Synthesis of 23-oxa-calcitriol derivatives

Article abstract of DOI:10.1016/S0040-4039(00)93431-2

A convenient synthetic strategy leading to 23-oxa-calcitriol and 23-oxa-10,19-methylene-calcitriol is disclosed.

Full text of DOI:10.1016/S0040-4039(00)93431-2

Tetrahedron Letters, Vo1.32, No.38, pp 5073-5076, 1991
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SYNTHESIS OF 23-OXA-CALC1TRIOL DERIVATIVES
Gtinter Neef* and Andreas Steinmeyer
Research Laboratories of Schering AG,
D-1000 Berlin 65, Germany
Summary: A convenient synthetic strategy leading to 23-oxa-calcitriol
and 23-oxa-lO,19-methylene-calcitriol is disclosed.
In recent years it has become evident that calcitriol (lct,25-dihydroxy-vitamin D3), besides
acting as a regulator of calcium homeostasis, exerts potent effects upon cell proliferation
and cell differentiation 1). A number of chemically modified calcitriols 2) have been
claimed to show dissociation of effects making these derivatives potentially valuable
drugs in the treatment of psoriasis 3) and cancers4) without the risk of hypercalcemia.
Although the mechanism of dissociation is not always clearly recognizable, the possibility
of separating the various effects of calcitriol has enormously stimulated chemical
activities in the vitamin D area.
We wish to report the synthesis of two calcitriol derivatives as a contribution to the
ongoing efforts of establishing structure-activity relations in the vitamin D series.
"'"
" ; ' r " ' o ' " - < "
" ; " r " ' o " ' , < "
o
°io
Caleitriol
1
_2
The calcitriol side chain is known to be the major site of metabolic attack 5).
Consequently, a great deal of work was concentrated upon side chain variations resulting
in the discovery of potent analogues 6).
Replacement of a methylene group by an oxygen atom has often proven a successful
strategy to modify a biologically active molecule without provoking dramatic structural
changes7). Therefore, a 23-oxa calcitriol could be expected to retain receptor affinity.
Assuming 24-hydroxylation to be the first degradative step of metabolism as in the natural
compound, a hemiacetal situation, highly unstable in an aqueous medium, would result
possibly giving rise to differences in biological action.
With this concept in mind, we began to look for synthetic strategies that would lead us to
compounds 1 and 2. Though a 23-oxa side chain was found to be part of several general
patent claims 8), only one experimental procedure was detected describing nucleophilic
5073

5074
opening of 1,2-epoxy-2-methyl-propane with the alcohol 3_ Sa). As we were unable to
reproduce the patent result, we turned our attention to a process successfully applied in the
prostacyclin series. Skuballa 9) found that the well-known problems associated with the
use of b r o m o acetates as O-alkylating agents can be overcome by reacting an alcohol with
tert.-butyl bromo acetate under phase transfer conditions. The viability of this key step
being ascertained we could synthesize compound I without difficulty (scheme I).
0
COOt.-butyl
OH
.{A
~
,
I
I
i4_
-
3
O~"~OH
0~'~OH
~
~
1
t_
5__
The starting material 3_ is conveniently accessible by the route recently described in detail
by Calverley 10). Phase-transfer alkylation (t.-butyl bromoacetate, 25% NaOH, toluene,
Bu4NHSO4) gives a 60% yield of ester 4_. Although it is difficult to drive the reaction to
completion, the only by-product is starting compound _3 that can be recycled. Standard
Grignard reaction, photochemical isomerisation of the triene system and subsequent ether
cleavage with tetrabutyl ammonium fluoride cleanly give target compound 1.
Our interest in calcitriol derivative _2 resulted from a recent observation made by DeLuca
Sb,n): Removal of C-19 to produce so-called 19-nor calcitriol appeared to favorably
modulate calcitropic effects of calcitriol without affecting its ability to inhibit cell
proliferation and to induce differentiation. We, therefore, reasoned that replacement of the
10,19-double bond by a spiro cyelopropane unit might produce compounds of interest.
Initially we hoped to synthesize compound _2 by a direct Simmons-Smith methylenation of
precursor _1 expecting selective double bond attack under the well-known assistance of an
allylic alcohol function. However, triol 1_ could not be made to react under typical

5075
Simmons-Smith conditions 12). Success was achieved by using a partially protected
intermediate (scheme 2).
O
~
o
H
0
" ~ OH
~
~
| P h
[.
i
i
I
-t- Si-O"" "~ "0-Si--~---
S,'i" 0""
Ph
H
--l~h
'
/
8_
"~xO " ~ O H
I
i •
2
$
W e made use of the different chemical stabilities observed for silyl ethers as protecting
groups. Whereas a tert.butyl-diphenyl silyl ether remains stable under the conditions of
mild acid treatment (In-HCI, methanol, 25°C), a tert.-butyl-dimethyl silyl ether becomes
smoothly cleaved.
The Calverley strategy conveniently allows to prepare precursor _7 with different
protecting groups, acid cleavage liberates the allylic alcohol function to give intermediate
8 and subsequent Simmons-Smith methylenation results in a 65% yield of compound _9.
Again it is difficult to achieve completion in the first run, but starting material can be
recovered unchanged.
Thus, new calcitriol derivatives 1 and 2_ were made accessible in gram quantifies.
Biological data will be reported elsewhere.

5076
REFERENCES ANDSPECTROSCOHCAL DATA
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b) E. Abe et al. FEBS Lett. 226, 58 (1987).
3. a) S. Morimoto et al. Calcif. Tissue Int. 39, 209 (1986).
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b) A. Kawaura et al. Carcinogenesis 10, 647 (1989).
c) C. Garland et al. Lancet 307 (1985).
5. H.F. DeLuca and H.K. Schoes Annu. Rep. Med. Chem. 19, 179 (1984).
6. a) H.F. DeLuca, N. Ikekawa and D. Tanaka US Pat. 4,851,400 (1989).
b) H.F. DeLuca, H.K. Schnoes, K.L. Perlman and A. Kumer
US PaL 4,851,401 (1989).
c) S.-J. Shiuey, J.J. Partridge and M.R. Uskokovic J. Org. Chem. 53, 1040 (1988).
7. a) N. Kubodera, K. Miyamoto, K. Ochi and I. Matsunaga
Chem. Pharm. Bull. 34, 2286 (1986) .
b) E. Murayama, K. Miyamoto, N. Kubodera, T. Mori and I. Matsunaga
'Chem. Pharm. Bull 34, 4410 (1986).
c) A.J. Brown et al. J. Clin. Invest. 84, 728 (1989).
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b) H.F. DeLuca, H.K. Schnoes, R.R. Sicinski and J.M. Prahl EP 0387077 .
9. W. Skuballa, E. Schillinger, C.-St. Stttrzebecher and H. Vorbrilggen
J. Med. Chem. 29, 313 (1986).
10. M.J. Calverley Tetrahedron 43, 4609 (1987) .
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Tetrahedron Lett. 31, 1823 (1990).
12. G. Neef, G. Cleve, E. Ottow, A. Seeger and R. Wiechert J. Org. Chem. 52, 4143 (1987).
/ f ~ L R spectra (300 MHz, CDC13):
/
1
/
: 8= 0,56 ppm (s, 3H, H-18); 1,04 (d, J=7 Hz, 3H, H-21); 1,22 (s, 6H, H-26 and H-27); 3 , 1 ~
(d, J=9 Hz, 1H, H-24); 3,22 (m, 1H, H-22); 3,26 (d, J--9
\ \
Hz, 1H,
H-24'); 3,43
(dd, J=9, 4,5
\
\
Hz, 1H, H-22'); 4,22 (m, 1H, H-3); 4,43 (m, 1H, H-l); 5,01 and 5,33 (s, 1H each, H-19); 6,03
and 6,39 (d, J=ll Hz, 1H each, H-6 andH-7).
\
/
2: 8= 0,53-0,68 ppm (m, 2H, Cyclopropyl); 0,56 (s, 3H, H-18); 0,85-1,01 (m, 2H,
XC~propyl); 1,04 (d, J=7 Hz, 3H, H-21); 1,20 (s, 6H, H-26 and,H-2~7T,, , , ~ d J-~9 H z , I H,
H - 2 4 ) ~ J ~ , J=9,5, 9 Hz, 1H, H-22); 3,26 (d, J--9 Hz, 1H, H-24'); 3,36 (m, 1H, H-l); 3,44
!
]
(dd, J=9,5, 9
H-7).
~
)
;
4,10 (m, 1H, H-3); 6,09 and 6,29 (d, J--ll Hz, 1H each, H-6 and//,/
~
(Received in Germany 27 June 1991)