Enantioselective organocatalytic formal [3 + 3]-cycloaddition of α,β-unsaturated aldehydes and application to the asymmetric synthesis of (-)-isopulegol hydrate and (-)-cubebaol

Article abstract of DOI:10.1021/ol060486+

The first highly enantioselective organocatalyzed carbo [3 + 3] cascade cycloaddition of α,β-unsaturated aldehydes is reported. Using this methodology, crotonaldehyde is converted to 6-hydroxy-4-methylcyclohex-1- enecarbaldehyde, which is used in the synthesis of (-)-isopulegol hydrate, (-)-cubebaol, and p-tolualdehyde as well as (-)-6-hydroxy-4-methyl-1- cyclohexene-1-methanol acetate, an intermediate in the total synthesis of lycopodium alkaloid magellanine. Other α,β-unsaturated aldehydes give rise to chiral cyclohexadienes via formal [4 + 2] reactions.

Full text of DOI:10.1021/ol060486+

ORGANIC
LETTERS
2006
Vol. 8, No. 11
2217-2220
Enantioselective Organocatalytic Formal
[3 3]-Cycloaddition of
-Unsaturated Aldehydes and
Application to the Asymmetric
Synthesis of ( )-Isopulegol Hydrate and
)-Cubebaol†
+
r,â
−
(−
Bor-Cherng Hong,* Ming-Fun Wu, Hsing-Chang Tseng, and Ju-Hsiou Liao
Department of Chemistry and Biochemistry, National Chung Cheng UniVersity,
Chia-Yi, 621, Taiwan, R.O.C
chebch@ccu.edu.tw
Received February 26, 2006
ABSTRACT
The first highly enantioselective organocatalyzed carbo [3
+
3] cascade cycloaddition of
r
,
â
-unsaturated aldehydes is reported. Using this
methodology, crotonaldehyde is converted to 6-hydroxy-4-methylcyclohex-1-enecarbaldehyde, which is used in the synthesis of (
hydrate, ( )-cubebaol, and p-tolualdehyde as well as ( )-6-hydroxy-4-methyl-1-cyclohexene-1-methanol acetate, an intermediate in the total
synthesis of lycopodium alkaloid magellanine. Other -unsaturated aldehydes give rise to chiral cyclohexadienes via formal [4 + 2] reactions.
−)-isopulegol
−
−
r,â
Cycloadditions, such as Diels-Alder reactions, have been
the most important and versatile reactions in organic
chemistry for the synthesis of six-membered rings. Recently,
considerable advances have been made in the development
of other new types of cycloadditions for the six-membered
ring synthesis, such as [6 + 3],1 oxa-[3 + 3],2 and aza-[3 +
3],3 etc. Notwithstanding the success of these formal [3 +
3]-cycloadditions and the pioneering work by Hsung et. al.,4
an efficient all-carbon [3 + 3]-cycloaddition for the synthesis
of cyclohexenes has never been realized. Herein, we report
the first example of an enantioselective carbo [3 + 3]-cy-
cloaddition in the presence of organocatalyst.5 Organocata-
lyzed reactions have been an important subject in modern
synthetic chemistry.6 Among them, proline, MacMillan
catalyst, and Jørgensen catalyst can promote Michael addition
by iminium ion formation with the acceptor enal.7 Alterna-
† Dedicated to Prof. J. D. Winkler on the occasion of his 50th birthday.
(1) (a) Hong, B.-C.; Gupta, A. K.; Wu, M.-F.; Liao J.-H.; Lee, G.-H.
Org. Lett. 2003, 5, 1689. (b) Hong, B.-C.; Chen, Z.-Y.; Chen, W. H. Org.
Lett. 2000, 2, 2647. (c) Hong, B.-C.; Sun, S.-S.; Tsai, Y.-C. J. Org. Chem.
1997, 62, 7717. (d) Barluenga, J.; Silvia Mart´ınez, S.; Sua´rez-Sobrino, A.
L.; Toma´s, M. J. Am. Chem. Soc. 2001, 123, 11113.
(2) (a) For a recent review, see: Hsung, R. P.; Kurdyumov, A. V.;
Sydorenko, N. Eur. J. Org. Chem. 2005, 23. (b) Cole, K. P.; Hsung, R. P.
Org. Lett. 2003, 5, 4843. (c) Shen, K.-H.; Lush, S.-F.; Chen, T.-L.; Liu,
R.-S. J. Org. Chem. 2001, 66, 8106. (d) Zehnder, L. R.; Wei, L.-L.; Hsung,
R. P.; Cole, K. P.; McLaughlin, M. J.; Shen, H. C.; Sklenicka, H. M.; Wang,
J.; Zificsak, C. A. Org. Lett. 2001, 3, 2141.
(3) (a) For a recent review, see: Harrity, J. P. A.; Provoost, O. Org.
Biomol. Chem. 2005, 1349. (b) Gerasyuto, A. I.; Hsung, R. P.; Sydorenko,
N.; Slafer, B. J. Org. Chem. 2005, 70, 4248. (c) Sydorenko, N.; Hsung, R.
P.; Darwish, O. S.; Hahn, J. M.; Liu, J. J. Org. Chem. 2004, 69, 6732. (d)
Luo, S.; Zhao, J.; Zhai, H. J. Org. Chem. 2004, 69, 4548. (e) Luo, S.;
Zificsak, C. A.; Hsung, R. P. Org. Lett. 2003, 5, 4709. (f) Hedley, S. J.;
Moran, W. J.; Price, D. A.; Harrity, J. P. A. J. Org. Chem. 2003, 68, 4286.
(4) Hsung, R. P.; Shen, H. C.; Douglas, C. J.; Morgan, C. D.; Degen, S.
J. Yao, L. J. J. Org. Chem. 1999, 64, 690.
(5) For recent example in enantioselective aza-[3 + 3] cycaloaddition,
see: Gerasyuto, A. I.; Hsung, R. P.; Sydorenko, N.; Slafer, B. J. Org. Chem.
2005, 70, 4248.
10.1021/ol060486+ CCC: $33.50
© 2006 American Chemical Society
Published on Web 05/02/2006

tively, the secondary amine on proline can activate a carbonyl
donor via an enamine formation and facilitate the ensuing
Michael reaction.8 Whereas these two types of recently dis-
covered reactions proceed according to an iminium ion mech-
anism or intermediate enamine formation, observation of both
mechanisms in one reaction has not been reported. As part
of our ongoing studies in cycloadditions,9 and organocataly-
sis,10 we were inspired to investigate whether the all-carbon
[3 + 3] reaction might be accomplished by the combination
of these two aforementioned mechanistic pathways.
We initially explored the reaction of crotonaldehyde with
50 mol % of L-proline (1) in CH3CN at room temperature
for 4 h. To our delight, the reaction afforded the two
diasteromeric [3 + 3] adducts 2 and 3 in a ratio of 1.8:1,
along with some p-tolualdehyde (4), Scheme 1. These
by benzoation (PhCOCl, CH2Cl2, Et3N, cat. DMAP; 85%)
afforded (-)-6, which proved to be identical to the product
obtained from the reduction 3 to 7 followed by Mitsunobu
reaction with benzoic acid. Chlorite oxidation of 2 to 8
(NaClO2, t-BuOH, 2-methyl-2-butene, NaH2PO4, 25 °C;
84%), followed by esterification (EtOH, cat. TsOH, 25 °C)
afforded 9 in 80% yield.13 Alkylation of ester 9 with MeLi
(THF, 0 °C, 80%) provided 10, which was hydrogenated
(Pd-C, H2, EtOAc; 75%) to give (-)-isopulegol hydrate
(11). Using the same reaction sequence, 3 was transformed
to (-)-cubebaol (15) via compounds 12, 13, and 14. The
enantiomer of 15, (+)-cubebaol, has been used for the
synthesis of the HIV-1 protease inhibitive didemnaketals.14
These 8-hydroxy menthols, p-menthane-3,8-diols, have been
reported to have biological activities, e.g., plant growth
inhibition, allelopathic effect, and strong mosquito repellent
activity.15 The cyclohexenol subunit is also quite prevalent
in various natural isolates and therapeutic agents. In a further
demonstration of the application of this methodology, 5 was
acetylated (Ac2O, CH2Cl2, Et3N, cat. DMAP; 85%) to 16,
an important intermediate for the total synthesis of lycopo-
dium alkaloid magellanine.16 The reaction has been examined
under various conditions, and selected results are summarized
in Table 1.17 Reaction in MeOH and THF gave many
unstable and unidentifiable compounds, and the reaction rate
decreases in the following order: DMF > DMSO > CH3-
CN > CH2Cl2 > MeOH ∼ THF.
Scheme 1
In CH3CN, the reaction is insensitive to substrate concen-
trations varying from 0.2 to 1.5 M. The enantioselectivity
of the reaction did not change in the presence of more catalyst
(20 versus 50 mol % of L-proline); however, the reaction
rate was slightly higher at 50 mol %. Prolonged reaction
times in CH3CN (8 days) led to the formation of 4. Reactions
catalyzed by D-proline gave the opposite enantiomers of 2
and 3. Lowering the temperature decreased the rate and the
yield of 4 but increased the enantioselectivity of 2 and 3,
and the best results were obtained in DMF at -10 °C (80%
ee for 2 and 95% ee for 3). Below -20 °C, L-proline gave
no reaction after a few days. In the presence of pyrrolidine
or (S)-indoline-2-carboxylic acid hydrochloride (21), the
reaction gave a complicated mixture. However, a mixture
of pyrrolidine (18) and acetic acid (19) afforded 4 exclusively
(10% yield after 3 h, 78% yield after 48 h), without any
trace of 2 or 3. Reaction with 5-oxo-L-proline (20) at room
temperature gave no reaction after 48 h, most likely due to
the unfavorable formation of the amide iminium ion.
Reaction with (4S)-4-(tert-butyldimethylsilyloxy)-L-proline
(22) gave lower enantioselectivity.
adducts may be produced through a stepwise cascade reaction
and equilibrium process as shown in Scheme 2. It is likely
that the proline-catalyzed Michael reaction of crotonaldehyde
proceeds via transition state (E)-T11 and affords the (S)-
Michael adduct,12 which subsequently adds to the aldehyde
(enamine aldol reaction) to yield the cyclohexenes product.
To our knowledge, this is the first example of carbo [3 +
3]-cycloaddition of R,â-unsaturated aldehyde. The structure
of 2 was assigned unambiguously by its single-crystal X-ray
analysis. Reduction of 2 to 5 (LiAlH4, THF; 90%) followed
(6) For recent review, see: (a) Dalko, P. I.; Moisan, L.Angew. Chem.,
Int. Ed. 2004, 43, 5138. (b) Notz, W.; Tanaka, F.; Barbas, C. F., III. Acc.
Chem. Res. 2004, 37, 580. (c) Seayad, J.; List, B. Org. Biomol. Chem. 2005,
3, 719. (d) Berkessel, A.; Gro¨ger, H. Asymmetric Organocatalysis: From
Biomimetic Concepts to Applications in Asymmetric Synthesis; Wiley: New
York, 2005.
(7) Huang, Y.; Walji, A. M.; Larsen, C. H.; MacMillan, D. W. C. J.
Am. Chem. Soc. 2005, 127, 15051.
(8) (a) Yang, J. Woon; Fonseca, M. T. H.; List, B. J. Am. Chem. Soc.
2005, 127, 15036. (b) Yang, J. W.; Fonseca, M. T. H.; Vignola, N.; List,
B. Angew. Chem., Int. Ed. 2005, 44, 108.
(9) For an example of [6 + 2] cycloaddition, see: Hong, B.-C.; Shr,
Y.-J.; Wu, J.-L.; Gupta, A. K.; Lin, K. J. Org. Lett. 2002, 4, 2249.
(10) Chen, S.-H.; Hong, B.-C.; Su, C.-F.; Sarshar, S. Tetrahedron Lett.
2005, 46, 8899.
(11) For the directed electrostatic activation with (Z)-proline-derived
iminium, see: Kunz, R. K.; MacMillan D. W. C.J. Am. Chem. Soc. 2005,
127, 3240.
(12) For (R)-selective Michael addition by L-proline derivative, see:
Marigo, M.; Schulte, T.; Franze´n, J.; Jørgensen, K. A. J. Am. Chem. Soc.
2005, 127, 15710.
(13) For an alternative preparation of the methyl ester (mixture of
isomers) by a tandem Morita-Baylis-Hillman (MBH) and ring-closing-
metathesis (RCM) sequence, see: Krafft, M. E.; Song, E.-H.; Davoile, R.
J. Tetrahedron Lett. 2005, 46, 6359.
(14) Jia, Y. X.; Wu, B.; Li, X.; Ren, S. K.; Tu, Y. Q.; Chan, A. S. C.;
Kitching, W. Org. Lett. 2001, 3, 847.
(15) Vaneˇk, T.; Novotny´, M.; Podlipna´, R.; Sˇaman, D.; Valterova´, I. J.
Nat. Prod. 2003, 66, 1239.
(16) ()-16 was used in the synthesis; see: Ishizaki, M.; Niimi, Y.;
Hoshino, O.; Hara, H.; Takahashi, T. Tetrahedron 2005, 61, 4053.
(17) Hydroxyaldehydes 2 and 3 are volatile; hence the reported yields
are those of the corresponding alcohols (5, 7, and tolylmethanol) obtained
from in situ NaBH4 reduction.
2218
Org. Lett., Vol. 8, No. 11, 2006

Scheme 2. Proposed Mechanism of the Cascade Catalysis of [3 + 3]-Cycloaddition of Crotonaldehyde
The Michael-type reaction is involved in many biosyn-
thetic pathways.18 The current organocatalyzed [3 + 3] reac-
tion has never been reported under conventional conditions.
Since crotonaldehyde,19 2 (or 3) derivatives,20 and p-
tolualdehyde21 have been isolated from natural sources, it is
interesting to speculatesabout whether this type of [3 + 3]
process is a biotransformation and can be observed in nature.
A series of homologous R,â-unsaturated aldehydes were
then reacted with L-proline in CH3CN to afford the corre-
sponding adducts (Table 2). Unlike crotonaldehyde, these
aldehydes give the diene products 23-30 via formal [4 + 2]
reactions, and whenever possible, less than 5% of the
corresponding aromatic adduct. These [4 + 2] adducts may
be produced through an indirect Mannich reaction pathway
as shown in Scheme 3. Reaction of 4-oxobut-2-enyl acetate
with L-proline in CH3CN at 0 °C for 8 h afford the diene
adduct (23) in 68% yield with 94% ee (entry 1, Table 2).
Reaction of 3-methyl-2-butenal with L-proline at 25 °C for
Table 1. Miscellaneous Effects of the [3 + 3]-Cycloaddition of Crotonaldehyde
product ratio (%)c
yieldd
(%)
entry
cat.a
solvent
concnb (M)
T (°C)
time (h)
4/2/3
ee for 2 (config)e
ee for 3 (config)e
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
1
MeOH
THF
CH2Cl2
DMSO
DMF
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH2Cl2
DMF
0.4
0.4
0.4
0.4
0.4
0.4
0.2
0.8
1.5
0.4
0.4
0.4
0.4
0.4
0.4
0.4
0.4
0.4
0.4
0.4
0.4
26
26
26
26
26
26
26
26
26
26
0
4
4
4
4
4
4
4
4
4
6
48
8
16
48
48
24
8
complex mixture
complex mixture
0:62:38
29:45:26
40:41:19
13:56:31
12:55:33
13:60:27
29:48:23
8:63:29
6:39:55
28:43:29
6:50:44
3:42:55
5:47:48
11:52:37
complex mixture
100:0:0
0
0
1
1
1
1
1
1
1
1
1f
1
1
1
1
38
40
62
75
63
58
54
72
42
68
73
78
70
70
0
8 (4R,6R)
2 (4R,6R)
23 (4R,6R)
9 (4R,6R)
12 (4R,6R)
10 (4R,6R)
33 (4R,6R)
9 (4R,6R)
30 (4R,6R)
76 (4R,6R)
80 (4R,6R)
69 (4R,6R)
62 (4S,6S)
61 (4S,6S)
62 (4R,6S)
66 (4R,6S)
73 (4R,6S)
65 (4R,6S)
60 (4R,6S)
62 (4R,6S)
70 (4R,6S)
62 (4R,6S)
55 (4R,6S)
91 (4R,6S)
95 (4R,6S)
71 (4R,6S)
82 (4S,6R)
94 (4S,6R)
0
DMF
-10
-5
0
-10
26
26
26
0
CH3CN
CH3CN
DMF
CH3CN
CH3CN
DMF
17
17
18
18, 19
20
3
48
4
10g
0
0
no reaction
complex mixture
0:62:38
21
22
DMF
DMF
-10
24
60
38 (4R,6R)
55 (4R,6S)
a 50 mol % of catalyst was used unless otherwise stated. b Concentration of crotonaldehyde. c Ratio determinated by 1H NMR. d Yields refer to the
isolated alcohols from in situ NaBH4 reduction. e Enantiomeric excesses (ee) were measured by GC-MS (Shimadzu QP 5000, chiral capillary column,
γ-cyclodextrin trifluoroacetyl, Astec Type G-TA, size 30 m × 0.25 mm, flow rate 24 mL/min, temperature range 60-120 °C, gradient 3 °C/min). Absolute
configuration was assigned by transforming the product to p-methane-3,8-diol and comparison with the literature. f 20 mol % of catalyst was used. g Yield
of 4-methylbenzene alcohol after in situ NaBH4 reduction.
Org. Lett., Vol. 8, No. 11, 2006
2219

Scheme 3
3 h afford the diene adduct (24) in 82% yield (entry 2, Table
the reactions gave the corresponding diene adducts in good
yield and slightly lower enantioselectivity.
2). The capacity of proline to catalyze asymmetric cross
reactions between nonequivalent R,â-unsaturated aldehydes
was next examined (entries 3-8, Table 2). For all examples,
In conclusion, we have developed an enantioselective [3
+ 3]-cycloaddition of crotonaldehyde catalyzed by proline
derivatives. The process provides a significant addition to
the arsenal of cycloaddition-based methodologies, which
provide practical tool for rapid and efficient access to six-
membered ring systems, and is practical for large scale
synthesis. Further applications of this methodology along
with mechanistic studies and synthetic extensions (e.g. [3 +
3] Vs. [4 + 2]) are under active investigation in our laboratory.
Table 2. Formal [4 + 2]-Cycloaddition of R,â-Unsaturated
Aldehydes
Acknowledgment. We thank Mr. Shang-Hung Chen
(CCU) and Mr. Cheng-Feng Su (CCU) for their assistance
in this study. Financial support from the National Science
Council, Taiwan, ROC, is gratefully acknowledged.
Supporting Information Available: Experimental pro-
cedures and characterization data for the new compounds
(2-30) and X-ray crystallographic data for compound 2
(CIF). This material is available free of charge via the Internet
at http://pubs.acs.org.
OL060486+
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a Isolated yield. b Enantiomeric excesses (ee) were measured by GC-
MS; absolute stereochemistry not determined. c Isolated yield of the cis
adduct; trans/cis ) 1:9. d Achiral product.
(21) Ecroyd, C. E.; Franich, R. A.; Kroese, H. W.; Steward, D.
Phytochemistry 1995, 40, 1387.
2220
Org. Lett., Vol. 8, No. 11, 2006