Stereospecific synthesis of dinosterol

Tetrahedron Letters,Vo1.22,No.46,pp Printed in Great Britain

0040-4039/81/464627-04$~2.00/0 01981 Pergamon Press Ltd.

4627-4630,1981

STEREOSPECIFIC Arthur Department

SYNTHESIS

OF DINOSTEROL

Y. L. Shu and Carl Djerassi* of Chemistry,

Stanford,

Stanford,

California

University

94305

the biogenetically important marine sterol Abstract: Using a Claisen ortho-ester rearrangement, dlnosterol and its C-24 epimer were synthesized stereospecifically by a sequence which is also attractive for selective isotope labelling in the side chain. Dinosterol

was first

isolated

from the toxic dinoflagellate,

et al' and its stereostructure

Shimizu

Dinosterol

(12) and/or

as possible In order

its naturally

key precursors

to verify

-12 was established

occurring 3 A5-3B-hydroxy

in the biosynthesis

such proposals,

We now report the first synthesis

of dinosterol

of 14; most importantly,

itself

tracers

The starting

was oxidized condensed at -60°C.

alcohol 1 (mp 193-194"C,

with pyridinium

8

dichromate7

The vinyl iodide

at 7O"C, followed

(9% yield,

mp 171-178"C,

mp 167-17O"C,

comitant

Claisen formation

Claisen the silyl reverse

reagent

prepared

and treatment

alcohols

easily

[a];' +11.9

[a];' +30.5

gorgosterol

1,2,4,5 (15).4

have to be synthesized.

applicable

incorporation

to the synthesis of isotopic

rearrangement

of 2 with triethyl gave a mixture

[a];' +4.6

-7 1 (CHC13), m/z 486.4060). --

and (E)-2-iodo-2-butene

of catecholborane

to 2-

with NaOH and 12.'

and the more

to the final

sterols

22s epimer _3 assignment

through

was

the

from C-22 to C-24 with con-

The stereochemical vinyl

polar

The

22R alcohol

lithium

assignment

reagent

is also con-

and aldehyde

Partisil

(CHC13),

Similar

configuration as _2. 12 orthopropionate and subsequent

yielded

11

with the same absolute

phase HPLC (column: Whatman

from 2, mp 159-160°C,

of a similar

which

The configurational

the chirality

of the

reduction, 4 was immediately

on silica gel: the less polar

(vide infra) of each epimer

a 22-alcohol

ether with LiBF413

by the addition

(CHC13), m/z 516.4354),

which transferred 22 of the trans-A double bond."

product

aldehyde

of the boranediol

separable

rearrangement

obtained by ozonolysis 6 and subsequent NaBH

from n-BuLi

(CHC13), -m/z-516.4306).

with the fact that condensation

the major

(CHC13)),

to the corresponding

in turn was synthesized

based upon further conversions well-known

[a]:" +26.6

lithium

by hydrolysis

gave two allylic

2 (73% yield,

as

sterol

would

is equally

to the selective

ether of 4a-methyl-5a-dihydrostigmasterol

at -78°C with the vinyl

condensation

sistent

(12) which

readily

marine

dinosterol

by

crystallography.'

in the side chain.

tert-butyldimethylsilyl

butyne

it lends

labelled

tamarensis,

by X-ray

14 have been proposed

analog

of the important

radioactively

Gonyaulax

unequivocally

of C-25 epimeric

esters,

which

M9 lo/50 ODS-2;

eluent:

absolute

m/z 486.4111),

transformation 4627

and 2

(22% yield,

deprotectlon

were

separated

MeOH):

4a (44% yield

mp 2'1-214"C,

of _3 and HPLC separation

of by

provided

[a]:'

-5a (50%

4628

yield,

[a]:' t11.9

mp 163-164"C,

obtained

(CHC13), m/z 4C6.4056);

the other C-25 el?ir;ler, 5b, could

not he

in pure form. Table

1. Physical

properties

of synthetic

products

6a-13

[Ci$

cd;o Compound

mp"C

(CHC1,)

-6a

145146

+12.3

-6b

187189

7a

Compound

mp"C

(CHC13)

600.4891

8a

178181

+9.7

558.4820

+3.7

600.4934

8b

202206

+12.7

558.4910

122124

+22.4

600.4961

9a

215220

+28.5

558.4828

-10

193196

+9.6

542.4935

211214

-2.2

428.4018

-11

210212

+29.0

542.4829

218221

+23.3

428.4015

m/z =

13

m/z =

a Ref. 1 reports mp 220-222°C (CHCl -MeOH), [a] +5(CHCl ) for the natural product. A samole of dinosterol isolated in our labora 2 ory from th g culture a zooxanthellae of the go$@jonian Briareum asbestinum and purified by HPLC exhlbited mp 212-215°C (hot MeOH), [a], -1 (CHC13). Each of the isomeric tion sequence: yield

protection

of 6a,6b,7a),

8a,8b,9a), and -11).

hydroxy

lithium

aluminum

With the resulting identical

sterols

(94% yield)

dinosterol

1.39; cholesterol, tion could Table

and 13.

be accomplished

II.

reduction

Both exhibited

The physical

with

by reverse

of dinosterol J in Hz)

phase

hydride

HPLC

are listed

(3% OV-17,

(retention

in Table

(cf. Table

(85% yield

(93% yield

center, the products

of the silyl ethers

the same GC mobility

by 360 MHz NMR comparison

'H Chemical Shifts coupling constants

aluminum

transforma-

chloride l4 (90%

of the C-26 ester function lithium

deprotection

constants

to a three-step

tert-butyldimethylsilyl

of the C-25 epimeric

Finally

but were separable

1.00).

was then subjected

group with

reduction

destruction

by NMR comparison. 7

(&,4&,5a)

hydride

mesylation l5 and subseauent

8b were

of natural

ester

of the 3B-hydroxy

of

of -10

(lO)from -

-8aand

gave the free 260°C)

times: E,

I; unambiguous

as that 1.48; 13, differenta-

II).

(12) and its C-24 epimer -

13 (36@ MHz, CDC13/TMS,

Isomer

C-18(s)

C-19(s)

C-21(d)a

C-22H(d)

-12(nat.)

0.678

0.826

0.917(5=6.5)

4.872(5=9.7)

12(synth.)

0.680

0.827

0.919(5=6.5)

4.873(5=9.7)

13

0.683

0.827

0.910(5=6.8)

4.875(5=9.7)

C-28(d)

C-29(d)

C-30(d)

12(nat.)

0.777(J=6.8)/0.835(J=6.5)

0.927(5=6.5)

1.495(5=1.1)

0.945(5=6.5)

E(synth.)

0.778(J=6.8)/0.837(J=6.5)

0.928(5=6.5)

1.495(5=0.7)

0.946(5=6.1)

-13

0.772(J=6.8)/0.848(J=6.5)

0.938(5=6.8)

1.484(5=1.1)

0.945(5=6.5)

C-26(d)

or C-27(d)b

a C-21 was determined by a decoupling experiment involving irradiation of the allylic proton around 2.3 ppm in both isomers. b C-26 and C-27 were determined by their simultaneous collapse when irradiation occurred around 1.5 ppm.

4629

RT '*.

OH

'\.

i, ii )

I!

.* /

vi,vii

“%mE. N

2 R;=OH,

R2=H

~&JR~'H,

2 R,=H,

R2=OH

-5a

R3

2 R4=CH3

R3=CH3,

R4

R3

~=r-i;cr,,.

<

R4=H

R4

L-.fiEt

vi

=I-?% M x

.;:

iii, iv '

:4 <

R3\

r+ M

I_

R3

R2 ,‘

M R3=H,

fl R3=CH3,

R4=CH3 R4=H

&,LJ

RjH,

R4=CH3

@,b

-9a

R3=CH3,

R4=H

7a

R3=H,

R4=CH3

R3=CH3,

R4=H

iv side cha

side chain

x4eHo& L

30=

-

H

fi X=OSi(Me2)t-Bu

(TBS)

!j X=OH

i. ii: iii: 1v. v: vi: vii:

Pyr. Dichr.,

CH2C12,

LiCH3C= CHCH~, EtC(OEt3),

-78°C

EtCOOH cat, llO"C,

LiBF4, CH2C12, TBSCl,

RT

CH3CN,

imidazole,

-16

65"C, 12h

DMF, CH2C12,

LAH, Et20, RT MsCl, Et3N, CH2C12,

CHO

3h

O"C, 15 min

5O"C, 12h

4630

By replacing

lithium

aluminum

hydride

one or both of the terminal

reduction

labelling

Furthermore,

can be effected.

well-known16

i-methyl

hydrocholesterol

Financial

at the Stanford

is gratefully

support

16, the naturally

was provided

(NSF Grant

We thank Dr. W.C.M.C.

for the NMR spectra

or deuterium

appropriate reaction

occurring3

tritium sequence

analog

In

or deuterium to the

23,24-dimethyl-22-de-

in our laboratory.

by NIH Grants

facility

tritlum

the identical

were also synthesized

360-MHz

acknowledged.

Dr. L. Durham

(6,1 + 8,z -+ -lO,ll),

by applying

ether of the aldehyde

the NMR/MS center

dinosterol,

steps

(14) and its 24-epimer -

Acknowledgements:

RR-0711)

with the corresponding

No. GM-06840 No. GP-23633

and GM-28352. and

Kokke for the isolation

and Ms. A. Wegmann

for mass

Use of

NIH Grant No.

spectral

of the natural determinations.

REFERENCES 1.

Y. Shimizu, M. Alam, and A. Kobayashi, J. Am. Chem. Sot., 98, 1059 (1976). J. Finer, J. Clardy, A. Kobayashi, M. Alam, and Y. Shimizu, J. Org. Chem., 43, 1990 (1978). Physiol., E, 317 (19m. :: A. Kanazawa, S. Teshima, and T. Ando, Comp.Biochem. 4. N. C. Ling, R. L. Hale, and C. Djerassi, J. Am. Chem. Sot., 92, 5281 (1970). 5. C. Djerassi, N. Theobald, W.C.M.C. Kokke, C. S. Pak, and R.M.K. Carlson, Pure & Appl. Chem., 51, 1815 (1979); C. Djerassi, ibid., 53, 873 (1981). F. F. Knapp and G. J. Schroepfer, Steroids, 26, 339 (1975). 76: E. J. Corey and G. Schmidt, Tetrahedron Lett., 399 (1979). 8. G. Cahiez, D. Bernard, and J. F. Normant, Synthesis, 245 (1976). 9. H. C. Brown, T. Hamaoka, and N. Ravindran, J. Am. Chem. Sot., 95, 5786 (1973). 10. W. Sucrow and B. Girgensohn, Chem. Ber., 103, 750 (1970); W. Sucrow, B. Schubert, W. Richter, and M. Slopianka, ibid., _, 104 368971); W. Sucrow, P. P. Caldeira, and M. Slopianka, ibid _., 106, 2236 (1973). 11. J. R. Wiersig, N. Waespe-Sarcevic, and C. Djerassi, J. Org. Chem., 44, 3374 (1979). 12. I. J. Bolton, R. G. Harrison, and B. Lythgoe, J. Chem. Sot. C, 2950 (1971). 13. B. W. Metcalf, J. P. Burkhart, and. K. Jund, Tetrahedron Lett., 35 (1980). 14. E. J. Corey and A. Venkateswarlu, J. Am. Chem. Sot., 94, 6190 (1972). 15. R. K. Crossland and K. L. Servis, J. Orq. Chem., 35, 3195 (1970). 16. D. J. Vanderah and C. Djerassi, J. Org. Chem., 43, 1442 (1978) and references cited therein.

(Received In USA 17 August 1981)