Approaches to the synthesis of (2R,3S)-2-hydroxymethylpyrrolidin-3-ol (CYB-3) and its C(3) epimer: A cautionary tale

Article abstract of DOI:10.1039/b200415a

The syntheses of (2R,3S)-2-tert-butyldiphenylsilyloxymethylpyrrolidin-3-ol (TBDPS-protected CYB-3) (21) and its C(3) epimer (25) have been achieved in 9 and 8 steps respectively from D-serine. However, chiral HPLC analysis of the key β-hydroxy ester intermediates in these syntheses (17 and 18) revealed that appreciable levels of racemisation had occurred in the aldol and Claisen condensation reactions used in this synthetic sequence.

Full text of DOI:10.1039/b200415a

View Article Online / Journal Homepage / Table of Contents for this issue
Approaches to the synthesis of (2R,3S)-2-hydroxymethylpyrrolidin-
3-ol (CYB-3) and its C(3) epimer: a cautionary tale
Alison N. Hulme* and Karen S. Curley
1
Department of Chemistry, The University of Edinburgh, Kings Buildings, West Mains Road,
Edinburgh, UK EH9 3JJ
Received (in Cambridge, UK) 14th January 2002, Accepted 22nd February 2002
First published as an Advance Article on the web 26th March 2002
The syntheses of (2R,3S)-2-tert-butyldiphenylsilyloxymethylpyrrolidin-3-ol (TBDPS-protected CYB-3) (21) and its
C(3) epimer (25) have been achieved in 9 and 8 steps respectively from -serine. However, chiral HPLC analysis of the
key β-hydroxy ester intermediates in these syntheses (17 and 18) revealed that appreciable levels of racemisation had
occurred in the aldol and Claisen condensation reactions used in this synthetic sequence.
Introduction
The hydroxypyrrolidine CYB-3 (1),1 shares its biological source
(a tree from Castanospermum australe sp.) with the more well
known indolizidine alkaloid castanospermine (2) (Fig. 1).2
Fig. 2 Chiral pool precursors to CYB-3.
(Fig. 2).13 One final approach from the chiral pool utilises the
olefin metathesis of a derivative of vinyl glycine (8) as the key
step.14
We have recently reported the syntheses of both the imino-
sugar DAB-1 (3),15 and the antibiotic anisomycin (9),16 utilising
stereocontrolled glycolate aldol couplings to -serine- and -
tyrosine-derived aldehydes 10 and 11 respectively to provide the
acyclic backbone of each of these natural products in high yield
(Fig. 3).
Fig. 1 Alkaloid glycosidase inhibitors.
As part of a continued interest in the synthesis of bioactive
iminosugars through the use of the aldol reaction, we were
Although CYB-3 exhibits only modest inhibitory activity
against several insect3 and mammalian4 glycosidase targets
when compared with other pyrrolidine alkaloids such as 1,4-
dideoxy-1,4-imino--arabinitol (DAB-1) (3),5 and (2R,3R,4R,
5R)-2,5-bis(hydroxymethyl)-3,4-dihydroxypyrrolidine (DMDP)
(4),6 it has been proposed as both a chemical7 and biosynthetic8
precursor for a number of more active indolizidine alkaloids
and has also been used in the synthesis of modified oligo-
nucleotides.9
Several chemical syntheses of CYB-3 (1) have been reported
recently which rely upon readily available chiral pool starting
materials. In approaches utilising the amino acid serine (5),
a number of different strategies have been used to achieve
the required two-carbon homologation; the most common of
these involving allylation and subsequent oxidative cleavage to
remove the “extra” carbon.10 However, two-carbon homolog-
ation has also been achieved through the use of vinyl Grignard
addition9 and Horner–Wadsworth–Emmons (HWE)/cyclo-
carbamation reactions,7 as well as the tandem Michael/Henry
reaction of a nitroethylene precursor.11 Other popular chiral
pool starting materials for the synthesis of CYB-3 include
pyroglutamic acid† (6)12 and sugars such as mannose (7)
Fig. 3 An aldol based approach to the syntheses of the hydroxylated
† Pyroglutamic acid is also known as 5-oxoproline.
DOI: 10.1039/b200415a
pyrrolidines DAB-1, anisomycin and CYB-3.
J. Chem. Soc., Perkin Trans. 1, 2002, 1083–1091
This journal is © The Royal Society of Chemistry 2002
1083

View Article Online
attracted to the possibility of an acetate aldol approach to the
synthesis of CYB-3 (1), combining the lithium enolate of
methyl, or ethyl acetate with our readily accessible -serine-
derived aldehyde 10. Previous reports of such acetate aldols
have shown that high levels of substrate-derived stereocontrol
might be achieved in the case of simple N,N-dibenzyl α-amino
aldehydes,17 and that this strategy might be successfully
extended to the reaction of more sterically demanding alde-
hydes such as that derived from isoleucinal.18
Results and discussion
Scheme 2 Reagents and conditions: i. LiHMDS, THF, Ϫ78 ЊC, 20 min;
Synthesis of (2R,3S)-2-tert-butyldiphenylsilyloxymethyl-
pyrrolidin-3-ol
10, THF, Ϫ78 ЊC
THF, 0 ЊC
(81% 19, 12% 20); iv. BH3ؒTHF, THF, 0 ЊC
0 ЊC, 3 h (85%); ii. (MeO)NHMeؒHCl, Me3Al,
35 ЊC, 3 h (98%); iii. Pd(OH)2/C cat., MeOH, H2, rt, 12 h
reflux, 24 h (85%).
The synthesis of aldehyde 10 from -serine (5) was carried out
in five steps as described in our previous paper (Scheme 1).15
yield (85%),‡ but disappointingly were obtained as a 6 : 1
inseparable mixture of diastereomers [as determined by integra-
tion of the C(2) signals in the crude proton NMR spectrum].§
To complete the synthesis of CYB-3 we chose to pursue a
similar route to that used in the synthesis of DAB-1,15 namely
cyclisation to give the pyrrolidin-2-one followed by
borane reduction to give the requisite protected pyrrolidine. To
facilitate the complete removal of the N-benzyl protecting
groups from the mixture of aldol adducts15 they were first con-
verted in excellent yield into the corresponding Weinreb amides.
These amides were then treated under standard deprotection
conditions [Pd(OH)2/C, H2] to yield a readily separable mixture
of products in which the Weinreb amide resulting from desired
aldol adduct 17 had undergone a spontaneous cyclisation to
give pyrrolidinone 19 (81%), whilst the minor diastereomer
was isolated as the acyclic amino amide 20 (12%). The
pyrrolidinone 19 was found to be a crystalline solid, allowing its
structure to be determined unequivocally by X-ray diffraction.
This fortuitous separation allowed the subsequent borane
reduction to be conducted on a single diastereomer, and con-
version of pyrrolidinone 19 to the desired protected pyrrolidine
21 was achieved in high yield (85%).
Thus a 9 step synthesis of TBDPS-protected CYB-3 21 has
been achieved in 50% overall yield. This protected derivative is
ideally suited towards further synthetic manipulation such as
that followed by Herdewijn et al. in the synthesis of modified
oligonucleotides.9 Furthermore, 21 and its protected pyrrol-
idinone precursor 19, offer the opportunity for the develop-
ment of new selective glycomimetic-based glycosyltransferase
inhibitors,21 through selective glycosylation of the CYB-3 core.
[There are for example, only a few reported syntheses of motifs
related to the oligosaccharide sialyl Lewis X currently reported
in the literature based on mono- or disaccharide derivatives of a
pyrrolidinone,22 or pyrrolidine core.23]
Scheme 1 Reagents and conditions: i. CH3COCl, MeOH, reflux, 3 h
(98%); ii. K2CO3, BnBr, CH3CN, rt, 24 h (95%); iii. TBDPSCl,
imidazole, DMF, rt, 18 h (100%); iv. DIBAL-H, PhCH3, Ϫ78 ЊC, 30
min (93%); v. LiBH4, Et2O : MeOH (60 : 1), 0 ЊC
reflux, 4 h (95%);
vi. (COCl)2, DMSO, CH2Cl2, Ϫ78 ЊC, 1 h, Et3N (100%).
However, on a gram scale the removal of copious quantities of
aluminium salts from the DIBAL-H reduction of methyl ester
12 was found to be troublesome, and LiBH4 reduction of the
ester 12 to the corresponding alcohol 13 was preferred (95%).
Using this modified protocol, aldehyde 10 could routinely be
prepared in 88% overall yield from serine.
High levels of substrate based stereocontrol have been
observed in the reactions of -serine-derived N,N-dibenzyl α-
amino aldehyde 14a and its TBDMS-protected analogue 14b
with simple nucleophiles, by ourselves19 and Andrés and
Pedrosa.20 Thus aldehydes 14a,b have been shown to react
with Grignard reagents to give the anti addition products 15a,b
with >95 : 5 selectivity due to Felkin–Anh control (Fig. 4),
Synthesis of (2R,3R)-2-tert-butyldiphenylsilyloxymethyl-
pyrrolidin-3-ol
Fig. 4 Felkin–Anh and chelation control in the reaction of simple
nucleophiles with N,N-dibenzyl α-amino aldehydes 14.
In tackling the synthesis of the C(3) epimer we felt that we
should make use of the high substrate-derived selectivity that is
normally observed in the Felkin–Anh controlled reduction of
N,N-dibenzyl α-amino ketones.17a The N,N-dibenzyl α-amino
ketone that was required for this strategy was obtained from the
whereas the reaction of dialkylzinc reagents has been shown
to proceed with excellent selectivity for the syn addition
products 16a,b, presumably due to a chelation controlled
mechanism.
With the knowledge that these simple nucleophilic addition
reactions to the enantiomeric protected serine-derived aldehyde
14a proceeded with excellent stereocontrol, and the precedent
of high substrate-derived selectivity in previous reactions of
methyl, or ethyl acetate aldol reactions with simple N,N-
dibenzyl α-amino aldehydes,17,18 we were confident in achieving
high levels of stereocontrol when following the synthetic path-
way towards CYB-3 1 outlined in Scheme 2. However, when
aldehyde 10 was condensed with the lithium enolate of ethyl
acetate the aldol adducts 17 and 18 were generated in good
‡ Rt anti diastereomers (aldol major) 17 and ent-17, 8.3 and 9.0 min;
Rt syn diastereomers (Claisen major) 18 and ent-18, 9.1 and 10.8 min
[4.6 × 250 mm Chiracel OD column, solvent (5% isopropyl alcohol
(IPA) in hexane), flow rate 0.5 mL minϪ1].
§ Unfortunately, all attempts to improve the diastereoselectivity of this
acetate aldol reaction through the use of ‘matched’ chiral acetate boron
enolates (from either the phenylalanine-derived acylated Evans oxazol-
idinone, or valine-derived acylated thiazolidinethione) were unsuccess-
ful. These reactions resulted in lower yields of reaction products, with
no significant improvement in the diastereoselectivity.
1084
J. Chem. Soc., Perkin Trans. 1, 2002, 1083–1091

View Article Online
methanol once again yielded pyrrolidinone 23 in high yield
(78%). Borane reduction of pyrrolidinone 23 gave the desired
protected pyrrolidine 25 in high yield (86%). Using the second
(shorter) of these routes, a 7 step synthesis of the TBDPS-
protected C(3) epimer of CYB-3 (25) from the amino acid
serine, has been achieved in 39% overall yield.
The cautionary tale
There is literature precedent for the aldol reactions of simple
lithium enolates with N,N-dibenzyl α-amino aldehydes, and
little discussion of any loss of stereochemical integrity during
the course of these reactions.17,18 However, it is known that
racemisation may occur in the Claisen condensation reaction
of simple N,N-dibenzyl α-amino esters,24 where the resultant
enantiomeric excess may be reduced to as low as 78–90%. We
were anxious to investigate whether, and if so the extent to
which, racemisation had occurred in our current synthetic work.
We have previously shown that the synthetic sequence
outlined in Scheme 1 allows the production of aldehyde 10
(and hence its precursors) with no appreciable racemisation
(>98% ee by chiral HPLC) and indeed that high yields of a
single diastereomer might be obtained in subsequent glycolate
aldol couplings, suggesting no appreciable racemisation in the
reaction of 10.15 In order to rapidly identify all four possible
stereoisomers from the acetate aldol coupling, the synthesis of
17 and 18 was carried out using the route shown in Scheme 2
starting from a sample of aldehyde 10 prepared from racemic
serine. The resultant β-hydroxy esters were separable by chiral
HPLC using a standard analytical Chiracel OD column and a
solvent mix of 5% IPA in hexane.‡ Comparison of this HPLC
trace with those obtained from the aldol reaction of chiral non-
racemic -serine-derived aldehyde 10, allowed us to draw the
unhappy conclusion that our aldol adduct 17 was of only 90%
ee. Worse still, the β-hydroxy ester 18 derived from the Claisen
reaction of methyl ester 12 and subsequent cyanoborohydride
reduction was shown to vary in enantiomeric excess from 0% to
70% in an extremely capricious manner.
In an effort to address the latter problem, alternative sub-
strates for the Claisen condensation were sought. Saponifi-
cation of the methyl ester to acid 26 and conversion to the
imidazolide (acylimidazole) 27 is well-precedented in the
literature for other α-amino esters.24,25 However, in itself this
presented problems in that methyl ester 12 was found to be
relatively unreactive towards saponification under a range of
standard conditions, including those recently published for
sterically congested methyl esters of this type.24 The most
efficient conditions were found to be heating ester 12 to reflux
in a THF–water solvent mixture in the presence of LiOH
(Scheme 4). There was a delicate balance between the yield of
Scheme 3 Reagents and conditions: i. LiHMDS, THF, Ϫ78 ЊC, 25 min;
12, THF, Ϫ78 ЊC
0 ЊC, 4 h (78%); ii. NaCNBH3, AcOH, Et2O :
MeOH (8 : 3), 0 ЊC
rt, 7 h (81%); iii. (MeO)NHMe, Me3Al, THF,
0 ЊC
35 ЊC, 3 h (95%); iv. Pd(OH)2/C, MeOH, H2, rt, 12 h; SiO2;
MeOH, reflux, 24 h (72%); v. Pd(OH)2, MeOH, H2, rt, 12 h; SiO2;
MeOH, reflux, 24 h (78%); vi. BH3ؒTHF, THF, 0 ЊC
reflux, 24 h
(86%).
Claisen condensation of methyl ester 12 (Scheme 1) with the
lithium enolate of ethyl acetate to give 22 in good yield (78%,
Scheme 3). Several different reagents, including sodium and
lithium borohydride, were used for the selective reduction of
the ketone functionality. Due to the hindered nature of this
protected α-amino ketone this reaction was found to be
extremely sluggish at 0 ЊC and heating to room temperature was
required to drive the reaction to completion. This resulted
in considerable concomitant reduction of the ester to give the
corresponding diastereomeric diols. Thus although reasonable
selectivity favouring the desired syn stereochemistry in 18
(typically 5 : 1 to 8 : 1) could be achieved, the yields of 18 and 17
were low. A solution was finally obtained with the use of
sodium cyanoborohydride which, despite longer reaction times
and the need for a greater excess of the reagent to drive the
reaction to completion, resulted in a marked decrease in ester
reduction. This allowed the synthesis of diastereomeric β-
hydroxy esters 18 and 17 as a 10 : 1 mixture of diastereomers
[as determined by integration of the C(2) signals in the crude 1H
NMR spectrum]. In this diastereomeric mixture, 18 was found
to be amenable to chromatographic separation and could be
isolated in 81% yield (along with 6% of 17).
Two separate routes to the completion of the synthesis of the
C(3) epimer of CYB-3 were pursued. In the first, the ester 18
was converted to the Weinreb amide as in the previous synthetic
sequence [(MeO)NHMeؒHCl, Me3Al, 95%] and this was sub-
jected to debenzylation [Pd(OH)2/C, H2] to give the amino
amide 20. This amide was filtered through a short pad of silica
and then heated at reflux in methanol for 24 h, to give the
pyrrolidinone 23 in 78% yield. The second, more direct route
made use of the relatively lower reactivity towards cyclisation
imparted on this stereoisomer by its conformation. (Thus
debenzylation of the amino ester 18 might be expected to go to
completion, without concomitant cyclisation to give a mixture
of the desired product 23 and the corresponding benzyl pro-
tected pyrrolidinone.) When 18 was treated under standard
conditions [Pd(OH)2/C, H2] for debenzylation, amino ester 24
was indeed isolated in excellent yield (100% crude material).
Filtration through a short pad of silica and heating to reflux in
Scheme 4 Reagents and conditions: i. LiOH, THF : H2O (4 : 1), reflux,
6 h (58%); ii. CDI, THF, rt, 2 h; iii. LiHMDS, THF, Ϫ78 ЊC, 20 min;
27, THF, Ϫ78 ЊC
0 ЊC, 2 h (91% from 26); iv. NaCNBH3, AcOH,
Et2O : MeOH (8 : 3), 0 ЊC
rt, 7 h (81%).
J. Chem. Soc., Perkin Trans. 1, 2002, 1083–1091
1085

View Article Online
acid 26 and the eventual enantiomeric excess of product 18;
longer reaction times (24 h) resulting in high yields of the acid
(90%) but with considerable racemisation and concomitant loss
of the TBDPS protecting group. Conversion to the imidazolide
27 using carbonyldiimidazole (CDI) was efficient, but in general
27 was not isolated, rather it was treated directly with the
lithium enolate of ethyl acetate to give the amino ketone 22 in
high yield (91% from acid 26). Reduction under the previously
optimised conditions (NaCNBH3) allowed the synthesis and
isolation of 18 and assessment of its enantiomeric purity by
chiral HPLC. Using this route we were able to produce the
β-hydroxy ester 18 with a reliable enantiomeric excess of 70%.
This material was then converted through to the desired
(2R,3S)-2-tert-butyldiphenylsilyloxymethylpyrrolidin-3-ol 25,
giving an 8 step synthesis of this protected hydroxypyrrolidine
in 26% overall yield.
Since the enantiomeric excess observed in β-hydroxy ester 18
produced via the route shown in Scheme 4 was shown to be
extremely dependent upon the conditions used for the saponifi-
cation of methyl ester 12, this suggested that in itself the use of
the CDI-mediated Claisen condensation was not contributing
greatly to the racemisation process (as compared to the direct
condensation of methyl ester 12). Indeed CDI-mediated
coupling has been used in conjunction with a number of
other N,N-dibenzylamino acids, without any apparent loss of
stereochemical integrity.24 This suggested that the problem
perhaps arose from the extremely hindered nature of methyl
ester 12, due in part to the choice of the TBDPS protecting
group. Thus a further solution to the problem of racemisation
in the condensation route to the C(3) epimer of CYB-3 was
sought through the synthesis of an O-benzyl protected
acid derivative, which it was hoped would offer the same
acid stability as its TBDPS counterpart, but with reduced steric
bulk.
sample of racemic material.|| However, in line with an observed
[α]D of 0Њ for both the acid 29 and α-amino ketone 31, chiral
HPLC confirmed that we once again had an enantiomeric
excess of 0%.26 Thus, despite this representing a higher-yielding
approach to the desired protected CYB-3 C(3) epimer, this
route was not pursued further.
Conclusions
We have shown that the aldol and imidazolide-mediated
Claisen reactions of the lithium enolate of ethyl acetate with
aldehyde 10 and acid 26 provide extremely attractive routes to
the synthesis of silyl-protected CYB-3 and its C(3) epimer, in
terms of both the number of steps and overall efficiency of the
process. However, chiral HPLC analysis has revealed that for
our TBDPS protected serine-derived system this efficiency
is achieved at a price. Thus aldol adduct 17 is isolated in only
90% ee and Claisen–reduction product 18 is isolated in a
modest 70% ee.
Our studies have highlighted in particular, problems with the
synthesis of certain O-protected serine-derived N,N-dibenzyl
α-amino acids required for use in this Claisen based approach
to the C(3) epimer of CYB-3. However, a recent report of
the synthesis of the tert-butyldimethylsilyl protected analogue
of acid 26, via deprotection of the corresponding allyl ester
suggests that alternative routes to the desired acid might be
possible.27 Preliminary studies in our laboratories with other
N,N-dibenzyl protected α-amino acids indicate that problems
of racemisation using this route appear to be confined to the
serine derivatives. Hence, we are currently undertaking studies
to investigate the application of this approach to the synthesis
of other pyrrolidine glycomimetics.
In order to test this hypothesis, the synthesis of methyl ester
28, was undertaken in two steps from commercially available
-O-benzyl serine (Scheme 5). Saponification of ester 28 was
Experimental
General
All reactions involving air or water sensitive reagents were
carried out under an atmosphere of argon using flame or oven-
dried glassware. Unless otherwise noted, starting materials and
reagents were obtained from commercial suppliers and were
used without further purification. THF was distilled from
Na–benzophenone ketyl immediately prior to use. Toluene,
CH2Cl2, Et3N, and DMF were distilled from calcium hydride.
Anhydrous methanol and acetonitrile were used as supplied by
Aldrich. Unless otherwise indicated, organic extracts were dried
over anhydrous magnesium sulfate and concentrated under
reduced pressure using a rotary evaporator. Purification by
flash column chromatography was carried out using Merck
Kieselgel 60 silica gel as the stationary phase. Chiral HPLC was
performed using a Waters instrument equipped with a UV
detector and a Chiracel OD column (internal diameter 4.6 mm,
length 250 mm). All solvents for use in HPLC analysis were
vacuum filtered and degassed prior to use, and a standard flow
rate of 0.5 mL minϪ1 was used. IR spectra were measured as
thin films on NaCl plates, unless otherwise stated. Melting
points were determined on a Gallenkamp Electrothermal
Melting Point apparatus and are uncorrected. Optical rotations
were measured (10Ϫ1 deg cm2 gϪ1) on a AA-1000 polarimeter
with a path length of 1.0 dm, at the sodium D line, at room
temperature. 1H and 13C NMR spectra were recorded on a
Varian Gemini 200, a Bruker AC250 or a Bruker AM360
spectrometer. Coupling constants J are reported in Hz.
Elemental analysis was carried on a Perkin Elmer 2400 CHN
Elemental Analyser. Fast atom bombardment (FAB) mass
Scheme 5 Reagents and conditions: i. CH3COCl, MeOH, reflux, 3 h
(96%); ii. K2CO3, BnBr, CH3CN, rt, 24 h (94%); iii. LiOH, THF : H2O
(4 : 1), reflux, 4 h (100%); iv. CDI, THF, rt, 2 h; v. LiHMDS, THF, Ϫ78
ЊC, 20 min; 30, THF, Ϫ78 ЊC
0 ЊC, 2.5 h (92% from 29); vi.
NaCNBH3, AcOH, Et2O : MeOH (2 : 1), 0 ЊC
rt, 8 h (90%).
found to be far more facile than its TBDPS counterpart 12, and
high yields of the desired acid 29 were achieved under a range
of conditions including the use of LiOH, Ba(OH)2, and KOH.
The most efficient conditions were found to mimic those used
for the TBDPS protected ester; heating a mixture of the
ester 28 and LiOH to reflux in a THF–water solution (100%).¶
CDI-mediated coupling with the lithium enolate of ethyl
acetate to give β-keto ester 31 was found to proceed extremely
smoothly (92% from acid 29). Finally, sodium cyanoboro-
hydride reduction to amino alcohol 32 was used to assess the
enantiomeric excess of the material that had been produced
through comparison with an HPLC trace produced from a
|| Rt syn diastereomers 32 and ent-32, 18.3 and 23.1 min [4.6 × 250 mm
Chiracel OD column, solvent (5% IPA in hexane), flow rate 0.5 mL
minϪ1].
¶ Prolonged exposure to these conditions (24 h) at room temperature
was found to result in no conversion of the ester 28 to acid 29.
1086
J. Chem. Soc., Perkin Trans. 1, 2002, 1083–1091

View Article Online
spectra were obtained using
spectrometer at The University of Edinburgh.
a
Kratos MS50TC mass
were apparent. The aqueous phase was extracted with DCM
(3 × 30 cm3). The combined organic phases were dried (MgSO4)
and concentrated under reduced pressure. The residue was
chromatographed on silica gel [hexane : EtOAc (4 : 1)] to give
a 6 : 1 mixture of diastereomeric amides (506 mg, 98%) as a
colourless oil. νmax (neat)/cmϪ1 3457, 3069, 2937, 2856, 1643,
1427; m/z (FAB) 611 ([M ϩ H]ϩ, 27%), 478 (36), 210 (11) 197
(20) 135 (41), 91 (100); HRMS (FAB) C37H47N2O4Si [M ϩ H]ϩ
requires 611.3305, found 611.3290.
Synthesis of TBDPS-protected CYB-3
(2S)-3-tert-Butyldiphenylsilyloxy-2-(N,N-dibenzylamino)-
propan-1-ol 13. To a solution of ester 12 (4.20 g, 7.82 mmol),15
in anhydrous ether (60 cm3) at 0 ЊC was added lithium boro-
hydride (0.99 g, 49.9 mmol) followed by anhydrous methanol
(1 cm3). The mixture was stirred at 0 ЊC until effervescence
ceased and then heated to reflux and held at reflux for
4 hours. Saturated aqueous NH4Cl (140 cm3) was added
cautiously and the aqueous phase was extracted with DCM
(3 × 100 cm3). The combined organic phases were washed with
brine (200 cm3), dried (MgSO4) and concentrated under
reduced pressure. The remaining residue was chromatographed
on silica gel [hexane : EtOAc (5 : 1)] to give alcohol 13 (3.80 g,
95%) as an oil. Rf [hexane : EtOAc (4 : 1)] 0.55; all spectroscopic
data were in good agreement with those reported previously.15
Spectroscopic data for major diastereomer (from 17):
(3S,4R)-5-tert-butyldiphenylsilyloxy-4-(N,N-dibenzylamino)-3-
hydroxy-N-methoxy-N-methylpentanamide. Rf [hexane : EtOAc
(4 : 1)] 0.35; δH (360 MHz, CDCl3) 7.83–7.24 (20H, m, ArH ),
4.39–4.32 (1H, m, C(3)HOH), 4.27 (1H, dd, J 10.9, 4.0,
C(5)HAHBOTBDPS), 4.14 (1H, dd, J 10.9, 6.4, C(5)HAHBOT-
BDPS), 3.99 (2H, d, J 13.7, NCHXHYPh × 2), 3.80 (2H, d,
J 13.7, NCHXHYPh × 2), 3.66 (3H, s, OMe), 3.21 (3H, s, Me),
2.89–2.82 (1H, m, C(4)H ), 2.80–2.73 (1H, br m, C(2)HAHB),
t
2.32–2.25 (1H, br m, C(2)HAHB), 1.18 (9H, s, Bu); δC (62.9
MHz) 174.8 (C), 140.7 (C), 136.3 (CH), 136.2 (CH), 133.8 (C),
133.6 (C), 130.2 (CH), 129.6 (CH), 129.4 (CH), 128.6 (CH),
128.3 (CH), 128.2 (CH), 127.3 (CH), 67.6 (CH), 66.6 (CH3),
62.2 (CH), 61.7 (CH2), 55.7 (CH2), 37.1 (CH2), 32.3 (CH3), 27.4
(CH3), 19.6 (C).
Spectroscopic data for minor diastereomer (from 18). Rf
[hexane : EtOAc (4 : 1)] 0.34; δH (360 MHz, CDCl3) data were in
good agreement with those reported below, diagnostic signals at
3.60 (3H, s, OMe), 2.69–2.58 (1H, br m, C(2)HCHD).
Ethyl (3S,4R)-5-tert-butyldiphenylsilyloxy-4-(N,N-dibenzyl-
amino)-3-hydroxypentanoate 17. To a solution of LiHMDS
(8.84 cm3, 1.06 M in THF, 9.37 mmol) at Ϫ78 ЊC was added
ethyl acetate (0.871 cm3, 8.84 mmol). The solution was stirred at
Ϫ78 ЊC for 20 minutes. A solution of the aldehyde 10 (1.49 g,
2.94 mmol) in THF (6 cm3) was added dropwise via cannula.
The reaction mixture was stirred at Ϫ78 ЊC for 30 minutes then
allowed to warm to 0 ЊC over a period of 2 hours, then stirred
at 0 ЊC for 20 minutes. Saturated aqueous NH4Cl (50 cm3)
was added and the aqueous phase extracted with DCM (3 ×
60 cm3). The combined organic phases were washed with brine
(60 cm3), dried (MgSO4) and concentrated under reduced
pressure. The remaining residue was chromatographed on silica
gel [hexane : Et2O (5 : 1)] to give the title compound (1.48 g,
85%) as a 6 : 1 mixture of diastereomers. νmax (neat)/cmϪ1 3469,
2930, 1736, 1720, 1427; m/z (FAB) 596 ([M ϩ H]ϩ, 14%), 478
(13), 268 (18), 135 (26), 91 (100); HRMS (FAB) C37H46NO4Si
[M ϩ H]ϩ requires 596.3196, found 596.3192.
Reaction of the Weinreb amides. To a solution of the 6 : 1
mixture of Weinreb amides (420 mg, 0.689 mmol) in methanol
was added 20% Pd(OH)2/C (420 mg), the flask was flushed with
argon before being stirred under an atmosphere of hydrogen for
12 hours. The reaction mixture was filtered through a layer of
Celite and concentrated under reduced pressure. The residue
was chromatographed on silica gel [DCM : MeOH (50 : 1)] to
give pyrrolidinone 19 (206 mg, 81%) as a white solid and amino
amide 20 (35 mg, 12%) as a colourless oil.
Spectroscopic data for major diastereomer 17. Rf [hexane :
Et2O (1 : 1)] 0.40; δH (250 MHz, CDCl3) 7.76–7.19 (20H, m,
ArH ), 4.39–4.32 (1H, m, C(3)HOH), 4.25 (2H, q, J 7.2,
OCH2CH3), 4.23–4.17 (1H, m, C(5)HAHBOTBDPS), 4.07 (1H,
dd, J 10.6, 5.3, C(5)HAHBOTBDPS), 3.89 (2H, d, J 13.6,
NCHXHYPh × 2), 3.58 (2H, d, J 13.6, NCHXHYPh × 2), 3.45
(1H, br s, OH ), 2.98 (1H, dd, J 16.3, 2.7, C(2)HCHD), 2.78 (1H,
br ddd, J 10.6, 8.7, 5.3, C(4)H ), 2.31 (1H, dd, J 16.3, 8.7,
Rf [DCM : MeOH (10 : 1)] 0.32; mp 117–118 ЊC (hexane :
EtOAc); [α]D ϩ17.2 (c 0.36, CHCl3) (90% ee); νmax (solution
cell)/cmϪ1 3200, 2910, 1678, 1426; δH (250 MHz, CDCl3) 7.64–
7.59 (4H, m, ArH ), 7.43–7.32 (6H, m, ArH ), 6.40 (1H, s, NH ),
4.30–4.28 (1H, m, C(4)HOH), 3.63–3.60 (4H, m, C(3)H2
ϩ
C(5)H ϩ OH ), 2.74 (1H, dd, J 17.2, 6.8, CHAHBOTBDPS),
t
2.30 (1H, dd, J 17.2, 2.9, CHAHBOTBDPS), 1.00 (9H, s, Bu);
δC (62.9 MHz) 176.4 (C), 135.4 (CH), 135.3 (CH), 132.6 (C),
132.4 (C), 129.8 (CH), 127.7 (CH), 69.5 (CH), 64.7 (CH2), 64.5
(CH), 40.0 (CH2), 26.6 (CH3), 18.9 (C); m/z (FAB) 370 ([M ϩ
H]ϩ, 68%), 312 (15), 292 (53), 234 (27), 214 (61), 135 (100);
HRMS (FAB) C21H28NO3Si [M ϩ H]ϩ requires 370.1838, found
370.1830.
(3R,4R)-4-Amino-5-tert-butyldiphenylsilyloxy-3-hydroxy-N-
methyl-N-methoxypentanamide 20. Rf [DCM : MeOH (10 : 1)]
0.12; δH (250 MHz, CDCl3) 8.14–8.12 (2H, br s, NH2), 7.60–
7.32 (10H, m, ArH ), 4.25–4.20 (1H, br m, C(3)HOH), 4.01–
3.85 (2H, m, C(5)H2OTBDPS), 3.50 (3H, s, OMe), 2.97 (3H, s,
Me), 2.90–2.82 (2H, br m, C(2)HCHD ϩ C(4)H ), 2.39–2.30
(1H, br m, C(2)HCHD), 1.08 (9H, s, tBu).
t
C(2)HCHD), 1.28 (3H, t, J 7.2, OCH2CH3), 1.09 (9H, s, Bu);
δC (62.9 MHz) 173.0 (C), 139.6 (C), 135.6 (CH), 132.8 (C),
132.7 (C), 128.9 (CH), 128.7 (CH), 128.2 (CH), 127.7 (CH),
126.9 (CH), 68.1 (CH), 61.2 (CH), 60.9 (CH2), 60.4 (CH2), 55.1
(CH2), 50.0 (CH2), 39.5 (CH2), 26.8 (CH3), 19.0 (C), 14.1 (CH3).
Spectroscopic data for minor diastereomer 18. Rf [hexane :
Et2O (1 : 1)] 0.38; δH (250 MHz, CDCl3) data were in good
agreement with those reported below, diagnostic signal at 2.45
(1H, dd, J 15.2, 3.0, C(2)HCHD).
(4S,5R)-5-tert-Butyldiphenylsilyloxymethyl-4-hydroxypyrrol-
idin-2-one 19. Preparation of the Weinreb amides. To a slurry of
N,O-dimethylhydroxylamineؒhydrochloride (494 mg, 5.04
mmol) in THF (3 cm3) at 0 ЊC was added trimethylaluminium
(2.52 cm3, 2.0 M in toluene, 5.04 mmol). The solution was
stirred at 0 ЊC for 5 minutes then allowed to warm to room
temperature over ca. 15 minutes, after which time a clear
solution remained. The (6 : 1) mixture of aldol adducts 17
and 18 (500 mg, 0.839 mmol) in THF (4 cm3) was added drop-
wise via cannula. The reaction mixture was warmed to 35 ЊC
and stirred for 3 hours. The reaction mixture was cooled and
then cannulated rapidly into a mixture of DCM (30 cm3)
and saturated aqueous potassium sodium tartrate (30 cm3) and
stirred vigorously for 5 hours whereupon two distinct phases
(2R,3S)-2-tert-Butyldiphenylsilyloxymethylpyrrolidin-3-ol 21.
To a solution of the pyrrolidinone 19 (120 mg, 0.332 mmol) in
THF (5 cm3) at 0 ЊC was added BH3ؒTHF complex (4.95 cm3,
1.0 M in THF, 4.95 mmol). The solution was stirred at 0 ЊC
until effervescence ceased and then stirred at reflux for 24 hours.
Methanol was added cautiously to the cooled (0 ЊC) reaction
mixture. The resulting mixture was concentrated under reduced
pressure. The residue was chromatographed on silica gel [DCM
: MeOH (50 : 1)] to give the pyrrolidine 21 (100 mg, 85%) as a
white solid. Rf [DCM : MeOH (10 : 1)] 0.27; mp 105–106 ЊC;
[α]D ϩ33.3 (c 0.09, CHCl3) (90% ee); δH (250 MHz, CDCl3)
J. Chem. Soc., Perkin Trans. 1, 2002, 1083–1091
1087

View Article Online
7.65–7.61 (4H, m, ArH ), 7.50–7.37 (6H, m, ArH ), 4.35 (1H,
ddd, J 11.0, 7.4, 4.3, C(3)HOH), 4.19 (1H, dd, J 11.1, 3.0,
CHAHBOTBDPS), 3.80 (1H, dd, J 11.1, 2.4, CHAHBOTBDPS),
3.37 (1H, ddd, J 11.7, 8.0, 7.4, C(5)HEHF), 3.21 (1H, ddd,
J 11.7, 9.4, 4.3, C(5)HEHF), 2.94 (1H, ddd, J 11.0, 3.0, 2.4
C(2)H ), 2.14 (1H, ddt, J 16.2, 9.4, 7.4, C(4)HCHD), 1.99 (1H,
ddt, J 16.2, 8.0, 4.3, C(4)HCHD), 1.74 (1H, br s, OH ), 1.06
(9H, s, tBu); δC (62.9 MHz) 135.4 (CH), 132.2 (CH), 131.8 (C),
130.1 (CH), 127.9 (CH), 74.0 (CH), 73.1 (CH), 59.5 (CH2),
53.0 (CH2), 34.1 (CH2), 26.8 (CH3), 19.2 (C); m/z (FAB)
356 ([M ϩ H]ϩ, 65%), 278 (26), 197 (53), 183 (22), 135 (100);
HRMS (FAB) C21H30NO2Si [M ϩ H]ϩ requires 356.2046, found
356.2046.
3.35 mmol). The solution was stirred at room temperature for 2
hours to generate imidazolide 27. Meanwhile to a solution of
LiHMDS (2.88 cm3, 1.0 M in THF, 2.88 mmol) at Ϫ78 ЊC was
added ethyl acetate (0.280 cm3, 2.88 mmol) and the resultant
solution was stirred for 20 min at Ϫ78 ЊC. The solution of
imidazolide 27 in THF was added via cannula. The reaction
mixture was stirred at Ϫ78 ЊC for 20 min and allowed to warm
to 0 ЊC over 30 min and stirred for a further 1 hour at 0 ЊC. The
reaction was quenched by the addition of saturated aqueous
NH4Cl (15 cm3) and the aqueous phase was extracted with
DCM (3 × 15 cm3). The combined organic phases were washed
with brine (30 cm3), dried (MgSO4) and concentrated under
reduced pressure. The residue was chromatographed on silica
gel [hexane : EtOAc (10 : 1)] to give the title compound 22 as a
pale yellow oil (510 mg, 90%). Rf [hexane : EtOAc (4 : 1)] 0.62;
[α]D ϩ33.6 (c 0.27, CHCl3) (70% ee); all other spectroscopic
data were identical to those obtained from the Claisen reaction
of methyl ester 12.
Synthesis of the C(3) epimer of TBDPS-protected CYB-3
(2R)-3-tert-butyldiphenylsilyloxy-2-(N,N-dibenzylamino)-
propanoic acid 26. To a solution of methyl ester 12 (500 mg,
0.931 mmol) in THF (15 cm3) was added dropwise a slurry of
LiOHؒH2O (195 mg, 4.65 mmol) in H2O (3.75 cm3). The solu-
tion was heated to reflux and held at reflux for 6 hours. The
solution was cooled to room temperature and H2O (15 cm3)
was added. The aqueous phase was extracted with EtOAc (2 ×
25 cm3) then the mixture was acidified to pH 3 with 1 M HCl
and the aqueous phase was extracted with Et2O (3 × 20 cm3).
The combined organic phases were dried (MgSO4) and concen-
trated under reduced pressure to give acid 26 (280 mg, 58%) as a
tacky solid. Rf [hexane : EtOAc (4 : 1)] 0.20; [α]D Ϫ15.45 (c 0.22,
CHCl3) (70% ee); νmax (neat)/cmϪ1 3200, 3069, 2930, 2856, 1709,
1428; δH (250 MHz, CDCl3) 7.79–7.29 (20H, m, ArH ), 4.21–
4.12 (2H, m, CH2OTBDPS), 4.09 (2H, d, J 13.5, NCHXHYPh ×
2), 4.03 (2H, d, J 13.5, NCHXHYPh × 2), 3.09 (1H, dd, J 8.5,
Ethyl (3R,4R)-5-tert-butyldiphenylsilyloxy-4-(N,N-dibenzyl-
amino)-3-hydroxypentanoate 18. To a solution of β-keto ester 22
(360 mg, 0.621 mmol) in Et2O (8 cm3) and MeOH (3 cm3) was
added acetic acid (ca. 1 cm3) until the solution was pH 4. The
solution was cooled to 0 ЊC and sodium cyanoborohydride
(385 mg, 6.22 mmol) was added. Once effervescence had ceased
the resulting solution was stirred at room temperature for 7
hours. The reaction was quenched by the addition of a satur-
ated solution of NH4Cl (30 cm3) and the aqueous phase was
extracted with DCM (3 × 30 cm3). The combined organic
phases were washed with brine (40 cm3), dried (MgSO4) and
concentrated under reduced pressure. The residue was chroma-
tographed on silica gel [hexane : Et2O (7 : 1)] to give the amino
alcohol 18 (290 mg, 81%) as a colourless oil and amino alcohol
17 (21 mg, 6%) as a colourless oil.
t
5.1, C(2)H ), 1.16 (9H, s, Bu); δC (62.9 MHz) 172.3 (C), 137.2
(C), 136.1 (CH), 135.9 (CH), 133.0 (C), 132.9 (C), 130.5 (CH),
129.5 (CH), 129.3 (CH), 128.5 (CH), 128.4 (CH), 128.1 (CH),
63.5 (CH), 62.3 (CH2), 55.6 (CH2), 27.4 (CH3), 19.6 (C);
m/z (FAB) 524 ([M ϩ H]ϩ, 56%), 154 (44), 136 (37), 107 (16), 91
(100); HRMS (FAB) C33H38NO3Si [M ϩ H]ϩ requires 524.2621,
found 524.2622.
Spectroscopic data for major diastereomer 18. Rf [hexane :
Et2O (1 : 1)] 0.38; [α]D Ϫ18.75 (c 1.6, CHCl3) (70% ee); νmax
(neat)/cmϪ1 3456, 3070, 2931, 2858, 1732, 1428; δH (250 MHz,
CDCl3) 7.76–7.24 (20H, m, ArH ), 4.24–4.20 (1H, m,
C(3)HOH), 4.19 (2H, q, J 7.1, OCH2CH3), 4.18–4.06 (2H, m,
CH2OTBDPS), 4.05 (2H, d, J 13.3, NCHXHYPh × 2), 3.60 (2H,
d, J 13.3, NCHXHYPh × 2), 2.77–2.72 (1H, m, C(4)H ), 2.45
(1H, dd, J 15.2, 3.0, C(2)HCHD), 2.30 (1H, dd, J 15.2, 9.0,
Ethyl
(4R)-5-tert-butyldiphenylsilyloxy-4-(N,N-dibenzyl-
amino)-3-oxopentanoate 22. From methyl ester 12. To a solution
of LiHMDS (2.79 cm3, 1.06 M in THF, 2.79 mmol) at Ϫ78 ЊC
was added ethyl acetate (0.270 cm3, 1.21 mmol) and the solution
stirred at Ϫ78 ЊC for 25 min. Methyl ester 12 (300 mg, 0.560
mmol) in THF (4 cm3) was added via cannula and the resultant
solution stirred at Ϫ78 ЊC for 3 hours then warmed to 0 ЊC and
stirred at 0 ЊC for 1 hour. The reaction was quenched by the
addition of saturated aqueous NH4Cl (10 cm3) and the aqueous
phase was extracted with DCM (3 × 10 cm3). The combined
organic phases were washed with brine (20 cm3), dried (MgSO4)
and concentrated under reduced pressure. The residue was
chromatographed on silica gel [hexane : Et2O (10 : 1)] to give the
β-keto ester 22 as a pale yellow oil (260 mg, 78%). Rf [hexane :
EtOAc (4 : 1)] 0.62; νmax (neat)/cmϪ1 3069, 2930, 2856, 1745,
1716, 1427; δH (250 MHz, CDCl3) 7.80–7.21 (20H, m, ArH ),
4.18 (2H, q, J 7.2, OCH2CH3), 4.17–4.09 (2H, m, CH2OTB-
DPS), 3.92 (2H, d, J 13.6, NCHXHYPh × 2), 3.81 (2H, d, J 13.6
NCHXHYPh × 2), 3.76–3.72 (1H, m, C(4)H ), 3.69 (1H, d,
J 16.0, C(2)HCHD), 3.58 (1H, d, J 16.0, C(2)HCHD), 1.27 (3H, t,
t
C(2)HCHD), 1.28 (3H, t, J 7.1, OCH2CH3), 1.15 (9H, s, Bu);
δC (62.9 MHz) 172.4 (C), 139.5 (C), 136.2 (CH), 136.1 (CH),
133.3 (C), 133.2 (C), 130.5 (CH), 130.4 (CH), 129.5 (CH), 128.9
(CH), 128.3 (CH), 127.7 (CH), 65.8 (CH), 63.4 (CH), 60.9
(CH2), 60.6 (CH2), 54.9 (CH2), 40.1 (CH2), 27.4 (CH3), 19.6 (C),
14.6 (CH3); m/z (FAB) 596 ([M ϩ H]ϩ, 40%), 478 (51), 326 (12),
197 (12), 135 (26), 91 (100); HRMS (FAB) C37H46NO4Si [M ϩ
H]ϩ requires 596.3196, found 596.3197.
Spectroscopic data for minor diastereomer 17. Rf [hexane :
Et2O (1 : 1)] 0.40; spectroscopic data were in good agreement
with those reported above.
(4R,5R)-5-tert-Butyldiphenylsilyloxymethyl-4-hydroxypyr-
rolidin-2-one 23. Via the Weinreb amide. To a slurry of N,O-
dimethylhydroxylamineؒhydrochloride (371 mg, 3.82 mmol) in
THF (4 cm3) at 0 ЊC was added trimethylaluminium (3.82 cm3,
2.0 M in toluene, 7.64 mmol). The solution was stirred at 0 ЊC
for 5 minutes then allowed to warm to room temperature over
ca. 15 minutes, after which time a clear solution remained. Ester
18 (380 mg, 0.637 mmol) in THF (4 cm3) was added dropwise
via cannula. The mixture was warmed to 35 ЊC and stirred for 3
hours. The reaction mixture was cooled and then rapidly trans-
ferred by cannula into a mixture of DCM (30 cm3) and satur-
ated aqueous potassium sodium tartrate (30 cm3) and stirred
vigorously for 5 hours whereupon two distinct phases were
apparent. The aqueous phase was extracted with DCM (3 ×
30 cm3).The combined organic phases were dried (MgSO4)
and concentrated under reduced pressure. The residue was
t
J 7.2, OCH2CH3), 1.14 (9H, s, Bu); δC (62.9 MHz) 203.3 (C),
167.8 (C), 139.6 (C), 136.1 (CH), 136.0 (CH), 135.7 (C), 135.2
(C), 130.3 (CH), 129.4 (CH), 128.9 (CH), 128.7 (CH), 128.2
(CH), 128.1 (CH), 127.2 (CH), 67.6 (CH), 61.6 (CH2), 60.7
(CH2), 55.6 (CH2), 47.5 (CH2), 27.3 (CH3), 19.6 (C), 14.5 (CH3);
m/z (FAB) 594 ([M ϩ H]ϩ, 12%), 478 (204), 199 (12), 181 (7),
135 (33), 91 (100); HRMS (FAB) C37H44NO4Si [M ϩ H]ϩ,
requires 594.3040, found 594.3039
From acid 26. To a solution of acid 26 (500 mg, 0.958 mmol)
in THF (10 cm3) was added 1,1’-carbonyldiimidazole (542 mg,
1088
J. Chem. Soc., Perkin Trans. 1, 2002, 1083–1091

View Article Online
chromatographed on silica gel [hexane : EtOAc (4 : 1) to give
the Weinreb amide (370 mg, 95%) as a colourless oil.
(CH), 60.1 (CH2), 59.9 (CH2), 45.6 (CH2), 25.5 (CH3), 18.2 (C),
14.9 (CH3); m/z (FAB) 416 ([M ϩ H]ϩ, 100%), 199 (20), 142 (7),
(3R,4R)-5-tert-Butyldiphenylsilyloxy-4-(N,N-dibenzylamino)- 135 (38), 105 (12), 95 (11); HRMS (FAB) C23H34NO4Si [M ϩ
3-hydroxy-N-methoxy-N-methylpentanamide. Rf [hexane : Et-
OAc (4 : 1)] 0.34; [α]D Ϫ4.74 (c 0.45, CHCl3) (70% ee); νmax
(neat)/cmϪ1 3460, 3075, 2925, 2826, 1644, 1428; δH (360 MHz,
CDCl3) 7.82–7.24 (20H, m, ArH ), 4.28–4.20 (1H, m,
C(3)HOH), 4.10 (1H, dd, J 10.9, 8.0, C(5)HAHBOTBDPS), 4.04
(2H, d, J 13.4, NCHXHYPh × 2), 4.00 (1H, dd, J 10.9, 5.4,
C(5)HAHBOTBDPS), 3.91 (2H, d, J 13.4, NCHXHYPh × 2),
3.60 (3H, s, OMe), 3.20 (3H, s, Me), 2.80–2.73 (1H, m, C(4)H ),
2.69–2.58 (1H, br m, C(2)HCHD), 2.30–2.19 (1H, br m,
H]ϩ requires 416.2257, found 416.2252.
A solution of amino ester 24 (186 mg, 0.448 mmol) in MeOH
(4 cm3) was heated to reflux and held at reflux for 24 hours. The
solution was cooled and concentrated under reduced pressure.
The remaining residue was chromatographed on silica gel gel
[DCM : MeOH (50 : 1) to give pyrrolidinone 23 (130 mg, 78%)
as an oil. Rf [DCM : MeOH (10 : 1)] 0.30; all spectroscopic data
were identical to those obtained from the cyclisation of the
Weinreb amide derived from ethyl ester 18.
t
C(2)HCHD), 1.12 (9H, s, Bu); δC (90.6 MHz) 173.6 (C), 140.2
(C), 136.2 (CH), 136.1 (CH), 133.6 (C), 133.5 (C), 130.4 (CH),
130.3 (CH), 129.6 (CH), 128.7 (CH), 128.3 (CH), 127.4 (CH),
66.7 (CH), 63.6 (CH3), 61.5 (CH), 61.4 (CH2), 55.4 (CH2), 37.2
(CH2), 32.4 (CH3), 27.4 (CH3), 19.6 (C); m/z (FAB) 416 ([M ϩ
H]ϩ, 72%), 478 (81), 341 (17), 197 (43), 181 (16), 135 (70), 105
(34), 91 (100); HRMS (FAB) C37H47N2O4Si [M ϩ H]ϩ requires
611.3305, found 611.3305.
(4R,5R)-2-tert-Butyldiphenylsilyloxymethylpyrrolidin-3-ol 25.
To a solution of pyrrolidinone 23 (120 mg, 0.330 mmol) in THF
(5 cm3) at 0 ЊC was added BH3ؒTHF complex (4.95 cm3, 1.0 M
in THF, 4.95 mmol). The solution was stirred at 0 ЊC until
effervescence ceased and then stirred at reflux for 24 hours.
Methanol (ca. 5 cm3) was added cautiously to the cooled (0 ЊC)
reaction mixture. The resulting mixture was concentrated under
reduced pressure. The residue was chromatographed on silica
gel [DCM : MeOH (50 : 1)] to give the pyrrolidine 25 (105 mg,
86%) as a white solid. Rf [DCM : MeOH (10 : 1)] 0.25; mp 100–
101 ЊC; [α]D ϩ8.5 (c 0.5, CHCl3) (70% ee); δH (250 MHz, CDCl3)
7.69–7.60 (4H, m, ArH ), 7.52–7.25 (6H, m, ArH ), 6.20 (1H, s,
NH ), 4.56 (1H, ddd, J 11.4, 6.5, 4.5, C(3)HOH), 4.52–4.51 (1H,
br s, OH ), 4.23 (1H, dd, J 11.2, 4.8, CHAHBOTBDPS), 4.20
(1H, dd, J 11.2, 8.0, CHAHBOTBDPS) 3.59 (1H, ddd, J 11.4,
8.0, 4.8, C(2)H ), 3.06 (1H, ddd, J 12.7, 7.6, 6.0, C(5)HEHF),
2.97 (1H, ddd, J 12.7, 6.5, 4.5, C(5)HEHF), 2.19 (1H, ddt, J 16.1,
6.0, 4.5, C(4)HCHD), 1.94 (1H, ddt, J 16.1, 7.6, 6.5, C(4)HCHD),
1.08 (9H, s, tBu); δC (62.9 MHz) 135.5 (CH), 135.3 (CH), 131.6
(C), 131.2 (C), 130.3 (CH), 128.0 (CH), 73.8 (CH), 69.0 (CH),
60.3 (CH2), 52.8 (CH2), 32.5 (CH2), 26.8 (CH3), 19.0 (C); m/z
(FAB) 356 ([M ϩ H]ϩ, 65%), 278 (26), 197 (53), 183 (22), 135
(100); HRMS (FAB) C21H30NO2Si [M ϩ H]ϩ requires 356.2046,
found 356.2043.
Synthesis of amino amide 20. To a solution of the Weinreb
amide derived from ester 18 (300 mg, 0.492 mmol) in methanol
(5 cm3) was added 20% Pd(OH)2/C (300 mg), the flask was
flushed with argon before being stirred under an atmosphere
of hydrogen for 12 hours. The reaction mixture was filtered
through a layer of Celite and concentrated under reduced
pressure. The residue was chromatographed on silica gel
[DCM : MeOH (50 : 1)] to give the amino amide 20 (210 mg,
100%) as an oil. Rf [DCM : MeOH (10 : 1)] 0.12; spectroscopic
data were in good agreement with those reported above.
Conversion to pyrrolidinone 23. A solution of amino amide 20
(100 mg, 0.234 mmol) in MeOH (3 cm3) was heated to reflux
and held at reflux for 24 hours. The solution was cooled and
concentrated under reduced pressure. The remaining residue
was chromatographed on silica gel [DCM : MeOH (50 : 1)] to
give pyrrolidinone 23 (62 mg, 72%) as a white solid; Rf [DCM :
MeOH (10 : 1)] 0.30; mp 110–112 ЊC; [α]D ϩ11.30 (c 0.2, CHCl3)
(70% ee); νmax (neat)/cmϪ1 3385, 2931, 1682, 1427; δH (250 MHz,
CDCl3) 7.66–7.25 (10H, m, ArH ), 6.20 (1H, br s, NH ), 4.61
(1H, ddd, J 10.4, 7.0, 4.2, C(4)HOH), 3.95 (1H, dd, J 10.5, 5.8,
CHAHBOTBDPS), 3.81 (1H, dd, J 10.5, 4.8, CHAHBOTBDPS),
3.78 (1H, dt, J 10.4, 5.5, C(5)H ), 3.29 (1H, br s, OH ), 2.68
(1H, dd, J 17.3, 7.0, C(3)HCHD), 2.41 (1H, dd, J 17.3, 4.2,
Methyl (2S)-2-(N,N-dibenzylamino)-3-benzyloxypropanoate 28
Synthesis of methyl ester hydrochloride salt. Acetyl chloride
(2.20 cm3, 30.8 mmol) was added dropwise to methanol
(24 cm3) at 0 ЊC. The mixture was stirred for 15 min and -O-
benzylserine (2.00 g, 10.3 mmol) was then added portionwise
to the solution. The resulting mixture was heated to reflux
and held at reflux for 3 hours. Concentration under reduced
pressure provided the methyl ester hydrochloride salt (2.25 g,
96%) as a solid.
Methyl (2S)-2-amino-3-benzyloxypropanoateؒhydrochloride
salt. Mp 162–164 ЊC (methanol); [α]D ϩ15.2 (c 1.4, MeOH);
δH (250 MHz, D2O) 7.37–7.26 (5H, m, ArH ), 4.57 (1H, d,
J 12.0, OCHEHFPh), 4.47 (1H, d, J 12.0, OCHEHFPh), 4.28
(1H, br t, J 3.7, C(2)H ), 3.93 (1H, dd, J 11.0, 4.2, C(3)HAHB),
3.83 (1H, dd, J 11.0, 3.0, C(3)HAHB), 3.71 (3H, s, OMe);
δC (62.9 MHz) 169.0 (C), 137.1 (C), 129.1 (CH), 128.9 (CH),
128.8 (CH), 73.5 (CH2), 66.7 (CH2), 54.1 (CH3), 53.5 (CH);
m/z (FAB) 210 ([M ϩ H]ϩ, 95%), 196 (8), 150 (5), 120 (10), 102
(10), 91 (100); HRMS (FAB) C11H16NO3 [M ϩ H]ϩ requires
210.1130, found 210.1133.
t
C(3)HCHD), 1.05 (9H, s, Bu); δC (62.9 MHz) 176.0 (C), 135.4
(CH), 135.3 (CH), 132.4 (C), 132.2 (C), 130.0 (CH), 128.0 (CH),
68.2 (CH), 63.0 (CH2), 59.2 (CH), 40.3 (CH2), 26.7 (CH3), 19.0
(C); m/z (FAB) 370 ([M ϩ H]ϩ, 59%), 292 (34), 234 (37), 214
(66), 199 (80), 135 (94), 105 (46); HRMS (FAB) C21H28NO3Si
[M ϩ H]ϩ requires 370.1838, found 370.1838.
Via amino ester 24. To a solution of β-hydroxy ester 18 (270
mg, 0.451 mmol) in methanol (5 cm3) was added 20% Pd(OH)2/
C (270 mg), the flask was flushed with argon before being
stirred under an atmosphere of hydrogen for 12 hours. The
reaction mixture was filtered through a layer of Celite and con-
centrated under reduced pressure. The residue was chromato-
graphed on silica gel [DCM : MeOH (50 : 1)] to give the amino
ester 24 (186 mg, 100%) as an oil.
Ethyl
(3R,4R)-5-tert-butyldiphenylsilyloxy-4-amino-3-
Conversion to N,N-dibenzyl protected methyl ester 28. To a
solution of the methyl ester (2.00 g, 8.71 mmol) in anhydrous
acetonitrile (30 cm3) was added anhydrous potassium carbonate
(5.55 g, 43.6 mmol) followed by benzyl bromide (2.38 cm3,
21.8 mmol). The mixture was stirred at room temperature for
24 hours. H2O (50 cm3) was added and the aqueous phase was
extracted with EtOAc (3 × 30 cm3). The combined organic
phases were washed with brine (100 cm3), dried (MgSO4) and
concentrated under reduced pressure. The remaining residue
was chromatographed on silica gel [hexane : EtOAc (10 : 1)] to
hydroxypentanoate 24. Rf [DCM : MeOH (10 : 1)] 0.20;
[α]D Ϫ11.1 (c 1.2, CHCl3) (70% ee); νmax (neat)/cmϪ1 3363, 2932,
2888, 1724, 1426; δH (250 MHz, CDCl3) 7.76–7.06 (10H, m,
ArH ), 4.22 (2H, q, J 7.0, OCH2CH3), 3.78–3.47 (5H, br m,
C(3)HOH ϩ C(5)H2 ϩ NH2), 3.10–3.00 (1H, m, C(4)H ), 2.65
(1H, dd, J 15.0, 3.2, C(2)HAHB), 2.30 (1H, dd, J 15.0, 8.9,
C(2)HAHB), 1.31 (3H, t, J 7.0, OCH2CH3), 1.13 (9H, s, Bu);
δC (50.3 MHz) 169.9 (C), 134.7 (CH), 132.2 (CH), 131.3 (C),
129.9 (C), 128.9 (CH), 128.0 (CH), 126.9 (CH), 64.7 (CH), 61.5
t
J. Chem. Soc., Perkin Trans. 1, 2002, 1083–1091
1089

View Article Online
give protected methyl ester 28 (3.20 g, 94%) as a colourless oil.
Rf [hexane : EtOAc (4 : 1)] 0.60; [α]D Ϫ48.5 (c 1.07, CHCl3);
νmax (neat)/cmϪ1 3062, 3028, 2948, 2855, 1735, 1602, 1494, 1453;
δH (250 MHz, CDCl3) 7.41–7.21 (15H, m, ArH ), 4.52–4.30
(2H, m, OCHEHFPh), 3.96 (2H, d, J 13.9, NCHXHYPh × 2),
3.89 (1H, t, J 2.8, C(2)H ), 3.85–3.79 (1H, m, C(3)HAHB), 3.78
(3H, s, OMe), 3.75–3.68 (1H, m, C(3)HAHB), 3.72 (2H, d,
J 13.9, NCHXHYPh × 2); δC (62.9 MHz) 171.8 (C), 139.5 (C),
137.9 (C), 128.6 (CH), 128.2 (CH), 128.1 (CH), 127.4 (CH),
126.9 (CH), 73.0 (CH2), 69.4 (CH2), 60.8 (CH), 55.2 (CH2), 51.2
(CH3); m/z (FAB) 390 ([M ϩ H]ϩ, 15%), 330 (32), 282 (8), 268
(41), 181 (9), 91 (100); HRMS (FAB) C25H28NO3 [M ϩ H]ϩ
requires 390.2069, found 390.2070.
Ethyl (3SR, 4SR)-5-benzyloxy-4-(N,N-dibenzylamino)-3-
hydroxypentanoate 32
To a solution of β-keto ester 31 (80 mg, 0.18 mmol) in Et2O
(4 cm3) and MeOH (2 cm3) was added acetic acid (ca. 0.5 cm3)
until the solution was pH 4. The solution was cooled to 0 ЊC
and sodium cyanoborohydride (60 mg, 1.4 mmol) was added.
Once effervescence ceased the solution was warmed to room
temperature and stirred for 8 hours. The solution was quenched
by the addition of a saturated solution of NH4Cl (15 cm3) and
the aqueous phase was extracted with DCM (3 × 15 cm3). The
combined organic phases were washed with brine (20 cm3),
dried (MgSO4) and concentrated under reduced pressure. The
residue was chromatographed on silica gel [hexane : EtOAc
(6 : 1)] to give the amino alcohol 32 (72 mg, 90%) as an oil. Rf
[hexane : EtOAc (4 : 1)] 0.38; νmax (neat)/cmϪ1 3371, 2936, 1726,
1452; δH (250 MHz, CDCl3) 7.43–7.19 (15H, m, ArH ), 4.59
(1H, d, J 12.0, OCHEHFPh), 4.52 (1H, d, J 12.0, OCHEHFPh),
4.19 (1H, ddd, J 11.2, 8.5, 3.6, C(3)HOH), 4.14 (2H, q, J 7.2,
OCH2CH3), 4.05 (2H, d, J 13.2, NCHXHYPh × 2), 3.80 (1H, dd,
J 10.2, 5.5, C(5)HAHB), 3.69 (1H, dd, J 10.2, 4.8, C(5)HAHB),
3.53 (2H, d, J 13.2, NCHXHYPh × 2), 3.47 (1H, s, OH ), 2.80–
2.72 (1H, m, C(4)H ), 2.50 (1H, dd, J 15.4, 3.6, C(2)HCHD), 2.37
(1H, dd, J 15.4, 8.5, C(2)HCHD), 1.23 (3H, t, J 7.2, OCH2CH3);
δC (62.9 MHz) 172.0 (C), 138.8 (C), 137.8 (C), 129.0 (CH),
128.4 (CH), 127.7 (CH), 127.5 (CH), 127.1 (CH), 73.2 (CH2),
66.3 (CH2), 65.7 (CH2), 61.3 (CH), 60.4 (CH), 54.3 (CH2), 39.45
(CH2), 14.0 (CH3); m/z (FAB) 448 ([M ϩ H]ϩ, 20%), 330 (19),
326 (5), 210 (2), 181 (4), 91 (100); HRMS (FAB) C28H34NO4
[M ϩ H]ϩ requires 448.2488, found 448.2489.
(2SR)-2-(N,N-Dibenzylamino)-3-benzyloxypropanoic acid 29
To a solution of the ester 28 (300 mg, 0.771 mmol) in THF
(8 cm3) was added a slurry of LiOHؒH2O (194 mg, 4.63 mmol)
in H2O (2 cm3). The mixture was heated to reflux and held
at reflux for 4 hours. The solution was cooled to room tempera-
ture, water (15 cm3) was added and the mixture was acidified
to pH 3 with 1 M HCl. The aqueous phase was extracted
with Et2O (3 × 15 cm3). The combined organic phases were
dried (MgSO4) and concentrated under reduced pressure to give
acid 29 (288 mg, 100%). Rf [hexane : EtOAc (4 : 1)] 0.13; νmax
(neat)/cmϪ1 4059, 3067, 3028, 2923, 2854, 1715, 1495; δH (250
MHz, CDCl3) 7.67–7.03 (15H, m, ArH ), 4.63 (1H, d, J 11.9,
OCHEHFPh), 4.55 (1H, d, J 11.9, OCHEHFPh), 4.17 (1H, dd,
J 10.3, 4.6, C(3)HAHB), 4.06 (2H, d, J 13.3, NCHXHYPh × 2),
4.01–3.67 (2H, m, C(3)HAHB ϩ C(2)H ), 3.94 (2H, d, J 13.3,
NCHXHYPh × 2); δC (62.9 MHz) 171.1 (C), 137.5 (C), 135.8
(C), 129.2 (CH), 128.7 (CH), 128.4 (CH), 128.1 (CH), 127.8
(CH), 127.2 (CH), 73.4 (CH2), 67.5 (CH2), 61.5 (CH), 55.1
(CH2); m/z (FAB) 376 ([M ϩ H]ϩ, 100%), 330 (16), 286 (31), 240
(12) 181 (20), 91 (91); HRMS (FAB) C24H26NO3 [M ϩ H]ϩ
requires 376.1913, found 376.1914.
Acknowledgements
We thank the EPSRC (GR/L60166/01 to K.S.C.) for support.
References
Ethyl (4SR)-5-benzyloxy-4-(N,N-dibenzylamino)-3-oxo-
1 R. J. Nash, A. E. Bell, G. W. J. Fleet, R. H. Jones and M. J. Williams,
J. Chem. Soc., Chem. Commun., 1985, 738.
pentanoate 31
To a solution of acid 29 (300 mg, 0.825 mmol) in THF (8 cm3)
was added 1,1Ј-carbonyldiimidazole (404 mg, 2.49 mmol).
The solution was stirred at room temperature for 2 hours to
generate imidazolide 30. Meanwhile to a solution of LiHMDS
(2.49 cm3, 1.0 M in THF, 2.49 mmol) at Ϫ78 ЊC was added ethyl
acetate (0.240 cm3, 2.49 mmol) and the solution stirred for
20 min. The solution of imidazolide 30 in THF was added via
cannula and the solution stirred at Ϫ78 ЊC for 30 min then
warmed to 0 ЊC over a period of 1 hour. The mixture was stirred
at 0 ЊC for 1 hour before being quenched with saturated
aqueous NH4Cl (20 cm3). The aqueous phase was extracted
with DCM (3 × 20 cm3). The combined organic phases were
washed with brine (30 cm3), dried (MgSO4) and concentrated
under reduced pressure. The residue was chromatographed on
silica gel [hexane : EtOAc (10 : 1)] to give the β-keto ester 31
(340 mg, 92%) as a pale yellow oil. Rf [hexane : EtOAc (4 : 1)]
0.53; νmax (neat)/cmϪ1 3062, 3029, 2081, 2926, 2860, 1744,
1716, 1494, 1453; δH (250 MHz, CDCl3) 7.43–7.22 (15H, m,
ArH ), 4.62 (1H, d, J 12.0, OCHEHFPh), 4.55 (1H, d, J 12.0,
OCHEHFPh), 4.14 (2H, q, J 7.2, OCH2CH3), 4.01 (1H, dd,
J 9.2, 6.5, C(5)HAHB), 3.94 (1H, dd, J 9.2, 4.0, C(5)HAHB), 3.85
(2H, d, J 13.1, NCHXHYPh × 2), 3.75–3.65 (1H, m, C(4)H ),
3.73 (1H, d, J 16.0, C(2)HCHD), 3.70 (2H, d, J 13.1, NC-
HXHYPh × 2), 3.54 (1H, d, J 16.0, C(2)HCHD), 1.23 (3H, t,
J 7.2, OCH2CH3); δC (62.9 MHz) 202.7 (C), 167.3 (C), 138.9
(C), 137.9 (C), 128.9 (CH), 128.5 (CH), 128.3 (CH), 127.5 (CH),
127.1 (CH), 126.8 (CH), 73.4 (CH2), 66.1 (CH), 65.4 (CH2),
61.0 (CH2), 55.0 (CH2), 46.5 (CH2), 13.9 (CH3); m/z (FAB) 446
([M ϩ H]ϩ, 100%), 356 (39), 330 (53), 240 (22), 196 (17), 132 (9),
106 (37), 91 (97); HRMS (FAB) C28H32NO4 [M ϩ H]ϩ requires
446.2331, found 446.2332.
2 L. D. Hohenschutz, E. A. Bell, P. J. Jewess, D. P. Leworthy,
R. J. Pryce, E. Arnold and J. Clardy, Phytochemistry, 1981, 20, 811.
3 A. M. Schofield, P. Witham, R. J. Nash, G. C. Kite and
L. E. Fellows, Comp. Biochem. Physiol., 1995, 112A, 187.
4 A. M. Schofield, L. E. Fellows, R. J. Nash and G. W. J. Fleet, Life
Sci., 1986, 39, 645.
5 (a) J. Furukawa, S. Okuda, K. Saito and S.-I. Hatanaka,
Phytochemistry, 1985, 24, 593; (b) R. J. Nash, E. A. Bell and
J. M. Williams, Phytochemistry, 1985, 24, 1620.
6 (a) A. D. Elbein, M. Mitchell, B. A. Stanford, L. E. Fellows and
S. V. Evans, J. Biol. Chem., 1984, 259, 12409; (b) S. V. Evans,
L. E. Fellows and E. A. Bell, Biochem. Syst. Ecol., 1985, 13, 271;
(c) A. Welter, J. Jadot, G. Dardenne, M. Marlier and J. Casimir,
Phytochemistry, 1976, 15, 747; (d ) absolute stereochemistry:
G. W. Fleet and P. W. Smith, Tetrahedron, 1987, 43, 971.
7 N. Dell’Uomo, M. C. DiGiovanni, D. Misiti, G. Zappia and
G. Delle Monache, Tetrahedron: Asymmetry, 1996, 7, 181.
8 N-Hydroxyethyl derivative of CYB-3 as biosynthetic precursor
for castanospermine and australine: R. J. Molyneux, Y. T. Pan,
J. E. Tropea, M. Benson, G. P. Kaushal and A. D. Elbein,
Biochemistry, 1991, 30, 9981.
9 G. Ceulemans, A. Van Aerschot, J. Rozenski and P. Herdewijn,
Tetrahedron, 1997, 53, 14957.
10 (a) Reaction with (allyl)B(Ipc)2: L. M. Mascavage, Q. Lu, J. Vey,
D. R. Dalton and P. J. Carroll, J. Org. Chem., 2001, 66, 3621; (b)
reaction with allyl bromide/CrCl2: Y Aoyagi, H. Inaba, Y. Hiraiwa,
A. Kuroda and A. Ohta, J. Chem. Soc., Perkin Trans. 1, 1998, 3975.
11 A. Barco, S. Benetti, C. De Risi, G. P. Pollini, R. Romagnoli and
V. Zanirato, Tetrahedron Lett., 1996, 37, 7599.
12 (a) C. Herdeis, H. P. Hubmann and H. Lotter, Tetrahedron:
Asymmetry, 1994, 5, 119; (b) D. Griffart-Brunet and N. Langlois,
Tetrahedron Lett., 1994, 35, 119.
13 (a) B. M. Malle, I. Lundt and R. H. Furneaux, J. Carbohydr. Chem.,
2000, 19, 573; (b) A. G. H. Wee, D. D. McLeod and T. J. Rankin,
Heterocycles, 1998, 48, 2263.
14 C. M. Huwe and S. Blechert, Synthesis, 1997, 61.
1090
J. Chem. Soc., Perkin Trans. 1, 2002, 1083–1091

View Article Online
15 A. N. Hulme, C. H. Montgomery and D. K. Henderson, J. Chem.
Soc., Perkin Trans. 1, 2000, 1837.
16 A. N. Hulme and E. M. Rosser, Org. Lett., 2002, 4, 265.
17 (a) M. T. Reetz, Chem. Rev., 1999, 99, 1121; (b) M. T. Reetz, Angew.
Chem., Int. Ed. Engl., 1991, 30, 1531.
23 (a) E. Dechaux, P. Savay, S. Bouyain, C. Monneret and J.-C.
Florent, J. Carbohydr. Chem., 2000, 19, 485; (b) K. Dax, M. Ebner,
R. Peinsipp and A. E. Stütz, Tetrahedron Lett., 1997, 38, 225.
24 R. V. Hoffmann and J. Tao, J. Org. Chem., 1997, 62, 2292 and
references cited therein.
18 (a) With isoleucine derived aldehyde: M. T. Reetz, M. W. Drewes,
A. Schmitz, X. Holdgrun, T. Wunsch and J. Binder, J. Philos. Trans.
R. Soc. London A, 1988, 326, 573; (b) with dimethyl tartrate derived
aldehyde: H. Ina and C. Kibayashi, J. Org. Chem., 1993, 58, 52.
19 A. N. Hulme, and C. H. Montgomery, unpublished results.
20 J. M. Andrés and R. Pedrosa, Tetrahedron, 1998, 5607.
21 P. Compain and O. R. Martin, Bioorg. Med. Chem., 2001, 9, 3077.
22 S. Hanessian, H. K. Huynh, G. V. Reddy, G. McNaughton-Smith,
B. Ernst, H. C. Kolb, J. Magnani and C. Sweeley, Bioorg. Med.
Chem. Lett., 1998, 8, 2803.
25 M. T. Reetz, M. W. Drewes, B. R. Matthews and K. Lennick,
J. Chem. Soc., Chem. Commun., 1989, 1474.
26 This result is somewhat surprising as a two-step synthesis of acid 29
from O-benzylserine (i. BnBr; ii. KOH) has been reported to occur
without racemisation; M. T. Reetz, M. W. Drewes, K. Lennick,
A. Schmitz and X. Holdgrün, Tetrahedron: Asymmetry, 1990, 1, 375.
However, experimental details for this conversion have not been
reported.
27 S. Chansrasekhar, Ch. R. Reddy and R. J. Rao, Tetrahedron, 2001,
57, 3435.
J. Chem. Soc., Perkin Trans. 1, 2002, 1083–1091
1091