Full text of DOI:10.1016/S0040-4020(01)00552-X

TETRAHEDRON
Pergamon
Tetrahedron 57 *2001) 6615±6626
Preparation of a-amino-carboxylic acid derivatives via
diastereoselective reactions of glycine enolate equivalents
S. Caddick,a,p N. J. Parra and M. C. Pritchardb
aSchool of Chemistry, Physics and Environmental Sciences, University of Sussex, Falmer, Brighton BN1 9QJ, UK
bP®zer-Warner Lambert, Forvie Site, Robinson Way, Cambridge CB2 2PZ, UK
Received 24 January 2001; revised 28 February 2001; accepted 27 March 2001
AbstractÐProtected glycine analogues tethered to an imidazolidinone auxiliary undergo diastereoselective alkylation and acylation reac-
tions in moderate to good yields *9±91%) with high levels of stereocontrol *generally .95% de). Subsequent alkylation of these derivatives
has been demonstrated for the production of non-racemic a,a-disubstituted amino acid precursors. Diastereoselective aldol reactions are also
found to proceed with good yields and excellent stereocontrol *62±84%, 93±95% de). Chiral auxiliary cleavage and hydrogenolysis of these
adducts affords the b-hydroxy-a-amino acid derivatives with no observed erosion of optical purity. q 2001 Elsevier Science Ltd. All rights
reserved.
1. Introduction
of amino acids we ideally require a concise and convergent
approach that allows structure variability and facile incor-
poration of functional groups and ring systems. For a-amino
acid synthesis the introduction of a diverse collection of
groups, for both mono- and di-substituted compounds, at
the a-position is paramount. Methods for the asymmetric
synthesis of sterically demanding a,a-disubstituted amino
acids are of great interest in the pharmaceutical industry
because of the biological activities exhibited by such
compounds.4 Our interest was targeted toward the synthesis
of a,a-disubstituted amino acids as potential neuropeptide
cholecystokinin *CCK), bombesin and tachykinin receptor
antagonists.5 In this article we report the ®ndings of our
research outlining a chiral auxiliary approach to the stereo-
selective preparation of a-substituted, a,b-disubstituted and
a,a-disubstituted carboxylic acid derivatives.
a-Amino acids exist as an integral part of many branches of
biology, chemistry and medicine. They are fundamental
constituents of proteins and act as mediators of nitrogen
metabolism, providing the raw materials for the production
of many primary and secondary metabolites. Of the large
numbers *,700) of naturally occurring a-amino acids many
have exhibited important biological properties. Amino acids
have played a pivotal role in the study of enzymatic reaction
mechanisms and thus in the synthesis of enzyme inhibitors.
Recently their potent biological activity in small drug mol-
ecules has prompted extensive pharmaceutical interest
in amino acids as building blocks for combinatorial and
parallel synthesis, chemistries that aid the identi®cation of
potential lead compounds. In addition proteinogenic amino
acids are extensively utilised as chiral reagents in organic
synthesis.
2. Results and discussion
Despite the myriad of syntheses that already exist for the
construction of a-amino acids, there is no single choice of
method that is applicable to every amino acid scenario.1
Current strategies include, for example, chemical and enzy-
matic resolution, or asymmetric synthesis using chiral
reagents or substrates.2 Whilst outstanding developments
have resulted, particularly in the arena of catalytic asymmetric
synthesis3 there is still a compelling case for the development
of additional methodologies which can offer a complement
to existing protocols. In devising a stereoselective synthesis
The imidazolin-2-one *1) has been reported as a versatile
auxiliary for stereoselective syntheses exhibiting excellent
levels of stereocontrol.6 From a practical perspective this
auxiliary is appealing as it is readily available in either
enantiomeric form, it is crystalline and it can be attached
and removed under mild conditions. These factors have
made this auxiliary a popular choice for a range of synthetic
endeavours.7 This chiral auxiliary has been employed for a
Dynamic Kinetic Resolution approach to the synthesis of
amino acids from within our group.8 The work described in
this paper will outline a complementary approach for the
preparation of a-substituted carboxylic acid derivatives
utilising diastereoselective reactions of glycine enolate
equivalents.9
Keywords: aldol reaction; alkylation; diastereoselective; chiral auxiliary;
imidazolidinone.
p
Corresponding author. Tel.: 144-1273-606755; fax: 144-1273-
677196678734; e-mail: s.caddick@sussex.ac.uk
0040±4020/01/$ - see front matter q 2001 Elsevier Science Ltd. All rights reserved.
PII: S0040-4020*01)00552-X

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S. Caddick et al. / Tetrahedron 57 22001) 6615±6626
Scheme 1. Reagents and conditions: *i) BrCOCH2Br. 2,6-lutidine, 278±08C, CH2Cl2, 99%; *ii) *a) PhCH2NH2, THF, 99%; then Boc2O, DMP, THF, 49%, *b)
*PhCH2)2NH, THF, 74%, *c) HCONH2, 2,6-lutidine, THF, 25%, *d) NaN*CHO)2, THF, 43%.
A series of chiral glycine enolate precursors with differing
electronic characteristics were prepared through the acyl-
ation of the imidazolidinone *1) with bromoacetylbromide.
The resulting a-bromo-amides were displaced using a
variety of primary and secondary amines, and protected
where necessary, to produce the desired substrates *3a±d)
*Scheme 1, Fig. 1).
The observed diastereoselectivity of the alkylations was
excellent with only a single diastereomer apparent in the
NMR spectra. The addition of anhydrous lithium chloride
to disassemble the lithium base aggregates present was
found to assist some reactions, but in others it provided no
discernible or even detrimental effects.13 A variety of
secondary bromides and alkyl iodides were used as the elec-
trophilic species, but none of the desired a-alkylated
products were isolated. This observation is in accordance
with prior work which showed deprotonations using LDA
on acylated quat auxiliaries proceeded with activated alkyl
bromides at 2788C but with methyl iodide, where the reac-
tion is slower, an elevated temperature *08C) was required.14
Reactions conducted at 08C using *5) were found to produce
alkylated imidazolidinone only. The reduced acidity of the
remaining a-proton in the substituted analogues *4±6) was
found to retard a second iterative alkylation step. Acylation
of *3b) was designed to increase the acidity of the remaining
a-proton suf®ciently to facilitate disubstitution. Rapid
quenching of the enolate was found to produce the highest
yield of the products *8,9) however, with compound *8) a
reduced level of selectivity was observed. Slow addition of
the electrophile, or recrystallisation of the diastereomeric
Carbanions adjacent to heteroatoms such as oxygen and
nitrogen are generally destabilised relative to their alkyl-
substituted counterparts. The lone-pairs of electrons situated
around the heteroatom impart an electrostatic repulsion on
the neighbouring anion causing increased instability. This
has led to some dif®culties in devising entirely general
protocols for high yielding and diastereoselective trans-
formations of glycine enolate equivalents. However in
recent times it has become apparent that the use of glycine
imine derivatives can offer a reliable class of substrate from
which functionalised amino-acids can be prepared.10 In our
preliminary studies the use of conventional methods for the
generation of chiral enolates using LDA or LHMDS were
found to cause signi®cant amounts of ketene formation
together with cleavage of the imidazolidinone from
the enolate precursors *3a±d).11 Employment of the more
sterically demanding bases lithium N,N-dicyclohexylamide
*LDCHA) and lithium N-isopropylcyclohexylamide12
*LICA) with enolate equivalent *3b) proved more successful
and we decided to study this species further. As can be seen
from the results presented in Table 1, formation of the
*Z)-enolate followed by directed alkylation with activated
electrophiles proceeded with moderate yields to afford the
products *4±9) *Scheme 2).
Table 1. Results of the alkylation and acylation of *3b)
Compound
Electrophile
Yield % *de)
4
5
6
7
8
8
9
Benzyl bromidea
59 *.95)
48 *.95)
23 *.95)
9 *.95)
91 *43)
Allyl bromideb
2-Bromoacetophenoneb,c
4-Bromobenzyl bromideb,c
Benzoyl chlorideb,c
Benzoyl chlorideb,c,d
4-Iodobenzoyl chlorideb,c
83 *95)
37 *.95)
a
LDCHA used as base.
LICA used as base.
Anhydrous LiCl *6 equiv.) was added.
Slow addition of electrophile.
b
c
d
Figure 1. X-ray crystal structure of protected chiral glycine *3a).
Scheme 2. Reagents and conditions: *i) LICA, THF, 2788C then RX.

S. Caddick et al. / Tetrahedron 57 22001) 6615±6626
6617
attributed to the generation of an enolate further removed
from the steric control element, thus diminishing its in¯u-
ence in directing the approach of the electrophile. Attempts
to increase selectivity by controlling the enolate geometry
using bulky silyl enol ethers groups or coordinatively
unsaturated Lewis acids proved unsuccessful.
Having investigated the use of lithium enolates attention
was then turned to the use of boron enolates. Diastereoselec-
tive boron mediated aldol condensation chemistries
have been widely explored and used in conjunction with
auxiliaries to produce b-hydroxypropionate derivatives.15
We felt an extension of this methodology to include chiral
glycine enolate synthons would prove extremely useful in
the synthesis of b-substituted a-phenylserine derivatives.16
Evaluation of the enolate precursors *3a±d) using standard
kinetic *Z)-boron enolate generation conditions was under-
taken and our early work established that the dibenzyl
protected analogue *3b) provided the best results. A selec-
tion of the experiments using dibutylboron tri¯ate for
enolate generation, followed by condensation with benzal-
dehyde *Scheme 4, *i)), are outlined in Table 2.
Figure 2. X-Ray crystal structure of 30-oxo-*S)-phenylalanine derivative
*8a).
mixture, to afford the enantiomerically pure 20-*S) dia-
stereomer could overcome this problem *Fig. 2). Non-
aromatic acyl chlorides and alkyl chloroformates failed to
produce the desired a-substituted analogues.
The a-acyl derivative *8a) was found to undergo facile
substitution at the a-position with activated electrophiles
with good chemical yields, but poor stereoselectivity
*Scheme 3).
It was observed that two of the four possible diastereomeric
compounds predominated in the mixtures formed. These
two diastereomers were at ®rst assigned as the syn and
anti 2*R) derivatives, however NMR analysis indicated
The poor levels of selectivity observed for this reaction were
Scheme 3. Reagents and conditions: *i) NaH, THF, 08C then RBr.
Scheme 4. Bu2BOTf mediated aldol condensation of *3b) with benzaldehyde. Reagents and conditions: *i) Bu2BOTf, 1.0 M in CH2Cl2 *5.0 equiv.), NEt3
*10 equiv.), CH2Cl2, 2788C, 5 min, then RCHO, 278±08C, 2 h.; pH 7 buffer, MeOH, H2O2*aq), *ii) 9-BBNOTf, 0.5 M in hexanes *5.0 equiv.), NEt3
*10 equiv.), CH2Cl2, 08C, 1 h, then RCHO, 2 h.; pH 7 *phosphate buffer). MeOH, H2O2*aq) 08C, 1 h.
Table 2. Condensation of 3b with benzaldehyde for the formation of syn-aldol products 12a,b
Enolate formation
temperature *8C)
Enolate formation
time *min)
Ratio of diastereomers of
12a 12a:12b
Diastereomeric
excess *%)
Yieldb *%)
278
278
22
0
288
5
13:1
0:1
0:1
5:14
4:32d
94
.95
.95
47
65 *87)
33
68
56
25
60
45
30
30c
62
a
1
Assignments made on H NMR coupling constants.
b
c
d
Isolated yields after puri®cation. Values in brackets based on 1H NMR of crude material.
Reaction performed using 2,6-lutidine as base.
A trace quantity of trans isomer could be identi®ed in the crude H NMR spectrum.
1

6618
S. Caddick et al. / Tetrahedron 57 22001) 6615±6626
Table 3. Aldol products derived from *3b) using 9-BBNOTf
Product
Aldehyde
Yield *%)
Non-Evans syn*a):Evans syn *b)
Diastereomeric excessa *%)
12
13
13
14
14
15
15
16
17
Benzaldehydeb
84
63
66
63
62
42
72
69
65
0:1
37:22
1:32
32:31
0:1
39:57
0:1
0:1
.95
2
94
0
.95
19
.95
.95
88
4-Methoxyaldehydec
4-Methoxyaldehydeb
2-Fluorobenzaldehydec
2-Fluorobenzaldehydeb
4-Nitrobenzaldehydec
4-Nitrobenzaldehydeb
Butyraldehydeb
Furfuraldehydeb
6:94
a
Diastereomeric excess of .95% assigned on the basis of only a single diastereomer apparent in the 1H NMR spectra.
Enolate generated at 08C.
Enolate generated at 2788C.
b
c
*12a) to have a 20*S) con®guration and further NMR and
further work was unable to identify a general procedure
using di-n-butylboron tri¯ate for the selective formation of
either syn isomer. A more general procedure was identi®ed
using 9-BBN tri¯ate as a reagent for the enolate generation
*Scheme 4, *ii)).17 The results of the aldol condensation of a
series of aldehydes with the glycine enolate equivalent *3b)
using 9-BBNOTf are shown *Table 3).
related crystallographic studies *on 13 and 14) con®rmed
the structures of the two syn products *12a,b). These results
illustrate that allowing enolisation to occur with short reac-
tion times and at low temperature, increased the ratio of the
so-called `non-Evans' syn product *12a). The use of longer
times for enolisation resulted in the formation of the 20*R)
i.e. the `Evans' syn isomer as the major product. These
experiments were found to be of a capricious nature and
Stereochemical assignments were made by comparison of
1H NMR chemical shifts and coupling constants of H20 and
H30 to the 400-methoxy derivatives *13a) and *13b).18 X-ray
crystallographic analysis of `non-Evans' syn adducts 13a
*not shown) and 14a *below) established the accuracy of
NMR assignments *Fig. 3).
Assuming *Z)-boron enolate generation under the reaction
conditions, the stereoselectivity observed for the BBN
enolates can be explained by invoking a chair-like transition
state. The chiral auxiliary adopts a conformation so as to
minimise the dipole±dipole repulsive energy between its
carbonyl groupand the enolate oxygen. This orientation
of the steric control element hinders approach of the alde-
hyde from the a face and directs attack from above
*Scheme 5).19
Figure 3. X-ray crystal structure of non-Evans syn aldol product 14a.
The cleavage of the chiral auxiliary for a selection of the
aldol products was achieved using sodium methoxide
*Table 4).20 Hydrogenation of the resultant compounds
afforded the b-hydroxy-a-amino esters with no observed
racemisation at either the 2 or 3 positions *Scheme 6).
A drawback of this cleavage method was that those
compounds bearing an electron withdrawing aryl substitu-
ent were found to produce signi®cant amounts of the retro-
aldol products on treatment with NaOMe. This pathway
resulted in poor yields of the desired methyl ester *19).
Scheme 5. Origin of `Evans syn' stereoselectivity.
Table 4. Auxiliary cleavage using sodium methoxide
Imide substrate
Methyl ester
Auxiliary recovery *%)
Yielda *%)
Diastereomeric excessb *%)
12b
14b
16b
17b
18
19
20
21
93
35
81
78
57
.95
.95
.95
.95
16 *29)
77 *86)
46 *59)
a
Values in brackets represent yields based on recovered starting material.
Diastereomeric excess of .95% assigned on the basis of only a single diastereomer apparent in the 1H NMR spectra.
b

S. Caddick et al. / Tetrahedron 57 22001) 6615±6626
6619
Scheme 6. Formation of b-hydroxy-a-amino acid methyl esters *22±24). Reagents and conditions: *i) NaOMe, MeOH, *ii) Pd*OH)2/C, H2, MeOH.
Attempted cleavage of *15a) was found to produce retro-
aldol product only. Employment of a less basic cleavage
protocol would be required for such sensitive substrates.
refers to solvent removal via a Buchi rotary evaporator at
water aspirator pressure followed by evaporation at 0.5 mm
for several hours. All melting points are uncorrected. IR
spectra were recorded using either a Perkin±Elmer FT-IR
298 or 2000 FT spectrometers by placing the neat
compound onto a sodium chloride disc. NMR spectra
were measured using Bruker 300 MHz and Varian Unity
Plus 400 MHz machines with coupling constants *J) being
quoted to the nearest 0.5 Hz. Mass spectra were recorded on
a Fisons autospec or Micromass Platform instruments. High
resolution spectra were performed at the National Service
Centre, University College, Swansea on a Thermoquest
Finnigan MAT900XT Spectrometer. Optical rotation
measurements were recorded on a Perkin±Elmer 241 polari-
meter *cont. Na 589).
²
Hydrogenation of the methyl esters *18±21) was achieved in
approaching quantitative yields using Pearlmanns catalyst
to afford the corresponding b-hydroxy-a-amino acid methyl
esters *22±24) *Scheme 6).21,22
3. Conclusions
In conclusion, the imidazolidinone derivative *3b) offers a
new chiral glycine enolate equivalent for the chemical
syntheses of natural and non-natural amino acid derivatives.
The asymmetric alkylation of *5) with activated alkyl
bromides has been demonstrated, and the principle of
increasing proton acidity at the a-position to achieve disub-
stitution has been attained. The simplicity of the 9-BBN
mediated experimental procedures, the excellent levels of
optical purity obtained and the uniformity of the chemical
yields make this an attractive procedure for the preparation
of b-hydroxy-a-amino acid derivatives. The intriguing
observation that the stereoselectivity can be in¯uenced by
the reaction conditions offers some interesting possibilities
for the further development of *3b) as a synthon in the
production of stereode®ned hydroxyamino acids.
4.1.1. 1--20-Bromo)ethanoyl-3,4-S)-dimethyl-5-R)-phenyl-
imidazolidin-2-one -2). 1,5*S)-dimethyl-4*R)-phenylimida-
zolidin-2-one *2.14 g, 11.20 mmol) and 2,6-lutidine *1.08 g,
1.28 mL, 11.0 mmol) were stirred in CH2Cl2 *50 mL) at
2788C for 15 min before the addition of freshly distilled
bromoacetylbromide *2.02 g, 0.96 mL, 10.5 mmol). The
reaction mixture was slowly warmed to 238C over ca. 2 h
and stirred for a further 24 h. The mixture was concentrated
in vacuo and partitioned with CH2Cl2 *3£100 mL) and satu-
rated NH4Cl*aq) solution *100 mL). The combined organic
extracts were then washed with water *100 mL), dried
*MgSO4), ®ltered and concentrated to afford 1-220-
Bromo)ethanoyl-3,42S)-dimethyl-52R)-phenylimidazolidin-
2-one *2) as a clear oil which solidi®ed on cooling *3.16 g,
4. Experimental
27
.99%) Rf 0.50 *30% EtOAc/petrol) [a]D ˆ2101.6 *c
0.39, MeOH); nmax 2979, 2937, 1729, 1605 cm21; dH
*CDCl3) 0.72 *d, Jˆ6.5 Hz, 3H, 4Me), 2.78 *s, 3H, NMe),
3.78 *m, 1H, H4), 4.37 *d, Jˆ12.0 Hz, 1H, H2), 4.45 *d,
Jˆ12.0 Hz, 1H, H20), 5.15 *d, Jˆ8.5 Hz, 1H, H5), 6.99 *d,
Jˆ8.0 Hz, 1.5, 2H, ArH), 7.20 *m, 3H, ArH); dC *CDCl3)
15.4, 28.7, 29.3, 54.5, 59.9, 127.4, 128.8, 129.0, 136.1,
155.4, 165.6; m/z *EI1) 337 *M1), 246, 232;
C13H15N2O2Br requires 310.0317 *M1) found 310.0317.
4.1. General procedures
All reactions were performed using oven-dried apparatus
under a dry nitrogen atmosphere at room temperature
*unless otherwise stated). Tetrahydrofuran and diethyl
ether were distilled from sodium/benzophenone ketyl prior
to use. Dichloromethane, toluene and dimethyl formamide
were distilled from CaH2. Methanol was distilled from
magnesium. The term petrol refers to distilled petroleum
ether with boiling temperatures of 40±608C. Chromato-
graphic puri®cation of compounds was carried out on
normal phase Merck no. 9385 *230±400 mesh) silica gel.
Analytical thin-layer chromatography *TLC) was
performed on E. Merck silica gel 60F-254 pre-coated plates
and the spots were visualised with a UV lamp and anisalde-
hyde, ninhydrin or permanganate dips. The term in vacuo
4.1.2. 1-[20--Phenylmethyl)amino]ethanoyl-3,4-S)-
dimethyl-5-R)-phenylimidazolidin-2-one -2b). To a stirred
solution of 1-*20-bromo)ethanoyl-3,4*S)-dimethyl-5*R)-
phenylimidazolidin-2-one *2) *3.15 g, 10.7 mmol) in THF
*30 mL) was added benzylamine *4.11 g, 38.6 mmol). The
reaction was stirred for 17 h before being concentrated in
vacuo. The residue was partitioned with EtOAc *3£100 mL)
and water *3£100 mL). The subsequent organic layer was
then washed with brine *100 mL), dried *MgSO4), ®ltered
and concentrated to afford 1-[20-2phenylmethyl)amino]
²
Compound 21 was found to be unstable preventing a HRMS spectrum of
the pure sample being obtained.

6620
S. Caddick et al. / Tetrahedron 57 22001) 6615±6626
ethanoyl-3,42S)-dimethyl-52R)-phenylimidazolidin-2-one -2b)
as a clear oil *3.60 g, .99%) Rf 0.3 *eluent 10% MeOH/
*M12Bn), 210, 91; C27H29N3O2 requires 427.2260 *M1)
found 427.2260.
27
CH2Cl2) [a]D ˆ241.1 *c 2.72, CH2Cl2); nmax 2979, 2937,
1729, 1605 cm21; dH *CDCl3) 0.76 *d, Jˆ6.5 Hz, 3H, 4Me),
2.80 *s, 3H, NMe), 3.80 *m, 2H, 20CH2), 4.10 *m, 2H, H5,
NH), 3.90 *m, 2H, NCH2Ph), 5.28 *d, Jˆ8.5 Hz, 1H, H4),
7.14±7.38 *m, 10H, ArH); dC *CDCl3) 15.4, 28.5, 54.7,
57.0, 57.8, 59.3, 126.3, 127.2, 127.4, 128.4, 128.5, 128.9,
129.5, 137.0, 139.6, 156.1, 171.3; m/z *EI1) 337 *M1), 246,
232; C20H23N3O2 requires 337.1786 *M1) found 337.1790.
4.1.5. Preparation of 1-[20--N-formyl)amino]ethanoyl-
3,4-S)-dimethyl-5-R)-phenylimidazolidin-2-one -3c). To
a stirred solution of 1-*20-bromo)ethanoyl-3,4*S)-dimethyl-
5*R)-phenylimidazolidin-2-one *2) *0.61 g, 2.0 mmol) in
THF *5 mL) was added formamide *1.00 mL, 51.1 mmol)
and 2,6-lutidine *0.50 mL, 4.3 mmol). The reaction was
heated at re¯ux for 16 h before the removal of solvent in
vacuo. The residue was partitioned with CH2Cl2 *20 mL)
and NH4Cl*aq) *2£20 mL). The organic phase was further
washed with water *20 mL) and brine *20 mL) then dried
*MgSO4), ®ltered and concentrated. Chromatography
afforded 1-[20-2N-formyl)amino]ethanoyl-3,42S)-dimethyl-
4.1.3. Preparation of 1-[20--N-phenylmethyl-N-tert-
butoxycarbonyl)amino]ethanoyl-3,4-S)-dimethyl-5-R)-
phenylimidazolidin-2-one -3a). To a stirred solution of the
1-[20-*phenylmethyl)amino]ethanoyl-3,4*S)-dimethyl-5*R)-
phenylimidazolidin-2-one *2b) *2.63 g, 7.8 mmol) in THF
*20 mL) was added di-tert-butoxycarbonyl anhydride
*3.49 g, 16.0 mmol, 2 equiv.). The solution was stirred for
5 min before the addition of DMAP *cat. 10 mg). The reac-
tion was stirred for 46 h then concentrated in vacuo. The
residue was partitioned with EtOAc *3£100 mL) and water
*3£100 mL). The organic phase was further washed with
brine *100 mL), dried *MgSO4), ®ltered and concentrated.
The product was then subjected to column chromatography
*eluent 20% EtOAc/petrol) and recrystallised *EtOAc) to
afford 1-[20-2N-phenylmethyl-N-tert-butoxycarbonyl)amino]
ethanoyl-3,42S)-dimethyl-52R)-phenylimidazolidin-2-one -3a)
as translucent crystals *1.61 g, 49%) Rf 0.5 *eluent 20%
52R)-phenylimidazolidin-2-one *3c) as
*0.48 g, 25%) Rf 0.3 *eluent 30% EtOAc/petrol);
a white solid
27
[a]D ˆ2113.7 *c 1.15, CHCl3) mp171±172 8C; nmax
2977, 2918, 1731, 1700, 1427, 1397, 1165 cm21; dH
*CDCl3) 0.77 *d, Jˆ6.5 Hz, 3H, 4Me), 2.79 *s, 3H, NMe),
3.95 *m, 1H, H4), 5.22 *2d, Jˆ17.0 Hz, Jˆ10.0 Hz, 2H,
H20, NH), 5.35 *d, Jˆ17.0 Hz, 1H, H5), 5.40 *d,
Jˆ17.0 Hz, 1H, H20), 7.08±7.55 *m, 5H, ArH), 8.10 *s,
1H, NCHO); dC *CDCl3) 15.3, 28.5, 55.3, 59.4, 63.4,
127.3, 128.7, 129.0, 136.2, 155.9, 160.6, 166.0; m/z
*FAB1) 277 *MH21), 231 *MH212NH[CHO]), 189 *xc ),
1
147.
4.1.6. Preparation of 1-[20--N,N-bis-diformyl)amino]-
ethanoyl-3,4-S)-dimethyl-5-R)-phenylimidazolidin-2-
one -3d). To a ¯ask charged with 1-*20-bromo)ethanoyl-
3,4*S)-dimethyl-5*R)-phenylimidazolidin-2-one *2) *1.05 g,
3.38 mmol) in THF *40 mL) was added sodium diformyl-
amide *1 equiv., 334 mg, 3.38 mmol) and reaction heated to
re¯ux for 12 h. The solvent was removed in vacuo and the
remaining residue redissolved in CH2Cl2 *30 mL), washed
with NH4Cl*aq) *2£20 mL), dried *Na2SO4), ®ltered and
concentrated to afford after chromatography *eluent 5%
MeOH/CHCl3) 1-[20-2N,N-bis-diformyl)amino]ethanoyl-
3,42S)-dimethyl-52R)-phenylimidazolidin-2-one *3d) as a
white solid *427 mg, 43%) Rf 0.3 *5% MeOH/CHCl3) mp
23
EtOAc/petrol); [a]D ˆ252.0 *c 1.19, CHCl3) mp144 8C;
nmax 2977, 1732, 1703 cm21; dH *DMSO, 393 K) 0.72 *d,
t
Jˆ6.5 Hz, 3H, 4Me), 1.32 *s, 9H, Bu), 2.72 *s, 3H, NMe),
3.93±4.08 *m, 1H, H4), 4.33 *s, 2H, H20), 4.49 *s, 2H,
NCH2Ph), 5.28 *d, Jˆ8.5 Hz, 1H, H5), 7.12±7.37 *m, 10H,
ArH); dC *CDCl3) 15.4, 28.7, 28.8, 50.8, 52.0, 54.7, 59.0,
127.6, 128.0, 128.1, 128.3, 128.4, 129.0, 129.1, 129.2,
129.3, 137.8, 138.9, 156.1, 156.2, 168.7; m/z *EI1) 437
*M1), 381 *M12tBu), 364, 337 *M12Boc) C25H31N3O4
requires 437.2315 *M1) found 437.2315; C25H31N3O4
requires *%) C 68.63, H 7.14, N 9.60; found *%) C 68.61,
H 7.15, N 9.59.
27
174±1758C; [a]D ˆ295.0 *c 0.65, CH2Cl2); nmax 2893,
2346, 1722, 1685, 1602, 1536 cm21; dH *CDCl3) 0.74 *d,
Jˆ6.5 Hz, 3H, 4Me), 2.78 *s, 3H, NMe), 3.92 *m, 1H, H4),
4.98 *d, Jˆ17.5 Hz, 1H, H20), 5.06 *d, Jˆ17.5 Hz, 1H, H20),
5.23 *d, Jˆ9.5 Hz, 1H, H5), 7.13±7.28 *m, 5H, ArH), 8.77
*s, 2H, CHO); dC *CDCl3) 15.4, 28.6, 42.8, 50.0, 59.8,
127.2, 128.7, 129.1, 136.1, 155.9, 163.5, 163.8; m/z *EI1)
303 *M1), 275 *M12CO), 191 *xcH1), 132; C15H17N3O4
requires 304.1297 *MH1) found 304.1298.
4.1.4. 1-[20-N,N-Di-methylphenyl)amino]ethanoyl-3,4-S)-
dimethyl-5-R)-phenylimidazolidin-2-one -3b). To a solution
of 1-*20-bromo)-ethanoyl-3,4*S)-dimethyl-5*R)-phenylimida-
zolidin-2-one *2) *4.20 g, 13.5 mmol) in THF *90 mL) was
added dibenzylamine *3 equiv., 40.5 mmol, 7.79 mL). The
reaction was stirred for 17 h then ®ltered and concentrated.
The residue was partitioned with EtOAc *3£100 mL) and
washed with saturated NaHCO3*aq) *2£100 mL) and water
*2£100 mL). The combined organic extracts were dried
*Na2SO4), ®ltered, and concentrated in vacuo. The crude
product was puri®ed by ¯ash chromatography *eluent 30%
EtOAc/petrol) to afford 1-[20-N,N-di2methylphenyl)amino]-
ethanoyl-3,42S)-dimethyl-52R)-phenylimidazolidin-2-one
-3b) as a hygroscopic white solid *2.33 g, 74%) Rf 0.4 *eluent
4.2. General procedure for alkylations and acylation of
1-[20-di-phenylmethyl)amino]ethanoyl-3,4-S)-dimethyl-
5-R)-phenylimidazolidin-2-one -4±9)
To a cold *08C) solution of secondary amine *1.5 mmol,
0.30 mL) in THF *5 mL) was added n-BuLi *1.5 mmol,
0.60 mL, 2.5 M solution in hexanes). The resulting solution
was stirred for 30 min before being transferred dropwise
via a double headed needle to a solution, at an internal
temperature of 2788C, of 1-[20-di*phenylmethyl)amino]-
ethanoyl-3,4*S)-dimethyl-5*R)-phenylimidazolidin-2-one
*3b) *1.01 mmol, 0.42 g) in THF *5 mL). The solution was
27
30% EtOAc/petrol) mp 116±1188C; [a]D ˆ249.1 *c 1.59,
CH2Cl2); nmax 3580, 1730, 1690 cm21; dH *CDCl3) 0.62 *d,
Jˆ6.5 Hz, 3H, 4Me), 2.61 *s, 3H, NMe), 3.71 *m, 5H, NCH2
and H4), 3.85 *s, 2H, H20), 5.15 *d, Jˆ8.5 Hz, 1H, H5), 7.00±
7.27 *m, 15H, ArH); dC *CDCl3) 15.5, 28.6, 53.5, 54.8, 57.9,
59.3, 127.3, 127.5, 128.6, 128.6, 128.7, 128.9, 129, 129.3,
140.1, 140.5, 156.2, 171.6; m/z *EI1) 427 *M1), 336

S. Caddick et al. / Tetrahedron 57 22001) 6615±6626
6621
stirred for 15 min at that temperature before the addition of
alkylating or acylating agent *1.10 mmol, 1.5 equiv.). The
mixture was warmed to 238C over a 2 h period, then concen-
trated in vacuo and partitioned with NH4Cl*aq) *2£30 mL)
and CH2Cl2 *4£20 mL). Column chromatography *15%
EtOAc/petrol) afforded the desired adducts.
Jˆ16.0, 8.0 Hz, 1H, H30), 3.51 *dd, Jˆ16.0, 7.5 Hz, 1H,
H30), 3.72 *m, 3H, H4 and PhCH2), 3.89 *d, Jˆ14.0 Hz,
2H, CH2Ph), 5.05 *d, Jˆ8.5 Hz, 1H, H5), 5.61 *t, Jˆ7.5 Hz,
1H, H20), 7.09 *s, 10H, ArH), 7.18±7.47 *m, 8H, ArH), 7.85
*d, Jˆ8.0 Hz, 2H, ArH); dC *CDCl3) 18.2, 26.6, 37.8, 52.5,
53.3, 56.5, 58.0, 125.2, 126.5, 126.7, 126.8, 127.0, 127.0,
127.2, 131.2, 134.8, 138.3, 153.8, 170.5, 197.4; m/z *EI1)
545 *M1), 454 *M12Bn), 348 *M12NBn2), 328, 264, 243;
C35H35N3O3 requires 454.2130 *M12Bn) found 454.2130.
4.2.1. Preparation of 1-[20-R)-diphenylmethyl)amino-30-
phenyl]propionoyl-3,4-S)-dimethyl-5-R)-phenylimidazo-
lidin-2-one -4). Prepared according to the general procedure
*dicyclohexylamine base) on a 1 mmol scale to afford the
desired compound which was subsequently recrystallised
*EtOAc) to afford 1-[202R)-diphenylmethyl)amino-30-
phenyl]propionoyl-3,42S)-dimethyl-52R)-phenylimidazoli-
din-2-one *4) as translucent crystals *0.31 g, 59%) Rf 0.6
4.2.4. Preparation of 1-[20-R)-di-phenylmethyl)amino-30-
oxo-30--400-bromo)phenyl]propionoyl-3,4-S)-dimethyl-
5-R)-phenylimidazolidin-2-one -7). Prepared according to
the general procedure *N-i-propyl-N-cyclohexylamine base,
1.5 equiv.) on a 0.9 mmol scale, in the presence of anhydrous
LiCl *6 equiv.) to afford after chromatography 1-[202R)-
di2phenylmethyl)amino-30-oxo-30-2400-bromo)phenyl]pro-
pionoyl-3,42S)-dimethyl-52R)-phenylimidazolidin-2-one *7)
as a white solid *54 mg, 9%) Rf 0.5 *30% EtOAc/petrol); dH
*CDCl3) 0.69 *d, Jˆ6.5 Hz, 3H, 4Me), 2.66 *s, 3H, NMe),
2.77 *dd, Jˆ14.0, 5.5 Hz, 1H, H30), 3.15 *dd, Jˆ14.0,
5.5 Hz, 1H, H30), 3.65 *d, Jˆ14.05 Hz, 2H, PhCH2), 3.80
*m, 1H, H4), 3.90 *d, Jˆ14.0 Hz, 2H, PhCH2), 5.16 *d,
Jˆ8.5 Hz, 1H, H5), 5.30 *m, 1H, H20), 6.90±7.27 *m,
19H, ArH); dC *CDCl3) 15.3, 28.5, 35.1, 54.4, 55.0, 59.5,
61.0, 120.3, 127.1, 127.2, 128.4, 129.0, 131.5, 131.8, 136.9,
137.6, 140.4, 155.4, 173.9.
23
*eluent 20% EtOAc/petrol) mp 1698C; [a]D ˆ222.3 *c
1.02, CHCl3); n max 2893, 2346, 1722, 1685, 1602,
1536 cm21; dH *CDCl3) 0.72 *d, Jˆ6.5 Hz, 3H, 4Me),
2.65 *s, 3H, NMe), 2.76 *dd, Jˆ14.0, 5.5 Hz, 1H, H30),
3.12 *dd, Jˆ14.0, 5.5 Hz, 1H, H30), 3.64 *d, Jˆ14.5 Hz,
2H, PhCH2), 3.80 *m, 1H, H4), 3.85 *d, Jˆ14.5 Hz, 2H,
PhCH2), 5.15 *d, Jˆ8.5 Hz, 1H, H5), 5.32 *m, 1H, H20),
6.91±7.26 *m, 20H, ArH); dC *CDCl3) 15.4, 28.5, 35.6,
54.4, 55.0, 59.5, 61.1, 126.5, 127.1, 127.2, 128.3, 128.5,
128.4, 128.7, 128.9, 129.0, 129.1, 130.0, 137.0, 138.5,
140.5, 155.4, 174.5; m/z *FAB1) 518 *MH1), 426
*MH12Bn), 300, 208; C34H35N3O2 requires *%) C 78.89,
H 6.81, N 8.11; found *%) C 78.77, H 6.84, N 8.10; HPLC
*spherisorb S5 chiral column, lˆ254 nm) ¯ow rateˆ0.25 -
mL min21, eluent 30% IPA/n-hexane, rt, 68.3 min, area
.99%.
4.2.5. Preparation of 1-[20--R,S)-di-phenylmethyl)-
amino-30-oxo-30-phenyl]propionoyl-3,4-S)-dimethyl-5-R)-
phenylimidazolidin-2-one -8a,b). Prepared according to
the general procedure *N-i-propyl-N-cyclohexylamine
base, 1.5 equiv.) on a 0.9 mmol scale, in the presence of
anhydrous LiCl *6 equiv.) to afford after chromatography
1-N-[20-2R,S)-di2phenylmethyl)amino-30-oxo-30-phenyl]-
propionoyl-3,42S)-dimethyl-52R)-phenylimidazolidin-2-one
*8a,b) *452 mg, 91%, de 20S 43%). Recrystallisation *ether/
petrol) afforded pure 20*S) diastereomer *166 mg, 33%) and
enrichment of the mother liquor in the 20*R) diastereomer.
Slow dropwise addition of benzoyl chloride caused a
reduced yield of product with an increase in selectivity
*8a) *83%, .95% de) 1-[20-2R)-di2phenylmethyl)amino-
30-oxo-30-phenyl]propionoyl-3,42S)-dimethyl-52R)-phenyli-
midazolidin-2-one *8a) Rf 0.4 *eluent 30% EtOAc/petrol);
4.2.2. Preparation of 1-[20-R)--diphenylmethyl)amino]-
pent-40,50-enoyl-3,4-S)-dimethyl-5-R)-phenylimidazo-
lidin-2-one -5). Prepared according to the general procedure
*N-i-propyl-N-cyclohexylamine base) on a 1.2 mmol scale
to afford the desired compound which was subsequently
recrystallised to afford 1-[202R)-2diphenylmethyl)amino]-
pent-40,50-enoyl-3,42S)-dimethyl-52R)-phenylimidazolidin-
2-one *5) as translucent crystals *0.27 g, 48%) Rf 0.5 *eluent
27
20% EtOAc/petrol) mp 157±1588C; [a]D ˆ214.1 *c 0.32,
CH2Cl2); nmax 3437, 3028, 2919, 1729, 1683, 1392 cm21
;
dH *CDCl3) 0.82 *d, Jˆ6.5 Hz, 3H, 4Me), 2.48±2.78 *m,
2H, H30), 2.80 *s, 3H, NMe), 3.82 *m, 3H, H4 and PhCH2),
4.11 *d, Jˆ14.5 Hz, 2H, PhCH2), 5.13 *m, 3H, H20, H50),
5.23 *d, Jˆ8.5 Hz, 1H, H5), 5.97 *m, 1H, H40), 7.12±7.52
*m, 15H, ArH); dC *CDCl3) 15.4, 28.5, 34.7, 54.4, 55.2,
59.6, 60.1, 117.4, 127.2, 127.3, 128.5, 129.0, 129.2, 135.7,
137.1, 140.8, 155.5, 174.4; m/z *FAB1) 468 *MH1), 426
*MH12C3H5), 336, 250; C30H33N3O2 requires 468.2651
*MH1) found 468.2638.
23
[a]D ˆ111.1 *c 0.94, CH2Cl2) mp159±160 8C; nmax 1723,
1693, 1562, 1495, 1288, 1029 cm21; dH *CDCl3) 0.69 *d,
Jˆ6.5 Hz, 3H, 4Me), 2.58 *s, 3H, NMe), 3.71 *d,
Jˆ14.0 Hz, 2H, CH2N), 3.88 *m, 3H, H4 and CH2N), 5.36
*d, Jˆ9.0 Hz, 1H, H5), 5.93 *s, 1H, H20), 6.93±7.64 *m,
20H, ArH); dC *CDCl3) 16.0, 28.9, 55.5, 56.4, 60.1, 68.3,
127.9, 128.2, 129.0, 129.0, 129.3, 130.0, 130.3, 133.6,
136.6, 137.1, 140.2, 156.3, 170.5, 197.5; m/z *EI1) 532
*MH1), 441, 428, 336, 314; C34H33N3O3 requires 531.252;
found 532.260 *MH1).
4.2.3. Preparation of 1-[20-R)--diphenylmethyl)amino-40-
oxo-40-phenyl]butanoyl-3,4-S)-dimethyl-5-R)-phenylimi-
dazolidin-2-one -6). Prepared according to the general pro-
cedure *N-i-propyl-N-cyclohexylamine base, 1.5 equiv.) on a
0.6 mmol scale, in the presence of anhydrous LiCl *6 equiv.)
to afford 1-[202R)-2diphenylmethyl)amino]-40-oxo-40-phenyl-
butanoyl-3,42S)-dimethyl-52R)-phenylimidazolidin-2-one *6)
as a clear gum *72 mg, 23%) Rf 0.4 *eluent 25% EtOAc/
4.2.6. Preparation of 1-[20--R)-di-phenylmethyl)amino-
30-oxo-30--400-iodo)-phenyl]propionoyl-3,4-S)-dimethyl-
5-R)-phenylimidazolidin-2-one -9). Prepared according to
the general procedure *N-i-propyl-N-cyclohexylamine base,
1.5 equiv.) on a 0.4 mmol scale, in the presence of anhy-
drous LiCl *6 equiv.) to afford after chromatography 1-[20-
2R)-di2phenylmethyl)amino-30-oxo-30-24-iodo)-phenyl]pro-
pionoyl-3,42S)-dimethyl-52R)-phenylimidazolidin-2-one *9)
25
petrol); [a]D ˆ233.1 *c 0.54, CHCl3); nmax 3063, 3029,
2918, 2850, 1730, 1681, 1392 cm21; dH *CDCl3) 0.72
*d, Jˆ6.5 Hz, 3H, 4Me), 2.75 *s, 3H, NMe), 2.95 *dd,

6622
S. Caddick et al. / Tetrahedron 57 22001) 6615±6626
as a white solid *106 mg, 37%, de .95%) Rf 0.4 *eluent
Jˆ6.5 Hz, 3H, 4Me), 2.63, 2.74 *s, 3H, NMe), 3.37±4.01
*m, 7H, H30, H4, PhCH2), 5.01 *m, 2H, H50, H5), 5.34 *m,
1H, H50), 5.72 *m, 1H, H40), 6.77±7.39 *m, 20H, ArH) m/z
*CI1) 574, 572 *MH1), 208, 198, 191, 106; C37H37N3O3
requires 572.2913 *MH1) found 572.2906.
30
30% EtOAc/petrol) mp 93±948C; [a]D ˆ1126.9 *c 0.25,
CH2Cl2); nmax 2917, 2850, 1724, 1694, 1582, 1393 cm21
;
dH *DMSO) 0.68 *d, Jˆ6.5 Hz, 3H, 4Me), 2.57 *s, 3H,
3Me), 3.71 *d, Jˆ14.0 Hz, 2H, CH2N), 3.88 *m, 3H, H4
and CH2N), 5.36 *d, Jˆ9.0 Hz, 1H, H5), 5.82 *s, 1H,
H20), 6.94±7.65 *m, 19H, ArH); dC *CDCl3) 15.6, 28.6,
55.1, 56.0, 59.6, 67.4, 101.1, 127.7, 127.7, 128.6, 128.7,
128.9, 129.6, 131.3, 136.0, 136.1, 137.9, 139.7, 155.8,
169.6, 195.7; m/z *EI1) 657 *M1), 566 *M12Bn), 467,
426 *M12COPhI), 376, 336; C34H32N3O3I requires
657.1488; found 657.1488.
4.3. General procedure for boron aldol condensations
Method A: To a solution *2788C) of 1-[20-di*phenylmethyl)
amino]ethanoyl-3,4*S)-dimethyl-5*R)-phenylimidazolidin-
2-one *3b) *0.7 mmol, 0.32 g) in CH2Cl2 *4 mL) was added
dropwise, over 1 min, freshly distilled di-n-butylboron
tri¯ate *1.0 M in CH2Cl2, 0.35 mL, 5 equiv.) and NEt3
*7.0 mmol, 0.56 mL, 10 equiv.). The mixture was stirred
at that temperature for 5 min before addition of aldehyde
*1.40 mmol, 150 mL, 2.0 equiv.). After 1 h the reaction was
slowly warmed to 08C and stirred for a further 1 h. The
reaction was quenched by the sequential addition of aqueous
pH 7 phosphate buffer *4.5 mL), methanol *10 mL), and
H2O2*aq) *30%, 4.5 mL). After 1 h at 08C the mixture was
concentrated and the residue partitioned between Et2O
*20 mL) and water *20 mL). The organic phase was washed
with cold HCl*aq) *5%, 20 mL), saturated NaHCO3 *20 mL)
and brine *20 mL). The organic phase was dried *Na2SO4)
and concentrated to afford, after chromatography, the
desired aldol adduct.
4.2.7. Preparation of 1-[20-R,S)-di-phenylmethyl)amino-
20-R,S)-phenylmethyl-30-oxo-30-phenyl]propionoyl-3,4-S)-
dimethyl-5-R)-phenylimidazolidin-2-one -10). To a solu-
tion of 1-[20*R,S)-di*phenylmethyl)amino-30-oxo-30-phenyl]-
propionoyl-3,4*S)-dimethyl-5*R)-phenylimidazolidin-2-one
*8a) *157 mg, 0.29 mmol) in THF *2 mL) was added NaH
*60% dispersion in mineral oil, 3 equiv., 42 mg). The solu-
tion was stirred at 08C for 30 min before the addition of
benzyl bromide *3 equiv., 0.85 mmol, 100 ml). TLC analy-
sis *eluent 30% EtOAc/petrol) indicated no reaction. NaH
*3 equiv.) was then added and the reaction stirred for 30 min
then heated to re¯ux for 1 h. After this period TLC showed
the reaction was complete. The reaction was quenched with
water *2 mL) and basi®ed to pH 9 with NaHCO3. Extraction
with CH2Cl2 *3£20 mL) followed by drying *Na2SO4),
®ltration and concentration afforded, after chromatography,
1-[202R,S)-di2phenylmethyl)amino-202R,S)-phenylmethyl-
30-oxo-30-phenyl]propionoyl-3,42S)-dimethyl-52R)-phenyli-
midazolidin-2-one *10) as a white solid *139 mg, 77%, dr
59:41, de 18%) Rf 0.3 *eluent 15% EtOAc/petrol) mp 159±
1608C; nmax 3580, 1730, 1690 cm21; dH *CDCl3) 0.56 and
0.61 *d, Jˆ6.5 Hz, 3H, 4Me), 2.48 and 2.63 *s, 3H, NMe),
3.51±3.78 *m, 5H, H40, 2NCH2Ph), 4.25±4.47 *m, 2H,
CH2Ph), 5.21±5.27 *d, 1H, H5), 6.89±7.36 *m, 25H,
ArH); dC *CDCl3) 14.7, 15.6, 16.4, 22.1, 28.1, 28.8, 25.2,
54.0, 56.4, 58.2, 59.9, 60.4, 61.0, 71.8, 127.2, 127.7, 127.9,
128.0, 128.3, 128.6, 128.9, 129.9, 130.0, 134.7, 134.8,
137.6, 138.0, 138.1, 139.2, 139.4, 139.7, 150.0, 154.3,
154.6, 155.2, 166.6, 167.2; m/z *EI1) 621 *M1), 530
*M2Bn), 426, 334, 312, 279, 248; C41H39N3O3 requires
621.299 *M1) found 621.299; C41H39N3O3 requires *%) C
79.20, H 6.32, N 6.75; found *%) C 79.35, H 6.37, N 6.69.
Method B: To a solution *08C) of 1-[20-di*phenylmethyl)-
amino]ethanoyl-3,4*S)-dimethyl-5*R)-phenylimidazolidin-
2-one *3b) *0.59 mmol, 0.25 g) in CH2Cl2 *4 mL) was added
9-BBN tri¯ate *0.5 M in hexanes, 5.85 mL, 5 equiv.). After
15 min NEt3 *5.9 mmol, 0.82 mL, 10 equiv.) was added.
The mixture was stirred at that temperature for 1 h and
then aldehyde *0.7 mmol, 1.2 equiv.) was added. After
30 min the reaction was warmed to 238C and stirred for
3 h. The reaction was quenched by the sequential addition
of aqueous pH 7 phosphate buffer *4.5 mL), methanol
*10 mL), and H2O2*aq) *30%, 4.5 mL). After 1 h at 08C the
mixture was concentrated and the residue partitioned
between CH2Cl2 *20 mL) and water *20 mL). The organic
phase was washed with saturated NaHCO3 *20 mL) and
brine *20 mL). The organic phase was dried *Na2SO4) and
concentrated to afford, after chromatography, the desired
aldol adduct.
4.3.1. Preparation of 1-[30-R)-hydroxy-20-S)-di-phenyl-
methyl)amino-3-phenyl]propionoyl-3,4-R)-dimethyl-5-S)-
phenylimidazolidin-2-one -12a). Prepared according to
method A on a 0.7 mmol scale *see Table 1) to afford,
after chromatography, 1-[302R,S)-hydroxy-202S,R)-di2phenyl-
methyl)amino-30-phenyl]propionoyl-3,42R)-dimethyl-52S)-
phenylimidazolidin-2-one *12a,b) as a pale foamÐ241 mg,
combined yield 65%, dr 97 *12a):3 *12b). 1-[302R)-hydroxy-
202S)-di2phenylmethyl)amino-3-phenyl]propionoyl-3,42R)-
dimethyl-52S)-phenylimidazolidin-2-one *12a): Rf 0.4 *eluent
30% EtOAc/petrol); dH *CDCl3) 0.61 *d, Jˆ6.5 Hz, 3H,
4Me), 2.65 *s, 3H, NMe), 3.60 *m, 1H, H4), 3.80 *d,
Jˆ14.5 Hz, 2H, CH2Ph), 4.20 *d, Jˆ14.5 Hz, 2H, CH2Ph),
4.83 *d, Jˆ9.5 Hz, 1H, H30), 4.99 *d, Jˆ8.5 Hz, 1H, H20),
5.66 *d, Jˆ9.5 Hz, 1H, H5), 6.50 *br. s, 1H, OH), 7.09±7.32
*m, 20H, ArH); dC *CDCl3) 15.2, 28.6, 54.0, 55.5, 60.0, 67.8,
72.7, 127.7, 127.7, 128.3, 128.7, 128.9, 129.1, 129.7, 137.4,
139.9, 140.1, 155.2, 171.3; m/z *FAB1) 534 *MH1), 426
4.2.8. Preparation of 1-[20-R,S)-di-phenylmethyl)amino-
20-R,S)-phenylmethyl-300-oxo-30-phenyl]pent-40,50-enoyl]-
3,4-S)-dimethyl-5-R)-phenylimidazolidin-2-one -11). To
a ¯ask containing NaH *31 mg, 8 equiv., 60% dispersion
in mineral oil), freshly washed with petrol and dried in
vacuo, was added a solution of 1-[20*R,S)-di*phenylmethyl)-
amino-30-oxo-30-phenyl]propionoyl-3,4*S)-dimethyl-5*R)-
phenylimidazolidin-2-one *8a) *50 mg, 94 mmol) in THF
*3 mL). The reaction was stirred at 258C for 30 min before
the addition of allyl bromide *2.6 equiv., 0.19 mmol,
17 mL). TLC indicated reaction completion after 60 h
*eluent 30% EtOAc/petrol). Chromatography afforded 1-
[202R,S)-di2phenylmethyl)amino-202R,S)-phenylmethyl-
300oxo-30-phenyl]pent-40,50-enoyl]-3,42S)-dimethyl-52R)-
phenylimidazolidin-2-one *11) *40 mg, 74% dr 61:39, de
22%) Rf 0.6 *eluent 30% EtOAc/petrol); nmax 2921, 2854,
1736, 1657, 1259 cm21; dH *CDCl3) 0.70, 0.77 *d,

S. Caddick et al. / Tetrahedron 57 22001) 6615±6626
6623
*M12PhCHO), 316, 191; C34H35N3O3 requires 534.2757
*d, Jˆ14.0 Hz, 2H, CH2Ph), 3.68 *s, 3H, OMe), 3.74 *br. s,
1H, OH), 3.80 *d, Jˆ14.0 Hz, 2H, CH2Ph), 4.74 *d,
Jˆ9.5 Hz, 1H, H30), 4.88 *d, Jˆ8.5 Hz, 1H, H5), 5.40 *d,
Jˆ9.5 Hz, 1H, H20), 6.73 *d, Jˆ9.0 Hz, 2H, ArH), 7.04±
7.31 *m, 17H, ArH); dC *CDCl3) 15.2, 28.5, 53.9, 55.3, 55.7,
59.8, 60.8, 67.6, 71.9, 113.6, 127.5, 127.7, 128.6, 128.8,
129.0, 129.4, 129.6, 132.0, 137.3, 139.8, 155.0, 159.7,
171.2; m/z *FAB1) 564 *MH1), 426 *M2MeOC6H4CHO),
336, 231; C35H37N3O4 requires 564.2862 *MH1) found
564.2865.
*MH1) found 534.2743.
4.3.2. Preparation of 1-[30-S)-hydroxy-20-R)-di-phenyl-
methyl)amino-3-phenyl]propionoyl-3,4-R)-dimethyl-5-S)-
phenylimidazolidin-2-one -12b). Prepared according to
method B, on a 0.5 mmol scale, to afford after chroma-
tography 1-[302S)-hydroxy-202R)di2phenylmethyl)amino-3-
phenyl]propionoyl-3,42R)-dimethyl-52S)-phenylimidazolidin-
2-one *12b) as a white foam *271 mg, 84%) Rf 0.4 *eluent
20
30% EtOAc/petrol) mp 63±648C; [a]D ˆ210.6 *c 0.81,
CH2Cl2); nmax 3447, 1728, 1674, 1494, 1453, 1421,
1391 cm21; dH *CDCl3) 0.52 *d, Jˆ6.5 Hz, 3H, 4Me),
2.40 *s, 3H, NMe), 3.02 *m, 1H, H4), 3.47 *d, Jˆ14.0 Hz,
2H, CH2Ph), 3.77 *br. s, 1H, OH), 3.99 *d, Jˆ14.0 Hz, 2H,
CH2Ph), 4.70 *d, Jˆ6.5 Hz, 1H, H30), 4.76 *d, Jˆ7.0 Hz,
1H, H20), 5.39 *d, Jˆ8.5 Hz, 1H, H5), 7.11±7.40 *m, 20H,
ArH); dC *CDCl3) 15.2, 28.5, 53.8, 55.2, 59.8, 66.2, 72.1,
126.3, 126.9, 127.6, 128.0, 128.2, 128.4, 128.7, 128.7,
128.8, 128.9, 129.1, 129.5, 136.1, 139.3, 139.8, 154.8,
169.8; m/z *ES1) 557 *MHNa21), 556 *MNa1), 534
*MH1), 429 *MH12PhCHO), 428 *M12PhCHO), 199;
C34H35N3O3 requires 534.2757 *MH1) found 534.2743.
4.3.5. Preparation of 1-[30-R)-hydroxy-20-S)-di-phenyl-
methyl)amino-3--200-¯uoro)phenyl]propionoyl-3,4-R)-
dimethyl-5-S)-phenylimidazolidin-2-one -14a,b). Prepared
according to method A on a 0.5 mmol scale to afford
1-[302R,S)-hydroxy-202R,S)-di2phenylmethyl)amino-3-2200-
¯uoro)phenyl]propionoyl-3,42R)-dimethyl-52S)-phenylimida-
zolidin-2-one *14a,b) as a mixture of the syn diastereomers.
Chromatography *eluent 15% EtOAc/petrol) afforded *14a)
and *14b) as pale foams *184 mg, 63%, dr 32:31). 1-[302R)-
hydroxy-202S)-di2phenylmethyl)amino-3-2200-¯uoro)phenyl]-
propionoyl-3,42R)-dimethyl-52S)-phenylimidazolidin-2-one
33
*14a) Rf 0.4 *eluent 30% EtOAc/petrol); [a]D ˆ2231.6 *c
0.11, CH2Cl2); nmax 3452, 2922, 1731, 1678, 1494,
1391 cm21; dH *CDCl3) 0.56 *d, Jˆ7.0 Hz, 3H, 4Me), 2.51
*s, 3H, NMe), 3.53 *m, 1H, H4), 3.76 *d, Jˆ14.0 Hz, 2H,
CH2Ph), 4.12 *d, Jˆ14.0 Hz, 2H, CH2Ph), 4.82 *d,
Jˆ8.5 Hz, 1H, H5), 5.01 *d, Jˆ9.5 Hz, 1H, H30), 5.61 *d,
Jˆ9.5 Hz, 1H, H20), 6.42 *br. s, 2H, ArH), 6.63±7.36 *m,
17H, ArH); dC *CDCl3) 15.2, 28.5, 53.9, 55.2, 59.8, 64.9,
65.7, 115.9, 116.2, 124.3, 126.7, 127.3, 127.5, 127.6, 128.0,
128.6, 128.7, 128.8, 129.0, 129.1, 129.3, 129.5, 129.7, 129.8,
130.8, 136.2, 139.8, 140.0, 154.9, 169.5; m/z *FAB1) 552
*MH1), 426 *M2FC6H4CHO), 334, 136; C34H34N3O3F
requires 552.2662 *MH1) found 552.2688.
4.3.3. Preparation of 1-[30-R,S)-hydroxy-20-S,R)-di-
-phenylmethyl)amino-30--400-methoxy)phenyl]propionoyl-
3,4-dimethyl-5-S)-phenylimidazolidin-2-one -13a,b,c).
Prepared according to method A on a 0.3 mmol scale to
afford, after chromatography *eluent 15% EtOAc/petrol),
1-[302R,S)-hydroxy-202S,R)-di2phenylmethyl)amino-30-2400-
methoxy)phenyl]propionoyl-3,4-dimethyl-52S)-phenylimi-
dazolidin-2-one as a mixture of diastereomers *13a,b) as a
pale foam *202 mg, combined yield 68%, dr 37:22:4).
Further chromatography *eluent 15% EtOAc/petrol) and
recrystallisation *EtOAc/petrol) provided 1-[302S)-hydroxy-
202R)-di2phenylmethyl)amino-3-2400-methoxy)phenyl]pro-
pionoyl-3,42R)-dimethyl-52S)-phenylimidazolidin-2-one
*13a) as a pale foam: Rf 0.4 *eluent 30% EtOAc/petrol) mp
4.3.6. Preparation of 1-[30-S)-hydroxy-20-R)-di-phenyl-
methyl)amino-3--200-¯uoro)phenyl]propionoyl-3,4-R)-
dimethyl-5-S)-phenylimidazolidin-2-one -14b). Prepared
according to method B on a 0.5 mmol scale to afford after
chromatography *eluent 15% EtOAc/petrol) 1-[302S)-hy-
droxy-202R)-di2phenylmethyl)amino-3-2200-¯uoro)phenyl]-
propionoyl-3,42R)-dimethyl-52S)-phenylimidazolidin-2-one
*14b) as a pale foam *200 mg, 62%, de .95%) Rf 0.3
20
75±768C; [a]D ˆ2149.0 *c 0.91, CH2Cl2); nmax 3445,
3029, 1728, 1673, 1613, 1514, 1389, 1249 cm21; dH
*CDCl3) 0.54 *d, Jˆ6.5 Hz, 3H, 4Me), 2.60 *s, 3H, NMe),
3.47±4.14 *m, 6H, OH, H4, 2CH2Ph), 3.75 *s, 3H, OMe),
4.92 *d, Jˆ8.5 Hz, 1H, H5), 5.58 *d, Jˆ9.5 Hz, 1H, H30),
5.66 *d, Jˆ9.5 Hz, 1H, H20), 6.67 *br. s, 2H, ArH), 6.85±
7.23 *m, 17H, ArH); dC *CDCl3) 17.3, 30.7, 56.0, 57.4, 57.8,
61.9, 68.3, 73.8, 116.2, 129.7, 130.1, 130.5, 130.9, 131.3,
131.7, 132.2, 133.5, 138.2, 142.1, 157.0, 161.8, 172.0; m/z
*FAB1) 564 *MH1), 426 *M2MeOC6H4CHO), 336, 231;
C35H37N3O4 requires *%) C 74.58, H 6.62, N 7.45; found
*%) C 74.32, H 6.58, N 7.41.
20
*eluent 30% EtOAc/petrol); [a]D ˆ19.2 *c 0.82,
CH2Cl2); nmax 3444, 2918, 1730, 1678, 1493, 1391 cm21
;
dH *CDCl3) 0.64 *d, Jˆ7.0 Hz, 3H, 4Me), 2.35 *s, 3H,
NMe), 3.20 *dq, Jˆ6.8, 8.5 Hz, 1H, H4), 3.43 *d,
Jˆ14.0 Hz, 2H, CH2Ph), 3.65 *m, 3H, OH and CH2Ph),
4.91 *d, Jˆ8.5 Hz, 1H, H5), 5.09 *d, Jˆ10.0 Hz, 1H,
H30), 5.61 *d, Jˆ10.0 Hz, 1H, H20), 6.64±7.36 *m, 19H,
ArH); dC *CDCl3) 17.2, 30.5, 56.2, 57.3, 62.1, 62.9, 67.5,
68.1, 116.8, 117.1, 126.5, 126.6, 129.3, 129.4, 129.7, 129.8,
130.7, 130.8, 130.9, 131.1, 131.6, 132.5, 132.6, 139.4,
141.7, 157.1, 172.7; m/z *FAB1) 552 *MH1), 426
*M2FC6H4CHO), 334, 136; C34H34N3O3F requires
552.2662 *MH1) found 552.2688; C34H34N3O3F requires
*%) C 74.03, H 6.21, N 7.61; found *%) C 73.24, H 6.42,
N 7.16.
4.3.4. Preparation of 1-[30-S)-hydroxy-20-R)-di-phenyl-
methyl)amino-3--400-methoxy)phenyl]propionoyl-3,4-R)-
dimethyl-5-S)-phenylimidazolidin-2-one -13b). Prepared
according to method B on a 0.5 mmol scale to afford after
chromatography *eluent 15% EtOAc/petrol) 1-[302S)-hy-
droxy-202R)-di2phenylmethyl)amino-3-2400-methoxy)phenyl]-
propionoyl-3,42R)-dimethyl-52S)-phenylimidazolidin-2-one
*13b) as a pale foam *211 mg, 66%, de 94%) Rf 0.3 *eluent
20
30% EtOAc/petrol) mp 153±1558C; [a]D ˆ28.91 *c 0.13,
CH2Cl2); nmax 3439, 1728, 1674, 1612, 1513, 1391,
1249 cm21; dH *CDCl3) 0.60 *d, Jˆ6.5 Hz, 3H, 4Me),
2.49 *s, 3H, NMe), 3.17 *dq, Jˆ6.5 Hz, 8.5, 1H, H4), 3.48
4.3.7. Preparation of 1-[30-R,S)-hydroxy-20-S,R)-di-
-phenylmethyl)amino-3--400-nitro)phenyl]propionoyl-
3,4-R)-dimethyl-5-S)-phenylimidazolidin-2-one -15a,b).

6624
S. Caddick et al. / Tetrahedron 57 22001) 6615±6626
Prepared according to method A on a 0.5 mmol scale to
afford, after chromatogaphy *eluent 15% EtOAc/petrol),
1-[302R,S)-hydroxy-202R,S)-di2phenylmethyl)amino-3-2400-
nitro)-phenyl]propionoyl-3,42R)-dimethyl-52S)-phenylimi-
dazolidin-2-one *15a,b) as a pale foam *110 mg, 42%, dr
39:57).
methyl)amino-30-furyl]propionoyl-3,4-R)-dimethyl-5-S)-
phenylimidazolidin-2-one -17b). Prepared according to
method B on a 0.5 mmol scale to afford after chromato-
graphy *eluent 15% EtOAc/petrol) 1-[302S)-hydroxy-202R)-
di2phenylmethyl)amino-30-furyl]propionoyl-3,42R)-dimethyl-
52S)-phenylimidazolidin-2-one *17b) as
*198 mg, 65%, de .95%) Rf 0.3 *eluent 30% EtOAc/petrol)
a pale foam
20
Comparison of this spectrum to *15b) reveals the NMR data
for the minor product 1-[302R)-hydroxy-202S)-di2phenyl-
methyl)amino-3-2200-nitro)-phenyl]propionoyl-3,42R)-
dimethyl-52S)-phenylimidazolidin-2-one *15a) dH *CDCl3)
0.58 *d, Jˆ6.5 Hz, 3H, 4Me), 2.60 *s, 3H, NMe), 3.45 *m,
1H, H4), 3.55 *m, 2H, CH2Ph), 4.09 *d, Jˆ14.5 Hz, 2H,
CH2Ph), 4.84 *d, Jˆ9.5 Hz, 1H, H30), 4.91 *d, Jˆ8.0 Hz,
1H, H5), 5.20 *d, Jˆ9.5 Hz, 1H, H20), 6.48 *br. s, 2H, ArH),
7.03±7.35 *m, 15H, ArH), 7.92 *d, Jˆ9.0 Hz, 2H, ArH); dC
*CDCl3) 14.9, 28.4, 53.9, 55.3, 60.0, 66.3, 71.2, 123.8,
127.3, 127.8, 128.6, 128.6, 128.7, 128.8, 128.9, 129.3,
129.5, 136.0, 139.0, 147.3, 147.8, 154.7, 169.3.
mp58±60 8C; [a]D ˆ134.1 *c 0.32, CH2Cl2); nmax 3446,
1729, 1674, 1391, 1072 cm21; dH *CDCl3) 0.63 *d,
Jˆ7.0 Hz, 3H, 4Me), 2.62 *s, 3H, NMe), 3.37 *d,
Jˆ14.0 Hz, 2H, NCH2), 3.50 *m, 1H, H4), 3.56 *br. s, 1H,
OH), 3.75 *d, Jˆ14.0 Hz, 2H, NCH2), 4.77 *d, Jˆ10.0 Hz,
1H, H30), 5.01 *d, Jˆ8.5 Hz, 1H, H5), 5.50 *d, Jˆ10.0 Hz,
1H, H20), 6.10±6.15 *m, 2H, ArH), 6.99±7.24 *m, 16H,
ArH); dC *CDCl3) 15.4, 28.8, 54.1, 55.3, 59.9, 65.1, 65.6,
108.6, 110.6, 127.6, 128.0, 128.8, 129.0, 129.5, 137.3,
139.6, 142.7, 153.4, 155.4, 170.3; m/z *CI1) 525 *MH21),
524 *MH1), 429, 428, 233; C32H33N3O4 requires 524.2549
*MH1) found 524.2554.
4.3.8. Preparation of 1-[30-S)-hydroxy-20-R)-di-phenyl-
methyl)amino-3--400-nitro)phenyl]propionoyl-3,4-R)-
dimethyl-5-S)-phenylimidazolidin-2-one -15b). Prepared
according to method B on a 0.5 mmol scale to afford after
chromatography *eluent 15% EtOAc/petrol) 1-[302S)-hy-
droxy-202R)-di2phenylmethyl)amino-3-2400-nitro)phenyl]-
propionoyl-3,42R)-dimethyl-52S)-phenylimidazolidin-2-one
*15b) as a hygroscopic yellow foam *244 mg, 72%, de
4.4. General procedure for the transesteri®cation of
boron aldol derivatives -12b, 14b, 16b, 17b)
To a solution of the aldol products, in MeOH, was added
freshly prepared NaOMe *1.02 equiv., unless stated) and the
mixture stirred until all starting material consumed. The
reaction was quenched with water *25 mL) and the MeOH
removed in vacuo. The residue was extracted with CH2Cl2
*3£25 mL) and the combined organic extracts dried
*Na2SO4), ®ltered and concentrated. Column chroma-
tography afforded the desired methyl esters.
31
.95%) Rf 0.4 *eluent 30% EtOAc/petrol); [a]D ˆ19.0
*c, 0.1); nmax 3437, 2918, 1729, 1676, 1603, 1522 cm21
;
dH *CDCl3) 0.69 *d, Jˆ6.5 Hz, 3H, 4Me), 2.56 *s, 3H,
NMe), 3.38 *d, Jˆ14.0 Hz, 2H, CH2Ph), 3.42 *m, 1H,
H4), 3.91 *d, Jˆ14.0 Hz, 2H, CH2Ph), 4.89 *d, Jˆ9.5 Hz,
1H, H30), 5.09 *d, Jˆ9.0 Hz, 1H, H5), 5.36 *d, Jˆ9.5 Hz,
1H, H20), 7.08±7.41 *m, 17H, ArH), 8.04 *d, Jˆ6.5 Hz, 2H,
ArH); dC *CDCl3) 15.4, 28.7, 53.9, 55.3, 59.6, 67.0, 71.1,
123.5, 127.8, 128.0, 128.9, 129.0, 129.1, 129.1, 129.6,
137.1, 139.4, 147.9, 148.1, 154.9, 170.1; m/z *CI1) 579
*MH1), 429, 428 *M2NO2PhCHO), 338, 336;
C34H34N4O5 requires 579.2607 *MH1) found 579.2600.
4.4.1. Preparation of 2-R)-di-phenylmethyl)amino-3-S)-
hydroxy-3-phenylpropionoic acid, methyl ester -18).
Prepared according to the general procedure on a
0.27 mmol scale, in MeOH *10 mL), to afford *18) as a
clear gum *58 mg, 57%) Rf 0.4 *eluent 10% EtOAc/petrol);
33
[a]D ˆ1102.2 *c 1.25, MeOH); nmax 3434, 2951, 2851,
1733, 1642, 1495, 1454 cm21; dH *CDCl3) 3.33 *d,
Jˆ10.0 Hz, 1H, H3), 3.37 *d, Jˆ13.0 Hz, 2H, NCH2),
3.55 *s, 3H, OMe), 4.06 *d, Jˆ13.0 Hz, 2H, CH2N), 4.13
*br. s, 1H, OH), 4.87 *d, Jˆ10.0 Hz, 1H, H2), 7.05±7.70 *m,
15H, ArH); dC *CDCl3) 51.7, 55.2, 68.0, 69.9, 127.7, 128.1,
128.4, 128.6, 128.7, 128.8, 129.1, 129.3, 129.7, 138.3,
140.8, 170.4; m/z *FAB1) 376 *MH1), 268, 91;
C24H25NO3 requires 376.1912 *MH1) found 376.1910.
4.3.9. Preparation of 1-[30-S)-hydroxy-20-R)-di-phenyl-
methyl)amino-40-methyl]pentanoyl-3,4-R)-dimethyl-
5-S)-phenylimidazolidin-2-one -16b). Prepared according
to method B on a 0.5 mmol scale to afford after chroma-
tography *eluent 15% EtOAc/petrol) 1-[302S)-hydroxy-
202R)-di2phenylmethyl)amino-40-methyl]pentanoyl-3,42R)-
dimethyl-52S)-phenylimidazolidin-2-one *16b) as a pale
foam *201 mg, 69%, de .95%) Rf 0.5 *eluent 30%
4.4.2. Preparation of 2-R)-di-phenylmethyl)amino-3-S)-
hydroxy-3--20-¯uoro)phenylpropionic acid, methyl ester
-19). Prepared according to the general procedure on a
0.39 mmol scale, in MeOH *10 mL), to afford *19) as a
clear gum *25 mg, 16%) Rf 0.3 *eluent 10% EtOAc/petrol);
20
EtOAc/petrol) mp 115±1168C; [a]D ˆ141.7 *c 0.89,
CH2Cl2); nmax 3436, 3029, 2957, 1728, 1673, 1494, 1454,
1421, 1389 cm21; dH *CDCl3) 0.86 *t, Jˆ7.0 Hz, 3H, H60),
0.89 *d, Jˆ6.5 Hz, 3H, 4Me), 1.32±1.58 *m, 4H, H40, H50),
2.87 *s, 3H, NMe), 3.32 *br. s, 1H, OH), 3.34 *d, Jˆ14.0 Hz,
2H, CH2Ph), 3.85 *d, Jˆ14.0 Hz, 2H, CH2Ph), 3.92 *m, 2H,
H30, H4), 5.11 *d, Jˆ9.5 Hz, 1H, H20), 5.44 *d, Jˆ9.0 Hz,
1H, H5), 7.11±7.44 *m, 15H, ArH); dC *CDCl3) 15.2, 16.3,
20.3, 29.6, 36.5, 54.7, 56.1, 60.5, 66.4, 69.0, 129.0, 129.3,
129.5, 129.6, 130.1, 138.2, 140.6, 156.3, 171.8; m/z *AP1)
500 *MH1), 482 *MH12H2O), 428; C31H37N3O3 requires
500.2913 *MH1) found 500.2910.
33
[a]D ˆ176.3 *c 1.08, MeOH); nmax 3436, 3030, 2951,
2925, 2851, 1735, 1642, 1494, 1455 cm21; dH *CDCl3)
3.46, *d, Jˆ13.5 Hz, 2H, NCH2), 3.55 *d, Jˆ9.5 Hz, 1H,
H3), 3.59 *s, 3H, OMe), 3.98 *br. s, 1H, OH), 4.06 *d,
Jˆ13.0 Hz, 2H, CH2N), 5.19 *d, Jˆ10.0 Hz, 1H, H2),
6.83±7.31 *m, 14H, ArH); dC *CDCl3) 51.8, 55.3, 64.5,
66.3, 115.7, 116.0, 124.5, 124.6, 127.6, 127.7, 128.0,
129.1, 129.4, 129.5, 129.7, 129.8, 129.9, 138.4, 170.6; m/z
*FAB1) 394 *MH1), 334, 268, 91; C24H24NO3F requires
394.1825 *MH1) found 394.1818.
4.3.10. Preparation of 1-[30-S)-hydroxy-20-R)-di-phenyl-

S. Caddick et al. / Tetrahedron 57 22001) 6615±6626
6625
4.4.3. Preparation of 2-R)--diphenylmethyl)amino-3-S)-
References
hydroxyhexanoic acid, methyl ester -20). Prepared
according to the general procedure on a 0.24 mmol scale,
in MeOH *10 mL), to afford *20) as a clear oil *63 mg, 77%)
1. Williams, R. M. Synthesis of Optically Active Amino Acids;
Pergamon: Oxford, 1989.
33
Rf 0.9 *eluent 30% EtOAc/petrol); [a]D ˆ187.8 *c 0.9,
2. *a) Cintas, P. Tetrahedron 1991, 47, 6079. *b) Studer, A.
Synthesis 1996, 793. *c) Duthaler, R. O. Tetrahedron 1994,
50, 1539. *d) Wirth, T. Angew. Chem., Int. Ed. Engl. 1997, 36,
225. *e) Bailey, P. D.; Clayson, J.; Boa, A. N. Cont. Org.
Synth. 1995, 173.
MeOH); nmax 3434, 2957, 1733, 1495, 1454 cm21; dH
*CDCl3) 0.79 *t, Jˆ7.0 Hz, 3H, 6Me), 1.04±1.47 *m, 4H,
H4, H5), 3.05 *d, Jˆ9.5 Hz, 1H, H2), 3.31 *d, Jˆ13.5 Hz,
2H, CH2N), 3.49 *s, 1H, OH), 3.74 *s, 3H, OMe), 3.84 *ddd,
Jˆ9.5, 2.0 Hz, 1H, H3), 3.95 *d, Jˆ213.5 Hz, 2H, NCH2),
7.16±7.28 *m, 10H, ArH); dC *CDCl3) 14.5, 19.4, 36.4,
51.8, 55.2, 66.2, 67.0, 128.0, 129.0, 129.6, 138.5, 171.2;
m/z *CI1) 342 *MH1), 270, 198, 106; C21H27NO3 requires
342.2069 *MH1) found 342.2068.
3. See for example: *a) Lygo, B.; Crosby, J.; Lowdon, T. R.;
Wainwright, P. G. Tetrahedron Lett. 1997, 38 *13), 2343.
*b) Lygo, B.; Wainwright, P. G. Tetrahedron Lett. 1997, 38
*49), 8595. *c) Horikawa, M.; Busch-Petersen, J.; Corey, E. J.
Tetrahedron Lett. 1999, 3843. *d) Lygo, B.; Crosby, J.;
Peterson, J. A. Tetrahedron Lett. 1999, 40, 8671 and refer-
ences therein.
4.4.4. Preparation of 2-R)-di-phenylmethyl)amino-3-S)-
hydroxy-3-furylpropionic acid, methyl ester -21).
Prepared according to the general procedure on a
0.17 mmol scale, in MeOH *10 mL), to afford *21) as a
red oil *27 mg, 46%) Rf 0.7 *eluent 30% EtOAc/petrol);
4. *a) Cativiela, C.; Diaz-de-Villegas, M. D. Tetrahedron: Asym-
metry 1998, 9, 3517. *b) Cativiela, C.; Diaz-de-Villegas, M. D.
Tetrahedron: Asymmetry 2000, 11, 645. *c) Heimgartner, H.
Angew. Chem., Int. Ed. Engl. 1991, 30, 238.
33
[a]D ˆ170.9 *c 1.27, MeOH); nmax 3473, 3029, 2923,
5. *a) Horwell, D. C.; Hunter, J. C.; Kneen, C. O.; Pritchard,
M. C. Bioorg. Med. Chem. Lett. 1995, 5, 2501. *b) Burgaud,
B. G. K.; Horwell, D. C.; Padova, A.; Pritchard, M. C.
Tetrahedron 1996, 52, 13035. *c) Ashwood, V.;
Brownhill, V.; Higgenbottom, M.; Horwell, D. C.; Hughes,
J.; Lewthwaite, R. A.; McKnight, A. T.; Pinnock, R. D.;
Pritchard, M. C.; Chauhan-Suman, N.; Webb, C.; Williams,
S. C. Bioorg. Med. Chem. Lett. 1998, 8, 2589. *d) Boulton,
L. T.; Stock, T. H.; Raphy, J.; Horwell, D. C. J. Chem. Soc.,
Perkin Trans. 1 1999, 1421. *e) Bernad, N.; Burgaud, B. G. M.;
Horwell, D. C.; Lewthwaite, R. A.; Martinez, J.; Pritchard,
M. C. Bioorg. Med. Chem. Lett. 2000, 10, 1245.
2852, 1734, 1603, 1496 cm21; dH *CDCl3) 3.42 *d,
Jˆ13.5 Hz, 2H, NCH2), 3.62 *s, 3H, OMe), 3.68 *d,
Jˆ10.0 Hz, 1H, H3), 3.88 *br. s, 1H, OH), 3.99 *d,
Jˆ13.5 Hz, 2H, CH2N), 4.92 *d, Jˆ10.0 Hz, 1H, H2),
6.17 *m, 2H, H5, H6), 7.18±7.31 *m, 11H, ArH); dC
*CDCl3) 52.0, 55.2, 63.8, 64.9, 108.7, 110.6, 126.3, 128.1,
129.1, 129.7, 138.2, 143.0, 153.0, 170.2; m/z *FAB1) 366,
268, 91.
4.5. General procedure for the hydrogenation of
di-phenylmethyl)amino esters -22±24)
6. For examples of the use of this auxiliary in asymmetric syn-
theses see: *a) Cardillo, G.; D'Amico, A.; Orena, M.; Sandri,
S. J. Org. Chem. 1988, 53, 2354. *b) Cardillo, G.; D'Amico,
A.; Orena, M.; Sandri, S. J. Org. Chem. 1988, 53, 2354.
*c) Langer, T.; Illich, M.; Helmchen, G. Synlett 1996, 1137.
For related imidazolidinones see: *d) Seebach, D.; Sting, A. R.;
Hoffmann, M. Angew. Chem. 1996, 35, 2708.
To a solution of the methyl esters in MeOH *0.5 mL) was
added Pearlmann's catalyst *Pd*OH)2 wet, 10% w/w). The
mixture was stirred under an atmosphere of H2 for 3 h then
®ltered through a pad of celite and washed with MeOH
*10 mL). The ®ltrate was concentrated to afford the amino
acid methyl esters 22 and 2322 in 100 and 96%, respectively.
7. For recent work on diastereoselective enolate alkylations
using as ephedrine as an auxiliary see: *a) Myers, A. G.;
Yang, B. H.; Chen, H.; Gleason, J. L. J. Am. Chem. Soc.
1994, 116, 9361. *b) Myers, A. G.; Gleason, J. L.; Yoon, T.;
Kung, D. W. J. Am. Chem. Soc. 1997, 119, 656.
4.5.1. Preparation of 2-R)-amino-3-S)-hydroxy-3--200-
¯uoro)phenylpropanoic acid, methyl ester -23). Prepared
according to the general procedure on a 0.04 mmol scale to
afford 22R)-amino-32S)-hydroxy-3-2200-¯uoro)phenylpropa-
noic acid, methyl ester *23) as a clear oil *9 mg, 98%); nmax
3411 *br. s) 2957, 2926, 2854, 1728, 1641 cm21; dH
*CDCl3) 2.91 *br. s, 3H, NH2, OH), 3.58 *d, Jˆ4.0 Hz,
1H, H3), 3.66 *s, 3H, OMe), 5.21 *d, Jˆ3.5 Hz, 1H, H2),
6.91±7.48 *m, 4H, ArH); dC *CDCl3) 56.7, 63.8, 70.4,
126.4, 128.2, 128.4, 130.1, 153.7, 166.9, 204.2; m/z
*FAB1) 214 *MH1), 136, 69; C10H12NO3F requires
214.0879 *MH1) found 214.0878.
8. *a) Caddick, S.; Jenkins, K. Chem. Soc. Rev. 1996, 447.
*b) Caddick, S.; Jenkins, K. Tetrahedron Lett. 1996, 37,
1301. *c) Caddick, S.; Jenkins, K.; Treweeke, N.; Candeias,
S.-X.; Afonso, C. A. M. Tetrahedron Lett. 1998, 35, 2203.
9. For a review on chiral enolate design see:Evans, D. A.;
Takacs, L. R.; McGee, L. R.; Ennis, M. D.; Mathre, D. J.;
Bartroli, J. Pure Appl. Chem. 1981, 53, 1109.
10. For recent work on alkylation reactions of glycine enolate
equivalents see: *a) Guillena, G.; Najera, C. Tetrahedron:
Asymmetry 1998, 9, 1125. *b) Guillena, G.; Najera, C.
Tetrahedron: Asymmetry 1998, 9, 3935. *c) Guillena, G.;
Najera, C. J. Org. Chem. 2000, 65, 7310.
Acknowledgements
11. *a) Evans, D. A. Asymmetric Synthesis, Vol. 3; Academic:
New York, 1984 p1. *b) Evans, D. A.; Ennis, M. D.;
Mathre, D. J. J. Am. Chem. Soc. 1982, 104, 1737.
We thank the EPSRC and P®zer-Warner Lambert for
®nancial support. We also thank GlaxoSmithKline, and
AstraZeneca for additional support. We gratefully acknow-
ledge the contributions of the EPSRC mass spectrometry
service, Swansea, *UK), Dr P. B. Hitchcock, Dr A. Abdul-
Sada and Dr A. G. Avent *Sussex).
12. Alberola, A.; Calvo, L.; Rodriguez, M. T. R.; Sanudo, M. C.
J. Heterocycl. Chem. 1995, 32 *2), 537.
13. *a) Myers, A. Tetrahedron Lett. 1992, 33, 6461. *b) Seebach,
D. Angew. Chem., Int. Ed. Engl. 1988, 27, 1624.

6626
S. Caddick et al. / Tetrahedron 57 22001) 6615±6626
14. Davies, S. G.; Doisneau, G.; Prodger, J. C.; Sanganee, H. J.
Tetrahedron Lett. 1994, 35, 2373.
elsewhere: *a) Caddick, S.; Parr, N. J.; Pritchard, M. C.
Tetrahedron Lett. 2000, 31, 5963. For the development of
9-BBN enolates see: *b) Inoue, T.; Uchimaru, T.;
Mukaiyama, T. Chem. Lett. 977, 153.
15. Gage, J. R.; Evans, D. A. Org. Syn. 1990, 68, 83.
16. For recent work on aldol reactions of glycine enolate equiva-
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Tararov, V. I.; Saveleva, T. F.; Churkina, T. D.; Ikonnikov,
N. S.; Kotchetkov, K. A.; Orlova, S. A.; Pysarevsky, A. P.;
Struchkov, Y. T.; Raevsky, N. I.; Belokon, Y. N. Tetrahedron:
Asymmetry 1995, 6, 1741. *b) Soloshonok, V. A.; Hayashi, T.
Tetrahedron: Asymmetry 1994, 5, 1091. *c) Solladie, G.;
Clair, J. F. S.; Phillippe, M.; Semeria, D.; Maignan, J.
Tetrahedron: Asymmetry 1996, 7, 2359. *d) Kanemasa, S.;
Mori, T.; Tatsukawa, A. Tetrahedron Lett. 1993, 34, 8293.
*e) Solladie-Cavallo, A.; Nsenda, T. Tetrahedron Lett. 1998,
39, 2191.
18. *a) Heathcock, C. H.; Pirrung, M. C.; Sohn, J. E. J. Org. Chem.
1979, 44, 4294. *b) Heathcock, C. H.; Buse, C. T.; Kleschick,
W. A.; Pirrung, M. C.; Sohn, J. E.; Lampe, J. J. Org. Chem.
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19. Drewes, S. E.; Malissar, D. G. S.; Roos, G. H. P. Chem. Ber.
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20. Kubo, A.; Kubota, H.; Takahashi, M.; Nunami, K. J. Org.
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22. Compounds 22 and 24 are known, see: Beulshausen, T.;
Groth, G.; Schoellkopf, U. Liebigs Ann. Chem. 1991, 1207.
17. A selection of these results has previously been published