Chiral amine-catalyzed asymmetric Baylis-Hillman reaction: A reliable route to highly enantiomerically enriched (α-methylene-β-hydroxy)esters [5]

Full text of DOI:10.1021/ja992655+

J. Am. Chem. Soc. 1999, 121, 10219-10220
10219
isopropyl acrylate8 (2) because this acrylate turned out to show
remarkable rate acceleration.
Chiral Amine-Catalyzed Asymmetric Baylis-Hillman
Reaction: A Reliable Route to Highly
Enantiomerically Enriched
To assay the ability of various hydroxylated amine catalysts,
we surveyed four quinidine derivatives,10 QD-1, QD-2, QD-3,
and QD-4, as well as quinidine itself in the reaction of 1a and 2
(Table 1). Although quinidine, QD-1, and QD-2 did not give
satisfactory results (entries1-3), the cyclic ether derivative QD-3
displayed remarkable catalytic activity, even at -55 °C in DMF,11
affording 4a and 6a in good total yield (entries 4 and 5). In these
cases, however, the level of the asymmetric induction was
disappointing. We were gratified to find that QD-4 provided a
dramatic increase in the optical purity of 4a (91% ee, entry 6).
This result suggests the crucial role of the phenolic hydroxy group
on the enantioselectivity, which is important to highlight. The
large discrepancy between the optical purity of 4a (91% ee) and
that of 6a (4% ee) was the key observation which led to our
proposed mechanistic explanation (vide infra). The rate enhance-
ment observed for QD-3 and QD-4 supposedly results from their
increased nucleophilicity due to reduced steric hindrance around
the nucleophilic nitrogen of the catalyst by restraining the
conformational freedom of the bulky aromatic moiety.12 The
results listed in entries 6 and 7 clearly indicate the temperature
dependency on enantioselectivity. In a control experiment using
3 and QD-4 (entry 8), only poor enantioselectivity (8% ee) was
observed, presumably due to the higher reaction temperature
employed, highlighting the advantage of 2.
Having demonstrated the superiority of the combination of
QD-4 and 2 in the reaction of 1a, we turned our efforts to
investigate its applicability (Table 2). It can be seen that aromatic
aldehydes including cinnamaldehyde (1c) preferentially gave ester
4 with very high optical purity (entries 1-3). This reaction system
was also found to be applicable to aliphatic aldehydes, giving
the corresponding esters 4 in excellent enantioselectivity, although
the yields were moderate. Interestingly, the accompanying dioxa-
nones 6 showed the reverse chirality and irregular ee values
(entries 4-7). It should be stressed that even sterically demanding
isobutyraldehyde (1f) and cyclohexanecarboxaldehyde (1g) pro-
duced optically pure esters 4f and 4g in moderate yields,
respectively (entries 6 and 7). Pivalaldehyde (1h), however,
resulted in quantitative dimerization of acrylate 2,13 thus defining
the steric limitation of the reaction. The intriguing switch of
enantioselectivity between 4 and 6 provided an important
mechanistic insight when we found that QD-4 does not promote
acetalization14 of racemic ester 4a with aldehyde 1a to dioxanone
6a. This observation suggests that highly enantiomerically
(r-Methylene-â-hydroxy)esters
Yoshiharu Iwabuchi, Mari Nakatani, Nobiko Yokoyama, and
Susumi Hatakeyama*
Faculty of Pharmaceutical Sciences, Nagasaki UniVersity
Nagasaki 852-8521, Japan
ReceiVed July 26, 1999
The tertiary amine-catalyzed C-C bond-forming reaction of
aldehydes with activated alkenes such as acrylates is widely
referred to as the Baylis-Hillman reaction.1 Both the synthetic
utility of the densely functionalized products1,2 and the exquisite
tandem Michael-aldol reaction process under nucleophilic amine
catalysis3 have spurred much research on an asymmetric version
of this reaction. However, the reported methods are far from ideal
because of low chemical yield and low optical purity of the
adducts.4 Except for one recent report by Leahy and co-workers5
describing the highly diastereoselective Baylis-Hillman reaction
of the acrylamide of Oppolzer’s sultam, albeit with the stipulation
that a large excess of the aldehyde must be employed, no other
method is currently available for this purpose. We report here
the first practical catalytic asymmetric Baylis-Hillman reaction
which allows conversion of a wide variety of aldehydes to the
corresponding (R-methylene-â-hydroxy)esters with high enan-
tiomeric excess in reasonable yields.
To realize an efficient catalytic asymmetric Baylis-Hillman
reaction, wherein a high level of asymmetric induction as well
as desired rate acceleration6 is obtained, the appropriate combina-
tion of chiral amine catalyst and suitably activated alkene is
required. Drewes6a and Marko´4a,7 independently reported that an
OH group suitably disposed on an amine catalyst exerts a marked
effect on rate acceleration as well as asymmetric induction. They
suggest that the OH group stabilizes the oxy anion intermediate
through hydrogen bonding, which accelerates the aldol addition
reaction and also creates an asymmetric environment in some
cases. These reports prompted us to survey a series of hydroxy-
lated amines derived from cinchona alkaloids. Regarding the
activated alkene, we decided to employ 1,1,1,3,3,3-hexafluoro-
* To whom correspondence should be addressed. Tel.: +81-95-847-1111
(ext. 2520). Fax: +81-95-848-4286. E-mail: susumi@net.nagasaki-u.ac.jp.
(1) For an eminent review, see: Ciganek, E. Org. React. 1997, 51, 201-
350.
(2) For leading references, see: (a) Marko´, I. E. Organometallic Reagents
in Organic Synthesis; Academic Press: London, 1994. (b) Piber, M.; Leahy,
J. W. Tetrahedron Lett. 1998, 39, 2043-2046. (c) Familoni, O. B.; Kaye, P.
T.; Klaas, P. J. J. Chem. Soc., Chem. Commun. 1998, 2563-2564.
(3) For mechanistic studies, see: (a) Hoffmann, H. M. R.; Rabe, J. Angew.
Chem. 1983, 95, 795-796. (b) Hill, J. S.; Isaacs, N. S. J. Phys. Org. Chem.
1990, 3, 285-293. (c) Bode, M. L.; Kaye, P. T. Tetrahedron Lett. 1991, 32,
5611-5614. (d) Fort, Y.; Berthe, M. C.; Caubere, P. Tetrahedron 1992, 48,
6371-6384. (e) Rosendaal, E. M. L.; Voss, B. M. W.; Scheeren, H. W.
Tetrahedron 1993, 31, 6931-6936.
(8) The acrylate was purchased form Tokyo Chemical Industry Co., Ltd.,
and used without purification. The acrylate displayed the highest productivity
in the preliminary study using 1a. For example, the reaction of p-nitroben-
zaldehyde (1a) with 2 in the presence of DABCO (10 mol %) required only
1.5 h even at 2 °C to give ester 4a (60%) and dioxanone 6a9 (15%), whereas
the reaction of 1a with methyl acrylate (3) took 12 days to achieve 94%
conversion.
(9) The dioxanones are often produced in the reactions using the reactive
acrylates. (a) Drewes, S. E.; Emslie N. D.; Karodia, N.; Khan, A. A. Chem.
Ber. 1990, 123, 1447. (b) Perlmutter, P.; Puniani, E.; Westman, G. Tetrahedron
Lett. 1996, 37, 1715. See also ref 5.
(4) (a) Marko´, I. E.; Giles, P. R.; Hindley, N. J. Tetrahedron 1997, 53,
1015-1024. (b) Hayase, T.; Shibata, T.; Soai, K.; Wakatsuki, Y. J. Chem.
Soc., Chem. Commun. 1998, 1271-1272. (c) Barret, A. G. M.; Cook, A. S.;
Kamimura, A. J. Chem. Soc., Chem. Commun. 1998, 2533-2534. (d) Kataoka,
T.; Iwama, T.; Tsujiyama, S.; Kanematsu, K.; Iwamura, T.; Watanabe, S.
Chem. Lett. 1999, 257-258. See also ref 1.
(10) The catalysts QD-1-QD-4 were prepared according to the literature
procedures. (a) von Riesen, C.; Hoffmann, H. M. R. Chem. Eur. J. 1996, 2,
680-684. (b) Braje, W.; Frackenpohl, J.; Langer, P.; Hoffmann, H. M. R.
Tetrahedron 1998, 54, 3495-3512. We found that a multigram sample of
QD-4 was synthesized (∼60%) in one step from (+)-quinidine by heating
with 10 equiv of KBr in 85% phosphoric acid at 100 °C for 5 days.
(11) Solvent effects could not be evaluated due to the low solubility of the
catalysts in solvents other than DMF.
(12) This supposition is well supported by their stereostructures deduced
from NOE experiments of QD-3 and QD-4 as well as X-ray crystallographic
analysis of QD-4. See Supporting Information.
(13) Basavaiah, D.; Gowriswari, V. V. L.; Bharathi, T. K. Tetrahedron
Lett. 1987, 28, 4591-4592.
(14) Reaction of racemic 4a with 1a in the presence of QD-4 in DMF at
-55 °C resulted in no reaction after 1 day. At room temperature, very small
production of 6 (<3%) was detected after 1 day.
(5) Brzezinski, L. J.; Rafel, S.; Leahy, J. W. J. Am. Chem. Soc. 1997, 119,
4317-4318.
(6) The Baylis-Hillman reaction is notorious for slow reaction rates, and
a number of attempts have been made to circumvent the sluggish nature of
this reaction. (a) Drewes, S. E.; Freese, S. D.; Emslie, N. D.; Roos, G. H. P.
Synth. Commun. 1988, 18, 1565. (b) Rafel, S.; Leahy, J. W. J. Org. Chem.
1997, 62, 1521-1522. (c) Kawamura, M.; Kobayashi, S. Tetrahedron Lett.
1999, 40, 1539-1542. See also ref 1.
(7) Bailey, M.; Marko´, I. E.; Ollis, D.; Rasmussen, P. R. Tetrahedron Lett.
1990, 31, 4509-4512.
10.1021/ja992655+ CCC: $18.00 © 1999 American Chemical Society
Published on Web 10/16/1999

10220 J. Am. Chem. Soc., Vol. 121, No. 43, 1999
Communications to the Editor
Table 1. Asymmetric Baylis-Hillman Reaction of
p-Nitrobenzaldehyde (1a) with Acrylates Catalyzed by Quinidine
Derivativesa
yield (%),b configc
(% eed)
temp time
entry acrylate catalyst solvent (°C) (h)
ester
dioxanonee
1
2
3
2
2
2
quinidine THF
2 24 12, ndf
2 72 2, nd
2 72 10, nd
22, R (33)
32, R (35)
26, R (10)
QD-1g
QD-2g
THF
THF-
DMFh
4
5
6
7
8
2
2
2
2
3
QD-3
QD-3i
QD-4i
QD-4i
QD-4
THF
2
-55
-55
0
1
1
1
63, R (35) 10, R (33)
74, R (10) 7, nd
58, R (91) 11, R (4)
DMF
DMF
DMF
DMF
Figure 1. Proposed reaction mechanism.
1.5 52, R (64) 11, S (10)
The following mechanistic consideration would rationalize the
absolute stereochemistry of the products and the key role played
by the phenolic hydroxy group of QD-4 (Figure 1). Michael
addition of QD-4 to acrylate 2 forms enolate A, which in turn
undergoes aldol reaction with an aldehyde to furnish an equilib-
rium mixture of several diastereomers. Among them, there are
two betaine intermediates, B and C,15 stabilized by an intramo-
lecular hydrogen bonding between the oxy anion and the phenolic
OH, the conformations of which are nearly ideal for the
subsequent E2 or E1cb reaction process for stereoelectronic
reasons,3a,16 as depicted in Newman projection D. However,
intermediate C suffers from severe steric interactions between Y
and the ester and quinuclidine moieties {see D (X ) H, Y )
substituent)}, and thus it undergoes reaction with a second
aldehyde molecule rather than elimination to form dioxanone 6.
On the other hand, intermediate B undergoes facile elimination
to produce (R)-ester 4 with regeneration of the catalyst because
of less steric hindrance {see D (X ) substituent, Y ) H)}. The
irregular ee values observed for dioxanones 6 in Table 2 can be
explained on the basis of the reactivity of the starting aldehyde.
Thus, as the reactivity of the aldehyde increases, the rate of
formation of (R)-dioxanone 6 from intermediate B also increases
in competition with elimination, which gives (R)-ester 4, leading
to decrease of the (S)-selectivity of 6.
20 14 69, S (8)
-
a Aldehyde (0.1 mmol) was reacted with acrylate (0.3 mmol) using
a 10 mol % of catalyst in 200 µL of the solvent at the indicated
temperature, unless otherwise stated. b Isolated yield. c Configuration
determined by comparison of the specific rotation of the corresponding
methyl ester 5 with that of the authentic sample obtained by kinetic
resolution under Sharpless asymmetric epoxidation conditions. d De-
termined by HPLC analysis using a chiral column. e cis:trans > 99:1.
f Not determined. g 20 mol % of catalyst was used. h 10% DMF was
added to dissolve the catalyst. i 0.13 mmol of 2 was used.
Table 2. QD-4-Catalyzed Asymmetric Baylis-Hillman Reaction
of Various Aldehydes with 2a
yield (%),b configc
(% eed)
In summary, we have developed a highly enantioselective
Baylis-Hillman reaction based on the discovery of two important
reagents, 1,1,1,3,3,3-hexafluoroisopropyl acrylate (2) as an acti-
vated alkene and (3R,8R,9S)-10,11-dihydro-3,9-epoxy-6′-hydroxy-
cinchonane (QD-4) as a chiral amine catalyst. The novel catalytic
behavior of QD-4 should also inspire new avenues for the design
of catalysts for the Baylis-Hillman reaction.
time
(h)
1
entry aldehyde
R
ester 4
dioxanone 6e
1
2
3
4
5h
6
7
8
1a
1b
1c
1d
1e
1f
p-NO2Ph
58, R (91) 11, R (4)
Ph
48 57, R (95)
-
-
(E)-PhCHdCH 72 50,f Rg (92)
CH3CH2
(CH3)2CHCH2
(CH3)2CH
c-Hex
4
4
40, R (97) 22, S (27)
51, R (99) 18, S (85)
16 36, R (99) 25, S (70)
72 31, R (99) 23, S (76)
72
1g
1h
Acknowledgment. This work is supported by the Ministry of
Education, Science, Sports, and Culture of Japan (No. 10771251). We
thank Prof. Dr. Istva´n E. Marko´ (Universite Catholique de Louvain) for
stimulating discussions on the reaction mechanisms.
t-Bu
-
-
a Reactions were carried out at -55 °C in DMF (1.0 M) using 1
(1.0 equiv), 2 (1.3 equiv), and QD-4 (10 mol %), unless otherwise
stated. b Isolated yield. c Determined by the comparison of the specific
rotation of the corresponding methyl esters, unless otherwise stated.
d Determined by HPLC analysis using a chiral column. e cis:trans >
95:5 for 6a,f-h and 69:31 for 6e. f Yield was calculated on the basis
Supporting Information Available: Experimental details and char-
acterization data for all new compounds, including tables of crystal data
for QD-4 (PDF). This material is available free of charge via the Internet
at http://pubs.acs.org.
of recovered 1c. g Determined by H NMR analysis of the (R)- and
1
(S)-MTPA derivatives of the corresponding methyl ester. h 20 mol %
JA992655+
of catalyst was used.
(15) We assumed that intermediates B and C would be thermodinamically
favorable aldol products generated through equilibration. However, based on
the mechanistic explanation proposed by Leahy and co-workers,5 it is also
assumed that intermediates B and C would be produced selectively from the
E-enolate, stabilized by electrostatic interactions, via an open transition state
where an aldehyde approaches to the re-face or si-face of the E-enolate.
(16) Deslongchamps, P. Stereoelectronic Effects in Organic Chemistry;
Pergamon: Oxford, 1983; pp 252-257.
enriched (R)-esters 4 are not obtained by virtue of kinetic
resolution through preferential acetalization of the antipodal (S)-
esters with aldehydes 1. It implies that (R)-enriched 4 and (S)-
enriched 6 are produced via different chemical pathways at the
enantio-divergent point.