Primary-amine-catalyzed enantioselective intramolecular aldolizations

Article abstract of DOI:10.1002/anie.200802497

Aldol cyclodehydration of 4-substituted-2,6-heptanediones leads to enantiomerically enriched 5-substituted-3-methyl-2-cyclohexene-1-ones, which serve as perfume ingredients and valuable synthetic building blocks.Primary amines derived from cinchona alkalo

Full text of DOI:10.1002/anie.200802497

Communications
DOI: 10.1002/anie.200802497
Organocatalysis
Primary-Amine-Catalyzed Enantioselective Intramolecular
Aldolizations**
Jian Zhou, Vijay Wakchaure, Philip Kraft, and Benjamin List*
Dedicated to Professor Manfred T. Reetz on the occasion of his 65th birthday
The enantioselective aldol cyclodehydration of 4-substituted
2,6-heptandiones 1 to cyclohexenones 2 [e.g., 1d to 2d,
Eq. (1)] has been a long-term challenge in asymmetric
catalysis. Pioneering investigations by Agami et al.[1] using
proline catalysis, in analogy to the Hajos–Parrish–Eder–
Sauer–Wiechert reaction,[2] have led to only moderate
enantioselectivity and poor yields. Catalytic antibody 38C2,
developed by Lerner, Barbas et al., turned out to be more
active, but the enantioselectivity remained moderate.[3] We
have now reinvestigated this reaction concentrating on
catalysis with primary amines, and have identified quinine
derivative 5·3HOAc, which gives high yields, excellent
enantioselectivity, and has a broad substrate scope.
As fragrances and building blocks for natural product
synthesis,[4] chiral non-racemic enones 2 are valuable syn-
thetic targets. In particular, the desymmetrizing intramolec-
ular aldol reaction of 4-substituted 2,6-heptandiones 1
represents a potentially attractive approach. First attempts
to conduct such aldol reactions by differentiating enantiotopic
groups were made in the 1980s by Agami et al. using proline
as catalyst. However, in these aldolizations, proline is rather
inefficient, giving only low yields of moderately enantioen-
riched aldol condensation products, along with the corre-
sponding aldol addition products and starting material.[1] The
other catalyst investigated, aldolase antibody 38C2, catalyzes
the aldol condensation of three diketones 1 to the corre-
sponding enones 2 in high yields (> 95%), but the reactions
have only been investigated on an analytical scale, and
enantioselectivity remained low (e.r. ꢀ 4.2).[3] Clearly, there
still remains much room for improvement regarding practi-
cality, enantioselectivity, and substrate scope.
Recently, low molecular weight primary amines have been
described as being effective aminocatalysts for transforma-
tions involving enamine and iminium ions.[5,6] Although only
limited success has previously been achieved in aldolizations
of ketones,[2,7] we reasoned that primary amines should be
suitable catalysts for such reactions. The generally lower
nucleophilicity of enamines derived from primary amines was
expected to be counterbalanced by two factors: 1) a higher
concentration of the iminium ion and enamine intermediates
owing to reduced steric requirements, and 2) possible general
ꢁ
Brønsted acid co-catalysis by the N H bond of the enamine in
ꢁ
the C C-bond-forming transition state, as proposed by Houk
et al. for primary amine-catalyzed aldol reactions.[8] With this
hypothesis in mind, and encouraged by the high activity of
aldolase antibody 38C2, which also features a primary amino
group at its active site, we decided to reexamine the
desymmetrization of acyclic heptandiones 1 to chiral enones
2 using primary aminocatalysts.
Initial studies confirmed that in addition to proline, most
other tested secondary amine catalysts are only moderately
active. Phenylalanine was also investigated as a primary amino
acid but gave unsatisfactory results. In contrast, salts of primary
amines 3–7 proved to be rather efficient. Whereas the (S)-
TRIP salt of p-anisidine (3), which we have employed in the
catalysis of a very similar 6-endo aldolization in an organo-
catalytic cascade sequence,[9] proved particularly active, its
enantioselectivity was poor (Table 1, entry 1). Remarkably,
chiral diamines 4–6, used recently used as bifunctional primary
amine catalysts in the epoxidation of cyclic enones, also turned
out to be highly enantioselective in the aldolization of 1d.[6g]
Although chiral diamine 4 in combination with (S)-TRIP failed
to promote the reaction (entry 2), it gave a promising
enantioselectivity (e.r. =9.3) as the trichloroacetate salt
(entry 3), although the reactivity of this salt was still insuffi-
cient. Gratifyingly, 9-amino-9-deoxyepiquinine 5, recently
introduced to primary iminium[6d–g] and enamine catalysis,[5g,h]
proved to be particularly powerful in this reaction. At room
temperature, it afforded comparable enantioselectivity, as with
catalyst 4, but had an improved reaction rate (entry 4).
Lowering the temperature to ꢁ158C improved the e.r. to
[*] Dr. J. Zhou, Dr. V. Wakchaure, Prof. Dr. B. List
Max-Planck-Institut für Kohlenforschung
Kaiser Wilhelm-Platz 1, 45470 Mülheim an der Ruhr (Germany)
Fax: (+49)208-306-2982
E-mail: list@mpi-muelheim.mpg.de
Dr. P. Kraft
Givaudan Schweiz AG
8600 Dübendorf (Switzerland)
[**] The authors acknowledge generous funding from the Max Planck
Society, the DFG (SPP 1179, Organocatalysis), the Fonds der
Chemischen Industrie, and Wacker Chemie AG.
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.200802497.
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Chemie
Table 1: Catalyst screening.
Table 2: Substrate scope.
Entry[a]
R
Product
Yield [%][b]
e.r.[c]
(ee [%])
1
2
3
4
5
6
7
8
Me
Me
Et
iPr
n-C5H11
CH2CH2Ph
P
p-ClC6H4
m-ClC6H4
p-MeC6H4
2-thienyl
2-furanyl
2a
2a
2b
2c
2d
2e
2 f
2g
2h
2i
91
87
80
97
96
98
93
94
92
94
92
95
23.9
26.1
20.6
13.4
28.1
19.8
21.6
22.0
26.4
24.5
25.2
36.3
(92)
(92)[d]
(90)
(86)
(93)
(90)
(91)
(91)
(92)
(91)
(92)
(94)
h
Entry
Catalyst[f]
amine, acid
t [h]
Conv. [%][a]
full
e.r.[b]
1.0
(ee [%])
9
10
11
12
1[c]
2[c]
3[c]
4[c]
5
6
7
8
9
10
11
12
13
14
3·(S)-TRIP[d]
4·2(S)-TRIP48
4·2Cl3CCO2H
5·2Cl3CCO2H
5·2Cl3CCO2H
5·3Cl3CCO2H
6·3Cl3CCO2H
7·3Cl3CCO2H
5·3CH3CO2H
5·3CF3CO2H
5·3pTsOH
48
trace
(2)
2j
2k
–
96
10
96
80
80
80
48
96
96
36
36
48
full
full
full
full
full
full
full
80
9.3
8.5
16.5
16.5
16.0
7.3
28.1
9.8
4.9
(80)
(79)
(88)
(88)
(88)[e]
(76)[e]
(93)
(81)
(66)
(92)
(91)
(89)
[a] Reaction scale: 0.5 mmol. [b] Yield of isolated product. [c] From
chiral-phase HPLC or GC analysis. [d] Opposite enantiomer.
enantioselectivity in providing the opposite enantiomer, as
demonstrated with 2a (entry 2).
Chiral enones 2 are valuable synthetic building blocks.
Enone 2a, for instance, has been used in the synthesis of
9-isocyanopupukeanane[4d] and HIV-1protease-inhibitive
didemnaketals.[11] Previously, at least five steps were required
to obtain (R)-2a from (R)-pulegone.[11,12] With our current
approach, both of its enantiomers can be easily accessed in
two steps from 2,4,6-lutidine.[13]
40
5·3EtCO2H
5·3iPrCO2H
5·3PhCO2H
full
full
full
25.3
23.4
17.8
[a] From GC analysis. [b] From chiral-phase HPLC analysis. [c] At room
temperature. [d] TRIP=3,3’-bis(2,4,6-triisopropylphenyl)-1,1’-bi-2-naph-
thol cyclic monophosphate. [e] Opposite enantiomer. [f] 20 mol% of
each amine was used.
The synthetic utility of our reaction was further exempli-
fied by the first asymmetric synthesis of both enantiomers of
celery ketone 2l (syn. Livescone), a synthetic fragrance
material with typical lovage and celery character, used as
modifier with basil and tarragon top notes, and to support
jasmine complexes in perfumery.[4a] The enantiomers of 2l
differ as strikingly in their olfactory properties as in the rare
case of carvone.[14] Only the stronger R enantiomer (odor
threshold 9.1ngL ꢁ1 air) is responsible for the characteristic
celery note of the racemate, whereas the S enantiomer, which
is five times weaker (odor threshold 45.5 ngLꢁ1 air), has an
aniseed-like liquorice smell with minty facets (Scheme 1).
It should be noted that, in the reaction catalyzed by salts 3
and 4, a substantial amount of the intermediate aldol addition
product could be detected during the reaction course. Using
the quinine-derived amine 5, only traces of the aldol product
were detected, suggesting that the higher reactivity obtained
by catalyst 5 may at least in part be due to faster dehydration.
The absolute configuration of the product obtained using
catalyst 5 was determined by comparison of the optical
rotation of compound 2a with the literature value.[12] As has
been proposed in related aldol reactions catalyzed by a
combination of diamine and protonic acid,[15] the protonated
quinine moiety of catalyst 5 might act as synergistic Brønsted
acid for the direction and activation of the electrophilic
carbonyl group by hydrogen bonding. This double-activation
model was also supported by the fact that when only one
equivalent of acid co-catalyst is used, the reaction is much
slower.
16.5 (entry 5). As expected, quinidine-derived catalyst 6
afforded the opposite enantiomer with equally high enantio-
selectivity (entry 7). Cinchonine-derived primary amine 7 was
also tested, but resulted in lower enantioselectivity than the
quinine-derived amine catalyst 6 (entry 8).
The acid co-catalyst significantly influenced both reactivity
and enantioselectivity (entries 5–6 and 9–14). The use of three
rather than two equivalents of acid slightly improved the
reactivity without loss of enantioselectivity (entry 5). The
general tendency is that salts of amine 5 with stronger acids
are less reactive and give lower enantioselectivity.[10] Acetic acid
turned out to be the best co-catalyst in terms of enantioselec-
tivity (entry 9), although the corresponding propionic acid and
isobutyric acid salts are slightly more active. We also investigated
a variety of solvents, and toluene turned out to be optimal.
Based on these optimization studies, we investigated the
reaction of different 2,6-diketones 1 in toluene at ꢁ158C using
20 mol% of quinine catalyst 5 in combination with three
equivalents of acetic acid (Table 2). A variety of aliphatic and
aromatic substituted 2,6-heptandiones 1 were effectively proc-
essed under the optimized reaction conditions, and furnished the
desired products in excellent yields. In general, diones 1 with an
aliphatic substitutent in the 4-position reacted faster than those
with an aromatic group. Of the eleven substrates examined, ten
afforded the desired enone 2 with e.r. >19.0. It should be noted
that the pseudoenantiomeric catalyst 6 also delivered excellent
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Scheme 1. Synthesis of both enantiomers of celery ketone (2l).
In conclusion, we have reported a solution to the long-
standing problem of enantiogroup-selective aldolizations of 4-
substituted-2,6-heptanediones 1 to enantiomerically enriched
5-substituted-3-methyl-2-cyclohexene-1-ones 2. Both 9-amino-
9-deoxyepiquinine 5 and its pseudoenantiomeric, quinidine-
derived analogue 6, in combination with acetic acid, proved to
be efficient and highly enantioselective catalysts for this
transformation, giving both enantiomers of enone 2 with high
e.r. values. Mechanistic investigations towards a better under-
standing of the details of this reaction as well as investigations
towards developing modular combinations of the process with
other reactions by iminium ion or enamine catalysis to develop
new organocatalytic cascades are ongoing.
[7] For enamine catalysis of intermolecular aldolizations of ketones,
see: a) O. Tokuda, T. Kano, W.-G. Gao, T. Ikemoto, K. Maruoka,
Org. Lett. 2005, 7, 5103 – 5105; b) S. Samanta, C. G. Zhao, J. Am.
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A.-Q. Mi, Y.-Z. Jiang, L.-Z. Gong, Org. Lett. 2006, 8, 1263 –
1266; d) J. Liu, Z. Yang, Z. Wang, F. Wang, X. Chen, X. Liu, X.
Feng, Z. Su, C. Hu, J. Am. Chem. Soc. 2008, 130, 5654 – 5655.
[8] S. Bahmanyar, K. N. Houk, J. Am. Chem. Soc. 2001, 123, 11273 –
11283.
[9] J. Zhou, B. List, J. Am. Chem. Soc. 2007, 129, 7498 – 7499.
[10] CH3CO2H (pKa = 4.76, e.r. = 28.1); PhCO2H (pKa = 4.31, e.r. =
17.8); Cl3CCO2H (pKa = 0.65, e.r. = 16.5); CF3CO2H (pKa =
ꢁ0.25, e.r. = 9.8); pTsOH (pKa = ꢁ2.80, e.r. = 4.9). For a dis-
cussion of acid co-catalyst effects in enamine catalytic aldoliza-
tions, see: A. Erkkilꢀ, P. M. Pihko, Eur. J. Org. Chem. 2007,
4205 – 4216.
[11] a) X. Z. Zhao, L. Peng, M. Tang, Y. Q. Tu, S. H. Gao, Tetrahe-
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[12] N. L. Allinger, C. K. Riew, J. Org. Chem. 1975, 40, 1316 – 1321.
[13] For the one-step synthesis of diketone 2a, see the Supporting
Information.
Experimental Section
Acetic acid (18.0 mg, 0.3 mmol) was added to a solution of amine 5
(32.5 mg, 0.1mmol) in toluene (0.5 mL). After cooling to ꢁ158C,
diketone 1 (0.5 mmol) was added. The resulting mixture was stirred at
ꢁ158C until TLC analysis indicated complete conversion of the
diketone. The reaction mixture was then directly subjected to column
chromatography to afford the desired product 2, using hexane or
pentane/diethyl ether (10:1!10:2) as eluent. To obtain pure com-
pounds, volatile enones 2 were carefully dried under vacuum at
ꢁ788C to remove residual solvent.
Received: May 28, 2008
Published online: August 20, 2008
Keywords: aldol reaction · asymmetric catalysis ·
.
bifunctional catalysis · enamines · organocatalysis
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