Tandem Use of Cobalt-Mediated Reactions to
Synthesize (+)-Epoxydictymene, a Diterpene
Containing a Trans-Fused 5-5 Ring System
Problem Set for January 15, 2010
12:00 pm in 3005
Christopher D. Thomas
Rare Trans-Bicyclo[3.3.0]Octane Ring System
Me
H
Me
Me
H
Me
H
Me
O
H
H
(+ )-e p o xy d ic ty m e n e
H
Me
HO Me
H
Me
Me
Me
 -fu n e b re n e
Me
H
H
Me
Me
Me H
Me
H
p a rd a lia n c h o l
HO
Me
 -8 -h y d ro x yp re s ilp h ip e rfo le n e
• Trans-5-5 systems are approximately 6 kcal/mol less stable than
their cis counterparts. (JACS, 1970, 92, 3109).
• For epoxydictymene’s ring system, it has been calculated this
discrepancy is over 10 kcal/mol more energetic (Naturforsch.
1989, 44b, 975).
-Funebrene: Kirtany, J. K.; Paknikar, S. K. J. Indian Chem. 1973, 11, 508.
Pandalianchol: Bohlmann, F.; Abraham, W. F. Phytochemistry 1979, 18, 668..
-8-Hydroxypresilphiperfolene: Bohlmann, W. F.; et al. Phytochemistry, 1981, 20, 2239.
2
Isolation and Biological Profile
• Isolated from the brown algae called
Dictyota dichotoma in 1983.
• Methanolic extraction (20 kg) from
algae collected from Ochoro Bay,
Hokkaido to give 215 mg of (+)epoxydictymene.
• Structure determined from X-ray after
dihydroxylation and acylation of primary
alcohol.
• To the best of my knowledge (which
doesn’t say a whole lot), the bioactivity
is not known.
Me
Me
H
Dictyota dichotoma
Me
Me
H
QuickTime™ and a
decompressor
are needed to see this picture.
H
1 ) O s O 4 , p yr.
H
Me
Me
H
H
O
H
Me
2 ) p -B rP h N = C = O
O
H
H
O
H
Me
QuickTime™ and a
decompressor
are needed to see this picture.
OH
(p -B r)P h H N
O
(a) Enoki, N.; et al. Tetrahedron Lett. 1983, 24, 4341. (b) Faulkner, D. J. Nat. Prod. Rep. 1999,
16, 155.
3
Retrosynthetic Plan
O
Me
H
Me
B H
A
Me
H
Me
C
D
H
D
B
A
Me
H
Me
C
O
H
H
(C O ) 3
Co
H
C o (C O ) 3
Me
Me
B
A
O
H
Me
Me
O
H
H
H
(+ )-e p o xy d ic ty m e n e
Me
Me
H
OH
H
H
O
O
A
Me
Me
A
Me
Me
O
O
H
H
Me
TM S
Me
Me
Me
TM S
Jamison, T. F.; Shambayati, S.; Crowe, W. E.; Schreiber, S. L. J. Am. Chem. Soc. 1997, 119, 4353.
Other Reported Synthesis: Paquette, L. A.; et al. J. Am. Chem. Soc. 1997, 119, 8438.
4
Construction of A-Ring/TMS-Allyl Fragment
Me
Me
H
C O 2M e
1 ) B r2
1 ) K O H , H 2O
Me
O
2) NaO M e
M eO H
Me
Me
O
1 ) L iA lH 4 ; A c 2 O , p y.
2 ) H 2S O 4
A
Me
H
A
O
2 ) A c 2 O , re flu x
56% over
4 s te p s
H
Me
3) N aO M e
Me
Me
(R )-p u le g o n e
Me
Me
Me
H
H
OH
A
1 ) n -B u L i, t-B u O K ; T M S C l
OH
OH
A
A
2 ) K 2C O 3, M e O H
Me
Me
H
Me
5 0 % yie ld o v e r 2 ste p s
+ 3 6 % o f sta rtin g m a te ria l
TMS
1 :2 R a tio o f D e s ire d
Jamison, T. F.; Shambayati, S.; Crowe, W. E.; Schreiber, S. L. J. Am. Chem. Soc. 1997, 119, 4353.
5
Favorskii Ring Contraction
Me
Me
H
C O 2M e
1 ) B r2
A
Me
2) N aO M e
O
M eOH
Me
Me
Me
(R )-p u le g o n e
E 1 -c b ?
or E2?
B r2
Me
Me
Me
Me
NaO M e
OMe
O
Br
O
O
OMe
O
Br
Me
Me
Br
Me
Me
Br
Me
Me
Br
Me
Me
Br
F a v o rs kii
In te rm e d ia te
Wolinsky, J.; Gibson, T.; Chan, D.; Wolf, H. Tetrahedron 1965, 21, 1247.
6
Synthesis of Acetal Fragment
1 ) M e 2 B B r, C H 2 C l 2 , -7 8 ºC
2 ) i-P r 2 N E t, 2 -M e -3 -b u te n -1 -o l
H
H
-7 8 ºC to 0 ºC
OEt
H
O
5 4 % y ie ld
OEt
OEt
3 -M e -1 ,3 -b u ta n e d io l
p -T sO H , P h H , re flu x
6 6 % yie ld
H
H
H
O
O
H
O
Me
Me
O
D e s ire d a c e ta l, n o t o b ta in e d .
Jamison, T. F.; Shambayati, S.; Crowe, W. E.; Schreiber, S. L. J. Am. Chem. Soc. 1997, 119, 4353.
7
Formation of B-Ring From Cyclic Acetal
Me
Me
H
OH
A
t-B u
N
t-B u
T f2 O , C H 2 C l2
-1 0 ºC
Me
H
TMS
-3 0 to 0 ºC
H
A
O
79%
Me
O
n -B u L i, T H F
H
H
Me
O
Me
HMPA
TM S
Me
-7 8 ºC to -3 5 ºC
O
1 ) C o 2 (C O ) 8
E t2 O
Me
(C O ) 3
Co
H
A
C o (C O ) 3
1 ) P B u 3 , o -N O 2 -P h S e C N
H
A
O
H
B
O
2)
PhHC
*
H
-7 8 ºC
> 2 0 :1 d r
O
N S O 2P h
C H 2 C l2
C o (C O ) 3
C H 2 C l 2 , rt
B
H
Me
2 ) E t 2 A lC l
(C O ) 3
Co
H
8 3 % y ie ld
OH
o ve r 2 s te p s
N a H C O 3 , H 2 O , C H 2 C l2
6 1 % o ve r 2 s te p s
Jamison, T. F.; Shambayati, S.; Crowe, W. E.; Schreiber, S. L. J. Am. Chem. Soc. 1997, 119, 4353.
8
Tandem Nicholas/Sakurai Cyclization
Me
H
(C O ) 3
Co
C o (C O ) 3
Me
(C O ) 3
Co
C o (C O ) 3
H
C o (C O ) 3
O
O
H
TM S
Me
L e w is A cid
H
O
(C O ) 3
Co
H
HO
Me
N ic h o la s
H
TMS
R e a c tio n
Me
Me
H
H
O
R
H
Me
H
M e3S i
Me
Me
H
H
R = C H 2C H 2O M
S a ku ra i
R e a c tio n
Me
H
(C O ) 3
Co
(C O ) 3
Co
H
Me
C o (C O ) 3
C o (C O ) 3
O
H
H
OH
O
H
R
H
Me
H
H
Me
H
H
Schreiber, S. L.; Sammakia, T.; Crowe, W. E. J. Am. Chem. Soc. 1986, 108, 3128.
Schreiber, S. L.; Klimas, M. T.; Sammakia, T. J. Am. Chem. Soc. 1987, 109, 5749.
9
Formation of B-Ring From Acyclic Acetal
Me
Me
H
OH
A
t-B u
N
t-B u
T f2 O , C H 2 C l2
-1 0 ºC
Me
H
TM S
-3 0 to 0 ºC
H
A
O
74%
E tO
n -B u L i, T H F
H
H
O
HMPA
Me
TMS
Me
-7 8 ºC to -3 5 ºC
O
1 ) C o 2 (C O ) 8
E t2 O
Me
R = O E t or
M o st c o n d itio n s re s u lte d
8 2 % y ie ld
in m ix tu re s fa v o rin g R = O E t
O
(C O ) 3
Co
H
A
C o (C O ) 3
B
2 ) E t 2 A lC l
C H 2 C l2
-7 8 ºC
*
o ve r 2 s te p s
OR
H
H
> 2 0 :1 d r
Jamison, T. F.; Shambayati, S.; Crowe, W. E.; Schreiber, S. L. J. Am. Chem. Soc. 1997, 119, 4353.
10
Cyclization and Problem with Constructing
Trans-5,5-bicyclic System
A ) M e C N , a ir, re flu x
Me
(C O ) 3
Co
H
O
1 5 m in , 8 5 % , 5 :1 d r
Me
B ) N M O , C H 2 C l2
C o (C O ) 3
H
C
7 0 % , 1 1 :1 d r
A
B
A
H
H
L i, N H 3
L iH M D S , L iC l, T H F
T H F , -7 8 ºC
-7 8 to 0 ºC
M eI
H M P A , -7 8 ºC
84%
N C C O 2M e
H
O
Me
O
H
C O 2M e
B
D
O
H
H
C
B H
Me
A
Me
Me
A
H
C
D e s ire d
D ia s te re o m e r
Me
O
4 0 ºC , 4 5 % , 3 :1 d r
Me
Me
D
B
C ) u ltra so u n d , M e C N
O
H
H
*
D
O
Me
H
Me
O n ly O b s e rv e d
D ia s te re o m e r
6 3 % yie ld
Selectivity in Metallic Reductions: (a) Stork, G.; et al. JACS 1960, 82, 1512. (b) Stork, G.; et al. JACS
1961, 83, 2783. (c) Stork, G.; et al. JACS 1961, 83, 2965. (d) Caine, D. Org. React. 1976, 23, 1.
11
Stability of Bicyclo[3.3.0]octane
Cis-Conformer vs. Trans-Conformer
Q uickTim e™ and a
decom pr es sor
ar e needed t o s ee t his pict ur e.
Q uickTim e™ and a
decom pr es sor
ar e needed t o s ee t his pict ur e.
H
H
H
H
 G = + 6 .4 k ca l/m o l
• The normal bond angle in cyclopentane is approximately 45º, when
putting the ring junction in a trans-conformation, the bond angles skew
to approximately 75º, in which the overall conformation suffers from
more severe torsional strain as well.
Boyd, R. H.; et al. J. Am. Chem. Soc. 1970, 92, 3109.
12
Stereochemistry of the Li-NH3 Reduction of Unsaturated Ketones
R
R
R'
H
H
R ''
L iO
R ''
O
R'
H
L i/N H 3
H
R
R'
L iO
R '''
R
R
R'
R'
H
H
H
L iO
R ''
R
H
R '''
R ''
R ''
F a v o re d
H
R'
H
R '''
R ''
R '''
R '''
R '''
OLi
OLi
P o ss ib le T ra n s itio n S ta te s fo r D e p ro to n a tio n o f A m m o n ia
• The developing orbital at the -carbon is more stable when it lies axially
to the ketone ring, due to perpendicular alignment in the -system.
• Interesting seeing if e.g. R, R’’= Me and R’=OMe and R’’’=H, in theory the
cis-product should be 3-4 kcal/mol more stable than the trans.
Stork, G.; Darling, S. D. J. Am. Chem. Soc. 1960, 82, 1512.
13
Opening of C-Ring to Construct Appropriate
Trans-Junction
O
O
L i, N H 3 , T H F
Me
H
H
C
-7 8 ºC , is o p re n e
1) KH M DS, TH F, HM PA
Me
H
H
Me
A
N H 4 C l, 6 6 % yie ld
Me
O
A
d ia s te re o m e r
2 ) N a H B (O A c) 3 , T H F
Me
O
7 4 % yie ld
H
OH
O
1 ) P b (O A c ) 4 , E tO A c
HO
C
H
B H
Me
H
2 ) D B U , C H 2 C l2
D
O
H
to s e t
O
C 1 2 -c e n te r
H
Me
A
N S O 2P h
E q u ilb ra te
HO
H
D
B H
+ 9 % o f m in o r
H
Me
PhHC
Me
D
B
O
H
C
Me
6 1 % y ie ld
A
B H
Me
D
O
Me
H
Jamison, T. F.; Shambayati, S.; Crowe, W. E.; Schreiber, S. L. J. Am. Chem. Soc. 1997, 119, 4353.
14
Completion of (+)-Epoxydictymene
Jamison, T. F.; Shambayati, S.; Crowe, W. E.; Schreiber, S. L. J. Am. Chem. Soc. 1997, 119, 4353.
15