Organocatalytic asymmetric Robinson annulation of α,β- unsaturated aldehydes: Applications to the total synthesis of (+)-palitantin

Article abstract of DOI:10.1021/jo701477v

(Chemical Equation Presented) The highly enantioselective organocatalytic Robinson annulation of α,β-unsaturated aldehydes was achieved, catalyzed by L-proline and trialkylamines and providing the formal [4 + 2] cycloaddition adducts. Additionally, in some examples in the catalysis with diarylpyrrolinol silyl ethers, the reactions afforded the [4 + 2] adducts with high enantioselectivity (>99.5% ee). The structure of the adduct, obtained from the reaction of 3-methylbut-2-enal and (E)-3-(2-nitrophenyl)acrylaldehyde, was confirmed by X-ray analysis. The absolute configurations of some [4 + 2] cycloadducts were investigated, and the methodology was applied in the synthesis of (+)-palitantin.

Full text of DOI:10.1021/jo701477v

Organocatalytic Asymmetric Robinson Annulation of
r,â-Unsaturated Aldehydes: Applications to the Total Synthesis of
(+)-Palitantin
Bor-Cherng Hong,* Ming-Fun Wu, Hsing-Chang Tseng, Guo-Fong Huang,
Cheng-Feng Su, and Ju-Hsiou Liao†
Department of Chemistry and Biochemistry, National Chung Cheng UniVersity, Chia-Yi, 621 Taiwan, ROC
chebch@ccu.edu.tw
ReceiVed July 16, 2007
The highly enantioselective organocatalytic Robinson annulation of R,â-unsaturated aldehydes was
achieved, catalyzed by L-proline and trialkylamines and providing the formal [4 + 2] cycloaddition adducts.
Additionally, in some examples in the catalysis with diarylpyrrolinol silyl ethers, the reactions afforded
the [4 + 2] adducts with high enantioselectivity (>99.5% ee). The structure of the adduct, obtained from
the reaction of 3-methylbut-2-enal and (E)-3-(2-nitrophenyl)acrylaldehyde, was confirmed by X-ray
analysis. The absolute configurations of some [4 + 2] cycloadducts were investigated, and the methodology
was applied in the synthesis of (+)-palitantin.
Introduction
imidazolidinone catalyst was first demonstrated in the highly
enantioselective Diels-Alder reaction of R,â-unsaturated alde-
hydes with dienes, such as cyclopentadiene, cyclohexadiene,
and 1,3-butadienes.3 The intramolecular Diels-Alder variant
with this catalyst has led to the successful total synthesis of
solanapyrone D4 and (+)-hapalindole Q.5 An examination of
imidazolidinone catalysis by density functional theory was
performed by Houk and Gordillo.6 Other organocatalysts for
The development of [4 + 2] cycloaddition, such as the Diels-
Alder reaction, for asymmetric synthesis remains an important
challenge in organic synthesis.1 Recently, organocatalysis in
asymmetric synthesis has received extensive attention and has
become a burgeoning subject due to its many merits, which
include its environmental benignness, high enantioselectivity,
low cost, ease of handling, and low toxicity.2 MacMillan’s
(3) (a) Ahrendt, K. A.; Borths, C. J.; MacMillan, D. W. C. J. Am. Chem.
Soc. 2000, 122, 4243. (b) Northrup, A. B.; MacMillan, D. W. C. J. Am.
Chem. Soc. 2002, 124, 2458.
(4) Wilson, R. M.; Jen, W. S.; MacMillan, D. W. C. J. Am. Chem. Soc.
2005, 127, 11616.
(5) Kinsman, A. C.; Kerr, M. A. J. Am. Chem. Soc. 2003, 125, 14120.
(6) Gordillo, R.; Houk, K. N. J. Am. Chem. Soc. 2006, 128, 3543.
(7) Schuster, T.; Bauch, M.; Du¨rner, G.; Go¨bel, M. W. Org. Lett. 2000,
2, 179.
(8) Kim, K. H.; Lee, S.; Lee, D.-W.; Ko, D.-H.; Ha, D.-C. Tetrahedron
Lett. 2005, 46, 5991.
* To whom correspondence should be addressed. E-mail: chebch@ccu.edu.tw.
Tel.: 886-5-2428174. Fax: 886-5-2721040.
† To whom correspondence regarding the X-ray crystal structure should be
addressed.
(1) For an excellent review of the asymmetric Diels-Alder reaction,
see: Corey, E. J. Angew. Chem., Int. Ed. 2002, 41, 1650.
(2) For recent reviews on organocatalysis, see: (a) Dalko, P. I., Ed.
EnantioselectiVe Organocatalysis: Reactions and Experimental Procedures;
Wiley-VCH: Weinheim, Germany, 2007. (b) Berkessel, A.; Gro¨ger, H.
Asymmetric Organocatalysis; Wiley-VCH: Weinheim, Germany, 2005. (c)
Dalko, P. I.; Moisan, L. Angew. Chem., Int. Ed. 2004, 43, 5138. (d) Seayad,
J.; List, B. Org. Biomol. Chem. 2005, 3, 719. (e) Gaunt, M. J.; Johansson,
C. C. C.; McNally, A.; Vo, N. C. Drug DiscoVery Today 2007, 2, 8. (f)
List, B. Chem. Commun. 2006, 819.
(9) Ishihara, K.; Nakano, K. J. Am. Chem. Soc. 2005, 127, 10504.
(10) Ramachary, D. B.; Chowdari, N. S.; Barbas, C. F., III. Tetrahedron
Lett. 2002, 43, 6743.
10.1021/jo701477v CCC: $37.00 © 2007 American Chemical Society
Published on Web 10/06/2007
J. Org. Chem. 2007, 72, 8459-8471
8459

Hong et al.
asymmetric Diels-Alder reactions include chiral amidinium for
the synthesis of the skeleton of estrone and norgestrel,7
protonated 1,2-diamino-1,2-diphenylethane,8 chiral triamines for
the reaction with R-acyloxyacroleins,9 chiral ammonium salt
of 1,2-diamine for the direct self-Diels-Alder reactions of R,â-
unsaturated ketones,10 hydrazide for the reaction in aqueous
media,11 as well as the hetero-Diels-Alder reaction by TAD-
DOL,12 inverse-electron-demand hetero-Diels-Alder reaction
of nitroso alkenes by pyrrolidine,13 domino Knoevenagel/hetero-
Diels-Alder/elimination reactions by proline,14 and organo-
catalytic Diels-Alder reactions on solid supports.15
While many organocatalytic [4 + 2] reactions have been
reported as described above, the organocatalytic [4 + 2] reaction
of R,â-unsaturated aldehydes with high enantioselectivity
remains elusive, even with considerable efforts.16 We report here
the highly enantioselective organocatalytic [4 + 2] reaction of
R,â-unsaturated aldehydes17 and its application to the synthesis
of (+)-palitantin.
Results and Discussion
1. Reactions and Optimizations in the Formal [4 + 2]
Cycloaddition of R,â-Unsaturated Aldehydes. At the outset
of our investigation, a series of organocatalysts was screened
for the [4 + 2] reactions of 3-methylbut-2-enal and crotonal-
dehyde (Table 1).18,19 Among them, L-proline (I) and the
catalysts IV, X, and XII were promising candidates for the
transformation at ambient temperature. Notwithstanding the fact
that MacMillan’s second-generation imidazolidinone catalyst (X)
has provided high enantioselectivity in the reaction of cyclo-
pentadiene with R,â-unsaturated aldehydes,3 moderate enanti-
oselectivity was observed in this reaction (see entries 13 and
14, Table 1). The reactions catalyzed by these promising
catalysts at lower temperature (e.g., 0 °C) resulted in slow
conversion and decreased enantioselectivity. However, in the
cases of I, XIV, and XV, higher enantioselectivity was achieved
at lower temperature (entries 2, 20, and 22, Table 1). Unfor-
tunately, when reacted below 0 °C, these reactions either proceed
very slowly (after a few days) or not at all. This is an obstacle
to increasing enantioselectivity by lowering the reaction tem-
perature. Recently, cocatalysts have been reported to affect the
reaction’s chemoselectivity and stereoselectivity.20 As such,
tertiary amines were used as the organocatalysts in cyclopro-
panation,21 the Baylis-Hillman reaction,22 and asymmetric
conjugate additions by cinchona alkaloids.23
(11) Lemay, M.; Ogilvie, W. W. Org. Lett. 2005, 7, 4141.
(12) Huang, Y.; Unni, A. K.; Tadani, A. N.; Rawal, V. H. Nature 2003,
424, 140.
(13) Wabnitz, T. C.; Saaby, S.; Jørgensen, K. A. Org. Biomol. Chem.
2004, 2, 828.
(14) Sabitha, G.; Fatima, N.; Reddy, E. V.; Yadav, J. S. AdV. Synth.
Catal. 2005, 347, 1353.
(15) Selka¨la¨, S. A.; Tois, J.; Pihko, P. M.; Koskinen, A. M. P. AdV. Synth.
Catal. 2002, 344, 941.
(16) (a) For a preliminary report of the reaction in moderate enantiose-
lectivity, see: Hong, B.-C.; Wu, M.-F.; Tseng, H.-C.; Liao, J.-H. Org. Lett.
2006, 8, 2217. (b) For an independent study with modest enantioselectivity,
see: Bench, B. J.; Liu, C.; Evett, C. R.; Watanabe, C. M. H. J. Org. Chem.
2006, 71, 9458.
Accordingly, in the attempts to improve the reaction rate and
ee value, we observed the acceleration of transformation in the
presence of trialkylamines.24 Encouraged by this observation,
we surveyed a range of trialkylamine cocatalysts as well as other
reaction conditions in an effort to facilitate the reaction and
improve enantioselectivity. The results are summarized in Table
2.25 Reaction of L-proline at -20 °C gave adduct 3a in higher
(17) For other recent organocatalysis reactions with R,â-unsaturated
aldehydes, see: (i) Conjugate additions: (a) Brandau, S.; Landa, A.; Franze´n,
J.; Marigo, M.; Jørgensen, K. A. Angew. Chem., Int. Ed. 2006, 45, 4305.
(b) Marigo, M.; Schulte, T.; Franze´n, J.; Jørgensen, K. A. J. Am. Chem.
Soc. 2005, 127, 15710. (c) Wu, F.; Hong, R.; Khan, J.; Lin, X.; Deng, L.
Angew. Chem., Int. Ed. 2006, 45, 4301. (d) Huang, Y.; Walji, A. M.; Larsen,
C. H.; MacMillilan, D. W. C. J. Am. Chem. Soc. 2005, 127, 15051. (e)
Hayashi, Y.; Gotoh, H.; Tamura, T.; Yamaguchi, H.; Masui, R.; Shoji, M.
J. Am. Chem. Soc. 2005, 127, 16028. (ii) Asymmetric conjugate reduction:
(a) Mayer, S.; List, B. Angew. Chem., Int. Ed. 2006, 45, 4193. (b) Ouellet,
S. G.; Tuttle, J. B.; MacMillan, D. W. C. J. Am. Chem. Soc. 2005, 127, 32.
(iii) Diels-Alder reaction: (a) Wilson, R. M.; Jen, W. S.; MacMillan, D.
W. C. J. Am. Chem. Soc. 2005, 127, 11616. (b) Taichi, T. Y.; Maruoka, K.
Org. Lett. 2006, 8, 2687. (iv) Reductive Michael cyclization: Yang, J. W.;
Fonseca, M. T.; List, B. J. Am. Chem. Soc. 2005, 127, 15036. (v) Triple
cascade reaction: Enders, D.; Hu¨ttle, M. R. M.; Grondal, C.; Raabe, G.
Nature 2006, 441, 861. (vi) Iminium cyclization: Sydorenko, N.; Hsung,
R. P.; Vera, E. L. Org. Lett. 2006, 8, 2611. (vii) Cyclopropanation: Kunz,
R. K.; MacMillan, D. W. C. J. Am. Chem. Soc. 2005, 127, 3240. (viii)
Friedel-Crafts alkylation: Paras, N. A.; MacMillan, D. W. C. J. Am. Chem.
Soc. 2001, 123, 4370. (ix) γ-Butylactone formation: Paras, N. A.;
MacMillan, D. W. C. J. Am. Chem. Soc. 2001, 123, 4370. (x) 1,3-Dipolar
cycloaddition: (a) Jen, W. S.; Wiener, J. M.; MacMillan, D. W. C. J. Am.
Chem. Soc. 2000, 122, 9874. (b) Chow, S. S.; Nevalainen, M.; Evans, C.
A.; Johannes, C. W. Tetrahedron Lett. 2007, 48, 277. (xi) [3 + 2]
Cycloadditions of azomethine imines with R,â-unsaturated aldehydes: Chen,
W.; Yuan, X.-H.; Li, R.; Du, W.; Wu, Y.; Ding, L.-S.; Chen, Y.-C. AdV.
Synth. Catal. 2006, 348, 1818. (xii) Tandem Michael-aldol: (a) Wang, W.;
Li, H.; Wang, J.; Zu, L. J. Am. Chem. Soc. 2006, 128, 10354. (b) Marigo,
M.; Bertelsen, S.; Landa, A.; Jørgensen, K. A. J. Am. Chem. Soc. 2006,
128, 5475. (xiii) Sequential conjugate additionaldol-dehydration reaction:
Li, H.; Wang, J.; Xie, H.; Zu, L.; Jiang, W.; Duesler, E. N.; Wang, W.
Org. Lett. 2007, 9, 965. (xiv) â-Hydroxylation: Bertelsen, S.; Dine´r, P.;
Johansen, R. L.; Jørgensen, K. A. J. Am. Chem. Soc. 2007, 129, 1536. (xv)
Domino oxa-Michael-aldol reaction: Li, H.; Wang, J.; E-Nunu, T.; Zu, L.;
Jiang, W.; Wei, S.; Wang, W. Chem. Commun. 2007, 507. (xvi) Asymmetric
γ-amination: Bertelsen, S.; Marigo, M.; Brandes, S.; Diner, P.; Jorgensen,
K. A. J. Am. Chem. Soc. 2006, 128, 12973. (xvii) Oxy-Michael addition:
Kano, T. Tanaka, Y.; Maruoka, K. Tetrahedron Lett. 2006, 47, 3039. (xviii)
Vinylogous Michael addition: Xie, J.-W.; Yue, L.; Xue, D.; Ma, X.-L.;
Chen, Y.-C.; Wu, Y.; Zhu, J.; Deng, J.-G. Chem. Commun. 2006, 1563.
(18) Refer to Supporting Information.
(19) Selected examples of the organocatalysis with these catalysts: For
(II), see: Angew. Chem., Int. Ed. 2005, 44, 3706. For (III), see: Levina,
A.; Muzart, J. Tetrahedron: Asymmetry 1995, 6, 147. For (IV), see: (a)
Hayashi, Y.; Sumiya, T.; Takahashi, J.; Gotoh, H.; Urushima, T.; Shoji,
M. Angew. Chem., Int. Ed. 2006, 45, 958. (b) Enders, D.; Grondal, C.;
Vrettou, M.; Raabe, G. Angew. Chem., Int. Ed. 2005, 44, 4079. For (VI),
see: Kunz, R. K.; MacMillan, D. W. C. J. Am. Chem. Soc. 2005, 127,
3240. For (VII), see: (a) Steiner, D. D.; Mase, N.; Barbas, C. F., III. Angew.
Chem., Int. Ed. 2005, 44, 3706. (b) Ramachary, D. B.; Chowdari, N. S.;
Barbas, C. F., III. Angew. Chem., Int. Ed. 2003, 42, 4233. For (VIII), see:
Cheong, P. H.-Y.; Zhang, H.; Thayumanavan, R.; Tanaka, F.; Houk, K.
N.; Barbas, C. F., III. Org. Lett. 2006, 8, 811. For (X), see: Robichaud, J.;
Tremblay, F. Org. Lett. 2006, 8, 597. For (XI), see: Aggarwal, V. K.; Lopin,
C.; Sandrinelli, F. J. Am. Chem. Soc. 2003, 125, 7596. For (XII), see:
Dambruoso, P.; Massi, A.; Dondoni, A. Org. Lett. 2005, 7, 4657. For (XIII),
see: (a) Mitchell, C. E. T.; Brenner, S. E.; Ley, S. V. Chem. Commun.
2005, 5346. (b) Kumarn, S.; Shaw, D. M.; Ley, S. V. Chem. Commun.
2006, 3211. For (XIV), see: Andreae, M. R. M.; Davis, A. P. Tetrahe-
dron: Asymmetry 2005, 16, 2487. For (XV), see: Ramachary, D. B.;
Chowdari, N. S.; Barbas, C. F., III. Angew. Chem., Int. Ed. 2003, 42, 4233.
(20) (a) Peelen, T. J.; Chi, Y.; Gellman, S. H. J. Am. Chem. Soc. 2005,
127, 11598. (b) Mase, N.; Nakai, Y.; Ohara, N.; Yoda, H.; Takabe, K.;
Tanaka, F.; Barbas, C. F., III. J. Am. Chem. Soc. 2006, 128, 734.
(21) Papageorgiou, C. D.; Gaunt, M. J. Angew. Chem., Int. Ed. 2004,
43, 4641.
(22) Iwabuchi, Y.; Hatakeyama, S. J. Am. Chem. Soc. 1999, 121, 10219.
(23) Wu, F.; Hong, R.; Khan, J.; Liu, X.; Deng, L. Angew. Chem., Int.
Ed. 2006, 45, 4301.
(24) For recent examples in amine-promoted organocatalysis, see:
Armstrong, A.; Baxter, C. A.; Lamont, S. G.; Pape, A. R.; Wincewicz, R.
Org. Lett. 2007, 9, 351.
(25) Individual exposure to L-Pro of 1a or 2a gave the corresponding
self-[4 + 2]- and self-[3 + 3]-cycloaddition adducts, respectively. However,
in the reaction of the mixture of 1a, 2a, and L-Pro, cross-[4 + 2]-cycload-
dition was dominant and less than 5% yields of the self-condensation adducts
were observed.
8460 J. Org. Chem., Vol. 72, No. 22, 2007

Organocatalytic [4 + 2] Cycloaddition
TABLE 1. Catalyst Screening for the Direct Catalytic Asymmetric [4 + 2] Reaction of 3-Methylbut-2-enal (1a) and Crotonaldehyde (2a) in
CH3CN
T
time
(h)
yielda
(%)
eeb
(%)
entry
catalyst
(oC)
1
2
3
4
5
I
I
II
II
III
IV
IV
25
1.5
24
40
8
24
1
82
84
NR
80
NR
74
22
32
NA
7
NA
24
-5
25
reflux
25
25
0
6
7
3
70
21
8
9
V
VI
VII
VIII
IX
X
X
XI
XII
XII
XIII
XIV
XIV
XV
XV
XVI
XVI
25
32
25
25
25
34
0
25
32
0
30
30
0
32
0
192
4
32
16
24
3
24
5
3
4
3
7
40
1.5
6
3
>72
60
4
∼0c
NR
NR
NR
52
NA
NA
NA
NA
24
24
12
38
26
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
15
71
70
60
∼0d
NA
∼0
30
75
71
79
80
∼0
17
32
0
82
24
ND
10e
a Isolate yield. b The 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). c Complex mixtures. d Decomposition
of crotonaldehydes and recovery of all of 1a. e Self reaction of 3-methyl-2-enal and 50% recovery of crotonaldehyde.
enantioselectivity (41% ee) than at ambient temperature (22%
ee; entry 1 in Table 1 and condition A, entry 1, in Table 2).
However, at such low temperature, the reaction was too slow
to be completed in 2 days. Further lowering of the reaction
temperature resulted in difficulty due to the high melting point
of CH3CN (-46 °C). Unfortunately, reaction in other solvents,
such as MeOH, THF, DMF, etc., gave either no reaction or
much lower yield. Nevertheless, addition of Et3N to the reaction
mixture increased the reaction rate and allowed the reaction to
be completed at -40 °C in 20 h, giving 78% ee in 81% yield
(condition B, entry 2, Table 2). Other chiral trialkylaminess
for example, (-)-sparteine, DHQD, and DHQswere screened
for their efficiency as cocatalyst in the reaction, and (-)-
sparteine gave the best results in up to 82% ee at -40 °C
(conditions C, D, and E, entries 3-7, Table 2). The reaction
attained high enantioselectivity (85%) and up to the maximum
of -90% when catalysts XVII and XVIII were employed26,27
(conditions F and G, entries 8-10, Table 2). Reaction of
MacMillian catalyst (X) and the diamine catalyst (XII) at lower
temperature (-20 and -40 °C), however, gave slow reaction
with low enantioselectivity (conditions H and I, entries 11-
13, Table 2). These studies implied that the conditions B, C, F,
(26) Recently, the pyrrolidine derivatives, such as diarylprolinol TMS
ether, catalysts XVII and XVIII, have emerged as a promising general
enamine organocatalysts. For review, see: Palomo, C.; Mielgo, A. Angew.
Chem., Int. Ed. 2006, 45, 7876.
J. Org. Chem, Vol. 72, No. 22, 2007 8461

Hong et al.
TABLE 2. Condition Screening for the Direct Catalytic Asymmetric [4 + 2] Reaction of 3-Methylbut-2-enal (1a) and Crotonaldehyde (2a)a
T
(°C)
time
(h)
yieldb %
entry
condition
(ee)c
1
2
3
4
5
6
7
8
9
10
11
12
13
A
B
C
C
D
D
E
F
G
G
H
I
-20
-40
-20
-40
-20
-40
-20
-20
0
-20
-20
-20
-40
48
20
4
82 (41)
81 (78)
82 (62)
79 (82)
75 (71)
65 (70)
72 (50)
63 (85)
68 (-80)e
72 (-90)e
∼0d,f
12
12
96
30
96
36
96
50
5
65 (49)
65 (52)
I
10
a Condition A: L-proline (50 mol %), CH3CN. Condition B: L-proline (50 mol %), Et3N (50 mol %), CH3CN. Condition C: L-proline (50 mol %),
(-)-sparteine (50 mol %), CH3CN. Condition D: L-proline (50 mol %), DHQD (50 mol %), CH3CN. Condition E: L-proline (50 mol %), DHQ (50 mol %),
CH3CN. Condition F: XVII (20 mol %), benzoic acid (20 mol %), toluene. Condition G: XVIII (20 mol %), benzoic acid (20 mol %), toluene. Condition
H: X (50 mol %), TFA (50 mol %), CH3CN. Condition I: XII (50 mol %), HOAc (50 mol %), CH3CN. b Isolated yield. c Enantiomeric excess determined
by GC-MS (Astec Type G-TA) unless otherwise noted. d With complicated mixtures, monitored by NMR. e Opposite enantioselectivity was observed.
f 50% of starting aldehydes remained with complicated mixtures. g Enantiomeric excess determined by HPLC (Chiracel OD).
and G were the promising ones for this [4 + 2] cycloaddition.
Taking these results into account, a series of the R,â-unsaturated
aldehydes were tested under these conditions, and the selected
results are summarized in Table 3.
gave 60% yield of 3c in 6% ee (entry 7, Table 3).30 The
enantioselectivity was increased up to 40% ee by lowering the
reaction temperature to -20 °C (entries 8 and 9, Table 3).
Unfortunately, replacement of Et3N with (-)-sparteine under
the same reaction conditions did not improve enantioselectivity
(entry 10, Table 3). Intriguingly, the reaction catalyzed by XVII
gave 73% yield and 92% ee at ambient temperature, with fast
conversion (entry 11, Table 3). However, further lowering of
the reaction temperature did not improve the enantioselectivity,
affording slow reaction and lower yields (entries 11-13, Table
3). The opposite enantiomer was obtained in good yield and
with high enantioselectivity when the reaction was catalyzed
by XVIII at ambient temperature (entry 14, Table 3). The
enantioselectivity was further increased to -99% when the
reaction temperature was reduced to -20 °C (entry 15, Table
3).
Reaction of 3-methylbut-2-enal and (E)-3-formylallyl acetate28
with L-proline and Et3N at -20 °C gave 72% yield of 3b in
45% ee (entry 1, Table 3).18 The enantioselectivity was nearly
doubled when the reaction was conducted at lower temperature
(-40 °C, 12 h for completion; entry 2, Table 3). Replacement
of Et3N with (-)-sparteine in the same reaction conditions
required 40 h for completion but gave high yield and excellent
enantioselectivity (81% yield; 93% ee; entry 3, Table 3). In
comparison with the catalysis by L-proline, the reactions
catalyzed by XVII and XVIII were slower, taking 36 h and 4
days for the completion at 0 and -20 °C, respectively (entries
4-6, Table 3).29
Reaction of 3-methylbut-2-enal and (E)-3-(2-nitrophenyl)-
acrylaldehyde with L-proline and Et3N at ambient temperature
Reaction of 3-methylbut-2-enal and cinnamaldehyde with
L-proline and Et3N at -20 °C for 24 h gave 78% yield of 3d in
52% ee (entry 16, Table 3). A slight increase in enantioselec-
tivity was achieved by the replacement of Et3N with (-)-
sparteine under the same reaction conditions (entry 17). Lengthy
reactions conducted at -20 °C with catalysts XVII and XVIII
had little effect on the yield of 3d but markedly improved the
enantioselectivities (entries 18-20).
(27) For recent examples of (S)-diphenylpyrrolinol silyl ethers as catalysts
in organocatalysis, see: (a) Ibrahem, I.; Co´rdova, A. Chem. Commun. 2006,
1760. (b) Wang, Y.; Liu, X.-F.; Deng, L. J. Am. Chem. Soc. 2006, 128,
3928. (c) Chi, Y.; Gellman, S. H. J. Am. Chem. Soc. 2006, 128, 6804. (d)
Marigo, M. T.; Bertelsen, S.; Landa, A.; Jørgensen, K. A. J. Am. Chem.
Soc. 2006, 128, 5475. (e) Wang, W.; Li, H.; Wang, J.; Zu, L. J. Am. Chem.
Soc. 2006, 128, 10354. (f) Marigo, M. T.; Wabnitz, C.; Fielenbach, D.;
Jørgensen, K. A. Angew. Chem., Int. Ed. 2005, 44, 794. (g) Hayashi, Y.;
Okano, T.; Aratake, S.; Hazelard, D. Angew. Chem., Int. Ed. 2007, 46, 4922.
(h) See ref 17 (xiv).
(28) For preparation, see: (a) De La Cruz, A.; He, A.; Thanavaro, A.;
Yan, B.; Spilling, C. D.; Rath, N. P. J. Organomet. Chem. 2005, 690, 2577.
(b) James, P.; Felpin, F.-X.; Landais, Y.; Schenk, K. J. Org. Chem. 2005,
70, 7985. (c) Maruta, Y.; Fukushi, Y.; Ohkawa, K.; Nakanishi, Y.; Tahara,
S.; Mizutani, J. Phytochemistry 1995, 38, 1169.
(29) The same reaction at -20 °C in the presence of racemic proline
(50 mol %) and (-)-sparteine (50 mol %) gave racemic 3a in 82% yield
(0% ee). No reaction was obtained by the combination of aldehydes with
(-)-sparteine alone. A smaller addition of Et3N resulted in less acceleration
of the reaction.
(30) One recrystallization from EtOAc/CH2Cl2 furnished 3c in 70% ee.
8462 J. Org. Chem., Vol. 72, No. 22, 2007

Organocatalytic [4 + 2] Cycloaddition
TABLE 3. Organocatalysts, Cocatalysts, and Temperature Effects in the [4 + 2] Reactions of r,â-Unsaturated Aldehydesa
entry
aldehydes
product
condition
T (°C)
time (h)
yieldb % (ee)c
1
2
R1 ) R2 ) Me; R3 ) CH2OAc
R1 ) R2 ) Me; R3 ) CH2OAc
R1 ) R2 ) Me; R3 ) CH2OAc
R1 ) R2 ) Me; R3 ) CH2OAc
R1 ) R2 ) Me; R3 ) CH2OAc
R1 ) R2 ) Me; R3 ) CH2OAc
R1 ) R2 ) Me; R3 ) (o-NO2)C6H4
R1 ) R2 ) Me; R3 ) (o-NO2)C6H4
R1 ) R2 ) Me; R3 ) (o-NO2)C6H4
R1 ) R2 ) Me; R3 ) (o-NO2)C6H4
R1 ) R2 ) Me; R3 ) (o-NO2)C6H4
R1 ) R2 ) Me; R3 ) (o-NO2)C6H4
R1 ) R2 ) Me; R3 ) (o-NO2)C6H4
R1 ) R2 ) Me; R3 ) (o-NO2)C6H4
R1 ) R2 ) Me; R3 ) (o-NO2)C6H4
R1 ) R2 ) Me; R3 ) Ph
3b
3b
3b
3b
3b
3b
3c
3c
3c
3c
3c
3c
3c
3c
3c
3d
3d
3d
3d
3d
3e
3e
3e
3e
3f
B
B
C
F
-20
-40
-40
0
5
72 (45)
12
40
36
96
96
5
75 (82)
3
81 (93)
4
65 (72)
5
F
-20
-20
25
67 (83)
6
G
B
B
B
C
F
61 (-85)e
60 (6)f
7
8
0
12
20
28
5
8
96
5
65 (25)f
9
-20
-20
25
60 (40)f
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
59 (39)
73 (92)f
F
F
0
72 (95)f
-20
53 (93)f
G
G
B
C
F
G
G
B
C
F
25
72 (-92)e,f
54 (-99)e,f
78 (52)
-20
-20
-20
-20
0
96
24
30
96
72
96
24
24
96
96
24
48
5
96
96
8
12
96
96
5
10
5
5
4
72
5
96
5
96
4
R1 ) R2 ) Me; R3 ) Ph
72 (57)
R1 ) R2 ) Me; R3 ) Ph
72 (95)
R1 ) R2 ) Me; R3 ) Ph
68 (-82)e
70 (-97)e
81 (86)
R1 ) R2 ) Me; R3 ) Ph
-20
-40
-40
-20
-20
-20
-40
25
R1 ) R2 ) Me; R3 ) Et
R1 ) R2 ) Me; R3 ) Et
78 (90)
R1 ) R2 ) Me; R3 ) Et
62 (94)
R1 ) R2 ) Me; R3 ) Et
G
B
C
F
62 (-85)e
70 (68)
R1 ) R2 ) Me; R3 ) i-Pr
R1 ) R2 ) Me; R3 ) i-Pr
3f
72 (90)
R1 ) R2 ) Me; R3 ) i-Pr
3f
16 (97)g
13 (98)g
14 (-98)e,g
70 (95)
R1 ) R2 ) Me; R3 ) i-Pr
3f
F
-20
-20
-20
-20
-20
-20
-20
-20
25
R1 ) R2 ) Me; R3 ) i-Pr
3f
G
B
C
F
R1 ) H; R2 ) R3 ) CH2OAc
R1 ) H; R2 ) R3 ) CH2OAc
R1 ) H; R2 ) R3 ) CH2OAc
R1 ) H; R2 ) R3 ) CH2OAc
R1 ) H; R2 ) CH2OAc; R3 ) Ph
R1 ) H; R2 ) CH2OAc; R3 ) Ph
R1 ) H; R2 ) CH2OAc; R3 ) Ph
R1 ) H; R2 ) CH2OAc; R3 ) Ph
R1 ) R2 ) -(CH2)5-; R3 ) Ph
R1 ) R2 ) -(CH2)5-; R3 ) Ph
R1 ) R2 ) -(CH2)5-; R3 ) Ph
R1 ) R2 ) -(CH2)5-; R3 ) Ph
R1 ) R2 ) -(CH2)5-; R3 ) Ph
R1 ) R2 ) -(CH2)5-; R3 ) Ph
R1 ) H; R2 ) R3 ) Me
3g
3g
3g
3g
3h
3h
3h
3h
3i
65 (69)
∼0d
G
B
C
F
∼0d
63 (77)
59 (70)
∼0h
G
A
A
F
25
∼0h
25
84 (7:1 dr); (1)i
85 (34:1 dr); (7)i
63 (100:0 dr); (98)i
45 (100:0 dr); (>99.5)i
64 (100:0 dr); (-95)e,i
46 (100:0 dr); (>-99)e,i
76 (10)
3i
0
3i
25
3i
F
-20
3i
G
G
A
B
B
B
F
25
3i
-20
reflux
reflux
35
tolualdehyde/3j (64:36)
tolualdehyde/3j
R1 ) H; R2 ) R3 ) Me
2
2
∼0d
R1 ) H; R2 ) R3 ) Me
tolualdehyde/3j (40:60)
tolualdehyde/3j (50:50)
tolualdehyde/3j
tolualdehyde/3j
tolualdehyde/3j (10:90)
81 (16)
R1 ) H; R2 ) R3 ) Me
0
10
96
3
80 (14)
R1 ) H; R2 ) R3 ) Me
-20
∼0d
R1 ) H; R2 ) R3 ) Me
G
J
25
∼0d
R1 ) H; R2 ) R3 ) Me
reflux
18
79 (12)
a Condition A: L-proline (50 mol %), CH3CN. Condition B: L-proline (50 mol %), Et3N (50 mol %), CH3CN. Condition C: L-proline (50 mol %),
(-)-sparteine (50 mol %), CH3CN. Condition F: XVII (20 mol %), benzoic acid (20 mol %), toluene. Condition G: XVIII (20 mol %), benzoic acid (20
mol %), toluene. Condition J: 4-hydroxyproline (20 mol %), CH3CN. b Isolated yield. c Enantiomeric excess determined by GC-MS (Astec Type G-TA)
unless otherwise addressed. d With complicated mixtures, monitored by NMR. e Opposite enantioselectivity was observed. f Enantiomeric excess determined
by HPLC (Chiracel OD). g More than 40% of the aldol product 4 was obtained. h Reaction at -20 °C for 96 h gave the same results, decomposition of
(E)-3-formylallyl acetate, recovered cinnamaldehyde. i Absolute stereochemistry not determined.
J. Org. Chem, Vol. 72, No. 22, 2007 8463

Hong et al.
Reaction of 3-methylbut-2-enal and pent-2-enal with L-proline
and Et3N at -40 °C for 24 h gave 81% yield of 3e in 86% ee
(entry 21, Table 3). The enantioselectivity was increased slightly
to 90% by the replacement of Et3N with (-)-sparteine under
the same reaction conditions (entry 22, Table 3). The reactions
catalyzed by XVII and XVIII at -20 °C for 4 days gave 62%
yield of 3e in 94 and -85% ee, respectively (entries 23 and
24, Table 3).
Reaction of 3-methylbut-2-enal and 4-methyl-pent-2-enal with
L-proline and Et3N at -20 °C for 24 h gave 70% yield of 3f in
68% ee (entry 25, Table 3). The enantioselectivity was increased
dramatically to 90% by the replacement of Et3N with (-)-
sparteine at -40 °C (entry 26, Table 3). The catalysts XVII
and XVIII afforded low yields of 3f but high enantioselectivities
(98% ee), along with the Baylis-Hillman side products 4
(entries 27-29, Table 3).
Self-condensation of (E)-3-formylallyl acetate with L-proline
and Et3N at -20 °C gave 70% yield of 3g in 95% ee (entry 30,
Table 3). Unfortunately, replacement of Et3N with (-)-sparteine
decreased the enantioselectivity to 69%, while the reaction
catalyzed by XVII and XVIII gave no observable 3g but rather
complicated mixtures of products (entries 31-33, Table 3).
Reaction of (E)-3-formylallyl acetate and cinnamaldehyde
with L-proline and Et3N at -20 °C was fast, completed in 5 h,
with 63% yield of 3h in 77% ee (entry 34, Table 3).
Replacement of Et3N with (-)-sparteine under the same reaction
conditions, however, did not improve the enantioselectivity
(entry 35, Table 3). Unfortunately, the reaction catalyzed by
XVII and XVIII gave virtually no 3h but the decomposition
of (E)-3-formylallyl acetate and recovered cinnamaldehyde
(entries 36 and 37, Table 3).
Reaction of cyclohexylidene acetaldehyde and cinnamalde-
hyde with L-proline at ambient temperature for 4 h gave 84%
yield of 3i in 7:1 diastereomeric ratio and almost no enanti-
oselectivity. The diastereomeric ratio of the reaction was
increased to 34:1 at 0 °C (entries 38 and 39, Table 3). Both the
diastereomeric ratio and the enantioselectivity of the reaction
were increased to >99% when catalyzed by XVII and XVIII
at -20 °C for 4 days (entries 40-43, Table 3).
Recently, we have reported the observation of [3 + 3]
cycloaddition adducts in the self-condensation of crotonaldehyde
with L-proline at low temperature.16a Addition of Et3N to the
reaction mixture increased the ratio of [4 + 2] versus [3 + 3]
adduct and attained a maximum of 1:1 in CH3CN (entries 44-
47, Table 3).31 The reaction catalyzed by XVII or XVIII gave
complicated mixtures with no observed [4 + 2] adduct (entries
48 and 49, Table 3). Interestingly, the reaction catalyzed by
4-hydroxyproline in refluxing CH3CN gave the [4 + 2] adduct
as the major product (entry 50, Table 3).
We draw the following conclusions from the results in Table
2 and 3: (1) Reactions at lower temperature gave better
enantioselectivity of the product than reactions at higher
temperature. Et3N plays a role in facilitating the reaction and
allows the reaction to proceed at lower temperature and, in
return, affords better enantioselectivity of the products. (2) In
many cases, the reactions catalyzed by L-proline/(-)-sparteine
provided better enantioselectivity than those reactions catalyzed
by L-proline/Et3N. (3) For the reaction of aldehyde 1 with
â-dialkyl substituents, XVII and XVIII gave better enantiose-
lectivity and in some cases gave >99% ee. However, if both of
FIGURE 1. ORTEP plot for X-ray crystal structure of 3c.
the two reactants were monoalkylunsaturated aldehydes, the
reactions catalyzed by XVII and XVIII yielded complicated
mixtures. (4) Although 4-hydroxyproline was a poor catalyst
in the reaction of 1 and 2, it was the best catalyst as the [4 +
2] promoter in the self-condensation of crotonaldehyde. (5) For
cross-annulation, such as in the mixtures of â-dialkyl- and
â-monounsaturated aldehydes, such as 1 and 2, the â-dialky-
lunsaturated aldehyde served as the donor in the dienamine
Michael reaction step for attacking the monoalkylunsaturated
aldehyde acceptor, rather than self-condensation or being
attacked by the monoalkyl counterpart. (6) Shorter reaction times
were obtained by raising the reaction temperature, but this
condition also decreased the enantioselectivity.
2. Structure and Stereochemistry Elucidation in the
Formal [4 + 2] Adducts. The structure of 3c was assigned
unambiguously by its single-crystal X-ray analysis (Figure
1).18,32 The formation of the [4 + 2] adduct may be produced
through a stepwise cascade reaction and equilibrium process
as shown in Scheme 1. It is likely that the proline-catalyzed
Michael reaction of R,â-unsaturated aldehyde proceeds via
transition state (E)-T, followed by an indirect Mannich reaction
(iminium-ion-activating) pathway to afford the adducts. The
mechanism also explains the chemoselectivity in the cross-
annulation: the â-dialkyl-R,â-unsaturated aldehydes, such as
1, are more easily enolized, providing the corresponding
dienamine, followed by their attacking the â-monoalkyl-R,â-
unsaturated aldehydes, such as compound 2. Recently, several
examples of organocatalysis have been observed to have better
yields in the presence of water.33 The current reactions are not
particularly sensitive to moisture or air. However, addition of
water to the reaction mixture reduced the reaction rate dramati-
(32) Crystallographic data for 3c: C14H13NO3, M ) 243.25, orthorhom-
bic, space group Pbca, T ) 294 K, a ) 8.4574(13), b ) 15.167(2), c )
19.340(3) Å, V ) 2480.8(6) Å3, Z ) 8, D ) 1.303 g/cm3, λ (Mo KR) )
0.71073 Å, 20 391 reflections collected, 3026 unique reflections, 165
parameters refined on F2, R ) 0.1066, wR2[F2] ) 0.1847 [1251 data with
F2 > 2σ(F2)].
(33) For recent advances and debates in the study of organocatalysis
“on water” and “in the presence of water”, see: (a) Hayashi, Y. Angew.
Chem, Int. Ed. 2006, 45, 8103. (b) Brogan, A. P.; Dickerson, T. J.; Janda,
K. D. Angew. Chem., Int. Ed. 2006, 45, 8100. (c) Gonzalez-Cruz, D.;
Tejedor, D.; de Armas, P.; Morales, E. Q.; Garcia-Tellado, F. Chem.
Commun. 2006, 2798. (d) Mase, N.; Nakai, Y.; Ohara, N.; Yoda, H.; Takabe,
K.; Tanaka, F.; Barbas, C. F., III. J. Am. Chem. Soc. 2006, 128, 734. (e)
Guizzetti, S.; Benaglia, M.; Raimondi, L.; Celentano, G. Org. Lett. 2007,
9, 1247.
(31) 3j is very volatile and is easily sublimated; it is necessary to
evaporate with caution.
8464 J. Org. Chem., Vol. 72, No. 22, 2007

Organocatalytic [4 + 2] Cycloaddition
SCHEME 1. Proposed Mechanism for the Formation of [4 + 2] Adduct via Dienamine Catalyzing Michael Reaction
SCHEME 2. Proposed Mechanism for the Formation of [4 + 2] Adduct via Dienamine-Catalyzed Diels-Alder Reaction
SCHEME 3. Reactions of (E)-3-Formylallyl Acetate and (Z)-3-Formylallyl Acetate
cally. This was probably due to the fact that excess water drives
the reverse reaction in the equilibrium process for the formation
of the dienamine. Another possible mechanism for the formation
of the [4 + 2] adducts could be via the Diels-Alder reaction
(Scheme 2). Unlike the well-documented examples in facilitating
Mannich reactions,34 the trialkylamines rarely accelerate the
Diels-Alder reaction.35
A few experiments have been conducted to shed some light
on the reaction mechanism. Self-dimerization of (Z)-4-acetoxy-
crotonaldehyde36 and (E)-4-acetoxycrotonaldehyde, individually,
gave the same adduct 3g with the same diastereoselectivity
(favoring cis in 80% de) and enantioselectivity (77%) (Scheme
3). Similar results were observed for the cross-[4 + 2]-reaction
of (E)-4-acetoxycrotonaldehyde and (Z)-4-acetoxycrotonalde-
hyde with cinnamaldehyde, affording 3h with >99% de, 63%
ee and >99% de, 66% ee, respectively (Scheme 3).
Typically, with only a few exceptions, the iminium-catalyzed
intermolecular Diels-Alder reaction favored endo-selectivity
due to secondary orbital effects, as depicted in Scheme 2. Diels-
Alder reaction of the dienamine and R,â-unsaturated aldehyde
via the endo-transition state would lead to the formation of the
trans- or cis-diene aldehyde depending on the geometry of the
starting compounds, while the reactions we observed afforded
cis-adducts preferentially (90 to ∼100%).37 The cis-selectivity
and the same enantioselectivity for the formation of adducts 3g
(34) For recent studies on the organocatalytic Mannich reactions with
trialkylamines, see: Fu, A.; List, B.; Thiel, W. J. Org. Chem. 2006, 71,
320.
(35) For the combination of Et3N and Lewis acid (LiCl) leading to
synergistic catalysis of the Diels-Alder reaction of anthrone with meth-
ylcrotonate, see: Harrison, R.; Rickborn, B. Org. Lett. 2002, 4, 1711.
(36) For the preparation, see: Inhoffen, H. H.; Heimann-Trosien, J.;
Muxfeldt, H.; Kramer, H. Chem. Ber. 1957, 90, 187.
(37) (a) For recent developments in the exo-selective binaphthyl-derived
diamine catalysis, see: Kano, T.; Tanaka, Y.; Maruoka, K. Org. Lett. 2006,
8, 2687. (b) For the exo-selective camphor-derived hydrazine catalyst, see:
Lemay, M.; Aumand, L.; Ogilvie, W. W. AdV. Synth. Catal. 2007, 349,
441.
J. Org. Chem, Vol. 72, No. 22, 2007 8465

Hong et al.
SCHEME 4. Total Synthesis of (+)-Palitantin from the [4 + 2] Adduct 3g
and 3h suggested that the reaction likely proceeded through a
dieniminium-enamine mechanism (dienamine and iminium-
ion-activating Michael reaction)38,39 rather than via the di-
enamine Diels-Alder reaction (accelerated by the formation
of the R,â-unsaturated iminium).40
cillium brefeldianum,44 having antifungal activity45 and antibiotic
activity46 as well as being an HIV-1 integrase inhibitor47
(Scheme 4). To date, one racemic48 and a few asymmetric
syntheses of palitantin or its enantiomer have been reported.49
Our approach started from the dihydroxylation of 3g to diol 9
(OsO4, NMO, t-BuOH-THF-H2O; 65%) followed by protec-
tion of the diol (Me2C(OMe)2, acetone, cat. p-TsOH; 85%),
affording acetonide 10. Hydrogenation of the alkene 10 afforded
the aldehydes 11 and 12 in a ratio of 7 to 1. An unusual
isomerization of the cis-acetoxy and acetoxymethyl group
toward the trans-product was observed during the hydrogenation
process. The trans-product arose probably due to the double-
bond isomerization by the allylic hydrogen exchange (via π-allyl
intermediate) that accompanies hydrogenation.50 11 was unstable
during the purification by silica gel flash chromatography, and
some of the 11 gradually isomerized to 12. The process was
facilitated by the addition of 1% Et3N in the eluent (EtOAc/
hexane) during the purification of 11 by silica gel flash
chromatography to give 12. Wittig reaction of aldehyde 12 with
(2E)-hexenyl triphenylphosphonium bromide51 provided dienes
13, along with the Z-isomer (Z)-13 in a ratio of 3:1 and 85%
yield. Hydrolysis of acetate 13 (K2CO3, MeOH; 90%), followed
by protection of 14 (TBSCl, imidazole, DMAP, CH2Cl2; 92%),
afforded 15. Oxidation of alcohol 15 by Dess-Martin perio-
dinane (DMP, CH2Cl2; 90%), followed by deprotection of TBS
ether 16 (HF/pyridine, CH3CN; 88%), provided the acetonide
17.52 Deprotection of acetonide 17 (cat. HCl-MeOH) afforded
Chlorite oxidation of 3j to 5 (NaClO2, t-BuOH, 2-methyl-2-
butene, NaH2PO4, 25 °C; 76%), followed by esterification
(CH2N2 in Et2O, 25 °C), afforded (-)-6 in 75% yield. The
enantiomer, (+)-6, has been used for the synthesis of (-)-
pumiliotoxin C,41 and this result disclosed the absolute stere-
ochemistry of 3j to be sinistrus as depicted in the structures in
Table 3. Chlorite oxidation of (-)-3d to (-)-7 (NaClO2,
t-BuOH, 2-methyl-2-butene, NaH2PO4, 25 °C; 80%), followed
by esterification (EtOH, cat. H2SO4, 25 °C), afforded (-)-8 in
85% yield. The absolute stereochemistry of (-)-8 has been
reported,42 and the absolute stereochemistry of 3d was deter-
mined to be that as shown in the structures in Table 3.
3. Applications of the Formal [4 + 2] Adducts in the Total
Synthesis of (+)-Palitantin. We envisioned diacetate 3g would
be a versatile synthon for other synthetically valuable building
blocks. To demonstrate the synthetic potential of this reaction,
diacetate 3g was transferred to (+)-palitantin, a polyketide
metabolite isolated from the Penicillium palitans43 and Peni-
(38) The mechanism of the L-proline-catalyzed aldol reaction has been
unequivocally established as proceeding through the enamine-iminium
catalysis, see: (a) List, B.; Hoang, L.; Martin, H. J. Proc. Natl. Acad. Sci.
U.S.A. 2004, 101, 5839. (b) Bahmanyar, S.; Houk, K. N. J. Am. Chem.
Soc. 2001, 123, 11273. (c) Hoang, L.; Bahmanyar, S.; Houk, K. N.; List,
B. J. Am. Chem. Soc. 2003, 125, 16. (d) Puchot, C.; Samuel, O.; Dunach,
E.; Zhao, S.; Agami, C.; Kagan, H. B. J. Am. Chem. Soc. 1986, 108, 2325.
(39) Dimerization of R,â-unsaturated ketones has been found to be likely
an enamine-iminium double conjugate addition instead of a one-step
enamine/Diels-Alder reaction. See: (a) Thayumanavan, R.; Dhevalapally,
B.; Sakthivel, K.; Tanaka, F.; Barbas, C. F., III. Tetrahedron Lett. 2002,
43, 3817. (b) Ramachary, D. B.; Chowdari, N. S.; Barbas, C. F., III.
Tetrahedron Lett. 2002, 43, 6743.
(40) The same hypothesis for the self-condensation of other R,â-
unsaturated aldehydes was supported independently by NMR and mass
spectrometry; see ref 16b.
(41) Davies, S. G.; Bhalay, G. Tetrahedron: Asymmetry 1996, 7, 1595-
1596.
(42) (a) Serebryakov, E. P.; Nigmatov, A. G.; Shcherbakov, M. A.;
Struchkova, M. I. Russ. Chem. Bull. Int. Ed. 1998, 47, 82. (b) Nigmatov,
A. G.; Serebryakov, E. P. Russ. Chem. Bull. Int. Ed. 1996, 45, 623.
(43) (a) Birkinshaw, J. H.; Raistvick, H. Biochem. J. 1936, 30, 801. (b)
Birkinshaw, J. H. Biochem. J. 1952, 51, 271. (c) Bowden, K.; Lythgoe, B.;
Marsden, D. J. S. J. Chem. Soc. 1959, 1662.
(45) Yamaji, K.; Fukushi, Y.; Hashidoko, Y.; Yoshida, T.; Tahara, S. J.
Chem. Ecol. 1999, 25, 1643.
(46) Curtis, P. J.; Hemming, H. G.; Smith, W. K. Nature 1951, 167,
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(47) Hong, H.; Neamati, N.; Wang, S.; Nicklaus, M. C.; Mazumder, A.;
Zhao, H.; Burke, T. R.; Pommier, Y., Jr.; Milne, G. W. A. J. Med. Chem.
1997, 40, 930.
(48) (a) Ichihara, A.; Ubukata, M.; Sakamura, S. Tetrahedron 1980, 36,
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(49) (a) Hanessian, S.; Sakito, Y.; Dhanoa, D.; Baptistella, L. Tetrahedron
1989, 45, 6623. (b) Deruyttere, X.; Dumortier, L.; Van der Eycken, J.;
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T.; Fumie Sato, F. Tetrahedron Lett. 1999, 40, 7493. (d) Angelaud, R.;
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(50) For similar examples of isomerization and hydrogenation, see: (a)
Haslinger, E.; Huefner, A. Monatsh. Chem. 1995, 126, 1109-1124. (b)
Snowden, R. L.; Linder, S. M. HelV. Chim. Acta 1988, 71, 1587. (c) Appel,
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8466 J. Org. Chem., Vol. 72, No. 22, 2007

Organocatalytic [4 + 2] Cycloaddition
added L-(-)-proline (6 mg, 0.05 mmol) and (DHQD)2PHAL (39
mg, 0.05 mmol). The solution was stirred for 12 h at -20 °C until
the reaction was completed, monitored by TLC. To the solution
was added H2O (10 mL), and extracted with EtOAc (30 mL × 2).
The organic solution was washed with brine (10 mL), dried over
Na2SO4, and concentrated in vacuo. The residue was purified by
flash column chromatography with 3% EtOAc/hexane (Rf ) 0.50
in 5% EtOAc/hexane) to give 3a (10.2 mg; 75% yield) as a colorless
oil. Method E: To a solution of crotonaldehyde (7 mg, 0.1 mmol)
and 3-methylbut-2-enal (8.4 mg, 0.1 mmol) in CH3CN (1 mL) were
added L-(-)-proline (6 mg, 0.05 mmol) and (DHQ)2PHAL (39 mg,
0.05 mmol). The solution was stirred for 30 h at -20 °C until the
reaction was completed, monitored by TLC. To the solution was
added H2O (10 mL), and extracted with EtOAc (30 mL × 2). The
organic solution was washed with brine (10 mL), dried over Na2-
SO4, and concentrated in vacuo. The residue was purified by flash
column chromatography with 3% EtOAc/hexane (Rf ) 0.50 in 5%
EtOAc/hexane) to give 3a (9.8 mg; 72% yield) as a colorless oil.
Method F: To a solution of crotonaldehyde (35 mg, 0.5 mmol)
and 3-methylbut-2-enal (42 mg, 0.5 mmol) in toluene (1 mL) were
added (S)-(diphenyltrimethylsiloxymethyl)pyrrolidine (XVII) (33
mg, 0.1 mmol) and benzoic acid (12 mg, 0.1 mmol). The solution
was stirred for 96 h at -20 °C until the reaction was completed,
monitored by TLC. To the solution was added H2O (3 mL), and
extracted with EtOAc (10 mL × 2). The organic solution was
washed with brine (10 mL), dried over Na2SO4, and concentrated
in vacuo. The residue was purified by flash column chromatography
with 3% EtOAc/hexane (Rf ) 0.50 in 5% EtOAc/hexane) to give
3a (42.8 mg; 63% yield) as a colorless oil. Method G: To a solution
of crotonaldehyde (35 mg, 0.5 mmol) and 3-methylbut-2-enal (42
mg, 0.5 mmol) in toluene (1 mL) were added (R)-2-{dinaphthalen-
2-yl[(trimethylsilanyl)oxy]methyl}pyrrolidine (XVIII) (42 mg, 0.1
mmol) and benzoic acid (12 mg, 0.1 mmol). The solution was stirred
for 36 h at 0 °C until the reaction was completed, monitored by
TLC. To the solution was added H2O (3 mL), and extracted with
EtOAc (10 mL × 2). The organic solution was washed with brine
(10 mL), dried over Na2SO4, and concentrated in vacuo. The residue
was purified by flash column chromatography with 3% EtOAc/
hexane (Rf ) 0.50 in 5% EtOAc/hexane) to give 3a (42.8 mg; 63%
yield) as a colorless oil. Method I: To a solution of crotonaldehyde
(35 mg, 0.5 mmol) and 3-methylbut-2-enal (42 mg, 0.5 mmol) in
CH3N (2.5 mL) were added (S)-(+)-(2-pyrrolidinylmethyl)pyrro-
lidine (XII) (39 mg, 0.25 mmol) and HOAc (15 mg, 0.25 mmol).
The solution was stirred for 5 h at -20 °C until the reaction was
completed, monitored by TLC. To the solution was added H2O (3
mL), and extracted with EtOAc (10 mL × 2). The organic solution
was washed with brine (10 mL), dried over Na2SO4, and concen-
trated in vacuo. The residue was purified by flash column
chromatography with 3% EtOAc/hexane (Rf ) 0.50 in 5% EtOAc/
hexane) to give 3a (44.2 mg; 65% yield) as a colorless oil. GC-
MS analysis, with chiral column: γ-cyclodextrin trifluoroacetyl 50
m × 0.25 mm, 60-120 °C, 2 °C/min; (S)-3a: tr ) 33.4 min, (R)-
3a: tr ) 35.8 min.
(+)-palitantin in 95% yield. Optical rotation data obtained from
17 and 18 obtained also verified the absolute stereochemistry
of 3g.
Conclusion
We have observed that the use of trialkylamines as cocatalysts
for the formal [4 + 2] reaction has a profound and appreciable
effect on both the yield and reaction rate of the reaction. The
methodology allows the reaction to proceed at low temperature
and yields the products with much higher enantioselectivity than
the products obtained at ambient temperature. Furthermore, some
reactions were achieved with the catalysis of diarylprolinol TMS
ether and afforded high enantioselectivity (>99% ee). The
structure of the [4 + 2] adduct produced from 3-methylbut-2-
enal and (E)-3-(2-nitrophenyl)acrylaldehyde was elucidated
unambiguously from the single-crystal X-ray analysis. The
absolute configuration of some [4 + 2] adducts was determined
by sequential transformation of the adducts to natural com-
pounds and comparison with the literature. Synthetic application
was successful in achieving the total synthesis of (+)-palitantin.
Experimental Section
Typical Procedure, Methods in Table 2, Preparation of 4,6-
Dimethylcyclohexa-1,3-dienecarbaldehyde (3a). Method A: To
a solution of crotonaldehyde (210 mg, 3.0 mmol) and 3-methylbut-
2-enal (252 mg, 3.0 mmol) in CH3CN (15 mL) was added L-(-)-
proline (172 mg, 1.5 mmol) for 48 h at -20 °C until the reaction
was completed, monitored by TLC. To the solution was added H2O
(10 mL), and extracted with EtOAc (30 mL × 2). The organic
solution was washed with brine (10 mL), dried over Na2SO4, and
concentrated in vacuo. The residue was purified by flash column
chromatography with 3% EtOAc/hexane (Rf ) 0.50 in 5% EtOAc/
hexane) to give 3a (334 mg; 82% yield) as a colorless oil. Method
B: To a solution of crotonaldehyde (210 mg, 3.0 mmol) and
3-methylbut-2-enal (252 mg, 3.0 mmol) in CH3CN (15 mL) were
added L-(-)-proline (172 mg, 1.5 mmol) and Et3N (150 mg, 1.5
mmol). The solution was stirred for 20 h at -40 °C until the reaction
was completed, monitored by TLC. To the solution was added H2O
(10 mL), and extracted with EtOAc (30 mL × 2). The organic
solution was washed with brine (10 mL), dried over Na2SO4, and
concentrated in vacuo. The residue was purified by flash column
chromatography with 3% EtOAc/hexane (Rf ) 0.50 in 5% EtOAc/
hexane) to give 3a (330 mg; 81% yield) as a colorless oil. Method
C: To a solution of crotonaldehyde (210 mg, 3.0 mmol) and
3-methylbut-2-enal (252 mg, 3.0 mmol) in CH3CN (15 mL) were
added L-(-)-proline (172 mg, 1.5 mmol) and (-)-sparteine (350
mg, 1.5 mmol). The solution was stirred for 4 h at -20 °C until
the reaction was completed, monitored by TLC. To the solution
was added H2O (10 mL), and extracted with EtOAc (30 mL × 2).
The organic solution was washed with brine (10 mL), dried over
Na2SO4, and concentrated in vacuo. The residue was purified by
flash column chromatography with 3% EtOAc/hexane (Rf ) 0.50
in 5% EtOAc/hexane) to give 3a (334 mg; 82% yield) as a colorless
oil. Method D: To a solution of crotonaldehyde (7 mg, 0.1 mmol)
and 3-methylbut-2-enal (8.4 mg, 0.1 mmol) in CH3CN (1 mL) were
4,6-Dimethylcyclohexa-1,3-dienecarbaldehyde (3a): Rf ) 0.50
in 5% EtOAc/hexane; 41% ee; [R]20 ) -5.7 (c 4.5, CHCl3); IR
D
1
(neat) 2925, 1685, 1255, 805, 738 cm-1; H NMR (CDCl3, 500
MHz) δ 9.39 (s, 1 H), 6.63 (d, J ) 5.5 Hz, 1 H), 5.90-5.92 (m, 1
H), 2.82-2.86 (m, 1 H), 2.46 (dd, J ) 18.0, 9.0 Hz, 1 H), 1.97 (d,
J ) 18.0 Hz, 1 H), 1.87 (s, 3 H), 0.88 (d, J ) 7.0 Hz, 3 H); 13C
NMR (CDCl3, 125 MHz) δ 192.4 (CH), 147.0 (C), 143.0 (CH),
140.1 (C), 118.6 (CH), 36.4 (CH2), 24.4 (CH3), 23.7 (CH), 18.0
(CH3); MS (m/z, relative intensity) 136 (M+, 43), 121 (22), 107
(68), 93 (58), 91 (100), 77 (61); exact mass calcd for C9H12O (M+)
136.0888; found 136.0885.
(51) For preparation and related applications, see: (a) Hanessian, S.;
Sakito, Y.; Dhanoa, D.; Baptistella, L. Tetrahedron 1989, 45, 6623. (b)
Millar, J. G. Tetrahedron Lett. 1997, 38, 7971. (c) Grieco, P. A.; Parker,
D. T. J. Org. Chem. 1988, 3658. (d) Fugami, K.; Miura, K.; Morizawa, Y.;
Oshima, K.; Utimoto, K.; Nozaki, H. Tetrahedron 1989, 45, 3089. (e)
Tsukuda, T.; Umeda, I.; Masubuchi, K.; Shirai, M.; Shimma, N. Chem.
Pharm. Bull. 1993, 41, 1191. (f) Paterson, I.; Nowak, T. Tetrahedron Lett.
1996, 37, 8243. (g) Mehta, G.; Roy, S. Org. Lett. 2004, 6, 2389.
Acetic Acid 2-Formyl-5-methylcyclohexa-2,4-dienylmethyl
ester (3b): Rf 0.50 in 30% EtOAc/hexane; 83% ee; [R]22 ) -43.6
(c 3.3, CHCl3); IR (neat) 1739, 1670, 1577, 1237, 1036, 808, 740
1
(52) The H and 13C spectra of 17 were identical to the spectra in the
1
cm-1; H NMR (CDCl3, 500 MHz) δ 9.45 (s, 1 H), 6.81 (d, J )
literature. See: Angelaud, R.; Babot, O.; Charvat, T.; Landais, Y. J. Org.
Chem. 1999, 64, 9613 and supporting information.
6.0 Hz, 1 H), 5.97-5.94 (m, 1 H), 3.96 (dd, J ) 10.5, 9.5 Hz, 1
J. Org. Chem, Vol. 72, No. 22, 2007 8467

Hong et al.
H), 3.80 (dd, J ) 10.5, 5.5 Hz, 1 H), 3.20-3.10 (m, 1 H), 2.44-
2.38 (m, 1 H), 2.40 (d, J ) 9.0 Hz, 1 H), 2.01 (s, 3H), 1.90 (s, 3
H); 13C NMR (CDCl3, 125 MHz) δ 191.9 (CH), 171.2 (C), 147.6
(C), 145.4 (CH), 134.3 (C), 119.0 (CH), 63.2 (CH2), 31.1 (CH2),
28.6 (CH), 24.1 (CH3), 20.9 (CH3); MS (m/z, relative intensity)
194 (M+, 3), 191 (15), 185 (7), 163 (16), 149 (53), 121 (42), 107
(34); exact mass calcd for C11H14O3 (M+) 194.0943; found
194.0943.
4-Methyl-6-(2-nitrophenyl)cyclohexa-1,3-dienecarbalde-
hyde (3c): Rf 0.50 in 30% EtOAc/hexane; 93% ee; [R]22D ) -195.5
(c 5.3, CHCl3); IR (neat) 12960, 1670, 1581, 1523, 1352, 1261,
1197, 804 cm-1; 1H NMR (CDCl3, 500 MHz) δ 9.44 (s, 1 H), 7.86-
7.84 (m, 1 H), 7.43-7.40 (m, 1 H), 7.33-7.31 (m, 1 H), 7.30-
7.24 (m, 1 H), 7.09-7.07 (m, 1 H), 6.08 (br s, 1 H), 4.60 (d, J )
11.5 Hz, 1 H), 3.01-2.94 (m, 1 H), 2.49 (d, J ) 19.0 Hz, 1 H),
1.84(s, 3 H); 13C NMR (CDCl3, 125 MHz) δ 191.4 (CH), 148.7
(C), 147.5 (C), 145.2 (CH), 137.2 (C), 135.8 (C), 132.8 (CH), 128.9
(CH), 127.4 (CH), 124.8 (CH), 118.9 (CH), 36.7 (CH2), 29.5 (CH),
24.1 (CH3); MS (m/z, relative intensity) 243 (M+, 1), 225 (1), 195
(100), 180 (48), 165 (48), 152 (39); exact mass calcd for C14H13-
NO3 (M+) 243.0895; found 243.0896.
CHCl3); IR (neat) 2825, 1739, 1678, 1577, 1372, 1233, 1178, 1038,
790, 755 cm-1; 1H NMR (CDCl3, 500 MHz) δ 9.55 (s, 1 H), 6.95
(d, J ) 5.0 Hz, 1 H), 6.46 (dd, J ) 5.0, 9.5 Hz, 1 H), 6.35 (dd, J
) 6.0, 9.5 Hz, 1 H), 5.39 (d, J ) 6.0 Hz, 1 H), 3.98 (dd, J ) 11.0,
5.0 Hz, 1 H), 3.83 (dd, J ) 11.0, 9.0 Hz, 1 H), 3.34 (dd, J ) 9.0,
5.0 Hz, 1 H), 2.01 (s, 3 H), 1.99 (s, 3 H); 13C NMR (CDCl3, 125
MHz) δ 191.8 (CH), 170.8 (C), 169.9 (C), 141.0 (CH), 136.6 (C),
130.1 (CH), 126.7 (CH), 65.2 (CH), 61.5 (CH2), 35.2 (CH), 20.9
(CH3), 20.8 (CH3); MS (m/z, relative intensity) 238 (M+, 0.8), 178
(4), 165 (11), 136 (10), 107 (42); exact mass calcd for C12H14O5
(M+) 238.0841; found 238.0843.
Acetic Acid 5-Formyl-6-phenylcyclohexa-2,4-dienyl ester
(3h): Rf 0.60 in 30% EtOAc/hexane; 77% ee; [R]22 +270.9 (c
D
6.7, CHCl3); IR (neat) 2959, 1735, 1678, 1370, 1238, 1015, 800,
1
700 cm-1; H NMR (CDCl3, 500 MHz) δ 9.59 (s, 1 H), 7.26-
7.18 (m, 5 H), 7.10-7.08 (m, 1 H), 6.60 (dd, J ) 9.5, 5.5 Hz, 1
H), 6.27 (dd, J ) 9.5, 5.5 Hz, 1 H), 5.40 (d, J ) 5.5 Hz, 1 H), 4.21
(s, 1H), 2.04 (s, 3 H); 13C NMR (CDCl3, 125 MHz) δ 191.9 (CH),
170.0 (C), 139.7 (CH), 139.5 (C), 139.6 (C), 129.7 (CH), 128.7
(two CH), 127.7 (CH), 127.55 (CH), 127.46 (two CH), 70.0 (CH),
41.2 (CH), 21.1 (CH3); MS (m/z, relative intensity) 242 (M+, 7),
213 (8), 200 (37), 181 (100), 171 (50), 380 (8), 365 (28); exact
mass calcd for C15H14O3 (M+) 242.0943; found 242.0947.
4-Methyl-6-phenylcyclohexa-1,3-dienecarbaldehyde (3d): Rf
0.70 in 10% EtOAc/hexane; 95% ee; [R]22 ) -230.1 (c 6.0,
D
CHCl3); IR (neat) 2924, 1670, 1577, 1195, 792, 755, 699 cm-1
;
1-Phenyl-1,5,6,7,8,8a-hexahydronaphthalene-2-carbalde-
1H NMR (CDCl3, 500 MHz) δ 9.49 (s, 1 H), 7.17-7.24 (m, 4 H),
7.14-7.16 (m, 1 H), 6.90 (d, J ) 5.5 Hz, 1 H), 6.02-6.05 (m, 1
H), 4.06 (d, J ) 9.5 Hz, 1 H), 2.80-2.87 (m, 1 H), 2.44 (dd, J )
18.5, 0.5 Hz, 1 H), 1.86 (s, 3 H); 13C NMR (CDCl3, 125 MHz) δ
191.9 (CH), 147.1 (C), 144.0 (CH), 143.0 (C), 137.1 (C), 128.2
(two CH), 126.8 (two CH), 126.5 (CH), 119.3 (CH), 36.8 (CH2),
34.0 (CH), 24.0 (CH3); MS (m/z, relative intensity) 198 (M+, 72),
183 (47), 169 (100), 154 (62), 91 (83), 77 (59); exact mass calcd
for C14H14O (M+) 198.1045; found 198.1042.
hyde (3i): Rf 0.6 in 17% EtOAc/hexane; 98% ee; [R]22D ) -475.9
(c 9.0, CHCl3); IR (neat) 2929, 2854, 1671, 1576, 1200, 699 cm-1
;
1H NMR (CDCl3, 500 MHz) δ 9.43 (s, 1 H), 7.25-7.22 (m, 4 H),
7.18-7.14 (m, 1 H), 6.81 (d, J ) 6.0 Hz, 1 H), 5.97 (d, J ) 5.5
Hz, 1 H), 3.62 (d, J ) 1.5 Hz, 1 H), 2.45 (d, J ) 11.5 Hz, 1 H),
2.39-2.37 (m, 1 H), 2.14-2.09 (m, 1 H), 1.99-1.97 (m, 1 H),
1.82-1.77 (m, 2 H), 1.60-1.25 (m, 3 H); 13C NMR (CDCl3, 125
MHz) δ 192.6 (CH), 157.2 (C), 145.5 (C), 142.5 (CH), 136.5 (C),
128.5 (two CH), 126.9 (two CH), 126.5 (CH), 114.8 (CH), 49.0
(CH), 42.1 (CH), 38.1 (CH2), 36.9 (CH2), 31.7 (CH2), 27.1 (CH2);
MS (m/z, relative intensity) 238 (M+, 70), 209 (84), 167 (80), 115
(28), 91 (100); exact mass calcd for C17H18O (M+) 238.1358; found
238.1351.
6-Ethyl-4-methylcyclohexa-1,3-dienecarbaldehyde (3e): Rf
0.50 in 5% EtOAc/hexane; 94% ee; [R]22D ) -41.7 (c 1.0, CHCl3);
IR (neat) 3019, 2925, 2858, 1688, 1459, 1216, 759 cm-1; 1H NMR
(CDCl3, 500 MHz) δ 9.43 (s, 1 H), 6.68 (d, J ) 5.5 Hz, 1 H),
5.92-5.90 (m, 1 H), 2.67-2.73 (m, 1 H), 2.37-2.43 (m, 1 H),
2.18 (d, J ) 18.0 Hz, 1 H), 1.89 (s, 3 H), 1.20-1.40 (m, 2 H),
0.82 (t, J ) 7.5 Hz, 3 H); 13C NMR (CDCl3, 125 MHz) δ 192.7
(CH), 147.5 (C), 143.9 (CH), 139.4 (C), 119.0 (CH), 33.2 (CH2),
30.2 (CH), 24.7 (CH2), 24.3 (CH3), 11.0 (CH3); MS (m/z, relative
intensity) 150 (M+, 22), 121 (23), 93 (100), 77 (58); exact mass
calcd for C10H14O (M+) 150.1045; found 150.1042.
6-Isopropyl-4-methylcyclohexa-1,3-dienecarbaldehyde (3f): Rf
0.50 in 5% EtOAc/hexane; 98% ee; [R]22D ) -27.1 (c 1.3, CHCl3);
IR (neat) 2924, 1671, 1577, 1456, 1200, 799, 750 cm-1; 1H NMR
(CDCl3, 500 MHz) δ 9.44 (s, 1 H), 6.73 (d, J ) 5.5 Hz, 1 H),
5.85-5.87 (m, 1 H), 2.63 (dd, J ) 9.5, 6.0 Hz, 1 H), 2.35 (dd, J
) 9.5, 18.0 Hz, 1 H), 2.25 (d, J ) 18.0 Hz, 1 H), 1.86 (s, 3 H),
1.72-1.77 (m, 1 H), 0.82 (d, J ) 7.0 Hz, 3 H), 0.76 (d, J ) 7.0
Hz, 3 H); 13C NMR (CDCl3, 125 MHz) δ 193.0 (CH), 148.3 (C),
144.9 (CH), 138.2 (C), 119.2 (CH), 34.7 (CH), 30.9 (CH2), 30.2
(CH), 23.9 (CH3), 20.3 (CH3), 18.7 (CH3); MS (m/z, relative
intensity) 164 (M+, 10), 121 (31), 120 (19), 119 (36), 107 (14), 93
(100), 77 (53); exact mass calcd for C11H16O (M+) 164.1201; found
164.1199.
6-Methylcyclohexa-1,3-dienecarbaldehyde (3j): Rf 0.50 in 5%
EtOAc/hexane; 10% ee; [R]22 -12.1 (c 2.98, CHCl3); IR (neat)
2924, 2854, 1687, 1458, 1377 cm-1; 1H NMR (C6D6, 500 MHz) δ
9.31 (s, 1 H), 6.12-6.08 (m, 1 H), 5.75-5.71 (m, 2 H), 2.81-
2.76 (m, 1 H), 2.20-2.00 (m, 1 H), 1.80-1.70 (m, 1 H), 0.85 (d,
J ) 7.0 Hz, 3 H); 13C NMR (C6D6, 125 MHz) δ 191.90 (CH),
42.74 (C), 140.4 (CH) 134.4 (CH), 123.3 (CH), 30.6 (CH2), 23.2
(CH), 17.8 (CH3); MS (m/z, relative intensity) 122 (M+, 56), 107
(21), 93 (83), 91 (59), 79 (74), 77 (100); exact mass calcd for
C8H10O (M+) 122.0732; found 122.0730.
6-Methylcyclohexa-1,3-dienecarboxylic acid (5). To a solution
of 3j (366 mg, 3.0 mmol) and 2-methyl-2-butene (1 mL, 9.4 mmol)
in t-BuOH (7.5 mL) was added a freshly prepared solution of
sodium chlorite (140 mg, 1.55 mmol) in 20% w/w aqueous NaH2-
PO4 (2.4 g in 12 mL of H2O) at room temperature, and the resulting
solution was stirred for 8 h. The mixture was diluted with ethyl
acetate (30 mL) and washed with water (4 mL). The aqueous phase
was extracted with ethyl acetate (30 mL), and the combined organic
layers were dried over Na2SO4 and concentrated in vacuo to give
the crude product. The residue was purified by flash column
chromatography with 20% EtOAc/hexane (Rf ) 0.50 in 30%
EtOAc/hexane) to give acid 5 as a colorless oil (315 mg, 76%
5-Methyl-2-(2-methylpropenyl)hexa-2,4-dienal (4): Rf 0.60 in
17% EtOAc/hexane; IR (neat) 2925, 2860, 1678, 1628, 1444, 1379,
1227, 1173, 1134, 850 cm-1; 1H NMR (CDCl3, 500 MHz) δ 9.45
(s, 1 H), 7.09 (d, J ) 12.0 Hz, 1 H), 6.11 (d, J ) 12.0 Hz, 1 H),
5.74 (br s, 1 H), 1.95 (s, 3 H), 1.93 (s, 3 H), 1.88 (s, 3 H), 1.49 (s,
3 H); 13C NMR (CDCl3, 125 MHz) δ 194.6 (CH), 148.2 (C), 145.0
(CH), 140.0 (C), 137.0 (C), 122.9 (CH), 116.1 (CH), 27.2 (CH3),
25.9 (CH3), 20.4 (CH3), 19.2 (CH3); MS (m/z, relative intensity)
165 (M+ + 1, 44), 152 (23), 135 (23), 105 (36), 69 (64), 57 (100);
exact mass calcd for C11H16O (M+) 164.1201; found 164.1209.
Acetic Acid 6-Acetoxy-2-formylcyclohexa-2,4-dienylmethyl
yield): 10% ee; [R]20 ) -10.2 (c 4.3, CHCl3); IR (neat) 3400-
D
3000, 2962, 1680, 1572, 1421, 1273, 700 cm-1; 1H NMR (CDCl3,
500 MHz) δ 7.08 (d, J ) 3.5 Hz, 1 H), 6.07-6.01 (m, 2 H), 2.80-
2.72 (m, 1 H), 2.58-2.44 (m, 1 H), 2.22-2.16 (m, 1 H), 0.97 (d,
J ) 6.5 Hz, 3 H); 13C NMR (CDCl3, 125 MHz) δ 172.7 (C), 134.1
(CH), 132.8 (CH), 131.6 (C), 123.0 (CH), 30.7 (CH2), 24.9 (CH),
17.6 (CH3); MS (m/z, relative intensity) 138 (M+, 30),123 (10),
105 (9), 93 (100), 91 (36), 79 (45), 77 (67); exact mass calcd for
C8H10O2 (M+) 138.0681; found 138.0681.
ester (3g): Rf 0.50 in 50% EtOAc/hexane; [R]20 +207.7 (c 2.5,
D
8468 J. Org. Chem., Vol. 72, No. 22, 2007

Organocatalytic [4 + 2] Cycloaddition
6-Methylcyclohexa-1,3-dienecarboxylic acid methyl ester (6).
To a solution of 5 (276 mg, 2.0 mmol) in CH2Cl2 (5 mL) was
added a solution of CH2N2-Et2O. The solution was stirred for 30
min and concentrated in vacuo to give the crude product. The
residue was purified by flash column chromatography with 3%
EtOAc/hexane (Rf ) 0.30 in 3% EtOAc/hexane) to give ester 6 as
a colorless oil (273 mg, 75% yield): 7% ee; [R]22D ) -6.7 (c 1.32,
Acetic Acid 2-Acetoxymethyl-3-formyl-5,6-dihydroxycyclo-
hex-3-enyl ester (9). To a solution of 3g (286 mg, 1.2 mmol) in
THF/t-BuOH-H2O (10:30:5 mL) was added N-methylmorpholine
N-oxide (NMO, 351 mg, 3 mmol), and the solution was stirred for
10 min at ambient temperature. OsO4 (0.1 mL, 2.5 wt % in t-BuOH)
was added, and stirring was maintained at ambient temperature for
ca. 36 h. The reaction was quenched by the addition of sodium
hydrosulfite (0.2 g), Florisil (2.0 g), and H2O (5 mL). The mixture
was stirred for 30 min, washed with acetone (30 mL), filtered
through filter paper, and extracted with EtOAc (20 mL × 2). The
combined organic layers were washed with brine (15 mL), dried
over Na2SO4, and concentrated in vacuo. The residue was purified
by flash column chromatography with 85% EtOAc/hexane (Rf 0.28
in 80% EtOAc/hexane) to give 9 (212 mg; 65% yield) as a pale
yellow oil: [R]22D ) -28.1 (c 13.3, CHCl3); IR (neat) 3550-3100,
2920, 1735, 1686, 1375, 1247, 1039 cm-1; 1H NMR (CDCl3, 500
MHz) δ 9.48 (s, 1 H), 6.79 (br s, 1 H), 5.32 (dd, J ) 5.5, 4.0 Hz,
1 H), 4.55-4.50 (m, 2 H), 4.20 (dd, J ) 5.5, 4.0 Hz, 1 H), 3.98
(br s, 1 H), 3.29 (br s, 1 H), 2.97 (br s, 1 H), 2.90 (br s, 1 H), 2.06
(s, 6 H); 13C NMR (CDCl3, 125 MHz) δ 192.8 (CH), 171.5 (C),
170.6 (C), 149.4 (CH), 138.4 (C), 69.9 (CH), 68.6 (CH), 66.0 (CH),
62.2 (CH2), 37.9 (CH), 21.0 (CH3), 20.9 (CH3); MS (m/z, relative
intensity) 272 (M+, 16), 229 (26), 133 (20), 119 (46), 57 (100);
exact mass calcd for C12H16O7 (M+) 272.0896; found 272.0893.
Acetic Acid 5-Acetoxymethyl-6-formyl-2,2-dimethyl-3a,4,5,-
7a-tetrahydrobenzo[1,3]dioxol-4-yl ester (10). To a solution of
9 (100 mg, 0.36 mmol) in dry acetone (7 mL) was added
2,2-dimethoxypropane (114 mg, 1.1 mmol). The resulting solution
was stirred for 5 min at ambient temperature, p-TsOH (28 mg, 0.15
mmol) was added, and stirring was maintained at ambient temper-
ature for 12 h. The reaction was quenched with aq NaHCO3 (15
mL), extracted with EtOAc (30 mL × 2), washed with brine (30
mL), dried over Na2SO4, and concentrated in vacuo. The crude
residue was purified by flash column chromatography with 40%
EtOAc/hexane (Rf 0.83 in 80% EtOAc/hexane) to give 10 (96 mg,
1
CHCl3);53 IR (neat) 2926, 1712, 1444, 1257, 1022, 771 cm-1; H
NMR (CDCl3, 500 MHz) δ 6.93 (s, 1 H), 6.05-5.95 (m, 2 H),
3.73 (s, 3 H), 2.80-2.72 (m, 1 H), 2.60-2.40 (m, 1 H), 2.15 (d, J
) 17.0 Hz, 1 H), 0.96 (d, J ) 7.0 Hz, 3 H); 13C NMR (CDCl3, 125
MHz) δ 167.7 (C), 132.3 (C), 131.9 (CH), 131.5 (CH), 123.0 (CH),
51.5 (CH3), 30.6 (CH2), 25.3 (CH), 17.7 (CH3);54 MS (m/z, relative
intensity) 152 (M+, 20), 137 (8), 121 (16), 105 (8), 93 (100); exact
mass calcd for C9H12O2 (M+) 152.0837; found 152.0835.
4-Methyl-6-phenylcyclohexa-1,3-dienecarboxylic acid (7). To
a solution of 3d (47.5 mg, 0.24 mmol, 56% ee) and 2-methyl-2-
butene (3 mL) in t-BuOH (12 mL) was added a freshly prepared
solution of sodium chlorite (140 mg, 1.55 mmol) in 20% w/w
aqueous NaH2PO4 (2.4 g in 12 mL of H2O) at room temperature,
and the resulting solution was stirred for 5 h. The mixture was
diluted with ethyl acetate (30 mL) and washed with water (4 mL).
The aqueous phase was extracted with ethyl acetate (30 mL), and
the combined organic layers were dried over Na2SO4 and concen-
trated in vacuo to give the crude product. The residue was purified
by flash column chromatography with 20% EtOAc/hexane (Rf )
0.3 in 20% EtOAc/hexane) to give acid 7 as a white solid (41 mg,
80% yield): mp 138-140 °C; [R]25 ) -146.6 (c 1.5, MeOH);
D
mp 138-140 °C; IR (neat) 3600, 2922, 1668, 1576, 1417, 1288,
1
1238, 698 cm-1; H NMR (CDCl3, 500 MHz) δ 7.35-7.10 (m, 6
H), 5.90 (br s, 1 H), 3.93 (d, J ) 10.5 Hz, 1 H), 2.90-2.80 (m, 1
H), 2.34 (d, J ) 17.5 Hz, 1 H), 1.77 (s, 3 H); 13C NMR (CDCl3,
125 MHz) δ 171.9 (C), 144.1 (C), 143.2 (C), 137.0 (CH), 128.4
(two CH), 127.0 (two CH), 126.5 (CH), 125.8 (C), 119.1 (CH),
37.6 (CH2), 36.3 (CH), 23.9 (CH3); MS (m/z, relative intensity)
214 (M+, 82), 181 (36), 169 (100), 154 (22); exact mass calcd for
C14H14O2 (M+) 214.0994; found 214.0994.
85% yield) as a colorless oil: [R]22 ) +15.1 (c 13, CHCl3); IR
D
1
(neat) 2921, 2850, 1743, 1697, 1458, 1225, 741 cm-1; H NMR
(CDCl3, 500 MHz) δ 9.54 (s, 1 H), 6.77 (d, J ) 3.5 Hz, 1 H), 5.61
(s, 1 H), 4.83 (dd, J ) 3.5, 4.0 Hz, 1 H), 4.39 (br s, 1 H), 4.24-
4.20 (m, 2 H), 3.09 (dd, J ) 7.0 Hz, 1 H), 2.09 (s, 3 H), 2.05 (s,
3 H), 1.43 (s, 3 H), 1.41 (s, 3 H); 13C NMR (CDCl3, 125 MHz) δ
192.9 (CH), 170.7 (C), 169.5 (C), 146.0 (CH), 138.0 (C), 110.6
(C), 73.3 (CH), 70.7 (CH), 67.7 (CH), 62.4 (CH2), 35.8 (CH), 27.5
(CH3), 25.6 (CH3), 20.93 (CH3), 20.88 (CH3); MS (m/z, relative
intensity) 297 (M+ - Me, 54), 297 (54), 177 (19), 165 (32), 135
(100); exact mass calcd for C15H20O7 (M+) 312.1209; found
312.1211.
4-Methyl-6-phenylcyclohexa-1,3-dienecarboxylic acid ethyl
ester (8). A solution of 7 (21 mg, 0.1 mmol), benzene (0.35 mL),
and concd H2SO4 (0.1 mL) in ethanol (5 mL) was heated to reflux
for 24 h. The solution was cooled to room temperature, saturated
aqueous NaHCO3 solution (10 mL) was added and stirred for 10
min. The solution was diluted with EtOAc (15 mL × 2) and washed
with brine. The combined organic layers were dried over Na2SO4
and concentrated in vacuo to give the crude product. The residue
was purified by flash column chromatography with 5% EtOAc/
hexane (Rf ) 0.3 in 5% EtOAc/hexane) to give ester 8 as a yellow
oil (20 mg, 85% yield): Rf 0.30 in 5% EtOAc.hexane; 56% ee;
[R]22D ) -90.7 (c 13, C6H6);55 IR (neat) 2927, 1705, 1589, 1267,
Acetic Acid 4-Acetoxy-6-formyl-2,2-dimethylhexahydrobenzo-
[1,3]dioxol-5-ylmethyl ester (11 and 12). A suspension of 10 (235
mg, 1.5 mmol) and Pd-C (20 mg, 10%) in EtOAc (30 mL) was
stirred at room temperature under hydrogen (1 atm) for 6 h. The
mixture was filtered through Celite, and the filtrate was concentrated
in vacuo to give the crude product. The two isomers of the product
1
1076, 760, 698 cm-1; H NMR (CDCl3, 500 MHz) δ 7.25-7.10
(m, 6 H), 5.89 (br s, 1 H), 4.14-4.06 (m, 2 H), 3.98 (d, J ) 10.5
Hz, 1 H), 2.90-2.83 (m, 1 H), 2.34 (d, J ) 17.5 Hz, 1 H), 1.77 (s,
3 H), 1.19 (t, J ) 7.0 Hz, 3 H); 13C NMR (CDCl3, 125 MHz) δ
167.4 (C), 144.0 (C), 142.8 (C), 134.8(CH), 128.6 (two CH), 127.33
(two CH), 127.26 (C), 126.7 (CH), 119.2 (CH), 60.4 (CH2), 37.7
(CH2), 37.1 (CH), 24.0 (CH3), 14.4 (CH3);54 MS (m/z, relative
intensity) 242 (M+, 100), 227 (22), 169 (84), 154 (36), 91 (66), 77
(79); exact mass calcd for C16H18O2 (M+) 242.1307; found
242.1309.
1
12 to 11 were shown to be 1:7, analyzed by H NMR analysis.
The residue was purified by flash column chromatography with
45% EtOAc/hexane (12: Rf ) 0.51; 11: Rf ) 0.39 in 50% EtOAc/
hexane) to give 12 and 11 as the colorless oils. Indeed, isomerization
of 11 to 12 was occurred gradually at ambient temperature and
that can be accelerated by the addition of Et3N and silica gel. In
practice, the crude residue was purified by silica gel column
chromatography with 1:45:54 Et3N/EtOAc/hexane (12: Rf ) 0.51;
11: Rf ) 0.39 in 50% EtOAc/hexane) over 2 h to give 12 (153
(53) For [R]23 ) +95.8 (c 1.17, CHCl3) for 100% ee of the R
D
mg, 65%) as a colorless oil: [R]22 ) -17.5 (c 6.9, CH3OH); IR
enantiomer, see: Davies, S. G.; Bhalay, G. Tetrahedron: Asymmetry 1996,
D
1
(neat) 2925, 1742, 1372, 1225, 1051 cm-1; H NMR (C6D6, 500
7, 1595.
(54) Moorhoff, C. M. Synlett 1997, 126.
MHz) δ 9.20 (s, 1 H), 5.36-5.25 (m, 1 H), 4.20-4.14 (m, 1 H),
4.04-4.00 (m, 1 H), 3.95-3.90 (m, 1 H), 3.80-3.70 (m, 1 H),
1.95-1.85 (m, 1 H), 1.82-1.75 (m, 1 H), 1.71 (s, 3 H), 1.65 (s, 3
H), 1.52 (s, 3 H), 1.40-1.20 (m, 2 H), 1.16 (s, 3 H); 13C NMR
(C6D6, 125 MHz) δ 200.5 (CH), 170.0 (C), 169.3 (C), 109.2 (C),
(55) (a) For [R]20 ) -14.5 (c 1.0, C6H6) for 7.8% ee of the
D
R-enantiomer, see: Serebryakov, E. P.; Nigmatov, A. G.; Shcherbakov,
M. A.; Struchkova, M. I. Russ. Chem. Bull. Int. Ed. 1998, 47, 82. (b) For
[R]20D ) -52 (c 1.0, C6H6) for 28% ee of the R-enantiomer, see: Nigmatov,
A. G.; Serebryakov, E. P. Russ. Chem. Bull. Int. Ed. 1996, 45, 623.
J. Org. Chem, Vol. 72, No. 22, 2007 8469

Hong et al.
76.9 (CH), 72.4 (CH), 70.6 (CH), 62.2 (CH2), 45.0 (CH), 38.2 (CH),
27.4 (CH3), 25.8 (CH2), 25.5 (CH3), 20.4 (CH3), 20.3 (CH3); MS
(m/z, relative intensity) 315 (M+ + 1, 45), 256 (38), 213 (41), 171
(32), 153 (100); exact mass calcd for C15H22O7 (M+) 314.1366;
6-Hepta-1,3-dienyl-5-hydroxymethyl-2,2-dimethylhexahydro-
benzo[1,3]dioxol-4-ol (14). To a solution of 13 (75 mg, 0.19 mmol)
in CH3OH (15 mL) was added K2CO3 (22 mg, 0.16 mmol) at room
temperature. The solution was stirred for 3 h at ambient temperature
until the reaction completed, monitored by TLC. The reaction was
quenched by the addition of H2O (8 mL); the solution was extracted
with EtOAc (20 mL × 2), dried over Na2SO4, and concentrated in
vacuo to give the crude product. The residue was purified by flash
column chromatography with 3% EtOAc/hexane (Rf ) 0.25 in 50%
EtOAc/hexane) to give 14 as a colorless oil (104 mg, 90% yield):
mp 104-105 °C; [R]22D ) -52.8 (c 4.6, CHCl3); IR (neat) 3600-
3200, 2927, 2862, 1728, 1668, 1460, 1379, 1244, 1221, 1070, 989
found 314.1371. For 11: [R]22 ) -27.8 (c 11.5, CH3OH); IR
D
(neat) 2925, 2853, 1742, 1372, 1225, 1051 cm-1; 1H NMR (CDCl3,
500 MHz) δ 9.77 (s, 1 H), 5.50-5.42 (m, 1 H), 4.41-4.30 (m, 2
H), 4.25-4.20 (m, 1 H), 4.03-4.00 (m, 1 H), 2.78 (br s, 1 H),
2.45-2.40 (m, 1 H), 2.20-2.00 (m, 2 H), 2.12 (s, 3 H), 2.03 (s, 3
H), 1.48 (s, 3 H), 1.34 (s, 3 H); 13C NMR (CDCl3, 125 MHz) δ
200.9 (CH), 170.5 (C), 170.0 (C), 109.9 (C), 77.9 (CH), 73.3 (CH),
70.9 (CH), 62.5 (CH2), 45.9 (CH), 39.6 (CH), 27.5 (CH3), 26.43
(CH2), 26.38 (CH3), 21.0 (CH3), 20.8 (CH3); MS (m/z, relative
intensity) 315 (M+ + 1, 5), 299 (100), 287 (13), 197 (30), 137
(71); exact mass calcd for C15H22O7 (M+) 314.1366; found
314.1371.
1
cm-1; H NMR (CDCl3, 500 MHz) δ 6.05-5.92 (m, 2 H), 5.62-
5.55 (m, 1 H), 5.28 (dd, J ) 14.5, 9.5 Hz, 1 H), 4.27 (br s, 1 H),
3.90-3.80 (m, 2 H), 3.69 (dd, J ) 10.0, 8.5 Hz, 1 H), 3.58 (dd, J
) 7.5, 7.0 Hz, 1 H), 3.43 (br s, 1 OH), 2.93 (br s, 1 OH), 2.25-
2.15 (m, 1 H), 2.10-1.95 (m, 3 H), 1.63-1.55 (m, 1 H), 1.50 (s,
3 H), 1.42-1.30 (m, 3 H), 1.34 (s, 3 H), 0.87 (t, J ) 7.0 Hz, 3 H);
13C NMR (CDCl3, 125 MHz) δ 134.1 (CH), 132.5 (CH), 131.9
(CH), 129.7 (CH), 108.9 (C), 81.2 (CH), 76.3 (CH), 73.6 (CH),
64.1 (CH2), 45.9 (CH), 36.4 (CH), 34.6 (CH2), 33.4 (CH2), 28.4
(CH3), 26.2 (CH3), 22.4 (CH2), 13.7 (CH3); MS (m/z, relative
intensity) 296 (M+, 1), 247 (10), 231 (34), 230 (20), 215 (14), 181
(12), 131 (19), 117 (100), 69 (33); exact mass calcd for C17H28O4
(M+) 296.1988; found 296.1988.
Acetic Acid 5-Acetoxymethyl-6-hepta-1,3-dienyl-2,2-dimethyl-
hexahydrobenzo[1,3]dioxol-4-yl ester (13). To a solution of (2E)-
hexenyltriphenylphosphonium bromide (74 mg, 0.17 mmol) in THF
(15 mL) was added a solution of n-BuLi (1.6 M in hexane, 0.1
mL, 0.17 mmol) at -78 °C. The solution was stirred at
-78 °C for 30 min, followed by the addition of a solution of 12
(41 mg, 0.13 mmol) in THF (5 mL) and was warmed up to room
temperature over 2 h. The reaction was quenched by the addition
of saturated aqueous NH4Cl (10 mL). The solution was extracted
with EtOAc (20 mL × 2). The combined organic layers were
washed with brine (10 mL), dried over Na2SO4, and concentrated
in vacuo. The residue was purified by flash column chromatography
with 20% EtOAc/hexane (Rf 0.83 in 50% EtOAc/n-hexane) to give
the mixture of 13 and (Z)-13 (42 mg; 85% yield) as a pale yellow
oil, in a ratio of 3:1. The isomers were separated by HPLC (Rainin
Solvent Delivery System Dynamax SD-200, detector: Dynamax
UV-C, Spherisorb Phase Sep S10 W, 25 cm × 10 cm, semi-prep
column, 25 cm × 10 mm, rate: 5 mL/min; for 13, Rt 18.19; for
(Z)-13, Rt 20.11). For 13: [R]22D ) -51.0 (c 14, CHCl3); IR (neat)
2925, 2856, 1745, 1462, 1377, 1240, 1049 cm-1; 1H NMR (CDCl3,
500 MHz) δ 6.06 (dd, J ) 10.5, 15.0 Hz, 1H), 5.95 (dd, J ) 14.0,
10.5 Hz, 1 H), 5.68-5.55 (m, 1 H), 5.27 (dd, J ) 15.0, 9.5 Hz, 1
H), 5.13 (dd, J ) 10.0, 8.5 Hz, 1 H), 4.30 (br s, 1 H), 4.18 (d, J )
11.5 Hz, 1 H), 3.99-3.96 (m, 1 H), 3.81 (d, J ) 11.5 Hz, 1 H),
2.58-2.41 (m, 1 H), 2.13 (d, J ) 15.5 Hz, 1 H), 2.04 (s, 3 H),
2.00 (s, 3 H), 2.04-2.00 (m, 2 H), 1.63-1.56 (m, 1 H), 1.55 (s, 3
H), 1.49 (dd, J ) 10.0, 11.0 Hz, 1 H), 1.41-1.36 (m, 2 H), 1.34
(s, 3 H), 0.88 (t, J ) 7.5 Hz, 3 H); 13C NMR (CDCl3, 125 MHz)
δ 171.0 (C), 170.0 (C), 134.4 (CH), 132.4 (CH), 131.5 (CH), 129.7
(CH), 109.2 (C), 78.2 (CH), 73.6 (CH), 72.3 (CH), 61.2 (CH2),
43.2 (CH), 36.0 (CH), 34.7 (CH2), 33.0 (CH2), 27.7 (CH3), 26.1
(CH3), 22.4 (CH2), 21.0 (CH3), 20.8 (CH3), 13.7 (CH3); MS (m/z,
relative intensity) 380 (M+, 1), 365 (28), 320 (27), 260 (19), 244
(20), 219 (18), 202 (100), 173 (79), 159 (55); exact mass calcd for
C21H32O6 (M+) 380.2199; found 380.2200.
5-(tert-Butyldimethylsilanyloxymethyl)-6-hepta-1,3-dienyl-2,2-
dimethylhexahydrobenzo[1,3]dioxol-4-ol (15). To a solution of
14 (20 mg, 0.07 mmol), imidazole (5 mg, 0.08 mmol), and
4-dimethylaminopyridine (1 mg, 0.01 mmol) in CH2Cl2 (10 mL)
was added tert-butyldimethylsilyl chloride (13 mg, 0.08 mmol) at
room temperature. The solution was stirred for 2 h at room
temperature. The reaction was quenched by the addition of H2O (5
mL); the solution was extracted with EtOAc (15 mL × 2), dried
over Na2SO4, and concentrated in vacuo to give the crude product.
The residue was purified by flash column chromatography with
20% EtOAc/hexane (Rf ) 0.26 in 20% EtOAc/hexane) to give
acetate 15 as a colorless oil (26 mg, 92% yield): [R]22 ) -37.2
D
(c 7.7, CHCl3); IR (neat) 3465, 2962, 2929, 2862, 1466, 1379, 1246,
1
1092, 839, 775 cm-1; H NMR (CDCl3, 500 MHz) δ 5.90-6.05
(m, 2 H), 5.52-5.60 (m, 1 H), 5.20-5.30 (m, 1 H), 4.26 (br s, 1
H), 3.82-3.88 (m, 1 H), 3.75 (dd, J ) 10.0, 8.5 Hz, 1H), 3.53 (dd,
J ) 10.0, 6.0 Hz, 1 H), 3.48 (br s, 1 OH), 2.20-2.30 (m, 1 H),
1.20-1.30 (m, 1 H), 1.34 (s, 3 H), 1.30-1.40 (m, 2 H), 1.50 (s, 3
H), 1.55-1.65 (m, 1 H), 1.95-2.08 (m, 3 H), 0.86 (s, 9 H), 0.88
(t, J ) 7.0 Hz, 3 H), 0.01 (s, 6 H); 13C NMR (CDCl3, 125 MHz)
δ 133.7 (CH), 132.5 (CH), 131.9 (CH), 129.8 (CH), 108.7 (C),
81.3 (CH), 74.8 (CH), 73.5 (CH), 63.5 (CH2), 45.9 (CH), 35.6 (CH),
34.7 (CH2), 33.2 (CH2), 28.4 (CH3), 26.3 (CH3), 25.8 (three CH3),
22.4 (CH2), 18.1 (C), 13.7 (CH3), -5.7 (two CH3); MS (m/z, relative
intensity) 410 (M+, 2), 395 (11), 353 (11), 295 (50), 277 (82), 189
(40), 75 (100); exact mass calcd for C23H42O4Si (M+) 410.2852;
found 410.2850.
Acetic Acid 4-Acetoxy-6-hepta-1,3-dienyl-2,2-dimethylhexa-
hydrobenzo[1,3]dioxol-5-ylmethyl ester ((Z)-13): [R]22D ) -7.2
(c 15.3, CHCl3); IR (neat) 2985, 2959, 2931, 2873, 1744, 1382,
5-(tert-Butyldimethylsilanyloxymethyl)-6-hepta-1,3-dienyl-2,2-
dimethyltetrahydrobenzo[1,3]dioxol-4-one (16). To a solution of
15 (26 mg, 0.06 mmol) in CH2Cl2 (10 mL) was added Dess-Martin
periodinane (31 mg, 0.07 mmol) at room temperature, and the
resulting solution was stirred for 1 h. The reaction was quenched
by the addition of saturated aqueous NaHCO3 (5 mL). The mixture
was extracted with ethyl acetate (10 mL × 2), washed with water
(5 mL), and the combined organic layers were dried over Na2SO4
and concentrated in vacuo to give the crude product. The residue
was purified by flash column chromatography with 20% EtOAc/
hexane (Rf ) 0.56 in 20% EtOAc/hexane) to give 16 as a yellow
oil (22 mg, 90% yield): [R]22D ) -17.9 (c 3.8, CHCl3); IR (neat)
2931, 2852, 1728, 1464, 1379, 1254, 1103, 837, 777 cm-1; 1H NMR
(CDCl3, 500 MHz) δ 6.08-5.93 (m, 2 H), 5.63-5.56 (m, 1 H),
5.39 (dd, J ) 9.5, 15.5 Hz, 1 H), 4.53 (br s, 1 H), 4.25 (d, J ) 5.0
Hz, 1 H), 3.79 (br s, 2 H), 2.75-2.65 (m, 1 H), 2.22-2.17 (m, 2
H), 2.05-1.92 (m, 2 H), 1.90 (dd, J ) 14.0, 12.5 Hz, 1 H), 1.42-
1
1239, 1050 cm-1; H NMR (CDCl3, 500 MHz) δ 6.28 (dd, J )
14.0, 11.5 Hz, 1H), 6.02 (dd, J ) 11.0, 10.5 Hz, 1 H), 5.70-5.60
(m, 1 H), 5.19 (dd, J ) 10.5, 8.0 Hz, 1 H), 4.92 (dd, J ) 10.5,
10.0 Hz, 1 H), 4.32 (br s, 1 H), 4.11 (d, J ) 11.0 Hz, 1 H), 3.97
(dd, J ) 7.5, 5.5 Hz, 1 H), 3.80 (dd, J ) 11.5, 3.0 Hz, 1 H), 2.20-
1.90 (m, 3 H), 2.04 (s, 3 H), 1.98 (s, 3 H), 1.65-1.52 (m, 1 H),
1.60 (s, 3 H), 1.50-1.30 (m, 4 H), 1.35 (s, 3 H), 0.88 (t, J ) 7.5
Hz, 3 H); 13C NMR (CDCl3, 125 MHz) δ 170.7 (C), 169.8 (C),
136.3 (CH), 130.8 (CH), 129.0 (CH), 125.2 (CH), 109.0 (C), 78.2
(CH), 73.5 (CH), 72.0 (CH), 60.7 (CH2), 43.0 (CH), 37.8 (CH2),
32.6 (CH2), 30.9 (CH), 27.6 (CH3), 26.0 (CH3), 22.3 (CH2), 20.8
(CH3), 20.6 (CH3), 13.5 (CH3); MS (m/z, relative intensity) 381
(M+ + 1, 2) 365 (47), 320 (58), 202 (60), 173 (48), 43 (100); exact
mass calcd for C21H32O6 (M+) 380.2199; found 380.2200.
8470 J. Org. Chem., Vol. 72, No. 22, 2007

Organocatalytic [4 + 2] Cycloaddition
1.30 (m, 2 H), 1.41 (s, 3 H), 1.36 (s, 3 H), 0.88 (t, J ) 7.0 Hz, 3
H), 0.83 (s, 9 H), 0.01 (s, 3 H), 0.00 (s, 3 H); 13C NMR (CDCl3,
125 MHz) δ 206.5 (C), 134.4 (CH), 131.8 (CH), 131.5 (CH), 129.7
(CH), 109.8 (C), 79.0 (CH), 76.0 (CH), 58.7 (CH2), 55.8 (CH),
38.2 (CH), 34.7 (CH2), 33.1 (CH2), 27.0 (CH3), 26.0 (CH3), 25.8
(three CH3), 22.4 (CH2), 18.2 (C), 13.7 (CH3), -5.57 (CH3), -5.63
(CH3); MS (m/z, relative intensity) 408 (M+, 2), 393 (12), 351 (100),
293 (62), 263 (75), 171 (76), 75 (55); exact mass calcd for C23H40O4-
Si (M+) 408.2696; found 408.2697.
completed, monitor by TLC. The reaction was quenched by the
addition of aqueous saturated NaHCO3 solution (2 mL). The
solution was diluted with EtOAc (10 mL), washed with brine (2
mL), dried over Na2SO4, and concentrated in vacuo to give the
crude product. The residue was purified by flash column chroma-
tography with 50% EtOAc/hexane (Rf ) 0.63 in 75% EtOAc/
hexane) to give 18 as white solid (10 mg, 95% yield): [R]22
)
D
23
+4.3 (c 2.3, CHCl3); lit. [R]23D ) +4.49 (c 0.32, CHCl3);57 [R]D
+4.4 (C 0.8, CHCl3);58 IR (neat) 3550-3100, 2923, 2851, 1718,
1670, 1460, 1108, 989 cm-1; 1H NMR (CDCl3, 500 MHz) δ 6.09
(dd, J ) 15.0, 10.5 Hz, 1H), 5.97 (dd, J ) 15.0, 10.0 Hz, 1H),
5.66-5.60 (m, 1H), 5.37 (dd, J ) 15.0, 9.5 Hz, 1H), 4.35 (br s, 1
H), 4.19 (br s, 1H), 3.82 (br s, 1 OH), 3.77 (br s, 2 H), 2.84-2.78
(m, 1 H), 2.52 (br s, 1 OH), 2.41-2.35 (m, 1 H), 2.32 (br s, 1
OH), 2.18-2.10 (m, 1 H), 2.00-2.08 (m, 2 H), 1.84 (dd, J ) 13.5,
13.5 Hz, 1 H), 1.40-1.32 (q, J ) 7.5 Hz, 2 H), 0.88 (t, J ) 7.5
Hz, 3 H); 13C NMR (CDCl3, 125 MHz) δ 211.5 (C), 135.2 (CH),
132.8 (CH), 131.0 (CH), 129.3 (CH), 77.1 (CH), 71.7 (CH), 59.7
(CH2), 54.6 (CH), 39.1 (CH), 35.3 (CH2), 34.7 (CH2), 22.4 (CH2),
13.7 (CH);57,59 MS (m/z, relative intensity) 254 (M+, 7), 236 (11),
223 (100), 205 (39), 149 (79); exact mass calcd for C14H22O4 (M+)
254.1518; found 254.1518.
6-Hepta-1,3-dienyl-5-hydroxymethyl-2,2-dimethyltetrahydro-
benzo[1,3]dioxol-4-one (17). To a solution of 16 (22 mg, 0.05
mmol) in CH3CN (8 mL) was added HF/pyridine (5 mg, 0.05 mmol)
at 25 °C, and the resulting solution was stirred for 2 h. The reaction
was quenched by the addition of silica gel (5 mg), and the resulting
mixture was passed through a small silica gel column; 50% EtOAc/
hexane was used as eluent for the flash column chromatography
separation to give 17 as a white solid (4 mg, 88% yield): [R]23
)
D
-39.8 (c 1.5, CHCl3); lit. [R]25D ) +34.8 (c 0.95, CHCl3) for (+)-
17.56 IR (neat) 3600-3300, 2953, 2925, 1726, 1460, 1380, 1273,
1123, 1074, 990 cm-1; 1H NMR (CDCl3, 500 MHz) δ 6.09 (dd, J
) 15.0, 10.5 Hz, 1 H), 5.99 (dd, J ) 15.0, 10.5 Hz, 1 H), 5.64 (dt,
J ) 15.0, 7.5 Hz, 1 H), 5.33 (dd, J ) 15.0, 9.0 Hz, 1 H), 4.55 (br
s, 1 H), 4.30 (d, J ) 5.5 Hz, 1 H), 3.73 (br s, 2 H), 2.70-2.60 (m,
1 H), 2.44 (t, J ) 7.0 Hz, 1 H), 2.45-2.40 (m, 1 H), 2.36-2.32
(m, 1 H), 2.03 (q, J ) 7.5 Hz, 2 H), 1.97-1.90 (m, 1 H), 1.42 (s,
3 H), 1.40-1.30 (m, 2 H), 1.37 (s, 3 H), 0.88 (t, J ) 7.5 Hz, 3 H);
13C NMR (CDCl3, 125 MHz) δ 210.3 (C), 135.3 (CH), 132.7 (CH),
130.2 (CH), 129.3 (CH), 109.9 (C), 79.1 (CH), 76.3 (CH), 59.9
(CH2), 54.9 (CH), 38.6 (CH), 34.7 (CH2), 33.0 (CH2), 27.0 (CH3),
26.0 (CH3), 22.3 (CH2), 13.7 (CH3);56 MS (m/z, relative intensity)
294 (M+, 11), 263 (70), 205 (20), 43 (100); exact mass calcd for
C17H26O4 (M+) 294.1831; found 294.1829.
Acknowledgment. We thank Mr. Su-Wei Hsu, Tzu-Yi
Chung, and Kwan-Liang Liu for their help in the study.
Financial support for this study from the National Science
Council, ROC, is gratefully acknowledged.
Supporting Information Available: Spectra data for the new
compounds (3a-18) and X-ray crystallographic data for compound
3c. This material is available free of charge via the Internet at
http://pubs.acs.org.
3-Hepta-1,3-dienyl-5,6-dihydroxy-2-hydroxymethylcyclohex-
anone (18). To a solution of 17 (12 mg, 0.041 mmol) in MeOH (3
mL) was added a solution of methanolic HCl (0.1 mL, prepared
from 0.05 mL concd HCl in 2 mL of MeOH). The resulting mixture
was stirred for 3 h at ambient temperature until the reaction was
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J. Org. Chem, Vol. 72, No. 22, 2007 8471