Toward an analogue of the transition state of preD3-D3 isomerization: Stereoselective synthesis of linearly fused 6-8-6 carbocyclic systems

Article abstract of DOI:10.1021/ol025756c

Matrix presented A stereoselective synthesis of 6-8-6 fused carbocyclic systems based on enol alkylation, ketone allylation, RCM, and Heck cyclization was developed to obtain compounds with a carbon framework that mimics the putative transition structure of the isomerization of previtamin D₃ to vitamin D₃.

Full text of DOI:10.1021/ol025756c

ORGANIC
LETTERS
2002
Vol. 4, No. 10
1651-1654
Toward an Analogue of the Transition
State of PreD −D Isomerization:
3
3
Stereoselective Synthesis of Linearly
Fused 6-8-6 Carbocyclic Systems1
Eva M. Codesido, J. Ramo´n Rodr´ıguez, 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, 15782 Santiago de Compostela, Spain
qojuangg@usc.es
Received February 21, 2002
ABSTRACT
A stereoselective synthesis of 6-8-6 fused carbocyclic systems based on enol alkylation, ketone allylation, RCM, and Heck cyclization was
developed to obtain compounds with a carbon framework that mimics the putative transition structure of the isomerization of previtamin D
3
to vitamin D .
3
Interest in polycyclic systems containing an eight-membered
ring stems both from the synthetic challenge associated with
their construction and from the wide-ranging biological
activities of many such compounds.2 We have recently
embarked on the preparation of 6-8-6 fused carbocyclic
systems with a view to obtaining steroid-like compounds of
type I (Figure 1),3 which as Figure 2 shows in the case of
Ib, mimic [1,7]-H TS, the putative cyclic transition state of
the isomerization4 of previtamin D3 (preD3) to vitamin D3
(D3) (note in particular the good match between the C3
hydroxy groups, the CD bicyclic systems, and the diene
systems). Our hope is that understanding of the mechanism
of this transformation may be furthered by study of the active
sites of isomerization-catalyzing antibodies raised against
compounds of this type.6 As locked 6-s-cis analogues of 1R,-
(1) This paper is partially based on the doctoral thesis of Eva Mar´ıa
Codesido, University of Santiago de Compostela, 2001.
(5) 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) For reviews, see: (a) Oishi, T.; Ohtsuka, Y. In Studies in Natural
Products Synthesis; Atta-ur-Rahman, Ed.; Elsevier: Amsterdam, 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.
(6) 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.
(7) The biological functions of the hormonally active form of D3, 1R,-
25-dihydroxyvitamin D3,5 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.
(3) Codesido, E. M.; Castedo, L.; Granja, J. R. Org. Lett. 2001, 3, 1483-
1486.
(4) This isomerization, one of two successive pericyclic reactions in the
photobiogenesis of vitamin D3 (Figure 1),5 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.
10.1021/ol025756c CCC: $22.00 © 2002 American Chemical Society
Published on Web 04/24/2002

Figure 1. Putative mechanism of the [1,7] sigmatropic hydrogen
shift of PreD3-D3 isomerization and the structure of the [1,7]-H
TS analogues I.
Figure 3. The synthetic approaches to 1 and 2 investigated in this
work.
cyclization. The RCM precursors 4 and 6 would be easy to
prepare by stereoselective alkylation and allylation of Grund-
mann’s ketone (7).14 Here we present the results of our
preliminary studies of these approaches, which show that
the second strategy (via 6 and 5) has substantial potential
for stereoselective construction of complex polycyclic frame-
works.
We initially aimed at compound 1 because of the presumed
ease of obtaining precursor 4 from 7 and the allyl bromide
derived from the known alcohol 8 (Scheme 1).13 Following
formation of the 12-membered ring by RCM of triene 4, a
subsequent intramolecular Heck reaction ought to produce
the 6-8 fused bicyclic system of 1 because of the usual
preference for 6-exo cyclization of Heck reactions.12,15 As
expected, alkylation of the kinetic enolate of 7 (formed by
LDA treatment at -78 °C) with bromide 9, followed by
allylation of the resulting ketone, gave alcohol 4.16 However,
Figure 2. The polycyclic system Ib (blue) superimposed on the
putative transition state structure of the PreD3-D3 isomerization
reaction ([1,7]-H TS, yellow).
25-(OH)2-D3,7-9 vitamin D analogues with this central eight-
membered ring might also be useful for studying nongenomic
vitamin D responses.
(10) For reviews of metathesis, see: (a) Fu¨rstner, A. Angew. Chem., In.
Ed. 2000, 39, 3012-3043. (b) Chang, S.; Grubbs, R. H. Tetrahedron 1998,
54, 4413-4450. For a recent view of the synthesis of medium-sized rings
by RCM, see: (c) Maier, M. E. Angew. Chem., Int. Ed. 2000, 39, 2073-
2077. For a more general review of the synthesis of medium-sized rings,
see: (d) Yet, L. Chem. ReV. 2000, 100, 2963-3007.
As potentially fast, versatile approaches to I that might
allow the introduction of further functional groups, we set
out to evaluate the strategies shown in Figure 3, both of
which are based on an RCM10 reaction forming the C5-
C611 double bond and an intramolecular Heck12 cyclization
for construction of ring A.13 We envisaged that in both cases
the initial RCM would involve the less substituted double
bonds, producing the appropriate precursor for the final Heck
(11) For convenience, steroid numbering is used.
(12) For recent uses of intramolecular Heck reactions for the construction
of 6-7 fused 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, 1998;
Chapter 6. (d) de Meijere, A.; Meyer, F. E. In Metal-Catalyzed Cross-
Coupling Reactions; Diederich, F., Stang, P. J., Eds.; Wiley-VCH: Wein-
heim, 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.
(8) The involvement of a preD3 h D3 type of equilibrium in nongenomic
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.; Hammond, M. W.; Rahman, N. A.;
Dormanen, M. C.; Nemere, I. Ann. N.Y. Acad. Sci. 1995, 761, 344-348.
(9) While this manuscript was under revision the synthesis of an analogue
of 1R,25-(OH)2-D3 bearing an eight-membered ring B has been published:
Hayashi, R.; Ferna´ndez, S. Okamura, W. H. Org. Lett. 2002, 4, 851-854.
(13) Preliminary studies had shown the viability of the Heck cyclization
of iododiene 8; see: Codesido, E. M.; Cid, M. M.; Castedo, L.; Mourin˜o,
A.; Granja, J. R. Tetrahedron Lett. 2000, 41, 5861-5864.
(14) Mascaren˜as, J. L.; Sarandeses, L.; Castedo, L.; Mourin˜o, A.
Tetrahedron 1991, 47, 3485-3498.
(15) Owczarczyk, Z.; Lamaty, F.; Vawter, E. J.; Neghisi, E.-i. J. Am.
Chem. Soc. 1992, 114, 10091-10092.
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Org. Lett., Vol. 4, No. 10, 2002

metalation of the silyl ether, and entrapment of the alkynyl-
lithium with p-formaldehyde, the resulting propargyl alcohol
was semihydrogenated to compound 12 in 63% overall yield.
Condensation with butyl vinyl ether in the presence of Hg-
(OAc)2, followed by Claisen rearrangement and in situ
reduction with sodium borohydride, provided alcohol 13a
in 69% yield from 12. After exposure of this alcohol to
triphenylphosphine, imidazole, and iodine, the resulting
iodide 13b was reacted with the kinetic enolate of 7 (formed
by reaction with potassium hexamethyldisilazide in 1:1 DMF/
toluene at -80 °C),18 and the resulting ketone was allylated,
giving diene 14 in 59% yield (from 7) as an inseparable 1:1
mixture of C10-epimers.
Scheme 1a
RCM of 14 with catalyst 10a (20%) was successful though
slow, the cyclooctene derivatives 15a and 15b being obtained
in 95% overall yield as an inseparable mixture after 1 week
in refluxing CH2Cl2. The use of benzene or the more reactive
catalyst 10b did not significantly decrease the reaction time,
which was much longer than in previous RCM assemblies
of eight-membered rings in similar systems.3 Clearly, the
additional substituents at the allyl position slow the reaction
regardless of the stereochemistry at C10.19 Fortunately, after
deprotection of 15a/15b with tetrabutylammonium fluoride,
the resulting alcohols 16a and 16b were easily separated,
although it was not possible to establish the configuration
of these compounds at C10 by NMR experiments.
a (a) Reference 13; (b) PPh3, CBr4, CH2Cl2, 89%; (c) LDA, 9,
THF, -78 °C, 42%; (d) allylMgBr, THF 85%; (e) 10a, CH2Cl2,
∆, 70%.
when this compound was subjected to RCM conditions using
Grubbs’ catalyst (10a) or 10b,17 instead of 3 we obtained
only compound 11, formation of the six-membered ring
having prevailed over macrocyclization even though it
involved reaction with the more substituted olefin.
We therefore turned to the second approach, focusing on
the preparation of compound 2 (Figure 3). The key step here
had initially been envisaged as formation of the central eight-
membered ring by RCM of triene 6, but in view of the
unexpected cyclization behavior of 4 we decided to install
the vinyliodide moiety only after the RCM (Scheme 2). As
Oxidation of isomer 16a with PCC and subsequent
olefination by Stork’s method20 produced the (Z)-vinyl iodide
17 in 72% yield (Scheme 3). Heck reaction using palladium
Scheme 3a
Scheme 2a
a (a) PCC, CH2Cl2, (56% from 16a, 66% from 16b); (b) Ph3P+
CH2I I-, NaHMDS, THF, (72% for 17, 70% for 20); (c) Pd(PPh3)4,
CH3CN, ∆, (15% for 19, 64% for 21).
a (a) TBSCl, Im, CH2Cl2, 92%; (b) nBuLi, THF, (H2CO)n, 82%;
(c) H2/Lindlar, hexanes, 83%; (d) CH2dCHOBu, Hg(OAc)2, 160
°C; (e) NaBH4, MeOH, 69% (from 12); I2, PPh3, Im, 76%; (f)
KHMDS, 13b, DMF/toluene (1:1), -80 °C, 72%; (g) allylMgBr,
THF 82%; (h) 10a, CH2Cl2, ∆, 6 days, 95%; (j) TBAF, THF, 87%.
tetrakistriphenylphosphine in refluxing acetonitrile for 2 h
yielded compound 19 as a single isomer, but in only 15%
(17) Scholl, M.; Ding, S.; Lee, C. W.; Grubbs, R. H. Org. Lett. 1999, 1,
953-956.
(18) Palomo, C.; Oiarbide, M.; Mielgo, A.; Gonza´lez, A.; Garc´ıa, J.;
Landa, C.; Lecumberri, A.; Linden, A. Org. Lett. 2001, 3, 3249-3252.
(19) The 15a/15b 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.
alkylating agent we therefore synthesized iodide 13b from
4-pentyn-1-ol. After protection of 4-pentyn-1-ol with TBSCl,
(16) The relative stereochemistry of 4 was determined by NOE experi-
ments as in ref 3.
Org. Lett., Vol. 4, No. 10, 2002
1653

yield, the major product being the protonated compound 18
(>40% yield). Other catalyst systems did not improve the
reaction yield. The relative stereochemistry 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 triplet21 with
a J value of 9.3 Hz, which in cyclohexanes is characteristic
of trans axial-axial orientation. The R configuration of C10
was established when a substantial cross-peak between H14
and H5 in a NOESY experiment showed them to be cis to
each other.
6-8-n fused systems starting from n-membered cycloal-
kanones. We are currently completing the route to potential
haptens I with a view to employing them to elicit catalytic
antibodies.
Acknowledgment. Financial support from Ministerio de
Educacio´n y Ciencia and the Xunta de Galicia under projects
PB97-0524 and PGIDT99PX120904B, respectively, is grate-
fully acknowledged. E.M.C. also thanks the Xunta de Galicia
and the University of Santiago for a fellowship.
Finally, oxidation and olefination of the second of the
isomeric alcohols, 16b, afforded (Z)-vinyl iodide 20 in 70%
yield, and intramolecular Heck reaction of this compound
gave, as the only product, a 64% yield of the trans-bicyclo
compound 21, the relative stereochemistry of which was
shown by an NOE enhancement between H5 and H9
suggestive of a cis relationship and an H5-H10 coupling
constant of 9.3 Hz indicating trans axial-axial orientation
(Scheme 3). Compound 21 is the isomer required for
preparation of the transition state analogue 22.
In conclusion, we have shown that tricyclo[10.4.0.04,9]-
hexadecane systems can be stereoselectively constructed by
appropriately combining enol alkylation,22 ketone allylation,23
RCM, and Heck cyclization. Whether the 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.24 It is
envisaged that this approach will allow access to general
Supporting Information Available: Experimental pro-
1
cedures and H and 13C NMR spectra of compounds 13a,
16a, 16b, 17, and 19-21. This material is available free of
charge via the Internet at http://pubs.acs.org.
OL025756C
(22) 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, 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,
1999; Chapter 34.2.
(23) 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.
(24) 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.
(20) Stork, G.; Zhao, K. Tetrahedron Lett. 1989, 30, 2173-2174.
(21) H4-H5 coupling was close to zero.
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Org. Lett., Vol. 4, No. 10, 2002