Organocatalytic sequential one-pot double cascade asymmetric synthesis of Wieland-Miescher ketone analogues from a knoevenagel/hydrogenation/robinson annulation sequence: Scope and applications of organocatalytic biomimetic reductions

Article abstract of DOI:10.1021/jo070277i

(Chemical Equation Presented) A practical and novel organocatalytic chemo- and enantioselective process for the cascade synthesis of highly substituted 2-alkyl-cyclohexane-1,3-diones and Wieland-Miescher (W-M) ketone analogs is presented via reductive alk

Full text of DOI:10.1021/jo070277i

Organocatalytic Sequential One-Pot Double Cascade Asymmetric
Synthesis of Wieland-Miescher Ketone Analogues from a
Knoevenagel/Hydrogenation/Robinson Annulation Sequence: Scope
and Applications of Organocatalytic Biomimetic Reductions
Dhevalapally B. Ramachary* and Mamillapalli Kishor
School of Chemistry, UniVersity of Hyderabad, Central UniVersity (PO), Hyderabad 500 046, India
ramsc@uohyd.ernet.in
ReceiVed February 8, 2007
A practical and novel organocatalytic chemo- and enantioselective process for the cascade synthesis of
highly substituted 2-alkyl-cyclohexane-1,3-diones and Wieland-Miescher (W-M) ketone analogs is
presented via reductive alkylation as a key step. First time, we developed the one-step alkylation of
dimedone and 1,3-cyclohexanedione with aldehydes and Hantzsch ester through an organocatalytic
reductive alkylation strategy. Direct combination of L-proline-catalyzed cascade Knoevenagel/hydrogena-
tion and cascade Robinson annulation of CH acids (dimedone and 1,3-cyclohexanedione), aldehydes,
Hantzsch ester, and methyl vinyl ketone furnished the highly functionalized W-M ketone analogues in
good to high yields and with excellent enantioselectivities. Many of the reductive alkylation products
show a direct application in pharmaceutical chemistry.
Introduction
reactions can facilitate ecologically and economically favorable
syntheses such as in vitro biological reactions.2
Critical objectives in modern organic chemistry include the
improvement of reaction efficiency, the avoidance of toxic
reagents, the reduction of waste, and the responsible utilization
of our resources. Organocatalytic cascade reactions, which
consist of several bond-forming reactions, address many of these
objectives.1 Organocatalytic cascade reactions involve two or
more bond-forming transformations that take place under the
same reaction conditions from simple starting materials cata-
lyzed by small molecular units of antibodies or enzymes.1 One
of the ultimate goals in organic synthesis is the catalytic
asymmetric assembly of simple and readily available precursor
molecules into bioactive products, a process that ultimately
mimics biological synthesis. Cascade reactions have gained wide
acceptance because they increase synthetic efficiency by
decreasing the number of laboratory operations required and
the quantities of chemicals and solvents used.2 Thus, these
We are in the “golden age of organocatalysis”, and organo-
catalytic reactions have in the past few years emerged as a
powerful synthetic tool for the construction of highly function-
alized and optically active compounds.3 Especially, organocata-
lytic cascade or tandem reactions have emerged as ideal
synthetic strategies for the synthesis of highly functionalized
compounds and drug-like small molecules in one-pot syntheses,
mimicking biological reactions.4
The use of natural and unnatural amino acids and chiral
secondary amines as catalysts for the R-functionalization of
(2) For recent reviews on general cascade reactions, see: (a) Nicolaou,
K. C.; Montagnon, T.; Snyder, S. A. Chem. Commun. 2003, 551-564. (b)
Wasilke, J.-C.; Obrey, S. J.; Baker, R. T.; Bazan, G. C. Chem. ReV. 2005,
105, 1001-1020. (c) Ramon, D. J.; Yus, M. Angew. Chem., Int. Ed. 2005,
44, 1602-1634. (d) Tietze, L. F. Chem. ReV. 1996, 96, 115-136. (e) Tietze,
L. F.; Haunert, F. Stimulating Concepts in Chemistry; Vogtle, F., Stoddart,
J. F., Shibasaki, M., Eds.; Wiley-VCH: Weinheim, 2000; pp 39-64. (f)
Tietze, L. F.; Modi, A. Med. Res. ReV. 2000, 20, 304-322. (g) Mayer, S.
F.; Kroutil, W.; Faber, K. Chem. Soc. ReV. 2001, 30, 332-339. (h) Cane,
D. E. Chem. ReV. 1990, 90, 1089-1103.
* Corresponding author. Tel.: 91-40-2313-4816; fax: 91-40-2301-2460.
(1) For recent reviews on organocatalytic cascade reactions, see: (a) Guo,
H.-C.; Ma, J.-A. Angew. Chem., Int. Ed. 2006, 45, 354-366. (b) Pellissier,
H. Tetrahedron 2006, 62, 2143-2173.
10.1021/jo070277i CCC: $37.00 © 2007 American Chemical Society
Published on Web 06/07/2007
5056
J. Org. Chem. 2007, 72, 5056-5068

Organocatalytic Biomimetic Reductions
aldehydes and ketones via iminium and enamine formation
represents an important breakthrough in modern asymmetric
synthesis, and a large variety of functionalizations, such as
C-C,5 C-N,6 C-O,7 C-S,8 and C-X (X ) halogen)9 bond-
forming reactions among others, has been developed. The
combination of two or more organocatalytic reactions with a
proper synthetic plan utilizing one or more organocatalysts in
a one-pot synthesis delivers complex products, which is pres-
ently being developed as a new strategy in cascade reactions.
A natural amino acid, proline, is certainly part of this noble
catalyst club, and in the recent past, it has been defined as a
universal catalyst and a simple enzyme because of its high utility
especially in enantioselective aldol,10 Mannich,11 amination,6
and R-aminoxylation reactions.7
As part of our program to engineer direct organocatalytic
cascade or multicomponent reactions,4a-e herein we report
the first organocatalytic asymmetric chemoselective direct
cascade Knoevenagel/hydrogenation (K/H) and Knoevenagel/
hydrogenation/Robinson annulation (K/H/RA) reactions that
produce very useful drug synthons, 2-alkyl-cyclohexane-1,3-
diones 7 and Wieland-Miescher (W-M) ketone analogues 10
from commercially available cyclohexane-1,3-diones 1,
aldehydes 2, Hantzsch ester 3, methyl vinyl ketone 9, and amino
acid 4 as shown in Scheme 1. 2-Alkyl-cyclohexane-1,3-diones
7 and W-M ketone analogues 10 are attractive intermediates
in the synthesis of natural products and in medicinal chemistry,12
while 2-alkyl-cyclohexane-1,3-diones 7 have a broad utility
in pharmaceutical chemistry13 and are excellent starting mat-
erials in the natural product synthesis as shown in Chart 1.
Hence, their preparation has continued to attract considerable
synthetic interest in developing new methods for their synthe-
ses.14
(3) For recent reviews on organocatalysis, see: (a) Notz, W.; Tanaka,
F.; Barbas, C. F., III. Acc. Chem. Res. 2004, 37, 580-591. (b) List, B.
Acc. Chem. Res. 2004, 37, 548-557. (c) Cordova, A. Acc. Chem. Res. 2004,
37, 102-112. (d) Dalko, P. L.; Moisan, L. Angew. Chem., Int. Ed. 2004,
43, 5138-5175. (e) Berkessel, A.; Groger, H. Asymmetric Organocatalysis;
WCH: Weinheim, 2004. (f) Seayed, J.; List, B. Org. Biomol. Chem. 2005,
3, 719-724. (g) Jarvo, E. R.; Scott, J. M. Tetrahedron 2002, 58, 2481-
2495. (h) List, B. Tetrahedron 2002, 58, 5573-5590. (i) List, B. Synlett
2001, 11, 1675-1686. (j) See also: Acc. Chem. Res. 2004, 37 (8). Special
edition devoted to asymmetric organocatalysis.
(4) For recent papers on organocatalytic cascade or domino reactions
from our group, see: (a) Ramachary, D. B.; Ramakumar, K.; Kishor, M.
Tetrahedron Lett. 2005, 46, 7037-7042. (b) Ramachary, D. B.; Kishor,
M.; Ramakumar, K. Tetrahedron Lett. 2006, 47, 651-656. (c) Ramachary,
D. B.; Kishor, M.; Babul Reddy, G. Org. Biomol. Chem. 2006, 4, 1641-
1646. (d) Ramachary, D. B.; Babul Reddy, G. Org. Biomol. Chem. 2006,
4, 4463-4468. (e) Ramachary, D. B.; Ramakumar, K.; Narayana, V. V. J.
Org. Chem. 2007, 72, 1458-1463. From other research groups, see: (f)
Chowdari, N. S.; Ramachary, D. B.; Cordova, A.; Barbas, C. F., III.
Tetrahedron Lett. 2002, 43, 9591-9595. (g) Chowdari, N. S.; Ramachary,
D. B.; Barbas, C. F., III. Org. Lett. 2003, 5, 1685-1688. (h) Ramachary,
D. B.; Chowdari, N. S.; Barbas, C. F., III. Angew. Chem., Int. Ed. 2003,
42, 4233-4237. (i) Ramachary, D. B.; Chowdari, N. S.; Barbas, C. F., III.
Synlett 2003, 12, 1910-1914. (j) Ramachary, D. B.; Anebouselvy, K.;
Chowdari, N. S.; Barbas, C. F., III. J. Org. Chem. 2004, 69, 5838-5849.
(k) Ramachary, D. B.; Barbas, C. F., III. Chem.sEur. J. 2004, 10, 5323-
5331. (l) Ramachary, D. B.; Barbas, C. F., III. Org. Lett. 2005, 7, 1577-
1580. (m) Yang, J. W.; Hechavarria Fonseca, M. T.; List, B. J. Am. Chem.
Soc. 2005, 127, 15036-15037. (n) Huang, Y.; Walji, A. M.; Larsen, C.
H.; MacMillan, D. W. C. J. Am. Chem. Soc. 2005, 127, 15051-15053. (o)
Halland, N.; Aburel, P. S.; Jorgensen, K. A. Angew. Chem., Int. Ed. 2004,
43, 1272-1277. (p) Marigo, M.; Schulte, T.; Franzen, J.; Jørgensen, K. A.
J. Am. Chem. Soc. 2005, 127, 15710-15711. (q) Brandau, S.; Maerten, E.;
Jorgensen, K. A. J. Am. Chem. Soc. 2006, 128, 14986-14991. (r) Marigo,
M.; Bertelsen, S.; Landa, A.; Jorgensen, K. A. J. Am. Chem. Soc. 2006,
128, 5475-5479. (s) Carlone, A.; Marigo, M.; North, C.; Landa, A.;
Jorgensen, K. A. Chem. Commun. 2006, 4928-4930. (t) Enders, D.; Huettl,
M. R. M.; Grondal, C.; Raabe, G. Nature 2006, 441, 861-863. (u) Enders,
D.; Huettl, M. R. M.; Runsink, J.; Raabe, G.; Wendt, B. Angew. Chem.,
Int. Ed. 2007, 46, 467-469. (v) Zhao, G.-L.; Liao, W.-W.; Cordova, A.
Tetrahedron Lett. 2006, 47, 4929-4932. (w) Rios, R.; Sunden, H.; Ibrahem,
I.; Zhao, G.-L.; Eriksson, L.; Cordova, A. Tetrahedron Lett. 2006, 47, 8547-
8551. (x) Rios, R.; Sunden, H.; Ibrahem, I.; Zhao, G.-L.; Cordova, A.
Tetrahedron Lett. 2006, 47, 8679-8682. (y) Wang, W.; Li, H.; Wang, J.;
Zu, L. J. Am. Chem. Soc. 2006, 128, 10354-10355. (z) Tejedor, D.;
Gonzalez-Cruz, D.; Santos-Exposito, A.; Marrero-Tellado, J. J.; de Armas,
P.; Garcia-Tellado, F. Chem.sEur. J. 2005, 11, 3502-3510. (aa) Rueping,
M.; Antonchick, A. P.; Theissmann, T. Angew. Chem., Int. Ed. 2006, 45,
3683-3686.
(5) (a) Ramasastry, S. S. V.; Zhang, H.; Tanaka, F.; Barbas, C. F., III.
J. Am. Chem. Soc. 2007, 129, 288-289. (b) Mase, N.; Watanabe, K.; Yoda,
H.; Takabe, K.; Tanaka, F.; Barbas, C. F., III. J. Am. Chem. Soc. 2006,
128, 4966-4967. (c) Mase, N.; Nakai, Y.; Ohara, N.; Yoda, H.; Takabe,
K.; Tanaka, F.; Barbas, C. F., III. J. Am. Chem. Soc. 2006, 128, 734-735.
(d) Mase, N.; Rajeswari, T.; Tanaka, F.; Barbas, C. F., III. Org. Lett. 2004,
6, 2527-2530. (e) Mase, N.; Tanaka, F.; Barbas, C. F., III. Angew. Chem.,
Int. Ed. 2004, 43, 2420-2423. (f) Tang, Z.; Jiang, F.; Yu, L.-T.; Cui, X.;
Gong, L.-Z.; Qiao, A.; Jiang, Y.-Z.; Wu, Y.-D. J. Am. Chem. Soc. 2003,
125, 5262-5263. (g) Pidathala, C.; Hoang, L.; Vignola, N.; List, B. Angew.
Chem., Int. Ed. 2003, 42, 2785-2787. (h) Melchiorre, P.; Jorgensen, K. A.
J. Org. Chem. 2003, 68, 4151. (i) Halland, N.; Aburel, P. S.; Jorgensen, K.
A. Angew. Chem., Int. Ed. 2003, 42, 661. (j) Brown, S. P.; Goodwin, N.
C.; MacMillan, D. W. C. J. Am. Chem. Soc. 2003, 125, 1192. (k) Raj, M.;
Vishnumaya Ginotra, S. K.; Singh, V. K. Org. Lett. 2006, 8, 4097-4099.
(l) Mosse, S.; Laars, M.; Kriis, K.; Kanger, T.; Alexakis, A. Org. Lett.
2006, 8, 2559-2562.
Surprisingly, there is no direct method for the synthesis of
useful 2-alkyl-cyclohexane-1,3-diones 7, and only two-step
methods are known to prepare them.14 Recently, Paquette et al.
developed the two-step synthesis of 2-alkyl-cyclohexane-1,3-
diones 7 in moderate to good yields via an in situ protection
and deprotection sequence on 2-alkylidene-1,3-diones 5 with
(7) (a) Zhong, G. Angew. Chem., Int. Ed. 2003, 42, 4247-4250. (b)
Brown, S. P.; Brochu, M. P.; Sinz, C. J.; MacMillan, D. W. C. J. Am.
Chem. Soc. 2003, 125, 10808-10809. (c) Momiyama, N.; Torii, H.;
Saito, S.; Yamamoto, H. Proc. Natl. Acad. Sci. U.S.A. 2004, 101, 5374-
5378. (d) Bogevig, A.; Sundeen, H.; Cordova, A. Angew. Chem., Int. Ed.
2004, 43, 1109-1112. (e) Hayashi, Y.; Yamaguchi, J.; Sumiya, T.; Shoji,
M. Angew. Chem., Int. Ed. 2004, 43, 1112-1115. (f) Merino, P.; Tejero,
T. Angew. Chem., Int. Ed. 2004, 43, 2995-2997. (g) Hayashi, Y.;
Yamaguchi, J.; Hibino, K.; Shoji, M. Tetrahedron Lett. 2003, 44, 8293-
8296. (h) Hayashi, Y.; Yamaguchi, J.; Sumiya, T.; Hibino, K.; Shoji, M. J.
Org. Chem. 2004, 69, 5966-5973. (i) Co´rdova, A.; Sunde´n, H.; Bøgevig,
A.; Johansson, M.; Himo, F. Chem.sEur. J. 2004, 10, 3673-3684. (j)
Yamamoto, Y.; Momiyama, N.; Yamamoto, H. J. Am. Chem. Soc. 2004,
126, 5962-5963. (k) Mathew, S. P.; Iwamura, H.; Blackmond, D. G. Angew.
Chem., Int. Ed. 2004, 43, 3317-3321. (l) Wang, W.; Wang, J.; Hao, L.;
Liao, L. Tetrahedron Lett. 2004, 45, 7235-7238. (m) Hayashi, Y.;
Yamaguchi, J.; Hibino, K.; Sumiya, T.; Urushima, T.; Shoji, M.; Hashizume,
D.; Koshino, H. AdV. Synth. Catal. 2004, 346, 1435. (n) Cheong, P. H. Y.;
Houk, K. N. J. Am. Chem. Soc. 2004, 126, 13912-13913. (o) Joseph, J.;
Ramachary, D. B.; Jemmis, E. D. Org. Biomol. Chem. 2006, 4, 2685-
2689. (p) Ramachary, D. B.; Rumpa, M. Tetrahedron Lett. 2006, 47, 7689-
7693.
(8) (a) Marigo, M.; Wabnitz, T. C.; Fielenbach, D.; Jørgensen, K. A.
Angew. Chem., Int. Ed. 2005, 44, 794-797. (b) Franzen, J.; Marigo, M.;
Fielenbach, D.; Wabnitz, T. C.; Kjaersgaard, A.; Jørgensen, K. A. J. Am.
Chem. Soc. 2005, 127, 18296-18304.
(9) For fluorination, see: (a) Steiner, D. D.; Mase, N.; Barbas, C. F.,
III. Angew. Chem., Int. Ed. 2005, 44, 3706-3710. (b) Beeson, T. D.;
MacMillan, D. W. C. J. Am. Chem. Soc. 2005, 127, 8826-8828. (c) Enders,
D.; Huttl, M. R. M. Synlett 2005, 991-993. (d) Marigo, M.; Fielenbach,
D.; Braunton, A.; Kjærsgaard, A.; Jørgensen, K. A. Angew. Chem., Int.
Ed. 2005, 44, 3703-3706. For chlorination, see: (e) Brochu, M. P.; Brown,
S. P.; MacMillan, D. W. C. J. Am. Chem. Soc. 2004, 126, 4108-4109. (f)
Halland, N.; Braunton, A.; Bachmann, S.; Marigo, M.; Jørgensen, K. A. J.
Am. Chem. Soc. 2004, 126, 4790-4791. For bromination, see: (g) Bertelsen,
S.; Halland, N.; Bachmann, S.; Marigo, M.; Braunton, A.; Jørgensen, K.
A. Chem. Commun. 2005, 4821-4823.
(6) (a) Bøgevig, A.; Juhl, K.; Kumaragurubaran, N.; Zhuang, W.;
Jørgensen, K. A. Angew. Chem., Int. Ed. 2002, 41, 1790-1793. (b) List,
B. J. Am. Chem. Soc. 2002, 124, 5656-5657. (c) Vogt, H.; Vanderheiden,
S.; Brase, S. Chem. Commun. 2003, 2448-2449. (d) Suri, J. T.; Steiner,
D. D.; Barbas, C. F., III. Org. Lett. 2005, 7, 3885-3888. (e) Chowdari, N.
S.; Barbas, C. F., III. Org. Lett. 2005, 7, 867-870. (f) Iwamura, H.; Mathew,
S. P.; Blackmond, D. G. J. Am. Chem. Soc. 2004, 126, 11770-11771.
J. Org. Chem, Vol. 72, No. 14, 2007 5057

Ramachary and Kishor
SCHEME 1. Direct Organocatalytic Asymmetric Cascade K/H and K/H/RA Reactions
CHART 1. Natural and Unnatural Products Library Generated from 2-Alkyl-cyclohexane-1,3-diones
thiophenol and Raney nickel, respectively.14f,g As shown in
Scheme 1, the well-recognized fact is the inability to arrest
Knoevenagel reactions involving CH acids 1 (dimedone and
1,3-cyclohexanedione) and aliphatic or aromatic aldehydes 2
at the monoaddition stage.15 Very few adducts such as 5 have
been isolated.16 This is because these Knoevenagel products 5
are highly reactive Michael acceptors capable of engaging the
unreacted CH acid reagent in kinetically rapid 1,4-addition to
5058 J. Org. Chem., Vol. 72, No. 14, 2007

Organocatalytic Biomimetic Reductions
TABLE 1. Preliminary Studies on Reductive In Situ Trapping of 2-Alkylidene-cyclohexane-1,3-dionesa
catalyst
4 (20 mol %)
aldehyde
2a (equiv)
H. ester
3 (equiv)
time
(h)
products
6ba
yield
entry
(%)b 7ba
1
2
3
4
5
5.0
5.0
2.0
3.0
3.0
3.0
3.0
3.0
3.0
3.0
3.0
2
1
24
24
12
3
3
3
20
24
24
>95
>95
50
17
10
10
95
95
33
proline 4a
1.0
1.0
1.0
1.0
1.0
1.0
1.0
1.0
1.0
50
83
90
90
5
proline 4a
proline 4a
triethyl amine 4c
quinine 4d
acetic acid 4e
pyridine 8
6c
7c
8c
9c
10c
11c
5
67
80
80
20
20
a Reactions were carried out in EtOH or CH2Cl2 (0.5 M) with 2.0-5.0 equiv of 2a and 1.0 equiv of 3 relative to 1b (0.5 mmol) in the presence of 20 mol
% of catalyst 4. b Yield refers to the column purified product. c CH2Cl2 (0.5 M) used as solvent.
TABLE 2. Effect of Solvent on Direct Amino Acid-Catalyzed
give bis-adducts such as 6. Also, there is no report on the
asymmetric synthesis of higher alkyl substituted W-M ketone
analogues 10. This has prompted us to investigate the cascade
synthesis of very useful 2-alkyl-cyclohexane-1,3-diones 7 and
W-M ketone analogs 10 in a single step through mild amino
acid-catalysis.
Reductive Alkylation of Dimedone 1b with 2a and 3a
We therefore set out to develop an amino acid-catalyzed
asymmetric cascade synthesis of W-M ketones 10 from simple
starting materials, which have not been prepared in the past. In
this article, we present the development and application of the
proline-catalyzed reductive alkylation of CH acids through the
cascade K/H reaction of reactive CH acids 1 (dimedone and
1,3-cyclohexanedione), aldehydes 2, and Hantzsch ester 3.
Furthermore, we will present mechanistic insight into the
reaction course, applying a new concept of self-catalysis leading
to an understanding of the cascade K/H reaction.
We envisioned that an amino acid would catalyze the cascade
Knoevenagel condensation of CH acid 1 with an aldehyde
2 to form substituted 2-alkylidene-cyclohexane-1,3-diones 5,
which are very reactive intermediates and further undergo
chemoselective reactions with both CH acids 1 and Hantzsch
ester 3 to produce bis-adducts 6 and hydrogenated 2-alkyl-
cyclohexane-1,3-diones 7, respectively, based on reaction condi-
tions. Proline-catalyzed Robinson annulation of products 7 with
methyl vinyl ketone 9 furnishes the W-M ketones 10 and
alcohols 11 in good yield with interesting enantioselectivity,
and alcohol 11 could be converted into ketone 10 without losing
enantioselectivity as shown in Scheme 1.
solvent
(0.5 M)
aldehyde
2a (equiv)
time
(h)
products
6ba
yield
entry
(%)b 7ba
1
2
3
4
5
6
7
8
9
EtOH
EtOH
MeOH
H2O
DMSO
DMF
CH3CN
CH2Cl2
CH2Cl2
5.0
3.0
3.0
3.0
3.0
3.0
3.0
3.0
1.0
12
12
24
24
24
24
24
12
12
5
10
10
13
20
15
10
3
95
90
90
87
80
85
90
97
95
5
a Reactions were carried out in solvent (0.5 M) with 1.0-5.0 equiv of
2a and 1.0 equiv of 3 relative to 1b (0.5 mmol) in the presence of 20 mol
% of proline 4a. b Yield refers to the column purified product.
Results and Discussion
Preliminary Studies on Reductive in Situ Trapping of
2-Alkylidene-cyclohexane-1,3-diones. On the basis of our
recent discovery of biomimetic reduction of novel active olefins
with Hantzsch ester 3 through self-catalysis by decreasing the
HOMO-LUMO energy gap between olefins and Hantzsch ester
3,4b-d we initiated our preliminary studies of the reductive in
situ trapping of 2-benzylidene-5,5-dimethyl-cyclohexane-1,3-
dione 5ba as shown in Table 1. (In all compounds denoted 5xy,
6xy, 7xy, 10xy, 11xy, 12xy, 13xy, and 14xy, x is incorporated
from reactant CH acids 1, and y is incorporated from the reactant
aldehydes 2.)
(10) (a) List, B.; Lerner, R. A.; Barbas, C. F., III. J. Am. Chem. Soc.
2000, 122, 2395-2396. (b) Sakthivel, K.; Notz, W.; Bui, T.; Barbas, C. F.,
III. J. Am. Chem. Soc. 2001, 123, 5260-5267. (c) Cordova, A.; Notz, W.;
Barbas, C. F., III. J. Org. Chem. 2002, 67, 301-303. (d) Northrup, A. B.;
MacMillan, D. W. C. J. Am. Chem. Soc. 2002, 124, 6798-6799. (e)
Bogevig, A.; Juhl, K.; Kumaragurubaran, N.; Jorgensen, K. A. Chem.
Commun. 2002, 620-621. (f) Nakadai, M.; Saito, S.; Yamamoto, H.
Tetrahedron 2002, 58, 8167-8177. (g) Darbre, T.; Machuqueiro, M. Chem.
Commun. 2003, 1090-1091. (h) Kotrusz, P.; Kmentova, I.; Gotov, B.;
Toma, S.; Solcaniova, E. Chem. Commun. 2002, 2510-2511. (i) List, B.;
Pojarliev, P.; Castello, C. Org. Lett. 2001, 3, 573-575. (j) Notz, W.; List,
B. J. Am. Chem. Soc. 2000, 122, 7386-7387. (k) Chandrasekhar, S.;
Narsihmulu, C.; Reddy, N. R.; Sultana, S. S. Chem. Commun. 2004, 2450-
2451. (l) Zhou, Y.; Shan, Z. J. Org. Chem. 2006, 71, 9510-9512.
The self-catalyzed reaction of dimedone 1b with 5 equiv of
benzaldehyde 2a furnished the only unexpected bis-adduct 6ba
without the expected Knoevenagel product 5ba (Table 1, entry
1). The same reaction under proline catalysis also furnished the
only bis-adduct 6ba without product 5ba with reduced reaction
time (Table 1, entry 2). Interestingly, the self-catalyzed reaction
of dimedone 1b and 2 equiv of benzaldehyde 2a with Hantzsch
J. Org. Chem, Vol. 72, No. 14, 2007 5059

Ramachary and Kishor
ester 3 furnished the bis-adduct 6ba and the expected reductive
alkylation product 7ba in a 1:1 ratio with 99% yield after 24 h
at 25 °C (Table 1, entry 3). The self-catalyzed reductive
alkylation reaction with 3 equiv of benzaldehyde 2a furnished
the product 7ba in 83% yield (Table 1, entry 4). Interestingly,
the same reaction under proline catalysis furnished the expected
reductive alkylation product 7ba with 90% yield after 12 h at
25 °C in EtOH as shown in Table 1, entry 5. The same reaction
(11) (a) Notz, W.; Sakthivel, K.; Bui, T.; Zhong, G.; Barbas, C. F., III.
Tetrahedron Lett. 2001, 42, 199-201. (b) Cordova, A.; Notz, W.; Zhong,
G.; Betancort, J. M.; Barbas, C. F., III. J. Am. Chem. Soc. 2002, 124, 1842-
1843. (c) Cordova, A.; Watanabe, S.; Tanaka, F.; Notz, W.; Barbas, C. F.,
III. J. Am. Chem. Soc. 2002, 124, 1866-1867. (d) Watanabe, S.; Cordova,
A.; Tanaka, F.; Barbas, C. F., III. Org. Lett. 2002, 4, 4519-4522. (e)
Chowdari, N. S.; Ramachary, D. B.; Barbas, C. F., III. Synlett 2003, 12,
1906-1909. (f) Cordova, A.; Barbas, C. F., III. Tetrahedron Lett. 2003,
44, 1923-1926. (g) List, B. J. Am. Chem. Soc. 2000, 122, 9336-9337. (h)
Hayashi, Y.; Tsuboi, W.; Ashimine, I.; Urushima, T.; Shoji, M.; Sakai, K.
Angew. Chem., Int. Ed. 2003, 42, 3677-3680. (i) List, B.; Pojarliev, P.;
Biller, W. T.; Martin, H. J. J. Am. Chem. Soc. 2002, 124, 827-833. (j)
Hayashi, Y.; Tsuboi, W.; Shoji, M.; Suzuki, N. J. Am. Chem. Soc. 2003,
125, 11208-11209. (k) Notz, W.; Tanaka, F.; Watanabe, S.; Chowdari, N.
S.; Turner, J. M.; Thayumanavan, R.; Barbas, C. F., III. J. Org. Chem.
2003, 68, 9624-9634. (l) Zhang, H.; Mifsud, M.; Tanaka, F.; Barbas, C.
F., III. J. Am. Chem. Soc. 2006, 128, 9630-9631. (m) Chowdari, N. S.;
Ahmad, M.; Albertshofer, K.; Tanaka, F.; Barbas, C. F., III. Org. Lett. 2006,
8, 2839-2842. (n) Cheong, P. H.-Y.; Zhang, H.; Thayumanavan, R.;
Tanaka, F.; Houk, K. N.; Barbas, C. F., III. Org. Lett. 2006, 8, 811-814.
(o) Mitsumori, S.; Zhang, H.; Cheong, P. H.-Y.; Houk, K. N.; Tanaka, F.;
Barbas, C. F., III. J. Am. Chem. Soc. 2006, 128, 1040-1041. (p) Janey, J.
M.; Hsiao, Y.; Armstrong, J. D., III. J. Org. Chem. 2006, 71, 390-392.
(12) (a) Gardner, J. N.; Anderson, B. A.; Oliveto, E. P. J. Org. Chem.
1969, 34, 107-111. (b) Eder, U.; Sauer, G.; Wiechert, R. Angew. Chem.,
Int. Ed. 1971, 10, 496-497. (c) Newkome, G. R.; Roach, L. C.; Montelaro,
R. C. J. Org. Chem. 1972, 37, 2098-2101. (d) Hajos, Z. G.; Parrish, D. R.
J. Org. Chem. 1973, 38, 3239-3243. (e) Hajos, Z. G.; Parrish, D. R. J.
Org. Chem. 1974, 39, 1615-1621. (f) Arseniyadis, S.; Yashunsky, D. V.;
Pereira de Freitas, R.; Dorado, M. M.; Potier, P. Tetrahedron 1996, 52,
12443-12458. (g) Paquette, L. A.; Wang, H.-L. J. Org. Chem. 1996, 61,
5352-5357. (h) Deng, W.; Jensen, M. S.; Overman, L. E.; Rucker, P. V.;
Vionnet, J.-P. J. Org. Chem. 1996, 61, 6760-6761. (i) Cheung, W. S.;
Wong, H. N. C. Tetrahedron 1999, 55, 11001-11016. (j) Bui, T.; Barbas,
C. F., III. Tetrahedron Lett. 2000, 41, 6951-6954. (k) Rajagopal, D.;
Narayanan, R.; Swaminathan, S. Proc. Ind. Acad. Sci. (Chem. Sci.) 2001,
113, 197-213. (l) Katoh, T.; Nakatani, M.; Shikita, S.; Sampe, R.; Ishiwata,
A.; Ohmori, O.; Nakamura, M.; Terashima, S. Org. Lett. 2001, 3, 2701-
2704. (m) Inomata, K.; Barrague, M.; Paquette, L. A. J. Org. Chem. 2005,
70, 533-539. (n) Shigehisa, H.; Mizutani, T.; Tosaki, S.; Ohshima, T.;
Shibasaki, M. Tetrahedron 2005, 61, 5057-5065. (o) Nagamine, T.;
Inomata, K.; Endo, Y.; Paquette, L. A. J. Org. Chem. 2007, 72, 123-131.
(13) For applications of 2-alkyl-cyclohexane-1,3-diones, see: (a) Fuku-
yama, T.; Dunkerton, L. V.; Aratani, M.; Kishi, Y. J. Org. Chem. 1975,
40, 2011-2012. (b) Coke, J. L.; Williams, H. J.; Natarajan, S. J. Org. Chem.
1977, 42, 2380-2382. (c) Shono, T.; Matsumura, Y.; Tsubata, K.; Sugihara,
Y. J. Org. Chem. 1979, 44, 4508-4511. (d) Carruthers, W.; Cumming, S.
A. J. Chem. Soc., Perkin Trans. 1 1983, 2383-2386. (e) Kotnis, A. S.
Tetrahedron Lett. 1991, 32, 3441-3444. (f) Edmondson, S. D.; Mastracchio,
A.; He, J.; Chung, C. C.; Forrest, M. J.; Hofsess, S.; MacIntyre, E.; Metzger,
J.; O’Connor, N.; Patel, K.; Tong, X.; Tota, M. R.; Van der Ploeg, L. H.
T.; Varnerin, J. P.; Fisher, M. H.; Wyvratt, M. J.; Weber, A. E.; Parmee,
E. R. Bioorg. Med. Chem. Lett. 2003, 13, 3983-3987. (g) Jones, D. M.;
Kamijo, S.; Dudley, G. B. Synlett 2006, 936-938. (h) Koch, M. A.;
Odermatt, A.; Waldmann, H.; Scheck, M. PCT Int. Appl. 2006, CODEN:
PIXXD2 WO 2006069787 A1 20060706, CAN 145:124765 (in English;
123 pp). (i) Briner, P. H. Eur. Pat. Appl. 1990, CODEN: EPXXDW EP
361560 A1 19900404, CAN 113:171862 (in English; 12 pp). (j) Eder, U.;
Sauer, G. Ger. Offen. 1971, CODEN: GWXXBX DE 2016750 19711014,
CAN 76:33860 (in German; 17 pp). (k) Gunar, V. I.; Ovechkina, L. F.;
Zav’yalov, S. I.; Pershin, G. N.; Milovanova, S. N. Ser. Khim. 1964, 10,
1827-1831. (l) Ina, S.; Yamana, K.; Noda, K.; Akiyama, T.; Takahama,
A. Jpn. Kokai Tokkyo Koho 1999, CODEN: JKXXAF JP 11189577 A2
19990713, CAN 131:87830 (in Japanese; 45 pp). (m) Los, Marinus. U.S.
Patent Appl. 1967, CODEN: USXXAM US 3321511 19670523, CAN 67:
108848 (in English; 10 pp). (n) Mochizuki, N.; Umeda, N.; Uchida, S. PCT
Int. Appl. 1996, CODEN: PIXXD2 WO 9615117 A1 19960523, CAN 125:
114663 (in Japanese; 18 pp). (o) Mochizuki, N.; Souma, S.; Sasaki, T.;
Kanaguchi, Y.; Umeda, N. PCT Int. Appl. 1994, CODEN: PIXXD2 WO
9409784 A1 19940511, CAN 121:99809 (in Japanese; 18 pp).
FIGURE 1. Crystal structure of 3-hydroxy-5,5-dimethyl-2-naphthalen-
1-ylmethyl-cyclohex-2-enone (7bb).
FIGURE 2. Crystal structure of 2-(3-chloro-benzyl)-3-hydroxy-5,5-
dimethyl-cyclohex-2-enone (7bh).
under proline catalysis in CH2Cl2 furnished the expected product
7ba in 90% yield with a reduced reaction time (Table 1, entry
6). The reductive alkylation reaction under base catalysis in CH2-
Cl2 furnished the bis-adduct 6ba as a major product (Table 1,
entries 7 and 8). The same reaction under acid catalysis in CH2-
Cl2 furnished the bis-adduct 6ba and reductive alkylation
product 7ba in a 1:2 ratio with 99% yield after 20 h at 25 °C
(Table 1, entry 9). There is not much effect of the byproduct
pyridine 8 on the reductive alkylation reaction as shown Table
1, entries 10 and 11. These preliminary results prompted us to
investigate the solvent effect on in situ trapping of the
Knoevenagel product of dimedone 1b with benzaldehyde 2a
through biomimetic hydrogenation as shown in Table 2.
Direct Organocatalyzed Cascade Reductive Alkylation of
Dimedone: Reaction Optimization. We were pleased to find
that proline-catalyzed reductive alkylation or the cascade K/H
reaction of dimedone 1b and benzaldehyde 2a (5 equiv) with
Hantzsch ester 3 furnished the expected product 7ba in 95%
yield after 12 h at 25 °C (Table 2, entry 1). Interestingly, there
is little solvent effect on the direct proline-catalyzed reductive
alkylation or cascade K/H reaction of 1b, 2a, and 3 as shown
in Table 2. The proline-catalyzed cascade K/H reaction can be
performed in three types of solvents (protic polar, aprotic polar,
and aprotic nonpolar) with good yields as shown in Table 2.
Surprisingly, the cascade K/H reaction of 1b, 2a, and 3 in H2O
also furnished the expected hydrogenated product 7ba in 87%
yield after 24 h at 25 °C (Table 2, entry 4). We envisioned the
optimized condition to be mixing the equivalent molar ratios
5060 J. Org. Chem., Vol. 72, No. 14, 2007

Organocatalytic Biomimetic Reductions
TABLE 3. Synthesis of Reductive Alkylation Library via Cascade K/H Reactions from Dimedone 1 and Aldehydes 2a
a Yield refers to the column purified product. b Acetaldehyde 2l was taken as 5 equiv, and reaction time was 1 h. c Butyraldehyde 2n was taken as 2
equiv, and reaction time was 0.5 h. d Benzaldehyde 2a was taken as 3 equiv.
of starting materials at 25 °C in CH2Cl2 under 20 mol % of
proline catalysis to furnish hydrogenated product 7ba in 95%
yield (Table 2, entry 9).
1b with naphthalene-1-carbaldehyde 2b furnished the reductive
alkylation product 7bb as a single isomer, in good yield (Table
3). The synthesis of 2-arylmethyl-5,5-dimethyl-cyclohexane-
1,3-diones 7ba-7bi from 1b, 2a-i, and 3 at 25 °C under proline
catalysis has a longer reaction time (24 h), as compared to
aliphatic aldehydes 2l-n (Table 3). Both aliphatic aldehydes
2l-n generated expected 2-alkyl-5,5-dimethyl-cyclohexane-1,3-
diones 7bl-7bn with dimedone 1b in excellent yields (Table
3). The results in Table 3 demonstrate the broad scope of this
reductive cascade methodology covering a structurally diverse
group of aldehydes 2a-n and CH acids 1b,c with many of the
yields obtained being very good, or indeed better, than previ-
ously published two-step alkylation reactions.14 Structure and
regiochemistry of 2-alkyl-5,5-dimethyl-cyclohexane-1,3-diones
7ba-7bn were confirmed by X-ray structure analysis on 7bb
and 7bh as shown in Figures 1 and 2.17
Direct Organocatalyzed Cascade Reductive Alkylation of
Cyclohexane-1,3-Dione: Reaction Optimization. Because of
the more pharmaceutical applications of 2-alkyl-cyclohexane-
1,3-diones 7, we further extended the application of the
organocatalyzed cascade reductive alkylation methodology to
cyclohexane-1,3-dione 1a and various aldehydes 2a-q as shown
in Tables 4 and 5. Surprisingly, the reactivity pattern of
Diversity-Oriented Synthesis of Reductive Alkylation
Products 7ba-7bn. With an efficient organocatalytic cascade
reductive alkylation protocol in hand, the scope of the proline-
catalyzed cascade K/H reactions was investigated with various
aldehydes 2a-n and CH acids 1b,c. A series of aromatic and
aliphatic aldehydes 2a-n was reacted with 1.0 equiv of
dimedone 1b or 5-phenyl-cyclohexane-1,3-dione 1c catalyzed
by 20 mol % of proline at 25 °C in CH2Cl2 (Table 3). The
2-alkyl-5,5-dimethyl-cyclohexane-1,3-diones 7ba-7bn and
2-alkyl-5-phenyl-cyclohexane-1,3-diones 7ca were obtained as
single isomers with excellent yields. The reaction of dimedone
(14) For two-step synthesis of 2-alkyl-cyclohexane-1,3-diones, see: (a)
Karl Wilhelm, R.; Hartwig, B. Chem. Ber. 1961, 94, 2394-2400. (b) Piers,
E.; Grierson, J. R. J. Org. Chem. 1977, 42, 3755-3757. (c) Wheeler, T. N.
J. Org. Chem. 1979, 44, 4906-4912. (d) Sardina, F. J.; Johnston, A. D.;
Mourino, A.; Okamura, W. H. J. Org. Chem. 1982, 47, 1576-1578. (e)
Bassetti, M.; Cerichelli, G.; Floris, B. Gazz. Chim. Ital. 1986, 116, 583-
585. (f) Fuchs, K.; Paquette, L. A. J. Org. Chem. 1994, 59, 528-532. (g)
Paquette, L. A.; Backhaus, D.; Braun, R.; Underiner, T. L.; Fuchs, K. J.
Am. Chem. Soc. 1997, 119, 9662-9671. (h) Pashkovsky, F. S.; Lokot, I.
P.; Lakhvich, F. A. Synlett 2001, 1391-1394.
(15) (a) Jones, G. Org. React. 1967, 15, 204. (b) Nagarajan, K.; Shenoy,
S. J. Ind. J. Chem., Sect. B 1992, 31, 73-87. (c) Hobel, K.; Margaretha, P.
HelV. Chim. Acta 1989, 72, 975-979. (d) Bolte, M. L.; Crow, W. D.;
Yoshida, S. Aust. J. Chem. 1982, 35, 1421-1429.
(17) CCDC-633527 for 7aa, CCDC-633528 for 7bb, CCDC-633529 for
7bh, and CCDC-633530 for 10aa contain the supplementary crystallographic
data for this paper. These data can be obtained free of charge via http://
www.ccdc.cam.ac.uk/conts/retrieving.html or from the Cambridge Crystal-
lographic Data Centre, 12 Union Road, Cambridge CB21EZ, U.K.; fax:
(+44)1223-336-033; or mail: deposit@ccdc.cam.ac.uk.
(16) (a) Margaretha, P.; Polansky, O. E. Monatsh. Chem. 1970, 101, 824.
(b) Eaton, P. E.; Bunnelle, W. H. Tetrahedron Lett. 1984, 25, 23-26. (c)
Eaton, P. E.; Bunnelle, W. H.; Engel, P. Can. J. Chem. 1984, 62, 2612-
2626. (d) Ogawa, T.; Murafuji, T.; Suzuki, H. Chem. Lett. 1988, 849-852.
J. Org. Chem, Vol. 72, No. 14, 2007 5061

Ramachary and Kishor
TABLE 4. Effect of Solvent on Direct Amino Acid-Catalyzed
Reductive Alkylation of Cyclohexane-1,3-dione 1a with 2a and 3a
solvent
(0.5 M)
aldehyde
2a (equiv)
time
(h)
products
6aa
yield
entry
(%)b 7aa
1
2
3
4
5
6
EtOH
THF
CH3CN
CH2Cl2
CH2Cl2
CH2Cl2
3.0
3.0
3.0
1.0
2.0
3.0
20
24
20
24
24
24
40
65
40
30
25
10
60
35
60
70
75
90
a Reactions were carried out in solvent (0.5 M) with 1.0-3.0 equiv of
2a and 1.0 equiv of 3 relative to 1a (0.5 mmol) in the presence of 20 mol
% of proline 4a. b Yield refers to the column purified product.
cyclohexane-1,3-dione 1a looks different as compared to
dimedone 1b in the proline-catalyzed cascade reductive alky-
lation reaction with benzaldehyde 2a and Hantzsch ester 3 as
shown in Table 4. Unexpectedly, the proline-catalyzed reductive
alkylation of cyclohexane-1,3-dione 1a, benzaldehyde 2a (3
equiv), and Hantzsch ester 3 furnished the expected product
7aa in only 60% yield, accompanied by 40% yield of the bis-
adduct 6aa at 25 °C for 20 h (Table 4, entry 1). Interestingly,
there is a large solvent effect on the direct proline-catalyzed
reductive alkylation or cascade K/H reaction of 1a, 2a, and 3
as shown in Table 4 as compared to dimedone 1b (see Tables
1 and 2). Proline-catalyzed cascade K/H reactions are performed
in three types of solvents (protic polar, aprotic polar, and aprotic
nonpolar) and furnished the expected product 7aa in good to
moderate yields as shown in Table 4 (some of the solvents are
not shown). Surprisingly, the cascade K/H reaction of 1a, 2a,
and 3 in THF furnished the expected hydrogenated product 7aa
in 35% yield accompanied by 65% yield of the bis-adduct 6aa
at 25 °C for 24 h (Table 4, entry 2). We envisioned the
optimized condition to be mixing the 3 equiv of benzaldehyde
2a with cyclohexane-1,3-dione 1a and Hantzsch ester 3 at 25 °C
in CH2Cl2 under 20 mol % of proline catalysis to furnish the
hydrogenated product 7aa in 90% yield (Table 4, entry 6). The
structure and regiochemistry of 2-benzyl-cyclohexane-1,3-dione
7aa were confirmed by X-ray structure analysis as shown in
Figure 3.17 Interestingly, the cascade product 7aa was obtained
in a completely enolic form in crystals as compared to in
solution.
FIGURE 3. Crystal structure of 2-benzyl-3-hydroxy-cyclohex-2-enone
(7aa).
Diversity-Oriented Synthesis of Reductive Alkylation
Products 7aa-7aq. With the optimized reaction conditions in
hand, the scope of the proline-catalyzed K/H cascade reactions
was investigated with cyclohexane-1,3-dione 1a, various alde-
hydes 2a-q, and Hantzsch ester 3 as shown in Table 5. A series
of aromatic and aliphatic aldehydes 2a-q (3 equiv) was reacted
with cyclohexane-1,3-dione 1a and Hantzsch ester 3 catalyzed
by 20 mol % of proline at 25 °C in CH2Cl2 (Table 5). The
2-arylmethyl-cyclohexane-1,3-diones 7aa-7ai and 2-alkyl-
cyclohexane-1,3-diones 7aj-7aq were obtained as single
isomers with excellent yields. The reaction of cyclohexane-1,3-
dione 1a with piperonal 2c and Hantzsch ester 3 under proline
catalysis furnished the reductive alkylation product 7ac in 70%
yield at 70 °C, and there was no reaction at 25 °C (Table 5).
The synthesis of 2-arylmethyl-cyclohexane-1,3-diones 7aa-7ai
from 1a, 2a-i, and 3 at 25 °C under proline catalysis took a
longer reaction time (24-48 h), as compared to aliphatic
aldehydes 2j-q as shown in Table 5. Interestingly, the proline-
catalyzed reductive alkylation reaction of cyclohexane-1,3-dione
1a, R,â-unsaturated aldehydes 2j,k, and Hantzsch ester 3
generated the expected 2-alkyl-cyclohexane-1,3-diones 7aj-
7ak in excellent yields with high regioselectivity (Table 5). The
FIGURE 4. Crystal structure of (+)-(R)-8a-benzyl-3,4,8,8a-tetrahydro-
2H,7H-naphthalene-1,6-dione (10aa).
results in Table 5 demonstrate the broad scope of this reductive
cascade methodology covering a structurally diverse group of
aldehydes 2a-q with many of the yields obtained being very
good, or indeed better, than the previously published two-step
alkylation reactions.14 The structure and regiochemistry of
2-alkyl-cyclohexane-1,3-diones 7aa-7aq were confirmed by
X-ray structure analysis on 7aa as shown in Figure 3.17
Applications of Reductive Alkylation Products 7. (A)
Aromatization of 2-Alkyl-cyclohexane-1,3-diones. 2-Alkyl-
cyclohexane-1,3-diones 7 were readily transformed into sub-
stituted monomethyl and dimethyl resorcinols with iodine and
methanol as shown in Scheme 2.13e The substituted resorcinol
unit is a basic building block of a large number of valuable
naturally occurring polyketide metabolites.18a-c Highly substi-
tuted resorcinols have gained importance in recent years as
starting materials and intermediates for the synthesis of can-
nabinoids and benzochroman derivatives, which possess a wide
5062 J. Org. Chem., Vol. 72, No. 14, 2007

Organocatalytic Biomimetic Reductions
TABLE 5. Synthesis of Reductive Alkylation Library via Cascade K/H Reactions from Cyclohexane-1,3-dione 1a and Aldehydes 2a
a Yield refers to the column purified product. b Reaction performed at 70 °C. c 3-(2-Nitrophenyl)-propenal 2k was taken as 1 equiv. d Acetaldehyde 2l
was taken as 5 equiv.
SCHEME 2. Synthesis of 2,5-Dialkylresorcinols from
Reductive Alkylation Products 7
I2/MeOH mediated aromatization of highly substituted cy-
clohexane-1,3-diones 7 gave good yields of medicinally im-
portant dimethyl and monomethyl resorcinols 12 and 13 as
shown in Scheme 2.13e For the pharmaceutical applications, the
(18) (a) Sammes, P. G.; Kennewell, P. D.; Jaxa-Chamiec, A. A. J. Chem.
Soc., Perkin Trans 1 1980, 170-175. (b) Barrett, A. G. M.; Morris, T. M.;
Barton, D. H. R. J. Chem. Soc., Perkin Trans 1 1980, 2272-2277. (c) Mann,
J. Secondary Metabolism; Oxford University Press: New York, 1980. (d)
Razdan, R. K.; Gordon, P. M.; Siegel, C. J. Org. Chem. 1989, 54, 5428-
5430. (e) Tius, M. A.; Kerr, M. A.; Gu, X. J. Chem. Soc., Chem. Commun.
1989, 62-63. (f) Chan, T. H.; Chaly, T. Tetrahedron Lett. 1982, 23, 2935-
2938. (g) Kowalski, C. J.; Lal, G. S. J. Am. Chem. Soc. 1988, 110, 3693-
3695. (h) Razdan, R. K.; Dalzell, H. C. J. Med. Chem. 1976, 19, 719-721.
(i) Razdan, R. K.; Pars, H. G.; Granchelli, F. E.; Keller, J. K.; Teiger, D.
G.; Rosenbeg, F. J.; Harris, L. S. J. Med. Chem. 1976, 19, 445-454. (j)
Hecht, S. M.; Reddy, K. S.; Murty, V. S.; Barr, J. R.; Scannell, R. T. J.
Am. Chem. Soc. 1988, 110, 3650-3651. (k) Hecht, S. M.; Chrisey, L. A.;
Bonjar, G. H. S. J. Am. Chem. Soc. 1988, 110, 644-646. (l) Tyman, J. H.
P.; Durrani, A. A. J. Chem. Soc., Perkin Trans 1 1980, 1658-1666. (m)
Altstiel, L. D.; Fleisch, J. H. Eur. Pat. Appl. 1996, CODEN: EPXXDW
EP 743064 A1 19961120, CAN 126:74591 (in English; 124 pp).
range of physiological and pharmacological properties.18d-i Long
chain 5-alkyl resorcinols have been successfully utilized as ideal
models for sequence-selective DNA strand scissions and as
leukotriene antagonists for the treatment or prevention of
Alzheimer’s disease.18j-m
(19) Ali, A.; Balkovec, J. M.; Beresis, R.; Colletti, S. L.; Graham, D.
W.; Patel, G. F.; Smith, C. J. PCT Int. Appl. 2004, CODEN: PIXXD2 WO
2004093805 A2 20041104, CAN 141:395547 (in English; 201 pp).
J. Org. Chem, Vol. 72, No. 14, 2007 5063

Ramachary and Kishor
TABLE 6. Direct Amino Acid-Catalyzed Robinson Annulation of
7aa with 9a
diversity-oriented library of resorcinols 12 and 13 could be
generated by using our amino acid-catalyzed diversity-oriented
library of highly substituted cyclohexane-1,3-diones 7 through
a simple I2/MeOH reaction.
solvent
(0.3 M)
catalyst
4 (30 mol %)
yield
ee (%)c
10aa
entry
(%)b 10aa
1d
2d
3d
4d
5d
6e
7e
THF
4a
4a
4a
4a
4b
4a
4b
70
85
50
65
65
50
50
33
51
64
65
-50
72
CH3CN
DMSO
DMF
DMF
DMF
DMF
-74
a Reactions were carried out in solvent (0.3 M) with 3.0 equiv of 9 in
the presence of 30 mol % of proline 4. b Yield refers to the column purified
product. c ee was determined by HPLC analysis. d Product 11aa was isolated
in 10-15% yield. e Freshly distilled methyl vinyl ketone 9 was used, and
product 11aa was isolated in 30-45% yield.
TABLE 7. Organocatalytic Asymmetric Synthesis of W-M
Ketone Analogues 10a,b
(B) Amino Acid-Catalyzed Asymmetric Robinson Annu-
lations. W-M ketone analogues 10 are very good intermediates
for the synthesis of steroids,12 and also recently, Ali et al.
reported in their patent19 that W-M ketone analogue 10aa is a
very good intermediate for the synthesis of pharmaceutically
acceptable salts or hydrates of spiro-heterocycles, which are
disclosed as selective glucocorticoid receptor modulators for
treating a variety of autoimmune and inflammatory diseases or
conditions (see eq 1). Surprisingly, to the best of our knowledge,
there is no report on the asymmetric synthesis of useful W-M
ketone analogues 10. In this article, we are presenting the
asymmetric synthesis of W-M ketone analogues 10 with
interesting ee and yields via amino acid-catalyzed asymmetric
RA of 2-alkyl-cyclohexane-1,3-diones 7 with methyl vinyl
ketone 9 as shown in Tables 6 and 7 and Scheme 3.
We were pleased to find that the L-proline-catalyzed RA
reaction of 2-benzyl-cyclohexane-1,3-dione 7aa with 3 equiv
of methyl vinyl ketone 9 in THF furnished the expected product
10aa in 70% yield with 33% ee and alcohol 11aa in 10-15%
yield at 25 °C for 5 days (Table 6, entry 1). Solvent screening
on the direct L-proline-catalyzed RA reaction of 7aa with 9
revealed that DMF and DMSO solvents were suitable to achieve
high ee values as shown in Table 6. Interestingly, the freshly
distilled methyl vinyl ketone 9 showed a large effect on the
a See Experimental Section. b Yield refers to the column purified product,
and ee was determined by HPLC analysis. c Reaction was carried out without
solvent. d Reaction was carried out without solvent with 1.0 equiv of 4a
and 2.0 equiv of 9 relative to 7al.
proline-catalyzed RA reaction of 7aa and 9 with respect to yield
and ee values as shown in Table 6. We envisioned the optimized
condition to be mixing the CH acid 7aa and 3 equiv of freshly
distilled methyl vinyl ketone 9 at 25 °C in DMF under 30 mol
% of L-proline catalysis to furnish W-M ketone analogue 10aa
in 50% yield with 72% ee and alcohol 11aa in 30-45% yield
(Table 6, entry 6). The D-proline-catalyzed RA reaction of 7aa
with 9 furnished the opposite enantiomer of the W-M ketone
analogue 10aa in 50% yield with 74% ee and alcohol 11aa in
30-45% yield (Table 6, entry 7).
The hydrolysis of bicyclic alcohols (+)/(-)-11aa obtained
from L/D-proline catalysis with 1 N HClO4 in DMSO at 90 °C
5064 J. Org. Chem., Vol. 72, No. 14, 2007

Organocatalytic Biomimetic Reductions
TABLE 8. Direct Organocatalytic One-Pot Double Cascade Asymmetric Synthesis of W-M Ketone Analogues 10a,b
c
a See Experimental Section. b Yield refers to the column purified product, and ee was determined by HPLC analysis. D-Proline 4b (20 mol %) was used
for the Robinson annulation step. d One-pot reaction was carried out without addition of second catalyst 4.
SCHEME 3. Hydrolysis of Alcohol 11aa and
Enantioenrichment of W-M Ketone Analogue 10aa by
Crystallization
for 24 h furnished the expected bicyclic ketones (+)/(-)-10aa
in good yields with 71-73% ee as shown in Scheme 3. The
crystallization of the 65% ee W-M ketone analogue (+)-10aa
in a 2:1 mixture of hexane and isopropyl alcohol at 25 °C for
2-6 h furnished the brown block-shaped crystals in 40% yield
with an enriched ee value of 97% (Scheme 3). The absolute
configuration of product (+)-10aa prepared under L-proline
catalysis was established by using X-ray crystallography and
also by comparison with the proline-catalyzed Hajos-Parrish-
Eder-Sauer-Wiechert reaction.20 The crystal structure of
product (+)-10aa is depicted in Figure 4.17
With an efficient organocatalytic asymmetric cascade RA
protocol in hand, the scope of the proline-catalyzed cascade
asymmetric RA reactions was investigated with various 2-alkyl-
cyclohexane-1,3-diones 7 and methyl vinyl ketone 9. A series
of 2-alkyl-cyclohexane-1,3-diones 7al-7an was reacted with
3.0 equiv of methyl vinyl ketone 9 catalyzed by 30 mol % of
L-proline at 25 °C in DMF for 5 days (Table 7). All expected
W-M ketone analogues 10al-10an were obtained in good
yields with 73-75% ee as shown in Table 7. Interestingly, in
these reactions, only trace amount of bicyclic alcohols 11al-
(20) (a) Hajos, Z. G.; Parrish, D. R. Ger. Offen. 1971, CODEN:
GWXXBX DE 2102623 19710729, CAN 76:59072 (in German: 42 pp).
(b) Eder, U.; Wiechert, R.; Sauer, G. Ger. Offen. 1971, CODEN: GWXXBX
DE 2014757 19711007, CAN 76:14180 (in German: 20 pp). (c) Zhong,
G.; Hoffmann, T.; Lerner, R. A.; Danishefsky, S.; Barbas, C. F., III. J. Am.
Chem. Soc. 1997, 119, 8131-8132. (d) Bahmanyar, S.; Houk, K. N. J.
Am. Chem. Soc. 2001, 123, 11273-11283. (e) Bahmanyar, S.; Houk, K.
N. J. Am. Chem. Soc. 2001, 123, 12911-12912. (f) Hoang, L.; Bahmanyar,
S.; Houk, K. N.; List, B. J. Am. Chem. Soc. 2003, 125, 16-17. (g)
Bahmanyar, S.; Houk, K. N.; Martin, H. J.; List, B. J. Am. Chem. Soc.
2003, 125, 2475-2479. (h) List, B.; Hoang, L.; Martin, H. J. Proc. Natl.
Acad. Sci. U.S.A. 2004, 101, 5839-5842. (i) Allemann, C.; Gordillo, R.;
Clemente, F. R.; Cheong, P. H-Y.; Houk, K. N. Acc. Chem. Res. 2004,
37, 558-569. (j) Cheong, P. H-Y.; Houk, K. N. Synthesis 2005, 1533-
1537.
11an were isolated. L-Proline-catalyzed asymmetric RA reac-
tions of 7al with 9 were effected by solvent and catalyst loading
on ee as shown in Table 7. Interestingly, ee values of product
10al were drastically smaller when the reaction was performed
under neat and L-proline 4a as compared to 1.0 equiv of 7al.
J. Org. Chem, Vol. 72, No. 14, 2007 5065

Ramachary and Kishor
SCHEME 4. Proposed Catalytic Cycle for Double Cascade Reactions
The same results were observed by Swaminathan et al. in their
attempt to synthesize the asymmetric W-M ketone analogue
10al.12k
tween 3 and 5, respectively.21 In the subsequent third step, the
Michael addition of 7 to methyl vinyl ketone 9 via most likely
iminium ion activation led to the formation of Michael adduct
14.20 In the fourth step, (S)-4 catalyzed the asymmetric
intramolecular aldol condensation of 14 via enamine catalysis,20
and subsequent hydrolysis returned the catalyst (S)-4 for further
cycles and released the desired W-M ketone analogue 10.
Taking into account the recent applications of amine-catalyzed
Knoevenagel reactions4k,22 and based on the different experi-
ments performed (Table 1), we proposed that the most likely
reaction course for the organocatalyzed direct addition of CH
acids 1 to aldehydes 2 is the one outlined through amino acid
catalysis in Scheme 5. Self- and acid-catalyzed olefin formation
is slow reaction, but base and amino acid-catalyzed olefin form-
ation is a very fast reaction and may be due to their high activa-
tion effect. The formation of active olefins 5 through proline
catalysis by means of Mannich and retro-Mannich reactions
support our hypothesis that aldol products 15 did not form in
these reactions. This hypothesis is also supported by the recent
discovery of organoclick reactions4k and the mechanistic
investigation of pyrrolidine-catalyzed enal formation through
aldehyde self-condensation reported by Saito et al.22b
(C) Amino Acid-Catalyzed Asymmetric Double Cascade
One-Pot Robinson Annulations. After successful demonstra-
tion of the L-proline-catalyzed cascade asymmetric K/H and RA
reactions, we decided to investigate the combination of these
two cascade reactions in one pot. The reaction of 5 equiv of
acetaldehyde 2l with CH acid 1a and Hantzsch ester 3 under
l-proline catalysis in CH2Cl2 at 25 °C for 3.0 h furnished the
expected 2-ethyl-cyclohexane-1,3-dione 7al in good yield.
Removing the solvent CH2Cl2 by vacuum pump and adding
solvent DMF and 30 mol % of L-proline 4a and methyl vinyl
ketone 9 to the reaction mixture of cascade asymmetric K/H/
RA furnished the expected W-M ketone analogue 10al in 35%
yield with 74% ee accompanied by bicyclic alcohol 11al in 30%
yield and the Michael adduct 14al in 30% yield as shown in
Table 8. In L-proline-catalyzed sequential one-pot double
cascade asymmetric K/H/RA reactions, the ee values were not
effected by the reaction byproduct 2,6-dimethyl-pyridine-3,5-
dicarboxylic acid diethyl ester 8, but a rate of the RA reaction
was affected, and the requirement came to add another 30 mol
% of catalyst to the one-pot reaction as shown in Table 8, entries
3- and 4. The successful combination of two cascade K/H and
RA reactions under L-proline catalysis was demonstrated by two
more examples as shown in Table 8, and this one-pot synthetic
strategy shows a large impact on the asymmetric synthesis of
functionalized small molecules.
Mechanistic Insights. The possible reaction mechanism for
L-proline-catalyzed regio- and chemoselective and enantiose-
lective synthesis of cascade products 7 and 10 through reaction
of CH acid 1, aldehyde 2, and Hantzsch ester 3 is illustrated in
Scheme 4. This catalytic sequential one-pot double cascade is
a four component reaction comprised of CH acid 1, aldehyde
2, Hantzsch ester 3, methyl vinyl ketone 9, and a simple chiral
amino acid 4, which is capable of catalyzing each step of this
double cascade reaction. In the first step (Scheme 4), the catalyst
(S)-4 activated component 2 by most likely iminium ion forma-
tion, which then selectively added to the CH acid 1 via a Man-
nich and retro-Mannich-type reaction to generate active olefin
5.4c,k The following second step was biomimetic hydrogenation4b-d
of active olefin 5 by Hantzsch ester 3 to produce 7 through
self-catalysis by decreasing HOMO-LUMO energy gap be-
Our proposal of the Michael addition of 7 to methyl vinyl
ketone 9 via iminium ion activation or base catalysis is sup-
ported by results presented in Table 9. The values for the
simultaneous proline-catalyzed Michael reaction followed
by aldol reaction of 7aa with 9 is shown in Table 9,
entry 1. Triethyl amine 4c and quinine 4d catalyzed the
only Michael addition of 7aa to 9 (Table 9, entries 2 and 3),
but there is not much product formation on acidic and
uncatalyzed conditions as shown in Table 9. On the basis of
the previous results, we proposed that the most likely activation
for the proline-catalyzed Michael reaction is iminium ion
activation.5h
(21) (a) Garden, S. J.; Guimara˜es, C. R. W.; Corre´a, M. B.; de Oliveira,
C. A. F.; Pinto, A. C.; de Alencastro, R. B. J. Org. Chem. 2003, 68, 8815-
8822. (b) Zhu, X.-Q.; Zhang, M.; Liu, Q.-Y.; Wang, X.-X.; Zhang, J.-Y.;
Cheng, J.-P. Angew. Chem., Int. Ed. 2006, 45, 3954-3957.
(22) (a) List, B.; Castello, C. Synlett 2001, 11, 1687-1689. (b) Ishikawa,
T.; Uedo, E.; Okada, S.; Saito, S. Synlett 1999, 4, 450-452. (c) Tanikaga,
R.; Konya, N.; Hamamura, K.; Kaji, A. Bull. Chem. Soc. Jpn. 1988, 61,
3211-3216.
5066 J. Org. Chem., Vol. 72, No. 14, 2007

Organocatalytic Biomimetic Reductions
SCHEME 5. Proposed Mechanisms for Olefin Formation
the synthetic application of reductive alkylation products 7.
Further work is in progress to utilize novel K/H and K/H/RA
reactions in synthetic chemistry.
Experimental Section
General Experimental Procedures for the Cascade Reac-
tions: Amino Acid-Catalyzed Cascade Knoevenagel/Hydroge-
nation Reactions with Dimedone. In an ordinary glass vial
equipped with a magnetic stirring bar, to 0.5 mmol of the aldehyde
2, 0.5 mmol of CH acid 1b, and 0.5 mmol of Hantzsch ester 3 was
added 1.0 mL of solvent, and then the catalyst amino acid 4 (0.10
mmol) was added, and the reaction mixture was stirred at 25 °C
for the time indicated in Tables 1-3. The crude reaction mixture
was directly loaded onto a silica gel column with or without aqueous
workup, and pure cascade products 7 were obtained by column
chromatography (silica gel, mixture of hexane/ethyl acetate).
Amino Acid-Catalyzed Cascade Knoevenagel/Hydro-
genation Reactions with Cyclohexane-1,3-diones. In an ordinary
glass vial equipped with a magnetic stirring bar, to 1.5 mmol of
the aldehyde 2, 0.5 mmol of CH- acid 1a or 1c, and 0.5 mmol of
Hantzsch ester 3 was added 1.0 mL of solvent, and then the catalyst
amino acid 4 (0.10 mmol) was added, and the reaction mixture
was stirred at 25 °C for the time indicated in Tables 4 and 5. The
crude reaction mixture was directly loaded onto a silica gel column
with or without aqueous workup, and pure cascade products 7 were
obtained by column chromatography (silica gel, mixture of hexane/
ethyl acetate).
Amino Acid-Catalyzed Robinson Annulation Reaction. In an
ordinary glass vial equipped with a magnetic stirring bar, to 1.0
mmol of 2-alkyl-cyclohexane-1,3-diones 7 and 3.0 mmol of methyl
vinyl ketone 9 was added 3.0 mL of DMF solvent, and then the
catalyst proline 4a (0.3 mmol) was added, and the reaction mixture
was stirred at 25 °C for 5 days. The crude reaction mixture was
worked up with aqueous NH4Cl solution, and the aqueous layer
was extracted with dichloromethane (3 × 20 mL). The combined
organic layers were dried (Na2SO4), filtered, and concentrated. Pure
products 10 were obtained by column chromatography (silica gel,
mixture of hexane/ethyl acetate).
TABLE 9. Effect of Catalyst on Robinson Annulation of 7aa
with 9a
Amino Acid-Catalyzed One-Pot Double Cascade Knoevena-
gel/Hydrogenation/Robinson Annulation Reactions. In an
ordinary glass vial equipped with a magnetic stirring bar, to 5.0
mmol of the aldehyde 2, 1.0 mmol of CH acid 1a, and 1.0 mmol
of Hantzsch ester 3 was added 2.0 mL of dichloromethane,
and then the catalyst amino acid 4 (0.2 mmol) was added, and the
reaction mixture was stirred at 25 °C for the time indicated in
Table 8. After evaporation of the solvent completely, to the crude
reaction mixture was added 3.0 mmol of methyl vinyl ketone 9,
3.0 mL of DMF solvent, and 0.30 mmol of L-proline 4a, and the
reaction mixture was stirred at 25 °C for 5 days. The crude reaction
mixture was worked up with aqueous NH4Cl solution, and the
aqueous layer was extracted with dichloromethane (3 × 20 mL).
The combined organic layers were dried (Na2SO4), filtered, and
concentrated. Pure one-pot products 10, 11, and 14 were obtained
by column chromatography (silica gel, mixture of hexane/ethyl
acetate).
General Procedure for Aromatization of 2-Alkyl-cyclohexane-
1,3-dione Compounds. A solution of 2-alkyl-cyclohexane-
1,3-dione compound 7 (1.0 mmol) and iodine (2.0 mmol) in
methanol was refluxed for 24 h. After cooling, the reaction mix-
ture was washed with aqueous sodium thiosulphate and brine
solution, and the aqueous layer was extracted with dichloromethane
(3 × 20 mL). The combined organic layers were dried (Na2SO4),
filtered, and concentrated. Pure products 12 and 13 were obtained
by column chromatography (silica gel, mixture of hexane/ethyl
acetate).
catalyst
4 (30 mol %)
time
(h)
conversion
(%)b
yield
yield
entry
(%)c 14aa
(%)c 11aa
1
2
3
4
5
4a
4c
4d
4e
11
8
11
24
24
99
99
99
<10
<10
50
90
90
5
24
5
a Reactions were carried out in solvent (0.3 M) with 3.0 equiv of 9 in
the presence of 30 mol % of catalyst 4. b Conversion based on TLC analysis.
c Yield refers to the column purified product.
Conclusion
In summary, we have developed a metal-free one-pot cascade
synthesis of highly substituted 2-alkyl-cyclohexane-1,3-diones
7 and chiral W-M ketone analogues 10 from simple starting
materials via cascade K/H, RA, and K/H/RA reactions under
amino acid catalysis. First time, we have reported the reductive
alkylation of highly reactive CH acids (cyclohexane-1,3-dione
and dimedone) with aldehydes and Hantzsch ester under amino
acid catalysis. The reductive alkylation’s strategy or cascade
K/H reaction proceeds in good yield with high chemo- and
regioselectivity using amino acids as the catalysts. In this article,
we demonstrated the concept of self-catalysis by decreasing the
HOMO-LUMO energy gap between in situ generated olefins
5 and Hantzsch ester 3. Furthermore, we have demonstrated
General Procedure for Dehydration of 8a-Alkyl-4a-hydroxy-
hexahydro-naphthalene-1,6-diones 11. Method (1). A solution
of alcohol compound 11 (0.5 mmol) and 1 N HClO4 (1.5 mmol) in
J. Org. Chem, Vol. 72, No. 14, 2007 5067

Ramachary and Kishor
DMSO (1.5 mL) was stirred at 90 °C for 24 h. After cooling, the
reaction mixture was washed with water, and the aqueous layer
was extracted with dichloromethane (3 × 20 mL). The combined
organic layers were dried (Na2SO4), filtered, and concentrated. Pure
products 10 were obtained by column chromatography (silica gel,
mixture of hexane/ethyl acetate).
Acknowledgment. This work was made possible by a grant
from the Department of Science and Technology (DST), New
Delhi. M.K. thanks the Council of Scientific and Industrial
Research (CSIR), New Delhi for his research fellowship. We
thank Prof. M. V. Rajasekharan, A. R. Biju, and P. Raghavaiah
for their help in X-ray structural analysis.
Method (2). A solution of alcohol compound 11 (0.5 mmol)
and p-TSA (0.15 mmol) in benzene (1.5 mL) was stirred at 80 °C
for 2 h. After cooling, the reaction mixture was washed with
aqueous sodium bicarbonate solution, and the aqueous layer was
extracted with dichloromethane (2 × 20 mL). The combined organic
layers were dried (Na2SO4), filtered, and concentrated. Pure products
10 were obtained by column chromatography (silica gel, mixture
of hexane/ethyl acetate).
Supporting Information Available: Complete experimental
procedures, compound characterization, X-ray crystal structures,
and analytical data (1H NMR, 13C NMR, HRMS, and elemental
analysis) for all new compounds. Copies of 13C NMR spectrum of
all new compounds. This material is available free of charge via
the Internet at http://pubs.acs.org.
JO070277I
5068 J. Org. Chem., Vol. 72, No. 14, 2007