Synthesis of 24,24-difluoro-25-hydroxyvitamin D3

Tetrahedron Letters No. 21, pp 1859 - 1862. @Pergamon Press Ltd. 1979. Printed in Great Britain.

SYNTHESIS

OF 24,24-DIFLUORO-25-HYDROXYVITAMIN Masayuki

Sachiko

Yamada,

Faculty

of Pharmaceutical

cially tion

lithocholic

By extensive have been

of vitamin

studies

Besides

to it, the metabolites

hydroxylated

attention with

of their

the corresponding vitamin

prepared

from commer-

the role of 24-hydroxyla-

the active

at 24-position

reduced

D3, a number

[i.e.

of metabo-

metabolite

(i.e. 25-hydroxyvitamin

(24R)-la,24,25-trihydroxyvitamin

because

hydroxylated

to study

of vitamin

D3) and the precursor

D 3 and

Japan

D3.

10!,25-dihydroxyvitamin

vitamin

Takayama*

University

(13) has been

D3

on the metabolism 1 and identified.

isolated

Teikyo

199-01

acid derivative

D3

and Hiroaki

Sciences,

24,24-Difluoro-25-hydroxyvitamin

available

in the metabolism

lites

Ohmori,

Kanagawa

Sagamiko, Summary:

0040-4049/79/0515-1859#02.00/0

(i.e.

D3) leading

(24R)-24,25-dihydroxy-

D31 have been

directed

much

but still

considerably high activity compared 2 vitamin. However, the role of 24-

non-hydroxylated D in the metabolism

of the vitamin

has still

been

remained

behavior,

fluorinated

to be clarified. Due to similar biological

the corresponding have

steric

compounds

chosen

have

and dissimilar

to act as antimetabolites with respect to 3 Based on this reason, we natural products.

compound

(g)

by substitution

D3 to study

the role

chemical

known

fluorine-free

the title

lic hydroxylation vitamin

bulk been

in which

with

24-position

fluorine

atoms

of 24-hydroxylation

is blocked

as an analog

for metaboof 25-hydroxy.

in the metabolism

of the

vitamin. Using chain

was

carbinol

commercially achieved

function

yield.

oxidation s), 0.97 2

was derived

Reduction

gave

1720 cm-';

acid,

1 in which

efficiently

of the ester

the aldehyde

(3H, s), 4.75

derived

lithocholic

in Scheme

construction

the desired

from the d-keto

24,24-difluoro-5P-cholestane-3d,25-diol

intermediate, overall

available

as shown

from NMR

1: IR

(lH, m),

the aldehyde (CDC13)

1 with

(CHC13)

9.82

s 0.63

followed

and the key

into

The

the ester

(3H, s), 1.34

in 20%

by Collins

(CDC13)

(lH, t, J = 2 Hz).

(3H, s), 0.91

ester,

(g), was obtained

LiA1H4

1715 cm -l; NMR

2 was transformed

of the side

OL,d-difluoro-t-

6 0.65

(3H,

1,3-dithiane 2

[IR (CHC13)

(3H, t, J = 6.5 Hz),

4.27

(2H, q, J = 6.5 Hz), 4.74 (lH, m)] via its lithium salt by reaction with 4 -1 ethyl chloroformate. The Ol-keto ester j [IR (CHC13) 1720 cm ; m/e 474, 4141 obtained acetyl

aminosulfur 1755,

by exchanging

followed

by removal

trifluoride

1720 cm-';

NMR

the protecting of the dithiane

(DAST) 6 to provide

(CDC13) 6

0.65

group group5

was

treated

the difluoro

(3H, s), 0.93 1859

of the alcohol

ester

from THP

with

to

diethyl-

2

[IR (CHC13)

(3H, s), 1.36

(3H, t, J =

1860

No. 21

7 Hz), 2.03 (3~, s), 4.35 (2H, q, J = 7 Hz), 4.73 (lH, ml) , which upon treatment with methyl magnesium bromide afforded the &-carbinol 5: 142-143'; NMR (CDC13) 5 0.66 (3~, s), 0.92 (3H, s), 1.31 (6H, s), 3.65 (lH, m); We

1 =

=2

&

H =4 (a)

=6

(b) Cr03.pyridine.HC1, CH2C12.

(c) 1,3_propanedithiol,

BF3. Et20, CH2C12, then dihydropyrane, p-TsOH.pyridine. then ClCOOEt.

(e) p-TsOH.pyridine, EtOH.

(g) NBS, aq. acetone.

H COOEt

H =5

LiA1H4, THF.

440, 422.

(h) DAST, CH2C12.

(d) "-BuLi, THF,

(f) Ac20, pyridine.

(i) CH3MgBr, THF.

Scheme 1 Having thus established the construction of the side chain, the stage was set to effect the transformation of the saturated steroid skelton to the vitamin D ring system.

Conversion to the 3@-hydroxy-d-sterol

m/e 438, 420; NMR (CDC13) b 0.70 (3H, s), 0.95

g

[mp 168- 1700;

(3H, d, J = 6 Hz), 1.02 (3H,

s), 1.32 (6H, s), 3.55 (lH, m, w/2 = 24 Hz), 5.40 (lH, d, J = 4 Hz)) was achieved by decon3ugation7 of the enone 1 (mp 177-178"; m/e 436 ),which was obtained by simultaneous oxidation bromination reaction8 of 5 followed by dehydrobromination, and subsequent reduction with NaBH The acetate Lb derived from $&a 4' was transformed to the corresponding vitamin in the usual manner. 9 Allylic bromination followed by dehydrobromination gave a mixture of the 5,7- and the 4,6-diene from which the former was isolated as the triazoline adduct 2

mp

194-1950; NMR (CDC13) & 0.82 (3H, s), 1.00 (3H, s), 1.32 (6H, s), 2.04 (3H, s), 3.25 (lH, dd, J = 14, 5 Hz), 5.50 (lH, tt, J = 10, 5 Hz), 6.36 (2H, ABq, J = 8 Hz) , which by reduction with LiA1H4 afforded the provitamin g: mp 177-179'; m/e 436, 403, 377; NMR (CDC13) 6 0.63 (3H, s), 0.94 (3H, s), 1.31 (6H, s), 3.60 (lH, m, w/2 = 26 Hz), 5.40 (lH, m), 5.60 (lH, dd, J = 6, 2 Hz). Irradiation

No.

21

1861

of the provitamin 2

in ether bv high pressure mercury lamp through Vycor

filter and chromatography of the products on Sephadex LH20 yielded the previtamin $=l (38.5%)

I;\,,, (95% EtOH) 262 nm], the tachysterol analog"

g

(25.5%) [Amax (95% EtOH) 271(sh), 281, 291 (sh) nm; NMR (CDC13) 6 0.72 (3H, s), 1.00 (3H, d, J = 6 Hz), 1.34 (6H, s), 1.82 (3H, s), 4.00 (lH, m), 5.75 (lH, bs) 6.40 (2H, ABq, J = 16 Hz)] , and unchanged g

(7.5%). Refluxinq in benzene (2 hr) and subsequent storage at room temperature (5 days) converted the pre-

vitamin g

exclusively to the vitamin 2

showed typical UV spectrum

(A,,,

(81%).

The vitamin thus obtained

(95% EtOH) 265 nm (log& = 4.24)) and mass

fragmentation pattern (m/e 436, 136, 118) of vitamin D derivatives supporting 1 the assigned structure. The H NMR spectrum of 12 afforded further supporting evidence for the structure showing the signals of methyl groups at 6 0.56 (3H, s), 0.95 (3H, d, J = 6 Hz), and 1.32 (6H, s), the 3dproton at& 3.95 as multiplet with w/2 = 20 Hz, the C-19 olefinic protons at64.85 and 5.08 as broad singlets, and the protons on C-6 and C-7 at 6 6.16 as AS quartet with J = 11 Hz.

(Scheme2 ).

The fluorovitamin obtained in the present work was now subjected to the biological testing.

The results will be reported elsewhere.

arb 6=

65%

(a)

NBA, HBr, aq. t_-BuOH.

(b)

LiCO

(d)

DMF. (c) t_-BuOK, DMSO. 3' NaBH4, aq. MeOH,then Ac20. F

F.

F

HO

HO

(e)

NBS, hexane, benzene.

(f)

collidine, xylene.

(9)

N-phenvl-s-triazoline3,5-drone.

/

(h) LiA1H4, THF.= (i) hv, Et20.

\

(j)a,

HD'& G

benzene.

.F

1862

No. 21

Synthesis of 24,24-difluoro-X,25-dihydroxyvitamin

D3 is

progressing

using the same synthetic intermediate 6. = References 1)

H. F. DeLuca and H. K. Schnoes, Ann. Rev. Biochem., 42, 631 (1976).

2)

I. T. Boyle, R. W. Gray, and H. F. DeLuca, Proc. Natl. Acad. Sci. U.S.A., 68,

2131 (1971). I. T. Boyle, J. L. Omdahl, R. W. Gray, and H. F. DeLuca, Y. Tanaka, H. F. DeLuca, N. Ikekawa,

J. Eiol. Chem., 248, 4174 (1973).

M. Morisaki, and N. Koisumi, Arch. Biochem. Biophys., 170, 620 (1975). M. F. Holick, L. A. Baxter, P. K. Schraufrogel, T. E. Tavela, and H. F. 3)

DeLuca, J. Biol. Chem. I _I 251 397 (1976). M. Schlosser, Tetrahedron, 34, 3 (1978), and references cited therein.

4)

E. J. Corey, and D. Seebach, Angew. Chem., 77, 1134 (1965).

5)

E.J.Coreyand

6)

Y . J. Middleton, J. Org. Chem., 42, 574 (1975).

and D. Seebach, Angew. Chem., 2,

7)

E. J. Corey

1135 (1965).

B. W. Erickson, J. Org. Chem., 2,

3553 (1971).

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C. Kaneko, S. Yamada

A. Sugimoto, Y. Eguchi, M. Ishikawa, T. Suda, M. Suzuki, S. Kakuta, and S. Sasaki, Steroids, 23, 75 (1974). 8)

E. B. Hershberg, C. Gerold, and E. P. Oliveto, J. Am. Chem. Sot., 72,

9)

S. Bernstein, L. J. Binovi, L. Dorfman, K. J. Sax, and Y. Subbarow,

3849 (1949). J. Orq. Chem., 12, 433 (1949). 10) A. L. Koevoet, A. Verloop, and E. Havinga, Reel. Trav. Chim. Pays-Bas, 2,

788 (1955).

(Receivedin Japan 16 March 1979)