Studies on the asymmetric reduction of β-oximino methyl ether boronates: Reagent control, double diastereocontrol and transmitted remote asymmetric induction

Article abstract of DOI:10.1039/b005837h

High asymmetric induction (94% ee) could be obtained in the reduction of the achiral E-oxime ether boronate 5 with a homochiral oxazaborolidine 13-BH₃-THF complex. Application of this homochiral reducing agent system to non-aromatic oxime ethers 21 produced low to moderate asymmetric induction. Application of the same homochiral reducing agent system to reduction of homochiral boronate E-oximes 3 and 4 produced extreme double diastereo-selection effects, i.e. 8 and 95% ee respectively, which demonstrated that remote asymmetry was being 'transmitted' by a suitable choice of a 'partner' molecule from the boronate moiety to the oxime during reduction. However, attempts to obtain direct remote asymmetric induction in the reduction of homochiral β-oximino boronate methyl ethers 3 and 4 to the corresponding amines produced zero, with for example BH₃-THF complex, up to 28% ee with an Et₃N-BH₃-THF mixture (after oxidative boronate ester cleavage).

Full text of DOI:10.1039/b005837h

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Studies on the asymmetric reduction of ꢀ-oximino methyl ether
boronates: reagent control, double diastereocontrol and transmitted
remote asymmetric induction
1
Helen E. Sailes,a John P. Wattsb and Andrew Whiting*a
a Department of Chemistry, Faraday Building, U.M.I.S.T., P.O. Box 88, Manchester,
UK M60 1QD
b Knoll Ltd., Pennyfoot Street, Nottingham, UK NG1 1GF
Received (in Cambridge, UK) 19th July 2000, Accepted 24th August 2000
First published as an Advance Article on the web 3rd October 2000
High asymmetric induction (94% ee) could be obtained in the reduction of the achiral E-oxime ether boronate 5
with a homochiral oxazaborolidine 13–BH3–THF complex. Application of this homochiral reducing agent system to
non-aromatic oxime ethers 21 produced low to moderate asymmetric induction. Application of the same homochiral
reducing agent system to reduction of homochiral boronate E-oximes 3 and 4 produced extreme double diastereo-
selection effects, i.e. 8 and 95% ee respectively, which demonstrated that remote asymmetry was being ‘transmitted’
by a suitable choice of a ‘partner’ molecule from the boronate moiety to the oxime during reduction. However,
attempts to obtain direct remote asymmetric induction in the reduction of homochiral β-oximino boronate methyl
ethers 3 and 4 to the corresponding amines produced zero, with for example BH3–THF complex, up to 28% ee
with an Et3N–BH3–THF mixture (after oxidative boronate ester cleavage).
Introduction
We recently reported the synthesis of a series of β-hydrazono,
oximino methyl ether and imino chiral boronate esters of
general type 1.1 The preparation of such derivatives was
initiated in order to study the ability of the chiral boronate
Fig. 1 Predicted trajectory of approach of a hydride-based reduced
agent.
function of derivatives 1 in directing remote asymmetric reduc-
tion2 of the C᎐N bond, via an activated complex as shown in
᎐
Fig. 1, to provide a new route to β-amino acids [eqn. (1)].3 In
(1)
this paper, we report the details of our unexpected results on
the reduction of systems of oxime methyl ether derivatives of 1,
which include the indirect effects of the remote chiral ester4 and
chiral reagent controlled hydride reductions.
Results and discussion
The synthesis of chiral β-boronate oxime ether (S,S)-3 and its
enantiomer (R,R)-4 has been recently reported and their oxime
hydrolysis of the intermediate B–N complex, to yield the amino
alcohol intermediate 6. Direct diacetylation provided racemic
derivative 7 (Scheme 1).7
ether geometries were shown to be E.1 Consequently, C᎐N
᎐
double bond reduction of these systems was investigated. In
keeping with previous work from our laboratories concerning
the reduction of β-keto boronate,2a,b initially model studies were
undertaken concerning the reduction of achiral β-boronate
E-O-methyloxime ether 5 with borane.5
In order to determine the asymmetric induction in subse-
quent reductions, it was necessary to develop an ee assessment
method, preferably using chiral HPLC. Fortunately, enantio-
meric separation of racemic acetate 7 was achieved using chiral
HPLC analysis (Table 1, entry 1). The HPLC peaks were
assigned by comparison with enantiopure (S)-7 (Table 1,
entry 2). A commercial sample of optically-pure γ-amino alco-
hol (S)-6 was kindly donated by Chirotech; acetylation with
acetic anhydride in pyridine yielded optically-pure (S)-diacetyl
derivative (S)-7 in 90% yield.
It has been reported that facile borane reduction of oxime
ethers occurs at room temperature to furnish the corresponding
primary amines upon acidic or basic hydrolysis, with C᎐N bond
᎐
reduction preceeding N–O bond reduction.6 Achiral oxime
ether 5 was therefore treated with an excess of borane–
tetrahydrofuran complex in THF, followed by cleavage of the
B–C bond with alkaline hydroperoxide and concomitant
A similar synthetic protocol to that described for the
reduction of achiral substrate 5 (i.e. as Scheme 1) was followed
3362
J. Chem. Soc., Perkin Trans. 1, 2000, 3362–3374
This journal is © The Royal Society of Chemistry 2000
DOI: 10.1039/b005837h

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Table
1
Chiral HPLC analysisa of 1-acetoxy-3-acetylamino-3-
phenylpropane 7
Table 2 Preparation of acetamide 8 via reduction of oxime ether
(S,S)-3
(R)-7
(S)-7
Entry
Reduction (reagents and conditions)
Yield (%)
Dr of 8
Entry
Product
tR/min
%
tR/min
%
1
2
3
BH3ؒSMe2, THF, Ϫ15 ЊC–rt, 16 h
BH3ؒTHF, 0 ЊC–rt, 2 d
DIBAL-H, THF, rt, 2 d
96
89
87
1:1
1:1
1:1
1
2
rac-7
(S)-7
5.06
5.04
49.7
0.9
8.01
7.97
50.3
99.1
a Chiralpak AS, SFC, λ = 205 nm, 35 ЊC, 2.98 kpsi, 2 ml minϪ1, 86%
CO2: 14% (isopropyl alcohol ϩ 0.2% Et2NH) elution.
Examination of the 13C NMR spectrum of acetamide 8 could
be used to determine the diastereomeric ratio. A 1:1 mixture of
diastereomeric boronates was observed for all reducing agents
(Table 2), as demonstrated by two peaks of equal intensity at
δ 169.4 and 171.1 ppm, corresponding to the diastereomeric
acetamide quaternary carbon atoms. Peaks of equal intensity
at δ 55.0 and 55.2 ppm corresponding to the CHN methine
tertiary carbon were also noted, confirming the presence of
a 1:1 mixture of diastereomeric acetamides 8. The lack of
stereocontrol observed for the reductions of (S,S)-3 was con-
firmed upon elaboration of the acetamide reduction product 8
to the diacetyl derivative 7 (Scheme 2). Chiral HPLC revealed
that in each case, diacetyl derivative 7 was obtained in racemic
form in all cases, confirming the results shown in Table 2.
The lack of asymmetric induction observed for the reduction
of oxime ether 3 is likely be the result of the E-oxime ether
stereochemistry of the substrate. B–N chelation in intermediate
3 is precluded, but could be replaced by B–O chelation as
shown by the intramolecular flattened chair chelate 10 (Scheme
3). However, even if chelation does occur as shown by 10, the
remote chirality of the boronate ester is presumably too far
from the oxime carbon to control asymmetric reduction. Hence,
intermediate 10 should result in a 1:1 mixture of diastereo-
isomers 12 and hence 8 upon acetylation. In contrast, if oxime
ether geometry 9 were accessible, B–N chelation could occur
as shown by 11, which in turn one would expect to direct
asymmetric induction efficiently to provide 12.
Scheme 1
for the reduction of chiral β-boronate oxime ether (S,S)-3 with
borane–tetrahydrofuran complex, without isolation of inter-
mediate 6. Direct acetylation with acetic anhydride in pyridine
provided 7 in 94% yield. Chiral HPLC analysis of the crude
product 7 revealed that no asymmetric induction was obtained
for the reduction.
In order to probe this reduction further, several additional
reducing agents were screened for the reduction of this chiral
β-boronate oxime ether (S,S)-3. The synthetic procedure was
altered for these subsequent reductions, by directly quenching
the reduction reactions with acetic anhydride to provide inter-
mediate acetamide 8, as shown in Scheme 2. This procedure was
A solution to this problem would therefore be the design of a
reducing system that either: a) allows reversible E–Z isomeris-
ation in the reduction process, with the assumption that chelate
11 reduces more rapidly and selectively than chelate 10; or b)
oxime 3 could be irreversibly converted to oxime 9. Previous
studies1 on these oxime ethers have shown that oxime 3 is
stable, shows little sign of isomerisation and is clearly not
reduced under the reaction conditions shown in eqn. (2) in a
(2)
stereoselective manner. This allows us to conclude that the
intramolecular boronate function of 3 is unable to effect
isomerisation of the oxime and subsequently direct reduction.
The alternative of “pushing” the equilibrium in favour of
isomer 9 may be possible, since oxime ethers are susceptible to
photochemical isomerisation,8 as well as isomerisation under
acidic or basic conditions,9 but are stable to thermal isomeris-
ation.10 Unfortunately, such conditions are unlikely to be
compatible with the desired reduction process outlined in the
conversion of 9 to 12.
In order to probe whether there was any further evidence for
the intervention of the remote boronate functionality in the
reduction of an oxime such as 3, we decided to employ a homo-
chiral reducing agent, since this would introduce the possibility
of double-diastereoisomeric effects.11 Such effects might be
expected to be highly sensitive to the remote functionality and
provide a much more sensitive probe for the possible effects of
the remote boronate chirality. Whilst the asymmetric reduction
of ketones has been intensively investigated,12 the correspond-
Scheme 2
found to be more convenient, enabling determination of the
diastereomeric excess of the resulting acetamide 8 by NMR.
Subsequent oxidative cleavage of the C–B bond of 8 in the
presence of alkaline hydrogen peroxide at room temperature
followed by acetylation of the resulting primary alcohol,
yielded the desired acetate 7 in good yield. Good yields were
obtained following this synthetic route due to the decreased
water-solubility of the intermediate N-acetylated product
compared to that of the free amino alcohol 6 intermediate.
Thus, chiral oxime ether (S,S)-3 was successfully reduced with
borane–dimethyl sulfide complex, borane–tetrahydrofuran
complex and DIBAL-H, yielding acetamide 8 upon treat-
ment with acetic anhydride. Reduction with L-Selectride and
lithium aluminium hydride was unsuccessful, and starting
materials were recovered.
ing enantioselective reduction of C᎐N double bonds is much
᎐
J. Chem. Soc., Perkin Trans. 1, 2000, 3362–3374
3363

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Scheme 3
less studied, including asymmetric hydrogenation and hydro-
silylation, as well as the use of chirally-modified reagents.13
However, prochiral oxime ethers have been enantioselectively
reduced using conditions reported by Itsuno et al.,14 employing
an in situ generated oxazaborolidine system 13 in the presence
of excess borane to provide primary amines with an (S)-
configuration. Sakito et al. subsequently reported the effect of
oxime ether geometry on the enantioselectivity of oxazaborol-
idine-based reductions15 using a (Ϫ)-norephedrine-derived
reducing system and found that the prochiral carbon does not
play a central role in the stereoselectivity of this reduction, with
the preferred absolute configuration of the amine formed found
to be dependent on the geometry of the oxime ether.
In order to test the compatibility of such oxazaborolidine
reducing systems with the β-boronate oxime ethers, we exam-
ined the reduction of oxime ether 5, initially using Itsuno’s
system under stoichiometric conditions. Thus, homochiral
β-amino alcohol 14 was prepared by treating (S)-valine ethyl
ester hydrochloride with an excess of phenylmagnesium brom-
ide as reported.16 Treatment of amino alcohol 14 in THF with
excess borane–tetrahydrofuran complex at 0 ЊC for 6 hours,
yielded the borane complex of 13 to which oxime ether 5 was
added. The reaction was allowed to warm to room temperature
overnight then quenched with acetic anhydride to afford acet-
amide 15 in 93% yield after column chromatography (Scheme 4).
The stereoselectivity of the reduction was assessed by
elaboration of boronate ester 15 to diacetyl derivative 7. The
major enantiomer formed was (S)-7, in 98–100% ee, which is
comparable to that obtained by Itsuno for the reduction of
acetophenone O-methyloxime.14 Oxidation of the boronate unit
of 15 was also accomplished using reported conditions,17 to
provide β-amino acid derivative 16 (Scheme 4).18
Scheme 4
Oxazaborolidine 13 could also be used catalytically (25
mol%) for the borane–THF reduction of β-boronate oxime
ether 5, to provide (S)-7 with reduced asymmetric induction,
i.e. 85% ee, after in situ acetylation, peroxide-mediated C–B
bond oxidation and acetylation (73% overall yield).
The excellent stereoselectivity obtained in the borane reduc-
tion of β-boronate oxime ether 5 in the presence of stoichio-
metric and catalytic oxazaborolidine 13, can be explained by
directly applying the mechanism proposed by Corey for the
reduction of prochiral ketones.19 Thus, complex 17 would be
responsible for delivery of hydride to the oxime carbon, to
provide intermediate 18 (Scheme 5). Since Itsuno and Sakito
found14,15 that the asymmetric reduction of ketone-derived
oxime ethers to the corresponding primary amines using an
oxazaborolidine reducing system required the presence of one
equivalent of borane, whereas the corresponding reduction of
aldehyde oxime ethers with borane only, required two equiv-
alents of BH3, one may conclude that cleavage of the N–O
bond is likely to proceed via an intramolecular hydride delivery
to intermediate 19 (Scheme 5). The resulting complex 20 is then
quenched with acetic anhydride to provide final product 7.
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J. Chem. Soc., Perkin Trans. 1, 2000, 3362–3374

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it is expected that the major enantiomers for 22a, b and d would
be (R), and 22c would be (S). The low to modest enantiomeric
excesses obtained for borane reduction of prochiral oxime
ethers 21 in the presence of oxazaborolidine 13 may be due to
the increased competition between intermolecular “B–H” addi-
tion, rather than intramolecular hydride attack via the sterically
less favourable complex 23 (compare with complex 17).19
Having demonstrated the high efficiency of catalyst 13 to
reduce achiral oxime 5, we turned to examine the potential for
the boronate function in systems 3 and 4 at influencing the
reduction process. If the reduction of both chiral systems 3 and
4 followed the mechanism outlined in Scheme 5, one would not
expect to observe any double diastereoselective effects, thus
confirming the redundant role of the boronate ester and the
zero asymmetric induction observed for system 3.
Treatment of (S)-valine-derived amino alcohol 14 in THF
with 4 equivalents of borane–tetrahydrofuran complex at
0 ЊC for 6 hours, yielded a reducing mixture to which chiral
β-boronate oxime ether (R,R)-5 was slowly added. The reaction
was allowed to warm to room temperature, then quenched with
acetic anhydride. Oxidative cleavage of the C–B bond using
alkaline hydrogen peroxide, followed by acetylation of the
resulting primary alcohol, furnished diacetyl derivative (S)-7
in 95% enantiomeric excess. The sense and magnitude of the
asymmetric induction obtained in the borane reduction of
chiral boronate (R,R)-4 in the presence of oxazaborolidine 13,
was comparable to that obtained for the corresponding achiral
oxime ether 5. However, and in direct contrast, a similar reduc-
tion of enantiomer, (S,S)-3 yielded the (R)-acetamide 7 in 8%
enantiomeric excess (Scheme 6)!
Scheme 5
The successful reduction of oxime 5 led us to examine other
aliphatic oxime ethers 211 in the presence of the Itsuno
oxazaborolidine 13. The reduction products were isolated as O-
benzoyl derivatives 22, as summarised in eqn. (3) and Table 3.
(3)
The magnitude of the stereoselectivity achieved for the oxime
ether 21 reductions in the presence of oxazaborolidine 13,
was obtained by chiral HPLC analysis of the O-benzoylated
reduction products 22. The corresponding racemic compounds
22 were obtained via reduction of β-boronate oxime ethers 21
with borane–tetrahydrofuran complex. The absolute stereo-
chemistry of the major enantiomers from the asymmetric
reduction of oximes 21 were not determined, except based upon
our knowledge of the starting material oxime ether C᎐N double
᎐
bond geometry, from which a similar outcome to that demon-
strated for α-phenyl oxime ether 5 may be predicted. Therefore,
Scheme 6
J. Chem. Soc., Perkin Trans. 1, 2000, 3362–3374
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Table 3 Borane reduction of oxime ethers 21
Entry
Oxime ether
R
Reduction (reducing agent and conditions)
Ee of 22 (%)
1
2
3
4
5
6
7
8
21a
21a
21b
21b
21c
21c
21d
21d
Et
Et
nPr
nPr
tBu
tBu
nC8H17
nC8H17
BH3–THF, THF, rt, 14 h
13, BH3–THF (300 mol%), THF, 2 d
BH3–THF, THF, rt, 2 h
13, BH3–THF (300 mol%), THF, 2 d
BH3–THF, THF, rt, 6 d
13, BH3–THF (300 mol%), THF, 6 d
BH3–THF, THF, rt, 16 h
—
26
—
62
—
47
—
16
13, BH3–THF (300 mol%), THF, 16 h
Table 4 Borane reduction of chiral β-boronate oxime ethers (S,S)-3 and (R,R)-4 in the presence of achiral “N–B”-type additives
(S) versus (R)-7
Yield Ee
Absolute
configuration
Entry
Oxime
Reduction (reagents and conditions)
(%)
(%)
1
2
3
4
5
6
7
8
(S,S)-3
(S,S)-3
(S,S)-3
(S,S)-3
(S,S)-3
(S,S)-3
(R,R)-4
(S,S)-3
BH3–pyridine (100 mol%), BH3–THF (400 mol%), rt, 14 h
Et3N (100 mol%), BH3–THF (400 mol%), rt, 14 h
Et3N (100 mol%), BH3–THF (100 mol%), rt, 20 h; BH3–THF (300 mol%), rt, 5 d
Et3N (100 mol%), BH3–THF (250 mol%), rt, 2 d; BH3–THF (150 mol%), rt, 4 d
25 (100 mol%), BH3–THF (400 mol%), rt, 14 h
25 (100 mol%), BH3–THF (250 mol%), rt, 2 d; BH3–THF (350 mol%), rt, 6 d
Ethanolamine (100 mol%), BH3–THF (400 mol%), rt, 14 h
90
81
82
83
67
96
69
95
1.4
0
28
3
2.2
13
0
R
—
R
R
R
S
—
S
Ethanolamine (100 mol%), BH3–THF (250 mol%), rt, 2 d; BH3–THF (350 mol%), rt, 6 d
2
Clearly the chiral boronate functionalities of oximes 3 and 4
borane–tetrahydrofuran complex), then treated with 3 further
equivalents of borane–tetrahydrofuran followed by acylation
and elaboration to the diacetyl derivative 7, chiral HPLC
analysis revealed the formation of (R)-7 in 28% ee (Table 4,
entry 3). No asymmetric induction was observed for the
reduction of oxime ethers 3 or 4 in the presence of complexes
prepared from β-amino alcohol 25 and ethanolamine with
are capable of influencing the C᎐N double bond reduction as
᎐
summarised in Scheme 6, resulting in extreme double diastereo-
selection effects when coupled with the oxazaborolidine 13-
based reducing system. The matched reducing agent–boronate
ester stereochemistry of 4 produces unperturbed, high asym-
metric induction, similar to that obtained for the reduction of
achiral boronate 5. However, the use of the corresponding
mismatched system of 3 and 13 and borane produced low
asymmetric induction, with reversal of the sense of asymmetric
induction. These results show that remote asymmetric effects
can be “transmitted” by a suitable choice of “partner” mol-
ecule. In the present example, it would seem that oxazabor-
olidine 13, presumably as its borane adduct, destructively
transmits stereochemical information from the homochiral
excess borane (Table 4, entries 5 and 7), i.e. achiral analogues of
the Itsuno’s oxazaborolidine 13 reducing system.
Asymmetric induction was, however, observed when oxime
ether 3 was slowly added to one equivalent of the complex
prepared by treatment of amino alcohol 25 with 2.5 equivalents
of borane–tetrahydrofuran complex (Table 4, entry 6). After 2
days at room temperature, stepwise addition of 3.5 equivalents
of borane–tetrahydrofuran was carried out. Upon conversion
to the diacetate 7, chiral HPLC analysis showed that (S)-7
was present in 13% ee. However, application of an identical
reaction procedure using diethanolamine in place of 25 resulted
in very low asymmetric induction (Table 4, entry 8).
Given these results, it is difficult to draw firm conclusions as
to the mechanism of the reduction in the presence of “N–B”-
type additives and borane–tetrahydrofuran complex. However,
given the dependence of the stereocontrol obtained in the
borane reduction of oxime ethers (R,R)-4 and (S,S)-5 in the
presence of the chiral Itsuno oxazaborolidine 13, on the chir-
ality of the boronate ester moiety, it is unlikely that the reaction
proceeds via the simple mechanistic route first proposed for
achiral boronate 5 outlined in Scheme 5. In order to influence
the stereoselectivity of the reduction, the remote chiral
boronate must be brought into proximity with the prochiral
oxime ether unit. It can be envisaged that in the presence of
oxazaborolidine 13–borane complex, oxime ether 4 could form
a half-chair boron–methoxy chelate of type 26 (Fig. 2). This
results in formation of the matched system, intramolecular
hydride delivery occurs to the Re-face and results in formation
boronate moiety to the remote C᎐N double bond in oxime ether
᎐
(S,S)-3. These effects are manifest despite the remote position
of the boronate ester and are contrary to the previous indi-
cations that boronate ester of either 3, 4 or 5 play no part in
their respective reductions. Clearly, if oxazaborolidine system
13 could exert such an effect, one might expect other, achiral,
systems to behave similarly. Hence, controlling the remote
asymmetric induction would become a matter of carefully
matching the structure of the reducing agent to these boronate
ester systems. To this end, further investigations of a range of
achiral additives, in place of the chiral catalyst oxazaborolidine
13, for the borane-based reducing system were undertaken
to more fully probe the nature of these transmitted remote
asymmetric interaction effects as shown in eqn. (2) and Table 4.
Negligible stereocontrol was observed in the reduction of
homochiral β-boronate ester (S,S)-3 with excess borane–
tetrahydrofuran complex, in the presence of one equivalent
of borane–pyridine complex (Table 4, entry 1) or borane–
triethylamine complex (Table 4, entries 2 and 4). Indeed,
borane–pyridine complex alone did not effect reduction of
oxime ether 3. However, the reduction in the presence of the
borane–triethylamine complex additive proved interesting.
When oxime ether (S,S)-3 was stirred at room temperature
overnight with one equivalent of borane–triethylamine com-
plex (prepared in situ by treatment of triethylamine with
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J. Chem. Soc., Perkin Trans. 1, 2000, 3362–3374

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Summary
β-E-Oximino ether boronates such as 3, 4, 5, and 21 are easily
accessed by simple lithiation methods and can be readily
converted to γ-amino alcohol or β-amino acid derivatives by
an oxime ether reduction, oxidative boronate ester cleavage
sequence. It is not possible to utilise a remote homochiral
boronate ester to directly control the asymmetric reduction of
the oxime ether functions with BH3–THF alone, e.g. in esters 3
and 4, due to the incorrect oxime ether geometry required for
boronate activation of the oxime nitrogen. However, probing
the application of a homochiral reducing system, i.e. 13–BH3–
THF, to the reduction of homochiral boronate esters 3 and
4 did demonstrate that remote asymmetric centres could
influence the oxime ether reduction if a suitable reducing agent
was selected. Hence, subsequent examination of different BH3–
THF–achiral amine reducing agent systems can effect remote
asymmetric reduction of ester 3 and 4 (albeit only 28% ee
to date), despite the unfavourable oxime ether geometry and
effectively greater distance between the remote chiral centres
and the oxime ether being reduced. Further studies on the
application of ‘partner’ molecules for transmitting remote
asymmetric information over more extreme distances are
underway.
Fig. 2 Possible oxime ether–oxaborolidine chelates involved in the
reduction of 4 (top) and 3 (bottom).
Experimental
of the (S)-7. In the mismatched system, shown by structure 27,
hydride delivery to the oxime carbon occurs predominantly
to the Si-face, but only marginally, presumably due to an
insufficient energy difference between the conformation shown
by structure 27 and the conformation that would result from
180Њ rotation around the oxime-N–oxazaborolidine-B bond.
Such an analysis is compatible with the notion that chelate 10
does intervene in the borane reduction (vide infra) of 3, and that
the explanation for the lack of asymmetric induction in that
case lies in the remoteness of the chiral centres of the boronate
ester due to the boronate-B–O-oxime chelation, as opposed to
boronate-B–N-oxime chelation, which would be expected to be
a more efficient directing system, i.e. system 11.
(S)-3-Amino-3-phenylpropan-1-ol was donated by Chirotech.
All other reagents were obtained from Acros, Aldrich or
Lancaster. Dimethyl sulfoxide and ethanolamine were stored
under argon, over activated 3 Å molecular sieves. Dry tetra-
hydrofuran was freshly distilled from sodium and benzo-
phenone immediately prior to use. Dry dichloromethane was
distilled from calcium hydride. Bromobenzene and triethyl-
amine were distilled from calcium hydride before use. Distil-
lations were carried out under an argon atmosphere. Flash
column chromatography was achieved using Acros silica gel,
pore size 60 Å, or Lancaster silica gel 60, 0.060–0.2 mm (70–230
mesh). Thin layer chromatography was performed on Merck
plastic or aluminium sheets coated with silica gel 60 F254 (Art.
5735). Chromatograms were initially examined under UV light
and then developed by spraying with either phosphomolybdic
acid (6 g in 125 ml of ethanol) or aqueous potassium perman-
ganate, followed by heating. All anhydrous reactions were
carried out in oven-dried (120 ЊC) glassware which was cooled
under a stream of argon. Organic extracts were dried over
MgSO4 before evaporation. Evaporations were achieved using
a Büchi rotary evaporator followed by drying at ca. 5 mmHg
using a vacuum pump. Bulb-to-bulb distillations were carried
out using a Büchi GKR-51 Kugelrohr apparatus. Melting
points were determined using an Electrothermal melting point
apparatus and are uncorrected. NMR spectra were recorded
The possible existence of complexes 26 and 27, and therefore
by implication 10 (vide supra) in equilibrium with their open-
chain versions 3 and 4, makes the picture clearer as to why zero-
low asymmetric induction is observed for the achiral reducing
systems reported in Table 4. Activation of the C᎐N bond
᎐
towards “B–H”-addition via a chelated species, may be neces-
sary for reduction with borane–triethylamine complex, whereas
in the presence of the more reactive borane–tetrahydrofuran
species, oxime reduction may proceed via the unactivated
open-chain species resulting in no asymmetric induction. In the
presence of one equivalent of borane–triethylamine complex
the reduction of oxime ether 3 proceeded slowly (Table 4, entry
3), possibly via B–O chelate 10 in which borane is delivered to
the Si-face of the oxime. The fact that asymmetric induction is
observed in this case, is presumably because the triethylamine–
borane complex is sufficiently sterically encumbered that it can
experience some level of steric repulsion from the rather remote
boronate ester. The reduction of oxime ether 4, in the presence
of the oxazaborolidine complex derived from β-amino alcohol
25 and borane–tetrahydrofuran complex results in (S)-7 in 13%
ee (Table 4, entry 6). This hindered oxazaborolidine has low
reactivity and hence slow external borane reduction of the
oxime may result in racemic product; some level of efficient
directed N-chelated oxazaborolidine-mediated reduction
from the same face as the chiral system, i.e. similar to complex
26, would result in the observed asymmetric induction. The
low stereoselectivity obtained for the corresponding
diethanolamine-based reduction of 4 suggests that the resulting
oxazaborolidine complex does not discriminate between
hydride delivery to either of the oxime faces.
1
using Bruker NMR spectrometers. H NMR and 13C NMR
spectra were recorded using CHCl3 and CDCl3 respectively,
as internal standards. Resonances for 11B NMR spectra are
quoted relative to BF3–Et2O (δ 11B = 0.00 ppm) as external
standard. Chemical shift values (δ) are given in ppm, coupling
constants (J) are given in Hz, and NMR peaks are described as
singlet (s), doublet (d), triplet (t), quartet (q) and multiplet (m).
Infra-red (IR) spectra were recorded on a Perkin-Elmer 298
spectrophotometer or a Matson Unicam FTIR spectrometer.
Electron impact (EI) (70 eV) and chemical ionisation (CI) were
recorded with a Kratos MS50 or a Finnigan MAT 95S spec-
trometer. Fast atom bombardment (FAB) spectra were recorded
on a Kratos MS50 using an m-nitrobenzyl alcohol matrix.
Accurate mass determinations were carried out on a Kratos
Concept IS spectrometer. Microanalyses were performed using
a Carlo-Erba 1106 elemental analyser. Optical rotation values
[α] were determined using a Perkin-Elmer Model 241 or an
Optical Activity AA-1000 polarimeter, and are recorded in
J. Chem. Soc., Perkin Trans. 1, 2000, 3362–3374
3367

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units of 10Ϫ1 deg cm2 gϪ1. High performance liquid chrom-
atography (HPLC) was carried out using a Shimadzu Class VP
model equipped with an autosampler and UV detector, or a
Gilson SF3 instrument. Chiralpak (AD, AS) and Chiralcel
(OD, OB, OJ) columns, dimensions 250 × 4.6 mm, were used.
complex (3.70 ml of a 1.0 M solution in THF, 3.70 mmol) was
slowly added. The solution was maintained at 0 ЊC for a further
2 hours, then allowed to warm to room temperature overnight.
The colourless solution formed was cooled in an ice bath and
NaOH (aq.) (3.70 ml of a 2.0 M solution, 7.40 mmol) and H2O2
(aq.) (0.63 ml of a 40% w/v solution, 7.40 mmol) added drop-
wise. A cloudy solution was formed which was heated at reflux
for 1 hour, then partitioned between dichloromethane and
saturated NaCl (aq.). The organic layers were combined and
evaporated, affording a cloudy oil which was re-dissolved in
pyridine (5 ml). Acetic anhydride (0.71 ml, 7.50 mmol) was
added and the solution was stirred at room temperature for 2
days yielding an orange solution. Saturated NaHCO3 (aq.) was
carefully added to this solution until no further effervescence
was observed. Extraction with ethyl acetate (3 × 10 ml),
washing of the combined organic phases with 1.6 M HCl (aq.)
(20 ml), then water (20 ml), and drying, yielded crude
1-acetoxy-3-acetylamino-3-phenylpropane 7 (0.082 g, 0.35
mmol, 94%), as a yellow oil upon evaporation: HPLC [SFC,
Chiralpak AS, 35 ЊC, 3000 psi, λ = 215 nm, 2 ml minϪ1, 86%
CO2: 14% (IPA ϩ 0.2% Et2NH) elution] tR/min 5.03 (49.5%),
8.02 (50.3%); all spectroscopic and analytical properties were
identical to those reported above.
Preparation of racemic 1-acetoxy-3-acetylamino-3-phenyl-
propane 7
To a stirred solution of 3-(4,4,5,5-tetramethyl-1,3,2-dioxa-
borolan-2-yl)propiophenone O-methyloxime 5 (0.11 g, 0.38
mmol) in dry THF (10 ml) at 0 ЊC under argon, borane–
tetrahydrofuran complex (4.00 ml of a 1.0 M solution in THF,
4.00 mmol) was slowly added. After 2 hours the reaction was
allowed to warm to room temperature and stirred overnight.
The solution was then cooled to 0 ЊC, and treated with NaOH
(aq.) (5.00 ml of a 1.0 M solution, 5.00 mmol) and H2O2 (aq.)
(0.33 ml of a 40% w/v solution, 3.90 mmol). Heating at reflux
for 1 hour yielded a colourless solution. This solution was par-
titioned between dichloromethane and saturated NaCl (aq.).
The combined organic phases were dried and evaporated,
affording a cloudy oil which was re-dissolved in pyridine (2 ml).
Acetic anhydride (1.00 ml, 10.60 mmol) was added. Stirring at
room temperature for 24 hours afforded an orange solution
which was cooled in an ice bath. Saturated NaHCO3 (aq.)
was then carefully added until no further effervescence was
observed. Extraction with ethyl acetate (3 × 10 ml), followed by
washing of the combined organic phases with 10% HCl (aq.)
(30 ml), then water (30 ml), and drying, yielded a pale yellow oil
upon evaporation. Trituration with cold diethyl ether furnished
the title compound racemic 7 (0.042 g, 0.18 mmol, 47%) as a
white solid upon filtration: mp 102–103 ЊC (lit.,7 84–85 ЊC,
Et2O); HPLC [SFC, Chiralpak AS, 35 ЊC, 3000 psi, λ = 215 nm,
2 ml minϪ1, 86% CO2: 14% (isopropyl alcohol (IPA) ϩ 0.2%
Et2NH) elution] tR/min 5.06 (49.7%), 8.01 (50.3%) (Found: C,
65.9; H, 7.4; N, 5.6. C13H17NO3 requires C, 66.4; H, 7.3; N,
6.0%); νmax (KBr)/cmϪ1 3300, 3060, 3029, 2972, 2924, 1732,
1642, 1548, 1468, 1420, 1244, 1052; δH (250 MHz; CDCl3) 2.00
Preparation of N-{3-[(4S,5S)-4,5-bis(1-methoxycyclopentyl)-
1,3,2-dioxaborolan-2-yl]-1-phenylpropyl}acetamide 8 via
reduction of (S,S)-3 with borane–dimethyl sulfide complex
To a stirred solution of 3-[(4S,5S)-4,5-bis(1-methoxycyclopent-
yl)-1,3,2-dioxaborolan-2-yl]propiophenone
O-methyloxime
(S,S)-3 (0.096 g, 0.22 mmol) in dry THF (0.50 ml) at Ϫ15 ЊC
under argon, borane–dimethyl sulfide complex (1.10 ml of a
2.0 M solution in THF, 2.20 mmol) was added dropwise. The
reaction was then allowed to warm to room temperature and
stirred for 16 hours. Quenching the reaction at 0 ЊC with acetic
anhydride (0.42 ml, 4.40 mmol), then stirring at room tem-
perature for 2 days afforded a yellow solution and a white pre-
cipitate. This mixture was cooled in an ice bath and saturated
NaHCO3 (aq.) was carefully added until no further efferves-
cence was observed. Extraction with ethyl acetate (3 × 10 ml),
washing the combined organic extracts with water (20 ml) and
drying, yielded a very pale yellow oil upon evaporation. Flash
column chromatography [3:2, ethyl acetate–petroleum ether
(40–60 ЊC) as eluent] yielded acetamide 8 (0.094 g, 0.21 mmol,
96%) as a 1:1 mixture of diastereoisomers: [α]D27.5 ϩ13 (c 0.15,
CHCl3); νmax (film)/cmϪ1 3460–3274, 2931, 2855, 1741, 1239,
1075, 1046; δH (300 MHz; CDCl3) 0.68–0.89 (2 H, m, CH2B),
1.56–1.94 (18 H, m, CH2 cyclopentyl, CH2CH2B), 1.98 (3 H,
(3 H, s, CH C᎐ON), 2.01 (3 H, s, CH C᎐OO), 2.08–2.20 (2 H,
᎐
᎐
3
3
m, CH2CHN), 4.01–4.11 (2 H, m, CH2O), 5.08–5.17 (1 H, m,
CH2CHN), 5.76 (1 H, br s, NH), 7.27–7.34 (5 H, m, H
aromatic) (addition of D2O caused peak at δ 5.76 to disappear,
and that at δ 5.08–5.17 to collapse to a triplet, J 7.2, δ 5.12);
δC (62.9 MHz; CDCl ) 20.9 (CH C᎐ON), 23.4 (CH C᎐OO),
᎐
᎐
3
3
3
34.7 (CH2CHN), 50.7 (CH2CHN), 61.4 (CH2O), 126.5,
127.7, 128.8, 141.1 (C aromatic), 169.2 (CH C᎐ON), 171.0
᎐
3
(CH C᎐OO); m/z (CI, NH ) 236 (M ϩ H)ϩ, 471 (2M ϩ H)ϩ
᎐
3
3
[Found (HRMS): m/z 235.1216. C13H17NO3 requires Mϩ
235.1208].
s, CH C᎐O), 3.23 (6 H, s, 2 × OCH ), 4.28 (1 H, s, CHO), 4.30
᎐
3
3
(1 H, s, CHO), 4.87–4.99 (1 H, m, CHNH), 5.96 (1 H, br d,
J 8.0, NH), 7.21–7.34 (5 H, m, H aromatic) (addition of
D2O caused the peak at δ 5.96 to disappear); δC (75.5 MHz;
CDCl3), 1:1 mixture of diastereomers, 20.9 (CH2CH2B), 23.3
Preparation of (S)-1-acetoxy-3-acetylamino-3-phenylpropane
(S)-7
Acetic anhydride (0.50 ml, 5.30 mmol) was added to a solution
of (S)-3-amino-3-phenylpropan-1-ol (S)-6 (0.050 g, 0.33 mmol)
in pyridine (0.50 ml). The solution was stirred at room temper-
ature for 24 hours, then partitioned between dichloromethane
and saturated NaHCO3 (aq.). The combined organic phases
were washed with 10% HCl (aq.) (20 ml), then water (20 ml),
and dried. Evaporation yielded the title compound (S)-7 (0.070
g, 0.301 mmol, 90%) as a white solid: mp 103 ЊC; [α]D23 Ϫ72.4
(c 0.468, MeOH); HPLC [SFC, Chiralpak AS, 35 ЊC, 3000 psi,
λ = 215 nm, 2 ml minϪ1, 86% CO2: 14% (IPA ϩ 0.2% Et2NH)
elution] tR/min 5.04 (0.9%), 7.97 (99.1%); all other spectro-
scopic properties were identical to those reported above.
(C᎐OCH ), 24.4, 25.2, 30.4, 30.6, 31.1, 31.2 (CH cyclopentyl),
᎐
3
2
50.3, 50.4 (OCH3), 55.0, 55.2 (CHNH), 63.9 (CH2CH), 81.0
(CHO), 87.8, 87.9 (COCH3), 126.4, 126.5, 127.1, 128.5, 142.1,
142.4 (C aromatic), 169.4, 171.1 (NC᎐OCH ); δ (64.2 MHz;
᎐
3
B
CDCl3) ϩ34.2; m/z (FAB) 444 (M ϩ H)ϩ [Found (HRMS):
m/z 444.2922. C25H38BNO5 requires (M ϩ H)ϩ 444.2921].
Preparation of acetamide 8 via reduction of (S,S)-3 with borane–
tetrahydrofuran complex
To a stirred solution of β-boronate O-methyloxime (S,S)-3
(0.014 g, 0.033 mmol) in dry THF (0.50 ml) at 0 ЊC under Ar,
borane–tetrahydrofuran complex (0.33 ml of a 1.0 M solution
in THF, 0.33 mmol) was slowly added. The solution was
allowed to warm to room temperature and stirred for 2 days.
The reaction was then quenched at 0 ЊC with acetic anhydride
(0.062 ml, 0.66 mmol) and stirred overnight at room temper-
Preparation of diacetyl derivative 7 via reduction of (S,S)-3 with
borane–tetrahydrofuran complex
To a solution of boronate ester (S,S)-3 (0.16 g, 0.37 mmol) in
dry THF (5 ml) at 0 ЊC under argon, borane–tetrahydrofuran
3368
J. Chem. Soc., Perkin Trans. 1, 2000, 3362–3374

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ature. The solution was cooled in an ice bath and saturated
NaHCO3 (aq.) was added dropwise until no further effer-
vescence was observed. Extraction with ethyl acetate (3 × 10
ml), washing the combined organic phases with water (20 ml),
and drying, yielded crude acetamide 8 (0.013 g, 0.029 mmol,
89%) upon evaporation, as a 1:1 mixture of diastereomers
by 13C NMR: all spectroscopic and analytical properties were
identical to those reported above.
[α]D25 Ϫ127.7 (c 0.639, CHCl3)]; δH (300 MHz; CDCl3) 0.91 [3 H,
d, J 6.8, (CH3)CH3CH], 0.95 [3 H, d, J 7.1, (CH3)CH3CH],
1.72–1.85 [1 H, m, (CH3)2CH], 3.87 (1 H, d, J 1.9, CHN),
7.16–7.36 (6 H, m, H aromatic), 7.50–7.53 (2 H, m, H
aromatic), 7.62–7.66 (2 H, m, H aromatic); 13C NMR and
IR were as reported in the literature;16 m/z (CI, NH3) 256
(M ϩ H)ϩ [Found (HRMS): m/z 256.1700. C17H21NO requires
(M ϩ H)ϩ 256.1701].
Preparation of acetamide 8 via reduction of (S,S)-3 with
diisobutylaluminium hydride
Preparation of N-[(S)-1-phenyl-3-(4,4,5,5-tetramethyl-1,3,2-
dioxaborolan-2-yl)propyl]acetamide 15 via borane reduction of
5 in the presence of oxazaborolidine 13
To a stirred solution of boronate O-methyloxime (S,S)-3 (0.11
g, 0.26 mmol) in dry THF (5 ml) at 0 ЊC under Ar, diisobutyl-
aluminium hydride (2.60 ml of a 1.0 M solution in THF, 2.60
mmol) was slowly added. The solution was allowed to warm to
room temperature and stirred for 2 days. The reaction was then
quenched at 0 ЊC with acetic anhydride (0.47 ml, 5.00 mmol)
and stirred overnight at room temperature. The solution was
cooled in an ice bath and saturated NaHCO3 (aq.) was added
dropwise until no further effervescence was observed. Extrac-
tion with ethyl acetate (3 × 10 ml), washing the combined
organic phases with water (20 ml) and drying, yielded crude
acetamide 8 (0.10 g, 0.23 mmol, 87%) as a colourless oil upon
evaporation: 1:1 mixture of diastereomers by 13C NMR; all
spectroscopic and analytical properties were identical to those
reported above.
To a stirred solution of homochiral amino alcohol 13 (0.041 g,
0.16 mmol) in dry THF (2 ml) at 0 ЊC under Ar, borane–
tetrahydrofuran complex (0.64 ml of a 1.0 M solution in THF,
0.64 mmol) was slowly added. After 6 hours, oxime ether 5
(0.046 g, 0.16 mmol) in THF (1 ml) was added, and the solution
allowed to warm to room temperature overnight. A colourless
solution was formed which was treated with acetic anhydride
(0.30 ml, 3.20 mmol) at 0 ЊC. After stirring at room temper-
ature for a further 1 hour, the THF was removed by rotary
evaporation. The cloudy residue was partitioned between
dichloromethane and saturated NaHCO3 (aq.). The combined
organic phases were dried and evaporated yielding a very vis-
cous colourless oil. Flash column chromatography [1:1, ethyl
acetate–petroleum ether (40–60 ЊC) as eluent] afforded 15
(0.045 g, 0.15 mmol, 93%) as a very viscous cloudy oil: [α]D27.5
Ϫ54 (c 0.92, CHCl3); νmax (film)/cmϪ1 3050, 2980, 1665, 1415,
1370, 1260, 1140; δH (300 MHz; CDCl3) 0.73–0.82 (2 H, m,
CH2B), 1.24 [12 H, s, 2 × (CH3)2C], 1.84–1.92 (2 H, m,
Preparation of acetate 7 from acetamide 8
Acetamide 8 (1:1 mixture of diastereoisomers) (0.022 g, 0.050
mmol) was dissolved in THF (1 ml) and treated with H2O2 (0.10
ml of a 40% w/v solution, 1.18 mmol) and NaOH (aq.) (0.60 ml
of a 2.0 M solution, 1.20 mmol). The cloudy solution was
stirred at room temperature for 2 days, then extracted with
dichloromethane (3 × 10 ml). The combined organic phases
were washed with water (20 ml) and dried. Evaporation yielded
a colourless oil which was re-dissolved in pyridine (0.50 ml).
Acetic anhydride (0.50 ml, 5.30 mmol) was added and the
reaction mixture stirred overnight at room temperature. After
cooling in an ice bath, saturated NaHCO3 (aq.) was carefully
added until no further effervescence was observed, and the
solution was then extracted with dichloromethane (3 × 10 ml).
The combined organic layers were washed with 10% HCl (aq.)
(20 ml), then water (20 ml), and dried. Evaporation yielded
crude acetate 7 (9 mg, 0.038 mmol, 77%) as an off-white solid:
HPLC [SFC, Chiralpak AS, 35 ЊC, 3000 psi, λ = 215 nm, 2 ml
minϪ1, 86% CO2: 14% (IPA ϩ 0.2% Et2NH) elution] tR/min
5.03 (49.5%), 8.02 (50.3%); all spectroscopic and analytical
properties were identical to those reported above.
CH CH B), 1.98 (3 H, s, CH C᎐O), 4.89 (1 H, q, J 7.5, CHNH),
᎐
3
2
2
5.96 (1 H, br d, J 7.2, NH) (addition of D2O caused peak at
δ 5.96 to disappear, and that at δ 4.89 to collapse to a triplet,
J 7.2, δ 4.88); δC (100.6 MHz; CDCl3) 7.9 (br, CH2B), 23.3
(CH C᎐O), 24.7 [(CH ) C], 24.8 [(CH ) C], 30.4 (CH CHN),
᎐
3
3
2
3
2
2
55.2 (CHN), 83.2 [(CH3)2C], 126.4, 127.0, 128.4, 142.3 (C
aromatic), 169.2 (C᎐O); δB (64.2 MHz; CDCl3) ϩ34.0;
᎐
m/z (FAB) 304 (M ϩ H)ϩ [Found (HRMS): m/z 304.2091.
C17H26BNO3 requires (M ϩ H)ϩ 304.2084].
Preparation of acetate (S)-7 from acetamide 15
Acetamide 15 (0.045 g, 0.15 mmol) was dissolved in THF (2 ml)
and H2O2 (aq.) (0.15 ml of a 40% w/v solution, 1.76 mmol) and
NaOH (aq.) (1.00 ml of a 2.0 M solution, 2.00 mmol) were
added. A cloudy solution was formed which was stirred at
room temperature for 2 hours then extracted with ethyl acetate
(3 × 10 ml). Drying and evaporating the combined organic
extracts yielded a residue which was treated with acetic
anhydride (0.15 ml, 1.60 mmol) in the presence of pyridine (2
ml) at room temperature for 2 hours. An orange solution was
formed which was partitioned between dichloromethane and
saturated NaHCO3 (aq.). The combined organic extracts were
washed with 10% HCl (aq.) (20 ml), dried and evaporated to
afford acetate (S)-7 (0.030 g, 0.13 mmol, 85%) after chrom-
atography [1:1, ethyl acetate–petroleum ether (40–60 ЊC) as
eluent]: HPLC [Chiralpak AS, SFC, 35 ЊC, 3000 psi, λ = 218
nm, 2 ml minϪ1, 90% CO2: 10% (IPA ϩ 0.2% Et2NH) elution]
tR/min 6.23 (1.2%), 8.92 (98.8%); all spectroscopic and
analytical properties were as reported above.
Preparation of (S)-2-amino-3-methyl-1,1-diphenylbutan-1-ol 14
Bromobenzene (9.28 ml, 0.088 mol) was carefully added
dropwise to magnesium turnings (2.56 g, 0.11 mol) and iodine
(1 crystal) in anhydrous diethyl ether (80 ml) under Ar. When
reaction was initiated, the solution was cooled in an ice bath
until addition of the aryl bromide was complete. The solution
was allowed to warm to room temperature then heated at reflux
for 2 hours. The reaction was again cooled in an ice bath and
L-valine ethyl ester hydrochloride (2.00 g, 0.011 mol) carefully
added. After refluxing for a further 5 hours, the reaction was
quenched by pouring onto ice (50 ml), and concentrated HCl
(aq.) (1 ml) was slowly added. The mixture was left to stand at
room temperature for 1 hour, then the ether layer was separ-
ated. The aqueous phase was basified (pH = 10) with 35%
NH4OH (aq.) and extracted with diethyl ether (3 × 25 ml). The
combined organic phases were dried and evaporated to furnish
14 (1.10 g, 4.31 mmol, 39%) as a white solid after flash column
chromatography (1:20, methanol–dichloromethane as eluent):
mp 89–91 ЊC (lit.,14a 94–95 ЊC); [α]D27 Ϫ121 (c 1.2, CHCl3) [lit.,10
Preparation of (S)-7 via borane reduction of 5 in the presence of
a catalytic amount of oxazaborolidine 13
To a solution of homochiral amino alcohol 14 (0.021 g, 0.082
mmol) in dry THF (0.30 ml) at 0 ЊC under argon, borane–
tetrahydrofuran complex (0.64 ml of a 1.0 M solution in THF,
0.64 mmol) was added dropwise. The solution was allowed to
warm to room temperature and stirred for 14 hours, then
cooled in an ice bath. Boronate ester 5 (0.094 g, 0.325 mmol)
J. Chem. Soc., Perkin Trans. 1, 2000, 3362–3374
3369

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in THF (0.50 ml) was added slowly and the reaction allowed
to warm to room temperature. The solution was stirred for 20
hours at ambient temperature, then cooled to 0 ЊC and treated
with acetic anhydride (0.30 ml, 3.20 mmol). This mixture was
stirred at room temperature for 1 hour then the THF was
evaporated. The cloudy residue was partitioned between
dichloromethane and saturated NaHCO3 (aq.). The combined
organic extracts were dried, evaporated, and the residue dis-
solved in THF (5 ml) and treated with H2O2 (aq.) (0.30 ml of
a 40% w/v solution, 3.52 mmol) and NaOH (aq.) (2.0 ml of a
2.0 M solution, 4.0 mmol). This cloudy solution was stirred at
room temperature for 2 hours then extracted with ethyl acetate
(3 × 10 ml). The combined organic phases were dried and evap-
orated. The residue was treated with acetic anhydride (0.30 ml,
3.20 mmol) in pyridine (4 ml) at room temperature for 2 hours,
then partitioned between dichloromethane and saturated
NaHCO3 (aq.). The organic extracts were combined, washed
with 10% HCl (aq.) (50 ml) then dried. Evaporation yielded
15 (0.055 g, 0.23 mmol, 73%) after purification by column
chromatography [1:1, ethyl acetate–petroleum ether (40–60 ЊC)
as eluent]: HPLC [Chiralpak AS, SFC, 35 ЊC, 3000 psi, λ = 218
nm, 2 ml minϪ1, 90% CO2: 10% (IPA ϩ 0.2% Et2NH) elution]
tR/min 6.57 (7.1%), 10.04 (88.1%); all other spectroscopic and
analytical properties were as reported above.
is then purified by flash column chromatography [1:4, ethyl
acetate–petroleum ether (40–60 ЊC) as eluent].
(a) Preparation of racemic benzoate 22a. The general
procedure outlined above was followed on a 0.12 mmol scale.
The reduction was complete after 14 hours, yielding racemic
acetamide 22a (0.010 g, 0.040 mmol, 33%) as a cloudy viscous
oil after column chromatography: HPLC (Chiralcel OJ, λ = 254
nm, 0.5 ml minϪ1, 90% hexane: 10% IPA elution) tR/min 18.46
(52.2%), 20.31 (49.8%); δH (300 MHz; CDCl3) 0.94 (3 H, t,
J 7.4, CH3CH2), 1.44–2.00 (4 H, m, CH3CH2, CH2CH), 1.98
(3 H, s, CH C᎐O), 4.05–4.11 (1 H, m, CHNH), 4.29–4.45 (2 H,
᎐
3
m, CH2O), 5.35 (1 H, br d, J 7.5, NH), 7.42–7.48 (2 H, m, H
meta), 7.52–7.59 (1 H, m, H para), 8.01–8.07 (2 H, m, H ortho)
(addition of D2O caused peak at δ 5.35 to disappear);
m/z (FAB) 250 (M ϩ H)ϩ [Found (HRMS): m/z 250.1439.
C14H19NO3 requires (M ϩ H)ϩ 250.1443].
(b) Preparation of racemic benzoate 22b. The general
procedure outlined above was followed on a 0.47 mmol scale.
Reduction was complete after 48 hours, yielding racemic
acetamide 22b (0.031 g, 0.12 mmol, 25%): HPLC (Chiralcel OJ,
λ = 254 nm, 1 ml minϪ1, 95% hexane: 5% IPA elution) tR/min
16.77 (48.6%), 18.38 (51.4%); δH (300 MHz; CDCl3) 0.91 (3 H,
t, J 7.0, CH3CH2), 1.23–1.57 (4 H, m, (CH2)2CH3), 1.97 (3 H, s,
Preparation of (S)-3-acetylamino-3-phenylpropionic acid 16 via
oxidation of acetamide 15
CH C᎐O), 1.76–2.05 (2 H, m, CH CH O), 4.10–4.15 (1 H, m,
᎐
3
2
2
CHNH), 4.31–4.44 (2 H, m, CH2O), 5.44 (1 H, br d, J 8.3, NH),
7.41–7.47 (2 H, m, H meta), 7.53–7.58 (1 H, m, H para),
8.02–8.05 (2 H, m, H ortho) (addition of D2O caused peak at
δ 5.44 to disappear); m/z (FAB) 264 (M ϩ H)ϩ [Found (HRMS):
m/z 264.1605. C15H21NO3 requires (M ϩ H)ϩ 264.1600].
To a solution of chromium trioxide (0.012 g, 0.12 mmol) in
glacial acetic acid (0.45 ml) and water (0.05 ml), acetamide 15
(0.012 g, 0.040 mmol) in dichloromethane (0.50 ml) was added
dropwise. The solution was stirred at room temperature for
4 hours, then extracted with dichloromethane (3 × 5 ml). The
organic phases were combined and evaporated to yield 16
(7 mg, 0.034 mmol, 85%) as a white solid after triturating with
cold chloroform: IR was as reported in the literature;18 δH [300
(c) Preparation of racemic benzoate 22c. The general
procedure described above was followed on a 0.37 mmol scale.
Reduction was complete after 6 days, yielding acetamide 22c
(0.015 g, 0.054 mmol, 15%) after column chromatography:
HPLC (Chiralpak AD, λ = 254 nm, 0.5 ml minϪ1, 90%
hexane: 10% IPA elution) tR/min 10.98 (49.5%), 11.89 (50.5%);
δH (300 MHz; CDCl3) 0.93 [9 H, s, (CH3)3C], 1.50–1.64 [1 H,
MHz; (CD ) CO] 1.90 (3 H, s, CH C᎐O), 2.81–2.87 (2 H, m
᎐
3
3
2
CH C᎐OOH), 5.37–5.44 (1 H, m, CHNH), 7.22–7.42 (5 H, m,
᎐
2
H aromatic), 7.55 (1 H, br d, J 6.0, NH), 10.80 (1 H, br s, OH)
(addition of D2O caused peaks at δ 7.55 and δ 10.80 to dis-
appear, and multiplet at δ 5.37–5.44 to collapse to a triplet,
m, CH(H)CHN], 2.02 (3 H, s, CH C᎐O), 2.04–2.18 [1 H, m,
᎐
3
CH(H)CHN], 3.94–4.02 (1 H, m, CHNH), 4.21–4.29 [1 H, m,
CH(H)O], 4.41–4.48 [1 H, m, CH(H)O], 5.25 (1 H, br d, J 10.5,
NH), 7.41–7.45 (2 H, m, H meta), 7.53–7.56 (1 H, m, H para),
8.03–8.05 (2 H, m, H ortho) (addition of D2O caused peak
at δ 5.25 to disappear); m/z (FAB) 278 (M ϩ H)ϩ [Found
(HRMS): m/z 278.1757. C16H23NO3 requires (M ϩ H)ϩ
278.1756].
J 7.4, δ 5.32); δC [100.6 MHz; (CD ) CO] 22.5 (CH C᎐O),
᎐
3
3
2
40.6 (CH C᎐O), 50.2 (CHNH), 127.4, 128.7, 132.9, 142.9 (C
᎐
2
aromatic), 168.6 (NC᎐O), 171.5 (C᎐OOH); m/z (CI, NH ) 208
᎐
᎐
3
(M ϩ H)ϩ [Found (HRMS): m/z 208.0967. C11H13NO3 requires
(M ϩ H)ϩ 208.0974].
General procedure for the preparation of racemic O-benzoyl
derivatives 22
(d) Preparation of racemic benzoate 22d. The procedure
described above was followed on a 0.18 mmol scale. Reduction
was complete after 16 hours, affording acetamide 22d (0.012 g,
0.036 mmol, 20%) as a white solid: HPLC (Chiralcel OD,
λ = 254 nm, 0.5 ml minϪ1, 90% hexane: 10% IPA elution) tR/min
12.83 (45.1%), 13.82 (54.9%); δH (300 MHz; CDCl3) 0.87 (3 H,
t, J 6.8, CH3CH2), 1.25–1.59 [14 H, m, CH3(CH2)7], 1.75–1.92
To a solution of oxime ether 21 (0.18 mmol) in dry THF (0.30
ml) at 0 ЊC under Ar, borane–tetrahydrofuran complex (1.80 ml
of a 1.0 M solution in THF, 1.80 mmol) is added dropwise. The
reaction is allowed to warm to room temperature. When reduc-
tion is complete, the solution is cooled in an ice bath, treated
with acetic anhydride (0.34 ml, 3.60 mmol), then stirred at room
temperature for 1 hour. The THF is removed by rotary evap-
oration and the residue partitioned between dichloromethane
and saturated NaHCO3 (aq.). The combined organic phases are
dried and evaporated. The resulting acetamide is dissolved in
THF (1 ml) and treated with NaOH (aq.) (1.50 ml of a 2.0 M
solution, 3.00 mmol) and H2O2 (aq.) (0.20 ml of a 40% w/v
solution, 2.35 mmol). After stirring at room temperature for
2 hours the solution is extracted with ethyl acetate (3 × 10 ml).
The organic extracts are combined, dried and evaporated,
yielding crude alcohol. The crude alcohol is dissolved in pyri-
dine (1 ml), treated with benzoyl chloride (0.10 ml, 0.90 mmol)
and stirred at room temperature for 2 hours. The resulting solu-
tion is partitioned between dichloromethane and saturated
NaHCO3 (aq.). The combined organic phases are dried and
evaporated yielding crude O-benzoylated product 22 which
[1 H, m, CH(H)CH O], 1.97 (3 H, s, CH C᎐O), 1.97–2.12 [1 H,
᎐
3
2
m, CH(H)CH2O], 4.06–4.17 (1 H, m, CHNH), 4.29–4.47 (2 H,
m, CH2O), 5.33 (1 H, br d, J 8.6, NH), 7.41–7.46 (2 H, m,
H meta), 7.53–7.59 (1 H, m, H para), 8.02–8.05 (2 H, m,
H ortho) (addition of D2O caused peak at δ 5.33 to disappear);
m/z (FAB) 334 (M ϩ H)ϩ. [Found (HRMS): m/z 334.2384.
C20H31NO3 requires (M ϩ H)ϩ 334.2382].
General procedure for preparation of O-benzoyl derivatives 22 via
borane reduction of 21 in the presence of oxazaborolidine 13
To a stirred solution of homochiral amino alcohol 14 (0.051 g,
0.20 mmol) in dry THF (0.25 ml) at 0 ЊC, borane–tetrahydro-
furan complex (0.80 ml of a 1.0 M solution in THF, 0.80 mmol)
is added dropwise. After 6 hours, oxime ether 21 (0.20 mmol) in
3370
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dry THF (0.25 ml) is slowly added and the reaction allowed to
warm to room temperature. When reduction is complete, the
reaction is quenched at 0 ЊC with acetic anhydride (0.19 ml, 2.00
mmol), and stirred at room temperature for 1 hour. The THF
is removed by rotary evaporation and the residue partitioned
between dichloromethane and saturated NaHCO3 (aq.). The
combined organic phases are dried and evaporated yielding the
crude acetamide. The acetamide is then dissolved in THF (1 ml)
and treated with NaOH (aq.) (1.50 ml of a 2.0 M solution, 3.00
mmol) and H2O2 (aq.) (0.20 ml of a 40% w/v solution, 2.35
mmol). After stirring at room temperature for 2 hours the
solution is extracted with ethyl acetate (3 × 10 ml). The organic
extracts are combined, dried and evaporated, yielding crude
alcohol residue. Crude alcohol is dissolved in pyridine (1 ml),
treated with benzoyl chloride (0.12 ml, 1.00 mmol) and stirred
at room temperature for 2 hours. The resulting solution is
partitioned between dichloromethane and saturated NaHCO3
(aq.). Combined organic phases are dried and evaporated
yielding crude O-benzoylated product 22 which is purified by
column chromatography [1:4, ethyl acetate–petroleum ether
(40–60 ЊC) as eluent].
orated and the residue partitioned between dichloromethane
and saturated NaHCO3 (aq.). The organic extracts were com-
bined and dried. Evaporation yielded a colourless oil which was
dissolved in THF (1 ml) and treated with NaOH (aq.) (0.50 ml
of a 2.0 M solution, 1.00 mmol) and H2O2 (aq.) (0.050 ml of a
40% w/v solution, 0.59 mmol) at room temperature for 2 hours.
The solution was extracted with ethyl acetate (3 × 10 ml). The
combined organic extracts were dried and evaporated. The
residue was dissolved in pyridine (1 ml) and acetic anhydride
(0.060 ml, 0.63 mmol), was added. This solution was stirred
at room temperature for 2 hours then partitioned between
dichloromethane and saturated NaHCO3 (aq.). The combined
organic phases were washed with 10% HCl (aq.) (20 ml) and
dried. Evaporation yielded acetate (S)-7 (0.011 g, 0.047 mmol,
74%) after purification by column chromatography [1:1, ethyl
acetate–petroleum ether (40–60 ЊC) as eluent]: HPLC [Chiral-
pak AS, SFC, 35 ЊC, 3000 psi, λ = 218 nm, 2 ml minϪ1, 90%
CO2: 10% (IPA ϩ 0.2% Et2NH) elution] tR/min 6.20 (2.4%),
8.73 (92.1%); all other spectroscopic and analytical properties
were identical to those reported above.
Borane reduction of (S,S)-3 in the presence of oxazaborolidine 13
(a) Preparation of 22a via borane reduction of 21a in the
presence of oxazaborolidine 13. The general procedure outlined
above was followed on a 0.41 mmol scale. Reduction was
complete after 48 hours, yielding acetamide 22a (0.025 g, 0.10
To a solution of aminoalcohol 14 (0.053 g, 0.21 mmol) in dry
THF (2 ml) at 0 ЊC under Ar, borane–tetrahydrofuran complex
(0.84 ml of a 1.0 M solution in THF, 0.84 mmol) was added
dropwise. This solution was stirred for 7 hours, then chiral
oxime ether (S,S)-3 (0.089 g, 0.21 mmol) in THF (1 ml) was
added, and the reaction allowed to warm to room temperature.
After 14 hours, the solution was cooled in an ice bath and acetic
anhydride (0.40 ml, 4.20 mmol) was added. After stirring at
room temperature for 2 hours the THF was removed by rotary
evaporation. The cloudy residue was partitioned between
dichloromethane and saturated NaHCO3 (aq.). Drying and
evaporation of the combined organic phases yielded a crude
acetamide. The acetamide was dissolved in THF (2 ml) and
treated with H2O2 (aq.) (0.20 ml of a 40% w/v solution, 2.35
mmol) and NaOH (aq.) (1.50 ml of a 2.0 M solution, 3.00
mmol) at room temperature for 2 hours. A cloudy solution was
formed which was extracted with ethyl acetate (3 × 10 ml). The
organic phases were combined, dried and evaporated. The
residue was dissolved in pyridine (2 ml) and treated with acetic
anhydride (0.20 ml, 2.10 mmol). This solution was stirred
at room temperature for 2 hours then partitioned between
dichloromethane and saturated NaHCO3 (aq.). The organic
extracts were combined, washed with 10% HCl (aq.) (20 ml)
and dried. Evaporation yielded diacetyl derivative 7 (0.037 g,
0.16 mmol, 75%) as a white solid after flash column chrom-
atography [1:1, ethyl acetate–petroleum ether (40–60 ЊC) as
eluent]: HPLC [Chiralpak AS, SFC, 35 ЊC, 3000 psi, λ = 218
nm, 2 ml minϪ1, 90% CO2: 10% (IPA ϩ 0.2% Et2NH) elution]
tR/min 6.79 (53.7%), 8.96 (46.2%); all spectroscopic and
analytical properties were identical to those reported above.
mmol, 24%): HPLC (Chiralcel OJ, λ = 254 nm, 0.5 ml minϪ1
,
90% hexane: 10% IPA elution) tR/min 18.29 (63.0%), 20.17
(37.0%); all spectroscopic properties were identical to those
reported above.
(b) Preparation of 22b via borane reduction of 21b in the
presence of oxazaborolidine 13. The general procedure
described above was followed on a 0.27 mmol scale. Reduction
was complete after 48 hours, affording 22b (0.016 g, 0.061
mmol, 23%) as a colourless oil: HPLC (Chiralcel OJ, λ = 254
nm, 1 ml minϪ1, 95% hexane: 5% IPA elution) tR/min 17.18
(81.2%), 18.88 (18.8%); all spectroscopic properties were
identical to those reported above.
(c) Preparation of 22c via borane reduction of 21c in the
presence of oxazaborolidine 13. The general procedure outlined
above was followed on a 0.37 mmol scale. Reduction was
complete after 6 days, furnishing acetamide 22c (0.010 g, 0.036
mmol, 10%) as a colourless oil: HPLC (Chiralpak AD, λ = 254
nm, 0.5 ml minϪ1, 90% hexane: 10% IPA elution) tR/min 11.00
(73.2%), 11.89 (26.7%); all spectroscopic properties were
identical to those reported above.
(d) Preparation of 22d via borane reduction of 21d in the
presence of oxazaborolidine 13. The general procedure outlined
above was followed on a 0.092 mmol scale. Reduction was
complete after 16 hours, yielding acetamide 22d (0.011 g, 0.033
mmol, 36%) as a white solid after chromatography: HPLC
(Chiralcel OD, λ = 254 nm, 0.5 ml minϪ1, 90% hexane: 10% IPA
elution) tR/min 12.87 (42.0%), 13.83 (58.0%); all spectroscopic
properties were identical to those reported above.
Reduction of (S,S)-3 with borane in the presence of borane–
pyridine complex
To a solution of borane–pyridine complex (5.0 µl, 0.049 mmol)
in dry THF (0.25 ml) at 0 ЊC under Ar, borane–tetrahydrofuran
complex (0.19 ml of a 1.0 M in THF, 0.19 mmol) was added
dropwise. After 5 hours (S,S)-3 (0.020 g, 0.047 mmol) in THF
(0.25 mmol) was added. The reaction was allowed to warm to
room temperature and stirred for 14 hours. The solution was
then cooled in an ice bath and treated with acetic anhydride
(0.090 ml, 0.95 mmol). After stirring at room temperature for
1 hour, THF was removed by rotary evaporation and the residue
partitioned between dichloromethane and saturated NaHCO3
(aq.). The organic extracts were combined, dried and evapor-
ated to yield a crude acetamide as a colourless oil. This oil was
treated with NaOH (aq.) (0.50 ml of a 2.0 M solution, 1.00
mmol) and H2O2 (aq.) (0.060 ml of a 40% w/v solution, 0.71
Borane reduction of (R,R)-4 in the presence of oxazaborolidine
13
To a solution of chiral amino alcohol 14 (0.016 g, 0.063 mmol)
in dry THF (1 ml) at 0 ЊC under argon, borane–tetrahydrofuran
complex (0.25 ml of a 1.0 M solution, 0.25 mmol) was slowly
added. The solution was stirred at 0 ЊC for 6 hours, then chiral
β-boronate oxime ether (R,R)-4 (0.027 g, 0.063 mmol) in THF
(1 ml) was added dropwise. The reaction allowed to warm to
room temperature. After 14 hours, the reaction was quenched
with acetic anhydride (0.12 ml, 1.26 mmol) at 0 ЊC, then allowed
to warm to room temperature. After 1 hour the THF was evap-
J. Chem. Soc., Perkin Trans. 1, 2000, 3362–3374
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mmol) in THF (1 ml) at room temperature for 2 hours. The
resulting cloudy solution was extracted with ethyl acetate
(3 × 10 ml). The combined organic phases were dried and evap-
orated affording a cloudy oil which was dissolved in pyridine
(1 ml) and treated with acetic anhydride (0.045 ml, 0.48 mmol).
After stirring at room temperature for 2 hours, the solution was
partitioned between dichloromethane and saturated NaHCO3
(aq.). The combined organic extracts were washed with 10%
HCl (aq.) (20 ml), then dried and evaporated, affording acetate
7 (0.010 g, 0.0425 mmol, 90%) after purification by column
chromatography [1:1, ethyl acetate–petroleum ether (40–60 ЊC)
as eluent]: HPLC [Chiralpak AS, SFC, 35 ЊC, 3000 psi, λ = 218
nm, 2 ml minϪ1, 90% CO2: 10% (IPA ϩ 0.2% Et2NH) elution]
tR/min 6.75 (49.0%), 11.01 (47.6%); all spectroscopic and
analytical properties were identical to those reported above.
Reduction of (S,S)-3 by treatment with one equivalent of borane–
triethylamine complex in the presence of 1.5 equivalents of
borane–tetrahydrofuran complex
To a solution of triethylamine (7.1 µl, 0.051 mmol) in dry THF
(0.10 ml) at 0 ЊC under argon, borane–tetrahydrofuran complex
(0.13 ml of a 1.0 M solution in THF, 0.13 mmol) was added
dropwise. The solution was allowed to warm to room temper-
ature and stirred for 4 hours. Oxime ether (S,S)-3 (0.022 g,
0.051 mmol) in THF (0.50 ml) was then added. The reaction
mixture was stirred at room temperature for 2 days, then
borane–tetrahydrofuran complex (0.025 ml of a 1.0 M solution
in THF, 0.025 mmol) was added. After 3 days, the reaction
was treated with borane–tetrahydrofuran (0.050 ml of a 1.0 M
solution in THF, 0.050 mmol), and stirred for a further 24
hours, after which time the reduction was quenched with acetic
anhydride (0.050 ml, 0.51 mmol). The C–B oxidation and
acetylation procedure described above was then followed,
yielding diacetyl derivative 7 (10 mg, 0.042 mmol, 83%) after
purification by flash column chromatography [1:1, ethyl
acetate–petroleum ether (40–60 ЊC) as eluent]: HPLC [Chiral-
pak AS, SFC, 35 ЊC, 3000 psi, λ = 218 nm, 2 ml minϪ1, 90%
CO2: 10% (IPA ϩ 0.2% Et2NH) elution] tR/min 6.37 (51.7%),
9.70 (48.3%); all spectroscopic and analytical properties were
identical to those reported above.
Reduction of (S,S)-3 with borane in the presence of borane–
triethylamine complex
To a solution of triethylamine (6.5 µl, 0.047 mmol) in dry THF
(0.25 ml) at 0 ЊC under argon, borane–tetrahydrofuran com-
plex (0.19 ml of a 1.0 M solution in THF, 0.19 mmol) was
slowly added. After 5 hours, the solution was treated with
(S,S)-3 (0.020 g, 0.047 mmol) in THF (0.25 ml). The reaction
was allowed to warm to room temperature overnight, then
quenched with acetic anhydride (0.089 ml, 0.94 mmol) at 0 ЊC.
The solution was stirred for a further 1 hour, then THF was
evaporated and the residue partitioned between dichlorometh-
ane and saturated NaHCO3 (aq.). Drying and evaporation of
the combined organic extracts yielded the crude acetamide as a
colourless oil. This oil was dissolved in THF (1 ml) and treated
with H2O2 (aq.) (0.060 ml of a 40% w/v solution, 0.71 mmol)
and NaOH (aq.) (0.50 ml of a 2.0 M solution, 1.00 mmol) for
2 hours at room temperature. The resultant solution was
extracted with ethyl acetate (3 × 10 ml). The organic phases
were dried and evaporated. The residue was treated with acetic
anhydride (0.045 ml, 0.48 mmol) in pyridine (1 ml) and stirred
at room temperature for 2 hours. The solution was then
partitioned between dichloromethane and saturated NaHCO3
(aq.). The combined organic phases were washed with 10% HCl
(aq.) (20 ml), dried and evaporated to yield diacetyl derivative 7
(9 mg, 0.038 mmol, 81%) after purification by flash column
chromatography [1:1, ethyl acetate–petroleum ether (40–60 ЊC)
as eluent]: HPLC [Chiralpak AS, SFC, 35 ЊC, 3000 psi,
λ = 218 nm, 2 ml minϪ1, 90% CO2: 10% (IPA ϩ 0.2% Et2NH)
elution] tR/min 6.73 (49.7%), 10.91 (50.3%); all spectro-
scopic and analytical properties were identical to those reported
above.
Preparation of 2-amino-2-methyl-1,1-diphenylpropan-1-ol 25
To magnesium turnings (1.42 g, 0.058 mol) and I2 (1 crystal) in
anhydrous diethyl ether (50 ml) under argon, bromobenzene
(5.11 ml, 0.049 mol) was added dropwise. The solution was
cooled in an ice bath upon initiation of the reaction until
addition of bromobenzene was complete. Heating at reflux for
2 hours afforded a dark grey solution which was then cooled in
an ice bath. 2-Aminoisobutyric acid (0.40 g, 3.88 mmol) was
added portionwise. The solution was allowed to warm to room
temperature and heated at reflux for 3 hours. The reaction was
then quenched by carefully pouring onto ice (30 ml). Concen-
trated HCl (aq.) (1 ml) was added and the mixture left to stand
at room temperature for 1 hour. The ether layer was separated
and the aqueous phase basified to pH 10 with 35% NH4OH
(aq.). The aqueous solution was then extracted with diethyl
ether (3 × 20 ml). Drying and evaporation of the combined
organic phases afforded 25 (0.213 g, 0.88 mol, 23%) as a white
solid: mp 116 ЊC [lit.20 120 ЊC (from Et2O)]; IR was as reported
in the literature;20 δH (300 MHz; CDCl3) 1.39 [6 H, s, (CH3)2C],
7.19–7.33 (6 H, m, H meta, H para), 7.59–7.61 (4 H, m, H
ortho); δC (75.5 MHz; CDCl3) 28.5 (CH3), 56.7 (CN), 80.7 (CO),
126.4, 127.4, 127.9, 144.9 (C aromatic); m/z (FAB) 242
(M ϩ H)ϩ [Found (HRMS): m/z 242.1545. C16H19NO requires
(M ϩ H)ϩ 242.1545].
Reduction of (S,S)-3 by treatment with one equivalent of
borane–triethylamine complex followed by excess borane–
tetrahydrofuran complex
Reduction of (S,S)-3 with borane in the presence of the complex
prepared from achiral amino alcohol 25 and borane
To a solution of triethylamine (3.6 µl, 0.026 mmol) in dry THF
(0.25 ml) at 0 ЊC under argon, borane–tetrahydrofuran complex
(0.03 ml of a 1.0 M solution in THF, 0.03 mmol) was slowly
added. After 5 hours, the solution was treated with (S,S)-3
(0.011 g, 0.026 mmol) in THF (0.25 ml). The reaction was
allowed to warm to room temperature, and after 20 hours
borane–tetrahydrofuran complex (0.08 ml of a 1.0 M solution
in THF, 0.08 mmol) was added. After 5 days the reaction was
quenched with acetic anhydride (0.20 ml, 2.08 mmol) at 0 ЊC.
The C–B oxidation and acetylation procedure described above
was then followed, yielding diacetyl derivative 7 (5 mg, 0.021
mmol, 82%) after purification by flash column chromatography
[1:1, ethyl acetate–petroleum ether (40–60 ЊC) as eluent]:
HPLC [Chiralpak AS, SFC, 35 ЊC, 3000 psi, λ = 218 nm, 2 ml
minϪ1, 90% CO2: 10% (IPA ϩ 0.2% Et2NH) elution] tR/min
6.86 (48.0%), 11.24 (27.0%); all spectroscopic and analytical
properties were identical to those reported above.
To a solution of achiral amino alcohol 25 (0.017 g, 0.070 mmol)
in THF (0.50 ml) at 0 ЊC under argon, borane–tetrahydrofuran
complex (0.28 ml of a 1.0 M solution in THF, 0.28 mmol) was
slowly added. After 5 hours, oxime ether (S,S)-3 (0.030 g, 0.070
mmol) in THF (0.50 ml) was added dropwise, and the solu-
tion allowed to warm to room temperature. The reaction was
quenched after 14 hours with acetic anhydride (0.13 ml, 1.40
mmol) at 0 ЊC, then stirred at room temperature for 1 hour.
The THF was evaporated and the residue partitioned between
dichloromethane and saturated NaHCO3 (aq.). The organic
extracts were combined and dried. Evaporation yielded crude
acetamide which was dissolved in THF (1 ml) and treated with
NaOH (aq.) (0.50 ml of a 2.0 M solution, 1.00 mmol) and H2O2
(aq.) (0.050 ml of a 40% w/v solution, 0.59 mmol). The solution
was stirred for 2 hours at room temperature then extracted with
ethyl acetate (3 × 10 ml). The combined organic layers were
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J. Chem. Soc., Perkin Trans. 1, 2000, 3362–3374

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dried and evaporated. The residue was dissolved in pyridine
(1 ml) and acetic anhydride (0.060 ml, 0.64 mmol) added. The
reaction was stirred at room temperature for 2 hours then
partitioned between dichloromethane and saturated NaHCO3
(aq.). The combined organic phases were washed with 10% HCl
(aq.) (20 ml), dried and evaporated, furnishing acetamide 7
(0.011 g, 0.047 mmol, 67%) after column chromatography [1:1,
ethyl acetate–petroleum ether (40–60 ЊC) as eluent]: HPLC
Reduction of (S,S)-3 by treatment with one equivalent of the
complex prepared from ethanolamine and borane, in the presence
of 1.5 equivalents of borane–tetrahydrofuran complex
To a solution of ethanolamine (3.2 µl, 0.054 mmol) in THF
(0.10 ml) at 0 ЊC under argon, borane–tetrahydrofuran complex
(0.14 ml of a 1.0 M solution in THF, 0.14 mmol) was added.
The solution was allowed to warm to room temperature and
stirred for 4 hours. Oxime ether (S,S)-3 (0.023 g, 0.054 mmol)
in THF (0.50 ml) was then added. After 2 days, borane–
tetrahydrofuran complex (0.025 ml of a 1.0 M solution in THF,
0.025 mmol) was added and the reaction stirred at room
temperature for 3 days. The reaction mixture was then treated
with borane–tetrahydrofuran complex (0.050 ml of a 1.0 M
solution in THF, 0.050 mmol) and stirred for a further 24
hours. Borane–tetrahydrofuran complex (0.10 ml of a 1.0 M
solution in THF, 0.10 mmol) was added and the reaction
quenched with acetic anhydride (0.050 ml, 0.51 mmol) after
2 days. The C–B oxidation and acetylation procedure described
above was then followed, yielding diacetyl derivative 7 (12
mg, 0.051 mmol, 95%) after purification by flash column
chromatography [1:1, ethyl acetate–petroleum ether (40–
60 ЊC) as eluent]: HPLC [Chiralpak AS, SFC, 35 ЊC, 3000 psi,
λ = 218 nm, 2 ml minϪ1, 90% CO2: 10% (IPA ϩ 0.2% Et2NH)
elution] tR/min 6.54 (49.0%), 10.60 (51.0%); all spectroscopic
and analytical properties were identical to those reported
above.
[Chiralpak AS, SFC, 35 ЊC, 3000 psi, λ = 218 nm, 2 ml minϪ1
,
90% CO2: 10% (IPA ϩ 0.2% Et2NH) elution] tR/min 6.63
(45.6%), 10.58 (43.6%); all spectroscopic and analytical
properties were identical to those reported above.
Reduction of (S,S)-3 by treatment with one equivalent of the
complex prepared from amino alcohol 25 and borane, in the
presence of 1.5 equivalents of borane–tetrahydrofuran complex
To a solution of amino alcohol 25 (0.012 g, 0.049 mmol) in
THF (0.10 ml) at 0 ЊC under argon, borane–tetrahydrofuran
complex (0.12 ml of a 1.0 M solution in THF, 0.12 mmol) was
added. The solution was allowed to warm to room temperature
and stirred for 4 hours. Oxime ether (S,S)-3 (0.021 g, 0.049
mmol) in THF (0.50 ml) was then added. After 2 days, borane–
tetrahydrofuran complex (0.025 ml of a 1.0 M solution in THF,
0.025 mmol) was added and the reaction stirred at room tem-
perature for 3 days. The reaction mixture was then treated with
borane–tetrahydrofuran complex (0.050 ml of a 1.0 M solution
in THF, 0.050 mmol) and stirred for a further 24 hours.
Borane–tetrahydrofuran complex (0.10 ml of a 1.0 M solution
in THF, 0.10 mmol) was added and the reaction quenched with
acetic anhydride (0.050 ml, 0.51 mmol) after 2 days. The C–B
oxidation and acetylation procedure described above was then
followed, yielding diacetyl derivative 7 (11 mg, 0.047 mmol,
96%) after purification by flash column chromatography [1:1,
ethyl acetate–petroleum ether (40–60 ЊC) as eluent]: HPLC
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[Chiralpak AS, SFC, 35 ЊC, 3000 psi, λ = 218 nm, 2 ml minϪ1
,
90% CO2: 10% (IPA ϩ 0.2% Et2NH) elution] tR/min 6.28
(27.8%), 9.87 (35.8%); all spectroscopic and analytical proper-
ties were identical to those reported above.
Reduction of (R,R)-4 with borane in the presence of complex
prepared from ethanolamine and borane
Borane–tetrahydrofuran complex (0.90 ml of a 1.0 M solution
in THF, 0.90 mmol) was slowly added to a solution of
ethanolamine (5.6 µl, 0.093 mmol) in dry THF (0.30 ml) at 0 ЊC.
After 5 hours, oxime ether (R,R)-4 (0.040 g, 0.093 mmol) in
THF (0.30 ml) was added dropwise. The reaction was allowed
to warm to room temperature, stirred for 14 hours, then
quenched with acetic anhydride (0.20 ml, 2.12 mmol) at 0 ЊC.
The solution was stirred at room temperature for 1 hour and
the THF evaporated. The residue was partitioned between
dichloromethane and saturated NaHCO3 (aq.). The combined
organic extracts were dried and evaporated yielding acetamide.
This residue was dissolved in THF (2 ml) and NaOH (aq.)
(1.50 ml of a 2.0 M solution, 3.00 mmol) and H2O2 (aq.) (0.20
ml of a 40% w/v solution, 2.35 mmol) added. Stirring at room
temperature for 2 hours yielded a cloudy solution that was
extracted with ethyl acetate (3 × 10 ml). The organic extracts
were combined, dried and evaporated. The residue was dis-
solved in pyridine (2 ml) and acetic anhydride (0.10 ml, 1.06
mmol) was added. The solution was stirred at room temper-
ature for 2 hours then partitioned between dichloromethane
and saturated NaHCO3 (aq.). The combined organic extracts
were washed with 10% HCl (aq.) (20 ml), dried and evaporated
to afford diacetyl derivative 7 (0.015 g, 0.064 mmol, 69%) after
flash chromatography [1:1, ethyl acetate–petroleum ether (40–
60 ЊC) as eluent]: HPLC [Chiralpak AS, SFC, 35 ЊC, 3000 psi,
λ = 218 nm, 2 ml minϪ1, 90% CO2: 10% (IPA ϩ 0.2% Et2NH)
elution] tR/min 6.57 (49.9%), 10.46 (50.1%); all spectroscopic
and analytical properties were identical to those reported above.
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