Access to [6.4.0]Carbocyclic Systems by Tandem Metathesis of Dienynes. A Step toward the Synthesis of a PreD3-D3 Transition State Analogue

Article abstract of DOI:10.1021/ol0158011

matrix presented A new approach to the synthesis of linearly fused 6-8-6 tricarbocyclic systems, tandem ring-closing metathesis of dienynes, allows access to compounds with a carbon framework analogous to the proposed transition state of the isomerization

Full text of DOI:10.1021/ol0158011

ORGANIC
LETTERS
2001
Vol. 3, No. 10
1483-1486
Access to [6.4.0]Carbocyclic Systems by
Tandem Metathesis of Dienynes. A Step
toward the Synthesis of a PreD −D
3
3
Transition State Analogue†
Eva M. Codesido, Luis Castedo, and Juan R. Granja*
Departamento de Qu´ımica Orga´nica e Unidade Asociada o´ C.S.I.C., Facultade de
Qu´ımica, UniVersidade de Santiago, 15706 Santiago de Compostela, Spain
qojuangg@usc.es
Received March 6, 2001
ABSTRACT
A new approach to the synthesis of linearly fused 6−8−6 tricarbocyclic systems, tandem ring-closing metathesis of dienynes, allows access
to compounds with a carbon framework analogous to the proposed transition state of the isomerization of previtamin D to vitamin D .
3
3
The photobiogenesis of vitamin D3 in the skin consists of
two successive pericyclic reactions (Figure 1): a UV-B-
induced electrocyclic ring opening of 7-dehydrocholesterol
(7-DHC) to produce previtamin D3 (preD3), followed by a
thermally induced isomerization of the latter to vitamin D3
(D3) by means of an antarafacial [1,7]-sigmatropic hydrogen
shift from C19 to C9. D3 is subsequently transported to the
liver and kidney, where it is transformed into its biologically
active form, 1R,25-dihydroxyvitamin D3 (1R,25-(OH)2-D3).1,2
The involvement of a preD3 h D3 type of equilibrium in
the biological activity has been suggested by experimental
results hinting at the existence of uncharacterized membrane
receptors for both 1R,25-(OH)2-PreD3 and 1R,25-(OH)2-D3
associated with nongenomic activity.3
Although preD3-D3 transformation is one of the best
known examples of a concerted reaction that occurs in vivo,4
its mechanism has not yet been completely elucidated. For
example, recent studies have revealed that both the kinetics
and thermodynamics of this equilibrium differ significantly
in many anisotropic microenvironments (such as lipid
membranes)5 from their behavior in isotropic media where,
(3) The nongenomic actions refer to rapid biological responses mediated
by a membrane receptor and believed to be independent of direct interaction
with the genome as, for example, transcaltachia. For studies implicating
the PreD3-D3 equilibrium in biological activity, 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.;
Hammond, M. W.; Dormanen, M. C.; Nemere, I. Ann. N.Y. Acad. Sci. 1995,
761, 344-348.
(4) (a) Havinga, E. Experientia 1973, 29, 1181-1192. (b) Dauben, W.
G.; Funhoff, D. J. H. J. Org. Chem. 1988, 53, 5070-5075. (c) 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.
† This paper is dedicated to Prof. Barry M. Trost in honor of his 60th
birthday.
(1) 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.
(2) (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.
(5) (a) Tian, X. Q.; Chen, T. C.; Matsuoka, L. Y.; Wortsman, J.; Holick,
M. F. J. Biol. Chem. 1993, 268, 14888-14892. (b) Tian, X. Q.; Holick, M.
F. J. Biol. Chem. 1995, 270, 8706-8711. (c) Tian, X. Q.; Holick, M. F. J.
Biol. Chem. 1999, 274, 4174-4179.
10.1021/ol0158011 CCC: $20.00 © 2001 American Chemical Society
Published on Web 04/17/2001

like other concerted reactions, no solvent effect was ob-
served.6 In the hope that investigation of the mechanism of
this physiologically important transformation will be facili-
tated by studying the active site of a tailor-made enzyme,
we have embarked on the development of catalytic antibodies
for this process.7 To this end we require molecules capable
of eliciting an immune response producing such antibodies,
and we envisaged that compounds of the type I (e.g., Ia), in
which the eight-membered ring B mimics the putative cyclic
transition state of the PreD3-D3 isomerization reaction ([1,7]-
H Ts), might be a suitable family of potencial haptens (Figure
1).
Figure 2. Synthetic approach for the preparation of haptens I.
involves the construction of the eight-membered ring by ring-
closing metathesis (RCM) of triene 2.9 We envisaged that
the RCM would take place through the less substituted
double bond to form the C5-C6 bond of I.10 Compound 2
would be prepared by alkylation of the kinetic enolate of 3
with bromide 5 (easily prepared from alcohol 4),11 followed
by allylation of the ketone group.
To test the viability of this strategy we decided to prepare
compound Ib, using Grundmann’s ketone (3b) as starting
material (Scheme 1).12 The kinetic enolate formed by LDA
Scheme 1a
Figure 1. Photobiogenesis of vitamin D3 and analogues of the
proposed transition state of preD3-D3 isomerization.
a (a) (i) LDA, THF, -78 °C, (ii) 5, 85%; (b) allylMgBr, THF,
88%; (c) HK, MeI, 18-crown-6, THF, 85%; (d) 8b, CH2Cl2, 4,
90% (9a), 87% (9b).
Furthermore, compounds of the type I, such as Ic, might
also be useful as locked analogues of the 6-s-cis conformer
of 1R,25-(OH)2-D3 in studies of the nongenomic responses.8
In this letter we describe the synthesis of compounds 1, which
exhibit the basic carbon framework of these type of systems
I.
treatment at -78 °C was trapped at the least hindered face
with freshly prepared bromide 5, affording ketone 6 in 85%
yield.13 Treatment of 6 with allylmagnesium bromide gave
Our initial strategy for the preparation of the tetracyclic
system of compounds I is outlined in Figure 2. The key step
(9) (a) For reviews on metathesis, see: Fu¨rstner, A. Angew. Chem., Int.
Ed. 2000, 39, 3012-3043. (b) Chang, S.; Grubbs, R. H. Tetrahedron 1998,
54, 4413-4450. (c) For a recent view on the synthesis of medium-sized
rings by RCM, see: Maier, M. E. Angew. Chem., Int. Ed. 2000, 39, 2073-
2077. (d) For a more general review on the synthesis of medium-sized rings,
see: Yet, L. Chem. ReV. 2000, 100, 2963-3007.
(6) Schlatmann, J. L. M. A.; Pot, J.; Havinga, E. Rec. TraV. Chim. Pays-
Bas 1964, 83, 1173-1184.
(7) 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.
(10) For convenience, steroid numbering is used.
(11) For enantioselective synthesis of 4, see: Codesido, E. M.; Cid, M.
M.; Castedo, L.; Mourin˜o, A.; Granja, J. R. Tetrahedron Lett. 2000, 41,
5861-5864.
(12) Ketone 3b is readily obtained by ozonolysis of vitamin D3; see:
Mascaren˜as, J. L.; Sarandeses, L.; Castedo, L.; Mourin˜o, A. Tetrahedron
1991, 47, 3485-3498.
(8) (a) Sarandeses, L. A.; Mascaren˜as, J. L.; Castedo, L.; Mourin˜o, A.
Tetrahedron Lett. 1992, 33, 5445-5448. (b) D´ıaz, M.; Ferrero, M.;
Fe´rnandez, S.; Gotor, V. J. Org. Chem. 2000, 65, 5647-5652.
1484
Org. Lett., Vol. 3, No. 10, 2001

alcohol 7a in almost quantitative yield. The relative stereo-
chemistry of these newly generated stereocenters was
confirmed by inspection of the NMR (NOE, NOESY) spectra
of 6 and 7b. The NOE relationship between H14 and both
H19 and the neighboring allyl protons in compound 6
(Scheme 1) reflects the axial (R) orientation of the enolate
alkylation, while the significant interaction between Me18
and the OMe group in the NOESY spectrum of 7b confirmed
their cis relationship.
Table 1. RCM Studies for Formation of Eight-Membered Ring
Unfortunately, when 7a or the methyl ether 7b were
submitted to RCM conditions using Grubbs’ catalyst (8a),
they were recovered unaltered; while treatment with the more
reactive ruthenium catalyst 8b14 furnished compounds 9a and
9b in very high yield, i.e., formation of the six-membered
ring prevailed over formation of the eight-membered ring,
even though it involved reaction with the more substituted
olefin. This result was not completely unexpected, because
the formation of eight-membered rings is especially difficult.
In particular, it has become increasingly apparent that the
formation of cyclooctene by metathesis requires a confor-
mationally predisposed diene or an adequately oriented polar
functional group acting as an internal ligand.10c,15 Further-
more, our cyclization precursor is a 1,2-cis disubstituted
cyclohexane, and previous studies have shown that substrates
of this kind undergo RCM to [6.4.0] systems less easily than
the corresponding trans systems.16 In our case, and to further
check if cyclooctene formation by RCM was indeed a viable
alternative for our synthetic purposes, we prepared com-
pounds 10a-f (Table 1), for which the otherwise preferred
cyclohexene pathway is not possible because they have no
internal double bond. Additional issues of interest were to
unveil how substitutents on the olefin and the presence of a
cyclohexyl precursor of ring A of I would affect the course
of the RCM reaction.
entry substrate
P
R2 R3
m
n
catalyst yield %a
1
2
3
4
5
6
7
10a
10b
10c
10d
10d
10e
10f
H
H
H
H
H
H
H
H
H
H
H
1
2
2
1
1
1
1
1
0
0
1
1
1
1
8a
86
8a /8b
8a /8b
8a
ndb
ndb
ndb
92
Me
Me Me
Me Me
H
Me
8b
Me
8b
8b
89
ndb
(CH2)4
a Isolated yields of 11. b nd ) not detected in reaction crude by 1H NMR
(a variety of solvents were used).
membered ring by RCM is possible, but they also suggest
that the constrains introduced by the cyclohexane ring do
not allow adoption of the conformation necessary for the
annulation.
In view of the above results we planned a new approach
in which initial formation of the ring B by RCM was to be
followed by a second cyclization to generate ring A (Figure
3). Specifically, we hoped for tandem RCM of dienyne 12a.17
The results of this study are listed in Table 1. Substrates
10a, 10d, and 10e afforded the desired eight-membered ring
(entries 1, 5, and 6). Entries 2 and 3 show that a methylene
group (n ) 1) between the olefin and the bicyclic system is
required: substrates 10b and 10c failed to cyclize regardless
of changes of solvent and catalyst and protection of the
hydroxyl group. For the gem-disubstituted terminal olefins
10d and 10e, catalyst 8b was required for RCM (entries
4-6). The attempted ring closure of the cyclohexyl derivative
10f [R2-R3) (CH2)4, entry 7] failed completely, lengthy
reaction in refluxing benzene bringing about metathetic
dimerization. These results show that formation of the eight-
Figure 3. The proposed tandem metathesis approach.
Although there was no precedent for the formation of a
[6.4.0] bicycle by RCM of dienynes,18 the observed readiness
of 10a, 10d, and 10e to form the eight-membered ring led
us to expect that intramolecular enyne metathesis of carbene
12b would give the first ring plus the regenerated carbene
(13) Bromide 5 was prepared in 81% yield by treatment of alcohol 4
with triphenylphosphine and carbon tetrabromide in dichloromethane.
(14) Scholl, M.; Ding, S.; Lee, C. W.; Grubbs, R. H. Org. Lett. 1999, 1,
953-956.
(15) (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.
(16) (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, D. L.; Garrat, S.; Fawcet, J.; Russell, D. R.; Ghosh, S. Angew.
Chem., Int. Ed. 1998, 37, 3298-3300. (c) 1, 2-cis disubstituted cyclopentane
derivatives were 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.
(17) (a) Kim, S.-H.; Bowden, N.; Grubbs, R. H. J. Am. Chem. Soc. 1994,
116, 10801-10802. (b) Kim, S.-H.; Zuercher, W. J.; Bowden, N. B.;
Grubbs, R. H. J. Org. Chem. 1996, 61, 1073-1081. (c) Zuercher, W. J.;
Scholl, M.; Grubbs, R. H. J. Org. Chem. 1998, 63, 4291-4298. (d) Fu¨rstner,
A.; Liebl, M.; Hill, A. F.; Wilton-Ely, J. D. E. T. Chem. Commun. 1999,
601-602.
(18) For recent eight-membered heterocycle ring formation using enyne
metathesis, see: Mori, M.; Kitamura, T.; Sakakibara, N.; Sato, Y. Org.
Lett. 2000, 2, 543-545.
Org. Lett., Vol. 3, No. 10, 2001
1485

13 and that a second diene RCM of 13 would produce ring
A. The methyl group on the terminal olefin was expected to
favor formation of the eight-membered ring by starting the
process at the monosubstituted double bond.
The iodide needed for enolate alkylation, 17, was prepared
from 5-hexyn-1-ol in four steps (Scheme 2). After alkyne
enolate of 3b (formed by reaction with potassium hexa-
methyldisilazide in 1:1 DMF/toluene at -80 °C).20 Subse-
quent desilylation with TBAF followed by allylation of the
ketone group furnished dienyne 12a in 53% yield (three
steps) as an inseparable 1:1 diastereomeric mixture. In this
case, dienyne RCM of 12a with 15% of ruthenium carbene
8a did indeed take place to render the desired tetracyclic
system 1 (48%), showing the feasibility of this new tandem
process.
Scheme 2a
In conclusion we have shown for the first time that [6.4.0]
systems can be constructed by tandem ring-closing metathesis
of dienynes, in which formation of the all-carbon cyclooctane
ring by enyne RCM is followed by closure of the six-
membered ring by olefin RCM. It is envisaged that this
approach should allow access to general linear 6-8-n fused
systems starting from conformationally locked n-membered
cycloalkanones. We are currently extending it to the synthesis
of potential haptens I with a view to their use to elicit
catalytic antibodies.
Acknowledgment. Financial support from Ministerio de
Educacio´n y Ciencia (PB97-0524) and Xunta de Galicia
(PGIDT99PX120904B) is gratefully acknowledged. We also
thank to Profs. A. Mourin˜o (University of Santiago de
Compostela), D. Hilvert (ETH), and S. Blechert (Technische
Universita¨t Berlin) for helpful discussions and Xunta de
Galicia for a fellowship awarded to E.M.C.
a (a) (i) n-BuLi, THF, TMSCl, (ii) AcOH, 97%; (b) PDC, CH2Cl2,
72%; (c) Ph3PCH2CH3+Br-, n-BuLi, THF, 0 °C, 88%; (d) n-BuLi,
ethylene oxide, THF, 28%; (e) I2, PPh3, imidazole, 75%; (f) (i)
KHMDS, 17, DMF/toluene (1:1), -80 °C; (ii) TBAF, THF, 65%
(two steps); (g) allylMgBr, THF, -80 °C, 82%; (h) 8a, CH2Cl2,
4, 48%, 6.5:1 diastereomeric mixture at C10.
Supporting Information Available: Experimental pro-
cedure and 1H and 13C NMR spectra of compounds 11a, 11d,
11e, 17, 12a, and 1. This material is available free of charge
via the Internet at http://pubs.acs.org.
silylation of 5-hexyn-1-ol by treatment with 2 equiv of
n-BuLi, followed by trapping of the resulting dianion with
trimethylsilyl chloride and washing with acetic acid to
remove the trimethylsilyloxy group, oxidation of the resulting
alcohol with PDC afforded aldehyde 14. Wittig alkenation
of 14 provided enyne 15, and the propargyl carbanion of
15, formed by deprotonation with n-BuLi, was alkylated with
ethylene oxide at 0 °C to obtain alcohol 16,19 which was
converted to iodide 17 by treatment with triphenylphosphine,
imidazole, and iodide. Iodide 17 was reacted with the kinetic
OL0158011
(19) Harris, G. D.; Herr, R. J.; Weinreb, S. M. J. Org. Chem. 1993, 58,
5452-5464.
(20) These reaction conditions were kindly suggested by Prof. Claudio
Palomo (Univ. Pa´ıs Vasco), who developed them in his studies of
asymmetric alkylations.
1486
Org. Lett., Vol. 3, No. 10, 2001