Intramolecular cyclization of 2,7- or 2,8-bis-unsaturated esters mediated by (η2-propene)Ti(O-i-Pr)2. Facile construction of mono- and bicyclic skeletons with stereoselective introduction of a side chain. A synthesis of d-sabinene

Article abstract of DOI:10.1021/ja9716160

tert-Butyl 2-en-7-ynoate 6 was treated with (η²-propene)Ti(O-i-Pr)₂ (3), generated in situ from Ti(O-i-Pr)₄ or Ti(O-i-Pr)₃Cl and i-PrMgCl, in ether at -50 to -20°C to afford the product 8 in good yield. The presence of the intermediate titanabicycle 7 was verified by bis-deuterolysis with excess D₂O. When the titanabicycle 7 was treated with 1.1 equiv of i-PrOD and then worked up as usual, the monodeuterated product 10 was obtained with high sight selectivity and stereoselectivity. Other electrophiles such as aldehydes and ketones also reacted with the titanabicycle in a highly stereoselective manner to give cyclopentanes having a stereo-defined side chain. On the contrary, treatment of the corresponding ethyl ester, ethyl 8-(trimethylsilyl)-(E)-2-octen-7-ynoate (28), with 3 under the same conditions followed by the addition of 1.1 equiv of s-BuOH afforded 2-(trimethylsilyl)-1-bicyclo[3.3.0]- octen-3-one (32) in 80% yield. Quenching the same reaction mixture with i-PrOD, EtCHO, and Et₂CO in place of s-BuOH gave 4-deuterio (with exclusive deuterium incorporation), 4-(1-hydroxypropyl), and 4-(1-ethyl-1-hydroxypropyl) derivatives of the above bicyclic ketone (34, 35, and 36) in good yields. These electrophiles were always introduced from the convex face of the bicyclic skeleton. The stereochemistry of the cyclization could be controlled by an allylic substituent such as (tert-butyl)dimethylsiloxy or butyl group to a high degree yet with a reversal diastereoselection to give 45 or 47. The reaction of ethyl 7-octen-2-ynoate (56) and 3 at -50 to 0°C took place in a quite different way to afford 1-[(ethoxycarbonyl)methyl]bicyclo[3.1.0]hexane (64) in 74% yield after hydrolysis. If the simple hydrolysis is replaced by deuterolysis or the action of diethylketone, 1-[(ethoxycarbonyl)dideuteriomethyl] (with 99% deuterium incorporation), or 1-[(ethoxycarbonyl)(3-pentylidene)methyl] derivative of the above product (65 or 66) was obtained in good yields. A 7-en-2-ynoate having an internal Z-double bond such as 80 afforded a single stereoisomer 82 with the substituent at the endo position, of the bicyclic skeleton, suggesting that the stereochemical integrity of the Z-double bond of the starting material was retained in the product. An alkyl substituent at the allylic position of the substrates like 74 and 76 nicely controlled the stereochemistry of the cyclization to afford single products 75 and 77 with the substituent being placed in the exo orientation of the bicyclic structure. This high diastereoselectivity was successfully applied to an enantioselective synthesis of d-sabinene from an optically active enynoate via nearly complete chirality transfer.

Full text of DOI:10.1021/ja9716160

10014
J. Am. Chem. Soc. 1997, 119, 10014-10027
Intramolecular Cyclization of 2,7- or 2,8-Bis-unsaturated Esters
Mediated by (η2-Propene)Ti(O-i-Pr)2. Facile Construction of
Mono- and Bicyclic Skeletons with Stereoselective Introduction
of a Side Chain. A Synthesis of d-Sabinene
Hirokazu Urabe, Ken Suzuki, and Fumie Sato*
Contribution from the Department of Biomolecular Engineering, Tokyo Institute of Technology,
4259 Nagatsuta-cho, Midori-ku, Yokohama, Kanagawa 226, Japan
ReceiVed May 19, 1997X
Abstract: tert-Butyl 2-en-7-ynoate 6 was treated with (η2-propene)Ti(O-i-Pr)2 (3), generated in situ from Ti(O-i-
Pr)4 or Ti(O-i-Pr)3Cl and i-PrMgCl, in ether at -50 to -20 °C to afford the product 8 in good yield. The presence
of the intermediate titanabicycle 7 was verified by bis-deuterolysis with excess D2O. When the titanabicycle 7 was
treated with 1.1 equiv of i-PrOD and then worked up as usual, the monodeuterated product 10 was obtained with
high site selectivity and stereoselectivity. Other electrophiles such as aldehydes and ketones also reacted with the
titanabicycle in a highly stereoselective manner to give cyclopentanes having a stereo-defined side chain. On the
contrary, treatment of the corresponding ethyl ester, ethyl 8-(trimethylsilyl)-(E)-2-octen-7-ynoate (28), with 3 under
the same conditions followed by the addition of 1.1 equiv of s-BuOH afforded 2-(trimethylsilyl)-1-bicyclo[3.3.0]-
octen-3-one (32) in 80% yield. Quenching the same reaction mixture with i-PrOD, EtCHO, and Et2CO in place of
s-BuOH gave 4-deuterio (with exclusive deuterium incorporation), 4-(1-hydroxypropyl), and 4-(1-ethyl-1-hydrox-
ypropyl) derivatives of the above bicyclic ketone (34, 35, and 36) in good yields. These electrophiles were always
introduced from the convex face of the bicyclic skeleton. The stereochemistry of the cyclization could be controlled
by an allylic substituent such as (tert-butyl)dimethylsiloxy or butyl group to a high degree yet with a reversal
diastereoselection to give 45 or 47. The reaction of ethyl 7-octen-2-ynoate (56) and 3 at -50 to 0 °C took place in
a quite different way to afford 1-[(ethoxycarbonyl)methyl]bicyclo[3.1.0]hexane (64) in 74% yield after hydrolysis.
If the simple hydrolysis is replaced by deuterolysis or the action of diethyl ketone, 1-[(ethoxycarbonyl)dideuteriomethyl]
(with 99% deuterium incorporation), or 1-[(ethoxycarbonyl)(3-pentylidene)methyl] derivative of the above product
(65 or 66) was obtained in good yields. A 7-en-2-ynoate having an internal Z-double bond such as 80 afforded a
single stereoisomer 82 with the substituent at the endo position of the bicyclic skeleton, suggesting that the
stereochemical integrity of the Z-double bond of the starting material was retained in the product. An alkyl substituent
at the allylic position of the substrates like 74 and 76 nicely controlled the stereochemistry of the cyclization to
afford single products 75 and 77 with the substituent being placed in the exo orientation of the bicyclic structure.
This high diastereoselectivity was successfully applied to an enantioselective synthesis of d-sabinene from an optically
active enynoate via nearly complete chirality transfer.
Introduction
Intramolecular cyclizations of olefins and acetylenes have
been achieved by a variety of transition metal complexes in
either a catalytic or a stoichiometric manner with respect to the
metal.1,2 Broad and easy availability of the open-chain, bis-
unsaturated precursors 1 (eq 1) makes this method very attractive
for the preparation of cyclic compounds. Particularly, the
stoichiometric reactions usually leave metallabicycles 2 as the
intermediate, which can be utilized for further synthetic elabora-
tion. Frequently encountered are the titana- or zirconabicycles
generated with low-valent Cp2Ti or Cp2Zr complexes, and their
applications to carbon-carbon bond formation or functional-
ization with second reagents such as an electrophile (El+) or
carbon monoxide (or equivalent isonitriles) have been amply
demonstrated as shown in eq 1 (MLn ) TiCp2 or ZrCp2).1
Recently, we reported that a low-valent titanium alkoxide,
(η2-propene)Ti(O-i-Pr)2 (3 ) MLm in eq 1) prepared in situ from
Ti(O-i-Pr)4 or Ti(O-i-Pr)3Cl and 2 equiv of i-PrMgCl,3-5 also
promotes the above bicyclization.6 This cyclization proved to
(2) For recent reviews for general survey, see: Trost, B. M. Angew.
Chem., Int. Ed. Engl. 1995, 34, 259. Ojima, I.; Tzamarioudaki, M.; Li, Z.;
Donovan, R. J. Chem. ReV. 1996, 96, 635. Lautens, M.; Klute, W.; Tam,
W. Chem. ReV. 1996, 96, 49. Cyclization with Co: Vollhardt, K. P. C.
Angew. Chem., Int. Ed. Engl. 1984, 23, 539; Schore, N. E. In ComprehensiVe
Organic Synthesis; Trost, B. M., Ed.; Pergamon Press: Oxford, U.K., 1991;
Vol. 5, p 1037. With Fe: Takacs, J, M.; Anderson, L. G.; Newsome, P. W.
J. Am. Chem. Soc. 1987, 109, 2542. Kno¨lker, H.-J.; Heber, J. Synlett 1993,
924. With Mo or W: Jeong, N.; Lee, S. J.; Lee, B. Y.; Chung, Y. K.
Tetrahedron Lett. 1993, 34, 4027. With Nb: Kataoka, Y.; Takai, K.; Oshima,
K.; Utimoto, K. J. Org. Chem. 1992, 57, 1615. With Ni-Cr: Trost, B. M.;
Tour, J. M. J. Am. Chem. Soc. 1987, 109, 5268. With Ni: Tamao, K.;
Kobayashi, K.; Ito, Y. Synlett 1992, 539. With Pd: Trost, B. M. Acc. Chem.
Res. 1990, 23, 34. With Ru or Rh: Chatani, N.; Murai, S. Synlett 1996,
414. With Ta: Takai, K.; Yamada, M.; Odaka, H.; Utimoto, K. J. Org.
Chem. 1994, 59, 5852. With Pt: Chatani, N.; Furukawa, N.; Sakurai, H.;
Murai, S. Organometallics 1996, 15, 901.
X Abstract published in AdVance ACS Abstracts, October 1, 1997.
(1) For reviews on early transition metal-mediated cyclizations, see: (a)
Yasuda, H.; Tatsumi, K.; Nakamura, A. Acc. Chem. Res. 1985, 18, 120.
(b) Buchwald, S. L.; Nielsen, R. B. Chem. ReV. 1988, 88, 1047. (c) Negishi,
E. In ComprehensiVe Organic Synthesis; Trost, B. M., Ed.; Pergamon
Press: Oxford, U.K., 1991; Vol. 5, p 1163. (d) Negishi, E.; Takahashi, T.
Acc. Chem. Res. 1994, 27, 124. (e) Ohff, A.; Pulst, S.; Lefeber, C.; Peulecke,
N.; Arndt, P.; Burkalov, V. V.; Rosenthal, U. Synlett 1996, 111. (f) Sato,
F.; Urabe, H. In Handbook of Grignard Reagents; Silverman, G. S., Rakita,
P. E., Eds.; Marcel Dekker: New York, 1996, p 23.
S0002-7863(97)01616-8 CCC: $14.00 © 1997 American Chemical Society

Cyclization of 2,7- or 2,8-Bis-unsaturated Esters
J. Am. Chem. Soc., Vol. 119, No. 42, 1997 10015
be quite general with respect to the substrates. To broaden the
scope, we were interested in the cyclization of substrates having
a functionalized unsaturated bond. So far, only vinyl and
alkynyl ethers or halides (R ) OR′ or halogen in eq 1) have
been examined as the reaction partner in early transition metal-
mediated cyclizations.7 Keeping the idea in mind that electron-
deficient olefins may be prone to interact with a low-valent,
hence electron-rich, metal center, we undertook to verify the
feasibility of the intramolecular cyclization of substrates like 4
having an R,â-unsaturated ester moiety (eq 2).8 Gratifyingly,
Scheme 1
Scheme 2
the cyclization proceeds smoothly with the ester group remaining
intact to give the titanabicycle 59 as a reasonably stable species.
In some cases, the cyclization of 4 was followed by some novel
transformations that were more than what we had expected.10
Scheme 1 illustrates such representative reactions. The
reaction patterns are simply classified according to the structure
of the substrates. The first type is a monocyclization, which is
observed for R,â-olefinic esters having a hindered ester group.
The intermediate titanabicycles generated herein have an
alkenyl-titanium bond as well as a titanium enolate moiety,
the latter of which preferentially reacts with an electrophile (El+)
in a highly diastereoselective manner to provide a potential
method for the stereoselective construction of the side chain in
addition to the cyclization. The same esters, yet having a less
hindered ester group such as methyl or ethyl, underwent the
monocyclization as well, but it is followed by a second ring
closure initiated by the reaction with an electrophile, giving
eventually bicyclic ketones (Scheme 1, type I of the tandem
cyclization).11 R,â-Acetylenic esters experienced another type
of tandem cyclization (type II), which led to the formation of a
cyclopropane ring via the addition of the alkyl-titanium bond
of the titanabicycle to an electron-deficient carbon in the same
molecule. An appropriate substituent in the tether portion of
these bis-unsaturated esters can favorably regulate the stereo-
chemistry of the cyclization, serving for substrate-controlled
asymmetric cyclization.
(3) The generation of olefin (derived from the added Grignard reagent)-
titanium complexes from Ti(OR)4 and Grignard reagents was first reported
by Kulinkovich et al. They utilized this complex as 1,2-bis-anionic species,
see: Kulinkovich, O. G.; Sviridov, S. V.; Vasilevski, D. A. Synthesis 1991,
234. See also: de Meijere, A.; Kozhushkov, S. I.; Spaeth, T.; Zefirov, N.
S. J. Org. Chem. 1993, 58, 502. Lee, J.; Kim, H.; Cha, J. K. J. Am. Chem.
Soc. 1995, 117, 9919. Corey, E. J.; Rao, S. A.; Noe, M. C. J. Am. Chem.
Soc. 1994, 116, 9345.
(4) A similar titanium species having aryloxy groups in place of the
alkoxy group is known. Balaich, G. J.; Rothwell, I. P. J. Am. Chem. Soc.
1993, 115, 1581. Balaich, G. J.; Rothwell, I. P. Tetrahedron 1995, 51, 4463.
(5) For the initial reports on the use of (η2-propene)Ti(O-i-Pr)2 prepared
in situ from Ti(O-i-Pr)4 and i-PrMgCl as a divalent titanium reagent, see:
Harada, K.; Urabe, H.; Sato, F. Tetrahedron Lett. 1995, 36, 3203. Kasatkin,
A.; Nakagawa, T.; Okamoto, S.; Sato, F. J. Am. Chem. Soc. 1995, 117,
3881. See also: Okamoto, S.; Kasatkin, A.; Zubaidha, P. K.; Sato, F. J.
Am. Chem. Soc. 1996, 118, 2208. Lee, J.; Kim, H.; Cha, J. K. J. Am. Chem.
Soc. 1996, 118, 4198.
(6) (a) Urabe, H.; Hata, T.; Sato, F. Tetrahedron Lett. 1995, 36, 4261.
(b) Urabe, H.; Takeda, T.; Sato, F. Tetrahedron Lett. 1996, 37, 1253. (c)
Urabe, H.; Sato, F. J. Org. Chem. 1996, 61, 6756.
(7) Nugent, W. A.; Thorn D. L.; Harlow, R. L. J. Am. Chem. Soc. 1987,
109, 2788. Takahashi, T.; Kondakov, D. Y.; Xi, Z.; Suzuki, N. J. Am. Chem.
Soc. 1995, 117, 5871.
(8) To our best knowledge, early transition metal-mediated bicyclization
of R,â-unsaturated ester and another olefin or acetylene has not been
reported. However, reductive homocoupling of dimethyl acetylenedicar-
boxylate or R,â-unsaturated aryl ketones with Cp2Ti(CO)2 has been reported.
Demerseman, B.; Dixneuf, P. H. J. Chem. Soc., Chem. Commun. 1981,
665. Schobert, R.; Maaref, F.; Du¨rr, S. Synlett 1995, 83.
(9) Although the structure of 5 (and the relevant species hereafter) is
tentatively drawn in the form of R-titana ester for simplicity, its exact nature
is unknown and, accordingly, it may be the corresponding titanium enolate
(for example, see Scheme 3).
Results and Discussion
Monocyclization and Diastereoselective Extension of the
Side Chain. tert-Butyl 2-en-7-ynoate 6 was treated with (η2-
propene)Ti(O-i-Pr)2 (3), generated in situ from Ti(O-i-Pr)4 (1.2
equiv) and i-PrMgCl (2.4 equiv) in ether, first at -78 °C and
finally at -20 °C to ensure the complete cyclization. This
procedure is an adaptation of our standard reaction conditions
reported previously.6 After aqueous workup, a virtually sole
product 8 was obtained in good yield (Scheme 2). The E
geometry of its double bond was confirmed by NOE study of
1H NMR spectroscopy. The presence of the intermediate
titanabicycle 7 was verified by the bis-deuterolysis with excess
D2O to give 9. Alternatively, the titanabicycle 7 was first treated
with 1.1 equiv of i-PrOD and then worked up as above to afford
the monodeuterated product 10, indicating the higher reactivity
of the titanated ester portion of 7 toward the proton as compared
to its alkenyltitanium moiety.12,13 This difference in the
reactivities between both carbon-titanium bonds is the key in
the following reactions.
In addition to this site selectivity, another important feature
is that the deuterium is exclusively incorporated in place of one
(11) For reviews on tandem reactions, see: Bunce, R. A. Tetrahedron
1995, 48, 13103. Parsons, P. J.; Penkett, C. S.; Shell, A. J. Chem. ReV.
1996, 96, 195.
(10) Portions of this work have been communicated. Suzuki, K.; Urabe,
H.; Sato, F. J. Am. Chem. Soc. 1996, 118, 8729.

10016 J. Am. Chem. Soc., Vol. 119, No. 42, 1997
Urabe et al.
Figure 3. NOE study on the structure of 12.
Figure 1. 1H NMR analysis on the structure of 10.
in the synthetic point of view. The titanacycle 7 and formal-
dehyde afforded a nearly single product 11 (eq 3). Only a small
Figure 2. Carbon-metal bond reacting with aldehydes and ketones.
particular hydrogen of the two R-protons of the ester group.
The stereochemical assignment to the deuterated position as
depicted in Scheme 2 was unambiguously made by the following
1H NMR analysis. Figure 1 shows a Newman projection (view
from ester R-carbon to ring carbon) of the most stable conformer
8-10. Both protons Ha and Hb R to the ester group (δ 2.11
and δ 2.50 ppm) were distinguished from each other on the
basis of following: (i) the downfield shift for Hb as compared
to Ha owing to the deshielding effect of the nearby olefinic
bond, (ii) the fact that the coupling constants observed between
Ha/Hc and Hb/Hc shown in the figure satisfy the calculated
values by the Karplus equation based on a molecular model,
and (iii) the NOE observed for the proton Hb and the vinylic
proton, but not between Ha and the vinylic proton. On
deuterolysis, proton Ha (δ 2.11 ppm) was exclusively exchanged
to deuterium to give 9 or 10.
Reaction of metallacycles with carbon electrophiles such as
carbonyl and related compounds should provide a straightfor-
ward method for the side-chain extension after the cyclization.
These reactions have been documented for representative types
of metallabicycles of early transitions metals. Figure 2 sum-
marizes the position where the carbon-metal bond is cleaved
with aldehydes. The titanacyclopentenes and -pentadienes react
with aldehydes at their alkenyl-titanium bond,6c,14 while Cp2-
zirconacyclopentanes and -pentenes afford adducts at their
alkyl-zirconium bond.1b,15 Both titana- and zirconabicycles
having an R-vinyl group are known to attack carbonyl com-
pounds at the terminal carbon of the vinyl group.1b,6b,16 The
degrees of the site selectivity generally fall within a very high
range.
amount of a byproduct which may be the minor diastereoisomer
of 11 was detected. The reaction took place at the titanated
ester in 7 without any complication, and no adduct arising from
the alkenyl-titanium moiety was observed under these reaction
conditions.17 The shown stereochemistry of 11 stems from its
cyclization to tetrahydrofuran 12 (eq 3), the structure of which
was determined by NOE study on H NMR spectroscopy to
have the (thermodynamically less stable) endo-ester group
(Figure 3).
It is noteworthy that the high diastereoselectivity found for
the deuterolysis (Scheme 2) was preserved in the carbonyl
addition, which means that the stereogenic centers with respect
to the cyclopentane ring and the ester R-carbon could be
efficiently created.18 This type of highly 1,2-diastereoselective
construction of the side chain from the metallacycles is the first
demonstration in the early transition metal-mediated cyclizations,
which complements the previously reported 1,3-15 or 1,4-
stereoselectivities6c involving the orientation of the hydroxy
group arising from the aldehyde addition. Other results are
summarized in Table 1. The same reactions of the titanabicycles
generated from 6, (Z)-6, 15, and 17 with a few carbonyl
compounds always realized the stereoselective extension of the
side chains (entries 2, 3, 5, 6, and 9). The depicted structures
of these products were deduced provided that the reaction took
place in the same sense as 10 and 11. It should be emphasized
that the stereochemical integrity of the olefinic portion of the
starting materials 6 and (Z)-6 was completely lost during the
1
(16) Negishi, E.; Miller, S. R. J. Org. Chem. 1989, 54, 6014. Dimmock,
P. W.; Whitby, R. J. J. Chem. Soc., Chem. Commun. 1994, 2323. Hanzawa,
Y.; Harada, S.; Nishio, R.; Taguchi, T. Tetrahedron Lett. 1994, 35, 9421.
Luker, T.; Whitby, R. J. Tetrahedron Lett. 1994, 35, 9465.
In relation to the above discussion, reaction of the new
titanabicycle 7 with carbonyl compounds should be of interest
(12) For the general reactivity of carbon-titanium bonds, see: Reetz, M.
T. In Organotitanium Reagents in Organic Synthesis; Springer-Verlag:
Berlin, 1986; p 116. See also the following: Ferreri, C.; Palumbo, G.;
Caputo, R. In ComprehensiVe Organic Synthesis; Trost, B. M., Ed.;
Pergamon Press: Oxford, U.K., 1991; Vol. 1, p 139. Reetz, M. T. In
Organometallics in Synthesis; Schlosser, M., Ed.; Wiley: Chichester, U.K.,
1994; p 195.
(13) Cf. For regioselection in protonation of other metallacyclopentenes
of early transition metal, see: (a) Aoyagi, K.; Kasai, K.; Kondakov, D. Y.;
Hara, R.; Suzuki, N.; Takahashi, T. Inorg. Chim. Acta 1994, 220, 319. (b)
Mori, M.; Uesaka, N.; Saitoh, F.; Shibasaki, M. J. Org. Chem. 1994, 59,
5643.
(17) Ordinary alkenyltitanium species were reported to react with
aldehydes. Boeckman, R. K., Jr.; O’Connor, K. J. Tetrahedron Lett. 1989,
30, 3271. Schick, H.; Spanig, J.; Mahrwald, R.; Bohle, M.; Reiher, T.;
Pivnitsky, K. K. Tetrahedron 1992, 48, 5579.
(18) 1,2-Diastereoselective introduction of a side chain to a ring structure
is often necessary transformation. With aldol reactions: Heathcock, C. H.
In ComprehensiVe Organic Synthesis; Trost, B. M., Ed.; Pergamon Press:
Oxford, U.K., 1991; Vol. 2, p 181. With 1,4-additions: Perlmutter, P.
Conjugate Addition Reactions in Organic Synthesis; Pergamon Press:
Oxford, U.K., 1992; p 137. With sigmatropy rearrangements: Hill, R. K.
In ComprehensiVe Organic Synthesis; Trost, B. M., Ed.; Pergamon Press:
Oxford, U.K., 1991; Vol. 5, p 785. Wipf, P. In ComprehensiVe Organic
Synthesis; Trost, B. M., Ed.; Pergamon Press: Oxford, U.K., 1991; Vol. 5,
p 827. Wilson, S. R. In Organic Reactions; Paquette, L. A., Ed.; Wiley:
New York, 1993; Vol. 43, p 93. With radical reactions: Curran, D. P.
Synthesis 1988, 417.
(14) Hill, J. E.; Balaich, G.; Fanwick, P. E.; Rothwell, I. P. Organome-
tallics 1993, 12, 2911.
(15) Cope´ret, C.; Negishi, E.; Xi, Z.; Takahashi, T. Tetrahedron Lett.
1994, 35, 695.

Cyclization of 2,7- or 2,8-Bis-unsaturated Esters
J. Am. Chem. Soc., Vol. 119, No. 42, 1997 10017
Table 1. Monocyclization of Bis-unsaturated Esters and Amides
Scheme 3
and Subsequent Reactions with Electrophilesa
Contrarily, path c assumes an electrophilic addition to the
carbon-titanium bond with retention of configuration.21 To
accommodate the tert-butoxycarbonyl group to this reaction
course, it should be located in axial direction in the reacting
species, although this position is considerably encumbered.
Finally, the most plausible path among the three would be path
b because one side of the π-plane of the titanium enolate in 25
may be effectively blocked owing to the seven-membered
oxatitanacycloheptadiene structure similar to those of enolates
of medium-ring ketones or lactones.22 This could reasonably
account for (i) the observed sense of the addition irrespective
of the kind of electrophiles, (ii) the uniformly high diastereo-
selectivities, and (iii) the loss of the geometrical integrity of
the starting R,â-unsaturated ester (E or Z) after the reaction.
Tandem Cyclization of r,â-Olefinic Esters (Type I).
Although we had successfully carried out the cyclization of the
tert-butyl enynoates as described above, we were rather confused
to encounter difficulties when we attempted to obtain the same
products starting from the corresponding ethyl esters. Ethyl
2-en-7-ynoate 28 (1 equiv) was treated with 3 (1.2 equiv,
prepared from Ti(O-i-Pr)3Cl) under the standard reaction
conditions to afford the desired cyclized product 31, but together
with a more polar product in varying ratios from run to run
(ca. 6:4-3:7) after aqueous workup (eq 4).
a See Scheme 2 and eq 3. b Diastereoselectivity with respect to bold
lines. “Single” refers to a case wherein the minor isomer could not be
identified even after careful analysis.
reaction to give the same deuterated and aldol-type products
(cf. Scheme 2 and entry 4 in Table 1, and entries 2 and 5),19
which is to be discussed afterward. The monocyclization was
the exclusive path also for an N,N-dialkylamide 21 as exempli-
fied in entries 10 and 11. The highly stereoselective deuterolysis
of the titanated amide was again observed, and the structure of
23 was assigned in an analogous way to that of 10 (Figure 1)
The structure of this byproduct was deduced by spectroscopic
analysis, which disclosed the lack of the ester moiety yet
revealed the presence of a cyclopentenone skeleton with a
vinylic trimethylsilyl group. Finally, the proposed structure 32
(El ) H) was firmly established in comparison with an authentic
1
by H NMR analysis.
The stereochemical outcome may be explained by the three
likely models of electrophilic attack to the titanabicycle, which
include an R-titana ester and/or titanium enolate12 and are
illustrated in Scheme 3. In path a, the sterically demanding
tert-butoxycarbonyl group of 24 occupies the equatorial position
and an electrophile must attack the carbon-titanium bond with
inversion of configuration20 to give the observed product 27.
(20) Even though we intensively searched the literature, we could not
find any dependable data on the stereochemistry of the electrophilic attack
to a titanium-carbon bond adjacent to an ester group.
(21) This stereochemistry was proposed for other early transition metal
complexes. Four-membered transition state was given in the reaction of a
zirconacyclopentene with aldehydes to rationalize the stereochemical result
(ref 15). Deuteration of a zirconacyclopentene most likely proceeded with
retention of configuration. See ref 13b.
(19) For the issue on transmission of olefin geometry to the product,
see and compare: Negishi, E.; Choueiry, D.; Nguyen, T. B.; Swanson, D.
R. J. Am. Chem. Soc. 1994, 116, 9751. Hicks, F. A.; Kablaoui, N. M.;
Buchwald, S. L. J. Am. Chem. Soc. 1996, 118, 9450.
(22) Evans, D. A. In Asymmetric Synthesis; Morrison, J. D., Ed.;
Academic Press: Orlando, FL, 1984; Vol. 3, p 73. Still, W. C.; Galynker,
I. Tetrahedron 1981, 37, 3981.

10018 J. Am. Chem. Soc., Vol. 119, No. 42, 1997
Urabe et al.
Table 2. Type I Tandem Cyclization of Enynoates and Subsequent
second ring closure as described above to give the products 35
and 36 in good yields. In all of these reactions, the electrophiles
were introduced to the convex face of the bicyclo[3.3.0]octene
system in high selectivities. This stereochemical outcome,
which apparently originates at the stage of the initial electrophilic
attack to the titanabicycle and is, of course, consistent with the
observation of 10 and 11 (Scheme 2 and eq 3), was indepen-
dently determined on the basis of the coupling constants and/
Reactions with Electrophilesa
1
or NOE studies of H NMR spectroscopy.
Additional results of the cyclization of type I starting from a
variety of substrates are summarized in entries 5-10 in Table
2.24,25 The reaction has broad applicability to 2-en-7-ynoates
and also a 2-en-8-ynoate. The stereochemical integrity of the
olefinic portion of the starting materials 28 and 37 was again
lost in the (deuterated) products (entries 2 and 5) in accord with
the observation discussed in the monocyclization. Control of
the stereochemistry of the cyclization by an appropriate sub-
stituent in the substrate is often a necessary operation in
conjunction with an asymmetric cyclization via chirality induc-
tion.26,27 The siloxy substituent at the propargylic position in
42 showed a moderate effect on the ratio of the diastereoisomers
43 (entry 8), which were separable by routine flash chroma-
tography. The same substrate having a benzyloxy group in place
of the siloxy substituent did not improve this selectivity. In
contrast, an allylic substituent of R,â-unsaturated ester 44 or
46 nicely controlled the direction of the cyclization to give the
products 45 and 47 in high selectivities. Pure samples of 45
and 47 free of the minor isomers could be easily obtained by
chromatography on silica gel. The prevailing influence of
nearby 1,2-interaction of the diastereomeric centers (45 and 47)
over that of remote 1,3-relationship (43) would account for the
higher degree of diastereoselectivities in the former. 1H NMR
analysis revealed that the stereochemistry of cyclization con-
trolled by the siloxy or the alkyl group is in reverse to each
other. It is also noteworthy that the siloxy group-directed
cyclization of 44 took place with the opposite orientation to
the carbonylative cyclization of a similar substrate 48 (eq 5),
which placed the benzyloxy group at the exo position to give
49.24a,25b Thus, these methods could be used complementarily
to prepare the oxygenated bicyclic structures, although the origin
a See eq 4. b H+ or D+ refers to 1.1 equiv of s-BuOH or i-PrOD.
c Major isomer is shown. d Diastereoselectivity with respect to bold or
dotted lines. “Single” refers to a case wherein the minor isomer could
not be identified even after careful analysis. e Exclusively deuterated.
sample.23 At this stage, we became aware that the ketone 32
was formed via intramolecular attack of the alkenyltitanium
moiety of 30 to its ester group, both of which were generated
through the fast and selective protonation to the titanabicycle
29 as described in the preceding section. The shaky product
ratios should reflect the subtle change in the noncontrolled
workup conditions which allow the following two reactions to
compete with each other: the resulting alkenyltitanium 30
suffered further protonation to afford 31, or it underwent the
intramolecular attack to the ester group to give 32. To suppress
the second proton delivery to 30, we terminated the reaction
with a limited amount of the proton source (1.1 equiv of s-BuOH
to 28), which, in fact, enabled a selective formation of the ketone
32 uniformly in good yields (80% in isolation or 90%
(24) An alternative approach to the preparation of the cyclic ketones in
type I involves transition metal-catalyzed or -mediated cyclization of dienes
and enynes followed by carbonylation with carbon monoxide or isonitriles.
For a comprehensive survey, see refs 1 and 2. For recent reports on early
transition metal-promoted carbonylation, see: with Cp2Ti complex: (a)
Berk, S. C.; Grossman, R. B.; Buchwald, S. L. J. Am. Chem. Soc. 1994,
116, 8593. (b) Hicks, F. A.; Buchwald, S. L. J. Am. Chem. Soc. 1996, 118,
11688. With (i-PrO)2Ti complex: (c) reference 6a. Preparation of bicyclic
ketone (or imine)-zirconium complexes via zirconium-mediated cyclization
and carbonylation of dienes and enynes and their reactions with electrophiles
were reported, see: (d) Probert, G. D.; Whitby, R. J.; Coote, S. J.
Tetrahedron Lett. 1995, 36, 4113. (e) Barluenga, J.; Sanz, R.; Fan˜ana´s, F.
J. J. Chem. Soc., Chem. Commun. 1995, 1009.
(25) For application of these bicyclic ketones as starting materials for
the synthesis of naturally occurring products, see: (a) Trost, B. M. Chem.
Soc. ReV. 1982, 11, 141. (b) Agnel, G.; Negishi, E, J. Am. Chem. Soc.
1991, 113, 7425. (c) Agnel, G.; Owczarczyk, Z.; Negishi, E. Tetrahedron
Lett. 1992, 33, 1543. (d) Uesaka, N.; Saitoh, F.; Mori, M.; Shibasaki, M.;
Okamura, K.; Date, T. J. Org. Chem. 1994, 59, 5633. (e) Magnus, P.;
Principe, L. M.; Slater, M. J. J. Org. Chem. 1987, 52, 1483. (f) Jeong, N.;
Lee, B. Y.; Lee, S. M.; Chung, Y. K.; Lee, S.-G. Tetrahedron Lett. 1993,
34, 4023. (g) Domon, K.; Masuya, K.; Tanino, K.; Kuwajima, I. Tetrahedron
Lett. 1997, 38, 465.
1
determined by H NMR spectroscopy) (entry 1 in Table 2). If
the titanium reagent 3 prepared from Ti(O-i-Pr)3Cl was replaced
by the one prepared from Ti(O-i-Pr)4, the yield of 32 determined
by 1H NMR dropped to 81%. Deuterolysis of the same reaction
mixture of 29 with excess D2O afforded a mixture of 33 (97%
D in place of one particular hydrogen R to the ester group and
89% D at the vinylic position) and 34, but 1.1 equiv of i-PrOD
gave cleanly 34 (eq 4 and entry 2 in Table 2). Gratifyingly,
the electrophile involves not only proton (or deuterium) but also
carbonyl compounds. Thus, the titanabicycle 29 could be
trapped with propionaldehyde or diethyl ketone to promote the
(26) Hoveyda, A. H.; Evans, D. A.; Fu, G. C. Chem. ReV. 1993, 93,
1307.
(27) Diastereoselectivities in substrate-controlled, early transition metal-
mediated ring closure were extensively studied. See ref 1c and the following
recent reports: RajanBabu, T. V.; Nugent, W. A.; Taber, D. F.; Fagan, P.
J. J. Am. Chem. Soc. 1988, 110, 7128. Taber, D. F.; Louey, J. P. Tetrahedron
1995, 51, 4495. Pagenkopf, B. L.; Lund, E. C.; Livinghouse, T. Tetrahedron
1995, 51, 4421. Miura, K.; Funatsu, M.; Saito, H.; Ito, H.; Hosomi, A,
Tetrahedron Lett. 1996, 37, 9059.
(23) Negishi, E.; Holmes, S. J.; Tour, J. M.; Miller, J. A.; Cederbaum,
F. E.; Swanson, D. R.; Takahashi, T. J. Am. Chem. Soc. 1989, 111, 3336.

Cyclization of 2,7- or 2,8-Bis-unsaturated Esters
J. Am. Chem. Soc., Vol. 119, No. 42, 1997 10019
Table 3. Type I Tandem Cyclization of 2,7-Dienoates and
Subsequent Reactions with Electrophilesa
of the unusual role of the allylic siloxy group in the present
cyclization can not be explained.
2,7-Dienoates 50 and 52 having a terminal double bond
behaved in a way similar to 2-en-7-ynoates (Table 3). We were
able to isolate only cis-fused bicyclic ketone as the product of
the tandem cyclization. Neither its trans-isomer nor the trans-
substituted monocyclic product that may be reluctant to undergo
the second ring closure could be seen. These facts could be
attributed to the good cis-selectivity in the first cyclization step,
which is in contrast to the cyclization of unfunctionalized 1,6-
dienes affording a trans-disubstituted cyclopentane as the major
product.6a The unsaturated ester having another internal olefin
such as 55 only resulted in a complicated reaction (entry 4).
We emphasize that the trapping of the titanabicycle, generated
from 52, with 1.5 equiv of propionaldehyde afforded the aldol
product 54 virtually as a single isomer (entry 3). While the
stereochemistry of its ring junction could be determined to be
cis, that of the aldol moiety has not been assigned yet. From
the synthetic point of view, this reaction demonstrated a one-
pot preparation of an aldol of the defined regiochemistry (eq
6). Although several transition metal-mediated transformations
a See eq 4. b H+ refers to 1.1 equiv of s-BuOH. c After dehydration
of the aldol product (TsOH, C6H6, reflux). d See text.
However, when the titanabicycle generated at -50 °C was
simply allowed to warm to a higher temperature up to 0 °C,
the above product 58 completely disappeared and a new product
64 was obtained in good yield (eq 9). Its structure having a
involving cyclization and carbonylation of dienes or enynes may
serve for the preparation of the parent ketone 53 itself,24 further
extension of a carbon chain is not usually possible and even a
successive aldol reaction will not guarantee the regioselection,
particularly in the case of nearly symmetrical 53.
Tandem Cyclization of r,â-Acetylenic Esters (Type II).
In contrast to the aforementioned reactions starting from an R,â-
olefinic ester, R,â-acetylenic esters underwent another type of
cyclization (type II in Scheme 1). 7-En-2-ynoate 56 afforded
the monocyclization product 58 (91%) after the reaction with 3
under the standard conditions (-50 °C, 2 h)6 followed by
aqueous workup (eq 7). The intermediate titanabicycle 57 was
confirmed by the isolation of 59 (>99% D2) after deuterolysis.
cyclopropane ring was first suggested by NMR and IR
spectroscopy and was eventually confirmed in comparison with
an authentic sample. As in type I reactions, 3 generated from
Ti(O-i-Pr)3Cl was again the reagent of choice, which increased
the yield of 64 by 10-20% as compared to the one prepared
from Ti(O-i-Pr)4. Formation of this new compound is most
likely rationalized as follows. The alkyl-titanium bond of the
titanacycle 57, the presence of which was confirmed by the
deuterolysis shown in eq 7, attacks the proximate terminus of
the electron-deficient carbon-carbon double bond to give the
new titanium compound 62/63, which, upon hydrolysis, afforded
the observed product 64. The intermediary of the titanium-
carbene complex 6228 and/or bis-titanated species 6329 was, in
fact, verified by the treatment of the reaction mixture with excess
DCl/D2O, which gave 65 with virtually complete deuterium
incorporation (>99% D2) in place of both hydrogens R to the
ester group (eq 9 and entry 2 in Table 4).30 The intermediate
62/63 underwent smooth alkylidenation of diethyl ketone at
around 0 °C to give 66, which demonstrated the titanium-
carbene complex-like behavior of this bimetallic species.28
No other isolable byproducts were found under these reaction
conditions. The monocyclic 58 was again produced in 80%
yield even when the reaction mixture of 57 was treated with
1.1 equiv of s-BuOH at -50 to 0 °C followed by aqueous
workup as shown in the foregoing section (eq 8). This
experiment clearly shows that the possible monotitanated
intermediate 60 and/or 61 does not undergo any subsequent
reactions.

10020 J. Am. Chem. Soc., Vol. 119, No. 42, 1997
Urabe et al.
Table 4. Type II Tandem Cyclization of 7-En-2-ynoates and
Subsequent Reactions with Electrophilesa
Figure 4. Substrates unsuitable for type II cyclization.
Scheme 4
although the first cyclization giving a titanabicycle was, in fact,
proved to be completed as evidenced by the hydrolysis of the
intermediate. For example, the cyclopropane formation from
69 did not proceed well at 0 °C so that it requires more forcing
conditions involving room temperature, at which the desired
product 70 could be obtained in an acceptable yield and with
moderate diastereoselectivity (entry 5). However, another
substrate 71 with a siloxy group (Figure 4) no longer afforded
the expected product (<20%) even at room temperature.
On the contrary, an allylic substituent does not seem to have
a detrimental effect on the cyclopropane cyclization. Enynoate
72 having an allylic siloxy group afforded a 62:38 mixture of
the diastereoisomers 73 in good yield under the standard reaction
conditions (entry 6). To our satisfaction, switching the sub-
stituent from the siloxy to an alkyl such as butyl or TBSOCH2-
group nearly completely controls the stereochemistry of the
cyclization to afford virtually a single product 75 or 77 carrying
the exo-substituent (entries 7 and 8). The less sterically hindered
path a prevailing over path b as shown in Scheme 4 would
rationalize the stereoselection observed herein. This highly
diastereoselective cyclopropane formation was subsequently
applied to a synthesis of d-sabinene (Vide infra).
a See eq 9. b Major isomer is shown. c Diastereoselectivity with
respect to bold or dotted lines. “Single” refers to a case wherein the
minor isomer could not be identified even after careful analysis. d The
reaction was finally performed at room temperature.
This cyclization proved to be general to a variety of 7-en-
2-ynoates having a substituent (Table 4). A heteroatomic moiety
in the tether of the enynoate could tolerate the reaction
conditions to give heterocyclic compounds 68 and 70 (entries
4 and 5). A substitution to the propargyl position showed a
retarding effect on the progress of the second cyclization,
(28) The presence of a titanium-carbene complex is invoked in several
synthetic reactions, see: Tebbe, F. N.; Parshall, G. W.; Reddy, G. S. J.
Am. Chem. Soc. 1978, 100, 3611. Pine, S. H.; Zahler, R.; Evans, D. A.;
Grubbs, R. H. J. Am. Chem. Soc. 1980, 102, 3270. Yoshida, T.; Negishi,
E. J. Am. Chem. Soc. 1981, 103, 1276. Hartner, F. W.; Schwartz, J. J. Am.
Chem. Soc. 1981, 103, 4979. Lombardo, L. Tetrahedron Lett. 1982, 23,
4293. Clawson, L.; Buchwald, S. L.; Grubbs, R. H. Tetrahedron Lett. 1984,
25, 5733. Okazoe, T.; Takai, K.; Oshima, K. Utimoto, K. J. Org. Chem.
1987, 52, 4410. Takai, K.; Fujimura, O.; Kataoka, Y.; Utimoto, K.
Tetrahedron Lett. 1989, 30, 211. Petasis, N. A.; Hu, Y.-H. J. Org. Chem.
1997, 62, 782. For a relevant review, see: Beckhaus, R. Angew. Chem.,
Int. Ed. Engl. 1997, 36, 687.
Equation 10 shows that enynoate 78 having an internal
E-double bond failed in the first cyclization to give any
titanabicycle 79 at all, as judged by the hydrolysis of the reaction
(29) Some compounds of a similar structure were characterized or have
even found applications in organic synthesis, see: Polse, J. L.; Andersen,
R. A.; Bergman, R. G. J. Am. Chem. Soc. 1995, 117, 5393. Lee, S. Y.;
Bergman, R. G. Tetrahedron 1995, 51, 4255. McGrane, P. L.; Livinghouse,
T. J. Am. Chem. Soc. 1993, 115, 11485.
(30) Cyclization of enynes with certain metal-carbonyl or -carbene
complexes afforded a similar class of compounds. However, a bimetallic
moiety is not involved in the products, which is again in marked contrast
to the reaction reported herein. For these reactions and also some synthetic
utility of the products, see: Katz, T. J.; Yang, G. X.-Q. Tetrahedron Lett.
1991, 32, 5895. Watanuki, S.; Mori, M. Organometallics 1995, 14, 5054.
Harvey, D. F.; Sigano, D. M. J. Org. Chem. 1996, 61, 2268. Lee, J. E.;
Hong, S. H.; Chung, Y. K. Tetrahedron Lett. 1997, 38, 1781. For other
representative methods for the synthesis of cyclopropanes, see the following.
By alkylation: House, H. O. Modern Synthetic Reactions, 2nd ed.;
Benjamin: Menlo Park, CA, 1972; Vol. 2, p 181. By addition-elimination
sequence: Chapdelaine, M.; Hulce, M. In Organic Reactions; Paquette, L.
A., Ed.; Wiley: New York, 1990; Vol. 38, p 225. By carbene or carbenoid
addition: Helquist, P. In ComprehensiVe Organic Synthesis; Trost, B. M.,
Ed.; Pergamon Press: Oxford, U.K., 1991; Vol. 4, p 951. Nair, V. In
ComprehensiVe Organic Synthesis; Trost, B. M., Ed.; Pergamon Press:
Oxford, 1991; Vol. 4, p 999. Davies, H. M. L. In ComprehensiVe Organic
Synthesis; Trost, B. M., Ed.; Pergamon Press: Oxford, U.K., 1991; Vol. 4,
p 1031.
mixture, which gave ethyl (2Z,7E)-tridecadienoate as the main
product. However, enynoate 80 having a Z-disubstituted double
bond did undergo the cyclization eventually to give the
substituted cyclopropane 82 as a single stereoisomer (eq 11).

Cyclization of 2,7- or 2,8-Bis-unsaturated Esters
J. Am. Chem. Soc., Vol. 119, No. 42, 1997 10021
Scheme 6a
Scheme 5
The observed stereochemical outcome, which obviously does
not arise from a thermodynamically controlled cyclization,
should reflect the initial geometry of the double bond in 80 via
the reaction with retention of configuration of the carbon-
titanium bond in 81.19 The attempted cyclization of an
8-enynoate 83 (Figure 4) afforded an intractable mixture of
several products, in which the desired bicyclic product is a very
minor constituent.
A Synthesis of d-Sabinene. d-Sabinene (84), widely dis-
tributed in essential oils from plants, is a monoterpene having
a chiral cyclopropane moiety.31 Sesquisabinene and its deriva-
tive (85a,b) also belong to the same class.31 A few racemic
syntheses of sabinene have been reported in the past 30 years.32
A synthetic plan taking advantage of the substrate-controlled
chirality transfer and starting from 86 (optically active form of
76) is shown in Scheme 5.
The optically active 2-vinyl-1-alkanol moiety in 86 was
readily prepared by deconjugative allylation of the known Evans
amide 87,33a which gave a 9:1 mixture of the diastereoisomers
88 (Scheme 6).33 We did not attempt to seek optimal conditions
for achieving better selectivity. The structure of the major
isomer was assigned by consideration of the precedents and
finally was certified by the completion of the synthesis of 84.
After removal of the chiral auxiliary by a reductive method,
the resultant alcohol was protected with the TBS group to give
89. 9-BBN was able to recognize a subtle difference between
the two terminal olefins in 89 (9:1 selectivity by a qualitative
estimation) in its hydroboration to give the alcohol 90, which
was converted to the acetylene ester 86 by standard methods.34,35
The ee of the sample 86 was determined to be 80%, reflecting
the isomeric ratio of 88. The cyclization was carried out under
standard conditions as above to give 91 in 78% yield and 80%
ee determined by chiral shift study ((+)-Eu(hfc)3) on 1H NMR
spectroscopy. Thus, the highly effective chirality transfer was
achieved. Methylation and reduction afforded the 1:1 mixture
of diastereomeric alcohols 92. It is interesting to note that these
alcohols showed significantly different Rf values on silica gel,
which is informative observation for the synthesis of 85, in
a Key: (a) LDA-HMPA, allyl bromide; (b) LiAlH4; (c) TBS-Cl,
imidazole; (d) 9-BBN, H2O2; (e) DMSO, SO3‚py, NEt3; (f) CBr4, PPh3;
(g) BuLi, ClCO2Et; (h) see text; (i) LDA, MeI; (j) Dibal-H; (k) TsCl,
py; (l) LiEt3BH; (m) TBAF; (n) 2-(O2N)C6H4SeCN, PBu3; (o) H2O2,
K2CO3.
which the separation of diastereoisomers at this stage will be
crucial. Deoxygenation of the alcohol via its tosylate36 and
deprotection of the TBS ether afforded the alcohol 94, the
enantiopurity of which is again 80% ee. Dehydration of the
alcohol with a selenium reagent37 completed the synthesis of
d-sabinene (84): [R]D23 +75.8 (c 0.65, n-pentane) for a sample
of 80% ee; lit. [R]D20 +107 ( 3 (in substance) for a 99% pure
sample;38a [R]D +89.38b
Conclusion
The low-valent titanium-mediated cyclization of bis-unsatur-
ated compounds having a conjugated ester moiety was found
to be a versatile method to obtain mono- and bicyclic com-
pounds. The diastereoselective reaction of carbonyl compounds
with the intermediate titanium species allows facile stereose-
lective extension of side chains from the cyclization product.
Alternatively, the stereoselective cyclization controlled by an
appropriate substituent in the substrate is also a useful tool for
construction of the ring structure of the defined stereochemistry.
In addition to these points, this transformation circumvents the
use of carbon monoxide in the preparation of bicyclic ketones
and provides an opportunity for regioselective aldol formation
from a nearly symmetrical ketone (in type I reaction). All of
these advantages make this method very attractive in the
preparation of stereogenic centers involving a cyclic structure,
a part of which is illustrated in the synthesis of d-sabinene.
(31) (a) Croteau, R. B. ACS Symp. Ser. 1992, 490, 8. (b) Devon, T. K.;
Scott, A. I. Handbook of Naturally Occurring Compounds; Academic
Press: New York, 1972; Vol. II, pp 30-31. (c) Glasby, J. S. Encyclopaedia
of the Terpenoids; Wiley: Chichester, U.K., 1982. (d) Hanson, J. R., Ed.
Terpenoids and Steroids; The Royal Society of Chemistry: London, 1981;
Vol. 10, p 17.
Experimental Section
General Procedure. 1H and 13C NMR spectra were taken on a
Varian Gemini-300 spectrometer at 300 and 75 MHz, respectively.
CDCl3 was used as the solvent unless otherwise noted. Chemical shifts
(32) For racemic synthesis, see: (a) Rousseau, G.; Slougui, N. J. Am.
Chem. Soc. 1984, 106, 7283. (b) Vig, O. P.; Bhatia, M. S.; Gupta, K. C.;
Matta, K. L. J. Ind. Chem. Soc. 1969, 46, 991. (c) Fanta, W. I.; Erman, W.
F. J. Org. Chem. 1968, 33, 1656. A synthetic sample of optically active
sabinene has been recorded, but no details are given. See ref 31b and the
references cited therein.
(33) For a review, see: (a) Ager, D. J.; Prakash, I.; Schaad, D. R. Chem.
ReV. 1996, 96, 835. (b) Evans, D. A.; Ennis, M. D.; Mathre, D. J. J. Am.
Chem. Soc. 1982, 104, 1737. (c) Koch, S. S. C.; Chamberlin, A. R. J. Org.
Chem. 1993, 58, 2725.
(36) Krishnamurthy, S.; Brown, H. C. J. Org. Chem. 1976, 41, 3064.
(37) Grieco, P. A.; Gilman, S.; Nishizawa, M. J. Org. Chem. 1976, 41,
1485. Sharpless, K. B.; Young, M. W. J. Org. Chem. 1975, 40, 947.
Ohshima, T.; Kagechika, K.; Adachi, M.; Sodeoka, M.; Shibasaki, M. J.
Am. Chem. Soc. 1996, 118, 7108.
(38) (a) Fluka Chemika-BioChemika; Fluka Chemie AG: Buchs, Swit-
zerland, 1995; Vol. 1995/96. (b) Padmanabhan, R.; Jatkar, S. K. K. J. Am.
Chem. Soc. 1935, 57, 334.
(39) Screttas, C. G.; Smonou, I. C. J. Organomet. Chem. 1988, 342,
143. Barluenga, J.; Alvarez, F.; Concellon, J.; Yus, M. Synthesis 1986, 654.
(40) Herrmann, J. L.; Kieczykowski, G. R.; Schlessinger, R. H.
Tetrahedron Lett. 1973, 2433.
(34) Tidwell, T. T. Synthesis 1990, 857. Tidwell, T. T. In Organic
Reactions; Wiley: New York, 1990; Vol. 39, p 297.
(35) Corey, E. J.; Fuchs, P. L. Tetrahedron Lett. 1972, 3769.

10022 J. Am. Chem. Soc., Vol. 119, No. 42, 1997
Urabe et al.
are reported in parts per million (δ value) from Me4Si (δ ) 0 ppm for
1H) or based on the middle peak of the solvent (CDCl3) (δ ) 77.00
Structural Determination of the Major 11. (1RS,4SR,5RS)-4-
(tert-Butoxycarbonyl)-2-oxa-1-[(trimethylsilyl)methyl]bicyclo[3.3.0]-
octane (12). To a stirred solution of the alcohol 11 (10.1 mg, 0.034
mmol) in Et2O (0.3 mL) was added a crystal of TsOH‚H2O (1.3 mg,
0.0068 mmol) at room temperature. After 2 days, the mixture was
poured into aqueous NaHCO3 solution. The organic layer was separated
off, dried over MgSO4, and concentrated in Vacuo to an oil. The crude
oil was purified on silica gel (hexane-ether) to afford the title
compound (6.6 mg, 65%): 1H NMR δ 0.04 (s, 9H), 0.93 (d, J ) 14.6
Hz, 1H), 1.14 (d, J ) 14.6 Hz, 1H), 1.44 (s, 9H), 1.48-1.80 (m, 5H),
1.82-1.94 (m, 1H), 2.36-2.48 (m, 1H), 3.20 (dt, J ) 9.6, 8.5 Hz,
1H), 3.90 (t, J ) 8.5 Hz, 1H), 3.94 (t, J ) 8.5 Hz, 1H). Irradiation of
the proton at δ 3.20 ppm (CHCO2-t-Bu) showed 4.9% NOE enhance-
ment to δ 2.36-2.48 ppm (bridgehead-CH) and 2.8% NOE enhance-
ment to δ 1.14 ppm (TMS-CH). And irradiation of the proton at δ
2.36-2.48 ppm (bridgehead-H) showed 2.4% NOE enhancement to δ
0.93 ppm (TMS-CH) and 2.3% NOE enhancement to δ 1.14 ppm
(TMS-CH). These facts support the structural assignment shown in
the text. 13C NMR: δ -0.01, 25.66, 27.74, 28.06, 29.39, 40.87, 48.60,
53.31, 67.56, 80.60, 95.47. IR (neat): 2950, 2900, 2870, 1730, 1390,
1
ppm for 13C NMR) as an internal standard. When H NMR spectra
were taken in C6D6, the peak of the residual proton of the solvent is
the internal standard (δ ) 7.20 ppm). Signal patterns are indicated as
br, broad; s, singlet; d, doublet; t, triplet; q, quartet; m, multiplet.
Coupling constants (J) are given in hertz. Infrared (IR) spectra were
recorded on a JASCO FT/IR-230 spectrometer. Broad or shoulder
peaks were specified as br or sh. Optical rotation was measured on
JASCO DIP-370 digital polarimeter. All reactions were performed
under nitrogen or argon. Solvents and chemicals were purified or dried
in a standard manner.
Starting Materials. Preparation and characterization data of all
starting materials are placed in the Supporting Information.
Typical Procedure for the Monocyclization. tert-Butyl [2-[(E)-
(Trimethylsilyl)methylene]cyclopent-1-yl]acetate (8). To a stirred
solution of Ti(O-i-Pr)4 (0.070 mL, 0.24 mmol) in Et2O (2 mL) were
successively added 6 (53.3 mg, 0.20 mmol) in 1 mL of Et2O and
i-PrMgCl (0.30 mL, 1.60 M solution in Et2O, 0.48 mmol) in this order
at -78 °C under an argon atmosphere. The solution was gradually
allowed to warm to -20 °C over 1 h and kept at this temperature for
an additional 2 h. Then the reaction was terminated by the addition of
1 N HCl and Et2O. The organic layer was separated off, washed with
aqueous NaHCO3 solution, dried over MgSO4, and concentrated in
Vacuo to an oil. The crude oil was purified on silica gel (hexane-
ether) to give the title compound (44.5 mg, 83%) as an oil: 1H NMR
δ 0.07 (s, 9H), 1.18-1.39 (m, 1H), 1.45 (s, 9H), 1.50-1.68 (m, 1H),
1.68-1.83 (m, 1H), 1.87-2.01 (m, 1H), 2.11 (dd, J ) 9.3, 15.0 Hz,
1H), 2.21-2.50 (m, 2H), 2.50 (dd, J ) 5.1, 15.0 Hz, 1H), 2.63-2.79
(m, 1H), 5.26 (q, J ) 2.3 Hz, 1H). Irradiation of the proton at δ 5.26
ppm (vinylic-H) showed 5.9% NOE enhancement to that at δ 2.50 ppm
(CHCO2-t-Bu). Therefore, the stereochemistry of the olefin moiety
was assigned to be E. The assignment to the protons R to the ester
group (δ 2.11 and δ 2.50 ppm) was described in the text. 13C NMR:
δ -0.35, 24.31, 28.15, 32.25, 32.52, 40.55, 43.71, 80.03, 117.63,
164.35, 172.58. IR (neat): 2950, 2870 (sh), 1730, 1620, 1370, 1320,
1250, 1150, 870, 840, 690 cm-1. Anal. Calcd for C15H28O2Si: C,
67.11; H, 10.51. Found: C, 66.96; H, 10.66.
1370, 1320, 1250, 1220, 1160, 1060, 690 cm-1
. Anal. Calcd for
C16H30O3Si: C, 64.38; H, 10.13. Found: C, 64.35; H, 10.04.
Typical Procedure for the Monocyclization and Subsequent
Reaction with Carbonyl Compounds. tert-Butyl (2RS)-3-Hydroxy-
2-[(1SR)-2-[(E)-(trimethylsilyl)methylene]cyclopent-1-yl]pen-
tanoate (13). To a stirred solution of Ti(O-i-Pr)4 (0.070 mL, 0.24
mmol) in Et2O (2 mL) were added 6 (53.3 mg, 0.20 mmol) in 1 mL of
Et2O and i-PrMgCl (0.30 mL, 1.60 M solution in Et2O, 0.48 mmol) in
this order at -78 °C under an argon atmosphere. The solution was
stirred for 30 min at -78 °C, gradually allowed to warm to -20 °C
over 1 h, and kept at this temperature for an additional 2 h. Then
propionaldehyde (0.021 mL, 0.30 mmol) was added at -78 °C. After
the mixture was stirred for 0.5 h, the reaction was terminated by the
addition of 1 N HCl and Et2O at -78 °C. The organic layer was
separated off, washed with aqueous NaHCO3 solution, dried over
MgSO4, and concentrated in Vacuo to an oil. The crude oil, 1H NMR
analysis of which showed the formation of diastereoisomers in a ratio
of 73:27, was purified on silica gel (hexane-ether) to give the title
compound (41.2 mg, 63%) as a 73:27 mixture of the diastereoisomers
with respect to the alcohol moiety. Careful chromatography on silica
gel enabled partial separation of the diastereoisomers in isomerically
pure forms.
tert-Butyl (RS)-Deuterio-[(1RS)-2-[(E)-Deuterio(trimethylsilyl)-
methylene]cyclopent-1-yl]acetate (9): 1H NMR δ 0.07 (s, 9H), 1.18-
1.39 (m, 1H), 1.45 (s, 9H), 1.50-1.68 (m, 1H), 1.68-1.83 (m, 1H),
1.87-2.01 (m, 1H), 2.28-2.52 (m, 2H), 2.47 (dt, J ) 5.3, 2 Hz, 1H),
2.65-2.75 (m, 1H). The peaks at δ 2.11 ppm (CHCO2-t-Bu) and at δ
5.26 ppm (vinylic-H) of 8 disappeared to show 91% and 95% deuterium
incorporation, respectively.
1
Major Diastereoisomer: H NMR δ 0.06 (s, 9H), 0.96 (t, J ) 7.4
Hz, 3H), 1.46 (s, 9H), 1.33-1.98 (m, 6H), 2.20-2.44 (m, 2H), 2.30
(dd, J ) 2.3, 9.8 Hz, 1H), 2.82-2.95 (m, 1H), 3.33 (d, J ) 10.2 Hz,
1H), 3.50-3.63 (m, 1H), 5.32 (br s, 1H); 13C NMR δ -0.29, 10.62,
23.99, 28.21, 29.58, 29.71, 32.26, 47.07, 52.57, 72.40, 81.55, 119.38,
163.12, 174.83; IR (neat) 3510 (br), 2960, 2890, 1730, 1700, 1620,
1450, 1390, 1370, 1250, 1150, 1120, 1050, 970, 870, 840, 770, 750,
tert-Butyl (RS)-Deuterio-[(1RS)-2-[(E)-(trimethylsilyl)methylene]-
1
cyclopent-1-yl]acetate (10): H NMR δ 0.07 (s, 9H), 1.18-1.39 (m,
1H), 1.45 (s, 9H), 1.50-1.68 (m, 1H), 1.68-1.83 (m, 1H), 1.87-2.01
(m, 1H), 2.28-2.52 (m, 2H), 2.47 (m, 1H), 2.65-2.75 (m, 1H), 5.26
(q, J ) 2.3 Hz, 1H). The peak at δ 2.11 ppm (CHCO2-t-Bu) of 8
disappeared to show 89% deuterium incorporation.
690 cm-1
.
1
Minor Diastereoisomer: H NMR δ 0.08 (s, 9H), 0.99 (t, J ) 7.3
Hz, 3H), 1.46 (s, 9H), 1.27-1.69 (m, 4H), 1.73-1.90 (m, 2H), 2.09
(d, J ) 6.7 Hz, 1H), 2.21-2.50 (m, 2H), 2.63 (t, J ) 6.4 Hz, 1H),
2.68-2.80 (m, 1H), 3.74-3.85 (m, 1H), 5.35 (br s, 1H); 13C NMR δ
-0.35, 10.40, 24.40, 27.95, 28.12, 29.40, 32.70, 46.40, 54.45, 72.91,
80.92, 118.78, 164.23, 173.16; IR (neat) 3500 (br), 2960, 2890, 1730,
1710 (sh), 1620, 1460, 1390, 1370, 1250, 1150, 970, 870, 840, 750,
690 cm-1. Anal. Calcd for C18H34O3Si: C, 66.21; H, 10.50. Found:
C, 65.92; H, 10.47 for the 73:27 mixture of the above diastereoisomers.
tert-Butyl (2RS)-3-Hydroxy-2-[(1SR)-2-[(E)-(trimethylsilyl)meth-
ylene]cyclopent-1-yl]propanoate (11). A >96:<4 mixture of dias-
tereoisomers. An ether solution of freshly cracked formaldehyde (ca.
3 equiv) was used as the electrophile according to the typical procedure
(Vide infra).
Major Diastereoisomer: 1H NMR δ 0.07 (s, 9H), 1.47 (s, 9H),
1.32-1.62 (m, 2H), 1.63-1.85 (m, 2H), 2.12-2.29 (m, 2H), 2.30-
2.47 (m, 2H), 2.74 (ddd, J ) 3.5, 5.5, 8.9 Hz, 1H), 2.78-2.90 (m,
1H), 3.60 (ddd, J ) 3.5, 7.4, 11.1 Hz, 1H), 3.81 (ddd, J ) 5.5, 8.6,
11.1 Hz, 1H), 5.34-5.40 (m, 1H); 13C NMR δ -0.37, 24.61, 28.13,
28.50, 33.10, 46.26, 50.47, 60.52, 81.10, 118.77, 162.20, 174.58; IR
(neat) 3450 (br), 2950, 2900 (sh), 1730, 1620, 1460, 1390, 1370, 1250,
1160, 1040, 870, 840 cm-1 for a >96:<4 mixture of the above
diastereoisomers. Anal. Calcd for C16H30O3Si: C, 64.38; H, 10.13.
Found: C, 64.13; H, 10.27 for a >96:<4 mixture of the above
diasteroisomers. The stereochemistry of the major isomer was unam-
biguously determined by the derivatization to 12.
The following derivatization of 13 to 96 established that the shown
diastereomeric ratio refers to that corresponding to the hydroxy group,
but not the one between the cyclopentane carbon and the ester R-carbon.
Thus, a 76:24 mixture of the diastereoisomers of 13 was silylated to
give an 84:16 mixture of 95. In this reaction, the minor isomer of 13
somewhat resisted the silylation so that a part of the minor isomer was
recovered unchanged, which is the reason why the composition of the
major diastereoisomer increased before and after the silylation. The
rest of the transformation was carried out in a standard manner to give
the dehydrated product 96, which still showed the same diastereomeric
ratio of 85:15, verifying the aforementioned point.
Minor Diastereoisomer: 1H NMR δ (only characteristic peaks are
shown) 1.45 (s, 9H), 3.86 (dd, J ) 7.5, 11.0 Hz, 1H).

Cyclization of 2,7- or 2,8-Bis-unsaturated Esters
J. Am. Chem. Soc., Vol. 119, No. 42, 1997 10023
Karplus equation based on a molecular model. On deuteration (Vide
infra), the proton at δ 2.20 ppm was exchanged to deuterium.
13C NMR: δ 13.12, 14.05, 14.49, 22.58, 24.01, 29.06, 29.30, 29.42,
31.60, 33.34, 38.09, 40.19, 41.00, 42.09, 120.48, 145.47, 171.70. IR
(neat): 2960, 2930, 2870, 2860, 1640, 1460, 1430, 1380, 1360, 1270,
1220, 1150, 1100 cm-1. Anal. Calcd for C17H31ON: C, 76.92; H,
11.77; N, 5.28. Found: C, 76.52; H, 11.59; N, 5.09.
tert-Butyl (2RS)-3-Methyl-3-hydroxy-2-[(1SR)-2-[(E)-(trimethyl-
1
silyl)methylene]cyclopent-1-yl]butanoate (14): H NMR δ 0.06 (s,
N,N-Diethyl-(RS)-deuterio[(1RS)-2-[(E)-1-deuterio-1-hexylidene]-
cyclopent-1-yl]acetamide (23): H NMR δ 0.87 (t, J ) 6.8 Hz, 3H),
1
9H), 1.21 (s, 3H), 1.28 (s, 3H), 1.44 (s, 9H), 1.51-1.68 (m, 1H), 1.68-
1.93 (m, 3H), 2.21-2.41 (m, 2H), 2.38 (d, J ) 6.4 Hz, 1H), 2.76-
2.88 (m, 1H), 3.66 (s, 1H), 5.35-5.45 (m, 1H); 13C NMR δ -0.24,
24.28, 28.16, 28.26, 29.84, 32.17, 32.84, 46.86, 58.38, 71.91, 81.19,
121.12, 162.52, 174.53; IR (neat) 3490 (br), 2990, 2980, 1700, 1620,
1380, 1360, 1310, 1250, 1210, 1140, 870, 840. Anal. Calcd for
C18H34O3Si: C, 66.21; H, 10.50. Found: C, 65.88; H, 10.60.
tert-Butyl (2RS)-3-Hydroxy-2-[(1SR)-2-[(E)-1-hexylidene]cyclo-
pent-1-yl]propanoate (16). A >93:<7 mixture of diastereoisomers.
Major Diastereoisomer: 1H NMR δ 0.87 (t, J ) 6.8 Hz, 3H), 1.17-
1.59 (m, 8H), 1.46 (s, 9H), 1.63-1.82 (m, 2H), 1.88-2.19 (m, 3H),
2.20-2.40 (m, 2H), 2.65 (ddd, J ) 3.6, 6.3, 8.4 Hz, 1H), 2.75-2.87
(m, 1H), 3.57-3.69 (m, 1H), 3.75-3.87 (m, 1H), 5.18-5.27 (m, 1H);
13C NMR δ 13.94, 22.46, 24.09, 28.02, 29.13, 29.24, 29.38, 31.49,
43.28, 50.85, 60.82, 81.00, 121.73, 142.86, 174.78; IR (neat) 3450 (br),
2960, 2930, 2870, 2860, 1730, 1460, 1390, 1370, 1250, 1160, 1040,
850 cm-1 for the >93:<7 mixture of the above diastereoisomers. Anal.
Calcd for C18H32O3: C, 72.93; H, 10.88. Found: C, 72.93; H, 10.81
for the >93:<7 mixture of the above diastereoisomers.
11.1 (t, J ) 7.7 Hz, 3H), 1.16 (t, J ) 7.7 Hz, 3H), 1.20-1.39 (m, 7H),
1.47-1.83 (m, 2H), 1.85-2.04 (m, 3H), 2.12-2.35 (m, 2H), 2.46 (br
d, J ) 5.1 Hz, 1H), 2.80-2.93 (m, 2H), 3.20-3.50 (m, 4H). The peaks
at δ 2.20 ppm (CHCONEt2) and at δ 5.14 ppm (vinylic-H) of 22
disappeared to show ca. 100% and 88% deuterium incorporation,
respectively.
Ethyl [2-(E)-(Trimethylsilyl)methylenecyclopent-1-yl]acetate (31):
1H NMR δ 0.09 (s, 9H), 1.25 (t, J ) 7.1 Hz, 3H), 1.19-1.37 (m, 1H),
1.49-1.67 (m, 1H), 1.68-1.83 (m, 1H), 1.89-2.02 (m, 1H), 2.18 (dd,
J ) 9.4, 15.0 Hz, 1H), 2.21-2.46 (m, 2H), 2.57 (dd, J ) 5.2, 15.0 Hz,
1H), 2.67-2.81 (m, 1H), 4.23 (q, J ) 7.1 Hz, 2H), 5.25 (br s, 1H); 13
C
NMR δ -0.37, 14.27, 24.29, 32.34, 32.49, 39.36, 43.55, 60.14, 117.84,
164.10, 173.18; IR (neat) 2950, 2870 (sh), 1740, 1620, 1370, 1320,
1240, 1170, 1100, 1030, 870, 840 cm-1. Anal. Calcd for C13H24O2-
Si: C, 64.95; H, 10.06. Found: C, 64.91; H, 10.07.
Typical Procedure for Type I Tandem Cyclization. 2-(Trim-
ethylsilyl)-1-bicyclo[3.3.0]octen-3-one (32). To a stirred solution of
Ti(O-i-Pr)3Cl (0.12 mL, 2 M solution in Et2O, 0.24 mmol) in Et2O
(1.6 mL) were added 28 (47.7 mg, 0.20 mmol) in 1 mL of Et2O and
i-PrMgCl (0.31 mL, 1.53 M solution in Et2O, 0.48 mmol) in this order
at -78 °C under an argon atmosphere. The solution was stirred for
30 min at -78 °C, gradually allowed to warm to -20 °C over 1 h, and
kept at this temperature for an additional 2 h. Then 2-butanol (0.12
mL, 2 M solution in Et2O, 0.24 mmol) was added. After the mixture
was stirred for 15 min at -20 °C, the reaction was terminated by the
addition of 1 N HCl and Et2O. The organic layer was separated off,
washed with aqueous NaHCO3 solution, dried over MgSO4, and
concentrated in Vacuo to an oil. The crude oil was purified on silica
gel (hexane-ether) to give the title compound (31.2 mg, 80%): 1H
NMR δ 0.19 (s, 9H), 1.10 (dq, J ) 7.9, 11.9 Hz, 1H), 1.87-2.20 (m,
3H), 2.03 (dd, J ) 3.9, 17.6 Hz, 1H), 2.54 (dt, J ) 19.4, 8.9 Hz, 1H),
2.57 (ddd, J ) 0.8, 6.5, 17.6 Hz, 1H), 2.66 (ddd, J ) 3.0, 10.7, 19.4
Hz, 1H), 2.74-2.87 (m, 1H). The assignments to the exo and endo
protons R to the ketone group were made on the basis of the following
facts: (i) the coupling constants shown in the following figure satisfy
the calculated values by the Karplus equation based on a molecular
model and (ii) a long-range coupling (J ) 0.8 Hz) was observed for
the exo proton at δ 2.57 ppm. This differentiation between two R
protons to the ketone group is crucial to determine the stereochemistry
of the deuteration (Vide infra).
Minor Diastereoisomer: 1H NMR δ (only characteristic peaks are
shown) 1.45 (s, 9H), 2.51 (dt, J ) 4.0, 7.8 Hz, 1H).
tert-Butyl [2-[(E)-(Trimethylsilyl)methylene]cyclohex-1-yl]acetate
(18): 1H NMR δ 0.07 (s, 9H), 1.14-1.28 (m, 1H), 1.32-1.59 (m, 2H),
1.42 (s, 9H), 1.62-1.85 (m, 3H), 2.04 (ddd, J ) 3.5, 10.2, 13.5 Hz,
1H), 2.17 (m, 1H), 2.38-2.58 (m, 3H), 5.03 (br s, 1H); 13C NMR δ
0.19, 24.85, 28.01, 28.68, 34.25, 34.48, 39.27, 43.34, 79.98, 118.08,
161.02, 172.67; IR (neat) 2960, 2930, 2860, 1730, 1610, 1450, 1370,
1290, 1250, 1150, 1130, 890, 870, 840, 690 cm-1. Anal. Calcd for
C16H30O2Si: C, 68.03; H, 10.70. Found: C, 67.90; H, 10.69.
tert-Butyl (RS)-Deuterio[(1RS)-2-[(E)-deuterio(trimethylsilyl)m-
1
ethylene]cyclohex-1-yl]acetate (19): H NMR δ 0.07 (s, 9H), 1.14-
1.28 (m, 1H), 1.32-1.59 (m, 2H), 1.42 (s, 9H), 1.62-1.85 (m, 3H),
2.04 (ddd, J ) 3.5, 10.2, 13.5 Hz, 1H), 2.38-2.58 (m, 2H), 2.43 (m,
1H). The peaks at δ 2.17 ppm (CHCO2-t-Bu) and at δ 5.03 ppm
(vinylic-H) of 18 disappeared to show 91% and 87% deuterium
incorporation, respectively.
tert-Butyl (2RS)-3-Hydroxy-2-[(1SR)-2-[(E)-(trimethylsilyl)meth-
ylene]cyclohex-1-yl]propanoate (20): H NMR δ 0.08 (s, 9H), 1.42
1
(s, 9H), 1.17-1.72 (m, 6H), 2.12-2.38 (m, 3H), 2.58 (dt, J ) 10.2,
4.9 Hz, 1H), 2.77 (ddd, J ) 3.5, 6.8, 10.2 Hz, 1H), 3.68-3.87 (m,
2H), 5.18 (br s, 1H); 13C NMR δ 0.21, 22.51, 28.03, 28.50, 30.03,
32.27, 46.31, 48.32, 61.53, 80.97, 121.60, 159.60, 174.87; IR (neat)
3440 (br), 2950, 2930, 2860, 1730, 1620, 1450, 1370, 1250, 1160, 1060,
870, 840, 690 cm-1. Anal. Calcd for C17H32O3Si: C, 65.33; H, 10.32.
Found: C, 65.21; H, 10.19.
N,N-Diethyl-[2-[(E)-1-hexylidene]cyclopent-1-yl]acetamide (22):
1H NMR δ 0.87 (t, J ) 6.8 Hz, 3H), 1.11 (t, J ) 7.7 Hz, 3H), 1.16 (t,
J ) 7.7 Hz, 3H), 1.20-1.39 (m, 7H), 1.47-1.83 (m, 2H), 1.87-2.00
(m, 3H), 2.20 (dd, J ) 8.8, 14.9 Hz, 1H), 2.11-2.35 (m, 2H), 2.48
(dd, J ) 5.6, 14.9 Hz, 1H), 2.80-2.93 (m, 1H), 3.20-3.50 (m, 4H),
5.14 (m, 1H). In a Newman projection analogous to Figure 1, the
assignment to the protons R to the amide group was made on the basis
of the following: (i) the downfield shift for Hb as compared to Ha
owing to the deshielding effect of the nearby olefinic bond (ii) the fact
that the coupling constants observed between Ha/Hb and cyclopentyl-
Hc shown in the following figure satisfy the calculated values by the
13C NMR: δ 1.11, 25.74, 27.54, 30.98, 43.14, 48.51, 135.16, 198.84,
214.70; IR (neat) 2970, 2920 (sh), 2870, 1690, 1610, 1420, 1250, 1230,
1140, 930, 870, 860 (sh), 840, 760, 690 cm-1. Anal. Calcd for C11H18-
OSi: C, 67.98; H, 9.34. Found: C, 67.62; H, 9.28. These spectral
properties were in good agreement with those of an authentic sample.23

10024 J. Am. Chem. Soc., Vol. 119, No. 42, 1997
Urabe et al.
Ethyl (RS)-Deuterio-[(1RS)-2-[(E)-deuterio(trimethylsilyl)meth-
ylene]cyclo-pent-1-yl]acetate (33): 1H NMR δ 0.09 (s, 9H), 1.25 (t, J
) 7.1 Hz, 3H), 1.19-1.37 (m, 1H), 1.49-1.67 (m, 1H), 1.68-1.83
(m, 1H), 1.89-2.02 (m, 1H), 2.27 (ddt, J ) 2.1, 17.0, 8.4 Hz, 1H),
2.40 (ddd, J ) 4.5, 8.7, 17.0 Hz, 1H), 2.56 (dt, J ) 5.0, 2.3 Hz, 1H),
2.73 (br q, J ) 7.4 Hz, 1H), 4.23 (q, J ) 7.1 Hz, 2H). The peaks at
δ 2.18 ppm (CHCO2Et) and at δ 5.25 ppm (vinylic-H) of 31 disappeared
to show 97% and 89% deuterium incorporation, respectively.
2-Pentyl-1-bicyclo[3.3.0]octen-3-one (39): 1H NMR δ 0.87 (t, J )
7.0 Hz, 3H), 1.04 (dq, J ) 8.3, 11.6 Hz, 1H), 1.17-1.51 (m, 6H),
1.89-2.28 (m, 5H), 2.02 (dd, J ) 3.1, 17.6 Hz, 1H), 2.45-2.66 (m,
2H), 2.61 (dd, J ) 6.2, 17.6 Hz, 1H), 2.67-2.81 (m, 1H); 13C NMR δ
13.95, 22.38, 23.79, 25.12, 25.71, 27.66, 31.32, 31.69, 41.73, 44.35,
136.30, 186.60, 210.68; IR (neat) 2960, 2930, 2850, 1710, 1670, 1480,
1460 cm-1. Anal. Calcd for C13H20O: C, 81.20; H, 10.48. Found:
C, 80.87; H, 10.83.
1
(4RS,5RS)-2-(Trimethylsilyl)-4-deuterio-1-bicyclo[3.3.0]octen-3-
9-(Trimethylsilyl)-9-bicyclo[4.3.0]nonen-8-one (41): H NMR δ
1
one (34): H NMR δ 0.19 (s, 9H), 1.10 (dq, J ) 7.9, 11.9 Hz, 1H),
0.21 (s, 9H), 1.11 (dq, J ) 3.5, 13.0 Hz, 1H), 1.36 (tq, J ) 3.5, 13.0
Hz, 1H), 1.51 (tq, J ) 3.5, 13.0 Hz, 1H), 1.76-1.87 (m, 1H), 1.91
(dd, J ) 1.7, 18.1 Hz, 1H), 1.96-2.07 (m, 1H), 2.10-2.25 (m, 2H),
2.50 (dd, J ) 6.9, 18.1 Hz, 1H), 2.53-2.64 (m, 1H), 2.95-3.05 (m,
1H); 13C NMR δ 0.34, 25.46, 27.53, 31.68, 35.60, 42.85, 43.60, 136.17,
191.66, 212.91; IR (neat) 2950, 2860, 1690, 1600, 1450, 1270, 1250,
1200, 870 (sh), 850, 770 cm-1. Anal. Calcd for C12H20OSi: C, 69.17;
H, 9.67. Found: C, 68.75; H, 9.63.
1.87-2.20 (m, 3H), 1.98-2.04 (m, 1H), 2.54 (dt, J ) 19.1, 9.1 Hz,
1H), 2.66 (ddd, J ) 3.3, 10.6, 19.1 Hz, 1H), 2.74-2.87 (m, 1H). Note
that the proton at δ 2.57 ppm (exo-CH2CdO) of 32 was exclusively
deuterated.
Typical Procedure for Type I Tandem Cyclization and Subse-
quent Reaction with Carbonyl Compounds. (4RS,5SR)-4-(1-Hy-
droxypropyl)-2-(trimethylsilyl)-1-bicyclo[3.3.0]octen-3-one (35). To
a stirred solution of Ti(O-i-Pr)3Cl (0.12 mL, 2 M solution in Et2O,
0.24 mmol) in Et2O (1.6 mL) were added 28 (47.7 mg, 0.20 mmol) in
1 mL of Et2O and i-PrMgCl (0.31 mL, 1.53 M solution in Et2O, 0.48
mmol) in this order at -78 °C under an argon atmosphere. The solution
was stirred for 30 min at -78 °C, gradually allowed to warm to -20
°C over 1 h, and kept at this temperature for an additional 2 h. Then
propionaldehyde (0.021 mL, 0.30 mmol) was added. After the mixture
was stirred at -20 °C for 1 h, the reaction was terminated by the
addition of 1 N HCl and Et2O. The organic layer was separated off,
washed with aqueous NaHCO3 solution, dried over MgSO4, and
concentrated in Vacuo to an oil. The crude oil was purified on silica
gel (hexane-ether) to give the title compound (39.2 mg, 78%) as a
63:37 mixture of the diastereoisomers with respect to the alcohol moiety.
8-[(tert-Butyl)dimethylsiloxy]-2-(trimethylsilyl)-1-bicyclo[3.3.0]octen-
3-one (43).
Major (5RS,8SR)-Diastereoisomer: 1H NMR δ 0.09 (s, 3H), 0.12
(s, 3H), 0.21 (s, 9H), 0.87 (s, 9H), 1.00-1.16 (m, 1H), 1.79-1.94 (m,
1H), 1.99 (dd, J ) 3.5, 17.7 Hz, 1H), 2.08-2.28 (m, 2H), 2.62 (dd, J
) 6.6, 17.7 Hz, 1H), 3.09-3.24 (m, 1H), 4.78-4.89 (m, 1H); 13C NMR
δ -4.30, -3.67, 0.96, 17.91, 25.77, 27.89, 36.54, 43.34, 43.82, 68.99,
135.82, 194.62, 215.42; IR (neat) 2950, 2930, 2900, 2860, 1700, 1620,
1470, 1250, 1070, 1030, 930, 840, 780, 700 cm-1
.
Minor (5RS,8RS)-Diastereoisomer: 1H NMR δ 0.14 (s, 3H), 0.15
(s, 3H), 0.22 (s, 9H), 0.91 (s, 9H), 1.29-1.47 (m, 1H), 1.91-1.20 (m,
3H), 2.10 (dd, J ) 3.9, 17.6 Hz, 1H), 2.57 (dd, J ) 6.6, 17.6 Hz, 1H),
2.70-2.83 (m, 1H), 5.03 (dd, J ) 2.7, 7.6, 1H); 13C NMR δ -3.50,
-3.13, -0.52, 18.37, 26.32, 28.38, 37.11, 43.36, 46.13, 71.11, 137.81,
198.12, 214.24; IR (neat) 2960, 2930, 2900, 2860, 1700, 1610, 1470,
1250, 1140, 1060, 840, 780 cm-1. Anal. Calcd for C17H32O2Si2: C,
62.90; H, 9.94. Found: C, 62.92; H, 9.92 for a mixture of the above
diastereoisomers.
1
Major Diastereoisomer: H NMR δ 0.20 (s, 9H), 1.01 (t, J ) 7.3
Hz, 3H), 1.22 (dq, J ) 10.0, 12.0 Hz, 1H), 1.37-1.74 (m, 2H), 1.87-
2.03 (m, 1H), 2.03-2.19 (m, 2H), 2.08 (dd, J ) 4.5, 10.0 Hz, 1H),
2.42-2.61 (m, 2H), 2.66 (ddd, J ) 3.0, 10.1, 19.8 Hz, 1H), 3.72 (ddd,
J ) 2.8, 7.6, 10.0 Hz, 1H), 4.86 (br s, 1H). The coupling constant (J
) 4.5 Hz) observed for the R proton to the ketone (δ 2.08 ppm) and
the bridgehead proton (δ 2.42-2.61 ppm) suggests that the CH(OH)-
Et group occupies the exo position. The observed NOE (4% peak
enhancement at the peak of δ 2.42-2.61 ppm (bridgehead-H) by
irradiation of the one at δ 3.72 ppm (CHOH)) also confirmed the
stereochemical assignment. 13C NMR: δ 1.31, 9.03, 26.01, 27.69,
28.73, 30.73, 52.13, 58.96, 73.03, 134.53, 198.32, 218.38. IR (neat):
3450 (br), 2970, 2930 (sh), 2880, 1670, 1610, 1420, 1250, 970, 840
cm-1. Anal. Calcd for C14H24O2Si: C, 66.14; H, 9.58. Found: C,
65.89; H, 9.51 for a mixture of the above diastereoisomers.
Irradiation of the proton at δ 4.78-4.89 ppm (CH-OTBS) of the
major isomer showed no NOE enhancement to that at δ 3.09-3.24
ppm (bridgehead-CH), while irradiation of the proton at δ 5.03 ppm
(CH-OTBS) of the minor isomer showed 3.2% NOE enhancement to
that at δ 2.70-2.83 ppm (bridgehead-CH). These facts support the
above structural assignments to both isomers.
1
Minor Diastereoisomer: H NMR δ 0.19 (s, 9H), 0.97 (t, J ) 7.4
Hz, 3H), 1.29 (dq, J ) 7.9, 11.7 Hz, 1H), 1.42-1.88 (m, 3H), 1.89-
2.20 (m, 3H), 2.22 (dd, J ) 2.8, 4.0 Hz, 1H), 2.54 (dt, J ) 19.3, 8.2
Hz, 1H), 2.66 (ddd, J ) 3.4, 10.2, 19.3 Hz, 1H), 2.91 (m, 1H), 4.13
(ddd, J ) 2.8, 5.7, 8.3 Hz, 1H). The coupling constant (J ) 4.0 Hz)
observed for the R proton to the ketone (δ 2.22 ppm) and the bridgehead
proton (δ 2.91 ppm) suggests that the CH(OH)Et group occupies the
exo position. The observed NOE (0.7% peak enhancement at the peak
of δ 4.13 ppm (CHOH) by irradiation of the one at δ 2.91 ppm
(bridgehead-CH)) also confirmed the stereochemical assignment. 13C
NMR: δ -1.20, 10.47, 26.15, 27.71, 28.21, 31.03, 48.94, 60.85, 70.52,
134.62, 198.75, 215.34. IR (neat): 3450 (br), 2970, 2950 (sh), 2880,
1680, 1610, 1250, 1150, 840 cm-1. Thus, both diastereoisomers have
the hydroxyethyl group at the exo position R to the ketone so that the
relative stereochemistries of the hydroxy groups should be different.
6-[(tert-Butyl)dimethylsiloxy]-2-(trimethylsilyl)-1-bicyclo[3.3.0]octen-
3-one (45).
Major (5RS,6SR)-Diastereoisomer: 1H NMR δ 0.01 (s, 3H), 0.03
(s, 3H), 0.18 (s, 9H), 0.79 (s, 9H), 1.98 (br ddd, J ) 3.6, 6.7, 13.6 Hz,
1H), 2.12 (ddt, J ) 3.6, 13.6, 9.8 Hz, 1H), 2.30 (d, J ) 5.4 Hz, 2H),
2.57-2.67 (m, 2H), 2.83-2.91 (dt, J ) 3.6, 5.4 Hz, 1H), 4.23 (br t, J
) 3.6 Hz, 1H); 13C NMR δ -5.15, -4.78, -1.40, 17.90, 25.40, 25.54,
36.01, 37.50, 54.27, 70.50, 136.54, 196.87, 215.50; IR (neat) 2950,
2930, 2900, 2860, 1690, 1610, 1250, 1230, 1120, 1080, 1050, 980,
890, 840, 800, 780, 700 cm-1. Anal. Calcd for C17H32O2Si2: C, 62.90;
H, 9.94. Found: C, 63.11; H, 10.05.
(4RS,5SR)-4-(1-Ethyl-1-hydroxypropyl)-2-(trimethylsilyl)-1-bicyclo-
[3.3.0]octen-3-one (36): 1H NMR δ 0.17 (s, 9H), 0.86 (t, J ) 7.5 Hz,
3H), 0.92 (t, J ) 7.4 Hz, 3H), 1.20 (dq, J ) 7.7, 11.8 Hz, 1H), 1.25-
1.54 (m, 3H), 1.64-1.81 (m, 1H), 1.86-2.19 (m, 3H), 2.38 (d, J )
4.4 Hz, 1H), 2.44-2.63 (m, 2H), 2.66 (ddd, J ) 2.8, 10.5, 19.7 Hz,
1H), 4.45 (br s, 1H). The coupling constant (J ) 4.4 Hz) observed for
the proton R to the ketone (δ 2.38 ppm) and the bridgehead proton (δ
2.44-2.63 ppm) suggests that the CEt2(OH) group occupies the exo
position. 13C NMR: δ 1.27, 7.55, 7.79, 25.88, 27.58, 29.92, 30.61,
31.15, 51.85, 59.91, 75.36, 135.52, 198.51, 218.69. IR (neat): 3440
(br), 2870, 2850 (sh), 2780, 1670, 1610, 1470, 1420, 1250, 1230, 1150,
Minor (5RS,6RS)-Diastereoisomer: 1H NMR δ 0.06 (s, 6H), 0.18
(s, 9H), 0.89 (s, 9H), 1.96 (ddt, J ) 11.7, 12.9, 9.2 Hz, 1H), 2.09 (dd,
J ) 3.8, 17.8 Hz, 1H), 2.15-2.26 (m, 1H), 2.48-2.62 (m, 1H), 2.57
(dd, J ) 6.6, 17.8 Hz, 1H), 2.73-2.96 (m, 2H), 3.72 (br dt, J ) 7.0,
9.2 Hz, 1H). Decoupling experiments determined the coupling constant
between CHOTBS and allylic bridgehead-CH is 7.0 Hz, consistent with
the previously reported value (7.4 Hz) for a similar structure in 49.24a
13C NMR: δ -4.75, -4.72, -1.32, 17.96, 25.71, 26.64, 35.01, 41.66,
55.43, 77.27, 137.75, 194.27, 214.01. IR (neat): 2950, 2930, 2900,
2860, 1700, 1610, 1470, 1250, 1210, 1130, 1100, 840, 780 cm-1
.
960, 850 cm-1
Found: C, 68.08; H, 10.29.
.
Anal. Calcd for C16H28O2Si: C, 68.52; H, 10.06.
Irradiation of the proton at δ 4.23 ppm (CH-OTBS) of the major
diastereoisomer showed 8.0% NOE enhancement to δ 2.83-2.91 ppm

Cyclization of 2,7- or 2,8-Bis-unsaturated Esters
J. Am. Chem. Soc., Vol. 119, No. 42, 1997 10025
(bridgehead-CH), while irradiation of the proton at δ 3.72 ppm (CH-
OTBS) of the minor diastereoisomer showed 1.1% NOE enhancement
to δ 2.87-2.96 ppm (bridgehead-CH) in addition to a 2.3% NOE
enhancement to the endo R-carbonyl proton. These facts support the
above structural assignments to both diastereoisomers.
43.44, 43.78, 45.96, 124.59, 125.31, 126.96, 127.17, 142.24, 144.92,
218.92; IR (neat) 3060, 3010, 2940, 2900, 2850, 1740, 1480, 1460,
1450 (sh), 1400, 1330, 1250, 1150, 750 cm-1
. Anal. Calcd for
C12H12O: C, 83.69; H, 7.23. Found: C, 83.72; H, 7.19. The shown
stereochemistry of the ring junction was deduced on the basis of the
assignment to 54 (Vide infra).
(1RS,5RS)-7,8-Benzo-2-(1-hydroxypropyl)-3-bicyclo[3.3.0]-
1
octanone (54): H NMR δ 1.06 (t, J ) 7.3 Hz, 3H), 1.61-1.89 (m,
2H), 2.19 (ddd, J ) 1.2, 7.6, 18.5 Hz, 1H), 2.47 (ddd, J ) 1.2, 4.4,
6.6, 1H), 2.60 (dd, J ) 8.3, 18.5 Hz, 1H), 2.81 (dd, J ) 3.1, 15.7 Hz,
1H), 3.07-3.20 (m, 1H), 3.25 (dd, J ) 7.6, 15.7 Hz, 1H), 3.27 (br s,
1H), 3.68 (dd, J ) 4.4, 7.7 Hz, 1H), 3.84 (ddd, J ) 3.0, 6.6, 11.0 Hz,
1H), 7.15-7.30 (m, 4H). Irradiation of the proton at δ 3.68 ppm
(benzylic-bridgehead-CH) showed 4% NOE enhancement to δ 3.07-
3.20 ppm (another bridgehead-CH), which verified that the ring junction
is cis. 13C NMR: δ 9.34, 28.07, 38.24, 38.38, 44.84, 49.83, 58.39,
73.63, 124.56, 125.27, 126.99, 127.21, 142.05, 144.97, 211.46. IR
(neat): 3400 (br), 2990, 2980, 2940, 2800, 1730, 1640, 1460, 1240,
1160, 1110, 1040, 970, 750, 640 cm-1. Anal. Calcd for C15H18O2:
C, 78.23; H, 7.88. Found: C, 78.25; H, 7.85.
6-Butyl-2-(trimethylsilyl)-1-bicyclo[3.3.0]octen-3-one (47).
Major (5RS,6SR)-Diastereoisomer: 1H NMR δ 0.18 (s, 9H), 0.89
(t, J ) 7.1 Hz, 3H), 1.21-1.64 (m, 7H), 2.02 (dd, J ) 3.8, 16.8 Hz,
1H), 2.08-2.21 (m, 1H), 2.40-2.60 (m, 2H), 2.54 (dd, J ) 6.5, 16.8
Hz, 1H), 2.69 (ddd, J ) 2.1, 10.8, 19.2 Hz, 1H); 13C NMR δ -1.31,
13.91, 22.83, 27.80, 30.29, 32.70, 34.66, 42.79, 44.98, 54.41, 135.11,
1-[(E)-(Ethoxycarbonyl)methylene]-2-methylcyclopentane (58):
1H NMR δ 1.12 (d, J ) 6.8 Hz, 3H), 1.28 (t, J ) 7.1 Hz, 3H), 1.17-
1.34 (m, 1H), 1.50-1.70 (m, 1H), 1.76-1.98 (m, 2H), 2.44-2.60 (m,
1H), 2.73 (dtt, J ) 19.8, 2.5, 8.6 Hz, 1H), 2.86-3.01 (m, 1H), 4.16 (q,
J ) 7.1 Hz, 2H), 5.69 (q, J ) 2.4 Hz, 1H); 13C NMR δ 14.39, 18.20,
24.09, 32.89, 34.34, 41.53, 59.45, 111.01, 167.23, 173.21; IR (neat)
2990 (sh), 2950, 2890, 1700, 1650, 1450, 1380, 1310, 1250, 1210, 1160,
1
199.30, 214.78; H NMR (C6D6) δ 0.39 (s, 9H), 0.91 (t, J ) 7.1 Hz,
3H), 0.86-1.03 (m, 1H), 1.04-1.30 (m, 7H), 1.73 (ddt, J ) 4.3, 12.9,
6.5 Hz, 1H), 1.87 (dd, J ) 3.8, 16.8 Hz, 1H), 1.91-2.01 (ddd, J )
3.8, 6.5, 10.5 Hz, 1H), 2.18-2.27 (m, 2H), 2.44 (dd, J ) 6.5, 16.8 Hz,
1H); 13C NMR (C6D6) δ -1.14, 14.01, 23.05, 27.55, 30.41, 32.64,
34.73, 42.70, 44.85, 54.12, 135.13, 197.31, 212.49; IR (neat) 2960,
2930, 2860, 1700, 1610, 1460, 1410, 1290, 1250, 1230, 1150, 910,
840, 760, 700, 660 cm-1. Anal. Calcd for C15H26OSi: C, 71.93; H,
10.46. Found: C, 71.80; H, 10.39.
1040, 870 cm-1
. Anal. Calcd for C10H16O2: C, 71.39; H, 9.59.
Found: 71.21; H, 9.63.
1-[(E)-(Ethoxycarbonyl)deuteriomethylene]-2-(deuteriomethyl)-
cyclopentane (59): 1H NMR δ 1.11 (dt, J ) 6.8, 1.8 Hz, 2H), 1.28 (t,
J ) 7.1 Hz, 3H), 1.17-1.34 (m, 1H), 1.50-1.70 (m, 1H), 1.76-1.98
(m, 2H), 2.44-2.60 (m, 1H), 2.73 (ddt, J ) 2.3, 19.8, 8.7 Hz, 1H),
2.94 (dddd, J ) 3.4, 5.0, 8.3, 19.8 Hz, 1H), 4.16 (q, J ) 7.1 Hz, 2H).
Both protons at δ 1.12 ppm (CH3) and at δ 5.69 ppm (vinylic-H) of 58
disappeared to show 99% deuterium incorporation.
Minor (5RS,6RS)-Diastereoisomer: 1H NMR δ 0.18 (s, 9H), 0.87
(t, J ) 7.5 Hz, 3H), 0.95-1.20 (m, 7H), 1.85-2.06 (m, 2H), 2.06-
2.16 (m, 1H), 2.20 (dd, J ) 4.3, 18.0 Hz, 1H), 2.38 (dd, J ) 6.3, 18.0
Hz, 1H), 2.44-2.68 (m, 2H), 3.04 (br dt, J ) 4.3, 6.3 Hz, 1H); IR
(neat) 2960, 2930, 2890, 1690, 1610, 1460, 1250, 840, 760, 690 cm-1
.
Irradiation of the proton at δ 3.04 ppm (bridgehead-CH) of the minor
diastereoisomer showed 6.6% NOE enhancement to δ 2.06-2.16 ppm
(Bu-CH). This fact supports the above structural assignment to the
minor diastereoisomer. The coupling constants observed for BuCH
and the bridgehead proton in both isomers are also consistent with the
proposed assignment.
Typical Procedure for Type II Tandem Cyclization. 1--
[(Ethoxycarbonyl)methyl]bicyclo[3.1.0]hexane (64). To a stirred
solution of Ti(O-i-Pr)3Cl (0.30 mL, 2 M solution in Et2O, 0.6 mmol)
in Et2O (3.8 mL) were added 56 (119 mg, 0.5 mmol) in 1 mL of Et2O
and i-PrMgCl (0.86 mL, 1.40 M solution in Et2O, 1.2 mmol) in this
order at -78 °C under an argon atmosphere. The solution was stirred
for 30 min at -78 °C, gradually allowed to warm to 0 °C over 1 h,
and kept at this temperature for an additional 1 h. The reaction was
terminated by the addition of 1 N HCl and Et2O. The organic layer
was separated off, washed with aqueous NaHCO3 solution, dried over
MgSO4, and concentrated in Vacuo to an oil. The crude oil was purified
on silica gel (hexane-ether) to give the title compound (60.3 mg,
72%): 1H NMR δ 0.36 (dd, J ) 4.8, 8.2 Hz, 1H), 0.45 (t, J ) 4.8 Hz,
1H), 1.08-1.22 (m, 1H), 1.25 (t, J ) 7.1 Hz, 3H), 1.50-1.86 (m, 6H),
2.37 (d, J ) 15.0 Hz, 1H), 2.47 (d, J ) 15.0 Hz, 1H), 4.12 (q, J ) 7.1
Hz, 2H); 13C NMR δ 12.09, 14.28, 21.37, 23.36, 25.23, 27.47, 31.77,
41.00, 59.99, 172.70; IR (neat) 2950, 2860, 1740, 1260, 1180, 1170,
(1RS,5RS)-2-[(E)-Propylidene]-3-bicyclo[3.3.0]octanone (51). The
primary product, a mixture of the two diastereoisomers of â-hydrox-
yketones and 51, was eventually converted to the title ketone by
treatment with TsOH in refluxing benzene. 1H NMR: δ 1.06 (t, J )
7.6 Hz, 3H), 1.31-1.50 (m, 2H), 1.50-1.74 (m, 2H), 1.84-1.90 (m,
1H), 2.02-2.26 (m, 4H), 2.58 (dd, J ) 9.7, 18.4 Hz, 1H), 2.58-2.72
(m, 1H), 3.25 (br q, J ) 7.4 Hz, 1H), 6.48 (dt, J ) 2.5, 7.7 Hz, 1H).
Irradiation of the angular allylic hydrogen at δ 3.25 ppm showed a
0.7% NOE enhancement to the acyclic allylic hydrogens at δ 2.02-
2.26 ppm. Thus, the olefinic stereochemistry was assigned to be E.
The shown stereochemistry of the ring junction was deduced based on
the assignment to 54 (Vide infra). 13C NMR: δ 12.94, 22.78, 26.35,
34.08, 34.64, 36.68, 43.26, 44.63, 138.73, 144.26, 208.25. IR (neat):
1150, 1040 cm-1
. Anal. Calcd for C10H16O2: C, 71.39; H, 9.59.
Found: C, 71.47; H, 9.49. An authentic sample, prepared by the
method illustrated in the following scheme, showed the same physical
properties.
2960, 2870, 1720, 1650, 1460, 1420, 1280, 1210, 1150, 1020 cm-1
.
Anal. Calcd for C11H16O: C, 80.44; H, 9.82. Found: C, 80.57; H,
9.98.
(1RS,5SR)-6,7-Benzo-3-bicyclo[3.3.0]octanone (53): 1H NMR δ
1.96 (dd, J ) 8.0, 18.5 Hz, 1H), 2.44-2.62 (m, 1H), 2.55 (dd, J )
3.4, 19.5 Hz, 1H), 2.70 (ddd, J ) 1.5, 9.2, 19.5 Hz, 1H), 2.82 (br d, J
) 15.2 Hz, 1H), 3.08-3.22 (m, 1H), 3.25 (dd, J ) 7.4, 15.2 Hz, 1H),
3.78-3.93 (m, 1H), 7.10-7.28 (m, 4H); 13C NMR δ 38.42, 39.41,
1-[(Ethoxycarbonyl)dideuteriomethyl]bicyclo[3.1.0]hexane (65):
1H NMR δ 0.36 (dd, J ) 4.8, 8.2 Hz, 1H), 0.45 (t, J ) 4.8 Hz, 1H),
1.08-1.22 (m, 1H), 1.25 (t, J ) 7.1 Hz, 3H), 1.50-1.86 (m, 6H), 4.12
(q, J ) 7.1 Hz, 2H). Note that the two protons at δ 2.37 and 2.47

10026 J. Am. Chem. Soc., Vol. 119, No. 42, 1997
Urabe et al.
ppm (d, J ) 15.0 Hz, CH2CO2Et) of 64 disappeared to show 99%
deuterium incorporation to both protons.
Major Isomer: 1H NMR δ 0.30 (t, J ) 4.6 Hz, 1 H), 0.46 (dd, J )
4.6, 7.5 Hz, 1 H), 2.28 (d, J ) 15 Hz, 1 H), 2.64 (d, J ) 15 Hz, 1 H).
Minor Isomer: 1H NMR δ 0.41 (dd, J ) 4.6, 7.5 Hz, 1 H), 2.37 (s,
2 H), 4.55 (dt, J ) 5, 7.7 Hz, 1 H).
IR (neat): 3060, 2960, 2930, 2885, 2860, 1740, 1470, 1460, 1380,
1360, 1250, 1160, 1100, 1080, 1040, 840, 770 cm-1 for the 62:38
mixture of diastereoisomers. Anal. Calcd for C16H30O3Si: C, 64.38;
H, 10.13. Found: C, 64.51; H, 10.21 for the 62:38 mixture of
diastereoisomers.
Typical Procedure for Type II Tandem Cyclization and Subse-
quent Reaction with Ketone. 1-[(Ethoxycarbonyl)(3-pentylidene)-
methyl]bicyclo[3.1.0]hexane (66). To a stirred solution of Ti(O-i-
Pr)3Cl (0.30 mL, 2 M solution in Et2O, 0.6 mmol) in Et2O (3.8 mL)
were added 56 (119 mg, 0.5 mmol) in 1 mL of Et2O and i-PrMgCl
(0.86 mL, 1.40 M solution in Et2O, 1.2 mmol) in this order at -78 °C
under an argon atmosphere. The mixture was stirred for 30 min,
gradually allowed to warm to 0 °C over 1 h, and kept at this temperature
for 1 h. 3-Pentanone (0.075 mL, 0.75 mmol) was added at 0 °C. After
the mixture was stirred at 0 °C for 3 h, the reaction was terminated by
the addition of 1 N HCl and Et2O. The organic layer was separated
off, washed with aqueous NaHCO3 solution, dried over MgSO4, and
concentrated in Vacuo to an oil. The crude oil was purified on silica
gel (hexane-ether) to give the title compound (68.3 mg, 58%): 1H
NMR δ 0.47 (dd, J ) 4.7, 8.3 Hz, 1H), 0.65 (t, J ) 4.7 Hz, 1H), 1.00
(t, J ) 7.5 Hz, 3H), 1.04 (t, J ) 7.6 Hz, 3H), 1.17-1.23 (m, 1H), 1.29
(t, J ) 7.1 Hz, 3H), 1.54-1.93 (m, 6H), 2.17 (dq, J ) 13.9, 7.5 Hz,
1H), 2.23 (dq, J ) 13.9, 7.5 Hz, 1H), 2.27 (dq, J ) 13.4, 7.6 Hz, 1H),
2.38 (dq, J ) 13.4, 7.6 Hz, 1H), 4.15 (dq, J ) 10.7, 7.1 Hz, 1H), 4.20
(dq, J ) 10.7, 7.1 Hz, 1H); 13C NMR δ 12.40, 13.31, 14.40, 14.45,
21.17, 24.28, 25.15, 27.66, 28.44, 33.57, 59.70, 130.47, 152.23, 170.42;
IR (neat) 2970, 2940, 2870, 1720, 1640, 1220, 1200, 1070 cm-1. Anal.
Calcd for C15H24O2: C, 76.23; H, 10.24. Found: C, 76.13; H, 10.26.
3-Aza-3-benzyl-1-[(ethoxycarbonyl)methyl]bicyclo[3.1.0]hex-
(1RS,4SR,5RS)-4-Butyl-1-(ethoxycarbonylmethyl)bicyclo[3.1.0]-
1
hexane (75): H NMR δ 0.39 (dd, J ) 5.0, 8.4 Hz, 1 H), 0.44 (dd, J
) 4.2, 5.0 Hz, 1 H), 0.88 (t, J ) 7 Hz, 3 H), 1.00 (dd, J ) 4.2, 8.4 Hz,
1 H), 1.26 (m, 8 H, alkyl-H), 1.26 (t, J ) 7.5 Hz, 3 H), 1.70 (m, 2 H),
1.84 (br q, J ) 6 Hz, 1 H), 2.38 (d, J ) 15 Hz, 1 H), 2.43 (d, J ) 15
Hz, 1 H), 4.10 (q, J ) 7.5 Hz, 2 H). The stereochemistry was assigned
based on negligible coupling constant (J ) ca. 0 Hz) between tertiary
cyclopropane-H and BuCH by analogy to the case of 77. 13C NMR:
δ 13.42, 14.03, 14.19, 22.80, 25.02, 26.99, 28.65, 29.44, 29.98, 35.11,
40.27, 41.27, 60.06, 172.92. IR (neat): 3060, 2960, 2920, 2870, 1740,
1460, 1370, 1250, 1200, 1140, 1040 cm-1
.
Anal. Calcd for
C14H24O2: C, 74.95; H, 10.78. Found: C, 75.15; H, 10.98.
(1RS,4SR,5RS)-4-[((tert-Butyl)dimethylsiloxy)methyl]-1--
[(ethoxycarbonyl)methyl]bicyclo[3.1.0]hexane (77). This is a racemic
form of 91. For physical properties, see those of 91.
(5RS,6SR)-1-[(Ethoxycarbonyl)methyl]-6-pentylbicyclo[3.1.0]-
hexane (82): 1H NMR δ 0.67 (q, J ) 7.5 Hz, 1 H), 0.86 (t, J ) 7 Hz,
3 H), 1.16 (m, 1 H), 1.24 (t, J ) 7.5 Hz, 3 H), 1.26 (m, 8 H), 1.5-2.05
(m, 6 H), 2.26 (d, J ) 15.4 Hz, 1 H), 2.47 (d, J ) 15.4 Hz, 1 H), 4.11
(q, J ) 7.5 Hz, 2 H). The stereochemical assignment to this product
was made based on the following 1H NMR NOE experiment. Irradia-
tion of the peak at δ 0.67 ppm (cyclopropane H geminal to the pentyl
side chain) effected a 3.5% enhancement to the peak at δ 2.26 ppm
(CHCO2Et) and 2.5% to the one at δ 2.47 ppm (CHCO2Et). 13C
NMR: δ 14.07, 14.32, 22.70, 23.78, 25.36, 27.26, 27.54, 28.37, 28.71,
29.97 (two peaks), 31.90, 43.23, 59.97, 172.99. IR (neat): 2960, 2920,
2860, 1740, 1460, 1370, 1250, 1180, 1040 cm-1. Anal. Calcd for
C15H26O2: C, 75.58; H, 11.00. Found: C, 76.06; H, 10.98.
1
ane (68): H NMR δ 0.42 (dd, J ) 4.0, 8.0 Hz, 1H), 1.11 (t, J ) 4.0
Hz, 1H), 1.23 (t, J ) 7.7 Hz, 3H), 1.23 (m, 1H), 2.28 (d, J ) 8.0 Hz,
1H), 2.35 (d, J ) 15.0 Hz, 1H), 2.40 (dd, J ) 2.5, 8.0 Hz, 1H), 2.52
(d, J ) 15.0 Hz, 1H), 2.91 (d, J ) 8.0 Hz, 1H), 3.03 (d, J ) 8.0 Hz,
1H), 3.60 (s, 2H), 4.11 (q, J ) 7.7 Hz, 2H), 7.18-7.38 (m, 5H); 13C
NMR δ 12.99, 14.28, 21.78, 23.70, 39.08, 54.70, 58.33, 58.99, 60.22,
126.70, 128.07, 128.46, 139.52, 172.23; IR (neat) 3080, 3050, 2980,
2930, 2800, 1745, 1470, 1380, 1350, 1260, 1220, 1160, 1040, 750,
710 cm-1. Anal. Calcd for C16H21O2N: C, 74.10; H, 8.16; N, 5.40.
Found: C, 74.04; H, 8.12, N, 5.16.
A 3:1 Mixture of (1RS,2RS)- and (1RS,2SR)-1-[(Ethoxycarbon-
yl)methyl]-3-oxa-2-pentylbicyclo[3.1.0]hexane (70).
(1R,4S,5R)-4-[[(tert-Butyl)dimethylsiloxy]methyl]-1--
[(ethoxycarbonyl)methyl]bicyclo[3.1.0]hexane (91). To a mixture of
the enynoate 86 (250 mg, 0.806 mmol) and Ti(O-i-Pr)3Cl (0.525 mL
of a 2 M solution in ether, 1.05 mmol) in ether (8 mL) was added
i-PrMgCl (1.31 mL of a 1.60 M in ether, 2.10 mmol) at -78 °C. After
-78 °C for 30 min, the resulting brown solution was gradually warmed
to 0 °C over 1.5 h and was kept at this temperature for another 1.25 h.
The reaction was terminated by the addition of 1 N HCl. The organic
phase was diluted with ether, separated off, washed successively with
1 N HCl and aqueous NaHCO3 solution, dried (Na2SO4), and
concentrated. Purification on silica gel (2.5% ether in hexane) afforded
the title compound (195 mg, 78%) as a colorless oil. 1H NMR analysis
of the crude and purified samples revealed that the product had been
formed virtually as a single diastereoisomer (>98-99% diastereo-
selectivity): 1H NMR δ 0.04 (s, 6 H), 0.46 (d, J ) 7.5 Hz, 1 H), 0.48
(d, J ) 4.7 Hz, 1 H), 0.88 (s, 9 H), 1.05 (dd, J ) 4.7, 7.5 Hz, 1 H),
1.25 (t, J ) 7 Hz, 3 H), 1.27 (m, 1 H), 1.44-1.60 (m, 1 H), 1.60-1.80
(m, 2 H), 2.08 (q, J ) 7.5 Hz, 1 H), 2.35 (d, J ) 15.3 Hz, 1 H), 2.46
(d, J ) 15.3 Hz, 1 H), 3.37 (dd, J ) 7.7, 9.2 Hz, 1 H), 3.48 (dd, J )
7.0, 9.2 Hz, 1 H), 4.11 (q, J ) 7 Hz, 2 H). The following NOE study
determined the stereochemistry of this compound. Irradiation of the
peaks at δ 0.46 and 0.48 ppm (exo- and endo-cyclopropane H) showed
9%, 5%, 5%, 2%, and 2% enhancements to the peaks at δ 1.05 (tertiary-
cyclopropane H), 1.27 (cyclopentane CH), 2.08 (TBSOCH2CH), 2.35
(CHCO2Et), and 2.46 ppm (CHCO2Et), respectively. The negligible
coupling constant (J ) ca. 0 Hz) between tertiary cyclopropane-H and
TBSOCH2CH also supports this stereochemical assignment. 13C
NMR: δ -5.30, 13.17, 14.30, 18.36, 23.97, 25.06, 25.80, 25.98, 29.73,
41.14, 43.57, 60.04, 66.36, 172.51. IR (neat): 3060, 2960, 2930, 2860,
1740, 1470, 1250, 1110, 1100, 840, 770 cm-1. [R]23D: -2.2 (c 2.1,
CHCl3) for a sample of 80% ee. Anal. Calcd for C17H32O3Si: C, 65.34;
H, 10.32. Found: C, 65.75; H, 10.60. The enantiopurity of this sample
was determined by 1H NMR chiral shift study with (+)-Eu(hfc)3 to be
80% ee. The following peaks of the cyclopropane moiety were
separated at 40 mol % of the Eu reagent: major enantiomer: δ 0.71
(t, J ) 4.6 Hz, 1 H); minor enantiomer: δ 0.67 (t, J ) 4.6 Hz, 1 H).
1
Major Diastereoisomer: H NMR δ 0.60 (dd, J ) 4.6, 8.0 Hz,
1H), 0.70 (t, J ) 4.6 Hz, 1H), 0.88 (t, J ) 7.0 Hz, 3H), 1.27 (t, J )
7.5 Hz, 3H), 1.28 (m, 6H), 1.39 (m, 1H), 1.50 (m, 2H), 2.17 (d, J )
15.0 Hz, 1H), 2.88 (d, J ) 15.0 Hz, 1H), 3.65 (d, J ) 8.0 Hz, 1H),
3.79 (d, J ) 8.0 Hz, 1H), 3.98 (br d, J ) 11.0 Hz, 1H), 4.14 (q, J )
7.0 Hz, 2H). The following NOE experiment determined the assigned
stereochemistry to the major diastereoisomer. Irradiation of the peak
at δ 0.70 ppm (endo-cyclopropane-CH2 of the major isomer) shows
2% and 4% enhancement of the peaks at δ 3.79 ppm (one of
cyclopentane-CH2) and δ 3.98 ppm (OCH-C5H11). Thus, the cyclo-
propane ring and the pentyl side chain should be trans in the major
diastereoisomer. IR (neat): 2970, 2940, 2860, 1740, 1480, 1380, 1250,
1160, 1080, 1040 cm-1 for the above 3:1 mixture of diastereoisomers.
Anal. Calcd for C14H24O3: C, 69.96; H, 10.06. Found: C, 69.71; H,
10.46 for the above 3:1 mixture of diastereoisomers.
Minor Diastereoisomer: 1H NMR δ (only characteristic peaks are
shown) 0.50 (dd, J ) 4.6, 8.0 Hz, 1H), 0.68 (t, J ) 4.6 Hz, 1H), 2.36
(d, J ) 15.0 Hz, 1H), 2.66 (d, J ) 15.0 Hz, 1H), 3.78 (m, 3H).
1-[(Ethoxycarbonyl)methyl]-4-[(tert-butyl)dimethylsiloxy]bicyclo-
[3.1.0]hexane. A 62:38 Mixture of the (1RS,4SR,5SR)- and
(1RS,4RS,5SR)-Diastereoisomers (73).
Major Isomer: 1H NMR (C6D6) δ 0.10 (s, 3 H), 0.12 (s, 3 H), 0.23
(t, J ) 4.6 Hz, 1 H), 0.46 (dd, J ) 4.6, 7.5 Hz, 1 H), 1.00 (m, 12 H),
1.10-2.15 (m, 5 H), 2.23 (d, J ) 14.6 Hz, 1 H), 2.59 (d, J ) 14.6 Hz,
1 H), 4.02 (q, J ) 7.5 Hz, 2 H), 4.10 (d, J ) 6 Hz, 1 H). The
stereochemistry of the major isomer was assigned based on negligible
coupling constant (J ) ca. 0 Hz) between tertiary cyclopropane-H and
TBSOCH by analogy to the case of 77.
Minor Isomer: 1H NMR (C6D6) δ 0.04 (t, J ) 4 Hz, 1 H), 0.12 (s,
3 H), 0.14 (s, 3 H), 0.37 (dd, J ) 4, 7.5 Hz, 1 H), 1.00 (m, 12 H),
1.10-2.15 (m, 5 H), 2.19 (d, J ) 15 Hz, 1 H), 2.25 (d, J ) 15 Hz, 1
H), 3.98 (q, J ) 7.5 Hz, 2 H), 4.58 (dt, J ) 5, 7.7 Hz, 1 H).
The separation of peaks of the diastereoisomers is less pronounced
in CDCl3, but the following few characteristic signals would be useful
to distinguish both isomers.

Cyclization of 2,7- or 2,8-Bis-unsaturated Esters
J. Am. Chem. Soc., Vol. 119, No. 42, 1997 10027
(1S,4S,5R)-4-[[(tert-Butyl)dimethylsiloxy]methyl]-1-[1-
(ethoxycarbonyl)ethyl]bicyclo[3.1.0]hexane. To a solution of diiso-
propylamine (0.103 mL, 0.735 mmol) in 3 mL of THF was added BuLi
(0.295 mL of a 2.40 M hexane solution, 0.708 mmol) at -78 °C. After
10 min, the ester 91 (192 mg, 0.615 mmol) in 2 mL of THF was added
at -78 °C and the solution was stirred at that temperature for 1 h.
Then methyl iodide (0.057 mL, 0.916 mmol) was added. After the
mixture was stirred for 10 min at -78 °C, the solution was gradually
warmed to room temperature over 20 min and was stirred at this
temperature for 10 min. The reaction was terminated with aqueous
NaHCO3 and Na2S2O3 solution, and organic products were extracted
with ether-hexane. Combined organic layers were dried (Na2SO4) and
concentrated to give a spectroscopically pure title compound (213 mg)
as a 1:1 mixture of diastereoisomers, which was directly used in the
next step. 1H NMR: δ 0.03 (s, 3 H), 0.05 (s, 3 H), 0.39 (dd, J ) 4.3,
7.5 Hz, 1/2H), 0.4-0.48 (m, 1/2H × 2), 0.56 (dd, J ) 4.5, 7.5 Hz, 1/2H),
0.87 (s, 9 H), 0.98-1.08 (m, 1/2H × 2), 1.13 (d, J ) 7.5 Hz, 1/2H × 3),
1.15 (d, J ) 7.5 Hz, 1/2H × 3), 1.23 (t, J ) 7.5 Hz, 1/2H × 3), 1.25 (t,
J ) 7.5 Hz, 1/2H × 3), 1.40-1.75 (m, 1/2H × 4), 2.07 (q, J ) 7 Hz, 1
ether-pentane (1:1) and was washed with water. The organic layer
was dried (Na2SO4), concentrated, and chromatographed on silica gel
(ether-hexane) to give the title compound (80 mg, quant.): 1H NMR
δ 0.325 (d, J ) 7.4 Hz, 1 H), 0.33 (d, J ) 5 Hz, 1 H), 0.89 (d, J ) 7.2
Hz, 3 H), 0.92 (d, J ) 7.2 Hz, 3 H), 1.20-1.70 (m, 7 H), 2.08 (q, J )
7.5 Hz, 1 H), 3.38 (dd, J ) 7.5, 9 Hz, 1 H), 3.49 (dd, J ) 7.5, 9 Hz.
1 H); 13C NMR δ 12.40, 19.62, 20.19, 23.58, 24.69, 25.05, 25.54, 32.43,
43.40, 66.60; IR (neat) 3320 (br), 3060, 2960, 2920, 2870, 1470, 1380,
1360, 1050, 1020 cm-1; [R]23D +7.9 (c 3.8, THF) for a sample of 80%
ee. The enantiopurity of this sample was determined by the integration
of the following peaks of the 1H NMR spectrum of the (S)-MTPA ester
prepared from (R)-(-)-MTPA-Cl. Major enantiomer: δ 4.03 (dd, J
) 7.9, 10.6 Hz, 1 H, CH2OMTPA), 4.15 (dd, J ) 7.6, 10.6 Hz, 1 H,
CH2OMTPA). Minor enantiomer: δ 4.06 (dd, J ) 7.9, 10.6 Hz, 1 H,
CH2OMTPA), 4.13 (dd, J ) 7.6, 10.6 Hz, 1 H, CH2OMTPA).
(1R,4S,5R)-1-Isopropyl-4-[[(2-nitrobenzene)selenenyl]methyl]-
bicyclo[3.1.0]hexane. To a solution of the alcohol 94 (76 mg, 0.493
mmol) and (2-nitrophenyl)selenocyanate (134 mg, 0.591 mmol) in 3
mL of THF was added PBu3 (0.147 mL, 0.590 mmol) at room
temperature. After the dark solution had been stirred at room
temperature for 2 h, the starting material still remained so that further
portions of the selenocyanate (90 mg, 0.394 mmol) and PBu3 (0.099
mL, 0.394 mmol) were added. Twenty minutes later, TLC analysis
showed the complete consumption of the starting material. The solution
was washed with aqueous NaHCO3 solution, dried (Na2SO4), and
concentrated. The resultant brown oil was roughly purified on silica
gel (ether-hexane) to give the title compound (195 mg, contaminated
with a small amount of byproducts) as a yellow oil, which was directly
used in the next step: 1H NMR: δ 0.36 (d, J ) 6 Hz, 2 H), 0.91 (d,
J ) 7 Hz, 3 H), 0.96 (d, J ) 7 Hz, 3 H), 1.09 (t, J ) 6 Hz, 1 H),
1.30-1.96 (m, 5 H), 2.28 (q, J ) 7.3 Hz, 1 H), 2.76 (dd, J ) 8, 11 Hz,
1 H), 2.88 (dd, J ) 6.9, 11 Hz, 1 H), 7.30 (t, J ) 8 Hz, 1 H), 7.52 (m,
2 H), 8.28 (d, J ) 8 Hz, 1 H).
1
1
H), 2.19 (q, J ) 7.5 Hz, /2H), 2.22 (q, J ) 7.5 Hz, /2H), 3.25 (dd, J
) 7, 9 Hz, 1/2H), 3.34 (dd, J ) 7, 9 Hz, 1/2H), 3.43 (dd, J ) 5.5, 9 Hz,
1/2H), 3.46 (dd, J ) 5.5, 9 Hz, 1/2H), 4.10 (m, 2 H). IR (neat): 3060,
2960, 2930, 2860, 1730, 1470, 1380, 1250, 1180, 1160, 1100, 840,
780 cm-1 for a 1:1 mixture of the diastereoisomers.
2-[(1R,4S,5R)-4-[[(tert-Butyl)dimethylsiloxy]methyl]bicyclo[3.1.0]-
hex-1-yl]propan-1-ol (92). The crude, methylated ester (213 mg)
obtained above was reduced with Dibal-H (1.94 mL of a 0.95 M hexane
solution, 1.84 mmol) in ether (10 mL) first at -78 °C and then at 0 °C
for 30 min. Aqueous workup with 1 N HCl and extraction with ether-
pentane afforded a crude sample of the title compound (180 mg) as a
1:1 mixture of diastereoisomers having rather different Rf values on
analytical TLC (Rf ) 0.53 and 0.37, Merck Cat. No. 1.05554, 20%
EtOAc in hexane). This product was used in the next step without
1
1
further purification. 1H NMR: δ 0.05 (s, /2H × 6), 0.10 (s, /2H ×
3), 0.11 (s, 1/2H × 3), 0.20 (m, 1/2H × 2), 0.41 (m, 1/2H × 2), 0.88 (m,
12 H), 1.1-1.8 (m, 7 H), 2.07 (q, J ) 7.5 Hz, 1 H), 3.3-3.75 (m, 4
H). IR (neat): 3400 (br), 3060, 2960, 2930, 2860, 1470, 1260, 1100,
(1R,5R)-(+)-1-Isopropyl-4-methylenebicyclo[3.1.0]hexane (d-Sab-
inene) (84). To a stirred solution of the above selenide (195 mg) in 1
mL of THF were added powdered K2CO3 (204 mg, 1.48 mmol) and
35% aqueous H2O2 (0.48 g, ca. 5 mmol) in this order at room
temperature. After the stirring was continued for 30 min, 0.4 mL of
THF, 70 mg of K2CO3, and water (0.4 mL) were added to the red
solution. The mixture was stirred at room temperature for 40 h and
eventually diluted with 4 mL of pentane. The pentane layer was washed
seven times with 3 mL portions of water to remove the bulk of THF.
The organic layer was dried over Na2SO4 and carefully concentrated
to a red oil, which was subjected to purification on silica gel (pentane)
to yield the pure title compound (34 mg, 51% overall from 93) as a
colorless oil: 1H NMR δ 0.64 (d, J ) 5.3 Hz, 2 H), 0.87 (d, J ) 7 Hz,
3 H), 0.94 (d, J ) 7 Hz, 3 H), 1.48 (quintet, J ) 7 Hz, 1 H), 1.58 (t,
J ) 5.5 Hz, 1 H), 1.68 (m, 1 H), 1.76 (dd, J ) 9.3, 12 Hz, 1 H), 1.99
(dtt, J ) 16, 2.3, 9.3 Hz, 1 H), 2.16 (br dd, J ) 8.6, 16 Hz, 1 H), 4.61
(br s, 1 H), 4.80 (br s, 1 H); 13C NMR δ 15.92, 19.58, 19.68, 27.40,
28.88, 30.04, 32.49, 37.58, 101.55, 154.69; IR (neat) 3080, 3060 (sh),
2960, 2940, 2880, 1650, 1470, 1450, 1380, 1360, 1330, 1315, 1300,
1280, 1240, 1200, 1160, 1150, 1130, 1105, 1090, 1070, 1020, 990,
960, 930, 915, 860, 805, 780, 730 cm-1. These spectral properties are
1040, 1000, 840, 780 cm-1
.
(1R,4S,5R)-4-[[(tert-Butyl)dimethylsiloxy]methyl]-1-iso-
propylbicyclo[3.1.0]hexane (93). A mixture of the crude alcohol 92
(180 mg), p-toluenesulfonyl chloride (TsCl, 176 mg, 0.923 mmol), and
a small amount of (dimethylamino)pyridine (7.5 mg) in pyridine (0.4
mL) was kept in a refrigerator (5 °C) overnight to give, after standard
workup, a mixture of the desired tosylate and the unreacted sulfonyl
chloride (1:0.35). This crude product was treated with LiBHEt3 (1.85
mL of a 1 M THF solution, 1.85 mmol) in 5 mL of THF at room
temperature for 3 h. At this stage, another 1 equiv of LiBHEt3 (0.62
mL) was added. After the mixture was stirred at room temperature
for 2 h, the starting material completely disappeared. To this solution
were added water (0.5 mL), 3 N aqueous NaOH solution (1 mL), and
aqueous 35% H2O2 solution (1 mL) in this order. After the mixture
was vigorously stirred for 30 min at room temperature, extractive
workup with ether-pentane (1:1) afforded a crude product, which was
purified on silica gel to give the title compound (140 mg, 85% overall
yield from 91) as a colorless oil: 1H NMR δ 0.04 (s, 6 H), 0.28 (d, J
) 5 Hz, 1 H), 0.28 (d, J ) 7 Hz, 1 H), 0.86 (d, J ) 7.5 Hz, 3 H), 0.88
(s, 9 H), 0.91 (d, J ) 7.5 Hz, 3 H), 1.0-1.6 (m, 6 H), 2.05 (q, J ) 7.5
Hz, 1 H), 3.31 (dd, J ) 8.0, 9.6 Hz, 1 H), 3.42 (dd, J ) 7.3, 9.6 Hz,
1 H); 13C NMR δ -5.43, 12.19, 18.30, 19.68, 20.18, 23.24, 24.78,
25.09, 25.91, 32.43, 33.52, 43.32, 66.51; IR (neat) 3060, 2960, 2930,
in good agreement with those reported in the literature.32b,c [R]23
:
D
+75.8 (c 0.65, n-pentane) for a sample of 80% ee; lit. [R]20D +107 (
3 (in substance) for a 99% pure sample;38a [R]D +89.38b
Acknowledgment. We thank the Ministry of Education,
Science, Sports and Culture (Japan) for financial support.
2860, 1470, 1380, 1360, 1250, 1100, 1080, 1020, 840, 770 cm-1; [R]23
D
+4.1 (c 2.1, CHCl3) for a sample of 80% ee. Anal. Calcd for C16H32-
OSi: C, 71.57; H, 12.01. Found: C, 72.00; H, 12.28.
(1R,4S,5R)-1-Isopropylbicyclo[3.1.0]hexane-4-methanol (94). A
mixture of the silyl ether 93 (140 mg, 0.521 mmol) and TBAF (0.626
mL of a 1 M solution in THF, 0.626 mmol) in 1 mL of THF was
stirred at room temperature for 3.5 h. The solution was diluted with
Supporting Information Available: Preparation and char-
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