC petrol/Et2O, 20:1;
increased to 40e60 ꢁC petrol/Et2O, 5:1) gave 79 as a colourless oil
(12 mg, 40%, 92:8 dr); nmax (film) 2935 (CeH), 1766 (C]O); dH
(400 MHz, CDCl3) 0.71 (3H, d, J 5.5, C(3)Me), 0.92 (3H, t, J 7.5, C(4)
CH2CH3), 1.34e1.47 (1H, m, C(4)CHAHBCH3),1.56 (3H, d, J 6.5, C(a)Me),
1.81 (1H, dq, J 14.8, 7.5, C(4)CHAHBCH3), 2.15 (1H, dd, J 14.2, 8.5, C(4)
CHAHBCH]CH2), 2.63 (1H, dd, J 14.2, 6.3, C(4)CHAHBCH]CH2), 3.40
Following general procedure 3, LiHMDS (1.0 M in THF, 0.28 mL,
0.28 mmol), 9 (70 mg, 0.24 mmol), p-bromobenzyl bromide (176 mg,
0.72 mmol) and THF (2 mL) gave 69:74 in 61:39 dr. Purification via
flash column chromatography (silica, gradient elution, 40e60 ꢁC
petrol/Et2O, 20:1; increased to 40e60 ꢁC petrol/Et2O, 5:1) gave 69:74
in 61:39 dr as a colourless oil (20 mg, 18%); nmax (film) 2980 (CeH),
1771 (C]O); dC (125 MHz, CDCl3) 12.2, 12.3, 18.1, 18.8, 37.0, 37.3, 37.7,
37.9, 54.5, 54.6, 64.5, 64.7, 65.9, 66.2, 121.0, 121.2, 127.0, 127.1, 127.6,
127.7, 127.8, 127.9, 128.0, 128.1, 128.5, 128.6, 130.2, 130.7, 131.2, 131.6,
131.9, 131.9, 132.4, 134.5, 135.2, 136.0, 141.1, 141.4, 174.7, 174.9; m/z
(ESIþ) 486 ([MþNa]þ, 79Br, 100%), 464 ([MþH]þ, 79Br, 38%); HRMS
(ESIþ) C26H2679BrNNaOþ2 ([MþNa]þ) requires 486.1039; found
486.1042.
(1H, q, J 5.5, C(3)H), 3.98 (1H, q, J 6.5, C(a)H), 5.09e5.14 (2H, m, C(4)
CH2CH]CH2), 5.83e5.92 (1H, m, C(4)CH2CH]CH2), 7.30e7.39 (5H,
m, Ph); dC (100 MHz, CDCl3) 8.5 (C(4)CH2CH3), 13.0 (C(3)CH2CH3), 19.2
(C(a)Me), 25.1 (CH3CH2), 35.5 (CH2]CHCH2), 52.5 (C(4)), 65.6 (C(3)),
66.8 (C(
a
)), 118.5 (CH2¼CH), 127.8, 127.9, 128.5 (o-, m-, p-Ph), 132.8
(CH2¼CH), (i-Ph), 176.3 (C(5)); m/z (ESIþ) 569 ([2MþNa]þ, 100%), 296
([MþNa]þ, 52%), 274 ([MþH]þ, 30%); HRMS (ESIþ) C17H23NNaOþ2
([MþNa]þ) requires 296.1621; found 296.1622.
Data for major diastereoisomer: dH (500 MHz, CDCl3) 0.81 (3H, d, J
6.3, C(3)Me), 1.32 (3H, d, J 6.5, C(
2.70 (1H, d, J 13.6, C(4)CHC), 3.17e3.19 (1H, m, C(3)H), 3.20 (1H, d, J
14.2, C(4)CHB), 3.30 (1H, d, J 13.6, C(4)CHD), 3.72 (1H, q, J 6.5, C( )H),
a)Me), 2.52 (1H, d, J 14.2, C(4)CHA),
4.37. (3S,4R,aS)-N(2)-a-Methylbenzyl-3-methyl-4-benzyl-
4-ethylisoxazolidin-5-one 80
a
7.10 (2H, d, J 8.2, Ar), 7.18e7.34 (10H, m, Ph), 7.44e7.45 (2H, d, J 8.2, Ar).
Data for minor diastereoisomer: dH (500 MHz, CDCl3) [selected
peaks] 1.39 (3H, d, J 6.6, C(
a)Me), 2.47 (1H, d, J 14.2, C(4)CHA), 2.72
(1H, d, J 13.8, C(4)CHC), 3.09e3.12 (1H, m, C(3)H), 3.16 (1H, d, J 14.2,
C(4)CHB), 3.38 (1H, d, J 13.8, C(4)CHD), 3.79 (1H, q, J 6.6, C(
a)H), 6.95
(2H, d, J, 8.2, Ar), 7.37 (2H, d, J 8.2, Ar).
Following general procedure 3, LiHMDS (1.0 M in THF,
0.13 mL, 0.13 mmol), 49 (25 mg, 0.11 mmol), benzyl bromide
(0.04 mL, 0.33 mmol) and THF (0.5 mL) gave 80:86 in 90:10 dr.
Purification via flash column chromatography (silica, gradient
elution, 40e60 ꢁC petrol/Et2O, 20:1; increased to 40e60 ꢁC petrol/
Et2O, 5:1) gave 80 as a colourless oil (19 mg, 53%, 90:10 dr); nmax
(film) 2928 (CeH), 1765 (C]O); dH (400 MHz, CDCl3) 0.62 (3H, d, J
4.35. (S,S,S)-N(2)-
4-ethylisoxazolidin-5-one 78
a-Methylbenzyl-3,4-dimethyl-
6.3, C(3)Me), 1.09e1.13 (3H, m, C(4)CH2CH3), 1.31 (3H, d, J 6.5, C(a)
Me), 1.54e1.63 (1H, m, C(4)CHAHBCH3), 1.95 (1H, dq, J 14.3, 7.4, C(4)
CHAHBCH3), 2.52 (1H, d, J 13.9, C(4)CHAHBPh), 3.16e3.21 (1H, d, J
6.3, C(3)H), 3.28 (1H, d, J 13.9, C(4)CHAHBPh), 3.67 (1H, q, J 6.5, C(
H), 7.13e7.30 (10H, m, Ph); dC (100 MHz, CDCl3) 8.5 (C(4)CH2CH3),
13.3 (C(3)Me), 19.0 (C( )Me), 27.7 (C(4)CH2CH3), 38.7 (C(4)CH2Ph),
53.7 (C(4)), 64.5 (C(3)), 69.1 (C( )), 127.2, 127.7, 128.1, 128.3, 128.8,
a)
Following general procedure 3, LiHMDS (1.0 M in THF, 0.13 mL,
0.13 mmol), 49 (25 mg, 0.11 mmol), methyl iodide (0.02 mL,
0.33 mmol) and THF (0.5 mL) gave 78:84 in 64:36 dr. Purification via
flash column chromatography (silica, gradient elution, 40e60 ꢁC
petrol/Et2O, 20:1; increased to 40e60 ꢁC petrol/Et2O, 5:1) gave 78 as
a
a
130.3 (o-, m-, p-Ph), 136.9, 140.7 (i-Ph), 175.6 (C(5)); m/z (ESIþ) 669
([2MþNa]þ, 100%), 346 ([MþNa]þ, 70%), 324 ([MþH]þ, 38%); HRMS
(ESIþ) C21H25NNaO2þ ([MþNa]þ) requires 346.1778; found 346.1780.
a colourless oil (10 mg, 38%, >99:1 dr); [
a
]
23 þ48.9 (c 0.5 in CHCl3);
D
nmax (film) 2918 (CeH),1763 (C]O); dH (400 MHz, CDCl3) 0.64 (3H, d,
J 5.7, C(3)Me), 0.95 (3H, t, J 7.4, C(4)CH2CH3), 1.17 (3H, s, C(4)Me),
4.38. (3S,4R,
aS)-N(2)-a-Methylbenzyl-3-phenyl-4-ethyl-
1.44e1.51 (1H, m, C(4)CHA), 1.56 (3H, d, J 6.6, C(
14.5, 7.4, C(4)CHB), 3.28 (1H, q, J 5.7, C(3)H), 3.98 (1H, q, J 6.6, C(
7.28e7.39 (5H, m, Ph); dC (100 MHz, CDCl3) 8.6 (C(4)CH2CH3), 13.2
(C(3)Me), 17.3 (C(4)Me), 19.2 (C( )Me), 27.6 (C(4)CH2), 53.0 (C(4)),
65.6 (C(3)), 70.7 (C(
a)Me), 1.69 (1H, dq, J
4-methylisoxazolidin-5-one 81
a)H),
a
a
)), 127.9, 128.0, 128.6 (o-, m-, p-Ph), 136.0 (i-Ph),
174.5 (C(5)); m/z (ESIþ) 517 ([2MþNa]þ, 100%), 270 ([MþNa]þ, 54%),
248 ([MþH]þ, 21%); HRMS (ESIþ) C15H21NNaOþ2 ([MþNa]þ) requires
270.1454; found 270.1464.

S.A. Bentley et al. / Tetrahedron 66 (2010) 4604e4620
4619
Following general procedure 3, LHMDS (1.0 M in THF, 0.08 mL,
0.08 mmol), 45 (23 mg, 0.08 mmol), methyl iodide (20 L,
H), 4.50 (1H, s, C(3)H), 7.16e7.41 (15H, m, Ph); dC (100 MHz, CDCl3)
m
8.2 (C(4)CH2CH3), 18.1 (C(a)Me), 27.4 (C(4)CH2CH3), 38.3 (C(4)
0.21 mmol) and THF (0.5 mL) gave 75:81 in 42:58 dr. Purification
via flash column chromatography (silica, gradient elution,
40e60 ꢁC petrol/Et2O, 20:1; increased to 40e60 ꢁC petrol/Et2O, 5:1)
CH2Ph), 54.8 (C(4)), 63.1 (C(
a)), 69.8 (C(3)), 127.1, 127.3, 127.7, 128.1,
128.4, 128.5, 128.8, 130.5 (o-, m-, p-Ph), 134.9, 137.0, 141.2 (i-Ph), 176.5
(C(5)); m/z (ESIþ) 408 ([MþNa]þ, 100%), 386 ([MþH]þ, 52%); HRMS
(ESIþ) C26H27NNaO2þ ([MþNa]þ) requires 408.1934; found 408.1929.
gave 81 as a colourless oil (6 mg, 25%, >99:1 dr); [
a]
24 þ69.1 (c 0.4
D
in CHCl3); nmax (film) 2977 (CeH),1767 (C]O); dH (400 MHz, CDCl3)
0.81 (3H, t, J 7.5, C(4)CH2CH3), 1.25 (3H, s, C(4)Me), 1.49 (3H, d, J 6.6,
4.41. (S,S)-2-Benzyl-2-methyl-3-amino-3-phenylpropanoic
acid 87
C(
4.13 (1H, q, J 6.6, C(
dC (125 MHz, CDCl3) 8.0 (C(4)CH2CH3), 17.1 (C(
25.4 (C(4)CH2), 49.3 (C(4)), 62.7 (C( )), 73.0 (C(3)), 127.5, 127.8,
a
)Me), 0.92e1.00 (1H, m, C(4)CHA), 1.86e1.95 (1H, m, C(4)CHB),
)H), 4.32 (3H, s, C(3)H), 7.11e7.36 (10H, m, Ph);
)Me), 18.7 (C(4)Me),
a
a
a
128.1, 128.2, 128.4, 128.6 (o-, m-, p-Ph), 134.0, 141.2 (i-Ph), 177.1 (C
(5)); m/z (ESIþ) 332 ([MþNa]þ, 42%), 310 ([MþH]þ, 15%); HRMS
(ESIþ) C20H23NNaO2þ ([MþNa]þ) requires 332.1621; found 332.1626.
Following general procedure 4, 53 (45 mg, 0.12 mmol), Pearl-
4.39. (S,S,S)-N(2)-a-Methylbenzyl-3-phenyl-4-allyl-
4-ethylisoxazolidin-5-one 82
man’s catalyst (23 mg) and tert-butanol (1 mL) gave 87 as a white
powder (29 mg, 90%, >99:1 dr); mp 168e170 ꢁC; [
a
]
25 ꢀ26.9 (c 1.0 in
D
MeOH); nmax (KBr) 3320 (NHþ3 st),1646 (COOꢀ as st),1454 (NH2þ
d
); dH
(400 MHz, CD3OD) 0.83 (3H, s, C(2)Me), 2.35 (1H, d, J 12.9, C(2)
CHAHBPh), 3.31 (1H, d, J 12.9, C(2)CHAHBPh), 4.20 (1H, s, C(3)H),
7.10e7.40 (10H, m, Ph); dC (100 MHz, CD3OD) 17.0 (C(2)Me),
44.6 (C(2)CH2Ph), 52.4 (C(2)), 63.2 (C(3)), 126.2, 127.8, 127.9,
128.2, 128.7, 130.5 (o-, m-, p-Ph), 138.8, 140.8 (i-Ph), 182.8 (C(1));
m/z (ESIþ) 292 ([MþNa]þ, 73%), 270 ([MþH]þ, 100%); HRMS (ESIþ)
C17H20NOþ2 ([MþH]þ) requires 270.1489; found 270.1487.
Following general procedure 3, LiHMDS (1.0 M in THF, 0.08 mL,
0.08 mmol), 45 (23 mg, 0.07 mmol), allyl iodide (30 mL, 0.21 mmol)
4.42. (S,S)-2-Benzyl-2-propyl-3-amino-3-phenylpropanoic
acid 89
and THF (0.5 mL) gave 77% conversion to 76:82 in 22:78 dr. Purifi-
cation via flash column chromatography (silica, gradient elution,
40e60 ꢁC petrol/Et2O, 20:1; increased to 40e60 ꢁC petrol/Et2O, 5:1)
gave 82 as a colourless oil (13 mg, 67%, 93:7 dr); [
CHCl3); nmax (film) 2975 (CeH), 1768 (C]O); dH (400 MHz, CDCl3)
0.83 (3H, t, J 7.5, C(4)CH2CH3),1.00e1.09 (1H, m, C(4)CHAHBCH3), 1.46
a
]
24 þ44.3 (c 0.5 in
D
(3H, d, J 6.7, C(
14.0, 10.7, C(4)CHAHBCH]CH2), 2.74 (1H, dd, J 14.0, 4.6, C(4)
CHAHBCH]CH2), 4.12 (1H, q, J 6.7, C( )H), 4.69 (1H, s, C(3)H), 5.29 (2H,
app d, J 13.4, C(4)CH2CH]CH2), 5.74e5.84 (1H, m, C(4)CH2CH]CH2),
7.21e7.34 (10H, m, Ph); dC (100 MHz) 8.0 (C(4)CH2CH3),13.9 (C( )Me),
25.3 (C(4)CH2CH3), 36.0 (C(4)CH2CH]CH2) 52.9 (C(4)), 62.9 (C( )),
71.3 (C(3)), 119.9 (C(4)CH2CH]CH2), 127.5, 127.9, 128.3, 128.4, 133.7,
134.5 (o-, m-, p-Ph),133.7 (C(4)CH2CH]CH2), 141.2, 143.4 (i-Ph),175.9
(C(5)); m/z (ESIþ) 693 ([2MþNa]þ, 100%), 358 ([MþNa]þ, 33%), 336
([MþH]þ, 21%); HRMS (ESIþ) C22H25NNaOþ2 ([MþNa]þ) requires
358.1778; found 358.1776.
a)Me),1.83e1.92 (1H, m, C(4)CHAHBCH3), 2.04 (1H, dd, J
Following general procedure 4, 65 (50 mg, 0.14 mmol), Pearl-
man’s catalyst (25 mg) and tert-butanol (3 mL) gave 89 as a white
a
powder (35 mg, 96%, >99:1 dr); mp 150e152 ꢁC; [
a]
D
25 ꢀ25.3 (c 1.0 in
a
MeOH); nmax (KBr) 3418 (NH3þ st), 1644 (COOꢀ as st); dH (400 MHz,
D2O) 0.59 (3H, t, J 7.2, C(2)CH2CH2CH3), 0.77e0.85 (1H, m, C(2)
CHAHBCH2CH3), 1.00e1.08 (1H, m, C(2)CHAHBCH2CH3), 1.28e1.41
(2H, m, C(2)CH2CH2CH3), 2.79 (1H, d, J 13.4, C(2)CHAHBPh), 3.18 (1H,
d, J 13.4, C(2)CHAHBPh), 4.22 (1H, s, C(3)H), 7.15e7.28 (10H, m, Ph); dC
(100 MHz, D2O) 14.0 (C(2)CH2CH2CH3), 16.3 (C(2)CH2CH2CH3), 33.2
(C(2)CH2CH2CH3), 39.4 (C(2)CH2Ph), 54.3 (C(2)), 59.4 (C(3)), 126.9,
128.0, 128.7, 128.8, 129.0, 130.2 (o-, m-, p-Ph), 138.2, 147.4 (i-Ph), 182.2
(C(1)); m/z (ESIꢀ) 296 ([MꢀH]ꢀ, 100%); HRMS (ESIꢀ) C19H22NOꢀ2
([MꢀH]ꢀ) requires 296.1656; found 296.1656.
a
4.40. (S,S,S)-N(2)-a-Methylbenzyl-3-phenyl-4-benzyl-
4-ethylisoxazolidin-5-one 83
4.43. (S,S)-2-Methyl-2-propyl-3-amino-3-phenylpropanoic
acid 90
Following general procedure 3, LiHMDS (1.0 M in THF, 0.08 mL,
0.08 mmol), 45 (23 mg, 0.07 mmol), benzyl bromide (40 mL,
0.21 mmol) and THF (0.5 mL) gave 77:83 in 21:79 dr. Purification via
flash column chromatography (silica, gradient elution, 40e60 ꢁC
petrol/Et2O, 20:1; increased to 40e60 ꢁC petrol/Et2O, 5:1) gave 83 as
Following general procedure 4, 52 (80 mg, 0.25 mmol), Pearl-
man’s catalyst (40 mg) and tert-butanol (3 mL) gave 90 as a white
a colourless oil (20 mg, 55%, >99:1 dr); [
a
]
24 þ55.4 (c 1.0 in CHCl3);
powder (43 mg, 78%, >99:1 dr); mp 144e146 ꢁC; [
a]
D
25 ꢀ29.0 (c 1.0 in
D
nmax (film) 2950 (CeH),1770 (C]O); dH (400 MHz, CDCl3) 0.94 (3H, t,
MeOH); nmax (KBr) 3385 (NHþ2 st),1644 (COOꢀ as st),1456 (NH3þ
d
); dH
J 7.6, C(4)CH2CH3), 1.10 (3H, d, J 6.7, C(
CHAHBCH3), 1.83e1.89 (1H, m, C(4)CHAHBCH3), 2.45 (1H, d, J 14.2, C
(4)CHAHBPh), 3.54 (1H, d, J 14.2, C(4)CHAHBPh), 3.80 (1H, q, J 6.7, C(
a
)Me), 1.17e1.25 (1H, m, C(4)
(500 MHz, CD3OD) 0.94 (3H, s, C(2)Me), 0.94 (3H, t, J 6.9, C(2)
CH2CH2CH3), 1.35e1.41 (1H, m, CH2), 1.43e1.53 (2H, m, CH2),
1.65e1.71 (1H, m, CH2), 4.21 (1H, s, C(3)H), 7.40e7.44 (5H, m, Ph); dC
a)

4620
S.A. Bentley et al. / Tetrahedron 66 (2010) 4604e4620
Smith, A. D.; Thomson, J. E. Tetrahedron: Asymmetry 2007, 18, 2510; Abraham, E.;
Davies, S. G.; Millican, N. L.; Nicholson, R. L.; Roberts, P. M.; Smith, A. D. Org.
Biomol. Chem. 2008, 6, 1655; Abraham, E.; Brock, E. A.; Candela-Lena, J. I.;
Davies, S. G.; Georgiou, M.; Nicholson, R. L.; Perkins, J. H.; Roberts, P. M.; Russell,
A. J.; Sánchez-Fernández, E. M.; Scott, P. M.; Smith, A. D.; Thomson, J. E. Org.
Biomol. Chem. 2008, 6, 1665; Davies, S. G.; Fletcher, A. M.; Roberts, P. M.; Smith,
A. D. Tetrahedron 2009, 65, 10192.
(125 MHz, CD3OD) 14.9 (C(2)CH2CH2CH3), 19.0 (C(2)CH2CH2CH3),
20.3 (C(2)Me), 41.9 (C(2)CH2CH2CH3), 49.5 (C(2)), 62.2 (C(3)), 129.4,
129.9, 130.0 (o-, m-, p-Ph), 137.6 (i-Ph), 182.0 (C(1)); m/z (ESIþ) 465
([2MþNa]þ, 100%), 244 ([MþNa]þ, 58%), 222 ([MþH]þ, 41%); HRMS
(ESIþ) C13H19NNaO2þ ([MþNa]þ) requires 244.1308; found 244.1305.
8. For selected examples from this laboratory, see: Davies, S. G.; Hermann, G. J.;
Sweet, M. J.; Smith, A. D. Chem. Commun. 2004, 1128; Cailleau, T.; Cooke, J. W.
B.; Davies, S. G.; Ling, K. B.; Naylor, A.; Nicholson, R. L.; Price, P. D.; Roberts, P.
M.; Russell, A. J.; Smith, A. D.; Thomson, J. E. Org. Biomol. Chem. 2007, 5, 3922;
Davies, S. G.; Durbin, M. J.; Goddard, E. C.; Kelly, P. M.; Kurosawa, W.; Lee, J. A.;
Nicholson, R. L.; Price, P. D.; Roberts, P. M.; Russell, A. J.; Scott, P. M.; Smith, A. D.
Org. Biomol. Chem. 2009, 7, 761.
4.44. (S,S)-2-Benzyl-2-methyl-3-aminobutanoic acid 91
9. For selected examples from this laboratory, see: Davies, S. G.; Garner, A. C.;
Long, M. J. C.; Morrison, R. M.; Roberts, P. M.; Smith, A. D.; Sweet, M. J.; Withey,
J. M. Org. Biomol. Chem. 2005, 3, 2762; Aye, Y.; Davies, S. G.; Garner, A. C.;
Roberts, P. M.; Smith, A. D.; Thomson, J. E. Org. Biomol. Chem. 2008, 6, 2195;
Abraham, E.; Davies, S. G.; Docherty, A. J.; Ling, K. B.; Roberts, P. M.; Russell, A. J.;
Thomson, J. E.; Toms, S. M. Tetrahedron: Asymmetry 2008, 19, 1356; Davies, S. G.;
Durbin, M. J.; Hartman, S. J. S.; Matsuno, A.; Roberts, P. M.; Russell, A. J.; Smith,
A. D.; Thomson, J. E.; Toms, S. M. Tetrahedron: Asymmetry 2008, 19, 2870.
10. Davies, S. G.; Smith, A. D.; Price, P. D. Tetrahedron: Asymmetry 2005, 16, 2833.
11. Bew, S. P.; Hughes, D. L.; Savic, V.; Soapi, K. M.; Wilson, M. A. Chem. Commun.
2006, 3513.
Following general procedure 4, 57 (22 mg, 0.07 mmol), Pearl-
man’s catalyst (11 mg) and tert-butanol (1 mL) gave 91 as a white
powder (13 mg, 90%, >99:1 dr); mp 184e186 ꢁC; [
a]
D
25 ꢀ17.6 (c 0.5 in
MeOH); nmax (KBr) 3443 (NH3þ st), 1643 (COOꢀ as st); dH (400 MHz,
D2O) 1.11 (3H, d, J 6.8, C(4)H3), 1.81 (3H, s, C(2)Me), 2.58 (1H, d, J 13.1,
C(2)CHAHBPh), 2.87 (1H, d, J 13.1, C(2)CHAHBPh), 3.12 (1H, q, J 6.8, C
(3)H), 7.09e7.23 (5H, m, Ph); dC (100 MHz, D2O) 15.4 (C(2)Me), 16.7
(C(2)), 44.4 (C(2)CH2Ph), 51.9 (C(2)), 59.3 (C(3)), 128.6,130.3,131.2 (o-
, m-, p-Ph),138.3 (i-Ph),183.2 (C(1)); m/z (ESIþ) 230 ([MþNa]þ,100%),
208 ([MþH]þ, 41%); HRMS (ESIþ) C12H17NNaOþ2 ([MþNa]þ) requires
230.1151; found 230.1152.
12. (a) da Costa, M. R. G.; Curto, M. J. M.; Davies, S. G.; Sanders, J.; Teixeira, F. C. J. Chem.
Soc., Perkin Trans. 2 2001, 2850; (b) Davies, S. G.; Goodwin, C. J.; Hepworth, D.;
Roberts, P. M.; Thomson, J. E. J. Org. Chem. 2010, 75, 1214.
13. Tokuyama, H.; Kuboyama, T.; Amano, A.; Yamashita, T.; Fukuyama, T. Synthesis
2000, 1299.
14. The enantiomeric excess of 20 was determined by 1H NMR spectroscopic
analysis in the presence of (S)-O-acetylmandelic acid as a chiral shift reagent,
and comparison with an authentic racemic sample.
15. Lambert, J. B.; Takeuchi, Y. In Acyclic Organonitrogen Stereodynamics; Marchand,
A. P., Ed.; Wiley-VCH: Germany, 1992.
4.45. (S,S)-2-Benzyl-2-propyl-3-aminobutanoic acid 92
16. Costello, J. F.; Davies, S. G.; Ichihara, O. Tetrahedron: Asymmetry 1994, 5, 3919.
17. Davies, S. G.; Fenwick, D. R. J. Chem. Soc., Chem. Commun. 1995, 109; Davies, S. G.;
Hedgecock, C. J. R.; McKenna, J. M. Tetrahedron: Asymmetry 1995, 6, 827; Davies,
S. G.; Hedgecock, C. J. R.; McKenna, J. M. Tetrahedron: Asymmetry 1995, 6, 2507;
Davies, S. G.; Fenwick, D. R. Chem. Commun. 1997, 565; Davies, S. G.; Fenwick, D.
R.; Ichihara, O. Tetrahedron: Asymmetry 1997, 8, 3387.
18. Davies, S. G.; Polywka, M. E. C.; Fenwick, D. R.; Reed, F. WO Patent 9518134 A1.
19. Smith, A. B., III; Ott, G. R. J. Am. Chem. Soc. 1996, 118, 13095.
20. Bou, V.; Vilarrasa, J. Tetrahedron Lett. 1990, 36, 9479.
Following general procedure 4, 67 (20 mg, 0.05 mmol), Pearl-
21. Farras, J.; Serra, C.; Vilarrasa, J. Tetrahedron Lett. 1998, 39, 327.
22. Prakesh, C.; Salah, S.; Blair, I. A. Tetrahedron Lett. 1989, 30, 19.
23. BF3 was also tested and although resulted in efficient reaction on a small scale,
results on scale-up were capricious.
man’s catalyst (10 mg) and tert-butanol (1 mL) gave 92 as a white
powder (10 mg, 86%, >99:1 dr); mp 156e158 ꢁC; [
a]
D
25 ꢀ23.4 (c 0.5 in
MeOH); nmax (KBr) 3424 (NH3þ st), 1643 (COOꢀ as st); dH (400 MHz,
D2O) 0.75 (3H, t, J 6.8, C(2)CH2CH2CH3), 1.13 (3H, d, J 6.8, C(4)H3),
1.16e1.21 (2H, m, CH2), 1.26e1.39 (2H, m, CH2), 2.77 (1H, d, J 13.4, C
(2)CHAHBPh), 2.88 (1H, d, J 13.4, C(2)CHAHBPh), 3.30 (1H, q, J 6.8, C(3)
H), 7.08e7.24 (5H, m, Ph); dC (100 MHz, D2O) 14.3 (C(2)CH2CH2CH3),
15.1 (C(2)CH2CH2CH3), 16.4 (C(4)), 33.3 (C(2)CH2CH2CH3), 39.3 (C(2)
CH2Ph), 51.3 (C(2)), 53.1 (C(3)), 127.1, 128.8, 130.1 (o-, m-, p-Ph), 138.0
(i-Ph), 182.3 (C(1)); m/z (ESIꢀ) 234 ([MꢀH]ꢀ, 100%); HRMS (ESIꢀ)
C14H20NOꢀ2 ([MꢀH]ꢀ) requires 234.1500; found 234.1499.
24. We have reported that LiTMP efficiently promotes the monoalkylation re-
actions of 4-aminolactams, see: Davies, S. G.; Garner, A. C.; Goddard, E. C.;
Kruchinin, D.; Roberts, P. M.; Smith, A. D.; Rodriguez-Solla, H.; Thomson, J. E.;
Toms, S. M. Org. Biomol. Chem. 2007, 5, 1961.
25. 1H NMR NOE analysis of 51 (68:32 dr) was not possible due to peak overlap in
a range of solvents.
26. Tomioka, K.; Kawasaki, H.; Yasuda, K.; Koga, K. J. Am. Chem. Soc. 1988, 110, 3597;
Moritani, Y.; Fukushima, C.; Ogiku, T.; Ukita, T.; Miyagishima, T.; Iwasaki, T.
Tetrahedron Lett. 1993, 34, 2787.
27. Bull, S. D.; Davies, S. G.; Fox, D. J.; Garner, A. C.; Sellers, T. G. R. Pure Appl. Chem.
1998, 70, 1501; Bull, S. D.; Davies, S. G.; Fox, D. J.; Sellers, T. G. R. Tetrahedron:
Asymmetry 1998, 9, 1483; Bull, S. D.; Davies, S. G.; Epstein, S. W.; Ouzman, J. V. A.
Chem. Commun. 1998, 659; Bull, S. D.; Davies, S. G.; Epstein, S. W.; Leech, M. A.;
Ouzman, J. V. A. J. Chem. Soc., Perkin Trans. 1 1998, 2321; Bull, S. D.; Davies, S. G.;
Garner, A. C.; Mujtaba, N. Synlett 2001, 781; Bull, S. D.; Davies, S. G.; Garner, A.
C.; O’Shea, M. D. J. Chem. Soc., Perkin Trans. 1 2001, 3281; Sibi, M. P.; Venka-
traman, L.; Liu, M.; Jasperse, C. P. J. Am. Chem. Soc. 2001, 123, 8444; Quaranta, L.;
Corminboeuf, O.; Renaud, P. Org. Lett. 2002, 4, 39; Corminboeuf, O.; Quaranta,
L.; Renaud, P.; Liu, M.; Jasperse, C. P.; Sibi, M. P. Chem.dEur. J. 2003, 9, 29;
Malkov, A. V.; Hand, J. B.; Kocovsky, P. Chem. Commun. 2003, 1948; Hitchcock, S.
R.; Casper, D. M.; Vaughn, J. F.; Finefield, J. M.; Ferrence, G. M.; Esken, J. M. J. Org.
Chem. 2004, 69, 714; Sibi, M. P.; Stanley, L. M. Tetrahedron: Asymmetry 2004, 15,
3353; Sibi, M. P.; Prabagaran, N. Synlett 2004, 2421; Clayden, J.; Vassiliou, N.
Org. Biomol. Chem. 2006, 4, 2667; Parrott, R. W., II; Hitchcock, S. R. Tetrahedron:
Asymmetry 2007, 18, 377; Bull, S. D.; Davies, S. G.; Epstein, S. W.; Garner, A. C.;
Mujtaba, N.; Roberts, P. M.; Savory, E. D.; Smith, A. D.; Tamayo, J. A.; Watkin, D. J.
Tetrahedron 2006, 62, 7911; Bull, S. D.; Davies, S. G.; Garner, A. C.; Parkes, A. L.;
Roberts, P. M.; Sellers, T. G. R.; Smith, A. D.; Tamayo, J. A.; Thomson, J. E.; Vickers,
R. J. New J. Chem. 2007, 31, 486.
References and notes
1. Cao, X.; Iqbal, A.; Patel, A.; Gretz, P.; Huang, G.; Crowder, M.; Day, R. A. Biochem.
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Krajewska, U.; Studzian, K.; Janecka, A. Bioorg. Med. Chem. Lett. 2006, 16, 1430.
2. Brown, J. M.; Davies, S. G. Nature 1989, 631.
3. Shindo, M.; Ohtsuki, K.; Shishido, K. Tetrahedron: Asymmetry 2005, 16, 2821.
4. Luisi, R.; Capriati, V.; Florio, S.; Vista, T. J. Org. Chem. 2003, 68, 9861.
5. (a) Ishikawa, T.; Nagai, K.; Kudoh, T.; Saito, S. Synlett 1995, 1171; (b) Sibi, M. P.;
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Jasperse, C. P. J. Am. Chem. Soc. 2003, 125, 11796.
6. Davies, S. G.; Ichihara, O. Tetrahedron: Asymmetry 1991, 2, 183; Davies, S. G.;
Garrido, N. M.; Kruchinin, D.; Ichihara, O.; Kotchie, L. J.; Price, P. D.; Price
Mortimer, A. J.; Russell, A. J.; Smith, A. D. Tetrahedron: Asymmetry 2006, 17, 1793.
7. For selected examples from this laboratory, see: Davies, S. G.; Kelly, R. J.; Price
Mortimer, A. J. Chem. Commun. 2003, 2132; Davies, S. G.; Burke, A. J.; Garner, A.
C.; McCarthy, T. D.; Roberts, P. M.; Smith, A. D.; Rodriguez-Solla, H.; Vickers, R. J.
Org. Biomol. Chem. 2004, 2, 1387; Davies, S. G.; Haggitt, J. R.; Ichihara, O.; Kelly,
R. J.; Leech, M. A.; Price Mortimer, A. J.; Roberts, P. M.; Smith, A. D. Org. Biomol.
Chem. 2004, 2, 2630; Abraham, E.; Candela-Lena, J. I.; Davies, S. G.; Georgiou,
M.; Nicholson, R. L.; Roberts, P. M.; Russell, A. J.; Sánchez-Fernández, E. M.;
28. Pangborn, A. B.; Giardello, M. A.; Grubbs, R. H.; Rosen, R. K.; Timmers, F. J.
Organometallics 1996, 15, 1518.
29. Betteridge, P. W.; Carruthers, J. R.; Cooper, R. I.; Prout, C. K.; Watkin, D. J. CRYS-
TALS; Chemical Crystallography Laboratory, University of Oxford: UK, 2001.