Angewandte
Communications
Chemie
Nitrogen Heterocycles Hot Paper
Stereoselective Synthesis of Functionalized Pyrrolidines by the
À
Diverted N H Insertion Reaction of Metallocarbenes with
b-Aminoketone Derivatives
Simon M. Nicolle, William Lewis, Christopher J. Hayes, and Christopher J. Moody*
Abstract: A highly stereoselective route to functionalized
pyrrolidines by the metal-catalyzed diverted NÀH insertion of
synthesis of pyrrolidines by the intramolecular trapping of
[10f,13]
transient ylides (Scheme 1).
Despite this recent progress,
a range of diazocarbonyl compounds with b-aminoketone
derivatives is described. A number of catalysts (rhodium(II)
carboxylate dimers, copper(I) triflate, and an iron(III) por-
phyrin) are shown to promote the process under mild
conditions to give a wide range of highly substituted proline
derivatives. The reaction starts as a metallocarbene NÀH
some limitations remain, including the absence of routes to
C4-substituted pyrrolidines, the variable diastereoselectivity,
and the preponderance of N-phenyl precursors, which seri-
ously limits the utility of the resulting heterocycles. We now
describe a new route to highly substituted pyrrolidines that
proceeds with excellent diastereoselectivity under mild con-
ditions in a single step (Scheme 1) by a process that is initiated
by a metallocarbene NÀH insertion, but is diverted by an
insertion but is diverted by an intermolecular aldol reaction.
[13]
P
yrrolidines are among the most important N-heterocyclic
intramolecular aldol reaction.
compounds of biological relevance and feature in a large
Following our interest in the use of bifunctional reagents
[1]
number of naturally occurring and unnatural compounds.
Examples include the mycotoxin paraherquamide (1), the
potent proteasome inhibitor salinosporamide A (2, a marine
product), and the glutamate receptor agonist kainic acid (3;
Figure 1).
for the preparation of heterocycles by diverted carbene
[
2]
[14]
insertion reactions,
we started investigating the use of
b-aminoketone derivatives for the preparation of substituted
pyrrolidines. Our initial study focused on the reaction of ethyl
phenyldiazoacetate (1a) with N-(4-methoxyphenyl)-b-amino-
ketone 2a; the para-methoxyphenyl (PMP) group serves both
to provide a suitably nucleophilic nitrogen atom and to allow
[
3]
[
4]
[15]
for later N deprotection of the product.
We rapidly
established that diazoester 1a and b-aminoketone 2a gave
N-PMP protected pyrrolidine 3a exclusively as the cis isomer
under rhodium(II) or copper(I) catalysis (Table 1, entries 1–
I
4
), with the (Cu OTf) ·toluene complex giving the best result
2
(entry 4).
Figure 1. Some naturally occurring pyrrolidines.
[a]
Table 1: Catalyst screening for the preparation of N-aryl pyrrolidine 3a.
Consequently, a wide range of strategies have been
employed for the construction of pyrrolidines and proline
[5]
derivatives, with common approaches based on azomethine
[
6]
[7]
ylide cycloaddition, alkene hydroamination, iodocycliza-
[
8]
[9]
tion, and cycloisomerization. Many routes for the de novo
construction of these five-membered heterocyclic rings are
based on carbene and metallocarbene intermediates, and give
a range of functionalized pyrrolidines through cyclization by
Entry
Catalyst (mol%)
Rh (oct) (1)
Yield [%]
1
2
3
4
5
52
74
62
90
2
4
Rh (piv) (1)
2
4
Rh (esp) (1)
2
2
[
10]
intramolecular carbene insertion into NÀH
or CÀH
(CuOTf) ·toluene (5)
2
[11]
[b]
bonds,
and related methods continue to be developed.
Fe(TPP)Cl (1)
0
For example, Sun and co-workers have reported the stereo-
divergent synthesis of N-heterocycles through the copper(I)-
or rhodium(II)-catalyzed reaction of diazo compounds and
[
a] Reaction conditions: 1a (0.39 mmol) in CH Cl (2 mL) was added to
2 2
a mixture of 2a (0.3 mmol) and the catalyst in CH Cl (1 mL) at reflux
2
2
over 30 min. 3a was always formed with >20:1 d.r. [b] No reaction.
esp=a,a,a’,a’-tetramethyl-1,3-benzenedipropionate, oct=octanoate,
piv=pivaloate, TPT=tetraphenylporphyrin.
[
12]
amino alkynes, and Hu and co-workers have described the
[
*] S. M. Nicolle, Dr. W. Lewis, Prof. Dr. C. J. Hayes, Prof. Dr. C. J. Moody
School of Chemistry, University of Nottingham
University Park, Nottingham NG7 2RD (UK)
To illustrate the utility of the process, a selection of diazo
compounds (1a–1e) and N-PMP b-aminoketones (2a–2c)
were used to access a diverse range of substituted N-PMP
pyrrolidines (3b–3g; Scheme 2). With diazo compounds 1a
and 1c–1e, copper triflate was found to be superior to
E-mail: c.j.moody@nottingham.ac.uk
Angew. Chem. Int. Ed. 2016, 55, 3749 –3753
ꢀ 2016 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
3749