Iridium-catalyzed reductive nitro-mannich cyclization

Article abstract of DOI:10.1002/chem.201405256

A new chemoselective reductive nitro-Mannich cyclization reaction sequence of nitroalkyl-tethered lactams has been developed. Relying on the rapid and chemoselective iridium(I)-catalyzed reduction of lactams to the corresponding enamine, subsequent nitro-

Full text of DOI:10.1002/chem.201405256

DOI: 10.1002/chem.201405256
Communication
&
Mannich Reaction
Iridium-Catalyzed Reductive Nitro-Mannich Cyclization
[
a]
Alex W. Gregory, Alan Chambers, Alison Hawkins, Pavol Jakubec, and Darren J. Dixon*
ductive nitro-Mannich cyclization of N-linked lactam substrates
[
5–7]
Abstract: A new chemoselective reductive nitro-Mannich
cyclization reaction sequence of nitroalkyl-tethered lac-
tams has been developed. Relying on the rapid and che-
moselective iridium(I)-catalyzed reduction of lactams to
the corresponding enamine, subsequent nitro-Mannich
cyclization of tethered nitroalkyl functionality provides
direct access to important alkaloid natural-product-like
structures in yields up to 81% and in diastereoselectivities
that are typically good to excellent. An in-depth under-
standing of the reaction mechanism has been gained
through NMR studies and characterization of reaction in-
termediates. The new methodology has been applied to
the total synthesis of (Æ)-epi-epiquinamide in four steps.
of type 3 was feasible.
Such chemistry would allow direct
access to fused nitrogen-containing bicycles of type 5 via reac-
tive iminium ion intermediates 4 (Scheme 2). These motifs
are abundant in nature, making up major classes of alkaloid
[8]
Scheme 2. Proposed partial reductive nitro-Mannich cyclization concept.
[9,10]
natural products which show important biological activity.
In addition, the presence of the versatile nitro group could be
[
11]
Reaction cascades are becoming mainstream in organic syn-
thesis, allowing the synthesis of advanced structures with
exploited as a handle to access, for example, ketone and
amine functionality. As such the new methodology would be
useful for natural product and library synthesis alike. Herein we
wish to report our findings.
[1,2]
fewer purification steps, increased speed and efficiency.
The
development of new cascade sequences can be either meth-
odology- or target-driven and in a few cases they can provide
the critical link from a late stage intermediate to the end-game
sequence in a total synthesis. To this end we recently reported
an unprecedented chemoselective reductive nitro-Mannich
cyclization of 1 proceeding via a putative iminium intermedi-
Readily prepared caprolactam-derived substrate 3a was se-
lected as a model system and initially subjected to the modi-
fied Buchwald conditions used in the synthesis of manza-
[
12,13]
mine A.
Pleasingly we were able to isolate the desired bi-
cycle 5a albeit in only 17% yield (Table 1, entry 1). A range of
typical hydridic reducing agents including DIBAL (diisobutylalu-
miniumhydride) and Schwartz reagent ([ZrCl(C H ) H]) were
[3,4]
ate to form the B ring in manzamine A (2) (Scheme 1).
Recognising the synthetic potential of this novel annulation
strategy, we wanted to investigate whether an analogous re-
5
5 2
screened. Unfortunately, in all cases poor yields and/or full re-
duction products were observed. However, inspired by the
[
14]
work of Nagashima,
substoichiometric
an attempted reduction of 3a using
[15]
Vaska’s
complex
[IrCl(CO)(PPh ) ]
3 2
[16]
(
2.5 mol%) and silane (TMDS or PMDS) resulted in the desir-
able formation of 5a in 23 and 36% yield, respectively
Table 1, entries 2 and 3). Quenching the reaction with 1m HCl
(
allowed efficient removal of excess silane and its by-products.
Basification, extraction and purification afforded 5a in im-
proved yield (Table 1, entry 4). With this promising method in
hand we attempted to lower the catalyst loading (Table 1, en-
tries 4–6). Pleasingly lowering to 0.1% had little detrimental
impact on the yield; however, for practicality (in weighing out
the catalyst) we chose to use 0.5 mol% of Vaska’s complex. A
solvent screen (Table 1, entries 7–9) revealed that toluene was
indeed the best solvent. The concentration of the reaction was
an important parameter, with high dilution leading to an in-
creased yield of 80% (Table 1, entries 10 and 11). After optimi-
zation we demonstrated the reaction was scalable; using 2 g
of 3a bicycle 5a was formed in good yield and excellent dia-
Scheme 1. Reductive nitro-Mannich cascade in the total synthesis of manza-
mine A.
[
3]
[a] A. W. Gregory, A. Chambers, Dr. A. Hawkins, Dr. P. Jakubec,
Prof. Dr. D. J. Dixon
Department of Chemistry, Chemistry Research Laboratory
University of Oxford, Mansfield Road, Oxford OX1 3TA (UK)
E-mail: darren.dixon@chem.ox.ac.uk
Supporting information for this article is available on the WWW under
http://dx.doi.org/10.1002/chem.201405256.
[17]
stereoselectivity (Table 1, entry 12).
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Table 1. Optimization results.
[
a]
[b]
[c]
Entry
T
Solvent
Conc.
m]
Catalyst
Cat. loading
[mol%]
Silane
Silane
[equiv]
Work
up
Yield
[%]
d.r.
[
[
d]
[e]
1
2
3
4
5
6
7
8
9
0
RT
RT
RT
RT
RT
RT
RT
RT
RT
RT
RT
RT
toluene
toluene
toluene
toluene
toluene
toluene
hexane
THF
0.05
0.05
0.05
0.05
0.05
0.05
0.05
0.05
0.05
0.25
0.01
0.01
[Ti(OiPr
4
)]
210
2.5
2.5
2.5
0.5
0.1
0.5
0.5
0.5
0.5
0.5
0.5
TMDS
TMDS
PMDS
TMDS
TMDS
TMDS
TMDS
TMDS
TMDS
TMDS
TMDS
TMDS
2.1
2.0
2.0
2.0
2.0
2.0
2.0
2.0
2.0
2.0
2.0
2.0
silica gel
silica gel
silica gel
17
23
36
53
68
55
53
50
48
54
80
71
98:2
97:3
88:12
88:12
89:11
91:9
[
[
e]
e]
[IrCl(CO)(PPh
[IrCl(CO)(PPh
[IrCl(CO)(PPh
[IrCl(CO)(PPh
[IrCl(CO)(PPh
[IrCl(CO)(PPh
[IrCl(CO)(PPh
[IrCl(CO)(PPh
[IrCl(CO)(PPh
[IrCl(CO)(PPh
[IrCl(CO)(PPh
3
3
3
3
3
3
3
3
3
3
3
)
)
)
)
)
)
)
)
)
)
)
2
]
2
]
2
]
2
]
2
]
2
]
2
]
2
]
2
]
2
]
2
]
[
[
[
[
[
[
[
[
f]
f]
f]
f]
f]
f]
f]
f]
HCl
HCl
HCl
HCl
HCl
HCl
HCl
HCl
HCl
91:9
86:14
88:12
91:9
88:12
98:2
2 2
CH Cl
1
toluene
toluene
toluene
1
1
[
g]
[f]
12
[a] All reactions carried out on 0.10 g of 3a unless otherwise started, the major by-product was the corresponding fully reduced lactam (1-(4-nitrobutyl)aze-
pane). [b] Isolated yield after purification. [c] d.r. measured by NMR spectroscopy of the isolated products. [d] Reaction time 28 h. [e] Reaction mixture was
concentrated in vacuo and injected directly onto a silica gel column for chromatography. [f] Reaction was extracted with HCl (1m), basified (K
tracted into ether. [g] Reaction performed on 2 g of 3a.
2 3
CO ) and ex-
NMR experiments were performed to identify the intermedi-
ates present at each stage of the reaction. Pure starting materi-
al is shown in Figure 1 spectrum A and starting material with
TMDS and mesitylene internal standard is shown in spec-
trum B. On addition of Vaska’s complex, rapid (5 mins) and
clean conversion to the enamine intermediate 7 was witnessed
smooth cyclization of the putative nitronate 10 to form prod-
uct bicycle 5a.
With optimized conditions in hand we proceeded to assess
the scope of the reaction (Figure 2). The size of the lactam ring
could be varied from five-membered up to eight-membered
with all substrates progressing in good to excellent d.r. (5a–
5d). The reaction also tolerated ether functionality as demon-
strated in the synthesis of oxazapane 5e. The method could
be extended by lengthening the nitroalkane tether to access
seven-membered rings on ring closure as exemplified by 5 f
and 5g. Shortening the nitroalkane tether was also possible,
with bicycles 5h and 5i being formed in good yield albeit
with a reduction in diastereoselectivity.
(Figure 1, spectrum C). On addition of HCl, iminium ion 8 was
clearly observed (Figure 1, spectrum D); subsequently, and in
a separate reaction, iminium ion 8 was isolated and fully char-
[
18]
acterized. Upon basification with solid K CO and extraction
2
3
the desired bicycle 5a was formed (Figure 1, spectrum E).
Given the direct evidence for the presence of each inter-
mediate at their respective stages in the reaction we can pos-
tulate that the reaction proceeds by the mechanism shown in
Scheme 3. The iridium complex catalyses the partial reduction
Substrates possessing an arene group in the nitroalkane
tether also cyclized to their respective tricyclic products (5j–5l)
in good to excellent yields (52–81%) and diastereoselectivities
up to 98:2 (Figure 3).
[
19]
of amide 3a to the siloxy intermediate 9, elimination and
subsequent loss of a proton reveals enamine 7. Only upon
acidic workup does the enamine reprotonate to give the
stable, water-soluble, iminium ion 8. Upon addition of solid po-
tassium carbonate, the resulting rise in pH to >10 facilitates
Application of the methodology to the synthesis of (Æ)-epi-
[20]
epiquinamide was demonstrated from bicycle 5c. Following
the key reductive nitro-Mannich cyclization step, Raney nickel
reduction and concommitant acetylation of bicycle 5c allowed
[
20]
the synthesis of natural product (Æ)-epi-epiquinamide in four
steps from valerolactam and dibromobutane starting materials
[
18]
(
Scheme 4). The synthesis of (Æ)-epi-epiquinamide confirmed
the relative stereochemistry of 5c as (R*,S*) by comparison
[20]
with literature data.
a seven-membered ring cyclization) were also assigned as
R*,S*) by NOE spectroscopy data from compound 5 f. All other
Compounds 5 f and 5g (formed by
(
compounds were assigned as (R*,S*) by analogy to 5c and 5 f.
In conclusion, we have developed a novel chemoselective
reductive cyclization. The process is unprecedented, fast, effi-
cient and stereoselective and provides heterocyclic com-
pounds with cores that are abundant in nature and make up
Scheme 3. Postulated reaction mechanism.
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Figure 1. H NMR spectra of starting material, intermediates and the desired product at selected stages of the reaction. Spectra A, B, and C were measured in
]toluene. Spectrum D was obtained in D O and spectrum E was measured in CDCl
[D
8
2
3
.
Figure 3. Reaction scope (aryl-linked tether).
Scheme 4. Total synthesis of (Æ)-epi-epiquinamide.
nism through NMR studies and have applied the new method-
ology to the total synthesis of (Æ)-epi-epiquinamide in four
steps. We are currently developing an asymmetric variant of
this reaction and expanding the concept of the reductive cycli-
Figure 2. Reaction scope (aliphatic tether).
classes of alkaloids that show potent biological activity. We
have gained a thorough understanding of the reaction mecha-
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Communication
zation to include a range of new substrates, all of which will
be disclosed in due course.
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TMDS (2.0 equiv) and [IrCl(CO)(PPh ) ] (0.005 equiv) were added to
3
2
a stirred solution of nitro-lactam 3 (1.0 equiv) in toluene (0.01m)
under an inert atmosphere at room temperature. The resulting so-
lution was stirred for 10 mins until complete conversion of the
starting material was observed (TLC), and then quenched with 1m
2
1
848–2849; c) R. D. Gless, H. Rapoport, J. Org. Chem. 1979, 44, 1324–
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2011, 123, 6128–6135.
À1
HCl (12 mLmmol 3). The aqueous layer was separated and the
À1
organic layer was extracted (1m HCl, 3ꢁ12 mLmmol 3). The
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À1
combined aqueous extracts were washed (Et O, 3ꢁ6 mLmmol 3)
2
and basified to pH>10 (K CO ). The aqueous layer was then ex-
2
3
À1
tracted (Et O, 3ꢁ6 mLmmol 3), and the organic phases com-
2
bined, dried (MgSO ), filtered and concentrated in vacuo. The resi-
4
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We gratefully acknowledge the EPSRC (Leadership fellowship
to D.J.D.; studentship to A.W.G and A.H.; postdoctoral fellow-
ship to P.J.) and AstraZeneca for funding.
[
[
11] R. Ballini, M. Petrini, Tetrahedron 2004, 60, 1017–1047.
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[
13] Lemair modification, exchanging SiPh
ane (TMDS).
2 2
H for 1,1,3,3-tetramethyldisilox-
Keywords: amide activation · domino reactions · iridium ·
Mannich reaction · reduction · silanes
[14] Y. Motoyama, M. Aoki, N. Takaoka, R. Aoto, H. Nagashima, Chem.
Commun. 2009, 13, 1574–1576.
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1] For recent reviews on cascade reactions see: a) K. C. Nicolaou, J. S.
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3 2
complex=[IrCl(CO)(PPh ) ]).
[16] TMDS=1,1,3,3-tetramethyldisiloxane,
PMDS=Polytetramethyldisilox-
ane.
2
006, 118, 7292–7344.
[17] The reduced yield and increased d.r. reflects the instability of the minor
diastereomer on larger scale purification.
[18] See Supporting Information for full details.
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[
[
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Received: September 13, 2014
Tsutsumi, Y. Motoyama, H. Nagashima, J. Am. Chem. Soc. 2009, 131,
Published online on && &&, 0000
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Communication
COMMUNICATION
&
Mannich Reaction
A. W. Gregory, A. Chambers, A. Hawkins,
P. Jakubec, D. J. Dixon*
&& – &&
Let’s all go Mannich! A new chemose-
lective reductive nitro-Mannich cycliza-
tion sequence of nitroalkyl-tethered lac-
tams has been developed. Catalyzed by
iridium(I) in the presence of a silane ter-
minal reductant, the methodology
allows direct and rapid access to alka-
loid natural-product-like structures in
good yield and typically in excellent dia-
stereoselectivity. The methodology was
applied to the synthesis of (Æ)-epi-epi-
quinamide.
Iridium-Catalyzed Reductive Nitro-
Mannich Cyclization
Chem. Eur. J. 2014, 20, 1 – 5
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&
These are not the final page numbers! ÞÞ