Prostagland1ns:total synthesis of pgd2 “via” 1,3 cyclopentanedione.

m404020/85 s3.m+ .m 0 1985Rrpmon Ptus Ltd.

TctrW,m Vol. 41. No. 7. pp. 1385to 1392.1985 Printedin Great Britain.

PROSTAGLANDINS:TOTAL

GIANFRANCO CAINELLla* GlORGlO

1,3

CYCLOPENTANEDIONE.

, DARIA GIACOMINla,MAURO

MARTELLlb

and

GIUSEPPE

PANUNZIOa*,

SPUNTAb.

Universita and C.S.F.M.-C.N.R. Chimico “G.Ciamician” Via Selmi 2 1 40126 Bologna (Italy) Composts de1 Carbonio Contenenti Eteroatomt e Loro Appltcazioni 1 4006.4 Ozzano Emilta Italy Via Tolara di Sotto 89

Istituto

a) lstituto

b)

OF PGD2 “via”

SYNTHESIS

dei C.N.R.

(Received ia LIK I2 February 1985) Abstract: precursor

A practtcal is reported.

z?trtp,sy;sat;esf;=;epd

ProstaRlandins was

(PGs)

little

ability

to

them

inhtbit

blood

avotd

parttcular

an

proper

stde

interest,

at

much

step

for

from

this

which

chains

their

recently la aggregation

platelet lc,d . Although

y-keto-esters

and

the

the

drawback

of

discrimtnattng solution system

between

to this as

this

in

this

The

synthetic

readtly

3

. The

a)

by

deprotection

the by

the

rtnq

been

introduction

of

of

position

was

followtnq exposure

to for

ttle

the in

C

our

siqntficance

of

their

potent

, and other

unique

to their

synthests2,

carbonyl 11 opinion, the

tnto

few

function.

Of

base-induced

suitably

elaboration

reliable

Recently

synthesis

proposed

of

includes

a

(5). of

functtonalized PGD

2’

chemoselecttve

we the

have

reported

highly

sequenttal

We wish

to

methods an

substituted

of

attracttve

cyclopentane

bis-acetaltzation-selective report

here

an

from

y-ketoester

application

PGD2. easily

(21,

easily

view lb

activtty

devoted

is,

of

carbonyls.

synthests

in

cyclopentanones

further

lack

cyclopentanedione to the

view,

bioloqtcal

.

the

allowed

antitumor

has

directly

cyclopentanedione

p-toluenesulfonic of

is

solution the

cyclrzation3c.

yteld

of

two

which

procedure

acetahzation

amount

of

avatlable

base-induced overall

the

problem (A)

mono-de-acetalizatton of

method

whose

revaluated

, thetr

potnt

lead

destred

been

effort

baas

The

metabolites.

have

oxidattve

synthetic of

D series

earlier.

properties

cyclizatton wtth

the

apprectated

physioloRica1 of

of

starting from an acycltc total syntheses of PGD A novel effictent tnve?sion of stereochemtstry at by tetrabutylammontum %a” a SN2 dtsplacement

converted

obtained

to

the

monoethylene

acttal

(1) (3)

tn

via 70%

sequence: to acid

Cg carbonyl

an

excess (PTSA)

RrouP

of in

by

ethylene

glycol

benzene

at

stirring

the

tn

reflux product

the for with

presence 8

of

hours,

St0

2

a catalytic b)

selective

and. a catalytic

1386

G. CAINELLIet al.

amount The

of aqueous

9-keto

group

selectrvely the

the

below

1.

of

(3)

produce

the

alcohol

(4)

desired

from

H2SO4 tn methylene

attack

tn

An alternative

route

to

the

of

reduction

of

fl-alcohol

13

the

in

C NMR spectra

Indeed

the

corresponding showed 9

numbertng) tosylate

($1

by

products

the

pentane

(DMF))‘l,

the

catalytic

(9)

amount

acetate next

purpose exposure

key

further

of

starting

was

then

Completton

of

borohydride and

of the In now (2)

to

Cti,Cl,

solution

of

the

at

to

then

synthesis of

was

the

a-8

of

in

(5)

Its

the

80

from

CL) and (Prostane

correspondtng tosylate

the

($1

nitric that

ester

by

to

ester

no

comparison

from

(1)

trace

of

Zn/Cll3COOH

wtth

authentic

(3).

lithium

an

oil

in

anydride

for

2 h,

the

alumtnum

hydride

90% yteld.

Finally

in

pyridlnc

furnished

and

a

quantitatively

with

Zn/CH3COOH.

to

the

practical formation

by

synthesis and of

of

efficient the

f+)

react

tn 12

of

a by

t.1.c.

of

ephedrtne

afford to

aldehyde

of

with

treatment

with

the

(3)

of

ester aldehyde

the

alcohol;

In (2)

sodium

salt

procedure.

procedure: epimeric

polar

the

to mild

standard

step

/CH3CN1’. aq from optically

The

by was

subjected

the

means

known

most

by

was

led by

mi.xture

the

obtained

(g1

three

(2)

solutton

a) C(15) c)

sodium alcohols

hydrolyses

to HF

PGD2 purely method

a

blue

dimethylsulfoxide

to

well a

deep

which

(16)

ketone

afforded

exposure

(12) -

To thts

aldehyde

ozontde

dlazomethane

effected

the

a

oxidation

preparative

Into

appendages.

until

product

by

which

ring

-78°C

bromide

coupled

unsaturated

then

necessary

converted at

following

15-ketone

ester

a

oy

as

0“C

allowed

Cr03/Pyridtne the

to PGD2 methyl complete

of

a -nitric

acetic

the

resultin

esteriflcatlon

by

the

of

of

oxtdattvely

give

separation

developed “via”

attack

was

sequential (2).

b)

(18);

latter

order

In

to

from

the

than Into

with

(2)

excess

was

reduction

converted

reduction

9-

reduction

(DMAP)

(2-oxohepthyl)phosphonate

dimethyl

(17) -

and

to FT

ppm upfleld

NMR spectra

mcnttoning

starting

(4-carboxybutyl)trtphenyl-phosphontum

hydrolysis

0.3

afforded

conformed

alcohol

slight

the

(10) -

purtficatton,

salt

yteld

a

is

ozone

the

methylsulfinylmethtde,

whtch

upon the

pyridine

synthesis

sodium

43%

was

stereospecifically

(4)

converted

the

Thus

oil.

of

by

In

Exposure

70% yield

In

,

whtch

with

dimethylamtne

stream

3c

of

for

~t-butyld~methylsilylchloride--in~~dazole--d~methylformamide-

treatment

sodium basic

group

intermediate

followed

structure

route

(8)

the

of

whose

afforded

an

wtthout

(A),

Reduction

ether

of

a

detected.

ether

as

to

be

procedure

MHz ‘H NMR and

90

13C

the

pyrtdtne.

‘H NMW (see

laboratories.

approx.

tube for 5 hours 10 yield. It is worth

silyl

(10) -

in

conventent

of

resulttng

alcohol.

at

was

13C and

proceeds

shielded

obtained

whtch

formation

group,

these

the

9 - a-

more

exclusive

by

tn

of

condtttons

hydroxyl

a

borohydrtde

to occur

-78’C,

shown

sealed

ethyl by

of

a

give

tnvolves

Moreover

be

chloride

alternattve

phase the

obtained, CG,,

the

of

The

an

anhydrous

acetylatton

thus

in

(3)

known

to

to the

was

Analysis

PG’s8.

C-9

quantitative

hydroxy

gave in

the

in could

by

of

and

12O’C

a-hydroxyacetal

obtained

(LAH)

at

displacement

Protectton

9-p-hydroxy C-8

p-toluenesulfonyl

eltmination

sample

in of

is

at

of

correspondtng

PG’s

THF

developed

sodium 6

of the

9-a-hydroxy

from

yteld.

fl-hydroxy-.acetal

tn

gave

0°C

in

stde,

recently

9 with

.

compounds5,

hindered

C

4

5 hours

configuration

starttng

at

absence

signal

But4N+NO 3 “via” SN2

similar

less

(L)

for

K-Selectride

The

quantitative

the

signals

The

.

the

at

tn

H tn

the

from

ethanol (5)

(C-9)

(5)

yield.

compound

shows

the

tn

70%

stereochemistry

(3)

with

9 a-hydroxyl

hydride

give

reduced

was

of

tnverston

dichloride

for

resolving

salt

of

acttve

precursors,,

cyclopentanedione the

correspondtng

we have

bis-acetal acid

(2)

3c and

1387

Prostaglandins

conversion into

the

Details

to

the

optIcally of

this

optIcally active

process

active natural

~111 be

intermediate PGD2

following

reported

shortly

SCHEME

(23) the

(SCHEME II), route

reported

which

can

in this

11

/ v

r

0

OG

3) CH$J,

(22):

O

‘-‘C02Me

2) H+

:

transformed

elsewhere.

1) (+I Ephedrine

(21)

be

paper.

Cal;’

R = C,H,

(c

R = H

[al;=

= tw.1

-16.5

(c 1.2 CHCI,)

1.2 Cl-ICI,)

(23)

EXPERIMENTAL 1 H and l3C 1.r. spectra were recorded as film on a Perkin-Elmer 710 B spectrophotometer or C6D6 solutions on Varlan Eh: 390 and Varian FT n.m.r. spectra were determlned In CDCl In p.p.m. from as d-values 80 Instruments respectively; chemical 3Shlfts are expressed Internal standard Sthie . Yass spectra were taken on a Varlan Mat 112 S instrument (70 eV). was perfo+med on silica T.1.c. gel sheets (Kirselgel 60 F2 ~ chromatography on a Chromatospac Prep. 10 (JobIn-Ivan instrument? uTinyr~~:lcaan$l cT:iuG h;erck). prior pur~flcatlon, Materials.--Commercially avallable starting materials were used without unless otherwise stated. THF was obtaIned anhydrous and oxye,en-free by dlstlllatlon over sodium benzophenone ketyl under argon. Methylene dlchlorlde was distilled over P 0 . Dllsopropylamlne was refluxed over molecolar sieves (Type /+A, Flukal and cllstllle b 5,t atmospheric pressure. Dlmethyl sulfoxide (DhlSO) was distilled at reduced pressure over Call . bromide and dimethyl-(2-oxo-heptyll(L-Carboxybutyl) triphenyl-phosphonlum phoz?phonatc were purchased from Aldrich. Preparation

of

compounds.

2,3-trans-3,L-trans-2-Ethoxycarbonyl-3-(prop-2-~)-l-hydroxy-cyclopentanone Acetal (5)

Ethylene

--A solution of ketone (3) (lg. 3.9 mmol) in ethanol (5 ml) was added dropwlse at O’C to a stIrred suspension of NaBH (0.6 g,15 mmol) In ethanol (20 ml., 95% solution). The resulting solution was stirredLat this temperature for 1 h, then the excess of the reagent was destroyed with 1% HCl. The mixture was extracted with ether (3 x 30 ml). The combined extracts were dried (MgSO ) and evaporated in vacua to qiv quantitatively the crude acetal (5) as an oil whose iurity was estimated by t.1.c. and 93C n.m . r . analysis to be 100%. m/z 256 (hl+), 238 CM+-H 0). _1 (film) 3 500 and 12735s cm bym&b MHz; CDCl 1 6.0-L.9 Cm 3 HI, L.2 (q 2 HI, 3.9 (m 5 H), 2.8 (bs 1 H 0111, 2.7-2 rcomplex pattern3 6 HI, 1.3 (t 3 H). 2,3-trans-3,L-trans-2-Ethoxycarbonyl-3-(prop-2-~)-l-p-toluen-sulfonyloxy Ethylene Acetal (6).

cyclopentanone

--To a solution of hydroxy ketone (5) (0.6g, 2.3 mmol) in dry methylene dichloride (10 ml) was added at 0°C triethyl amIne (1 ml, 3.5 mmol), p-toluenesulfonyl chloride (0.5g. 2.6 mmol), L-dlmethylamlnopyridyne (DMAP) (0.03Og). The mixture was stlrred overnight at room temperature. After filtration, the reaction mixture was quenched with cold dll. HCl and extracted with methylene dichloride. The organic layers were washed several times with residue was removed in vacua and the water, the solvent was dried ( Na2SOL),

1388

G. CAINELLI

at medium chromatographed (2) (0.99 95%). m/z 410 (M+), 369, 365.

pressure

er

01.

(Cyclohexane/ethyl

(m 5 H),

2.3-1.65

(m 6 H),

l/l)

to

give

the

tosylate

-1

;&%I (film) hiHZ, 1CDCl 73Os,) 17.85 600, (d 1 2370, H), 1 7.35 180. (d 1 090 2 HI, cm 5.45 . g.9

acetate

2.4

(s

3 HI,

1.2

(t

(m 1 H), 3 H).

4.85

(m 2 H),

2,3-trans-3,4-cls-2-Ethoxycarbonyl-3-(prop-2-~)-4-nitroxy-cyclopentanone

4.2

Ethylene

(q

2 H),

Acetal

(1).

tetrabutylammonium nitrate (1 .lg 3.6 solution of tosylate (6) (0.5g, 1.2 mmol) and in pentane was heated In sealed tube at 12O’C for 5 h. The pentane solution was and the solvent removed in vacua to give essentially pure (1) separated from oily-residue (0.35g 97%). m/z 301 (MC), 260, 256, 255. -1 (film) 1 730s. 1 630, 1 280 cm . sVmHz CDCl ) 5.75 (m 1 It), 5.4 (bs 1 II), 5.15 (m 2 HI, 4.2 (q 2 HI, 3.9 (m 4 HI, 2.9 4 HI, 1.2 (t 3 H). r m 2 HI, 2.33(m

--A

mmol)

2,3-trans-3,4-cis-2-Ethoxycarbonyl-3-(prop-2-~)-l-hydroxy (I) (From reduction of nitric ester). --A solution of nitric ester (1) (0.359 1.16 powder in small portions, at room temperature, The reaction mixture was filtered, by t.1.c. washed several times with aq. (5%) NaHC03, stripped off and the residue chromatographed l/l) to give (2) (0.22~ 74%) ldentlc$ in reduction of ketone (3) with K-Selectride . m/z 256 (M+), 238 (M*-tl 0) -1 (film) 3 500 and I2735 cm . 6ymf% MHz C D ) 5.8 (m 1 HI, 5.15 (m 2 7 II), 1.3 (t 3 HI. y-. 1.5 (comp16ex6 pattern

cyclopentanone

Ethylene

Acetal

mmol) in C113COOH (5 ml) was treated with Zn until no more starting material was detected diluted with ether and the organic layers were brine, and dried (Na2S0 ). The solvent was at medium pressure (cycle k exane/ethyl acetate all respects to the product obtalned from

Ii),

4.2

(m

1 H),

4.1

(q

2 HI,

3.9

(m 4 ii),

cyclopentanone

2,3-trans-3,4-cls-2-Ethoxycarbonyl-3-(prop-2-~)-l-t-butyldlmethylsllyloxy Ethylene Acetal (8).

19.5 mmol) In dry dimethylformamide (10 ml) t-butyl--To a solution of alcohol (2) (Sg, 23.6 mmol) and freshly crystallized imldazole (3.54 51 mmol) dlmethylsilyl chloride (3.45g, The mixture was stirred overnight at room temperature, poured Into ice-water were added. The extracts were washed with water, dried over MgSO4 and extracted with ethylacetate. 97%) with a good degree of purity for and concentrated in vacua to give (2, (7.03g, further elaboration. m/z

370 (M+) , 325, (film) 1 750,

tjYPtjb”MHz #,,

0.9

CDCI

1

(s 9 H?,

313 -1 1 650, 1 250, 1 100, 1 040 cm . 6.0-4.7 (m 3 H), 4.05 (q 2 tl), 3.8 0.08 (s 6 HI.

(m 5 H),

3.1-1.9

(m 6 II),

2,3-trans-3,4-cis-2-(~lydroxy-methyl)-3-(~-2-~)-4-t-butyldimethylsi~yloxy Ethylene Acetal (9). (0.759g 20 mmol) was added in small portions --LiAIH After (60 ml) at O’C. mmol) f;, anhydrous ethyl ether solution of NH,+Cl and treated with saturated aqueous Usual work-up gave (2) (5.6g, 90.3%) homogeneous acetate l/l). m/z 328 (M+), 271. -1 (film) 3 530, 1 650 and 1 250 cm . 4.15 (m 1 HI, 3.85 dVw MHz CDCl 1 6.0-4.8 (m 3 Ii) 8H). 2.4-1.8 (2 6 H), 0.88 (s 9 t;,, 0.05 (s 6 HI.

1.3

(t

3

cyclopentanone

to a solution of ester (i) (7g. 18.9 stlrrlng for 1 h, the mixture was extracted with ether (3 x 150 ml). on t.1.c. (silica gel, Hexane/Ethyl

(bs

4

HI, 3.7

(d

2 H),

2.65

(bs

1 H

2,3-trans-3,~-cis-2-(Methyl-acetyloxy)-3-(prop-2-~~-4-t-butyldimethyls~lyloxy-cyclopentanone Ethylene

Acetal

(IO).

-A mixture of alcohol (2) (5.4g, 16.4 mmol), pyridine (5 ml), acetic anhydride The solution is partitioned and OhlAP (0.2q) is allowed to stand for 1 h at O’C. ethylacetate and cold HCl (30 ml 1 NJ, the organic phase IS washed with saturated

(5 ml), between NaHC03,

1389

Rostaglandins dried over MgSO,,, and yield (64). m/z 370 (hi+), 313, 253 dv?&? u ).

the

solvent

removed

3 ~),~0.88

(s

vacua.

Was

obtained

(10) -

as

an

oil

in

96%

-1

(film) MHz CDCl 1 750, 1 6.0-4.7 1 650 and (m 31 2.40 H) cm 4.25 2 (s

in

9 Ii).

0.05’(s

(m

1 HI,

4.15

(d

2 It),

3.8

(bs

4 HI,

2.5-1.6

(m 6

6 11).

2,3-trans-3,4-c~s-2-~Methyl-acetyloxy~-3-(methyl-formyl~-4-t-butyldimethylsililoxy-cyclopentanone Ethylene Acetal (11). --A solution of (10) (6~ 16.1 mmol) in methylene dichloride (50 ml) was cooled to -78°C. Ozone was passed through the solution at the rate of 0.5 ml/mln until deep blue solution. the system was flushed with nitrogen until colourless solution, the While still at -78°C temperature was then allowed to rise to O’C and acetic acid (10 ml) was added, followed by Zn powder In small portlons at room temperature monitorlnq by t.1.c. (S102, Hexane/EthylThe resulting mixture was fIltered, acetate 6/4) until the reduction of ozonide was complete. washed several times with water. The organic layer the pll adjusted at 7 with NaHC03 (5%). solvent removed In vacua to give the 011~ aldehyde (5.3g 88.5%) which was employed as such in successive step. m/z

372 (M+), 315, 313 -1 (film) 2 700, 1 740, 1 725, 1 250, 1 040 cm . 4.2 (m 1 H), 4.15 (d 2 It), bvw MHz CDCI ) 9.8 (s 1 II CHO) #,, 2.05 (s 3 ?i,, 0.9 (s 9 H), 0.d5 (s 3 HI, 0.025 (s 3 HI.

3.9

(s

4 H),

2.7-2.2

(m 6

2,3-trans-3,4-c~s-2-O~ydroxy-methyl)-3-~6-methoxycarbonyl-hex-2~Z)-enyl~-4-t-butyld~methylsllyloxy-cyclopentanone Ethylene Acetal (14). (4.2~) and dimethylsulfoxide (50 ml --A rnlxture of 50% sodium hydride-dlsperslon-in-oil freshly distilled over calcium hydride) was stirred under argoIt at 75°C until gas evolution ceased (1 h). To the resulting solution (33.6 ml, 67 mmol, 2 M in sodium methylsulflnylmethide) cooled to room temperature, (4-carboxybutyl)-triphenyl-phosphonlum bromide (15.64, 35 mmol) in DMSO (40 ml) was added dropwise. After the deep red liquid had been stirred for a further 20 min, 14 mnol) in DMSO (40 ml) was added. The a solution of the aldehyde (11) (5.3g. temperature was raised to 5O”C, and stlrring continued for 1 h. The mixture was poured into Ice-water and extracted with ethyl acetate. The cooled aqueous layer was acidified with dll. HCl and extracted with ethyl acetate (3 x 100 ml). The combined organic extracts were washed with water, dried (MgS04) and concentrated. The resulting crude product (5~) was dissolved in methanol (100 ml) and treated with K2CO3 (3!33 at reflux for 1 h. The methanol was stripped off and the mixture was poured Into ice-water, acidified with dil. HCl, extracted with ethyl acetate, washed with brine, dried and concentrated. To the oil-residue ethereal dlazomethane was added and the solution stlrred at 0°C for 1 h. To this solution were added few drops of acetlc acid In order to destroy the excess of reagent and the solvent was removed In vacua. The final product was purified by chromatography at medium pressure on silica gel elutlng with ethyl acetate/hexane l/l to yield the alcohol (g) as colourless oil (2.69, 43% from 2). m/z 428 (M+), 410, 397, 371. -1 3 530, 1 735, 1 250, 1 080, 1 040 cm . CDCl_) 5.3 (m 2 tl), 4.02 (m 1 HI, 3.75 (m 7 Ii), 3.5 (s 3 HI, 2.4(bs 1 H OH), 11 d), 0.8 (s 9 II), 0.05 (s 6 HI. 2,3-trans-3,4-c~s-2-Formyl-3-/6-methoxycarbonyl-hex-2~Z~-~/-4-t-butyldimethylsilyloxy-~ pentanone Ethylene Acetal (15). --To a solution of chromium trioxide (0.87q)-pyridine (1.5 ml)-complex in anhydrous methylene dichloride (20 ml), was added at O’C with stirring under argon, a solution of alcohol (14) (0.5g 1.2 mmol) In methylene dichloride (10 ml). After 20 mln the mixture was filtered on dry diatomaceous earth (Celite 2Og0, washed with ice-cooled HCl (1 N) and the solvent removed in vacua to give the aldehyde (15) (0.45g 90%). m/z 426 CM+), 395, 369. -1 dyw 2.0-1.5 (film) MHz (m CDCl 12 2 710, d),1 9.7 0.8 1 735, (s (d 9H), 11 720, HIA.05 15.4250. (s (m 6 1 HI. 2100HI,and4.25 1 040 (m cm 1 HI, .

3.9

(m 4 HI,

3.65

(s

3 H),

1391

Prostaglandins

Table--

4 CInf 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 1% 19 20

46.8 71.0 47.1 117.5 57.8 171.2

13

5

48.7 73.5 45.7 116.5 58.2 171.7

C N.m.r.

chemical

8

115.7 137.3 33.3 47.1 71.6 47.9 117.0 57.8 170.8

2

115.5 137.9 32.6 44.8 71.3 47.1 117.7 51.3 59.3

shifts

and

for

Compounds 11 14

10

115.7 137.6 32.7 47.2 71.1 67.2 116.1 68.8 63.0

asslgnements

200.3 63.3 61.8 71.0 47.2 115.8 48.6 63.1

Chemical shifts in p.p,m. downfleld from Me4Sl. fourier mode with a Varian FT 80 spectrometer. b) Prostane numbering. c) Assignements may be

173.3 25.1 c 26.0 i 27.0 129.7 129.7 33.4 45.6 71.5 47.1 117.6 51.6 60.0

Spectra

were

cyclopentanoids

15

16

qz;;

+;

128.6 130.6 33.3 45.8 71.9 47.8 117.5 63.0 200.1

taken

17 173.1

173.1

173.1

+zi 129.1 129.8

tn

33.3 50.4 71.5 68.3 117.7 55.1 146.3 132.9 198.3 60.14 31.8

129.4 128.0 33.1 50.9 71.0 48.3 117.6 55.0 138.1 130.0 72.9 37.9 32.3

16.1

14.3

C6D6

a,b

derivative

at

20.00

1% 173.1 27.0 c 25.6 t 25.2 129.4 128.5 33.3 50.6 71.0 48.2 117.5 56.9 137.5 129.8 72.4 37.9 32.3

IL.2 MHz in

reversed.

References and notes. and W.L.killler, j.Aied.Chem., D.R.Yorton, D.C.Petersen, E.E.Nlehlzawa, 1. (a) G.L.Bundy, 26, 790. (1983); (b) M.Fukushima, T.Kato, R.Ueda, K.Ota, S.Narumiya, and O.Havalshl, Ic) R.Ueno, K.Ifonda, S.lno&, and ~ochem.Biophys.Res.~ommun., 9, 956, (1982). O.Hayaishl, Proc.Natl.Acad.Scl.USA, 80, 1735, (1983): (d) E.J.Corey, K.Shlnoli. J.Am.Chem. 105, 1662, (1983) and references cited hereln. s0c.E chemical synthesis of PGDs: PGD (a) t:,tIayashi and T.Tanouchi, j.Org.Chem., 2. Previoz W.L.&ller, R.R.Gorman, and G.L.Bundy, Prostaglan2, 2115, (1973); (b) E.E.Nishizawa, dins. 2, 109, (1975); (cl N.H.Andersen, S.lmamoto, and D.H.Plcker, Prostaglandtns, G, 61,(1977). See also reference la. (d) E.F.Jenny, P.Schaublin, H.Fritz, and H.Fuhrer, Tetrahedron Lett., te) E.W.Collinston, C.J.Wallis, and I.Waterhouse, 2235, (1974); Tetrahedron Lett., 26, 3125, (1983): (f) D.P.Reynolds, R.F.Newton, and S.M.Roberts, j.Chem.Soc.,Chem.Comyun., 1150, (1979); (g) R.F.Newton, D.P.Reynold, C.F.Webb, and S.hi.Roberts, j.Chem.Soc.,Perkin Trans.1, 2055, 11981); (h) T.W.iIart, D.A.hletcalfe and F.Scheinmann, j.Chem.Soc.,Chem.Commun., 156, (1979); (if A.G.Cameron, A.T.Hewson and A.H. Wadsworth, Tetrahedron Lett., 2, 561, (19821; (1) M.Suzuki, A.Yanagisawa, and R.Noyori, Tetrahedron Lett., 1383, (1984). G.Catnelll, M.Panunzlo, L.Plessi, G.Martelll, G,Spunta, Gazz.Ch~m.ltal.,ll4, 327, 3. (a) (b) A.Bonginl, G.Cainelll, D.Giacomlni, M.Panunzio, R.Danleli, Gxrtellt, (1984); G.Spunta, j.Chem.Soc.; Perkin Trans. 1, 000, (cl A.Bonqini, G.Cainelli, 1985 : D.Slacomlni, M.Panunzio, G.Martelll, G.Spunta, Tetrahedron, lo, 2861 (1984) A.Lechevallier, kl.Pellet, J.ht.Conia, Synthesis, 63, (197%). 6. F.Huet, H.C.Brown, S.Krlshmamurty, Tetrahedron, 35, 567, (19791; (bf E.J.Corey, R.K.Varma, 5. (a) J.Am.Chem.Soc., 93, 7319, (1971). stereospeclflcally reductton 6. This is rather surprisingly sance NaBH 1s known to g’ve a 47 mixture of diastereomerlc alcohols in molecules of similar structure . However previous studies in prostaglandins field have shown that the same stereospe yf;c l$gductlon takes place when the C-11 carbonyl group 1s protected by a dlthiane ring . The reason of remarkable this stereospecific reduction is currently u.~der investigation in our laboratory. E.G.Daniels, F.H.Lincoln, J.E.Pike. j.Am.Chem.Soc., 2, 2124, 11972) and 7. G.L.Bundy, references cited thereln. (a) F.H.Lincoln, 8. W.P.Schneider, and J.E.Pike, J.Org.Chem., 951, 3&, i 1973). H.J.Schnelder, N.Nguyan-Ba, and F.Thomas, Tetrahedron, 23, 2327, (1982). 9. 10. G.Catnelli, F.Manescalchl, G,Martelli, M.Panunzio, L.Plessi, Work in preparation. 11. E.J.Corey, A.Venkateswarlu, j.Am.Chem.Soc., 94, 6190, (19721. 12. (a) E.J.Corey, G.T.Kwlatkowski, j.Am.Chem.Soc., 88, 5654, (1966): (b) E.J.Corey,

the

G. CNNELLIet al.

1392 E.Hamanaka,

Ibid,,

g,

2758,

(1967);

(c)

A.p.Grieco,

Ch.Pogonowskt, x,

95. 3071,

(1973). (1979); (b) A.G.Cameron, 13, (a) R.F.Newton and D.P.Rcynolds, Tetrahedron Latt-9 3981, A_T.Hewwn, A.H.Wadsworth, J.Chem.Soc.Perkin 1, 2337, (1984).

SCHEME

1

(2)

(4): R = OH;

R’ = H

4s) : R = H

(5): R = l-4;

R’ = OH

(10) : R = COCH,

IS): R = H;

R’ = OTs

(7): R =ONO,;

R’ = H

(8): R = OSiMe,;

R’ = H

ill):

R = COW,

4

(121:R = COW,;

R’= H

(13): R=

H;

R=N

(14): R=

H;

R’= Me

0

(I@):

117): R=H;

R’ =OH

120): ~~014

(18):

R’=H

(16):

R=R’=

R=OH;

R=H;

R’=OH R*=H