Organocatalytic entry to chiral bicyclo[3.n.1]alkanones via direct asymmetric intramolecular aldolization

Article abstract of DOI:10.1021/ol051569d

(Chemical Equation Presented) The facile stereoselective syntheses of endo-8-hydroxybicyclo[3.3.1]nonan-2-one and encto-7-hydroxybicyclo[3.2.1]octan- 2-one, featuring an α-amino acid catalyzed intramolecular aldolization of σ-symmetric substrates, are des

Full text of DOI:10.1021/ol051569d

ORGANIC
LETTERS
2005
Vol. 7, No. 19
4185-4188
Organocatalytic Entry to Chiral
Bicyclo[3.n.1]alkanones via Direct
Asymmetric Intramolecular Aldolization
Noriaki Itagaki, Mari Kimura, Tsutomu Sugahara, and Yoshiharu Iwabuchi*
Graduate School of Pharmaceutical Sciences, Tohoku UniVersity,
Aobayama, Sendai 980-8578, Japan
iwabuchi@mail.pharm.tohoku.ac.jp
Received July 5, 2005
ABSTRACT
The facile stereoselective syntheses of endo-8-hydroxybicyclo[3.3.1]nonan-2-one and endo-7-hydroxybicyclo[3.2.1]octan-2-one, featuring an
-amino acid catalyzed intramolecular aldolization of -symmetric substrates, are described. A high enantioselectivity and a high catalytic
r
σ
efficiency have been exhibited by (4R,2S)-tetrabutylammonium 4-TBDPSoxy-prolinate in the aldolization of 3-(4-oxocyclohexyl)propionaldehyde
to give highly enantiomerically enriched (1S,5R,8R)-8-hydroxybicyclo[3.3.1]nonan-2-one.
Reaction processes that bring about significant increases in
molecular complexity play enormous roles in synthetic
organic chemistry.1,2 In this regard, the direct aldol reaction3
is noteworthy because it offers access to a variety of cyclic
and acyclic molecules via the generation of a new C-C bond
and up to two new adjacent stereocenters with ideal atom
efficiency.4 The landmark discoveries in the early 1970s by
Hajos-Parrish5 and Eder-Sauer-Wiechert6 and in 2000 by
List-Lerner-Barbas7 showing that proline catalyzes highly
enantioselective direct asymmetric aldol reactions spurred
extensive research on the use of proline and its derivatives
in catalyzing aldol and related reactions.8-10 Proline is now
widely recognized as the simplest enzyme11 whose suitable
modifications could principally bring about evolution in
catalytic activity.12 With this encouraging prospect in mind,
(8) Reviews: (a) Drauz, K.; Kleeman, A.; Martens, J. Angew. Chem.,
Int. Ed. Engl. 1982, 21, 584. (b) List, B. Synlett 2001, 1675. (c) Gro¨ger,
H.; Wilken, J. Angew. Chem., Int. Ed. 2001, 40, 529. (d) Dalko, P. I.;
Moisan, L. Angew. Chem., Int. Ed. 2001, 40, 3727 (e) Jarvo, E. R.; Miller,
S. J. Tetrahedron 2002, 58, 2481. (f) List, B. Tetrahedron 2002, 58, 5573.
(g) List, B. Acc. Chem. Res. 2004, 37, 548 (h) Saito, S.; Yamamoto, H.
Acc. Chem. Res. 2004, 37, 548; Acc. Chem. Res. 2004, 37, 570. (i) Notz,
W.; Tanaka, F.; Barbas, C. F., III. Acc. Chem. Res. 2004, 37, 580. (j) Dalko,
P. I.; Moisan, L. Angew. Chem., Int. Ed. 2004, 43, 5138, 5175. (k) Seayad,
J.: List, B. Org. Biomol. Chem. 2005, 3, 719.
(1) Whitlock, H. W. J. Org. Chem. 1998, 63, 7982.
(2) Taylor, M. S.; Jacobsen, E. N. Proc. Nat. Acad. Sci. U.S.A. 2004,
101, 5368.
(3) Recent reviews: (a) Machajewski, T. D.; Wong, C.-H. Angew. Chem.,
Int. Ed. 2000, 39, 1353. (b) Palomo, C.; Oiarbide, M.; Garc´ıa, J. M. Chem.
Eur. J. 2002, 8, 37. (c) Alcaide, B.; Almendros, P. Angew. Chem., Int. Ed.
2003, 42, 858.
(9) For selected references on intramolecular asymmetric aldolization,
see: (a) Hiroi, K.; Yamada, S.-i. Chem. Pharm. Bull. 1975, 23, 1103. (b)
Terashima, S.; Sato, S.; Koga, K. Tetrahedron Lett. 1979, 36, 3469. (c)
Bui, T.; Barbas, C. F., III. Tetrahedron Lett. 2000, 41, 6951. (d) Li, Y.;
Nassim, B.; Crabbe´, P. J. Chem. Soc., Perkin Trans. 1 1983, 2349. (e)
Hagiwara, H.; Uda, H. J. Org. Chem. 1988, 53, 2308. (f) Pidathala, C.;
Hoang, L.; Vignola, N.; List, B. Angew. Chem., Int. Ed. 2003, 42, 2785,
2788. (g) Mans, D. M.; Pearson, W. H. Org. Lett. 2004, 6, 3305-3308. (h)
Inomata, K.; Barrague´, M.; Paquette, L. A. J. Org. Chem. 2005, 70, 533-
539. (i) Kurteva, V. B.; Afonso, C. A. M. Tetrahedron 2005, 61, 267. (j)
Shigehisa, H.; Mizutani, T.; Tosaki, S.; Ohshima, T.; Shibasaki, M.
Tetrahedron 2005, 61, 5057.
(4) Trost, B. M. Science 1991, 254, 1471.
(5) (a) Hajos, Z. G.; Parrish, D. R. German Patent DE 2102623, July
29, 1971. (b) Hajos, Z. G.; Parrish, D. R. J. Org. Chem. 1974, 39, 1615.
(6) (a) Eder, U.; Sauer, G.; Wiechert, R. (Schering, A.-G.) German Patent
DE 2014757, Oct 7, 1971. (b) Eder, U.; Sauer, G.; Wiechert, R. Angew.
Chem., Int. Ed. Engl. 1971, 10, 496.
(7) List, B.; Lerner, R. A.; Barbas, C. F., III. J. Am. Chem. Soc. 2000,
122, 2395.
10.1021/ol051569d CCC: $30.25
© 2005 American Chemical Society
Published on Web 08/18/2005

we envisaged the enantioselective synthesis of bicyclo[3.n.1]-
alkanones (n ) 3 or 2) 213 from σ-symmetric keto-aldehydes
1 via enolexo mode9f of intramolecular aldolization with
amino acid catalysis (Scheme 1).
Scheme 2. Preparation of the Substrates
Scheme 1. Issues in the Selectivity of the Aldolization of 1
(>99% ee) by single recrystallization (diisopropyl ether/
hexane). The absolute stereochemistry of (-)-endo-2 was
unequivocally established to be 1S,5R,8R by connecting to
the known compound (R)-615 via a retro-Dieckmann reaction
of 5 as shown in Scheme 3.14
Our hope of using 2 as building blocks and the mechanistic
interest in the issue of selectivity prompted us to investigate
the feasibility of the process. We report herein an organo-
catalytic entry to chiral bicyclo[3.n.1]alkanones (n ) 3 or
2) and the discovery of several interesting factors that
markedly enhance the efficiency of aldolization.
The σ-symmetric keto-aldehydes 1a and 1b were prepared
from ethyl 4-hydroxycinnamate and 1,4-cyclohexanedione
monoethylene acetal, respectively, as shown in Scheme 2.14
To scout the inherent reactivity toward aldolization, 1a
and 1b were subjected to typical conditions employing K2-
Scheme 3. Determination of Absolute Stereochemistry of
(-)-2
12
CO3 or pyrrolidine as the catalyst. In both cases, bicyclo-
[3.n.1]-type products 2 were produced as the mixtures of
endo-/exo-diastereomers, and bicyclo[2.2.m]-type products
3 were not detected (entries 1-4). It was, therefore,
interesting to find that L-proline catalyzed the highly dias-
tereoselective aldolization of 1b to furnish endo-2b in 52%
yield with 94% de, although ee was 10% (entry 5). To our
satisfaction, the L-proline-catalyzed aldolization of 1a to
furnish (-)-endo-8-hydroxy-bicyclo[3.3.1]nonan-2-one (endo-
2a) in 60% yield with an excellent de of 98% and a high ee
of 78% under the standard conditions (25 mol % catalyst,
DMSO, rt, 72 h, entry 6), which was easily optically purified
Since the preliminary experiments revealed that L-proline
cannot be used to examine various reaction conditions
because of its inherent low solubility in conventional organic
solvents, we designed a series of proline derivatives 7-1114
with the hope of conferring a lipophilic property onto the
proline motif, thereby securing the basis for the evolution
of the catalytic activity.16 It was found that both 7 and 8
showed improved solubilities17 in MeCN and enhanced
catalytic potencies to convert 1a to a bicyclo[3.3.1]-type
product with opposite enantiopreferences and different enan-
tiocontrolling proficiencies. Thus, although 7 gave diastereo-
and enantioselectivities almost comparable with those of
(10) For selected references on intermolecular aldolization, see: (a) Notz,
W.; List, B. J. Am. Chem. Soc. 2000, 122, 7386. (b) List, B.; Pojarliev, P.;
Castello, C. Org. Lett. 2001, 3, 573. (c) Sakthivel, K.; Notz, W.; Bui, T.;
Barbas, C. F., III. J. Am. Chem. Soc. 2001, 123, 5260. (d) Northup, A. B.;
MacMillan, D. W. C. J. Am. Chem. Soc. 2002, 124, 6798. (e) Chowdari,
N. S.; Ramachary, D. B.; Co´rdova, A.; Barbas, C. F., III. Tetrahedron Lett.
2002, 43, 9591. (f) Casas, J.; Engqvist, M.; Ibrahem, I.; Kaynak, B.;
Co´rdova, A. Angew. Chem., Int. Ed. 2004, 43, 2-4. (g) Northup, A. B.;
Mangion, I. K.; Hettche, F.; MacMillan, D. W. C. Angew. Chem., Int. Ed.
2004, 43, 2152 (h) Chan, V.; Kim, J. G.; Jimeno, C.; Carroll, P. J.; Walsh,
P. J. Org. Lett. 2004, 6, 2051. (i) Thayumanavan, R.; Tanaka, F.; Barbas,
C. F., III. Org. Lett. 2004, 6, 3541. (j) Northup, A. B.; MacMillan, D. W.
C. Science 2004, 305, 1752. (k) Ward, D. E.; Jheengut, V.; Akinnusi, O.
T. Org. Lett. 2005, 7, 1181. (l) Suri, J. T.; Ramachary, D. B.; Barbas, C.
F., III. Org. Lett. 2005, 7, 1383.
(11) Movassaghi, M.; Jacobsen, E. N. Science 2002, 298, 1904.
(12) (a) Saito, S.; Nakadai, M.; Yamamoto, H. Synlett 2001, 1245. (b)
Tang, Z.; Jiang, F.; Yu, L.-T.; Cui, X.; Gong, L.-Z.; Mi, A.-Q.; Jiang, Y.-
Z.; Wu, Y.-D. J. Am. Chem. Soc. 2003, 125, 5263. (c) Cobb, A. J. A.;
Shaw, D. M.; Ley, S. V. Synlett 2004, 558. (d) Mase, N.; Tanaka, F.; Barbas,
C. F., III. Angew. Chem., Int. Ed. 2004, 43, 2420.
(13) A highly enantioselective synthesis of (+)-endo-2 by yeast-mediated
asymmetric reduction of bicyclo[3.3.1]nonan-2,8-dione has been reported.
Mori, K.; Takayama, S.; Kido, M. Bioorg. Med. Chem. 1994, 2, 395.
(14) See Supporting Information.
(15) Elliot, M. L.; Urban, F. J. Border. J. Org. Chem. 1985, 50, 1752.
(16) (a) Hoang, L.; Bahmanya, S.; Houk, K. N.; List, B. J. Am. Chem.
Soc. 2003, 125, 16. (b) Allemann, C.; Gordillo, R.; Clemente, F. R.; Cheong,
P. H.-E.; Houk, N. K. Acc. Chem. Res. 2004, 37, 558. (c) Bahmanyar, S.;
Houk, K. N. J. Am. Chem. Soc. 2001, 123, 11273. (d) Bahmanyar, S.; Houk,
K. N.; Martin, H. J.; List, B. J. Am. Chem. Soc. 2003, 125, 2475.
(17) For discussions on solubility and reactivity of organocatalysts, see:
(a) Cobb, A. J. A.; Shaw, D. M.; Longbottom, D. A.; Gold, J. B.; Ley, S.
L. Org. Biomol. Chem. 2005, 3, 84. (b) Darbre, T.; Machuqueiro, M. Chem.
Commun. 2003, 1090.
4186
Org. Lett., Vol. 7, No. 19, 2005

Table 1. Exploratory Studies of Intramolecular Aldolization of
s-Symmetric Keto-aldehydes 1a
Table 2. Organocatalytic Desymmetric Aldolization of
σ-Symmetric Keto-aldehydes 1
sub-
catalyst
(mol %)
additive time pro- yieldb
sub-
catalyst
(mol %)
time pro- yieldb
entry strate
(equiv)
(h)
duct
(%)
dec eed
entry strate
solvent (h) duct (%)
dec eed
0
1
1a
1a
1a
1a
1a
1a
1a
1a
1a
1a
1b
1b
L-proline (25)
7 (15)
92 2a
16 2a
45
84
88 77
98 78
1
2
3
4
5
6
1a
1b
1a
1b
1b
1a
K2CO3 (9)
K2CO3 (9)
pyrrolidine (25) MeCN
pyrrolidine (25) MeCN 24
L-proline (25)
L-proline (25)
MeOH
1
2a
2b
2a
2b
2b
2a
60
2
MeOH 12
83 -24
3
8 (25)
23 ent-2a 68 >99 94
8
70
38
52
60
59
0
94 10
99 78
4
9 (5)
3
8
7
2a
2a
2a
70
71
81
85
68
77
96 72
99 89
99 95
85 76
99 76
98 94
99 81
5
7 (15)
H2O (1)
DMF
54
6
7 (15)
H2O (10)
DMSO 72
7
7 (15)
H2O (50) 96 2a
a Reactions were carried out in the indicated solvent (0.125 or 0.18 M).
b Isolated after chromatographic purification. c Determined by 1H NMR;
refers to preference of endo selectivity. Negative value corresponds to
enrichment in the exo isomer. d Determined by 1H NMR analysis of the
(R)- and (S)-MTPA derivatives of 2 or chiral HPLC analysis of the benzoyl
ester of 2.
8
L-proline (25) H2O (1)
48 2a
2a
9
10 (5)
11 (25)
9 (25)
3
10
11
12
18 ent-2a 74
2
2
2b
2b
46
40
84
0
12 (25)
98 33
a Reactions were carried out in the indicated solvent (0.1 or 0.125 M).
b Isolated after chromatographic purification. c Determined by 1H NMR;
refers to preference of endo selectivity. d Determined by 1H NMR analysis
of the (R)-and (S)-MTPA derivatives of 2 or chiral HPLC analysis of the
benzoyl ester of 2.
proline, 8 exhibited a high enantioselectivity of 94% ee,
suggesting some productive role of the cis-oriented TBDP-
Soxy group in crucial enantio-discriminating events (Table
2, entries 1-3). It was also an important clue in this venture
that the tetrabutylammonium salt 9 was found not only to
exist as an oil at ambient temperature and be miscible in
MeCN but also to markedly enhance the aldolization rate
(entry 4). We then surveyed factors leading to the further
improvement of catalysis. Regarding 7, the addition of some
portions of H2O18 brought about a notable rate acceleration
and an increment in enantioselectivity (entries 5 and 6), while
excess (50 equiv) H2O in turn attenuated the enantioselec-
tivity to 76% ee (entry 7). No such phenomenon was
observed in proline, indicating the supportive role played
by the TBDPS group in enantio-discriminating events (entry
8). We found that the tetrabutylammonium salt 1019,20 gave
good results as the use of 5 mol % of 10 completed the
reaction within 3 h at room temperature to furnish 77% 2a
with 94% ee (entry 9). In contrast, the use of 11 resulted in
a slight decrease in enantioselectivity (entry 10). On the other
hand, any modification proved less effective for the aldoliza-
tion of 1b to 2b. To date, the catalyst 12 was found to mark
33% ee at best (entries 11 and 12).
the observed chemo-, diastereo-, and enantioselectivities in
the amino acid catalyzed reaction of 1a to endo-2a (Figure
1). The reaction of the catalyst 7 with 1a furnishes an
equilibrium mixture22 of several enamines and H2O. Under
the provided conditions, transition state B is allowed to enjoy
both a dipole interaction between the developing oxyanion
and the iminium ion as well as a hydrogen bonding between
the oxyanion and the carboxy group on the catalyst within a
less strained chairlike conformation on the way to (1S,5R,8R)-
2a. On the other hand, transition state A is discouraged as a
result of the lack of an intramolecular hydrogen bonding
between oxy-anion and carboxy group. The nonappearance
of the bicyclo[2.2.2]octane 3 in the reaction products
could be attributed to the constrained nature of the transition
state C.24
Although the roles of the TBDPSoxy group, H2O, and
tetrabutylammonoium salt in the reaction system are not yet
clear,20,21 the following mechanistic rationale would explain
(18) For the unique effect of H2O on organocatalysis, see: (a) Itoh, T.;
Yokoya, M.; Miyauchi, K.; Nagata, K.; Ohsawa, A. Org. Lett. 2003, 5,
4301. (b) Torii, H.; Nakadai, M.; Ishihara, K.; Saito, S.; Yamamoto, H.
Angew. Chem., Int. Ed. 2004, 43, 1983.
To summarize, we have described the facile diasetereo-
selective synthesis of the bicyclo[3.3.1]nonane 2a and
(19) Yamaguchi et al. reported that 9 catalyzes the Hajos-Wiechert
reaction much faster than proline itself but with low ee. Yamaguchi, M.;
Shiraishi, T.; Hirama, M. J. Org. Chem. 1996, 61, 3520.
(20) The remarkable rate acceleration exhibited by the tetrabutylammo-
nium salt 10 would be attributed to the increment in the effective
concentration of the catalytically active, nucleophilic secondary amine form
compared with that of 7, most of which tends to equilibrate to zwitterionic
form under typical conditions.
(21) For the amino group to be nucleophilic, it must be in its unchanged
form. We presumed that the hydrophobic environment generated by the
TBDPS group and the tetrabutylammonium ion perturbed the pKa of the
amino group. (a) Barbas, C. F., III; Heine, A.; Zhong, G.; Hoffman, T.;
Gramatikova, S.; Bjo¨rnested, R.; List, B.; Anderson, J.; Stura, E. A.; Wilson,
I.; Lerner, R. A. Science 1997, 278, 2085. (b) Lee, J. K.; Houk, K. N.
Science 1997, 276, 942.
Org. Lett., Vol. 7, No. 19, 2005
4187

H2O, and tetrabutylammonoium salt in amino acid catalyzed
aldolization and the search for a catalyst that enables
asymmetric construction of chiral bicyclo[3.2.1]octane-type
products are now the subjects of our extensive studies.
Acknowledgment. The authors are grateful to Prof.
Masahiko Yamaguchi for useful suggestions and discussions.
Supporting Information Available: Experimental pro-
cedures, compound characterization, and analytical data (1H
NMR, 13C NMR, and HRMS) for all new compounds. This
material is available free of charge via the Internet at
http://pubs.acs.org.
OL051569D
(22) It is important to point out that all of the amino acid catalysts
described in this study promoted neither the aldolization of the R-methyl
congeners 1c to 2c nor the reverse aldolization of 2a, whereas methanolic
K2CO3 promoted both reactions with considerable efficacies. These observa-
tions suggest that (i) proline-catalyzed aldolization is sensitive to steric
hindrance around the carbonyl group and thus suffers from the formation
of an enamine moiety,23 (ii) the reverse aldolization of 2a to 1a is not
operative under proline-type catalysis, and (iii) the enantioselectivity is not
a result of thermodynamically equilibrated processes but is determined by
a kinetically controlled step.
Figure 1. Mechanistic rationale on chemo-, diastereo-, and
enantioselectivity.
bicyclo[3.2.1]octanone 2b entailing an amino acid catalyzed
aldolization as the key step, in which the former is efficiently
constructed in a highly enantiomerically enriched fashion
using 10. This methodology complements the highly enan-
tioselective Baker’s yeast reduction.13 The product is poten-
tially useful as a chiral building block in target-oriented
synthesis. The elucidation of the roles of TBDPSoxy group,
(23) It has been reported that proline catalyzes the asymmetric transfer
aldol reaction between diacetone alcohol and aldehydes but not the reaction
of 5-ethyl-5-hydroxy-4-methyl-3-heptanone. Chandrasekhar, S,; Narsihmulu,
C.; Reddy, N. R.; Sultana, S. Chem. Commun. 2004, 2450.
(24) The main reason that 3 was not formed could be the constraint of
the bicyclo[2.2.2]-product and not because of the proline-based catalysts,
since K2CO3 and pyrrolidine also did not afford 3.
4188
Org. Lett., Vol. 7, No. 19, 2005