Asymmetric synthesis of β2-amino acids: 2-substituted-3-aminopropanoic acids from N-acryloyl SuperQuat derivatives

Article abstract of DOI:10.1039/b707689d

Conjugate addition of lithium dibenzylamide to (S)-N(3)-acryloyl-4- isopropyl-5,5-dimethyloxazolidin-2-one (derived from l-valine) and alkylation of the resultant lithium β-amino enolate provides, after deprotection, a range of (S)-2-alkyl-3-aminopropanoic acids in good yield and high ee. Alternatively, via a complementary pathway, conjugate addition of a range of secondary lithium amides to (S)-N(3)-(2′-alkylacryloyl)-4-isopropyl-5,5- dimethyloxazolidin-2-ones, diastereoselective protonation with 2-pyridone, and subsequent deprotection furnishes a range of (R)-2-alkyl- and (R)-2-aryl-3-aminopropanoic acids in good yield and high ee. Additionally, the boron-mediated aldol reaction of β-amino N-acyl oxazolidinones is a highly diastereoselective method for the synthesis of a range of β-amino- β′-hydroxy N-acyl oxazolidinones. The Royal Society of Chemistry.

Full text of DOI:10.1039/b707689d

View Article Online / Journal Homepage / Table of Contents for this issue
PAPER
www.rsc.org/obc | Organic & Biomolecular Chemistry
Asymmetric synthesis of b2-amino acids: 2-substituted-3-aminopropanoic
acids from N-acryloyl SuperQuat derivatives†
James E. Beddow, Stephen G. Davies,* Kenneth B. Ling, Paul M. Roberts, Angela J. Russell, Andrew D. Smith
and James E. Thomson
Received 22nd May 2007, Accepted 20th June 2007
First published as an Advance Article on the web 25th July 2007
DOI: 10.1039/b707689d
Conjugate addition of lithium dibenzylamide to (S)-N(3)-acryloyl-4-isopropyl-5,5-
dimethyloxazolidin-2-one (derived from L-valine) and alkylation of the resultant lithium b-amino
enolate provides, after deprotection, a range of (S)-2-alkyl-3-aminopropanoic acids in good yield and
high ee. Alternatively, via a complementary pathway, conjugate addition of a range of secondary
lithium amides to (S)-N(3)-(2ꢀ-alkylacryloyl)-4-isopropyl-5,5-dimethyloxazolidin-2-ones,
diastereoselective protonation with 2-pyridone, and subsequent deprotection furnishes a range of
(R)-2-alkyl- and (R)-2-aryl-3-aminopropanoic acids in good yield and high ee. Additionally, the
boron-mediated aldol reaction of b-amino N-acyl oxazolidinones is a highly diastereoselective method
for the synthesis of a range of b-amino-bꢀ-hydroxy N-acyl oxazolidinones.
Introduction
Results and discussion
a-Substituted-b-amino acids (b2-amino acids), like their b-
substituted-b-amino acid counterparts (b3-amino acids), are of
immense chemical and biological interest.1 They occur naturally
within pseudopeptides2 and highly potent biological effects are
observed with both naturally occurring and synthetic derivatives.3
They have also been shown to display interesting structural
properties as constituents of b-peptides.4 Despite their importance
in biology and peptide chemistry, the synthesis of b2-amino acids
has received little attention in the literature when compared to
their b3-amino acid counterparts.5 To date the stereoselective
Mannich reaction6 and the asymmetric alkylation of chiral b-
alanine derivatives7,8 have received most attention as synthetic
routes to b2-amino acids; other routes based upon conjugate
addition,9,10 Curtius rearrangement,11 catalytic C–H insertion,12
dynamic kinetic resolution,13 enantioselective hydrogenation14
and catalytic asymmetric addition of cyanide to a,b-unsaturated
imides15 amongst others16 have also proved successful. Previous
investigations from this laboratory have shown that the conjugate
addition of a homochiral secondary lithium amide derived from
a-methylbenzylamine to an a,b-unsaturated ester or amide rep-
resents an efficient entry to b3-amino acids and derivatives.17 We
wished to extend our methodology to incorporate the synthesis
of b2-amino acids and their derivatives, and report herein our full
investigations within this area concerning the conjugate addition
of lithium amides to N-acryloyl SuperQuat derivatives, followed
by stereoselective enolate functionalisation. Part of this work has
been communicated previously.18
Conjugate addition of lithium amides to N-acryloyl
oxazolidin-2-ones
Although a range of amines have been shown to add in a conjugate
fashion to acrylates,10 conjugate addition of metal amides to
this type of a,b-unsaturated carbonyl system is rare, presumably
due to facile polymerisation of the activated olefin.19 In order
to test the susceptibility of N-acryloyl oxazolidinones toward
conjugate addition of lithium amides, N-acryloyl oxazolidin-2-
ones 3 and 4 were prepared.20 The standard protocol for N-
acylation of an oxazolidin-2-one (via the lithium anion) could
not by employed in the synthesis of the 3-acryloyl acceptors, as
the oxazolidin-2-one anion is itself able to undergo a conjugate
addition reaction with an acrylate.21 A milder procedure using
acrylic anhydride was therefore employed,21 giving N-acryloyl
Evans derivative 3 and N-acryloyl SuperQuat 4 in 65 and 72%
yield, respectively (Scheme 1). The conjugate addition reaction of
lithium dibenzylamide 5 to N-acryloyl Evans 3 was attempted
at high dilution (40 lM w. r. t. 3) in an attempt to suppress
polymerisation; however, a mixture of products was obtained
from which 6 was isolated in 66% yield. Similar reaction of
N-acryloyl SuperQuat 4 under identical conditions gave, after
5 min, complete conversion to a single product 7, which was
isolated in 92% yield (Scheme 1). The incorporation of the 5,5-
dimethyl group into the oxazolidin-2-one skeleton not only serves
to suppress the endocyclic cleavage pathway upon cleavage but also
restricts the conformation of the C(4)-stereodirecting isopropyl
group such that it mimics the steric demands of a tert-butyl
group.22 It is apparent from this study that the conformational
restriction also decreases the extent of unwanted side reactions
of N-acryloyl SuperQuat 4 upon conjugate addition of lithium
dibenzylamide 5, relative to the corresponding N-acryloyl Evans
derivative 3. The conjugate addition of both antipodes of lithium
N-benzyl-N-(a-methylbenzyl)amide 8 to N-acryloyl SuperQuat
Department of Organic Chemistry, Chemistry Research Laboratory, Uni-
versity of Oxford, Mansfield Road, Oxford, UK OX1 3TA. E-mail:
steve.davies@chem.ox.ac.uk
† Electronic supplementary information (ESI) available: Experimental
details. See DOI: 10.1039/b707689d
2812 | Org. Biomol. Chem., 2007, 5, 2812–2825
This journal is
The Royal Society of Chemistry 2007
©

View Article Online
Scheme 1 Reagents and conditions: (i) acrylic anhydride, Et3N, LiCl,
THF, rt, 2 h; (ii) lithium dibenzylamide 5, THF, −78 ◦C, 5 min, then
NH4Cl (sat., aq.); (iii) lithium (R)-N-benzyl-N-(a-methylbenzyl)amide
8, THF, −78 ◦C, 5 min, then NH4Cl (sat., aq.); (iv) lithium (S)-N-
benzyl-N-(a-methylbenzyl)amide 8, THF, −78 ◦C, 5 min, then NH4Cl
(sat., aq.).
Fig. 1 Chem 3D representation of the X-ray crystal structure of anti-11
(some H atoms removed for clarity).
reaction diastereoselectivity was next assessed. Conjugate addition
of lithium amide (R)-8 to N-acryloyl SuperQuat 4 and quenching
with methyl iodide gave anti-12 in 93% de, whilst an analogous
reaction using lithium amide (S)-8 gave anti-13 in 95% de,
indicating that the oxazolidinone auxiliary has the dominant effect
on determining the alkylation selectivity, with the configuration of
the a-methylbenzyl stereocentre having little effect (Scheme 2).
A stepwise procedure was next investigated, with deprotonation
of 7 with LiHMDS followed by alkylation with methyl iodide
giving anti-11 in an identical 96% de to that observed in the tandem
reaction, indicating that both tandem and stepwise alkylation
procedures may be employed with equal efficiency within this
system (Scheme 3). Deprotonation of (4S,aR)-9 and (4S,aS)-10
gave preferentially the corresponding anti diastereoisomers, 12 and
13 respectively, in 96% de in each case, indicating that the presence
of a homochiral a-methylbenzyl stereocentre has no effect on the
reaction diastereoselectivity of the stepwise alkylation reaction
(Scheme 3).
4 was next investigated and, in each case, the corresponding b-
alanine derivatives (4S,aR)-9 and (4S,aS)-10 were isolated in 75
and 85% yields respectively (Scheme 1).
Tandem conjugate addition and enolate alkylation
Having demonstrated that the conjugate addition of lithium
dibenzylamide 5 to N-acryloyl SuperQuat 4 proceeds efficiently,
the utility of this methodology for the synthesis of a-alkyl-b2-
amino acid derivatives was probed via the in situ alkylation of
the lithium b-amino enolate arising from the conjugate addition
reaction; methyl iodide was chosen as a representative electrophile
for pilot studies. In this manner, conjugate addition of lithium
dibenzylamide 5 to N-acryloyl SuperQuat 4 followed by addition
of 1.5 eq. of methyl iodide after 5 min gave anti-11 as the major
diastereoisomer in 96% de.23 Purification gave anti-11 in 88% yield
and 96% de (Scheme 2). The relative stereochemistry of the major
diastereoisomer anti-11 was determined unambiguously by single
crystal X-ray analysis, with the absolute (4S,2ꢀS) configuration
assigned from the L-valine derived stereocentre of the oxazolidin-
2-one (Fig. 1). The effect of incorporation of a homochiral
a-methylbenzyl substituent within the lithium amide upon the
Scheme 3 Reagents and conditions: (i) LiHMDS, THF, −78 ◦C, 30 min;
(ii) MeI, −78 ◦C to rt.
With these results in hand, the generality of this conjugate
addition and enolate alkylation protocol was explored further by
employing the conjugate addition of lithium dibenzylamide fol-
lowed by quenching with a range of alkylating agents (Scheme 4).
In all cases, the diastereoselectivity for the alkylation was excellent
(≥96% de); alkylation with the activated electrophiles benzyl
Scheme 2 Reagents and conditions: (i) lithium dibenzylamide 5, THF,
−78 ◦C, 5 min, then MeI, −78 ◦C to rt; (ii) lithium (R)-N-benzyl-
N-(a-methylbenzyl)amide 8, THF, −78 ◦C, 5 min, then MeI, −78 ◦C to
rt; (iii) lithium (S)-N-benzyl-N-(a-methylbenzyl)amide 8, THF, −78 ◦C,
5 min, then MeI, −78 ◦C to rt.
This journal is
The Royal Society of Chemistry 2007
Org. Biomol. Chem., 2007, 5, 2812–2825 | 2813
©

View Article Online
Fig. 2 NOE enhancements for 18.
Scheme 4 Reagents and conditions: (i) lithium dibenzylamide 5, THF,
−78 ◦C, 5 min; (ii) RX, −78 ◦C to rt.
bromide and allyl bromide gave good conversion to the corre-
sponding products 14 and 15 which were isolated in good yields,
whilst the less reactive electrophiles ethyl iodide and isopropyl
iodide gave lower conversions to the corresponding 2ꢀ-substituted
products 16 and 17, particularly in the latter case (8% isolated
yield of 17). In these two cases, the mass balance was made up by
N-(b-aminoacyl) SuperQuat 7. The stereochemistry of the major
diastereoisomeric alkylation products 14–17 from this protocol
was assigned as anti-(4S,2ꢀS) by analogy to that unambiguously
proven for 2ꢀ-methyl 11.
Scheme
(ii) TESCl.
6
Reagents and conditions: (i) LiHMDS, THF, −78 ◦C;
Having demonstrated unambiguously that both the tandem
and stepwise protocols generate stereoselectively the (2ꢀS)-
configuration upon enolate alkylation, the mechanism of these
transformations was explored via the trapping of the lithium
enolates arising from both the stepwise and tandem procedures.
Conjugate addition of lithium amide (R)-8 to N-acryloyl Su-
perQuat 4 and treatment of the resultant enolate with triethylsilyl
chloride (TESCl) gave 80% conversion to the corresponding silyl
enol ether 18 (Scheme 5). NOE enhancements within 18 were
consistent with the enol ether having the (Z)-geometry, with free
rotation around the N(3)-vinylic bond (Fig. 2). Irradiation of the
scopic analysis indicated that the enol ethers formed had the same
respective geometry as those formed in the corresponding tandem
reactions.
With these data in hand, the selectivity in these alkylation
reactions was postulated to arise as follows. Initial lithium amide
conjugate addition occurs to the N-acryloyl oxazolidinone 4 in
the anti-s-cis conformation 20 to generate the (Z)-b-amino enolate
21.24 In the stepwise protocol, deprotonation of 7 in accordance
with the Ireland model 22 also furnishes (Z)-enolate 21. Enolate
21 may switch from conformation 21a to conformation 21b with
the lithium chelated between the two oxygen atoms. The high
levels of stereoselectivity upon alkylation in favour of the (4S,2ꢀS)
diastereoisomer 23 are consistent with alkylation of the chelated
intermediate 21b from the least hindered face (Fig. 3).25
ꢀ
vinylic proton H2 showed an enhancement into protons H4, H3, H3
and Ha, with no enhancement to the triethylsilyl group. Irradiation
of the triethylsilyl SiCH2 protons gave only an enhancement
ꢀ
ꢀ
into H4, H3, H3 , H5, and H5 (Fig. 2). Following an identical
experimental procedure, conjugate addition of lithium amide (S)-
8 to 4 and subsequent addition of TESCl gave 66% conversion
to the corresponding silyl enol ether 19, for which NOE data was
also consistent with a (Z)-geometry.
In order to validate the utility of this strategy for the synthesis
of homochiral b2-amino acids, deprotection to furnish the amino
acids was pursued. 2ꢀ-Methyl 11 was subjected to catalytic hy-
drogenolysis conditions, giving a mixture of products presumably
arising from the intramolecular nucleophilic ring opening of the
oxazolidinone ring by the free 3ꢀ-amino group.26 It was therefore
envisaged that removal of the auxiliary prior to the hydrogenolysis
of the N-benzyl protecting groups would circumvent this problem.
2ꢀ-Methyl 11 was stirred with lithium hydroxide in THF–H2O
to furnish the tertiary b-amino acid (S)-24 in quantitative yield.
The auxiliary 2 was not separated from the product at this stage;
instead the mixture of (S)-24 and 2 was subjected to catalytic
hydrogenolysis, the crude product (S)-25 was transformed to the
HCl salt and purified by ion-exchange chromatography to furnish
the free amino acid (S)-25 in 84% yield over two steps, with
spectroscopic properties in good agreement with those in the
literature {[a]D25 +17.0 (c 1.0 in H2O); lit.27 for enantiomer [a]1D7
−14.2 (c 1.0 in H2O)} (Scheme 7). Application of this protocol to
(4S,2ꢀS,aR)-12 and (4S,2ꢀS,aS)-13 similarly gave tertiary b-amino
acids 26 and 27 as single diastereoisomers, indicating there was no
epimerisation in the hydrolysis step. Subsequent hydrogenolysis
of 26 and 27 followed by ion-exchange chromatography gave
Scheme 5 Reagents and conditions: (i) lithium (R)- or (S)-N-benzyl-N-
(a-methylbenzyl)amide 8; (ii) TESCl.
Enolate trapping was subsequently carried out on the enolates
formed from the deprotonation of (4S,aR)-9 and (4S,aS)-10, in
each case furnishing the corresponding enol ethers 18 and 19,
1
respectively, in 80% conversion (Scheme 6). H NMR spectro-
2814 | Org. Biomol. Chem., 2007, 5, 2812–2825
This journal is
The Royal Society of Chemistry 2007
©

View Article Online
Fig. 3 Postulated origin of the diastereoselectivity in the alkylation of enolate 21.
Scheme 8 Reagents and conditions: (i) BuLi, MeOH, 0 ◦C; (ii) H2 (1atm),
Pd/C, MeOH, AcOH, H2O, rt, 24 h; (iii) LiOH, THF, H2O, D, 15 h, then
HCl (aq.); (iv) Dowex 50WX8-200. [* Yields quoted are overall from the
corresponding N-(b-aminoacyl) oxazolidinone.]
Scheme 7 Reagents and conditions: (i) LiOH, THF, H2O, rt, 15 h; (ii) H2
(1 atm), Pd/C, MeOH, AcOH, H2O, rt, 24 h, then HCl (aq.); (iii) Dowex
50WX8-200.
b2-amino acid (S)-25 in 90 and 93% yield respectively over two
steps with spectroscopic properties again consistent with those in
the literature.
(S)-32 [a]2D5 −6.8 (c 0.4 in H2O); lit.28 for enantiomer [a]2D8 +4.6 (c
1.0 in H2O)} (Scheme 8).
In order to confirm that no epimerisation had occurred under
the reaction conditions, b2-amino acids 2-methyl (S)-25 and 2-
benzyl (S)-31 were derivatised with both homochiral and racemic
Mosher’s acid chloride to give the corresponding amides,29 and
shown to be of 96 and 97% ee, respectively, in accordance
with the observed diastereoselectivities of the corresponding acyl
oxazolidinones 2ꢀ-methyl 11 (96% de) and 2ꢀ-benzyl 14 (97% de),
indicating no loss of stereochemical integrity.
Under the same conditions, attempted hydrolysis of 2ꢀ-benzyl 14
and 2ꢀ-ethyl 16 with lithium hydroxide returned only starting ma-
terial. Likewise, attempted cleavage of the auxiliary with lithium
hydroperoxide showed only low (<10%) conversion. However,
treatment of 2ꢀ-methyl 11 (96% de), 2ꢀ-benzyl 14 (97% de) and
2ꢀ-ethyl 16 (96% de) with lithium methoxide resulted in clean
conversion to the corresponding methyl esters (S)-28, (S)-29 and
(S)-30. Hydrogenolysis of the b-amino esters (S)-28, (S)-29 and
(S)-30 followed by saponification with lithium hydroxide furnished
b2-amino acids (S)-25, (S)-31 and (S)-32 in excellent overall yields
from the corresponding oxazolidinones 11, 14 and 16, and with
spectroscopic properties consistent with those of the literature {2-
Bn (S)-31 [a]2D5 −13.1 (c 0.3 in H2O); lit.8 for enantiomer [a]2D5 +11.3
(c 1.0 in H2O); lit.27 for enantiomer [a]D25 +17.8 (c 1.0 in H2O); 2-Et
With a procedure for the diastereoselective synthesis of (S)-2ꢀ-
alkyl-3ꢀ-amino acids delineated, attention was turned to conjugate
addition of lithium dibenzylamide 5 to 2-substituted acrylates
and subsequent diastereoselective protonation of the resulting
enolates. It was anticipated that, in addition to furnishing the
enantiomeric b2-amino acids, this complementary approach would
also provide a means to synthesise a-substituted-b-amino acids not
This journal is
The Royal Society of Chemistry 2007
Org. Biomol. Chem., 2007, 5, 2812–2825 | 2815
©

View Article Online
readily accessible via the tandem conjugate addition and alkylation
procedure, e.g. a-isopropyl and a-aryl-b-amino acids.
Conjugate addition and diastereoselective protonation
A series of acrylic acids substituted with an alkyl group at the 2-
position was synthesised from ethyl acetoacetate.10 Monoalkyla-
tion with an alkyl halide, followed by deprotonation and treatment
with paraformaldehyde gave the 2-substituted ethyl acrylates 36–
38. Finally, saponification produced the 2-substituted acrylic acids
39–41 in good overall yields (Scheme 9).
Scheme 11 Reagents and conditions: (i) (COCl)2, Et2O, NEt3, rt, 1 h;
(ii) 2, BuLi, THF, −78 ◦C to rt, 2 h. [*Yield over 2 steps; **yield over 1
step from commercially available methacryloyl chloride.]
nation of the resulting enolate with a variety of proton sources.
In a preliminary study, 3-methacryloyl oxazolidinone 45 was
treated with lithium dibenzylamide 5 and quenched with saturated
aqueous NH4Cl to give an inseparable mixture of syn-50 and
anti-11 in a ratio of 66 : 34. However, when the procedure was
repeated using the bulky 2,6-di-tert-butylphenol (2,6-DTBP),31 or
2-pyridone32 as the proton sources, the ratio of 50–11 increased to
92 : 8 and 98 : 2, respectively. Recrystallisation gave syn-50 as a
single diastereoisomer, indicating that the reaction proceeds to give
the opposite diastereoisomer as the tandem conjugate addition
and enolate alkylation (Scheme 12).
With this result in hand, the remaining 2ꢀ-substituted acceptors
46–49 were treated with lithium dibenzylamide 5 followed by
saturated aqueous NH4Cl, 2,6-DTBP or 2-pyridone (Scheme 13).
A trend was observed in the case of 2ꢀ-alkyl acryloyl derivatives,
2ꢀ-methyl 45, 2ꢀ-ethyl 47 and 2ꢀ-isopropyl 48. The ratio of syn–anti
diastereoisomers increases when saturated aqueous NH4Cl is used
as the proton source; when 2,6-DTBP or 2-pyridone is used as the
proton source, the resultant syn–anti ratios observed are generally
higher than those for NH4Cl, with 2-pyridone delivering the
highest selectivity upon protonation. The ratios decrease, however,
with the increasing steric bulk of the a-substituent; this effect
is more pronounced with 2,6-DTBP. Meanwhile, protonation of
the enolate derived from 2ꢀ-benzyl 46 with saturated aqueous
NH4Cl gave the corresponding anti diastereoisomer 14 as the
major product; a reversal of selectivity was observed with both 2,6-
DTBP and 2-pyridone, giving a syn–anti ratio of 79 : 21 and 90 :
10, respectively. Protonation of the enolate derived from 2ꢀ-phenyl
49 with saturated aqueous NH4Cl gave the syn diastereoisomer
54 as the major product in a 62 : 38 syn–anti ratio, whilst 2,6-
DTBP and 2-pyridone both formed the anti diastereoisomer 55
as the major product, giving syn–anti ratios of 40 : 60 and 12 :
88, respectively. In all cases, 2-pyridone gave the highest levels
of diastereoselectivity upon protonation. Subsequent tandem
addition–protonation studies therefore focused on the use of 2-
pyridone as the proton source.
Scheme 9 Reagents and conditions: (i) KOtBu, tBuOH, THF, reflux, 0 ◦C,
30 min; (ii) RX, 70 ◦C, 12 h; (iii) LiHMDS, THF, −78 ◦C, 30 min;
(iv) (CH2O)n, −78 ◦C to rt; (v) LiOH, THF, H2O, reflux, 15 h. [* Yields
quoted are overall from ethyl acetoacetate.]
2-Phenylacrylic acid 44 was prepared via a two-step procedure
from methyl pyruvate (Scheme 10).30 The addition of one equiv-
alent of phenyl magnesium bromide to methyl pyruvate followed
by dehydration of the intermediate a-hydroxy ester 42 with TsOH
generated methyl 2-phenyl acrylate 43 in 70% yield over two steps.
Saponification furnished 2-phenyl acrylic acid 44 in 97% isolated
yield.
Scheme 10 Reagents and conditions: (i) PhMgBr, THF, 60 ◦C, 30 min;
In an effort to improve the diastereoselectivity upon con-
jugate addition and protonation, and to probe the possibility
of double diastereodifferentiation, the conjugate additions of
both antipodes of lithium N-benzyl-N-(a-methylbenzyl)amide 8,
and subsequent diastereoselective protonation with 2-pyridone,
were investigated.33 Thus, the 2ꢀ-substituted acceptors 45–49 were
treated with either lithium (R)- or (S)-N-benzyl-N-(a-methyl-
benzyl)amide 8 followed by 2-pyridone (Scheme 14). For 2ꢀ-methyl
45 and 2ꢀ-ethyl 47, (R)-8 gave rise to the “matched” combination,
(ii) TsOH, PhMe, reflux, 4 h; (iii) LiOH, THF, H2O, reflux, 15 h.
N-Acryloyl-2ꢀ-substituted-oxazolidinones 45–49 were synthe-
sised via the coupling of the lithium anion of oxazolidinone 2
with commercially available methacryloyl chloride and the acid
chlorides produced from treatment of acrylic acids 39–41 and 44
with oxalyl chloride (Scheme 11).
With 45–49 in hand, attention was turned to the conjugate
addition of lithium dibenzylamide 5 and stereoselective proto-
2816 | Org. Biomol. Chem., 2007, 5, 2812–2825
This journal is
The Royal Society of Chemistry 2007
©

View Article Online
Scheme 12 Reagents and conditions: (i) lithium dibenzylamide 5, THF, −78 ◦C, 2 h; (ii) NH4Cl (sat., aq.); (iii) 2,6-DTBP; (iv) 2-pyridone. [*Yields
quoted are for the inseparable mixture of diastereoisomers.]
Scheme 13 Reagents and conditions: (i) lithium dibenzylamide 5, THF,
Scheme 14 Reagents and conditions: (i) lithium dibenzylamide 5, THF,
−78 ◦C, 2 h; (ii) NH4Cl (sat., aq.), −78 ◦C to rt, 12 h; (iii) 2,6-DTBP,
−78 ◦C, 2 h; (ii) lithium (R)-N-benzyl-N-(a-methylbenzyl)amide 8,
−78 ◦C to rt, 12 h; (iv) 2-pyridone, −78 ◦C to rt, 12 h.
THF, −78 ◦C, 2 h; (iii) lithium (S)-N-benzyl-N-(a-methylbenzyl)amide
8, THF, −78 ◦C, 2 h; (iv) 2-pyridone, −78 ◦C to rt, 12 h.
giving improved diastereoselectivities with syn–anti products in a
ratio of 98 : 2 and 97 : 3 respectively, whereas (S)-8 gave rise to
the “mismatched” combination, furnishing syn–anti products in a
ratio of 84 : 16 and 89 : 11, respectively. Similarly, for 2ꢀ-phenyl 49,
(R)-8 offered the “matched” combination, offering an increase in
diastereoselectivity (anti–syn ratio 93 : 7), whereas (S)-8 offered the
“mismatched” combination (anti–syn ratio 66 : 34). Syn-70 and
anti-71 proved partially seperable by chromatography, affording
anti-71 in an improved 96% de. Conversely, for 2ꢀ-benzyl 46 and
2ꢀ-isopropyl 48, (S)-8 appeared to be the “matched” combination,
affording improved diastereoselectivities (syn–anti ratio 92 : 8 and
97 : 3, respectively), and (R)-8 appeared to be the “mismatched”
combination (syn–anti ratio 86 : 14 and 92 : 8, respectively).
Assuming that the conjugate addition of lithium amides 5, (R)-
8 and (S)-8 to a 2ꢀ-substituted acryloyl oxazolidinone 74 occurs
via a similar transition state to that for conjugate addition to 4
(75, Fig. 4), protonation of the enolate in conformation 76a would
lead to the anti-product 23 whilst protonation in conformation 76b
would lead to syn-product 77 (Fig. 4). When saturated aqueous
NH4Cl is used as the proton source, protonation may occur on
oxygen as well as on carbon and the resultant enol tautomerises
upon warming, thus affecting the reaction diastereoselectivity,
which is highly dependent on the nature of the 2ꢀ-substituent of
74. When 2,6-DTBP is used as the proton source, protonation
is anticipated to occur mostly on carbon, with the major product
arising from protonation anti to the C(4)-isopropyl directing group
of the oxazolidinone. The use of 2-pyridone as the proton source is
postulated to occur via a relay mechanism: binding of the carbonyl
of the 2-pyridone to the b-amino lithium enolate 76 (resulting
from conjugate addition) anti to the stereodirecting C(4)-isopropyl
group of the oxazolidinone directs the regio- and facial selectivity
of C-protonation. The change in the sense of selectivity at C(2ꢀ)
from the alkyl to the aryl cases arises from the preference of the
b-amino enolate for the conformations 76a and 76b. In the cases
of 2ꢀ-benzyl and the 2ꢀ-alkyl series, conformer 76b is preferred,
leading to the (4S,2ꢀR) configuration upon protonation. In the 2ꢀ-
phenyl series, conformer 76b is precluded due to steric interactions
between the C(4)-isopropyl group of the oxazolidinone and the
C(2ꢀ)-phenyl group. Conformer 76a is therefore preferred, with
protonation giving rise to the observed (4S,2ꢀS) configuration of
the major product (Fig. 4).
With b-amino oxazolidin-2-ones in hand, attention turned
towards their deprotection to the corresponding b2-amino acids.
Treatment of 2ꢀ-Me 50 (96% de) with lithium hydroxide followed by
hydrogenation and ion-exchange chromatography afforded 2-Me
(R)-25 in 89% yield and >95% ee29 with spectroscopic properties
consistent with those of the literature {[a]2D5 −12.4 (c 1.0 in
H2O); lit.27 [a]D17 −14.2 (c 1.0 in H2O)}. Treatment of 2ꢀ-Et 52
(94% de) and 2ꢀ-iPr 53 (90% de) under the same conditions
This journal is
The Royal Society of Chemistry 2007
Org. Biomol. Chem., 2007, 5, 2812–2825 | 2817
©

View Article Online
Fig. 4 Proposed origin of the diastereoselectivity in the protonation of enolate conformations 76a and 76b.
gave only returned starting material. However, treatment with
lithium methoxide gave clean conversion to the methyl esters (R)-
30 and (R)-78 respectively; subsequent sequential hydrogenation
and saponification gave (R)-a-alkyl-b-amino acids 2-Et (R)-32 in
70% yield and 94% ee,29 and 2-iPr (R)-79 in 73% yield and 88%
ee,29 with spectroscopic properties consistent with those of the
literature {2-Et (R)-32 [a]2D2 +4.5 (c 1.0 in H2O); lit.28 [a]2D8 +4.6
(c 1.0 in H2O); 2-iPr (R)-79 [a]D25 −10.0 (c 0.1 in H2O), lit.27 [a]2D5
−11.4 (c 1.0 in H2O)} (Scheme 15). In the case of deprotection of
2ꢀ-Ph 71 (96% de), however, treatment with lithium methoxide
gave extensive epimerisation of the C(2ꢀ)-stereocentre. Stirring
with lithium hydroperoxide gave clean conversion to a mixture
of the corresponding tertiary b-amino acid (S)-80 and SuperQuat
2, which was subjected to catalytic hydrogenolysis and subsequent
purification by ion-exchange chromatography to give 2-Ph (S)-
81 in 95% yield and >95% ee,29 with spectroscopic properties
consistent with those of the literature {[a]2D5 +93.0 (c 1.0 in H2O),
lit.34 [a]2D1 +95.0 (c 1.0 in H2O)} (Scheme 15).
Aldol reactions
Scheme 15 Reagents and conditions: (i) LiOH, THF, H2O, D, 15 h; (ii) H2
(1 atm), Pd/C, MeOH, AcOH, H2O, rt, 24 h; (iii) HCl (aq.); (iv) Dowex
50WX8-200; (v) BuLi, MeOH, 0 ◦C; (vi) LiOH, H2O2, THF, H2O, 0 ◦C
to rt, 24 h. [* Yields quoted are overall from the corresponding N-acryloyl
oxazolidinone.]
In order to expand the scope and utility of the lithium amide
conjugate addition–alkylation/protonation protocol for the syn-
thesis of b2-amino acids, attention was next turned toward
aldol reactions of the enolate of 7 for the synthesis of b-
amino-bꢀ-hydroxy-acids. Members of this sub-class include b2-
homothreonine (b2hThr), residues of which are found in a range
of carbapenem antibiotics.35 The pharmaceutical importance of
b2hThr and its derivatives as precursors to the b-lactam sub-unit
of antibiotics has led to several highly stereoselective and high
yielding syntheses of this motif, including catalytic asymmetric
hydrogenation of a b-amino-bꢀ-ketoester,36 conjugate addition of
secondary amines to homochiral alkenoate species,37 addition of
homochiral silyl ketene acetals to nitrones38 and asymmetric aldol
reactions of N-acyl oxazolidinones.39 Our approach centred upon
an aldol reaction of the enolates derived from b-amino-N-acryloyl
oxazolidinones 7, 9 and 10. Initial investigations focused on the
development of a tandem addition–aldol protocol. However, the
attempted treatment of 4 with lithium dibenzylamide 5 and an
aldehyde gave mixtures of inseparable diastereoisomeric products.
Attempted in situ transmetallation of the lithium enolate to the
titanium enolate and subsequent aldol reaction gave none of
the desired aldol products, whilst transmetallation to boron gave
no significant improvement in diastereoselectivity in the aldol
reaction. The tandem approach was therefore abandoned in favour
of a stepwise protocol, involving enolisation of a b-amino-N-
acryloyl oxazolidinone followed by addition of the aldehyde. Thus
formation of the boronenolate of 7, followedbyaldol reactionwith
acetaldehyde was investigated as a model system. Thus, treatment
2818 | Org. Biomol. Chem., 2007, 5, 2812–2825
This journal is
The Royal Society of Chemistry 2007
©

View Article Online
of 7 at 0 ◦C with 1.2 eq. of 9-BBNOTf and 1.4 eq. of Hu¨nig’s base,
followed by addition of acetaldehyde at −78 ◦C, revealed that
the aldol reaction had proceeded to <10% conversion, consistent
with the diminished reactivity of the boron enolate when compared
to the corresponding lithium enolate. Optimisation showed that
formation of the boron enolate at 0 ◦C followed by addition of
acetaldehyde at −78 ◦C and subsequent warming to 0 ◦C over
1 h gave good conversion (∼70%), giving aldol product 83 as
a single diastereoisomer in 65% isolated yield. The relative syn-
configuration of the product was assigned by analogy to standard
boron aldol reactions of N-acyl oxazolidinones,40 assuming that
the reaction proceeds preferentially via a Zimmermann–Traxler
chelated transition state 82 in which the aldehyde substituent
adopts a pseudo-equatorial position (Scheme 16).41
With the conditions for the aldol reaction with acetaldehyde
optimised, the aldol reaction of N-acyl oxazolidinone 7 with
alternative aldehydes was investigated. Using the optimised con-
ditions, reaction of 7 with benzaldehyde and isobutyraldehyde
proceeded in moderate to good conversion (40–70%) to give aldol
products 84 and 85 respectively, as single diastereoisomers,23 which
were isolated in moderate yield (36–64%) after chromatography
(Scheme 16).
The stereochemistry of the major diastereoisomer aldol prod-
ucts 84 and 85 arising from this protocol was unambiguously
established by single crystal X-ray analysis, confirming the ex-
pected relative syn-configuration between C(2ꢀ) and C(3ꢀ), with
the absolute (4S,2ꢀS,3ꢀS)-84 and (4S,2ꢀS,3ꢀR)-85 configurations
determined relative to the known (S)-configuration of the auxiliary
(Fig. 5). The relative stereochemistry within aldol product 83 was
therefore assigned by analogy.
1H NMR analysis indicated a larger coupling constant (J2 -3
ꢀ
ꢀ
∼9 Hz) for the syn configuration than would be expected upon
the basis of intramolecular hydrogen bonding between the C(3ꢀ)-
hydroxyl and the C(1ꢀ) carbonyl.42 Analysis of the X-ray crystal
structures of 84 and 85 revealed that an intramolecular hydrogen
bond was present within the solid state structures of these
compounds, but between the C(3ꢀ) hydroxyl and the C(3) amino
group, giving a dihedral angle of φ ∼180◦ for C(2ꢀ)H-C(3ꢀ)H.
Assuming a similar hydrogen-bonded structure also exists in
solution, this would account for the larger than expected 3J values
(Fig. 5).
Although the aldol reactions of b-amino-N-acyl oxazolidinone
7 have proven to be highly diastereoselective, the reactions
suffer from low conversions in many cases. It was postulated
that incomplete conversion could be attributable to incomplete
formation of the boron enolate; however, use of 2 eq. of 9-
BBNOTf decreased the conversion of the reaction, and varying
the temperature of enolisation had very little effect. An alternative
explanation to account for the relatively modest reactivity of the
boron enolate derived from 7 is that the amino group binds to
the 9-BBNOTf, thereby hampering reactivity. This effect could
potentially be overcome by increasing the steric bulk of the amino
group to disfavour binding of the bulky boron reagent, thereby
increasing the reactivity of the boron reagent towards an aldehyde.
Investigations turned towards the effect of incorporation of a
Scheme 16 Reagents and condit◦ions: (i) 9-BBNOTf (1.2 eq.), 10 min, 0 ◦◦C,
then iPr2NEt (1.4 eq.), 20 min, 0 C; (ii) RCHO, −78 ◦C, 30 min, then 0 C,
1 h, then MeOH, H2O2 (aq.). [N. D. = not determined.]
Fig. 5 Chem 3D representations of the X-ray crystal structures of 84 and 85 (some H atoms removed for clarity).
The Royal Society of Chemistry 2007 Org. Biomol. Chem., 2007, 5, 2812–2825 | 2819
This journal is
©

View Article Online
N-benzyl-N-(a-methylbenzyl)amino moiety in an attempt to
increase the reactivity and to allow the possibility of double
asymmetric induction. The aldol reactions of the boron enolates
derived from N-benzyl-N-(a-methylbenzyl) derivatives (4S,aR)-9
and (4S,aS)-10 were therefore investigated.
Treatment of (4S,aR)-9 with 9-BBNOTf and Hu¨nig’s base,
followed by addition of acetaldehyde gave >90% conversion to
a 92 : 8 mixture of syn-86 and anti-87, whilst the analogous
reaction of (4S,aS)-10 gave >90% conversion to a 94 : 6 mixture
of two products syn-88 and anti-89. The syn-configurations of the
major reaction products were assigned by analogy to 84 and 85,
and on the assumption that the N-a-methylbenzyl group has a
relatively small effect on the stereoselectivity of the reaction. The
relative configurations of the minor diastereoisomers 87 and 89
were arbitrarily assigned as anti (Scheme 17).
a significant effect on the stereochemical outcome of the aldol
reaction in this case. Although the absolute configurations of the
aldol products 90–93 were not proven unambiguously, comparison
with the analogous dibenzylamino aldol products 84 and 85
suggests that, based on analysis of coupling constants for the
C(2ꢀ) and C(3ꢀ) protons, the syn-configuration is produced, with
ꢀ
ꢀ
8.6 Hz ≤ J2 -3 ≤ 9.1 Hz in all cases (Scheme 18).
These results demonstrate that, in both cases, the conversion
of the reaction improved dramatically in comparison to the
simple dibenzylamino case although a concomitant decrease in
the reaction diastereoselectivity is observed (84% de for 9 and
88% de for 10). Both observations may be attributed to the greater
reactivity of the enolates in the systems when compared to the
dibenzylamino case; a possible result of decreased binding of the
amino nitrogen to boron. It was therefore postulated that the
reaction of N-(b-aminoacyl) SuperQuats (4S,aR)-9 and (4S,aS)-
10 with less reactive aldehydes may proceed with similarly high
conversions but with improved diastereoselectivities. The aldol
reactions of 9 and 10 with benzaldehyde and isobutyraldehyde
were therefore investigated. Treatment of (4S,aR)-9 and (4S,aS)-
10 with 9-BBNOTf and Hu¨nig’s base followed by isobutyraldehyde
gave the corresponding aldol products 90 and 92, as single
diastereoisomers, in 42 and 28% yield respectively, the mass
balance being returned starting materials in both cases. These
data suggest that the N-a-methylbenzyl group has little effect
on the diastereoselectivity of the reaction, with the dominant
stereocontrol originating from the SuperQuat auxiliary. However,
while treatment of (4S,aR)-9 with 9-BBNOTf and Hu¨nig’s base
followed by benzaldehyde gave 91 in 52% yield and >98% de,
(4S,aS)-10 gave a 77 : 23 mixture of diastereoisomers, with 93
as the major product, in 68% yield under the same conditions
(54% de), indicating that the (R)-N-a-methylbenzyl group has
Scheme 18 Reagents and conditi◦ons: (i) 9-BBNOTf (1.2 eq.), 10 min, 0 ◦C,
then iPr2NEt (1.4 eq.), 20 min, 0 C; (ii) RCHO (1.5 eq.), −78 ◦C, 30 min,
then 0 ◦C, 1 h, then MeOH, H2O2 (aq.).
In order to confirm the stereochemistry of the aldol product 83,
the auxiliary was cleaved by treatment with LiOMe, with 1H NMR
spectroscopic analysis revealing no epimerisation had occurred.
Methyl ester 94 was successfully deprotected to give the known b-
amino-bꢀ-hydroxy methyl ester hydrochloride (b2-homothreonine
methyl ester) 95 in quantitative yield, and with spectroscopic data
in excellent agreement with that in the literature {[a]2D3 −6.7 (c 0.9
in MeOH), lit.38 [a]D30 −7.0 (c 0.9 in MeOH)} (Scheme 19).
Scheme 17 Reagents and conditions: (i) 9-BBNOTf (1.2 eq.), 10 min, 0 ◦C, then iPr2NEt (1.4 eq.), 20 min, 0 ◦C; (ii) MeCHO (1.5 eq.), −78 ◦C, 30 min,
then 0 ◦C, 1 h, then MeOH, H2O2 (aq.).
2820 | Org. Biomol. Chem., 2007, 5, 2812–2825
This journal is
The Royal Society of Chemistry 2007
©

View Article Online
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
apparatus and are uncorrected. Optical rotations were recorded
on a Perkin-Elmer 241 polarimeter with a water-jacketed 10 cm
cell. Specific rotations are reported in 10−1 deg cm2 g−1 and
concentrations in g/100 mL. IR spectra were recorded on a Bruker
Tensor 27 FTIR spectrometer as either a thin film on NaCl plates
(film), a chloroform cell (CHCl3) or a KBr disc (KBr), as stated.
Selected characteristic peaks are reported in cm−1. NMR spectra
were recorded on Bruker Avance spectrometers in the deuterated
solvent stated. The field was locked by external referencing to
the relevant deuteron resonance. 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 and were internally calibrated with
polyanaline in positive and negative modes, or a Micromass GCT
instrument fitted with a Scientific Glass Instruments BPX5 column
(15 m × 0.25 mm) using amyl acetate as a lock mass.
Scheme 19 Reagents and conditions: (i) LiOMe, MeOH, THF, 0 ◦C to
rt, 5 h; (ii) H2 (1 atm), Pd/C (10% w/w), MeOH, H2O, AcOH; (iii) HCl
(2.0 M in Et2O).
Conclusion
In conclusion, conjugate addition of lithium dibenzylamide to
homochiral (S)-N-acryloyl SuperQuat 4 and alkylation of the
resultant b-amino enolate with an alkyl halide allows access to
homochiral (S)-2-alkyl b2-amino acids. Conjugate addition of
lithium amides to 2ꢀ-substituted (S)-N-acryloyl SuperQuats 45–
49 and stereoselective protonation with 2-pyridone gives access
to the enantiomeric (R)-2-alkyl b2-amino acids, as well as (S)-
2-aryl b2-amino acids. As both enantiomers of the SuperQuat
chiral auxiliary are readily available, the combination of these
complementary strategies allows a general synthetic pathway to
either enantiomer of 2-substituted-3-aminopropanoic acids with
a range of substituents.
The boron mediated aldol reaction between b-amino-N-acyl
oxazolidinones 7, 9 and 10 and a range of aldehydes has been
investigated and shown to proceed with excellent levels of diastere-
oselectivity to give syn-aldol products. Cleavage of the auxiliary
and debenzylation to give a highly functionalised b-amino-bꢀ-
hydroxy methyl ester has been shown to proceed efficiently for
a model system. The further application of this methodology for
the synthesis of highly functionalised b-amino-bꢀ-hydroxy-N-acyl
SuperQuats as building blocks for natural product synthesis is
currently under investigation in our laboratory.
(S)-5,5-Dimethyl-4-isopropyl-3-[3ꢀ-(N,N-
dibenzylamino)propanoyl]oxazolidin-2-one 7
n-BuLi (0.91 mL, 2.3 mmol, 1.6 eq.) was added dropwise to a
stirred solution of dibenzylamine (0.44 mL, 2.30 mmol, 1.6 eq.)
in THF (0.3 mL) at −78 ◦C. After stirring for 30 min at −78 ◦C,
a solution of N-acryloyl-oxazolidinone 4 (296 mg, 1.40 mmol,
1.0 eq.) in THF (0.1 mL), also at −78 ◦C, was added dropwise
via cannula. The resulting solution was stirred for between 2 h
before the addition of sat. aq. NH4Cl solution (0.1 mL). The
product was extracted with ether (3 ×), the combined organic
extracts were washed with aq. citric acid solution (10% w/v), sat.
aq. NaHCO3 solution and brine. The resultant organic solution
was dried and concentrated in vacuo. Purification of the residue via
column chromatography (silica, 9 : 1 pentane–ether, v/v) afforded
7 (525 mg, 92%) as a viscous, colourless oil; [a]2D5 +17.5 (c 1.6,
CHCl3); mmax/cm−1 (CHCl3) 1772, 1700; dH (400 MHz, CDCl3) 0.96
(3H, d, J 6.8, CHMe2), 1.04 (3H, d, J 7.0, CHMe2), 1.37 (3H, s,
CMe2), 1.52 (3H, s, CMe2), 2.11–2.19 (1H, m, CHMe2), 2.93–3.00
(2H, m, CH2NBn2), 3.16–3.23 (1H, m, COCH2), 3.28–3.35 (1H, m,
COCH2), 3.68 (4H, app s, N(CH2Ph)2), 4.16 (1H, d, J 3.2, NCH),
7.25–7.44 (10H, m, Ph); dC (100 MHz, CDCl3) 17.1, 21.4, 28.8,
29.5, 33.0, 49.0, 57.9, 66.2, 82.8, 126.9, 128.2, 128.9, 140.4, 153.6,
172.6; m/z (ESI+) 409 ([M+H]+, 100%); HRMS (ESI+) 409.2488
(C25H33N2O3 requires 409.2491).
Experimental
General experimental
All reactions involving organometallic or other moisture sensitive
reagents were carried out under a nitrogen or argon atmosphere
using standard vacuum line techniques and glassware that was
flame dried and cooled under nitrogen before use. The solvents
were dried according to the procedure outlined by Grubbs and
(2ꢀS,4S)-5,5-Dimethyl-4-isopropyl-3-[3ꢀ-(N,N-dibenzylamino)-2ꢀ-
methylpropanoyl]oxazolidin-2-one 11
Method A. n-BuLi (4.34 mL, 11.5 mmol, 1.6 eq.) was added
dropwise to a stirred solution of dibenzylamine (2.18 mL,
11.5 mmol, 1.6 eq.) in THF (6.0 mL) at −78 ◦C. After stirring
R
co-workers.43 Water was purified by an Elixꢀ 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. The plates were visualised using UV
light (254 nm), iodine, 1% aq. KMnO4 or 10% ethanolic phospho-
molybdic acid. Flash column chromatography was performed on
Kieselgel 60 silica.
for 30 min at −78 C, a solution of N-acryloyl-oxazolidinone 4
(1.48 g, 7.0 mmol, 1.0 eq.) in THF (0.6 mL), also at −78 ◦C, was
added via cannula. The resulting solution was stirred for between
2 h at −78 ◦C before methyl iodide (0.65 mL, 10.5 mmol, 1.5 eq.)
◦
was added. The mixture was stirred at −78 C for a further 2 h
before allowing it to warm to rt over 16 h. The solvent was removed
in vacuo and the resulting residue was taken up in ether. The
This journal is
The Royal Society of Chemistry 2007
Org. Biomol. Chem., 2007, 5, 2812–2825 | 2821
©

View Article Online
organic layer was washed with aq. citric acid solution (10% w/v)
and sat. aq. NaHCO3 solution, then dried and concentrated in
vacuo to give 11 in 96% de. Purification of the residue via column
chromatography (silica, 19 : 1 pentane–ether, v/v) afforded 11
(2.60 g, 88%) as a white crystalline solid (Found: C, 73.8; H, 7.8;
N, 6.6%. C26H34N2O3 requires C, 73.9; H, 8.1; N, 6.6%); mp 82–
83 ◦C; [a]2D5 +12.0 (c 1.6, CHCl3); mmax/cm−1 (CHCl3) 1772, 1700; dH
(400 MHz, CDCl3) 0.96 (3H, d, J 6.8, CHMe2), 1.01 (3H, d, J 7.0,
CHMe2), 1.22 (3H, d, J 6.8, COCHMe), 1.43 (3H, s, CMe2), 1.53
(3H, s, CMe2), 2.10–2.20 (1H, m, CHMe2), 2.50 (1H, dd, JAB 12.7,
JAX 6.7, CH2NBn2), 2.90 (1H, dd, JBA 12.7, JBX 7.5, CH2NBn2),
3.52 (2H, d, J 13.7, NCH2Ph), 3.68 (2H, d, J 13.8, NCH2Ph), 4.19
(1H, d, J 3.4, NCHiPr), 4.21–4.24 (1H, m, COCHMe), 7.21–7.39
(10H, m, Ph); dC (100 MHz, CDCl3) 16.5, 17.0, 21.4, 21.5, 28.7,
29.6, 36.3, 56.9, 58.3, 66.1, 82.5, 126.8, 128.1, 129.0, 139.1, 153.2,
176.8; m/z (ESI+) 423 ([M+H]+, 100%); HRMS (ESI+) 423.2652
(C26H35N2O3 requires 423.2648).
methyl-oxazolidinone 11 (200 mg, 0.47 mmol, 1.0 eq.) in MeOH
(1◦.0 mL) was added dropwise. The resulting mixture was stirred at
0 C for 30 min before being allowed to warm to rt, then stirred
for a further 15 h. The solvent was removed in vacuo and the
residue was partitioned between sat. aq. NH4Cl solution and
EtOAc. The aqueous layer was extracted with EtOAc (2 ×)
and the combined organic extracts were washed with brine, dried
and then concentrated in vacuo. Purification of the residue via
column chromatography (silica, 49 : 1 to 19 : 1 pentane–ether,
v/v) afforded (S)-28 as a colourless oil (137 mg, 98%); [a]2D5 +9.9
(c 0.5, CHCl3); mmax/cm−1 (CHCl3) 1728; dH (400 MHz, CDCl3)
1.13 (3H, d, J 6.2, CHMe), 2.44 (1H, dd, JAB 16.1, JAX 10.1,
CCHCH2), 2.75–2.82 (2H, m, CCHCH2, CCHCH2), 3.50 (2H,
d, J 13.4, NCH2Ph), 3.64 (2H, d, J 13.4, NCH2Ph), 3.66 (3H, s,
OMe), 7.22–7.42 (10H, m, Ph); dC (100 MHz, CDCl3) 15.3, 38.6,
51.4, 57.4, 58.4, 126.9, 128.1, 128.9, 139.2, 176.2; m/z (ESI+) 298
([M+H]+, 100%); HRMS (ESI+) 298.1803 (C19H24NO2 requires
298.1807).
Method B. LiHMDS (0.30 mL, 0.2 mmol, 1.1 eq.) was added
dropwise to a solution of b-amino-oxazolidinone 7 (100 mg,
0.24 mmol, 1.0 eq.) in THF (0.1 mL) at −78 ◦C. After 30 min,
methyl iodide (23 lL, 0.37 mmol, 1.5 eq.) was added and the
(S)-3-Amino-2-methyl propanoic acid 25
Pd (50 mg, 10% wt on C) was added to a degassed solution of
b-amino ester 28 (100 mg, 0.34 mmol, 1.0 eq.) in MeOH (2.0 mL)–
H2O (0.2 mL)–AcOH (0.05 mL). The suspension was stirred under
◦
resultant mixture was stirred at −78 C for a further 2 h before
allowing it to warm to rt over 16 h. The solvent was then removed
in vacuo and the residue was taken up in ether. The organic layer
was washed with sat. aq. NH4Cl solution and brine then dried
and concentrated in vacuo to give 11 in 96% de. Purification of
the residue via column chromatography (silica, 9 : 1 pentane–
ether, v/v) afforded 11 (95 mg, 94%) with identical physical and
spectroscopic properties to those described above.
R
H2 (1 atm) for 24 h before being filtered though Celiteꢀ (eluent
MeOH) and the filtrate was concentrated in vacuo. The residue was
re-dissloved in THF (5.0 mL) and a solution of lithium hydroxide
(71 mg, 1.70 mmol, 5.0 eq.) in water (0.5 mL) was subsequently
added. After 15 h stirring at rt, the solvents were removed in vacuo
and the residue co-evaporated with aq. HCl (2 M). Purification
of the residue via ion exchange chromatography yielded the free
amino acid (S)-25 (33 mg,◦95%) as a white crystalline solid; mp
175–177 ◦C {lit.27 179–181 C}; [a]D25 +17.0 (c 1.0, H2O) {lit.27 [a]2D5
+14.2 (c 1.0, H2O)}; dH (200 MHz, CDCl3) 1.05 (3H, d, J 7.3,
CHMe), 2.44–2.51 (1H, m, CCHCH2), 2.84 (1H, dd, JAB 12.8, JAX
7.3, CCHCH2), 2.97 (1H, dd, JBA 12.8, JBX 8.3, CCHCH2).
X-Ray crystal structure determination for 11
Data were collected using an Enraf-Nonius j-CCD diffractometer
with graphite monochromated Mo-Ka radiation using standard
procedures at 190 K. The structure was solved by direct methods,
all non-hydrogen atoms were refined with anisotropic thermal
parameters. Hydrogen atoms were added at idealised positions.
The structure was refined using CRYSTALS.44
(2ꢀR,4S)-5,5-Dimethyl-4-isopropyl-3-[3ꢀ-(N,N-dibenzylamino)-2ꢀ-
methyl-propanoyl]oxazolidin-2-one 50 and (2ꢀS,4S)-5,5-
dimethyl-4-isopropyl-3-[3ꢀ-(N,N-dibenzylamino)-2ꢀ-methyl-
propanoyl] oxazolidin-2-one 11
X-Ray crystal structure data for 11 [C26H34N2O3]: M = 422.57,
˚
˚
monoclinic, space group P 21, a = 14.1180(3) A, b = 6.1198(2) A,
◦
3
˚
˚
c = 14.4072(4) A, b = 108.4415(11) , V = 1180.85(6) A , Z =
4, l = 0.077 mm−1, colourless block, crystal dimensions = 0.2 ×
0.2 × 0.2 mm3. A total of 2840 unique reflections were measured
for 5 < h < 27 and 2657 reflections were used in the refinement.
The final parameters were wR2 = 0.0354 and R1 = 0.0335 [I >
3r(I)].‡ Crystallographic data (excluding structure factors) have
been deposited with the Cambridge Crystallographic Data Centre
as supplementary publication number CCDC 616167. Copies of
the data can be obtained, free of charge, on application to CCDC,
12 Union Road, Cambridge CB2 1EZ, UK [fax: +44(0)-1223-
336033 or e-mail: deposit@ccdc.cam.ac.uk].
Method A. n-BuLi (0.712 mL, 1.78 mmol, 2.0 eq.) was
added dropwise to a stirred solution of dibenzy◦lamine (0.34 mL,
1.78 mmol, 2.0 eq.) in THF (0.25 mL) at −78 C. After stirring
for 30 min at −78 ◦C, a solution of N-acryloyl-oxazolidinone 45
(200 mg, 0.89 mmol, 1.0 eq.) in THF (0.1 mL), also at −78 ◦C, was
added dropwise via cannula. The resulting solution was stirred for
2 h before the addition of sat. aq. NH4Cl solution. The product
was extracted with ether (3 ×) and the combined organic extracts
were washed with aq. citric acid solution (10% w/v), sat. aq.
NaHCO3 solution and brine. The resultant organic solution was
dried and concentrated in vacuo to give a non-separable mixture of
diastereoisomers 50 and 11 in a ratio of 66 : 34. Purification of the
residue via column chromatography (silica, 9 : 1 pentane–ether,
v/v) afforded the 66 : 34 mixture of diastereoisomers 50 and 11 as
a colourless, viscous oil (360 mg, 96%).
Methyl (S)-3-(N,N-dibenzylamino)-2-methyl propanoate 28
n-BuLi (890 lL, 1.6 M,◦1.42 mmol, 3.0 eq.) was added dropwise
to MeOH (2.8 mL) at 0 C. After 5 min, a solution of 3ꢀ-amino-2ꢀ-
Method B. n-BuLi (0.71 mL, 1.78 mmol, 2.0 eq.) was added
dropwise to a stirred solution of dibenzylamine (0.34 mL,
‡ CCDC reference numbers 616167–616169. For crystallographic data in
CIF or other electronic format see DOI: 10.1039/b707689d
2822 | Org. Biomol. Chem., 2007, 5, 2812–2825
This journal is
The Royal Society of Chemistry 2007
©

View Article Online
1.78 mmol, 2.0 eq.) in THF (1.0 mL) at −78 ◦C. After stirring
for 30 min at −78 ◦C, a solution of N-acryloyl-oxazolidinone 45
(200 mg, 0.89 mmol, 1.0 eq.) in THF (0.1 mL), also at −78 ◦C, was
added via cannula. The resulting solution was stirred for 30 min
at −78 ◦C and then a solution of 2,6-di-tert-butylphenol (551 mg,
2.67 mmol, 3.0 eq.) in THF (0.5 mL) was added dropwise via
solvent was removed in vacuo and the residue was taken up in ether.
The organic layer was washed with aq. citric acid solution (10%
w/v) and sat. aq. NaHCO3 solution, then dried and concentrated
in vacuo, giving a mixture of diastereoisomers 56 and 12 in a ratio
of 98 : 2. Purification of the residue via column chromatography
(silica, 9 : 1 pentane–ether, v/v) furnished 56 (240 mg, 82%) as
a colourless oil; [a]2D5 +51.4 (c 1.5, CHCl3); vmax/cm−1 (CHCl3)
1769, 1698; dH (400 MHz, CDCl3) 0.95 (3H, d, J 6.8, CHMe2),
1.02 (3H, d, J 6.8, CHMe2), 1.17 (3H, d, J 6.8, COCHMe),
1.35 (3H, s, CMe2), 1.43 (3H, d, J 6.8, NCHMe), 1.50 (3H, s,
CMe2), 2.08–2.17 (1H, m, CHMe2), 2.60 (1H, dd, JAB 12.6, JAX
8.3, COCHCH2), 2.77 (1H, dd, JBA 12.6, JBX 6.1, COCHCH2),
3.43 (1H, d, J 14.4, NCH2Ph), 3.82 (1H, d, J 14.4, NCH2Ph), 3.98
(1H, q, J 7.1, NCHPh), 4.06–4.16 (1H, m, COCHMe), 4.14 (1H,
d, J 3.3, NCHiPr), 7.19–7.40 (10H, m, Ph); dC (100 MHz, CDCl3)
15.5, 16.7, 17.0, 21.3, 21.3, 28.8, 29.5, 36.6, 53.1, 54.6, 57.8, 66.3,
82.5, 126.6, 127.8, 128.1, 128.2, 128.7, 128.9, 140.3, 141.6, 153.5,
176.7; m/z (ESI+) 437 ([M+H]+, 100%); HRMS (ESI+) 437.2814
(C27H36N2O3 requires 437.2804).
◦
syringe. The mixture was stirred at −78 C for a further 30 min
before being allowed to warm to rt over 16 h. The solvent was
removed in vacuo and the residue was taken up in ether. The or-
ganic layer was washed with aq. citric acid solution (10% w/v) and
sat. aq. NaHCO3 solution, then dried and concentrated in vacuo
to give a mixture of diastereoisomers 50 and 11 in a ratio of 92 :
8. Purification of the residue via column chromatography (silica,
49 : 1 to 9 : 1 pentane–ether, v/v) followed by recrystallisation
(pentane–ether) afforded 50 as a white crystalline solid (342 mg,
91%); mp 74–75 ◦C; [a]D25 +53.7 (c 1.3, CHCl3); mmax/cm−1 (CHCl3)
1769, 1697; dH (400 MHz, CDCl3) 1.00 (3H, d, J 6.9, CHMe2),
1.07 (3H, d, J 7.0, CHMe2), 1.17 (3H, d, J 6.8, COCHMe), 1.36
(3H, s, CMe2), 1.54 (3H, s, CMe2), 2.12–2.21 (1H, m, CHMe2),
2.48 (1H, dd, JAB 12.4, JAX 7.8, CH2NBn2), 2.95 (1H, dd, JBA
12.4, JBX 6.7, CH2NBn2), 3.54 (2H, d, J 13.8, NCH2Ph), 3.77
(2H, d, J 13.8, NCH2Ph), 4.19 (1H, d, J 3.4, NCHiPr), 4.22–4.30
(1H, m, COCH), 7.16–7.41 (10H, m, Ph); dC (100 MHz, CDCl3)
15.6, 17.1, 21.3, 21.5, 28.8, 29.5, 36.1, 57.1, 58.3, 66.3, 82.6, 126.9,
128.1, 129.0, 139.2, 153.4, 176.5; m/z (ESI+) 423 ([M+H]+, 100%);
HRMS (ESI+) 423.2658 (C26H35N2O3 requires 423.2658).
(4S,2ꢀR,aS)-5,5-Dimethyl-4-isopropyl-3-{3ꢀ-[N-benzyl-N-(a-
methylbenzyl)amino]-2ꢀ-methyl-propanoyl}oxazolidin-2-one 57
and (4S,2ꢀS,aS)-5,5-dimethyl-4-isopropyl-3-{3ꢀ-[N-benzyl-N-(a-
methylbenzyl)amino]-2ꢀ-methyl-propanoyl}oxazolidin-2-one 13
To a stirred solution of (S)-N-benzyl-(N-a-methylbenzyl)amine
(283 mg, 1.34 mmol, 2.0 eq.) in THF (0.8 mL) at −78 ◦C was added
n-BuLi (0.84 mL, 1.34 mmol, 2.0 eq.) dropwise. After stirring
for 30 min at −78 ◦C, a solution of N-acryloyl-oxazolidinone 45
(150 mg, 0.67 mmol, 1.0 eq.) in THF (0.06 mL), also at −78 ◦C, was
added v◦ia cannula. The resulting solution was stirred for 30 min
at −78 C before a solution of 2-pyridone (127 mg, 1.34 mmol,
2.0 eq.) in THF (0.08 mL) was added dropwise via syringe. The
Method C. To a stirred solution of dibenzylamine (0.26 mL,
1.34 mmol, 2.0 eq.) in THF (0.8 mL) at −78 ◦C was added n-BuLi
(0.84 mL, 1.34 mmol, 2.0 eq.) dropwise. After stirring for 30 min
at −78 ◦C, a solution of N-acryloyl-oxazolidinone 45 (150 mg,
0.67 mmol, 1.0 eq.) in THF (0.05 mL), also at −78 ◦C, was added
via cannula. The resulting solution was stirred for 30 min at −78 ◦C
before a solution of 2-pyridone (127 mg, 1.34 mmol, 2.0 eq.) in
THF (0.08 mL) was added dropwise via syringe. The mixture was
stirred at −78 ◦C for a further 30 min before being allowed to warm
to rt over 16 h. The solvent was removed in vacuo and the residue
taken up in ether. The organic layer was washed with aq. citric acid
solution (10% w/v) and sat. aq. NaHCO3 solution, then dried and
concentrated in vacuo to give a mixture of diastereoisomers 50
and 11 in a ratio of 98 : 2. Purification of the residue via column
chromatography (silica, 9 : 1 pentane–ether, v/v) furnished 50
(245 mg, 87%) with identical physical and spectroscopic properties
as those described above.
◦
mixture was stirred at −78 C for a further 30 min before being
allowed to warm to rt over 16 h. The solvent was removed in vacuo
and the residue taken up in ether. The organic layer was washed
with aq. citric acid solution (10% w/v) and sat. aq. NaHCO3
solution, then dried and concentrated in vacuo, giving a mixture
of diastereoisomers 57 and 13 in a ratio of 84 : 16. Purification
of the residue via column chomatography (silica, 9 : 1 pentane–
ether, v/v) furnished an inseparable mixture of 57 and 13 (349 mg,
90%) as a yellow oil; [a]2D5 +12.9 (c 0.7, CHCl3); vmax/cm−1 (CHCl3)
1770, 1694. Data for the major diastereoisomer 57; dH (400 MHz,
CDCl3) 1.02 (3H, d, J 6.1, CHMe2), 1.04 (3H, d, J 7.2, CHMe2),
1.07 (3H, d, J 5.8, COCHMe), 1.36 (3H, s, CMe2), 1.41 (3H, d,
J 6.8, NCHMe), 1.52 (3H, s, CMe2), 2.12–2.22 (1H, m, CHMe2),
2.24 (1H, dd, JAB 12.6, JAX 7.5, COCHCH2), 3.11 (1H, dd, JBA
12.6, JBX 6.5, COCHCH2), 3.63 (2H, d, J 2.4, NCH2Ph), 4.02
(1H, q, J 7.1, NCHPh), 4.06–4.15 (1H, m, COCHMe), 4.17 (1H,
d, J 2.8, NCHiPr), 7.18–7.40 (10H, m, Ph); dC (100 MHz, CDCl3)
13.3, 15.4, 17.1, 21.4, 21.5, 28.7, 29.5, 36.6, 52.6, 54.5, 56.6, 66.3,
82.5, 126.7 127.8, 128.1, 128.3, 128.6, 128.9, 140.3, 142.4, 153.4,
176.8; m/z (ESI+) 437 ([M+H]+, 100%); HRMS (ESI+) 437.2802
(C27H36N2O3 requires 437.2804).
(4S,2ꢀR,aR)-5,5-Dimethyl-4-isopropyl-3-{3ꢀ-[N-benzyl-N-(a-
methylbenzyl)amino]-2ꢀ-methyl-propanoyl}oxazolidin-2-one 56
and (4S,2ꢀS,aR)-5,5-dimethyl-4-isopropyl-3-{3ꢀ-[N-benzyl-N-(a-
methylbenzyl)amino]-2ꢀ-methyl-propanoyl}oxazolidin-2-one 12
To a stirred solution of (R)-N-benzyl-(N-a-methylbenzyl)amine
(283 mg, 1.34 mmol, 2.0 eq.) in THF (0.8 mL) at −78 ◦C was
added n-BuLi (0.84 mL, 1.34 mmol, 1.6 eq.) dropwise. After
stirring for 30 min at −78 ◦C, a solution of the acceptor N-
acryloyl-oxazolidinone 45 (150 mg, 0.67 mmol, 1.0 eq.) in THF
◦
(0.05 mL), also at −78 C, was added via cannula. The resulting
solution was stirred for 30 min at −78 ◦C before a solution of
2-pyridone (127 mg, 1.34 mmol, 2.0 eq.) in THF (0.08 mL) was
added dropwise via syringe. The mixture was stirred at −78 ◦C for
a further 30 min before being allowed to warm to rt over 16 h. The
(R)-3-Amino-2-methyl propanoic acid 25
LiOH (596 mg, 14.2 mmol, 5.0 eq.) in H2O (40 mL) was added to
a stirred solution of 3ꢀ-amino-2ꢀ-methyl-oxazolidinone 50 (1.20 g,
This journal is
The Royal Society of Chemistry 2007
Org. Biomol. Chem., 2007, 5, 2812–2825 | 2823
©

View Article Online
1 petrol–ether, v/v) gave 94 as a colourless oil (103 mg, 97%); [a]D22
+80.0 (c 0.4, CHCl3); mmax/cm−1 (film) 3443, 1643; dH (400 MHz,
CDCl3) 1.14 (3H, d, J 6.1, CHMe), 2.71 (1H, dd, JAB 12.5, JAX
4.2, CHCH2N), 2.76–2.82 (1H, m, COCH), 3.05 (1H, dd, JBA
11.9, JBX 10.9, CHCH2N), 3.31 (2H, d, J 13.1, N(CH2Ph)2), 3.66
(3H, s, OMe), 3.79–3.86 (1H, m, CHOH), 3.91 (2H, d, J 13.1,
N(CH2Ph)2), 7.27–7.38 (10H, m, Ph); dC (100 MHz, CDCl3) 21.7,
50.4, 52.1, 55.8, 59.0, 70.8, 127.9, 129.0, 129.7, 137.7, 173.3; m/z
(ESI+) 328 ([M+H]+, 100%); HRMS (ESI+) 328.1912 (C20H26NO3
requires 328.1913).
2.84 mmol, 1.0 eq.) in THF (80 mL) and the resultant solution was
stirred at rt for 24 h, after which time the solution was acidified
to pH 3 with sat. aq. KHSO4 solution. The product was then
extracted with EtOAc (3 ×), the combined organic extracts were
dried and concentrated in vacuo. The crude reaction mixture was
re-dissolved in MeOH (20 mL)–H2O (2 mL)–AcOH (0.5 mL). The
resultant solution was degassed and treated with Pd (400 mg, 10%
wt on C). The resultant suspension was stirred under H2 (1 atm) for
R
24 h before being filtered though Celiteꢀ (eluent MeOH) and the
filtrate was concentrated in vacuo. The residue was co-evaporated
with aq. HCl (2 M) and purified by ion exchange chromatography
(Dowex 50W-X8, 1 M aq. NH4OH eluent) to afford the free
amino acid (R)-25 as a white ◦crystalline solid (260 mg, 89%);
Acknowledgements
◦
mp 175–177 C {lit.27 179–181 C}; [a]D25 −12.4 (c 1.0, H2O) {lit.
The authors would like to thank the BBSRC and Yamanouchi, UK
for an industrial CASE studentship (A. J. R.), and New College,
Oxford for a Junior Research Fellowship (A. D. S.).
for enantiomer27 [a]D25 +14.2 (c 1.0, H2O)}.
(4S,2ꢀS,3ꢀR)-5,5-Dimethyl-4-isopropyl-3-{[2ꢀ-(N,N-
dibenzylamino)methyl]-3ꢀ-hydroxybutanoyl} oxazolidin-2-one 83
References and Notes
To a stirred solution of 3ꢀ-amino-oxazolidinone 7 (100 mg,
0.24 mmol, 1.0 eq.) in DCM (2.0 mL) at 0 ◦C was added 9-BBNOTf
(0.58 mL, 0.29 mmol, 1.2 eq.) followed by Hu¨nig’s base (0.06 mL,
0.34 mmol, 1.4 eq.) after 10 min. The resultant solution was stirred
for a further 20 min at 0 ◦C before being cooled to −78 ◦C followed
by addition of acetaldehyde (0.02 mL, 0.36 mmol, 1.5 eq., distilled
from CaCl2). The resultant solution was stirred for a further 30 min
at −78 ◦C before being allowed to warm to 0 ◦C and stirring was
continued for a further 1 h before addition of a 1 : 1 (v/v) mixture
of MeOH–H2O2 (30% aq. solution). The reaction mixture was
then allowed to warm to rt and extracted with DCM (3 ×). The
combined organic extracts were washed with sat. aq. NaHCO3,
dried and concentrated in vacuo. Purification of the residue via
column chromatography (silica, 9 : 1 petrol–ether v/v) gave 83 as
a viscous, pale yellow oil (72 mg, 65%); [a]2D2 +119.4 (c 0.5, CHCl3);
mmax/cm−1 (film) 3425, 1771, 1693; dH (400 MHz, CDCl3) 0.96 (3H,
d, J 6.8, CHMe2), 1.00 (3H, d, J 7.2, CHMe2), 1.12 (3H, d, J
5.8, C(OH)Me), 1.39 (3H, s, CMe2), 1.52 (3H, s, CMe2), 2.04–2.22
(1H, m, CHMe2), 2.72–2.78 (1H, m, CH2NBn2), 3.02–3.07 (1H,
m, CH2NBn2), 3.26 (2H, d, J 13.3, N(CH2Ph)2), 3.89–4.03 (1H,
m, CHOH), 4.06–4.22 (3H, m, N(CH2Ph)2, NCHiPr), 4.28–4.49
(1H, m, COCH), 6.35 (1H, br s, OH), 7.17–7.45 (10H, m, Ph);
dC (100 MHz, CDCl3) 17.1, 20.9, 21.3, 21.6, 28.6, 29.4, 46.7, 56.2,
58.4, 67.6, 70.9, 82.9, 127.5, 128.2, 129.3, 137.2, 153.5, 172.9; m/z
(ESI+) 453 ([M+H]+, 100%); HRMS (ESI+) 453.2746 (C27H37N2O4
requires 453.2753).
1 M. Liu and M. P. Sibi, Tetrahedron, 2002, 58, 7991–8035.
2 G. Trimurtula, I. Ohtani, G. M. L. Patterson, R. E. Moore, T. H.
Corbett, F. A. Valeroite and L. Demchik, J. Am. Chem. Soc., 1994,
116, 4729–4737; C. Shih, L. S. Gossett, J. M. Gruber, C. S. Grossman,
S. L. Andis, R. M. Schulz, J. F. Worzalla, T. H. Corbett and J. T. Metz,
Bioorg. Med. Chem. Lett., 1999, 9, 69–74; J. Schmidt and J. Langner,
J. Chem. Soc., Chem. Commun., 1994, 2381–2382.
3 L. M. Pratt, R. P. Beckett, S. J. Davies, S. B. Launchbury, A. Miller,
Z. M. Spavold, R. S. Todd and M. Whittaker, Bioorg. Med. Chem.
Lett., 2001, 11, 2585–2588.
4 T. Hintermann and D. Seebach, Synlett, 1997, 5, 437–438; D. Seebach,
S. Abele, K. Gademann and B. Juan, Angew. Chem., Int. Ed., 1999, 38,
1595–1597.
5 D. C. Cole, Tetrahedron, 1994, 50, 9517–9582; M. Liu and M. P. Sibi,
Tetrahedron, 2002, 58, 7991–8035; O. Munoz-Muniz and E. Juaristi,
Tetrahedron, 2003, 59, 4223–4229.
6 E. Arvanitis, H. Ernst, A. A. Ludwig, A. J. Robinson and P. B. Wyatt,
J. Chem. Soc., Perkin Trans. 1, 1998, 521–528; Y. Chi, E. P. English,
W. C. Pomerantz, W. S. Horne, L. A. Joyce, L. R. Alexander, W. S.
Fleming, E. A. Hopkins and S. H. Gellman, J. Am. Chem. Soc., 2007,
129, 6050–6055.
7 E. Juaristi, D. Quintana, B. Lamatsch and D. Seebach, J. Org. Chem.,
1991, 56, 2553–2557; G. Nagula, V. J. Huber, C. Lum and B. A.
Goodman, Org. Lett., 2000, 2, 3527–3529; R. Ponsinet, G. Chassaing, J.
Vaissermann and S. Lavielle, Eur. J. Org. Chem., 2000, 1, 83–90; V. M.
Gutie´rrez-Garc´ıa, H. Lo´pez-Ruiz, G. Reyes-Rangel and E. Juaristi,
Tetrahedron, 2001, 57, 6487–6496.
8 E. Juaristi, D. Quintana, M. Balderas and E. Garcia´-Pe´rez, Tetrahe-
dron: Asymmetry, 1996, 7, 2233–2246.
9 J. d’Angelo, D. Desmaele, F. Dumas and A. Guingant, Tetrahedron:
Asymmetry, 1992, 3, 459–505; I. T. Barnish, M. Corless, P. J. Dunn,
D. Ellis, P. W. Finn, J. D. Hardstone and K. James, Tetrahedron Lett.,
1993, 34, 1323–1326; F. Ferna´ndez, J. M. Otero, J. C. Este´vez and R. J.
Este´vez, Tetrahedron: Asymmetry, 2006, 17, 3063–3066; A. Duursma,
A. J. Minnaard and B. L. Feringa, J. Am. Chem. Soc., 2003, 125,
3700–3711; U. Eilitz, F. Lessmann, O. Seidelmann and V. Wendisch,
Tetrahedron: Asymmetry, 2003, 14, 189–191; U. Eilitz, F. Lessmann,
O. Seidelmann and V. Wendisch, Tetrahedron: Asymmetry, 2003, 14,
3095–3097; A. Rimkus and N. Sewald, Org. Lett., 2003, 5, 79–80.
10 H. S. Lee, J. S. Park, B. M. Kim and S. H. Gellman, J. Org. Chem.,
2003, 68, 1575–1578.
Methyl (2S,3R)-2-(N,N-dibenzylamino)methyl-
3-hydroxybutanoate 94
n-BuLi (2.5 M, 0.13 mL, 0.32 mmol, 1.0 eq.) was added dropwise
to MeOH (0.6 mL) at 0 ◦C. After 5 min, a solution of aldol adduct
83 (147 mg, 0.32 mmol, 1.0 eq.) in MeOH (0.6 mL) was added
dropwise. The resultant mixture was stirred at 0 ◦C for 30 min
before being allowed to warm to rt, then stirred for a further 15 h.
The solvent was removed in vacuo and the residue was partitioned
between sat. aq. NH4Cl solution and EtOAc. The aqueous layer
was extracted with EtOAc (2 ×) and the combined organic extracts
were washed with brine, dried and then concentrated in vacuo.
Purification of the residue via column chromatography (silica, 4 :
11 M. P. Sibi and P. K. Deshpande, J. Chem. Soc., Perkin Trans. 1, 2000,
1461–1466.
12 H. M. L. Davies and C. Venkataramani, Angew. Chem., Int. Ed., 2002,
41, 2197–2199.
13 A. Kubo, H. Kubota, M. Takahashi and K. I. Nunami, J. Org. Chem.,
1997, 62, 5830–5837.
14 J. Elaridi, A. Thaqi, A. Prosser, W. R. Jackson and A. J. Robinson,
Tetrahedron: Asymmetry, 2005, 16, 1309–1319; H. Huang, X. Liu, J.
Deng, M. Qiu and Z. Zheng, Org. Lett., 2006, 8, 3359–3362; R. Hoen,
2824 | Org. Biomol. Chem., 2007, 5, 2812–2825
This journal is
The Royal Society of Chemistry 2007
©

View Article Online
T. Tiemersma-Wegman, B. Procuranti, L. Lefort, J. G. De Vries, A. J.
Minnaard and B. L. Feringa, Org. Biomol. Chem., 2007, 5, 267–275.
15 G. M. Sammis and E. N. Jacobsen, J. Am. Chem. Soc., 2003, 125,
4442–4443.
16 M. P. Sibi and K. Patil, Tetrahedron: Asymmetry, 2006, 17, 516–519;
M. P. Sibi and K. Patil, Angew. Chem., Int. Ed., 2004, 43, 1235–
1238.
31 S. G. Davies, O. Ichihara and I. A. S. Walters, Synlett, 1993, 461–461;
S. G. Davies, O. Ichihara, I. Lenoir and I. A. S. Walters, J. Chem. Soc.,
Perkin Trans. 1, 1994, 1411–1415.
32 2-Pyridone has been shown to effect a rate enhancement upon the
mutarotation of glucose, potentially through its ability to act as both a
base and an acid at the same time; see: M. Kuzuya, A. Noguchi and T.
Okuda, Bull. Chem. Soc. Jpn., 1984, 57, 3461–3465.
17 S. G. Davies, N. M. Garrido, D. Kruchinin, O. Ichihara, L. J. Kotchie,
P. D. Price, A. J. Price Mortimer, A. J. Russell and A. D. Smith,
Tetrahedron: Asymmetry, 2006, 17, 1793–1811. For a review see: S. G.
Davies, A. D. Smith and P. D. Price, Tetrahedron: Asymmetry, 2005,
16, 2833–2891.
18 J. E. Beddow, S. G. Davies, A. D. Smith and A. J. Russell, Chem.
Commun., 2004, 2778–2779.
33 S. Masamune, W. Choy, J. S. Petersen and L. R. Sita, Angew. Chem.,
Int. Ed. Engl., 1985, 24, 1–30; W. Harb, M. F. Ruiz-Lopex, F. Coutrot,
C. Grison and P. Coutrot, J. Am. Chem. Soc., 2004, 126, 6996–7008.
34 J. A. Garbarino and O. Nunez, J. Chem. Soc., Perkin Trans. 1, 1981,
906–908.
35 M. Sunagawa, H. Matsumura, T. Inoue, M. Fukasawa and M. Kato,
J. Antibiot., 1990, 43, 519–532.
19 For addition of other nucleophiles to N-acryloyl-oxazolidinones see: G.
Li, X. Xu, D. Chen, C. Timmons, M. D. Carducci and A. D. Headley,
Org. Lett., 2003, 5, 329–331.
20 S. D. Bull, S. G. Davies, S. Jones and H. J. Sanganee, J. Chem. Soc.,
Perkin Trans. 1, 1999, 387–398.
21 D. A. Evans, S. J. Miller, T. Lectka and P. von Matt, J. Am. Chem. Soc.,
1999, 121, 7559–7573.
22 S. D. Bull, S. G. Davies, A. C. Garner, D. Kruchinin, M. S. Key, P. M.
Roberts, E. D. Savory, A. D. Smith and J. E. Thomson, Org. Biomol.
Chem., 2006, 4, 2945–2964.
36 R. Noyori, T. Ikeda, T. Ohkuma, M. Widhalm, M. Kitamura, H.
Takaya, S. Akutagawa, N. Sayo, T. Saito, T. Taketomi and H.
Kumobayashi, J. Am. Chem. Soc., 1989, 111, 9134–9135; K. Mashima,
K. H. Kusano, N. Sato, Y. Matsumura, K. Nozaki, H. Kumobayashi, N.
Sayo, Y. Hori, T. Ishizaki, S. Akutagawa and H. Takaya, J. Org. Chem.,
1994, 59, 3064–3076; H. U. Blaser, C. Malan, B. Pugin, F. Spindler,
H. Steiner and M. Studer, Adv. Synth. Catal., 2003, 345, 103–151; T.
Saito, T. Yokozawa, T. Ishizaki, T. Moroi, N. Sayo, T. Miura and H.
Kumobayashi, Adv. Synth. Catal., 2001, 343, 264–267.
37 P. Perlmutter and M. Tabone, J. Org. Chem., 1995, 60, 6515–6522 and
23 In all cases, the reaction diastereoselectivity was assessed by peak
integration of the 400 MHz 1H NMR spectrum of the crude reaction
product.
references cited therein.
38 H. Ohtake, Y. Imada and S. I. Murahashi, J. Org. Chem., 1999, 64,
3790–3791.
24 N. Asao, T. Uyehara and Y. Yamamoto, Tetrahedron, 1988, 44, 4173–
4180; N. Asao, T. Uyehara and Y. Yamamoto, Tetrahedron, 1990, 46,
4563–4572; S. G. Davies, G. J. Hermann, A. D. Smith and M. J. Sweet,
Chem. Commun., 2004, 1128–1129.
25 S. Hosokawa, K. Sekiguchi, M. Enemoto and S. Kobayashi, Tetrahe-
dron Lett., 2000, 41, 6429–6433.
39 D. Seebach, L. Schaeffer, F. Gessier, P. Bindscha¨dler, C. Ja¨ger, D. Josien,
S. Kopp, G. Lelais, Y. R. Mahajan, P. Micuch, R. Sebesta and B. W.
Schweizer, Helv. Chim. Acta, 2003, 86, 1852–1861.
40 D. A. Evans, J. Bartroli and T. L. Shih, J. Am. Chem. Soc., 1981, 103,
2127–2129.
41 D. A. Evans, J. M. Takacs, L. R. McGee, M. D. Ennis, D. J. Mathre
and J. Bartroli, Pure Appl. Chem., 1981, 53, 1109–1127.
42 According to the Heathcock model, syn-aldol products of N-acyl
26 A similar observation has been reported following the ring opening
of an aziridine attached to an oxazolidinone; see: G. Cardillo, L.
Gentilucci and V. De Matteis, J. Org. Chem., 2002, 67, 5957–5962.
27 Y. Jin and D. H. Kim, Synlett, 1998, 11, 1189–1190.
28 E. Juaristi, M. Balderas, H. Lo´pez-Ruiz, V. M. Jime´nez-Pe´rez, M. L.
Kaiser-Carril and Y. Ram´ırez-Quiro´s, Tetrahedron: Asymmetry, 1999,
10, 3493–3505.
ꢀ
ꢀ
oxazolidinones are expected to have J2 –3 2–6 Hz, while anti-aldol
ꢀ
ꢀ
products are expected to have J2 –3 7–10 Hz. See: C. H. Heathcock,
C. T. Buse, W. A. Kleschick, M. C. Pirrung, J. E. Sohn and J. Lampe,
J. Org. Chem., 1979, 44, 4294–4299.
43 A. B. Pangborn, M. A. Giardello, R. H. Grubbs, R. K. Rosen and F. J.
Timmers, Organometallics, 1996, 15, 1518–1520.
44 P. W. Betteridge, J. R. Carruthers, R. I. Cooper, C. K. Prout and
D. J. Watkin, CRYSTALS, 2004, Issue 12, Chemical Crystallography
Laboratory, University of Oxford, UK.
29 J. A. Dale, D. L. Dull and H. S. Mosher, J. Org. Chem., 1969, 34,
2543–2549.
30 M. Y. Chang, S. T. Chen and N. C. Chang, Tetrahedron, 2002, 58,
3623–3628.
This journal is
The Royal Society of Chemistry 2007
Org. Biomol. Chem., 2007, 5, 2812–2825 | 2825
©