Synthesis of spiro[4.5]decane CF-ring analogues of 1α,25- dihydroxyvitamin D3

Article abstract of DOI:10.1021/ol061575p

(Chemical Equation Presented) A novel series of analogues of calcitriol (1) is developed featuring a spirocyclic central core resulting from C18/C21-connection and C15/ C16-deletion (2a, 2b). The synthesis of the key intermediate involves an Eschenmoser r

Full text of DOI:10.1021/ol061575p

ORGANIC
LETTERS
2006
Vol. 8, No. 19
4247-4250
Synthesis of Spiro[4.5]decane CF-Ring
Analogues of 1 ,25-Dihydroxyvitamin D3
r
Wim Schepens,† Dirk Van Haver,† Maurits Vandewalle,† Roger Bouillon,‡
Annemieke Verstuyf,‡ and Pierre J. De Clercq*,†
Department of Organic Chemistry, Ghent UniVersity, Krijgslaan 281,
B-9000 Gent, Belgium, and Laboratory of Experimental Medicine and Endocrinology,
Catholic UniVersity of LeuVen, Gasthuisberg, Herestraat 49, B-3000 LeuVen, Belgium
pierre.declercq@UGent.be
Received June 27, 2006
ABSTRACT
A novel series of analogues of calcitriol (1) is developed featuring a spirocyclic central core resulting from C18/C21-connection and C15/
C16-deletion (2a, 2b). The synthesis of the key intermediate involves an Eschenmoser rearrangement of an enantiomerically pure bromo-
substituted cyclohexenol.
1R,25-Dihydroxyvitamin D3 (1, calcitriol), the hormonally
active metabolite of vitamin D3, has been shown to inhibit
cellular proliferation and to induce cellular differentiation,
next to its classical calciotropic activity.1 Its therapeutic utility
is, however, limited for effective doses leading to calcemic
side effects. This has originated in a search for structural
analogues of 1 that show a separation in calcemic and
antiproliferative-prodifferentiating activities.2,3
One may distinguish three different parts in the structure
of 1: a central rigid CD-bicyclic entity to which are
connected at C-20 and at C-8 two flexible portions, the side
chain and the seco-B,A-ring system, respectively (Figure 1).
For more than a decade our laboratories have focused on
the development of nonsteroidal analogues possessing struc-
tural modifications in the central part of the molecule.4 In
the present work we report on the synthesis of spirocyclic
CF-ring analogues 2a and 2b featuring a spiro[4.5]decane5
to which are attached (i) the classical side chain in the two
epimeric configurations at C-206 and (ii) the 19-nor modified
seco-B,A-ring at C-8.7 The two epimeric configurations at
C-20 are relevant in that molecular modeling studies have
shown the prodifferentiating activity to be dependent in
certain cases on the preferred spatial orientation of the side
(4) (a) Bouillon, R.; Verlinden, L.; Eelen, G.; De Clercq, P.; Vandewalle,
M.; Mathieu, C.; Verstuyf, A. J. Steroid Biochem. Mol. Biol. 2005, 97,
21-30. (b) Chen, Y.-J.; Gao, L.-J.; Murad, I.; Verstuyf, A.; Verlinden, L.;
Verboven, C.; Bouillon, R.; Viterbo, D.; Milanesio, M.; Van Haver, D.;
Vandewalle, M.; De Clercq, P. J. Org. Biomol. Chem. 2003, 1, 257-267,
and references therein. (c) Bouillon, R.; Vandewalle, M.; De Clercq, P. J.,
patent PCT Int. Publ. No. WO 95/01960 (1995); CAN 122: 314933.
(5) For spiro[5.5]undecane analogues, see: Schepens, W.; Van Haver,
D.; Vandewalle, M.; De Clercq, P. J.; Bouillon, R.; Verstuyf, A. Bioorg.
Med. Chem. Lett. 2004, 14, 3889-3892.
(6) Epimerization at C-20 often generates analogues with enhanced
biological activity, see: Binderup, L.; Latini, S.; Binderup, E.; Bretting,
C.; Calverley, M.; Hansen, K. Biochem. Pharmacol. 1991, 42, 1569-1575.
(7) Removal of C-19 usually leads to a reduction of calcemic activity,
see: Perlman, K. L.; Sicinski, R. R.; Schnoes, H. K.; DeLuca, H. F.
Tetrahedron Lett. 1990, 31, 1823-1824.
† Ghent University.
‡ Catholic University of Leuven.
(1) (a) Proceedings of the 12th Workshop on Vitamin D: Bouillon, R.;
Norman, A. W.; Pasqualini, J. R., Eds. J. Steroid Biochem. Mol. Biol. 2004,
89-90, 1-633, and the previous 11 volumes in this series. (b) Vitamin D;
Feldman, D., Glorieux, F. H., Eds.; Academic Press: San Diego, CA, 1997;
1285 pages.
(2) (a) Nagpal, S.; Na, S.; Rathnachalam, R. Endocr. ReV. 2005, 26, 662-
687. (b) Bouillon, R.; Okamura, W. H.; Norman, A. W. Endocr. ReV. 1995,
16, 200-257.
(3) (a) Posner, G. H.; Kahraman, M. Eur. J. Org. Chem. 2000, 3889-
3895. (b) Zhu, G.-D.; Okamura, W. H. Chem. ReV. 1995, 95, 1877-1952.
(c) Dai, H.; Posner, G. H. Synthesis 1994, 1383-1398.
10.1021/ol061575p CCC: $33.50
© 2006 American Chemical Society
Published on Web 08/24/2006

chain.4b,8 Deletion of C-19 on the other hand prevents the
[1,7]-sigmatropic hydrogen shift typical of the vitamin-
Figure 3. Key intermediates in the synthesis of 2a and 2b.
appendage of the seco-B,A-ring.10 The two epimeric alcohols
3a and 3b are obtained from the enantiopure cyclohexene
derivative (S)-4. It is noteworthy that (()-4 was used
previously in the synthesis of 22-oxa-spiro[5.5]undecane CF-
ring analogues.5,11 We will further distinguish three stages
in the synthesis: (i) the enantioselective synthesis of the
spirocyclic enone (-)-4 (Scheme 1); (ii) its conversion
into epimers (+)-16a and (+)-16b (Scheme 2); and (iii)
their eventual transformation into 2a and 2b, respectively
(Scheme 4).
Figure 1. Spirocyclic CF-ring analogues 2a and 2b.
The major challenge in the synthesis of spirocyclic (-)-4
resides in the asymmetric synthesis of the stereogenic
quaternary spirocenter.12,13 In this work this is realized via
the Eschenmoser [3,3]-sigmatropic rearrangement of bro-
mocyclohexenol (+)-7 to amide (-)-9.14 Subsequently, the
spiro ring system was obtained via Dieckmann cyclization.13
The required enantiopure allylic alcohol (+)-7 was obtained
through CBS (Corey-Bakshi-Shibata) reduction of the
corresponding enone 6.15 Functional group manipulation of
(-)-9 led to diester (-)-12, which after Dieckmann cycliza-
tion and demethoxycarbonylation gave (-)-4. Although
somewhat lengthy, 9 steps from the known bromocyclohex-
enone 5,16 the overall yield is satisfactory (44%) and the
sequence is suitable for large-scale preparation.
previtamin equilibrium, which in the absence of the natural
trans-fused CD-ring system would favor the more substituted
previtamin form (Figure 2).9
The presence of the bromo substituent was crucial for the
successful completion of the sequence: (i) by enhancing the
(10) (a) Baggiolini, E. G.; Iacobelli, J. A.; Hennessy, B. M.; Batcho, A.
D.; Sereno, J. F.; Uskokovic, M. R. J. Org. Chem. 1986, 51, 3098-3108.
(b) Lythgoe, B.; Moran, T. A.; Nambudiry, M. E. N.; Ruston, S.; Tideswell,
J.; Wright, P. W. J. Chem. Soc., Perkin Trans. 1 1978, 590-595.
(11) For previous syntheses of racemic 4, see: (a) Godleski, S. A.;
Valpey, R. S. J. Org. Chem. 1982, 47, 381-384. (b) Trost, B. M.;
Murayama, E. J. Am. Chem. Soc. 1981, 103, 6529-6530.
(12) For examples of the enantioselective construction of quaternary
stereogenic carbon centers, see: (a) Breit, B.; Demel, P.; Studte, C. Angew.
Chem., Int. Ed. 2004, 43, 3786-3789. (b) Christoffers, J.; Mann, A. Angew.
Chem., Int. Ed. 2001, 40, 4591-4597. (c) Corey, E. J.; Guzman-Perez, A.
Angew. Chem., Int. Ed. 1998, 37, 388-401. (d) Fuji, K. Chem. ReV. 1993,
93, 2037-2066.
Figure 2. The vitamin-previtamin equilibrium.
The key intermediates involved in the synthesis of
analogues 2a and 2b are shown in Figure 3. Analogues 2a
and 2b are accessed from 3a and 3b, respectively. The
hydroxymethyl group at C-20 allows for the introduction of
the side chain,3b the carbonyl at C-8 for Wittig-Horner
(8) (a) Gabrie¨ls, S.; Van Haver, D.; Vandewalle, M.; De Clercq, P.;
Verstuyf, A.; Bouillon, R. Chem. Eur. J. 2001, 7, 520-532. (b) Zhou, X.;
Zhu, G.-D.; Van Haver, D.; Vandewalle, M.; De Clercq, P. J.; Verstuyf,
A.; Bouillon, R. J. Med. Chem. 1999, 42, 3539-3556. (c) Van Haver, D.;
De Clercq, P. J. Bioorg. Med. Chem. Lett. 1998, 8, 1029-1034. (d) Yamada,
S.; Yamamoto, K.; Masuno, H.; Ohta, M. J. Med. Chem. 1998, 41, 1467-
1475.
(9) (a) Bouillon, R.; Sarandeses, L. A.; Allewaert, K.; Zhao, J.;
Mascaren˜as, J. L.; Mourin˜o A.; Vrielynck, S.; De Clercq, P.; Vandewalle,
M. J. Bone Miner. Res. 1993, 8, 1009-1015. (b) Havinga, E. Experientia
1973, 29, 1181-1193.
(13) For the synthesis of spirocyclic systems, see: (a) Pradhan, R.; Patra,
M.; Behera, A. K.; Mishra, B. K.; Behera, R. K. Tetrahedron 2006, 62,
779-828. (b) Sannigrahi, M. Tetrahedron 1999, 55, 9007-9071.
(14) For a sequential Claisen/ring-closing metathesis approach to spi-
rocyclic cyclopentanes and cyclohexanes, see: Beaulieu, P.; Ogilvie, W.
W. Tetrahedron Lett. 2003, 44, 8883-8885.
(15) (a) He, F.; Bo, Y.; Altom, J. D.; Corey, E. J. J. Am. Chem. Soc.
1999, 121, 6771-6772. (b) Corey, E. J.; Helal, C. J. Angew. Chem., Int.
Ed. 1998, 37, 1986-2012.
(16) Hara, R.; Furukawa, T.; Kashima, H.; Kusama, H.; Horiguchi, Y.;
Kuwajima, I. J. Am. Chem. Soc. 1999, 121, 3072-3082.
4248
Org. Lett., Vol. 8, No. 19, 2006

and (-)-8, which showed diagnostic chemical shift differ-
ences for the olefinic protons (Figure 4).20
Scheme 1
Figure 4. 1H NMR stereochemical assignment of enantiomeric
alcohols (+)-8 and (-)-8.
The further conversion of spirocyclic enone (-)-4 into the
epimeric alcohols (+)-16a and (+)-16b is shown in Scheme
2. After acetal protection of (-)-4 (95% yield), the cyclo-
Scheme 2
prochiral nature of the carbonyl group in enone 6, a very
high enantiomeric excess (>98%) is achieved upon CBS
reduction with (S)-methyloxazaborolidine as catalyst (0.2
equiv) and catecholborane as reducing agent (-95 °C,
toluene; 97% yield);17 (ii) by stabilizing the cyclohexenol
moiety, both racemization and elimination upon [3,3]-
sigmatropic rearrangement are prevented.14,15a,18 Upon chro-
matographic purification of (+)-8, obtained by debromination
of (+)-7 (t-BuLi, -50 °C), some racemization was observed
that was found to be induced by neighboring group participa-
tion of the ether oxygen of the methoxybutyl group. The
latter participation is prevented by the presence of Br in (+)-
7, probably for both steric and electronic reasons. Since
elimination was observed upon acid-catalyzed ortho ester
Claisen type rearrangement, the Eschenmoser variant with
N,N-dimethylacetamide dimethyl acetal in refluxing toluene
was applied instead (95% yield).19 Under the neutral condi-
tions of the process no racemization was observed.
hexene ring in (-)-14 is oxidatively cleaved (ozone, metha-
nol; (MeO)3P workup) and the resulting dialdehyde is directly
subjected to intramolecular aldol condensation (dibenzylam-
monium trifluoroacetate) yielding ring-closed unsaturated
aldehyde (-)-15 (72% yield). Upon catalytic hydrogenation
of the latter a 1:1 mixture of the desired alcohols (+)-16a
and (+)-16b (88% yield) is obtained, which can be separated
by HPLC.
Since the structural assignment of (+)-16a and (+)-16b
The expected (R)-configuration of alcohol (+)-7 following
the well-established transition state model of the CBS
reduction was further confirmed by 1H NMR analysis of the
diastereomeric MPA esters obtained from (S)-R-methoxy-
phenylacetic acid and the two enantiomeric alcohols (+)-8
1
was not successful by H NMR, we devised a chemical
sequence to assign unequivocally the epimeric structures
(Scheme 3). Both epimers (+)-3a and (+)-3b, obtained after
acid hydrolysis of (+)-16a and (+)-16b, respectively, were
subjected to the following sequence: (i) Baeyer-Villiger
oxidation, followed by transesterification of the resulting
seven-membered lactones to yield a mixture of methyl esters
17 and 18 (ratio 8:2), which was separated by HPLC. Upon
(17) Corey, E. J.; Bakshi, R. K. Tetrahedron Lett. 1990, 31, 611-614.
(18) For examples of Claisen related rearrangements on 2-bromocyclo-
hexenol derivatives, see: (a) Hudlicky, T.; Oppong, K.; Duan, C.; Stanton,
C.; Laufersweiler, M. J.; Natchus, M. G. Bioorg. Med. Chem. Lett. 2001,
11, 627-629. (b) Jackson, R. W.; Shea, K. J. Tetrahedron Lett. 1994, 35,
1317-1320.
(20) Trost, B.; 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.
(19) Felix, D.; Gschwend-Steen, K.; Wick, A. E.; Eschenmoser, A. HelV.
Chim. Acta 1969, 52, 1031-1042.
Org. Lett., Vol. 8, No. 19, 2006
4249

the side chain is realized via Ni(0) catalyzed oxidative
addition of iodide (+)-21a (obtained from (+)-16a in two
steps) to ethyl acrylate,21 an efficient method introduced by
Mourin˜o in the vitamin D field.22 Subsequently, Grignard
reaction followed by acid hydrolysis leads to spirocyclic
ketone (+)-22a (57% overall). The final Lythgoe coupling
of the A-ring is performed by using the known phosphine
oxide 2423 and trimethylsilyloxy protected 23a (obtained
from (+)-22a and trimethylsilylimidazole). After silyl ether
deprotection a 3:1 mixture of desired 2a and the correspond-
ing (Z)-isomer 25a is obtained (68% yield). Both isomers
could be separated after repeated HPLC purification. The
identification of the major isomer as (E)-derivative 2a and
Scheme 3
1
the minor isomer as (Z)-derivative 25a rests on H NMR
COSY and NOE measurements, which were performed on
both isomers. A comparable result was obtained when the
sequence was performed starting with epimeric alcohol (+)-
16b (not shown), which eventually led to the isolation of
the desired (E)-analogue 2b and its (Z)-isomer 25b (ratio
3:1, respectively; 85% yield).
Following the same strategy as described above another
series of stereoisomeric analogues was obtained from (+)-
(R)-4 as key intermediate. Although the synthetic approach
is not stereoselective (cf. hydrogenation of 15 and A-ring
coupling), hence reducing the overall yield, it allows for the
preparation of several analogues, the biological evaluation
of which will be reported in a full account.24
Fetizon oxidation of the major 1,5-diol (+)-17b obtained in
the b-series a separable mixture (HPLC) of two γ-lactones
(-)-19 and (+)-20 (87%; ratio 85:15) was formed.
The final conversion of spirocyclic alcohols (+)-16a and
(+)-16b into analogues 2a and 2b follows the sequence that
is shown for the a-series in Scheme 4. The introduction of
Acknowledgment. Financial assistance of the FWO-
Vlaanderen” (project G.0150.02, G.0036.00) is gratefully
acknowledged. W.S. thanks the IWT and the FWO-Vlaan-
deren for a scholarship.
Scheme 4
Supporting Information Available: Experimental pro-
cedures and full characterization of all intermediates and
1R,25(OH)2D3 analogues 2a, 2b, 25a, and 25b. This material
is available free of charge via the Internet at http://pubs.acs.org.
OL061575P
(21) Sustmann, R.; Hopp, P.; Holl, P. Tetrahedron Lett. 1989, 30, 689-
692.
(22) Mascaren˜as, J. L.; Pe´rez-Sestelo, J.; Castedo, L.; Mourin˜o, A.
Tetrahedron Lett. 1991, 32, 2813-2816.
(23) Perlman, K. L.; Swenson, R. E.; Paaren, H. E.; Schnoes, H. K.;
DeLuca, H. F. Tetrahedron Lett. 1991, 32, 7663-7666.
(24) For bridged 1R,25(OH)2D3 analogues with an intact D-ring, but a
connection between positions 18 and 20, see: (a) Cornella, I.; Pe´rez-
Sestelo, J.; Mourin˜o, A.; Sarandeses, L. A. J. Org. Chem. 2002, 67, 4707-
4714. (b) Varela, C.; Nilsson, K.; Torneiro, M.; Mourin˜o, A. HelV. Chim.
Acta 2002, 85, 3251-3261.
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