Doubly diastereoselective conjugate addition of homochiral lithium amides to homochiral α,β-unsaturated esters containing cis- and trans-dioxolane units

Article abstract of DOI:10.1039/b818298a

As part of a long-term goal directed towards the ab initio asymmetric synthesis of unnatural amino sugars, the doubly diastereoselective conjugate addition reactions of the antipodes of lithium N-benzyl-N-(α-methylbenzyl) amide to a range of homochiral α,β-unsaturated esters containing cis- and trans-dioxolane units was investigated. These reactions resulted in "matching" and "mismatching" effects. In the "matched" cases a single diastereoisomer of the corresponding β-amino ester (containing three contiguous stereocentres) is produced. Upon conjugate addition to a homochiral α,β-unsaturated ester containing a cis-dioxolane unit, in the "mismatched" case it is the stereocontrol of the substrate which is dominant over that of the lithium amide, whilst upon addition to homochiral α,β-unsaturated esters containing a trans-dioxolane unit the stereocontrol of the homochiral lithium amide is dominant. Hydrogenolytic N-deprotection of the β-amino ester products of conjugate addition gives access to polyoxygenated β-amino acid derivatives.

Full text of DOI:10.1039/b818298a

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www.rsc.org/obc | Organic & Biomolecular Chemistry
Doubly diastereoselective conjugate addition of homochiral lithium amides to
homochiral a,b-unsaturated esters containing cis- and trans-dioxolane units†
Stephen G. Davies,* Matthew J. Durbin, Euan C. Goddard, Peter M. Kelly, Wataru Kurosawa, James A. Lee,
Rebecca L. Nicholson, Paul D. Price, Paul M. Roberts, Angela J. Russell, Philip M. Scott and Andrew D. Smith
Received 16th October 2008, Accepted 5th November 2008
First published as an Advance Article on the web 7th January 2009
DOI: 10.1039/b818298a
As part of a long-term goal directed towards the ab initio asymmetric synthesis of unnatural amino
sugars, the doubly diastereoselective conjugate addition reactions of the antipodes of lithium
N-benzyl-N-(a-methylbenzyl)amide to a range of homochiral a,b-unsaturated esters containing cis-
and trans-dioxolane units was investigated. These reactions resulted in “matching” and “mismatching”
effects. In the “matched” cases a single diastereoisomer of the corresponding b-amino ester (containing
three contiguous stereocentres) is produced. Upon conjugate addition to a homochiral a,b-unsaturated
ester containing a cis-dioxolane unit, in the “mismatched” case it is the stereocontrol of the substrate
which is dominant over that of the lithium amide, whilst upon addition to homochiral a,b-unsaturated
esters containing a trans-dioxolane unit the stereocontrol of the homochiral lithium amide is dominant.
Hydrogenolytic N-deprotection of the b-amino ester products of conjugate addition gives access to
polyoxygenated b-amino acid derivatives.
(containing a single stereogenic centre at the g-position) generally
show lower levels of substrate control in this reaction manifold.8
Upon conjugate addition of the antipodes of lithium N-benzyl-
N-(a-methylbenzyl)amide 1 to the homochiral a,b-unsaturated
esters 2 and 3, “matching” and “mismatching” effects were
noted, although the additions proceeded under the dominant
stereocontrol of the lithium amide in each case,8c consistent with
the exceptionally high level of stereofacial bias shown by lithium
amide 1 in its conjugate addition reactions9 (Fig. 1).
As part of our strategy towards the ab initio asymmetric syn-
thesis of unnatural amino sugars, and in order to simultaneously
probe further double asymmetric induction,8c an investigation into
the conjugate addition of the antipodes of lithium N-benzyl-N-
(a-methylbenzyl)amide 1 to a range homochiral a,b-unsaturated
esters 12, containing cis- and trans-dioxolane units, was proposed.
It was envisaged that these reactions would show “matching” and
“mismatching” effects, with the level and sense of stereoinduction
in the “mismatched” case giving an indication of the magnitude of
stereoinduction exerted by the chiral (multiple stereocentre) a,b-
unsaturated ester 12; this could be further quantified by conjugate
additions of achiral lithium amides. N-Deprotection of the
b-amino ester adducts 13 would give access to polyoxygenated
b-amino acid derivatives 15 (Fig. 2). We report herein the conjugate
additions of lithium amides to three homochiral a,b-unsaturated
esters containing dioxolane units, derived from either D-ribose
or dimethyl L-tartrate. Part of this work has been communicated
previously.10
Introduction
Enantioselective molecular recognition phenomena are of extreme
importance to the fields of both chemistry and biology. Synthetic
chemists can contribute to the understanding of this arena through
the development of novel kinetic,1 dynamic kinetic2 and parallel
kinetic resolution protocols,3 or through the application of double
asymmetric induction.4 In the latter protocol, the reactions of a
homochiral substrate with the enantiomeric forms of a homochiral
reagent can proceed under the stereocontrol of either the sub-
strate or the reagent, with the “matched” stereochemical pairing
generally leading to very high levels of stereoselectivity. In the
“mismatched” stereochemical pairing lower selectivity is observed,
with the agent (reagent or substrate) with the higher levels of direct-
ing ability dictating the stereochemical outcome of the reaction.
Previous investigations from this laboratory have demonstrated
that the conjugate addition of homochiral, secondary lithium
amides (derived from a-methylbenzylamine) to a,b-unsaturated
esters proceeds with high levels of diastereoselectivity, provid-
ing an efficient and general strategy for the synthesis of b-
amino acid derivatives.5,6 This methodology has found use in a
plethora of synthetic applications, including molecular recogni-
tion phenomena.6 Chiral 3-alkyl-, 3-alkoxy- and 5-alkyl cyclopent-
1-ene-carboxylates, for instance, show high levels of substrate
control, facilitating their kinetic and parallel kinetic resolution
upon addition of homochiral or a 50:50 pseudoenantiomeric
mixture of homochiral lithium amides, respectively.7 In contrast
to these cyclic examples, chiral acyclic a,b-unsaturated esters
Results and discussion
Department of Chemistry, Chemistry Research Laboratory, University of
Oxford, Mansfield Road, Oxford, OX1 3TA, UK.
E-mail: steve.davies@chem.ox.ac.uk
† Electronic supplementary information (ESI) available: Additional ex-
perimental information. CCDC reference number 668996. For ESI
and crystallographic data in CIF or other electronic format see DOI:
10.1039/b818298a
Conjugate addition of lithium amides to tert-butyl
(2E,4S,5R)-4,5-O-isopropylidene-hepta-2,6-dienoate
a,b-Unsaturated ester 18 was prepared in 4 steps, in 45% overall
yield, from D-ribose. Following literature procedures, D-ribose
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Scheme 1 Reagents and conditions: (i) HCl, acetone/MeOH (1:1), reflux,
1 h; (ii) I2, PPh3, imidazole, PhMe/MeCN (5:1), 60 ◦C, 1 h; (iii) Zn, MeOH,
reflux, 1 h; (iv) tert-butyl diethylphosphonoacetate, MeMgBr, THF, rt,
15 min, then 17, reflux, 2.5 h.
was 18:82). Purification furnished the desired b-amino ester 20
in 50% yield and >98% de, with 19 being isolated in 11% yield
as a single diastereoisomer. As no minor diastereoisomeric b-
1
amino ester product was observed in the H NMR spectrum of
the crude reaction mixture it was inferred that this pairing of
substrate and reagent represented the doubly diastereoselectively
“matched” case. On this basis, the configuration of the newly
formed stereocentre at C(3) within 20 was assigned by reference
to the transition state mnemonic developed to rationalise the high
facial bias observed upon conjugate addition of lithium amide
(R)-1 to a range of achiral a,b-unsaturated esters,9 which therefore
allowed assignment of the absolute (3S,4S,5R,aR)-configuration
of 20 (Scheme 2).
Due to the presence of the g-oxygen atom, the resultant increase
in acidity of the g-hydrogen atom in this system as compared
to hydrocarbon analogues presumably evokes the basic nature
of the lithium amide, promoting the competing g-deprotonation
pathway.14 The formation of (Z)-b,g-unsaturated ester 19 as a
single diastereoisomer in this reaction is consistent with literature
precedent concerning the deprotonation of enones,15 with the g-
deprotonation of g-alkoxy substituted enones generally thought
to proceed from the enone in a conformation which places
Fig.
1
Double asymmetric induction in the addition of homo-
chiral lithium N-benzyl-N-(a-methylbenzyl)amide 1 to homochiral a,b-
unsaturated esters 2 (R = Ph) and 3 (R = Me).
was converted in two steps to 16, in 70% yield.11 Treatment
of 16 with activated zinc dust gave aldehyde 17,11 which was
immediately subjected to olefination with the anion derived
from deprotonation of tert-butyl diethylphosphonoacetate with
MeMgBr.12 This furnished exclusively (E)-18 [(E):(Z) >180:1],13
which was isolated in 64% overall yield from 16 (Scheme 1).
With homochiral a,b-unsaturated ester 18 in hand, the dou-
bly diastereoselective conjugate additions of the antipodes of
lithium N-benzyl-N-(a-methylbenzyl)amide 1 were investigated.
Conjugate addition of lithium amide (R)-1 to 18 gave a single
diastereoisomeric b-amino ester 20 (>98% de) as the major
product, along with (Z)-b,g-unsaturated ester 19, derived from
g-deprotonation of 18 by the lithium amide (the ratio of 19:20
Fig. 2 Double asymmetric induction in the addition of chiral lithium amides to a,b-unsaturated esters 12 containing cis- and trans-dioxolane units.
[Si] = TBDMS.
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Scheme 2 Reagents and conditions: (i) lithium (R)-N-benzyl-N-(a-
methylbenzyl)amide (R)-1, THF, -78 ◦C, 2 h.
the g-C–O s-bond coplanar with the enone system, via in
this case conformation 18A.15l,m A variety of models have been
proposed to explain the selectivity seen in the conjugate addition
of nucleophiles to g-alkoxy-a,b-unsaturated esters, with these
proposals either citing modified Felkin-Anh theory16 or being
based on molecular modelling of the preferred conformations of
the g-alkoxy-a,b-unsaturated ester. It is generally assumed that the
preferred transition states for such reactions proceed with an allylic
s-bond antiperiplanar to the trajectory of the approaching
reagent, although the conformational preference around the
vinylic C–C bond may be biased by steric effects (approach
anti to the largest allylic substituent), stereoelectronic effects
(approach anti to the best electron acceptor), and minimisation
of 1,3-allylic strain (preferred orientation of an allylic C–H in
the same plane or the same sector as the a-vinylic hydrogen).
Studies by Morokuma,17 Leonard,18 Dias19 and Branchadell20
concerning conjugate additions in related systems concluded that
transition states in which the g-oxygen is nearly eclipsing the
a-hydrogen atom of the alkene may be favoured. This precedent
therefore suggests that a,b-unsaturated ester 18 may undergo both
conjugate addition and deprotonation in conformation 18A. In
this conformation, approach of the lithium amide reagent to C(3)
would be expected to be favoured from the Si face, syn to the
g-hydrogen atom and opposite the large alkoxyalkyl substituent.
Such substrate control, when combined with the known fa-
cial selectivity of lithium (R)-N-benzyl-N-(a-methylbenzyl)amide
(reagent control)9 would imply that this pairing of substrate and
reagent represents the doubly diastereoselectively “matched” case,
which is supported by the production of a single diastereoisomeric
b-amino ester product 20 (Fig. 3).
The detritic formation of b,g-unsaturated ester 19 via a compet-
ing g-deprotonation pathway in this system compromised the yield
of the desired b-amino ester product 20. Sewald observed marked
differences in the reactivity of lithium N-trimethylsilyl-N-(a-
methylbenzyl)amide upon addition to a range of chiral g-alkoxy-
a,b-unsaturated esters depending on the solvent employed for the
reaction (THF versus Et2O).8b However, longer reaction times and
increased equivalents of the lithium amide were required for the
reaction to proceed efficiently in Et2O: 2 eq of the lithium amide
in Et2O at -20 ◦C for 5 hours was necessary for optimal reaction
conversion.8b The conjugate addition of (R)-1 to a,b-unsaturated
ester 18 was performed under these conditions, and gave a 93:7
(86% de) mixture of the b-amino esters 20:21 exclusively, with
complete suppression of the g-deprotonation pathway. Although
a decrease in the stereoselectivity of the addition was observed
Fig. 3 Proposed transition states for g-deprotonation of and lithium
amide conjugate addition to 18.
under these reaction conditions (86% de in Et2O at -20 ◦C versus
>98% de in THF at -78 ◦C) chromatographic purification allowed
the isolation of b-amino ester 20 as a single diastereoisomer
(>98% de) in a greatly improved 70% yield. Given the marked
diffe◦rence in the reactivity of lithium amide (R)-1 in Et2O at
-20 C, the effect of changing reaction temperature and solvent
upon the product distribution was screened. Addition of lithium
amide (R)-1 to a,b-unsaturated ester 18 in Et2O at -78 ◦C
proceeded to only approximately 40% conversion, consistent with
decreased reactivity of lithium amide (R)-1 in Et2O, and in
accordance with the observations of Sewald concerning lithium N-
trimethylsilyl-N-(a-methylbenzyl)amide.8b Complete suppression
of g-deprotonation occurs at -20 ◦C in both THF and Et2O,
although the diastereoselectivity is higher in Et2O (86% de in
Et2O at -20 ◦C versus 68% de in THF at -20 ◦C). As lithium
amides are widely recognised to form various aggregates in a
range of solvents,21 the observed differences in stereoselectivity
and product distribution may be due to a change in amide
aggregation with solvent, although the nature of the active species
in both the conjugate addition and deprotonation manifolds
is currently unknown. Alternatively, a change in the rate of
interconversion of the conformers of a,b-unsaturated ester 18 with
solvent and temperature may also explain the variations in product
distribution in these reactions (Scheme 3).
The minor diastereoisomer 21 resulting from these studies
proved crystalline, allowing the relative 3,4-syn-configuration to
be unambiguously established by single crystal X-ray analysis.
The absolute (3R,4S,5R,aR)-configuration within 21 was thus as-
signed relative to the known configurations of the a-methylbenzyl
group, and the stereocentres within the dioxolane unit (Fig. 4).
This analysis also unambiguously establishes the assigned absolute
(3S,4S,5R,aR)-configuration within the major b-amino ester
diastereoisomer 20.
Conjugate addition of lithium amide (S)-1 to 18 was next
investigated in THF at -78 ◦C, and gave a 40:36:24 mixture
of (Z)-b,g-unsaturated ester 19 and b-amino esters 22 and 23,
respectively. The competing formation of 19 in this reaction again
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Scheme 3 Reagents and conditions: (i) lithium (R)-N-benzyl-N-(a-methylbenzyl)amide (R)-1, solvent, temperature. [a Crude ratio of products;
b
purified–isolated yield; c reaction proceeded to 40% conversion.]
(>98% de). In light of this result, the conjugate addition reaction
of lithium amide (S)-1 in both THF and Et2O at -20 ◦C was
investigated. Total suppression of the g-deprotonation pathway
was observed irrespective of the solvent although in this case
THF offered higher (yet only modest) levels of diastereoselectivity
(Scheme 4).
The product distributions observed upon conjugate addition
of the antipodes of lithium amide 1 to 18 in THF at -78 ◦C
are consistent with the conjugate addition of lithium amide
(R)-1 representing the doubly diastereoselectively “matched”
combination of reagent and substrate, with conjugate addition
of (S)-1 being “mismatched”. In order to determine whether
the reagent or substrate exerted the dominant stereocontrol in
the doubly diastereoselectively “mismatched” reaction [18/(S)-
1], the configurations at C(3) within the b-amino ester products
of conjugate addition 20–23 were correlated via hydrogenolytic
removal of the N-protecting groups to furnish the corresponding
primary b-amino esters. Tandem hydrogenolysis/hydrogenation
of 20 gave primary b-amino ester 24 in 94% yield; analogous treat-
ment of 22 (the major diastereoisomer from conjugate addition
of lithium amide (S)-1) also furnished 24. Meanwhile, tandem
hydrogenolysis/hydrogenation of 23 (the minor diastereoisomer
from conjugate addition of lithium amide (S)-1) gave primary b-
amino ester 25 in 61% yield (Scheme 5).
In the “mismatched” addition, therefore, it is the stereocontrol
Fig. 4 Chem 3D representation of the X-ray crystal structure of 21 (some
of the a,b-unsaturated ester substrate 18 which is dominant
over that of lithium amide (S)-1, resulting in a small preference
for formation of the 3,4-anti-diastereoisomer 22. This implies
that the chiral a,b-unsaturated ester 18 shows very high levels
of substrate control. In order to probe this hypothesis, the
levels of substrate control displayed upon conjugate addition of
H atoms omitted for clarity).
compromised the yields of the desired b-amino ester products of
conjugate addition, with chromatographic purification giving 19
in 40% yield, 22 in 14% yield (>98% de) and 23 in 11% yield
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Scheme 4 Reagents and conditions: (i) lithium (S)-N-benzyl-N-(a-methylbenzyl)amide (S)-1, solvent, temperature.
Scheme 5 Reagents and conditions: (i) H2 (5 atm), Pd(OH)2/C, MeOH, rt. [All compounds are single diastereoisomers (>98% de).]
achiral lithium dibenzylamide 267b,c,e,g,h,8c and lithium N-benzyl-N-
isopropylamide 277g,h were investigated, the latter being employed
as it has been previously shown by us to closely mimic the
behaviour of lithium N-benzyl-N-(a-methylbenzyl)amide. Addi-
tion of lithium dibenzylamide 26 to a,b-unsaturated ester 18 in
THF at -78 ◦C gave a 2:65:33 mixture of (Z)-b,g-unsaturated
ester 19 and the diastereoisomeric b-amino esters 28 and 29,
respectively. Chromatography allowed the purification of 28 and
29 to homogeneity, giving 28 in 54% yield and 29 in 9% yield.
When the reaction was performed in THF at -20 ◦C, the di-
astereoselectivity of addition increased, giving an 80:20 mixture of
28:29, with complete suppression of the g-deprotonation pathway
(Scheme 6).
Conjugate addition of lithium N-benzyl-N-isopropylamide 27
to a,b-unsaturated ester 18 in THF at -78 ◦C gave a 13:87
mixture of 19 and b-amino ester 30 (>98% de), respectively,
with purification furnishing 30 in 55% yield (>98% de). The g-
deprotonation pathway was again suppressed when the reaction
was performed at -20 ◦C in either THF or Et2O, with the
conjugate addition proceeding in >98% de in both solvents
(Scheme 7).
The configuration at C(3) within b-amino esters 28–30
was determined by chemical correlation. Tandem hydrogenoly-
sis/hydrogenation of 28 (the major diastereoisomer from conju-
gate addition of lithium dibenzylamide 26) gave primary b-amino
ester 24 in 96% yield. Tandem hydrogenolysis/hydrogenation of N-
benzyl-N-isopropyl-b-amino ester 30 gave N-isopropyl-b-amino
ester 31 in good yield, which was identical to the product of
reductive amination of primary b-amino ester 24 with acetone
(Scheme 8). Tandem hydrogenolysis/hydrogenation of 29 (the
minor diastereoisomer arising from conjugate addition of lithium
dibenzylamide 26) gave primary b-amino ester 25 (Scheme 9).
The preference for formation of the 3,4-anti-diastereoisomer
and the propensity for competitive g-deprotonation displayed
upon addition of lithium dibenzylamide 26, lithium N-
benzyl-N-isopropylamide 27 and lithium (S)-N-benzyl-N-(a-
methylbenzyl)amide 1 to 18 is consistent with the conjugate
addition reaction proceeding with the a,b-unsaturated ester in
conformation 18A (Fig. 3). Partial shielding of the Re face of the
a,b-unsaturated ester system by the terminal vinyl group in this
conformation rationalises the high levels of stereocontrol exerted
by the homochiral substrate upon conjugate addition of lithium
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Scheme 9 Reagents and conditions: (i) H2 (5 atm), Pd(OH)2/C, MeOH,
rt; (ii) H2 (1 atm), Pd(OH)2/C, MeOH, rt. [All compounds are single
diastereoisomers (>98% de)].
N-benzyl-N-isopropylamide 27, promoting exclusive formation
of the 3,4-anti-diastereoisomer 30. However, upon conjugate
addition of lithium dibenzylamide 26 only a modest (~2:1)
preference for the formation of the 3,4-anti diastereoisomer 28 is
observed. Taken with the outcome of the doubly diastereoselective
conjugate addition reactions (in which the stereocontrol of the
chiral a,b-unsaturated ester 18 overwhelms the exceptionally high
facial bias of lithium amide (S)-1 in the “mismatched” reaction
pairing), these data indicate that lithium dibenzylamide 26 does
not closely mimic the behaviour of lithium N-benzyl-N-(a-
methylbenzyl)amide 1 or lithium N-benzyl-N-isopropylamide 27
within this system. In order to better understand the differences in
the diastereoselectivity of addition of lithium amides 1, 26 and 27
to a,b-unsaturated ester 18, a series of competition experiments
was performed in order to facilitate a qualitative rate comparison.
In these experiments, BuLi (2 eq) was added to a 50:50 mixture of
amines (2 ¥ 1 eq) in THF at -78 ◦C to generate the corresponding
lithium amides, before addition of a,b-unsaturated ester 18
(1 eq). No marked change in the diastereoselectivity of any of
the addition products was observed in the resulting product
distributions, indicating that the lithium amides react analogously
in both the competitive and individual conjugate addition
reactions. Assuming that the conjugate addition is irreversible
and that the reaction proceeds under kinetic control, analysis
of the product distributions from these reactions was used to
qualify the rates of conjugate addition. For instance, addition of
a mixture of lithium dibenzylamide 26 and lithium N-benzyl-N-
isopropylamide 27 to a,b-unsaturated ester 18 gave a 4:63:28:5
mixture of 19:28:29:30. The total amount of b,g-unsaturated
ester 19 was partitioned into the amounts generated by the
g-deprotonation of 18 by lithium amides 26 and 27: the amount
of 19 generated by lithium N-benzyl-N-isopropylamide 27 was
calculated on the basis of the ratio of 19:30 being 13:87 (vide
supra). This corresponds to lithium N-benzyl-N-isopropylamide
27 being responsible for consumption of approximately 5% of
a,b-unsaturated ester 18, with lithium dibenzylamide 26 being
responsible for consumption of the remaining 95%, i.e. addition
of 26 and 27 in a ratio of approximately 19:1 (Scheme 10).
Scheme 6 Reagents and conditions: (i) lithium dibenzylamide 26, solvent,
temperature.
Scheme 7 Reagents and conditions: (i) lithium N-benzyl-N-isopropyl-
amide 27, solvent, temperature.
The product distributions obtained upon competitive ad-
dition of lithium dibenzylamide 26 with both antipodes of
lithium amide 1, and those of lithium N-benzyl-N-isopropylamide
27 with both antipodes of 1, were determined in an anal-
ogous manner (Table 1). From these data, it is concluded
that the rates of addition of the four lithium amides to a,b-
unsaturated ester 18 are in the order lithium dibenzylamide >>
lithium (R)-N-benzyl-N-(a-methylbenzyl)amide (“matched”) ~
lithium N-benzyl-N-isopropylamide > lithium (S)-N-benzyl-N-
(a-methylbenzyl)amide (“mismatched”). It therefore appears that
Scheme 8 Reagents and conditions: (i) H2 (1 atm), Pd(OH)2/C, MeOH,
rt, 15 h; (ii) acetone, NaBH3CN, MeOH, rt, 18 h. [All compounds are
single diastereoisomers (>98% de).]
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Table 1 Consumption of 18 upon competitive addition of lithium amides
(R)-1, (S)-1, 26 and 27
Lithium amides
Ratio of addition products
26 vs 27
19:1
12:1
52:1
1:1
26 vs (R)-1
26 vs (S)-1
27 vs (R)-1
27 vs (S)-1
4:1
Scheme 11 Reagents and conditions: (i) Zn, MeOH, reflux, 1 h; (ii) K2CO3,
MeOH, rt, 2.5 h; (iii) tert-butyl diethylphosphonoacetate, MeMgBr, THF,
rt, 15 min, then 32, reflux, 2 h.
represented the doubly diastereoselectively “matched” case. The
(3R)-configuration within b-amino ester (3R,4R,5R,aS)-34 was
thus assigned by reference to the transition state mnemonic
developed to rationalise the stereoselectivity observed during
addition of lithium amide 1 to achiral a,b-unsaturated esters.9
Addition of lithium amide (R)-1 gave a 35:65 mixture (30% de)
of the b-amino esters 35:36, suggesting that this represented
the “mismatched” reaction pairing. Purification enabled partial
separation of the mixture, with 35 isolated in 14% yield and >98%
de, and 36 in 21% yield and >98% de, and a mixed fraction (35:36,
42:58) in 19% yield. It is notable that even at -78 ◦C in THF the g-
deprotonation pathway forming 19, which competed with lithium
amide conjugate addition upon reaction with the a,b-unsaturated
ester 18, is not observed upon addition to a,b-unsaturated ester
33 (Scheme 12).
Scheme 10 Reagents and conditions: (i) lithium dibenzylamide 26 (1 eq),
lithium N-benzyl-N-isopropylamide 27 (1 eq), THF, -78 ◦C, 2 h.
lithium N-benzyl-N-isopropylamide 27 mimics the behaviour of
the homochiral lithium amides (R)-1 and (S)-1 in this system due
to the similar rates of addition of lithium amides 1 and 27.
Conjugate addition of lithium amides to tert-butyl
(2E,4R,5R)-4,5-O-isopropylidene-hepta-2,6-dienoate
Having demonstrated that a,b-unsaturated ester 18 exerts high
levels of substrate control upon conjugate addition of lithium
N-benzyl-N-isopropylamide 27, and overwhelms the very high
stereocontrol of lithium amide (S)-1 in the doubly diastereose-
lective “mismatched” reaction pairing, subsequent studies were
focused upon the conjugate addition of lithium amides to a,b-
unsaturated ester 33, containing a trans-dioxolane unit. Sharpless
and co-workers have noted the base catalysed epimerisation of
cis-substituted dioxolane aldehydes to the corresponding trans-
substituted aldehydes.22 Following this precedent, under optimised
conditions, treatment of 16 with activated zinc dust and immediate
addition of K2CO3 to the crude reaction mixture was followed
by aqueous work-up and olefination with the anion derived
from deprotonation of tert-butyl diethylphosphonoacetate with
MeMgBr.12 This furnished 33 as the only diastereoisomeric
product [(E):(Z) >180:1],13 which was isolated in 48% overall yield
from 16 (Scheme 11).
Conjugate addition of lithium amide (S)-1 to 33 gave a single
b-amino ester product 34 (>98% de), which was isolated in 76%
yield and >98% de. As in the series of conjugate additions to
a,b-unsaturated ester 18, the absence of a minor diastereoiso-
meric product in the H NMR spectrum of the crude reaction
mixture suggested that this pairing of substrate and reagent
Scheme 12 Reagents and conditions: (i) lithium (S)-N-benzyl-N-(a-
methylbenzyl)amide (S)-1, THF, -78 ◦C, 2 h; (ii) lithium (R)-N-benzyl-
N-(a-methylbenzyl)amide (R)-1, THF, -78 ◦C, 2 h.
1
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In order to determine the configuration of the major di-
astereoisomer in the “mismatched” reaction pairing, the C(3)
configurations within the b-amino ester products of conjugate
addition 34–36 were correlated via hydrogenolytic removal of the
N-protecting groups. Tandem hydrogenolysis/hydrogenation of b-
amino ester 34 furnished primary b-amino ester 37 in 83% yield
as a single diastereoisomer; similar treatment of b-amino ester 36
(the major diastereoisomer from conjugate addition of (R)-1) gave
primary b-amino ester 38 in 52% yield as a single diastereoisomer
(Scheme 13).
Scheme 14 Reagents and conditions: (i) lithium dibenzylamide 26, THF,
-78 ◦C, 2 h; (ii) lithium N-benzyl-N-isopropylamide 27, THF, -78 ◦C, 2 h.
[a 45:55 mixture of diastereoisomers 39:40.]
Scheme 13 Reagents and conditions: (i) H2 (5 atm), Pd(OH)2/C, MeOH,
rt, 15 h. [All compounds are single diastereoisomers (>98% de).]
The formation of the C(3)-epimeric b-amino esters 37 and 38
in these reactions suggest that in the “mismatched” conjugate
addition of lithium amide (R)-1 to a,b-unsaturated ester 33, it is
the stereocontrol of the lithium amide which is dominant. This is
in contrast to the outcome of the studies into conjugate addition of
the antipodes of 1 to a,b-unsaturated ester 18. In order to further
investigate this result, the level of substrate control exerted by a,b-
unsaturated ester 33 was evaluated by conjugate addition of achiral
lithium amides 26 and 27. Addition of lithium dibenzylamide 26
gave exclusively the b-amino ester products of conjugate addition
39 and 40 in a 65:35 ratio, respectively, with chromatographic
purification giving the major diastereoisomer 39 in 32% yield
(>98% de), and a 45:55 mixture of 39:40 in 44% yield. Conjugate
addition of lithium N-benzyl-N-isopropylamide 27 also gave
exclusively the b-amino ester products of conjugate addition, 41
and 42, in a 91:9 ratio (82% de) respectively. Purification gave a
94.5:5.5 (89% de) mixture of 41:42 in 72% yield (Scheme 14).
The configuration at C(3) within b-amino esters 39–42
was determined by chemical correlation. Tandem hydrogenoly-
sis/hydrogenation of b-amino ester 39 (the major diastereoisomer
from conjugate addition of lithium dibenzylamide 26) furnished
primary b-amino ester 37 in 61% yield. Tandem hydrogenol-
ysis/hydrogenation of N-benzyl-N-isopropyl-protected b-amino
ester 41 (89% de) gave N-isopropyl-b-amino ester 43 in 98% yield
and 89% de, which was identical to the product of reductive
amination of primary b-amino ester 37 with acetone (Scheme 15).
Additionally, tandem hydrogenolysis/hydrogenation of the
45:55 mixture of diastereoisomers 39:40 (from addition of lithium
dibenzylamide 26) gave a 45:55 mixture of diastereoisomers 37:38
in 74% yield, and treatment of 36 with Pearlman’s catalyst in
MeOH/acetone under hydrogen gave 44, which was identical by
Scheme 15 Reagents and conditions: (i) H2 (1 atm), Pd(OH)2/C, MeOH,
rt, 15 h; (ii) acetone, NaBH3CN, MeOH, rt, 18 h. [All compounds are single
diastereoisomers (>98% de) unless stated; a 94.5:5.5 (89% de) mixture of
diastereoisomers 41:42 or 43:44.]
1H NMR to the minor product observed upon hydrogenolysis of
41 (89% de) (Scheme 16).
The product distributions arising from conjugate addition of
the achiral lithium amides 26 and 27 to a,b-unsaturated ester
33 indicate reasonable substrate control, resulting in preference
for the 3,4-anti-diastereoisomer in both cases. The stereocontrol
using lithium N-benzyl-N-isopropylamide 27 is again markedly
higher than that with lithium dibenzylamide 26, although the
magnitude of the stereoinduction (82% de) is not as great as that
observed upon the addition to a,b-unsaturated ester 18 (>98%
de). Consistent with the lower levels of substrate control shown
by 33 (versus 18) upon conjugate addition of lithium N-benzyl-N-
isopropylamide 27, in the doubly diastereoselective “mismatched”
reaction it is the lithium amide (R)-1 that has the dominant
stereocontrol. Addition to the a,b-unsaturated ester system 33
in conformation 33A, with the large alkoxyalkyl group anti to the
768 | Org. Biomol. Chem., 2009, 7, 761–776
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ing 1,3-dioxolane, with subsequent reduction with an excess of
NaBH4 and mono-silylation of the resultant diol allowing Swern
oxidation of the free alcohol to give aldehyde 45.23 Olefination
of aldehyde 45 with tert-butyl diethylphosphonoacetate and
MeMgBr12 furnished (E)-46 as the only diastereoisomeric product
[(E):(Z) >180:1],13 which was isolated in 24% overall yield from
dimethyl L-tartrate (Scheme 17).
Scheme 16 Reagents and conditions: (i) H2 (5 atm), Pd(OH)2/C, MeOH,
rt, 15 h; (ii) H2 (5 atm), Pd/C, MeOH/acetone (9:1), rt, 16 h. [All
a
compounds are single diastereoisomers (>98% de) unless stated; 45:55
mixture of diastereoisomers 37:38 or 39:40.]
incoming nucleophile, is able to rationalise the observed 3,4-anti
preference for conjugate addition of the achiral lithium amides
26 and 27 to a,b-unsaturated ester 33, as well as the “matched”
and “mismatched” pairings of 33 with the antipodes of lithium
amide 1. The propensity for competing g-deprotonation of 33
in this conformation would be expected to be diminished due
to poor overlap of the sC - H bond with the p-system of the a,b-
unsaturated ester. Furthermore, in comparison to a,b-unsaturated
ester 18, the configurational change at C(4) within 33 results in
the terminal vinyl group being orientated away from the a,b-
unsaturated system, resulting in less effective shielding of one face
of the enone, and therefore potentially rationalising the lower levels
of diastereofacial control shown by 33 (Fig. 5).
Scheme 17 Reagents and conditions: (i) 2,2-dimethoxypropane, TsOH,
reflux, 16 h; (ii) NaBH4, MeOH, rt, 16 h; (iii) NaH (1 eq), TBDMSCl
(1 eq), THF, rt, 16 h; (iv) DMSO, (COCl)2, DCM, -78 ◦C, then Et3N,
-78 ◦C to rt; (v) tert-butyl diethylphosphonoacetate, MeMgBr, THF, rt,
15 min, then 45, reflux, 2.5 h. [Si] = TBDMS.
Conjugate addition of lithium amide (S)-1 to a,b-unsaturated
ester 46 gave a single diastereoisomeric product 47, which was
isolated in 69% yield after chromatography. On the basis that this
represented the “matched” reaction pairing, b-amino ester 47 was
assigned the absolute (3R,4S,5R,aS)-configuration by reference
to the transition state mnemonic developed to rationalise the
selectivity observed during addition of lithium amide 1 to achiral
a,b-unsaturated esters.9 The effect of solvent and temperature
on the product distribution was also investigated, and although
addition in THF at -20 ◦C proceeded to give 47 as a single product,
the diastereoselectivity was eroded in Et2O at -20 ◦C, giving a
63:37 mixture of 47:48. Purification allowed isolation of 47 in 60%
yield and 48 in 11% yield, as single diastereoisomers in each case.
No trace of competing g-deprotonation of the a,b-unsaturated
ester by the lithium amide was observed in any of these addition
reactions (Scheme 18).
Conjugate addition of lithium amide (R)-1 to 46 gave a separable
30:70 mixture of b-amino esters 49:50, respectively, with 49
isolated in 24% yield and >98% de, and 50 in 42% yield and
>98% de. This suggests that the pairing of (R)-1 and 46 is
doubly diastereoselectively “mismatched”. When the reaction was
performed in Et2O at -20 ◦C, the diastereoselectivity of addition
increased, giving a 15:85 mixture of diastereoisomers 49:50 from
which 49 was isolated in 8% yield, and 50 in 60% yield, as single
diastereoisomers in both cases (Scheme 19).
In order to determine the sense of stereoinduction in the
“mismatched” case, the configurations at C(3) within b-amino
esters 47–50 were correlated via hydrogenolysis. Treatment of 47
with Pd(OH)2/C under hydrogen gave primary b-amino ester 51
as a single diastereoisomer, whilst analogous treatment of 50 (the
major diastereoisomer resulting from addition of lithium amide
(R)-1) and 48 (the minor diastereoisomer resulting from addition
Fig. 5 Postulated transition state for lithium amide conjugate addition
to 33.
Conjugate addition of lithium amides to tert-butyl (2E,4S,5R)-4,5-
O-isopropylidene-6-(tert-butyldimethylsilyloxy)hex-2-enoate
Having demonstrated that lithium amide addition to a,b-
unsaturated ester 33 is preferentially anti-selective, and that the
doubly diastereoselective conjugate additions of lithium amide
1 proceed under the predominant stereocontrol of the lithium
amide, the stereoselectivity observed upon addition to an alterna-
tive a,b-unsaturated ester 46 containing a trans-dioxolane unit
derived from dimethyl L-tartrate was investigated. Following
literature procedures, dimethyl L-tartrate was heated to reflux in
dimethoxypropane with catalytic TsOH to afford the correspond-
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“matched” case, and preferentially the 3,4-anti-diastereoisomeric
product in the “mismatched” case. This is in contrast to the
results pertaining to a,b-unsaturated esters 18 and 33, in which the
“matched” case gave the corresponding 3,4-anti-diastereoisomer.
In order to further probe the levels of substrate control offered in
this system, the conjugate addition of lithium dibenzylamide 26
and lithium N-benzyl-N-isopropylamide 27 to a,b-unsaturated
ester 46 was next investigated. Conjugate addition of lithium
dibenzylamide 26 gave an approximate 50:50 mixture of 53:54,
from which 53 and 54 were isolated in 50 and 40% yield
respectively. When the addition was performed in Et2O at -20 ◦C
a complex mixture of products was formed, although reaction in
THF at -20 ◦C gave a 64:36 mixture of 53:54 (Scheme 21).
Scheme 18 Reagents and conditions: (i) lithium (S)-N-benzyl-N-(a-
methylbenzyl)amide (S)-1, solvent, temperature. [Si] = TBDMS.
Scheme 21 Reagents and conditions: (i) lithium dibenzylamide 26, solvent,
temperature. [Si] = TBDMS.
The conjugate addition of lithium N-benzyl-N-isopropylamide
27 gave a 25:75 mixture (50% de) of 55:56, with chromatographic
separation giving 55 in 15% yield and 56 in 48% yield, in >98% de
in each case. The sensitivity of this product distribution to changes
in solvent and temperature was also investigated, although 56 was
produced as the major diastereoisomer in all cases and the highest
selectivity was offered by reaction in THF at -78 ◦C (Scheme 22).
The absolute configurations at C(3) within b-amino esters 53–56
were next assigned by chemical correlation. Tandem hydrogenol-
ysis/reductive amination of 47, 49 and 53 furnished, in each case,
primary b-amino ester 57, which was identical to the product
of hydrogenolysis of 55 (Scheme 23). In an analogous fashion,
Scheme 19 Reagents and conditions: (i) lithium (R)-N-benzyl-N-(a-
methylbenzyl)amide (R)-1, solvent, temperature. [Si] = TBDMS.
of lithium amide (S)-1) furnished primary b-amino ester 52 in
both cases (Scheme 20).
The product distributions arising from the conjugate addition
of the antipodes of chiral lithium amide 1 to 46 indicate that the
lithium amide has the dominant stereocontrol in each of these
reactions, giving a single 3,4-syn-diastereoisomeric product in the
Scheme 20 Reagents and conditions: (i) H2 (1 atm), Pd(OH)2/C, EtOAc, rt, 16 h. [Si] = TBDMS.
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Scheme 22 Reagents and conditions: (i) lithium N-benzyl-N-isopro-
pylamide 27, solvent, temperature. [Si] = TBDMS.
Scheme 24 Reagents and conditions: (i) H2 (5 atm), Pd/C, MeOH/
acetone (9:1), rt, 16 h; (ii) H2 (5 atm), Pd/C, EtOAc, rt, 15 h. [Si] =
TBDMS.
a,b-unsaturated ester 46, however, the doubly diastereoselective
“matched” and “mismatched” pairings with homochiral lithium
N-benzyl-N-(a-methylbenzyl)amide cannot be accounted for by
reaction through conformation 46A. This suggests that the origin
of the reversal in selectivity may be due to the presence of an
alternative reactive conformation of 46, although the mechanistic
origin for this observed stereoselectivity cannot be fully explained
(Fig. 6).
Scheme 23 Reagents and conditions: (i) H2 (5 atm), Pd/C, MeOH/
acetone (9:1), rt, 16 h; (ii) H2 (5 atm), Pd/C, EtOAc, rt, 15 h. [Si] =
TBDMS.
the C(3)-configurations within 48, 50, 54 and 56 were similarly
correlated (Scheme 24).
The results obtained upon conjugate addition of lithium amides
1 and 27 to a,b-unsaturated ester 46 therefore present an intriguing
mechanistic paradox, viz. the doubly diastereoselective “matched”
Fig. 6 Proposed transition state for conjugate addition of lithium
N-benzyl-N-isopropylamide 27 to 46. [Si] = TBDMS.
◦
addition of lithium amide (S)-1 in THF at -78 C occurs to the
Re face of the a,b-unsaturated system to give 3,4-syn-b-amino
ester 47 whereas the substrate directed addition of lithium N-
benzyl-N-isopropylbenzylamide 27 occurs with modest levels of
selectivity to the Si face, furnishing 3,4-anti-b-amino ester 56 as
the major diastereoisomeric product. The stereocontrol exerted
by homochiral a,b-unsaturated ester 46 upon addition of lithium
N-benzyl-N-isopropylamide 27 is consistent with the reaction
proceeding with the a,b-unsaturated ester in conformation 46A,
which is analogous to conformation 33A, proposed to rationalise
the product distributions upon conjugate addition of the range
of lithium amides to a,b-unsaturated ester 33. In the case of
Conclusion
In conclusion, doubly diastereoselective conjugate addi-
tion reactions of the antipodes of lithium N-benzyl-N-(a-
methylbenzyl)amide to a range of homochiral a,b-unsaturated
esters containing cis- and trans-dioxolane units result in “match-
ing” and “mismatching” effects. In the “matched” cases a single
diastereoisomer of the corresponding b-amino ester is produced.
Upon conjugate addition to an a,b-unsaturated ester containing a
cis-dioxolane unit in the “mismatched” case it is the stereocontrol
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of the substrate which is dominant over that of the lithium amide,
whilst upon addition to a,b-unsaturated esters containing a trans-
dioxolane unit the stereocontrol of the homochiral lithium amide
is dominant. Consistent with these observations, upon conjugate
addition of lithium N-benzyl-N-isopropylamide to homochiral
a,b-unsaturated esters, modest to high levels of substrate control
leading to the corresponding 3,4-anti-diastereoisomeric b-amino
ester product are observed in each case, which can be rationalised
by invoking a modified Felkin-Anh transition state. In one case,
however, an unprecedented reversal in the sense of substrate
control upon addition of lithium N-benzyl-N-isopropylamide
than that suggested by the doubly diastereoselectively “matched”
and “mismatched” reaction pairings is potentially indicative of
alternative transition states for the conjugate addition reaction,
reflecting the sensitivity of this system to changes in both the
structure of the chiral a,b-unsaturated ester and the nature
of the lithium amide reagent. Further investigations toward
both bettering our understanding of these phenomena, and the
application of this double induction strategy for the asymmetric
synthesis of unnatural amino sugars and other polyfunctionalised
products are currently underway within our laboratory.
General Procedure 1: Lithium amide conjugate addition
BuLi was added dropwise to a stirred solution of the requisite
amine in the solvent stated (THF or Et2O), at the temperature
stated (-78, -40 or -20 ◦C), and the resulting solution was stirred
for 30 min. A solution of the requisite a,b-unsaturated ester in the
solvent stated (THF or Et2O), at the temperature stated (-78, -40
or -20 ◦C) was added dropwise via cannula. The reaction mixture
was stirred for either 2 h (for reactions at -78 ◦C) or 5 h (for
reactions at -40 or -20 ◦C) before addition of sat aq NH4Cl. The
reaction mixture was warmed to rt and concentrated in vacuo. The
residue was dissolved in DCM and washed sequentially with 10%
aq. citric acid, sat aq NaHCO3 and brine, dried, and concentrated
in vacuo.
General Procedure 2: Hydrogenolysis with Pearlman’s catalyst
Pd(OH)2/C (20% w/w of substrate) was added to a vigorously
stirred, degassed solution of the requisite substrate in either EtOAc
or MeOH, and placed under a hydrogen atmosphere (either 1 or
5 atm). Stirring was continued for 15 h at rt, after which time
the reaction mixture was filtered through Celite (eluent EtOAc or
MeOH) and concentrated in vacuo.
General Procedure 3: Tandem hydrogenolysis/reductive amination
with Pearlman’s catalyst
Experimental
General Experimental
Pd(OH)2/C (50% w/w of substrate) was added to a vigor-
ously stirred, degassed solution of the requisite substrate in
EtOAc/acetone (v:v 9:1), and placed under a hydrogen atmo-
sphere (1 atm). Stirring was continued for 16 h at rt, after which
time the reaction mixture was filtered through Celite (eluent
EtOAc) and concentrated in vacuo.
All reactions involving organometallic or other moisture-sensitive
reagents were carried out under a nitrogen or argon atmosphere
using standard vacuum line techniques and glassware that was
flame dried and cooled under nitrogen before use. Solvents were
dried according to the procedure outlined by Grubbs and co-
R
workers.24 Water was purified by an Elixꢀ UV-10 system. All other
tert-Butyl (3S,4S,5R,aR)- and (3R,4S,5R,aR)-3-[N-benzyl-N-
(a-methylbenzyl)amino]-4,5-O-isopropylidene-hepta-6-enoate
(3S,4S,5R,aR)-20 and (3R,4S,5R,aR)-21
solvents were used as supplied (analytical or HPLC grade) without
prior purification. Organic layers were dried over MgSO4. Thin
layer chromatography was performed on aluminium plates coated
with 60 F254 silica. Plates were visualised using UV light (254 nm),
iodine, 1% aq KMnO4, or 10% ethanolic phosphomolybdic acid.
Flash column chromatography was performed on Kieselgel 60
silica.
Elemental analyses were recorded by the microanalysis service
of the Inorganic Chemistry Laboratory, University of Oxford,
UK. Melting points were recorded on a Gallenkamp Hot Stage
apparatus and are uncorrected. Optical rotations were recorded
on a Perkin-Elmer 241 polarimeter with a water-jacketed 10 cm
cell. Specific rotations are reported in 10-1 deg cm2 g-1 and
concentrations in g/100 mL. IR spectra were recorded on a Bruker
Tensor 27 FT-IR spectrometer as either a thin film on NaCl plates
(film) or a KBr disc (KBr), as stated. Selected characteristic peaks
are reported in cm-1. NMR spectra were recorded on Bruker
Avance spectrometers in the deuterated solvent stated. Spectra
were recorded at rt unless otherwise stated. The field was locked
by external referencing to the relevant deuteron resonance. Low-
resolution mass spectra were recorded on either a VG MassLab
20–250 or a Micromass Platform 1 spectrometer. Accurate mass
measurements were run on either a Bruker MicroTOF internally
calibrated with polyalanine, or a Micromass GCT instrument
fitted with a Scientific Glass Instruments BPX5 column (15 m ¥
0.25 mm) using amyl acetate as a lock mass.
Method A. Following General Procedure 1, BuLi (2.5 M
in hexanes, 0.61 mL, 1.53 mmol), (R)-N-benzyl-N-(a-
methylbenzyl)amine (332 mg, 1.57 mmol) in THF (4 mL) at
-78 ◦C, and 18 (200 mg, 0.79 mmol) in THF (4 mL) at
-78 ◦C gave a 18:82 mixture of 19:20. Purification via flash
column chromatography (eluent pentane/Et2O, 25:1) gave 19 as
a colourless oil (22 mg, 11%, >98% de); Rf 0.26 (pentane/Et2O,
20:1); [a]24 -35.8 (c 1.15 in CHCl3); nmax (film) 1733 (C O); dH
=
D
(400 MHz, CDCl3) 1.43 (3H, s, MeCMe), 1.45 (9H, s, CMe3),
1.52 (3H, s, MeCMe), 2.98–3.12 (2H, m, C(2)H2), 4.32 (1H, app
td, J 7.0, 1.8, C(3)H), 4.94–4.97 (1H, m, C(5)H), 5.29 (1H, dd,
J 10.1, 0.4, C(7)HA), 5.38 (1H, app d, J 17.0, C(7)HB), 5.74–5.83
(1H, m, C(6)H); dC (100 MHz, CDCl3) 25.2, 26.8 (CMe2), 28.1
(CMe3), 32.0 (C(2)), 78.8 (C(5)), 80.3 (CMe3), 88.2 (C(3)), 111.0
(CMe2), 119.3 (C(7)), 135.3 (C(6)), 152.9 (C(4)), 171.7 (C(1));
m/z (CI+) 272 ([M + NH4]+, 13%), 255 (16), 199 (100). Further
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elution gave 20 as a colourless oil (184 mg, 50%, >98% de); Rf
0.07 (pentane/Et2O, 25:1); [a]22D +1.7 (c 0.3 in CHCl3); nmax (film)
1729 (C O); dH (400 MHz, CDCl3) 1.28 (3H, s, MeCMe), 1.36
methylbenzyl)amine (166 mg, 0.79 mmol) in Et2O (2 mL) at -20 ◦C
and 18 (100 mg, 0.39 mmol) in Et2O (2 mL) at -20 ◦C gave a 93:7
mixture of 20:21. Purification via flash column chromatography
(eluent pentane/Et2O, 25:1) gave 20 as a colourless oil (128 mg,
70%, >98% de).
=
(3H, d, J 7.0, C(a)Me), 1.40 (3H, s, MeCMe), 1.44 (9H, s, CMe3),
2.12–2.22 (2H, m, C(2)H2), 3.75 (2H, app d, J 4.2, NCH2), 3.79
(1H, app q, J 6.0, C(3)H), 3.92 (1H, q, J 7.0, C(a)H), 4.18 (1H,
app t, J 6.0, C(4)H), 4.59 (1H, app t, J 7.6, C(5)H), 5.30 (1H,
app d, J 10.0, C(7)HA), 5.37 (1H, app d, J 17.1, C(7)HB), 5.95
(1H, ddd, J 17.1, 10.0, 7.6, C(6)H), 7.22–7.34 (10H, m, Ph); dC
(50 MHz, CDCl3) 15.3 (C(a)Me), 25.1, 27.5 (CMe2), 28.1 (CMe3),
36.0 (C(2)), 50.2 (NCH2), 54.3 (C(3)), 59.1 (C(a)), 78.8 (C(4)),
79.7 (C(5)), 79.8 (CMe3), 107.9 (CMe2), 119.1 (C(7)), 126.6, 127.0
(p-Ph), 128.0, 128.1, 128.2 (o-, m-Ph), 134.7 (C(6)), 141.4, 142.8
(i-Ph), 171.5 (C(1)); m/z (APCI+) 466 ([M + H]+, 100%); HRMS
(ESI+) C29H40NO4 ([M + H]+) requires 466.2957; found 466.2951.
X-ray crystal structure determination for 21
Data were collected using an Enraf-Nonius k-CCD diffractometer
with graphite monochromated Mo-Ka radiation using standard
procedures at 190 K. The structure was solved by direct methods
(SIR92); all non-hydrogen atoms were refined with anisotropic
thermal parameters. Hydrogen atoms were added at idealised
positions. The structure was refined using CRYSTALS.25
X-ray crystal structure data for 21 [C29H39NO4]: M = 465.63,
˚
orthorhombic, space group P 21 21 21, a = 11.5712(2) A, b =
3
Method B. Following General Procedure 1, BuLi (2.5 M
in hexanes, 0.31 mL, 0.77 mmol), (R)-N-benzyl-N-(a-
methylbenzyl)amine (166 mg, 0.79 mmol) in THF (2 mL) at
-40 ◦C, and 18 (100 mg, 0.39 mmol) in THF (2 mL) at
-40 ◦C gave an 89:11 mixture of 20:21. Purification via flash
column chromatography (eluent pentane/Et2O, 25:1) gave 20 as
a colourless oil (69 mg, 38%, >98% de). Further elution gave 21
as a colourless oil (5 mg, 3%, >98% de); Rf 0.03 (pentane/Et2O,
˚
˚
˚
13.9737(2) A, c = 17.0380(2) A, V = 2754.92(7) A , Z = 4, m =
0.074 mm-1, colourless block, crystal dimensions = 0.2 ¥ 0.2 ¥
0.2 mm3. A total of 3491 unique reflections were measured for 5 <
q < 27 and 2932 reflections were used in the refinement. The final
parameters were wR2 = 0.040 and R1 = 0.032 [I>3s(I)]. CCDC
668996.†
tert-Butyl (3S,4S,5R)-3-amino-4,5-O-isopropylidene-
heptanoate 24
25:1); [a]26D +22.7 (c 1.05 in CHCl3); nmax (film) 1731 (C O), 1602
=
=
(C C); dH (400 MHz, CDCl3) 1.29 (3H, d, J 7.0, C(a)Me), 1.34
(3H, s, MeCMe), 1.50 (9H, s, CMe3), 1.53 (3H, s, MeCMe), 1.95
(1H, dd, J 14.9, 2.8, C(2)HA), 2.23 (1H, dd, J 15.0, 10.0, C(2)HB),
3.49 (1H, app td, J 10.0, 2.8, C(3)H), 3.84 (1H, d, J 15.4, NCHA),
4.05 (1H, d, J 15.4, NCHB), 4.18 (1H, dd, J 10.0, 5.4, C(4)H), 4.25
(1H, dd, J 8.8, 5.4, C(5)H), 4.31 (1H, q, J 7.0, C(a)H), 5.11–5.19
(2H, m, C(7)H2), 5.67 (1H, ddd, J 17.0, 9.3, 8.8, C(6)H), 7.20–
7.33 (7H, m, Ph), 7.44–7.47 (3H, m, Ph); dC (100 MHz, CDCl3)
20.4 (C(a)Me), 25.5 (MeCMe), 28.2 (CMe3), 28.3 (MeCMe), 37.6
(C(2)), 50.1 (NCH2), 55.3 (C(3)), 61.8 (C(a)), 78.8 (C(4)), 79.7
(C(5)), 80.3 (CMe3), 108.4 (CMe2), 119.0 (C(7)), 126.4, 126.7 (p-
Ph), 127.8, 127.9, 128.0, 128.5 (o-, m-Ph), 134.2 (C(6)), 142.8,
145.0 (i-Ph), 170.7 (C(1)); m/z (ESI+) 466 ([M + H]+, 100%);
HRMS (ESI+) C29H40NO4 ([M + H]+) requires 466.2957; found
466.2951.
Following General Procedure 2, 20 (200 mg, 0.43 mmol),
Pd(OH)2/C (50 mg) and H2 (5 atm) in MeOH (5 mL) gave 24
as a colourless oil (110 mg, 94%, >98% de); [a]25 +19.4 (c 1.2 in
D
=
CHCl3); nmax (film) 3390, 3322 (N–H), 1726 (C O); dH (400 MHz,
CDCl3) 1.01 (3H, t, J 7.5, C(7)H3), 1.31 (3H, s, MeCMe), 1.40
(3H, s, MeCMe), 1.44 (9H, s, CMe3), 1.48–1.65 (2H, m, C(6)H2),
2.20 (1H, dd, J 16.2, 9.0, C(2)HA), 2.71 (1H, dd, J 16.2, 2.7,
C(2)HB), 3.20 (1H, app td, J 9.0, 2.7, C(3)H), 3.80 (1H, dd, J
9.0, 5.6, C(4)H), 4.03–4.08 (1H, m, C(5)H); dC (100 MHz, CDCl3)
10.6 (C(7)), 22.7 (C(6)), 25.8 (MeCMe), 28.1 (CMe3, MeCMe),
41.6 (C(2)), 47.9 (C(3)), 79.3 (C(5)), 80.6 (C(4)), 80.9 (CMe3),
107.7 (CMe2), 171.9 (C(1)); m/z (ESI+) 274 ([M + H]+, 100%),
218 (18); HRMS (ESI+) C14H28NO4 ([M + H]+) requires 274.2018;
found 274.2013.
Method C. Following General Procedure 1, BuLi (2.5 M
in hexanes, 0.31 mL, 0.77 mmol), (R)-N-benzyl-N-(a-
methylbenzyl)amine (166 mg, 0.79 mmol) in Et2O (2 mL) at -40 ◦C
and 18 (100 mg, 0.39 mmol) in Et2O (2 mL) at -40 ◦C gave a 4:91:5
mixture of 19:20:21. Purification via flash column chromatography
(eluent pentane/Et2O, 25:1) gave 20 as a colourless oil (105 mg,
57%, >98% de). Further elution gave 21 as a colourless oil (9 mg,
5%, >98% de).
tert-Butyl (3R,4R,5R,aS)-3-[N-benzyl-N-(a-
methylbenzyl)amino]-4,5-O-isopropylidene-hepta-6-enoate 34
Method D. Following General Procedure 1, BuLi (2.5 M
in hexanes, 0.24 mL, 0.61 mmol), (R)-N-benzyl-N-(a-
methylbenzyl)amine (133 mg, 0.63 mmol) in THF (2 mL) at -20 ◦C
and 18 (100 mg, 0.39 mmol) in THF (2 mL) at -20 ◦C gave an 84:16
mixture of 20:21. Purification via flash column chromatography
(eluent pentane/Et2O, 25:1) gave 20 as a colourless oil (71 mg,
40%, >98% de). Further elution gave a mixture of 20:21 (32 mg,
18%).
Following General Procedure 1, BuLi (2.5 M in hexanes, 0.24 mL,
0.60 mmol), (S)-N-benzyl-N-(a-methylbenzyl)amine (131 mg,
0.62 mmol) in THF (2 mL) at -78 ◦C, and 33 (99 mg, 0.39 mmol)
Method E. Following General Procedure 1, BuLi (2.2 M
in hexanes, 0.35 mL, 0.77 mmol), (R)-N-benzyl-N-(a-
◦
in THF (2 mL) at -78 C, gave 34 in >98% de. Purification via
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=
flash column chromatography (eluent pentane/Et2O, 25:1) gave
1728 (C O); dH (400 MHz, CDCl3), 0.10 (6H, s, SiMe2), 0.94
(9H, s, SiCMe3), 1.25–1.39 (9H, m, CMe2, C(a)Me), 1.45 (9H, s,
OCMe3), 1.70 (1H, dd, J 15.2, 2.8, C(2)HA), 2.44 (1H, dd, J 15.2,
10.6, C(2)HB), 3.50–3.58 (2H, m, C(3)H, NCHA), 3.63 (1H, dd,
J 10.9, 2.1, C(6)HA), 3.81–3.85 (2H, m, C(6)HB, C(a)H), 4.07
(1H, dd, J 7.9, 2.8 C(4)H), 4.34 (1H, d, J 14.7, NCHB), 4.53–
4.55 (1H, m, C(5)H), 7.22–7.40 (8H, m, Ph), 7.51 (2H, d, J 7.5,
Ph); dC (100 MHz, CDCl3) -5.5, -5.3 (SiMe2), 18.5 (SiCMe3),
19.9 (C(a)Me), 25.9 (SiCMe3), 26.3, 27.1 (CMe2), 28.1 (OCMe3),
34.2 (C(2)), 50.8 (C(a)), 53.0 (NCH2), 57.6 (C(3)), 63.2 (C(6)),
77.7, 80.0 (C(4), C(5)), 80.2 (OCMe3), 108.2 (CMe2), 126.5, 127.1
(p-Ph), 128.0, 128.1, 128.2, 128.2 (o-, m-Ph), 141.5, 141.3 (i-Ph),
171.5 (C(1)); m/z (ESI+) 584 ([M + H]+, 100%); HRMS (ESI+)
C34H54NO5Si ([M + H]+) requires 584.3771; found 584.3776.
34 as a colourless oil (138 mg, 76%, >98% de); [a]20 +9.4 (c 1.1
D
=
=
in CHCl3); nmax (film) 1728 (C O), 1602 (C C); dH (500 MHz,
CDCl3) 1.39 (3H, s, MeCMe), 1.40 (3H, s, MeCMe), 1.41 (3H,
obsc d, C(a)Me), 1.44 (9H, s, CMe3), 2.15 (1H, dd, J 15.9, 4.7,
C(2)HA), 2.36 (1H, dd, J 15.9, 6.9, C(2)HB), 3.66 (1H, d, J 14.5,
NCHA), 3.68–3.72 (1H, m, C(3)H), 3.82 (1H, d, J 14.5, NCHB),
3.94 (1H, q, J 6.9, C(a)H), 3.97 (1H, dd, J 8.3, 3.9, C(4)H),
4.14 (1H, app t, J 6.9, C(5)H), 5.29 (1H, app d, J 10.3, C(7)HA),
5.39–5.43 (1H, m, C(7)HB), 5.88–5.95 (1H, m, C(6)H), 7.23–7.39
(10H, m, Ph); dC (125 MHz, CDCl3) 18.8 (C(a)Me), 26.8, 26.9
(CMe2), 28.0 (CMe3), 33.9 (C(2)), 51.0 (NCH2), 54.0 (C(3)), 57.6
(C(a)), 79.9 (C(5)), 80.8 (C(4)), 82.5 (CMe3), 108.9 (CMe2), 118.4
(C(7)), 126.6, 126.8 (p-Ph), 127.9, 128.0, 128.4, 128.5 (o-, m-Ph),
135.9 (C(6)), 140.8, 142.8 (i-Ph), 171.7 (C(1)); m/z (ESI+) 466
([M + H]+, 100%); HRMS (ESI+) C29H40NO4 ([M + H]+) requires
466.2957; found 466.2953.
Method B. Following General Procedure 1, BuLi (1.6 M
in hexanes, 0.52 mL, 0.83 mmol), (S)-N-benzyl-N-(a-
methylbenzyl)amine (0.18 mL, 0.86 mmol) in Et2O (5 mL) at
-20 ◦C, and 46 (200 mg, 0.54 mmol) in Et2O (5 mL) at -20 ◦C
gave a 63:37 mixture of 47:48. Purification via flash column
tert-Butyl (3R,4R,5R)-3-amino-4,5-O-isopropylidene-
heptanoate 37
◦
◦
chromatography (eluent 30–40 C petrol, increased to 30–40 C
petrol/Et2O, 50:1) gave 47 as a colourless oil (187 mg, 60%, >98%
de). Further elution gave 48 as a colourless oil (64 mg, 11%,
>98% de); [a]22D -51.0 (c 0.5 in CHCl3); nmax (film) 1730 (C O); dH
=
(400 MHz, CDCl3) 0.08 (3H, s, MeSiMe), 0.12 (3H, s, MeSiMe),
0.94 (9H, s, SiCMe3), 1.24 (3H, s, MeCMe), 1.29 (3H, s, MeCMe),
1.37 (3H, d, J 7.07, C(a)Me), 1.51 (9H, s, OCMe3), 2.47 (1H, dd,
J 15.7, 6.1, C(2)HA), 2.64 (1H, dd, J 15.7, 5.4, C(2)HB), 3.11–
3.18 (1H, m, C(5)H), 3.41–3.57 (3H, m, C(3)H, C(6)H2), 3.75
(1H, d, J 14.2, NCHA), 3.88 (1H, d, J 14.2, NCHB), 3.92–4.00
(2H, m, C(4)H, C(a)H), 7.19–7.37 (8H, m, Ph), 7.44–7.47 (2H,
m, Ph); dC (100 MHz, CDCl3) -5.2, -5.1 (SiMe2), 15.5 (SiCMe3),
18.5 (C(a)Me), 26.1 (SiCMe3), 26.9, 27.1 (CMe2), 29.2 (OCMe3),
35.5 (C(2)), 51.3 (NCH2), 54.9 (C(3)), 57.3 (C(a)), 63.0 (C(6)),
77.7 (C(4)), 80.2 (C(5)), 80.4 (OCMe3), 108.5 (CMe2), 126.8,
127.0 (p-Ph), 128.0, 128.2, 129.0 (o-, m-Ph), 141.2, 143.7 (i-Ph),
172.2 (C(1)); m/z (ESI+) 548 ([M + H]+, 100%); HRMS (ESI+)
C34H54NO5Si ([M + H]+) requires 584.3771; found 584.3776.
Following General Procedure 2, 34 (75 mg, 0.16 mmol),
Pd(OH)2/C (35 mg) and H2 (5 atm) in MeOH (5 mL) gave 37 as a
colourless oil (36 mg, 83%, >98% de); [a]23D +27.7 (c 0.8 in CHCl3);
=
nmax (film) 3389 (N - H), 1727 (C O); dH (400 MHz, CDCl3) 1.01
(3H, t, J 7.5, C(7)H3), 1.37 (6H, app s, CMe2), 1.45 (9H, s, CMe3),
1.48–1.61 (1H, m, C(6)HA), 1.64–1.73 (1H, m, C(6)HB), 2.23 (1H,
dd, J 15.8, 9.7, C(2)HA), 2.55 (1H, app d, J 15.8, C(2)HB), 3.26
(1H, br s, C(3)H), 3.57 (1H, app t, J 5.5, C(4)H), 3.83 (1H, app td,
J 7.7, 3.6, C(5)H); dC (100 MHz, CDCl3) 10.3 (C(7)), 27.2 (C(6)),
27.3, 27.4 (CMe2), 28.1 (CMe3), 40.0 (C(2)), 50.3 (C(3)), 79.7
(C(5)), 80.8 (C(4)), 83.5 (CMe3), 108.3 (CMe2), 171.7 (C(1)); m/z
(ESI+) 274 ([M + H]+, 100%), 218 (75); HRMS (ESI+) C14H28NO4
([M + H]+) requires 274.2018; found 274.2013.
tert-Butyl (3R,4S,5R)- and (3S,4S,5R)-3-(N-benzyl-N-
isopropylamino)-4,5-O-isopropylidene-6-(tert-
butyldimethylsilyloxy)hexanoate (3R,4S,5R)-55 and
(3S,4S,5R)-56
tert-Butyl (3R,4S,5R,aS)- and (3S,4S,5R,aS)-3-[N-benzyl-N-
(a-methylbenzyl)amino]-4,5-O-isopropylidene-6-(tert-
butyldimethylsilyloxy)hexanoate (3R,4S,5R,aS)-47 and
(3S,4S,5R,aS)-48
Following General Procedure 1, BuLi (1.6 M in hexanes, 1.3 mL,
2.08 mmol), N-benzyl-N-isopropylamine (3.53 mL, 2.14 mmol)
in THF (10 mL) at -78 ◦C, and 46 (500 mg, 1.34 mmol) in THF
(10 mL) at -78 ◦C gave a 25:75 mixture of 55:56. Purification
Method A. Following General Procedure 1, BuLi (1.6 M
in hexanes, 0.56 mL, 0.41 mmol), (S)-N-benzyl-N-(a-
methylbenzyl)amine (89 mL, 0.43 mmol) in THF (10 mL) at -78 ◦C,
and 46 (100 mg, 0.27 mmol) in THF (5 mL) at -78 ◦C gave 47 in
>98% de. Purification via flash column chromatography (eluent
30–40◦C petrol, increased to 30–40 ◦C petrol/Et2O, 50:1) gave
47 as a colourless oil◦that solidified on standing (107 mg, 69%,
◦
via flash column chromatography (eluent 30–40 C petrol/Et2O,
100:1, increased to 50:1) gave 55 as a colourless oil (102 mg, 15%,
>98% de); [a]18 +4.8 (c 1.0 in CHCl3); nmax (film) 1726 (C O);
=
D
dH (400 MHz, CDCl3) 0.03 (6H, s, SiMe2), 0.88 (9H, s, SiCMe3),
1.01 (3H, d, J 6.6, MeCHMe), 1.08 (3H, d, J 6.6, MeCHMe), 1.32
>98% de); mp 44–45 C; [a]21 -1.5 (c 1.1 in CHCl3); nmax (film)
D
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(6H, s, CMe2), 1.48 (9H, s, OCMe3), 2.62–2.74 (2H, m, C(2)H2),
3.07–3.18 (1H, m, CHMe2), 3.22–3.32 (2H, m, C(3)H, C(6)HA),
3.65 (1H, d, J 13.9, NCHA), 3.64 (1H, dd, J 11.4, 3.8, C(6)HB), 4.01
(1H, dd, J 8.1, 3.3, C(4)H), 4.09 (1H, d, J 13.9, NCHB), 4.21–4.29
(1H, m, C(5)H), 7.17–7.39 (5H, m, Ph); dC (100 MHz, CDCl3) -5.5,
-5.4 (SiMe2), 17.3 (SiCMe3), 18.5, 22.5 (CHMe2), 26.0 (SiCMe3),
26.3, 27.2 (CMe2), 28.1 (OCMe3), 36.0 (C(2)), 49.0 (CHMe2), 52.0
(NCH2), 52.0 (C(3)), 62.5 (C(6)), 77.8 (C(5)), 79.7 (OCMe3), 80.3
(C(4)), 107.9 (CMe2), 126.5 (p-Ph), 128.0, 128.7 (o-, m-Ph), 141.5
(i-Ph), 172.0 (C(1)); m/z (ESI+) 522 ([M + H]+, 100%), 466 (98);
HRMS (ESI+) C33H52NO5Si ([M + H]+) requires 522.3615; found
522.3609. Further elution gave 56 as a colourless oil (331 mg, 48%,
tert-Butyl (3S,4S,5R)-3-(N-isopropylamino)-4,5-O-
isopropylidene-6-(tert-butyldimethylsilyloxy)hexanoate 58
From 48. Following General Procedure 3, Pd(OH)2/C (40 mg)
and 48 (26 mg, 0.12 mmol) in MeOH/acetone (v:v 9:1, 2 mL)
under H2 (1 atm) gave 58 as a colourless oil (15 mg, 79%, >98% de);
>98% de); [a]18D -124 (c 1.0 in CHCl3); nmax (film) 1728 (C O); dH
[a]19D -3.8 (c 3.2 in CHCl3); nmax (film) 1729 (C O); dH (500 MHz,
=
=
(400 MHz, CDCl3) 0.10 (6H, s, SiMe2), 0.93 (9H, s, SiCMe3), 1.02–
1.09 (6H, m, CHMe2), 1.34 (3H, s, MeCMe), 1.37 (3H, s, MeCMe),
1.50 (9H, s, OCMe3), 2.41 (1H, dd, J 15.4, 5.3, C(2)HA), 2.63 (1H,
dd, J 15.4, 7.2, C(2)HB), 2.98–2.99 (1H, m, CHMe2), 3.46–3.48
(1H, m, C(3)H), 3.63–3.71 (2H, m, C(5)H, NCHA), 3.73–3.86 (3H,
m, C(6)H2, NCHB), 4.22 (1H, dd, J 8.1, 4.1, C(4)H), 7.19–7.24
(1H, m, Ph), 7.29 (2H, t, J 7.5 Ph), 7.34–7.39 (2H, m, Ph); dC
(100 MHz, CDCl3) -5.3, -5.2 (SiMe2), 18.5 (SiCMe3), 19.8, 20.2
(CHMe2), 26.0 (SiCMe3), 27.1, 27.2 (CMe2), 28.2 (OCMe3), 35.5
(C(2)), 48.4 (CHMe2), 50.1 (NCH2), 55.0 (C(3)), 63.2 (C(6)), 78.1
((C(4)), 80.0 (OCMe3), 80.7 (C(5)), 108.7 (CMe2), 126.6 (p-Ph),
128, 128.7 (o-, m-Ph), 141.2 (i-Ph), 172.4 (C(1)); m/z (ESI+) 522
([M + H]+, 100%), 466 (92); HRMS (ESI+) C33H52NO5Si ([M +
H]+) requires 522.3615; found 522.3609.
CDCl3) 0.08 (6H, s, SiMe2), 0.90 (9H, s, SiCMe3), 1.03 (6H, app
t, J 6.3, CHMe2), 1.38 (3H, s, MeCMe), 1.39 (3H, s, MeCMe),
1.46 (9H, s, OCMe3), 2.38 (1H, dd, J 15.1, 6.6, C(2)HA), 2.53
(1H, dd, J 15.1, 4.4, C(2)HB), 2.89–3.98 (1H, m, CHMe2), 3.11–
3.16 (1H, m, C(3)H), 3.76–3.86 (3H, m, C(4)H, C(6)H2), 3.91–
3.96 (1H, m, C(5)H); dC (125 MHz, CDCl3) -5.4, -5.3 (SiMe2),
18.5 (SiCMe3), 22.9, 23.7 (CHMe2), 26.0 (SiCMe3), 27.1, 27.2
(CMe2), 28.2 (OCMe3), 36.6 (C(2)), 45.6 (CHMe2), 54.3 (C(3)),
64.5 (C(6)), 79.4 (C(4)), 80.1 (C(5)), 80.1 (OCMe3), 108.9 (CMe2),
171.9 (C(1)); m/z (ESI+) 432 ([M + H]+, 10%), 376 (58), 318 (100);
HRMS (ESI+) C26H45NO5Si ([M + H]+) requires 432.3145; found
432.3142.
From 56. Following General Procedure 2, Pd(OH)2/C (77 mg)
and 56 (153 mg, 0.29 mmol) in EtOAc (5 mL) under H2 (1 atm)
gave 58 as a colourless oil (82 mg, 65%, >98% de).
tert-Butyl (3R,4S,5R)-3-(N-isopropylamino)-4,5-O-
isopropylidene-6-(tert-butyldimethylsilyloxy)hexanoate 57
Acknowledgements
The authors would like to thank Ajinomoto Co., Inc. for funding
(W. K.) and New College, Oxford for a Junior Research Fellowship
(A. D. S.).
References
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5 S. G. Davies and O. Ichihara, Tetrahedron: Asymmetry, 1991, 2, 183;
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Smith, Tetrahedron: Asymmetry, 2006, 17, 1793.
From 47. Following General Procedure 3, Pd(OH)2/C (40 mg)
and 47 (78 mg, 0.12 mmol) in MeOH/acetone (v:v 9:1, 2 mL)
under H2 (1 atm) gave 57 as a colourless oil (42 mg, 74%, >98%
de); [a]19 -20.5 (c 0.9 in CHCl3); nmax (film) 1729 (C O); dH
=
D
(500 MHz, CDCl3) 0.08 (6H, s, SiMe2), 0.91 (9H, s, SiCMe3),
1.00 (3H, d, J 6.0, MeCHMe), 1.05 (3H, d, J 6.3, MeCHMe),
1.38 (3H, s, MeCMe), 1.41 (3H, s, MeCMe), 1.46 (9H, s, OCMe3),
2.35 (1H, dd, J 14.8, 6.6, C(2)HA), 2.48–2.51 (1H, m, C(2)HB),
2.87–2.94 (1H, m, CHMe2), 3.19–3.22 (1H, m, C(3)H), 3.75 (2H,
app t, J 4.4, C(6)H2), 3.96 (1H, dd, J 7.7, 3.3, C(4)H), 4.07–4.10
(1H, m, C(5)H); dC (125 MHz, CDCl3) -5.4, -5.3 (SiMe2), 18.4
(SiCMe3), 22.8, 24.0 (CHMe2), 26.0 (SiCMe3), 27.2 (CMe2), 28.1
(OCMe3), 38.8 (C(2)), 45.6 (CHMe2), 52.2 (C(3)), 64.1 (C(6)), 77.8
(C(4)), 80.3 (OCMe3), 80.4 (C(5)), 108.7 (CMe2), 171.1 (C(1)); m/z
(ESI+) 432 ([M + H]+, 26%), 376 (82), 318 (100); HRMS (ESI+)
C26H45NO5Si ([M + H]+) requires 432.3145; found 432.3141.
6 For a review see:S. G. Davies, A. D. Smith and P. D. Price, Tetrahedron:
Asymmetry, 2005, 16, 2833.
7 For kinetic resolution of 3-alkyl-cyclopent-1-ene-carboxylates see:
(a) S. Bailey, S. G. Davies, A. D. Smith and J. M. Withey, Chem.
From 55. Following General Procedure 2, Pd(OH)2/C (42 mg)
and 55 (83 mg, 0.16 mmol) in EtOAc (5 mL) under H2 (1 atm)
gave 57 as a colourless oil (64 mg, 93%, >98% de).
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Org. Biomol. Chem., 2009, 7, 761–776 | 775
©

View Article Online
Commun., 2002, 2910; (b) M. E. Bunnage, A. M. Chippindale, S. G.
Davies, R. M. Parkin, A. D. Smith and J. M. Withey, Org. Biomol.
Chem., 2003, 1, 3698; (c) M. E. Bunnage, S. G. Davies, R. M. Parkin,
P. M. Roberts, A. D. Smith and J. M. Withey, Org. Biomol. Chem.,
2004, 2, 3337; (d) For parallel kinetic resolution of 3-alkyl-cyclopent-1-
ene-carboxylates see: S. G. Davies, A. C. Garner, M. J. C. Long, A. D.
Smith, M. J. Sweet and J. M. Withey, Org. Biomol. Chem., 2004, 2,
3355; (e) For parallel kinetic resolution of 3-oxy-substituted cyclopent-
1-ene-carboxylates see:Y. Aye, S. G. Davies, A. C. Garner, P. M. Roberts,
A. D. Smith and J. E. Thomson, Org. Biomol. Chem., 2008, 6, 2195;
(f) For kinetic and parallel kinetic resolution of 5-alkyl-cyclopent-1-
ene-carboxylates see: S. G. Davies, D. D´ıez, M. M. El Hammouni,
A. C. Garner, N. M. Garrido, M. J. C. Long, R. M. Morrison, A. D.
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