Highly enantioselective organocatalysis of the Hajos-Parrish-Eder-Sauer- Wiechert reaction by the β-amino acid cispentacin

Article abstract of DOI:10.1039/b506780b

The β-amino acid cispentacin promotes the Hajos-Parrish-Eder-Sauer- Wiechert reaction with levels of enantioselectivity comparable to or higher than proline. The Royal Society of Chemistry 2005.

Full text of DOI:10.1039/b506780b

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Highly enantioselective organocatalysis of the Hajos–Parrish–Eder–
Sauer–Wiechert reaction by the b-amino acid cispentacin
Stephen G. Davies,* Ruth L. Sheppard, Andrew D. Smith* and James E. Thomson
Received (in Cambridge, UK) 12th May 2005, Accepted 1st June 2005
First published as an Advance Article on the web 30th June 2005
DOI: 10.1039/b506780b
Hajos–Parrish–Eder–Sauer–Wiechert reaction with high selecti-
vity. The cis-relative orientation of the carboxylic acid and amine
functionalities within cispentacin was predicted to provide a
defined asymmetric environment, with the reaction proceeding
preferentially via the s-cis enamine geometry and hydrogen
bonding activation of the carbonyl as shown in transition state 5
[Fig. 1, illustrated for D-proline and (1R,2S)-cispentacin for ease of
comparison].
The b-amino acid cispentacin promotes the Hajos–Parrish–
Eder–Sauer–Wiechert reaction with levels of enantioselectivity
comparable to or higher than proline.
Organocatalysis is at the forefront of much current research,
fuelled by the search for efficient reactions that do not rely upon
the use of metals for their promotion.1 Among the array of
catalysts that promote enamine based organocatalysis, proline2
and its derivatives3 have received the most attention for a range of
asymmetric transformations such as the aldol, Mannich and
Michael reactions. The first widely recognised catalytic asymmetric
application of proline concerned the enantioselective intramo-
lecular aldol reaction of triketone 1 to the bicyclic alcohol 2 in
quantitative yield and 93% e.e. (commonly known as the Hajos–
Parrish–Eder–Sauer–Wiechert reaction).4 Proline has remained
unrivalled as the most efficient catalyst for this often studied
reaction,5 with enantioselectivity thought to be due to the
constraints of transition state 4. Key to the stability of this
transition state is the preference for reaction via the s-trans rather
than the s-cis geometry,6 and intramolecular acid catalysis due to
hydrogen bonding of the carboxylic acid proton to the carbonyl
undergoing nucleophilic attack.7 As an extension of our research
concerned with the synthesis and chemistry of enantiomerically
pure b-amino acids,8 their ability to promote asymmetric
organocatalysis was probed. Limited previous studies detailing
b-amino acid catalysis of the cyclisation of triketone 1 have been
reported, with (S)-homoproline9 and (S)-3-amino-4-phenylbuta-
noic acid10 reported to give enone (R)-3 in 58% and 83% optical
yield respectively. In our hands however, the cyclisation of
triketone 1 using the enantiomerically pure b-amino acids
(S)-homoproline and (R)-3-amino-4-phenylbutanoic acid gave
enone (R)-3 in 36% e.e. and (S)-3 in 64% e.e. respectively; under
identical conditions L-proline gave enone (S)-3 in 93% e.e.,
consistent with the literature.4b
It is well recognised that the pyrrolidine ring within proline is
necessary to enforce conformational rigidity and impart high
enantiocontrol in this reaction.7 Following this analysis, we
proposed that a b-amino acid capable of providing a fixed
orientation of the carboxylic acid and amino functionalities should
also be able to provide high enantiocontrol in this reaction
manifold. Comparison with the proposed transition state for the
cyclisation of triketone 1 using proline as the catalyst11 led to the
prediction that the conformationally constrained a-substituted-
b-amino acid (1R,2S)-cispentacin12 would also promote the
Department of Organic Chemistry, University of Oxford, Chemistry
Research Laboratory, Mansfield Road, Oxford, UK OX1 3TA.
E-mail: steve.davies@chem.ox.ac.uk; andrew.smith@chem.ox.ac.uk
Fig. 1 Proposed transition state models for the reaction of D-proline and
(1R,2S)-cispentacin with triketone 1.
3802 | Chem. Commun., 2005, 3802–3804
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As
a model substrate, treatment of triketone 1 with
(1R,2S)-cispentacin (30 mol%) promoted complete conversion to
the corresponding alcohol 2 after 48 hours,13 which after
dehydration upon treatment with p-TsOH, gave as predicted
enone (R)-3 in 90% e.e.14 The e.e. of (R)-3 was established
unambiguously by GC analysis and comparison with an authentic
racemic sample, while the absolute configuration of 3 was
established both by comparison of specific rotation {[a]2D2 2282
(c 1.00 in CHCl3), (ent). [a]2D2 + 287 (c 0.40 in CHCl3)} and chiral
GC data with an authentic sample of enone (S)-3 (93% e.e.),
prepared using L-proline (30 mol%). The high stereoselectivity
using (1R,2S)-cispentacin (90% e.e.) is comparable to that using
L-proline (93% e.e.) and is the highest enantioselectivity reported to
date for this particular transformation using an amino acid
containing a primary amino functionality (Scheme 1).
Scheme 2 Reagents and conditions: (i). (1R,2S)-cispentacin (30 mol%),
DMF, rt; (ii). p-TsOH, toluene, D; (iii). L-proline, (30 mol%), DMF, rt.
Scheme 1 Reagents and conditions: (i). (1R,2S)-cispentacin, (30 mol%),
DMF, rt; (ii). p-TsOH, toluene, D.
Scheme 3 Reagents and conditions: (i). (1R,2S)-10 (30 mol%), DMF, rt.
The generality of this protocol with (1R,2S)-cispentacin was
next established through the enantioselective cyclisation of
triketones 6 and 7, that differ in both alkyl substitution and ring
size; the same cyclisation using L-proline was also evaluated under
the same conditions to afford a direct comparison of the
stereoselectivity of the reaction. The cyclisations promoted by
(1R,2S)-cispentacin proceeded to complete conversion, giving the
corresponding enones (R)-8 and (R)-9 respectively after dehydra-
tion. In each case, higher levels of enantioselectivity using the
b-amino acid (1R,2S)-cispentacin were noted than using the
a-amino acid L-proline for the same cyclisation {formation of 8;
cispentacin 78% e.e. [(R)], L-proline 74% e.e. [(S)]; formation of 9,
cispentacin 86% e.e. [(R)], L-proline 72% e.e. [(S)]} (Scheme 2).15
A spate of recent publications has demonstrated that tetrazole
equivalents of amino acids (proline and homoproline) are
enhanced organocatalysts for a range of transformations,3b,3c,16
with the tetrazole considered an efficient mimic for the carboxylic
acid. As part of our investigations within this area, the ability of
the tetrazole equivalent of cispentacin (1R,2S)-10 to promote the
cyclisation of triketone 1 was examined. Notably, the reaction of
triketone 1 with tetrazole (1R,2S)-10 proceeded with a marked rate
enhancement in comparison to cispentacin (100% conversion,
1 day) and with a remarkable change in product distribution,
giving only the racemic bicyclic species 1117 (Scheme 3). It is
apparent that the incorporation of the tetrazole moiety within this
framework completely changes the reaction manifold; the
incorporation of the tetrazole motif within organocatalysts as a
carboxylic acid replacement should not therefore be regarded as a
panacea strategy.
In conclusion, the conformational constraints offered by the
homochiral b-amino acid cispentacin confer high efficiency and
enantioselectivity during the promotion of the Hajos–Parrish–
Eder–Sauer–Wiechert reaction. 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.
The authors wish to thank New College, Oxford for a Junior
Research Fellowship (A. D. S.).
Notes and references
1 For recent reviews see: P. I. Dalko and L. Moisan, Angew. Chem., Int.
Ed., 2001, 40, 3726; B. List, Synlett, 2001, 1675; B. List, Acc. Chem. Res.,
2004, 37, 548; W. Notz, F. Tanaka and C. F. Barbas, III, Acc. Chem.
Res., 2004, 37, 580.
2 For a review see: B. List, Tetrahedron, 2002, 58, 5573.
3 For instance see (a) P. H.-Y. Cheong, K. N. Houk, J. S. Warrier and
S. Hanessian, Adv. Synth. Catal., 2004, 346, 1111; (b) A. J. A. Cobb,
D. M. Shaw and S. V. Ley, Synlett, 2004, 558; (c) A. J. A. Cobb,
D. M. Shaw, D. A. Longbottom, J. B. Gold and S. V. Ley, Org. Biomol.
Chem., 2005, 3, 84; (d) A. Berkessel, B. Koch and J. Lex, Adv. Synth.
Catal., 2004, 346, 1141.
4 (a) U. Eder, G. Sauer and R. Wiechert, Angew. Chem., Int. Ed. Engl.,
1971, 10, 496; (b) Z. G. Hajos and D. R. Parrish, J. Org. Chem., 1974,
39, 1615.
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5 C. Agami, J. Levisalles and C. Puchot, J. Chem. Soc., Chem. Commun.,
1985, 441; C. Agami, Bull. Soc. Chim. Fr., 1988, 3, 499; L. Hoang,
S. Bahmanyar, K. N. Houk and B. List, J. Am. Chem. Soc., 2003, 125,
16.
of (1R,2S)-cispentacin after 24 hours. In MeCN, no reaction was
observed using (1R,2S)-cispentacin for the cyclisation of 1 to 2; (1R,2S)-
N-methyl-cispentacin was inactive as a catalyst in this reaction
manifold.
6 The s-cis and s-trans nomenclature used herein refers to the relative
orientation of the methylene carbon of the enamine and C(2) of proline
and cispentacin.
7 S. Bahmanyar and K. N. Houk, J. Am. Chem. Soc., 2001, 123, 12911;
C. Allemann, R. Gordillo, F. R. Clemente, P. H.-Y. Cheong and
K. N. Houk, Acc. Chem. Res., 2004, 37, 558.
8 For examples see: S. G. Davies and O. Ichihara, Tetrahedron:
Asymmetry, 1991, 2, 183; 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; S. G. Davies, J. Dupont, R. J. C. Easton, O. Ichihara,
J. M. McKenna, A. D. Smith and J. A. A. de Sousa, J. Organomet.
Chem., 2004, 689, 4184.
9 T. Wakabayashi, K. Watanabe and Y. Kato, Synth. Commun., 1977, 7,
239.
10 P. Buchshacher, J.-M. Cassal, A. Fu¨rst and W. Meier, Helv. Chim. Acta,
1977, 60, 2747.
11 Only two transition states for the cyclisation of triketone 1 with proline
are shown in Fig. 1; two alternative transition states may be discounted
as hydrogen bonding between the carboxylate and the carbonyl under
nucleophilic attack by the enamine is prohibited.
12 S. G. Davies, O. Ichihara and I. A. S. Walters, Synlett, 1993, 461;
S. G. Davies, O. Ichihara, I. Lenoir and I. A. S. Walters, J. Chem. Soc.,
Perkin Trans. 1, 1994, 1411.
14 Typical experimental protocol: (1R,2S)-cispentacin (26 mg, 0.20 mmol)
was added to a stirred solution of triketone 1 (124 mg, 0.68 mmol) in
anhydrous DMF (1.0 mL). After 48 hours, the reaction mixture was
filtered through a short plug of silica (eluent DMF) then concentrated in
vacuo (Genevac2). The residue was then re-dissolved in toluene and
treated with p-TsOH (13 mg, 0.07 mmol). The resultant mixture was
heated at reflux for 5 hours before being allowed to cool to ambient
temperature. Addition of sat. aq. NaHCO3 solution, followed by
extraction with EtOAc gave an organic solution which was dried over
MgSO4 and concentrated in vacuo to furnish enone (R)-3 (104 mg, 94%);
{[a]2D2 2282 (c 1.00 in CHCl3), (ent). [a]D22 + 287 (c 0.40 in CHCl3)}. The
e.e. of (R)-3 was determined using a ThermoQuest TRACE GC fitted
with a Cydex-b column; 120 uC isotherm, 120 min, (R)-3 tR 5 91.5 min
and (S)-3 tR 5 100.5 min and comparison with an authentic racemic
sample.
15 In the literature, the cyclisations of 6 to furnish (S)-8 and 7 to give (S)-9
using L-proline have been reported, but optical yields rather than e.e.s of
the initial products were determined; see references 2, 4(a) and 4(b).
16 H. Torii, M. Nakadai, K. Ishihara, S. Saito and H. Yamamoto, Angew.
Chem. Int. Ed., 2004, 43, 1983; Y. Yamamoto, N. Momiyama and
H. Yamamoto, J. Am. Chem. Soc., 2004, 126, 5962; A. Hartikka and
P. I. Arvidsson, Tetrahedron: Asymmetry, 2004, 15, 1831; A. J. A. Cobb,
D. M. Shaw, D. A. Longbottom and S. V. Ley, Chem. Commun., 2004,
1808; C. E. T. Mitchell, A. J. A. Cobb and S. V. Ley, Synlett, 2005, 611.
17 The bicyclic species 11 was shown to be racemic by 1H NMR studies in
the presence of O-acetyl mandelic acid.
13 The cyclisation of 1 to 2 is slower with (1R,2S)-cispentacin than
L-proline; for example 30 mol% L-proline promotes the cyclisation of
triketone 1 to 2 in 24 hours; 70% conversion to 2 is seen with 30 mol%
3804 | Chem. Commun., 2005, 3802–3804
This journal is ß The Royal Society of Chemistry 2005