Expert System Applications in Chemistry - American Chemical Society

Chapter 6

New Directions in the S Y N G E N Program for Synthesis Design James B. Hendrickson, Zmira Bernstein, Todd M . Miller, Camden Parks, and A. Glenn Toczko

Downloaded by CORNELL UNIV on May 20, 2017 | http://pubs.acs.org Publication Date: September 1, 1989 | doi: 10.1021/bk-1989-0408.ch006

Department of Chemistry, Brandeis University, Waltham, MA 02254-9110

We describe here the SYNGEN program for generating the shortest, sequential-construction routes to any target structure from a catalog of starting materials. The system of abstracting structures and reactions to d i g i t a l generalizations for fast computer manipulation is described, as well as i t s u t i l i z a t i o n to generate and mechanistically test all possible sequences of construction reactions. Various new ways are described for the operator to make selections from the output. A program under development is described for interfacing SYNGEN with external reaction databases, i n order to seek literature precedent for the generated reactions. Finally, a program is also described which proceeds from all starting materials i n a forward direction to synthesize close analogs of a target using refunctionalization reactions as well as constructions. A complete synthesis tree of a l l possible sequences to a synthetic target would be enormous, far larger than generally appreciated. An i l l u s t r a t i o n of such a tree is shown as Figure 1, with reactions as lines (direction: left to right), the compounds as points, increasing generally in complexity from starting materials at the l e f t , through many intermediates to the target molecule at the far right. Yields for each level back from the target are shown below. While the generation of such a tree is conceptually simple, i t s vast size dictates the paramount importance of creating stringent selection c r i t e r i a to generate only the optimal routes. In the SYNGEN program we elected to seek only the shortest, most efficient routes. This focus resulted i n a twofold protocol*-: f i r s t , only the skeleton is considered and only convergent skeletal assemblies from real, available starting material skeletons are accepted. These are derived by cutting the target skeleton a l l ways into two pieces, and each of these into two again, creating 0097-6156/89/0408-0062$06.00/0 o 1989 American Chemical Society

Hohne and Pierce; Expert System Applications in Chemistry ACS Symposium Series; American Chemical Society: Washington, DC, 1989.

New Directions in the SYNGEN Program


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EXPERT SYSTEM APPLICATIONS IN CHEMISTRY

o r d e r e d c o n v e r g e n t b o n d s e t s ; o n l y those w i t h a l l f o u r s t a r t i n g s k e l e t o n s found i n a c a t a l o g are then accepted. Second, t h e program g e n e r a t e s t h e n e c e s s a r y f u n c t i o n a l i t y on those s k e l e t o n s t o a f f o r d t h e s h o r t e s t r o u t e s , those w i t h s e q u e n t i a l c o n s t r u c t i o n s o n l y t h r o u g h t h e o r d e r e d bonds o f the b o n d s e t . Such r o u t e s a r e r e g a r d e d as " i d e a l " syntheses*-. This proceeds i n a r e t r o d i r e c t i o n from t h e t a r g e t f u n c t i o n a l i t y f o r each b o n d s e t and ends w i t h f u n c t i o n a l i t y d e f i n e d on t h e f o u r s t a r t i n g s k e l e t o n s ; t h e program a c c e p t s o n l y r o u t e s w i t h a l l f o u r r e a l s t a r t i n g m a t e r i a l s f o u n d i n t h e c a t a l o g . The o v e r a l l p r o c e d u r e c o n t a i n s t h r e e s t r i n g e n t s e l e c t i o n c r i t e r i a w h i c h v e r y much reduce t h e number o f possible routes: ( a ) o n l y c o n v e r g e n t assembly modes from f o u r s t a r t i n g p i e c e s (two s u c c e s s i v e s k e l e t a l c u t s ) ; (b) o n l y t h e s h o r t e s t r o u t e s o f s u c c e s s i v e c o n s t r u c t i o n r e a c t i o n s o n l y ; and ( c ) o n l y those w h i c h d e r i v e from f o u r r e a l s t a r t i n g m a t e r i a l s a v a i l a b l e i n a c a t a l o g (our c a t a l o g h a s about 6000 s t a r t i n g m a t e r i a l s ) . I t can be c a l c u l a t e d , f o r example, t h a t t h e f i r s t c r i t e r i o n , t h e c o n v e r g e n t s k e l e t a l d i s s e c t i o n , reduces t h e p o s s i b l e assembly modes f o r t h e C^g s t e r o i d s k e l e t o n o f e s t r o n e from 42 m i l l i o n down to l e s s t h a n 900. The f i r s t phase o f s e l e c t i o n , t h e s k e l e t a l bondsets, i s described i n F i g u r e 2 w h i c h shows how d i s s e c t i o n o f the b o n d s e t bonds (k i n number) d i r e c t l y d e f i n e s t h e s t a r t i n g m a t e r i a l (SM) s k e l e t o n s . By itself a b o n d s e t does n o t i n d i c a t e an o r d e r o f c o n s t r u c t i o n s f o r the s k e l e t o n . W h i l e t h e r e a r e bt/k!(b-k)! p o s s i b l e bondsets o f k bonds, each one c a n be o r d e r e d i n k! ways, and, w h i l e t h e t o t a l number p o s s i b l e i s v e r y l a r g e , o n l y a few a r e c o n v e r g e n t . One such o r d e r e d b o n d s e t i s shown f o r t h e C^g s t e r o i d s k e l e t o n , w i t h i t s c o r r e s p o n d i n g assembly plan, t h e sequence o f l i n k i n g t h e k bonds t o g e t h e r from SM t o t a r g e t . Such p l a n s a r e i n f a c t g e n e r a l i z e d s y n t h e t i c r o u t e s d e s c r i b i n g independent f a m i l i e s o f sequences, taken from the s y n t h e s i s t r e e , a l l o f which a r e c o n s t r u c t i n g the same s e t o f k s k e l e t a l bonds. F u r t h e r m o r e , t h i s c o n v e r g e n t p r o t o c o l a f f o r d s a maximum o f k - 6. Indeed, t h e s i m p l e s t g r o s s o v e r v i e w d e s c r i p t i o n o f any s y n t h e s i s i s s i m p l y i t s o r d e r e d b o n d s e t , w h i c h a f f o r d s i t s assembly p l a n ( F i g u r e 2 ) . The program does n o t u s e a database l i b r a r y o f known r e a c t i o n s b u t simply generates a l l p o s s i b l e c o n s t r u c t i o n r e a c t i o n s i n a g e n e r a l i z e d form, u s i n g a s i m p l e b u t r i g o r o u s and n u m e r i c a l d e s c r i p t i o n o f m o l e c u l e s and reactions*-"-*. The form d e r i v e s from a s y n t h e t i c a l l y fundamental d e f i n i t i o n o f f o u r k i n d s o f a t t a c h m e n t on any s k e l e t a l c a r b o n : H f o r h y d r o g e n ( o r e l e c t r o p o s i t i v e e l e m e n t ) ; R f o r r-bond t o a n o t h e r c a r b o n ; P f o r p-bond t o c a r b o n ; and Z f o r bond ( r - o r p-) t o e l e c t r o n e g a t i v e h e t e r o a t o m . The numbers o f each k i n d o f a t t a c h m e n t a r e t h e n h , r , p, z, r e s p e c t i v e l y , and add up t o f o u r . T h i s i s summarized i n F i g u r e 3, w h i c h a l s o i n d i c a t e s t h a t , i f i t s s k e l e t o n i s known and numbered, any m o l e c u l e c a n be d e s c r i b e d by a d i g i t a l z p - l i s t , g e n e r a l i z i n g i t s f u n c t i o n a l i t y , o v e r t h e numbered s k e l e t a l atoms. T h i s y i e l d s a s p e c i f i c , though a b s t r a c t e d , f u l l d e s c r i p t i o n o f any m o l e c u l e i n a l i n e a r b i t l i s t s u i t e d t o computer m a n i p u l a t i o n . The s k e l e t o n i t s e l f i s d i g i t a l l y




HENDRICKSON ET AL.


66


d e s c r i b e d , and u n i q u e l y numbered, b y a s i m p l e m a n i p u l a t i o n o f i t s c o n n e c t i v i t y , o r adjacency, matrix^; t h i s l i n e a r b i t - l i s t d e s c r i p t i o n i s a l s o u s e d t o d e r i v e t h e b o n d s e t s from t h e t a r g e t skeleton. F i g u r e 3 shows an example, w h i c h a l s o i l l u s t r a t e s t h a t the o x i d a t i o n s t a t e ( x ) o f each atom, as w e l l as t h a t o f t h e whole m o l e c u l e (Rx), c a n be s i m p l y and a c c u r a t e l y computed.


A u n i t reaction i s t h e u n i t exchange o f one k i n d o f a t t a c h m e n t f o r a n o t h e r and may be d e s c r i b e d a t each c a r b o n b y two l e t t e r s : t h e f i r s t t h e bond made, t h e second t h e bond b r o k e n . Hence t h e 16 p o s s i b l e u n i t r e a c t i o n s d e p i c t a l l p o s s i b l e changes a t any c a r b o n atom, l i s t e d a t t h e bottom o f F i g u r e 3. F u r t h e r m o r e , t h e s e d i g i t a l d e s c r i p t o r s a l l o w t h e c a l c u l a t i o n o f t h e reaction distance (N^) between any two compounds, i . e . , t h e minimum number o f u n i t r e a c t i o n s r e q u i r e d t o c o n v e r t one i n t o t h e other-*. The

B a s i c SYNGEN Program

The c o n s t r u c t i o n r e a c t i o n s (RH, RZ, RP) a r e c e n t r a l t o o u r p r o c e d u r e and a g e n e r a l i z e d form o f any c o n s t r u c t i o n r e a c t i o n i s shown i n F i g u r e 4. Three carbons on each s i d e , l a b e l e d a, b, c o u t from t h e bond formed, v i r t u a l l y always b e a r a l l t h e f u n c t i o n a l i t y t h a t changes i n a u n i t c o n s t r u c t i o n . A l l p o s s i b l e c o n s t r u c t i o n s a c r o s s any d e s i g n a t e d b o n d s e t bond may t h u s be g e n e r a t e d from t h e u n i t r e a c t i o n changes, shown a t t h e bottom; t h e v a r i o u s c o n s t r u c t i o n s w i l l change a t t a c h m e n t s on 2-6 atoms and t h e o n l y c o n s t r u c t i o n s u s e d a r e t h o s e w h i c h a r e i s o h y p s i c ^ (RDx - 0). A c o n s t r u c t i o n r e a c t i o n c a n be seen as a c o m b i n a t i o n o f two h a l f r e a c t i o n s , one n u c l e o p h i l i c (Dx - +1) and t h e o t h e r e l e c t r o p h i l i c (Dx - - 1 ) , and g e n e r a l l y t h e s e may be t r e a t e d i n d e p e n d e n t l y . Any g e n e r a l i z e d k i n d o f c o n s t r u c t i o n w i l l a l s o be c h a r a c t e r i z e d b y Dzp on each i n v o l v e d c a r b o n and so c a n be d e s c r i b e d b y a D z p - l i s t o v e r the s t r a n d o f s i x atoms s p a n n i n g t h e bond formed. Hence t h e a d d i t i o n o f t h e d i g i t a l D z p - l i s t f o r any p a r t i c u l a r c o n s t r u c t i o n t o the z p - l i s t o f t h a t s t r a n d o f atoms i n a p r o d u c t m o l e c u l e w i l l g e n e r a t e t h e new z p - l i s t f o r t h e s u b s t r a t e m o l e c u l e i n t h e retrosynthetic d i r e c t i o n . Equally, subtraction of a c o n s t r u c t i o n D z p - l i s t from t h e z p - l i s t o f t h e s u b s t r a t e c r e a t e s t h e p r o d u c t i n t h e f o r w a r d d i r e c t i o n . T h i s i s shown i n F i g u r e 5 i n w h i c h t h e D z p - l i s t f o r t h e M i c h a e l c o n s t r u c t i o n i s a p p l i e d t o atom s t r a n d s a c r o s s t h e d e s i g n a t e d c o n s t r u c t i o n bond t o g e n e r a t e t h e s u b s t r a t e from a p a r t i c u l a r p r o d u c t r e t r o s y n t h e t i c a l l y . E i t h e r the d e s c r i p t o r l i s t o f F i g u r e 3 (RH, RZ, e t c . ) o r t h e D z p - l i s t g e n e r a t o r s i l l u s t r a t e d i n F i g u r e 4 s e r v e t o summarize t h e net s t r u c t u r a l change i n a g i v e n r e a c t i o n . W i t h t h i s d i g i t a l f o r m a l i s m d e v e l o p e d i t i s now an easy m a t t e r t o g e n e r a t e a l l p o s s i b l e s y n t h e t i c sequences o f c o n s t r u c t i o n s o n l y , from t h e p r e v i o u s l y s e l e c t e d c o n v e r g e n t b o n d s e t s . These b o n d s e t s are c r e a t e d b y c u t t i n g t h e t a r g e t s k e l e t o n i n t o two p a r t s ( c u t t i n g no more t h a n two bonds) and t h e two p a r t s i n t o two more each. Thus each o p t i m a l b o n d s e t d e f i n e s up t o s i x bonds t h a t w i l l be c o n s t r u c t e d and t h e o r d e r o f t h e i r c o n s t r u c t i o n . S t a r t i n g


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r e t r o s y n t h e t i c a l l y , the t a r g e t f u n c t i o n a l i t y i s d e f i n e d as z p - l i s t s f o r a l l s t r a n d s o f up t o t h r e e atoms o u t from each end o f the f i n a l c o n s t r u c t e d bond. To each such p r o d u c t z p - l i s t i s added t h e D z p - l i s t f o r each c o n s t r u c t i o n h a l f - r e a c t i o n t o g e n e r a t e s u b s t r a t e z p - l i s t s ; o n l y g e n e r a t e d z p - l i s t s o f (z+p) \ (4-r) a r e v i a b l e . Then n u c l e o p h i l i c h a l f - r e a c t i o n s f o r each s i d e a r e p a i r e d o n l y w i t h e l e c t r o p h i l i c ones on the o t h e r t o d e f i n e f u l l i s o h y p s i c c o n s t r u c t i o n s and the s u b s t r a t e s f o r t h e s e (as z p - l i s t s ) . These s u b s t r a t e z p - l i s t s now become the p r o d u c t s f o r r e p e a t i n g t h e o p e r a t i o n w i t h the n e x t bond d e f i n e d i n the b o n d s e t o r d e r . When a l l the b o n d s e t bonds have been s e q u e n t i a l l y t r e a t e d i n t h i s way, t h e r e w i l l r e s u l t the z p - l i s t s o f the f o u r g e n e r a t e d s t a r t i n g m a t e r i a l s and t h e s e can now be l o o k e d up i n the c a t a l o g . I f a l l f o u r are found t o be a v a i l a b l e compounds a s u c c e s s f u l s y n t h e t i c sequence h a s been found and i s r e c o r d e d . When t h i s p r o c e d u r e i s a p p l i e d , u s i n g the n i n e p o s s i b l e p a i r s o f t h r e e n u c l e o p h i l i c and t h r e e e l e c t r o p h i l i c h a l f - r e a c t i o n s ( F i g u r e 4 ) , the r e s u l t s o b t a i n e d show many v i a b l e sequences b u t r e v e a l two s h o r t c o m i n g s . F i r s t , some common o n e - s t e p c o n s t r u c t i o n s do n o t appear and, second, many o f the g e n e r a t e d r e a c t i o n s a r e c h e m i c a l l y non-viable. The c o n s t r u c t i o n s w h i c h do not appear a r e t h o s e i n w h i c h the a c t u a l "one-step" r e a c t i o n i s i n f a c t two s u c c e s s i v e u n i t r e a c t i o n s , a c o n s t r u c t i o n and a r e f u n c t i o n a l i z a t i o n . Thus t h e W i t t i g r e a c t i o n i s a c o n s t r u c t i o n f o l l o w e d by an e l i m i n a t i o n , w h i l e the common G r i g n a r d h a l f - r e a c t i o n c o n s i s t s o f a p r i o r r e d u c t i o n o f RfX t o RfMgBr f o l l o w e d b y c o n s t r u c t i o n . We d i s c e r n e d t h r e e k i n d s o f r e f u n c t i o n a l i z a t i o n u n i t r e a c t i o n s w h i c h can u s e f u l l y c o u p l e w i t h a c o n s t r u c t i o n i n a n o n s t o p , o r onestep, procedure: p r i o r reduction t o carbanion n u c l e o p h i l e s , elimination following construction, or various tautomerizations b e f o r e o r a f t e r c o n s t r u c t i o n . The o v e r a l l n e t s t r u c t u r a l changes f o r t h e s e c o m p o s i t e c o n s t r u c t i o n s were t h e n added t o o u r l i s t o f c o n s t r u c t i o n h a l f - r e a c t i o n s and, a f t e r some f u r t h e r s u b d i v i s i o n o f common t y p e s i n t o c h e m i c a l l y r e c o g n i z a b l e s u b h e a d i n g s , we h a d expanded the l i s t from the s i x o f F i g u r e 4 t o 24 h a l f - r e a c t i o n s : 16 n u c l e o p h i l e s and 8 e l e c t r o p h i l e s w h i c h combine t o a f f o r d 100 f u l l construction reactions. (Note t h a t the t o t a l s h o u l d be 16 x 8 - 128, b u t t h r e e h a l f - r e a c t i o n s a r e l i m i t e d t o f o r m i n g d o u b l e bonds a c r o s s the c o n s t r u c t e d bond.) These 24 h a l f - r e a c t i o n s are sampled i n F i g u r e 6, t a k e n from the " h e l p s c r e e n " o f SYNGEN. They are b r i e f l y l a b e l e d w i t h t w o - c h a r a c t e r d e s c r i p t o r s . The f i r s t c h a r a c t e r i s a l e t t e r f o r n u c l e o p h i l e s o r a number f o r e l e c t r o p h i l e s , w h i c h g e n e r a l l y d e p i c t i n g the minimum r e q u i r e d s u b s t r a t e f u n c t i o n a l i t y ( z + p) on the a-carbon. The second c h a r a c t e r g e n e r a l l y d e p i c t the span, o r s t r a n d l e n g t h o f c h a n g i n g c a r b o n s - 1-3. This expansion o f p o s s i b l e c o n s t r u c t i o n h a l f - r e a c t i o n s t o i n c o r p o r a t e c o m p o s i t e c a s e s now a f f o r d e d a l l e x p e c t e d c o n s t r u c t i o n s , b u t the number o f c h e m i c a l l y n o n - v i a b l e r e a c t i o n s w h i c h were a l s o p r o d u c e d remained l a r g e . To prune t h e s e down t o



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Samples o f SYNGEN H a l f - R e a c t i o n s


6.

HENDRICKSONETAL.



more r e a s o n a b l e c h e m i s t r y r e q u i r e d an o v e r l a y o f mechanism t e s t i n g for chemical v i a b i l i t y . I t i s a p p a r e n t t h a t any such t e s t s may e l i m i n a t e p o s s i b l y i n t e r e s t i n g new c h e m i s t r y , b u t w i t h o u t them t h e output i s excessive. We p r o p o s e d t o s o l v e t h i s p r o b l e m by e n c o d i n g the t e s t s as modules a t t a c h e d t o each h a l f - r e a c t i o n g e n e r a t o r so t h a t t h e y may be e a s i l y a l t e r e d i n d e p e n d e n t l y , a l l o w i n g t h e n a t u r e and p r o p o r t i o n o f " n o n - v i a b l e s " t o be v a r i a b l e . The mechanism t e s t s a r e o f two k i n d s : " r e q u i r e " and " r e j e c t " ; t h e f o r m e r t e s t s f o r t h e p r e s e n c e o f r e q u i r e d a c t i v a t i o n and r e g i o s e l e c t i v i t y on t h e atoms n e a r t h e c o n s t r u c t i o n bond; t h e l a t t e r s e a r c h e s f o r t h e p r e s e n c e o f i n c o m p a t i b l e f u n c t i o n a l groups and i n t e r f e r i n g s i d e r e a c t i o n s . To do t h i s we c a n make q u i c k n u m e r i c a l checks o f t h e v a l u e s o f h , r, p, o r z on t h e p r o x i m a l atoms, b u t we q u i c k l y r e c o g n i z e d t h a t t h e merging o f a l l e l e c t r o n e g a t i v e heteroatoms as " z " was t o o s e v e r e a g e n e r a l i z a t i o n f o r m e c h a n i s t i c t e s t s . Hence we d e f i n e d a s u b s e t o f " z " t o i n d i c a t e t h e mechanistic function o f t h e h e t e r o a t o m as e l e c t r o n w i t h d r a w i n g , e l e c t r o n - d o n a t i n g o r l e a v i n g group. A d i g i t a l c h e c k l i s t s t r i n g o f s i n g l e b i t s f o r t h e r e l e v a n t h , r , p, z, and z-function v a l u e s f o r each atom on (and a d j a c e n t t o ) a r e a c t i v e a , b , c - s t r a n d i s e s t a b l i s h e d f i r s t f o r s t r a n d s a t each end o f a c o n s t r u c t e d bond, d e f i n e d by t h e b o n d s e t . Then, f o r each h a l f r e a c t i o n t o be g e n e r a t e d , two t e s t l i s t s ( b i t s t r i n g s ) a r e a p p l i e d , each by a s i n g l e AND o p e r a t i o n over a l l t h e atoms a t once, one l i s t f o r " r e q u i r e " f o l l o w e d by one f o r " r e j e c t " . A z e r o r e s u l t f o r t h e f i r s t AND o p e r a t i o n d i s a l l o w s g e n e r a t i o n o f t h e r e a c t i o n , as does a n o n - z e r o r e s u l t f o r t h e second. These s i m p l e mechanism t e s t s a r e v e r y f a s t ( j u s t two AND o p e r a t i o n s ) and a l s o a l l o w an i m p o r t a n t e x p a n s i o n o f o u r p r i m a r y d e f i n i t i o n o f t h e s k e l e t o n . Up t o now t h e " s k e l e t o n " o f t h e m o l e c u l e s ( t a r g e t , i n t e r m e d i a t e s , s t a r t i n g m a t e r i a l s ) was c o n s i d e r e d t o be o n l y a c a r b o n frame. The mechanism t e s t s a l l o w f o r i n c o r p o r a t i o n o f N, 0, S atoms i n t o t h e s k e l e t a l frame s i n c e t h e y may be r e g a r d e d s i m p l y as s p e c i a l c a r b o n s , u s i n g t h e same construction h a l f - r e a c t i o n s but applying d i f f e r e n t mechanistic t e s t s f o r a c t i v a t i o n and r e j e c t i o n . Hence t h e c h e c k l i s t s and t e s t l i s t s above a r e now expanded t o i n c l u d e t h e n a t u r e o f t h e s k e l e t a l atoms N, 0, S as w e l l as h , r, p, z, and z - f u n c t i o n f o r a l l s k e l e t a l atoms on and n e x t t o t h e r e a c t i v e s t r a n d . Target s k e l e t o n s may now be seen as i n c l u d i n g t h e s e heteroatoms and t h e c a t a l o g i s d e f i n e d t h e same way. W i t h a l l t h e above o p e r a t i o n s i n c o r p o r a t e d , t h e program y i e l d s r e s u l t s which are i n general chemically r e a l i s t i c . I n p r a c t i c e the program has now been adapted from p r e v i o u s DEC 11/23 and microVAX I v e r s i o n s t o a form (-50,000 l i n e s o f FORTRAN) w h i c h r u n s on a microVAX 3500 o r f u l l VAX computer. The t a r g e t m o l e c u l e i s drawn onto t h e s c r e e n i n a r a p i d and f a c i l e d r a w i n g program, u s i n g a mouse- o r thumbwheels- d i r e c t e d c u r s o r , i n a f l u i d , s e q u e n t i a l bonds i n p u t and u s i n g t h e k e y b o a r d f o r l e t t e r - s t r i n g a d d i t i o n s (-OR, -C00H, e t c . ) where d e s i r e d . The s t r u c t u r e s may be drawn i n


71

72



any c r u d e form w h i c h m a i n t a i n s atom c o n n e c t i v i t y s i n c e n o r m a l i z a t i o n t o s i z e and c o r r e c t bond l e n g t h s and a n g l e s t a k e s p l a c e a u t o m a t i c a l l y on p r o c e s s i n g . Once the t a r g e t s t r u c t u r e i s drawn, the program p r o c e e d s w i t h o u t o p e r a t o r i n p u t , as d e s c r i b e d above, f i r s t t o i d e n t i f y o r d e r e d c o n v e r g e n t b o n d s e t s from the s k e l e t o n and the a v a i l a b l e s t a r t i n g skeletons c a t a l o g , then to proceed through s e q u e n t i a l c o n s t r u c t i o n r e a c t i o n g e n e r a t i o n r e t r o s y n t h e t i c a l l y b a c k t h r o u g h each b o n d s e t ( t h r o u g h two l e v e l s o f c u t s ) from t a r g e t f u n c t i o n a l i t y t o the f u n c t i o n a l i t y r e q u i r e d f o r each o f the s t a r t i n g m a t e r i a l s . These are t h e n sought i n the c a t a l o g o f f u l l y f u n c t i o n a l i z e d s t a r t i n g m a t e r i a l s , a c c e p t i n g o n l y r o u t e s g e n e r a t i n g r e a l compounds. The f i n a l s e t o f r e s u l t s , w h i c h r e q u i r e s 2-3 minutes computer time f o r the i l l u s t r a t e d s t e r o i d example, i s t h e n summarized as i n F i g u r e 7, showing the t a r g e t as drawn and i t s atom numbering. The summary below i t shows f o r each o f the two l e v e l s o f c u t s the numbers o f s u c c e s s f u l bondsets, s t a r t i n g m a t e r i a l s , intermediates and reactions. I n the example o f F i g u r e 7 f o u r f i r s t - l e v e l c u t s p r o d u c e d seven s t a r t i n g m a t e r i a l s d i r e c t l y and 26 i n t e r m e d i a t e s , w h i c h combine i n 61 r e a c t i o n s . The 26 i n t e r m e d i a t e s are t h e n a l l c o n s t r u c t e d a t second l e v e l v i a 34 d i f f e r e n t b o n d s e t c o m b i n a t i o n s u t i l i z i n g 161 s t a r t i n g m a t e r i a l s and 393 r e a c t i o n s . O p e r a t o r S e l e c t i o n s from the Output When the program i s u s e d on a v a r i e t y o f d i f f e r e n t t a r g e t s , the number o f r e a c t i o n sequences o b t a i n e d i s h i g h l y v a r i a b l e , depending o f c o u r s e on the s t r u c t u r a l a r t i c u l a t i o n o f the t a r g e t and the a v a i l a b i l i t y o f s u i t a b l e s t a r t i n g m a t e r i a l s . C o n s i d e r i n g the s t r i n g e n c y o f the s e l e c t i o n c r i t e r i a summarized a t the o u t s e t , we were i n f a c t s u r p r i s e d a t the g e n e r a l l y l a r g e numbers o f sequences commonly p r o d u c e d by SYNGEN. T h i s l e d t o a c o n s i d e r a t i o n o f f l e x i b l e modes s u i t a b l e f o r e x a m i n i n g e i t h e r l a r g e o r s m a l l o u t p u t s , i . e . , v a r i o u s ways i n w h i c h the o p e r a t o r can s e l e c t s u b s e t s o f the o u t p u t w h i c h a c c o r d w i t h h i s own p r a c t i c a l interests. S u c c e s s i v e s u b s e t s o f the t o t a l o u t p u t can be s e l e c t e d , and the number o f consequent r e a c t i o n s d i s p l a y e d , by making manual s e l e c t i o n s ( d e l e t e o r r e t a i n ) from the d i s p l a y e d e n t r i e s i n each category: bondsets, s t a r t i n g m a t e r i a l s , intermediates or r e a c t i o n s a t e i t h e r c u t l e v e l (summary b e l o w F i g u r e 7 ) . T h i s i s shown i n F i g u r e 8, w i t h the s e l e c t i o n menu, f o r d e l e t i o n o f two o f the f o u r f i r s t - l e v e l b o n d s e t s o f the summary; " b o n d s e t s " a t the top o f the menu i s now marked D f o r d e l e t e . "VIEW SEL" w i l l s u b s e q u e n t l y o f f e r o n l y t h o s e e n t r i e s i n any c a t e g o r y ( t o p o f menu) r e l e v a n t t o the r e t a i n e d b o n d s e t s . I n t h i s way the o p e r a t o r can examine s u c c e s s i v e l y s m a l l e r chosen s u b s e t s o f the o u t p u t . F i g u r e 9 shows a t y p i c a l d i s p l a y s c r e e n o f r e a c t i o n e n t r i e s , h e r e a t f i r s t l e v e l f o r the two b o n d s e t s s e l e c t e d i n F i g u r e 8. Each e n t r y shows two m o l e c u l e s t o be j o i n e d a t two b o n d s e t bonds ( a n n e l a t i o n ) t o form the t a r g e t ( F i g u r e 7 ) . These bonds are marked w i t h one dot o r two t o show the o r d e r o f r e a c t i o n s . The top l i n e



LEVEL

B'SETS

ST. MAT.

F i g u r e 7.

B:l

B:2

(1)

SYNGEN S c r e e n :

B:3

REACTIONS

26 3

IB0N0SET5-0 1 ST. MAT. (1)

INTERMED.

7 169

4 34

TARGET

73


6. HENDRICKSONETAL.

Output Summary

INTERMED

(1)

61 393

RERXIONS LEVEL 1

B:4 (1)

VIEW ALL VIEW BEL NXT PAOE D C

E

F

# RXNS;

4 # RXNS:

H G 8 » RXNS;

K

J

• DELETE
B and C—+D). T h i s w i l l c r e a t e l o n g e r sequences b u t m i g h t o f f e r more r e a l i s t i c c h e m i s t r y o r l o c a t e p r o m i s i n g r o u t e s n o t g e n e r a t e d so f a r by SYNGEN. Thus the f u n c t i o n a l i t y g e n e r a t e d by the program f o r a c e r t a i n s t a r t i n g m a t e r i a l m i g h t be somewhat d i f f e r e n t from any a c t u a l l y a v a i l a b l e f o r t h a t s k e l e t o n i n the s t a r t i n g m a t e r i a l c a t a l o g . We can c a l c u l a t e f o r each a c t u a l s t a r t i n g m a t e r i a l o f a d e s i r e d s k e l e t o n the number o f u n i t r e a c t i o n s ( N : F i g u r e 3) s e p a r a t i n g i t f r o m the g e n e r a t e d compound, e s s e n t i a l l y the number o f s t e p s r e q u i r e d t o c o n v e r t i t . I f the s k e l e t o n i s l a r g e enough t o w a r r a n t the e x t r a s t e p s we can a c c e p t the r o u t e , i n e f f e c t s p e c i f y i n g r e f u n c t i o n a l i z a t i o n o f an a v a i l a b l e s t a r t i n g m a t e r i a l b e f o r e i t s use i n the g e n e r a t e d c o n s t r u c t i o n sequence (we c u r r e n t l y a l l o w one s t e p , N - 1, f o r SM > C and two s t e p s > C ) . The o u t p u t w i l l t h e n f l a g t h e s e r o u t e s f o r s e p a r a t e e x a m i n a t i o n ( F i g u r e 1 0 ) , and the d i s p l a y w i l l show b o t h the r e a l s t a r t i n g m a t e r i a l and i t s a l t e r e d f u n c t i o n a l groups r e q u i r e d f o r the c o n s t r u c t i o n sequence. I n F i g u r e 12 t h i s e x p a n s i o n a f f o r d s r o u t e s d e s c r i b e d by A—•B—>C, and i s i n c o r p o r a t e d i n the p r e s e n t SYNGEN program. R

R

5

8

D e f i n i n g r e f u n c t i o n a l i z a t i o n s a t the end o f the c o n s t r u c t i o n sequence i s h a r d e r . Here, the c o n s t r u c t i o n s b u i l d the t a r g e t s k e l e t o n b u t w i t h i n c o r r e c t f u n c t i o n a l groups (T' i n F i g u r e 1 2 ) , r e q u i r i n g some r e f u n c t i o n a l i z a t i o n t o a r r i v e a t the a c t u a l t a r g e t , T. The p r o b l e m i s c l e a r l y seen i n the s t e r o i d c h o s e n as t a r g e t i n F i g u r e 7. T h i s i s a c t u a l l y an i n t e r m e d i a t e i n the T o r g o v - S m i t h synthesis of e s t r o n e . I t has the s k e l e t o n o f e s t r o n e b u t e x t r a f u n c t i o n a l groups w h i c h must be removed i n the l a s t s t e p s o f the s y n t h e s i s ; t h i s i n t e r m e d i a t e i s a c t u a l l y made by an " i d e a l " s y n t h e s i s , f o u n d by SYNGEN. When e s t r o n e i t s e l f i s e n t e r e d as t a r g e t t h i s r o u t e cannot be f o u n d s i n c e i t i n v o l v e s a f i n a l r e f u n c t i o n a l i z a t i o n , and t h o s e r o u t e s w h i c h a r e f o u n d a r e few and n o t so p r a c t i c a l . 1 2

Here we propose t o c r e a t e the b o n d s e t s and s t a r t i n g s k e l e t o n s as b e f o r e and t h e n , i n a f o r w a r d d i r e c t i o n , t o combine p a i r w i s e a l l the c a t a l o g s t a r t i n g m a t e r i a l s o f t h e s e s k e l e t o n s . T h i s w i l l use the same h a l f - r e a c t i o n s i n the f o r w a r d d i r e c t i o n , c r e a t i n g the i n t e r m e d i a t e s and u l t i m a t e l y the t a r g e t s k e l e t o n b e a r i n g t h a t f u n c t i o n a l i t y (T') w h i c h i s a n a t u r a l r e s u l t o f the c o n s t r u c t i o n


6. HENDRICKSONETAL.

79


r e q u i r e m e n t s from the f o u r s t a r t i n g m a t e r i a l s o f each c o m b i n a t i o n . The i n t e r m e d i a t e s , T', must t h e n be r e f u n c t i o n a l i z e d t o t a r g e t , T. T h i s e x p a n s i o n a f f o r d s r o u t e s d e s c r i b e d b y B—•C—>D i n F i g u r e 11. The two p r o c e d u r e s may be summarized as (1) f o r SYNGEN and (2) f o r the FORWARD program, where C - c o n s t r u c t i o n sequence and A refunctionalizations.

1.

T ;Skeleton

2.

T

FG

SM FG c

;Skeleton J, ( c a t a l o g ) T' FG

Expert System Applications in Chemistry - American Chemical Society

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