Retrosynthesis is the process of “deconstructing” a target molecule into readily available starting materials by means of

A topological strategic bond is identified on the basis of purely mathematical techniques.. To achieve maximum simplification of the cyclic system, strategic bonds should be in the ring

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.

H

introduction of auxiliary functional groups

O H

N H

H

H O

X H

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)

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

degradation

HO

Hstructure

Structure Assignement

1) acetylation 2) !

HO

Patchouli Alcohol

Büchi's synthesis started with camphor which was converted to

homocamphor:

Strategic Bonds

The first bonds to be broken in a retrosynthetic direction have been termed

“strategic bonds”

General methods for synthetic analysis Strategic bond disconnections for

bridged polycyclic structures

- Corey, E J.; Howe, W J.; Orf, H W.; Pensak, D A.; Petersson, G J Am.

Chem Soc 1975, 97, 6116.

Ruecker, C.; Ruecker, G.; Bertz, S H., "Organic synthesis - art or science?" J Chem Inf.

Rule 1 Because of the relative ease of formation of

common-sized rings, a strategic bond must be in a

four-, five,- six-, or seven-membered “primary ring” A

primary ring is one which cannot be expressed as the

envelope of two or more smaller rings bridged or

fused to one another.

The six-membered ring in this compound is a

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

Only bonds 1 and 2 are strategic

1

2

Rule 2 B Due to the paucity of ring closure methods

in which bonds are formed to preexisting

three-membered rings, strategic bonds may not be exo to

a

b

OH OH

Rule 3 To achieve maximum simplification of the cyclic system, strategic bonds should be

in the ring (or rings) which exhibit the greatest degree of bridging.

Rule 4 To avoid the formation of rings having

greater than seven members during antithetic bond

cleavage, any bond common to a pair of bridged or

fused primary rings whose envelope is 8-membered

or larger cannot be considered strategic These

bonds which are eliminated from further consideration

are termed “core bonds”

core bond

perimeter bond

Rule 5 Bonds within aromatic rings are not

considered to have potential strategic character.

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 since the synthetic

introduction of chiral centers in chains is much less

subject to stereochemical control than for centers in

rings

OH

H

OH H

R R'

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 in the newly generated

A strategic bond must satisfy all these rules.

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 the collection of bonds in the cyclic network between C and O, N, and S

which satisfy rules 2B, 4, 5, and 6.

Practice Example.

N1

2

34

5

6

789

10 1114

e Strategic bond determination: Carbocyclic procedure

(using bond numbers)

34

5

6

789

14

f Strategic bond determination: C-heterobond

234

5

6

789

6 7

14 15

16 17 18

20 (a) Sample structure (lycopodine) with arbitrary bond numbering

Mathematics Applied to Synthetic Analysis

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.

Mathematics Applied to Synthetic Analysis

One-bond disconnections of a tricyclic 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

Mathematics Applied to Synthetic Analysis

More advanced example:

c d e f

Entire molecule

Mathematics Applied to Synthetic Analysis

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

c d e f

Mathematics Applied to Synthetic Analysis

Close literature analogies:

c d e f

O

O H

H

O

CHO OHC

O

OH

O O

d

O

O MeO

R PhOC

Mathematics Applied to Synthetic Analysis

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

c d e f

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:

6

OH

a b c

7

a b c

8

a b c

9

O

a c

b c b a

c

a b

c

12

13

a b c

a b

c d e

OH