Synthetic studies toward to 1α-hydroxyvitamin D3 — stereoselective synthesis of (±)-(Z)-2-(3β, 5α-dihydroxy-2-methylenecyclohexylidene) ethylidenecyclohexane

Tetrahedron Letters,Vol.24,No.39,pp Printed in Great Britain

SYNTHETIC OF

STUDIES

TOWARD

0040-4039/83 $3.00 + .OO 01983 Perqamon Press Ltd.

4257-4260,1983

TO la-HYDROXYVITAMIN

D3 -

STEREOSELECTIVE

SYNTHESIS

(')-(Z)-2-(3R,5a-DIHYDROXY-2-METHYLENECYCLOHEXYLIDENE)ETHYLIDENECYCLOHEXANE

Hideo

Nemoto,

Xiao-Ming

Pharmaceutical Tetsuji

Institute,

Tohoku

Kurobe,

University,

Ihara,

Aobayama,

Keiichiro

Sendai

Fukumoto

980, Japan

of Medicinal

Chemistry,

Hoshi

University,

Ebara

2-4-41,

Shinagawa-ku,

142, Japan

Summary:

As a model

experiment

title compound lysis of

for a synthesis

(,Q,) was

In the course Mazur's

the conversion

stereoselective

of this observation, (2) I the highly

via the solvo-

(,+2).

study of vitamin

of vitamin

reconversion

compound.

active

D3

total

analog

D', we attentioned

(&) to 3,5-cyclovitamin

to the starting

a stereocontrolled

biological

via the 3,5-cycle

synthesized

D3, the

(f)-2-hydroxy-2-[(3B-methoxymethoxy-2-methylenebicyclo[3.1.

of our synthetic

report,

of la-hydroxyvitamin

stereoselectively

Olhexane)-llethylidenecyclohexane

their

Masataka

Kametani

Institute Tokyo

Flu, Hiroshi

vitamin

synthesis

D3

to describe

.

D3

On the basis

a stereoselective

(f)-(Z)-2-(3B,5a-dihydroxy-2-methylenecyclohexylidene)ethylidenecyclo-

hexane

(,Q) according

as a model

experiment. / \\

I

fl

/

4257

D3

has been planned

sis of

to this strategy

(2) and

of la-hydroxyvitamin

of cholecalciferol,

Here we wish

2

the

synthe-

4258

Synthesis reaction

of bicyclo[3.l.O]hexyl

between

the aldehyde

ring A and the vinyl Still's

method3.

anion derived

prepared

tetrahydrofuran, verted,

(&$) having

Thus, treatment

stannyllithium,

phenylphosphine

and carbon

ture for 2 h 4,s .

tetrabromide

Dehydrobromination

of dimethylformamide

in 64 % yield,

the olefin

reaction

was

carboxaldehyde

(&X), which

1-carboxylate

(Ej6 in three

nium bromide lithium

hydride

dichloromethane

column

of the aldehyde

the product

at -78OC,

chromatography

(J&), m/e

of two epimers

ing shift

reagents

catalytic

amount

to give ed.

7

the Z-triene

3.89

(lH, m),

s), which

were

possessing

ed via the allylic

nantly

oxidation

in methylene

formed

with

over

chloride.

the u-hydroxy

chlorochromate

(PCC) in

rn tetrahydrofuran

at -20°C

for 2 h,

After

isolated

in 76.1

by

1

H-NMR

by heating

5.05

ones

8

by

on TLC and utilizof

at 55'C for 10 min

of E-isomer

was observ-

(M+), indicated

218

the following

signals,

(lH, d, 3 = 3 Hz),

(CDC13)

6.12

(2H,

.

hydroxylgroupat selenium

8 yield

J.$ in the presence

of ,JJ, m/e

showed

for 30 min

spectroscopy

dioxane

No formation

the reported

stirring

was homogeneous

in aqueous

= 4 Hz),

dioxide

The S-hydroxylated isomer.

with

proceeded

spectrum

of 2 with

triphenylmethylphospho-

Coupling

acid

a protecting

The

(%)I.

(E 10,500),

Awh/2

(lH, m,

consistent

The aldehyde

oxideg'10

and the 'H-NMR

4.82

pyridinium

was conducted

(MeOH) 260 nm

tempera-

2-oxo-bicyclo[3.1.0Ihexane-

compound

(&I) in 66.3 % yield.

The UV spectrum,

tri-

for 2 h afforded,

(47 ei), reduction

not be established

Solvolysis

reflux

using

The product

gel.

was con-

with

at room

in

2-methylenebicyclo[3.l.Olhexane-l-

CM+), was

of p-toluenesulfonic -

the Z-configuration 6

.

could

3.

and lithium

(lH, d, J = 4 Hz).

(,&2J at -78OC.

218

on silica

the ratio

6 5.24

reaction

with

of ;I with n-butyllithium

by addition

under

in tetrahydrofuran

and oxidation

tributyl-

(,5), which

chloride

from methyl

[85 % from the exomethylene

via lithiation followed

using

Wittig

steps;

and c-butyllithium

aluminum

(CDC13)

was prepared

chloride

to the

1, 5-diazabicyclo[5.4.0]undecene-

and toluene

examined

($) with

(fi) on the reaction

of g with

of the

(1) according

the stannylcarbinol

in methylene

(Jo, ’ H-NMR

firstly

functionalities

of tributylstannyl

into the bromide

5 in a mixture

coupling

the requisite

by the coupling

of cyclohexanecarboxaldehyde

for 5 min gave

purification,

(.&J,) was achieved

from the organostannane

by reaction

at -78OC

without

alcohol

C3 position and t-butyl

compound

The oxidation

was obtainhydroper-

(,&,Q) was predomi-

of the c-hydroxy

com-

4259

pound

to the corresponding

Therefore

the oxidation

the products

by column

ketone

chromatography

(&IL) (96 8) by the action

(83.4 %) and KC

reaction

under

epimeric

alcohols

(JJ) was

the same reaction (A>), m/e

(3H, s), 4.14

(lH, m),

were

inseparable.

Solvolysis

% yield,

(3H, s), 4.16

m/e

278

(lH, m),

transformed,

(M+); NMR

4.68

4.28

(2H, s), 4.84

CHO

-

(2H, m),

gave

(Et201 265 nm

hydride

(j.4). Coupling

in 76.8

% yield,

the

(lH, t, J = 4 Hz), 5.18

(2H, m), which

the desired

Z-triene

(E 13,200);&MR(CDC13)

(A@), 6 3.36

(lH, m) ,4.58 (2H, m), 5.20 (W, m), 6.04 and 6.30 (each lH,

each d, J = 12 Hz), as a sole product.

($1

(CDC13) 6 0.56

of J/J as above

(M+); UV

gave,

of diiso-

aluminum

(71 %), into the aldehyde as above

(MOM) ether

in the presence

by lithium

of

and the ketone

as methoxymethyl

chloride

(,J$)lO.

by purification

,&Q in 41.3 % yield

conditions

278

followed

was protected

oxidation

3.38

in 65.3

gave

group

than that of the former

temperature

of methoxymethyl

propylethylamine. The ester reduction

faster

for 3 h at room

The hydroxyl

in 33.6 % yield.

was

“B”

Deprotection

of the MOM group

,5?

,‘,,

X=OH

(@

X=Br

(1)

X=H

C&J) X=H

X=OH

(,I$,,

X=OMOM

X=OMOM

J

HO <

C&C) X=H (A?,

X=OMOM

by heating

4260

@

in the presence

of small amount

60°C for 1.5 h produced 234

(M+); UV

m),

5.00

(lH, br s), 5.31

the solvolysis C&k) route

Thus

(E 18,400);

stereoselective

synthetic

(&xl, mp 118 - 119'C,

(CDC13) 6 4.20

strategy

would

(lH, m),

at

m/e

4.41

(lH,

(each lH, each d, J = 12

of Z-trienes preferred

in methanol

would

be accounted

carbonium

provide

by

ion intermediate

an efficient

synthetic

D3.

$3, 1123

synthetic

study

K. Minemura,

M. Tsubuki,

3)

W. C. Still,

J. Am. Chem.

4)

R. G. Weiss,

5)

Y. Torisawa,

6)

K. Kondo,

7)

M. Sheves,

8)

J. V. Frosch,

Y. Mazur,

T. Kametani,

II. Nemoto,

H. Furuyama,

Sot.,

Sot.,

K. Suzuki, Tetrahedron,

(1975).

E. I. Snyder,

J. Org. Chem.,

J$, 403

(1971).

M. Shibasaki,

S. Ikegami,

Tetrahedron

Lett.,

D. Tunemoto,

Y. Mazur,

Tetrahedron

I. T. Harrison,

&QQ,

21, 6249 (1978).

E. Hiro,

D. Arigoni,

J. Am. Chem.

1481

I, 2005

Tetrahedron Lett.,

Lett.,

2987

B. Lythgoe,

4489

22, 2397

(1981).

(1976).

(1976).

A. K. Saksena,

J. Chem.

SOc.,

(1974).

A. Vasella,

H. P. Jensen,

K. B. Sharpless,

J. Am. Chem.

Sot.,

(1973).

10) H. E. Paaren, (Received

laboratories;

(1983).

M. Sheves,

22, 7917

from these

K. Fukumoto,

2)

9)

formation

acid

and Notes

The previous

Perkin

the diol

'H-NMR

via the thermodynamically

the above

hydrochloric

(lH, br s), 6.16 and 6.32

to lc-hydroxyvitamin

References 1)

in 69.5 % yield,

(Et20) 261 nm

Such high

Hz).

of cont.

H. F. Dehuca,

in Japan

24 June

H. K. Schnoes,

1983)

J. Org. Chem.,

$2, 3253

(1980).