Doubly diastereoselective conjugate addition of enantiopure lithium amides to enantiopure N-enoyl oxazolidin-2-ones: A mechanistic probe

Article abstract of DOI:10.1016/j.tetasy.2010.03.033

The doubly diastereoselective conjugate addition of the antipodes of lithium N-benzyl-N-(α-methylbenzyl)amide to a range of enantiopure N-enoyl oxazolidin-2-ones has been used as a mechanistic probe to determine that the reactive conformation is the anti-s-cis form. The β-amino carbonyl products resulting from these conjugate addition reactions are useful templates for further elaboration into an α,β,α-pseudotripeptide.

Full text of DOI:10.1016/j.tetasy.2010.03.033

Tetrahedron: Asymmetry 21 (2010) 1635–1648
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Tetrahedron: Asymmetry
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Doubly diastereoselective conjugate addition of enantiopure lithium
amides to enantiopure N-enoyl oxazolidin-2-ones: a mechanistic probe
*
Stephen G. Davies , Ai M. Fletcher, Gesine J. Hermann, Giovanna Poce, Paul M. Roberts, Andrew D. Smith,
Miles J. Sweet, James E. Thomson
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:
The doubly diastereoselective conjugate addition of the antipodes of lithium N-benzyl-N-(a-methylben-
zyl)amide to a range of enantiopure N-enoyl oxazolidin-2-ones has been used as a mechanistic probe to
determine that the reactive conformation is the anti-s-cis form. The b-amino carbonyl products resulting
Received 15 March 2010
Accepted 26 March 2010
Available online 3 May 2010
from these conjugate addition reactions are useful templates for further elaboration into an
pseudotripeptide.
a,b,a-
Dedicated to Professor Henri Kagan on the
occasion of his 80th birthday
Ó 2010 Elsevier Ltd. All rights reserved.
1. Introduction
conformation 3B has been proposed to account for the reversal
of selectivity noted in TMSI-promoted additions of monoorgano-
cuprates,6 and a similar reversal of selectivity has been reported
in conjugate addition reactions promoted by Et2AlCl and TiCl4.7
The conjugate addition of nucleophiles other than copper-based
species to N-enoyl oxazolidin-2-ones 3 has been less widely ex-
plored8,9 (Scheme 1).
The conjugate addition of nucleophiles to
a,b-unsaturated
carbonyl compounds plays a fundamental role in the stereoselec-
tive formation of b-functionalised carbonyl compounds. Stereo-
control in these reactions has been achieved by the use of
chiral nucleophiles (‘donors’), chiral
a,b-unsaturated carbonyl
compounds (‘acceptors’) and chiral catalysts.1,2 Within this arena,
the diastereoselective conjugate addition of organocuprates to N-
enoyl derivatives of oxazolidin-2-one chiral auxiliaries (e.g., 1)
has been used extensively, with Lewis acids traditionally em-
ployed to facilitate reactivity.3 It is possible for an N-enoyl oxa-
zolidine-2-one derivative to undergo diastereoselective 1,4-
addition via any of the four possible syn- or anti- and s-cis or
s-trans conformations 3A–3D. An intriguing mechanistic dichot-
omy exists in this system, since the expected favoured nucleo-
philic attack on the face of the double bond opposite to the
C(4)-stereodirecting group of the oxazolidin-2-one scaffold in
either the syn-s-cis 3A or the anti-s-trans 3C conformation leads
to the same stereochemical result; the same argument may be
applied to the anti-s-cis 3B or the syn-s-trans 3D pair of conform-
ers. In single asymmetric transformations an assessment of the
product distribution does not therefore allow conclusive deter-
mination of the reactive conformation of these systems. It has
been proposed however that the diastereoselective conjugate
addition of organocuprates occurs preferentially via the (Lewis
acid chelated) syn-s-cis conformation 3A,4 with the reaction dia-
stereoselectivity postulated to reflect the populations of the reac-
tive conformers of these substrates;5 however, the anti-s-cis
We have demonstrated extensively that the conjugate addition
of secondary lithium amides such as lithium N-benzyl-N-
(a-methylbenzyl)amide 4 to a,b-unsaturated esters and amides
represents a versatile and efficient method for the preparation
of b-amino esters and b-amino amides and their derivatives.10
This methodology has found numerous synthetic applications,
including the total synthesis of natural products,11 molecular
recognition phenomena12 and resolution protocols.13 We envis-
aged that this reaction protocol could be extended to encompass
N-enoyl oxazolidin-2-ones 3 as chiral
a,b-unsaturated carbonyl
components. In addition to these synthetic studies, it was antici-
pated that an evaluation of the levels of double asymmetric
induction14 displayed upon conjugate addition of enantiopure
lithium N-benzyl-N-(a-methylbenzyl)amide 4 to a chiral N-enoyl
oxazolidin-2-one 3 might serve as a tool with which to examine
the reactive conformation of the oxazolidinone systems, given
the established requirement for lithium amides to add to (E)-
a
,b-unsaturated esters and amides exclusively in the s-cis confor-
mation,15 conjugate addition to an N-enoyl oxazolidin-2-one 3
may be expected to occur only via either the syn- or anti-s-cis
conformation 3A or 3B, respectively. Furthermore, elaboration of
the conjugate addition products 5 would facilitate the preparation
of a series of
2-one auxiliary as a latent
a
,b-pseudopeptides 6 by unmasking the oxazolidin-
-amino acid. The results of these
a
studies are delineated herein; part of this work has been commu-
* Corresponding author.
E-mail address: steve.davies@chem.ox.ac.uk (S.G. Davies).
nicated previously16 (Fig. 1).
0957-4166/$ - see front matter Ó 2010 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetasy.2010.03.033

1636
S. G. Davies et al. / Tetrahedron: Asymmetry 21 (2010) 1635–1648
O
O
O
Me
O
(i)
Ph
N
O
Ph
N
O
Ph
1
Ph
2, 95%, >95:5 dr
R'
R'
O
O
O
O
O
O
R'
N
O
O
N
O
O
N
O
N
O
R'
R
R
R
R
syn-s-cis 3A
anti-s-cis 3B
anti -s-trans 3C
syn-s-trans 3D
Scheme 1. Reagents and conditions: (i) CuBrꢀDMS, MeMgBr, BF3ꢀEt2O, DMS, THF, ꢁ40 °C to rt.
Ph
Ph
Ph
N
Li
O
O
O
NH2
O
R
Ph
N
O
4
R'
N
O
R'
N
H
CO2H
R'
N
O
conjugate
addition of
R
an enantiopure
lithium amide
R
3
5
α,β-pseudopeptides 6
Figure 1. Conjugate addition of the antipodes of lithium N-benzyl-N-(
a
-methylbenzyl)amide 4 to enantiopure N-enoyl oxazolidin-2-ones 3 as a mechanistic probe, and
elaboration of the 1,4-addition products 5 to a,b-pseudopeptides 6.
The configurations at C(30) within N-30-aminoacyl oxazolidin-2-
ones 12–16 were established unambiguously by a separate chem-
ical synthesis in each case. The b-amino esters 22–24 obtained
from the conjugate addition of lithium amide (S)-4 to the corre-
2. Results and discussion
2.1. Conjugate addition of lithium amides to N-enoyl
oxazolidin-2-ones
sponding
a,b-unsaturated tert-butyl esters were treated with TFA
to give the corresponding carboxylic acids which were coupled
with (S)-4-benzyl- and (S)-4-phenyl-oxazolidin-2-ones 25 and 26
to give 12–16. The spectroscopic properties, including specific
rotation values, of the samples of 12–16 prepared in this manner
were identical to the major diastereoisomers arising from the
conjugate addition of lithium amide (S)-4 to the N-enoyl oxazoli-
din-2-ones 7–11, providing unequivocal evidence of the sense of
stereoinduction observed in these reaction pairings (Scheme 3).
The conjugate addition reaction of the enantiomeric lithium
amide (R)-4 to N-enoyl oxazolidin-2-ones 7–11 under identical
reaction conditions furnished 1,4-addition products 27–36 exclu-
sively although with only modest levels of diastereoselectivity
The conjugate addition of lithium (S)-N-benzyl-N-(
a
-methyl-
benzyl)amide (S)-4 to a range of N-enoyl (S)-4-benzyl- and (S)-4-
phenyl-oxazolidin-2-ones 7–11 proceeded with excellent levels
of diastereoselectivity (P94:6 dr) to furnish 12–16 as the major
products. Initial attempts to purify 12–16 proved difficult, as it
was found that a retro conjugate addition reaction to return the
corresponding starting materials occurred readily on extended
exposure to silica gel. Nevertheless, filtration through a pad of
silica gave mixtures of diastereoisomers 12–21 in P72% yield, with
further purification by crystallisation or chromatography giving
access to the major diastereoisomers 12–16 in >99:1 dr and in
moderate to good isolated yields (Scheme 2).
Ph
Ph
O
O
O
O
Ph
N
O
Ph
N
O
(i)
R'
N
O
+
R'
N
O
R'
N
O
R
R
R
7-11
Major diastereoisomer
Minor diastereoisomer
12-16
17-21
R
R'
dra
yield %b
7
8
9
Ph Ph
Ph Me
12:17, 96:4
13:18, 95:5
79 (64)
75 (53)
(84)
Bn Ph 14:19, >99:1
10 Bn Me
11 Bn iPr
15:20, 96:4
16:21, 94:6
73 (51)
72 (51)
Scheme 2. Reagents and conditions: (i) lithium (S)-N-benzyl-N-(
a
-methylbenzyl)amide (S)-4, THF, ꢁ78 °C, 2 h [a Diastereoisomeric ratios determined by 1H NMR analysis of
the crude reaction mixture. b Isolated yield of purified mixture of diastereoisomers after chromatography (isolated yield of major diastereoisomer, in >99:1 dr, after further
purification)].

S. G. Davies et al. / Tetrahedron: Asymmetry 21 (2010) 1635–1648
1637
Ph
Ph
O
O
Ph
Ph
O
O
Ph
N
O
Ph
N
O
(i)
(i)
HN
R
O
HN
R
O
Ph
N
Ph
N
then (ii)
or (iii)
R'
N
O
then (ii)
or (iii)
R'
N
O
CO2tBu
CO2tBu
R'
R'
or (iv)
25, R = Ph
25, R = Ph
22, R' = Ph, >99:1 dr
23, R' = Me, >99:1 dr
24, R' = iPr, >99:1 dr
R
22, R' = Ph, >99:1 dr
23, R' = Me, >99:1 dr
24, R' = iPr, >99:1 dr
R
26, R = Bn
26, R = Bn
12-16
27-31
product yield %
product yield %
R
R' method
R
R' method
22 Ph Ph
23 Me Ph
22 Ph Bn
23 Me Bn
24 iPr Bn
(i), (ii)
(i), (ii)
(i), (iii)
(i), (iii)
(i), (iii)
12
13
14
15
16
48
26
90
56
59
22 Ph Ph
23 Me Ph
22 Ph Bn
23 Me Bn
24 iPr Bn
(i), (ii)
(i), (ii)
(i), (iii)
(i), (iii)
(i), (iv)
27
28
29
30
31
25
31
34
22
43
Scheme 3. Reagents and conditions: (i) TFA, CH2Cl2, rt, 2 h; (ii) (COCl)2, DMF, Et3N,
CH2Cl2, 0 °C to rt, 1 h, then 25, BuLi, THF, ꢁ78 °C to rt, 3 h; (iii) pivaloyl chloride,
Et3N, ꢁ30 °C, 2 h, then 26, LiCl, THF, ꢁ30 °C to rt, 12 h.
Scheme 5. Reagents and conditions: (i) TFA, CH2Cl2, rt, 2 h; (ii) (COCl)2, DMF, Et3N,
CH2Cl2, 0 °C to rt, 1 h, then 25, BuLi, THF, ꢁ78 °C to rt, 3 h; (iii) (COCl)2, DMF, Et3N,
CH2Cl2, 0 °C to rt, 1 h, then 26, BuLi, THF, ꢁ78 °C to rt, 3 h; (iv) pivaloyl chloride,
Et3N, ꢁ30 °C, 2 h, then 26, LiCl, THF, ꢁ30 °C to rt, 12 h.
(ꢂ85:15 dr in each case), as determined by 1H NMR analysis of the
crude reaction mixtures. The adducts 27–36 were similarly diffi-
cult to purify due to their instability with respect to retro conjugate
addition upon prolonged exposure to silica, and mixtures of diaste-
reoisomers were obtained in 52–74% yield after chromatography
(Scheme 4).
framework. Addition of lithium dibenzylamide 37 to the range of
N-enoyl oxazolidin-2-ones 7–11 proceeded, in each case, with
modest levels of diastereoselectivity (ꢂ75:25 dr) to furnish a dia-
stereoisomeric mixture of the corresponding 1,4-addition products
38–47. In the case of addition to C(30)-isopropyl substituted 11, the
conjugate addition reaction was accompanied by the formation of
racemic 48,17 which is presumably a result of the steric bulk of the
C(30)-substituent retarding the conjugate addition reaction and
promoting a competitive 1,2-addition pathway with subsequent
cleavage of the N-enoyl fragment from the chiral auxiliary followed
The C(30)-configurations within the major diastereoisomers 27–
31 arising from the addition of lithium amide (R)-4 to the N-enoyl
oxazolidin-2-ones 7–11 were also confirmed by a separate chemi-
cal synthesis in each case. b-Amino esters 22–24 obtained from the
conjugate addition of (R)-4 to the requisite
a,b-unsaturated tert-
by 1,4-addition to the resultant achiral a,b-unsaturated amide. The
butyl esters were transformed into the corresponding carboxylic
acids followed by coupling with either (S)-4-benzyl- or (S)-4-phe-
nyl-oxazolidin-2-one 25 or 26 to give authentic samples of 27–31
(Scheme 5).
1,4-addition products 38–47 exhibited some instability upon pro-
longed exposure to silica gel chromatography, but good yields
(80–91%) of purified mixtures of diastereoisomers were obtained.
Subsequent recrystallisation facilitated the isolation of major dia-
stereoisomers 39 and 40 in 44% and 53% yield, respectively, and
>99:1 dr in each case. The similarity in the observed reaction dia-
stereoselectivities indicated that there is no significant difference
in terms of selectivity for the conjugate addition to chiral N-enoyl
oxazolidin-2-ones with different substitution patterns (Scheme 6).
The configuration at C(30) within 40 (>99:1 dr) was determined
by deprotection via sequential hydrolysis and hydrogenolysis, giv-
Comparison of the diastereoselectivities observed for conjugate
addition of the enantiomeric lithium amides (S)-4 and (R)-4 to N-
enoyl oxazolidin-2-ones (S)-7–11 revealed that the additions of
lithium amide (S)-4 represent the ‘matched’ reaction pairings,
and the additions of lithium amide (R)-4 are the ‘mismatched’ pair-
ings. Furthermore, the sense of asymmetric induction observed for
the additions of both (S)-4 and (R)-4 to the N-enoyl oxazolidin-2-
ones (S)-7–11 is consistent with the stereocontrol of the lithium
amides, not the oxazolidin-2-one chiral auxiliary, dominating the
reaction selectivity. In order to enable a more complete under-
standing of the levels of selectivity displayed in this system, the
conjugate addition of an achiral lithium amide to the range of N-
enoyl (S)-4-benzyl- and (S)-4-phenyl-oxazolidin-2-ones (S)-7–11
was next investigated to determine the sense and magnitude of
stereoinduction by the C(4)-substituent of the oxazolidin-2-one
ing the b-amino acid (R)-b-phenylalanine 50 {½a D22
¼ þ6:2 (c 0.6,
ꢃ
H2O); lit.18
½
a 1D9
ꢃ
¼ þ6:5 (c 1.0, H2O)} in 86% yield after purification
by ion exchange chromatography (Scheme 7). The configurations
within the major 1,4-addition products 38, 39, 41 and 42 were as-
signed by analogy. The substrate directed addition of the lithium
amide nucleophile to the Re face of the a,b-unsaturated system is
therefore consistent with the facial selectivity displayed by the
Ph
Ph
O
O
O
O
Ph
N
O
Ph
N
O
(i)
R'
N
O
+
R'
N
O
R'
N
O
R
R
R
7-11
Major diastereoisomer
Minor diastereoisomer
32-36
27-31
yield %b
R
R'
dra
7
8
9
Ph Ph 27:32, 80:20
Ph Me 28:33, 89:11
Bn Ph 29:34, 83:17
52
74
64
64
64
10 Bn Me 30:35, 80:20
11 Bn iPr 31:36, 85:15
Scheme 4. Reagents and conditions: (i) lithium (R)-N-benzyl-N-(
the crude reaction mixture. Isolated yield of purified mixture of diastereoisomers after chromatography].
a
-methylbenzyl)amide (R)-4, THF, ꢁ78 °C, 2 h [a Diastereoisomeric ratios determined by 1H NMR analysis of
b

1638
S. G. Davies et al. / Tetrahedron: Asymmetry 21 (2010) 1635–1648
Ph Ph
O
O
O
O
Ph
N
O
Ph
N
O
(i)
R'
N
O
+
R'
N
O
R'
N
O
R
R
R
7-11
Major diastereoisomer
Minor diastereoisomer
38-42
43-47
Ph
yield %b
R
R'
dra
7
8
9
Ph Ph 38:43, 75:25
Ph Me 39:44, 78:22
Bn Ph 40:45, 79:21
80
82 (44)
91 (53)
85
Ph
N
O
i
10 Bn Me 41:46, 76:24
11 Bn iPr 42:47, 73:27
Pr
N
Ph
17
(RS)-48
Ph
Scheme 6. Reagents and Conditions: (i) lithium dibenzylamide 37, THF, ꢁ78 °C, 2 h [a Diastereoisomeric ratios determined by 1H NMR analysis of the crude reaction mixture.
b
Isolated yield of purified mixture of diastereoisomers after chromatography (isolated yield of major diastereoisomer, in >99:1 dr, after further purification)].
Ph
Ph
O
O
O
Ph
(ii)
O
O
Ph
N
O
Ph
N
OTES
N
(i)
(i)
HN
O
Ph
N
O
+
Ph
N
Ph
O
Ph
N
O
CO2H
Ph
Ph
26, quant
Ph
Ph
Ph
40, >99:1 dr
49
9
(Z)-51, >95:5 dr
72% conversion
Scheme 8. Reagents and conditions: (i) lithium (S)-N-benzyl-N-(
zyl)amide 4 (1.6 equiv), THF, ꢁ78 °C, 3 h, then TESCl, ꢁ78 °C to rt, 5 h.
a-methylben-
NH2
CO2H
Ph
50, 43%
conformation 9A, but is consistent with addition of lithium
amides (S)-4 and (R)-4 to (S)-9 in the anti-s-cis conformation
9B. In this model, the preferential addition of lithium amide (S)-
4 to the Re face of the double bond (reagent control) coincides
with addition opposite to the stereodirecting C(4)-benzyl group
of the oxazolidin-2-one auxiliary (substrate control), and is con-
sistent with the formation of 14 in the ‘matched’ case. The forma-
tion of 29 as the major diastereoisomer in the ‘mismatched’ case
most likely occurs via approach of the lithium amide (R)-4 on the
same face as the stereodirecting C(4)-benzyl group in the anti-s-
cis conformation 9B, although these data do not discount the pos-
sibility that the formation of 29 may occur via preferential addi-
tion of lithium amide (R)-4 to (S)-9 in the syn-s-cis conformation
9A. In order to investigate this possibility, the conjugate addition
reactions of lithium amides (S)-4 and (R)-4 to 9 were repeated in
the presence of the Lewis acids LiBr, MeMgBr, Ti(OiPr)3Cl and
Zn(OTf)2: under these conditions, the carbonyl groups of the N-
enoyl oxazolidinone 9 may be expected to be held in the syn con-
formation. However, although 70–90% of the starting material
was recovered even upon extended reaction times (up to 48 h),
the observed levels of diastereoselectivity remained unchanged
in both cases [>99:1 dr for ‘matched’ addition of (S)-4; 83:17 dr
for ‘mismatched’ addition of (R)-4]. Thus, assuming that addition
of a Lewis acid increases the ratio of syn:anti conformers, a
change in the level of diastereoselectivity upon addition of both
lithium amides (S)-4 and (R)-4 would have been expected, which
was not observed, suggesting that the syn-s-cis conformation 9A
is less reactive towards conjugate addition of the lithium amides,
and providing further evidence that the formation of 29 as the
major diastereoisomer from the ‘mismatched’ addition of lithium
amide (R)-4 to (S)-9 more than likely derives from reaction
through the anti-s-cis conformation 9B (Fig. 2).
Scheme 7. Reagents and Conditions: (i) LiOH, H2O2, THF/H2O (v:v, 3:1), 0 °C to rt,
16 h; (ii) H2, Pd(OH)2/C, MeOH/H2O/AcOH (v:v:v, 40:4:1), rt, 12 h, then HCl (1 M,
aq), then Dowex 50WX8-200 ion exchange chromatography.
substrate and reagent in the doubly diastereoselectively ‘matched’
conjugate addition of lithium amide (S)-4 to the range of N-enoyl
oxazolidin-2-ones (S)-7–11.
It was envisaged that the reactive conformation of these systems
could be further investigated by examining the geometry of the
lithium enolate arising from the conjugate addition procedure, as
such an analysis would differentiate between the possible s-cis
and s-trans conformations, as a (Z)-enolate would arise from
addition to an s-cis conformer and an (E)-enolate via addition to
an s-trans conformer. The doubly diastereoselective ‘matched’
conjugate addition of lithium amide (S)-4 to N-cinnamoyl-4-ben-
zyl-oxazolidin-2-one (S)-9 followed by treatment of the resultant
enolate with triethylsilylchloride gave 72% conversion to the silyl
enol ether (Z)-51 exclusively, the geometry of which was estab-
lished by 1H NMR NOE experiments, and which is consistent with
other enolate trapping studies of this class of conjugate addition
reactions15,19 (Scheme 8).
These data from the enolate trapping study determine conclu-
sively that the addition of homochiral lithium amide (S)-4 to N-
enoyl oxazolidin-2-one (S)-9 proceeds via an s-cis conformation.
Considering the double asymmetric induction observed upon
addition to N-cinnamoyl (S)-4-benzyl-oxazolidin-2-one (S)-9, in
the ‘matched’ case the addition of lithium amide (S)-4 to (S)-9 re-
sults in the preferential formation of 14 in >99:1 dr. In the ‘mis-
matched’ case, conjugate addition of lithium amide (R)-4 to (S)-9
results in the formation of 29:34 in 83:17 dr. This empirical
‘matched’ and ‘mismatched’ product distribution cannot be
achieved if the reaction were to proceed through the syn-s-cis
These results were then considered in the context of the low
diastereoselectivities observed for the 1,4-conjugate addition of

S. G. Davies et al. / Tetrahedron: Asymmetry 21 (2010) 1635–1648
1639
Ph
tion of neither lithium amide (S)-4 nor (R)-4 would result in high
levels of diastereoselectivity; the product distributions arising
from double asymmetric induction clearly demonstrate that this
is not the case. The observation of ‘matched’ and ‘mismatched’
reaction pairings in these reactions also eliminates the possibility
that the reaction proceeds under Curtin-Hammett control [sce-
nario (2)]. In this mechanistic scheme, reaction with both lithium
amides (S)-4 and (R)-4 would have been ‘matched’ and would have
progressed with equal and high levels of diastereocontrol. There-
fore, by process of elimination, it is determined that the reaction
must proceed with moderate facial selectivity via exclusive addi-
tion of lithium dibenzylamide 37 to the anti-s-cis conformation of
N-enoyl oxazolidine-2-one 9 [scenario (3)].
O
O
Ph
N
Predict
Predict
Ph
N
O
"matched"
"mismatched"
X
⇒ Observed
⇒ Not observed!
Bn
"matched"
14
Ph
84%, >99:1 dr
Ph
Ph
N
Li
Ph
N
(S)-4
(
(
(S)-4
Li
)
)
anti-s-cis 9B
Bn
O
N
O
O
O
N
O
O
Bn
Ph
Ph
Ph
syn-s-cis 9A
)
)
Ph
(
(
2.2. Synthetic application: preparation of pseudopeptides
Ph
N
Li
Ph
N
Li
(R)-4
(R)-4
Elaboration of the b-amino acid moieties resulting from these
conjugate addition reactions was envisaged as part of a novel
asymmetric approach towards the preparation of pseudopeptides.
In this strategy, the protected functionality within the oxazolidine-
Ph
Predict
Predict
"matched"
"mismatched"
X
O
O
Ph
N
⇒ Not observed!
⇒ Observed
"mismatched"
Ph
N
O
2-one chiral auxiliary would be unmasked as a latent a-amino acid
equivalent via endocyclic cleavage of the auxiliary, a process that
typically predominates under standard hydrolysis conditions of
Reagent control
Substrate control
Bn
29
64%, 83:17 dr
either bulky a-substituted or b-heteroatom derivatives of oxazoli-
din-2-ones.20 Following this plan, treatment of 14 with Pearlman’s
catalyst in glacial acetic acid under hydrogen gave primary amine
52 in 89% yield. Amine 52 was coupled with N-Boc phenylalanine
to give 53 in 82% yield. Endocyclic cleavage of the oxazolidin-2-
one auxiliary upon treatment with LiOH gave alcohol 54 in 53%
yield. Oxidation of 54 to the corresponding acid with the Jones
Figure 2. Model to rationalise the observed ‘matched’ and ‘mismatched’ double
asymmetric induction; given the observed ‘matched’ and ‘mismatched’ reaction
pairing from the double asymmetric induction, the reactive conformation cannot be
syn-s-cis 9A.
the achiral lithium amide 37 to the range of chiral N-enoyl oxazoli-
din-2-one systems. As an example, the observed product distribu-
tion upon addition of lithium dibenzylamide 37 to (S,E)-N-
cinnamoyl-4-benzyl-oxazolidin-2-one 9 may arise from a number
of mechanistic scenarios: (1) addition of lithium dibenzylamide
37 occurs with exclusive facial selectivity (opposite to the C(4)-ste-
reodirecting benzyl group) to an unequilibrating 79:21 mixture of
anti-s-cis to syn-s-cis conformers of (S)-9; (2) addition of lithium
dibenzylamide 37 occurs with unknown facial selectivity to both
anti-s-cis and syn-s-cis conformers of (S)-9 which are rapidly equil-
ibrating; (3) addition of lithium dibenzylamide 37 occurs with
moderate (79:21) facial selectivity via exclusive addition to the
anti-s-cis conformation of (S)-9; or (4) a combination of any of
these scenarios. If the reaction proceeded under scenario (1), addi-
reagent followed by N-Boc deprotection of 55 furnished a,b,a-
tri(phenylalanine) 56 in 68% yield, isolated as its TFA salt, after
purification (Scheme 9).
3. Conclusion
The doubly diastereoselective conjugate additions of the antip-
odes of lithium N-benzyl-N-(a-methylbenzyl)amide to a range of
enantiopure N-enoyl oxazolidin-2-ones has been used as a mecha-
nistic probe to determine that the reactive conformation is the
anti-s-cis form. The synthetic utility of these b-amino carbonyl
products resulting from conjugate has been demonstrated by the
elaboration to the a,b,a-pseudotripeptide a,b,a-triphenylalanine.
Ph
O
H
O
O
NH2
N
O
O
O
Ph
N
O
Boc
NH
(i)
(ii)
Ph
N
O
Ph
N
O
Ph
Ph
N
O
14
52, 89%
53, 82%
Ph
Ph
Ph
(iii)
O
O
H
N
H
N
O
R
NH
Ph
(iv)
O
Boc
NH
Ph
Ph
NH
Ph
Ph
NH
Ph
OH
CO2H
55, R = Boc, 84%
54, 53%
(v)
56, R = H•TFA, 68%
Scheme 9. Reagents and conditions: (i) H2 (5 atm), Pd(OH)2/C, AcOH, rt, 24 h; (ii) Boc-Phe, DCC, THF, 0 °C, 3 h; (iii) LiOH (4.8 equiv), THF/H2O (2:1), 60 °C, 5 h; (iv) CrO3,
H2SO4, acetone, 0 °C, 3 h; (v) TFA/CH2Cl2 (1/1), rt, 2 h, then purification on RP-18 gel.

1640
S. G. Davies et al. / Tetrahedron: Asymmetry 21 (2010) 1635–1648
a further 3 h, followed by addition of satd aq NH4Cl. The resultant
4. Experimental
4.1. General experimental
mixture was extracted three times with EtOAc and the combined
organic extracts were washed sequentially with satd aq NaHCO3
and brine, then dried and concentrated in vacuo.
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. Sol-
vents were dried according to the procedure outlined by Grubbs
and co-workers.21 Water was purified by an ElixÒ UV-10 system.
All other solvents were used as supplied (analytical or HPLC grade)
without prior purification. Organic layers were dried over MgSO4.
Thin layer chromatography was performed on aluminium 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 performed on Kieselgel 60
silica or neutral alumina.
4.2.2. General procedure 2: lithium amide conjugate addition
BuLi (1.55 equiv) was added to a solution of the requisite amine
(1.6 equiv) in THF at ꢁ78 °C. After 30 min, a solution of the requi-
site N-enoyl oxazolidin-2-one (1 equiv) in THF at ꢁ78 °C was
added via cannula and the reaction mixture was stirred for a fur-
ther 2 h, followed by the addition of satd aq NH4Cl and warming
to rt. The resultant mixture was extracted three times with EtOAc
and concentrated in vacuo. The residue was dissolved in CH2Cl2
and washed sequentially with 10% aq citric acid, satd aq NaHCO3,
and brine, then dried and concentrated in vacuo.
4.3. (S,E)-N(3)-(30-Phenylpropenoyl)-4-phenyloxazolidin-2-one 7
Elemental analyses were recorded by the microanalysis service
of the Inorganic Chemistry Laboratory, University of Oxford, UK.
Melting points were recorded on a Gallenkamp Hot Stage appara-
tus and are uncorrected. Optical rotations were recorded on a Per-
kin-Elmer 241 polarimeter with a water-jacketed 10 cm cell.
Specific rotations are reported in 10ꢁ1 deg cm2 gꢁ1 and concentra-
tions in g/100 mL. IR spectra were recorded on a Bruker Tensor 27
FT-IR spectrometer either as a thin film on NaCl plates (film) or as a
KBr disc (KBr), as stated. Selected characteristic peaks are reported
in cmꢁ1. NMR spectra were recorded on Bruker Avance spectrom-
eters in the deuterated solvent stated. The field was locked by
external referencing to the relevant deuteron resonance. Low-res-
olution mass spectra were recorded on either a VG MassLab 20–
250 or a Micromass Platform 1 spectrometer. Accurate mass mea-
surements were run on either a Bruker MicroTOF internally cali-
brated with polyalanine or a Micromass GCT instrument fitted
with a Scientific Glass Instruments BPX5 column (15 ꢄ 0.25 mm)
using amyl acetate as a lock mass.
O
O
Ph
N
O
Ph
Following general procedure 1A, a solution of 25 (132 mg,
0.81 mmol) in THF (5 mL) at ꢁ78 °C was treated with BuLi
(1.38 M, 0.64 mL, 0.89 mmol) and trans-cinnamoyl chloride
(175 mg, 1.00 mmol). Purification via flash column chromatogra-
phy (silica, eluent 30–40 °C petrol/EtOAc, 4:1) gave 7 as a white so-
lid (185 mg, 78%);23 mp 167–168 °C; {lit.23 mp 169–171 °C};
½
a 2D2
ꢃ
¼ þ3:5 (c 0.75, CHCl3); {lit.23
½
a 2D2
ꢃ
¼ þ3:4 (c 0.7, CHCl3)}; dH
(400 MHz, CDCl3) 4.34 (1H, dd, J 8.8, 3.9, C(5)HA), 4.76 (1H, app t,
J 8.8, C(5)HB), 5.57 (1H, dd, J 8.8, 3.9, C(4)H), 7.33–7.43 (8H, m,
Ph), 7.59–7.62 (2H, m, Ph), 7.80 (1H, d, J 15.7, C(20)H), 7.95 (1H,
d, J 15.7, C(30)H).
4.4. (S,E)-N(3)-But-20-enoyl-4-phenyloxazolidin-2-one 8
O
O
4.2. General experimental procedures
Me
N
O
4.2.1. General procedure 1: N-acylation of oxazolidin-2-ones
Method A: BuLi (1.1 equiv) was added to a solution of either 25
or 26 (1 equiv) in THF at ꢁ78 °C. After 20 min, the requisite acid
chloride (1.3 equiv) was added. The reaction mixture was allowed
to warm to rt over 12 h, followed by addition of satd aq NH4Cl. The
resultant mixture was extracted three times with EtOAc and the
combined organic extracts were washed with satd aq NaHCO3,
then dried and concentrated in vacuo.
Ph
Following general procedure 1A,
a
solution of 25 (1.00 g,
6.13 mmol) in THF (20 mL) at ꢁ78 °C was treated with BuLi
(1.51 M, 4.06 mL, 6.13 mmol) and trans-crotonoyl chloride
(705 mg, 6.74 mmol). Purification via flash column chromatography
(silica, eluent 30–40 °C petrol/EtOAc, 7:3) gave 8 as a white solid
(731 mg, 53%);23 mp 76–78 °C; {lit.23 mp 77–79 °C};
Method B:22 A solution of the requisite carboxylic acid deriva-
tive (1 equiv) in THF at ꢁ30 °C was treated with Et3N (3 equiv)
and pivaloyl chloride (1.1 equiv). The resultant suspension of
mixed anhydride was stirred for 2 h, followed by the addition of
LiCl (1.2 equiv) and either 25 or 26 (1.1 equiv). The reaction mix-
ture was allowed to warm to rt over 12 h, followed by addition
of satd aq NH4Cl. The resultant mixture was extracted three times
with EtOAc and the combined organic extracts were washed
sequentially with satd aq NaHCO3 and brine, then dried and con-
centrated in vacuo.
½
a 2D3
ꢃ
¼ þ121:4 (c 1.1, CHCl3); {lit.23
½
a 2D2
ꢃ
¼ þ111:8 (c 1.1, CHCl3)};
dH (200 MHz, CDCl3) 1.95 (3H, d, J 6.6, C(40)H3), 4.28 (1H, dd, J 8.8,
3.9, C(5)HA), 4.71 (1H, dd, J 8.8, 8.7, C(5)HB), 5.50 (1H, dd, J 8.7, 3.9,
C(4)H), 7.05–7.20 (2H, m, C(20)H, C(30)H), 7.26–7.45 (5H, m, Ph).
4.5. (S,E)-N(3)-(30-Phenylpropenoyl)-4-benzyloxazolidin-2-one 9
O
O
Method C: A solution of the requisite carboxylic acid derivative
(1 equiv) in CH2Cl2 at 0 °C was treated with (ClCO)2 (1.5 equiv) and
one drop of DMF. The reaction mixture was allowed to warm to rt
over 1 h, then one drop of Et3N was added, which gave a white sus-
pension. The suspension was concentrated in vacuo and the resi-
due was suspended in THF. In a separate vessel, BuLi (3 equiv)
was added to a solution of either 25 or 26 (3 equiv) in THF at
ꢁ78 °C. After 20 min, the acid chloride suspension was added via
cannula, and the reaction mixture was allowed to warm to rt over
Ph
N
O
Ph
Following general procedure 1A,
a
solution of 26 (4.95 g,
28.0 mmol) in THF (60 mL) at ꢁ78 °C was treated with BuLi
(1.54 M, 22.4 mL, 33.6 mmol) and trans-cinnamoyl chloride
(5.13 g, 30.8 mmol). Purification via recrystallisation (EtOAc/

S. G. Davies et al. / Tetrahedron: Asymmetry 21 (2010) 1635–1648
1641
hexane) gave 9 as white needles (6.54 g, 76%);24 mp 117–118 °C;
From 7: Following general procedure 2, a solution of (S)-N-benzyl-
N-( -methylbenzyl)amine (115 mg, 0.55 mmol) in THF (10 mL) at
{lit.24 mp 122–123 °C};
½
a 2D5
ꢃ
¼ þ51:3 (c 1.0, CHCl3); {lit.24
a
½
a 2D0
ꢃ
¼ þ56:3 (c 1.8, CHCl3)}; dH (400 MHz, CDCl3) 2.83–2.91 (1H,
ꢁ78 °C was treated with BuLi (1.51 M, 0.36 mL, 0.54 mmol) and 7
(100 mg, 0.34 mmol) to give a 96:4 mixture of 12:17. Purification
via flash column chromatography (silica, gradient elution, 30–
40 °C petrol/EtOAc, 9:1; increased to 30–40 °C petrol/EtOAc, 1:1)
gave a 96:4 mixture of 12:17 as a colourless oil (135 mg, 79%). Crys-
tallisation from CH2Cl2/Et2O gave 12 as a white solid (102 mg, 64%,
>99:1 dr); C33H32N2O3 requires C, 78.55; H, 6.4; N, 5.55; found C,
m, CHAHBPh), 3.37–3.42 (1H, m, CHAHBPh), 4.20–4.30 (2H, m,
C(5)H2), 4.79–4.84 (1H, m, C(4)H), 7.25–7.43 (8H, m, Ph), 7.65–
7.66 (2H, m, Ph), 7.93–7.95 (2H, m, C(20)H, C(30)H).
4.6. (S,E)-N(3)-But-20-enoyl-4-benzyloxazolidin-2-one 10
78.5; H, 6.4; N, 5.4; mp 73–76 °C; ½a D21
¼ þ42:7 (c 1.0, CHCl3); mmax
ꢃ
O
O
(KBr) 1779 (C@Oendo), 1702 (C@Oexo); dH (500 MHz, CDCl3) 1.28
(3H, d, J 6.8, C(
dd, J 16.6, 9.3, C(20)HB), 3.73 (1H, d, J 15.1, NCHA), 3.77 (1H, d, J
15.1, NCHB), 4.03 (1H, q, J 6.8, C( )H), 4.11 (1H, dd, J 8.8, 3.9,
a
)Me), 3.01 (1H, dd, J 16.6, 5.0, C(20)HA), 3.62 (1H,
Me
N
O
a
Ph
C(5)HA), 4.51 (1H, dd, J 8.8, 8.7, C(5)HB), 4.58 (1H, dd, J 9.3, 5.0,
C(30)H), 5.24 (1H, dd, J 8.7, 3.9, C(4)H), 6.95–6.97 (2H, m, Ph), 7.18–
Following general procedure 1A,
a
solution of 26 (1.00 g,
7.43 (18H, m, Ph); dC (125 MHz, CDCl3) 16.5 (C(
50.8 (NCH2), 57.0 (C(4)), 57.9 (C(30)), 58.9 (C(
)), 69.6 (C(5)), 125.4,
a
)Me), 36.8 (C(20)),
5.64 mmol) in THF (25 mL) at ꢁ78 °C was treated with BuLi
(1.50 M, 4.51 mL, 6.77 mmol) and trans-crotonoyl chloride
(649 mg, 6.21 mmol). Purification via recrystallisation (Et2O) gave
10 as a white solid (910 mg, 66%);25 mp 86–87 °C; {lit.25 mp 85–
a
126.5, 126.8, 127.1, 127.7, 127.9, 128.0, 128.1, 128.2, 128.3, 129.0
(Pho,m,p), 138.6, 141.6, 141.6, 144.0 (Phi), 153.4 (C(2)), 170.8 (C(10));
m/z (CI+) 505 ([M+H]+, 100%); HRMS (CI+) C33H33N2O3+ ([M+H]+) re-
quires 505.2486; found 505.2488.
86 °C}; ½a 2D3
ꢃ
¼ þ77:1 (c 1.0, CHCl3); {lit.25
½
a 2D5
ꢃ
¼ þ77:9 (c 2.0,
CHCl3)}; dH (200 MHz, CDCl3) 2.00 (3H, d, J 5.1, C(40)H3), 2.80 (1H,
dd, J 13.3, 9.5, CHAHBPh), 3.34 (1H, dd, J 13.3, 2.9, CHAHBPh),
4.15–4.26 (2H, m, C(5)H2), 4.68–4.79 (1H, m, C(4)H), 7.16–7.39
(7H, m, C(20)H, C(30)H, Ph).
From 22: A solution of (3R,aS)-22 (115 mg, 0.28 mmol) in
CH2Cl2 (5 mL) was treated with TFA (5 mL). After 2 h the reaction
mixture was concentrated in vacuo. The residue was dissolved in
CH2Cl2 (5 mL), washed with satd aq NaHCO3 (5 mL), dried and con-
centrated in vacuo. The residue was again dissolved in CH2Cl2
(5 mL) and cooled to 0 °C. Following general procedure 1C, the resul-
tant solution was treated with (ClCO)2 (67 mg, 0.53 mmol), one
drop of DMF and one drop of Et3N. A suspension of the resultant
acid chloride in THF (5 mL) was added to a solution of 25
(137 mg, 0.84 mmol) and BuLi (1.58 M, 0.53 mL, 0.84 mmol) in
THF (10 mL) at ꢁ78 °C. Purification via flash column chromatogra-
phy (silica, eluent 30–40 °C petrol/Et2O, 1:1) gave 12 as a white so-
lid (67 mg, 48%, >99:1 dr).
4.7. (S,E)-N(3)-(40-Methylpent-2-0enoyl)-4-benzyloxazolidin-2-
one 11
O
O
i-Pr
N
O
Ph
4.9. (S,S,S)-N(3)-{30-[N-Benzyl-N-(
oyl}-4-phenyloxazolidin-2-one 13
a
-methylbenzyl)amino]butan-
Following general procedure 1B, a solution of (E)-4-methylpent-
2-enoic acid (600 mg, 5.26 mmol) in THF (25 mL) at ꢁ30 °C was
treated with Et3N (2.20 mL, 15.8 mmol) and pivaloyl chloride
(0.7 mL, 5.78 mmol), followed after 2 h by LiCl (270 mg,
6.31 mmol) and 26 (1.00 g, 5.78 mmol). Purification via flash col-
umn chromatography (silica, eluent 30–40 °C petrol/EtOAc, 10:1)
gave 11 as a white solid (1.06 g, 76%); C16H19NO3 requires C,
70.3; H, 7.0; N, 5.1; found C, 70.0; H, 7.5; N, 5.1; mp 59–60 °C;
Ph
O
Ph
N
O
Me
N
O
½
a 2D5
ꢃ
¼ þ59:0 (c 1.0, CHCl3); dH (400 MHz, CDCl3) 1.11–1.13 (6H,
Ph
m, C(40)Me2), 2.54–2.62 (1H, m, C(40)H), 2.79 (1H, dd, J 13.4, 9.7,
CHAHBPh), 3.36 (1H, dd, J 13.4, 3.2, CHAHBPh), 4.16–4.24 (2H, m,
C(5)H2), 4.74 (1H, app dq, J 13.1, 3.5, C(4)H), 7.15–7.37 (7H, m,
C(20)H, C(30)H, Ph); dC (125 MHz, CDCl3) 21.1, 21.2 (C(40)Me2),
31.4 (C(40)), 37.8 (CH2Ph), 55.2 (C(4)), 66.0 (C(5)), 117.7 (C(20)),
127.2, 128.8, 129.3 (Pho,m,p), 135.3 (Phi), 153.3 (C(2)), 157.7
(C(30)), 165.3 (C(10)); mmax (film) 1781 (C@Oendo), 1683 (C@Oexo),
1634 (C@C); m/z (ESI+) 332 ([M+59]+, 100%), 274 ([M+H]+, 30%);
From 8: Following general procedure 2, a solution of (S)-N-benzyl-
N-( -methylbenzyl)amine (138 mg, 0.65 mmol) in THF (14 mL) at
a
ꢁ78 °C was treated with BuLi (1.51 M, 0.43 mL, 0.65 mmol) and 8
(100 mg, 0.43 mmol) to give a 95:5 mixture of 13:18. Purification
via flash column chromatography (silica, eluent 30–40 °C petrol/
Et2O, 1:1) gave a 95:5 mixture of 13:18 as a white solid (143 mg,
75%). Recrystallisation (Et2O/30–40 °C petrol) gave 13 as a white so-
lid (102 mg, 53%, >99:1 dr); C28H30N2O3 requires C, 76.0; H, 6.8; N,
HRMS (ESI+) C16H20NO3 ([M+H]+) requires 274.1438; found
+
6.3; found C, 75.9; H, 6.7; N, 6.4; mp 130–131 °C; ½a D21
¼ þ29:2 (c
ꢃ
274.1454.
1.0, CHCl3); mmax (KBr) 1790 (C@Oendo), 1694 (C@Oexo); dH
(500 MHz, CDCl3) 1.03 (3H, d, J 6.6, C(40)H3), 1.32 (3H, d, J 6.9,
4.8. (4S,30R, S)-N(3)-{30-[N-Benzyl-N-(
a a-methylbenzyl)amino]-
C(
C(20)HB), 3.55–3.59 (1H, m, C(30)H), 3.71 (1H, d, J 15.0, NCHA), 3.82
(1H, d, J 15.0, NCHB), 3.91 (1H, q, J 6.9, C( )H), 4.20 (1H, dd, J 8.8,
a
)Me), 2.85 (1H, dd, J 16.3, 8.3, C(20)HA), 2.90 (1H, dd, J 16.3, 5.3,
30-phenylpropanoyl}-4-phenyloxazolidin-2-one 12
a
Ph
3.6, C(5)HA), 4.55 (1H, dd, J 8.8, 8.7, C(5)HB), 5.29 (1H, dd, J 8.7, 3.6,
O
Ph
N
O
C(4)H), 7.19–7.42 (15H, m, Ph); dC (125 MHz, CDCl3) 18.2, 19.5
a
(C(40), C( )Me), 39.0 (C(20)), 49.7 (C(30)), 49.9 (NCH2), 57.5 (C(4)),
Ph
N
O
58.5 (C(
a
)), 69.7 (C(5)), 125.8, 126.5, 126.7, 127.6, 128.1, 128.6,
129.1 (Pho,m,p), 139.1, 142.0, 144.5 (Phi), 153.5 (C(2)), 171.4 (C(10));
m/z (APCI+) 443 ([M+H]+, 100%).
Ph

1642
S. G. Davies et al. / Tetrahedron: Asymmetry 21 (2010) 1635–1648
From 23: A solution of (S,S)-23 (595 mg, 1.68 mmol) in CH2Cl2
From 10: Following general procedure 2, a solution of (S)-N-
benzyl-N-( -methylbenzyl)amine (138 mg, 0.65 mmol) in THF
(5 mL) was treated with TFA (5 mL). After 2 h the reaction mixture
was concentrated in vacuo. The residue was dissolved in CH2Cl2
(5 mL), washed with satd aq NaHCO3 (5 mL), dried and concen-
trated in vacuo. The residue was again dissolved in CH2Cl2 (5 mL)
and cooled to 0 °C. Following general procedure 1C, the resultant
solution was treated with (ClCO)2 (319 mg, 2.52 mmol), one drop
of DMF and one drop of Et3N. A suspension of the resultant acid
chloride in THF (5.00 mL) was subsequently added to a solution
of 25 (823 mg, 5.04 mmol) and BuLi (1.58 M, 3.19 mL, 5.04 mmol)
in THF (10 mL) at ꢁ78 °C. Purification via flash column chromatog-
raphy (silica, eluent 30–40 °C petrol/Et2O, 1:1) gave 13 as a white
solid (196 mg, 26%, >99:1 dr).
a
(14 mL) at ꢁ78 °C was treated with BuLi (1.51 M, 0.43 mL,
0.65 mmol) and 10 (100 mg, 0.41 mmol) to give a 96:4 mixture
of 15:20. Purification via flash column chromatography (silica,
eluent 30–40 °C petrol/Et2O, 1:1) gave a 96:4 mixture of 15:20
as a colourless oil (136 mg, 73%). Crystallisation from CH2Cl2/
Et2O gave 15 as
a white solid (98 mg, 51%, >99:1 dr);
C
29H32N2O3 requires C, 76.3; H, 7.1; N, 6.1; found C, 76.5; H,
7.2; N, 6.0; mp 88–89 °C; ½a D21
¼ þ6:6 (c 0.9, CHCl3); mmax (KBr)
ꢃ
1782 (C@Oendo), 1699 (C@Oexo); dH (500 MHz, CDCl3) 1.22 (3H,
d, J 6.6, C(40)H3), 1.38 (3H, d, J 6.9, C(
a)Me), 2.60 (1H, dd, J
13.3, 10.0, C(4)CHAHBPh), 2.86 (1H, dd, J 16.3, 8.0, C(20)HA),
2.95 (1H, dd, J 16.3, 5.6, C(20)HB), 3.25 (1H, dd, J 13.3, 3.3,
C(4)CHAHBPh), 3.64–3.71 (1H, m, C(30)H), 3.77 (1H, d, J 14.9,
4.10. (4S,30R, S)-N(3)-{30-[N-Benzyl-N-(
a a-methylbenzyl)amino]-
30-phenylpropanoyl}-4-benzyloxazolidin-2-one 14
NCHA), 3.83 (1H, d, J 14.9, NCHB), 3.96 (1H, q, J 6.9, C(a)H),
4.03–4.08 (2H, m, C(5)H2), 4.50–4.55 (1H, m, C(4)H), 7.18–7.38
Ph
(13H, m, Ph), 7.43–7.48 (2H, m, Ph); dC (125 MHz, CDCl3) 18.4,
18.9 (C(40), C( )Me), 37.9, 39.4 (C(20), C(4)CH2Ph), 49.6 (C(30)),
a
O
Ph
N
O
49.9 (NCH2), 55.2 (C(4)), 58.1 (C(a)), 66.0 (C(5)), 126.5, 126.6,
127.2, 127.3, 127.6, 128.1, 128.2, 128.9, 129.4 (Pho,m,p), 135.5,
Ph
N
O
141.9, 144.6 (Phi), 153.2 (C(2)), 171.9 (C(10)); m/z (CI+) 457
([M+H]+, 100%); HRMS (CI+) C29H33N2O3 ([M+H]+) requires
+
457.2486; found 457.2490.
Ph
From 23: A solution of (S,S)-23 (1.97 g, 5.58 mmol) in CH2Cl2
(10 mL) was treated with TFA (10 mL). After 2 h the reaction
mixture was concentrated in vacuo. The residue was dissolved
in CH2Cl2 (10 mL), washed with satd aq NaHCO3 (10 mL), dried
and concentrated in vacuo. The residue was dissolved in THF
(10 mL) and cooled to ꢁ30 °C. Following general procedure 1B,
the resultant solution was treated with Et3N (2.30 mL,
16.7 mmol) and pivaloyl chloride (0.76 mL, 6.14 mmol), followed
after 2 h by LiCl (280 mg, 6.70 mmol) and 26 (1.09 g, 6.14 mmol).
Purification via flash column chromatography (neutral alumina,
gradient elution, 30–40 °C petrol/Et2O, 10:1; increased to 30–
40 °C petrol/Et2O, 5:1) gave 15 as a white solid (1.43 mg, 56%,
>99:1 dr).
From 9: Following general procedure 2, a solution of (S)-N-benzyl-
N-( -methylbenzyl)amine (2.75 g, 13.0 mmol) in THF (40 mL) at
ꢁ78 °C was treated with BuLi (1.35 M, 9.60 mL, 13.0 mmol) and 9
(2.50 g, 8.13 mmol) to give 14 in >99:1 dr. Crystallisation from
EtOAc/Et2O gave 14 as a white solid (3.54 g, 84%, >99:1 dr);
a
C
34H34N2O3 requires C, 78.7; H, 6.6; N, 5.4; found C, 78.5; H, 6.9; N,
5.3; mp 140–142 °C; ½a D21
¼ þ35:6 (c 1.0, CHCl3); mmax (KBr) 1785
ꢃ
(C@Oendo), 1686 (C@Oexo); dH (500 MHz, CDCl3) 1.30 (3H, d, J 6.8,
C(a)Me), 2.44 (1H, dd, J 13.5, 9.7, C(4)CHAHBPh), 2.97 (1H, dd, J
13.5, 3.2, C(4)CHAHBPh), 3.07 (1H, dd, J 16.6, 5.1, C(20)HA), 3.61 (1H,
dd, J 16.6, 9.3, C(20)HB), 3.77 (1H, d, J 14.9, NCHA), 3.83 (1H, d, J
14.9, NCHB), 4.00–4.05 (2H, m, C(5)H2), 4.08 (1H, q, J 6.8, C(a)H),
4.46–4.50 (1H, m, C(4)H), 4.68 (1H, dd, J 9.3, 5.1, C(30)H), 7.04–7.07
(2H, m, Ph), 7.18–7.39 (14H, m, Ph), 7.44–7.48 (4H, m, Ph); dC
4.12. (4S,3’R,a a-methylbenzyl)amino]-
S)-N(3)-{30-[N-Benzyl-N-(
(125 MHz, CDCl3) 16.2 (C(
a
)Me), 37.1, 37.5 (C(20), C(4)CH2Ph), 50.8
40-methylpentanoyl}-4-benzyloxazolidin-2-one 16
(NCH2), 55.1 (C(4)), 56.9 (C(30)), 58.9 (C(
a)), 66.0 (C(5)), 126.8,
Ph
127.0, 127.2, 127.4, 127.7, 127.9, 128.2, 128.5, 128.9, 129.1, 129.4,
129.6 (Pho,m,p), 135.5, 141.8, 142.1, 144.4 (Phi), 153.4 (C(2)), 171.6
O
Ph
N
O
(C(10)); m/z (CI+) 519 ([M+H]+, 100%); HRMS (ESI+) C34H35N2O3
+
([M+H]+) requires 519.2642; found 519.2635.
i
Pr
N
O
From 22: A solution of (3R,aS)-22 (1.09 g, 2.62 mmol) in CH2Cl2
(10 mL) was treated with TFA (10 mL). After 2 h the reaction mix-
ture was concentrated in vacuo. The residue was dissolved in
CH2Cl2 (10 mL), washed with satd aq NaHCO3 (10 mL), dried and
concentrated in vacuo. The residue was dissolved in THF (10 mL)
and cooled to ꢁ30 °C. Following general procedure 1B, the resultant
solution was treated with Et3N (1.10 mL, 7.85 mmol) and pivaloyl
chloride (0.35 mL, 2.88 mmol), followed after 2 h by LiCl (133 mg,
3.14 mmol) and 26 (510 mg, 2.88 mmol). Trituration with MeOH
furnished 14 as a white solid (1.17 g, 90%, >99:1 dr).
Ph
From 11: Following general procedure 2, a solution of (S)-N-ben-
zyl-N-( -methylbenzyl)amine (247 mg, 1.17 mmol) in THF (20 mL)
a
at ꢁ78 °C was treated with BuLi (2.5 M, 0.50 mL, 1.13 mmol) and
11 (200 mg, 0.73 mmol) to give a 94:6 mixture of 16:21. Purifica-
tion via flash column chromatography (neutral alumina, eluent
30–40 °C petrol/Et2O, 5:1) gave a 94:6 mixture of 16:21 as a pale
yellow oil (255 mg, 72%). Further flash column chromatography
(silica, eluent 30–40 °C petrol/Et2O, 1:1) gave 16 as a colourless
4.11. (S,S,S)-N(3)-{30-[N-Benzyl-N-(
a-methylbenzyl)amino]buta-
oil (180 mg, 51%, >99:1 dr); ½a D20
ꢃ
¼ þ10:4 (c 1.0, CHCl3);
mmax (film)
noyl}-4-benzyloxazolidin-2-one 15
1782 (C@Oendo), 1700 (C@Oexo); dH (400 MHz, CDCl3) 0.92 (3H, d, J
Ph
6.7, C(40)MeA), 1.19 (3H, d, J 6.5, C(40)MeB), 1.44 (3H, d, J 7.4,
C(a
)Me), 1.72–1.81 (1H, m, C(40)H), 2.21 (1H, app d, J 18.4,
O
Ph
N
O
C(20)HA), 2.64 (1H, dd, J 13.2, 10.0, C(4)CHAHBPh), 2.90 (1H, dd, J
18.4, 8.6, C(20)HB), 3.27 (1H, dd, J 13.2, 3.4, C(4)CHAHBPh), 3.49–
3.53 (1H, m, C(30)H), 3.64 (1H, d, J 15.1, NCHA), 3.81 (1H, q, J 7.4,
Me
N
O
C(a)H), 3.86 (1H, d, J 15.1, NCHB), 4.11 (2H, app d, J 5.2, C(5)H2),
4.53–4.59 (1H, m, C(4)H), 7.19–7.41 (13H, m, Ph), 7.51–7.53 (2H,
Ph

S. G. Davies et al. / Tetrahedron: Asymmetry 21 (2010) 1635–1648
1643
m, Ph); dC (100 MHz, CDCl3) 19.7 (C(
32.6 (C(40)), 35.2 (C(20)), 37.9 (C(4)CH2Ph), 51.4 (NCH2), 55.2
(C(4)), 56.4 (C(30)), 57.1 (C(
)), 66.0 (C(5)), 126.0, 126.6, 126.8,
a
)Me), 19.8, 21.7 (C(40)Me2),
4.14. (4S,30R,
butanoyl}-4-phenyloxazolidin-2-one 28
a
R)-N(3)-{30-[N-Benzyl-N-(
a-methylbenzyl)amino]-
a
Ph
127.2, 128.0, 128.4, 128.7, 128.9, 129.4 (Pho,m,p), 135.4, 141.2,
141.7 (Phi), 153.2 (C(2)), 172.5 (C(10)); m/z (ESI+) 485 ([M+H]+,
O
Ph
N
O
100%); HRMS (ESI+) C31H37N2O3 ([M+H]+) requires 485.2799;
+
found 485.2817.
Me
N
O
From 24: A solution of (3R,aS)-24 (470 mg, 1.23 mmol) in
CH2Cl2 (10 mL) was treated with TFA (10 mL). After 2 h the reac-
tion mixture was concentrated in vacuo. The residue was dis-
solved in CH2Cl2 (10 mL), washed with satd aq NaHCO3 (10 mL),
dried and concentrated in vacuo. The residue was dissolved in
THF (10 mL) and cooled to ꢁ30 °C. Following general procedure
1B, the resultant solution was treated with Et3N (0.50 mL,
3.69 mmol) and pivaloyl chloride (0.17 mL, 1.35 mmol), followed
after 2 h by LiCl (63 mg, 1.47 mmol) and 26 (240 mg, 1.35 mmol).
Purification via flash column chromatography (neutral alumina,
gradient elution, 30–40 °C petrol/Et2O, 10:1; increased to 30–
40 °C petrol/Et2O, 5:1) gave 16 as a colourless oil (350 mg, 59%,
>99:1 dr).
Ph
From 8: Following general procedure 2, a solution of (R)-N-ben-
zyl-N-( -methylbenzyl)amine (220 mg, 1.04 mmol) in THF
a
(10 mL) at ꢁ78 °C was treated with BuLi (1.50 M, 0.68 mL,
1.02 mmol) and 8 (150 mg, 0.65 mmol) to afford an 89:11 mixture
of 28:33. Purification via flash column chromatography (neutral
alumina, eluent 30–40 °C petrol/Et2O, 5:1) gave an 89:11 mixture
of 28:33 as a colourless oil (212 mg, 74%).
From 23: A solution of (R,R)-23 (177 mg, 0.50 mmol) in CH2Cl2
(5 mL) was treated with TFA (5 mL). After 2 h the reaction mix-
ture was concentrated in vacuo. The residue was dissolved in
CH2Cl2 (5 mL), washed with satd aq NaHCO3 (5 mL), dried and
concentrated in vacuo. The residue was again dissolved in CH2Cl2
(5 mL) and cooled to 0 °C. Following general procedure 1C, the
resultant solution was treated with (ClCO)2 (96 mg, 0.75 mmol),
one drop of DMF and one drop of Et3N. A suspension of the resul-
tant acid chloride in THF (5 mL) was subsequently added to a
solution of 25 (245 mg, 1.50 mmol) and BuLi (1.58 M, 0.95 mL,
1.50 mmol) in THF (10 mL) at ꢁ78 °C. Purification via flash col-
umn chromatography (silica, eluent 30–40 °C petrol/Et2O, 1:1)
4.13. (4S,30S, R)-N(3)-{30-[N-Benzyl-N-(
a a-methylbenzyl)amino]-
30-phenylpropanoyl}-4-phenyloxazolidin-2-one 27
Ph
O
Ph
N
O
Ph
N
O
gave 28 as a white foam (69 mg, 31%, >99:1 dr); ½a D21
¼ þ44:6
ꢃ
(c 1.6, CHCl3); mmax (film) 1780 (C@Oendo), 1706 (C@Oexo); dH
(500 MHz, CDCl3) 1.20 (3H, d, J 6.7, C(40)H3), 1.35 (3H, d, J 6.9,
Ph
C(
5.9, C(20)HB), 3.50–3.54 (1H, m, C(30)H), 3.72 (1H, d, J 14.2, NCHA),
3.82 (1H, d, J 14.2, NCHB), 3.87 (1H, q, J 6.9, C( )H), 4.10 (1H, dd,
a
)Me), 2.73 (1H, dd, J 14.2, 7.3, C(20)HA), 2.91 (1H, dd, J 14.2,
From 7: Following general procedure 2, a solution of (R)-N-ben-
zyl-N-( -methylbenzyl)amine (172 mg, 0.82 mmol) in THF
a
a
(10 mL) at ꢁ78 °C was treated with BuLi (1.5 M, 0.54 mL,
0.81 mmol) and 7 (150 mg, 0.51 mmol) to give an 80:20 mixture
of 27:32. Purification via flash column chromatography (neutral
alumina, eluent 30–40 °C petrol/Et2O, 5:1) gave an 80:20 mixture
of 27:32 as a colourless oil (134 mg, 52%).
8.8, 3.4, C(5)HA), 4.40 (1H, dd, J 8.8, 8.6, C(5)HB), 5.10 (1H, dd, J
8.6, 3.4, C(4)H), 7.19–7.52 (15H, m, Ph); dC (125 MHz, CDCl3)
16.2, 19.7 (C(40), C(
57.1, 57.8 (C(4), C(
a
)Me), 41.5 (C(20)), 49.5 (C(30)), 50.0 (NCH2),
a
)), 70.0 (C(5)), 126.2, 126.8, 127.1, 128.2,
128.5, 128.6, 128.9, 129.2, 129.5 (Pho,m,p), 139.8, 141.9, 144.8
From 22: A solution of (3S,aR)-22 (510 mg, 1.23 mmol) in
(Phi), 153.8 (C(2)), 171.0 (C(10)); m/z (CI+) 443 ([M+H]+, 100%);
CH2Cl2 (5 mL) was treated with TFA (5 mL). After 2 h the reaction
mixture was concentrated in vacuo. The residue was dissolved in
CH2Cl2 (5 mL), washed with satd aq NaHCO3 (5 mL), dried and
concentrated in vacuo. The residue was again dissolved in CH2Cl2
(5 mL) and cooled to 0 °C. Following general procedure 1C, the
resultant solution was treated with (ClCO)2 (114 mg, 0.90 mmol),
one drop of DMF and one drop of Et3N. A suspension of the resul-
tant acid chloride in THF (5 mL) was subsequently added to a
solution of 25 (274 mg, 1.68 mmol) and BuLi (1.58 M, 1.06 mL,
1.67 mmol) in THF (10 mL) at ꢁ78 °C. Purification via flash col-
umn chromatography (silica, eluent 30–40 °C petrol/Et2O, 1:1)
HRMS (CI+) C28H31N2O3 ([M+H]+) requires 443.2329; found
+
443.2328.
4.15. (4S,30S, R)-N(3)-{30-[N-Benzyl-N-(
a a-methylbenzyl)amino]-
30-phenylpropanoyl}-4-benzyloxazolidin-2-one 29
Ph
O
Ph
N
O
Ph
N
O
gave (4S,30S,
¼ þ63:5 (c 0.65, CHCl3); mmax (film) 1781 (C@Oendo), 1706
aR)-27 as a white foam (71 mg, 25%, >99:1 dr);
½ ꢃ
a 2D1
(C@Oexo); dH (500 MHz, CDCl3) 1.23 (3H, d, J 6.9, C(a)Me), 2.88
Ph
(1H, dd, J 16.1, 5.0, C(20)HA), 3.55 (1H, dd, J 16.1, 9.2, C(20)HB),
3.71 (1H, d, J 14.5, NCHA), 3.80 (1H, d, J 14.5, NCHB), 3.99 (1H,
From 9: Following general procedure 2, a solution of (R)-N-ben-
zyl-N-( -methylbenzyl)amine (274 mg, 1.30 mmol) in THF
a
q, J 6.9, C(a)H), 4.16 (1H, dd, J 8.8, 3.4, C(5)HA), 4.46 (1H, dd, J
8.8, 8.7, C(5)HB), 4.56 (1H, dd, J 9.2, 5.0, C(30)H), 5.17 (1H, dd, J
8.7, 3.4, C(4)H), 7.19–7.41 (20H, m, Ph); dC (125 MHz, CDCl3)
(15 mL) at ꢁ78 °C was treated with BuLi (1.50 M, 0.86 mL,
1.30 mmol) and 9 (250 mg, 0.81 mmol) to give an 83:17 mixture
of diastereoisomers 29:34. Purification via flash column chroma-
tography (neutral alumina, eluent 30–40 °C petrol/Et2O, 5:1) gave
an 83:17 mixture of 29:34 as a colourless oil (270 mg, 64%).
15.9 (C(
a
)Me), 37.7 (C(20)), 50.7 (NCH2), 56.4 (C(4)), 57.4, 57.9
(C(30), C(
a
)), 69.7 (C(5)), 126.0, 126.6, 126.7, 127.1, 127.5, 127.8,
128.1, 128.2, 128.6, 129.0 (Pho,m,p), 139.0, 141.2, 141.8, 143.5
(Phi), 153.4 (C(2)), 170.4 (C(10)); m/z (CI+) 505 ([M+H]+, 100%);
From 22: A solution of (3S,aR)-22 (233 mg, 0.56 mmol) in
CH2Cl2 (5 mL) was treated with TFA (5 mL). After 2 h the reaction
HRMS (CI+) C33H33N2O3 ([M+H]+) requires 505.2486; found
+
mixture was concentrated in vacuo. The residue was dissolved in
505.2494.

1644
S. G. Davies et al. / Tetrahedron: Asymmetry 21 (2010) 1635–1648
CH2Cl2 (5 mL), washed with satd aq NaHCO3 (5 mL), dried and con-
centrated in vacuo. The residue was again dissolved in CH2Cl2
(5 mL) and cooled to 0 °C. Following general procedure 1C, the resul-
tant solution was treated with (ClCO)2 (114 mg, 0.90 mmol), one
drop of DMF and one drop of Et3N. A suspension of the resultant
acid chloride in THF (5 mL) was subsequently added to a solution
of 26 (298 mg, 1.68 mmol) and BuLi (1.58 M, 1.06 mL, 1.67 mmol)
in THF (10 mL) at ꢁ78 °C. Purification via flash column chromatog-
raphy (silica, eluent 30–40 °C petrol/Et2O, 1:1) gave 29 as a white
129.4 (Pho,m,p), 135.4, 141.4, 144.4 (Phi), 153.1 (C(2)), 171.2
+
(C(10)); m/z (CI+) 457 ([M+H]+, 100%); HRMS (CI+) C29H33N2O3
([M+H]+) requires 457.2486; found 457.2494.
4.17. (4S,30S, R)-N(3)-{30-[N-Benzyl-N-(
a a-methylbenzyl)amino]-
40-methylpentanoyl}-4-benzyloxazolidin-2-one 31
Ph
O
Ph
N
O
foam (98 mg, 34%, >99:1 dr); ½a D21
¼ þ44:2 (c 1.0, CHCl3); mmax
ꢃ
(film) 1780 (C@Oendo), 1700 (C@Oexo); dH (500 MHz, CDCl3) 1.26
i
Pr
N
O
(3H, d, J 6.9, C(a)Me), 2.60 (1H, dd, J 13.4, 9.9, C(4)CHAHBPh), 3.05
(1H, dd, J 15.9, 5.2, C(20)HA), 3.19 (1H, dd, J 13.4, 3.2, C(4)CHAHBPh),
3.55 (1H, dd, J 15.9, 9.2, C(20)HB), 3.75 (1H, d, J 14.7, NCHA), 3.87
(1H, d, J 14.7, NCHB), 3.90–3.96 (1H, m, C(5)HA), 4.02 (1H, dd, J
Ph
9.0, 2.6, C(5)HB), 4.07 (1H, q, J 6.9, C(
C(4)H), 4.62 (1H, dd, J 9.2, 5.2, C(30)H), 7.14–7.47 (20H, m, Ph); dC
(125 MHz, CDCl3) 15.6 (C(
)Me), 37.7, 38.1 (C(20), C(4)CH2Ph),
50.8 (NCH2), 55.1 (C(4)), 56.5 (C(30)), 58.6 (C(
)), 65.9 (C(5)),
a)H), 4.38–4.43 (1H, m,
From 11: Following general procedure 2, a solution of (R)-N-ben-
zyl-N-( -methylbenzyl)amine (247 mg, 1.17 mmol) in THF (10 mL)
a
a
at ꢁ78 °C was treated with BuLi (2.5 M, 0.50 mL, 1.13 mmol) and
11 (200 mg, 0.73 mmol) to give an 85:15 mixture of 31:36. Purifi-
cation via flash column chromatography (neutral alumina, eluent
30–40 °C petrol/Et2O, 5:1) gave an 85:15 mixture of 31:36 as a pale
yellow oil (228 mg, 64%).
a
126.6, 126.8, 127.2, 127.9, 128.1, 128.2, 128.3, 128.7, 128.9,
129.3, 129.5, 130.7 (Pho,m,p), 135.3, 141.4, 141.8, 143.9 (Phi),
153.1 (C(2)), 171.0 (C(10)); m/z (CI+) 519 ([M+H]+, 100%); HRMS
(CI+) C34H35N2O3 ([M+H]+) requires 519.2642; found 519.2643.
+
From 24: A solution of (3S,aR)-24 (469 mg, 1.23 mmol) in
CH2Cl2 (5 mL) was treated with TFA (5 mL). After 2 h the reaction
mixture was concentrated in vacuo. The residue was dissolved in
CH2Cl2 (5 mL), washed with satd aq NaHCO3 (5 mL), dried and con-
centrated in vacuo. The residue was dissolved in THF (5 mL) and
cooled to ꢁ30 °C. Following general procedure 1B, the resultant
solution was treated with Et3N (0.44 mL, 3.13 mmol) and pivaloyl
chloride (0.14 mL, 1.15 mmol), followed after 2 h by LiCl (53 mg,
1.25 mmol) and 26 (204 mg, 1.15 mmol). Purification via flash col-
umn chromatography (neutral alumina, gradient elution, 30–40 °C
petrol/Et2O, 10:1; increased to 30–40 °C petrol/Et2O, 4:1) gave 31
4.16. (4S,30R, R)-3-{30-[N-Benzyl-N-(
a a-methylbenzyl)-amino]-
butanoyl}-4-benzyloxazolidin-2-one 30
Ph
O
Ph
N
O
Me
N
O
as a colourless oil (216 mg, 43%, >99:1 dr); ½a D20
¼ þ58:3 (c 1.0,
ꢃ
Ph
CHCl3); mmax (film) 1781 (C@Oendo), 1699 (C@Oexo); dH (400 MHz,
CDCl3) 0.88 (3H, d, J 6.7, C(40)MeA), 1.16 (3H, d, J 6.6, C(40)MeB),
From 10: Following general procedure 2, a solution of (R)-N-ben-
zyl-N-( -methylbenzyl)amine (277 mg, 1.31 mmol) in THF (15 mL)
1.45 (3H, d, J 7.1, C(a
)Me), 1.70–1.78 (1H, m, C(40)H), 2.13 (1H,
a
dd, J 18.2, 1.9, C(20)HA), 2.67 (1H, dd, J 13.3, 9.6, C(4)CHAHBPh),
3.03 (1H, dd, J 18.2, 8.8, C(20)HB), 3.29 (1H, dd, J 13.3, 3.1,
C(4)CHAHBPh), 3.59 (1H, app td, J 8.8, 1.9, C(30)H), 3.68 (1H, d, J
at -78 °C was treated with BuLi (1.50 M, 0.86 mL, 1.29 mmol) and
10 (200 mg, 0.82 mmol) to give an 80:20 mixture of 30:35. Purifi-
cation via flash column chromatography (neutral alumina, eluent
30–40 °C petrol/Et2O, 5:1) gave an 80:20 mixture of 30:35 as a col-
ourless oil (238 mg, 64%).
15.0, NCHA), 3.80 (1H, q, J 7.1, C(a)H), 3.84 (1H, d, J 15.0, NCHB),
4.08–4.13 (2H, m, C(5)H2), 4.55–4.61 (1H, m, C(4)H), 7.20–7.24
(3H, m, Ph), 7.27–7.41 (10H, m, Ph), 7.52–7.54 (2H, m, Ph); dC
From 23: A solution of (R,R)-23 (130 mg, 0.37 mmol) in CH2Cl2
(5 mL) was treated with TFA (5 mL). After 2 h the reaction mixture
was concentrated in vacuo. The residue was dissolved in CH2Cl2
(5 mL), washed with satd aq NaHCO3 (5 mL), dried and concen-
trated in vacuo. The residue was again dissolved in CH2Cl2 (5 mL)
and cooled to 0 °C. Following general procedure 1C, the resultant
solution was treated with (ClCO)2 (70 mg, 0.56 mmol), one drop
of DMF and one drop of Et3N. A suspension of the resultant acid
chloride in THF (5 mL) was subsequently added to a mixture of
26 (197 mg, 1.11 mmol) and BuLi (1.58 M, 0.70 mL, 1.11 mmol)
in THF (10 mL) at ꢁ78 °C. Purification via flash column chromatog-
raphy (silica, eluent 30–40 °C petrol/Et2O, 1:1) gave 30 as a white
(100 MHz, CDCl3) 19.4 (C(
(C(40)), 35.6 (C(20)), 37.8 (C(4)CH2Ph), 51.5 (NCH2), 55.3 (C(4)),
55.9 (C(30)), 57.1 (C(
)), 65.8 (C(5)), 126.6, 126.9, 127.3, 128.0,
a
)Me), 19.7, 20.9 (C(40)Me2), 32.6
a
128.1, 128.2, 128,3, 129.0, 129.4 (Pho,m,p), 135.3, 141.3, 141.6
(Phi), 153.1 (C(2)), 172.3 (C(10)); m/z (ESI+) 485 ([M+H]+, 100%);
HRMS (ESI+) C31H37N2O3 ([M+H]+) requires 485.2799; found
+
485.2807.
4.18. (4S,30R)- and (S,S)-N(3)-[30-(N,N-Dibenzylamino)-30-phenyl-
propanoyl]-4-phenyloxazolidin-2-one 38 and 43
Ph
Ph
foam (38 mg, 22%, >99:1 dr); ½a D21
¼ þ42:9 (c 0.5, CHCl3); mmax
ꢃ
(film) 1781 (C@Oendo), 1700 (C@Oexo); dH (500 MHz, CDCl3) 1.25
O
O
Ph
N
O
Ph
N
O
(3H, d, J 6.6, C(40)H3), 1.39 (3H, d, J 6.9, C(
a)Me), 2.67 (1H, dd, J
+
13.4, 9.6, C(4)CHAHBPh), 2.80 (1H, dd, J 14.3, 7.7, C(20)HA), 2.98
(1H, dd, J 14.3, 5.7, C(20)HB), 3.23 (1H, dd, J 13.4, 3.2, C(4)CHAHBPh),
3.52–3.58 (1H, m, C(30)H), 3.75 (1H, d, J 14.2, NCHA), 3.88–3.95 (3H,
Ph
N
O
Ph
N
O
Ph
(4S,3'R)-38
Ph
(S,S)-43
m, C(5)HA, C(
(1H, m, C(4)H), 7.18–7.40 (13H, m, Ph), 7.54–7.56 (2H, m, Ph); dC
(125 MHz, CDCl3) 15.5, 19.2 (C(40), C( )Me), 37.5, 41.3 (C(20),
C(4)CH2Ph), 49.2 (C(30)), 49.6 (NCH2), 54.9 (C(4)), 56.5 (C(
)), 65.7
(C(5)), 126.4, 126.7, 127.3, 127.7, 128.1, 128.2, 128.8, 128.9,
a)H, NCHB), 4.00 (1H, dd, J 8.9, 2.5, C(5)HB), 4.34–4.39
Following general procedure 2, a solution of dibenzylamine
(0.98 mL, 5.11 mmol) in THF (40 mL) at ꢁ78 °C was treated with
BuLi (1.58 M, 3.23 mL, 5.10 mmol) and 7 (1.00 g, 3.41 mmol) to
a
a

S. G. Davies et al. / Tetrahedron: Asymmetry 21 (2010) 1635–1648
1645
give a 75:25 mixture of 38:43. Purification via flash column chro-
matography (silica, gradient elution, 30–40 °C petrol/Et2O, 9:1; in-
creased to 30–40 °C petrol/Et2O, 1:1) gave a 75:25 mixture of
38:43 as a colourless oil (1.31 g, 80%); mmax (film) 1779 (C@Oendo),
1702 (C@Oexo); m/z (APCI+) 491 ([M+H]+, 100%).
Data for 38: dH (500 MHz, CDCl3) [selected peaks] 1.05 (2H, d, J
14.0, N(CHAHBPh)2), 3.56 (1H, dd, J 15.9, 6.1, C(20)HA), 3.77 (1H, d, J
14.0, N(CHAHBPh)2), 3.83 (1H, dd, J 15.9, 9.1, C(20)HB), 4.18 (1H, dd, J
8.8, 4.0, C(5)HA), 4.46 (1H, dd, J 9.1, 6.1, C(30)H), 4.59 (1H, dd, J 8.8,
8.7, C(5)HB), 5.37 (1H, dd, J 8.7, 4.0, C(4)H), 7.21–7.43 (20H, m, Ph).
C(4)CHAHBPh), 3.35 (2H, d, J 13.9, N(CHAHBPh)2), 3.61 (1H, dd, J
15.9, 6.9, C(20)HA), 3.74 (1H, dd, J 15.9, 8.4, C(20)HB), 3.82 (2H, d, J
13.9, N(CHAHBPh)2), 4.09–4.13 (2H, m, C(5)H2), 4.55 (1H, dd, J 8.4,
6.9, C(30)H), 4.60–4.65 (1H, m, C(4)H), 7.10–7.12 (2H, m, Ph),
7.22–7.42 (18H, m, Ph); dC (125 MHz, CDCl3) 36.1 (C(20), 37.8
C(4)CH2Ph), 54.0 (C(30)), 55.2 (C(4)), 59.0 (N(CH2Ph)2), 66.0 (C(5)),
126.9, 127.2, 127.4, 128.1, 128.2, 128.6, 128.7, 128.9, 129.3
(Pho,m,p), 135.3, 137.9, 139.8 (Phi), 153.4 (C(2)), 171.0 (C(10)); m/z
(CI+) 505 ([M+H]+, 100%).
4.21. (S,S)- and (4S,30R)-N(3)-[30-(N,N-Dibenzylamino)butanoyl]-
4-benzyloxazolidin-2-one 41 and 46
4.19. (S,S)-N(3)-[30-(N,N-Dibenzylamino)butanoyl]-4-phenyl-
oxazolidin-2-one 39
Ph
Ph
Ph
O
O
Ph
N
O
Ph
N
O
O
Ph
N
O
+
Me
N
O
Me
N
O
Me
N
O
Ph
Ph
Ph
(4 ,3' )-46
(
,
)-41
S S
S
R
Following general procedure 2, a solution of dibenzylamine
(0.78 mL, 4.09 mmol) in THF (20 mL) at ꢁ78 °C was treated with
BuLi (1.58 M, 2.59 mL, 4.09 mmol) and 8 (630 mg, 2.72 mmol) to
give a 78:22 mixture of 39:44. Purification via flash column chro-
matography (silica, gradient elution, 30–40 °C petrol/Et2O, 9:1; in-
creased to 30–40 °C petrol/Et2O, 1:1) gave a 78:22 mixture of
39:44 as a white solid (957 mg, 82%). Recrystallisation (30–40 °C
petrol/Et2O) gave 39 as a white solid (512 mg, 44%, >99:1 dr);
Following general procedure 2, a solution of dibenzylamine
(1.06 mL, 5.50 mmol) in THF (20 mL) at ꢁ78 °C was treated with
BuLi (1.58 M, 3.48 mL, 5.50 mmol) and 10 (900 mg, 3.67 mmol)
to give a 76:24 mixture of 41:46. Purification via flash column
chromatography (silica, gradient elution, 30–40 °C petrol/Et2O,
10:1; increased to 30–40 °C petrol/Et2O, 1:1) gave a 76:24 mixture
of 41:46 as a colourless oil (1.38 g, 85%).
Data for 41: dH (500 MHz, CDCl3) 1.20 (3H, d, J 6.4, C(40)H3), 2.57
(1H, dd, J 13.3, 10.1, C(4)CHAHBPh), 3.02 (1H, dd, J 14.9, 7.2,
C(20)HA), 3.28 (1H, dd, J 14.9, 7.1, C(20)HB), 3.33 (1H, dd, J 13.3,
3.7, C(4)CHAHBPh), 3.37–3.58 (3H, m, C(30)H, N(CHAHBPh)2), 3.72
(2H, d, J 14.5, N(CHAHBPh)2), 4.05–4.11 (2H, m, C(5)H2), 4.60–4.64
(1H, m, C(4)H), 7.18–7.34 (15H, m, Ph).
C
27H28N2O3 requires C, 75.7; H, 6.6; N, 6.5; found C, 75.9; H, 6.4;
N, 6.5; mp 131–133 °C; ½a D21
¼ þ50:3 (c 1.0, CHCl3); mmax (KBr)
ꢃ
1792 (C@Oendo), 1694 (C@Oexo); dH (500 MHz, CDCl3) 1.05 (3H, d,
J 6.6, C(40)H3), 3.00 (1H, dd, J 15.3, 8.3, C(20)HA), 3.33 (1H, dd, J
15.3, 5.9, C(20)HB), 3.40–3.45 (1H, m, C(30)H), 3.57 (2H, d, J 14.0,
N(CHAHBPh)2), 3.65 (2H, d, J 14.0, N(CHAHBPh)2), 4.24 (1H, dd, J
8.8, 3.6, C(5)HA), 4.60 (1H, dd, J 8.8, 8.7, C(5)HB), 5.39 (1H, dd, J
8.7, 3.6, C(4)H), 7.19–7.22 (2H, m, Ph), 7.26–7.40 (13H, m, Ph); dC
(125 MHz, CDCl3) 15.1 (C(40)), 38.4 (C(20)), 51.0 (C(30)), 53.6
(N(CH2Ph)2), 57.7 (C(4)), 69.7 (C(5)), 126.0, 126.7, 128.1, 128.5,
128.6, 129.1 (Pho,m,p), 139.1, 140.1 (Phi), 153.6 (C(2)), 171.4
(C(10)); m/z (CI+) 429 ([M+H]+, 100%).
4.22. (4S,30R)- and (S,S)-N(3)-[30-(N,N-Dibenzylamino)-40-methyl-
pentanoyl]-4-benzyloxazolidin-2-one 42 and 47 and N,N-diben-
zyl (RS)-3-(N,N-dibenzylamino)-4-methylpentanamide 48
Ph
Ph
Ph
4.20. (4S,30R)-N(3)-[30-(N,N-Dibenzylamino)-30-phenylpropanoyl]-
O
O
Ph
N
O
Ph
N
O
Ph
N
O
4-benzyloxazolidin-2-one 40
+
+
i
i
iPr
N
O
Pr
N
O
Pr
N
Ph
Ph
Ph
O
Ph
N
O
Ph
(4 ,3' )-42
Ph
(
,
)-47
(
)-48
RS
S
R
S S
Ph
N
O
Following general procedure 2, a solution of dibenzylamine
(0.41 mL, 2.12 mmol) in THF (5 mL) at ꢁ78 °C was treated with
BuLi (1.6 M, 1.28 mL, 2.05 mmol) and 11 (362 mg, 1.32 mmol)
to give a 37:13:50 mixture of 42:47:48. Purification via flash col-
umn chromatography (silica, gradient elution, 30–40 °C petrol/
Et2O, 9:1; increased to 30–40 °C petrol/Et2O, 1:1) gave 48 as a
colourless oil (200 mg, 31%); mmax (film) 1648 (C@O); dH
(400 MHz, CDCl3) 0.88 (3H, d, J 6.7, C(4)MeA), 1.04 (3H, d, J
6.6, C(4)MeB), 1.81–1.90 (1H, m, C(4)H), 2.47 (1H, dd, J 15.9,
7.0, C(2)HA), 2.70 (1H, dd, J 15.9, 3.9, C(2)HB), 3.27–3.32 (1H,
m, C(3)H), 3.41 (2H, d, J 13.7, C(3)N(CHAHBPh)2), 3.77 (2H, d, J
13.7, C(3)N(CHAHBPh)2), 4.43–4.81 (4H, m, C(1)N(CH2Ph)2),
7.21–7.45 (20H, m, Ph); dC (100 MHz, CDCl3) 20.2, 20.9
(C(4)Me2), 31.2 (C(2)), 31.6 (C(4)), 48.7, 50.2 (C(1)N(CH2Ph)2),
Ph
Following general procedure 2, a solution of dibenzylamine
(0.28 mL, 1.46 mmol) in THF (25 mL) at ꢁ78 °C was treated with
BuLi (1.58 M, 0.92 mL, 1.45 mmol) and 9 (300 mg, 0.98 mmol) to
give a 79:21 mixture of 40:45. Purification via flash column chro-
matography (silica, gradient elution, 30–40 °C petrol/Et2O, 9:1; in-
creased to 30–40 °C petrol/Et2O, 1:1) gave a 79:21 mixture of
40:45 as a white solid (450 mg, 91%). Recrystallisation (30–40 °C
petrol/Et2O) gave 40 as a white solid (264 mg, 53%, >99:1 dr);
C
33H32N2O3 requires C, 78.55; H, 6.4; N, 5.55; found C, 78.6; H,
6.3; N, 5.5; mp 142–144 °C; ½a D21
¼ þ91:4 (c 1.2, CHCl3); mmax
ꢃ
(KBr) 1772 (C@Oendo), 1710 (C@Oexo); dH (500 MHz, CDCl3) 2.53
(1H, dd, J 13.4, 9.8, C(4)CHAHBPh), 3.11 (1H, dd, J 13.4, 3.3,

1646
S. G. Davies et al. / Tetrahedron: Asymmetry 21 (2010) 1635–1648
54.7 (C(3)N(CH2Ph)2), 61.3 (C(3)), 126.5, 126.8, 127.5, 127.7,
128.1, 128.6, 129.0, 129.1 (Pho,m,p), 136.9, 137.6, 140.2 (Phi),
173.0 (C(1)); m/z (ESI+) 491 ([M+H]+, 100%); HRMS (ESI+)
(2.5 M, 0.20 mL, 0.50 mmol). After 30 min, a solution of 9
(100 mg, 0.33 mmol) in THF (2 mL) was added via cannula. The
mixture was stirred for 3 h at ꢁ78 °C, then TESCl was added
(78 mg, 0.52 mmol) and the reaction mixture was allowed to warm
to rt over 5 h. The solvent was removed in vacuo to give 51 (72%
conversion, >95:5 dr); dH (500 MHz, CDCl3) 0.46 (6H, q, J 7.8,
Si(CH2CH3)3), 0.79 (9H, t, J 7.8, Si(CH2CH3)3), 1.24 (3H, d, J 6.7,
C
34H38N2O+ ([M+H]+) requires 491.3057; found 491.3063. Further
elution gave
a 73:27 mixture of 42:47 as a colourless oil
(103 mg, 17%); mmax (film) 1780 (C@Oendo), 1699 (C@Oexo); m/z
(ESI+) 471 ([M+H]+, 100%); HRMS (ESI+) C30H35N2O3 ([M+H]+) re-
+
quires 471.2642; found 471.2650.
C(a)Me), 2.68–2.74 (1H, m, C(4)CHAHBPh), 3.26–3.29 (1H, m,
Data for 42: dH (400 MHz, CDCl3) 0.90 (3H, d, J 6.6, C(40)MeA),
1.07 (3H, d, J 6.6, C(40)MeB), 1.92–2.00 (1H, m, C(40)H), 2.65 (1H,
dd, J 13.2, 10.3, C(4)CHAHBPh), 3.11–3.37 (4H, m, C(20)H2, C(30)H,
C(4)CHAHBPh), 3.43 (2H, d, J 13.7, N(CHAHBPh)2), 3.83 (2H, d, J
13.7, N(CHAHBPh)2), 4.15–4.21 (2H, m, C(5)H2), 4.69–4.78 (1H, m,
C(4)H), 7.22–7.41 (15H, m, Ph); dC (100 MHz, CDCl3) 20.0, 21.7
(C(40)Me2), 31.5 (C(40)), 32.6 (C(20)), 37.9 (C(4)CH2Ph), 54.5
(N(CH2Ph)2), 55.4 (C(4)), 60.7 (C(30)), 66.1 (C(5)), 126.5, 126.7,
127.3, 128.1, 128.6, 129.0, 129.1, 129.4, 129.5 (Pho,m,p), 135.4,
140.0 (Phi), 153.6 (C(2)), 172.8 (C(10)).
Data for 47: dH (400 MHz, CDCl3) [selected peaks] 1.14–1.16
(6H, m, C(40)Me2), 2.56–2.64 (1H, m, C(40)H), 2.78–2.84 (1H, m,
C(4)CHAHBPh), 3.55 (2H, d, J 13.6, N(CHAHBPh)2), 3.77 (2H, d, J
13.6, N(CHAHBPh)2), 4.06–4.14 (2H, m, C(5)H2), 4.58–4.65 (1H,
m, C(4)H).
C(4)CHAHBPh), 3.74 (1H, d, J 15.3, NCHA), 4.03 (1H, d, J 15.3, NCHB),
4.07–4.10 (2H, m, C(4)H, C(5)HA), 4.17–4.19 (2H, m, C(5)HB, C(a)H),
4.86 (1H, d, J 8.4, C(30)H), 5.20 (1H, d, J 8.4, C(20)H), 7.17–7.39 (16H,
m, Ph), 7.56–7.59 (4H, m, Ph).
4.25. (4S,30R)-N(3)-(30-Amino-30-phenylpropanoyl)-4-benzyloxaz-
olidin-2-one 52
O
NH2
O
Ph
N
O
Ph
A vigorously stirred solution of 14 (520 mg, 1.00 mmol) in glacial
AcOH (5 mL) was treated with Pd(OH2)/C (130 mg). The reaction
vessel was flushed with hydrogen and the reaction mixture was left
to stir under a hydrogen atmosphere. After 24 h, the reaction mix-
ture was filtered through CeliteÒ (eluent MeOH) and the filtrate
was concentrated in vacuo. The residue was dissolved in CH2Cl2
(10 mL) and washed with satd aq NaHCO3, then dried and concen-
trated in vacuo. Crystallisation from Et2O gave 52 as a white solid
(289 mg, 89%); C19H20N2O3 requires C, 70.35; H, 6.2; N, 8.6; found
4.23. (R)-3-Amino-3-phenyl propanoic acid 50
NH2
CO2H
Ph
A solution of 40 (100 mg, 0.20 mmol) in THF/H2O (v:v 3:1, 4 mL)
at 0 °C was treated with 35% aq H2O2 (0.10 mL, 1.00 mmol) and LiOH
(10 mg, 0.40 mmol). After being allowed to warm to rt over 16 h, 10%
aq. Na2SO4 (5 mL) was added and the reaction mixture was stirred
for a further 30 min. The mixture was then basified to pH 9–10 with
satd aq NaHCO3 and extracted with CH2Cl2 (10 mL). The organic
layer was dried and concentrated in vacuo to give 26 (35 mg, quant).
The aqueous layer was then acidified to pH 1–2 with 2 M aq. HCl and
extracted with EtOAc (3 ꢄ 25 mL). The combined organic extracts
were dried and concentrated in vacuo. The residue was dissolved
in degassed MeOH (5 mL) and Pd(OH)2/C (10 mg) was added. The
reaction vessel was flushed with hydrogen and the reaction mixture
was left to stir under a hydrogen atmosphere. After 24 h, the reaction
mixture was filtered through CeliteÒ (eluent MeOH) and the filtrate
was concentrated in vacuo. Purification via ion exchange chroma-
tography (Dowex 50WX8-200, eluent 1 M aq NH4OH) gave (R)-50
as a white solid (14 mg, 43% from 40);26 mp 232–235 °C; {lit.26 mp
C, 70.1; H, 6.2; N, 8.6; mp 129–131 °C; ½a D21
¼ ꢁ49:9 (c 2.1, CHCl3);
ꢃ
mmax (KBr) 3442, 3331 (N–H), 1692 (C@Oendo), 1664 (C@Oexo); dH
(500 MHz, CDCl3) 2.62–2.67 (1H, m, C(20)HA), 2.78–2.82 (1H, m,
C(20)HB), 3.12 (1H, dd, J 13.7, 7.0, CHAHBPh), 3.18 (2H, br s, NH2),
3.23 (1H, dd, J 13.7, 9.6, CHAHBPh), 3.84 (1H, dd, J 11.9, 3.3,
C(5)HA), 4.02–4.05 (1H, m, C(5)HB), 4.37 (1H, app br s, C(30)H),
5.10–5.16 (1H, m, C(4)H), 7.18–7.38 (10H, m, Ph); dC (125 MHz,
CDCl3) 34.6 (CH2Ph), 40.0 (C(20)), 51.0 (C(30)), 56.6 (C(4)), 63.4
(C(5)), 125.9, 126.6, 128.4, 128.9, 129.3 (Pho,m,p), 138.1, 138.6 (Phi),
155.4 (C(2)), 169.6 (C(10)); m/z (CI+) 325 ([M+H]+, 100%).
4.26. (4S,30R,200S)-N(3)-(30-{N0-[200-N00-(tert-Butoxycarbonyl)-
amino-300-phenylpropanoyl]amino}-30-phenylpropanoyl)-4-
benzyloxazolidin-2-one 53
O
H
N
234–237 °C}; ½a 2D2
ꢃ
¼ þ6:2 (c 0.6, H2O); {lit.18
½
a 1D9
ꢃ
¼ þ6:5 (c 1.0,
O
Boc
NH
O
H2O)}; dH (400 MHz, D2O) 2.71 (1H, dd, J 16.2, 6.8, C(2)HA), 2.80
(1H, dd, J 16.2, 7.9, C(2)HB), 4.52 (1H, dd, J 7.9, 6.8, C(3)H), 7.30–
7.37 (5H, m, Ph).
Ph
Ph
N
O
Ph
4.24. (4S,30R, S,Z)-N(3)-{10-Triethylsilyloxy-30-[N-benzyl-N-(
a a-
methylbenzyl)amino]-30-phenylprop-20-enyl}-4-benzyl-
oxazolidin-2-one 51
A solution of 52 (1.11 g, 3.42 mmol) in THF (5 mL) at 0 °C was
treated with N-Boc -phenylalanine (907 mg, 3.42 mmol) and
L
DCC (705 mg, 3.42 mmol). After 3 h, the reaction mixture was fil-
tered and concentrated in vacuo. Purification via flash column
chromatography (silica, eluent hexane/EtOAc, 4:1) gave 53 as a
white solid (1.61 g, 82%); C33H37N3O6 requires C, 69.3; H, 6.5; N,
7.35; found C, 69.5; H, 6.6; N, 7.1; mp 200–202 °C (EtOAc/Et2O);
Ph
O
Ph
N
OTES
N
Ph
O
½
a 2D1
ꢃ
¼ þ58:2 (c 1.6, CHCl3); mmax (KBr) 3365 (N–H), 1790, 1694,
1661 (C@O); dH (500 MHz, CDCl3) 1.42 (9H, s, CMe3), 2.62 (1H,
Ph
dd,
J 13.6, 9.7, C(4)CHAHBPh), 3.03 (1H, dd, J 13.6, 7.7,
A solution of (S)-N-benzyl-N-(
a
-methylbenzyl)amine (110 mg,
C(4)CHAHBPh), 3.12–3.15 (2H, m, C(20)HA, C(300)HA), 3.25–3.28
(1H, m, C(20)HB), 3.52 (1H, dd, J 16.4, 6.5, C(300)HB), 4.07–4.11 (2H,
0.52 mmol) in THF (2 mL) at ꢁ78 °C was treated with BuLi

S. G. Davies et al. / Tetrahedron: Asymmetry 21 (2010) 1635–1648
1647
m, C(5)H2), 4.38 (1H, app br s, C(200)H), 4.52–4.56 (1H, m, C(4)H),
5.05 (1H, br s, NH), 5.50 (1H, dd, J 14.4, 6.3, C(30)H), 6.76 (1H, br
s, NH), 7.10–7.11 (2H, m, Ph), 7.10–7.11 (13H, m, Ph); dC
(125 MHz, CDCl3) 28.2, 37.5, 38.4, 40.7, 49.7, 54.9, 55.8, 66.1,
80.1, 126.4, 126.9, 127.3, 127.6, 128.6, 128.7, 128.9, 129.3, 129.4,
135.0, 136.8, 140.3, 153.3, 155.4, 170.2, 170.3; m/z (CI+) 572
([M+H]+, 100%).
126.3, 126.7, 126.9, 128.2, 128.3, 128.4, 129.2, 129.4, 137.6,
138.5, 142.5, 155.4, 169.6, 170.9, 172.9; m/z (CI+) 560 ([M+H]+,
100%); HRMS (ESI+) C32H38N3O6 ([M+H]+) requires 560.2755;
+
found 560.2767.
4.29. H-[(S)-Phe-(R)-b-Phe-(S)-Phe]-OH trifluoroacetic acid salt 56
O
TFA•H2N
4.27. (S)-N-10-Hydroxy-30-phenylpropan-20-yl (3R,200S)-3-{N0-[200-
N00-(tert-butoxycarbonyl)amino-300-phenylpropanoyl]amino}-3-
phenylpropanamide 54
NH
O
Ph
Ph
NH
Ph
O
CO2H
H
N
Boc
NH
O
A solution of 55 (100 mg, 0.18 mmol) in CH2Cl2 (3 mL) was trea-
ted with TFA (3 mL). After 2 h the reaction mixture was concen-
trated in vacuo. Purification via flash column chromatography
(RP-18 gel, gradient elution, H2O (0.1% TFA); increased to H2O
(0.1% TFA)/MeOH, 1:1) gave 56 as a white foam (71 mg, 68%);
Ph
Ph
NH
Ph
OH
A solution of 53 (1.00 g, 1.75 mmol) in THF/H2O (v:v 1:1, 12 mL)
was treated with LiOH (350 mg, 8.45 mmol) and heated at 60 °C for
5 h. The reaction mixture was concentrated in vacuo and the resi-
due was neutralised by the dropwise addition of 5% aq citric acid.
The resultant precipitate was filtered and washed sequentially
with cold water (10 mL) and CH2Cl2 (10 mL). Purification via flash
column chromatography (silica, eluent CH2Cl2/MeOH, 9:1) gave 54
½
a 2D3
ꢃ
¼ þ48:8 (c 0.9, DMF); mmax (KBr) 3411, 3302 (O–H, N–H),
1670 (C@O); dH (500 MHz, DMSO-d6) 2.39 (1H, dd, J 14.7, 6.8),
2.56 (1H, dd, J 14.7, 8.0), 2.80 (1H, dd, J 13.9, 8.3), 2.91 (1H, dd, J
13.9, 5.3), 2.96 (1H, dd, J 13.9, 7.7), 3.07 (1H, dd, J 13.9, 6.3), 4.00
(1H, br s), 4.37–4.41 (1H, m), 5.16–5.23 (1H, m), 7.03–7.07 (2H,
m), 7.17–7.36 (13H, m), 8.14 (3H, br s), 8.28 (1H, d, J 7.9), 8.87
(1H, d, J 8.4); dC (125 MHz, DMSO-d6) 35.1, 35.2, 39.6, 48.3, 51.7,
51.9, 124.8, 125.2, 125.6, 126.6, 126.7, 127.0, 127.4, 128.0, 133.4,
135.7, 140.0, 156.4, 165.4, 167.3, 171.2; m/z (CI+) 460 ([M+H]+,
as a white solid (506 mg, 53%); mp 202–204 °C; ½a D21
¼ ꢁ19:1 (c
ꢃ
0.6, DMF); mmax (film) 3309 (N–H, O–H), 1688, 1658 (C@O); dH
(500 MHz, DMSO-d6) 1.29 (9H, s), 2.48–2.52 (2H, m), 2.55 (1H,
dd, J 13.8, 7.8), 2.73–2.78 (2H, m), 2.94 (1H, dd, J 13.8, 4.4), 3.17–
3.29 (2H, m), 3.82–3.86 (1H, m), 4.16–4.19 (1H, m), 4.73 (1H, br
s), 5.17 (1H, dd, J 13.1, 6.7), 6.94 (1H, d, J 8.6), 7.11–7.29 (15H,
m), 7.77 (1H, d, J 8.2), 8.43 (1H, d, J 8.2); dC (125 MHz, DMSO-d6)
28.3, 36.5, 37.5, 42.1, 49.9, 52.4, 56.0, 62.3, 78.2, 126.0, 126.3,
126.5, 126.8, 128.2, 128.3, 129.2, 138.5, 139.2, 142.6, 155.4,
100%); HRMS (ESI+) C27H30N3O4 ([M+H]+) requires 460.2231;
+
found 460.2246.
References
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169.3, 170.9; m/z (CI+) 546 ([M+H]+, 100%); HRMS (ESI+)
+
C
32H39N3NaO5 ([M+Na]+) requires 568.2782; found 568.2791.
4.28. Boc-[(S)-Phe-(R)-b-Phe-(S)-Phe]-OH 55
3. Bull, S. D.; Davies, S. G.; Nicholson, R. L.; Sanganee, H. J.; Smith, A. D. Org. Biomol.
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O
H
N
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O
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Ph
CO2H
Jones reagent (2.2 M, 0.15 mL) was diluted with acetone (2 mL)
and added dropwise to a solution of 54 (100 mg, 0.18 mmol) in
acetone (10 mL) at 0 °C. After 3 h at 0 °C the reaction mixture chan-
ged colour from orange to green; IPA (0.50 mL) was then added,
and the reaction mixture was stirred for a further 30 min. The reac-
tion mixture was evaporated in vacuo, and the resultant green so-
lid was dissolved in H2O (10 mL). The solution was extracted with
EtOAc (3 ꢄ 10 mL) and the combined organic extracts were con-
centrated in vacuo. The residue was filtered over Sephadex LH
20Ò gel, washing with EtOAc/MeOH/H2O (v:v:v 8:2:1) to remove
any traces of chromium. Purification via flash column chromatog-
raphy (silica, eluent PhMe/MeOH/AcOH, 5:1:1) gave 55 as a white
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solid (85 mg, 84%); mp 193–194 °C; ½a D23
¼ þ13:8 (c 0.5, DMF);
ꢃ
9. For a review of organoaluminiums see: Maruoka, K.; Yamamoto, H. Angew.
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mmax (KBr) 3329 (N–H, O–H), 1687, 1655 (C@O); dH (500 MHz,
DMSO-d6) 1.29 (9H, s), 2.49 (1H, dd, J 14.6, 6.8), 2.56 (1H, dd, J
14.6, 7.2), 2.74 (1H, dd, J 13.8, 10.2), 2.82 (1H, dd, J 13.8, 8.4),
2.91–3.34 (2H, m), 4.13–4.17 (1H, m), 4.37–4.41 (1H, m), 5.14–
5.19 (1H, m), 6.96 (1H, d, J 8.5), 7.08–7.09 (2H, m), 7.16–7.28
(13H, m), 8.24 (1H, d, J 7.4), 8.41 (1H, d, J 8.3); dC (125 MHz,
DMSO-d6) 28.3, 37.0, 37.4, 41.7, 49.7, 53.5, 56.0, 78.2, 126.2,
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