(2,5)-Ene cyclization catalyzed by mesoporous solid acids: Isotope labeling study and ab initio calculation for continuum from concerted to stepwise ene mechanism

Article abstract of DOI:10.1021/jo020634j

(2,5)-Ene reactions catalyzed by mesoporous solid acids are reported from the mechanistic point of view. The continuum (2,5)-ene mechanism from the concerted to the cationic cyclization followed by 1,2-hydride shift is evaluated. The solid-acid-catalyzed

Full text of DOI:10.1021/jo020634j

(2,5)-En e Cycliza tion Ca ta lyzed by Mesop or ou s Solid Acid s:
Isotop e La belin g Stu d y a n d a b In itio Ca lcu la tion for Con tin u u m
fr om Con cer ted to Step w ise En e Mech a n ism
Koichi Mikami,* Hirofumi Ohmura, and Masahiro Yamanaka
Department of Applied Chemistry, Tokyo Institute of Technology, O-okayama,
Meguro-ku, Tokyo 152-8552 J apan
kmikami@o.cc.titech.ac.jp
Received October 3, 2002
(2,5)-Ene reactions catalyzed by mesoporous solid acids are reported from the mechanistic point of
view. The continuum (2,5)-ene mechanism from the concerted to the cationic cyclization followed
by 1,2-hydride shift is evaluated. The solid-acid-catalyzed cyclization of the oxonium ion intermediate
4 derived from cyclic allylic lactol ether 3 bearing allylic hydroxy group affords the (2,5)-ene product
as the enol form, eventually tautomerizing to the corresponding aldehyde 6. The continuum from
the concerted to stepwise mechanism is experimentally and theoretically verified in the present
ene cyclization of the oxonium ion intermediate such as 4. The stepwise cyclization leading to
aldehyde 6 is thus shown to associate with the concerted version as a result of the stabilization of
the â-hydroxycarbenium ion intermediate.
In tr od u ction
Intramolecular ene reactions are a powerful tool for
carbocyclization and hence receive much attention from
synthetic and mechanistic viewpoints.1,2 Conceptually,
ene cyclizations are classified into six different types of
cyclization, since ene and enophile moieties can be
connected at three and two different positions, respec-
tively (Figure 1). The positions, where the shortest tether
connecting the 1,5-hydrogen shift system is attached, are
expressed in (m,n) fashion.3-5 The ring size may be shown
in numerical prefix l-.6 Among these types, the (2,5)-ene
cyclization had never been reported.
Recently, we reported the first example of (2,5)-ene
cyclization7 involving the oxonium ion as an enophile8
F IGURE 1. Classification of the intramolecular ene cycliza-
tion
(1) Comprehensive reviews on ene reactions: (a) Hoffmann, H. M.
R. Angew. Chem., Int. Ed. Engl. 1969, 8, 556. (b) Snider, B. B. Acc.
Chem. Res. 1980, 13, 426. (c) Snider, B. B. In Comprehensive Organic
Synthesis; Trost, B. M., Fleming, I., Eds.; Pergamon Press: Oxford,
1991; Vol. 1, p 1 and Vol. 2, p 527. (d) Mikami, K.; Shimizu, M. Chem.
Rev. 1992, 92, 1021.
(2) Comprehensive reviews on intramolecular ene reactions (ene
cyclizations): (a) Conia, J . M.; Le Perchec, P. Synthesis 1975, 1. (b)
Oppolzer, W.; Snieckus, V. Angew. Chem., Int. Ed. Engl. 1978, 17, 476.
(c) Taber, D. F. Intramolecular Diels-Alder and Alder Ene Reactions;
Springer-Verlag: Berlin, 1984.
in the presence of mesoporous solid acids such as mont-
morillonite K10 and Amberlyst 15E9-11 (Scheme 1). How-
ever, (2,5)-ene product 2 isomerized under the reaction
conditions. Therefore, it was planned to trap the (2,5)-
ene product as an enol form, so that the (2,5)-ene product
(3) For l-(m,n) terminology of ene cyclization, see the review Mikami,
K.; Shimizu, M. Chem. Rev. 1992, 92, 1021.
(4) Account on l-(m,n) ene cyclization: Sarkar, T. K. J . Indian Inst.
Sci. 1994, 74, 329.
(5) l-(m,n) Ene cyclization: (a) Mikami, K.; Sawa, E.; Terada, M.
Tetrahedron: Asymmetry 1991, 2, 1403. (b) Mikami, K.; Osawa, A.;
Isaka, A.; Sawa, E.; Shimizu, M.; Terada, M.; Kubodera, N.; Nakagawa,
K.; Tsugawa, N.; Okano, T. Tetrahedron Lett. 1998, 39, 3359. (c) Okano,
T.; Nakagawa, K.; Kubodera, N.; Ozono, K.; Isaka, A.; Osawa, A.;
Terada, M.; Mikami, K. Chem. Biol. 2000, 7, 173. (e) Sarkar, T. K.;
Ghorai, B. K.; Nandy, S. K.; Mukherjee, B.; Banerji, A. J . Org. Chem.
1997, 62, 6006. (f) Noguchi, M.; Mizukoshi, T.; Nishimura, S. Bull.
Chem. Soc. J pn. 1997, 70, 2201. (g) Loh, T.-P.; Hu, Q.-Y.; Tan, K.-T.;
Cheng, H.-S. Org. Lett. 2001, 3, 2669.
(7) Ohmura, H.; Smyth, G. D.; Mikami, K. J . Org. Chem. 1999, 64,
6056.
(8) Ene reaction using oxonium ion as an enophile: (a) Overman,
L. E.; Thompson, A. S. J . Am. Chem. Soc. 1988, 110, 2248. (b)
Blumenkopf, T. A.; Bratz, M.; Castaneda, A.; Look, G. C.; Overman,
L. E.; Rodriguez, D.; Thompson, A. S. J . Am. Chem. Soc. 1990, 112,
4386. (c) Blumenkopf, T. A.; Look, G. C.; Overman, L. E. J . Am. Chem.
Soc. 1990, 112, 4399. (d) Mikami, K.; Kishino, H. J . Chem. Soc., Chem.
Commun. 1993, 1843. (e) Sonawane, H. R.; Maji, D. K.; J ana, G. H.;
Pandey, G. Chem. Commun. 1998, 1773.
(9) (a) In porphyrin synthesis, the cyclization is efficiently catalyzed
in the mesopore of clay: Onaka, M.; Shinoda, T.; Izumi, Y.; Nolen, E.
Chem. Lett. 1993, 117. (b) Shinoda, T.; Onaka, M.; Izumi, Y. Chem.
Lett. 1995, 493; 495. (c) Izumi, Y.; Urabe, K.; Onaka, M. Microporous
Mesoporous Mater. 1998, 21, 227.
(6) Also see the numerical prefix in Baldwin’s rule: Baldwin, J . E.
Chem. Commun. 1976, 734.
10.1021/jo020634j CCC: $25.00 © 2003 American Chemical Society
Published on Web 01/14/2003
J . Org. Chem. 2003, 68, 1081-1088
1081

Mikami et al.
SCHEME 1
SCHEME 3
SCHEME 2
TABLE 1. Solid -Acid -Ca ta lyzed Cycliza tion
would be transformed to the corresponding aldehyde and,
consequently, regioisomerization would be terminated.
Therefore, cyclic allylic lactol ether 3 was selected as a
substrate (Scheme 2).12
acid
(g/mmol)
solvent
(M)
time yielda
(h)
entry
(%) syn:antib
1c
2
3
4
5
6
7
8
9
TMSOTf (0.1 equiv) CH2Cl2 (0.1)
K10 (0.8)
3
tr
CH2Cl2 (0.1) 96
CH2Cl2 (0.1)
THF
toluene
CH2Cl2 (0.3)
(0.01)
(0.1)
(0.1)
(0.01)
21
46
43
39
32
65
41
44
72
58:42
54:46
55:45
56:44
54:46
55:45
55:45
54:46
54:46
Resu lts a n d Discu ssion
Amberlystd (0.5)
Amberlystd (0.5)
Amberlystd (0.5)
Amberlystd (0.5)
Amberlystd (0.5)
Amberlystd (0.1)
Amberlystd (1)
Amberlystd (1)
9
78
11
4
16
84
P r ep a r a tion of Cyclic Allylic La ctol Eth er 3. The
preparation of cyclic ether 3a is shown in Scheme 3.
Homoallylic bromide 9 was prepared via regiospecific
formaldehyde-ene reaction of methallyl ether 713 followed
by bromination. Bromide 9 was converted to the Grignard
reagent, which was treated with the lithium salt of
o-phthalaldehydic acid to give lactone 10. Lactone 10 was
reduced to lactol 11a and then desilylated to give diol
12. Finally, diol 12 was treated with TsOH to give the
cyclic allylic lactol ether 3a without any O f C rear-
ranged product 6a .
(2,5) En e Cycliza tion . The key reaction of the cyclic
ether 3a was then examined in the presence of an acid
(Table 1). In a manner similar to that employed in our
early report on the intermolecular oxonium-ene reaction
of allylic lactol ether,14 a homogeneous Lewis acid,
TMSOTf, was first used. However the substrate 3a
1.5
5
10
a
b
Combined yield of syn- and anti-6a . Determined by capillary
GC. c -78 °C f rt. Amberlyst 15E.
d
decomposed in the presence of TMSOTf (entry 1). On the
other hand, mesoporous solid acids were found to be
effective for this reaction. Montmorillonite K10 gave the
desired aldehyde 6a though in low yield even after long
reaction times (entry 2). Amberlyst 15E gave aldehyde
6a in better yield within shorter reaction time; the yield
was increased when the reaction was performed in
CH2Cl2 rather than in THF or toluene (entries 3-5).
Dilution of the substrate concentration also improved the
yield (entries 3, 6, and 7). The time required for the
reaction greatly depends on the amount of Amberlyst 15E
(entries 8 and 9). Finally, the yield of 6a was increased
up to 72% in dilute (0.01 M) CH2Cl2 solution with 1 g of
Amberlyst 15E (entry 10). In all cases, the isomer ratio
of the aldehyde 6 was 1:1. As shown in Table 2, the ratio
of syn and anti isomers of the aldehyde 6 was not
changed throughout the reaction (5 min to 6 h). In
contrast, the aldehyde 6 slowly isomerized to the other
isomer after several hours as shown in the isomerization
experiments of the separated syn and anti diastereomeric
products 6a (Table 3). These results indicate that the
(10) Ballantine, J . A. In Solid Supports and Catalysts in Organic
Synthesis; Smith, K., Ed.; Ellis Horwood: London, 1992; Part 2,
Chapter 4, pp 101-102. Kellendonk, F. J . A.; Heinerman, J . J . L.; van
Santen, R. A. In Preparative Chemistry Using Supported Reagents;
Laszlo, P., Ed.; Academic Press: New York, 1987; Part 8, Chapter 23,
pp 456-457. Adams, J . M. In Preparative Chemistry Using Supported
Reagents; Laszlo, P., Ed.; Academic Press: New York, 1987; Part 8,
Chapter 27, pp 509-511.
(11) (a) Tateiwa, J .; Hashimoto, K.; Yamauchi, T.; Uemura, S. Bull.
Chem. Soc. J pn. 1996, 69, 2361. (b) Tateiwa, J .; Kimura, A.; Takasuka,
M.; Uemura, S. J . Chem. Soc., Perkin Trans. 1 1997, 2169.
(12) Recent communication: Ohmura, H.; Mikami, K. Tetrahedron
Lett. 2001, 42, 6859.
(13) Mikami, K.; Shimizu, M.; Nakai, T. J . Org. Chem. 1991, 56,
2952.
(14) Intermolecular ene reaction of allylic lactol ethers: Mikami,
K.; Kishino, H. Tetrahedron Lett. 1996, 37, 3705.
1082 J . Org. Chem., Vol. 68, No. 3, 2003

(2,5) Ene Cyclization
TABLE 2. Stea d y Isom er Ra tio th r ou gh th e Rea ction a
a siloxy group at the allylic position was investigated (X
) Si; Scheme 4). The concerted product would be obtained
as the silyl enol ether 15 to give eventually the aldehyde
6a . Thus, the reaction of the siloxy lactol 11a (Si ) TDS)
with K10 and Amberlyst 15E was investigated (Table 4).
First, the reaction of the lactol 11a possessing thexyl-
dimethylsilyl ether was studied with Amberlyst 15E to
give aldehyde 6a exclusively (entry 1). On the other hand,
the reaction with K10 gave the silyl enol ether 15a (entry
2). Then, lactol 11b (Si ) TBDPS) possessing the acid-
stable tert-butyldiphenylsilyl ether group was investi-
gated. The silyl enol ether 15b was obtained in 8% yield
in the presence of Amberlyst 15E (entry 3) and, eventu-
ally, in 16% yield using K10 (entry 4).
The isolated silyl enol ether 15a was then protonated
with Amberlyst 15E to the aldehyde 6a (Table 5).
Interestingly, aldehyde 6a obtained by protonation of silyl
enol ether 15a was anti major at the early stage of the
reaction. By contrast, in the reaction of siloxy lactol 11,
the isomer ratio of aldehyde 6a inclined to syn as the
yield of silyl enol ether 15a increased (Table 4, entry 4).
These results imply the involvement of the other cycliza-
tion pathway leading to syn-aldehyde 6a ; the syn-
selective stepwise cyclization associates with anti-
selective concerted cyclization.
time
syn:antib
5 min
15 min
6 h
54:46
53:47
54:46
a
b
Amberlyst 15E (0.5 g/mmol), CH2Cl2, 0.1 M. Determined by
capillary GC.
TABLE 3. Slow Isom er iza tion betw een syn a n d a n ti
Isom er a
time
syn:antib
syn:antib
start
5 min
15 min
5 h
89:11
90:10
85:15
53:47
14:86
16:84
22:78
53:47
a
b
Ab In itio Ca lcu la tion s on Con cer ted a n d Step -
w ise Tr a n sition Sta tes. To evaluate the continuum
mechanism of the (2,5)-ene reaction, from the cationic to
the concerted cyclization, we carried out ab initio molec-
ular orbital calculation17 by the use of allyl alcohols 16
as a chemical model (Scheme 5). Two comparable transi-
tion states of 17 in the concerted cyclization and 18 in
the stepwise cyclization were optimized at the HF/6-31G*
level. In the case of n ) 1 (e.g., the chemical model of
6a ), the 21.2 kcal/mol activation energy of the concerted
transition state 17a is larger than the 5.9 kcal/mol
activation energy of the cationic transition state 18a . This
indicates that the cationic cyclization is favored over the
concerted cyclization in the reaction of 6a . As shown in
Figure 2, the concerted (2,5)-ene transition state of 17a
has a significant amount of zwitterionic character
(C1-C2 1.37 Å; C2-C3 1.53 Å) in comparison with the
Amberlyst 15E (1 g/mmol), CH2Cl2, 0.01 M. Determined by
capillary GC.
SCHEME 4
(15) For a concerted (pericyclic) mechanism of internal [1,2] hydride
(pinacol) migration to carbenium ion, see: (a) Mislow, K.; Siegel, M.
J . Am. Chem. Soc. 1952, 74, 1060. (b) Ley, J . B.; Vernon, C. A. J . Chem.
Soc. 1957, 2987. (c) Collins, C. J .; Rainey, W. T.; Smith, W. B.; Kaye,
I. A. J . Am. Chem. Soc. 1959, 81, 460. (d) Smith, W. B.; Bowman, R.
E.; Kmet, T. J . Am. Chem. Soc. 1959, 81, 997. (e) Nakamura, K.;
Osamura, Y. J . Am. Chem. Soc. 1993, 115, 9112. (f) Wennerberg, J .;
Frejd, T. Acta Chem. Scand. 1998, 52, 95.
(16) For Overman’s elegant and important works on Prins/pinacol
reactions, see: (a) Overman, L. E. Acc. Chem. Res. 1992, 25, 352. For
leading recent references: (b) MacMillan, D. W. C.; Overman, L. E. J .
Am. Chem. Soc. 1995, 117, 10391. (c) Cloninger, M. J .; Overman, L.
E. J . Am. Chem. Soc. 1999, 121, 1092.
(17) All calculations were performed with a Gaussian 98 pakage.
Frisch, M. J .; Trucks, G. W.; Schlegel, H. B.; Scuseria, G. E.; Robb, M.
A.; Cheeseman, J . R.; Zakrzewski, V. G.; Montgomery, J r. J . A.;
Stratmann, R. E.; Burant, J . C.; Dapprich, S.; Millam, J . M.; Daniels,
A. D.; Kudin, K. N.; Strain, M. C.; Farkas, O.; Tomasi, J .; Barone, V.;
Cossi, M.; Cammi, R.; Mennucci, B.; Pomelli, C.; Adamo, C.; Clifford,
S.; Ochterski, J .; Petersson, G. A.; Ayala, P. Y.; Cui, Q.; Morokuma,
K.; Salvador, P.; Dannenberg, J . J .; Malick, D. K.; Rabuck, A. D.;
Raghavachari, K.; Foresman, J . B.; Cioslowski, J .; Ortiz, J . V.; Baboul,
A. G.; Stefanov, B. B.; Liu, G.; Liashenko, A.; Piskorz, P.; Komaromi,
I.; Gomperts, R.; Martin, R. L.; Fox, D. J .; Keith, T.; Al-Laham, M. A.;
Peng, C. Y.; Nanayakkara, A.; Challacombe, M.; Gill, P. M. W.;
J ohnson, B.; Chen, W.; Wong, M. W.; Andres, J . L.; Gonzalez, C.; Head-
Gordon, M.; Replogle, E. S.; Pople, J . A. Gaussian 98, revision A.11;
Gaussian, Inc.: Pittsburgh, PA, 2001.
ratio of syn and anti isomers of the aldehyde 6a was
kinetically determined (vide infra).
Con tin u u m fr om Con cer ted to Step w ise Mech a -
n ism . Two possible mechanisms are conceivable for the
ene reaction of 3a to 6a (X ) H; Scheme 4). One is the
concerted cyclization followed by tautomerization of enol
5a to aldehyde 6a . The other is stepwise cyclization to
give â-hydroxy carbenium ion intermediate 13a followed
by 1,2-hydride shift.15,16 To examine the continuum from
the concerted to cationic mechanism in the (2,5)-ene
reaction of 3a to 6a , the reaction using lactol 11 bearing
J . Org. Chem, Vol. 68, No. 3, 2003 1083

Mikami et al.
TABLE 4. Solid -Acid -Ca ta lyzed Cycliza tion of La ctol 11a
entry
substrate
acid (g/mmol)
time
yieldb of 6a (%)
syn:antic
yieldd of 15 (%)
1
2
3
4
11a
Amberlyste (1)
K10 (0.8)
1.5 h
10 min
3 h
64
65
73
60
52:48
58:42
53:47
67:33
0f
9
8
11b
Amberlyste (1)
K10 (0.8)
10 min
16
a
b
The reactions was carried out in the presence of MS 4Å in CH2Cl2 (0.01 M) at rt. Combined yield of syn and anti isomers of 6a .
c dSetermined by capillary GC. Combined yield of Z/E mixture of 15. e Amberlyst 15E. f Trace amount of 15a was detected by quenching
d
the reaction in 20 min.
TABLE 5. Con ver sion of Silyl En ol Eth er 15a to
Ald eh yd e 6a a
time
syn:antib
1 min
5 min
10 min
22:78
24:76
27:73
a
Reaction was carried out in the presence of Amberlyst 15E (1
b
g/mmol) in 0.01 M at rt. 15a was consumed in 30 min. Deter-
mined by capillary GC.
SCHEME 5
F IGURE 2. 3D structures of the transition states for the
concerted (17a and 18a ) and cationic (17b and 18b) cyclization
(HF/6-31G*). Bond lengths are shown in Å.
be continuum, depending on the structures of substrates
and acids.
Isotop e La belin g Stu d y.1919 To confirm the con-
tinuum mechanism, the deuterated cyclic allylic lactol
ether 3b was considered as a substrate (Scheme 6). The
intermediate 5b could be obtained via concerted mech-
anism,20 followed by protonation with Amberlyst 15E
leading to R-protonated anti-aldehyde 6b. Through cat-
ionic mechanism, R-deuterated syn-aldehyde 6c would be
obtained through [1,2] deuteride shift.21 Therefore, by
measuring the R-D ratio of 6, the continuum could be
evaluated.
transition structure of the normal ene reaction reported
by Houk18 and an almost dissociated C-H bond (C1-H
2.04 Å) because the hydroxy group on C1 facilitates
stabilization of the cationic charge on C1. The concerted
transition state 17a is destabilized by the electrostatic
factors as well as the geometrical requirement by forming
a highly distorted tricyclo structure in the concerted
mechanism. On the other hand, in the case of n ) 2, the
transition state of 17b also shows zwitterionic character
(C1-C2 1.53 Å; C2-C3 1.37 Å) but smaller dissociation of
the C1-H bond (C1-H ) 1.93 Å). The activation energy
of 17b (16.9 kcal/mol) is only 1.0 kcal/mol larger than
that of 18b (15.9 kcal/mol). At this stage, these two
concerted and cationic pathways become comparable. The
concerted and cationic mechanisms can be regarded to
The deuterated cyclic allylic lactol ether 3b was treated
with Amberlyst 15E and quenched within 5 min to
(18) Loncharich, R. J .; Houk, K. N. J . Am. Chem. Soc. 1987, 109,
6947.
(19) General reviews on isotope effects: (a) Carpenter, B. K.
Determination of Organic Reaction Mechanisms; Wiley: New York,
1984. (b) Kwart, H. Acc. Chem. Res. 1982, 15, 401.
(20) H/D Isotope effect is observed in ene reactions, see: (a)
Stephenson, L. M.; Mattern, D. L. Acc. Chem. Res. 1980, 13, 419. (b)
Snider, B. B.; Eyal, R. J . Am. Chem. Soc. 1985, 107, 8160. (b) Song,
Z.; Chrisope, D. R.; Beak, P. J . Org. Chem. 1987, 52, 3938. (c) Singleton,
D. A.; Hang, C. J . Org. Chem. 2000, 65, 895.
(21) It is known that H/D isotope effect in 1,2-migrations is quite
small: Westheimer, F. H. Chem. Rev. 1961, 61, 265.
1084 J . Org. Chem., Vol. 68, No. 3, 2003

(2,5) Ene Cyclization
SCHEME 6
SCHEME 7
TABLE 6. Syn :An ti Ra tio in 6b:6c
optimized at the HF/6-31G* level illustrates the presence
of stereoelectronic interaction between oxygen lone pair
orbital and vacant p-orbital on C2 (O-C2 ) 1.53 Å)22 and
the suitable position of duteride in the concave face for
the 1,2-shift. Therefore, 1,2-deuteride shift readily pro-
ceeds from the convex face. Overall, the ca. 1:1 ratio of
syn and anti isomers of the aldehydes as the mixture of
6b and 6c were kinetically determined as the result of
the continuum mechanism (vide supra).
6b
6c
(syn/anti)
(syn/anti)
(M + Na)+
49:51
42:58
Con clu sion
(M + K)+
(M + Na)+
(M + K)+
(34/66)
(31/69)
(74/26)
(71/29)
The (2,5)-ene cyclizations of cyclic allylic lactol ethers
3 have thus been reported from the mechanistic point of
view. Since the oxonium ion intermediate 4 derived from
3 bears an allylic hydroxy group, the concerted product
is obtained as the enol form so that this can tautomerize
to the corresponding aldehyde 6. In this ene cyclization,
the continuum from the concerted to cationic mechanism
is evaluated by ab initio molecular orbital calculation.
The choice of the concerted versus cationic mechanism
of the ene cyclization depends on the structural features
of the substrate and additional acids. Indeed, the in-
volvement of the cationic cyclization followed by 1,2-
hydride shift leading to the syn-aldehyde R-D-6c (CDd
O) is experimentally verified in the labeling study, while
the involvement of the concerted cyclization in the
reaction of cyclic allylic lactol ether 3 is also confirmed
by the formation of anti-aldehyde 6c (CDdO) in the
labeling study and silyl enol ether 15 leading eventually
to anti-aldehyde 6a (CHdO).
prevent isomerization (replacement of R-D with H) of the
resultant aldehyde 6. The syn and anti isomers 6 were
separated, and their molecular weight was measured by
LCMS to show that the 6b (H):6c (D) ratio was ca. 1:1
and that 6b was anti major along with syn major 6c
(Table 6).
The continuum mechanism is thus exemplified in
Scheme 7. The concerted cyclization preferentially af-
forded the anti product via protonation of the resultant
enol from the convex face. Indeed, the 3D structure of
the enol 19 optimized at the HF/6-31G* level clearly
shows that protonation readily occurs from the less
hindered convex face. The cationic cyclization preferen-
tially provided the syn-deuterated product by 1,2-deu-
teride shift from the concave face. The resultant cationic
intermediate in the cationic pathway has a different
structure from the resultant enol in the concerted path-
way. The 3D structure of the cationic intermediate 20
(22) Paquett, L. A.; Scott, M. K. J . Am. Chem. Soc. 1972, 94, 6760
and references therein.
J . Org. Chem, Vol. 68, No. 3, 2003 1085

Mikami et al.
was washed with brine, dried over anhydrous magnesium
sulfate, filtered, and concentrated in vacuo. The residue was
purified by column chromatography on silica gel (hexane/ether
) 10:1) to afford 8.1 g (93%) of 1-bromo-3-(dimethylthexylsi-
lyloxymethyl)-3-butene (9). 1H NMR (300 MHz, CDCl3) δ
0.11 (s, 6H), 0.86 (s, 6H), 0.89 (d, J ) 6.9 Hz, 6H), 1.64 (set,
J ) 6.9 Hz, 1H), 2.61 (t, J ) 7.8 Hz, 2H), 3.49 (t, J ) 7.8
Hz, 2H), 4.08 (s, 2H), 4.90 (s, 1H), 5.12 (s, 1H). 13C NMR
(75 MHz, CDCl3) δ -3.5, 18.5, 20.3, 25.2, 31.0, 34.1, 36.3,
65.5, 111.5, 145.7. IR (neat) 2962, 2868, 1466, 1255, 1089, 832,
Exp er im en ta l Section
1
Gen er a l. Chemical shifts (δ) of H NMR are expressed in
parts per million downfield from tetramethylsilane as an
internal standard (δ ) 0) or CHCl3 within a solvent (δ ) 7.26).
Multiplicity is indicated as bs (broad singlet), s (singlet), d
(doublet), t (triplet), q (quartet), sept (septet), and m (multip-
let), and coupling constants (J ) are reported in Hz. Chemical
shifts (δ) of 13C NMR are expressed in parts per million in
CDCl3 as an internal standard (δ ) 77).
Capillary gas chromatographic (GC) analyses were carried
out on a capillary column coated with OV-1701 by using N2
as a carrier gas. High-performance liquid chromatographic
(HPLC) analyses were carried out on an ultraviolet (UV)
spectrophotometric detector (254 nm). Analytical thin-layer
chromatography (TLC) was performed on glass plates pre-
coated with silica gel (layer thickness 0.25 and 0.2 mm).
Visualization was accomplished by UV light (254 nm), anis-
aldehyde, potassium permanganate, and 2,4-dinitrophenylhy-
drazine. Column chromatography was performed on silica gel
60N (spherical, neutral, 100-210 µm) employing hexane-
diethyl ether mixture as an eluent, unless otherwise noted.
All experiments were carried out under argon atmosphere
unless otherwise noted. Tetrahydrofuran, diethyl ether, and
toluene were distilled from sodium/benzophenone ketyl im-
mediately prior to use.
777 cm-1
.
3-(Dim et h ylt h exylsilyloxym et h yl)-3-b u t en ylm a gn e-
siu m br om id e. A round-bottom, two-necked, 100-mL flask
equipped with reflux condenser was charged with magnesium
(1.8. g, 74 mmol) and iodide, which was stirred for 12 h. To
this reaction vessel was added THF (2 mL) and a solution of
1-bromo-3-(dimethylthexylsilyloxymethyl)-3-butene 9 (7.3 g,
23.6 mmol) 1,2-dibromoethane in THF (22 mL) dropwise, and
the mixture was stirred for several hours.
3-(3-Dim et h ylt h exylsilyloxym et h yl-3-b u t en yl)-1,3-d i-
h yd r o-2-ben zofu r a n -1(3H)-on e (10). To a stirred solution
of diisopropylamine (1.9 mL, 14.3 mmol) in dry THF (70 mL)
at -78 °C was added n-BuLi (6.2 mL of 1.5 M solution in
hexane, 9.3 mmol). The reaction mixture was kept at -78 °C
for 20 min and at 0 °C for 30 min and then cooled to -78 °C
again. To this mixture was added a solution of o-phthalalde-
hydic acid (1.4 g, 9.5 mmol) in dry THF (27 mL). The resulting
solution was kept at -78 °C for 1 h, and 3-(dimethylthexyl-
silyloxymethyl) butenylmagnesium bromide (THF solution,
23.6 mmol) was added. The reaction mixture was allowed to
warm to room temperature, stirred for 3 h, and then poured
into 1 N HCl. The aqueous phase was extracted with ethyl
acetate several times, and the combined organic phase was
rinsed with brine, dried over anhydrous magnesium sulfate,
and concentrated in vacuo. The residue was purified by column
chromatography on silica gel (hexane/ether ) 3:1) to afford
2.4 g (70%) of 3-(3-dimethylthexylsilyloxymethyl-3-butenyl)-
1,3-dihydro-2-benzofuran-1(3H)-one 10. 1H NMR (300 MHz,
CDCl3) δ 0.09 (s, 9H), 0.85 (s, 6H), 0.87 (d, J ) 6.9 Hz, 6H),
1.62 (sept, J ) 6.9 Hz, 1H), 1.81-1.97 (m, 1H), 2.12-2.30 (m,
3H), 4.06 (s, 2H), 4.86 (s, 1H), 5.08 (s, 1H), 5.50 (dd, J ) 3.3,
8.7 Hz, 1H), 7.44 (dd, J ) 1.2, 7.5 Hz, 1H), 7.53 (t, J ) 7.5 Hz,
1H), 7.67 (dt, J ) 1.2, 7.5 1H), 7.89 (d, J ) 7.5 Hz, 1H). 13C
NMR (75 MHz, CDCl3) δ -3.5, 18.5, 20.3, 25.2, 27.9, 33.1, 34.1,
65.8, 80.8, 109.6, 121.68, 125.7, 126.2, 129.1, 134.0, 147.1,
P r ep a r a tion of (1R*,7R*)-4-Meth ylen e-2,12-d ioxa ben -
zobicyclo[5.2.1]d eca n e (3a ). 3-Dim eth ylth exylsilyloxy-2-
m eth ylp r op en e (7). To a stirred solution of thexyldimethyl-
silyl chloride (27.4 g, 153.1 mmol) and dry DMF (70 mL) was
added a solution of â-methallyl alcohol (9.2 g, 127.6 mmol) in
DMF (50 mL) and imidazole (22 g, 323 mmol) at room
temperature. The reaction mixture was stirred for 1.5 h and
then poured into 1 N hydrochloric acid. The aqueous phase
was extracted with ether several times, and then the combined
organic phase was washed with a saturated aqueous solution
of sodium bicarbonate, water, and brine, dried over anhydrous
magnesium sulfate, filtered, and concentrated in vacuo. The
residue was distilled (85 °C, 7 mmHg) to afford 26.9 g (98%)
of 3-dimethylthexylsilyloxy-2-methylpropene 7. 1H NMR (300
MHz, CDCl3) δ 0.11 (s, 6H), 0.87 (s, 6H), 0.90 (d, J ) 7.2 Hz,
6H), 1.59-1.67 (m, 1H), 1.70 (s, 3H), 4.02 (s, 2H), 4.80 (s, 1H),
4.98 (s, 1H). 13C NMR (75 MHz, CDCl3) δ -3.5, 18.5, 19.0, 20.3,
25.3, 34.2, 66.6, 109.1, 144.7. IR (neat) 2962, 2870, 1464, 1253,
1116, 1087, 847, 832, 777 cm-1
.
3-(Dim eth ylth exylsilyloxym eth yl)-3-bu ten e-1-ol (8). To
a stirred solution of 3-dimethylthexylsilyloxy-2-methylpropene
7 (32.3 g, 150.6 mmol), paraformaldehyde (4.5 g, 150.6 mmol)
and dry dichloromethane (350 mL) in the presence of MS 4Å,
was added dimethylaluminum chloride (145 mL of 1.04 M
solution in hexane, 151 mmol) at -78 °C. The reaction tem-
perature was gradually raised to room temperature, and the
mixture was stirred for 10 h. To the reaction mixture was then
added a saturated aqueous solution of sodium sulfate and
ether. After 12 h, to the mixture was added anhydrous sodium
sulfate. The mixture was filtered and concentrated in vacuo.
The residue was purified by column chromatography on silica
gel (hexane/ether ) 2:1) to afford 10.7 g (29%) of 3-(dimeth-
ylthexylsilyloxymethyl)-3-butene-1-ol 8. 1H NMR (300 MHz,
CDCl3) δ 0.11 (s, 6H), 0.85 (s, 6H), 0.88 (d, J ) 6.9 Hz, 6H),
1.63 (set, J ) 6.9 Hz, 1H), 2.31 (t, J ) 6.3 Hz, 2H), 3.70 (t, J
) 6.3 Hz, 2H), 4.07 (s, 2H), 4.91 (s, 1H), 5.10 (s, 1H). 13C NMR
(75 MHz, CDCl3) δ -3.5, 18.4, 20.2, 25.2, 34.1, 36.8, 61.3, 66.2,
112.6, 145.5. IR (neat) 3338, 2962, 2870, 1657, 1466, 1255,
149.8, 170.5. IR (neat) 2962, 1769, 1466, 1253, 1079, 833 cm-1
.
cis/tr a n s Mixtu r e of 3-(3-Dim eth ylth exylsilyloxy-
m eth yl-3-bu ten yl)-1,3-d ih yd r o-2-ben zofu r a n -1-ol (11a ).
To a stirred solution of 3-(3-dimethylthexylsilyloxymethyl-3-
butenyl)-2-benzofuran-1(3H)-one 10 (2.4 g, 6.6 mmol) in dry
dichloromethane (36.5 mL) at -78 °C was added DIBAL-H
(7.7 mL of 0.95 M solution in toluene, 7.3 mmol). The reaction
was kept at -78 °C for 2.5 h and then quenched by addition
of saturated aqueous solution of sodium sulfate and allowed
to warm to room temperature. To the mixture was added
anhydrous sodium sulfate and ether. The mixture was stirred
for 1 h, filtered, and concentrated in vacuo. The residue was
purified by column chromatography on silica gel (hexane/ether
) 3:1) to afford 2.2 g (90%) of a cis/trans mixture of 3-(3-
dimethylthexylsilyloxymethyl-3-butenyl)-1,3-dihydro-2-benzo-
furan-1-ol 11a . 1H NMR (300 MHz, C6D6, cis/trans mixture) δ
0.09 (s, 12H), 0.90 (s, 6H), 0.91 (s, 6H), 0.94 (d, J ) 6.9 Hz,
6H), 0.95 (d, J ) 6.9 Hz, 6H), 1.58-2.07 (m, 6H), 2.14-2.36
(m, 4H), 3.59 (t, J ) 7.2 Hz, 2H), 4.01 (s, 2H), 4.03 (s, 2H),
4.89 (s, 1H), 4.92 (s, 1H), 5.03 (dd, J ) 3.9, 7.5 Hz, trans-1H),
5.20 (s, 1H), 5.22 (s, 1H), 5.31-5.35 (m, cis-1H), 6.36 (d, J )
7.2 Hz, trans-1H), 6.43 (dd, J ) 1.8, 7.2 Hz, cis-1H), 6.83-
6.87 (m, 2H), 7.02-7.10 (m, 4H), 7.23-7.26 (m, 2H). 13C NMR
(75 MHz, CDCl3, cis/trans mixture) δ-3.3, 18.8, 20.6, 25.5,
28.4, 28.7, 34.5, 34.6, 36.0, 66.1, 82.1, 82.8, 101.1, 108.9, 121.1,
121.3, 123.3, 123.4, 129.1, 129.2, 140.2, 140.5, 142.8, 142.9,
1083, 1050, 832, 777 cm-1
.
Br om o-3-(d im eth ylth exylsilyloxym eth yl)-3-bu ten e (9).
To a stirred solution of 3-(dimethylthexylsilyloxymethyl)-3-
butene-1-ol 8 (6.9 g, 28.3 mmol) in dry dichloromethane (190
mL) was added triphenylphosphine (8.9 g, 33.9 mmol) and
carbontetrabromide (14.1 g, 42.45 mmol). The reaction mixture
was stirred for 5 min and then poured into saturated aqueous
sodium bicarbonate. The aqueous phase was extracted with
CH2Cl2 several times, and then the combined organic phase
148.6, 148.7. IR (neat) 3364, 2960, 1464, 1253, 1112, 832 cm-1
.
1086 J . Org. Chem., Vol. 68, No. 3, 2003

(2,5) Ene Cyclization
cis/tr a n s Mixtu r e of 3-(4-Hyd r oxy-3-m eth ylen ebu tyl)-
1,3-d ih yd r o-2-ben zofu r a n -1-ol (12). To a stirred solution of
Gen er a l P r oced u r e for Solid -Acid -Ca ta lyzed Oxon iu m
En e Rea ction of cis/tr a n s-Mixtu r e of 3-(3-Dim eth yltex-
ylsilyloxym eth yl-3-bu ten yl)-1,3-dih ydr o-2-ben zofu r an -1-ol
(7a ) a n d cis/tr a n s-Mixtu r e of 3-(3-ter t-Bu tyld ip h en ylsi-
lyloxym et h yl-3-b u t en yl)-1,3-d ih yd r o-2-b en zofu r a n -1-ol
(11b). To a stirring solution of 11 and dichloromethane at room
temperature in the presence of MS 4Å was added solid acid.
The reaction was kept at room temperature for the reported
time, filtered through Celite, and concentrated in vacuo. The
residue was purified by column chromatography on silica gel
(hexane/ether ) 3:1) to afford the aldehyde 6.
a
cis/trans mixture of 3-(3-dimethyltexylsilyloxymethyl-3-
butenyl)-1,3-dihydro-2-benzofuran-1-ol 11a (2.2 g, 6.0 mmol)
and dry THF (70 mL) at 0 °C was added tetrabutylammonium
fluoride (6.6 mL of 1.0 M solution in THF, 6.6 mmol). The
reaction was kept at room temperature for 2 h and then
quenched by addition of water. The aqueous phase was
extracted with ether, and the combined organic phase was
rinsed with brine, dried over anhydrous magnesium sulfate,
and concentrated in vacuo. The residue was purified by column
chromatography on silica gel (hexane/ether ) 1:3) to afford
1.1 g (85%) of cis/trans mixture of 3-(4-hydroxy-3-methyl-
enebutyl)-1,3-dihydro-2-benzofuran-1-ol 12. 1H NMR (300
MHz, CDCl3, cis/trans mixture) δ 1.75-2.01 (m, 2H), 2.04-
2.34 (m, 6H), 4.04 (s, 2H), 4.05 (s, 2H), 4.88 (bs, 2H), 5.01 (s,
1H), 5.04 (s, 1H), 5.21 (dd, J ) 3.6, 7.5 Hz, 1H), 5.46 (dt,
J ) 2.1, 7.2 Hz, 1H), 6.42 (s, 1H), 6.48 (d, J ) 2.1 Hz, 1H),
7.21-7.23 (m, 2H), 7.33-7.44 (m, 6H). 13C NMR (75
MHz, CDCl3, cis/trans mixture) δ 28.1, 28.3, 33.9, 35.2, 65.8,
82.0, 82.7, 100.6, 100.7, 109.8, 110.0, 121.0, 121.1, 123.0,
123.1, 128.0, 128.1, 129.2, 129.3, 139.2, 139.3, 142.0, 142.1,
148.3, 148.5. IR (neat) 3294, 2922, 1657, 1441, 1249, 1017, 903,
(1S *,3R *,6R *)-3-F or m yl-11-oxa b e n zob icyclo[4.2.1]-
1
n on a n e (a n ti-6a ). H NMR (300 MHz, C6D6) δ 0.51 (dddd, J
) 3.0, 10.5, 12.3, 14.1 Hz, 1H), 1.35-1.44 (m, 2H), 1.49-1.56
(m, 1H), 1.68 (dddd, J ) 3.3, 4.2, 11.7, 13.8 Hz, 1H), 2.27 (dddd,
J ) 1.2, 5.7, 8.4, 13.8 Hz, 1H), 2.35-2.45 (m, 1H), 5.22 (d, J )
8.4 Hz, 1H), 5.27 (d, J ) 4.2 Hz, 1H), 6.68-6.78 (m, 2H), 6.96-
7.02 (m, 2H), 9.10 (s, 1H). 13C NMR (75 MHz, C6D6) δ 21.3,
35.5, 36.4, 50.6, 79.5, 83.4, 120.5, 120.7, 127.6, 127.8, 141.1,
146.1, 201.5. IR (neat) 2930, 1723, 1462, 1367, 1249, 1069,
1002, 756 cm-1. EI-MS m/z ) 202 (M+•). HRMS (EI) calcd for
C
13H14O2 202.0994, found 202.0998 (M+•). Capillary GC (OV-
1701, 170 °C, inj/det 200 °C). tR ) 21.1 min.
758 cm-1
.
(1S *,3S *,6R *)-3-F or m yl-11-oxa b e n zob icyclo[4.2.1]-
n on a n e (syn -6a ). 1H NMR (300 MHz, C6D6) δ 1.20 (dddd,
J ) 0.9, 5.1, 9.6, 14.1 Hz, 2H), 1.38-1.51 (m, 2H), 1.59 (dt, J
) 5.1, 9.9 Hz, 1H), 1.62-1.69 (m, 1H), 1.97 (ddd, J ) 5.7,
9.6, 14.1 Hz, 1H), 2.10 (ddt, J ) 5.1, 7.5, 14.1 Hz, 1H), 5.19
(d, J ) 7.5 Hz, 1H), 5.29 (d, J ) 4.5 Hz, 1H), 6.68-6.78
(m, 2H), 6.96-7.04 (m, 2H), 9.14 (s, 1H). 13C NMR (75
MHz, C6D6) δ 24.2, 33.5, 37.5, 46.8, 81.1, 81.5, 120.5, 120.7,
127.5, 127.8, 142.2, 145.4, 202.2. IR (neat) 2966, 2910, 1725,
1412, 1263, 1062, 1013, 801 cm-1. EI-MS m/z ) 202 (M+•).
HRMS (EI) calcd for C13H14O2 202.0994, found 202.0989
(1R*,7R*)-4-Meth ylen e-2,12-d ioxa ben zobicyclo[5.2.1]-
d eca n e (3a ). To a stirring solution of a cis/trans mixture of
3-(4-hydroxy-3-methylenebutyl)-1,3-dihydro-2-benzofuran-1-
ol 12 in dry dichloromethane (500 mL) (1.1 g, 5.1 mmol) at
room temperature in the presence of MS 4Å (2.3 g) was added
p-toluenesulfonic acid monohydrate (97 mg, 0.51 mmol). The
reaction was kept at room temperature for 15 min and poured
into a saturated aqueous solution of sodium bicarbonate. The
aqueous phase was extracted with dichloromethane, and the
combined organic phase was rinsed with brine, dried over
anhydrous magnesium sulfate, and concentrated in vacuo. The
residue was purified by column chromatography (hexane/ether
) 6:1) to afford 637 mg (62%) of (1R*,7R*)-4-methylene-2,12-
(M+•). Capillary GC (OV-1701, 170 °C, inj/det 200 °C). tR
21.8 min.
)
(Z/E)-(1S*,6R*)-3-(Dim eth ylth exylsilyloxym eth ylen e)-
11-oxa ben zobicyclo[4.2.1]n on a n e (15a ). The assignments
1
dioxabenzobicyclo[5.2.1]decane 3a . H NMR (300 MHz, C6D6)
δ 1.48 (dt, J ) 3.6, 12.6 Hz, 1H), 1.64-1.70 (m, 1H), 1.95 (dt,
J ) 4.5, 13.2 Hz, 1H), 2.24 (ddt, J ) 4.2, 12.9, 14.4 Hz, 1H),
3.45 (d, J ) 12.9 Hz, 1H), 4.10 (d, J ) 12.9 Hz, 1H), 4.90 (s,
1H), 5.06 (s, 1H), 5.15 (t, J ) 3.3, 1H), 6.55 (s, 1H), 6.76 (d, J
) 6.9 Hz, 1H), 7.01-7.12 (m, 3H). 13C NMR (75 MHz, CDCl3)
δ 30.6, 38.0, 67.6, 82.6, 104.7, 117.2, 121.4, 123.4, 128.0, 129.5,
136.9, 143.1, 148.6. IR (neat) 2932, 1640, 1462, 1255, 1087,
915 cm-1. EI-MS m/z ) 202 (M+•). HRMS (EI) calcd for
1
1
of E/Z isomers were performed by H NMR, 13C NMR, H-1H
COSY, and 13C-1H COSY. 1H NMR (300 MHz, C6D6, E/Z
mixture) δ -0.15 (s, E-3H), -0.07 (s, Z-3H), -0.06 (s, E-3H),
-0.01 (s, Z-3H), 0.73 (s, E-3H), 0.75 (s, E-3H), 0.82 (s, Z-6H),
0.83 (d, J ) 6.9 Hz, E-6H), 0.87 (d, J ) 6.6 Hz, Z-6H), 1.39-
1.67 (m, E/Z-5H), 1.95 (d, J ) 13.8 Hz, E-1H), 1.96-2.18 (m,
E/Z-3H), 2.28-2.43 (m, E-2H), 2.57 (dt, J ) 1.2, 14.7 Hz, Z-1H),
2.63 (ddd, J ) 1.5, 5.7, 13.8 Hz, E-1H), 3.07 (ddd, J ) 1.2, 6.6,
14.7 Hz, Z-1H), 5.35 (appd, J ) 6.3 Hz, E/Z-3H), 5.41 (d, J )
6.0 Hz, Z-1H), 5.61 (s, E-1H), 5.96 (s, Z-1H), 6.72-7.03 (m,
E/Z-8H). 13C NMR (75 MHz, C6D6, E/Z mixture) δ -3.5, -3.3,
18.8, 18.9, 20.2, 20.3, 23.6, 25.3, 25.4, 27.6, 33.9, 34.4, 36.5,
37.6, 42.2, 81.4, 81.9, 82.0, 82.3, 116.6, 117.6, 120.3, 120.4,
120.7, 120.9, 127.1, 127.2, 127.3, 127.4, 136.2, 136.3, 143.6,
144.1, 144.3, 145.1. IR (neat) 2960, 1667, 1462, 1255, 1143,
C
13H14O2 202.0994, found 202.0997 (M+•).
cis/tr a n s-3-(3-ter t-Bu tyldiph en ylsilyloxym eth yl-3-bu te-
n yl)-1,3-d ih yd r o-2-ben zofu r a n -1-ol (11b). The titled com-
pound was prepared from 3-tert-butyldiphenylsilyloxy-2-
methylpropene according to the procedure described for cis/
trans mixture of 3-(3-dimethylthexylsilyloxymethyl-3-butenyl)-
1
1,3-dihydro-2-benzofuran-1-ol 11a . H NMR (300 MHz, C6D6,
835 cm-1
.
cis/trans mixture) δ 1.16 (s, 18H), 1.57-1.95 (m, 4H), 2.09-
2.30 (m, 4H), 3.58 (bs, 1H), 3.65 (bs, 1H), 4.16 (s, 2H), 4.18 (s,
2H), 4.93-4.99 (m, 3H), 5.24-5.28 (m, 1H), 5.35-5.37 (m, 2H),
6.33 (d, J ) 4.5 Hz, 1H), 6.38 (s, 1H), 6.76-6.79 (m, 2H), 6.99-
7.08 (m, 4H), 7.19-7.23 (m, 14 H), 7.75-7.80 (m, 5H). 13C NMR
(75 MHz, C6D6, cis/trans mixture) δ 19.5, 27.0, 28.5, 28.8, 34.5,
36.1, 66.8, 81.9, 82.6, 101.0, 109.1, 109.2, 121.1, 121.3, 123.3,
123.4, 127.7, 128.1, 128.3, 129.0, 129.1, 130.0, 140.1, 140.4,
142.8, 142.9, 148.1. IR (neat) 3364, 2934, 1657, 1464, 1112,
(Z/E)-(1S*,6R*)-3-(ter t-Bu t yld ip h en ylsilyloxym et h yl-
en e)-11-oxa ben zobicyclo[4.2.1]n on a n e (15b). The assign-
1
ments of E/Z isomers were performed by H NMR, 13C NMR,
1
1H-1H COSY, and 13C-1H COSY. H NMR (300 MHz, C6D6,
E/Z mixture) δ 1.05 (s, E-9H), 1.11 (s, Z-9H), 1.27-1.37 (m,
Z-1H), 1.49-1.57 (m, Z-1H), 1.73 (dddd, J ) 1.2, 5.7, 9.3, 13.2
Hz, E-1H), 1.81 (d, J ) 13.8 Hz, E-1H), 1.90-2.02 (m, Z-2H),
2.26 (ddt, J ) 5.4, 7.2, 13.2 Hz, E-1H), 2.48-2.64 (m, E-3H),
2.89 (dt, J ) 1.2, 14.4 Hz, Z-1H), 3.11 (ddd, J ) 1.2, 5.7, 14.4
Hz, Z-1H), 5.30 (d, J ) 5.4 Hz, E-1H), 5.37 (d, J ) 5.7 Hz,
Z-1H), 5.41 (d, J ) 6.9 Hz, E-1H), 5.50 (d, J ) 5.7 Hz, Z-1H),
5.78 (s, E-1H), 6.04 (s, Z-1H), 6.67-7.75 (m, Z/E-28H). 13C
NMR (75 MHz, C6D6, E/Z mixture) δ 19.3, 19.4, 23.9, 26.6,
26.7, 27.6, 33.7, 36.7, 37.2, 41.8, 81.7, 81.8, 81.9, 82.3, 116.8,
117.5, 120.4, 120.6, 120.9, 127.1, 127.2, 127.3, 127.4, 128.1,
130.0, 130.1, 133.2, 133.3, 133.4, 133.5, 135.6, 135.7, 135.9,
136.8, 136.9, 143.4, 143.9, 144.7, 145.2. IR (neat) 2932, 1667,
704 cm-1
.
Gen er a l P r oced u r e for Solid -Acid -Ca ta lyzed Oxon iu m
En e Reaction of (1R*,7R*)-4-m eth ylen e-2,12-dioxaben zobi-
cyclo[5.2.1]d eca n e (3a ). To a stirred solution of 3a (49 mg,
0.24 mmol) in dichloromethane (24 mL) at room temperature
was added solid acid. The reaction was kept at room temper-
ature for reported time, filtered through Celite, and concen-
trated in vacuo. The residue was purified by column chroma-
tography on silica gel (hexane/ether ) 3:1) to afford the
aldehyde 6.
1429, 1141, 1114, 702 cm-1
.
J . Org. Chem, Vol. 68, No. 3, 2003 1087

Mikami et al.
(1R*,7R*)-3-Dideu ter ated-4-m eth ylen e-2,12-dioxaben zo-
bicyclo[5.2.1]d eca n e (3b). The titled compound was pre-
pared from of 3-dideuterated-3-dimethylthexylsilyloxy-2-me-
thylpropene according to the procedure described for (1R*,7R*)-
4-methylene-2,12-dioxabenzobicyclo[5.2.1]decane 3a . 1H NMR
(300 MHz, C6D6) δ 1.47 (dt, J ) 3.0, 13.2 Hz, 1H), 1.65 (ddt, J
) 3.0, 5.1, 14.4 Hz, 1H), 1.95 (dt, J ) 4.2, 13.2 Hz, 1H), 2.24
(ddt, J ) 4.2, 12.9, 14.4 Hz, 1 H), 4.91 (d, J ) 0.9 Hz, 1H),
5.06 (s, 1H), 5.15 (t, J ) 3.3 Hz, 1H), 6.57 (s, 1H), 6.74-6.77
(m, 1H), 6.99-7.12 (m, 3H).13C NMR (75 MHz, C6D6) δ 30.5,
38.0, 82.5, 104.8, 116.1, 121.5, 123.4, 129.3, 138.2, 143.6, 149.3.
3,12-Did eu t er a t ed -3-for m yl-11-oxa b en zob icyclo[4.2.1]-
n on a n e (a n ti-6c). The titled compound was synthesized
according to the general procedure described for the solid-acid-
catalyzed oxonium ene reaction of the (1R*,7R*)-4-methylene-
2,12-dioxabenzobicyclo[5.2.1]decane 3a . 1H NMR (300 MHz,
C6D6) δ 0.52 (dddd, J ) 3.0, 10.5, 12.3, 14.4 Hz, 1H), 1.36-
1.45 (m, 2H), 1.47-1.57 (m, 1H), 1.70 (ddd, J ) 4.2, 12.3, 13.8
Hz, 1 H), 2.27 (dddd, J ) 1.2, 6.0, 8.4, 13.8 Hz, 1H), 2.35-
2.44 (m, 0.7H), 5.22 (d, J ) 8.4 Hz, 1H), 5.27 (d, J ) 4.2 Hz,
1H), 6.68-6.78 (m, 2H), 6.96-7.02 (m, 2H). 13C NMR (75 MHz,
C6D6) δ 21.2, 21.3, 35.4, 35.5, 36.4, 50.3, 50.4, 79.5, 83.4, 120.5,
120.7, 127.6, 127.8, 141.1, 146.1. IR (neat) 3030, 2928, 1711,
IR (neat) 3074, 2930, 1634, 1371, 1255, 1094, 1009 cm-1
.
P r ep a r a tion of 3-Did eu ter a ted -3-d im eth ylth exylsilyl-
oxy-2-m eth ylp r op en e. To a stirred suspension of lithium
aluminum deuteride (4.5 g, 107.2 mmol) and ether (450 mL)
at -78 °C was added methyl methacrylate (10.5 g, 104.9 mmol)
in ether (50 mL), and reaction temperature was gradually
warmed to room temperature. To this reaction mixture was
then added water (4.6 mL), 15% sodium hydroxide (4.6 mL),
water (13.8 mL), and ethyl acetate. The mixture was stirred
for 1 h, filtered, and concentrated. The crude product obtained
(8.1 g) was subjected to the next treatment without purifica-
tion. To a stirring solution of crude product (8.1 g) and dry
DMF (40 mL) were added dimethylthexylsilyl chloride (20.6
g, 136.6 mmol) in DMF (15 mL) and imidazole (14.3 g, 210
mmol) at 0 °C. The temperature of the reaction mixture was
warmed to room temperature and immersed for 3 h and then
poured into 1 N hydrochloric acid. The aqueous phase was
extracted with ether several times, and then the combined
organic phase was washed with saturated aqueous sodium
bicarbonate, water, and brine, dried over anhydrous magne-
sium sulfate, filtered, and concentrated in vacuo. The residue
was purified by column chromatography on silica gel (hexane/
ether ) 50:1) to afford 15.4 g (68%, 2 steps) of 3-dideuterated-
3-dimethylthexylsilyloxy-2-methylpropene. 1H NMR (300 MHz,
CDCl3) δ 0.11 (s, 6H), 0.87 (s, 6H), 0.90 (d, J ) 6.9 Hz, 6H),
1.64 (sept, J ) 6.9 Hz, 1H), 1.70 (s, 3H), 4.80 (s, 1H), 4.97 (s,
1H). 13C NMR (75 MHz, CDCl3) δ -3.4, 18.5, 19.0, 20.3, 25.3,
34.2, 109.2, 144.7. IR (neat) 2962, 1659, 1466, 1253, 1139,
1462, 1064, 1006 cm-1
.
Mixtu r e of (1S*,3S*,6R*)-12-Deu ter a ted -3-for m yl-11-
oxaben zobicyclo[4.2.1]n on an e (syn -6b) an d (1S*,3S*,6R*)-
3,12-Did eu t er a t ed -3-for m yl-11-oxa b en zob icyclo[4.2.1]-
n on a n e (syn -6c). The titled compound was synthesized
according to the general procedure described for the solid-acid-
catalyzed oxonium ene reaction of the (1R*,7R*)-4-methylene-
2,12-dioxabenzobicyclo[5.2.1]decane 3a . 1H NMR (300 MHz,
C6D6) δ 1.20 (dddd, J ) 1.2, 5.1, 9.9, 14.4 Hz, 1H), 1.38-1.51
(m, 1.3H), 1.59 (dt, J ) 5.4, 9.9 Hz, 1H), 1.62-1.68 (m, 1 H),
1.92-2.02 (m, 1H), 2.10 (ddt, J ) 5.1, 7.5, 14.1 Hz, 1H), 5.19
(d, J ) 7.5 Hz, 1H), 5.29 (dd, J ) 0.9, 5.4 Hz, 1H), 6.67-6.79
(m, 2H), 6.96-7.04 (m, 2H). 13C NMR (75 MHz, C6D6) δ 24.1,
24.2, 33.6, 37.3, 37.4, 46.6, 81.1, 81.5, 120.5, 120.7, 127.5, 127.8,
142.2, 145.4. IR (neat) 3030, 2928, 1711, 1462, 1071, 1007 cm-1
.
Ack n ow led gm en t. We thank J apan Waters Co.
Ltd. for its kind support to make LC/MS analysis.
Generous allotment of computational time from the
Institute for Molecular Science, Okazaki, J apan, and the
Global Scientific Information and Computing Center,
Tokyo Institute of Technology, is gratefully acknowl-
edged.
Su p p or tin g In for m a tion Ava ila ble: Geometries of the
representative stationary points. This material is available free
of charge via the Internet at http://pubs.acs.org.
1118, 830 cm-1
.
Mixt u r e of (1S*,3R*,6R*)-12-Deu t er a t ed -3-for m yl-11-
oxaben zobicyclo[4.2.1]n on an e (a n ti-6b) an d (1S*,3R*,6R*)-
J O020634J
1088 J . Org. Chem., Vol. 68, No. 3, 2003