Evaluating β-amino acids as enantioselective organocatalysts of the Hajos-Parrish-Eder-Sauer-Wiechert reaction

Article abstract of DOI:10.1039/b711171a

A systematic study of the effect of substitution within the β-amino acid framework indicates that both β²- and β³- amino acids catalyse the Hajos-Parrish-Eder-Sauer-Wiechert reaction with poor to reasonable levels of enantioselectivity. These results led to the evaluation of the conformationally constrained β-amino acid (1R,2S)-cispentacin, which catalyses the Hajos-Parrish-Eder-Sauer-Wiechert reaction with comparable or higher levels of enantioselectivity to l-proline. The Royal Society of Chemistry.

Full text of DOI:10.1039/b711171a

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www.rsc.org/obc | Organic & Biomolecular Chemistry
Evaluating b-amino acids as enantioselective organocatalysts of the
Hajos–Parrish–Eder–Sauer–Wiechert reaction†
Stephen G. Davies,* Angela J. Russell, Ruth L. Sheppard, Andrew D. Smith and James E. Thomson
Received 20th July 2007, Accepted 13th August 2007
First published as an Advance Article on the web 29th August 2007
DOI: 10.1039/b711171a
A systematic study of the effect of substitution within the b-amino acid framework indicates that both
b2- and b3-amino acids catalyse the Hajos–Parrish–Eder–Sauer–Wiechert reaction with poor to
reasonable levels of enantioselectivity. These results led to the evaluation of the conformationally
constrained b-amino acid (1R,2S)-cispentacin, which catalyses the Hajos–Parrish–Eder–Sauer–
Wiechert reaction with comparable or higher levels of enantioselectivity to L-proline.
Jung questioned the stereochemical outcome of this model in
Introduction
1976.11 An enamine mechanism was suggested by various groups
throughout the 1970s and 1980s,11,12 before Agami et al. proposed
a two-proline mechanism, based on non-linear effects (transition
state model 6).13 Reinvestigation of these latter results by List and
The study of organocatalytic reactions has undergone enormous
expansion in the last decade.1 A range of catalysts of varying struc-
tural complexity have been developed within this field that encom-
pass imidazolidinones,2 phosphines,3 peptides,4 N-heterocyclic
carbenes,5 thioureas6 and bifunctional catalyst systems,7 among
others.8 The most readily available catalysts within this field
are undoubtedly the proteinogenic a-amino acids, with proline
arguably the most commonly used organocatalyst. One of the
first enantioselective organocatalytic reactions catalysed by L-
proline 1 was the intramolecular Hajos–Parrish–Eder–Sauer–
Wiechert reaction.9 This asymmetric variant of the Robinson ring
annelation was initially developed for the synthesis of steroid and
terpenoid intermediates. Enantioselective cyclisation of triketones
2 produces enone products (S)-3 in good yield and with high levels
of enantioselectivity (up to 93% e.e.) and has proven useful in
the generation of synthetic building blocks for the preparation of
natural products and their analogues such as 19-nortestosterone
4 (Scheme 1).10
co-workers found that a non-linear effect was not observed,14 and a
possible reconciliation of these results has recently been proposed
by Blackmond.15 In 1999 Swaminathan proposed a heterogeneous
aldolisation mechanism on the surface of crystalline proline
(transition state model 7).16 Recently Houk et al. have proposed a
one-proline enamine mechanism (transition state model 8) based
on both experimental evidence and computational modelling
studies, which is now widely accepted as an explanation for
the stereoselectivity of the Hajos–Parrish–Eder–Sauer–Wiechert
reaction (Fig. 1).17
Scheme 1 Reagents and conditions: (i) L-proline 1 (30 mol%), DMF, rt,
24 h; (ii) p-TsOH, toluene, D, 5 h.
The mechanism of the Hajos–Parrish–Eder–Sauer–Wiechert
reaction has been heavily disputed with several alternatives
proposed, although it is now widely accepted that an enamine
mechanism is operating. Hajos first suggested a model that
involves “activation” of one of the enantiotopic acceptor carbonyl
groups as a carbinol amine (transition state model 5), although
Fig. 1 Proposed mechanisms and transition state models for the Hajos—
Parrish–Eder–Sauer–Wiechert reaction.
Many different catalysts have been screened for reactivity and
enantioselectivity in the Hajos–Parrish–Eder–Sauer–Wiechert re-
action, with the most common based upon proline derivatives.
While (S)-prolinol 12 and (S)-proline methyl ester 13 both produce
enone (S)-11 in 17% e.e.,18,19 Hanessian et al. have also shown that
cis-(2S,4S,5S)-4,5-methanoproline 14 has a comparable catalytic
Department of Organic Chemistry, University of Oxford, Chemistry Research
Laboratory, Mansfield Road, Oxford, OX1 3TA, UK. E-mail: steve.
davies@chem.ox.ac.uk
† Electronic supplementary information (ESI) available: Experimental
details. See DOI: 10.1039/b711171a
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activity to L-proline 1, giving (S)-11 in 93% e.e. and good yield,
whereas catalysis with trans-(2R,4R,5R)-4,5-methanoproline 15
proceeded at a much slower rate, producing enone (S)-11 in
83% e.e. (Scheme 2).20 There are relatively few examples of
highly enantioselective catalysts that incorporate a primary amino
functionality; for example, L-phenylalanine 16 gives enone (S)-
11 in 85% yield and 25% e.e. while L-tert-leucine 17 gives (S)-11
in 95% yield but only 2% e.e.21 Notable exceptions include the
use of L-phenylalanine 16 in the presence of an acid co-catalyst
for the cyclisation of terminally substituted ketones22 2 (Rꢀ =
H, Scheme 1), and (S)-a-methylbenzylamine 18, which produces
enone (S)-11 in 81% yield and 45% e.e.9 Despite these numerous
investigations, L-proline 1 still remains the most enantioselective
catalyst known for this reaction (Scheme 2).23
11 in 58% and 83% e.e. respectively. As an extension of our research
concerned with the synthesis and chemistry of enantiomerically
pure b-amino acids,25 we envisaged that a systematic study of the
effects of substitution within the b-amino acid framework would
allow efficient asymmetric organocatalysts to be developed. Our
strategy was to screen a range of simple enantiomerically pure
b3-, b2- and N-alkyl-b3-amino acid catalysts for their reactivity
in the Hajos–Parrish–Eder–Sauer–Wiechert reaction in order to
gain an insight into the structural factors that allow high catalyst
turnover and enantioselectivity. This would enable the prediction
of the structural characteristics necessary for the design of a
second-generationb-amino catalyst that would catalyse the desired
reaction with high selectivity.
Subsequent to the communication of our preliminary work
in this field,26 Limbach reported the use of b3-amino acids
in the Hajos–Parrish–Eder–Sauer–Wiechert reaction and inter-
molecular aldol reactions,27 and the application of b-amino acid
organocatalysts in other systems has also increased.28 Herein
we delineate our full investigations concerning the ability of b-
amino acids to promote the Hajos–Parrish–Eder–Sauer–Wiechert
reaction.
Results and discussion
Assessing b3- and b2-amino acids as organocatalysts
Initial studies focused upon screening a range of enantiomerically
pure b3-amino acids 19–35 (prepared in each case via the applica-
tion of our lithium amide conjugate addition methodology)25 for
their catalytic efficiency in the cyclisation of triketone 9. The stan-
dard conditions used in this catalyst screen involved treatment of
triketone 9 with a b-amino acid (30 mol%) in DMF to give ketol 10.
Ketol 10 was purified to homogeneity by chromatography before
subsequent p-TsOH-promoted dehydration to give enone 11.
The e.e. of enone 11 was unambiguously determined by chiral
GC analysis with reference to racemic enone 11. Purification of
ketol 10 to homogeneity is essential to ensure a true measure of
the enantioselectivity in this process, as treatment of triketone 9
with p-TsOH in toluene at reflux gives quantitative conversion
to racemic enone 11. As a model catalyst, (S)-3-aminobutanoic
acid 19 was evaluated, giving ketol 10 in only low conversion
(28%) after 72 hours. Purification to homogeneity and subsequent
dehydration gave enone (R)-11 in 15% isolated yield (over two
steps) and 47% e.e. Under identical conditions, (R)-3-amino-4-
phenylbutanoic acid 20 gave 89% coversion to ketol 10, giving
enone (S)-11 in 73% yield and 64% e.e. However, b-amino acids
21 and 22 bearing a- or b-branched C(3)-alkyl substituents
displayed greater levels of conversion to ketol 10 than C(3)-
methyl b-amino acid 19, with (R)-3-amino-5-methylhexanoic acid
22 giving enone (S)-11 in 86% e.e. The application of N-alkyl-
3-aminobutanoic acids 23–25 as catalysts for the cyclisation
of triketone 9 was next investigated, resulting in decreased
catalytic activity and diminished enantioselectivities relative to
the analogous N-unsubstituted-b-amino acid catalyst 19. (S)-
Homoproline 26 was subsequently tested, giving quantitative
conversion to ketol 10, and giving enone (R)-11 in 64% yield and
36% e.e. (Scheme 3). Subsequent studies investigated the catalytic
propensity of C(3)-aryl substituted b-amino acids in the cyclisation
of triketone 9. With (R)-3-amino-3-phenylpropanoic acid 27, only
Scheme 2 Reagents and conditions: (i) catalyst, DMF, rt; (ii) p-TsOH,
toluene, D.
Employing b-amino acids as asymmetric organocatalysts in-
volves the introduction of an additional carbon unit between
the amino and carboxylate functionalities relative to a-amino
acids. While this may intuitively lead to greater conformational
flexibility, it allows bespoke catalyst systems to be designed
through appropriate substitution at either the N- or the a- and b-
positions (Fig. 2). At the onset of these investigations, only limited
previous studies detailing b-amino acid catalysis of the cyclisation
of triketone 9 have been reported, with (S)-homoproline24 and (S)-
3-amino-4-phenylbutanoic acid21 being reported to give enone (R)-
Fig. 2 Comparision of a- and b-amino acid organocatalysts.
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low conversion to ketol 10 (38%) was noted after 72 hours, giving
enone (R)-11 in 36% isolated yield and 40% e.e. Further C(3)-
aryl substituted b-amino acids 28–35 were all catalytically active
in this reaction, giving varying levels of conversion to ketol 10
(49%–quantitative) and enantioselectivities (37–81% e.e.) in the
formation of enone 11 (Scheme 3).
in this cyclisation reaction, as both b3- and b2-amino acids
promote the Hajos–Parrish–Eder–Sauer–Wiechert reaction with
average to good conversion and enantioselectivity. The primary
amino functionality is also tolerated, although non-cyclic N-
substituted b3-amino acids gave poor conversions. It was therefore
proposed that a,b-disubstituted b2,3-amino acids would restrict
the conformational flexibility of the catalysts, providing a fixed
orientation of the carboxylic acid and amino functionalities that
should provide high enantiocontrol in this reaction manifold.
Assessing conformationally constrained b-amino acids as
organocatalysts
Cyclic a,b-disubstituted-b-amino acids containing five- and six-
membered rings in which the primary amino and carboxylate
functionalities can adopt either the cis or trans relative configura-
tion were next investigated as organocatalysts. The desired cyclic
b-amino acids (1R,2S)-cispentacin 38, (1S,2S)-transpentacin 40,
(1R,2S)-cishexacin 39 and (1S,2S)-transhexacin 41 were prepared
in diastereo- and enantiomerically pure form following our
established literature protocol.29 Treatment of triketone 9 with
the cyclic b-amino acids (1S,2S)-transpentacin 40 and (1S,2S)-
transhexacin 41 gave full conversion to ketol 10, producing
enone (R)-11 in 66% and 63% e.e. respectively. With (1R,2S)-
cispentacin 38 and (1R,2S)-cishexacin 39, quantitative conversion
to ketol 10 was also observed, giving enone (R)-11 in 94%
and 92% isolated yield respectively and with greatly improved
levels of stereoselectivity; (1R,2S)-cishexacin 39 gave enone (R)-
11 in 87% e.e. while (1R,2S)-cispentacin 38 gave enone (R)-11
in 90% e.e. The high stereoselectivity using (1R,2S)-cispentacin
38 (90% e.e.) is comparable to that using L-proline 1 (93% e.e.)
and is the highest enantioselectivity reported to date for this
particular transformation using an amino acid containing a pri-
mary amino functionality (Scheme 5). Given this promising result,
further b-amino catalysts that incorporate either an additional
C(3)-alkyl substituent30 42–44 or an oxygen atom within the
cispentacin framework31 45 were screened for their reactivity in
the cyclisation of 9. All of the catalysts screened produced ketol
10 with quantitative conversion, giving enone (R)-11 in high
yield and in good to excellent enantioselectivity (84–90% e.e.)
(Scheme 5).
Scheme 3 Reagents and conditions: (i) catalyst (30 mol%), DMF, rt, 3 days;
(ii) p-TsOH, toluene, D, 5 h.
Attention next turned to the use of b2-amino acids 36 and 37 as
catalysts for this reaction, with (S)-2-isopropyl-3-aminopropanoic
acid 37 giving good conversion to ketol 10 (94%) and producing
enone 11 in 56% e.e. (Scheme 4).
Having demonstrated that (1R,2S)-cispentacin 38 promotes the
highly enantioselective cyclisation of triketone 9, the generality of
this protocol was evaluated through the enantioselective cyclisa-
tion of triketones 46 and 48 that differ in both alkyl substitution
and ring size with respect to triketone 9. Cyclisation using L-
proline 1 was also evaluated under the same reaction conditions to
afford a direct comparison of the stereoselectivity of the reaction
in each case. The cyclisations promoted by (1R,2S)-cispentacin
38 proceeded to complete conversion, giving the corresponding
enones (R)-47 and (R)-49 respectively after dehydration. In each
case, higher levels of enantioselectivity using the b-amino acid
(1R,2S)-cispentacin 38 were noted than using the a-amino acid
L-proline 1 for the same cyclisation {formation of 47; (1R,2S)-
cispentacin 38 78% e.e. [(R)], L-proline 1 74% e.e. [(S)]; formation
of 49, (1R,2S)-cispentacin 38 86% e.e. [(R)], L-proline 1 72% e.e.
[(S)]} (Scheme 6).
Scheme 4 Reagents and conditions: (i) catalyst (30 mol%), DMF, rt, 3 days;
(ii) p-TsOH, toluene, D, 5 h.
These results suggest that the b-amino acid skeleton can tolerate
substitution at C(2) and C(3) and still maintain catalytic activity
Subsequent studies focused upon the enantioselective cy-
clisation of terminally substituted triketone 50 using both
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Scheme 7 Reagents and conditions: (i) L-proline 1 or (1R,2S)-cispentacin
38 (30 mol%), DMF, 60 ◦C; (ii) p-TsOH, toluene, D.
Synthesis and evaluation of conformationally constrained b-amino
tetrazole derivatives as asymmetric organocatalysts
A number of recent publications have demonstrated that tetra-
zole equivalents of amino acids (proline and homoproline) are
efficient organocatalysts for a range of transformations.32 Having
demonstrated that conformationally constrained b-amino acid
derivatives offer high levels of enantioselectivity in the cyclisation
of triketones 9, 46 and 48, subsequent studies turned to the
synthesis and evaluation of the tetrazole equivalents of cispentacin
and transpentacin as organocatalysts. Starting from the known
protected cis- and trans-b-amino esters 53 and 54 (>98% d.e.
in each case), hydrogenolysis and N-Cbz-protection gave cis-
(1R,2S)-55 and trans-(1S,2S)-56 (>98% d.e.) in good yield.
Subsequent TFA-mediated ester deprotection, amide formation
and dehydration with cyanuric chloride furnished the N-Cbz-
protected nitriles cis-(1R,2S)-57 and trans-(1S,2S)-58 in 80% and
82% yield respectively over 3 steps. Attempted formation of the
tetrazole derivative of cis-(1R,2S)-57 under a range of conditions
was investigated, which demonstrated that treatment of an excess
of NaN3 (10 eq.) in a H2O–i-PrOH solvent mixture with ZnBr2
as a Lewis acid was necessary for high reaction conversion,33
with subsequent N-Cbz deprotection by hydrogenolysis giving
cis-b-amino tetrazole (1ꢀR,2ꢀS)-59 in >98% d.e. and 81% yield
over 2 steps. Application of this optimised procedure upon trans-
(1S,2S)-58 gave the desired trans-b-amino tetrazole (1ꢀS,2ꢀS)-60
in >98% d.e. and 62% yield over 2 steps (Scheme 8). Arvidsson
and Hartikka have observed that the L-proline-derived tetrazole
exists in solution as a mixture of tautomers.34 This phenomena
was also observed for the cis- and trans-b-amino tetrazoles 59 and
60. cis-b-Amino tetrazole (1ꢀR,2ꢀS)-59 exists as an 88 : 12 ratio
of tautomers in MeOD and an 81 : 19 ratio in D2O, while trans-
b-amino tetrazole (1ꢀS,2ꢀS)-60 appears to exist almost exclusively
as one tautomer in MeOD (99 : 1) and as an 81 : 19 mixture
of tautomers in D2O. Although the 1H- and 2H-tautomers could
not be unambiguously assigned in each case, for simplicity cis- and
trans-b-amino tetrazoles (1ꢀR,2ꢀS)-59 and (1ꢀS,2ꢀS)-60 respectively
are represented as the 1H-tautomers.
Scheme 5 Reagents and conditions: (i) catalyst (30 mol%), DMF, rt, 3 days;
(ii) p-TsOH, toluene, D, 5 h.
Scheme 6 Reagents and conditions: (i) (1R,2S)-cispentacin 38 (30 mol%),
DMF, rt; (ii) p-TsOH, toluene, D; (iii) L-proline 1 (30 mol%), DMF, rt.
(1R,2S)-cispentacin 38 and L-proline 1. In each case, elevated
temperatures (60 ◦C) and extended reaction times were necessary
to promote consumption of starting material. Treatment of 50
with L-proline 1 at 60 ◦C for 7 days gave 95% conversion to
ketol (3aS,4S,7aS)-51, with purification giving ketol 51 in 81%
isolated yield. Subsequent dehydration with p-TsOH furnished
enone (S)-52 in 94% yield and 71% e.e. Treatment of triketone 50
with (1R,2S)-cispentacin 38 at 60 ◦C for 9 days gave quantitative
conversion to ketol (3aR,4R,7aR)-51, which gave enone (R)-52
in 83% yield and 27% e.e. after dehydration and purification
(Scheme 7).
The catalytic activity of cis-(1ꢀR,2ꢀS)-59 and trans-(1ꢀS,2ꢀS)-
60 was then probed. Treatment of triketone 9 with cis-b-amino
tetrazole (1ꢀR,2ꢀS)-59 proceeded with a marked rate enhancement
(quantitative conversion within 1 day) in comparison to (1R,2S)-
cispentacin 38 and with a remarkable change in product distribu-
tion, giving only the racemic bicyclic species 61 that was isolated
in 67% yield (Scheme 9).35 The trans relative configuration of the
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Scheme 8 Reagents and conditions: (i) H2 (5 atm), Pd(OH)2/C, MeOH, rt; (ii) CbzCl, Et3N, THF, 0 ◦C to rt; (iii) TFA–DCM (1 : 4), rt; (iv) Boc2O,
NH4HCO3, MeCN, pyridine (cat.), rt; (v) cyanuric chloride, DMF, 0 ◦C; (vi) NaN3 (10 eq.), ZnBr2, i-PrOH–H2O (1 : 2), D; (vii) Pd(OH)2/C, H2 (1 atm),
MeOH, rt.
dehydration conditions to afford enone (S)-11 in 86% isolated
yield and 20% e.e (Scheme 9).
Treatment of triketone 46 with b-amino tetrazoles 59 and 60 was
next investigated: addition of cis-b-amino tetrazole (1ꢀR,2ꢀS)-59
gave a chromatographically inseparable 80 : 20 mixture of racemic
bicyclic alcohol (1RS,4RS,5SR)-62 and ketol (3aR,7aR)-63 after
4 days. Fractional crystallisation of this mixture gave an analytical
sample of alcohol (1RS,4RS,5SR)-62 in 27% yield.36 The trans-
relative configuration of the C(1) and C(5) alkyl substituents in bi-
cyclic alcohol (1RS,4RS,5SR)-62 was unambiguously established
through single crystal X-ray crystallographic analysis‡ (Fig. 4).
Treatment of a 64 : 36 mixture of alcohol (1RS,4RS,5SR)-62
and ketol (3aR,7aR)-63 with p-TsOH gave enone (R)-47 in 98%
isolated yield and 12% e.e. The isolation of enone 47 in 98%
yield from the 64 : 36 mixture of 62 and 63 indicates that both
ketol 63 and bicyclic alcohol 62 can be converted to enone 47.
The conversion of bicyclic alcohol 62 to enone 47 presumably
occurs via acid catalysed retro-aldol reaction to generate triketone
46, followed by acid-promoted cyclisation to give (RS)-enone 47.
Consistent with this scenario, treatment of triketone 46 with p-
TsOH gave quantitative conversion to (RS)-enone 47. Using this
hypothesis, the e.e. of (R)-47 from the tetrazole-catalysed protocol
is calculated to be 33%.37 However, treatment of triketone 46 with
trans-b-amino tetrazole (1ꢀS,2ꢀS)-60 for 1 day gave 89% conversion
to ketol (3aS,7aS)-63, which was isolated by chromatography in
80% isolated yield. Subsequent dehydration afforded enone (S)-47
in 81% isolated yield and 7% e.e. (Scheme 10).
Scheme 9 Reagents and conditions: (i) (1ꢀR,2ꢀS)-59 (30 mol%), DMF, rt;
(ii) (1ꢀS,2ꢀS)-60, (30 mol%), DMF, rt; (iii) p-TsOH, toluene, D.
Fig. 3 Chem 3DꢀR representation of the X-ray crystal structure of ( )-61
(some H atoms omitted for clarity).
C(1) and C(5) methyl substituents in alcohol (1RS,4RS,5SR)-
61 was unambiguously established through single crystal X-ray
crystallographic analysis‡ (Fig. 3). Triketone 9 was subsequently
treated with trans-b-amino tetrazole (1ꢀS,2ꢀS)-60 under identical
conditions, giving quantitative conversion to ketol (3aS,7aS)-
10 after 24 hours. Chromatographic purification furnished ketol
(3aS,7aS)-10 in 90% yield, which was subjected to standard
Fig. 4 Chem 3DꢀR representation of the X-ray crystal structure of ( )-62
(some H atoms omitted for clarity).
‡ CCDC reference numbers 650320 (61) and 650321 (62). For crystallo-
graphic data in CIF or other electronic format see DOI: 10.1039/b711171a
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Scheme 10 Reagents and conditions: (i) (1ꢀR,2ꢀS)-59 (30 mol%), DMF, rt;
(ii) (1ꢀS,2ꢀS)-60 (30 mol%), DMF, rt; (iii) p-TsOH, toluene, D.
Conversely, when triketone 48 was treated with cis- and trans-
b-amino tetrazoles (1ꢀR,2ꢀS)-59 and (1ꢀS,2ꢀS)-60 according to our
standard procedures, enone (R)-49 was furnished exclusively in
both cases, in 81% yield and 40% e.e. and 67% yield and 28% e.e.
respectively (Scheme 11).
Fig. 5 Product distributions in the Hajos–Parrish–Eder–Sauer–Wiechert
reaction.
The high enantioselectivity observed for the cyclisation of
triketones 9, 46 and 48 using (1R,2S)-cispentacin 38 can be
rationalised using a simplistic model. Assuming hydrogen bonding
activation between the carboxylic acid and carbonyl undergoing
nucleophilic attack is a prerequisite for high enantioselectivity, it
is proposed that the reaction proceeds preferentially via the s-cis
enamine geometry and through transition state 68 that minimises
steric interactions (Fig. 6).
Scheme 11 Reagents and conditions: (i) (1ꢀR,2ꢀS)-59 or (1ꢀS,2ꢀS)-60
(30 mol%), DMF, rt.
Product distribution and enantioselectivity in the b-amino acid
catalysed Hajos–Parrish–Eder–Sauer–Wiechert reaction
These investigations have demonstrated that b-amino acid
catalysed Hajos–Parrish–Eder–Sauer–Wiechert reactions using
(1R,2S)-cispentacin 38 generally give the corresponding ketol as
the major reaction product with high enantioselectivity, while cis-
b-amino tetrazole (1ꢀR,2ꢀS)-59 gives alternative racemic bicyclic
alcohol products. This is a remarkable change in product distri-
bution on simply changing the acid functionality to a tetrazole. If
it is assumed that Hajos–Parrish–Eder–Sauer–Wiechert reactions
catalysed by b-amino acids or tetrazoles proceed via enamine
formation to give these products, the formation of ketol products
65 presumably occurs via enamine 64 derived from the exocyclic
carbonyl, while bicyclic alcohol products 67 arise from enamine
66 derived from either of the endocyclic carbonyls (Fig. 5). As
racemic bicyclic alcohols are observed using cis-b-amino tetrazole
(1ꢀR,2ꢀS)-59 as a catalyst, the ability of this conformationally
constrained tetrazole to hydrogen bond in the transition state
and therefore undergo highly enantioselective ketol cyclisations
seems to be precluded, with the reaction pathway preferentially
proceeding through endocyclic enamine 66 (Fig. 5).
Fig. 6 Proposed transition state models for the reaction of (1R,2S)-
cispentacin 38 with triketones 9, 46 and 48.
In conclusion, the conformational constraints offered by the
homochiral b-amino acid (1R,2S)-cispentacin 38 confer high
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efficiency and enantioselectivity in the Hajos–Parrish–Eder–
Sauer–Wiechert reaction, with comparable enantioselectivity to
L-proline 1 for a number of substrates. The use of b-amino
tetrazole catalysts cis-(1ꢀR,2ꢀS)-59 and trans-(1ꢀR,2ꢀS)-60 show a
marked rate enhancement in comparison with the corresponding
b-amino acid catalysts, although with much lower levels of
enantioselectivity than the corresponding b-amino acid catalysts
and with varying product distributions. Further applications of
the use of b-amino acids and their derivatives as organocatalysts
for a range of synthetic transformations are currently under
investigation in this laboratory.
Part B. The residue was then re-dissolved in toluene and
treated with p-TsOH (0.1 eq.). The resultant mixture was heated at
reflux under Dean–Stark conditions for 5 h before being allowed
to cool to rt. Addition of sat. aq. NaHCO3 solution, followed by
extraction with two portions of EtOAc gave an organic solution
which was dried over MgSO4, filtered and concentrated in vacuo.
(R)-7a-Methyl-2,3,7,7a-tetrahydro-6H-indene-1,5-dione 11
Following the general procedure, (1R,2S)-cispentacin 38 (26 mg,
0.20 mmol) was added to triketone 9 (124 mg, 0.68 mmol) in
anhydrous DMF (1.0 mL). After 2 days the reaction was worked-
up to furnish (R)-1◦1 in 90% e.e.39 (104 m◦g, 94%) as a pale yellow
solid;40 mp 52–54 C (lit.,41 mp 61–63 C); [a]2D2−282 (c 1.0 in
CHCl3) {lit.,42 ent. [a]D22 +287 (c 0.4 in CHCl3)}; mmax/cm−1 (KBr
Experimental
=
=
disc) 1732 (C(1) O), 1695 (C(5) O); dH (400 MHz, CDCl3) 1.32
(3H, s, C(7a)CH3), 1.81–1.91 (1H, m, C(7)HAHB), 2.08–2.15 (1H,
m, C(7)HAHB), 2.39–2.58 (3H, m, C(2)HAHB, C(6)H2), 2.72–2.85
(2H, m, C(2)HAHB, C(3)HAHB), 2.91–3.02 (1H, m, C(3)HAHB),
5.98 (1H, d, J 2.3, C(4)H); dC (100 MHz, CDCl3) 20.6 (C(7a)CH3),
26.8 (C(3)H2), 29.2 (C(7)H2), 32.9 (C(6)H2), 35.9 (C(2)H2), 48.7
(C(7a)CH3), 123.9 (C(4)H), 169.7 (C(3a)), 198.1 (C(5)O), 216.2
(C(1)O); m/z (GC ToF CI+) 165 ([M + H]+, 60%); HRMS (GC
ToF CI+) C10H13O3 ([M + H]+) requires 165.0916; found 165.0910.
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-
R
workers.38 Water was purified by an Elixꢀ UV-10 system. All other
solvents were used as supplied (analytical or HPLC grade) without
prior purification. 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. Reaction conversion was
assessed, in each case, by analysis of the 400 MHz 1H NMR
spectrum of the crude reaction mixture.
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 per 100 mL. IR spectra were recorded on
Bruker Tensor 27 FT-IR spectrometer as either a thin film on
NaCl plates (thin film) or a KBr disc (KBr disc), 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 on either a VG MassLab 20–250 or a Micromass
Platform 1 spectrometer. Accurate mass measurements were run
on either a Bruker MicroTOF and were internally calibrated with
polyaniline in positive and negative modes, 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.
(R)-7a-Ethyl-2,3,7,7a-tetrahydro-(6H)-indene-1,5-dione 47
Following the general procedure, (1R,2S)-cispentacin 38 (20 mg,
0.15 mmol) was added to triketone 46 (100 mg, 0.51 mmol) in
anhydrous DMF (2.0 mL). After 4.5 days a 1.0 mL aliquot was
removed and worked-up to furnish enone (R)-47 in 78% e.e.,43
(28 mg, 79%) as a brown oil;44 [a]D23 −19.2 (c 0.25 in CHCl3)
{lit.,45 ent. [a]D25 +18.9 (c 1.0, CHCl3)}; mmax/cm−1 (thin film)
=
=
=
1742 (C(1) O), 1667 (C(5) O), 1614 (C C); dH (400 MHz,
CDCl3) 0.97 (3H, t, J 7.5, CH2CH3), 1.69–1.81 (3H, m, CH2CH3,
C(7)HAHB), 2.23–2.29 (1H, m, C(7)HAHB), 2.36–2.46 (3H, m,
C(2)HAHB, C(6)H2), 2.66–2.83 (2H, m, C(2)HAHB, C(3)HAHB),
2.92–3.02 (1H, m, C(3)HAHB), 5.97 (1H, s, C(4)H); dC (100 MHz,
CDCl3) 8.9 (CH2CH3), 25.7 (C(7)H2), 26.9, 27.0 (CH2CH3,
C(3)H2), 32.6 (C(6)H2), 35.8 (C(2)H2), 52.6 (C(7a)Et), 124.1
(C(4)H), 170.2 (C(3a)OH), 198.2 (C(1)O), 215.9 (C(5)O); m/z
(GC ToF CI+) 179 ([M + H]+, 100%); HRMS (GC ToF CI+)
C11H15O2 ([M + H]+) requires 179.1072 found 179.1076.
(R)-8a-Methyl-3,4,8,8a-tetrahydronapthalene-(2H,7H)-1,
6-dione 49
Following the general procedure, (1R,2S)-cispentacin 38 (20 mg,
0.15 mmol) was added to triketone 48 (100 mg, 0.51 mmol) in
anhydrous DMF (2.0 mL). After 4.5 days a 1.0 mL aliquot was
removed and worked-up to furnish enone (R)-49 in 86% e.e.46
(34 mg, 75%) as a pale brown oil;47 [a]D23 −45.3 (c 0.75 in EtOH)
{lit.,48 [a]2D5 −130 (c 0.7, EtOH)}; mmax/cm−1 (thin film) 1714
General procedure: Hajos–Parrish–Eder–Sauer–Wiechert reaction
=
=
=
(C(1) O), 1667 (C(6) O), 1620 (C C); dH (400 MHz, CDCl3)
1.43 (3H, s, CH3), 1.69 (1H, app qt, J 13.4, 4.4, C(3)HAHB), 2.08–
2.17 (3H, m, C(3)HAHB, C(8)H), 2.41–2.52 (4H, m, C(2)HAHB,
C(4)HAHB, C(7)H2), 2.65–2.76 (2H, m, C(2)HAHB, C(4)HAHB),
5.83 (1H, s, C(5)H); dC (100 MHz, CDCl3) 22.9 (C(3)H2), 23.3
(C(8a)CH3), 29.6 (C(8)H2), 31.7 (C(4)H2), 33.6 (C(7)H2), 37.6
(C(2)H2), 50.6 (C(8a)CH3), 125.8 (C(5)H), 165.8 (C(4a)), 198.3
Part A. A catalyst (30 mol%) was added to a stirred solution of
triketone (1.0 eq.) in anhydrous DMF at either rt or 60 ◦C. After
the designated reaction time, the reaction mixture was filtered
through a short plug of silica (eluent DMF) then concentrated
in vacuo (GenevacTM). Removal of any remaining starting material
was achieved by flash column chromatography.
3196 | Org. Biomol. Chem., 2007, 5, 3190–3200
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(C(6)O), 211.0 (C(1)O); m/z (GC ToF CI+) 179 ([M + H]+, 100%);
HRMS (GC ToF CI+) C11H15O2 ([M + H]+) requires 179.1072
found 179.1064.
1.64–1.75 (1H, m, C(3)HAHB), 1.79–1.89 (2H, m, C(3)HAHB,
C(5)HAHB), 2.19 (1H, app q, J 8.3, C(2)H), 3.26 (1H, app q, J
7.3, C(1)H); dC (100 MHz, CDCl3) 22.4 (C(4)H2), 27.9 (C(5)H2),
28.0 (C(CH3)3), 35.1 (C(3)H2), 54.5 (C(1)H), 57.0 (C(2)H), 79.9
(C(CH3)3), 174.5 (CO2 Bu); m/z (GC ToF CI+) 186 ([M + H]+,
t
tert-Butyl (1R,2S)-2-[N-(benzyloxycarbonyl)amino]cyclopentane-
1-carboxylate 55
100%); HRMS (GC ToF CI+) C10H20NO2 ([M + H]+) requires
186.1494; found 186.1489
Pd(OH)2/C (7.75 g, 25% w/w) was added to a stirred, degassed
solution of b-amino ester tert-butyl (1R,2S,aS)-2-[N-benzyl-N-
(a-methylbenzyl)amino]cyclopentane-1-carboxylate25 53 (31.0 g,
81.7 mmol) and AcOH (3 mL) in MeOH (150 mL). The
resulting suspension was vigorously stirred under an atmosphere
of hydrogen (5 atm) for 16 h. The reaction mixture was then filtered
Et3N (5.80 mL, 41.6 mmol) and CbzCl (5.93 mL, 41.5 mmol)
were added successively to a solution of tert-butyl (1S,2S)-2-
aminocyclopentane-1-carboxylate (7.00 g, 37.8 mmol) in anhy-
drous THF (100 mL) at 0 ◦C. The resultant mixture was allowed
to warm to rt and then stirred for 16 h. The reaction mixture
was then washed with brine (150 mL) and the aqueous layer
was extracted with two portions of DCM (2 × 100 mL). The
combined organic extracts were then dried over MgSO4, filtered
and concentrated in vacuo. Purification of the residue by flash
column chromatography (eluent 9 : 1 pentane–Et2O) furnished
(1S,2S)-56 (10.2 g, 85%) as a colourless oil; [a]2D4–44.5 (c 0.7 in
R
through a short plug of Celiteꢀ (eluent MeOH) and concentrated
in vacuo. The residue was then re-dissolved in DCM and the
resultant solution was washed with sat. aq. NaHCO3 solution then
dried over MgSO4, filtered and concentrated in vacuo to afford tert-
butyl (1R,2S)-2-aminocyclopentane-1-carboxylate (14.01 g, 93%)
as a colourless oil; [a]D22 −5.1 (c 1.0 in CHCl3) {lit.,29b [a]2D4–5.6 (c
0.6 in CHCl3)}.
CHCl3); mmax/cm−1 (thin film) 3338 (N–H), 1725 (C O carbamate,
=
=
C O ester); dH (400 MHz, CDCl3) 1.43 (9H, m, C(CH3)3),
Et3N (0.26 mL, 1.840 mmol) and CbzCl 0.26 mL, 1.84 mmol)
were added successively to a solution of tert-butyl (1R,2S)-2-
aminocyclopentane-1-carboxylate (310 mg, 1.67 mmol) in anhy-
drous THF (3.0 mL) at 0 ◦C. The resultant mixture was allowed
to warm to rt then stirred for 16 h. The reaction mixture was then
washed with brine (5 mL) and the aqueous layer was extracted with
two portions of DCM (2 × 5 mL). The combined organic extracts
were then dried over MgSO4, filtered and concentrated in vacuo.
Purification of the residue via flash column chromatography
(eluent 4 : 1 30–40 petrol–Et2O) furnished (1R,2S)-55 (400 mg,
75%) as a colourless oil, which slowly crystallised upon standing to
a white solid; (Found: C, 67.7; H, 7.9; N, 4.4. C14H16N2O2 requires
1.39–1.51 (1H, m, C(3)HAHB), 1.67–1.74 (2H, m, C(4)H2), 1.83–
1.99 (2H, m, C(5)H2), 2.10–2.18 (1H, m, C(3)HAHB), 2.90 (1H,
app q, J 8.1 C(1)H), 4.13–4.20 (1H, m, C(2)H), 4.82 (1H, app
br s, NH), 5.10 (2H, s, CH2Ph), 7.27–7.38 (5H, m, Ph); dC
(100 MHz, CDCl3) 22.8 (C(4)H2), 28.0 (C(5)H2), 28.0 (C(CH3)3),
33.2 (C(3)H2), 51.7 (C(1)H), 56.2 (C(2)H), 65.4 (CH2Ph), 80.6
(C(CH3)3), 128.1, 128.5, 128.6 (o,m,p-Ph), 136.6 (i-Ph), 155.6
(CONH), 173.6 (COtBu); m/z (ESI+) 342 ([M + Na]+, 100%);
HRMS (ESI+) C18H25N1O4Na ([M + Na]+) requires 342.1681;
found 342.1677.
(1R,2S)-2-[N-(Benzyloxycarbonyl)amino]cyclopentane-
1-carbonitrile 57
◦
C, 67.7; H, 4.4; N, 4.4%); mp 42–43 C; [a]2D0 −41.5 (c 1.1 in
CHCl3); mmax/cm−1 (thin film) 3336 (N–H), 1724 (C O carbamate,
=
=
C O ester); dH (400 MHz, CDCl3) 1.41 (9H, m, C(CH3)3), 1.54–
TFA (15 mL) was added to a solution of ester (1R,2S)-55 (12.9 g,
40.4 mmol) in DCM (60 mL) at 0 ◦C. The resultant mixture was
then allowed to warm to rt and was stirred for 4 h. After this time
all volatiles were removed in vacuo. Purification of the residue by
flash column chromatography (eluent 1 : 1 30–40 petrol–Et2O) fur-
nished (1R,2S)-2-[N-(benzyloxycarbonyl)amino]cyclopentane-1-
carboxylic acid (10.6 g, quant) as a colourless oil; [a]2D2 −44.7
1.71 (2H, m, C(3)H2), 1.74–2.02 (4H, m, C(4)H2, C(5)H2), 2.90
(1H, app q, J 7.4 C(1)H), 4.23–4.31 (1H, m, C(2)H), 5.10 (2H, s,
CH2Ph), 5.24–5.34 (1H, br m, NH) 7.28–7.42 (5H, m, Ph); dC
(100 MHz, CDCl3) 22.2 (C(4)H2), 27.7 (C(5)H2), 28.0 (C(CH3)3),
32.4 (C(3)H2), 47.6 (C(1)H), 54.2 (C(2)H), 66.6 (CH2Ph), 80.8
(C(CH3)3), 128.0, 128.1, 128.5 (o,m,p-Ph), 136.6 (i-Ph), 155.8
(CONH), 173.6 (COtBu); m/z (ESI+) 378 ([M + MeCN + NH4]+,
100%); HRMS (ESI+) C18H26N1O4 ([M + H]+) requires 320.1862;
found 320.1866.
(c 1.1 in CHCl3); mmax/cm−1 (thin film) 2963 (N–H), 1716 (C O
=
=
carbamate, C O acid); dH (400 MHz, MeOD) 1.54–1.75 (2H, m,
C(3)HAHB, C(4)HAHB), 1.80–2.06 (4H, m, C(3)HAHB, C(4)HAHB,
C(5)H2), 2.99 (1H, app q, J 7.4 C(1)H), 4.25 (1H, app q, J 7.1,
C(2)H), 5.07 (2H, s, CH2Ph), 7.26–7.43 (5H, m, Ph); dC (100 MHz,
MeOD) 22.1 (C(4)H2), 27.2 (C(5)H2), 31.6 (C(3)H2), 47.6 (C(1)H),
54.7 (C(2)H), 66.4 (CH2Ph), 127.7, 127.9, 128.5 (o,m,p-Ph), 137.4
(i-Ph), 157.3 (CONH), 176.3 (CO2H); m/z (ESI+) 286 ([M +
Na]+, 100%); HRMS (ESI+) C14H17N1O4Na ([M + Na]+) requires
286.1053; found 286.1005.
tert-Butyl (1S,2S)-2-[N-(benzyloxycarbonyl)amino]cyclopentane-
1-carboxylate 56
Pd(OH)2/C (7.75 g, 25% w/w) was added to a stirred,
degassed solution of tert-butyl (1S,2S,aS)-2-[N-benzyl-N-(a-
methylbenzyl)amino]cyclopentane-1-carboxylate25 54 (20.6 g,
54.3 mmol) in MeOH (100 mL). The resulting suspension was
vigorously stirred under an atmosphere of hydrogen (5 atm.) for
16 h. The reaction mixture was then filtered through a short plug of
Pyridine (0.03 mL, 0.35 mmol) was slowly added to a solu-
tion of (1R,2S)-2-[N-(benzyloxycarbonyl)amino]cyclopentane-1-
carboxylic acid (150 mg, 0.57 mmol), Boc2O (162 mg, 0.741 mmol)
and NH4HCO3 (57 mg, 0.70 mmol) in MeCN (2.0 mL) at
rt.49 The reaction mixture was then left to stir for 16 h at rt,
after which time H2O (0.5 mL) was added and the volatiles
were removed in vacuo prior to filtration. The residue was
then washed with H2O (10 mL) and hexane (10 mL) then
R
Celiteꢀ (eluent MeOH) and concentrated in vacuo to afford tert-
butyl (1S,2S)-2-aminocyclopentane-1-carboxylate (7.00 g, 71%)
as a colourless oil; [a]2D2 +34.7 (c 1.0 in CHCl3); mmax/cm−1 (film)
=
1727 (C O); dH (400 MHz, CDCl3) 1.25 (1H, m, C(5)HAHB), 1.29
(2H, s, NH2), 1.33 (9H, s, C(CH3)3), 1.49–1.60 (2H, m, C(4)H2),
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re-dissolved in DCM (20 mL). The resultant organic solution
was dried over MgSO4, filtered and concentrated in vacuo to
furnish (1R,2S)-2-[N-(benzyloxycarbonyl)amino]cyclopentane-1-
carboxamide (120 mg, 80%) as a white solid; (Found: C, 64.4;
H, 6.7; N, 10.◦3. C14H16N2O2 requires C, 64.1; H, 6.9; N, 10.7%);
mp 171–172 C; [a]D23 −13.5 (c 1.0 in CHCl3; mmax/cm−1 (KBr
(o,m,p-Ph), 138.4 (i-Ph), 158.4 (CONH), 178.7 (CO2H); m/z
(ESI−) 262 ([M − H]−, 85%); HRMS (ESI−) C14H16N1O4 ([M −
H]−) requires 262.1079; found 262.1078.
Pyridine (13 lL, 0.17 mmol) was slowly added to a solu-
tion of (1S,2S)-2-[N-(benzyloxycarbonyl)amino]cyclopentane-1-
carboxylic acid (70 mg, 0.27 mmol), Boc2O (76 mg, 0.35 mmol)
and NH4HCO3 (27 mg, 0.33 mmol) in MeCN (1.0 mL) at rt.49 The
reaction mixture was then left to stir for 16 h at rt, after which
time H2O (0.5 mL) was added and the volatiles were removed
in vacuo prior to filtration. The residue was washed with H2O
(10 mL) and hexane (10 mL) then re-dissolved in MeOH (20 mL),
filtered and concentrated in vacuo to furnish (1S,2S)-2-[N-
(benzyloxycarbonyl)amino]cyclopentane-1-carboxamide (57 mg,
=
=
disc) 3336 (N–H), 1668 (C O carbamate), 1633 (C O amide);
dH (500 MHz, MeOD) 1.55–1.64 (1H, m, C(3)HAHB), 1.71–1.78
(1H, m, C(4)HAHB), 1.82–2.02 (4H, m, C(3)HAHB, C(4)HAHB,
C(5)H2), 2.91–2.96 (1H, m, C(1)H), 4.16–4.22 (1H, m, C(2)H),
5.08 (2H, s, CH2Ph), 7.28–7.37 (5H, m, Ph); dC (125 MHz, MeOD)
22.1 (C(4)H2), 27.4 (C(5)H2), 32.0 (C(3)H2), 47.6 (C(1)H), 54.4
(C(2)H), 66.0 (CH2Ph), 127.3, 127.5, 128.0 (o,m,p-Ph), 136.9 (i-
Ph), 156.9 (CO2CH2Ph), 177.3 (CONH2); m/z (ESI+) 285 ([M +
Na]+, 100%); HRMS (ESI+) C14H18N2O3Na ([M + Na]+) requires
285.1215; found 285.1207.
◦
82%) as a white solid; mp 193–197 C; [a]2D4 +30.8 (c 0.25 in
CHCl3); mmax/cm−1 (KBr disc) 3415, 3319 (N–H), 1662 (C O
=
=
carbamate, C O amide); dH (500 MHz, DMSO-d6) 1.39–1.45 (1H,
Cyanuric chloride (3.27 g, 17.7 mmol) was added to a
flask containing a solution of (1R,2S)-2-[N-(benzyloxycarbonyl)-
amino]cyclopen◦tane-1-carboxamide (7.15 g, 27.3 mmol) in DMF
(140 mL) at 0 C.49 The reaction mixture was then allowed to
warm to rt and stirred for 16 h. H2O (500 mL) was then added
and the resultant mixture was extracted with three portions of
EtOAc (3 × 400 mL). The combined organic extracts were washed
with five portions of H2O (5 × 500 mL) then dried over MgSO4,
filtered and concentrated in vacuo. The residue was then dissolved
in a 1 : 2 mixture of EtOAc and hexane and passed through a
short plug of silica (eluent 1 : 2 EtOAc–hexane). The resultant
solution was concentrated in vacuo to furnish nitrile (1R,2S)-57
(6.90 g, quant) as a colourless oil; (Found: C, 68.65; H, 6.7; N,
11.5. C14H16N2O2 requires C, 68.8; H, 6.6; N, 11.5%); [a]2D2 −91.0
(c 1.0 in CHCl3); mmax/cm−1 (thin film) 3333 (N–H), 2240 (C≡N),
m, C(3)HAHB), 1.52–1.67 (3H, m, C(4)H2, C(5)HAHB), 1.81–1.92
(2H, m, C(3)HAHB, C(5)HAHB), 2.46–2.51 (1H, m, C(1)H), 3.31
(1H, app obsc s CONH) 3.94–4.01 (1H, m, C(2)H), 5.00 (2H, s,
CH2Ph), 6.77, 7.19 (2H, 2 × app br s, CONH2) 7.31–7.39 (5H,
m, Ph); dC (125 MHz, DMSO-d6) 23.2 (C(4)H2), 28.9 (C(5)H2),
32.9 (C(3)H2), 50.2 (C(1)H), 55.4 (C(2)H), 65.2 (CH2Ph), 127.8,
127.9, 128.4 (o,m,p-Ph), 137.1 (i-Ph), 155.5 (CO2CH2Ph), 175.7
(CONH2); m/z (ESI+) 285 ([M + Na]+, 100%); HRMS (ESI+)
C14H19N2O3 ([M + H]+) requires 263.1396; found 263.1390.
Cyanuric chloride (2.92 g, 15.8 mmol) was added to a solu-
tion of (1S,2S)-2-[N-(benzyloxycarbonyl)amino]cyclopentane-1-
carboxamide (6.38 g, 24.3 mmol) in DMF (120 mL) at 0 ◦C.49 The
reaction mixture was then allowed to warm to rt and stirred for
16 h. H2O (500 mL) was then added and the resultant mixture
was extracted with three portions of EtOAc (3 × 400 mL). The
combined organic extracts were washed with five portions of H2O
(5 × 500 mL) then dried over MgSO4, filtered and concentrated
in vacuo. The residue was then dissolved in a 1 : 2 mixture of EtOAc
and hexane and passed through a short plug of silica (eluent 1 : 2
EtOAc–hexane). The resultant solution was concentrated in vacuo
to furnish nitrile (1S,2S)-58 (6.00 g, quant.) as a pale yellow
oil that slowly solidified upon standing to a pale yellow solid;
(Found: C, 68.3; H, 6.8; N, 11.2. C14H16N2O2 requires C, 68.8;
=
1698 (C O); dH (500 MHz, MeOD) 1.64–1.72 (2H, m, C(3)HAHB,
C(4)HAHB), 1.85–2.17 (4H, m, C(3)HAHB, C(4)HAHB, C(5)H2),
3.23 (1H, app q, J 6.9, C(1)H), 4.18 (1H, app q, J 7.4, C(2)H),
5.13 (2H, s, CH2Ph), 7.29–7.39 (5H, m, Ph); dC (125 MHz, MeOD)
21.9 (C(4)H2), 28.8 (C(5)H2), 30.0 (C(3)H2), 34.4 (C(1)H), 53.6
(C(2)H), 66.2 (CH2Ph), 120.0 (CN), 127.3, 127.6, 128.1 (o,m,p-
Ph), 136.9 (i-Ph), 171.6 (NHCO); m/z (CI+) 245 ([M + H]+, 100%);
HRMS (CI+) C14H17N2O2 ([M + H]+) requires 245.129003; found
245.129085.
◦
H, 6.6; N, 11.5%); mp 53–56 C; [a]2D2 +71.0 (c 1.0 in MeOH);
mmax/cm−1 (KBr disc) 3327 (N–H), 2239 (C≡N), 1688 (C O);
=
dH (500 MHz, MeOD) 1.53–1.63 (1H, m, C(3)HAHB), 1.75–1.85
(2H, m, C(4)H2), 1.85–1.93 (1H, m, C(5)HAHB), 2.06–2.20 (2H,
C(3)HAHB, C(5)HAHB), 2.80–2.85 (1H, m, C(1)H), 4.16–4.21
(1H, m, C(2)H), 5.11 (2H, s, CH2Ph), 7.29–7.43 (5H, m, Ph); dC
(125 MHz, MeOD) 23.5 (C(4)H2), 30.2 (C(5)H2), 32.4 (C(3)H2),
36.0 (C(1)H), 58.2 (C(2)H), 67.6 (CH2Ph), 122.9 (CN), 128.9,
129.1, 129.5 (o,m,p-Ph), 138.2 (i-Ph), 158.2 (NHCO); m/z (CI+)
267 ([M + Na]+, 100%); HRMS (CI+) C14H17N2O2 ([M + H]+)
requires 245.1290; found 245.1282.
(1S,2S)-2-[N-(Benzyloxycarbonyl)amino]cyclopentane-
1-carbonitrile 58
TFA (12 mL) was added to a solution of ester (1S,2S)-56
(9.30 g, 29.1 mmol) in DCM (50 mL) at 0 ◦C. The resul-
tant mixture was then allowed to warm to rt and was stirred
for 4 h. After this time all volatiles were removed in vacuo.
Purification of the residue by recrystallisation (DCM–pentane)
furnished (1S,2S)-2-[N-(benzyloxycarbonyl)amino]cyclopentane-
1-ca◦rboxylic acid (7.66 g, quant) as a white solid; mp 100–
101 C (CHCl3–n-heptane); [a]2D3 +23.5 (c 1.3 in CHCl3); mmax/cm−1
(1ꢀR,2ꢀS)-5-(2ꢀ-aminocyclopentan-1ꢀ-yl)tetrazole 59
=
=
(KBr disc) 3320 (N–H), 1710 (C O carbamate, C O acid); dH
(500 MHz, MeOD) 1.52–1.59 (1H, m, C(3)HAHB),1.65–1.77 (2H,
m, C(4)H2), 1.78–1.91 (1H, m, C(5)HAHB), 1.96–2.07 (2H, m,
C(3)HAHB, C(5)HAHB), 2.64–2.72 (1H, m, C(1)H), 4.19–4.26
(1H, m, C(2)H), 5.06 (2H, s, CH2Ph), 7.26–7.37 (5H, m, Ph); dC
(100 MHz, MeOD) 24.3 (C(4)H2), 30.0 (C(5)H2), 33.9 (C(3)H2),
51.6 (C(1)H), 57.4 (C(2)H), 67.5 (CH2Ph), 128.9, 129.0, 129.6
Nitrile (1R,2S)-57 (1.02 g, 4.15 mmol), NaN3 (2.70 g, 41.5 mmol)
and ZnBr2 (1.40 g, 6.22 mmol) in propan-2-ol (6 mL) and H2O
(12 mL) was heated at reflux for 5 days. After this time 3.0 M
aq. HCl solution (6 mL) and EtOAc (6 mL) were added to the
mixture, and stirring was continued until all solid residues had
dissolved. The organic layer was then separated and the aqueous
3198 | Org. Biomol. Chem., 2007, 5, 3190–3200
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layer was extracted with three portions of EtOAc (3 × 5 mL).
The combined organic extracts were dried over MgSO4, filtered
and concentrated in vacuo to furnish an 89 : 11 mixture of the
desired tetrazole and hydrolysis product respectively. The residue
was partitioned between 1.0 M aq. NH4OH (15 mL) and CHCl3
(15 mL). The aqueous layer was then washed with CHCl3 (3 ×
15 mL) and concentrated in vacuo to afford (1ꢀR,2ꢀS)-5-{2ꢀ-[N-
(benzyloxycarbonyl)amino]cyclopentan-1ꢀ-yl}tetrazole (970 mg,
m, C(3ꢀ)HAHB), 1.81–1.87 (2H, m, C(4ꢀ)H2), 1.92–2.00 (1H, m,
C(5ꢀ)HAHB), 2.13–2.23 (2H, m, C(3ꢀ)HAHB, C(5ꢀ)HAHB), 3.31–
3.36 (1H, m, C(1ꢀ)H), 4.25–4.29 (1H, m, C(2ꢀ)H), 5.00 (2H, s,
CH2Ph), 7.24–7.39 (5H, m, Ph); dC (125 MHz, MeOD) 23.7
(C(4ꢀ)H2), 32.3 (C(5ꢀ)H2), 33.6 (C(3ꢀ)H2), 43.6 (C(1ꢀ)H), 59.5
(C(2ꢀ)H), 67.3 (CH2Ph), 128.7, 128.9, 129.5 (o,m,p-Ph), 138.4
(i-Ph), 158.3 (NHCO), 165.0 (C(5)N); m/z (ESI+) 310 ([M +
Na]+ 100%); HRMS (ESI+) C14H17N5O2Na ([M + H]+) requires
310.1274; found 310.1263.
◦
81%) as a white solid; mp 220 C (dec.); [a]2D2 +5.4 (c 1.0
in MeOH); mmax/cm−1 (KBr disc) 3441 (N–H), 1631 (C N,
Pd(OH)2/C (170 mg, 25% w/w) was added to a stirred solution
of (1ꢀS,2ꢀS)-5-{2ꢀ-[N-(benzyloxycarbonyl)amino]cyclopentan-1ꢀ-
yl}tetrazole (694 mg, 2.42 mmol) in degassed MeOH (20 mL).
The resulting suspension was stirred under a H2 atmosphere
(1 atm) for 16 h, after which time the reaction mixture was filtered
=
=
=
C O), 1524 (N N); dH (500 MHz, MeOD) 1.64–1.73 (1H, m,
C(4ꢀ)HAHB), 1.80–1.86 (1H, m, C(3ꢀ)HAHB), 1.90–1.98 (1H, m,
C(4ꢀ)HAHB), 2.03–2.18 (3H, m, C(3ꢀ)HAHB, C(5ꢀ)H2), 3.79–3.84
(1H, m, C(1ꢀ)H), 4.34–4.38 (1H, m, C(2ꢀ)H), 4.86 (2H, obsc s,
CH2Ph), 7.21–7.37 (5H, m, Ph); dC (125 MHz, MeOD) 21.9
(C(4ꢀ)H2), 29.4 (C(5ꢀ)H2), 32.1 (C(3ꢀ)H2), 39.4 (C(1ꢀ)H), 54.9
(C(2ꢀ)H), 66.0 (CH2Ph), 127.3, 127.5, 128.1 (o,m,p-Ph), 136.7 (i-
Ph), 156.6 (NHCO), 162.2 (C(5)N); m/z (ESI−) 286 ([M − H]−
100%); HRMS (ESI−) C14H16N5O2 ([M − H]−) requires 245.1304;
found 245.1308.
R
through Celiteꢀ (eluent MeOH) and concentrated in vacuo to
furnish trans-b-amino tetrazole (1ꢀS,2ꢀS)-60 (370 mg, quant) as
◦
a white solid; mp 194 C (dec); [a]2D3 +47.2 (c 1.0 in MeOH);
mmax/cm−1 (KBr disc) 3407 (N–H), 1650 (C N), 1583 (C N), 1412
=
=
ꢀ
ꢀ
=
=
(N N), 1395 (N N); dH (500 MHz, MeOD) [(1 S,2 S)-60 exists as
a mixture of 1H- and 2H-tautomers in solution, only data for the
major tautomer is given] 1.55–1.63 (1H, m, C(3ꢀ)HAHB), 1.80–1.92
(2H, m, C(4ꢀ)H2), 1.92–1.99 (1H, m, C(5ꢀ)HAHB), 2.11–2.18 (1H,
m, C(3ꢀ)HAHB), 2.20–2.26 (1H, m, C(5ꢀ)HAHB), 3.05–3.11 (1H,
m, C(1ꢀ)H), 3.42–3.51 (1H, m, C(2ꢀ)H); dC (125 MHz, MeOD)
23.4 (C(4ꢀ)H2), 32.3 (C(3ꢀ)H2), 33.5 (C(5ꢀ)H2), 46.3 (C(1ꢀ)H), 59.8
(C(2ꢀ)H), 165.2 (C(5)N); m/z (ESI+) 154 ([M + H]+ 100%); HRMS
(ESI+) C6H12N5 ([M + H]+) requires 154.1093; found 154.1098.
Pearlman’s catalyst (260 mg, 25% w/w) was added to
a stirred solution of (1ꢀR,2ꢀS)-5-{2ꢀ-[N-(benzyloxycarbonyl)-
amino]cyclopentan-1ꢀ-yl}tetrazole (1.05 g, 3.65 mmol) in degassed
MeOH (20 mL). The resulting suspension was stirred under a H2
atmosphere (5 atm) for 40 h, after which time the reaction mixture
R
was filtered through Celiteꢀ (eluent MeOH) and concentrated
in vacuo to furnish cis-b-amino tetrazole (1ꢀR,2ꢀS)-59 (552 mg,
◦
quant.) as a white solid; mp 250–252 C; [a]2D3 −1.2 (c 1.0 in
MeOH); mmax/cm−1 (KBr disc) 1387 (N N), 1473 (N N), 1618
=
=
Acknowledgements
(C N) 1639 (C N), 3418 (N–H); dH (500 MHz, D2O) [(1ꢀR,2ꢀS)-
59 exists as a mixture of 1H- and 2H-tautomers in solution,
only data for the major tautomer is given] 1.42–1.51 (1H, m,
C(3ꢀ)HAHB), 1.55–1.67 (1H, m, C(4ꢀ)HAHB), 1.74–1.83 (1H, m,
C(4ꢀ)HAHB), 1.88–2.03 (3H, m, C(3ꢀ)HAHB, C(5ꢀ)H2), 3.31 (1H,
app q, J 7.7, C(1ꢀ)H), 3.45–3.52 (1H, m, C(2ꢀ)H); dC (125 MHz,
D2O); 21.4 (C(4ꢀ)H2), 27.5 (C(5ꢀ)H2), 31.7 (C(3ꢀ)H2), 38.4 (C(2ꢀ)H),
40.7 (C(1ꢀ)H), 163.0 (C(5)N); m/z (ESI+) 217 ([M + MeCN + Na]+
100%); HRMS (ESI+) C6H12N5 ([M + H]+) requires 154.1093;
found 154.1089.
=
=
The authors wish to thank New College, Oxford, for a Junior
Research Fellowship (A. D. S.).
References and notes
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(1ꢀS,2ꢀS)-5-(2ꢀ-aminocyclopentan-1ꢀ-yl)tetrazole 60
Nitrile (1S,2S)-58 (954 mg, 3.91 mmol), NaN3 (2.53 g, 38.9 mmol)
and ZnBr2 (1.32 g, 5.86 mmol) in i-PrOH (6 mL) and H2O
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aq. HCl solution (1 mL) and EtOAc (6 mL) were added to
the mixture, and stirring was continued until all solid residues
had dissolved. H2O (10 mL) was added and the aqueous layer
was then extracted with three portions of EtOAc (3 × 10 mL).
The combined organic extracts were dried over MgSO4, filtered
and concentrated in vacuo to furnish a 98 : 2 mixture of
the desired tetrazole and hydrolysis product. The residue was
partitioned between 1.0 M aq. NH4OH (15 mL) and CHCl3
(15 mL). The aqueous layer was then washed with CHCl3 (3 ×
15 mL) and concentrated in vacuo to afford (1ꢀS,2ꢀS)-5-{2ꢀ-[N-
(benzyloxycarbonyl)amino]cyclopentan-1ꢀ-yl}tetrazole (694 mg,
2 G. Lelais and D. W. C. MacMillan, Aldrichimica Acta, 2006, 39, 79.
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◦
62%) as a white solid; mp 230 C (dec.); [a]2D2 +43.4 (c 1.0
in MeOH); mmax/cm−1 (KBr disc) 3392 (N–H), 1699 (C N,
=
=
=
C O), 1553 (N N); dH (500 MHz, MeOD) 1.61–1.68 (1H,
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presence of O-acetyl mandelic acid.
36 Bicyclic species 62 was shown to be racemic by 1H NMR studies in the
presence of O-acetyl mandelic acid.
37 The theoretical e.e. was calculated using the formula: theoretical e.e.
(%) = [calculated e.e. (%)] × [% of ketol in mixture] × 100.
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isotherm, 120 min and comparison with an authentic racemic sample,
(R)-11 tR = 91.5 min, (S)-11 tR = 100.5 min.
40 Ketol 10 has been reported previously but not fully characterised: Z. G.
Hajos and D. R. Parrish, J. Org. Chem., 1974, 39, 1615.
41 L. G. Sevillano, C. P. Melero, E. T. F. Caballero, L. G. Lelievre, K.
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42 A sample of (S)-11 (93% e.e.) was prepared under standard conditions
using L-proline 1 catalysis.
43 The e.e. of enone 47 was determined using chiral GC analysis;
ThermoQuest TRACE GC, fitted with a Cydex-b column, 130 ◦C
isotherm, 120 min and comparison with an authentic racemic sample,
(R)-47 tR = 85.0 min, (S)-47 tR = 88.2 min.
44 Enone 47 has previously been reported but not fully characterised:
Z. G. Hajos and D. R. Parrish, J. Org. Chem., 1974, 39, 1615.
45 R. A. Michelli, Z. G. Hajos, N. Cohen, D. R. Parrish, L. A. Portland,
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46 The e.e. of enone 49 was determined using chiral GC analysis;
ThermoQuest TRACE GC, fitted with a Cydex-b column, 110 ◦C
isotherm, 300 min and comparison with an authentic racemic sample,
(R)-49 tR = 260.8 min, (S)-49 tR = 277.5 min.
29 (a) S. G. Davies, O. Ichihara and I. A. S. Walters, Synlett, 1993, 461;
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48 V. Prelog and W. Acklin, Helv. Chim. Acta, 1956, 39, 748.
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3200 | Org. Biomol. Chem., 2007, 5, 3190–3200
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©