Direct catalytic asymmetric enolexo aldolizations

Article abstract of DOI:10.1002/anie.200351266

32 years after the first, and still the only, catalytic asymmetric intramolecular aldol reaction was published in this journal, the proline-catalyzed Hajos-Parrish-Eder-Sauer-Wiechert reaction is extended for the first time to catalytic asymmetric enolexo

Full text of DOI:10.1002/anie.200351266

Angewandte
Chemie
Enolexo Aldol Reactions
Direct Catalytic Asymmetric Enolexo
Aldolizations**
Chandrakala Pidathala, Linh Hoang, Nicola Vignola,
and Benjamin List*
À
The aldol reaction is an exceptionally useful strategic C C
bond-forming reaction for the stereoselective construction of
cyclic and acyclic molecules. As a result, several catalytic
[*] Dr. B. List, C. Pidathala, L. Hoang, N. Vignola
The Scripps Research Institute
Department of Molecular Biology
10550 North Torrey Pines Road, La Jolla, CA 92037 (USA)
Fax: (+1)858-784-7028
E-mail: blist@scripps.edu
[**] Generous support by the NIH (RO1 GM-63914) is most gratefully
acknowledged. The cover picture was designed by Mike Pique
(Scripps Institute) using a proline image attributed to K. N. Houk
and S. Bahmanyar (UCLA). Chicken artwork courtesy of Sheri
Hoeger, www.madstencilist.com ꢀ 2000.
Angew. Chem. Int. Ed. 2003, 42, 2785 – 2788
DOI: 10.1002/anie.200351266
ꢀ 2003 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
2785

Communications
asymmetric intermolecular variants, both indirectly, with
preformed enolate equivalents, and directly involving
unmodified carbonyl compounds have been described.[1]
Remarkably, however, there is still only one catalytic
asymmetric intramolecular aldol reaction, the proline-cata-
lyzed Hajos–Parrish–Eder–Sauer–Wiechert reaction.[2] While
the usefulness of this process has been illustrated in a broad
context,[3] only 6-enolendo aldolizations [Eq. (1), n = 1]have
been described so far. Direct catalytic asymmetric enolexo
aldolizations [Eq. (2)]are unknown. Herein we describe the
first and highly enantioselective examples of this process.
proline-catalyzed 6-enolexo aldolization. Various pentane-
1,5-dialdehydes (pimelaldehydes; 1) were prepared[18] and
then treated with a catalytic amount of (S)- or (R)-proline in
dichloromethane [Eq. (4), Table 1]. Both 1b and 1c provided
6-Enolendo aldolizations are very common and favored
according to the Baldwin rules.[4,5] The only catalytic asym-
metric variant of this process, the Hajos–Parrish–Eder–
Sauer–Wiechert reaction has not been extended to different
the corresponding cyclic aldols 2b and 2c in high yields and
excellent diastereo- and enantioselectivities. Surprisingly, we
found that a single substituent in the 4-position has an
unfavorable effect on the stereoselectivity of the cycloaldo-
ring sizes, nor have any proline-catalyzed enolexo aldoliza-
[6]
tions [Eq. (2)]been described.
Although Baldwin-favored
in the formation of 3–7 membered rings, enolexo aldolizations
are less studied[7] and direct cata-
lytic asymmetric variants are
unknown.[8]
Table 1: Proline-catalyzed enolexo aldolizations of dicarbonyl compounds. Yields refer to diols obtained
after in situNaBH 4 reduction.
Dicarbonyl
Yield [%]
Products
ee [%]
d.r. [%]
10:1
Recently, we discovered the
first proline-catalyzed asymmetric
intermolecular aldol reactions[9–11]
and proposed a unified one-proline
enamine catalysis mechanism of
both inter- and intramolecular
aldol reactions.[12–14] By inspecting
possible transition-state models,
we realized that in addition to the
established 6-enolendo aldoliza-
tions via transition state A, proline
should also catalyze corresponding
6-enolexo aldolizations via the
chairlike assembly B. Such reac-
tions should provide a highly ster-
eoselective pathway to useful
trans-1,2-disubstituted cyclohex-
anes.
95
99
74
75
98
97
>20:1
>20:1
76
75,89,95,8
22:5:5:1
Indeed, the reaction of hepta-
nedial[15] (1a) with
a catalytic
amount of (S)-proline in dichloro-
methane gave aldol 2a in high yield
and diastereoselectivity, and with
88
99
99
1:1
2:1
excellent
enantioselectivity
[Eq. (3)].[16,17]
92
With this encouragement, we
decided to study the scope of this
2786
ꢀ 2003 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.angewandte.org
Angew. Chem. Int. Ed. 2003, 42, 2785 – 2788

Angewandte
Chemie
389; f) M. Shibasaki, H. Sasai, T. Arai, T. Iida, Pure Appl.
Chem. 1998, 70, 1027 – 1034; g) E. M. Carreira, R. A. Singer,
Drug Discovery Today 1996, 1, 145 – 150.
lization. This effect was demonstrated with 4-methyl-substi-
tuted 1d, which provided all four possible diastereomeric
aldols of 2d upon treatment with proline; the resulting aldols
were obtained in a 22:5:5:1 ratio and in 75, 89, > 95, and 8%
ee, respectively. Explaining the lowered stereoselectivity in
this case is difficult without calculating the relative energies of
all reasonable transition states.[12] Even if the enamine is fixed
to having E geometry, and boat conformations are excluded
(as in B), the transition states may still vary in an axial versus
equatorial 4-substituent and/or enamine double bond, and in
the anti versus syn relationship of the carboxylic acid to the
olefin. We also investigated the behavior of the meso-
configured dialdehyde 1e under our reaction conditions.
Four stereogenic centers may be created simultaneously in a
catalytic asymmetric desymmetrization of this substrate. We
found the two expected anti-configured aldols (2e and 2e’) to
be formed in equal amounts and in 99 and 75% ee,
respectively. That the proline-catalyzed enolexo aldolization
is not limited to dialdehydes was illustrated in the reaction of
ketoaldehyde 1 f, which gave tertiary aldol 2 f (d.r. = 2:1), in
99% ee (minor isomer 95% ee).
[2]a) Z. G. Hajos, D. R. Parrish, German Patent DE 2102623, 1971;
b) U. Eder, G. R. Sauer, R. Wiechert, German Patent
DE 2014757, 1971; c) U. Eder, G. Sauer, R. Wiechert, Angew.
Chem. 1971, 83, 492 – 493; Angew. Chem. Int. Ed. Engl. 1971, 10,
496 – 497; d) Z. G. Hajos, D. R. Parrish, J. Org. Chem. 1974, 39,
1615 – 1621; Related enantiogroup-differentiating aldol cyclo-
dehydrations have been described, see: C. Agami, N. Platzer, H.
Sevestre, Bull. Soc. Chim. Fr. 1987, 2, 358 – 360.
[3]Reviews: a) N. Cohen, Acc. Chem. Res. 1976, 9, 512 – 517; b) K.
Drauz, A. Kleemann, J. Martens, Angew. Chem. 1982, 94, 590 –
613; Angew. Chem. Int. Ed. Engl. 1982, 21, 584 – 608; c) E. R.
Jarvo, S. J. Miller Tetrahedron 2002, 58, 2481 – 2495; d) B. List,
Tetrahedron 2002, 58, 5572 – 5590; e) P. I. Dalko, L. Moisan,
Angew. Chem. 2001, 113, 3840 – 3864; Angew. Chem. Int. Ed.
2001, 40, 3726 – 3748.
[4]a) J. E. Baldwin, M. J. Lusch, Tetrahedron 1982, 38, 2939 – 2947;
b) J. E. Baldwin, J. Chem. Soc. Chem. Commun. 1976, 734 – 736.
[5]Cycloaldolizations are formally enolexo- or enolendo-exo-trig
processes. However, since all intramolecular aldolizations are by
definition exo-trig processes, we refer to these processes simply
as enolexo or enolendo aldolizations.
In summary, we have described the first and highly
enantioselective proline-catalyzed enolexo aldolization of
dicarbonyl compounds. This reaction provides b-hydroxy
cyclohexane carbonyl derivatives that are of potential wide-
spread usage in target-oriented synthesis. This anti-diaster-
eoselective proline-catalyzed enolexo aldolization nicely
complements alternative methodologies such as the highly
enantio- and syn-diastereoselective baker's yeast reduction of
b-keto esters.[19] An advantage of the aldolization method-
ology is that both enantiomeric products can be accessed
simply by using either (S)- or (R)-proline, whereas the
biocatalysis route is limited to products of a single absolute
configuration.[20] Applications in natural product synthesis
and further extensions of proline-catalyzed inter- and intra-
molecular aldolizations are forthcoming.
[6]For a proline-catalyzed enolexo aldolization in a dynamic kinetic
resolution, see: R. B. Woodward et al. , J. Am. Chem. Soc. 1981,
103, 3210 – 3213; Also see: C. Agami, N. Platzer, C. Puchot, H.
Sevestre, Tetrahedron 1987, 43, 1091 – 1098.
[7]For selected non-enantioselective variants, see: a) R. B. Wood-
ward, F. Sondheimer, D. Taub, K. Heusler, W. M. MacLamore, J.
Am. Chem. Soc. 1952, 74, 4223 – 4251; b) E. J. Corey, R. L.
Danheiser, S. Chandrasekaran, P. Siret, G. E. Keck, J. L. Gras, J.
Am. Chem. Soc. 1978, 100, 8031 – 8034; c) H. Hagiwara, H. Ono,
N. Komatsubara, T. Hoshi, T. Suzuki, M. Ando, Tetrahedron Lett.
1999, 40, 6627 – 6630.
[8]For two indirect catalytic enantioselective enolexo aldolizations,
see: a) Romo's organocatalytic asymmetric syn-diastereospe-
cific intramolecular, nucleophile-catalyzed aldol-lactonization
(NCAL): G. S. Cortez, R. L. Tennyson, D. Romo, J. Am. Chem.
Soc. 2001, 123, 7945 – 7946; b) Krische's catalytic asymmetric
carbometallative aldol cycloreduction, which is
a tandem
catalytic asymmetric conjugate addition followed by a syn-
diastereoselective enolexo aldolization: D. F. Cauble, J. D.
Gipson, M. J. Krische, J. Am. Chem. Soc. 2003, 125, 1110 – 1111.
[9]a) B. List, R. A. Lerner, C. F. Barbas III, J. Am. Chem. Soc. 2000,
122, 2395 – 2396; b) W. Notz, B. List, J. Am. Chem. Soc. 2000,
122, 7386 – 7387; c) B. List, P. Pojarliev, C. Castello, Org. Lett.
2001, 3, 573 – 575.
Experimental Section
Typical aldolization procedure: Dicarbonyl 1 (1 mmol) was dissolved
in dry dichloromethane (10 mL) and treated with (S)- or (R)-proline
(12 mg, 0.1 mmol, 10%). The mixture was stirred at room temper-
ature until the starting material had disappeared (8–16 h). Aldols 2
can be isolated after standard aqueous work-up, but are unstable over
extended time periods at room temperature. Stable diols are obtained
by in situ reduction with NaBH4 followed by an aqueous work-up, as
described elesewhere.[11d, 21]
[10]a) A. B. Northrup, D. W. C. MacMillan, J. Am. Chem. Soc. 2002,
124, 6798 – 6799 (This important paper describes an intermolec-
ular variant of the reaction discussed here); b) A. Córdova, W.
Notz, C. F. Barbas III, J. Org. Chem. 2002, 67, 301 – 303; c) A.
Bøgevig, N. Kumaragurubaran, K. A. Jørgensen, Chem.
Commun. 2002, 620 – 621, Also see: A. Bøgevig, K. Juhl, N.
Kumaragurubaran, W. Zhuang, K. A. Jørgensen, Angew. Chem.
2002, 114, 1868 – 1871; Angew. Chem. Int. Ed. 2002, 41, 1790 –
1793; N. Halland, P. S. Aburel, K. A. Jørgensen, Angew. Chem.
2003, 115, 685 – 689; Angew. Chem. Int. Ed. 2003, 42, 661 – 665.
[11]For the first proline-catalyzed asymmetric intermolecular Man-
nich, Michael, and a-amination reactions, see a) B. List, J. Am.
Chem. Soc. 2000, 122, 9336 – 9337; b) B. List, P. Pojarliev, W. T.
Biller, H. J. Martin, J. Am. Chem. Soc. 2002, 124, 827 – 833; c) B.
List, P. Pojarliev, H. J. Martin, Org. Lett. 2001, 3, 2423 – 2425;
d) B. List, J. Am. Chem. Soc. 2002, 124, 5656 – 5657. For recent
highlights, see: a) M. Movassaghi, E. N. Jacobsen, Science 2003,
298, 1904 – 1905; b) S. Borman, Chem. Eng. News 2002, 80, 35 –
Received: February 24, 2003 [Z51266]
Keywords: aldol reaction · amino acids · asymmetric catalysis ·
.
organocatalysis
[1]For some recent reviews and accounts, see: a) J. S. Johnson,
D. A. Evans, Acc. Chem. Res. 2000, 33, 325 – 335; b) T. D.
Machajewski, C.-H. Wong, Angew. Chem. 2000, 112, 1406 – 1430;
Angew. Chem. Int. Ed. 2000, 39, 1352 – 1374; c) B. Alcaide, P.
Almendros, Eur. J. Org. Chem. 2002, 1595 – 1601; d) S. E.
Denmark, R. A. Stavenger, Acc. Chem. Res. 2000, 33, 432 –
440; e) S. G. Nelson, Tetrahedron: Asymmetry 1998, 9, 357 –
Angew. Chem. Int. Ed. 2003, 42, 2785 – 2788
www.angewandte.org
ꢀ 2003 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
2787

Communications
37; c) H. Gröger, J. Wilken, Angew. Chem. 2001, 113, 545 – 548;
Angew. Chem. Int. Ed. 2001, 40, 529 – 532.
[12]a) S. Bahmanyar, K. N. Houk, J. Am. Chem. Soc. 2001, 123,
9922 – 9923; b) S. Bahmanyar, K. N. Houk, J. Am. Chem. Soc.
2001, 123, 11273 – 11283; c) S. Bahmanyar, K. N. Houk, H. J.
Martin, B. List, J. Am. Chem. Soc. 2003, 125, 2475 – 2479; d) L.
Hoang, S. Bahmanyar, K. N. Houk, B. List, J. Am. Chem. Soc.
2003, 125, 16 – 17.
[13]For additional supporting density functional theory calculations,
see: a) K. N. Rankin, J. W. Gauld, R. J. Boyd, J. Phys. Chem. A
2002, 106, 5155 – 5159; b) M. Arnó, L. R. Domingo, Theor.
Chem. Acc. 2002, 108, 232 – 239.
[14]B. List, Synlett 2001, 1675 – 1686.
[15]M. Daumas, Y. Vo-Quang, L. Vo-Quang, F. Le Goffic, Synthesis
1989, 64 – 65.
[16]Comparison of the literature NMR data and optical rotation of
the known diol of aldol 2a (T. Kakuchi, A. Namuri, H. Kaga, T.
Ishibashi, M. Obata, K. Yokota, Macromolecules 2000, 33, 3964 –
3969) confirmed the expected absolute and relative configura-
tion. The ee value of the aldol products was typically determined
from chiral-phase HPLC after in situ conversion to a chromo-
genic enone by
a Horner–Wadsworth–Emmons reaction
(MeCOCH2PO(OMe)2, LiOH, THF).
[17]The analogous proline-catalyzed 5- enolexo aldolization of
hexanedial is less selective (d.r. = 2:1; ee(anti) = 79%,
ee(syn) = 37%).
[18]Substituted pimelaldehydes 1 were routinely prepared from
commercially available substituted cyclohexanones through a-
carbomethoxylation (NaH, MeOCO2Me) and retro-Dieckman
condensation using either NaOMe or Cs2CO3 (R. G. Salomon,
M. F. Salomon, J. Org. Chem. 1975, 40, 1488 – 1492; P. Tundo, S.
Memoli, M. Selva, , WO 02/14257, 2000.) Diisobutylaluminium
hydride reduction (or LAH reduction followed by PCC oxida-
tion) of the resulting diesters then provided the desired
pimelaldehydes 1 in acceptable overall yields.
[19]See for example: a) M. Bertau, M. Bürli, E. Hungerbühler, P.
Wagner, Tetrahedron: Asymmetry 2001, 12, 2103 – 2107; b) V.
Spiliotis, D. Papahatjis, N. Ragoussis, Tetrahedron Lett. 1990, 31,
1615 – 1616.
[20]Alternative highly efficient and enantioselective ruthenium-
catalyzed b-keto ester reductions can be diastereounselective:
a) R. Noyori, T. Ohkuma, M. Kitamura, H. Takaya, N. Sayo, H.
Kumobayashi, S. Akutagawa, J. Am. Chem. Soc. 1987, 109,
5856 – 5858; b) M. Kitamura, T. Ohkuma, M. Tokunaga, R.
Noyori, Tetrahedron: Asymmetry 1990, 1, 1 – 4; c) J. P. GenÞt, X.
Pfister, V. Ratovelomanana-Vidal, C. Pinel, J. A. Laffitte,
Tetrahedron Lett. 1994, 35, 4559 – 4562.
[21]All new compounds gave satisfactory 1H and 13C NMR spectra,
as well as high-resolution mass spectroscopic analysis.
2788
ꢀ 2003 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.angewandte.org
Angew. Chem. Int. Ed. 2003, 42, 2785 – 2788