C–H FUNCTIONALIZATION: A NEW STRATEGY FOR THE SYNTHESIS OF BIOLOGICALLY ACTIVE NATURAL PRODUCTS - Modern Tools for the Synthesis of Complex Bioactive Molecules - page 21

the origin for this regioselectivity is not well understood, reversible boron or iridium
binding to the nitrogen lone pair has been proposed to activate the substrate toward
C-H bond functionalization while blocking the C2 reaction site [84].
The mechanism of bipyridine-ligated Ir-catalyzed C-H borylation has been
extensively studied [84,85]. The isolation of kinetically competent catalytic inter-
mediates, NMR experiments, kinetic studies, and theoretical investigations using
DFT calculations have led to the proposed catalytic cycle shown in Scheme 1.23d.
The active catalytic species is believed to be the trisboryl iridium-dtbpy complex
generated from the iridium precatalyst, dtbpy, and B 2 pin 2 . This Ir(III) complex is
involved in the rate-limiting C-H bond cleaving event, whichmost likely proceeds via
oxidative addition of the aryl C-H bond, leading to the formation of an Ir(V)
intermediate. Reductive elimination of the borylated arene, followed by oxidative
addition of B 2 pin 2 and reductive elimination of HBpin, regenerates the active Ir(III)
catalyst. It should be noted that an alternative mechanism for C-H bond cleavage via
s -bond metathesis between Ir(dtbpy)(Bpin) 3 and Ar-H has also been proposed.
A concise synthesis of the pyrrole alkaloid rhazinicine ( ), a member of the

Aspidosperma family of natural products (see Section 1.7), featuring two different
key C-H bond functionalization events was reported by Gaunt and coworkers in 2008
(Scheme 1.24) [65]. The densely functionalized pyrrole nucleus of

92

was elaborated
using a C3-selective C-H borylation reaction and a Pd(II)-catalyzed oxidative Heck
cyclization (see Section 1.5). Based on the strategy previously outlined for C-H
borylation of electron-rich heteroarenes (Scheme 1.23c) [83], N -Boc-protected
pyrrole

92

was submitted to a one-pot Ir-catalyzed C-H borylation and Pd(0)-
catalyzed Suzuki coupling sequence. The borylation protocol occurred with excellent
regioselectivity for the most sterically accessible C-H bond to give 95 in 78% yield as
a single isomer. Boc removal followed by N -acylation provided

93

in 69% yield over
two steps. With this intermediate in hand, the second key C-H bond functionalization
was performed to access the tetrahydroindolizine ring. The prior installation of a TMS
group on the pyrrole nucleus offered the advantage of temporarily blocking the more
accessible C5 position and therefore favoring Pd(II)-catalyzed oxidative Heck
cyclization at C2. Treatment of

97

with Pd(TFA) 2 (10mol%), using t -BuOOBz as
the oxidant, in a dioxane/DMSO/AcOH solvent mixture at 70 C for 24 h afforded

97

98

Me

Cl O

NO2 (1 equiv)

TMS

I

O 2 N

96

O O O

[Ir(COD)Cl] 2 (2 mol%)
dtbpy (4 mol%)
B 2 pin 2 (1 equiv)
n -Hexane, 100°C
μ wave, 50 min

Pd(OAc) 2 (2-3 mol%)
SPhos (4-6 mol%)
K 3 PO 4 (1.3 equiv)

H B O

1. DMF, 120°C
2. LiHMDS then 96
THF, -78°C to 0°C

TMS TMS TMS

N
Boc

N
Boc

n -BuOH/H 2 O
100°C, 2 h
78% (2 steps, one-pot)

N
Boc

93 94 95

69%

O 2 N

O 2 N

HN

TMS

1. 10% Pd/C (5 mol%)
H 2 (1 atm), MeOH, rt, 1 h

Pd(TFA) 2 (10 mol%)
t -BuOOBz (1.2 equiv)

O

TMS H

O

TMS N

N 2. AlCl 3 (5 equiv), CH 2 Cl 2 , 0°C, 2 h

3. Mukaiyama's reagent (10 equiv)
Et 3 N (20 equiv), PhMe, rt, 14 h

N Dioxane/DMSO/AcOH

70°C, 24 h
53%

O Me

O

O O

( ± )-Rhazinicine 92

98 97

74%

TMS

O O

SCHEME 1.24 Synthesis of ( )-rhazinicine by Gaunt and coworkers.