Enantioselective construction of quaternary N-heterocycles by palladium-catalysed decarboxylative allylic alkylation of lactams

Article abstract of DOI:10.1038/nchem.1222

The enantioselective synthesis of nitrogen-containing heterocycles (N-heterocycles) represents a substantial chemical research effort and resonates across numerous disciplines, including the total synthesis of natural products and medicinal chemistry. In

Full text of DOI:10.1038/nchem.1222

ARTICLES
PUBLISHED ONLINE: 18 DECEMBER 2011 | DOI: 10.1038/NCHEM.1222
Enantioselective construction of quaternary
N-heterocycles by palladium-catalysed
decarboxylative allylic alkylation of lactams
Douglas C. Behenna, Yiyang Liu, Taiga Yurino, Jimin Kim, David E. White, Scott C. Virgil
and Brian M. Stoltz
*
The enantioselective synthesis of nitrogen-containing heterocycles (N-heterocycles) represents a substantial chemical
research effort and resonates across numerous disciplines, including the total synthesis of natural products and medicinal
chemistry. In this Article, we describe the highly enantioselective palladium-catalysed decarboxylative allylic alkylation of
readily available lactams to form 3,3-disubstituted pyrrolidinones, piperidinones, caprolactams and structurally related
lactams. Given the prevalence of quaternary N-heterocycles in biologically active alkaloids and pharmaceutical agents, we
envisage that our method will provide a synthetic entry into the de novo asymmetric synthesis of such structures. As an
entry for these investigations we demonstrate how the described catalysis affords enantiopure quaternary lactams that
intercept synthetic intermediates previously used in the synthesis of the Aspidosperma alkaloids quebrachamine and
rhazinilam, but that were previously only available by chiral auxiliary approaches or as racemic mixtures.
itrogen-containing heterocycles are ubiquitous in natural
products1, pharmaceuticals2 and materials science3–5
Stereoselective methods for the synthesis of 3,3-disubstituted
a
N
H
.
N
N
OH
pyrrolidinones, piperidinones and caprolactams, as well as the
corresponding amines, are valuable for the preparation of a wide
array of important structures in these areas of research (Fig. 1).
Despite the prevalence of such architectures and the potential of
lactam enolate alkylation as a direct method for their synthesis, a
paucity of enantioselective lactam alkylations leading to Ca-quaternary
centres are known. Although most methods rely on chiral auxiliary
chemistry6–8, the few catalytic examples that exist are specific to
the oxindole lactam nucleus9–13, a-carbonyl stabilized enolates14
or cyclic imides15. Importantly, enolate stabilization is critical for
success in all of these catalytic systems, thereby limiting the scope
of each transformation. To the best of our knowledge, there are
no examples of catalytic asymmetric alkylations of simple piperidi-
none, pyrrolidinone and caprolactam scaffolds for the formation of
Ca-quaternary or Ca-tetrasubstituted tertiary centres. We describe
the stereoselective synthesis of a wide range of structurally diverse,
functionalized lactams by means of palladium-catalysed enantio-
selective enolate alkylation. The importance of this chemistry to
the synthesis of bioactive alkaloids is specifically demonstrated,
and the potential utility of this transformation for the construction
of novel building blocks for medicinal and polymer chemistry can
be readily inferred.
N
H
H
H
O
Aspidospermidine
(Aspidosperma alkaloid)
Fawcettimine
(Lycopodium alkaloid)
OH
N
N
N
H
H
N
H
N
OH
N
N
H
OH
MeO2C
MeO
N
OAc
Me CO2Me
Vinblastine
(chemotherapeutic
alkaloid)
H
NH2
Manzamine A
(marine alkaloid)
O
O
H
N
N
O
O
O
HN
N
Ph
O
Ph
Doxapram
Ethosuximide
(anticonvulsant)
Aminoglutethimide
(aromatase inhibitor)
(respiratory stimulant)
b
X
X
R1
X
R1
R2
R1
R2
R3N
R3N
R3N
R2
Transition metal-catalysed allylic alkylation is a key method for
the enantioselective preparation of chiral substances and ranks
among the best general techniques for the catalytic alkylation of
prochiral enolates16–19. We sought to develop a general method
for catalytic asymmetric a-alkylation, given the importance of
a-quaternary lactams (vide supra). Over the past seven years, our
laboratory has reported an array of methods for the synthesis
of a-quaternary ketones20–23 and demonstrated the use of these
Pyrrolidine (X=H2)
Pyrrolidinone (X=O)
Piperidine (X=H2)
Piperidinone (X=O)
Hexahydroazepine (X=H2)
Caprolactam (X=O)
Figure 1 | Natural products and pharmaceuticals containing chiral
N-heterocycles. a, An array of bioactive alkaloids and drug substances
demonstrating the ubiquitous nature of quaternary carbon stereochemistry
in these structures. b, Lactam and cyclic amine sub-types targeted in
this study.
methods in a number of complex molecule syntheses24–27
.
The Warren and Katharine Schlinger Laboratory for Chemistry and Chemical Engineering, Division of Chemistry and Chemical Engineering and The Caltech
Center for Catalysis and Chemical Synthesis, California Institute of Technology, Pasadena, California 91125, USA. e-mail: stoltz@caltech.edu
*
130
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NATURE CHEMISTRY DOI: 10.1038/NCHEM.1222
ARTICLES
Pd2(dba)3 (5 mol%)
(S)-t-BuPHOX or
(S)-(CF3)3-t-BuPHOX (12.5 mol%)
a
b
Pd-catalysed enantioselective alkylation
O
O
O
O
O
O
R1
R
R1
R
Pd2(pmdba)3 (5 mol%)
(S)-(CF3)3-t-BuPHOX (12.5 mol%)
N
O
N
R
N
R
N
O
Solvent (0.033 M), 40 °C
R2
R2
Toluene, 40 °C
( )n
( )n
(
)-1a–h
2a–h
CF3
α-Quaternary δ-lactams
CO2Me
O
O
O
O
Ph
Bz
Bz
O
O
Bz
Bz
N
N
N
N
Ph2P
N
(4-CF3C6H4)2P
N
t-Bu
(S)-t-BuPHOX
t-Bu
(S)-(CF3)3-t-BuPHOX
2h
85% yield
99% e.e.
3
4
5
97% yield
99% e.e.
85% yield
99% e.e.
92% yield
99% e.e.
CN
OSi(t-Bu)Me2
100
90
80
O
O
O
N
O
2
2
Bz
Bz
Bz
Bz
N
N
N
70
60
50
40
30
20
10
0
Cl
6
7
8
9
88% yield
99% e.e.
85% yield
96% e.e.
78% yield
97% e.e.
60% yield
95% e.e.
c
Other ring sizes and frameworks
Hex:Tol 2:1
Ts
(2a)
CF3
Bz
Boc
(2b)
Tol
O
O
Cbz
(2c)
Fmoc
(2d)
MTBE
THF
Ac
(2e)
O
O
O
4-OMe-
Bz
(2f)
F
4-F-Bz
(2g)
N
Bz
(2h)
Bz
Bz
N
N
N
R group
MeO
10
90% yield
98% e.e.
11
89% yield
93% e.e.
12
86% yield
98% e.e.
13
83% yield
93% e.e.
Figure 2 | Solvent, N-substituent-group and ligand screen. Reactions were
performed with lactam 1 (33.6 mol), Pd2(dba)3 (5 mol%) and ligand
m
(12.5 mol%) in solvent (1.0 ml) at 40 8C for 72 h (dba, dibenzylideneacetone).
In all cases, complete consumption of starting material and product
formation was observed by thin layer chromatography on silica gel.
Pd2(pmdba)3 (5 mol%) was used for lactams 1a,b, at 50 8C (pmdba,
bis(4-methoxybenzylidene)acetone). Enantiomeric excess (e.e.) was
determined by chiral gas chromatography, superfluid critical chromatography
or high-performance liquid chromatography. See Supplementary Information
for details.
O
O
F
O
O
Bz
Bz
Bz
Bz
O
N
N
N
N
O
O
14
91% yield
99% e.e.
15
89% yield
99% e.e.
16
81% yield
94% e.e.
17
86% yield
96% e.e.
d
Other N-acyl groups
Ph
O
O
O
O
Concurrent to our efforts, the Trost laboratory28–32 and others28–36
have developed a series of related allylic alkylation methods. In
the course of our investigations of ketone enolate allylic alkylation
and other alkylation processes, we have often encountered interest-
ing ligand electronic effects and, in certain cases, pronounced
solvent effects37. In keeping with our ultimate goal of N-heterocycle
alkylation, we set out to further probe these subtle effects by
examining enolate reactivity in a lactam series that would be
amenable to both steric and electronic fine-tuning.
Ac
Cbz
N
PhO
N
N
18
19
20
90% yield
88% e.e.
82% yield
94% e.e.
86% yield
91% e.e.
O
N
O
O
N
O
O
N
O
Ph
We prepared a collection of racemic lactam substrates (1a–h)
for palladium-catalysed decarboxylative allylic alkylation and
performed a reactivity and enantioselectivity screen across an array
of solvents using two chiral ligands, (S)-t-BuPHOX ((S)-t-Bu
21
85% yield
99% e.e.
22
86% yield
99% e.e.
23
82% yield
97% e.e.
phosphinooxazoline) and (S)-(CF3)3-t-BuPHOX38–40. Preliminary Figure 3 | Scope of palladium-catalysed decarboxylative alkylation of
data suggested that electron-rich N-alkyl lactam derivatives were lactams. a, Palladium-catalysed enantioselective decarboxylative lactam
poor substrates for decarboxylative alkylation because of their low alkylation reactions were generally conducted by stirring of the
reactivity. Thus, electron withdrawing N-protecting groups were corresponding lactam substrate (0.50 mmol), Pd2(pmdba)3 (5 mol%) and
chosen for use in our study. We screened these substrates across a (S)-(CF3)3-t-BuPHOX (12.5 mol%) in toluene (15 ml) at 40 8C for 11–172 h.
series of four solvents (tetrahydrofuran (THF), methyl tert-butyl In all cases, complete consumption of starting material and product
ether (MTBE), toluene and 2:1 hexane–toluene) while using two formation was observed by thin layer chromatography on silica gel. Isolated
electronically distinct ligands on palladium. The results of this yields are reported. Enantiomeric excess (e.e.) was determined by chiral gas
broad screen were highly encouraging (Fig. 2; see Supplementary chromatography, superfluid critical chromatography or high-performance
Information). Reactivity across all substrates with either ligand liquid chromatography. See Supplementary Information for details and minor
was uniformly good, as all of the compounds were completely con- alterations to the conditions described above. b, a-Quaternary d-lactams
verted to the desired product. Strikingly, as the N-substituent group are accessed in excellent yield and with exceptional enantioselectivity.
was changed from sulfonyl to carbamoyl to acyl functionalities, the c, Additional chiral lactams such as pyrrolidinone, caprolactam and
enantioselectivity rose from nearly zero to nearly perfect. There was morpholinone, in addition to glutarimides, are accessed by the
also a substantial difference between the two ligands, and electron- enantioselective alkylation method. d, A variety of N-acyl groups are also
poor (S)-(CF3)3-t-BuPHOX was clearly superior. As the solvent tolerated in the asymmetric reaction.
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NATURE CHEMISTRY DOI: 10.1038/NCHEM.1222
ARTICLES
O
O
by parallel screening of reaction parameters and led to the identifi-
cation of a sterically and electronically tuned system for highly
enantioselective alkylation. We have applied this method to the
catalytic asymmetric synthesis of key intermediates previously
used for the construction of Aspidosperma alkaloids. Finally, the
asymmetric products formed in this investigation are envisaged to
be widely useful as building blocks for the preparation of range of
nitrogen-containing heterocycles in materials science, medicinal
chemistry and natural products synthesis.
LiOH•H2O
LiAlH4
BzN
HN
HN
MeOH, 23 °C
(96% yield)
Et2O, 35 °C
(91% yield)
3
24
25
H
N
O
N
ref. 8
ref. 42
N
N
H
(+)-Quebrachamine
(+)-Rhazinilam
Received 13 October 2011; accepted 7 November 2011;
published online 18 December 2011
Figure 4 | Utility of the lactam products. Conversion of N-Bz lactam 3 to
lactam 24, alkaloids quebrachamine and rhazinilam, and amine 25.
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.
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Acknowledgements
This publication is based on work supported by award from the King Abdullah University
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NIGMS (R01GM080269-01 and a postdoctoral fellowship to D.E.W.), the Gordon and
Betty Moore Foundation, Amgen, Abbott, Boehringer Ingelheim and Caltech for financial
support. T.Y. acknowledges the Japan Society for the Promotion of Science for a
predoctoral fellowship.
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Author contributions
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D.E.W. and S.C.V. took part in the initial reaction development and screening experiments.
B.M.S. conceived, initiated and directed the project and wrote the manuscript. All authors
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Additional information
The authors declare no competing financial interests. Supplementary information and
chemical compound information accompany this paper at www.nature.com/
naturechemistry. Reprints and permission information is available online at http://www.
nature.com/reprints. Correspondence and requests for materials should be addressed to B.M.S.
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