Sul one di ec ed alkyla i e b idge clea age
o
oxabicyclic inyl sul ones wi h o ganoli hium
eagen s (1)
Oxabic
ic1
o inil sul onas: Ro u a alquilan e di ec a del puen e con eac i os
o ganolí icos
ARJONA, O. and PLUMET. J.
Depa amen o de Química O gánica 1, Facul ad de Química, Uni e sidad Complu ense,
28040 Mad id, Spain.
ABSTRACT
An
e icien egio-and s e eocon olled me hodology o he alkyla i e b idge
clea age
o
oxabicyclic inyl sul ones is desc ibed. A ange
o
7 -oxabicyclic[2.2.1. ]hep enyl
and 8-oxabicyclic [3.2.1.]oc enyl sul ones has been ound o unde go an o e all syn
S~'
opening when ea ed wi h a wide a ie y
o
o ganoli hium eagen s and li hium
aluminum hyd ide. In his manne , higWy unc ionalized cyclohexenyl and cyclohep enyl
sul ones, e sa ile syn he ic in e media es, a e now a ailable in high yields. The
comple e s e eoselec i i y encoun e ed in he exo conjuga e addi ion may be explained
by chela ion
o
he o ganome allic eagen wi h he oxygen b idge and s e ic ac o s.
Fu he mo e, less-s ained subs a es allow o comple e con ol
o
he addi ion and
elimina ion s ages.
Key
wo ds:
Oxabicyclic compounds. Syn
S~'
.
Exo conjuga e addi ion.
RESUMEN
Se desc ibe una in e esan e o u a alquilan e egio-y es e eocon olada del puen e de
oxabiciclo inil sul onas. Las 7-oxabiciclo[2.2.
1]
hep enil y 8-oxabiciclo [3.2.
1.]
oc enil
sul onas su en ape u as syn
S~'
cuando se a an con una amplia a iedad de eac i os
o ganolí icos e hidu o de li io y aluminio. De es a o ma, se ob ienen ciclohexenil y
ciclohep enil sul onas, al amen e uncionalizadas, que son in e medios sin é icos e sá iles.
La comple a es e eoselec i idad encon ada en la adición conjugada exo puede explica se
en base a la quelación del eac i o o ganome álico con el oxígeno puen e.
Palab as
cla e: Compues os oxabiciclicos. Syn S~
'
.
Adición conjugada exo.
Recibido: 5-4-1995.
Acep ado: 28-4-1 995.
BIBLID [0004-2927(1995) 36:3; 417-432]
A s Pha maceu ica, 36:3; 417-432,
1995
418 ARJONA, O. and PLUMET. J.
INTRODUCTION
Oxabicyclic compounds a e aluable in e media es (2) o he syn hesis
o
a a ie y
o
molecules
o
biological in e es (3). Recen ad ances in asymme ic
Diels-Alde p ocesses (4), enzyma ic (5) and chemical (6) esolu ions should
ende hese in e media es e en mo e a ac i e o o ganic chemis s and encou age
he sea ch o new egio- and s e eocon olled unc ionaliza ions
o
hese subs a es.
A c ucial ans o ma ion in many syn heses employing oxabicyclic in e me-
dia es A (Scheme
1)
has been he clea age
o
he oxygen b idge o p oduce
unc ionalized cyclohexane o cyclohep ane de i a i es B. To his end, many
g oups ha e de eloped di e en solu ions including [3-elimina ions
o
sui able
de i a i es (7), ea men wi h s ong acids (8), educ i e elimina ion
o
endo
unc ionali ies such as Cl o S02Ph (9), agmen a ion (10) and hyd oly ic
condi ions (11). Howe e , all hese me hods ha e ailed in se e al cases (9,
12)
and none
o
he aboye p o ocols allow o he cons uc ion
o
ca bon-ca bon
bonds h oughou he b idge clea age s ep. Thus, he igid bicyclic s uc u es,
powe ul elemen s o s e eo- and egiocon ol, a e no u ilized o his c ucial
ans o ma ion.
Se e al yea s ago we epo ed a new egio- and s e eoselec i e clea age
o
he oxygen b idge
o
simple oxano bomenic aleohols 4 and 5 wi h o ganoli hium
eagen s o p oduce cyclohexenediols 10 (13) (Scheme
1).
While his me hodology,
coupled wi h ou p ocedu es o p epa e endo 4 o exo 5 subs a es (14) was la e
ound o be qui e gene al (15), he inhe en lack o egiocon ol became appa en
a
an ea ly s age; namely, egiocon olled condi ions
o
p epa e isome ic cyclohexenols
14 could no be ound.
In
ac , ei he p o ec ion
o
he ee aleohol, 7, o
sepa a ion
o
he ee aleohol om he eac i e cen e by a me hylene b idge,
9, esul ed in d ama ic losses
o
egioselec i i y. The same beha io was
obse ed in he case
o
8-oxabicyclo[3.2.1.]oc enyl ca binols 6 and 8 (16a).
Thus, he eac ion
o
6 wi h -BuLi a o ds compound 11 egioselec i ely
whe eas in he case
o
8, a ca. equimolecula mix u e
o
egioisome ic
hyd oxycyclohep enes 13 and 15 was ob ained. These limi a ions and ou in e es
in he de elopmen
o
egiospeci ic me hodology o achie e he alkyla i e
b idge clea age owa ds ei he isome (12-13 o 14-15) was a ma e o in ensi e
esea ch in ou labo a o y.
The in oduc ion
o
an elec on wi hd awing subs i uen on he double bond
was en isaged o be an appealing and s aigh o wa d solu ion o his p oblem.
In
his manne , he egiochemis y
o
he p ocess should
be
eadily con olled
and u he mo e he syn he ic po en ial
o
he opening p oduc s would be inc eased
subs an ially. A phenylsul onyl unc ionali y (Scheme JI) appea ed pa icula ly
a ac i e a his s age since he equi ed subs a es e and E should be eadily
a ailable om a a ie y
o
oxabicyclic compounds (17) (see below) and he
syn he ic e sa ili y
o
inyl sul ones is well documen ed (18, 19).
I
was
A s Pha maceu ica, 36:3; 417-432, 1995
SULFONE DIRECTED ALKYLATIVE BRIDGE CLEAVAGE OF OXABICYCLIC VINYL... 419
Scheme 1
,
( E
, O
n1
, '
,
,
A
~x
y
1
X=
CN,
y=
OAc, n= 1
2
X=Y=O
,n= 1
3
X=Y=O,n=2
n=
1,2
4 X=
H,
alkyl, inyl, a yl,
Y=
OH
,
n=
1
5 X= OH, Y= alkyl, inyI, a yl,
n=
1
6 X= Me, Y =
OH,
n=
2
7 X=
Me,
Y= OBn, n= 1
8 X=Me,
Y=OBn,n=2
9 X=
H,
Y= CH2
0H
, n= 1
•
OH
ó:
n1
I '
I I
" ,
, I
,
,
B
OH
~)n
VX
y
10 X=
H,
alkyl, inyl, a yl,
Y=
OH,
R=
Me,
n-Bu,
Ph,
e c.,
n=
1
11
X= Me,
Y=
OH,
R=
-Bu,
n=
2
12 X= Me, Y= OBn,
R=
n-Bu,
n=
1
13 X=
Me,
Y=
OBn,
R=
-Bu,
n=
2
~x
OH
14 X=
Me,
Y= OBn R= n-BuLi,
n=
1
15 X=
Me,
Y=OBn, R= -BuLi,
n=
2
expec ed ha conjuga e addi ion
o
an o ganoli hium eagen
(R
3
Li)
o inyl
sul ones e and E would gene a e an a-sul onyl ca banion which would unde go
B-eli nina ion gi ing ise o adduc s D and F espec i ely.
In
his pape we epo a ull accoun
o
ou e o s in his ield (16) which
ha e esul ed
in
an e icien egio- and s e eocon olled me hodology o achie e
he alkyla i e b idge clea age
o
oxabicyclic inyl sul ones o p oduce subs i u ed
hyd oxycyclohexenyl
o
cyclohep enyl inyl sul ones.
A s Pha maceu ica, 36:3; 417-432,
19
95
SULFONE DIRECTED ALKYLA TIVE BRIDGE CLEA V AGE OF OXAB
TC
YCLIC VTNYL... 419
Scheme 1
OH
I
I I
(
:
,On
I
I I
I
I
I
..
cJ:
ni
I I
A
1 X= CN, Y= OAc,
n=
1
2
x=
Y=
O,
n=
1
3
X=Y=0,n=2
n=
1,2
I
4 X=
H,
alkyI, inyI,
a yI,
Y =
OH,
n= 1
5 X=
OH,
y = alkyI, inyI,
a yI,
n=
1
6 X=Me,
Y=OH,n=2
7 X=
Me,
Y= OBn,
n=
1
8 X=
Me,
Y= OBo,
n=
2
9 X=
H,
Y= CH2
0H
, n= 1
I I
" I
, I
B
OH
~)n
Vx
y
10 X= H, alkyI, inyI,
a yI,
Y=
OH
,
R=
Me,
n-Bu,
Ph,
e c.,
n=
1
11
X=
Me,
Y=
OH
,
R=
-Bu, 0= 2
12 X= Me,
Y=
OBn, R= n-Bu,
n=
1
13 X=
Me,
Y=
OBn,
R=
-Bu,
n=
2
~x
OH
14 X=
Me,
Y=
OBn
R=
n-BuLi,
n=
1
15 X=
Me,
Y=OBn,
R=
-BuLi,
n=
2
expec ed ha conjuga e addi ion
o
an o ganoli hium eagen (R3Li) o inyl
sul ones e and E would gene a e an
a-
sul onyl ca banion which would unde go
B-eli nina ion gi ing ise o adduc s D and F espec i ely.
In
his pape we epo a ull accoun
o
ou e o s in his ield (16) which
ha e esul ed in an e icien egio- and s e eocon olled me hodology o achie e
he alkyla i e b idge clea age
o
oxabicyclic inyl sul ones o p oduce subs i u ed
hyd oxycyclohexenyl o cyclohep enyl inyl sul ones.
A s P
ha
maceu ic
a,
36:3; 417-432,
19
95
420 ARJONA, O. and
PL
UMET. J.
Scheme
11
OH
0=0,1
e D
0=0,1
E F
RESULTS AND DISCUSSION
P epa a ion
o
subs a es. Scheme III ou lines he syn he ic ou es o ob ain
inyl sul ones 26-28 as well as hei egioisome s 37-39. The key s ep
o
hese
syn heses is he egioselec i e addi ion
o
sul enyl halides unde kine ic con ol
o bicyc1ic subs a es, such as 1 and
2,
con olled by emo e subs i u ion on C-
2 (17). Thus, addi ion
o
phenylsul enyl chlo ide o ke ones 2 and 3 ollowed by
unc ional g oup manipula ions a o ds chlo osul ides 20,
21
and 22 (20).
Al ema i ely, cyanoace oxy de i a i e 1 and he endo-benzyl e he s ( esul ing
om eac ion
o
MeMgB wi h 2 and 3 (14, 16a) and subsequen benzyla ion)
gi e ise o egioisome ic chlo osul ides 31, 32 and 33, p esumably unde s e ic
con ol (17). Subsequen oxida ion and elimina ion comple e he sequence (21).
In
o de o ex end he scope
o
he me hodology, we p epa ed subs a es 45,
49 and 55
as
shown in Scheme IV (see expe imen al sec ion). Oxano bomene
me hanol 9 was benzoyla ed and PhSCI was' added wi h comple e s e ic con ol
(22).
Remo al o he benzoa e g oup and ea men wi h sodium hyd ide, in e es ingly,
esul ed in smoo h o ma ion
o
inyl sul ide 43 (23). S anda d benzyla ion and
oxida ion a o ded 45. Al ema i ely, icyc1ic sul ide 46 (22) was ea ed wi h
an excess
o
n-BuLi in an e o o es he applicabili y
o
ou s ain-di ec ed
A s Pha maceu ica, 36:3; 417-432,
1995

SULFONE DIRECTED ALKYLA TIVE BRIDGE CLEA V AGE OF OXA
BI
CYCLIC VINYL... 421
2,3
2
2,3
1
a,
b, e •
a, g
Scheme
lIJ
a
PhS~
O n
el""
~
x
y
20 X= Me, Y= OBn, n= 1
21 X= Me, Y= OBn, n= 2
d,e
--------<.~
22 X= y = OCH2CH2
0,
n= 1
b,c,a
CI~x
d,e
•
PhS =
y
31 X= Me, Y= OBn, n= 1
32 X= Me, Y= OBn, n= 2
a,
,
g
33 X= y = OCH2
CH
2
0,
n= 1
•
•
PhS02~))D
~x
y
26 X= Me, Y= OBn, n= 1
27 X= Me, Y= OBn, n= 2
PhS02~X
37 X= Me, Y= OBn, n= 1
38 X= Me, Y= OBn, n= 2
39 X= y = OCH2CH2
0,
n= 1
aKey: (a) PhSCl, CHCl3 o CH3CN, O o
c.
(b) MeMgB , E 20 O o
c.
(e) NaH, BnB , (ea . n-Bu4Nl
o 21 and
32=
THF, O oc
o
e lux. (d) mCPBA, K2
C0
3, O oc
o
. . o 26, 28, 37 and 39;
MMPP; MeOH, O oC
o
.
.
o 27 and 38. (e) DBU, CR2
Cl
2, O
oC
. ( )
1.
NaOMe, MeOR. 2.
aq CR2
0,
O oC
o
. . (g) E hyleneglyeol,
p-
TsOR,
CJI
6,
e lux. O e all yields, 26: 26% om
2;
27: 54% om 3; 28: 62% om 2;
37
: 33% om 5; 38: 64% om 3; 39: see e e enee 21.
B-elimina ions (24) o his case, o a o d an excellen yield
o
inyl sul ide 47.
Vinyl sul one 49 was p epa ed as aboye. On he o he hand, diol 50 (25) was
con e ed o he highly subs i u ed and di e en ially p o ec ed inyl sul one 55
using an analogous syn he ic ou e, i. e., o ma ion
o
he icyc1ic sul ide,
s ained-di ec ed ing opening and unc ional g oup manipula ions.
Alkyla i e B idge Clea age
7-0xabicyclo[2.2.1.}hep enes sys ems. In iew o p e ious e o s in ol ing
SN2' addi ions
o
o ganome allic eagen s o cyclic inyl sul ones (26, 27),
we selec ed G igna d, cup a e and o ganoli hium eagen s o ou s udy.
P elimina y expe imen s wi h me hyl G igna d and cup a e eagen s did no
A
s Pha maceu ica, 36:3; 417-432,1995
422 ARJONA, O. and PLUMET. J.
Scheme ¡ a
Q:(-OH
a, b,
c,d
e,
-J1J
-)]J
PhS ""
'-OH
PhS0
2 ""'
-08n
9
Z=H
43 43
50
Z=C
H2O
H_
I
b o,9
b, h o
50
PhS
u
g
PhS~
e,
PhSo,,~
-I O ""'
-OH
• I O
0-
' ""'
-08n
46
Z=H
47
Z=H
49
Z=
H
52
Z=
CH
2OMOM 53
Z=
CH
2OMOM
55
Z=
CH
2OMOM
aKey: (a) PhCOC1, py , O
oC.
(b) PhSCl, CHCI3, O
oC.
(e) NaOMe, MeOH, O oC o
.
. (d) NaH,
THF, O
oC
o . . (e) NaH, BnB , (ea . n-Bu4Nl o 55), THF,
.
.
o e lux. ( ) MMPP; MeOH,
O
oC
o .
.
(g)
n-BuLi,
THF,
-78
oC
. (h) CH2(OMe
h,
p-TsOH, CH2CI2, e lux. O e alI yields,
45:
61
% o o 9; 49: 58% o o 46;
55
: 37% o o 50.
p oduce he desi ed ans o ma ion. Acco dingly, we examined he eac ion
be ween 37 and an excess
o
MeLi
(3
equi ,
-78
oC,
THF,
10
min) and an
excellen yield
o
56a
was ob ained. Encou aged by his smoo h ans o ma ion,
we explo ed o he o ganoli hium eagen s and hese esul s a e ga he ed in
Table
1.
In
clea con as o MeLi, he eac ion be ween 37 and n-
BuLi
(2
equi , THF) was ema kably slow, e en a O
oC,
and, mo e impo an ly, he
isola ed yield
o
56b
we e e y low and a iable amoun s
o
o he by-
p oduc s, en a i ely cha ac e ized as desul onyla ed 37 and
56b
, we e also
p oduced. A e conside able expe imen a ion, we ound ha he use
o
oluene, a less coo dina ing sol en (28) a o ded excellen yields
o
alkyla i e
opening p oduc
56b
(en y 2). Simila ly, PhLi and inylli hium (29) (2
equi ) ga e excellen yields
o
56c and
56d
espec i ely (en ies 3 and 4).
While we do no ully unde s and he di e ences ound be ween MeLi and
n-BuLi in THF, he c ucial e ec o he use
o
oluene o he la e is
no ewo hy (30).
A s Pha maceu ica, 36:3; 417-432,1995
SULFONE
D1RE
CTED ALKYLA TIVE BRIDGE CLEA V AGE OF OXABICYCLlC VINYL...
423
Table
I.
- SN2' Opening Reac ions
o
7
-0
xano bomenic Vinyl Sul ones wi h O ganoli ium
Reagen s and LiAllI4
En y
lb
2C
3C
4C
5b
6c
7d
8d
9d
JO
b
Il
b
12b
13
b
14b
15
d,
16
d
17
b
4 OH
RLi
~
3
I O2 X
R~
6
------~~~
2
PhSO 6 =
2 1 Y
37
X=Me
,
Y=OBn
39
X=
y = OCH2
aI
20
45
X=
H, y =
CH
2
0Bn
4
PhS0
2
1j
3 Z
I O2 X
6
:.
1 y
26
X=Me
,
Y=OBn
28
X=
Y=
OCH2aI20
49
X=
Z= H, Y = CH2
0Bn
5 X
PhSO
3
~
~
2 4 Y
56
RLi
4
PhS02Q~
5 Z
2 6 X
~
57
55
X
=H
,
Y=
CH
2
0Bn
, Z=
CH
2
0MOM
Subs a e R P oduc
37
Me
56a
37 n-
Bu
56b
37 Ph 56c
37 Vinyl 56d
39 Me 56e
45
Me
56
45 n-Bu 56g
45 AlIyl 56h
45 2-P openyl 56i
39 He 56j
26 He 57a
26
Me 57b
28
Me
57c
49 Me 57d
49
I-
Hexynyl 57e
49 2-Fu yl
57
55 Me 57g
Yi
el
d(
%)"
87
78
86
95
85
81
78
64
67
62
65
80
75
82
74
69
88
NOTES: aUnop imized yields o pu e
p od
uc s.
bIn
THF, - 78 oc . cIn Toluene,
-7
8 oC.
dIn
a
mix u e ToU
E p
, 1:1, - 78 oC. eLiAlH4.
O
o
c.
A s Pha maceu ica, 36:3; 417-432,
1995
424
ARJONA,
O.
and PLUMET. J,
To explo e he an icipa ed egiocon olled b idge opening, inyl sul one 26
was ea ed wi h MeLi, and adduc 57b esul ing om nucleophilic addi ion o
C-6 and subsequen B-elimina ion was ob ained in good yield (en ies
11
and
12). Simila ly, ke als 28 and 39 smoo hly p oduced cyclohexenyl sul ones 57c
and 56e (en ies
13
and 5) espec i ely. The me hodology was also applied o
subs a es 45, 49 and 55 wi h simila esul s (en ies 6-9 and 14-17). O he
syn he ically use ul o ganoli hium eagen s such as allylli hium
(31
, 32), 2-
u ylli hium (33) and l-hexynylli hium (34) we e also employed wi h simila
esul s.
In o de o ex end he scope
o
his me hodology, he eac ions be ween
oxano bo nenic sul ones 26 and 39 and li hium aluminum hyd ide (4 mola
equi ,
-78
oC)
we e s udied. Thus, ai yields
o
cyclohexenyl sul ones 57a and
56j we e ealized in wha , o ou knowledge,
is
he s case
o
SN2'
displacemen s
o
a hyd ide eagen on o a inyl sul one (en ies
10
and 11) (35).
I
should be
men ioned ha he eac ion was e y dependen on he amoun
o
hyd ide used
and on he eac ion empe a u e. Thus, sa u a ed sul one 59 (Scheme V) was
ob ained a O
oC
(4 mola equi LAR); howe e , a -78
oC
(1.5 mola equi
LAR), bicyclic sul one 58 (49%) was he majo p oduc .
26
Scheme V
PhSO
Z
Y1:'l
-----------
~Me
THF
LAH
OBn
58
PhSOZ'Q,
Me
+
~
OBn
UO
57a
PhSOZI" 'Q Me
+ ,
OBn
UO
59
The egio- and s e eochemis y
o
hese p oduc s we e eadily es ablished
by spec oscopic echniques, pa icula ly
by
'H
NMR
wi h he aid
o
selec i e
decouplings and DNOE expe imen s. Fo ins ance,
56a
and 57b p esen ed qui e
di e en spli ing pa e ns o he inylic p o ons (56a,
d,
J =
1.3
Hz; 57b, ddd,
J=
5.4,3.0
,2.4 Hz). In addi ion,
H-l
exhibi s a ans diaxial coupling (12.6 Hz)
in
56a
and an equa o ial-axial coupling (3.7 Hz) in 57b. The la ge homoallylic
coupling ound o 57b
(J
25ax = 3.0 Hz)
is
also no ewo hy.
8-0xabicyclo[3.2.1.}oc enesys ems. The ex ension
o
his me hodology o 8-
oxabicyclic[3.2.1.]oc ene sul ones 27 and 38 was explo ed in o de o assess he
in luence
o
a less s ained oxygen b idge in he o e all SN
2'
p ocess. Addi ionally,
he syn he ic po en ial
o
he esul ing p oduc s (no easily a ailable highly
unc ionalized cyclohep enes) was pa icula ly a ac i e (36). In his con ex ,
A s Pha maceu i
ca.
36:3; 417-432, 1995