C–H FUNCTIONALIZATION: A NEW STRATEGY FOR THE SYNTHESIS OF BIOLOGICALLY ACTIVE NATURAL PRODUCTS - Modern Tools for the Synthesis of Complex Bioactive Molecules - page 13

I

N

N cat Pd(OAc) 2 Hydrolysis

H 2 N

O O

AgOAc (1 equiv)

HN H HN

R

52 53 54 R R

N

Pd

O

R

N

Picolinamide-directed Pd(II)-catalyzed sp 3 C-H bond arylation. SCHEME 1.14

In 2005, Daugulis and coworkers reported a highly selective Pd(OAc) 2 -
catalyzed arylation of aliphatic C-H bonds using pyridine directing groups as
removable auxiliaries (Scheme 1.14) [57]. For example, N -alkylpicolinamides

52
efficiently underwent regioselective arylation in the presence of catalytic Pd(OAc) 2 ,
stoichiometric AgOAc, and an excess of the aryl iodide coupling partner. Subsequent
hydrolysis of the auxiliary yielded the g -arylated amine . Inspired by the efforts of

Daugulis and coworkers, Corey and coworkers reported the Pd(OAc) 2 -catalyzed
auxiliary-directed acetoxylation and arylation of b sp 3 C-H bonds of a -amino acid
derivatives in 2006 [58]. These contributions allowed Feng and Chen to develop a
strategy for the total synthesis of celogentin C [59], a bicyclic nonribosomal peptide
that acts as an antimitotic agent by inhibiting tubulin polymerization [60].
Celogentin C (

54

55

) possesses a highly unusual peptidic structure characterized
by its Trp C2-His N1 and Trp C6-Leu C b linkages (Scheme 1.15). The latter is an
extremely rare linkage between amino acids and poses a significant synthetic
challenge; however, Feng and Chen were able to apply an auxiliary-directed Pd(II)-
catalyzed sp 3 C-H arylation reaction to form this key carbon-carbon bond. The
6-iodotryptophan coupling partner 57 was prepared from commercially available
Boc-protected tryptophan using a five-step sequence, including a nitration, a reduc-
tion, and a Sandmeyer reaction. The sp 3 C-H arylation of N -phthaloyl leucine
derivative 56 (2 equiv) with 57 was effected by Pd(OAc) 2 (0.2 equiv) and AgOAc

NH

NH 2

BocHN

N

HN

BocHN

CO 2 t -Bu

N

NH

CO 2 t -Bu O O

O

CO 2 H

N

Pd(OAc) 2 (20 mol%)
AgOAc (1.5 equiv)
t -BuOH, 110°C, 36 h
85%

i -Pr HN

NTs N

18 steps

O

N

57

NTs

NH N

NH O 2

I 1

O 4.7%

NH +

NH

O

i -Pr

O H

HN

i -Pr 6

PhthN

58 Celogentin C 55

N

i -Pr β

PhthN O

HN i -Pr

56

O

N N N

Pd

N N

L

L Ar I

L

57

Pd(OAc) 2

Pd
H

NH N N i -Pr N Pd I NH

OAc

O H O O O Ar

Ar

O NPhth

i -Pr i -Pr i -Pr i -Pr

PhthN PhthN PhthN PhthN

56 59 60 61 58

isolated Pd(II) intermediate proposed Pd(IV) intermediate

AgOAc

IPdOAc

catalyst regeneration

AgI

SCHEME 1.15 Synthesis of celogentin C by Feng and Chen.