SCIENCE
Highly Efficient Route to Synthesis Of Complex Alkaloids Developed Berkeley scientists use polycyclization reaction that may mimic biosynthesis to achieve total synthesis of Daphniphyllum alkaloids A new route to the synthesis of the Daphniphyllum alkaloids developed by chemists at the University of California, Berkeley, features a unique polycyclization process in which five bonds and four rings are created. The polycyclization reaction was first reported late last year [/. Am. Chem. Soc, 110, 8734 (1988)] for the synthesis of (±)-methyl homosecodaphniphyllate, research that was carried out by Berkeley chemistry department chairman and professor Clayton H. Heathcock and graduate students Roger B. Ruggeri and Marvin M. Hansen. The total synthesis of the compound is highly efficient, involving 10 linear steps with 42% overall yield from homogeranyl iodide. According to Heathcock, it is likely that a related tetracyclization process is involved in the biosynthesis of the Daphniphyllum alkaloids, a group of squalene-derived compounds that are among the most complex natural products known. More recently, Heathcock, Ruggeri, and undergraduate student Kim F. McClure have reported the synthesis of (±)-daphnilactone A, an unusual Daphniphyllum alkaloid that contains 23 skeletal carbon atoms [/. Am. Chem. Soc, 111, 1530 (1989)]. The synthesis, which requires 11 steps starting with methyl 2-ethoxycyclopentenecarboxylate, involves the tetracyclization process as well as two other unusual transformations, Heathcock says. 22
February 20, 1989 C&EN
Berkeley's Ruggeri (left) and Heathcock The synthesis of (±)-daphnilactone A also provides access to an important unsaturated amino ester, analogs of which are attractive candidates for conversion into even
more complex Daphniphyllum alkaloids such as yuzurimine. The research has been supported by the National Science Foundation, and by fellowships that were
Key step in Daphniphyllum alkaloid syntheses is polycyclization reaction CfiHs
xCK/C6H5
|/C 6 H 5
CRH 5
NH 3) CH 2 CI 2 , CH3COOH
OHC OHC
HN-i
C0 2 CH 3
Methyl homosecodaphniphyllate
Daphnilactone A
Ac = COCH3 Note: Reaction shown is for synthesis of methyl homosecodaphniphyllate.
Only S e s s i o n T h i s Year!
granted to Ruggeri by Smith Kline & F r e n c h Research Laboratories a n d by Pfizer. Heathcock has been working on t h e synthesis of t h e D a p h n i p h y l l u m alkaloids since t h e early 1980s. T h e y are c o m p o u n d s t h a t w e r e first isolated a n d c h a r a c t e r i z e d by t h e Japanese n a t u r a l p r o d u c t s c h e m i s t Yoshimasa Hirata, w h o w a s t h e n at Nagoya University. T h e c o m p o u n d s w e r e isolated from Daphniphyllum macropoda, a n u n u s u a l t r e e t h a t goes by t h e n a m e " Y u z u r i h a " in Japan. T h e tree p r o d u c e s a full set of n e w leaves before it loses its p r e v i o u s foliage. T h e D a p h n i p h y l l u m alkaloids are primarily of interest because of their c o m p l e x s t r u c t u r e s . H e a t h c o c k rep o r t e d t h e first c o m p l e t e s y n t h e s i s of o n e of t h e c o m p o u n d s in 1986. " T h a t s y n t h e s i s w a s n ' t bad by curr e n t s t a n d a r d s , " H e a t h c o c k says. "It r e q u i r e d fewer t h a n 20 steps, a n d it w a s f a i r l y t r a d i t i o n a l i n its a p proach."
By contrast, t h e c u r r e n t s y n t h e ses reflect H e a t h c o c k ' s interest in " f i n d i n g w a y s to p u t t o g e t h e r complicated s t r u c t u r e s w i t h t h e m i n i m u m n u m b e r of steps a n d t h e m i n i m u m a m o u n t of ' h i g h - t e c h ' c h e m istry. W e ' v e f o u n d a w a y to p u t t h e w h o l e D a p h n i p h y l l u m alkaloid skele t o n t o g e t h e r almost in o n e s t e p . " T h e key reaction i n v o l v e s m u l t i p l e c y c l i z a t i o n s t h a t are i n i t i a t e d w i t h t h e f o r m a t i o n of a cation, a strategy t h a t recalls t h e a p p r o a c h d e v e l o p e d by William S. J o h n s o n , e m e r i t u s p r o f e s s o r of c h e m i s t r y , Stanford University, for t h e s y n t h e sis of steroids by m u l t i p l e cyclizations, H e a t h c o c k says. H e a t h c o c k ' s strategy differs from t h e J o h n s o n a p p r o a c h to steroids in that, for t h e D a p h n i p h y l l u m alkaloids, t h e "essential template switches from being first electrophilic, t h e n nucleophilic, t h e n e l e c t r o p h i l i c a g a i n , a n d finally n u c l e o p h i l i c as this assembly of r i n g s is built u p , " h e says. Rudy Baum
Formulation Development of Therapeutic Proteins and Drug Delivery Systems for Peptides and Protein Drugs An intensive s h o r t course cosponsored by the American Chemical Society and the ACS Division of Microbial and Biotechemical Technology Friday-Saturday, May 5-6, 1 9 8 9 Chicago, Illiniois
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Organic Intermediates
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P-203
P-202
c/
c/M^N-c/
r ii
/>CF, N' 4.2.6-CBTF
'l^Y'
3,5.2.6 DCBTF
3.5-BTFP
P-205
P-206 CF,
P 204
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F.C-M MCF.
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' f^Y '
F C
1ST 2.3.5-CBTF
N 2.6.3.5-DCBTF
P-207
P 208
P 209
'Y~~i
F.C-MM
' MT
CF
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f i T
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2.4.5-CBTF
CF,
Ml
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/^CF, N 2.4.6-CBTF
kJL.
2.5-BTFP
P-210 CF,
P-211 NH,
M
Ml
F . C ^ MNH, N 2.4,6 ABTF
F,C^\
/^CF, N 4.2.6 ABTF
C f M x^CF,
ISHIHARA SANGYO has added the above new compounds to its product line. Although these new developmental compounds are only in the research stage, small samples can be prepared for research and development purposes. We wish to make the best use of our processes to assist in the synthesis of your products.
N 2.3.6-CBTF P-212
F.C^^MCF,
M
MNH,
N 2.3.5 ABTF
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ISHIHARA SANGYO KAISHA, LTD. 10 30, Fujimi 2-Chome, Chiyoda-ku. Tokyo, Japan, Telex:2324306 ISK J I S K ( E U R O P E ) S . A . 33 31 Rue Montoyer, Box 8 1040 Bruxelles Tel (02)512-54-50-512-72-78 Telex 23362 ITDD B I S H I H A R A C O R P O R A T I O N ( U . S . A . ) Transamenca Pyramid 42nd Floor 600 Montgomery Street, San Francisco, Ca 941 1 1 Tel 415-421-8207 Telex:278010 ICUSA UR
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February 20, 1989 C&EN
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