Parallel kinetic resolution of tert-butyl (RS)-3-oxy-substituted cyclopent-1-ene-carboxylates for the asymmetric synthesis of 3-oxy-substituted cispentacin and transpentacin derivatives

Article abstract of DOI:10.1039/b802428f

tert-Butyl (RS)-3-methoxy- and (RS)-3-tert-butyldiphenylsilyloxy-cyclopent- 1-ene-carboxylates display excellent levels of enantiorecognition in mutual kinetic resolutions with both lithium (RS)-N-benzyl-N-(α-methylbenzyl) amide and lithium (RS)-N-3,4-dim

Full text of DOI:10.1039/b802428f

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Parallel kinetic resolution of tert-butyl (RS)-3-oxy-substituted
cyclopent-1-ene-carboxylates for the asymmetric synthesis of
3-oxy-substituted cispentacin and transpentacin derivatives†
Yimon Aye, Stephen G. Davies,* A. Christopher Garner, Paul M. Roberts, Andrew D. Smith and
James E. Thomson
Received 12th February 2008, Accepted 12th March 2008
First published as an Advance Article on the web 21st April 2008
DOI: 10.1039/b802428f
tert-Butyl (RS)-3-methoxy- and (RS)-3-tert-butyldiphenylsilyloxy-cyclopent-1-ene-carboxylates display
excellent levels of enantiorecognition in mutual kinetic resolutions with both lithium (RS)-N-benzyl-
N-(a-methylbenzyl)amide and lithium (RS)-N-3,4-dimethoxybenzyl-N-(a-methylbenzyl)amide. A 50 :
50 pseudoenantiomeric mixture of lithium (S)-N-benzyl-N-(a-methylbenzyl)amide and lithium
(R)-N-3,4-dimethoxybenzyl-N-(a-methylbenzyl)amide allows for the efficient parallel kinetic resolution
of the tert-butyl (RS)-3-oxy-substituted cyclopent-1-ene-carboxylates, affording differentially protected
3-oxy-substituted cispentacin derivatives in high yield and >98% de. Subsequent N-deprotection and
hydrolysis provides access to 3-oxy-substituted cispentacin derivatives in good yield, and in >98% de
and >98% ee, while stereoselective epimerisation and subsequent deprotection affords the
corresponding transpentacin analogues in good yield, and in >98% de and >98% ee.
Introduction
The asymmetric synthesis of vicinal amino alcohols has attracted a
great deal of interest in both academic and industrial arenas due to
the ubiquitous nature of this functionality in natural products, and
the potent biological activity of substrates containing this moiety.1
In this laboratory the asymmetric synthesis of vicinal amino
alcohols has been approached through conjugate addition of a
homochiral lithium amide to an a,b-unsaturated ester, either cou-
pled with in situ oxidation of the intermediate b-amino enolate,2 or
through addition to acyclic a,b-unsaturated esters bearing a c-oxy
functionality.3 In the latter category, acyclic a,b-unsaturated esters
2 and 3 (bearing a c-stereogenic centre) show only low levels of
substrate control and, although “matching” and “mismatching”
effects have been noted,4 the additions proceed, in each case, under
the dominant stereocontrol of the homochiral lithium amide 1
(reagent control), with high levels of diastereofacial selectivity
being observed (Fig. 1).3b
In contrast to these acyclic examples, 3- and 5-alkyl-substituted
cyclopent-1-ene-carboxylates display high levels of substrate con-
trol, and we have demonstrated the efficient kinetic and parallel
kinetic resolution of these substrates upon treatment with either
homochiral or a pseudoenantiomeric mixture of homochiral
lithium amides, respectively.5 High levels of substrate bias for
Fig. 1 Addition of homochiral lithium amide 1 to acyclic a,b-unsaturated
esters 2 and 3 bearing a c-oxy functionality.
addition of the homochiral lithium amide 1 anti to the 3- or
5-alkyl substituent, coupled with the exceptional diastereofacial
preference of 1, provides highly selective resolutions. High levels
of facial selectivity upon kinetic protonation of the intermediate
enolates, anti to the newly installed nitrogen substituent,6 allow
ready access to single diastereoisomers of homochiral 3- or
5-alkyl-substituted 2-amino-cyclopentane-carboxylic acids.7 The
synthetic utility of these processes is greatly enhanced by the
Department of Chemistry, Chemistry Research Laboratory, University of
Oxford, Mansfield Road, Oxford, UK OX1 3TA.
E-mail: steve.davies@chem.ox.ac.uk
† Electronic supplementary information (ESI) available: Full experimental
details. See DOI: 10.1039/b802428f
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utilization of a parallel resolution protocol,8,9 employing a pseu-
doenantiomeric mixture of lithium amides, which provides access
to both enantiomeric series of addition products. Given the current
interest in b-peptide secondary structure,10,11 cyclic c-hydroxy-
b-amino acids are attractive targets for asymmetric synthesis.12
The parallel kinetic resolution of racemic, cyclic a,b-unsaturated
esters bearing a c-oxy-substituted stereogenic centre represents
an interesting synthetic challenge as the conjugate addition of
a lithium amide reagent in the presence of a c-heteroatom may
potentially give rise to either syn stereocontrol, due to chelation,
or anti stereocontrol, due to steric effects or dipolar repulsion
(Fig. 2).13,14 We report herein our full results within this area,
and delineate the parallel kinetic resolution of 3-oxy-substituted
cyclopent-1-ene-carboxylates.
13 with tert-butyl hydroperoxide19 gave 15 in 37% isolated yield.
Subsequent Luche reduction20 of enones 14 and 15 furnished 16
and 17 in 98% isolated yield in both cases. O-Methylation was
next investigated and although treatment of 16 and 17 with methyl
iodide under strongly basic conditions led to decomposition of the
starting material, methylation under neutral conditions, with silver
oxide and excess methyl iodide,21 furnished the corresponding
methyl ethers 18 and 19 in 88 and 85% isolated yield respectively.
O-Silylation of 16 and 17 was readily achieved with TBDPSCl,
imidazole and DMAP,22 yielding 20 and 21 in 99 and 85% yield
respectively (Scheme 1).
Fig. 2 Substrate control via chelation or steric/dipolar factors during
conjugate addition of lithium amides.
Scheme 1 Reagents and conditions: (i) CrO3, AcOH, Ac2O, DCM, 0–5 ◦C,
30 min, then NaHCO3, H2O–THF, rt, 12 h; (ii) Pd(OH)2/C, K2CO3,
tBuOOH, DCM, 0 ◦C, 4 h; (iii) NaBH4, CeCl3·7H2O, MeOH, 0 ◦C, 10 min;
(iv) MeI, Ag2O, MeCN, 43 ◦C, 20 h; (v) TBDPSCl, imidazole, DMAP,
DMF, 0 ◦C to rt, 12 h.
Results and discussion
In investigating parallel kinetic resolution it is prudent to follow
a strategy5 of first evaluating the level of substrate control—in
this system through the addition of an achiral lithium amide to
the racemic a,b-unsaturated ester. In cases where high levels of
substrate control are observed, the conjugate addition of a racemic
lithium amide to the racemic a,b-unsaturated ester (mutual kinetic
resolution) may then be performed, allowing the selectivity factor
E to be directly determined in the absence of complicating mass
action effects.15 Finally, having established the maximum levels of
enantiorecognition with each of the pseudoenantiomeric parallel
kinetic resolution components, the parallel kinetic resolution
utilizing a 50 : 50 mixture of pseudoenantiomeric lithium amide
reagents can be performed.
Evaluation of substrate control
Having established a route to 3-oxy-substituted esters 18–21, the
inherent substrate diastereofacial control was evaluated via the
conjugate addition of lithium dibenzylamide 22.23 Preliminary
experiments established that the direct treatment of unprotected
hydroxy esters 16 and 17 with excess lithium amide 22 did not
afford any addition products and extensive decomposition of the
starting materials was observed in both cases. Addition of lithium
dibenzylamide 22 to 3-O-TBDPS methyl ester 20, meanwhile,
afforded a 58 : 42 mixture of b-amino amide (1RS,2RS,3RS)-
23 (the result of sequential 1,2- and 1,4-addition) in >98% de,
and a,b-unsaturated amide (RS)-24, isolated in 28 and 21%
yield respectively (Scheme 2). The relative configuration within b-
amino amide 23 was unambiguously established by single crystal
Preparation of 3-oxy-substituted cyclopent-1-ene-carboxylates
It was envisaged that addition to an unprotected alcohol
would be disfavoured for electrostatic reasons and thus two
hydroxyl-protecting groups were proposed, viz. methyl and tert-
butyldiphenylsilyl. O-tert-Butyldiphenylsilyl (TBDPS) protection
was expected to preclude chelation of the lithium amide and
direct the addition under steric control, while O-methyl pro-
tection offered potential for either syn reagent delivery under
chelation control, or anti addition due to dipolar repulsion. The
desired racemic 3-oxy-substituted cyclopent-1-ene-carboxylates
18–21 were readily prepared from methyl and tert-butyl cyclopent-
1-ene-carboxylates 12 and 13.16 Allylic oxidation17 of 12 with CrO3
in acetic anhydride and acetic acid18 afforded enone 14 in 60% yield
after chromatography and analogous oxidation of 13 gave enone
15 in 50% yield. Alternatively, palladium catalysed oxidation of
Scheme 2 Reagents and conditions: (i) lithium dibenzylamide 22 (2 eq.),
THF, −78 ◦C, 4 h, then NH4Cl (sat., aq.).
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X-ray analysis (Fig. 3). Despite the undesirable 1,2-addition,
b-amino amide 23 was produced as a single diastereoisomer,
demonstrating high levels of diastereofacial control both for 1,4-
addition anti to the 3-O-TBDPS substituent5a,b and protonation
of the intermediate enolate anti to the amino group.6
Scheme 3 ◦Reagents and conditions: (i) lithium dibenzylamide 22 (5 eq.),
THF, −78 C, 4 h, then NH4Cl (sat., aq.). [a Crude. Isolated yields refer to
single diastereoisomers (>98% de).]
conjugate addition of lithium dibenzylamide 22, the mutual
kinetic resolution of 18–21 with lithium (RS)-N-benzyl-N-(a-
methybenzyl)amide 1 was investigated in order to determine the
maximum value of the stereoselectivity factor E.15
Mutual kinetic resolution
In mutual kinetic resolutions, mass action effects are negated and
the selectivity factor E is independent of reaction conversion, and
furthermore is equivalent to the ratio of products.15 The conjugate
addition of racemic lithium amide (RS)-1 to the racemic 3-oxy-
substituted methyl esters 18 and 20 was initially examined. In both
cases high levels of enantiorecognition between the lithium amide
reagent and a,b-unsaturated ester substrate were observed, with
both additions proceeding with high selectivity (E >99 in both
cases). The minor diastereoisomeric products were derived from
incomplete selectivity in protonation of the intermediate enolates
(Scheme 4). The relative configurations of the cyclopentane ring
stereogenic centres within of all these addition products were
Fig. 3 Chem3D representation of the X-ray crystal structure of 23 (some
H atoms removed for clarity).
1
assigned from H NMR NOE difference data, while the relative
The addition of lithium dibenzylamide 22 to the 3-oxy-
substituted tert-butyl esters 19 and 21 was next investigated, and
afforded only 1,4-addition products. Conjugate addition to 3-O-
TBDPS tert-butyl ester 21, and protonation with sat. aq. NH4Cl,
gave a 91 : 9 mixture (82% de) of the C(1)-epimeric b-amino
esters (1RS,2RS,3RS)-27 and (1RS,2SR,3SR)-28, respectively.
Chromatography furnished b-amino esters 27 and 28 in 74 and
7% isolated yield respectively, and in >98% de in each case.
Analogous addition of lithium dibenzylamide 22 to 3-O-Me tert-
butyl ester 19 furnished a 79 : 21 mixture (58% de) of b-amino esters
(1RS,2RS,3RS)-25 and (1RS,2SR,3SR)-26, which were isolated in
40 and 10% yield respectively, as single diastereoisomers (>98%
de) in both cases (Scheme 3).
The high levels of 2,3-anti selectivity observed in all the
conjugate additions are consistent with the reactions proceeding
under steric substrate bias. While this may be expected in the
case of the 3-O-TBDPS substituent, the 3-O-Me ether also acts
as an effective polar steric blocking group, directing addition anti
to itself, and not participating in chelation with the incoming
lithium amide. Having demonstrated that 3-oxy-substituted esters
19–21 demonstrate very high levels of substrate control upon
Scheme
4 Reagents and conditions: (i) lithium (RS)-N-benzyl-N-
(a-methylbenzyl)amide (RS)-1 (5 eq.), THF, −78 ◦C, 4 h, then NH4Cl
(sat., aq.). [a Crude. Isolated yields refer to single diastereoisomers (>98%
de).]
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(1RS,2RS,3RS,aSR)-configurations of major diastereoisomers 29
and 31 were unambiguously confirmed by single crystal X-ray
structure analysis (Fig. 4 and Fig. 5). These analyses also affirmed
that the relative configurations of the C(2) and N-a-methylbenzyl
stereocentres were consistent with the diastereofacial preference
of both the chiral lithium amide (reagent) and the chiral a,b-
unsaturated ester (substrate). Notably, no evidence of amide
formation was observed in the addition of lithium (RS)-N-
benzyl-N-(a-methylbenzyl)amide 1 to the methyl esters 18 and
20, reflecting the sensitivity of 1,2- versus 1,4-addition to the steric
bulk of the lithium amide reagent.
Fig. 5 Chem3D representation of the X-ray crystal structure 31 (some H
atoms removed for clarity).
Fig. 4 Chem3D representation of the X-ray crystal structure 29 (some H
atoms removed for clarity).
The addition of lithium amide (RS)-1 to tert-butyl esters 19
and 21 was next investigated (Scheme 5). Addition of (RS)-1 to
3-O-Me 19, and quenching with sat. aq. NH4Cl, gave a >99 :
<1 mixture of 33 : 34, from which 33 was isolated in 86% yield
and >98% de. Addition to 3-O-TBDPS 21 and quenching with
sat. aq. NH4Cl gave a 90 : 10 mixture of b-amino esters 35 : 36;
however the enolate protonation selectivity could be improved by
changing the proton source to 2,6-di-tert-butylphenol,5a,b giving
a 97 : 3 mixture of 35 : 36. The 2,3-anti arrangement, and the
correlation of the C(2) and N-a-methylbenzyl stereogenic centres
observed within b-amino esters 33–36 is indicative of excellent
enantiorecognition in this system, consistent with E >99.15 The
observation of C(1)-epimeric products 35 and 36 in the case of
the 3-O-TBDPS substituent is consistent with the steric bulk
of the 3-substituent competing with the 2-amino functionality
in controlling protonation selectivity, as previously observed
in the kinetic resolution of 3-alkyl-substituted cyclopent-1-ene-
carboxylates.5a,b The relative configurations of the stereogenic
centres of the cyclopentane ring within addition products 33–36
Scheme
5 Reagents and conditions: (i) lithium (RS)-N-benzyl-N-
(a-methylbenzyl)amide (RS)-1 (5 eq.), THF, −78 ◦C, 4 h, then NH4Cl
(sat., aq.); ◦(ii) lithium (RS)-N-benzyl-N-(a-methylbenzyl)amide (RS)-1,
THF, −78 C, 4 h, then 2,6-di-tert-butylphenol. [a Crude. Isolated yields
refer to single diastereoisomers (>98% de).]
were assigned from 1H NMR NOE difference data. Furthermore,
the C(1)-epimeric nature of the diastereoisomers was confirmed by
epimerisation of the major 1,2-syn-diastereoisomers 33 (>98% de)
and 35 (>98% de) to the thermodynamically more stable 1,2-anti-
diastereoisomers 34 (>98% de) and 36 (>98% de) upon treatment
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with KOtBu. The epimerisation of 33 was accompanied by partial
ester hydrolysis, however, yielding a separable 71 : 29 mixture of
ester 34 and carboxylic acid 37, in quantitative combined yield
(Scheme 6).
Scheme 8 Reagents and conditions: (i) KOtBu, tBuOH–THF (1 : 1), 80 ◦C,
12 h.
Scheme 6 Reagents and conditions: (i) KOtBu, tBuOH–THF (1 : 1), 80 ◦C,
12 h.
intermediates. The conjugate addition of a 50 : 50 mixture of
lithium amides (S)-1 and (R)-38 to tert-butyl 3-O-TBDPS 21,
followed by protonation with 2,6-di-tert-butylphenol afforded a
45 : 5 : 45 : 5 mixture of b-amino esters (1R,2R,3R,aS)-35,
(1S,2R,3R,aS)-36, (1S,2S,3S,aR)-41 and (1R,2S,3S,aR)-42. This
selectivity is consistent with identical reactivity and complemen-
tary stereoselectivities in the initial conjugate addition of the
pseudoenantiomeric mixture of lithium amides (S)-1 and (R)-38
(E >99 in each case) to give a 50 : 50 mixture of addition products
derived from each lithium amide. The minor diastereoisomers
(1S,2R,3R,aS)-36 and (1R,2S,3S,aR)-42 derive from incomplete
protonation selectivity, consistent with that previously observed in
the mutual kinetic resolutions of this substrate. Facile chromato-
graphic separation, due to the disparate polarities of the N-benzyl
and N-3,4-dimethoxybenzyl protecting groups, gave 35 in 40%
yield and >98% de, and 41 in 36% yield and >98% de (Scheme 9).
The mutual kinetic resolution of the racemic 3-O-Me and 3-
O-TBDPS tert-butyl esters 19 and 21 and lithium (RS)-N-3,4-
dimethoxybenzyl-N-(a-methylbenzyl)amide (RS)-38 was next ex-
amined, employing the optimized reaction conditions (Scheme 7).
These additions showed near identical selectivities (E >99)
to the mutual kinetic resolutions with lithium amide (RS)-1,
with authentic samples of the minor diastereoisomers in these
reactions isolated by epimerisation of the major addition products
(Scheme 8).
Scheme 7 Reagents and conditions: (i) lithium (RS)-N-3,4-dimethoxy-
benzyl-N-(a-methylbenzyl)amide (RS)-38 (5 eq.), THF, −78 ◦C, 4 h, then
NH4Cl (sat., aq.). [a Crude. Isolated yields refer to single diastereoisomers
(>98% de).]
Parallel kinetic resolution
Having successfully established separately the mutual kinetic
resolutions of tert-butyl esters 19 and 21 with lithium amides (RS)-
1 and (RS)-38, the parallel kinetic resolution of 19 and 21 with a
pseudoenantiomeric mixture of (S)-1 and (R)-38 was investigated,
to facilitate the asymmetric synthesis of each enantiomer of 3-
oxy-substituted cispentacin. Furthermore, it was anticipated that
the corresponding 3-oxy-substituted transpentacin derivatives
would be available from the epimerisation of the b-amino ester
Scheme
9
Reagents and conditions: (i) lithium (S)-N-benzyl-N-
(a-methylbenzyl)amide (S)-1 (2.5 eq.), lithium (R)-N-3,4-dimethoxy-
benzyl-N-(a-methylbenzyl)amide (R)-38 (2.5 eq.), THF, −78 ◦C, 4 h, then
2,6-di-tert-butylphenol.
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Similar treatment of 3-O-Me tert-butyl ester 19 with a 50 : 50
mixture of (S)-1 and (R)-38 gave equally excellent stereoselectivity,
affording a 50 : 50 mixture of b-amino esters (1R,2R,3R,aS)-33
and (1S,2S,3S,aR)-39 only (E >99). Chromatographic separation
gave 33 in 25% yield and 39 in 30% yield (Scheme 10).
Scheme 10 Reagents and conditions: (i) lithium (S)-N-benzyl-N-
(a-methylbenzyl)amide (S)-1 (2.5 eq), lithium (R)-N-3,4-dimethoxy-
benzyl-N-(a-methylbenzyl)amide (R)-38 (2.5 eq.), THF, −78 ◦C, 4 h, then
NH4Cl (sat., aq.).
Preparation of 3-methoxy-substituted cispentacin and
transpentacin
Subsequent investigations focused upon deprotection and epimeri-
sation of the 3-O-Me substituted derivatives to the par-
ent 3-O-Me substituted cispentacin and transpentacin. N-3,4-
Dimethoxybenzyl b-amino ester (1S,2S,3S,aR)-39 was epimerised
to give (1R,2S,3S,aR)-40 in 61% yield and in >98% de. A three-
step deprotection procedure of 39 and 40 was then implemented.
Oxidative removal of the N-3,4-dimethoxybenzyl protecting
group from 39 and 40 with DDQ gave the corresponding N-a-
methylbenzyl protected amines 43 and 44 in 98% isolated yield
in each case. Subsequent hydrogenolysis furnished the primary
b-amino esters (1S,2S,3S)-45 and (1R,2S,3S)-46 in 90 and 96%
yield respectively, and in >98% de and >98% ee24 in each case.
Acid catalysed ester hydrolysis and purification by ion-exchange
chromatography gave the enantiomers of 3-O-Me cispentacin and
transpentacin (1S,2S,3S)-47 and (1R,2S,3S)-48, respectively, in
good yield and >98% de in each case (Scheme 11).
In a related strategy, epimerisation of N-benzyl b-amino ester
(1R,2R,3R,aS)-33 gave a 85 : 15 mixture of the C(1)-epimeric
b-amino ester (1S,2R,3R,aS)-34 and the corresponding acid
derivative (1S,2R,3R,aS)-37 only, from which 34 was isolated in
85% yield and >98% de after chromatography. N-Debenzylation
of b-amino esters 33 and 34 with Pearlman’s catalyst under H2 (5
atm), gave the corresponding primary b-amino esters (1R,2R,3R)-
45 and (1S,2R,3R)-46 in 89 and 94% yield, and in >98% de and
>98% ee in each case.24 The b-amino esters (1R,2R,3R)-45 and
(1S,2R,3R)-46 were then hydrolysed by treatment with TFA, with
subsequent purification by ion-exchange chromatography afford-
ing 3-O-Me cispentacin and transpentacin analogues (1R,2R,3R)-
47 and (1S,2R,3R)-48 in 77 and 65% yield respectively, and in
>98% de in each case (Scheme 12).
t
Scheme 11 Reagents and conditions: (i) KOtBu, BuOH–THF (1 : 1),
80 ◦C, 12 h; (ii) DDQ, DCM–H2O (5 : 1), rt, 48 h; (iii) H2 (5 atm.),
Pd(OH)2/C, MeOH, rt, 24 h; (iv) TFA, DCM, rt, 16 h, then HCl, Et2O,
then Dowex 50WX8-200.
Conclusion
In conclusion, racemic tert-butyl 3-oxy-substituted cyclopent-
1-ene-carboxylates display excellent levels of selectivity in
mutual kinetic resolution with lithium (RS)-N-benzyl-N-(a-
methylbenzyl)amide and lithium (RS)-N-3,4-dimethoxybenzyl-
N-(a-methylbenzyl)amide, with E >99 in both cases. Homochi-
ral lithium (S)-N-benzyl-N-(a-methylbenzyl)amide and lithium
(R)-N-3,4-dimethoxybenzyl-N-(a-methylbenzyl)amide were then
employed as pseudoenantiomeric resolving agents in the par-
allel kinetic resolution of tert-butyl 3-methoxy- and 3-tert-
butyldiphenylsilyloxy-cyclopent-1-ene-carboxylate. These reac-
tions afforded differentially protected 3-oxy-substituted cis-
pentacin analogues in high yield and >98% de. Subsequent N-
deprotection and hydrolysis provides access to 3-oxy-substituted
cispentacin derivatives in good yield, >98% de and >98% ee,
while highly stereoselective epimerisation and deprotection af-
fords 3-oxy-substituted transpentacin analogues in good yield,
>98% de and >98% ee. The application of these substrates as
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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 polyanaline, 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.
Parallel kinetic resolution of 19: tert-butyl (1R,2R,3R,aS)-2-
[N-benzyl-N-(a-methylbenzyl)amino]-3-methoxy-cyclopentane-
carboxylate 33 and tert-butyl (1S,2S,3S,aR)-2-[N-3,4-
dimethoxybenzyl-N-(a-methylbenzyl)amino]-3-methoxy-
cyclopentane-carboxylate 39
Scheme 12 Reagents and conditions: (i) KOtBu, BuOH–THF (1 : 1),
t
80 ◦C, 12 h; (ii) H2 (5 atm), Pd(OH)2/C, MeOH, rt, 24 h; (iii) TFA, DCM,
rt, 16 h, then HCl, Et2O, then Dowex 50WX8-200.
BuLi (2.5 M in hexanes, 0.75 mL, 1.87 mmol) was added
dropwise via syringe to a stirred solution of (S)-N-benzyl-N-
(a-methylbenzyl)amine (200 mg, 0.95 mmol) and (R)-N-3,4-
dimethoxybenzyl-N-(a-m◦ethylbenzyl)amine (257 mg, 0.95 mmol)
in THF (52 mL) at −78 C. After stirring for 30 min a solution
of 19 (75 mg, 0.38 mmol) in THF (3.2 mL) at −78 ◦C was added
dropwise via a cannula. After stirring for a further 4 h at −78 ◦C
the reaction mixture was quenched with a solution of 2,6-di-tert-
butylphenol in THF and allowed to warm to rt over 1 h before
being concentrated in vacuo. The residue was partitioned between
DCM (50 mL) and 10% aq. citric acid (10 mL). The organic
layer was separated and the aqueous layer was extracted with
DCM (2 × 50 mL). The combined organic extracts were washed
sequentially with sat aq. NaHCO3 (50 mL) and brine (50 mL),
dried and concentrated in vacuo to give a 50 : 50 mixture of 33 :
39. Purification by chromatography (3% Et2O in pentane) gave
(1R,2R,3R,aS)-33 as a colourless oil (39 mg, 25%, >98% de); [a]D24
organocatalysts, and as monomers for the construction of b-
peptides is currently ongoing within our laboratory.
Experimental
General experimental
All reactions involving organometallic or other moisture-sensitive
reagents were carried out under a nitrogen or argon atmosphere
using standard vacuum line techniques and glassware that was
flame dried and cooled under nitrogen before use. Solvents were
dried according to the procedure outlined by Grubbs and co-
workers.25 Water was purified by an Elixꢀ UV-10 system. All other
R
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.
=
−91.1 (c 1.0 in CHCl3); mmax (film) 1722 (C O); dH (400 MHz,
CDCl3) 1.37 [3H, d, J 6.9, C(a)Me], 1.52 (9H, s, CMe3), 1.72–1.80
[2H, m, C(5)H2], 2.18–2.29 [2H, m, C(4)H2], 2.78–2.83 [1H, m,
C(1)H], 3.10 (3H, s, OMe), 3.19 [1H, app t, J 7.6, C(2)H], 3.95–
4.00 [1H, m, C(3)H], 3.99 (2H, app d, J 15.7, NCH2), 4.24 [1H,
q, J 6.9, C(a)H], 7.21–7.49 (10H, m, Ph); dC (100 MHz, CDCl3)
17.3, 25.0, 28.2, 28.3, 48.4, 50.9, 56.6, 57.9, 68.8, 79.9, 82.2, 126.1,
126.7, 127.9, 128.0, 128.6, 128.7, 129.7, 142.8, 143.1, 174.9; m/z
(ESI+) 410 ([M + H]+, 100%); HRMS (ESI+) found 410.2704;
C26H36NO3 ([M + H]+) requires 410.2695. Further elution gave
(1S,2S,3S,aR)-39 as a pale yellow oil (53 mg, 30%, >98% de);
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.
The field was locked by external referencing to the relevant
deuteron resonance. Low-resolution mass spectra were recorded
[a]2D4 +67.4 (c 1.2 in CHCl3); mmax (film) 1721 (C O); dH (400 MHz,
=
CDCl3) 1.37 [3H, d, J 6.8, C(a)Me], 1.48 (9H, s, CMe3), 1.67–1.77
[2H, m, C(5)H2], 2.17–2.26 [2H, m, C(4)H2], 2.74–2.78 [1H, m,
C(1)H], 3.14 [3H, s, C(3)OMe], 3.16–3.20 [1H, m, C(2)H], 3.83–
3.98 (2H, m, NCH2), 3.87 (3H, s, ArOMe), 3.91 (3H, s, ArOMe),
4.01–4.06 [1H, m, C(3)H], 4.21 [1H, q, J 6.8, C(a)H], 6.80–7.42
(8H, m, Ar, Ph); dC (100 MHz, CDCl3) 16.7, 24.9, 28.0, 28.1, 48.2,
50.7, 55.7, 55.8, 57.6, 68.7, 79.9, 82.0, 110.6, 111.3, 119.5, 126.5,
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127.9, 135.2, 143.4, 147.3, 148.6, 174.6; m/z (ESI+) 470 ([M + H]+,
100%); HRMS (ESI+) found 470.2903; C43H56NO5Si ([M + H]+)
requires 470.2906.
174.9; m/z (ESI+) 694 ([M + H]+, 100%); HRMS (ESI+) found
694.3920; C43H56NO5Si ([M + H]+) requires 694.3928.
Acknowledgements
Parallel kinetic resolution of 21: tert-butyl (1R,2R,3R,aS)-2-
[N-benzyl-N-(a-methylbenzyl)amino]-3-tert-butyldiphenyl-
silyloxy-cyclopentane-carboxylate 35 and tert-butyl
(1S,2S,3S,aR)-2-[N-3,4-dimethoxybenzyl-N-(a-
methylbenzyl)amino]-3-tert-butyldiphenylsilyloxy-cyclopentane-
carboxylate 41
The authors would like to thank New College, Oxford for a Junior
Research Fellowship (A. D. S.).
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BuLi (2.5 M in hexanes, 469 lL, 1.17 mmol) was added
dropwise via syringe to a stirred solution of (S)-N-benzyl-
N-(a-methylbenzyl)amine (125 mg, 0.59 mmol), (R)-N-3,4-
dimethoxybenzyl-N-(a-methylbenzyl)amine (161 mg, 0.59 mmol)
in THF (16 mL) at −78 ◦C. After stirring for 30 min a solution of 21
(100 mg, 0.24 mmol) in THF (2 mL) at −78 ◦C was added dropwise
via a cannula. After stirring for a further 4 h at −78 ◦C the reaction
mixture was quenched with a solution of 2,6-di-tert-butylphenol in
THF and allowed to warm to rt over 1 h before being concentrated
in vacuo. The residue was partitioned between DCM (50 mL) and
10% aq. citric acid (10 mL). The organic layer was separated and
the aqueous layer was extracted with DCM (2 × 50 mL). The
combined organic extracts were washed sequentially with sat. aq.
NaHCO3 (50 mL) and brine (50 mL), dried and concentrated in
vacuo to give a 45 : 5 : 45 : 5 mixture of 35 : 36 : 41 : 42. Purification
by chromatography (1% Et2O in pentane) gave (1R,2R,3R,aS)-35
as a colourless oil (60 mg, 40%, >98% de); [a]2D4 −22.6 (c 1.0 in
=
CHCl3); mmax (film) 1722 (C O); dH (400 MHz, CDCl3) 1.09 (9H, s,
SiCMe3), 1.33–1.34 [1H, m, C(4)HA], 1.35 [3H, d, J 6.6, C(a)Me],
1.41 (9H, s, OCMe3), 1.52–1.28 [3H, m, C(4)HB, C(5)H2], 2.48–
2.49 [1H, m, C(1)H], 3.41 [1H, app t, J 7.7, C(2)H], 4.04–4.07 [3H,
m, C(a)H, NCH2], 4.65–4.70 [1H, m, C(3)H], 7.24–7.72 (20H, m,
Ph); dC (100 MHz, CDCl3) 16.5, 19.2, 25.0, 27.0, 28.1, 31.5, 47.3,
51.6, 57.2, 69.6, 76.0, 80.0, 126.4, 126.6, 127.4, 127.6, 128.0, 128.2,
128.3, 129.4, 129.5, 134.0, 134.9, 135.8, 135.9, 142.0, 144.1, 174.8;
m/z (ESI+) 634 ([M + H]+, 100%); HRMS (ESI+) found 634.3759;
C41H52NO3Si ([M + H]+) requires 634.3787. Further elution gave
(1S,2S,3S,aR)-41 as a colourless oil (59 mg, 36%, >98% de); [a]D24
=
+13.1 (c 1.0 in CHCl3); mmax (film) 1721 (C O); dH (400 MHz,
CDCl3) 1.07 (9H, s, SiCMe3), 1.21–1.47 [13H, m, C(4)HA, C(a)Me,
OCMe3], 1.52–1.60 [2H, m, C(5)H2], 1.61–1.68 [2H, m, C(4)HB],
2.46–2.49 [1H, m, C(1)H], 3.38–3.41 [1H, m, C(2)H], 3.86 (3H, s,
ArOMe), 3.88 (3H, s, ArOMe), 3.95 (2H, AB system, JAB 14.3,
NCH2), 4.05 [1H, q, J 6.7, C(a)H], 4.66–4.70 [1H, m, C(3)H],
6.76–7.71 (18H, m, Ar, Ph); dC (100 MHz, CDCl3) 15.5, 19.1,
24.8, 26.9, 28.0, 31.5, 47.7, 51.1, 55.5, 55.6, 56.4, 69.3, 75.9, 79.7,
110.6, 111.4, 119.9, 126.4, 129.4, 133.9, 135.8, 143.9, 147.5, 148.7,
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©