RCM for the construction of novel steroid-like polycyclic systems. 1. Studies on the synthesis of a PreD3-D3 transition state analogue

Article abstract of DOI:10.1021/jo050568w

Natural and nonnatural polycyclic systems containing eight-membered carbocycles constitute a large class of compounds of importance in organic chemistry, biology, and medicine. Here we describe a new strategy by which complex polycyclic steroid-like systems can be constructed on the steroid CD framework, by a combination of RCM and Heck cyclizations. The method is exemplified by its application to the stereoselective synthesis of 6-8-6 fused carbocyclic systems that mimic the putative transition structure of the isomerization of previtamin D₃ to vitamin D₃.

Full text of DOI:10.1021/jo050568w

RCM for the Construction of Novel Steroid-like Polycyclic
Systems. 1. Studies on the Synthesis of a PreD3-D3 Transition
State Analogue‡
Rebeca Garc´ıa-Fandin˜o, Mar´ıa Jose´ Aldegunde, Eva M. Codesido, Luis Castedo, and
Juan R. Granja*
Departamento de Quı´mica Orga´nica e Unidade Asociada o´ C.S.I.C., Facultade de Quı´mica,
Universidade de Santiago, 15782 Santiago de Compostela, Spain
qojuangg@usc.es
Received March 21, 2005
Natural and nonnatural polycyclic systems containing eight-membered carbocycles constitute a
large class of compounds of importance in organic chemistry, biology, and medicine. Here we describe
a new strategy by which complex polycyclic steroid-like systems can be constructed on the steroid
CD framework, by a combination of RCM and Heck cyclizations. The method is exemplified by its
application to the stereoselective synthesis of 6-8-6 fused carbocyclic systems that mimic the putative
transition structure of the isomerization of previtamin D3 to vitamin D3.
Introduction
the repertoire of transition-metal-catalyzed reactions,
ring-closing metathesis (RCM) has become one of the
most powerful tools for the construction of a variety of
cyclic structures that would be difficult to achieve with
Steroids constitute an extensive and important class
of biologically active polycyclic compounds that are widely
used for therapeutic purposes.1 Many functional and
structural modifications of steroids have recently been
investigated in order to extend their already broad range
of biological activities and to increase their selectivity.
In this article we describe our results on the preparation
of novel steroid-like compounds containing an eight-
membered B ring. Medium-sized carbocycles, particularly
eight-membered ones, constitute the structural core of a
large number of biologically important natural and
nonnatural products.2 The difficulty in constructing rings
of this size by conventional cyclization routes is due to
well-understood unfavorable entropic and enthalpic fac-
tors,3 making their preparation a great synthetic chal-
lenge. However, in this respect transition-metal-catalyzed
reactions have proven to be versatile tools both for
construction of the steroid skeleton from easily available
building blocks,4 and for its functionalization;5 and within
(2) For reviews, see: (a) Oishi, T.; Ohtsuka, Y. In Studies in Natural
Products Synthesis; Atta-ur-Rahman, Ed.; Elsevier: Amsterdam, The
Netherlands, 1989; Vol. 3, pp 73-115. (b) Petasis, N. A.; Patane, M.
A. Tetrahedron 1992, 48, 5757-5821. (c) Rousseau, G. Tetrahedron
1995, 51, 2777-2849. (d) Molander, G. A. Acc. Chem. Res. 1998, 31,
603-609. (e) Mehta, G.; Singh, V. Chem. Rev. 1999, 99, 881-990. For
recent approaches to eight rings see: (f) Paquette, L. A.; Sun, L. Q.;
Watson, T. J. N.; Friedrich, D.; Freeman, B. T. J. Org, Chem. 1997,
62, 4908-4909. (g) Li, C. J.; Chen, D.-L.; Lu, Y.-Q.; Haberman, J. X.;
Mague, J. T. Tetrahedron 1998, 54, 2347-2364. (h) Paquette, L. A.;
Nakatani, S.; Zydowsky, T. M.; Edmonson, S. D.; Sun, L.-Q.; Skerlj,
R. J. Org. Chem. 1999, 64, 3244-3254. (i) Rabdall, M. L.; Lo, P. C.-K.;
Bonitatebus, P. J.; Snapper, M. L. J. Am. Chem. Soc. 1999, 121, 4534-
4535. (j) Imai, A. E.; Sato, Y.; Nishida; Mori, M. J. Am. Chem. Soc.
1999, 121, 1217-1225. (k) Molander, G. A.; Ko¨llner, C. J. Org. Chem.
2000, 65, 8333-8339. (l) Wender. P. A.; Correa, A. G.; Sato, Y.; Sun,
R. J. Am. Chem. Soc. 2000, 122, 7815-7816. (m) Molander, G. A.;
George, K. M.; Monovich, L. G. J. Org. Chem. 2003, 25, 9533-9540.
(n) Gilbertson, S. R.; de Boef, B. J. Am. Chem. Soc. 2002, 124, 8784-
8785. (o) Evans, P. A.; Robinson, J. E.; Baum, E. W.; Fazal, A. N. J.
Am. Chem. Soc. 2002, 124, 8782-8783. (p) Arrayal, R. G.; Lieberkind,
S. J. Am. Chem. Soc. 2003, 125, 9026-9027.
(3) (a) Illuminati, G.; Mandolini, L. Acc. Chem. Res. 1981, 14, 95-
102. (b) Mandolini, L. Adv. Phys. Org. Chem. 1986, 22, 1-111. (c)
Kreiter, C. G.; Lehr, K.; Leyendecker, M.; Sheldrik, W. S.; Exner, R.
Chem. Ber. 1991, 124, 3-12. (d) Eliel, E. L.; Wilen, S. H. Stereochem-
istry of Organic Compounds; Wiley: New York, 1994.
‡ This paper is dedicated to Prof. Pierre Potier in honor of his 70th
birthday.
(1) (a) Amagata, T.; Amagata, A.; Tenney, K.; Valeriote, F. A.;
Lobkovsky, E.; Clardy, J.; Crews, P. Org. Lett. 2003, 5, 4393-4396.
(b) Wu, J. H.; Batist, G.; Zamir, L. O. Anti-Cancer Drug Des. 2001, 16,
129-133. (c) Biellmann J.-F. Chem. Rev. 2003, 103, 2019-2033.
(4) Yet, L. Chem. Rev. 2000, 100, 2963-3007
(5) Skoda-Fo¨ldes, R.; Kolla´r, L. Chem. Rev. 2003, 103, 4095-4129.
10.1021/jo050568w CCC: $30.25 © 2005 American Chemical Society
Published on Web 09/21/2005
J. Org. Chem. 2005, 70, 8281-8290
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Garc´ıa-Fandin˜o et al.
FIGURE 1. General structure of novel steroid-like compounds containing an eight-membered ring B, and the structures of [1,7]-
H Ts analogues I and II and the putative mechanism of the [1,7] sigmatropic hydrogen shift of preD3-D3 isomerization.
other methods.6 In particular, despite the above-men-
tioned unfavorable thermodynamic factors, olefin RCM
has been successfully applied to the synthesis of eight-
membered rings, though only when the substrate has
some feature, such as conformation-constraining, preex-
isting rings or a polar group, that facilitates deployment
of the reaction sites within the coordination sphere of the
metal.7,8 In the work described in this article, we con-
structed steroid-like polycycles with a linearly fused 6-8-6
carbocyclic system (I and II, Figure 1) by combining RCM
(used to form ring B or a 12-membered precursor) with
another of the most powerful transition-metal-catalyzed
processes: the intramolecular Heck9 reaction (used to
form the six-membered ring A).10 These synthetic targets
mimic [1,7]-H Ts, the putative cyclic transition state of
the isomerization11,12 of previtamin D3 (preD3) to vitamin
D3 (D3);13 our hope is that antibodies raised against
compounds of this type may catalyze this isomerization
process, and that understanding of its mechanism may
be furthered by the study of the active sites of such
antibodies.14 As locked 6-s-cis analogues of 1R,25-(OH)2-
D3,15-17 vitamin D derivatives with this central eight-
membered ring might also be useful for studying nonge-
nomic responses to vitamin D.
Results and Discussion
Our initial target was the preparation of compounds
1 (Figure 2). Initially, we designed three synthetic
strategies for the preparation of its basic carbon frame-
work. In all three, the C5-C618 double bond would be
incorporated in ring B or in a 12-membered precursor
carbocycle by a RCM reaction of a diene precursor formed
by R-alkylation of the kinetic enolate of ketone 2 followed
by allylation of the carbonyl carbon. In path A, the RCM
reaction would form the eight-membered ring in a
substrate in which the six-membered ring A would be
present already. The six-membered ring of the precursor
of the alkylating agent 4 would be formed by a Heck9
(6) For reviews on metathesis, see: (a) Handbook of Metathesis;
Grubbs, R. H., Ed.; Wiley-VCH: Weinheim, Germany, 2003. (b)
Fu¨rstner, A. Angew. Chem., Int. Ed. 2000, 39, 3012-3043. (c) Chang,
S.; Grubbs, R. H. Tetrahedron 1998, 54, 4413-4450. (d) Schuster, M.;
Blechert, S. Angew. Chem., Int. Ed. Engl. 1997, 36, 2036-2056. (e)
Connon, S. J.; Blechert, S. Angew. Chem., Int. Ed. 2003, 42, 1900-
1923.
(7) (a) For a view on the synthesis of medium-sized rings by RCM,
see: Maier, M. E. Angew. Chem., Int. Ed. 2000, 39, 2073-2077. For
some recent examples of eight-membered ring formation by RCM,
see: (b) Paquette, L.; Efremov, I. J. Am. Chem. Soc. 2001, 123, 4492-
4495. (c) Sibi, M. P.; Aasmul, M.; Hasegawa, H.; Subramanian, T. Org.
Lett. 2003, 5, 2883-2886. (d) Kariuki, B. M.; Owton, W. M.; Percy, J.
M.; Pintat, S.; Smith, C. A.; Spencer, N. S.; Thomas, A. C.; Watson,
M. Chem. Commun. 2002, 228-229. (e) Boyer, F.-D.; Hanna, I.; Nolan,
S. P. J. Org. Chem. 2001, 66, 4094-4096. (f) Bourgeois, D.; Pancrazi,
A.; Ricard, L.; Prunet, J. Angew. Chem., Int. Ed. 2000, 39, 725-728.
(8) (a) Fu¨rstner, A.; Langemann, K. J. Am. Chem. Soc. 1997, 119,
9130-9136. (b) Crimmins, M. T.; Choy, A. L. J. Am. Chem. Soc. 1999,
121, 5653-5660. (c) Paquette, L. A.; Tae, J.; Arrington, M. P.; Sadoun,
A. H. J. Am. Chem. Soc. 2000, 122, 2742-2748.
(9) For recent uses of intramolecular Heck reactions for the con-
struction of fused 6-7 bicyclic systems, see: (a) Lee, K.; Cha, J. K. J.
Am. Chem. Soc. 2001, 123, 5590-5591. For recent reviews of this
reaction, see: (b) Beletskaya, I. P.; Cheprakov, A. V. Chem. Rev. 2000,
100, 3009-3066. (c) Link, J. T.; Overman, L. E. In Metal-Catalyzed
Cross-Coupling Reactions; Diederich, F., Stang, P. J., Eds.; Wiley-
VCH: Weinheim, Germany, 1998; Chapter 6. (d) de Meijere, A.; Meyer,
F. E. In Metal-Catalyzed Cross-Coupling Reactions; Diederich, F.,
Stang, P. J., Eds.; Wiley-VCH: Weinheim, Germany, 1998; Chapter
3. (e) Link, J. T.; Overman, L. E. ChemTech 1998, 19-26. (f) Neghisi,
E.-i.; Coperet, C.; Ma, S.; Liou, S.-Y.; Liu, F. Chem. Rev. 1996, 96, 6,
365-393.
(10) For some examples of sequential RCM/Heck reactions, see:
Grigg, R.; Sridharan, V.; York, M. Tetrahderon Lett. 1998, 39, 4139-
4142. Grigg, R.; York, M. Tetrahderon Lett. 2000, 41, 7255-7258.
(11) This isomerization, one of two successive pericyclic reactions
in the photobiogenesis of vitamin D3 (Figure 1),12 consists of a thermally
induced antarafacial [1,7]-sigmatropic hydrogen shift from C19 to C9.
For studies of the mechanism of this physiologically important
transformation, see: (a) Havinga, E. Experientia 1973, 29, 1181-1192.
(b) Okamura, W. H.; Midland, M. M.; Hammond, M. W.; Rahman, N.
A.; Dormanen, M. C.; Nemere, I.; Norman, A. W. J. Steroid Biochem.
Mol. Biol. 1995, 53, 603-613. (c) Tian, X. Q.; Holick, M. F. J. Biol.
Chem. 1999, 274, 4174-4179.
(12) Henry, H. L.; Norman, A. W. Metabolism of Vitamin D. In
Disorders of Bone and Mineral Metabolism; Coe, F. L., Favus, M. J.,
Eds.; Raven Press: New York, 1991; pp 149-162.
(13) For preliminary studies, see: (a) Codesido, E. M.; Castedo, L.;
Granja, J. R. Org. Lett. 2001, 3, 1483-1486. (b) Codesido, E. M.;
Rodr´ıguez, J. R.; Castedo, L.; Granja, J. R. Org. Lett. 2002, 4, 1651-
1654.
(14) The catalytic antibody strategy is a powerful method for the
design of enzymes that achieve transformations that are rare or do
not occur in nature, see: (a) Schultz, P. G.; Lerner, R. A. Science 1995,
269, 1835-1842. (b) Wentworth, P.; Janda, K. D. Curr. Opin. Chem.
Biol. 1998, 2, 138-144. (c) Hilvert, D. Top. Stereochem. 1999, 22, 83-
135.
(15) The biological functions of the hormonally active form of D3,
1R,25-dihydroxyvitamin D3,16 are now thought to include promotion
of cell differentiation, inhibition of tumor cell proliferation, and
induction of functions related to the immunological system. For some
studies of the biological activity of this hormone, see: (a) Bouillon, R.;
Okamura, W. H.; Norman, A. W. Endocr. Rev. 1995, 16, 200-257. (b)
Vitamin D: Chemistry, Biology and Clinical Applications of the Steroid
Hormone; Norman, A. W., Bouillon, R., Thomasset, M., Eds; Vitamin
D Workshop, Inc.; Riverside, CA, 1997.
(16) The involvement of a preD3 a D3-type equilibrium in nonge-
nomic activities is hinted at by experimental results suggesting that
these activities are mediated by membrane receptors for 1R,25-(OH)2-
PreD3 as well as by 1R,25-(OH)2-D3, see: (a) Norman, A. W.; Okamura,
W. H.; Farach-Carson, M. C.; Allewaert, K.; Branisteanu, D.; Nemere,
I.; Muralidharan, K. R.; Bouillon, R. J. Biol. Chem. 1993, 268, 13811-
13819. (b) Okamura, W. H.; Midland, M. M.; Norman, A. W.; Ham-
mond, M. W.; Rahman, N. A.; Dormanen, M. C.; Nemere, I. Ann. N.Y.
Acad. Sci. 1995, 761, 344-348.
(17) For the synthesis of an analogue of 1R,25-(OH)2-D3 bearing an
eight-membered ring B, see: Hayashi, R.; Ferna´ndez, S.; Okamura,
W. H. Org. Lett. 2002, 4, 851-854.
(18) For convenience, steroid numbering is used.
8282 J. Org. Chem., Vol. 70, No. 21, 2005

Construction of Novel Steroid-like Polycyclic Systems
FIGURE 2. Proposed strategies for preparation of compounds 1.
SCHEME 1. Preparation of Compounds 4, 5, and
14ba
and metalation of its silyl ether 11b with butyllithium,
followed by reaction of the resulting lithium derivate with
p-formaldehyde, afforded propargyl alcohol 12, successive
treatment of which with sodium bis(2-methoxyethoxy)-
aluminum hydride and freshly sublimed iodine produced
the Z-vinyl iodide 5.
For the synthesis of 1 it is the 4S enantiomer of 11a
that is of interest. Although it can be prepared enantio-
selectively in 66% yield by treating 4-pentynal with an
equimolecular amount of an allylborane prepared from
(-)-â-methoxydiisopinylcampheylborane,21 we evaluated
a catalytic strategy. Treatment of 4-pentynal under
Carreira conditions, with a 150 mol % excess of allyltri-
methylsilane in the presence of 10 mol % of (R)-BINOL
and TiF4,22 gave alcohol (4S)-1-octen-7-yn-4-ol [(4S)-11a]
in only 62% yield and 70% ee.23 However, higher yield
(81%) and an enantiomeric excess of 97% were obtained
when the reaction was carried out at 0 °C with allyl-
tributylstannane and 10 mol % of catalyst prepared by
heating a 2:1 mixture of (R)-BINOL and Ti(O-i-Pr)4.24
In pursuance of path A, compound 4 was prepared as
the only detectable product of the Heck cyclization of
iodide 5 with (Ph3P)4Pd/Et3N in refluxing acetonitrile.25
Although alcohol 4 was obtained in good yield, we decided
to explore the feasibility of the RCM reaction using a
substrate prepared from the more readily available
alcohol 14a instead of bromide 13.26 Thus, treatment of
alcohol 14a with triphenylphosphine and carbon tetra-
bromide in dichloromethane provided bromide 14b in
81% yield; reaction of the freshly prepared bromide with
a Reagents and conditions: (a) (COCl)2, DMSO, Et3N; (b) (i) (R)-
Binol/Ti(OiPr)4, CH2Cl2, (ii) CH2CHCH2SnBu3, ∆, 81% (from
4-pentynol); (c) TBSCl, Im, DMF, 92%; (d) nBuLi, (CH2O)n, 91%;
(e) Red-Al, I2, 70%; (f) (Ph3P)4Pd, Et3N, CH3CN, 85%; (g) CBr4,
Ph3P, CH2Cl2, 81%.
reaction of iodide 5.19 Alternatively, the RCM reaction
can be used as the first key step to form the C5-C6
double bond of either the 12-membered ring to obtain
iodide 6 (path B) or the 8-membered ring of compound 8
(path C), in which Y can denote an halomethylidene
group or its synthetic precursor. The second key step
would be the intramolecular Heck cyclization of the
corresponding iodides to construct the ring A. A key factor
in the formation of the AB system by strategy B would
be the preference of Heck reactions for 6-exo cycliza-
tion.9,20 We envisaged that in both cases the initial RCM
would involve the less-substituted double bonds, starting
the process at the monosubstituted double bond and
producing the appropriate precursor for the final Heck
cyclization.
(21) White, J. D.; Kim, T.-S.; Nambu, M. J. Am. Chem. Soc. 1997,
119, 103-111. Alcohol (4R)-11a was obtained in 95% ee; [R]25D +35.4
(c 2.36, CHCl3).
(22) Gauthier, D. R., Jr.; Carreira, E. M. Angew. Chem., Int. Ed.
Engl. 1996, 35, 2363-2365.
(23) The absolute configuration of (4S)-11a was inferred from the
effects of the phenyl groups of its R and S methoxyphenylacetic esters
on the chemical shifts of the C3 and C5 protons. Trost, B. M.; Belletire,
J. L.; Godleski, S.; McDougal, P. G.; Balkovec, J. M.; Baldwin, J. J.;
Christy, M. E.; Ponticello, G. S.; Varga, S. L.; Springer, J. P. J. Org.
Chem. 1986, 51, 2370-2374.
Our first target for both paths A and B was iodide 5,
which was prepared from 4-pentyn-1-ol (Scheme 1).
Swern oxidation followed by addition of allylmagnesium
bromide afforded alcohol 11a in 70% yield (two steps),
(19) Preliminary studies had shown the viability of the Heck
cyclization of iododiene 5, see: Codesido, E. M.; Cid, M. M.; Castedo,
L.; Mourin˜o, A.; Granja, J. R. Tetrahedron Lett. 2000, 41, 5861-5864.
(20) Owczarczyk, Z.; Lamaty, F.; Vawter, E. J.; Negishi, E.-i. J. Am.
Chem. Soc. 1992, 114, 10091-10092.
(24) Keck, G. E.; Tarbet, K. H.; Geraci, L. S. J. Am. Chem. Soc. 1993,
115, 8467-8468
(25) Mascaren˜as, J. L.; Garc´ıa, A. M.; Castedo, L.; Mourin˜o, A.
Tetrahedron Lett. 1992, 33, 4365-4368.
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Garc´ıa-Fandin˜o et al.
SCHEME 2. Preparation and RCM Products of
Trienes 3a and 3ba
SCHEME 3. Preparation of Triene 7a and
Evaluation of Its RCM Reactiona
a Reagents and conditions: (a) CBr4, Ph3P, CH2Cl2, 98%; (b)
LDA, 2a, THF, -78 °C, 55%; (c) AllylMgBr, THF, 85%; (d) 16a/
16b, CH2Cl2, ∆, 70-85%.
unexpected, given that 1,2-cis disubstituted cyclohexanes
such as 3 are known to undergo RCM to [6.4.0] systems
less readily than the corresponding trans systems.29,7a
Apparently, 3 did not possess those features (a confor-
mationally predisposed diene or an adequately oriented
polar functional group) that have allowed previous RCM
constructions of cyclooctene.8
In view of the above results, we turned to the other
strategy starting from 5, path B (Figure 2), in which the
formation of a 12-membered ring by RCM of triene 7
would precede 6-exo intramolecular Heck cyclization.
Compound 7a was straightforwardly obtained by alkyl-
ation of the LDA-formed kinetic enolate of 2a with
bromide 18 (prepared by treatment of alcohol 5 with
carbon tetrabromide and triphenylphosphine), followed
by allylation of the resulting ketone,30 but when 7a was
subjected to RCM conditions using Grubbs’ catalyst (16a)
or 16b, compound 17a was obtained instead of the
desired iodide 6. Once more, formation of the six-
membered ring had prevailed over macrocyclization, even
though it involved reaction with the more substituted
olefin (Scheme 3).13b
In view of the discouraging behavior of 3 and 7, we
decided to check whether the formation of cyclooctene on
2a or 2b31 by RCM was feasible in the absence of the
competing double bonds featured by the substrates of
paths A-C. An additional issue of interest was how the
presence of the ring A precursor or other substituents
would affect the course of the RCM reaction. We therefore
aimed to prepare compounds 21a-i from compounds 20
(Scheme 4), for which the otherwise competing and
preferred cyclohexene pathway was now not possible
because they have no internal double bond. However,
preparation of compounds 20 by alkylation of the enolate
of 2a/b was more troublesome than preparation of 15 or
its path B counterpart because of the lower reactivity of
the alkyl halides required for compounds 20. Thus,
addition of 1-iodopent-4-ene or 5-iodo-2-methylpent-1-ene
a Reagents and conditions: (a) (i) LDA, THF, -78 °C, (ii) 14b,
85%; (b) allylMgBr, THF, 91%; (c) HK, MeI, 18-crown-6, THF, 85%;
(d) 16b, CH2Cl2, ∆, 90% (17a), 87% (17b).
the kinetic enolate of Grundmann’s ketone (2a),27 formed
by LDA treatment of 2a at -78 °C, afforded ketone 15
in high yield (Scheme 2), and treatment of 15 with 4
equiv of allylmagnesium bromide gave the desired RCM
substrate, alcohol 3a, in almost quantitative yield. The
relative stereochemistry of the newly generated stereo-
centers was confirmed by inspection of the two-dimen-
sional NMR spectra of 15 and 3b: the clear NOE
relationship between H14 (δ 2.40 ppm) and both H19 (δ
5.04 ppm) and the neighboring allyl protons H19a (δ 1.81
ppm) in compound 15 showed the axial orientation of
pentadienyl moiety, while the significant interaction
between Me18 and the methoxy group in the NOESY
spectrum of 3b showed their cis relationship. Compound
3b was prepared by heating a THF solution of 3a in the
presence of KH, 18-crown-6, and MeI, because only very
low yields were obtained with NaH as base, even after
long reaction times in the presence of 15-crown-5. Also,
even under typical conditions for hindered alcohols, all
attempts to introduce different protecting groups, such
as tertbutydimethylsilyl, benzyl, acetate, or tosylate, were
unsuccessful, showing the inaccessibility of this hydroxy
group.
Unfortunately, when 3a was subjected to RCM condi-
tions using 15% Grubbs’ catalyst (16a)28 in refluxing
methylene chloride or benzene, no reaction took place,
only unaltered starting material was recovered; only after
long reaction times in refluxing benzene was a dimeric
byproduct resulting from a cross-metathesis reaction of
the least substituted double bond obtained. Reaction of
3b also failed, showing that it was not the homoallylic
hydroxy group that was responsible for the lack of
reactivity. When the more reactive ruthenium catalyst
16b was used, both 3a and 3b reacted, but the products
containing the steroidal CD fragment (obtained in high
yield) were 17a and 17b, i.e., formation of the six-
membered ring had prevailed over formation of the eight-
membered ring even though it involved reaction with the
more substituted olefin. This result was not completely
(29) (a) Miller, S. J.; Kim, S.-H.; Chen, Z.-R.; Grubbs, R. H. J. Am.
Chem. Soc. 1995, 117, 2108-2109. (b) For an example of tricyclic
system formation using a cis-diene, see: Holt, D. J.; Barker, W. D.;
Jenkins, P. R.; Davies, P. R.; Garrat, S.; Fawcet, J.; Russell, D. R.;
Ghosh, S. Angew. Chem., Int. Ed. 1998, 37, 3298-3300. (c) 1,2-Cis
disubstituted cyclopentane derivatives are also worse substrates than
the trans dienes: Paquete, L. A.; Mendez-Andino, J. Tetrahedron Lett.
1999, 40, 4301-4304. (d) Fu¨rstner, A.; Langemann, K. J. Org. Chem.
1996, 61, 8746-9749.
(30) The relative stereochemistries of both enolate alkylation and
ketone allylation were determined by NOE.
(31) (a) Leyes, G. A.; Okamura, W. H. J. Am. Chem. Soc. 1982, 104,
6099-6105. (b) Sardina, F. J.; Mourin˜o, A.; Castedo, L. J. Org. Chem.
1986, 51, 1264-1269.
(26) Toh, H. T.; Okamura, W. H. J. Org. Chem. 1983, 48, 1414-
1417.
(27) Ketone 2a is readily obtained by ozonolysis of vitamin D3, see:
Mascaren˜as, J. L.; Sarandeses, L.; Castedo, L.; Mourin˜o, A. Tetrahe-
dron 1991, 47, 3485-3498.
(28) The amount of Grubbs’ catalyst has not been optimized and
15% has been routinely used in this work.
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Construction of Novel Steroid-like Polycyclic Systems
SCHEME 4. r-Alkylations of Ketones 2a or 2ba
Addition of 4 equiv of allymagnesium bromide to
ketones 20a-g and of 4 equiv of vinylmagnesium bro-
mide to 20d gave the required dienes 21a-g in good
yields. The results of subjecting them to RCM conditions
are listed in Table 1. With the appropriate catalyst (16b
in the case of the gem-disubstituted olefins 21b and
21bMe), substrates 21a, 21b, 21bMe, 21c, and 21g afforded
the desired eight-membered rings in yields of 86-99%
(entries 1, 3, 5, 6, and 12), although 21g needed a week
in refluxing solvent (methylene chloride or benzene)
regardless of whether the catalyst was 16a or 16b.
Compound 21i,33 a ketone derivative of 21g, also cyclized
in very high yield (although like 21g it needed long
reaction times), suggesting that a small modification of
substrate geometry does not significantly affect the
reaction (entry 14), while a diasteromic mixture of diols
21h did not cyclize (entry 13).34 Moreover, elongation of
the longer alkenyl chain by one carbon (m ) 2, entry 7)
allowed the formation of a nine-membered ring, also in
good yield, showing that these systems are well pre-
organized for the formation of medium-size rings by
RCM. However, entries 8 and 9 show that cyclization
does not take place unless there is at least one methylene
group between the oxygenated carbon and the double
bond of the olefin chain it bears, since 21e and 21eMe
failed to cyclize regardless of changes of solvent, catalyst,
and alcohol-protecting group. The cyclohexyl derivative
21f [R1R2 ) (CH2)4, entry 10] also completely failed to
cyclize, lengthy heating in refluxing benzene only bring-
ing about metathetic dimerization. These results show
that the constrains introduced by the cyclohexane ring,
more than olefin substitution, play the most important
role in the formation of cyclooctene in this system.
a Reagents and conditions: (a) LDA, CH2dCR1CHR2(CH2)mCH2I,
THF, -78 °C; (b) KHMDS, CH2dCR1CHR2(CH2)mCH2I, DMF/
toluene (1:1), -78 °C; (c) LDA,CH2dCHCH[(CH2)3OTBS]CH2CHO,
THF, -78 °C.
SCHEME 5. Preparation of
2-Methylene-1-(2-iodoethyl)cyclohexanea
a Reagentsandconditions: (a)LiAlH4,Et2O,90%;(b)CH2dCHOBu,
Hg(OAc)2, 160 °C; (c) NaBH4, MeOH, 82% (two steps); (d) I2, Ph3P,
Im, 67%.
to the LDA-generated enolate of 2a under the conditions
used in the earlier alkylations gave 20a and 20b in yields
of only 13% and 15%, respectively (Scheme 4). In experi-
ments seeking to improve the yield of the 1-iodopent-4-
ene reaction, no significant advantage was achieved by
using lithium hexamethyldisilazide (LiHMDS) as base,
or by changing the leaving group to the more reactive
triflate, or by adding chelating agents such as HMPA or
TMEDA, or by using Na or K as the counterion of the
base (even when 15-crown-5 ether was added to complex
the Na ion, in which case a large amount of epimerized
ketone was detected). Only the use of Palomo conditions
(1:1 DMF/toluene as solvent, KHMDS as base)32 provided
a high yield of 20a (76%). Yields of 65-78% were also
achieved with other alkylating agents (Scheme 4), the
lowest corresponding to the most hindered, 2-methylene-
1-(2-iodoethyl)cyclohexane (25), the precursor of ketone
20f. This iodide, a monoene analogue of 4, was prepared
from 1-cyclohexenecarboxylic acid by reduction with
lithium aluminum hydride and condensation of the
resulting alcohol (22) with butyl vinyl ether in the
presence of Hg(OAc)2 to obtain the corresponding vinyl
ether 23 (80% yield). Claisen rearrangement of 23 by
heating it in silane in a sealed tube, in situ reduction of
the rearrangement product with sodium borohydride
gave alcohol 24 (yield, 69%); 24 can also be obtained from
22 in one step and 82% yield by heating a solution of
this alcohol in butyl vinyl ether at 160 °C followed by in
situ reduction (Scheme 5). Final treatment of 24 with
triphenylphosphine, imidazole, and iodine gave the cor-
responding iodide in overall yield (49%) for the four steps.
The reactions of 21c, 21g, and 21i, in which the
products were obtained in yields of 95-99% as ap-
proximately 1:1 mixtures of diastereomers, show that
formation of the eight-membered ring is not impeded by
a substituent R2 at C10, whatever its stereochemistry at
this position.35 That the reactions of 21g and 21i were
so much slower than that of 21c (or 21a and 21b) may
perhaps be due to coordination of their OTBS oxygens
to the ruthenium catalyst (27g-II),36 which would delay
the olefin coordination (27g-I) that is necessary for ring
formation (Figure 3);37 and such coordination may also
(33) Compound 21h was prepared by addition of aldehyde 31
(Scheme 6) to the LDA-generated enolate of 2a in THF, followed by
treatment of the resulting ketone with allylmagnesium bromide and
oxidation with PDC.
(34) The presence of two nucleophilic hydroxy goups has been
proposed to decompose the catalyst, see: Hyldtoft, L.; Madsen, R. J.
Am. Chem. Soc. 2000, 122, 8444-8452 and also ref 7d.
(35) The (10S)-26g/(10R)-26g ratio was almost 1:1 after 48 and after
76 h. For an example of stereocontrolled RCM, see: Huwe, C. M.;
Velder, J.; Blechert, S. Angew. Chem., Int. Ed. Engl. 1996, 35, 2376-
2378.
(36) (a) Heteroatom coordination has been reported to participate
in and help the formation of medium sized rings, Fu¨rstner, A.;
Langemann, K. J. Am. Chem. Soc. 1997, 119, 9130-9136. (b) Hetero-
atom coordination has also been thought to be responsible for the
remarkable stability of certain ruthenium carbene complexes that have
been isolated: Kingsbury, J. S.; Harrity, J. P. A.; Bonittatebus, P. J.;
Hoveyda, A. H. J. Am. Chem. Soc. 1999, 121, 791-799. (c) A similar
ligation has been exploited in a robust and reusable polymer-bound
ruthenium carbene catalyst: Yao, Q. Angew. Chem., Int. Ed. 2000,
39, 3896-3898.
(37) For recent studies of metathesis mechanisms, see: Adlhart, C.;
Chen, P. J. Am. Chem. Soc. 2004, 126, 3496-3510. Cavallo, L. J. Am.
Chem. Soc. 2002, 124, 8965-8973.
(32) Palomo, C.; Oiarbide, M.; Mielgo, A.; Gonza´lez, A.; Garc´ıa, J.;
Landa, C.; Lecumberri, A.; Linden, A. Org. Lett. 2001, 3, 3249-3252.
J. Org. Chem, Vol. 70, No. 21, 2005 8285

Garc´ıa-Fandin˜o et al.
TABLE 1. Results of RCM of Dienes 21a-i
entry
substrate
P
R1
R2
R3
R4
m
n
catalyst
yield, %a
1
2
21a
H
H
H
Me
Me
Me
MeH
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
1
1
1
1
1
1
2
2
2
1
1
1
1
1
1
1
1
1
1
1
1
0
0
1
1
1
1
1
16a
16a
86
21b
ndb
86
3
21b
H
H
H
16b
4
21bMe
21bMe
21c
Me
Me
H
H
H
Me
H
Me
H
H
H
Me
H
H
H
H
16a
nd
89
5
H
16b
6
H
16a
99c
63
7
21d
H
H
16a
8
21e
H
H
H
16a/16b
16a/16b
16a/16b
16a/16b
16a
nd
nd
nd
nd
95c
nd
97c
9
21eMe
21f
H
10
11
12
13
14
(CH2)4
(CH2)4
H
21fMe
21g
H
H
H
H
(CH2)3OTBS
(CH2)3OTBS
(CH2)3OTBS
H
21h
21i
H
H
OH/H
dO
16a/16b
16a
a Isolated yields of 26. b nd, not detected in reaction crude by 1H NMR (a variety of solvents were used). c 26c, 26g, and 26i were
obtained as inseparable mixtures of C10 epimers.
FIGURE 3. Possible cause of the longer reaction time of
dienes 21g and 21h.
FIGURE 4. Structure of transition state analogue IIb and
explain why the Ru methylidene catalyst survived for so
much longer than its normal half-life, 40 min.
superimposition of its ring system (blue) on that of the putative
transition state structure of the preD3-D3 isomerization reac-
tion ([1,7]-H Ts, yellow).
38
To sum up, all these results showed that formation of
the eight-membered ring by RCM was possible. Although
they also suggested that the constrains introduced by the
cyclohexane rings of 21f and 3 prevented adoption of the
conformation required for the annulation, they left open
the possibility of successful approach to compounds 1 by
path C.
In evaluating path C, we focused on the preparation
of IIb, the conformity of which with [1,7]-H Ts is
illustrated in Figure 4. To avoid competition from the
dY olefin of 9 during RCM, RCM would be applied to
diene 21g, after which the OTBS group of the product,
26g, would be replaced by the vinyliodide moiety required
for formation of ring A by Heck cyclization.
the resulting anion with p-formaldehyde, and semihy-
drogenation afforded compound 28 in 63% overall yield;
condensation of 28 with butyl vinyl ether in the presence
of Hg(OAc)2, followed by Claisen rearrangement and in
situ reduction with sodium borohydride, then provided
alcohol 29 in 69% yield from 28; and exposure of this
alcohol to triphenylphosphine, imidazole, and iodine gave
the desired iodide 30 (Scheme 6).39 Diene 21g was
obtained as an inseparable 1:1 mixture of C10-epimers
as was 26g (obtained as described above by a one-week
RCM reaction in refluxing CH2Cl2). However, after
removal of the TBS group with TBAF, the resulting
alcohols, 32a and 32b (Scheme 7), were easily separated,
although it was not possible to establish their C10-
stereochemistries at this stage by NMR experiments.
Oxidation of isomer 32a with PDC and subsequent
olefination by Stork’s method40 produced the (Z)-vinyl
iodide 34a in 72% yield (Scheme 7), and a 2-h Heck
reaction with palladium tetrakistriphenylphosphine in
Diene 21g was prepared as sketched above, by alkyl-
ation of the enolate of 2a under Palomo conditions
followed by allylation. The required alkylating agent,
iodide 30, was prepared from 4-pentyn-1-ol:13b protection
with TBSCl, metalation with n-BuLi and entrapment of
(38) (a) Ulman, M.; Grubbs, R. H. J. Org. Chem. 1999, 64, 7202-
7207. (b) Sanford, M. S.; Love, J. A. In Handbook of Metathesis; Grubbs,
R. H., Ed.; Wiley-VCH: Weinheim, Germany, 2003; Vol. 1, pp 112-
131. (c) Hong, S. H.; Day, M. W.; Grubbs, R. H. J. Am. Chem. Soc.
2004, 126, 7414-7415.
(39) PDC oxidation of alcohol 29 gave aldehyde 31, which was used
in the preparation of diene 21h.
(40) Stork, G.; Zhao, K. Tetrahedron Lett. 1989, 30, 2173-2174.
8286 J. Org. Chem., Vol. 70, No. 21, 2005

Construction of Novel Steroid-like Polycyclic Systems
tion,43 RCM, and Heck cyclization) is stereoselective. In
particular, whether the final product is a cis-cisoid-trans
or a cis-transoid-trans system is determined by the
stereochemistry of the alkylating agent, which in our case
ultimately derives from a Claisen rearrangement.44 It is
envisaged that this approach will allow access to general
fused 6-8-n systems starting from n-membered cycloal-
kanones.
SCHEME 6. Synthesis of Iodide 30 and Aldehyde
31a
Experimental Section
a Reagents and conditions: (a) TBSCl, Im, CH2Cl2, 92%; (b)
n-BuLi, THF, (H2CO)n, 82%; (c) H2, Lindlar, hexanes, 83%; (d)
CH2dCHOBu, Hg(OAc)2, 160 °C; (e) NaBH4, MeOH, 69% (from
28); (g) I2, Ph3P, Im, 76%; (h) PDC, CH2Cl2, 69%.
Preparation of Ketone 15. Carbon tetrabromide (232 mg,
0.70 mmol) was added to a solution of alcohol 14a26 (150 mg,
0.56 mmol) in CH2Cl2 (6 mL). The resulting solution was cooled
to 0 °C and Ph3P (220 mg, 0.84 mmol) was added. The reaction
mixture was stirred for 30 min at room temperature and the
solvent was removed under reduced pressure, giving a residue
that when flash chromatographed (1% EtOAc/hexanes) af-
forded 150 mg of bromide 14b and used without further
characterization [81%, Rf 0.8 (10% EtOAc/hexanes), colorless
oil]. 1H NMR (CDCl3, 300 MHz) δ 5.54 (1H, t, J ) 8.3 Hz),
5.02 (1H, s), 4.93 (1H, s), 4.11 (2H, d, J ) 8.2 Hz), 3.85 (1H,
m), 0.87 (9H, s), 0.05-0.04 (6H, 2s).
refluxing acetonitrile yielded compound 36a as a single
isomer. Disappointingly, the yield of 36a was only 15%,
the major product being the protonated compound 35
(>40% yield). The use of other catalyst systems, such us
Pd(OAc)2/PPh3/Et3N in DMF or acetonitrile, did not
achieve any improvement. By contrast, applying the same
reaction sequence to 32b gave a 64% yield of the trans-
bicyclo compound 36b as the only product. These differ-
ences in reactivity of iodides 34a and 34b must be due
to conformational restrictions introduced by the eight-
membered ring fused to the CD-bicyclic system. The trans
relative stereochemistry of 36a at C5 and C10 was
established on the basis of the coupling of the C5 proton
to those on C6 and C10, C5-H appearing as a triplet41
with a J value, 9.3 Hz, that in cyclohexanes is charac-
teristic of the trans axial-axial orientation. The R
configuration of C10 was then established when a
substantial NOESY cross-peak between H14 and H5
showed them to be cis to each other.13 The 10S stereo-
chemistry of 36b was similarly shown by an H5-H10
coupling constant of 9.3 Hz and a NOE enhancement
between H5 and H9 suggestive of a cis relationship.
A solution of ketone 2a27 (100 mg, 0.38 mmol) in THF (4
mL) was added under Ar to a freshly prepared solution of LDA
in THF (1 M, 760 µL, 0.76 mmol) at -78 °C. The reaction
mixture was stirred at that temperature for 30 min and then
a solution of 14b (251 mg, 0.75 mmol) in THF (6 mL) was
added. The resulting solution was stirred at -78 °C for 3 h,
and the reaction was quenched by adding H2O (5 mL). The
aqueous layer was extracted with Et2O and the combined
organic extracts were washed with brine, dried over Na2SO4,
and concentrated under reduced pressure, giving a residue that
upon flash chromatography (2% EtOAc/hexanes) afforded 165
mg of ketone 15 [85%, Rf 0.6 (10% EtOAc/hexanes), colorless
oil]. 1H NMR (CDCl3, 300 MHz) δ 5.04 (1H, t, J ) 7.2 Hz),
4.94 (1H, s), 4.63 (1H, s), 3.78 (1H, tt, J ) 7.2 and 3.6 Hz),
2.46 (1H, dd, J ) 11.5 and 7.4 Hz), 2.30 (4H, m), 2.22 (1H, m),
2.09 (1H, dd, J ) 12.9 and 7.5 Hz), 0.91 (3H, d, J ) 6.2 Hz),
0.85 (9H, s), 0.84 (6H, overlapped d, J ) 6.6 Hz), 0.61 (3H, s),
0.03 (6H, s). 13C NMR (CDCl3, 75 MHz) δ 214.9, 145.9, 139.0,
122.9, 110.7, 69.9, 58.2, 56.8, 50.3, 49.8, 46.4, 39.4, 36.1, 35.9,
35.5, 35.4, 32.4, 31.1, 28.0, 27.7, 27.6, 25.8, 23.8, 22.8, 22.5,
19.0, 18.6, 18.1, 12.9, -4.7, -4.8. IR νmas (KBr, cm-1) 2954,
2858, 1712, 1469, 1381, 1253, 1093, 1009, 898, 836, 774. MS
m/z 515 (MH+, 41), 499 (M+ - CH3, 35), 457 (M+ - tBu, 100),
383 (83), 365 (62). HRMS calcd for C33H59O2Si (MH+) 515.4284,
found 515.4276.
Conclusion
In conclusion, we have shown that RCM is a suitable
method for formation of the eight-membered carbocycle
of the novel steroid-like framework of compounds 1 and
that it can be followed by Heck cyclization to build
tricyclo[10.4.0.04,9]hexadecane systems. Notably, the com-
plete reaction sequence (enol alkylation,42 ketone allyla-
Preparation of Ketone 20a (KHMDS Method). A solu-
tion of ketone 2a (313 mg, 1.18 mmol) in DMF (3.0 mL) was
SCHEME 7. Preparation of Vinyl Iodides 34a and 34b (path C) and Cyclization To Provide the Wished
Tetracyclic System by Heck Reactiona
a Reagents and conditions: (a) 16a, CH2Cl2, 6 days, 95%; (b) TBAF, THF, 87%; (c) PDC, CH2Cl2, 57% for 33a, 66% for 33b; (d) Ph3P+CH2I
I-, NaHMDS, THF, 72% for 34a, 70% for 34b; (e) Pd(PPh3)4, CH3CN, ∆, 15% for 36a, 64% for 36b.
J. Org. Chem, Vol. 70, No. 21, 2005 8287

Garc´ıa-Fandin˜o et al.
added under Ar to a solution of KHMDS in toluene (0.5 M,
4.70 mL, 2.35 mmol) and DMF (3 mL). The reaction mixture
was stirred for 30 min and then 1-iodopent-4-ene (464 mg, 2.36
mmol) was added. The reaction mixture was stirred for 2 h at
-78 °C, and the reaction was quenched by addition of a
solution of NH4Cl (4 mL). The aqueous layer was extracted
with Et2O (2 × 25 mL). The combined organic extracts were
washed with H2O, dried over Na2SO4, and concentrated under
reduced pressure, giving a residue that when flash chromato-
graphed (3% EtOAc/hexanes) afforded 210 mg of ketone 20a
[76%, Rf 0.6 (10% EtOAc/hexanes), colorless oil]. 1H NMR
(CDCl3, 300 MHz) δ 5.74 (1H, ddt, J ) 17.0, 10.3, and 6.7 Hz),
4.95 (1H, dq, J ) 17.0 and 1.7 Hz), 4.92 (1H, ddt, J ) 10.3,
1.9, and 0.9 Hz), 2.57 (1H, dd, J ) 11.6 and 7.4 Hz), 2.26 (1H,
q, J ) 7.5 Hz), 0.92 (3H, d, J ) 6.4 Hz), 0.85 and 0.84 (6H,
overlapped d, J ) 6.6 Hz), 0.62 (3H, s). 13C NMR (CDCl3, 75
MHz) δ 215.2, 138.3, 114.7, 57.9, 56.8, 50.0, 49.7, 39.4, 35.9,
35.5, 35.5, 33.4, 33.2, 28.6, 28.0, 27.5, 26.8, 23.7, 22.7, 22.5,
18.9, 18.6, 12.8. IR νmas (CHCl3, cm-1) 3068, 2948, 2952, 2864,
2247, 1708, 1640, 1459, 1383, 1238, 991. MS m/z 333 (MH+,
100), 315 (MH+ - H2O, 54), 264 (30), 221 (28). HRMS calcd
for C23H41O (MH+) 333.3157, found 333.3157. Elemental Anal.
Calcd: C 83.06; H 12.13. Found: C 83.32; H 12.02.
(10% EtOAc/hexanes), colorless oil]. 1H NMR (CDCl3, 300
MHz) δ 5.43 (1H, m), 5.06 (2H, m), 3.58 (2H, t, J ) 6.3 Hz),
3.22 (1H, ddd, J ) 9.5, 8.0, and 5.5 Hz), 3.02 (1H, dt, J ) 9.5
and 8.0 Hz), 0.88 (9H, s), 0.03 (6H, s). 13C NMR (CDCl3, 75
MHz) δ 140.9, 116.1, 63.0, 44.6, 38.5, 30.7, 30.2, 26.0, 18.3,
5.0, -5.3.
Using the conditions described for the preparation of 20a,
233 mg of ketone 20g was obtained from ketone 2a and iodide
1
30 [72%, Rf 0.5 (10% EtOAc/hexanes), colorless oil]. H NMR
(CDCl3, 300 MHz) δ 5.44 (1H, m), 4.92 (1H, dt, J ) 8.5 and
1.0 Hz), 4.90 (1H, dd, J ) 7.3 and 1.9 Hz), 3.54 (2H, t, J ) 6.2
Hz), 2.51 (1H, m), 0.91 (3H, d, J ) 6.1 Hz), 0.86 (9H, s), 0.85
(6H, d, J ) 6.6 Hz), 0.60 (3H, s), 0.008 (6H, s). 13C NMR
(CDCl3, 75 MHz) δ 215, 142.6, 114.8, 63.1, 57.9, 56.7, 50.1,
50.0, 43.9, 39.4, 35.9, 35.4, 33.0, 31.0, 30.5, 30.3, 28.8, 28.5,
28.0, 27.5, 25.9, 23.7, 22.7, 22.5, 18.9, 18.7, 18.3, 12.7, -5.3.
IR νmas (CHCl3, cm-1) 3072, 2957, 2929, 2855, 1710, 1634, 1469,
1384, 1363, 1254. MS m/z 505 (MH+, 100), 489 (46), 447 (92),
373 (33). HRMS calcd for C32H61O2Si (MH+) 505.4441, found
505.4416.
General Method for Ketone Allylation: Preparation
of Alcohol 3a. A solution of ketone 15 (77 mg, 0.15 mmol) in
THF (2 mL) was added under Ar to a solution of allylmagne-
sium bromide (1 M in THF, 450 µL, 0.45 mmol) in THF (1.5
mL) at -78 °C. The reaction mixture was stirred at that
temperature for 3 h and NH4Cl (sat. dil., 4 mL) was added.
The aqueous layer was extracted with Et2O and the combined
organic extracts were washed with brine, dried over Na2SO4,
and concentrated under reduced pressure, giving a residue that
when flash chromatographed (2% EtOAc/hexanes) afforded 76
mg of compound 3a [91%, Rf 0.6 (10% EtOAc/hexanes),
Ketone 20b (LDA Method). A solution of ketone 2a (330
mg, 1.25 mmol) in THF (12 mL) was added under Ar to a
freshly prepared solution of LDA in THF (1 M, 2.5 mL, 2.5
mmol) at -78 °C. The reaction mixture was stirred at that
temperature for 30 min and then a solution of 5-iodo-2-
methylpent-1-ene (520 mg, 2.5 mmol) in THF (18 mL) was
added. The resulting solution was stirred at -78 °C for 3 h,
and the reaction was quenched by adding H2O (10 mL). The
aqueous layer was extracted with Et2O and the combined
organic extracts were washed with brine, dried over Na2SO4,
and concentrated under reduced pressure, giving a residue that
upon flash chromatography (2% EtOAc/hexanes) afforded 65
mg of ketone 20b31 [15%, Rf 0.6 (10% EtOAc/hexanes), colorless
1
colorless oil]. H NMR (CDCl3, 300 MHz) δ 5.84 (1H, dddd, J
) 16.8, 10.3, 8.3, and 6.5 Hz), 5.15 (1H, dd, J ) 10.1 and 2.2
Hz), 5.12 (1H, dd, J ) 17.1 and 1.9 Hz), 5.08 (1H, t, J ) 7.0
Hz), 4.94 (1H, dt, J ) 2.6 and 1.3 Hz), 4.65 (1H, d, J ) 2.7
Hz), 3.90 (1H, tt, J ) 6.6 and 3.3 Hz), 0.92 (3H, s), 0.86 (9H,
s), 0.85 and 0.84 (6H, overlapped d, J ) 6.6 Hz), 0.04-0.03
(6H, 2s). 13C NMR (CDCl3, 75 MHz) δ 146.6, 137.4, 133.4,
125.4, 119.2, 110.3, 75.8, 69.5, 57.3, 51.5, 46.3, 43.5, 43.3, 39.5,
36.0, 35.9, 35.3, 34.8, 32.0, 28.0, 27.2, 27.1, 25.8, 23.9, 22.8,
22.5, 21.0, 20.0, 18.3, 18.1, 13.4, -4.7, -4.8. IR νmas (CHCl3,
cm-1) 3667, 3599, 3568, 3078, 2952, 2860, 1724, 1635, 1469,
1366, 1253, 1199, 1086, 1007. MS m/z 539 (M+ - H2O, 77),
515 (27), 499 (42), 407 (100). HRMS calcd for C36H63OSi (M+
- H2O) 539.4648, found 539.4639.
1
oil]. H NMR (CDCl3, 300 MHz) δ 4.68 (1H, s), 4.63 (1H, s),
2.57 (1H, dd, J ) 11.8 and 7.4 Hz), 2.27 (1H, q, J ) 6.6 Hz),
0.92 (3H, d, J ) 6.4 Hz), 0.85 and 0.84 (6H, overlapped d, J )
6.6 Hz), 0.62 (3H, s). 13C NMR (CDCl3, 75 MHz) δ 215.2, 145.3,
110.1, 57.9, 56.7, 50.0, 49.8, 39.4, 37.4, 35.9, 35.5, 35.5, 32.3,
28.6, 28.0, 27.5, 25.4, 23.7, 22.7, 22.5, 18.9, 18.6, 12.8. IR νmas
(KBr, cm-1) 2954, 2869, 1711, 1465, 1380, 886. MS m/z 347
(MH+, 72), 329 (MH+ - H2O, 31), 279 (100). HRMS calcd for
C24H43O (MH+) 347.3313, found 347.3306. Elemental Anal.
Calcd: C 83.16; H 12.22. Found: C 83.01; H 12.06.
Ketone 20g. To a solution of alcohol 29 (0.50 g, 1.90 mmol)
in THF (10 mL) at 0 °C and under Ar were successively added
Ph3P (610 mg, 2.32 mmol), imidazole (396 mg, 5.80 mmol), and
I2 (541 mg, 2.13 mmol). The resulting mixture was stirred at
room temperature for 30 min and then H2O (8 mL) was added.
The aqueous layer was extracted with Et2O. The combined
organic extracts were washed with brine, dried over Na2SO4,
and concentrated under reduced pressure, giving a residue that
upon flash chromatography (hexanes) afforded 0.5 g of iodide
30 and used without further characterization [76%, Rf 0.85
Alcohol 21a. Using the conditions described for the prepa-
ration of 3a, 53 mg of alcohol 21a was obtained from 20a [94%,
1
Rf 0.6 (10% EtOAc/hexanes), colorless oil]. H NMR (CDCl3,
300 MHz) δ 5.82 (2H, m), 5.15 (1H, dd, J ) 10.2 and 2.2 Hz),
5.11 (1H, ddt, J ) 17.0, 2.2, and 1.1 Hz), 5.00 (1H, ddd, J )
17.0, 3.5, and 1.6 Hz), 4.93 (1H, ddt, J ) 10.2, 1.9, and 1.0
Hz), 2.25, (1H, dd, J ) 14.2 and 6.6 Hz), 2.11 (1H, dd, J )
14.2 and 8.2 Hz), 0.93 (3H, s), 0.88 (3H, d, J ) 6.8 Hz), 0.86
and 0.85 (6H, overlapped d, J ) 6.6 Hz). 13C NMR (CDCl3, 75
MHz) δ 138.9, 133.3, 119.2, 114.4, 76.0, 57.1, 51.5, 43.5, 43.4,
42.5, 39.5, 39.4, 35.9, 35.2, 34.8, 34.0, 28.0, 27.5, 27.2, 23.7,
22.8, 22.5, 20.3, 20.0, 18.4, 13.4. IR νmas (CHCl3, cm-1) 3667,
3076, 2950, 2872, 1639, 1466, 1382, 994, 910. MS m/z 375
(MH+, 38), 357 (MH+ - H2O, 64), 333 (100), 315 (80). HRMS
calcd for C26H47O (MH+) 375.3627, found 375.3613.
Alcohol 21g. Using the conditions described for the prepa-
ration of 3a, 720 mg of alcohol 21g were obtained from 20g
[82%, Rf 0.5 (10% EtOAc/hexanes), colorless oil]. 1H NMR
(CDCl3, 300 MHz) δ 5.80 (1H, m), 5.51 (1H, m), 5.16-4.90 (4H,
m), 3.57 (2H, t, J ) 6.3 Hz), 2.21 (1H, dd, J ) 13.9 and 6.5
Hz), 2.08 (1H, dd, J ) 13.9 and 8.2 Hz), 0.93 (3H, s), 0.88 (9H,
s), 0.85 and 0.84 (6H, overlapped d, J ) 6.6 Hz), 0.03 (6H, s).
13C NMR (CDCl3, 75 MHz) δ 143.1, 133.4, 119.2, 114.5, 76.1,
63.3, 57.0, 51.6, 51.6, 43.8, 43.4, 42.6, 39.5, 35.9, 35.3, 34.8,
33.6, 31.2, 30.4, 28.0, 27.2, 26.0, 25.1, 23.8, 22.8, 22.5, 20.3,
20.0, 18.4, 18.3, 13.4, -5.3. MS m/z 529 (MH+ - H2O, 49), 505
(41) H4-H5 coupling was close to zero.
(42) For some examples of stereoselective enol alkylation, see: (a)
Hughes, D. L. In Comprehensive Asymmetric Catalysis; Jacobsen, E.
N., Pfaltz, A., Yamamoto, H., Eds.; Springer-Verlag: Berlin, Germany,
1999; Chapter 34.1. For a review of asymmetric protonation of enolates,
see: (b) Yanagisawa, A.; Yamamoto, H. In Comprehensive Asymmetric
Catalysis; Jacobsen, E. N., Pfaltz, A., Yamamoto, H., Eds.; Springer-
Verlag: Berlin, Germany, 1999; Chapter 34.2.
(43) For a recent study of the diastereoselectivity of cycloalkanone
alkylation, see: (a) Gung, B. W. Chem. Rev. 1999, 99, 1377-1386. (b)
Ohwada, T. Chem. Rev. 1999, 99, 1337-1376.
(44) For reviews of asymmetric Claisen rearrangement, see: (a) Ito,
H.; Taguchi, T. Chem Soc. Rev. 1999, 28, 43-50. (b) Enders, D.; Knopp,
M.; Schiffers, R. Tetrahedron: Asymmetry 1996, 7, 1847-1882. For
recent reports of enantioselective catalytic Claisen rearrangement,
see: (c) Yoon, T. P.; MacMillan, D. W. C. J. Am. Chem. Soc. 2001,
123, 2911-2912. (d) Abraham, L.; Czerwonka, R.; Hiersemann, M.
Angew. Chem., Int. Ed. 2001, 40, 4700-4703.
8288 J. Org. Chem., Vol. 70, No. 21, 2005

Construction of Novel Steroid-like Polycyclic Systems
(100), 487 (28), 471 (30), 397 (48). HRMS calcd for C35H65OSi
Preparation of Alcohols 32a and 32b. Using the condi-
tions described for the preparation of 26a, 210 mg of a 1:1
diastereomeric mixture of (10S)-26g and (10R)-26g was ob-
tained from 21g [95%, Rf 0.4 (10% EtOAc/hexanes), colorless
oil]. This mixture was dissolved in THF (5 mL), treated with
TBAF (1 M in THF, 0.75 mL, 0.75 mmol), and stirred for 5 h
at room temperature. A saturated solution of NH4Cl was added
and the resulting mixture was extracted with Et2O. The
combined organic extracts were dried, filtered, and concen-
trated in vacuo, giving a residue that when flash chromato-
graphed (20% EtOAc/hexanes) afforded 73 mg of 32a and 69
mg of 32b. 32a [Rf 0.2 (25% EtOAc/hexanes), colorless oil]. 1H
NMR (CDCl3, 300 MHz) δ 5.58 (1H, q, J ) 9.0 Hz), 5.26 (1H,
t, J ) 9.4 Hz), 3.59 (2H, t, J ) 6.5 Hz), 0.89 (3H, s), 0.86 (3H,
d, J ) 6.6 Hz), 0.84 and 0.83 (6H, overlapped d, J ) 6.6 Hz).
13C NMR (CDCl3, 75 MHz) δ 137.2, 125.3, 76.9, 62.9, 57.0, 49.3,
45.2, 43.3, 41.0, 39.5, 35.8, 35.6, 35.1, 34.9, 32.2, 31.1, 29.6,
29.5, 27.9, 27.1, 23.7, 22.8, 22.5, 20.1, 18.3, 13.6. MS m/z 405
(MH+, 30), 387 (MH+ - H2O, 93), 371 (50), 369 (37). HRMS
calcd for C27H49O2 (MH+) 405.3733, found 405.3731. 32b [Rf
0.3 (25% EtOAc/hexanes), colorless oil]. 1H NMR (CDCl3, 500
MHz) δ 5.6 (2H, m), 3.6 (2H, t, J ) 6.4 Hz), 0.9 (3H, s), 0.86
(3H, d, J ) 6.6 Hz), 0.85 and 0.84 (6H, overlapped d, J ) 6.6
Hz). 13C NMR (CDCl3, 125.8 MHz) δ 138.4, 125.8, 79.0, 62.9,
57.1, 52.0, 43.1, 42.9, 39.4, 38.6, 37.6, 37.5, 35.8, 35.2, 35.1,
34.1, 33.3, 30.5, 28.1, 28.0, 27.1, 23.7, 22.7, 22.5, 19.8, 18.3,
12.8. MS m/z 405 (MH+, 64), 387 (MH+ - H2O, 100). HRMS
calcd for C27H49O2 (MH+) 405.3733, found 405.3735. Elemental
Anal. Calcd: C 80.13; H 11.96. Found: C 79.87; H 12.08.
Aldehyde 33a. PDC (119 mg, 0.31 mmol) was added to a
solution of alcohol 32a (85 mg, 0.21 mmol) in CH2Cl2 (4 mL)
containing molecular sieves. The reaction mixture was stirred
under Ar for 2 h at room temperature and filtered through a
Celite pad and the filtrate was washed with Et2O. Concentra-
tion of the solvent in vacuo gave a residue that when flash
chromatographed (15% EtOAc/hexanes) afforded 56 mg of 33a
[57%, Rf 0.4 (25% EtOAc/hexanes), white solid]. 1H NMR
(CDCl3, 300 MHz) δ 9.73 (1H, s), 5.74-5.30 (2H, m), 0.89 (3H,
s), 0.87 (3H, d, J ) 6.5 Hz), 0.85 and 0.84 (6H, overlapped d,
J ) 6.6 Hz). 13C NMR (CDCl3, 75 MHz) δ 202.5, 137.1, 126.9,
78.9, 57.1, 51.9, 43.1, 42.7, 41.9, 39.5, 38.3, 37.6, 37.4, 35.8,
35.1, 35.1, 33.9, 29.1, 28.1, 28.0, 27.1, 23.7, 22.7, 22.5, 19.8,
18.4, 12.8. MS m/z 402 (M+, 36), 387 (25), 359 (21), 277 (82),
264 (100). HRMS calcd for C27H46O2 (M+) 402.3498, found
402.3496.
Aldehyde 33b. Prepared in the same way from alcohol 32b
as 33a from 32a. Yield 46 mg [66%, Rf 0.7 (50% EtOAc/
hexanes), white solid]. 1H NMR (CDCl3, 300 MHz) δ 9.70 (1H,
s), 5.61 (1H, q, J ) 9.4 Hz), 5.23 (1H, t, J ) 9.0 Hz), 0.9 (3H,
s), 0.87 (3H, d, J ) 6.5 Hz), 0.85 and 0.84 (3H, overlapped d,
J ) 6.6 Hz). 13C NMR (CDCl3, 75 MHz) δ 202.5, 136.0, 126.4,
76.8, 56.9, 49.2, 45.2, 43.2, 42.4, 41.0, 39.4, 35.8, 35.4, 35.1,
34.9, 34.9, 29.6, 29.3, 28.0, 28.0, 27.0, 23.6, 22.8, 22.5, 20.1,
18.2, 13.6. MS m/z 402 (M+, 40), 387 (12), 359 (30), 277 (72),
264 (100). HRMS calcd for C27H46O2 (M+) 402.3498, found
402.3493.
Vinyl Iodide 34a. A solution of NaHMDS (156 µL, 0.16
mmol) in THF was added under Ar to a suspension of
iodomethyltriphenylphosphonium iodide (86 mg, 0.16 mmol)
in the same solvent. The resulting solution was cooled to -60
°C and treated with HMPA (27 µL, 0.16 mmol) and aldehyde
33a (50 mg, 0.12 mmol). After 30 min at room temperature,
H2O was added and the aqueous layer was extracted with
Et2O. The combined organic extracts were washed with brine,
dried over Na2SO4, and concentrated under reduced pressure,
giving a residue that when flash chromatographed (5% EtOAc/
hexanes) afforded 35 mg of the (Z)-vinyl iodide 34a [72%, Rf
0.7 (20% EtOAc/hexanes), colorless oil]. 1H NMR (CDCl3, 300
MHz) δ 6.16 (2H, m), 5.58 (1H, dd, J ) 18.2 and 8.5 Hz), 5.30
(1H, dd, J ) 10.2 and 8.3 Hz), 2.56 (1H, br s), 0.93 (3H, s),
0.82 and 0.81 (6H, overlapped d, J ) 6.6 Hz). 13C NMR (CDCl3,
75 MHz) δ 141.1, 136.9, 125.5, 82.3, 76.9, 57.1, 49.4, 45.3, 43.3,
(MH+ - H2O) 529.4805, found 529.4806.
Compound 3b. A solution of alcohol 3a (38 mg, 0.07 mmol)
in THF (0.5 mL) was treated under Ar with KH (6 mg, 0.15
mmol) and MeI (9 µL, 0.15 mmol). After the resulting solution
was stirred for 8 h, the reaction was quenched by addition of
H2O and the resulting mixture was extracted with hexanes.
The combined organic layers were dried over Na2SO4, filtered,
and concentrated under reduced pressure, giving a residue that
when flash chromatographed (hexanes) afforded 33 mg of
compound 3b [85%, Rf 0.75 (10% EtOAc/hexanes), colorless oil].
1H NMR (CDCl3, 300 MHz) δ 5.90 (1H, m), 5.12-5.03 (3H,
m), 4.94 (1H, d, J ) 2.8 Hz), 4.65 (1H, d, J ) 2.4 Hz), 3.90
(1H, tt, J ) 6.2 and 3.1 Hz), 3.21 (3H, s), 0.91 (3H, s), 0.87
(9H, s), 0.85 and 0.84 (6H, overlapped d, J ) 6.6 Hz), 0.04-
0.03 (6H, 2s). 13C NMR (CDCl3, 75 MHz) δ 146.7, 137.2, 135.1,
125.7, 116.3, 110.2, 75.9, 69.4, 57.1, 52.5, 49.6, 46.3, 43.5, 40.2,
39.5, 39.1, 35.9, 35.3, 34.9, 32.0, 28.0, 27.4, 26.8, 25.8, 23.9,
22.8, 22.6, 21.6, 21.1, 18.3, 18.1, 13.2, -4.7, -4.8. IR νmas
(CHCl3, cm-1) 3072, 2958, 2934, 2864, 2247, 1636, 1469, 1368,
1252, 1083, 1011, 909. MS (m/z, I) 571 (MH+, 19), 540 (MH+
- OMe, 26), 538 (20), 440 (3), 438 (3), 405 (29). HRMS calcd
for C37H67O2Si (MH+) 571.4910, found 571.4913.
General Procedure for RCM: Preparation of Com-
pound 26a. Ruthenium catalyst 16a (40 mg, 0.11 mmol) was
added to a solution of dienyne 21a (13 mg, 0.16 mmol) in CH2-
Cl2 (20 mL), and the resulting mixture was refluxed under Ar
for 2 h, concentrated under reduced pressure, and purified by
flash chromatography (2% EtOAc/hexanes), giving 32 mg of
compound 26a [86%, Rf 0.5 (10% EtOAc/hexanes), colorless oil].
1H NMR (CDCl3, 300 MHz) δ 5.89 (1H, td, J ) 10.3 and 7.7
Hz), 5.58 (1H, td, J ) 10.2 and 6.5 Hz), 2.33 (1H, dd, J ) 13.0
and 10.1 Hz), 0.91 (3H, s), 0.88 (3H, d, J ) 6.5 Hz), 0.86 and
0.85 (6H, overlapped d, J ) 6.6 Hz). 13C NMR (CDCl3, 75 MHz)
δ 133.0, 126.7, 78.5, 57.1, 51.8, 43.2, 43.0, 39.5, 36.9, 35.9, 35.2,
34.5, 30.0, 29.6, 28.1, 28.0, 27.8, 27.2, 23.7, 22.8, 22.5, 19.9,
18.4, 12.9. IR νmas (CHCl3, cm-1) 3602, 3010, 2932, 2360, 2340,
1717, 1647, 1607, 1466, 1380, 1275, 1248, 1214, 1170, 1020.
MS (m/z, I) 346 (M+, 22), 331 (18), 277 (26), 264 (17). HRMS
calcd for C24H42O (M+) 346.3236, found 346.3229. Elemental
Anal. Calcd: C 83.16; H 12.22. Found: C 83.12; H 11.97.
Compound 26b. Using the conditions described for the
preparation of 26a, but with catalyst 16b instead of 16a, 24
mg of alcohol 26b was obtained from 21b [86%, Rf 0.4 (10%
1
EtOAc/hexanes), colorless oil]. H NMR (CDCl3, 300 MHz) δ
5.31 (1H, t, J ) 7.4 Hz), 1.75 (3H, s), 0.9 (3H, s), 0.87 (3H, d,
J ) 6.1 Hz), 0.86 and 0.85 (6H, overlapped d, J ) 6.6 Hz). 13
C
NMR (CDCl3, 75 MHz) δ 140.5, 119.7, 78.9, 57.2, 51.8, 43.2,
43.0, 39.4, 37.6, 35.9, 35.2, 35.1, 33.3, 29.6, 29.1, 28.2, 28.0,
27.2, 25.1, 23.7, 22.7, 22.5, 19.8, 18.4, 12.9. MS (m/z, I) 361
(MH+, 35), 343 (MH+ - H2O, 100), 327 (41). HRMS calcd for
C25H44O (M+) 360.3392, found 360.3383. Elemental Anal.
Calcd: C) 83.26%; H) 12.31%; found: C) 83.48%; H)
12.07%.
3-Ethenyl-6-(tert-butyldimethylsilyloxy)hexan-1-ol (29).
Alcohol 28 (6.00 g, 26.00 mmol) was dissolved in n-butyl vinyl
ether (60 mL), and Hg(OAc)2 (4.15 g, 13.00 mmol) was added.
The resulting solution was heated in a sealed flask at 160 °C
for 26 h. The reaction mixture was cooled to 0 °C, and MeOH
(20 mL) and NaBH4 (1.20 g, 31.30 mmol) were added. After
10 min, H2O was added and the aqueous layer was extracted
with Et2O. The combined organic extracts were washed with
brine, dried over Na2SO4, and concentrated under reduced
pressure, giving a residue that upon flash chromatography (3%
EtOAc/hexanes) afforded 233 mg of alcohol 29 [69%, Rf 0.3
(20% EtOAc/hexanes), colorless oil]. 1H NMR (CDCl3, 300
MHz) δ 5.52 (1H, m), 4.97 (2H, m), 3.58 (2H, m), 3.55 (2H, t,
J ) 6.3 Hz), 2.12 (1H, m), 1.98 (1H, m), 0.85 (9H, s), 0.006
(6H, s). 13C NMR (CDCl3, 75 MHz) δ 142.6, 114.9, 63.1, 60.9,
40.8, 37.8, 31.2, 30.2, 25.9, 18.3, -5.3. MS m/z 241 (MH+
-
H2O, 35), 109 (100). HRMS calcd for C14H29OSi (MH+ - H2O)
241.1988, found 241.1977.
J. Org. Chem, Vol. 70, No. 21, 2005 8289

Garc´ıa-Fandin˜o et al.
41.2, 39.5, 35.9, 35.2, 35.0, 34.3, 35.6, 34.3, 33.3, 29.7, 29.5,
28.0, 27.1, 23.7, 22.8, 22.5, 20.2, 18.3, 13.6. MS m/z 527 (MH+,
7), 509 (MH+ - H2O, 17), 381 (18). HRMS calcd for C28H48IO
(MH+) 527.2750, found 527.2746.
Vinyl Iodide 34b. Prepared from 33b in the same way as
34a from 33a [37 mg, 70%, Rf 0.7 (20% EtOAc/hexanes),
colorless oil]. 1H NMR (CDCl3, 300 MHz) δ 6.16 (2H, m), 5.58
(2H, m), 0.92 (3H, s), 0.88 (3H, d, J ) 6.6 Hz), 0.86 and 0.85
(6H, overlapped d, J ) 6.6 Hz). 13C NMR (CDCl3, 75 MHz) δ
140.9, 138.0, 126.0, 82.4, 79.0, 57.2, 52.1, 43.2, 43.0, 39.6, 38.5,
37.7, 37.4, 36.0, 35.5, 35.3, 35.3, 34.1, 32.8, 28.3, 28.1, 27.3,
23.8, 22.9, 22.7, 20.0, 18.5, 13.0. MS m/z 527 (MH+, 2), 509
(MH+ - H2O, 13), 381 (21). HRMS calcd for C28H48IO (MH+)
527.2750, found 527.2762.
Tetracyclic Compound 36a. A solution of (Z)-vinyl iodide
34a (65 mg, 0.12 mmol), (PhP)4Pd (13.7 mg, 0.012 mmol), and
Et3N (80 µL, 0.6 mmol) in MeCN (3.5 mL) was heated under
Ar at 80 °C for 2 h. After cooling, a solution of HCl (10%) was
added, and the resulting mixture was extracted with Et2O.
The combined organic extracts were dried over Na2SO4, and
concentration under reduced pressure gave a residue that
when flash chromatographed (2% EtOAc/hexanes) afforded 7
mg of the tetracyclic product 36a [15%, Rf 0.7 (50% EtOAc/
hexanes), white solid]. 1H NMR (CDCl3, 500 MHz) δ 5.63 (1H,
m), 5.56 (1H, d, J ) 9.7 Hz), 5.40 (1H, d, J ) 12.3 Hz), 5.12
(1H, dd, J ) 9.7 and 12.3 Hz), 2.80 (1H, t, J ) 9.7 Hz), 1.96
(1H, dd, J ) 13.3 and 7.2 Hz), 0.94 (3H, s), 0.89 (3H, d, J )
6.2 Hz), 0.86 and 0.85 (6H, overlapped d, J ) 6.6 Hz). 13C NMR
(CDCl3, 125.76 MHz) δ 138.7, 131.4, 130.5, 126.9, 77.9, 57.3,
49.8, 47.7, 42.6, 39.5, 38.5, 37.7, 35.8, 35.8, 35.3, 32.5, 29.7,
28.9, 28.4, 28.0, 26.9, 26.2, 23.9, 22.8, 22.5, 20.2, 18.3, 14.0.
MS m/z 399 (MH+, 20), 381 (MH+ - H2O, 100), 365 (23), 338
(22). HRMS calcd for C28H47O (MH+) 399.3627, found 399.3622.
Elemental Anal. Calcd: C 84.35; H 11.64. Found: C 84.68; H
11.42.
Tetracyclic Compound 36b. Under the conditions de-
scribed for preparation of 36a, 10 mg of iodide 36b was
obtained from 34b [64%, Rf 0.5 (10% EtOAc/hexanes), white
solid]. 1H NMR (CDCl3, 500 MHz) δ 5.72 (1H, m), 5.55 (1H, d,
J ) 12.0 Hz), 5.43 (1H, d, J ) 9.9 Hz), 5.15 (1H, dd, J ) 12.0
and 9.3 Hz), 3.41 (1H, t, J ) 9.3 Hz), 2.23 (1H, m), 0.94 (3H,
s), 0.88 (3H, d, J ) 6.6 Hz), 0.85 and 0.84 (6H, overlapped d,
J ) 6.6 Hz). 13C NMR (CDCl3, 125.76 MHz) δ 136.2, 133.5,
131.1, 126.3, 77.9, 57.1, 52.3, 46.5, 42.7, 39.5, 39.2, 38.6, 38.3,
35.8, 35.4, 35.3, 31.1, 31.0, 28.0, 27.1, 26.9, 25.0, 23.7, 22.8,
22.5, 19.7, 18.4, 14.2. MS m/z 399 (MH+, 5), 381 (MH+ - H2O,
100), 379 (76), 365 (26). HRMS calcd for C28H47O (MH+)
399.3627, found 399.3609.
Acknowledgment. This work was supported by the
Ministerio de Educacio´n y Ciencia and the Xunta de
Galicia under projects SAF2001-3120 and PGIDIT02-
PXIC20902PN, respectively. R.G.-F. thanks the Xunta
de Galicia and Ministerio de Educacio´n y Ciencia (FPI)
and M.J.A. thanks the Ministerio de Educacio´n Ciencia
(FPU) for fellowships awarded.
Supporting Information Available: General methods,
synthetic method for the preparation of 5, 17a, 18, 20c-f,
1
21b-f, 26bMe-h, and 28, and H and 13C NMR spectra of all
compounds. This material is available free of charge via the
Internet at http://pubs.acs.org.
JO050568W
8290 J. Org. Chem., Vol. 70, No. 21, 2005