A new strategy for the synthesis of cyclic terpenoids based on the radical opening of acyclic epoxypolyenes

Full text of DOI:10.1021/jo0155207

4074
J . Org. Chem. 2001, 66, 4074-4078
A New Str a tegy for th e Syn th esis of Cyclic
Ter p en oid s Ba sed on th e Ra d ica l Op en in g
of Acyclic Ep oxyp olyen es
Alejandro F. Barrero,* J uan M. Cuerva,
M. M. Herrador, and Mo´nica V. Valdivia
Institute of Biotechnology, Departamento de Quı´mica
Orga´nica, Facultad de Ciencias, 18071 Granada, Spain
F igu r e 1. Selected cyclohexanic natural products.
Sch em e 1. Str a tegies for Ar r ivin g a t
F u n cion a lized Cycloh exa n es
afbarre@goliat.ugr.es
Received J anuary 12, 2001
In tr od u ction
The cationic cyclization of polyenes has proved to be a
useful tool in the synthesis of natural terpenic products.1
During recent years biomimetic approaches using radical
chemistry have also been described.2,3 One of the most
efficient is based on Mn(III) chemistry, which in the
presence of Cu(II) resolves one of the main problems
involved in radical reactions, the loss of funcionality.4,5
Another method is that of using Ti(III)6 complexes to
promote the homolytic opening of epoxides and the
addition of the resulting radical to an alkene, forming
five-membered rings.7,8 In this case the reaction normally
ends in the protonolysis of the organometallic intermedi-
ate, although the use of other electrophiles leads to more
functionalized final products.7a
enes.9 This approach leads to oxabicyclic compounds,
which can be further elaborated (Scheme 1). Our inten-
tion in this note is to describe a more efficient approach
to obtain this kind of terpene skeleton and if possible to
generalize to other types of skeleton under mild reaction
conditions, since direct policyclizations of epoxides of
natural polyenes usually give complex mixtures of prod-
ucts and low yields (less than 10%) of polycyclic com-
punds.10 To this end we decided to apply a technique
involving the homolytic opening of epoxides with Ti(III)
complexes to acyclic epoxypolyenes under reaction condi-
tions that give rise to an oxidative termination step.11
Our recent research has been into the synthesis of
terpenes with functionalized cyclohexane skeletons (Fig-
ure 1) via the electrophilic opening of acyclic epoxypoly-
* Fax: +34 958 243318.
(1) For a review see: Sutherland, J . K. In Comprehensive Organic
Synthesis; Trost, B. M., Fleming, I., Eds.; Pergamon: Oxford, 1991;
Vol. 3, p 341.
Resu lts a n d Discu ssion
(2) (a) Mn complexes: Snider, B. B.; Mohan, R.; Kates, S. A. J . Org.
Chem. 1985, 50, 3661. Snider, B. B.; Mohan, R.; Kates, S. A.
Tetrahedron Lett. 1987, 28, 841. Zoretic, P. A.; Fang, H.; Ribeiro, A.
A. J . Org. Chem. 1998, 63, 7213. Zoretic, P. A.; Zhang, Y.; Fang, H. J .
Org. Chem. 1998, 63, 1162. Yang, D.; Ye, X.-Y.; Xu, M.; Pang, K.-W.;
Cheung, K.-K. J . Am. Chem. Soc. 2000, 122, 1658. (b) Acyl radicals:
Pattenden, G.; Roberts, L.; Blake, A. J . J . Chem. Soc., Perkin Trans.
1 1998, 863. Handa, S.; Pattenden, G. J . Chem. Soc., Perkin Trans. 1
1999, 843.
(3) For the preparation of terpene skeletons via cation radicals see:
Warzecha, K.-D.; Xing, X.; Demuth, M. Pure Appl. Chem. 1997, 69,
109. Warzecha, K.-D.; Xing, X.; Demuth, M.; Goddard, R.; Kessler, M.;
Kru¨ger, C. Helv. Chim. Acta 1995, 2065. Hoffmann, U.; Gao, Y.;
Pandey, B.; Klinge, S.; Warzecha, K.-D.; Kru¨ger, C.; Roth, H. D.;
Demuth, M. J . Am. Chem. Soc. 1993, 115, 10358.
When 6,7-epoxygeranyl acetate 1 was made to react
with stoichiometric quantities of Cp2TiCl, a cyclization
product mixture, 2-4, was obtained (71%)12 (Table 1),
in which the predominant products derive from a 6-endo-
trig cyclization mode (63%) since the 5-exo-trig process
(8%) is sterically unfavorable.13
The cis/ trans stereoselection in the six-membered
carbocycles comes from a chairlike (cis) or boatlike (trans)
transition state of the cyclization (Scheme 2). An isomer-
ization process of ∆2,3 double bonding under the reaction
conditions in question can be ruled out because when the
cyclization reaction is carried out with the isomeric
substrate, 6,7-epoxyneryl acetate 5, no cyclization prod-
ucts are obtained, only the acyclic products 6 and 714
(4) Transition-metal radical chemistry has the advantage of final
functionalizing reaction steps. For a review see: Iqbal, J .; Bhatia, B.;
Nayyar, N. K. Chem. Rev. 1994, 94, 519. Gansa¨uer, A.; Bluhm, H.
Chem. Rev. 2000, 100, 2771.
(5) (a) Mn review: Snider, B. B. Chem. Rev. 1996, 96, 339. (b) Recent
references: Cole, B. M.; Han, L.; Snider, B. B. J . Org. Chem. 1996,
61, 7832. O’Neil, S. V.; Quickley, C. A.; Snider, B. B. J . Org. Chem.
1997, 62, 1970. Garcia-Ruano, J . L.; Rumbero, A. Tetrahedron:
Asymmetry 1999, 10, 4427. Pettus, T. R. R.; Inoue, M.; Chen, X.-T.;
Danishefsky, S. J . J . Am. Chem. Soc. 2000, 122, 6160.
(9) Barrero, A. F.; Alvarez-Manzaneda, E. J .; Chahboun, R.; Rod-
riguez, A.; Linares, P. Tetrahedron 2000, 56, 6099.
(10) Van Tamelen, E. E. Acc. Chem. Res. 1975, 8, 152.
(11) For a precedent see: Chakraborty, T. K.; Dutta, S. Tetrahedron
Lett. 1998, 39, 101.
(12) . The stereochemical assigments for all new compounds were
established on the basis of NOE diff experiments.
(6) For a recent review of Cp2TiCl chemistry see: Spencer, R. P.;
Schwartz, J . Tetrahedron 2000, 56, 2103.
(7) (a) RajanBabu, T. V.; Nugent, W. A. J . Am. Chem. Soc. 1994,
116, 986 and references therein. (b) Merlic, C. A.; Xu, D. J . Am. Chem.
Soc. 1991, 113, 9855. For the Ti catalytic version see: (c) Gansa¨uer,
A.; Bluhm, H.; Pierobon, M. J . Am. Chem. Soc. 1998, 120, 12849.
(8) The reaction has hardly been used in natural product synthe-
sis: Clive, D. J . L.; Magnuson, S. R.; Manning, H. W.; Mayhew, D. L.
J . Org. Chem. 1996, 61, 2095. Mandal, P. K.; Maiti, G.; Roy, S. C. J .
Org. Chem. 1998, 63, 2829.
(13) For a regio- and stereochemical study of radical cyclizations
see: (a) Curran, D. P.; Porter, N. A.; Giese, B. Stereochemistry of
Radical Reactions; VCH Publishers: New York, 1996. (b) Walling, C.;
Cioffari, A. J . Am. Chem. Soc. 1972, 94, 6059. (c) Spellmeyer, D. C.;
Houk, K. N. J . Org. Chem. 1987, 52, 959.
(14) Similar products with E configuration in ∆2,3 double bond were
obtained in the cyclization of 1. See Supporting Information.
10.1021/jo0155207 CCC: $20.00 © 2001 American Chemical Society
Published on Web 04/27/2001

Notes
J . Org. Chem., Vol. 66, No. 11, 2001 4075
Ta ble 1. Cycliza tion Rea ction s
a
b
d
Product 2 presents an exo:endo ratio of 6.3:1. Product 3 presents an exo:endo ratio of 7.3:1. c 1:1 mixture of diastereoisomers. The
6:7 ratio was 10:1. e Product 19 is a mixture of three diastereoisomers at a ratio of 1:1:1.
Sch em e 2. Na tu r e of th e Ster eoselection in th e
Cycliza tion of Ep oxid e 1
Sch em e 3. P r op osed Mech a n ism
organotitanium (Scheme 3).16,17,18 The regiochemistry of
the mainly exocyclic elimination of hydrogen is well
probably as the result of a decrease of the cyclization rate
toward others secondary processes.
(16) It is known that the â-hydrid elimination process in d0 metal
complexes is slow: Crabtree, R. H. The Organometallic Chemistry of
the Transition Metals; Wiley & Sons: New York, 1994; pp 45-48.
Although some examples of this process in Ti(IV) chemistry have been
described: Okamoto, S.; Livinghouse, T. J . Am. Chem. Soc. 2000, 122,
1223. Sturla, S. J .; Kablaoui, N. M.; Buchwald, S. L. J . Am. Chem.
Soc. 1999, 121, 1976. Moreover this is the final step in some Co-
mediated radical cyclizations: Branchaud, B. P.; Meier, M. S.; Choi,
Y. Tetrahedron Lett. 1988, 29, 167. Begley, M. J .; Bhandal, H.;
Hutchinson, J . H.; Pattenden, G. Tetrahedron Lett. 1987, 28, 1317.
(17) A cationic pathway can be ruled out because of the regiochem-
istry of the final double bond.
The most interesting result is that the cyclic products
produced had an alkene function. Cyclopentane 4 shows
a double bond that derives from â-acetoxy elimination of
the intermediate organotitanium.15 The formation of
cyclohexenes 2 and 3 can in this case be attributed to a
â-hydride elimination of hydrogen in the intermediate
(15) The reaction has wide precedents in early transition-metal
chemistry: (a) Ti: ref 7a. Takayama, Y.; Okamoto, S.; Sato, F. J . Am.
Chem. Soc. 1999, 121, 3559. Spencer, R. P.; Cavallaro, C. L.; Schwartz,
J . J . Org. Chem. 1999, 64, 3987. (b) Zr: Takahashi, T.; Kondanov, D.
Y.; Xi, Z.; Suzuki, N. J . Am. Chem. Soc. 1995, 117, 5871. (c) Sm:
Molander, G. A.; Mckie, J . A. J . Org. Chem. 1994, 59, 3186.
(18) A mixed radical disproportionation between the cyclic radical
and some type of titanium-based radical cannot be ruled out. For a
review of radical disproportionation see: Gibian, M. J .; Corley, R. C.
Chem. Rev. 1973, 73, 441.

4076 J . Org. Chem., Vol. 66, No. 11, 2001
Notes
documented in the literature concerning organometallic
transition complexes.19 An intermediate cyclic radical was
detected when a Michael acceptor such as methyl acrylate
was added to the reaction mixture, leading to the more
functionalized product 8, which can be used in the
synthesis of other kinds of compound.
The reaction made with the 10,11-epoxynerolidyl ac-
etate 16 yields only the interesting bicyclic product 17,32
derived from consecutive 6-endo and 7-endo-trig cycliza-
tions, concerning which there are no references in the
literature. Once more the reaction ends with a â-acetoxy
elimination process.
To expand the possibilities of these cyclizations with
regard to their cationic analogues we performed the
reaction with epoxide 18, thus obtaining the bicyclic diols
19 and 20, which derive from consecutive 6-endo and
5-exo-trig cyclizations.33,34
When the reaction was carried out with 6,7-epoxyli-
nalyl acetate 9, we expected to obtain a mixture of
functionalized cyclohexanes structurally related to some
natural products. Instead we obtained good yields (77.5%)
of a mixture of seven- (10) and six- (11) membered
carbocycles. It is worth noting that the main product was
the seven-membered carbocycle 10 karahanahenol,20
derived from a 7-endo-trig cyclization, an unfavorable
process for nucleophilic radicals.21-24 This result may be
due to the exertion of a Thorpe-Ingold effect of the
methyl and acetate group upon C-3 carbon. The double
bond is formed once more in a â-acetoxy elimination
process. The cyclohexane 11 was obtained via 6-exo-trig
cyclization with a consecutive protonolysis of primary
alkyltitanium.25,26
Con clu sion s
In summary, this work represents a extension of
biomimetic radical cyclizations in the context of the
synthesis of terpene skeletons to obtain a wide range of
structures under controlled conditions, with the added
value of using simple, readily available primary materi-
als, thus rendering this approach highly attractive for
the synthesis of natural products. Moreover it represents
one of few examples of final functionalization in radical
reactions. Although the yields in some cases are low and
an improvement in reaction conditions might be seen as
desirable, we are now working in this direction to develop
a titanium catalytic version35 of the reaction and its
application to the synthesis of polycyclic natural products
with medium-sized rings.
When the reaction was performed with 10,11-epoxy-
farnesyl acetate 12, we obtained bicyclization products
13-15 (55%)27 with drimane skeletons, derived from two
consecutive 6-endo-trig cyclizations.28,29 Thus the reaction
was completely stereospecific, generating only the trans
decalin with the acetylcarbinol group being disposed
equatorially.28 The termination process of the bicyclic
radical is similar to that described for epoxide 1 showing
as well a preferential exocyclic elimination unlike the
cationic process. The formation of bicyclic product 15 is
probably due to the transfer of a hydrogen atom from the
solvent.30,31
Exp er im en ta l Section
Melting points were determined with a Kofler hot stage
melting point apparatus. NMR spectra were recorded on Bruker
AMX300 (300 MHz) and ARX400 (400 MHz) instruments. Mass
spectra were obtained on a Micromass Platform 2 spectrometer.
HMRS were obtained on a trisector WG AutoSpecQ spectrom-
eter. Only the most significant molecular ions and/or base peaks
in the MS are given. Microanalysis were recorded at the
Servicios Te´cnicos (UGR) with a Perkin-Elmer 2400 apparatus.
Chromatography was performed with flash grade silica gel using
hexane/MeOtBu mixtures. All reactions were carried out under
an atmosphere of argon. Dry THF was obtained by distillation
under Ar from sodium/benzophenone ketyl. The epoxides 1, 5,
9, 12, and 18 were prepared according to known procedures.36,37
The following known compounds were isolated as pure samples
and showed NMR spectra identical with the reported data: 2,38
10,39 14,40 and 15.3
(19) Hegedus, L. S. In Transition Metals in the Synthesis of Complex
Organic Molecules; University Science Books: Sausalito, CA, 1999.
(20) Odorant product related structurally with natural terpene
Karahanaenone: Miyazawa, M.; Tsuruno, K.; Kameoka, H. Tetrahe-
dron: Asymmetry 1995, 6, 2121.
(21) For a review of the preparation of medium-sized rings via
radicals see: Yet, L. Tetrahedron 1999, 55, 9349.
(22) The 7-endo-trig cyclization mode of the 6-heptenyl radical is
unfavorable towards the 6-exo-trig cyclization mode. Theoretical
study: Beckwith, A. L. J .; Moad, G. J . Chem. Soc., Chem. Commun.
1974, 472. Some examples of these cyclizations in low yield: Porter,
N. A.; Chang, V. H-T. J . Am. Chem. Soc. 1987, 109, 4976. Porter, N.
A.; Magnin, D. R.; Wright, B. T. J . Am. Chem. Soc. 1986, 108, 2787.
(23) For precedents with electrophilic radicals see: Snider, B. B.;
Merritt, J . E. Tetrahedron 1991, 47, 8663. Colombo, M. I.; Signorella,
S.; Mischne, M. P.; Gonzalez-Sierra, M.; Ruveda, E. A. Tetrahedron
1990, 46, 4149. White, J . D.; Somers, T. C.; Yager, K. M. Tetrahedron
Lett. 1990, 31, 59. Curran, D. P.; Chang, C.-T. J . Org. Chem. 1989,
54, 3140.
Gen er a l P r oced u r e. A mixture of Cp2TiCl2 (2.2 mmol) and
Mn dust (8 mmol) in strictly deoxygenated THF (50 mL) was
stirred at room temperature until the red solution turned green.
(32) This bicyclic terpene skeletom is related to widdrol, a natural
sesquiterpene.
(33) Fernandez-Mateos, A.; Martin de la Nava, E.; Coca, G. P.; Silva,
R. R.; Gonzalez, R. R. Org. Lett. 1999, 1, 607.
(24) There are few reports in cationic cyclization of the formation
of seven-membered rings: Armstrong, R. J .; Weiler, L. Can. J . Chem.
1986, 64, 584.
(25) The stereochemistry of 11 is in accordance with a cyclization
via a chairlike transition state.
(26) Other three stereoisomers of 11 (11.5%) can be isolated from
the reaction mixture. See Supporting Information.
(34) In this case the cationic cyclization usually ends with an
O-nucleophile capture: Parker, K. A.; Resnick, L. J . Org. Chem. 1995,
60, 5726.
(35) The use of previously described reaction conditions did not lead
to the results hoped for, probably because the intermediate species
were not the same (see ref 7c).
(36) The epoxides 1, 5, and 9 were prepared by m-CPBA epoxida-
tion: Barrero, A. F.; Alvarez-Manzaneda, E. J .; Palomino, P. L.
Tetrahedron 1994, 50, 13239 and references therein. Sakaguchi, S.;
Nishiyama, Y.; Ishii, Y. J . Org. Chem. 1996, 61, 5307 and references
therein. 12: van Tamelen, E. E.; Storni, A.; Hessler, E.; Schwartz, M.
J . Am. Chem. Soc. 1963, 85, 3295. 18: Corey, E. J .; Sodeoka, M.
Tetrahedron Lett. 1991, 32, 7005.
(37) The epoxide 9 is a mixture 1:1 of diastereoisomers.
(38) Barrero, A. F.; Alvarez-Manzaneda, E. J .; Chahboun, R.;
Rodriguez, A.; Linares, P. Tetrahedron 2000, 56, 6099.
(39) Wang, D.; Chan, T. H. J . Chem. Soc., Chem. Commun. 1984,
1273.
(27) 5-Exo and 6-endo-trig monocyclic products can also be isolated
(14%, 4:1 ratio), the latter being the acetate of elegansidiol, a natural
product: Barrero, A. F.; Alvarez-Manzaneda, E. J .; Herrador, M. M.;
Alvarez-Manzaneda, R.; Quilez, J .; Chahboun, R.; Linares, P.; Rivas,
A. Tetrahedron Lett. 1999, 40, 8273. See Supporting Information.
(28) . The yields of analogous cationic cyclizations are generally low,
and the double bond has an endocyclic regiochemistry: Corey, E. J .;
Sodeoka, M. Tetrahedron Lett. 1991, 48, 7005 and references therein.
(29) Related cationic cyclization with loss of stereochemistry: van
Tamelen, E. E.; Storni, A.; Hessler, E.; Schwartz, M. J . Am. Chem.
Soc. 1963, 85, 3295. The cyclization of a derivative of 12 was described
in low yield (9%): Taylor, S. K. Org. Prep. Proc. Int. 1992, 24, 245
(30) Neither can it be ruled out that this product was obteined via
a radical disproportionation process.
(31) Similar products (6.5%) were obtained in the cyclization of 1.
See Supporting Information.
(40) Synthesis: ref 29. Natural product: Ayer, W. A.; Craw, P. A.
Can. J . Chem. 1989, 67, 1371.

Notes
J . Org. Chem., Vol. 66, No. 11, 2001 4077
Then the solution of Cp2TiCl was slowly added to epoxide (1
mmol) in strictly deoxygenated THF (150 mL, 0.005M). The
reaction was stirred for 1 h, quenched with 10% aqueous HCl,
extracted with MeOtBu, washed with water, dried (Na2SO4), and
concentrated. The residue was chromatographed (hexane/
MeOtBu mixtures, Rf ) 0.3).
(s, 3H), 1.33 (td, J ) 14.3, 4.1 Hz, 1H), 1.01 (d, J ) 4.6 Hz, 3H),
1.00 (s, 3H), 0.88 (s, 3H); 13C NMR (75 MHz, CDCl3; DEPT) δ
170.25 (C), 83.20 (C), 78.27 (CH), 49.79 (CH), 39.51 (C), 33.16
(CH2), 27.66 (CH3), 27.04 (CH2), 25.45 (CH3), 22.54 (CH3), 14.04
(CH3), 8.35 (CH3); MS m/z 154 (18), 72 (100). Anal. calcd for
C
12H22O3: C, 67.26; H, 10.35. Found: C, 67.14; H 10.58.
(1SR,3SR)-3-Acetoxym eth yl-2,2-dim eth yl-4-m eth ylen ecy-
cloh exa n ol (3-exo) a n d (1SR,3SR)-3-Acetoxym eth yl-2,2,4-
tr im eth yl-4-cycloh exen ol (3-en d o). The compounds 3-exo and
3-en d o were obtained as a mixture in a 7.3:1 ratio. 3-exo:
(2SR,4a SR,5SR,8a RS,)-5-Acet oxim et h yl-2-h yd r oxy-1,1,
4a -t r im et h yl-6-m et h ylen e-d eca h yd r on a p h t h a len e (13).
White solid (hexane/MeOtBu 7:3): mp 77-79 °C; 1H NMR (300
MHz, CDCl3) δ 4.80 (bs, 1H), 4.47 (bs, 1H), 4.25 (dd, J ) 11.3,
3.9 Hz, 1H), 4.12 (dd, J ) 11.3, 8.6 Hz, 1H), 3.21 (dd, J ) 11.5,
4.4 Hz, 1H), 2.35 (ddd, J ) 13.0, 4.0, 2.3 Hz, 1H), 2.00-1.00 (m,
6H), 1.95 (s, 3H), 1.39 (dd, J ) 12.7, 4.3 Hz, 1H), 1.30 (dd, J )
12.7, 4.1 Hz, 1H), 1.06 (dd, J ) 12.4, 2.6 Hz, 1H), 0.94 (s, 3H),
0.72 (s, 3H), 0.69 (s, 3H); 13C NMR (75 MHz, CDCl3; DEPT) δ
171.40 (C), 146.30 (C), 107.64 (CH2), 78.66 (CH), 61.54 (CH2),
54.59 (CH), 54.39 (CH), 39.23 (C), 38.78 (C), 37.51 (CH2), 37.06
(CH2), 28.40 (CH3), 27.81 (CH2), 23.57 (CH2), 21.17 (CH3), 15.53
(C), 15.18 (C); MS m/z 220 (22, M+ - HOAc), 202 (35), 135 (89).
The compound 13 was chemically correlated with its diol
derivative, a previously known natural product, showing identi-
cal spectroscopic data.41
P r ep a r a tion of 10,11-Ep oxy-3,7,11-tr im eth yl-1,6-d od eca -
d ien -3-yl Aceta te (16). To a solution of nerolidyl acetate (674
mg, 2.55 mmol) in a mixture of DME/water (20 mL, 1:1) at 0 °C
was slowly added NBS (500 mg, 2.80 mmol). The reaction was
stirred for 30 min, diluted with MeOtBu, washed with water,
dried (Na2SO4), and evaporated. The residue was chromato-
graphed (9:1 hexane/MeOtBu) to give 16 (330 mg, 46%) 2.5:1
mixture of two stereoisomers as a colorless oil: 1H NMR (400
MHz, CDCl3) δ 5.95 (dd, J ) 17.4, 10.9 Hz, 1H, minor isomer),
5.94 (dd, J ) 17.4, 10.9 Hz, 1H, major isomer), 5.16-5.09 (m,
2H), 2.68 (t, J ) 6.3 Hz, 1H, major isomer), 2.67 (t, J ) 6.3 Hz,
1H, minor isomer), 1.99 (s, 3H), 1.67 (s, 3H, major isomer), 1.59
(s, 3H, minor isomer), 1.52 (s, 3H), 1.29 (s, 3H, major isomer),
1.28 (s, 3H, minor isomer), 1.25 (s, 3H, major isomer), 1.23 (s,
3H, minor isomer); 13C NMR (75 MHz, CDCl3; DEPT) δ 169.99
(C), 141.82 (CH), 134.63 (C), 125.21 (CH), 124.34 (CH), 113.23
(CH2), 82.89 (C), 82.84 (C), 64.20 (CH), 64.11 (CH), 58.38 (C),
39.97 (CH2), 39.72 (CH2), 36.34 (CH2), 28.50 (CH2), 27.44 (CH2),
24.98 (CH3), 24.95 (CH3), 23.69 (CH3), 23.66 (CH3), 23.38 (CH3),
22.32 (CH3), 22.25 (CH2), 22.19 (CH2), 18.81 (CH3), 18.77 (CH3),
15.97 (CH3), (some carbon signals were not observed); MS m/z
221 (7), 119 (88), 80 (100); HRMS m/z calcd for C17H28O3Na
303.1936, found 303.1933.
(2SR,4a RS,9a RS)-2-Hyd r oxy-1,1,4a ,7-tetr a m eth yl-2,3,4,
4a ,5,8,9,9a -octa h yd r o-1H-ben zocycloh ep ten e (17). Vitreous
solid (hexane/MeOtBu 4:1): 1H NMR (400 MHz, CDCl3) δ 5.33
(m, 1H), 3.21 (dd, J ) 9.2, 6.8 Hz, 1H), 2.09 (bd, J ) 14.5 Hz,
1H), 2.10 (bdd, J ) 14.5, 6.4 Hz, 1H), 1.85 (bd, J ) 14.0 Hz,
1H), 1.72 (bs, 3H), 1.67-1.57 (m, 4H), 1.14 (bs, OH), 1.35 (dt, J
) 13.4, 3.7 Hz, 1H), 1.31-1.12 (m, 2H), 1.02-0.98 (m, 1H), 0.99,
(s, 3H), 0.82 (s, 3H), 0.71 (s, 3H); 13C NMR (100 MHz, CDCl3;
DEPT) δ 141.31 (C), 122.45 (CH), 79.01 (CH), 59.29 (CH), 45.91
(CH2), 40.71 (CH2), 40.14 (C), 35.58 (C), 34.83 (CH2), 28.13 (CH3),
27.98 (CH2), 25.54 (CH3), 21.53 (CH2), 19.37 (CH3), 15.17 (CH3);
MS m/z 222 (8), 135 (39).
1,5-Dih ydr oxy-1,4,4,7a-tetr am eth yl-octah ydr oin den e (19).
White solid (hexane/MeOtBu 1:1), mixture of three isomers in a
1:1:1 ratio: 1H NMR (300 MHz, CDCl3) δ 3.42 (t, J ) 3.1 Hz,
1H, one isomer), 3.23 (dd, J ) 10.6, 5.0 Hz, 1H, one isomer),
3.16 (dd, J ) 10.5, 5.5 Hz, 1H, one isomer), 2.10-1.00 (m, 9H),
1.14 (s, 3H, one isomer), 1.08 (s, 3H, one isomer), 1.05 (s, 3H,
one isomer), 0.92 (s, 3H, one isomer), 0.90 (s, 3H), 0.86 (s, 3H,
one isomer), 0.85 (s, 3H, one isomer), 0.80 (s, 3H, one isomer),
0.79 (s, 3H, one isomer), 0.74 (s, 3H, one isomer); 13C NMR (75
MHz, CDCl3; DEPT) δ 83.07 (C), 81.87 (C), 80.99 (C), 80.02 (CH),
79.82 (CH), 75.15 (CH), 51.86 (CH), 51.15 (CH), 50.82 (CH), 47.14
(C), 45.79 (C), 44.54 (C), 38.82 (CH2), 38.64 (C), 38.28 (CH2),
37.95 (C), 36.88 (CH2), 36.25 (C), 30.07 (CH2), 29.41 (CH3), 29.03
(CH3), 28.80 (CH3), 28.53 (CH2), 28.32 (CH2), 26.38 (CH3), 26.29
(CH2), 25.34 (CH3), 24.62 (CH3), 23.07 (CH3), 22.87 (CH2), 22.22
(CH2), 21.97 (CH3), 19.70 (CH2), 19.03 (CH2), 16.97 (CH3), 15.52
1
colorless oil (hexane/MeOtBu 7:3); H NMR (400 MHz, CDCl3)
δ 4.84 (bs, 1H), 4.63 (bs, 1H), 4.28-4.18 (m, 2H), 3.58 (dd, J )
8.4, 4.0 Hz, 1H), 2.41 (dd, J ) 9.1, 5.1 Hz, 1H), 2.35-2.15 (m,
2H), 2.01 (s, 3H), 1.85-1.75 (m, 1H), 1.61-1.51 (m, 1H), 0.97
(s, 3H), 0.96 (s, 3H); 13C NMR (100 MHz, CDCl3; DEPT) δ 174.22
(C), 145.80 (C), 111.04 (CH2), 74.77 (CH), 62.49 (CH2), 50.78
(CH), 38.74 (C), 31.07 (CH2), 30.29 (CH2), 23.53 (CH3), 22.42
(CH3), 21.21 (CH3); HRMS m/z calcd for C12H20O3Na 235.1310,
found 235.1315. 3-en d o: 1H NMR (400 MHz, CDCl3) δ (only
distinctive signals) 5.36 (bs, 1H), 4.28 (dd, J ) 11.8, 4.9 Hz, 1H),
4.09 (dd, J ) 11.8, 3.8 Hz, 1H), 3.71 (dd, J ) 7.7, 5.6 Hz, 1H),
2.02 (s, 3H), 1.72 (s, 3H), 0.99 (s, 3H), 0.94 (s, 3H); 13C NMR
(100 MHz, CDCl3; DEPT) δ (only distinctive signals) 121.12 (CH),
72.13 (CH), 63.22 (CH2), 49.58 (CH), 32.91 (CH2), 23.11 (CH3),
21.61 (CH3).
2,2,3-Tr im eth yl-3-vin ylcyclop en ta n ol (4). Colorless vola-
tile oil (hexane/MeOtBu 4:1), 1:1 mixture of two isomers: 1H
NMR (300 MHz, CDCl3) δ 5.97 (dd, J ) 17.5, 10.9 Hz, 1H, one
isomer), 5.84 (dd, J ) 17.4, 10.9 Hz, 1H, one isomer), 5.03-4.87
(m, 2H), 4.00 (dd, J ) 8.5, 6.4 Hz, 1H, one isomer), 3.90 (dd, J
) 8.5, 6.4 Hz, 1H, one isomer), 2.30-1.2 (m, 4H), 1.01 (s, 3H,
one isomer), 0.94 (s, 3H, one isomer), 0.87 (s, 3H, one isomer),
0.85 (s, 3H, one isomer), 0.82 (s, 3H, one isomer), 0.79 (s, 3H,
one isomer); 13C NMR (75 MHz, CDCl3; DEPT) δ 145.72 (CH),
145.67 (CH), 111.58 (CH2), 111.03 (CH2), 80.99 (CH), 80.75 (CH),
48.32 (C), 46.63 (C), 46.37 (C), 33.16 (CH2), 33.00 (CH2), 30.48
(CH2), 22.72 (CH3), 22.68 (CH3), 21.62 (CH3), 21.58 (CH3), 17.71
(CH3), 17.06 (CH3), (two carbon signals were not observed); MS
m/z 139 (3), 136 (4, M+ - H2O), 84 (43).
(Z)-6-Hyd r oxy-3,7-d im eth yl-2-octen yl Aceta te (6) a n d
(Z)-6-Hyd r oxy-3,7-d im eth yl-2,7-octa d ien yl Aceta te (7). The
compounds 6 and 7 were obtained as an inseparable mixture in
a 10:1 ratio. Compound 6: colorless oil (hexane/MeOtBu 7:3);
1H NMR (300 MHz, CDCl3) δ 5.38 (t, J ) 7.2 Hz, 1H), 4.65 (dd,
J ) 12.3, 7.2 Hz, 1H), 4.59 (dd, J ) 12.3, 7.2 Hz, 1H), 3.32 (ddd,
J ) 9.0, 5.2, 3.0 Hz, 1H), 2.45-2.15 (m, 2H), 2.06 (s, 3H), 1.78
(s, 3H), 1.71-1.40 (m, 3H), 0.93 (d, J ) 6.9 Hz, 6H); 13C NMR
(75 MHz, CDCl3; DEPT) δ 170.64 (C), 142.68 (C), 119.53 (CH),
75.90 (CH), 61.12 (CH2), 33.72 (CH), 32.19 (CH2), 28.51 (CH2),
23.36 (CH3), 21.09 (CH3), 18.84 (CH3), 17.34 (CH3); HRMS m/z
calcd for C12H22O3Na 237.1466, found 237.1469. Compound 7:
1H NMR (300 MHz, CDCl3) δ (only distinctive signals) 4.97 (bs,
1H), 4.86 (bs, 1H), 4.12 (dd, J ) 7.0, 4.8 Hz, 1H).
(1SR,3RS,4SR)-3-Acetoxym eth yl-4-(2-(m eth oxyca r bon -
yl)et h yl)))-2,2,4-t r im et h ylcycloh exa n ol (8a ) a n d (1SR,3
RS,4RS)-3-Acetiloxym eth yl-4-(2-(m eth oxycar bon yl)eth yl)))-
2,2,4-tr im eth ylcycloh exa n ol (8b). The compounds 8a and 8b
were obtained as a mixture in a 5:1 ratio. Compound 8a :
vitreous solid (hexane/MeOtBu 7:3); 1H NMR (300 MHz, CDCl3)
δ 4.23 (dd, J ) 12.2, 3.6 Hz, 1H), 4.11 (dd, J ) 12.2, 4.9 Hz,
1H), 3.65 (s, 3H), 3.22 (dd, J ) 10.8, 4.9 Hz, 1H), 2.30-2.20 (m,
2H), 2.03 (s, 3H), 1.75-1.25 (m, 7H), 1.07 (s, 3H), 0.92 (s, 3H),
0.87 (s, 3H); 13C NMR (75 MHz, CDCl3; DEPT) δ 174.61 (C),
171.17 (C), 78.42 (CH), 63.05 (CH2), 51.70 (CH3), 50.54 (CH),
39.40 (C), 38.37 (CH2), 35.92 (C), 35.32 (CH2), 28.46 (CH2), 28.40
(CH3), 27.23 (CH2), 21.17 (CH3), 20.96 (CH3), 16.09 (CH3); HRMS
m/z calcd for C16H28O5Na 323.1834, found 323.1839. Anal. calcd
for C16H28O5: C, 63.97; H, 9.40. Found: C, 63.81; H 9.66.
Compound 8b: 1H NMR (300 MHz, CDCl3) δ (only distinctive
signals) 4.19 (dd, J ) 12.0, 4.3 Hz, 1H), 4.12 (dd, J ) 12.0, 5.3
Hz, 1H), 0.94 (s, 3H); 13C NMR (75 MHz, CDCl3; DEPT) δ (only
distinctive signals) 75.91 (CH), 63.21 (CH2), 44.48 (CH), 38.76
(CH2), 30.02 (CH2), 25.17 (CH2), 21.36 (CH3).
(1SR,3SR,4SR)-4-Acet oxy-2,2,3,4-t et r a m et h ylcycloh ex-
a n ol (11). White solid (hexane/MeOtBu 7:3): mp 62-64 °C; 1H
NMR (400 MHz, CDCl3) δ 3.29 (dd, J ) 11.4, 4.4 Hz, 1H), 2.84
(dt, J ) 14.7, 3.3 Hz, 1H), 1.98 (s, 3H), 1.75-1.50 (m, 3H), 1.46
(41) Fleck, W. F.; Schlegel, B.; Hoffmann, P.; Ritzau, M.; Heinze,
S.; Gra¨fe, U. J . Nat. Prod. 1996, 59, 780.

4078 J . Org. Chem., Vol. 66, No. 11, 2001
Notes
(CH3), 15.41 (CH3), 14.52 (CH3), (one carbon signal was not
observed); HRMS m/z calcd for C13H24O2Na 235.1674, found
235.1678.
Ack n ow led gm en t. This research was supported by
the Spanish Direccio´n General de Investigacio´n Cien-
t´ıfica y Te´cnica (DGICYT; Proyecto PB 98-1365). M.
Valdivia thanks the Spanish Ministry of Education and
Culture for a grant enabling her to pursue these studies.
(1RS,3aSR,5SR,7aRS)-1,5-Dih ydr oxy-1,4,4,7a-tetr am eth yl-
octa h yd r oin d en e (20). White solid (hexane/MeOtBu 2:3): mp
1
78-80 °C; H NMR (300 MHz, CDCl3) δ 3.55 (dd, J ) 10.5, 5.0
Su p p or tin g In for m a tion Ava ila ble: Copies of the 1H and
13C NMR spectra for all new compounds and spectroscopic data
for some minor products. This material is available free of
charge via the Internet at http://pubs.acs.org.
Hz, 1H), 1.80-1.25 (m, 9H), 1.08 (s, 3H), 0.94 (s, 3H), 0.92 (s,
3H), 0.88 (s, 3H); 13C NMR (75 MHz, CDCl3; DEPT) δ 82.93 (C),
74.32 (CH), 54.10 (CH), 44.85 (C), 37.05 (C), 36.36 (CH2), 28.81
(CH2), 27.81 (CH2), 26.53 (CH3), 25.49 (CH3), 22.09 (CH3), 21.79
(CH2), 20.82 (CH3); MS m/z 194 (10, M+ - H2O), 176 (12, M+
-
2H2O).
J O0155207