Efforts toward the synthesis of (+)-Lyconadin A

Article abstract of DOI:10.1007/s12039-020-01771-8

Abstract: Synthetic efforts toward the synthesis of (+)-lyconadin A are described. B-Alkyl Suzuki coupling is utilized for combining 2-iodo cyclohexenone with the piperidine subunit. The piperidine subunit is derived from 5-bromo-3-nicotinic acid, and iod

Full text of DOI:10.1007/s12039-020-01771-8

J. Chem. Sci. ( 2 0 2 0 ) 1 3 2 : 9 6
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REGULAR ARTICLE
Efforts toward the synthesis of (+)-Lyconadin A
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i s u t i l i z e d f o r c o m b i n i n g 2 - i o d o c y c l o h e x e n o n e w i t h t h e p i p e r i d i n e s u b u n i t . T h e p i p e r i d i n e s u b u n i t i s d er i ve d
f r o m 5 - b ro m o - 3 - n i c o t i n i c a c i d , a n d i o d o c y c lo h e x e n o n e f r o m c o m m e r c i a l l y a v a il a b l e ( R) - p u l e g o n e. A n
i n t r am o l e c u l a r M i c h a e l r e a c t i o n i s e m p l o y e d f o r t h e c r e a ti o n o f t h e C 6 - C 7 b o n d .
Keywords. L y c o n a d i n - A; 5 - b ro m o - 3 - n i c o t i n i c a c i d ; B - a l k y l S u z u k i c o u p l i n g ; i n t r a m o l e c u la r M i c h ae l
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* F o r c o r re s p o n d e n c e
Electronic supplementary material: The online version of this article (https://doi.org/10.1007/s12039-020-01771-8) contains supple-
mentary material, which is available to authorized users.

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Scheme 1. E a r l i e r a p p r o a c h e s t o L y c o n a d i n - A .

J. Chem. Sci. ( 2 0 2 0 ) 1 3 2 : 9 6
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1 4
2
m ix tu r e w a s c o ol e d t o 0 °C , c a re fu l l y a c i d i fie d w i t h 2 N
tert-Butyl
3-hydroxy-5-(hydroxymethyl)piperidine-1-
H C l t o p H 3 a n d t h e r e a f t e r b a s i fi e d w i t h s o l i d N a C O t o
2
3
carboxylate (27): T o a s t ir r e d s o l u t io n o f p i p e r i di n ol
d e r iv a t i v e 26 ( 5 .1 2 g , 3 9 . 1 2 m m o l ) a n d T E A ( 1 1 m L, 7 8. 2 4
m m o l ) i n d i c h l o r o me th a n e ( 8 0 m L ) w a s a d d e d d i - tert- bu t yl
d i c a r b o n a t e ( 9 .2 m L , 4 0 m m o l ) i n d r o p w i s e m a n n e r a t 0 °C .
T h e m i x t u r e w a s s t ir r e d a t r t f o r 4 h . T h e r e a c ti o n m i x t ur e
w a s d i l u t e d w i t h w a t e r ( 5 0 m L ) a n d t h e p h a s e s w e re s e p -
a r a te d . T h e a q l a y e r w a s e x t r a c te d w i t h d i c h l o r o m e th a ne
( 2 x 1 0 0 m L ) , t h e c o m b in e d o r g a n i c l a y e r s w e r e w a s h ed
w i t h w a t e r ( 1 0 0 m L ) , b r in e ( 1 0 0 m L ) a n d d r i e d o ve r
N a S O . T h e s o l v e n t w a s e v a p o r a t e d u n d e r r e d u c e d p re s -
p H 8 . T h e m i x t u r e w a s fi l t e r e d t h r o u g h a C e l i t e p a d . T h e
fi lt r a t e w a s e xt r a ct e d w i t h e t h y l a c e t a t e ( 3 x 3 0 0 m L ) . T h e
c o m b i n e d o r g a n i c l a y e rs w e re w a s h e d s u c c e s s i v e l y w i t h
w a t er ( 3 0 0 m L ) , b r i n e ( 3 0 0 m L ) a n d d r i e d o v e r N a S O .
2
4
T h e s o l v e n t w a s e v a p o r a t e d u n d e r r e d u c e d p r e s s u r e t o
f ur n i sh t h e c r u d e c o m p o u n d w h i c h w a s p u r i fi e d b y c o l u m n
c h r o m at o g r a p h y o n s i l i c a g e l ( m e t h a n o l / d i c h l o r o m e th a n e ,
1 : 9 ) t o a f f o r d c om p o u n d 24 ( 9 g , 7 2 . 6 8 m m o l ) i n 8 5 % y i e l d
- 1
a s a n o il . I R ( K Br ) : 3 3 25 , 2 9 3 3, 1 5 96 , 1 4 4 4, 1 0 17 , 5 4 4 c m ;
1
H N M R ( 3 00 M H z , A c e to n e- d ) d 7 . 9 2 ( d , J = 1 . 7 H z , 1 H ) ,
2
4
6
s u r e t o f u r n i s h t h e c r u d e c o m p o u n d w h ic h w a s p u r i fi e d b y
c o l u m n c h r o m a t o g r a p h y o n s i li c a g e l ( e t h y l a c e t a t e : h ex a n es ,
8 : 2 ) t o a f f o r d t h e p r o d u c t 27 ( 8 .5 g , 3 6 . 8 m m o l ) i n 9 4%
y i e l d a s a s o l i d . T L C R f: 0 . 2 ( e t h y l a c e t a t e : h e x a ne , 8 :2 ) .
M . p . 9 3 - 9 5 °C . I R ( n e a t ) : 3 4 0 4 , 2 9 7 4 , 2 9 2 8 , 1 6 6 7, 1 42 9,
7 . 80 ( b s, 1 H ) , 7 . 01 ( d d, J = 2 . 5, 1 . 7 H z 1 H) , 4 . 8 1 ( bs , 2 H ) ,
1 3
4 . 52 ( s , 2 H) , 4 . 33 ( b s, 1 H ); C N M R ( 7 5 M H z , A ce t on e -d )
6
d 1 4 5. 2 , 1 3 8. 6 , 1 3 7 .7 , 1 3 6. 5 , 1 1 9. 7 , 6 2 . 5. M S ( E S I) : m / z 1 2 5
[ M?H ]?. H R MS ( E SI ): c a lc d . f o r C H N O : 1 2 5 .0 7 09 ;
f oun d : 1 2 5. 0 7 07 .
6
9
2
-
1
1
1
1
5
2
,
1
0
5
5
,
8
8
0
c
m
;
H
N
M
R
(
3
0
0
M
H
z
,
C
D
C
l
)
3
5-(Hydroxymethyl)pyridin-3-ol (25): T h e a m i n o p y r i d i n e d 3 . 8 8 – 3 .7 7 ( m , 1 H ) , 3 . 7 6 – 3 .6 4 ( m , 1 H ) , 3 . 6 4 – 3 .4 7 ( m , 2 H ),
d e r i va t i v e 24 ( 6 . 2 g , 5 0 . 0 m m o l ) w a s d i s s o l v e d i n a q s u l - 3 . 0 3 – 2 .6 3 ( m , 3 H ) , 2 . 0 6 ( d , J = 1 2 . 6 H z , 1 H ) , 1 . 8 5 – 1. 6 7 ( m ,
1 3
f ur i c a ci d ( 2 . 5 M , 7 5 m L ) a n d c o o l e d i n a n i c e b a t h . S m a l l 1 H ) , 1 . 4 5 ( s , 9 H ) , 1 . 3 5 – 1 .2 2 ( m , 1 H ) ; C N M R ( 1 2 5 M H z ,
p
o
r
t
i
o
n
s
o
f
N
a
N
O
(
3
.
4
5
g
,
5
0
m
m
o
l
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w
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r
e
a
d
d
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d
o
v
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1
5
5
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2
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8
0
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1
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6
6
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0
,
6
4
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8
,
5
1
.
0
,
4
6
.
5
,
3
7
.
4
,
3
6
.
3
,
2
3
1 0 m i n p e r i od . T h e s o l u t i o n w a s s t i rr e d f o r a f u r t h e r p e r io d 2 8 . 4 . M S ( E S I ) : m / z 2 5 4 [ M ?N a ] ?. H R M S ( E S I ) : c al c d f or
o f 3 0 m i n w h e r e a f t e r a q s u l f u r i c a c i d ( 1 M , 2 0 0 m L ) w a s z C H N O N a : 2 5 4 .1 3 6 8 ; f o u n d : 2 5 4 .1 3 6 8 .
1
1
2
1
4
a d d ed a n d t h e m i x t u r e h e a t e d t o 7 0 °C f o r 2 h . T h e r e a c t io n
m ix tu r e w a s c o ol e d t o 0 °C a n d s o l i d N a C O a d d e d t o
tert-Butyl 3-(((tert-butyldimethylsilyl)oxy)methyl)-5-hy-
droxypiperidine-1-carboxylate (28): T o a s t ir r e d s o l u t i on
o f d i o l 27 ( 8 .3 g , 3 5 . 9 m m o l ) i n a n h y d r o u s d i c h l o r o m e th a ne
( 7 0 m L ) w a s a d d e d i m id a z o l e ( 3 .7 3 g , 5 4 m m o l ) f o l lo w e d
b y T B S Cl ( 8 .3 g , 6 1 . 3 m m o l ) a t 2 5 °C . A f t e r 4 5 m i n , t he
2
3
a d j u s t t h e p H t o 8 . W a t e r w a s e v a p o r a t e d a n d t h e r e s i d u e
w a s e xt r a ct e d b y w a s h i n g w i t h M e OH : D C M ( 1 :1 )
( 20 0 m L ) . T h e s o l v e n t w a s e v a p o r a t e d u n d e r r e d u c e d
p re s su r e t o f u r ni sh t h e c r u d e c o m p o u n d w h i c h w a s p u r ifi e d
b y c o lu m n c h r o m a t o g r a p h y o n s i l i c a g e l ( m e t h a n o l: d i -
c h l o r o m e th a n e, 1 : 9 ) t o a f f o r d t h e p r o d u c t 25 ( 5 .8 g ,
r
e
a
c
t
i
o
n
m
i
x
t
u
r
e
w
a
s
q
u
e
n
c
h
e
d
w
i
t
h
s
a
t
u
r
a
t
e
d
a
q
N
H
C
l
4
( 2 5 m L ) a n d t h e p h a s e s w e r e s e p a r a t e d . T h e a q l ay e r w a s

9 6 P a g e 4 o f 1 4
J. Chem. Sci. ( 2 0 2 0 ) 1 3 2 : 9 6
e x t r a ct e d w i t h d i ch l o r o m e t h a n e ( 4 0 m L ) , t h e c o m b i n e d N M R ( 1 0 0 M H z , C D C l ) d 1 7 0 .0 , 1 5 5 .0 , 8 0 . 0 , 6 8 . 2 , 6 3. 8 ,
3
o rg a n i c l ay e r s w e r e w a s h e d w i t h w a t e r ( 5 0 m L) , b r in e 4 7 . 8 , 4 5 . 2 , 3 6 . 9 , 3 2 . 1 , 2 8 . 2 , 2 1 . 1 . M S ( E S I ) : m / z 2 96
( 50 m L ) a n d d r i e d o v e r N a S O . T h e s o l v e n t w a s e v a p o - [ M ?N a ] ?. H R M S ( E S I ) : c a l c d f o r C H O N N a :
2
4
1
3
2
3
5
r a t ed u n d e r r e d u c e d p r e s s u r e t o f u r n i s h t h e c r u d e c o m p o u n d 2 9 6 .1 4 7 4 ; f o u n d : 2 9 6 .1 4 6 1 .
w h i c h w a s p u r i fi e d b y c o l u m n c h ro m a t o g ra p h y o n s i l i c a g e l
tert-Butyl-3-acetoxy-5-(iodomethyl)piperidine-1-carbox-
ylate (31): T o a s t ir r e d s o l u t i o n o f p r im a r y a l c o h o l 30 ( 6. 4
g , 2 3 . 4 m m o l ) i n a n h y d r o u s d i c h l o r o m e t h a n e ( 50 m L )
u n d e r n i t r o g e n a t m o s p h e r e a t 0 °C , w e r e a d d e d i m i d a z ol e
( 5 .2 6 g , 3 5 . 1 m m o l ) , t r i p h e n y l p h o s p h i n e ( 9 .2 g , 3 5. 1
m m o l ) a n d i o d i n e ( 8 .9 8 g , 3 5 . 1 m m o l ) . T h e r ea ct i o n
m i x t u r e w a s s t ir r e d a t 0 °C f o r 1 h . A f te r c o m p l e t i on o f
t h e r e a c ti o n , d i l u t e t h e r e a c t io n m i x t u r e w i t h d ic h l or -
o m e t h a n e ( 5 0 m L ) a n d t h e e x c e s s i o d i n e w a s r e m ov ed b y
w a s h in g w i t h s a t . a q . N a S O s o l u t io n ( 5 0 m L ) a nd t he
( E t O A c /h e x a ne , 4 : 6 ) t o a f f o r d t h e p r o d u c t 28 ( 1 2 . 0 g , 3 4 . 7 8
m m ol ) i n 9 7 % y i e l d a s a s o l i d . T L C R f: 0 . 2 ( e t h y l
a c e ta t e :h e x an e , 4 : 6 ) . M . p . 8 8 - 9 0 °C . I R ( KB r) : 3 4 6 8 , 2 9 5 3 ,
-
1
1
2 9 3 1 , 2 8 5 7 , 1 6 7 6 , 1 4 3 8 , 1 0 9 4 , 8 4 1 , 5 8 1 c m ; H N M R
(
4
0
0
M
H
z
,
C
D
C
l
)
d
4
.
3
1
–
4
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1
4
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m
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1
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4
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0
8
(
d
d
,
J
=
1
3
.
2
,
3
4 . 1 H z , 1 H ) , 3 . 7 1 – 3 . 6 1 ( m , 1 H ) , 3 . 5 3 ( d d , J = 1 0 . 0 , 5 . 0 H z ,
1 H ) , 3 . 4 0 – 3 . 4 0 ( m , 1 H ) , 2 . 5 2 – 2 . 3 6 ( m , 2 H ) , 2 . 0 9 – 1 . 9 3 ( m ,
1 H ) , 1 . 7 9 – 1 . 5 9 ( m , 1 H ) , 1 . 4 4 ( s , 9 H ), 1 . 1 8 – 1 . 0 5 ( m , 1 H ) ,
1 3
0 . 8 9 ( s , 9 H ) , 0 . 0 4 ( s , 6 H ) ; C N M R ( 1 0 0 M H z , C D C l )
3
d 1 5 4 . 8 , 7 9 . 7 , 6 6 . 3 , 6 5 . 3 , 5 0 . 5 , 4 7 . 3 , 3 8 . 1 , 3 6 . 1 , 2 8 .4 , 2 5 . 8 ,
1 8 . 2 , - 5 . 5 . M S ( E S I) : m / z 3 6 8 [ M ?N a ] ?. H R M S ( E S I ) :
c a l cd f o r C H N O N a S i : 3 6 8 . 2 2 3 3 ; f o u n d : 3 6 8 . 2 2 3 3 .
2
2
3
p h a s e s w e r e s e p a r a t e d . T h e a q l a y e r w a s e x t r a c t e d w i t h
d i c h l o r o m e t h a n e ( 5 0 m L ) , t h e c o m b in e d o r g a n i c l ay e rs
w e r e w a s h e d w i t h w a t e r ( 5 0 m L ) , b r in e ( 5 0 m L ) a n d d ri e d
o v e r N a S O . T h e s o l v e n t w a s e v a p o r a t e d u n d e r r ed uc e d
1
7
3
5
4
tert-Butyl 3-acetoxy-5-(((tert-butyldimethylsilyl)oxy)met-
hyl)piperidine-1-carboxylate (29): T o a s t i rr e d s o l u t i o n o f
s e c o n d a r y a lc o h o l 28 ( 1 0 . 0 g , 2 9 . 0 m m o l ) i n a n h y d r o u s
2
4
p r e s s u r e t o f u r n i s h t h e c r u d e c o m p o u n d w h ic h w a s p ur i -
fi e d b y c o l u m n c h r o m a t o g r a p h y o n s i li c a g e l ( Et O A c /
h e x a n e , 0 . 2 : 9 . 8 ) t o a f f o r d t h e p r o d u c t 31 ( 7 .8 8 g , 2 0. 6
m m o l ) i n 8 8 % y i e l d a s a v i s c o u s o i l . T L C R f: 0 . 2 ( et h yl
a c e t a t e : h e x a n e , 0 . 2 : 9 . 8 ) . I R ( K Br ) : 2 9 6 8 , 2 8 5 5, 1 73 5,
d i c h l o r o m et h a n e ( 6 0 m L ) w a s a d d e d E t N ( 8 . 1 m L ,
3
z 5 8 m m ol ) f o l l o w ed b y a c e t y l c h l o ri d e ( 2 . 0 m L , 3 0 m m o l )
a t 0 °C . A f te r 1 h , t h e r e a c t i o n m i x t u r e w a s q u e n c h e d b y
-
1
1
a d d i n g s at u r at e d a q N H C l ( 5 0 m L ) . D i c h l o r o me h t a n e w a s
4
1 6 8 3 , 1 4 1 5 , 1 2 4 8 , 1 1 5 5 , 1 0 3 2 , 8 7 9 c m ; H N M R ( 50 0
M H z , C D C l ) : d 4 . 8 4 – 4 . 6 6 ( m , 1 H ) , 4 . 0 8 – 3 .7 9 ( m , 2 H ),
a d d e d ( 5 0 m L ) a nd a q l a y e r w a s s e p a r a t e d . T h e o r g a n i c
l a ye r w a s w a s h ed w i t h b r i n e ( 5 0 m L ) a n d d r i e d o v e r N a
3
2
-
3 . 1 5 ( d , J = 6 . 3 H z , 2 H ) , 2 . 9 9 – 2 .4 9 ( m , 2 H ) , 2 . 2 0 ( dt , J =
1 2 . 7 , 4 . 0 H z , 1 H ) , 2 . 0 6 ( s , 3 H ) , 1 . 8 6 – 1 .6 9 ( m , 1 H ) , 1 .4 7
S O . T h e s o l ve n t w a s e v a p o r a t e d u n d e r r e d u c e d p r e s s u r e t o
4
1 3
( s , 9 H ) , 1 . 4 0 – 1 .3 6 ( m , 1 H ) ; C N M R ( 1 0 0 M H z , C D C l ) :
f ur n i sh t h e c r u d e c o m p o u n d w h i c h w a s p u r i fi e d b y c o l u m n
c h r o m at o g r a p h y o n s i l i c a g e l ( E t O Ac : h e x a n e , 1 : 9 ) t o a f f o r d
t h e p r o d u c t 29 ( 1 0 . 4 g , 2 7 . 0 m m o l ) i n 9 3 % y i e l d a s a n o i l .
T L C R f: 0 . 2 ( e t h y l a c e t a t e : h e x a n e , 1 : 9 ) . I R ( KB r ) : 2 9 5 4 ,
3
d 1 7 0 .0 , 1 5 4 .6 , 8 0 . 3 , 6 7 . 9 , 4 8 . 5 , 4 7 . 5 , 3 6 . 7 , 3 6 . 4, 2 8. 4 ,
2 1 . 2 , 8 . 7 . M S ( E S I ) : m / z 4 0 6 [ M ?N a ] ?. H R M S ( ES I) :
c a l c d f o r C H O N N a I : 4 0 6 .0 4 9 1 ; f o u n d : 4 0 6 .0 4 9 2 .
1
3
2
2
4
-
1
1
2 8 5 8 , 1 7 4 3 , 1 6 9 8 , 1 4 2 1 , 1 2 3 5 , 1 1 0 6 , 8 3 7 , 7 7 6 c m ; H
N M R ( 5 0 0 M H z , C D C l ) : d 4 . 7 8 – 4 . 6 3 ( m , 1 H ) , 4 . 2 8 – 4 .1 1
3
tert-Butyl-3-acetoxy-5-((4,4,5,5-tetramethyl-1,3,2-dioxa-
borolan-2-yl)methyl)piperidine-1-carboxylate (20): T o a
s u s p e n s i o n o f C u I ( 3 8 m g , 0 . 2 m m o l ) , L i O tB u ( 3. 2 g ,
4 0 . 2 m m o l ) a n d b i s ( p i n a c o la to ) d ib o r o n ( 1 0 .1 5 g , 4 0. 0
m m o l ) i n t e t r a h y d r o f u r a n ( 4 0 m L ) w a s a d d e d t h e s o l u t i on o f
a l k y l i o d i d e 31 ( 7 .7 g , 2 0 . 1 m m o l ) i n t e t r a h y d r o f ur a n ( 30
m L ) . T h e r e s u lt i n g r e a c ti o n m i x t u r e w a s s t ir r e d v i g o r o us l y
a t 2 5 °C f o r 1 8 h . T h e r e a c t io n m i x t u r e w a s t h e n d il u te d
w i t h e t h y l a c e t a t e ( 1 m L ) a n d fi l te r e d t h r o u g h a p ad o f
C e l it e . T h e s o l v e n t w a s e v a p o r a t e d u n d e r r e d u c e d p re s s u r e
( m, 1 H ) , 4 . 0 7 ( d d , J = 1 3 . 1 , 4 . 0 H z , 1 H ) , 3 . 5 3 ( d d , J = 1 0 . 0 ,
5 . 0 H z , 1 H ) , 3 . 5 0 – 3 . 3 8 ( m , 1 H ) , 2 . 6 7 – 2 . 5 8 ( m , 1 H ) , 2 . 4 9
( dd , J = 1 3 . 1 , 1 0 . 8 H z , 1 H ), 2 . 1 0 – 1 . 9 9 ( m , 4 H ) , 1 . 8 3 – 1 .7 4
1 3
( m, 1 H ) , 1 . 4 9 – 1 . 4 1 ( m , 1 0 H) , 0 . 8 9 ( s , 9 H ) , 0 . 0 3 ( s , 6 H ) ;
C
N M R ( 7 5 M H z, C DC l ) : d 1 7 0 . 0 , 1 5 4 . 6 , 7 9 . 8 , 6 8 . 6 , 6 4 . 9 ,
3
4 7 . 1 , 4 5 . 9 , 3 7 . 4 , 3 2 . 8 , 2 8 . 3 , 2 5 . 8 , 2 1 . 1 , 1 8 . 2 , - 5 . 5 . M S ( E S I ) :
m /z 4 1 0 [ M ?N a ] ?. H R M S ( E S I) : c a l c d f o r C H O N a :
4 1 0 . 2 3 3 9 ; f o u n d : 4 1 0 . 2 3 3 9 .
2 0 1 6
2
tert-Butyl 3-acetoxy-5-(hydroxymethyl)piperidine-1-car- t o f u r n i s h t h e c r u d e c o m p o u n d w h ic h w a s p u r i fie d b y c ol -
boxylate (30): T o a s o l u t i o n o f c o m p o u n d 29 ( 1 0 . 3 g , 2 6 . 6 u m n c h r o m a t o g r a p h y o n s i li c a g e l ( E t O A c : h e x a n e , 0 .5 : 9 .5 )
m m ol ) i n T H F ( 2 5 m L ) c o o l e d t o 0 °C , T B A F ( 1 M i n t o a f f o r d t h e p r o d u c t 20 ( 6 .7 g , 1 7 . 6 8 m m o l ) i n 8 8 % y ie l d a s
T H F , 2 7 m L , 2 7 m m o l ) w a s a d d e d . T h e r e a c t i o n m i x t u r e a v i s c o u s o i l . T L C R f: 0 . 2 ( e t h y l a c e t a t e : h e x a n e , 0 . 2 :9 . 8) . I R
w a s a ll o w e d t o w a r m t o r t a n d s t i rr e d f o r 1 2 h . T h e s o l - ( n e a t ) : 2 9 7 7 , 2 9 3 1 , 1 7 4 1 , 1 6 9 6 , 1 4 1 8 , 1 3 7 1 , 1 2 3 7 , 1 15 0,
- 1
1
v e n t w a s e v ap o r a t e d u n d e r r e d u c e d p r e s s u re t o a f f o r d t h e 1 0 3 4 , 8 7 3 c m ; H N M R ( 4 0 0 M H z , C D C l ) d 4 . 7 4– 4. 6 3
3
c r u d e c o m p o u n d w h i c h w a s p u r i fi e d b y c o l u m n c h r o - ( m , 1 H ) , 4 . 3 2 – 4 .1 0 ( m , 1 H ) , 4 . 0 8 – 3 .9 3 ( m , 1 H ) , 2 . 5 4 ( t , J =
m a t o g r a ph y o n s i li c a g e l ( E t O A c : h e x a n e , 1 : 9 ) t o a f f o r d t h e 1 1 . 2 H z , 1 H ) , 2 . 3 1 ( t , J = 1 1 . 2 H z , 1 H ) , 2 . 2 3 – 2 .1 1 ( m , 1 H ),
p ro d u c t 30 ( 6 . 5 g , 2 3 . 9 m m o l ) i n 9 0 % y i e l d a s a s o l i d . 2 . 0 4 ( s , 3 H ) , 1 . 8 8 – 1 .7 3 ( m , 1 H ) , 1 . 4 5 ( s , 9 H ) , 1 . 2 5 ( s , 1 2H ) ,
1 3
T L C Rf: 0 . 2 ( e t h y l a c e t a t e : h e x a n e , 3 . 0 : 7 . 0 ). M . p . 9 6 - 9 8 °C . 1 . 1 6 – 1 .0 6 ( m , 1 H ) , 0 . 8 – 0 .7 ( m , 2 H ) ; C N M R ( 1 25 M H z ,
I
R
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4
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9
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2
9
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2
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6
7
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.
7
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6
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7
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3
1 0 7 0 , 1 0 2 9 , 8 6 3 , 5 7 0 c m ; H N M R ( 5 0 0 M H z , C D Cl ) d 3 1 . 1 , 2 8 . 4 , 2 4 . 8 , 2 1 . 2 , 1 5 . 9 . M S ( E S I ) : m / z 4 0 6 [ M ?N a ] ?.
- 1
1
3
4 . 7 8 – 4 . 70 ( m , 1 H ) , 4 . 0 5 – 3 . 4 7 ( m , 4 H ) , 3 . 3 0 – 2 . 6 9 ( m , 2 H ) , H R M S ( E S I ) : c a l c d f o r C H B O N N a : 4 0 6 .2 3 7 7 ; f ou nd :
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4 0 6 .2 3 9 7 .

J. Chem. Sci. ( 2 0 2 0 ) 1 3 2 : 9 6
P a g e 5 o f 1 4 9 6
(6R)-2,2,6-Trimethyl-1-oxaspiro[2.5]octan-4-one (34): T o - 7 8 °C w a s a d d e d m C P BA ( 7 0 w t % , 1 9 . 6 g , 7 9 . 8 m m o l) .
a m i x tu r e o f ( R) - p u l e g o n e 33 ( 1 5 . 2 2 g , 1 0 0 m m o l ) a n d a q A f te r 1 0 m i n t h e r e a c t io n m i x t u r e w a s d i l u t e d w i t h s a t u ra t ed
H O ( 3 0 % , 5 6 . 7 m L , 5 0 0 m m o l ) i n m e t h a n o l ( 3 0 0 m L ) a q N a S O ( 5 0 m L ) . T h e l a y e r s w e r e s e p a r a t e d a n d t he a q
2
2
2
3
c o o l e d a t 1 5 °C w a s a d d e d a q L i O H ( 0 . 5 M , 2 0 m L ) i n a l a y e r w a s e x t r a c te d w i t h D C M ( 2 x 5 0 m L ) . T h e c o m b in e d
d ro p w i s e m an n er o v e r a p e ri o d o f 1 5 m i n s . S t i rr i n g w a s o r g a n i c l a y e r s w e r e w a s h e d w i t h s a t u r a te d a q N aH C O
c o n ti n u e d f o r 4 h a t 2 0 °C . T h e r e a c t i o n m i x t u re w a s t h e n ( 5 0 m L ) , w a t e r ( 5 0 m L ) , b r i n e ( 5 0 m L ) a n d d r i e d o ve r
3
p o u r e d i n t o b r i n e s o l u t i o n ( 1 5 0 m L ) a n d t h e a q l a y e r w a s N a S O . T h e s o l v e n t w a s e v a p o r a t e d u n d e r r e d u c e d p re s -
2
4
e x t r ac t ed w i t h e th y l a c e t a t e ( 2 x 2 5 0 m L ) . T h e c o m b i n e d s u r e t o f u r n i s h t h e c r u d e s u l f o x i d e . W h ic h w i t h o u t f ur t he r
o rg a n i c l ay e r s w e r e w a s h e d w i t h w a t e r ( 1 0 0 m L) , b r in e p u r ifi c a t i o n a n d c h a r a c t e r i z a t io n w a s t a k e n a h e a d t o t he
( 10 0 m L ) a n d d r i e d o v e r N a S O . T h e s o l v e n t w a s e v a p o - n e x t s t e p . T h e c r u d e s u l f o x i d e w a s d i s s o l v e d i n C C l
4
2
4
r a t ed u n d e r r e d u c e d p r e s s u r e t o f u r n i s h t h e c r u d e c o m p o u n d ( 8 0 0 m L ) a n d C a C O ( 7 9 0 m g , 7 . 9 m m o l ) w a s a d d ed a nd
3
w h i c h w a s p u r i fi e d b y c o l u m n c h ro m a t o g ra p h y o n s i li c a g e l t h e m i x t u r e w a s r e fl u x e d f o r 2 4 h . T h e r e a c ti o n m i x t ur e w a s
( E t O A c /h e x a ne , 0 . 5 : 9 . 5 ) t o a f f o r d t h e e p o x i d e 34 a s a 1 : 1 fi l te r e d t h r o u g h a p a d o f C e l it e a n d t h e fi l tr a te w a s e va po -
m ix tu r e o f d i as t er o m e rs ( 1 5 . 9 6 g , 9 5 . 0 m m o l ) i n 9 5 % y i e l d r a t e d u n d e r r e d u c e d p r e s s u r e t o a f f o r d t h e c r u d e c o m p ou nd .
a s a n o i l . T L C R f: 0 . 2 ( e t h y l a c e t a t e : h e x a n e , 1 : 9 ) . I R ( K Br ) : D i s t il l a t io n u n d e r r e d u c e d p r e s s u r e a f f o r d e d e n o n e 11 ( b. p .
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2 . 1 9 – 2 . 1 2 ( m , 1 H ) , 2 . 0 4 – 1 . 9 3 ( m , 5 H ) , 1 . 7 9 – 1 . 6 8 ( m , 2 H ) , C D C l ) d 6 . 9 6 ( d d d , J = 1 0 . 1 , 5 . 5 , 2 . 6 H z , 1 H ) , 6 . 0 6 –5 . 97
3
1 . 4 5 – 1 . 3 9 ( m , 8 H ) , 1 . 1 8 ( s , 3 H ) , 1 . 1 7 ( s , 3 H ) , 1 . 0 4 ( d , J = ( m , 1 H ) , 2 . 5 2 – 2 .3 6 ( m , 2 H ) , 2 . 2 9 – 2 .1 7 ( m , 1 H ) , 2 . 1 7– 1. 9 9
1 3
6 . 3 H z , 3 H ) , 1 . 0 2 ( d , J = 7 . 1 H z , 3 H ) ; C N M R ( 1 0 0 M H z , ( m , 2 H ) , 1 . 0 8 ( d , J = 6 . 5 H z , 3 H ) . M S ( E S I ) : m / z 1 11
C D C l ) d 2 0 7 . 2 , 2 0 6 . 1 , 6 9 . 9 , 6 9 . 8 , 6 3 . 0 , 6 2 . 9 , 5 1 . 0 , 4 9 . 2 , [ M ?H ] ?.
3 3 . 7 , 3 2 . 6 , 3 0 . 3 , 2 9 . 8 , 2 9 . 6 , 2 5 . 9 , 2 1 . 7 , 1 9 . 6 , 1 9 . 4 , 1 9 . 3 ,
3
1 9 . 0 , 1 8 . 6 . M S ( E S I ): m / z 1 9 1 [ M ?N a ] ?. H R M S ( E S I ) :
c a l cd f o r C H O N a : 1 9 1 . 1 0 4 8 ; f o u n d : 1 9 1 . 1 0 4 9
(R)-2-Iodo-5-methylcyclohex-2-enone (19): T o a s o l u t i on
o f I ( 1 2 .4 g , 4 8 . 5 4 m m o l ) a n d p y r i d i n e ( 3 .9 m L , 4 8 . 5 4 m m o l)
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(5R)-5-Methyl-2-(phenylthio)cyclohexanone (35): T o a 11 ( 5 .3 4 g , 4 8 . 5 4 m m o l ) i n D C M ( 5 0 m L ) . T h e m i x t u r e w a s
s u sp e n s i o n o f s o d i u m h y d r i d e ( 6 0 % i n m i n e r a l o il , 5 . 7 g s t ir r e d a t 0 °C f o r 3 0 m i n , a l l o w e d t o w a r m t o r o o m t em p er -
1 4 2 . 5 m m o l ) i n a n h y d r o u s T H F ( 1 4 0 m L ) c o o l e d a t 0 °C a t u r e a n d s t ir r e d f u r t h e r f o r a p e r io d o f 2 h . T h e r ea ct i o n
w a s a dd ed a s o l u t i o n o f t h i o p h e n o l ( 1 4 . 5 m L , 1 4 2 . 5 m m o l ) m i x t u r e w a s q u e n c h e d w i t h H C l ( 1 N , 5 0 m L ) . T h e l ay e rs
i n a n hy dr o u s T H F ( 1 4 0 m L ) . A ft e r t h e e v o l u t i o n o f w e r e s e p a r a t e d a n d t h e a q l a y e r w a s e x t r a c te d w i t h D C M ( 2 x
h y d r o g e n h ad c ea s e d , t h e m i x t u re w a s s t i rr e d a t r o o m 5 0 m L ) . T h e c o m b in e d o r g a n i c e x t r a c ts w e r e w a s h e d w i t h
t e m p e r a tu r e f o r 0 . 5 h a n d a s o l u t i o n o f d i a s t e r e o m e r i c s a t u r a te d N a S O s o l u t i o n ( 5 0 m L ) , b r in e ( 5 0 m L ) a n d d ri e d
2
2 3
m ix tu r e o f p u l eg o n e e p o x i d e 34 ( 1 5 . 8 6 g , 9 4 . 4 m m o l ) i n o v e r N a S O . T h e s o l v e n t w a s e v a p o r a t e d u n d e r r ed uc e d
2
4
a n h y dr o u s T H F ( 9 5 m L ) w a s a d d e d . T h e r e s u l t i n g m i x t u r e p r e s s u r e t o f u r n i s h t h e c r u d e c o m p o u n d w h ic h w a s p u ri fi e d b y
w a s t h en r e fl u x e d f o r 2 4 h , c o o l e d t o r t a n d q u e n c h e d w i t h c o l u m n c h r o m a t o g r a p h y o n s i li c a g e l ( E t O A c / h ex an e ,
s a t u r at e d a q N H C l ( 1 0 0 m L ) . T h e l a y e r s w e re s e p a r a t e d 0 . 3 : 9 . 7 ) t o a f f o r d t h e p r o d u c t 19 ( 1 0 .2 3 g , 4 3 . 6 9 m m o l ) i n
4
a n d t h e a q l ay e r w a s e x t r a c t e d w i t h e t h y l a c e t a t e ( 2 x 1 0 0 9 0 % y i e l d a s a n o i l . T L C R f: 0 . 2 ( e t h y l a c e t a t e : h ex an e ,
2 0
m L ) . T h e c om b in e d o r g a n i c l a y e r s w e r e w a s h e d w i t h w a t e r 0 . 3 : 9 . 7 ) . [ a] = - 8 0 .2 ( c 1 . 0 , C H C l ) ; I R ( K Br ) : 2 9 1 9, 1 67 8,
D
3
- 1 1
( 10 0 m L ) , b r i n e ( 1 0 0 m L ) a n d d r i e d o v e r N a S O . T h e 1 5 8 7 , 1 4 5 0 , 1 4 0 8 , 1 1 1 7 , 1 0 1 6 , 8 7 5 , 5 4 6 c m ; H N M R ( 50 0
2
4
s o lv e n t w a s e va p o r a t e d u n d e r r e d u c e d p r e s s u re t o f u r n i s h M H z , C D C l ) : d 7 . 7 1 ( d d , J = 5 . 9 , 3 . 0 H z , 1 H ) , 2 . 7 6 ( dd , J =
3
t h e c r u d e c o m p o u n d w h i c h w a s p u r i fi e d b y c o l u m n c h r o - 1 2 . 1 , 1 . 6 H z , 1 H ) , 2 . 5 0 – 2 .4 1 ( m , 1 H ) , 2 . 3 4 – 2 .2 5 ( m , 2 H ),
1 3
m a t o g r a ph y o n s i l ic a g e l ( E t O Ac / h e x a n e , 0 . 5 : 9 . 5 ) t o a f f o r d 2 . 2 1 – 2 .1 1 ( m , 1 H ) , 1 . 0 7 ( d , J = 6 . 3 H z , 3 H ) ; C N M R ( 10 0
t h e p r o d u c t 35 a s a n i n s e p a ra b l e m i x t u r e o f d i a s t e ro m e r s i n M H z , C D C l ) : d 1 9 2 .5 , 1 5 8 .5 , 1 0 3 .5 , 4 5 . 1 , 3 8 . 0 , 3 0 . 4, 2 0. 7 .
3
1 : 3 r a t i o ( 1 7 . 6 5 g , 8 0 . 2 4 m m o l ) i n 8 5 % y i e l d a s a n o i l . T L C M S ( E S I ) : m / z 2 5 8 [ M ?N a ] ?. H R M S ( E S I ) : c a l c d f or
1
Rf: 0 . 2 ( e t h y l a ce t at e : h e x a n e , 0 . 5 : 9 . 5 ). H N M R ( 5 0 0 M H z , z C H O N a : 2 3 6 .9 7 7 6 ; f o u n d : 2 3 6 .9 7 7 4 .
2 0 1 6
2
C D C l ) ( A s t er is k m a r k i n d i c a t e s s i g n a l s f o r t h e m i n o r i s o -
3
*
(3S,5R)-tert-Butyl 3-(((tert-butyldimethylsilyl)oxy)met-
hyl)-5-(((S)-2-(4-methylphenylsulfonamido)-3-phenylpro-
panoyl)oxy)piperidine—carboxylate (37) & (3R,5S)-tert-
Butyl 3-(((tert-butyldimethylsilyl)oxy)methyl)-5-(((S)-2-
(4-methylphenylsulfonamido)-3-phenylpropanoyl)oxy)
piperidine—carboxylate (38): T o a s t ir r e d s o l u ti o n o f
s e c o n d a r y a l c o h o l 28 ( 1 .7 7 g , 5 . 1 2 m m o l ) i n a n h yd r o us
d i c h l o r o m e t h a n e ( 1 0 m L ) w a s a d d e d p y r i d i n e ( 0 . 8 m L ,
1 0 . 2 5 m m o l ) f o ll o w e d b y s o l u t i o n o f a c i d c hl o r i de
m e r ) d 7 . 4 2 – 7 . 37 ( m , 4 H ) , 7 . 3 1 – 7 . 2 2 ( m , 6 H ) , 3 . 8 6 ( d d , J =
1 1 . 3 , 5 . 8 H z , 1 H ) , 3 . 7 6 – 3 . 7 0 ( m , 1 H ) , 2 . 7 9 ( d d , J = 1 3 . 7 ,
*
*
1 2 . 2 H z , 1 H ) , 2 . 7 1 – 2 . 6 7 ( m , 2 H ) , 2 . 3 7 – 2 . 2 8 ( m , 1 H ) ,
*
2 . 2 8 – 2 . 20 ( m , 2 H ) , 2 . 1 8 – 2 . 0 9 ( m , 2 H ), 2 . 0 5 – 1 . 9 9 ( m , 1 H ) ,
*
1 . 9 5 – 1 . 87 ( m , 1 H ) , 1 . 8 0 – 1 . 7 6 ( m , 1 H ) , 1 . 7 2 – 1 . 6 5 ( m , 2 H ) ,
*
1 . 2 2 – 1 . 1 3 ( m , 1 H ) , 1 . 0 6 ( d , J = 6 . 5 H z , 3 H ) , 1 . 0 3 ( d , J =
6 . 5 H z , 3 H ) . M S ( E S I) : m / z 2 2 1 [ M ?H ] ?. H R M S ( E S I ) :
c a l cd f o r C H O N a : 2 2 1 . 1 0 0 0 ; f o u n d : 2 2 1 . 0 9 9 5 .
2 0 1 6
2
(R)-5-Methylcyclohex-2-enone (11): T o s t i rr e d s o l u t io n o f 36 ( 2 .6 g , 7 . 6 8 m m o l ) i n a n h y d r o u s d i c h l o r o me th a n e ( 10
s u lfi d e 35 ( 1 7 . 55 g , 7 9 . 8 m m o l ) i n D C M ( 1 6 0 m L ) c o o l e d a t m L ) a t 0 °C . A f te r 6 h , t h e r e a c ti o n m i x t u r e w a s q ue nc h e d

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J. Chem. Sci. ( 2 0 2 0 ) 1 3 2 : 9 6
2 0
w i t h s a tu r at e d a q N H C l ( 2 0 m L ) a n d t h e p h a s e s w e r e T L C R f: 0 . 2 ( e t h y l a c e t a t e : h e x a n e , 4 : 6 ) . [a] = ?0 . 3 ( c 1 .0 ,
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( 20 m L ) , t h e c om b i n e d o r g a n i c l a y e rs w e r e w a s h e d w i t h d 4 . 3 1 – 4 .1 4 ( m , 1 H ) , 4 . 0 8 ( d d , J = 1 3 . 2 , 4 . 3 H z , 1 H ),
w a t er ( 3 0 0 m L ) , b r i n e ( 3 0 0 m L ) a n d d r i e d o v e r N a S O . 3 . 7 1 – 3 .6 1 ( m , 1 H ) , 3 . 5 3 ( d d , J = 1 0 . 0 , 5 . 1 H z , 1 H ),
T h e s o l v e n t w a s e va p o r a t e d u n d e r r e d u c e d p r e s s u re t o f u r n i s h 3 . 4 0 – 3 .4 0 ( m , 1 H ) , 2 . 5 2 – 2 . 3 6 ( m , 2 H ) , 2 . 0 9 – 1 .9 3 ( m , 1 H ),
2
4
t h e c r u d e c o m p o u n d w h i c h w a s p u r i fi e d b y c o l u m n c h r o - 1 . 7 9 – 1 .5 9 ( m , 2 H ) , 1 . 4 4 ( s , 9 H ) , 1 . 1 8 – 1 .0 5 ( m , 1 H ) , 0 .8 9 ( s ,
1 3
m a t o g r a ph y o n s i l i c a g e l ( E t O A c / h e x a n e , 1 : 9 ) t o a f f o r d 9 H ) , 0 . 0 4 ( s , 6 H ) ; C N M R ( 1 0 0 M H z , C D C l ) d 1 54 . 8,
3
p ro d u c t s 37 a n d 38 ( 3 g , 4 . 6 3 m m o l ) i n 9 0 % y i e l d a s a s o l i d . 7 9 . 7 , 6 6 . 3 , 6 5 . 3 , 5 0 . 5 , 4 7 . 3 , 3 8 . 1 , 3 6 . 1 , 2 8 . 4 , 2 5 . 8, 1 8. 2 ,
T L C Rf: 0 . 2 ( e t h yl a c e t a t e : h e x a n e , 1 : 9 ) .
- 5 .5 . M S ( E S I ) : m / z 3 6 8 [ M ?N a ] ?. H R M S ( E S I ) : c a l c d f or
C H N O N a S i : 3 6 8 .2 2 3 3 ; f o u n d : 3 6 8 .2 2 3 3 .
(R)-Mandelate ester of compound 39:
1
7
3
5
4
2 0
Compound 37: M . p . 9 0 - 9 2 °C . [ a] = - 9 . 3 ( c 1 . 0 , C H C l ) ;
D
3
I R ( K B r ) : 3 5 4 0 , 2 9 3 7 , 2 8 6 1 , 1 6 9 9 , 1 4 2 8 , 1 1 5 8 , 1 0 9 5 , 8 4 0 ,
- 1
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H z , 2 H ) , 7 . 3 1 – 7 . 1 9 ( m , 5 H ) , 7 . 1 2 – 7 . 0 5 ( m , 2 H ) , 5 . 0 6 ( d , J =
9 . 3 H z , 1 H ) , 4 . 4 3 – 4 . 3 1 ( m , 1 H ) , 4 . 1 7 ( q , J = 6 . 6 H z , 1 H ) ,
4 . 0 6 ( d , J = 1 1 . 0 H z , 1 H ) , 3 . 9 7 ( b s , 1 H ) , 3 . 4 6 ( d d , J = 1 0 . 1 ,
4 . 9 H z , 1 H ) , 3 . 3 7 ( b s , 1 H ) , 3 . 0 9 – 2 . 9 3 ( m , 2 H ) , 2 . 4 1 ( s , 3 H ) ,
2 . 3 7 – 2 . 21 ( m , 2 H ) , 1 . 8 1 – 1 . 6 9 ( m , 1 H ) , 1 . 7 0 – 1 . 5 9 ( m , 2 H ) ,
1
3
1 . 4 5 ( s , 9 H ) , 0 . 8 9 ( s , 9 H ) , 0 . 0 4 ( s , 6 H ) ; C N M R ( 1 0 0
M H z, C D C l ) d 1 7 0 . 0 , 1 5 4 . 3 , 1 4 3 . 9 , 1 3 6 . 7 , 1 3 4 . 8 , 1 2 9 .7 ,
3
1 2 9 . 5 , 1 2 8 . 5 , 1 2 7 . 2 , 1 2 7 . 1 , 8 0 . 0 , 7 0 . 0 , 6 4 . 8 , 5 6 . 5 , 4 6 . 9 , 3 9 . 5 ,
3 7 . 4 , 3 2 . 5 , 2 8 . 3 , 2 5 . 8 , 2 1 . 4 , 1 8 . 2 , - 5 . 5 . M S ( E S I) : m / z 6 6 9
[ M ?N a ] ?. H R M S ( E S I) : c a l c d f o r C H N O N a S S i :
(3S,5R)-tert-butyl 3-(((tert-butyldimethylsilyl)oxy)met-
hyl)-5-((R)-2-methoxy-2-phenylacetoxy)piperidine-1-car-
boxylate: T o a s o l u t i o n o f a l c o h o l 39 ( 1 5 m g , 0 . 0 4 3 m m o l)
i n d i c h l o r o me th a n e ( 0 .5 m L ) c o o le d a t 0 °C w a s a d de d (R) -
m e t h o x y p h e n y l a c e t i c a c i d ( 9 m g , 0 . 0 5 m m o l ) , D M A P
( 2 m g , 2 0 m o l %) a n d E D C . H C l ( 8 m g , 0 . 0 5 1 m m o l ) . T he
r e a c ti o n m i x t u r e w a s s t ir r e d a t r t f o r 2 h . A f t e r c om pl e t e
c o n s u m p t i o n o f s t a r t i n g m a t e r i a l , t h e r e a c t io n m i x t u r e w a s
3 3 5 0
2
7
6 6 9 . 3 0 0 6 ; f o u n d : 6 6 9 . 2 9 9 9 .
2 0
Compound 38: M . p . 9 2 - 9 4 °C . [ a] = ?6 . 7 ( c 1 . 0 , C H C l ) ;
D
3
I R ( K B r ) : 3 3 2 7 , 2 9 3 3 , 2 8 5 7 , 1 7 2 6 , 1 7 0 0 , 1 4 2 4 , 1 2 6 0 , 1 0 8 5 ,
- 1
1
8 4 0 , 5 5 9 c m ; H N M R ( 4 0 0 M H z , C D C l ) d 7 . 6 4 ( d , J =
3
8 . 3 H z , 2 H ) , 7 . 2 5 – 7 . 2 1 ( m , 5 H ) , 7 . 1 2 – 7 . 0 4 ( m , 2 H ) , 5 . 0 5 ( d ,
J = 9 . 4 H z , 1 H ) , 4 . 5 1 – 4 . 3 6 ( m , 1 H ) , 4 . 1 7 ( d t , J = 9 . 3 , 6 . 2
H z , 1 H ) , 4 . 0 5 ( d , J = 1 2 . 7 H z , 1 H ) , 4 . 0 0 – 3 . 8 7 ( m , 1 H ) , 3 . 4 8
( dd , J = 1 0 . 1 , 4 . 6 H z , 1 H ) , 3 . 4 3 – 3 . 3 5 ( m , 1 H ) , 3 . 0 8 – 2 . 9 2
d i l u t e d w i t h d i c h l o r o m e t h a n e ( 2 m L ) a n d H O ( 2 m L) . T he
2
l a y e r s w e r e s e p a r a t e d a n d t h e a q l a y e r w a s e x t r a c t e d w i t h
d i c h l o r o m e t h a n e ( 2 x 5 m L ) . T h e c o m b in e d o r g a n i c l ay e rs
w e r e s e q u e n t ia l l y w a s h e d w i t h s a t d a q N a H C O ( 5 m L ) ,
3
( m, 2 H ) , 2 . 4 0 ( s , 3 H ), 2 . 3 8 – 2 . 2 3 ( m , 2 H ) , 1 . 7 6 – 1 . 6 1 ( m ,
1 3
1 N H C l ( 5 m L ) , H O ( 2 x 5 m L ) , b r in e ( 1 0 m L ) , d r i ed o ve r
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N a S O a n d c o n c e n t r a t e d u n d e r r e d u c e d p r e s s u r e t o a ff o rd
2
4
N M R ( 1 0 0 M H z , C D C l ) d 1 7 0 . 0 , 1 5 4 . 4 , 1 4 3 . 5 , 1 3 6 .7 ,
3
t h e c o r r e s p o n d i n g e s t e r i n 9 5 % y i e l d a s a l iq u i d . T L C R f:
0 . 2 ( e t h y l a c e t a t e : h e x a n e , 1 : 9 ) .
1 3 4 . 8 , 1 2 9 . 6 , 1 2 9 . 4 , 1 2 8 . 6 , 1 2 7 . 3 , 1 2 7 . 1 , 8 0 . 0 , 7 0 . 0 , 6 4 . 9 ,
5 6 . 6 , 4 7 . 2 , 3 9 . 6 , 3 7 . 4 , 3 2 . 5 , 2 8 . 3 , 2 5 . 8 , 2 5 . 6 , 2 1 . 5 , 1 8 . 2 ,
- 5. 5 . M S ( E S I ) : m / z 6 6 9 [ M ?N a ] ?. H R M S ( E S I) : c a l c d f o r
C H N O N a S S i: 6 6 9 . 3 0 0 6 ; f o u n d : 6 6 9 . 2 9 9 0 .
1
H N M R ( 4 0 0 M H z , C D C l ) d 7 . 4 5 – 7 .3 9 ( m , 2 H ),
3
7 . 3 8 – 7 .3 0 ( m , 3 H ) , 4 . 8 3 – 4 .6 6 ( m , 2 H ) , 4 . 1 3 – 3 .9 4 ( m , 2 H ),
3 . 5 1 d d , J = 1 0 . 0 , 4 . 8 H z , 1 H ) , 3 . 4 7 – 3 .3 4 ( m , 4 H ),
3 3 5 0
2 7
(3S,5R)-tert-Butyl 3-(((tert-butyldimethylsilyl)oxy)met- 2 . 5 6 – 2 .3 6 ( m , 2 H ) , 2 . 1 2 – 2 .0 0 ( m , 1 H ) , 1 . 8 3 – 1 .6 8 ( m , 1 H ),
hyl)-5-hydroxypiperidine-1-carboxylate (39): T o a s t ir r e d 1 . 4 2 ( s , 9 H ) , 1 . 3 3 – 1 .2 8 ( m , 1 H ) , 0 . 8 8 ( s , 9 H ) , 0 . 0 3 ( s , 6 H ).
s o lu t io n o f e st e r 37 ( 1 . 1 5 g , 1 . 7 8 m m o l ) i n t e t r a h y d r o f u r a n
( 2 m L ) w a s a d de d a q N a OH s o l u t i o n ( 5 N , 2 m L ) a t 2 5 °C .
NOTE: T h e a b s o lu t e c o n fi g u r a t i o n o f c a r b i n o l s t e r e-
o g e n i c c e n te r i n c o m p o u n d 39 w a s e s t a b l i s h e d a s ‘R’ . T he
T h e m i x tu r e w a s s t i rr e d a t r t f o r 4 h . T h e r e a c t i o n m i x t u r e C - 6 e q u a to r i a l a n d a x i a l p r o to n s o f ( R) - m a n d e l a t e e s t e r o f
w a s d i l u te d w i t h w a t e r ( 1 0 m L ) a n d t h e p h a s e s w e r e s e p - 39 a p p e a r a t u p fi e l d r e g io n a t d 4 . 0 5 ( 1 H ) a n d 2 . 4 7 ( 1H )
a r a t e d . T h e a q l ay e r w a s e x t r a c t e d w i t h d i c h l o ro m e t h a n e r e s p e c t i v e l y .
( 20 m L ) , t h e c om b i n e d o r g a n i c l a y e rs w e r e w a s h e d w i t h
w a t er ( 1 0 m L ) , b r i n e ( 1 0 m L ) a n d d r i e d o v e r N a S O . T h e
(3R,5S)-tert-Butyl 3-(((tert-butyldimethylsilyl)oxy)met-
2
4
hyl)-5-hydroxypiperidine-1-carboxylate (epi-39): C o m -
p o u n d 38 ( 1 .1 5 g , 1 . 7 8 m m o l ) w a s c o n v e r t e d t o t he s e c -
o n d a r y a l c o h o l epi-39 ( 6 0 0 m g , 1 . 7 4 m m o l ) i n 9 8 % y ie l d
f o ll o w i n g t h e p r o c e d u r e d e t a i le d f o r t h e p r e p a r a t i o n o f
s o lv e n t w a s e va p o r a t e d u n d e r r e d u c e d p r e s s u re t o f u r n i s h
t h e c r u d e c o m p o u n d w h i c h w a s p u r i fi e d b y c o l u m n c h r o -
m a t o g r a ph y o n s i li c a g e l ( E t O A c / h e x a n e , 4 : 6 ) t o a f f o r d t h e
p ro d u c t 39 ( 6 0 0 m g , 1 . 7 4 m m o l ) i n 9 8 % y i e l d a s a s o l i d .

J. Chem. Sci. ( 2 0 2 0 ) 1 3 2 : 9 6
P
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3 7 . 6 , 3 7 . 1 , 2 8 . 3 , 2 6 . 9 , 2 5 . 9 , 1 9 . 2 , 1 8 . 2 , - 5 .5 . M S ( ES I) :
= - 0 . 3 ( c 1 . 0 , C H C l ) ; I R ( KB r) : 3 4 7 3 , 2 9 8 5 , 2 8 5 7 , 1 6 7 6 , m / z 5 8 4 [ M ?H ] ?. H R M S ( E S I ) : c a l c d f o r C H N O
f
3
3 3 5 3
4
-
- 1
1 4 3 7 , 1 1 5 7 , 1 0 9 2 , 1 0 4 1 , 8 4 1 , 5 9 1 c m ; H R M S ( E S I ) : c a l c d N a S i : 6 0 6 .3 4 1 1 ; f o u n d : 6 0 6 .3 4 0 6 .
2
f or C H N O N a S i : 3 6 8 . 2 2 3 3 ; f o u n d : 3 6 8 . 2 2 3 7 .
1 7 3 5
4
(3R,5S)-tert-Butyl 3-((tert-butyldiphenylsilyl)oxy)-5-(hy-
droxymethyl)piperidine-1-carboxylate (41): T o a s t i r re d
s o l u t i o n o f s i ly l e t h e r 40 ( 6 4 1 m g , 1 . 1 m m o l ) i n
m e t h a n o l : te t r a h y d r o f u r a n ( 9 :1 , 1 0 m L ) w a s a d d ed P P TS
( 2 5 m g , 0 . 1 m m o l ) a t r t . T h e r e a c ti o n m i x t u r e w a s s t i r r ed
o v e r n i g h t . T h e s o l v e n t w a s e v a p o r a t e d u n d e r r ed uc e d
p r e s s u r e t o f u r n i s h t h e c r u d e c o m p o u n d w h ic h w a s p ur i fi e d
b y c o l u m n c h r o m a t o g r a p h y o n s i li c a g e l ( E t O A c / h ex an e ,
(R)-Mandelate ester of compound epi-39:
3 : 7 ) t o a f f o r d t h e p r o d u c t 41 ( 4 5 0 m g , 0 . 9 9 m m o l ) i n 9 0%
2 0
y i e l d a s a n o i l . T L C R f: 0 . 2 ( e t h y l a c e t a t e : h e x a n e , 3 : 7 ) . [ a]
D
= ?5 . 3 ( c 1 . 0 , C H C l ) ; I R ( n e a t ) : 3 4 4 7 , 2 9 3 2 , 2 8 5 8, 1 69 2,
3
- 1
1 4 2 6 , 1 1 5 6 , 1 1 0 8 , 7 0 3 c m ; H N M R ( 4 0 0 M H z , C D C l )
1
z (3R,5S)-tert-butyl 3-(((tert-butyldimethylsilyl)oxy)meth-
yl)-5-((R)-2-methoxy-2-phenylacetoxy)piperidine-1-car-
boxylate: C o m po u n d epi-39 ( 1 5 m g , 0 . 0 4 3 m m o l ) w a s
c o n v er t ed t o t h e m a n d e l a t e e s t e r o f epi-39 i n 9 5 % y i e l d
f ol l o w i n g t h e p r o c e d u r e d e t a i l e d f o r t h e p r e p a r a t i o n o f
3
d 7 . 6 8 – 7 .6 1 ( m , 4 H ) , 7 . 4 6 – 7 .3 3 ( m , 6 H ) , 4 . 0 5 – 3 .7 8 ( m , 2 H ),
3 . 7 1 – 3 .6 2 ( m , 1 H ) , 3 . 5 7 – 3 .4 3 ( m , 2 H ) , 2 . 7 8 ( d d , J = 1 2. 8 ,
9 . 0 H z , 1 H ) , 2 . 6 0 ( d d , J = 1 2 . 8 , 1 0 . 5 H z , 1 H ) , 1 . 9 2 – 1 . 77 ( m ,
1 3
1 H ) , 1 . 4 5 – 1 .1 8 ( m , 1 1 H ) , 1 . 0 6 ( s , 9 H ) ; C N M R ( 10 0
M H z , C D C l ) d 1 5 4 . 8 , 1 3 5 .7 , 1 3 3 .8 , 1 2 9 . 7 , 1 2 7 . 6 , 7 9. 6 ,
6 7 . 9 , 6 4 . 9 , 5 1 . 3 , 4 5 . 7 , 3 7 . 4 , 3 6 . 5 , 2 8 . 3 , 2 6 . 9 , 1 9 . 1 . M S
m a n d e l a te e st e r 39. T L C R f: 0 . 2 ( e t h y l a c e t a t e : h e x a n e , 1 : 9 ) .
1
3
H N M R ( 4 0 0 M H z , C D C l ) d 7 . 4 6 – 7 . 3 8 ( m , 2 H ) ,
3
( E S I ) : m / z 4 9 2 [ M ?N a ] ?. H R M S ( E S I ) : c a l c d f or C
H N O N a S i : 4 9 2 .2 5 4 6 ; f o u n d : 4 9 2 .2 5 3 9 .
7 . 3 8 – 7 . 30 ( m , 3 H ) , 4 . 8 4 – 4 . 6 8 ( m , 2 H ) , 4 . 2 7 – 4 . 1 1 ( m , 1 H ) ,
4 . 1 0 – 3 . 97 ( m , 1 H ) , 3 . 4 7 – 3 . 3 3 ( m , 5 H ) , 2 . 6 3 ( d d , J = 1 2 . 6 ,
1 0 . 3 H z , 1 H ) , 2 . 4 3 ( t , J = 1 2 . 6 H z , 1 H ) , 1 . 9 6 – 1 . 8 3 ( m , 1 H ) ,
1 . 8 1 – 1 . 6 5 ( m , 1 H ) , 1 . 4 4 ( s , 9 H ) , 1 . 3 3 – 1 . 2 7 ( m , 1 H ) , 0 . 8 6 ( s ,
9 H ) , - 0 . 0 1 ( s , 6 H ) .
2 7 -
3 9
4
(3R,5S)-tert-Butyl
3-((tert-butyldiphenylsilyl)oxy)-5-
(iodomethyl)piperidine-1-carboxylate (42): C o m p o u n d
41 ( 3 7 0 m g , 0 . 7 8 4 m m o l ) w a s c o n v e r t e d t o t h e a l k y l i od i d e
42 ( 4 0 0 m g , 0 . 6 9 m m o l ) i n 8 8 % y i e l d f o ll o w i n g t he p ro -
c e d u r e d e t a i l e d f o r t h e p r e p a r a ti o n o f i o d i d e 31. T L C R f: 0 .2
NOTE: T h e a b s o l u t e c o n fi g u r a t i o n o f c a rb i n o l s t e r e -
o g e n i c c en t er i n c o m p o u n d s epi-39 w a s e s t a b l i s h e d a s ‘S’ .
T h e C - 6 e q ua t o r ia l a n d a x i a l p r o t o n s o f ( R) -m a n d e l a t e e s t e r
o f epi-39 a p pe a r a t d o wn fi e l d r e g i o n a t d 4 . 1 8 ( m , 1 H ) a n d
2 . 6 3 ( d d , 1 H ) , r e s p e c t i v e l y .
2 0
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I R ( n e a t ) : 2 9 3 1 , 2 8 5 7 , 1 6 9 5 , 1 4 2 3 , 1 1 5 7 , 1 1 0 8 , 7 0 3 c m ;
1
H N M R ( 4 0 0 M H z , C D C l ) d 7 . 6 9 – 7 .6 3 ( m , 4 H ),
3
(3S,5R)-tert-Butyl 3-(((tert-butyldimethylsilyl)oxy)met-
hyl)-5-((tert-butyldiphenylsilyl)oxy)piperidine-1-carboxy-
late (40): T o a s t i r r e d s o l u t i o n o f a l c o h o l 39 ( 4 3 0 m g , 1 . 2 5
m m ol ) i n a n hy dr o u s d i c h l o r o m e t h a n e ( 2 4 m L ) w as a d d e d
i mi d a z ol e ( 2 . 6 g , 1 7 . 4 m m o l ) f o l l o w e d b y T B D P S C l ( 3 .6 m L ,
1 3 . 9 m m ol ) a t 2 5 °C . A ft e r 4 5 m i n , t h e r e a c t i o n m i x t u r e w a s
7 . 4 6 – 7 .3 4 ( m , 6 H ) , 4 . 1 6 – 3 .9 0 ( m , 2 H ) , 3 . 7 2 – 3 .5 6 ( m , 1 H ),
3 . 0 3 ( d , J = 6 . 3 H z , 2 H ) , 2 . 7 6 – 2 .2 6 ( m , 2 H ) , 2 . 0 9 – 1. 8 3 ( m ,
1 H ) , 1 . 5 4 – 1 .3 1 ( m , 1 0 H ) , 1 . 2 9 – 1 .2 0 ( m , 1 H ) , 1 . 0 7 ( s , 9 H ) ;
1 3
C N M R ( 1 2 5 M H z , C D C l ) d 1 5 4 . 4 , 1 3 5 .7 , 1 3 3 . 9 , 1 29 . 8,
3
1 2 7 .7 , 7 9 . 8 , 6 7 . 7 , 5 0 . 9 , 4 8 . 7 , 4 0 . 7 , 3 6 . 3 , 2 8 . 3 , 2 6 . 9, 1 9. 1 ,
8 . 9 . M S ( E S I ) : m / z 6 0 2 [ M ?N a ] ?. H R M S ( E S I ) : c a lc d f or
C H N O I N a S i: 6 0 2 .1 5 6 3 ; f o u n d : 6 0 2 .1 5 7 0 .
q u en ch e d w i t h s at u r a t e d a q N H C l ( 1 5 m L ) a n d t h e p h a s e s
4
2 7 3 8
3
w e r e s e pa r a te d . T h e a q l a y e r w a s e x t r a c t e d w i t h d i c h l o r -
o m et h a n e ( 2 5 m L ) , t h e c o m b i n e d o r g a n i c l a y e r s w e re w a s h e d
w i t h w a t er ( 2 0 m L ) , b r i n e ( 2 0 m L ) a n d d r i e d o v e r N a S O .
(R)-tert-Butyl 3-((tert-butyldiphenylsilyl)oxy)-5-methyle-
nepiperidine-1-carboxylate (44): T o t h e s u s p e n s i o n o f
K O tB u ( 5 6 m g , 0 . 5 m m o l ) a t 2 5 °C w a s a d d e d a s o l u t i on o f
i o d o c o m p o u n d 42 ( 2 8 4 m g , 0 . 4 9 m m o l ) i n a n h yd r o us
d i m e t h o x y e t h a n e ( 2 m L ) . A f te r 4 5 m i n , t h e r e a c t io n m i x t ur e
2
4
T h e s o l v e n t w a s e va p o r a t e d u n d e r r e d u c e d p r e s s u re t o f u r n i s h
t h e c r u d e c o m p o u n d w h i c h w a s p u r i fi e d b y c o l u m n c h r o -
m a t o g r a ph y o n s i l ic a g e l ( E t O Ac / h e x a n e , 0 . 2 : 9 . 8 ) t o a f f o r d
w a s q u e n c h e d w i t h s a t u r a te d a q N H C l ( 1 0 m L ) a nd t he
4
t h e p r o d u c t 40 ( 7 0 0 m g , 1 . 2 m m o l ) i n 9 6 % y i e l d a s a n o i l .
2 0
p h a s e s w e r e s e p a r a t e d . T h e a q l a y e r w a s e x t r a c t e d w i t h
d i c h l o r o m e t h a n e ( 1 0 m L ) , t h e c o m b in e d o r g a n i c l ay e rs
w e r e w a s h e d w i t h b r i n e ( 5 m L ) a n d d r i e d o v e r N a S O . T he
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( c 2 . 0 , C H C l ) ; I R ( n e a t ) : 2 9 3 1 , 2 8 5 7 , 1 6 9 6 , 1 4 6 7 , 1 1 5 6 ,
1
3
- 1
1 1 0 6 , 7 0 3 c m ; H N M R ( 4 0 0 M H z , C D C l ) d 7 . 5 6 – 7 . 6 2
2
4
3
s o l v e n t w a s e v a p o r a t e d u n d e r r e d u c e d p r e s s u r e t o f ur n i s h
t h e c r u d e c o m p o u n d w h ic h w a s p u r ifi e d b y c o l u m n c hr o-
m a t o g r a p h y o n s i li c a g e l ( E t O A c / h e x a n e , 0 . 1 : 9 . 9 ) t o a ff or d
( m, 4 H ) , 7 . 4 5 – 7 . 34 ( m , 6 H ) , 4 . 0 2 ( d d , J = 1 3 . 1 , 3 . 6 H z ,
1 H ) , 3 . 6 8 – 3 . 53 ( m , 1 H ) , 3 . 3 9 ( d , J = 4 . 7 H z , 2 H ) , 2 . 5 6
( dd , J = 1 2 . 6 , 1 0 . 1 H z , 1 H ) , 2 . 3 1 ( d d , J = 1 2 . 6 , 1 1 . 3 H z ,
1 H ) , 2 . 0 0 – 1 . 6 5 ( m , 1 H ) , 1 . 5 6 – 1 . 4 4 ( m , 1 H ) , 1 . 3 7 ( s , 9 H ) ,
t h e p r o d u c t 44 ( 2 0 0 m g , 0 . 4 5 m m o l ) i n 9 2 % y i e l d a s a n o il .
2 0
1 3
T L C R f: 0 . 2 ( e t h y l a c e t a t e : h e x a n e , 0 . 1 : 9 . 9 ) . [ a] = ?3 .8
1 . 0 6 ( s , 9 H ) , 0 . 9 2 – 0 . 8 2 ( m , 1 0 H) , - 0 . 0 0 ( s , 6 H ) ; C N M R
( 10 0 M H z , C D C l ) ( As t e r i s k m a r k i n d i c a t e s s i g n a l s f o r t h e
D
( c 2 . 0 , C H C l ) ; I R ( n e a t ) : 2 9 6 1 , 2 8 5 7 , 1 6 9 7 , 1 4 2 1, 1 16 9,
1
3
3
- 1
1 1 1 2 , 7 0 3 c m ; H N M R ( 4 0 0 M H z , C D C l ) d 7 . 6 8– 7. 6 2
( m , 4 H ) , 7 . 4 5 – 7 .3 5 ( m , 6 H ) , 4 . 8 4 ( s , 1 H ) , 4 . 6 4 ( s , 1 H ),
r ot a m e r ) d 1 5 4 . 6 , 1 3 5 . 7 , 1 3 4 . 2 , 1 3 3 . 9 * , 1 2 9 . 7 , 1 2 9 .6 * ,
1 2 7 . 6 , 1 2 7 . 5 * , 7 9 . 4 , 6 8 . 2 , 6 5 . 3 , 5 1 . 2 , 5 0 . 3 * , 4 7 . 1 , 4 5 . 6 * ,
3

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J. Chem. Sci. ( 2 0 2 0 ) 1 3 2 : 9 6
4 . 1 2 – 3 . 8 9 ( m , 1 H ) , 3 . 8 0 – 3 . 6 8 ( m , 2 H ) , 3 . 6 3 ( d , J = 1 3 . 7 H z , ( E S I ) : m / z 3 6 8 [ M ?N a ] ?. HR M S (E S I ): ca l c d. fo r C H
1 H ) , 3 . 2 3 – 3 . 0 7 ( m , 1 H ) , 2 . 4 1 – 2 . 2 4 ( m , 1 H ) , 2 . 1 9 – 2 . 1 1 ( m , N O N a S i : 3 6 8 . 2 2 3 3 ; f o u n d : 3 6 8 . 2 2 4 0
1
7
3
5
-
4
1 3
1 H ) , 1 . 3 9 ( s , 9 H ) , 1 . 0 6 ( s , 9 H ) ; C N M R ( 1 0 0 M H z , (3R,5R)-tert-Butyl 3-(((tert-butyldimethylsilyl)oxy)met-
C
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1 5 4 . 5 , 1 3 9 . 7 , 1 3 5 . 7 , 1 3 4 . 1 * , 1 3 3 . 7 , 1 2 9 . 7 , 1 2 7 . 6 , 1 2 7 .5 * , late (47): C o m p o u n d 46 ( 4 00 m g, 1 .1 6 m m o l ) c on v e r te d t o
1 1 2 . 0 , 7 9 . 5 , 6 8 . 2 , 5 0 . 4 , 4 8 . 8 , 4 1 . 9 , 2 8 . 3 , 2 6 . 9 , 1 9 . 1 . M S T B D P S e t h er 47 ( 6 4 0 m g , 1 . 1 m m o l ) i n 9 6 % y i e l d f o l l o wi n g
( E S I ) : m / z 4 7 4 [ M ?N a ] ?. H R M S ( E S I) : c a l c d f o r C
H N O N a S i : 4 7 4 . 2 4 4 0 ; f o u n d : 4 7 4 . 2 4 3 7 .
t h e pr o c e d u r e d e t a i l e d fo r t h e p r e p a r a t i o n o f 40. T LC R f: 0.2
2 0
2 7 -
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?
1
.
4
(
c
2
.
0
,
C
H
C
l
)
;
I
R
3
7
3
D
3
- 1 1
( K B r ) : 2 95 6 , 2 85 6 , 1 69 6 , 1 42 7 , 1 11 1 , 1 02 1 , 8 37 , 6 0 9 c m ; H
N M R (5 0 0 M H z , C D C l ) : d 7. 75 – 7. 6 0 (m , 4 H ), 7 . 45 – 7. 32 (m ,
3
(R)-tert-Butyl 3-(((tert-butyldimethylsilyl)oxy)methyl)-5-
oxopiperidine-1-carboxylate (45): T o a s o l u t i o n o f a l c o h o l
epi-39 ( 5 5 0 m g , 1 . 5 9 m m o l ) i n a n h y d r o u s d i c h l o r -
o me t h a n e ( 3 m L ) w a s a d d e d D e s s -M a r t i n p e r i o d i n a n e
( 1 .0 2 g , 2 . 4 m m ol ) a n d t h e m i x t u r e w a s s t i rr e d a t r o o m
t e m p er a tu r e f o r 5 h . D i l u t e d t h e r e a c t i o n m i x t u r e w i t h
d i c h l o r o m et h a n e ( 1 0 m L ) , t h e r e a c t i o n m i x t u r e w a s fi l t e r e d ,
t h e fi l t r at e w a s w a s h e d w i t h w a t e r ( 5 m L ) , b r i n e ( 5 m L ) a n d
d r ie d o v er N a S O . T h e s o l v e n t w a s e v a p o r a t e d u n d e r
6 H ), 4 . 15 – 3. 8 3 (m , 3H ) , 3 .4 6 –3 . 23 ( m , 2H ) , 2 .8 0 ( d, J = 11.6
H z , 1H ) , 2. 65 – 2. 4 8 (m , 1 H ) , 2 .2 5 –2 . 16 ( m , 1 H ) , 1 . 71 – 1. 5 8 (m ,
1 H ) , 1 . 43 ( s , 9H ) , 1. 3 1– 1 .1 9 ( m , 1 H ) , 1 . 07 ( s , 9 H ) , 0. 8 6 ( s , 9 H ) ,
1 3
0 .0 0 ( s , 6 H ) ; C N M R ( 1 0 0 M H z , C D C l ) ( A s te r i s k m a r k
3
*
*
d e not e s s i gn a l s f o r the r ot a m er ) d 1 55. 3, 15 5.0 , 13 6 .0 , 13 5.7 ,
1 34 . 1, 1 34 . 0 , 1 2 9 . 6 , 1 2 7 . 5 , 7 9 . 3 , 7 9 . 0 , 66 . 0, 6 5. 4 , 50 .4 , 4 9. 6 ,
*
*
*
*
4 7. 2 , 45 . 7, 3 4. 6, 3 3. 7 , 33 . 2, 2 8. 4 , 2 7. 0 , 2 5.9 , 1 9.3 , 18 . 3, -5 .4 .
*
M S ( E SI ) : m / z 6 0 6 [ M ?N a ]?. H R M S ( E SI ) : c a l c d f o r C
H N O N aS i : 6 06 . 34 11; fo un d: 6 06. 3 39 5.
3
3
-
2
4
5
3
4
2
r e d u c ed p r e s su r e t o f u r n i s h t h e c r u d e d i k e t o n e w h i c h w a s
p u ri fi e d b y c o lu m n c h ro m a t o g ra p h y o n s i l i c a g e l ( E t O A c /
h e x an e , 1 : 9 ) t o a f f o r d t h e p r o d u c t 45 ( 5 2 0 m g , 1 . 5 2 m m o l )
i n 9 6 % y i el d a s a n o i l . T L C R f: 0 . 2 ( e t h y l a c e t a t e :h e x a n e ,
(3R,5R)-tert-Butyl 3-((tert-butyldiphenylsilyl)oxy)-5-(hy-
droxymethyl)piperidine-1-carboxylate (48): S i ly l e th e r
47 ( 6 0 0 m g , 1 . 0 3 m m o l ) w a s d e p r o t e c t e d t o f u r n i s h p ri m ar y
a l c o h o l 48 ( 4 3 5 m g , 0 . 9 2 7 m m o l ) i n 9 0 % y i e l d f o l lo w i n g
t h e p r o c e d u r e d e t a i le d f o r t h e p r e p a r a ti o n o f 41. T L C R f: 0 .2
2 0
D
1 : 9 ) . [ a] = - 3 . 5 (c 2 . 0 , C H C l ) ; I R ( n e a t ) : 2 9 3 7 , 2 8 6 0 ,
3
- 1
1 7 0 6 , 1 4 6 8 , 1 1 6 0 , 1 0 0 4 , 7 7 6 c m ; H N M R ( 4 0 0 M H z ,
1
2 0
D
C D C l ) : d 4 . 0 9 ( d , J = 1 8 . 0 H z , 1 H ) , 3 . 9 6 – 3 . 7 6 ( m , 2 H ) ,
3
( e t h y l a c e t a t e : h e x a n e , 3 : 7 ) . [ a] = ?0 . 4 ( c 1 . 0 , C HC l ) ; I R
3
3 . 6 5 – 3 . 5 0 ( m , 2 H ) , 3 . 2 2 ( d d , J = 1 3 . 2 , 9 . 0 H z , 1 H ) , 2 .5 1 ( d d ,
J = 1 6 . 0 , 5 . 0 H z , 1 H ) , 2 . 4 1 – 2 . 2 8 ( m , 1 H ) , 2 . 2 7 – 2 .1 9
1 3
( m, 1 H ) , 1 . 4 6 ( s , 9 H ) , 0 . 8 9 ( s , 9 H ) , 0 . 0 5 ( s , 6 H ) ; C N M R
( n e a t ) : 3 4 3 8 , 2 9 3 0 , 2 8 5 9 , 1 6 8 0 , 1 4 2 8 , 1 1 4 7 , 1 0 7 1 , 7 04 , 5 04
- 1
1
c m ; H N M R ( 4 0 0 M H z , C D C l ) d 7 . 7 1 – 7 .6 0 ( m , 4 H ),
3
7 . 4 7 – 7 .3 3 ( m , 6 H ) , 3 . 9 6 – 3 .5 9 ( m , 2 H ) , 3 . 5 9 – 3 .4 3 ( m , 1 H ),
3 . 4 5 – 2 .8 3 ( m , 4 H ) , 2 . 2 0 – 2 .0 6 ( m , 1 H ) , 1 . 7 3 – 1 .5 4 ( m , 2 H ),
( 12 5 M H z , C D C l ) d 2 0 6 . 1 , 1 5 4 . 4 , 8 0 . 5 , 6 4 . 5 , 5 4 . 4 , 4 4 . 1 ,
3
1 3
4 1 . 2 , 3 6 . 6 , 2 8 . 3 , 2 5 . 8 , 1 8 . 2 , - 5 . 6 . M S ( E S I) : m / z 3 6 6
[ M ?N a ] ?.
1 . 3 9 ( s , 9 H ) , 1 . 0 7 ( s , 9 H ) ; C N M R ( 1 0 0 M H z , C D C l ) d
3
1 5 5 .6 , 1 3 5 .5 , 1 3 3 . 9 , 1 2 9 .6 , 1 2 7 .5 , 7 9 . 6 , 6 5 . 5 , 6 3 . 6 , 5 0. 9 ,
4 5 . 0 , 3 4 . 7 , 3 4 . 4 , 2 8 . 2 , 2 6 . 8 , 1 9 . 1 ; M S ( E S I ) : m / z 4 92
[ M ?N a ] ?. H R M S ( E S I ) : c a l c d f o r C H N O N a S i :
(3R,5R)-tert-Butyl 3-(((tert-butyldimethylsilyl)oxy)met-
hyl)-5-hydroxypiperidine-1-carboxylate (46): T o a c o o l e d
( -7 8 °C ) s ol u t io n o f c o mp o u n d 45 ( 4 8 0 m g , 1 . 4 m mo l ) i n
a n hy d r o u s t e t r a h yd r o f u r a n ( 3 m L ) w a s a d d ed a s o l u t i o n o f
L - S e l e c t r id e ( 1 M , 1 . 5 m L , 1 .5 m m o l ) u n de r n i tr o g e n a t m o -
s p h e r e a n d th e m i x t u r e w a s g r a d u a l l y wa r m e d to 0 °C and
s t i r r e d fo r 1 h. Th e r ea c t i on mi xt u re w as fu rt he r a l l o w ed t o
w a rm t o r t a n d s t i rr e d f o r 1 h . T h e re a c t i o n m i x t ur e w as
2
7
3
9
4
4 9 2 .2 5 4 6 ; f o u n d : 4 9 2 .2 5 5 0 .
(3R,5R)-tert-Butyl 3-((tert-butyldiphenylsilyl)oxy)-5-
(iodomethyl)piperidine-1-carboxylate (49): P r i m a r y
a l c o h o l 48 ( 4 0 0 m g , 0 . 8 5 m m o l ) w a s c o n v e r t e d t o t he i od o
c o m p o u n d 49 ( 4 3 4 m g , 0 . 7 5 m m o l ) i n 8 8 % y i e l d f o l lo w i n g
t h e p r o c e d u r e d e t a i le d f o r t h e p r e p a r a ti o n o f 31. T L C R f: 0 .2
2 0
D
q u e n c he d w i t h a s a t u r a te d a q N H C l ( 5 m L ). T h e la y er s we r e
4
( e t h y l a c e t a t e : h e x a n e , 0 . 2 : 9 . 8 ) . [ a] = - 6 .1 (c 1 . 0 , C H C l ) ;
3
s e p a r a t e d a n d t h e a q la y e r w a s e x tr a c t ed w it h e t h y l a c e t a t e
( 1 0 m L ) . Th e c o m b i n e d o rg a n i c l a y e r s we r e w a s h e d w i th w a t e r
(10 mL), brine (10 mL) and dried over Na S O . The solvent
I R ( n e a t ) : 2 9 3 0 , 2 8 5 8 , 2 3 6 3 , 1 6 9 2 , 1 4 2 4 , 1 1 5 6 , 1 1 06 , 7 02 ,
1
- 1
5 0 5 c m ; H N M R ( 4 0 0 M H z , C D C l ) : d 7 . 7 3 – 7. 6 2 ( m ,
3
2
4
4 H ) , 7 . 4 7 – 7 . 3 4 ( m , 6 H ) , 4 . 2 7 – 3 . 8 0 ( m , 3 H ) , 3 . 1 2 – 2 . 3 9 ( m ,
4 H ) , 2 . 2 0 – 2 . 0 7 ( m , 1 H ) , 1 . 8 2 – 1 .6 6 ( m , 1 H ) , 1 . 4 5 ( s , 9 H ),
1 3
1 . 2 3 – 1 .1 2 ( m , 1 H ) , 1 . 0 6 ( s , 9 H ) . C N M R ( 1 0 0 M H z ,
w a s e v a po r a t e d u n d er r e du c e d p re s s u r e t o f u r n is h t h e c r u d e
c o m p o u n d w h i c h w a s p ur i fie d b y c o l um n c h r o m a to gr a p h y o n
s i l i c a g e l (E tO A c : h e x a n e , 3 : 7 ) t o a f f o r d t h e pr o d uc t 46
( 4 3 9 m g , 1 . 2 7 mm o l ) i n 9 1 % y i e l d a s a s o l i d . T LC R f: 0.2
C D C l ) : d 1 5 5 .1 , 1 3 5 .7 , 1 3 3 .8 , 1 2 9 . 7 , 1 2 7 .6 , 7 9 . 7, 6 5. 8 ,
3
5 0 . 2 , 4 8 . 6 , 3 8 . 5 , 3 2 . 6 , 2 8 . 4 , 2 6 . 9 , 1 9 . 2 , 1 0 . 2 . M S ( E S I) : m / z
6 0 2 [ M ?N a ] ?. H R M S ( E S I ) : c a l c d f o r C H N O I N aS i :
6 0 2 .1 5 6 3 ; f o u n d : 6 0 2 .1 5 6 9 .
2 0
D
( e t h y l a cet at e : h ex a n e , 3 : 7 ) . [a] = -4.7 (c 1 . 0 , C H C l ) ; M . p .
3
2 7 3 8
3
7
0
-
7
2
°
C
.
I
R
(
K
B
r
)
:
3
4
3
0
,
2
9
3
3
,
2
8
6
0
,
1
6
8
4
,
1
4
2
9
,
1
1
5
8
,
1
0
0
4
,
-
1
1
8 40 , 7 7 5 c m ; H N M R ( 4 0 0 M H z , C D C l ) : d 4 . 0 5– 3 . 7 9 ( m ,
3
3 H ) , 3 . 4 8 ( d d , J = 1 0. 1, 4 . 9 Hz , 1 H) , 3 . 4 3– 3. 2 9 ( m , 1 H ) , 2 . 9 4 (3R,5S)-tert-Butyl 3-((tert-butyldiphenylsilyl)oxy)-5-(((R)-
( d , J = 1 3 . 1 Hz , 1 H ) , 2 . 6 0 ( d d , J = 1 3. 1, 1 0. 1 H z , 1 H) , 4-methyl-6-oxocyclohex-1-en-1-yl)methyl)piperidine-1-
2 . 1 1 – 1 . 9 3 ( m , 2 H ), 1 . 8 0 –1 . 7 3 ( m , 1 H) , 1 . 4 2 ( s , 9 H ) , 0 . 8 5 ( s , carboxylate (50): T o a s o l u t i o n o f 9- B B N d i m e r ( 4 0 m g ,
1 3
9 H ) , 0 . 0 0 ( s , 6 H ) ; C NM R ( 1 0 0 M H z , C D C l ) : d 1 56 . 1, 7 9 . 8 , 0 .1 53 m m ol ) in a nh ydr o us t e t r ah yd r o fu r a n ( 0. 5 mL ) w a s ad d e d
3
6 5 . 3 , 6 4 . 9 , 5 0 . 0 , 4 7 . 8 , 3 3 . 6 , 3 3. 4, 2 8. 4, 2 5. 9, 1 8. 2, - 5 . 5 . M S a s o l uti on of co m p ou n d 44 ( 70 mg , 0 . 15 3 m m ol ) i n a n hy d r o us
t e tra hy dr of ur an ( 1 mL ) a t r t a nd t he m ix tu re wa s he ate d at

J. Chem. Sci. ( 2 0 2 0 ) 1 3 2 : 9 6
P a g e 9 o f 1 4 9 6
r e flux for 2 h. In a no t h e r fl a s k a l k e n yl io di de 19 ( 3 6 m g , 0 . 1 5 3 2 . 2 8 – 2 .0 4 ( m , 7 H ) , 1 . 4 6 ( s , 9 H ) , 1 . 0 6 ( d , J = 6 . 4 H z , 3 H );
1 3
m m o l ) a n d P d C l ( d p p f ). C H C l ( 1 6 m g, 0 .0 2 m m o l ) w e r e
2
C
N
M
R
(
1
2
5
M
H
z
,
C
D
C
l
)
d
2
0
5
.
6
,
1
9
9
.
4
,
1
5
4
.
4
,
1
4
7
.
4
,
2
2
3
d i s s olv e d in a m i xtu r e o f te t r a hy d r of ur a n ( 2 m L) an d a q. Na O H 1 3 6 .0 , 8 0 . 5 , 5 4 . 3 , 4 6 . 5 , 4 4 . 6 , 3 4 . 4 , 3 3 . 6 , 3 0 . 6 , 2 8 . 3, 2 8. 1 ,
( 15 % , 2 m L ) at rt . T o t h i s s o l u t i o n w a s a d d ed th e a b o v e 2 7 . 9 , 2 1 . 1 . M S ( E S I ) : m / z 3 4 4 [ M ?N a ] ?. H R M S ( ES I) :
s o lu t i o n co n t ai n in g th e b o r o n re a ge n t a n d th e r e s u l ta n t m i x t u r e c a l c d f o r C H N O N a : 3 4 4 .1 8 3 8 ; f o u n d : 3 4 4 .1 8 4 5.
1 8 2 7
4
w as s t ir r e d a t th e s a m e t em p e r at u r e fo r 3 0 m i n . A f t er di l u t i o n
w it h E t O A c , t h e r e ac ti o n m i xt u re w a s q u en c he d w i t h aq .
N H C l (5 m L ). T he aq la ye r w a s e xtr ac t ed w i t h et hy l ac et at e
(3R,4aR,5S,8R,9aS)-tert-Butyl
3-methyl-1-oxodecahy-
dro-1H-5,8-(epiminomethano)benzo[7]annulene-11-car-
boxylate (52) & (3R,4aR,5R,8S,9aS)-3-methyloctahydro-
1H-5,8-(epiminomethano)benzo[7]annulene-1,6(2H)-
dione (53): T o a s t ir r e d s o l u t i o n o f d i k e t o n e 18 ( 1 0 m g , 0 .0 3
m m o l ) i n a n h y d r o u s D M S O ( 2 m L ) w a s a d d e d a q H C l
( 3 5 w t % , 0 . 1 0 m L ) . T h e r e s u lt i n g m i x t u r e w a s h e a t ed a t 6 0
°C f o r 4 h . A f t e r c o o l i n g , t h e r e a c ti o n m i x t u r e w a s d i l ut e d
w i t h e t h e r ( 1 0 m L ) , w a t e r ( 1 0 m L ) a n d t h e l a y e r s w e re
s e p a r a t e d . T h e a q l a y e r w a s e x t r a c te d w i t h e t h e r ( 2 x 5 m L )
a n d t h e c o m b i n e d o r g a n i c l a y e r s w e r e w a s h e d w i t h w a t er
( 1 0 m L ) , b r in e ( 1 0 m L ) a n d d r ie d o v e r N a S O . T h e s o l v e nt
4
( 5 m L ) , t h e c o m b i n e d o r g a n i c l a y e rs w er e w a s h e d w i t h w at e r
( 5 m L ) , b r in e (5 m L ) a nd d r i e d o v e r N a S O . The solvent was
2
4
e v a po r a t ed u nd e r re du ce d pr e s s ur e t o f u r ni s h th e c ru de co m-
p ou n d w h i c h wa s p ur i fie d b y c o l um n ch r o ma t og r a p hy on si li c a
g e l (E t O A c / h e x a ne , 1 :9 ) t o a f f o r d t he pr od u c t 50 ( 7 0 mg , 0 .1 3
m m ol ) i n 8 5% y i e l d a s an oi l . T L C R f: 0.2 (ethyl
2 0
D
1
a
c
e
t
a
t
e
:
h
e
x
a
n
e
,
1
:
9
)
.
[
a
]
=
-
2
9
.
8
(
c
2
.
0
,
C
H
C
l
)
;
H
N
M
R
3
( 50 0 M H z , C D C l ) d 7 .6 9 –7 . 60 ( m , 4 H ) , 7 .4 6– 7 .3 2 ( m , 6 H ),
3
6 .6 6 –6 .4 9 ( m , 1 H ) , 4 . 12 –3. 72 ( m , 2H ) , 3. 6 3– 3.5 3 ( m , 1 H ) , 2 .5 1
( t , J = 1 1 .4 H z 1 H ) , 2. 4 3 (d d, J = 1 5. 8 , 3. 5 Hz , 1H ) , 2 .3 9– 2 .2 0
( m , 2 H ) , 2 . 19 –1. 9 1 (m , 6H ) , 1 .51 – 1. 41 (m , 2H ) , 1 .36 ( s , 9 H ) ,
2
4
w a s e v a p o r a t e d u n d e r r e d u c e d p r e s s u r e t o f u r n i s h t he c ru de
c o m p o u n d w h ic h w a s p u r i fie d b y c o l u m n c h r o m a t o g r a ph y
o n s i li c a g e l ( E t O A c : h e x a n e , 0 . 5 : 9 . 5 ) t o a f f o r d t h e p ro d uc t
52 a s r o t a m e r s i n 1 : 1 r a t i o ( 4 .4 m g , 0 . 0 1 3 7 m m o l ) i n 4 6%
y i e l d a s a v i s c o u s o i l . T h e a q l a y e r w a s b a s i fi e d w i t h a q
1 3
1 .0 5 ( s , 9 H ), 1 . 02 ( d, J = 6. 5 H z , 3 H ) ; C N M R ( 12 5 M H z ,
C D C l ) d 19 9 .3 , 1 54 . 3, 1 4 5. 9 , 13 6 .6 , 1 35 . 6, 1 3 3. 9 , 12 9 .6 ,
3
1 27 . 6, 79 . 3, 6 8. 2 , 5 1. 1 , 4 8 .1 , 46 .4 , 40 . 8, 3 4. 3, 3 3. 6 , 3 3 .3 , 3 0 .5 ,
2 8. 3 , 26 . 9, 21 .1 , 1 9 .1 .
M S ( E S I ) : m / z 5 8 4 [ M ?N a ] ?. H R M S ( E S I) : c a l c d f o r
C H N O N a S i : 5 8 4 . 3 1 7 2 ; f o u n d : 5 8 4 . 3 1 8 1 .
N a H CO ( 5 m L ) a n d e x t r a c te d w i t h e t h e r ( 2 x 5 m L ) a nd
3
t h e c o m b in e d o r g a n i c l a y e r s w e r e w a s h e d w i t h w a t er
( 5 m L ) , b r in e ( 5 m L ) a n d d r ie d o v e r N a S O . T h e s o l v e nt
3 4 4 7
4
2
4
w a s e v a p o r a t e d u n d e r r e d u c e d p r e s s u r e t o a f f o r d t he B o c
d e p r o t e c t e d c o m p o u n d 53 ( 1 .6 m g , 0 . 0 0 7 2 m m o l ) i n 2 4%
y i e l d a s a v i s c o u s o i l .
(3R,5S)-tert-Butyl 3-hydroxy-5-(((R)-4-methyl-6-oxocy-
clohex-1-en-1-yl)methyl)piperidine-1-carboxylate (51):
T o a s t i r r e d s o l u ti o n o f c o m p o u n d 50 ( 3 5 m g , 0 . 0 6 4 m m o l )
i n a n h y d r o u s t et r ah y d ro f u r a n ( 2 m L ) w a s a d d e d T B A F
( 1 M , 0 . 1 m L ) a t r t . T h e r e a c t i o n m i x t u r e w a s s t i r r e d f o r
4 5 m i n a t t h e s am e t e m p e r a t u r e . T h e s o l v e n t w a s r e m o v e d
u n d e r r e d u c ed p r e s s u r e a n d t h e r e s i d u a l m a s s w a s p u r i fie d
b y c o l u m n c h r o m a t o g ra p h y ( E t O Ac / h e x a n e , 4 : 6 ) t o a f f o r d
1
Compound 52: T L C R f: 0 . 2 ( e t h y l a c e t a t e : h e x a n e , 1 :9 ) . H
N M R ( 5 0 0 M H z , C D C l ) ( A s te r i sk m a r k i n d i c a t e s s i g n a ls
3
f o r t h e m i n o r r o t a m e r ) d 4 . 5 7 * ( s , 1 H ) , 4 . 4 0 ( s , 1 H ) , 3 .5 6 *
( t , J = 1 . 7 H z , 1 H ) , 3 . 5 3 ( t , J = 1 . 7 , H z , 1 H ) , 3 . 4 7 ( dd , J =
1 1 . 9 , 4 . 0 H z , 2 H ) , 2 . 6 6 – 2 .3 5 ( m , 1 6 H ) , 2 . 2 4 – 2 .1 2 ( m , 4 H ),
2 . 0 7 – 1 .9 2 ( m , 6 H ) , 1 . 8 9 – 1 .7 8 ( m , 2 H ) , 1 . 5 0 ( s , 1 8H ) ,
0 . 9 6 – 0 .9 4 ( m , 6 H ) .
c o m p o u n d 51 ( 2 0 m g , 0 . 0 6 m m o l ) i n 9 3 % y i e l d a s a n o i l .
2 0
T L C R f: 0 . 2 ( e t h y l a c e t a t e : h e x a n e , 4 : 6 ) . [ a] = - 2 6 .2
D
( c 0 . 2 5 , C H C l ) ; I R ( n e a t ) : 3 4 2 3 , 2 9 2 7 , 1 6 7 0 , 1 4 2 4 , 1 1 4 8 ,
3
- 1
1
(3R,4aR,5R,8S,9aS)-3-methyloctahydro-1H-5,8-(epimi-
nomethano)benzo[7]annulene-1,6(2H)-dione (53): T o a
s t ir r e d s o l u t i o n o f t r i c y c l ic c o m p o u n d 52 ( 4 .4 m g , 0 .0 1 37
m m o l ) i n a n h y d r o u s D C M ( 0 .3 m L ) w a s a d d e d T F A
( 0 .3 m L ) a t 0 °C a n d r e s u lt a n t r e a c t io n m i x t u r e w a s w a r m e d
t o r o o m t e m p e r a t u r e a n d s t ir r e d f o r 2 h . T h e r e a c t i o n w a s
1 0 7 1 , 8 8 9 c m ; H N M R ( 5 0 0 M H z , C D C l ) d 6 . 7 4 – 6 .6 9
3
( m, 1 H ) , 4 . 3 1 – 4 . 0 6 ( m , 1 H ) , 4 . 0 6 – 3 . 6 6 ( m , 1 H ) , 3 . 6 6 – 3 .5 1
( m, 1 H ) , 2 . 5 0 ( d d , J = 1 5 . 4 , 3 . 3 H z , 1 H ) , 2 . 4 6 – 2 . 3 7 ( m , 2 H ) ,
2 . 2 6 – 1 . 96 ( m , 7 H ) , 1 . 7 1 – 1 . 6 6 ( m , 2 H ) , 1 . 4 3 ( s , 9 H ) , 1 . 0 5 ( d ,
1 3
J = 6 . 4 H z , 3 H ) ; C N M R ( 1 0 0 M H z , C D C l ) d 1 9 9 .5 ,
3
1 5 4 . 6 , 1 4 6 . 4 , 1 3 6 . 7 , 7 9 . 7 , 6 6 . 7 , 5 0 . 9 , 4 9 . 4 , 4 6 . 5 , 4 0 . 5 , 3 4 . 4 ,
3 4 . 0 , 3 3 . 6 , 3 0 . 6 , 2 8 . 4 , 2 1 . 1 . M S ( E S I) : m / z 3 4 6 [ M ?N a ] ?.
H R M S ( E S I ) : c al cd f o r C H N O N a : 3 4 6 . 1 9 9 4 ; f o u n d :
q u e n c h e d b y a d d in g s a t u r a te d a q N a H CO ( 2 m L ) a nd
3
e x t r a c te d w i t h d i c h l o r o m e t h a n e ( 2 x 5 m L ) . T h e c o m b i ne d
o r g a n i c l a y e r s w e r e w a s h e d s u c c e s s i v e l y w i t h w a t e r ( 2 m L ) ,
b r in e ( 2 m L ) a n d d r ie d o v e r N a S O . T h e s o l v e nt w a s
1 8 2 9
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(S)-tert-Butyl
3-(((R)-4-methyl-6-oxocyclohex-1-en-1- e v a p o r a t e d u n d e r r e d u c e d p r e s s u r e t o f u r n i s h t h e c ru de
yl)methyl)-5-oxopiperidine-1-carboxylate (18): A l c o h o l c o m p o u n d w h ic h w a s p u r ifi e d b y c o l u m n c h r o m a t og r a ph y
51 ( 1 7 m g , 0 . 0 . 5 4 m m o l ) w a s c o n v e r t e d t o t h e d i k e t o o n s i li c a g e l ( E t O A c / h e x a n e , 1 : 1 ) t o a f f o r d t h e p r o d uc t 53
c o m p o u n d 18 ( 1 5 m g , 0 . 0 5 m m o l ) i n 9 2 % y i e l d f o ll o w i n g ( 2 .6 m g , 0 . 0 1 1 9 m m o l ) i n 8 7 % y i e l d a s g u m m y g e l . T LC R f:
1
t h e p r o c e du re d et a i l e d f o r t h e p r e p a r a t i o n o f 45. T L C R f: 0 . 2 0 . 2 ( e t h y l a c e t a t e : h e x a n e , 1 : 1 ) . H N M R ( 5 0 0 M H z , C D C l )
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2 0
( e t h yl a ce t at e :h e x a n e , 1 : 9 ) . [ a] = - 1 1 . 3 (c 0 . 9 , C H C l ) ; I R d 3 . 1 6 ( d , J = 1 2 . 0 H z , 1 H ) , 3 . 0 8 ( d d , J = 1 1 . 8 , 4 . 7 H z, 1 H ),
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3
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( KB r ) : 2 9 5 8 , 2 9 2 7 , 1 6 2 7 , 1 4 1 7 , 1 1 6 4 , 7 6 6 c m ; H N M R 3 . 0 4 ( s , 1 H ) , 2 . 7 3 ( t d , J = 1 2 . 3 , 4 . 0 H z , 1 H ) , 2 . 5 7 ( dd , J =
1
( 40 0 M H z, C D C l ) d 6 . 7 5 – 6 . 6 9 ( m , 1 H ) , 4 . 0 ( d , 1 8 . 0 H z , 1 3 . 8 , 6 . 7 H z , 1 H ) , 2 . 5 3 – 2 .4 8 ( m , 2 H ) , 2 . 4 5 – 2 .4 1 ( m , 2 H ),
3
1 H ) , 3 . 8 9 ( d , J = 1 8 . 0 H z , 1 H ) , 3 . 7 4 ( d , J = 1 1 . 7 H z , 1 H ) , 2 . 2 2 – 2 .1 2 ( m , 3 H ) , 1 . 8 7 ( t d , J = 1 2 . 3 , 3 . 8 H z , 1 H ) , 1 .5 8 ( d,
3 . 0 9 ( d d , J = 1 1 . 7 , 6 . 9 H z , 1 H ) , 2 . 5 5 – 2 . 3 8 ( m , 3 H ) , J = 1 3 . 8 H z , 1 H ) , 1 . 5 0 ( d d , J = 1 5 . 1 , 1 2 . 3 H z , 1 H ) , 0 .9 5 ( d,

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c a l cd . f o r C H O N : 2 2 2 . 1 4 9 5 ; f o u n d : 2 2 2 . 1 4 8 9 .
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2 . K o b a y a s h i J , H i r a s a w a Y , Y o sh id a N a n d M o ri t a H
2 0 0 1 L y c o n a d i n A , a n o v e l a l k a l o i d f r o m Lycopodium
complanatum J. Org. Chem. 66 5 9 0 1
3 . I s h iu c h i K , K u b o t a T , H o s h i n o T , O b a r a Y , N a k ah a t a N
a n d K o b a y a s h i 2 0 0 6 L y c o p l a d i n e s B - D a n d l yc o n a di n
B , n e w a l k a l o i d s f r o m Lycopodium complanatum J.
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4 . ( a ) B e s h o r e D C a n d S m i th A B 2 0 0 7 T o t a l s y n t h es i s o f
( ?) - L y c o n a d i n A a n d ( - ) - L y c o n a d i n B J. Am. Chem.
Soc. 129 4 1 4 8 ; ( b ) B e s h o r e D C a n d S m it h A B 2 00 8
T h e L y c o n a d i n s : E n a n t i o s e l e c t i v e t o t a l s y n t h es i s o f
( ?) - L y c o n a d i n A a n d ( - ) - L y c o n a d i n B J. Am. Chem.
Soc. 130 1 3 7 7 8
5 . ( a ) B is a i A , W e st S P a n d S a r p o n g R 2 0 0 8 U n i fi e d
s t r a t e g y f o r t h e s y n t h e si s o f t h e ‘‘ M is c e l l a ne o u s ’’
Lycopodium a l k a l o i d s : T o t a l s y n t h e si s o f ( ) -L y-
c o n a d i n A J. Am. Chem. Soc. 130 7 2 2 2 ; ( b ) W es t S P ,
B is a i A , L i m A D , N a r a y a n R R a n d S a r p o n g R 2 00 9
T o t a l s y n t h e s i s o f (?) - L y c o n a d in A a n d r e l a t e d c om -
p o u n d s v i a o x i d a ti v e C - N b o n d f o r m a t i o n J. Am. Chem.
Soc. 131 1 1 1 8 7
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6 . ( a ) N i s h i m u r a T , U n n i A K , Y o k o s h i m a S a n d F u k uy am a
T 2 0 1 1 C o n c i s e t o t a l s y n t h e s i s o f (?) - L y c o n a d i n A J. Am.
Chem. Soc. 133 4 1 8 ; ( b ) N i s h i m u r a T , U n ni A K ,
Y o k o s h i m a S a n d F u k u y a m a T 2 0 1 3 T o t a l s y n t he s e s o f
L y c o n a d i n s A - C J. Am. Chem. Soc. 135 3 2 4 3
7 . Y a n g Y , H a s k i n s C W , Z h a n g W , L o w P L a n d D a i M
2 0 1 4 D i v e r g e n t t o t a l s y n t h e s e s o f L y c o n a d i n s A a nd C
Angew. Chem. Int. Edit. 53 3 9 2 2
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Supplementary Information (SI)
1
1 3
H N M R , C N M R s p e c t r a d a t a i s a v a i l a b l e a t w ww . ia s . a c .
i n /c h e ms c i .
8 . K o s h ib a T , Y o k o s h i m a S a n d F u k u y a m a T 2 0 0 9 T ot a l
s y n t h e si s o f ( - ) - H u p e r z i n e A Org. Lett. 11 5 3 5 4
9 . C a s t a ld i G , P e r d o n c i n G , G i o r d a n o C a n d M i n i s c i F
1 9 8 3 S t e r e o c h e m i s tr y o f r e d u c t io n o f c y c l i c k e t o ne s b y
a l k a l i m e t a l s a n d b y s o d i u m d i t h i o n i t e Tetrahedron Lett.
24 2 4 8 7
1 0 . J e n s e n H H , L y n g b y e L , J e n s e n A a n d B o l s M 2 00 2
S t e r e o e le c t r o n ic s u b s t i tu e n t e f f e c t s i n p o l y h y d r ox y la t ed
p i p e r id i n e s a n d h e x a h y d r o p y r i d a z i n e s Chem. Eur. J. 8
1 2 1 8
Acknowledgements
S a t i sh K a r e l l a i s t h a n k fu l t o C o u n c i l o f S c i e n t i fi c a n d
I nd u s t r i a l R es e ar c h ( C S IR )- N e w D e l h i f o r f e l l o w s h i p . S . R .
i s g r at e f u l t o C S I R , N e w D e l h i f o r f u n d i n g u n d e r t h e X I I
fi v e y e ar p l an p r o g r a m m e e n t i t l e d O R I G I N ( C S C - 1 0 8 ) .
I IC T / P u b s . / 2 0 19 / 3 7 7 .
1 1 . R o l f A 1 9 7 5 T e r ti a r e s p h o s p h a n / t e t r a c h l o r m e t ha n , e in
v i e l s e i t i g e s R e a g e n s z u r c h l o r i e r u n g , D e h y d r a t i s i e ru ng
u n g P N - V e r k n u p f u n g Angew. Chem. 87 8 6 3 ; R o l f A
1 9 7 5 T e r t i a r y P h o s p h a n e / t e t r a c h l o r o m e t h a n e , a v er s a -
t il e r e a g e n t f o r c h l o r i n a t i o n , d e h y d r a t i o n , a nd P - N
l in k a g e Angew. Chem. Int. Edit. Engl. 14 8 0 1
1 2 . Y a n g C - T , Z h a n g Z - Q , T a j u d d i n H , W u C - C , L i a n g J , L iu
J - H , F u Y , C z y z e w s k a M , S t e e l P G , M a r d e r T B a n d L iu L
2 0 1 2 A l k y l b o r o n i c e s t e r s f r o m c o p p e r - c a ta ly z e d b or yl a -
t io n o f p r i m a r y a n d s e c o n d a r y a l k y l h a l i d e s a n d p s e ud o -
h a l i d e s Angew. Chem. Int. Edit. 51 5 2 8
1 3 . ( a ) F u s t n e r A , N e v a d o C , W a se r M , T r e m bl a y M ,
C h e v r ie r C , T e p l y F , A i s s a C , M o u li n E a n d M u l le r O
2 0 0 7 T o t a l s y n t h e si s o f i e j im a l i d e a - d a n d a s s e s s m e nt o f
t h e r e m a r k a b l e a c t i n - d e p o l y m e r iz in g c a p a c i ty o f t he s e
p o l y e n e m a c r o li d e s J. Am. Chem. Soc. 129 9 15 0;
( b ) M o l a n d e r G A a n d I t o T 2 0 0 1 C r o s s - c o up l i ng
r e a c ti o n s o f p o t a s s iu m a l k y l t r i fl u o r o b o r a t e s w i t h a ry l
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3 9 3 ; ( c ) Z o u G , K r is h n a R e d d y Y a n d F a l c k J R 2 00 1
A g ( I ) - p r o m o t e d S u z u k i - M iy a u r a c r o s s - c o u p l i n g s o n n-
a l k y l b o r o n i c a c i d s Tetrahedron Lett. 42 7 2 1 3
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