Biomedical Engineering Reference
In-Depth Information
Pt-mediated
alkyl dehydrogenation
HN
HN
HN
Ir(I)-catalyzed
pyrrole borylation
Pd(0)-catalyzed
pyrrole direct arylation
O
O
O
R
N
N
N
Pd(II)-catalyzed
pyrrole alkenylation
O
(
±
)-Rhazinilam, R=H (Trauner
et al.
, 2005)[63c]
(
±
)-Rhazinal, R=CHO (Trauner
et al.
, 2009)[64]
(
±
)-Rhazinilam (Sames
et al.
, 2000)[63a]
(
−
)-Rhazinilam (Sames
et al.
, 2002)[63b]
(
±
)-Rhazinicine (Gaunt
et al.
, 2008)[65]
SCHEME 1.18
Various C-H bond functionalization strategies for the synthesis of rhazinilam,
rhazinal and rhazinicine.
(synthesis of rhazinilam by Sames and coworkers) and in Section 1.9 (synthesis of
rhazinicine by Gaunt and coworkers.).
In 2000, Johnson and Sames reported the total synthesis of (
)-rhazinilam
using a Pt(II)-mediated alkane dehydrogenation strategy [63a]. Two years later,
enantioenriched (
) was prepared with the assistance of a chiral
oxazoline-derived auxiliary to guide the key C-H functionalization event
(Scheme 1.19) [63b]. Their synthesis began with the preparation of intermediate
72
)-rhazinilam (
71
possesses two
enantiotopic ethyl groups whose selective dehydrogenation via asymmetric C-H
bond functionalization poses a formidable synthetic challenge. Schiff base formation
from
in five steps from readily available starting materials. Compound
72
72
73
followed by the addition of [Me
2
Pt
(
m
-SMe
2
)]
2
(0.5 equiv) afforded platinum complex
and chiral oxazolinyl ketone
in 29% yield over two steps.
Treatment of this intermediate with 1 equiv of triflic acid generated cationic platinum
species
75
(3:2 mixture of isomers) with concomitant loss of methane. Upon addition
of 2,2,2-trifluoroethanol and heating for 72 h, diastereospecific dehydrogenation took
place to provide
74
. The diastereoselectivity and yield of this process were found to be
highly dependent on the reaction temperature and the steric bulk of the auxiliary.
Greater yields were obtained at higher temperatures, unfortunately at the expense of
diastereoselectivity. In addition, while bulkier substituents at the auxiliary stereo-
center improved diastereoselectivities, the preparation of the corresponding platinum
complexes was often problematic and low yielding (
76
10%). On the basis of these
results, the authors settled on heating at 70
C for 72 h to perform the desired
transformation, obtaining
G
76
as a 4.5:1 ratio of isomers. With intermediate
76
in
Cy
O
Ph
N
MeO
2
C
NO
2
CO
2
Me
73
N
MeO
2
C
1.
O
NH
2
N
cat
p
-TsOH, PhMe
reflux, 30 h (65%)
Br
N
5 steps
55%
TfOH (1 equiv)
CH
2
Cl
2
, -40°C
+
≡
Me
Me
N
Me
2
S
N
2.
Pt
NH
2
Me
Me
Me
Pt
Pt
Ph
N
72
Me
Me
2
Cy
O
PhMe, rt, 24 h (45%)
CH
4
74
1. 10% Pd/C (5 mol%)
dppb (20 mol%)
HCOOH (2 equiv)
CO (10 atm)
DME, 150°C, 4 d
2. aq NaOH, 30 min
then aq HCl, 4 h
MeOH, 50°C
52% (2 steps)
MeO
2
C
MeO
2
C
1. KCN (140 equiv)
CH
2
Cl
2
, rt, 30 h
2. Preparative HPLC
3. NH
2
OH, NaOAc
MeOH, rt, 0.5 h
MeO
2
C
N
N
N
CF
3
CH
2
OH
70°C, 72 h
N
H
Pt
H
NH
2
N
Pt
Me
N
TfO
H
CH
3
TfO
O
N
N
42% (5 steps)
Ph
Cy
Cy
)-Rhazinilam
71
77
(ee = 96%)
Ph
(
−
O
O
76
(dr = 4.5:1)
75
(dr = 3:2)
SCHEME 1.19
Synthesis of (-)-rhazinilam by Johnson and Sames.
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