Dr P Wipf Page of 34 4/14/2008 III-A RETROSYNTHETIC ANALYSIS The Synthetic Route to a Target Molecule Sierra, M A.; De La Torre, M C., "Dead ends and detours en route to total syntheses of the 1990s." Angew Chem Int Engl 2000, 39, 1538-1550 Zaragoza, D F "Side reactions in organic synthesis: A guide to successful synthesis design; Wiley 2004 Dr P Wipf Page of 34 4/14/2008 Retrosynthesis of Ambergris-type Ether O H introduction of auxiliary functional groups (oxy-Cope retron) O H O Dr P Wipf Page of 34 4/14/2008 Retrosynthesis of Precapnelladiene (by Oxy-Cope) H H O Dr P Wipf Page of 34 4/14/2008 Retrosynthesis of Pumiliotoxin C (by Oxy-Cope) X H N HH O H N HH R Dr P Wipf Page of 34 4/14/2008 Dr P Wipf Page of 34 Strategic Bonds The first bonds to be broken in a retrosynthetic direction have been termed “strategic bonds” A topological strategic bond is identified on the basis of purely mathematical techniques For modern topological mathematical approaches, see: Bertz, S H.; Sommer, T J Chem Commun 1997, 2409 Bertz, S H.; Ruecker, C.; Ruecker, G.; Sommer, T J Eur J Org Chem 2003, 4737-4740 Barone, R.; Chanon, M Tetrahedron 2005, 61, 8916-8923 A heuristic strategic bond is often chosen on the basis of current methodology: • Identify complicated fragments • If you are having difficulty understanding ring connections, draw pictures • Work backward from potential intermediates • Try solving a more general problem first (the "inventor's paradox": the more ambitious plan may have more chances of success) 4/14/2008 Dr P Wipf Page of 34 4/14/2008 Patchouli Alcohol Patchouli alcohol is the main constituent of patchouli oil used in the perfume industry The structure determination led to an interesting error propagation: Patchouli alcohol synthesis degradation HO structure H G Büchi et al J Am Chem Soc 1962, 84, 3205 Direct comparison of synthetic and natural compound revealed that they are equivalent Dr P Wipf Page of 34 4/14/2008 Structure Assignement 1) acetylation Patchouli Alcohol 2) ! (ester pyrolysis) Patchoulene H unambiguous structure proof HO Patchouli Alcohol Dr P Wipf Page of 34 Büchi's synthesis started with camphor which was converted to homocamphor: 4/14/2008 Dr P Wipf Page 10 of 34 4/14/2008 Dr P Wipf Page 20 of 34 4/14/2008 Heterobonds The above rules not take into accound the powerful methodology developed for the formation of C-heteroatom bonds Therefore, to the set of strategic bonds determined by application of rules 1-6 above is added the collection of bonds in the cyclic network between C and O, N, and S which satisfy rules 2B, 4, 5, and H HO H H HO H H H H O H + H H O Dr P Wipf Page 21 of 34 Practice Example 4/14/2008 13 14 N a target structure 12 11 10 b primary rings N N N c no synthetically significant ([...]... Wipf Page 34 of 34 4/14/2008 Mathematics Applied to Synthetic Analysis Structures used to illustrate strategic bond disconnections in Corey’s JACS 1975, 97, 6116 LHASA strategic bonds are indicated by bold lines, and MASA strategic bonds based on twc are shown by dashed lines The hashed bonds are both heuristic and topological: b c aN cb c a a b a c N Nb b a a c 2 3 c a OH b 6 5 7 OH O a b 8 4 c c a c... Page 18 of 34 4/14/2008 Rule 5 Bonds within aromatic rings are not considered to have potential strategic character OH OH a Rule 6 A If a cyclic arc linking a pair of common atoms contains a chiral carbon atom, then none of the bonds in the cyclic arc may be considered strategic Thus those cleavages which would leave stereocenters on side chains are avoided In general, such a situation is undesirable... n Entire molecule k a c b h o j i Dr P Wipf Page 31 of 34 4/14/2008 Mathematics Applied to Synthetic Analysis l m d One-bond disconnections; topological strategic bonds based on MASA are shown in dashed lines in b, a, and d; heuristic strategic bonds from LHASA are shown for f and h g f e n b f a h d k a c b h o j i Dr P Wipf Page 32 of 34 4/14/2008 Mathematics Applied to Synthetic Analysis m g CHO... target molecule: All possible substructures (NT) counts all connected substructures Total walk count (twc) counts all walks of length 1 to n-1, where n is the number of non-hydrogen atoms in a molecule For example, propane as an NT of 6, cyclopropane has NT=7, showing that the latter structure is more complex 4/14/2008 Dr P Wipf Page 30 of 34 Mathematics Applied to Synthetic Analysis More advanced example:... R=geranyl O PhOC O OH b O j e n O O k d Close literature analogies: O l a c b h o j i Dr P Wipf Page 33 of 34 4/14/2008 Mathematics Applied to Synthetic Analysis l m Two-bond disconnections: topological strategic bonds based on NT are shown in dashed lines in b,c and b,f; on twc in a, b and b,e; and heuristic strategic bonds from LHASA are shown for a, g and d,e d g f e n b,c a c b h j i o b,f a, g a, b... in the newly generated side chain O2N HO O2N O Dr P Wipf Page 19 of 34 4/14/2008 A strategic bond must satisfy all these rules OH OH a OH c OH b d OH Dr P Wipf Page 20 of 34 4/14/2008 Heterobonds The above rules do not take into accound the powerful methodology developed for the formation of C-heteroatom bonds Therefore, to the set of strategic bonds determined by application of rules 1-6 above is added... envelope of two or more smaller rings bridged or fused to one another 4/14/2008 OH OH a OH c OH b d OH The six-membered ring in this compound is a “secondary” ring Rule 2 A A strategic bond must be directly attached to another ring (exo to another ring) In synthesis, a ring disconnection which produces two functionalized appendages leads to an overall more complex synthetic target 1 Only bonds 1 and 2 are... on the basis of purely mathematical techniques For modern topological mathematical approaches, see: Bertz, S H.; Sommer, T J Chem Commun 1997, 2409 Bertz, S H.; Ruecker, C.; Ruecker, G.; Sommer, T J Eur J Org Chem 2003, 4737-4740 Barone, R.; Chanon, M Tetrahedron 2005, 61, 8916-8923 4/14/2008 Dr P Wipf Page 29 of 34 Mathematics Applied to Synthetic Analysis One-bond disconnections of a tricyclic target. .. since the synthetic introduction of chiral centers in chains is much less subject to stereochemical control than for centers in rings OH c OH b d OH R R' H OH H OH Rule 6 B If the chiral center on the arc is directly attached to the bridgehead carbon, this bond is not excluded from the set of possible strategic bonds Disconnection here can remove chirality, and therefore does not lead to undesired chirality... P Wipf Page 24 of 34 4/14/2008 Dr P Wipf Page 25 of 34 4/14/2008 Practice Example (a) Sample structure (lycopodine) with arbitrary bond numbering CH3 H 11 7 1 6 2 N N 15 4 18 N 12 13 14 16 19 (b) Primary rings H 5 8 3 9 20 O 17 N N Dr P Wipf Page 26 of 34 4/14/2008 Dr P Wipf Page 27 of 34 4/14/2008 Dr P Wipf Page 28 of 34 Mathematics Applied to Synthetic Analysis A topological strategic bond is identified