Trends in Synthetic Carbohydrate Chemistry - American Chemical

Chapter 6

Synthesis of Chiral Pyrrolidines from Carbohydrates

Downloaded by MONASH UNIV on May 21, 2013 | http://pubs.acs.org Publication Date: December 30, 1989 | doi: 10.1021/bk-1989-0386.ch006

J. Grant Buchanan, Alan R. Edgar, Brian D. Hewitt, Veerappa B. Jigajinni, Gurdial Singh, and Richard H. Wightman Department of Chemistry, Heriot-Watt University, Riccarton, Edinburgh EH14 4AS, United Kingdom We have extended our work on a new synthesis of the anti protozoal antibiotic anisomycin to the necine bases of the pyrrolizidine alkaloids, in particular retronecine and crotanecine. The key intermediate, (2R,3S,4R)-2-(alkoxy carbonylmethyl)-3,4—isopropylidenedioxypyrrolidine, has been prepared by three distinct routes from D-ribose and D-erythrose, using reactions of high stereoselectivity. A new approach to anisomycin from D-erythrose using Wittig methodology is outlined. We were f i r s t a t t r a c t e d t o c h i r a l p y r r o l i d i n e s by the p o s s i b i l i t y o f a p p l y i n g methods used i n C - n u c l e o s i d e s y n t h e s i s (1) t o the s y n t h e s i s of the a n t i p r o t o z o a l a n t i b i o t i c a n i s o m y c i n (1) from D - r i b o s e ( 2 ) . The approach, w h i c h d i f f e r s from o t h e r r e c e n t syntheses ( 3 , 4 , 5 ) , i s o u t l i n e d i n Scheme 1. Three p o i n t s may be n o t e d : ( i ) i n the Grignard a d d i t i o n to 2,3-0-isopropylidene-D-ribose (2) the D - a l l o c o n f i g u r a t i o n i n (3) i s i n accordance w i t h the F e l k i n - A n h model (6) and i s t o be expected from our e a r l i e r work (1) ; ( i i ) methanes u l f o n y l a t i o n o f the oxime (4) serves not o n l y t o dehydrate the oxime but t o i n t r o d u c e a l e a v i n g group f o r r i n g c l o s u r e a t the next step; ( i i i ) the i n t r a m o l e c u l a r d i s p l a c e m e n t t o form the p y r r o l i d i n e r i n g [(5) ( 6 ) ] proceeds c l e a n l y and w i t h complete i n v e r s i o n o f c o n f i g u r a t i o n 03,5,2) . The Geissman-Waiss l a c t o n e (7) (8) i s a well-known p r e c u r s o r o f (+)- r e t r o n e c i n e (j8) ( 8 - 1 1 ) , one o f the most common n e c i n e bases d e r i v e d from the p y r r o l i z i d i n e a l k a l o i d s . We envisaged t h a t t h e p y r r o l i d i n e e s t e r (9) c o u l d be c o n v e r t e d i n t o the l a c t o n e ( 7 ) , r e p r e s e n t i n g a f o r m a l s y n t h e s i s o f ( + ) - r e t r o n e c i n e (8) (12). I n a d d i t i o n , (9) s h o u l d be capable o f t r a n s f o r m a t i o n i n t o the r e l a t e d n e c i n e base c r o t a n e c i n e (10) ( 1 3 ) . Scheme 2 i l l u s t r a t e s a s y n t h e s i s o f the b e n z y l o x y c a r b o n y l d e r i v a t i v e (11) o f the e s t e r (9a) u s i n g c h e m i s t r y analogous t o t h a t f o r a n i s o m y c i n (Scheme 1 ) . I n the f o r m a t i o n o f the D - a l l o - t r i o l ( 1 2 ) , NOTE: This chapter is dedicated to Professor Luis F. Leloir on the occasion of his 80th birthday.

c

0097-6156/89/0386-0107$06.00/0 1989 American Chemical Society

In Trends in Synthetic Carbohydrate Chemistry; Horton, D., et al.; ACS Symposium Series; American Chemical Society: Washington, DC, 1989.

108

TRENDS IN SYNTHETIC CARBOHYDRATE CHEMISTRY

ÇH Ar

ÇH Ar

2


Η0

Me

H

OH

Ί

qJ) *Me

Ç

CH Ar

2

HÇ0H

0 H

HÇ0H CH 0H

2

...

HCOMs

c

HCNOH 4

H

V

6

zl

H

5

vjjj

M

OAc

Reagents:

4

{J

Me ~ ^N.

6

5

H

Q Me

Ar = p-MeOC H -

N

2

OAc

Ms = MeS0 -

A l l = CH :CHCH -

2

2

i , ArCH MgCl-THF; 2

i i i , MsCl-C H N; 5

5

v i , A110H-HC10 ; 4

i i , NaI0

iv, LiAlH^;

2

4>

Bzl = PhCH 2

then H0NH C1-C H N; 3

5

5

v, HBr-HOAc, then KOH;

v i i , BzlCl, then Ac^O-C^N;

+

v i i i , PdC-H , then PdC-H . 2

Scheme 1


6. BUCHANAN ET AL.

Synthesis of Chiral PyrrolidinesfromCarbohydrates


d i a l l y l z i n c , formed from the G r i g n a r d r e a g e n t i n s i t u gave h i g h e r s t e r e o s e l e c t i v i t y compared to the G r i g n a r d r e a g e n t i t s e l f ( 1 4 ) . The y i e l d of the f i n a l o x i d a t i o n s t e p was poor and o t h e r avenues to e s t e r s (9) were e x p l o r e d . The f i r s t of these used the W i t t i g r e a c t i o n as an important s t e p , as o u t l i n e d i n Scheme 3.

(10) R = OH

(9a) R = Me (9b) R = E t

2 , 3 - 0 - I s o p r o p y l i d e n e - p - e r y t h r o s e (13) (15), o b t a i n e d e i t h e r by a c e t o n a t i o n of D-erythrose""(16) or by p e r i o d a t e o x i d a t i o n of 3,4-0isopropylidene-£-arabinose (15,17), r e a c t e d w i t h ethoxycarbonylmethyl e n e t r i p h e n y l p h o s p h o r a n e i n r e f l u x i n g benzene (18) to g i v e the Ea l k e n e (14) as the major p r o d u c t (56%) t o g e t h e r w i t h the Z-alkene (15) (21%). As expected (18-20) the a l k e n e s (14) and (157 r e a d i l y c y c l i z e d to t e t r a h y d r o f u r a n s (16) under v e r y m i l d b a s i c c o n d i t i o n s . I n i t i a l l y the 3 anomer of (16)'was f a v o r e d [86% from (14) and 100% from (15,)]; at e q u i l i b r i u m the α anomer p r e p o n d e r a t e d (82%) (19). Our i n t e n t i o n was to c o n v e r t the a l c o h o l s (14) and (15) i n t o the c o r r e s p o n d i n g amines and then to e f f e c t c y c l i z a t i o n to the p y r r o l i d i n e (9b). In the event, t h i s o b j e c t i v e was a c h i e v e d more e a s i l y and w i t h complete s t e r e o s e l e c t i v i t y . Treatment of the a l c o h o l (14) w i t h t r i f l u o r o m e t h y l s u l f o n i c a n h y d r i d e ( t r i f l i c anhydride) a t -78°C a f f o r d e d the e s t e r (17) which c o u l d be i s o l a t e d and c h a r a c t e r i z e d . We knew from p r e v i o u s e x p e r i e n c e (2) t h a t s u l f o n y l e s t e r s v i c i n a l t o an i s o p r o p y l i d e n e a c e t a l are r e l a t i v e l y s t a b l e . The t r i f l a t e (17) r e a c t e d c l e a n l y w i t h p o t a s s i u m a z i d e and 18-crown-6 i n d i c h l o r o m e t h a n e a t room temperature. The c r y s t a l l i n e p r o d u c t ^ [68% o v e r a l l from ( 1 4 ) ] was n o t the a z i d e (18) but the i s o m e r i c Δ - t r i a z o l i n e ( 1 9 ) . C l e a r l y the i n i t i a l l y formed a z i d e (18) had undergone i n t r a m o l e c u l a r 1 , 3 - c y c l o a d d i t i o n to the double bond of the u n s a t u r a t e d e s t e r (21-24). The s t e r e o c h e m i s t r y of the t r i a z o l i n e ( l g ) , determined by p r o t o n nmr s p e c t r o s c o p y , showed t h a t the r e a c t i o n was s t e r e o s p e c i f i c . There a r e s e v e r a l known examples of t h i s r e a c t i o n (24), i n c l u d i n g one i n the c a r b o h y d r a t e s e r i e s ( 2 5 ) . When the t r i a z o l i n e was t r e a t e d w i t h sodium e t h o x i d e (26) the d i a z o e s t e r (20) was r a p i d l y formed by r i n g - o p e n i n g and was i s o l a t e d i n 85% y i e l d . H y d r o g e n o l y s i s of the d i a z o group of (20) gave the r e q u i r e d p y r r o l i d i n e e s t e r (9b) ( 9 0 % ) . The Z-alkene (15) was s u b j e c t e d to the same sequence (Scheme 4 ) . The t r i f l a t e (21) was e a s i l y o b t a i n e d , but i n t h i s case r e a c t i o n w i t h a z i d e i o n gave d i r e c t l y the d i a z o e s t e r (22) . M o l e c u l a r models show t h a t the t r i a z o l i n e c o r r e s p o n d i n g to (19) has s e v e r e s t e r i c i n t e r a c t i o n s (27) and i s more a c c e s s i b l e t o d e p r o t o n a t i o n ( c f . réf. 23). S t e r e o c h e m i c a l and m e c h a n i s t i c a s p e c t s of the a z i d e c y c l o a d d i t i o n s


109

110


i 2 CH H

/

/

f 2 - HCOH

?

HCOH

—

I

90%

H C 0

Hçcr

C M e

2

/

CH

iii

H

2

HCOMs

V

M

H t 0 *

M

98% e

H

K e M

2

Hco' CN

HC:N0H

HÇOH

CH n 2 CH 9

H

CH1 1

S 2 CH

L M e

:

CH 0H 2

CO.Bzl

C0 Bzl o


70%

C0 Me 2

V

°X° Me

Reagents:

Me

Me

i, All^n;

11

Me

~

i i , NalO^,, then HON^Cl-C^N;

i i i , MsCl-C H N; 5

iv, LiAlH^, then BzlOCOCl;

5

v, NaIO.-ΚΜηΟ,, then CH_N . 4 4 2 2 0

Scheme 2

C0 Et o

l L

°v?

H

H

σ

C

• 2- isomer 15

^

i

ÇΗ

9

1

Ο Λ

v . "·'· ϊίΐ**» Μ

M

Χ

CH R

e

2

13

(— 14

17 R = oTf

_ ,V

C

R=0H

Ci8

R= N

V^CH C0 Et 2

Ô J

3

M

e

A

2

β - V M

e

*

16

68%,

y Me

Reagents:

ÇJN

85% Me

1

i

Me

9

2

Me

20

0

H

%

M

e

X

co Et 2

M e

n

u

9b

i , Ph P=CHC0 Et-C H , 80 C; i i , NaOEt-EtOH; 3

2

6

6

i i i , Tf 0-C H N-CH C1 , - 78°C; 7 ~ 2

5

5

2 2

2 2

iv, KN -18 crown 63

CH C1 , RT; v, PdC-H 2

2

2

Scheme 3



6.

BUCHANAN ET AL.

Synthesis ofChiral Pyrrolidines from Carbohydrates 111

are discussed i n a f u l l paper (Buchanan, J.G.; Edgar, A.R. : Hewitt, B.D. J . Chem. S o c , Perkin Trans. 1, i n press). Hydrogenolysis of (22) gave the 3-ester (23). A further route to the α-ester (9b) emerged when (22) was heated i n b o i l i n g toluene to give the expected vinylogous urethane (24) (28). When (24) was treated with sodium cyanoborohydride under acidic conditions reduction occurred at the 3-face to give ester (9b). This reduction played a part i n another synthesis of (9a) which i s now described (Scheme 5). 2,3-O-Isopropylidene-D-erythrose (13) was converted, v i a the oxime, into the cyanomethanesulfonate (25). In a Blaise reaction (29), the zinc enolate derived from methyl bromoacetate reacted with (25) to give the enamino esters (26). Cyclization was effected with l,8-diazabicyclo[5.4.0]undec-7-ene (DBU) and the product ( 2 J ) reduced with cyanoborohydride. The resulting pyrrolidine α-ester (9a) was i d e n t i f i e d by reaction with benzyl chloroformate to give the amide (11), whose structure had been rigorously assigned. The amide (11.) > prepared by this method, was used for the subsequent transformations. The conversion of (11) into the Geissman-Waiss lactone i s shown in Scheme 6. Acidic hydrolysis of the isopropylidene group was accompanied by lactone ring formation to give (28) i n 82% y i e l d . Deoxygenation by the Barton procedure (30) afforded the lactone (29) (90%) which was e a s i l y deprotected to give the Geissman-Waiss lactone as the hydrochloride (7), constituting a formal synthesis of (+)-retronecine (8)(£-10). The ester (9a) contains the necessary oxygen f u n c t i o n a l i t y , of the correct stereochemistry, for a synthesis of crotanecine (10) (Scheme 7). A l k y l a t i o n of the p y r r o l i d i n e ring nitrogen was achieved using ethyl bromoacetate, producing the diester (30) i n 85% y i e l d . Attempts to induce Dieckmann c y c l i z a t i o n of diester (30) d i r e c t l y under several conditions f a i l e d , so i t was converted by acidic hydro l y s i s , into the lactone (31). Protection of the hydroxyl group i n (31) was effected as the t e r t r b u t y l d i m e t h y l s i l y l ether (32). When treated i n toluene at room temperature with potassium ethoxide (32) underwent the Dieckmann condensation. The intermediate ketoester (33) was reduced with borohydride and the r e s u l t i n g diastereomeric mixture acetylated to give the diacetates (34) i n 40% y i e l d . Elim ination of acetic acid from (34) (DBU) afforded the unsaturated ester (35) (70%). The ester group i n (35) has been reduced, by means of diisobutylaluminium hydride, to give the protected crotanecine (36)» but we have experienced great d i f f i c u l t y i n i s o l a t i n g crotanecine i n substance after fluoride ion deprotection. (Buchanan, J.G.; J i g a j i n n i , V.B.; Singh, G.; Wightman, R.H. J . Chem. Soc., Perkin Trans 1, i n press). At this stage i n our work, Benn and his colleagues (31) described a synthesis of crotanecine from (2S,4R)-4-hydroxyproline (37) i n which the s i l y l ether (32) i s an intermediate. The sub sequent reactions are similar to our own projected synthesis, involving both (33) and (34). We have also investigated an alternative route to anisomycin (I) from 2,3-O-isopropylidene-D-erythrose (13) using a Wittig reaction as the f i r s t step. It was argued that p-nitrophenylmethylenetriphenylphosphorane (38) (32) would be an ideal reagent for construction of the carbon skeleton of anisomycin (Scheme 8). I t was envisaged that the p-nitro group i n the alkene products Ε(39) and (40)3 would enable



E

,

¥ S „ HC0'

C M e

2

A

CH R 2

R= OH

15


^21

if Me

R= OTf

J

ii

Me

Me

Me

ν

70%

I

66%

»

Me

Me

23

Reagents:

Λ.

Me

Me

22

24

i , Tf 0-C H N--CH Cl ,-78°C; 2

5

5

2

CH C1 , RT; 2

i i , KN -18 crown 6-

2

3

i i i , PdC-H ;

2

iv, PhMe, 110°C;

2

+

v, NaBH^CN, EtOH, H . Scheme 4

C0 Me 2

13 «

idL f°YMe

«i

H

— ~

HCO>

M e

2

f°^CMe - H C 0 ' 2 H

C

25

/

η °X° 9a /\ ~ Me Me

Reagents.

M

°X° / \ Me

Me

i , HONl^Cl-C^N, RT;

e

26

27

i i , MsCl(12 equiv.)-C H N-23 C; 5

i i i , Zn, BrCH C0 Me (5 equiv.)-THF, reflux; 2

2

(3 equiv.)-CH Cl , RT; 2

2

5

iv, DBU

v, NaBH^N, MeOH, HC1;

v i , BzlOCOCl-Et N-CH Cl . 3

2

2

Scheme 5


Synthesis of Chiral PyrrolidinesfromCarbohydrates

BUCHANAN ET AL.

C N

°2

B z l

.

< ^

2

I f

Reagents:

i , 80% aq. CF C0 H, RT; 3

2

i i , 1,1 -thiocarbonyl--

diimidazole-C^N-THF, r e f l u x , (2.2 equiv.)-C H , r e f l u x ; 6

i i i , Bu^SnH

i v . PdC-H

6

2


Scheme 6

^C0 Ef 2

r

9a

Vr-CQ-Me 85% f — J *-CQJ

85%

0 0

2S

H O

Me

2

\n\

^ Me

C0 Et

31

HO O ^ o 30

iii I 7 0 % Bu

/^4-CO H

Me Si0 2

Η

(

2

"VN

2

,C0 Et 2

H

37

32

"I

HO

μ r

HO

0 H

H

Ç°2 * E 1

R0 36 R = B u ^ M e S i 7

. AcO

υ

C 0

9 " E t

Bu'Me Si0-

Si Ο Me

OAc

2

70%

9

Reagents:

33

10 R = H

;

i , BrCH^O^t-NEt^-THF; iii,

i i , 80% aq. TFA, RT;

t-BuMe SiCl-imidazole-DMF; 2

RT, then HOAc; C H N; 5

5

i v , KOEt-PhMe,

v, NaBH^-EtOH, then Ac 02

v i , DBU-CH C1 , RT; 2

2

v i i , DIBAL-

hexane-CH Cl , -78°C. 2

2

Scheme 7


114



H

1

0

°χ°

OAc Arcu H N0

13

Ç /i

2

• LU

ï&

—

CH r

H

£-

'HJ 7o9 % 70

/

U

C H

\iv.vii

A

HÇ0'

51%

i s o m e r

~

2

iv v

°X°

2

C M e

Π

2 3

«

Me Me

N

A

Ν

Me

Reagents:

+

CH 0H?i

23 ~

PhJ "3

\»

2

M e

πι

M E

*

Y

i ,

Me

~

80 C;

t-BuOH;

i i , NaOMe-MeOH;

i v , Tf 0-C H N-CH Cl , -78°C; 2

5

5

v, KN ~18 crown 6-CH Cl , RT; 3

v i i , NH

3

i i i , KOt-Bu-

2

2

2

2

v i , CH C1 2

2>

RT;

( l i q u i d ) - C H C l , RT. 2

2

Scheme 8



6.

BUCHANAN ET AL.

Synthesis ofChiral PyrrolidinesfromCarbohydrates 115

conjugate addition to take place (33) and permit the formation of a pyrrolidine ring. Reaction of (38) with (13) i n b o i l i n g benzene gave mainly the Z-isomer (39) (65%) together with some E-isomer (40) (5%). When each was treated with sodium methoxide i n methanol ring closure to the tetrahydrofurans (41,) occurred, but much more slowly than i n the analogous esters (14) and (15) (Scheme 3). The 3-isomer of (4^) was the sole product from (39) and the major product (5:1) from (40). The two isomers of (41) could be equilibrated using potassium tert-butoxide to give a mixture favouring the α-isomer (3:1), i n agreement with the ester series (19). When the t r i f l a t e of the Z-alkene (39) was treated with azide ion, the corresponding azide (42) could be isolated i n 79% y i e l d . Clearly the 1,3-cycloaddition occurs less readily than i n the ester series (Schemes 3,4). Attempts to convert the azide (42) into the Δ - t r i a z o l i n e (43) were unsatisfactory. When (42) was heated i n benzene solution the a z i r i d i n e (44) was the major product (51%). The structure was determined by Dr K.J. McCullough by X-ray c r y s t a l lography. At room temperature, dissolved i n dichloromethane, the azide (42) decomposed slowly (~50% after 7 days) to give low y i e l d s of a z i r i d i n e (44) and t r i a z o l i n e (43). The t r i f l a t e of (39) has been converted into the pyrrolidine (

Trends in Synthetic Carbohydrate Chemistry - American Chemical

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