Enantioselective organocatalytic conjugate reduction of β-AzoleContaining α,β-unsaturated aldehydes

Article abstract of DOI:10.1021/ol900893e

β-Azole-contalnlng α,β-unsaturated aldehydes were successfully reduced under highly enantloselectlve organocatalytlc transfer hydrogenation conditions. The products were obtained In good yields and up to 94% optical purity. This simple process was success

Full text of DOI:10.1021/ol900893e

ORGANIC
LETTERS
2009
Vol. 11, No. 13
2756-2759
Enantioselective Organocatalytic
Conjugate Reduction of ꢀ-Azole-
Containing r,ꢀ-Unsaturated Aldehydes
Thomas J. Hoffman, Jyotirmayee Dash,† James H. Rigby,‡ Stellios Arseniyadis,*
and Janine Cossy*
Laboratoire de Chimie Organique, ESPCI ParisTech, CNRS, 10 rue Vauquelin,
F-75231 Paris Cedex 05, France
stellios.arseniyadis@espci.fr; janine.cossy@espci.fr
Received April 23, 2009
ABSTRACT
ꢀ-Azole-containing r,ꢀ-unsaturated aldehydes were successfully reduced under highly enantioselective organocatalytic transfer hydrogenation
conditions. The products were obtained in good yields and up to 94% optical purity. This simple process was successfully applied to the
synthesis of the C7-C14 fragment of ulapualide A, a natural product which exhibits promising antitumor activity.
In recent years, the development of asymmetric hydrogena-
tion processes has been undertaken by several groups in the
pursuit of installing chirality onto prochiral alkene scaffolds.
In this context, the use of catalytic amounts of transition metals,
such as Ru,1 Rh,2 or Ir,3 in conjunction with well-defined chiral
ligands, has resulted in a number of attractive and practical
protocols, making asymmetric hydrogenation a powerful tool
for both industrials and academics. Despite the advantages
offered by these processes, they usually suffer from various
drawbacks such as the use and storage of hydrogen gas, the
need of high catalyst loadings, the toxicity of the catalysts, or
the difficulties associated with their removal. With global
environmental legislation becoming stricter, sustainable devel-
opment has been playing an increasingly important role in the
strategy of chemical and pharmaceutical industries, allowing
enantioselective organocatalysis to emerge as a very promising
alternative.4 Inspired by biological processes which involve
specific metalloenzymes that use dihydropyridine-based cofac-
tors, such as nicotinamide adenine dinucleotide (NADH) and
flavine adenine dinucleotide (FADH2),5 to perform highly
stereoselective reductions, several research groups have shown
that it was possible to replace both the enzymes and the
cofactors by small molecule organocatalysts and dihydropyri-
dine analogues.6 For example, MacMillan et al.7 showed that
(2) (a) Dang, T. P.; Kagan, H. B. J. Am. Chem. Soc. 1972, 94, 6429. (b)
Evans, D. A.; Morrissey, M. J. Am. Chem. Soc. 1984, 106, 3866. (c) Evans,
D. A.; Fu, G. C.; Hoveyda, A. M. J. Am. Chem. Soc. 1988, 110, 6917. (d)
Zhang, W.; Chi, Y.; Zhang, X. Acc. Chem. Res. 2007, 40, 1278, and
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Vries, J. G. Acc. Chem. Res. 2007, 40, 1267, and references cited therein.
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M. In Modern Synthetic Methods; Scheffold, R., Ed.; Springer: Berlin, 1989;
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Wiley-VCH: New York, 1994; Chapter 2. (i) Ohkuma, T.; Noyori, R.;
Blaser, H. U.; Spindler, F. In ComprehensiVe Asymmetric Catalysis;
Jacobsen, E. N., Pfaltz, A., Yamamoto, H., Eds.; Springer: Berlin, 1999;
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Springer: Berlin, 1999; Vol. I, Chapter 5. (k) Ohkuma, T.; Kitamura, M.;
Noyori, R. In Catalytic Asymmetric Synthesis, 2nd ed.; Ojima, I., Ed.; Wiley-
VCH: New York, 2000; Chapter 1.
† Current address: Department of Chemistry, IISER, Kolkata, India.
‡ Current address: Department of Chemistry, Wayne State University,
Detroit, MI 48202.
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R. Angew. Chem., Int. Ed. 2002, 41, 2008. (c) Knowles, W. S. Angew.
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10.1021/ol900893e CCC: $40.75
Published on Web 06/08/2009
 2009 American Chemical Society

chiral imidazolidinones could, in the presence of Hantzsch
esters, catalyze the enantioselective reduction of a wide range
of ꢀ,ꢀ′-disubstituted R,ꢀ-unsaturated aldehydes in good yields
(up to 95%) and high enantioselectivities (up to 97% ee).
Concurrently, List et al.8 introduced the concept of asymmetric
counter anion directed catalysis (ACDC) by developing a highly
selective organocatalyst for the asymmetric reduction of enals
which consists of an achiral ammonium ion and a chiral phosphate
anion derived from 3,3′-bis(2,4,6-triisopropylphenyl)-1,1′-binaph-
thyl-2,2′-diyl hydrogen phosphate (TRIP). Thus, examples of both
ꢀ,ꢀ′-disubstituted enals were reduced in good yields (up to 90%)
and excellent enantioselectivities (up to 99% ee).
Interestingly, while these methods have been applied suc-
cessfully to a wide range of substrates, to our knowledge, there
has been no report of an enantioselective organocatalytic transfer
hydrogenation applied to ꢀ-azole R,ꢀ-unsaturated aldehydes of
type I (Scheme 1). As this motif is present in various natural
products of significant biological value, such as myxothiazole
Z,9 calyculin A,10 and ulapualide A (Figure 1),11 we were
particularly interested in investigating this key transformation
which would allow a straightforward access these molecules.
In this paper, we wish to report the results of our endeavor
which have led to the first examples of enantioselective
organocatalytic transfer hydrogenations applied to ꢀ-azole R,ꢀ-
unsaturated aldehydes (Scheme 1).
Figure 1. Structure of myxothiazole Z, calyculin A, and ulapualide A.
Scheme 1. Enantioselective Organocatalytic Transfer
Hydrogenation of ꢀ-Azole-Containing R,ꢀ-Unsaturated Aldehydes
This study initially began when synthesizing myxothiazole
Z, a secondary metabolite isolated from myxobacteria Myxo-
coccus fulVus,9 which displays interesting antifungal, antibacte-
rial, and anticancer properties.12,13 Our strategy for the
synthesis of myxothiazole Z was similar to the one we have
previously used to prepare two related natural products:
melithiazole C14 and cystothiazole A.15 Hence, we planned
to employ a cross-metathesis between a vinylthiazole16 and
a ꢀ-methoxy acrylate, and a Stille coupling which would
allow us to link the two thiazole rings together. Finally, an
enantioselective organocatalytic transfer hydrogenation was
conceived as a key step to control the stereogenic center at
the R-position of the thiazole ring.
(4) (a) Berkessel, A.; Gro¨ger, H. Asymmetric Organocatalysis: From
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New York & London, 2002.
With no precedent on such systems, a thorough investigation
of the reaction conditions was first undertaken on aldehyde 1.
The results are reported in Table 1.
As depicted, we began by screening two catalysts derived
from (S)-proline (3 and 4). The reactions were typically carried
out in CHCl3 at -35 °C using 20 mol % of chiral organocatalyst
in combination with 1.2 equiv of either tert-butyl or ethyl
Hantzsch ester 9 and 10, or the corresponding methyl ketone
11, while the selectivities were determined by supercritical fluid
chromatography (SFC) analysis after reduction of the aldehyde
into the corresponding alcohol with NaBH4.17
(6) (a) Hantzsch, A. Justus Liebigs Ann. Chem. 1882, 215, 1. (b) Meijer,
L. H. P.; Pandit, U. K. Tetrahedron 1985, 41, 467. (c) Stout, D. M.; Meyers,
A. I. Chem. ReV. 1982, 82, 223.
Our initial attempts using catalysts 3 and 4 resulted, unfor-
tunately, in inefficient and nonselective reductions (Table 1,
entries 1-3). In contrast, by switching to imidazolidinone-type
(7) (a) Ouellet, S. G.; Tuttle, J. B.; MacMillan, D. W. C. J. Am. Chem.
Soc. 2005, 127, 32. (b) Huang, Y.; Walji, A. M.; Larsen, C. H.; MacMillan,
D. W. C. J. Am. Chem. Soc. 2005, 127, 15051. (c) LeLais, G.; MacMillan,
D. W. C. Aldrichimica Acta 2006, 39, 79. (d) Ouellet, S. G.; Walji, A. M.;
MacMillan, D. W. C. Acc. Chem. Res. 2007, 40, 1327.
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Vingola, N.; List, B. Angew. Chem., Int. Ed. 2005, 44, 108. (c) Mayer, S.;
List, B. Angew. Chem., Int. Ed. 2006, 45, 4193.
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M. J. Am. Chem. Soc. 1986, 108, 847. (c) Allingham, J. S.; Tanaka, J.;
Marriot, G.; Rayment, I. Org. Lett. 2004, 6, 597. (d) Pattenden, G.; Ashweek,
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Antibiot. 1980, 33, 1474. (b) Trowitzsch, W.; Reifenstahl, G.; Wray, V.;
Gerth, K. J. Antibiot. 1980, 33, 1480. (c) Trowitzsch, W.; Ho¨fle, G.;
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(17) See Supporting Information.
Org. Lett., Vol. 11, No. 13, 2009
2757

Table 1. Evaluation of the Catalyst on the Enantioselective
Organocatalytic Transfer Hydrogenation Reaction
Table 2. Evaluation of the Solvent and the Counterion on the
Enantioselective Organocatalytic Transfer Hydrogenation Reaction
a Hydride donor: R ) Ot-Bu (9), R ) OEt (10), R ) Me (11).
b Conversion determined by crude 1H NMR analysis. c Isolated yield.
d Enantiomeric ratio determined by chiral SFC analysis (ChiralPack AD-
H, MeOH). e Reaction performed at 0 °C. f Reaction performed at rt. TFA
) trifluoroacetic acid, TCA ) trichloroacetic acid.
a Conversion determined by crude NMR analysis. b Isolated yield.
c Enantiomeric ratio determined by chiral SFC analysis (ChiralPack AD-
H, MeOH). d Reaction performed at rt. TFSI ) trifluoromethanesulfonimide.
The absolute configuration of 2 was confirmed by converting
the latter into a known compound 2′ and by comparing their
optical rotation (Scheme 2).18
catalysts such as 5, 7, and 8, a dramatic increase in both
reactivity and selectivity was observed, allowing the isolation
of the desired reduced product in high yields and high
selectivities (up to 84% ee; Table 1, entry 12). Interestingly,
the relative size of the ester moiety on the 3,5-dihydropyridine
ring appeared to have a tremendous impact on the selectivity
(R ) Ot-Bu, 84% ee; R ) OEt, 60% ee; Table 1, entries 12
and 13), while the ketone analogue 11 turned out to be rather
inefficient (Table 1, entries 7, 11, and 14). With these promising
results in hand, catalysts 5 and 8 were selected for further
study.
Scheme 2. Assignment of the Absolute Configuration of 2
The influence of the solvent was next examined. As shown
in Table 2, catalyst 5 exhibited higher selectivities in toluene
(94% ee; Table 2, entry 2) than in CHCl3 (64% ee; Table 2,
entry 1), while catalyst 8 appeared to be much more selective
in CHCl3 (84% ee; Table 2, entry 4) than in CH3CN (44% ee;
Table 2, entry 5), THF (72% ee; Table 2, entry 6), CH2Cl2 (76%
ee; Table 2, entry 7), or toluene (78% ee; Table 2, entry 8). In
addition, changing the counterion from trifluoroacetate to
trichloroacetate or trifluoromethanesulfonimidate did not im-
prove the selectivity (Table 2, entry 2 vs 3 and entry 4 vs 9)
nor did the use of a chiral counterion such as (+)- or (-)-
camphorsulfonate which, it is worth noting, both led to the iso-
lation of the same major enantiomer (Table 2, entries 10 and
11).
The substrate scope was then examined, and the results are
summarized in Table 3. Hence, the analogous 4-trifluorometh-
ylsulfonate derivative 16a was subjected to the enantioselective
organocatalytic transfer hydrogenation conditions (i.e., 20 mol
% of chiral organocatalyst 5 or 8 in combination with 1.2 equiv
of tert-butyl Hantzsch ester 9 in either toluene or CHCl3 at -35
°C). To our delight, the corresponding alcohol 17a was obtained
in good yield and excellent enantioselectivity (81% yield, 92%
ee; Table 3, entry 2). Similarly, thiazole 16b, which exhibits
(18) Uenishi, J.; Kawahama, R.; Yonemitsu, O. J. Org. Chem. 1997,
62, 1691.
2758
Org. Lett., Vol. 11, No. 13, 2009

Scheme 3. Application of the Enantioselective Organocatalytic
Table 3. Scope of the Enantioselective Organocatalytic Transfer
Hydrogenation Reaction
Transfer Hydrogenation to the Synthesis of the C7-C14 Fragment
of Ulapualide A
and the oxazoline intermediate was immediately aromatized to
the corresponding oxazole 22 using the conditions developed
by Williams et al. [BrCCl3, DBU, CH2Cl2, 60% yield over 2
steps].22 The ester moiety was then reduced with DIBAL-H to
the ꢀ,ꢀ′-disubstituted R,ꢀ-unsaturated aldehyde 23; however,
as over-reduction to the allylic alcohol was also observed,
subsequent oxidation using Dess-Martin periodinane allowed
us to isolate the desired aldehyde 23 in 83% overall yield.
Finally, aldehyde 23 was subjected to the enantioselective
organocatalytic transfer hydrogenation conditions using ethyl
Hantzsch ester 10 and catalyst 8 to provide 24 in 62% yield
and an 85:15 diastereomeric ratio.
In summary, we have demonstrated that enal-substituted ox-
azoles and thiazoles can be readily reduced in a highly enantiose-
lective fashion using organocatalytic transfer hydrogenation con-
ditions with ee up to 94%. In all the cases studied, the 4-enal-
substituted azoles proved less reactive and gave lower selectivities
than their 2-enal-substituted counterparts. We suspect that the
difference in reactivity is related to the electron-withdrawing
character of the azole ring when substituted by an enal moiety at
the 2-position. The 4-enal-substituted azoles are, on the other hand,
much less reactive and therefore require higher temperatures, which
lead to slightly lower selectivities. This key transformation is
currently being applied in the total syntheses of myxothiazole Z
and ulapualide A, which will be reported in due course.
a Isolated yield. b Enantiomeric ratio determined by chiral SFC analysis
(ChiralPack AD-H, MeOH). c 57% conversion after 36 h in step 1. d NaBH4
reduction was not performed on this substrate. e 70% conversion after 48 h
in step 1.
an enal motif at the 4-position of the ring, was reduced using
catalyst 8 in fair yield and good selectivity (78% yield, 76%
ee; Table 3, entry 3). Surprisingly, however, very little conver-
sion was observed when using catalyst 5 in toluene under
otherwise identical conditions. Oxazole derivatives also ap-
peared as suitable substrates, as 2- and 4-enal-substituted
oxazoles 16c and 16d were both reduced with high enantiose-
lectivity (16c: 76% yield, 90% ee, Table 3, entry 4; 16d: 55%
yield, 80% ee, Table 3, entry 5) using catalysts 5 and 8,
respectively. However, as observed previously for the 4-enal-
substituted thiazoles, catalyst 5 failed to convert the analogous
oxazole substrate 16d. Hence, as a general trend, comparable
reactivities, yields, and selectivities were observed between
oxazoles and thiazoles bearing similar substitution patterns.
Finally, in order to demonstrate the synthetic utility of this
enantioselective organocatalytic transfer hydrogenation, we
undertook a synthesis of the C7-C14 fragment of ulapualide
A, which contains the requisite C9 stereogenic center R to the
oxazole ring (Scheme 3).
The synthesis began with a Horner-Wadsworth-Emmons
olefination between ketone 1819 and commercially available
ethyl dimethylphosphonoacetate, which provided the corre-
sponding R,ꢀ-unsaturated ester 19 in 91% isolated yield (E/Z
) 9/1). Removal of the acetonide and the t-butyl carbamate in
an HCl/EtOH solution, followed by peptide coupling with acid
2020 using standard conditions [EDC·HCl, HOBt, NMM,
CH2Cl2],21 resulted in the formation of ꢀ-hydroxy amide 21 in
67% yield. The latter was then cyclodehydrated using DAST,
Acknowledgment. We would like to thank the Ministe`re
de l’Enseignement Supe´rieur et de la Recherche for financial
support to T.J.H.
Supporting Information Available: Experimental details
and characterization data for all new compounds. This material
is available free of charge via the Internet at http://pubs.acs.org.
OL900893E
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