Facile and stereoselective synthesis of 25-hydroxyvitamin d2

Tetrahedron Printed in

Letters,Vol.25,No.31,pp Great Britain

3347-3350,1984

FACILE AND STEREOSELECTIVE

Sachiko

Masami

Yamada,

Faculty

SYNTHESIS

Shiraishi,

Sagamiko,

OF 25-HYDROXYVITAMIN

Masayuki

of Pharmaceutical

Ohmori,

Sciences,

Kanagawa

0040-4039/84 $3.00 + .oo 01984 Pergamon Press Ltd.

and

D2

Hiroaki

Takayama"

Teikyo University

199-01, Japan

Summary: 25-Hydroxyvitamin D was synthesized conveniently and stereoselectively for the first time by utilizing Sharp 1 ess' chiral epoxidation and the subsequent regio- and stereoselective methylation with lithium dimethylcuprate to introduce the desired chirality at C(24) and the reductive elimination of the vicinal hydroxy sulfone to introduce stereoselectively the & double bond at C(22) of the target molecule.

Similarly

to the natural

at the 25-position expressing

in the

its biological

hydroxyvitamin

D3 derivatives

latters

in birds.

uncertain has

been

studies.

additional

chiral

complicated. olites lective and

in mammals

because the synthesis

biological

Compared

chiral

vitamin

The gross

structure

synthon

reports

in this series.

molecule

l/5 to l/10

25-hydroxyvitamin

of 25-

to the corresponding less

active

however,

than

the

has remained

D2 nor la,25_dihydroxyvitamin

compounds

D3 derivatives,

D2

has not been available

vitamin

D2 derivatives

bond at C(22), making

on the stereoselective

We report

activity

synthesis

developed

common

for

have

their synthesis of vitamin

a facile

an

more

D metab-

and stereose-

to 25-hydroxyvitamin

now the first and stereoselective

D2 (la) synthesis

D2 (la)." -

steroid

was synthesized

are

the side chain structure

D2 (z).

in the kidney 3p4 before

1s similar

D2 (lJ)6

of these

must be hydroxylated

that the biological

center on the side chain, we have

for constructing

of 25-hydroxyvitamin

la-position

of these metabolites,

at C(24) and an 1 double

la,25_dihydroxyvitamin

target

material

As a part of our studies7

method

at the

but the formers importance

with

D2 (ergocalciferol)

It has been known

of neither

and enough

center

possessing

then

and la,25_dihydroxyvitamin

The biological

established

D3,l vitamin

liver 2,3 and activity.

D2 (la)5

vitamin

vitamin

of the target

2 and Cg-chiral

starting la was r\r

synthon

The chiral with prenol introduced

compound

was constructed

3b, in a similar

synthon

2

by utilizing

3347

manner as described

to constitute

(4) and the desired

from the two segments,

in our previous

the C(23)-C(28) side chain part

chirality

Sharpless'

C22-

chiral

for the 24-position epoxidation9

of the

followed

by

3348

regio- and stereoselective trans-double sulfoneL

bond

(1 equiv)

chiral

epoxide

in the presence 2

r.t.) gave

proceeded

The

spectrum

2

(92%).

optical

The

established

purity

stereochemical

cupper

reagent. lo

was converted

90%), reaction

70 "C,

99%),12 and protection

0 "C) of 2

proceeded

by deprotection

Liin

with thiophenol

of the hydroxyl

good yield

(65%).

95% EtOH,

side chain

was in good agreement

into

25-hydroxyvitamin

The all

118;

spectrum,

UV

spectral

(95% EtOH)

1.03 (3 H, d, J = 6.5 HZ),

with

265 nm; 1.13

by the standard

Reductive

the desired

sole 1H NMR

provitamin

introduced pattern

method;

D 2

of 6a -

tosylation

(Na2W04, H202,

95%).

The

reaction

from ergosterol,7'13 (5% Na-Hg,

Na2HP04,

product which

D (8b) (95%) Cv

22(23) double

of the olefinic The provitamin followed

with

by deprotection

8a (52%) as the sole -

irradiation

of the vitamin (CDC13)

obtained

of the well

of epoxides

6 Hz), 1.14 (3H, s), 1.17

that of ergosterol.

(3 H, s), 1.16

-20 "C)

by its

oxidation

desulfonylation9

E olefin

the coupling

'H NMR

NaH,

(93%) as the

and alkylation

THF, -78"C),

D2 (la) (31%) by UV rV

properties

(Et20,

S on the basis

group (DHP, PPTS, CH2C12,

of the newly

where

isopro-

(PhCH2C1,

LiCuMe2 e

3b. -

-20' C) to give

90% as determined

(_t-BuOK, DMF, 91%),

affording

40 "C) gave

titanium

(CH2C12,

alcohol

6a was assigned rV

3b (71%, overall) N

The _E stereochemistry

by the 'H NMR

with

to give

exceeds

and

by benzylation 2

8-hydroxy-

2 and the sulfone

([o]22 D -2.5", 0.18% CHC13) obtained

stereoselectively

(PPTS,

m)].

supported

zation.

epoxide

6 1.00 (3 H, d, J = 7 Hz), 1.06 (3 H, d, J =

-5.6(48,

which

of the epoxidation9

with C(22)-aldehydeA(LDA,

gave 8-hydroxysulfone

(1 equiv)

of

The 22(23)

3-(heptafluoropropylhydroxymethylene)-d-

of the alcohol

Diol 2

pyridine,

%

shift reagent,

consequence

(TsCl,

2

tartrate

of the

desulfonylation"

(1.1 equiv)

(25%),

of the alcohol

to the phenylsulfone

of the sulfone

1% CHC13)

(LiCuMe2).1°

of the aldehyde

regio- and stereoselectivity

The configuration

camphorate.

formed

by the coupling

reaction

in the presence of chiral

(CDC13)

by reductive

of D-(-)-dibutyl

([cx]~~ D +17.12",

with exclusive

product.

136,

selectively

dimethylcuprate

(4) was treated with m-butylhydroperoxide N

poxide

organ0

was introduced

with lithium

which in turn was obtained

Prenol

DMSO,

methylation

[lH NMR

(3H, s), 5.3

bond in 2 protons Ds

at the

was trans-

by thermal

isomeri-

[MS m/e 412 (M+), 394, 271, 253,

6 0.56 (3 H, s), 0.99 (3 H, d, J = 7.5 Hz),

(3 H, s), 3.95 (1 H, m), 4.81 (1 H, d, J = 2

Hz), 5.03 (1 H, m), 5.33 (2 H, m), 6.01 (1 H, d, J = 11 Hz), 6.23 (1 H, d, J = 11 Hz)] synthesized olite. 2

support

the structure

was

and are in good agreement

with

those of the natural

thus

metab-