Enantioselective Silver and Amine Co-catalyzed Desymmetrizing Cycloisomerization of Alkyne-Linked Cyclohexanones

Article abstract of DOI:10.1002/anie.201612048

A silver(I) and amine co-catalyzed desymmetrization of 4-propargylamino cyclohexanones for the direct enantioselective synthesis of 2-azabicyclo[3.3.1]nonanes is described. Exploiting reactivity arising from dual activation of the pendant terminal alkyne by silver(I) and the ketone moiety through transient enamine formation, this synthetically relevant transformation is easy to perform, efficient and broad in scope. High enantioselectivity (up to 96 % ee) was achieved by exploiting a significant matching effect between the chirality of a cinchona alkaloid-derived aminophosphine ligand for the silver(I) salt and the 2-bis(aryl)methylpyrrolidine catalyst which was rationalized by DFT calculations. This allowed for the preparation of both enantiomers of the bicyclic product with near-identical stereocontrol.

Full text of DOI:10.1002/anie.201612048

Angewandte
Communications
Chemie
International Edition: DOI: 10.1002/anie.201612048
German Edition: DOI: 10.1002/ange.201612048
Asymmetric Catalysis
Enantioselective Silver and Amine Co-catalyzed Desymmetrizing
Cycloisomerization of Alkyne-linked Cyclohexanones
Rubꢀn Manzano, Swarup Datta, Robert S. Paton,* and Darren J. Dixon*
Abstract: A silver(I) and amine co-catalyzed desymmetriza-
tion of 4-propargylamino cyclohexanones for the direct
enantioselective synthesis of 2-azabicyclo[3.3.1]nonanes is
described. Exploiting reactivity arising from dual activation
of the pendant terminal alkyne by silver(I) and the ketone
moiety through transient enamine formation, this synthetically
relevant transformation is easy to perform, efficient and broad
in scope. High enantioselectivity (up to 96% ee) was achieved
by exploiting a significant matching effect between the chirality
of a cinchona alkaloid-derived aminophosphine ligand for the
silver(I) salt and the 2-bis(aryl)methylpyrrolidine catalyst
which was rationalized by DFT calculations. This allowed
for the preparation of both enantiomers of the bicyclic product
with near-identical stereocontrol.
formations we took inspiration from nature. A wide variety of
natural products and biologically relevant molecules contain
the morphan core (2-azabicyclo[3.3.1]nonane) in their struc-
tures, including the daphniphyllum and strychnos alkaloid
families,[7] and accordingly the development of new, efficient
and stereoselective methods for the construction of this motif
is highly desirable. In this context, an organocatalyzed
intramolecular Michael addition to a,b-unsaturated esters[8a]
and an enantioselective arylation of cyclohexanones have
been reported.[8b]
We envisaged that an enantioselective desymmetrizing[9]
cycloisomerization of prochiral scaffold I (Scheme 1) to
afford the 6,6-bicyclic morphan skeleton II could possibly
I
n recent years, the demand for ever-increasing efficiency in
the synthesis of structurally complex and stereochemically
defined molecular constructs has spawned numerous lines of
research in the field of enantioselective catalysis. One
particular strand, where multiple catalytically competent
and compatible species are employed simultaneously to
achieve reactivity unattainable by a single catalytic entity
alone, has been particularly successful.[1] In this regard, the co-
operative combination of aminocatalysis and transition metal
catalysis has been demonstrated to be a powerful and
Scheme 1. Metal and amine co-catalyzed desymmetrization concept.
versatile catalytic strategy for the enantioselective construc-
[2]
À
tion of C C bonds, which has found applications in both
library synthesis and natural product synthesis alike.[3]
The use of terminal alkynes as electrophilic partners for
carbonyl compounds in co-operative metal and amine co-
catalysis was first reported independently by the Kirsch group
and our group in 2008.[4] Racemic cyclopentane derivatives
were prepared by a gold-catalyzed intramolecular cyclization
of 1,7-ynals in the former case, and by a copper-catalyzed
cascade reaction between a,b-unsaturated ketones and prop-
argylmalonates in the latter. Enantioselective variants of both
5-exo-dig cyclizations with aldehydes as starting materials
were later disclosed.[5,6]
be realized using a co-operative metal and amine co-catalyst
system. Under appropriate reaction conditions, the amino-
catalyst would generate in situ a nucleophilic enamine
intermediate, which would be poised to react intramolecularly
with the pendant alkyne when suitably activated by a “soft”
late transition metal ion, such as a copper or silver species.[10]
Such an enantioselective transformation to a strained 6,6-
bicyclic morphan core has not previously been described
despite its potential use in synthesis and herein we wish to
disclose our findings.
Our hypothesis was validated following a series of experi-
ments with substrate 1a, which was accessible on scale from
simple commercial starting materials. Treatment of 1a with
catalytic amounts of pyrrolidine, Cu(OTf)2 and triphenyl-
phosphine (as a reducing agent and ligand for copper) in
DMF at 708C for 12 hours provided the racemic morphan
product 2a in good yield (Scheme 2). Control experiments
omitting any one of these three components produced no or
insignificant amounts of 2a (see the Supporting Information
(SI) for details). Additionally, N-methylpyrrolidine was found
to be catalytically incompetent in the reaction. Taken
together these preliminary studies suggested that both
enamine activation of the ketone group and transition metal
In a continuation of our research program into expanding
the synthetic possibilities of co-operative co-catalytic trans-
[*] Dr. R. Manzano, Dr. S. Datta, Prof. Dr. R. S. Paton,
Prof. Dr. D. J. Dixon
Department of Chemistry, Chemistry Research Laboratory
University of Oxford
Mansfield Road, Oxford OX1 3TA (UK)
E-mail: robert.paton@chem.ox.ac.uk
darren.dixon@chem.ox.ac.uk
Supporting information and the ORCID identification number(s) for
the author(s) of this article can be found under:
https://doi.org/10.1002/anie.201612048.
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provided very low enantiocontrol and variable reactivity
(entry 2 and SI for full details). Although the typically
successful diarylprolinol silyl ether catalyst 3b was inefficient
in this transformation (entry 1),[12] a sterically less demanding
desilyloxy derivative[13] (3d) was found to be very promising,
especially when combined with the readily available cinchon-
idine-derived aminophosphine 4a (entries 3 and 4). Whereas
copper salts provided enhanced reactivity, silver acetate
induced higher enantiocontrol (entries 4 and 5) and conse-
quently the remainder of our studies focused on silver salts as
the metal co-catalyst. Modifications to the catalyst structure
3d led to the identification of the 3,5-bis(trifluoromethyl)-
phenyl-derived pyrrolidine (3e) as the most enantioselective
catalyst, which afforded 2a in 92% ee (entry 6).
The poor catalytic turnover was greatly improved by the
use of inexpensive 2,4-dinitrophenol (DNP) as an acidic
additive (entry 7).[14,15] Furthermore, protic solvents had
previously been reported to accelerate some reactions[14]
and indeed 2-propanol was found to be the optimal solvent
for this transformation (entry 8). It is likely that the protic
medium assists the protodemetallation step[16] and/or facili-
tates enamine formation.[17] After fine tuning of the silver
source and the temperature (see SI for details), we found that
the combination of chiral pyrrolidine 3e, AgNTf2, amino-
phosphine 4a and 2,4-dinitrophenol smoothly promoted the
targeted reaction in 2-propanol at 608C, and product 2a was
isolated quantitatively with 95% ee (entry 9). The related
ligand 4b, possessing an N-Me group on the amide, provided
good enantioselectivity, but a very low yield (entry 10).
Control experiments showed that all components were
either essential or important for the excellent reactivity and
enantioselectivity.
Scheme 2. Proof of concept.
activation of the alkyne were required for a productive
carbocyclization.
Consequently, we continued our investigations by evalu-
ating the enantioselective version of this reaction. Consider-
ing the literature precedents[4–6] and the preliminary studies
described above, an obvious approach was to investigate the
combination of a soft transition metal species with chiral
amines and/or chiral phosphines.
Initial experiments demonstrated that a combination of
chiral 2-bis(aryl)methylpyrrolidines (3d,e) and cinchonidine-
derived aminophosphine (4a)[11] in conjunction with a copper
salt made an excellent starting point for a co-catalytic system
(Figure 1 and Table 1). Primary amines or proline (3c)
As initially proposed, a significant match/mismatch effect
was in operation between both chiral components of the
catalytic system (Scheme 3). The matched combination of
Figure 1. Chiral amines and aminophosphine ligands.
Table 1: Development of an enantioselective variant.
Entry[a]
3
M
ligand
Yield [%][b]
ee [%][c]
1
2
3
4
5
6
3b
3c
3d
3d
3d
3e
3e
3e
3e
3e
Cu(OTf)2
Cu(OTf)2
Cu(OTf)2
Cu(OTf)2
AgOAc
AgOAc
AgOAc
AgOAc
AgNTf2
PPh3
PPh3
PPh3
4a
4a
4a
4a
4a
4a
4b
20
82
74
70
20
11
82
99
99
15
15
0
Scheme 3. Match/mismatch effects. (Conditions as for Table 1,
entry 9).
52
71
83
92
91
90
95
90
7[d]
8[d,e]
9[d,e,f]
10[d,e,f]
R-configured pyrrolidine ent-3e with cinchonine-derived
aminophosphine 4c afforded the enantiomeric morphan
product ent-2a with the same high efficiency and high
enantioselectivity as 3e and 4a (Scheme 3, compare top-left
and bottom-right).[18] On the contrary, the use of the
mismatched pairs 3e/4c or ent-3e/4a (Scheme 3, compare
bottom-left, top-right) provided the product with a diminished
AgNTf2
[a] Conditions: 1a (0.1 mmol), 3 (20 mol%), ligand (20 mol%), Cu-
(OTf)2 (5 mol%) or AgOAc (10 mol%) in THF (0.5 mL) at 908C for 72 h.
[b] Isolated yield. [c] ee determined by chiral HPLC. [d] 2,4-Dinitrophenol
(20 mol%) was used. [e] i-PrOH instead of THF. [f] At 608C.
2
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enantioselectivity. The use of achiral pyrrolidine 3a and
cinchonidine-derived aminophosphine 4a gave rise to mini-
mal enantiocontrol in the reaction (36% ee), whereas the use
of achiral ligand 4d and chiral pyrrolidine 3e afforded
product 2a with a substantial 80% ee. These results demon-
strate that the pyrrolidine is exerting the dominant stereo-
controlling force in the reaction.
With a reliable and optimal procedure in hand, we then
assessed the scope of this enantioselective morphan-generat-
ing desymmetrization reaction (Scheme 4). Electron-rich and
Scheme 5. Computed (SMD-M06-2X/def2-TZVPP//def2-SVP) transition
À
structures for C C formation of major and minor enantiomers.
aminophosphine-silver complex is likely formed rapidly by
coordination of the quinuclidine nitrogen, the phosphorus
atom and the amide nitrogen to the silver center. Condensa-
tion of the pyrrolidine catalyst with the carbonyl group of 1a
generates a nucleophilic enamine intermediate poised for
À
C C bond formation upon alkyne activation. The terminal
alkyne of this adduct can be accommodated as a p-ligand by
the silver complex. Although the s-trans rotamer of aldehyde-
derived enamines is clearly favored,[21] the reactive confor-
mation of ketone-derived enamines depends on the function-
ality at the 2-position of the pyrrolidine ring, as demonstrated
in the well-studied reaction between cyclohexanone and
nitrostyrene catalyzed by chiral pyrrolidines.[22] For reactions
catalyzed by pyrrolidines with a substituent able to establish
H-bond interactions with the substrate, s-trans enamines have
been proposed and calculated,[23] but when the substituent on
the catalyst acts simply as a bulky group, the stereochemical
outcome is explained through s-cis enamines.[24] Significantly,
in this type of transformations it has also been observed that,
with the same catalyst system, the enantioselectivity is
reversed when an aldehyde is used instead of a ketone.[25]
With catalyst 3d an SMD-M06-2X/def2-TZVP//def2-SVP
conformational analysis reveals a 3 kcalmolÀ1 preference for
the s-cis enamine geometry in the ground state, in which the
sterically demanding diarylmethyl group is positioned pref-
erably above the flat olefinic sp2 carbon rather than above the
bulkier tetrahedral sp3 carbon by 3 kcalmolÀ1. This prefer-
ence is maintained in the competing TSs, in which the
electrophile must approach from the opposite side to this
Scheme 4. Scope of the enantioselective desymmetrization reaction.
[Conditions: 1 (0.2 mmol), 3e (20 mol%), 4a (20 mol%), AgNTf2
(10 mol%) and 2,4-dinitrophenol (20 mol%) in 2-propanol (1.0 mL) at
608C for 72 h. Isolated yield. ee determined by chiral HPLC].
electron-poor aromatic sulfonamides (1b,c), as well as an
aliphatic one (1e) were good substrates affording products in
high yield and enantioselectivity. It was observed that strongly
electron-deficient sulfonamides, like 4-nosyl and triflyl deriv-
atives 2d and 2 f, were obtained with a moderate yield but
good enantioselectivity. Carbamates 1h,i were well-tolerated
and the respective products 2h,i were obtained with good
enantiocontrol. Acetamide protected product 2j was afforded
in only moderate yield and with a slightly reduced enantio-
control. Importantly, additional substituents at the 4-position
of the cyclohexanone ring were perfectly tolerated, and
a variety of morphan products possessing a quaternary
stereocenter (2k–n) were prepared in excellent yields with
high enantioselectivity.
À
bulky group. A secondary H-bonding interaction (N H···O
À
< 2.5 ꢀ) between sulfonate and amidic N H group of the
aminophosphine 4a or 4d was found in the computed TSs.[26]
For chiral aminophosphine 4a, the matched TS has a shorter
Based on a quinine-derived aminophosphine-silver com-
plex recently characterized by X-ray analysis,[19] we have
performed DFT computations of enamine intermediates and
competing transition structures (TSs) which account for the
stereochemical outcome of the reaction (Scheme 5).[20] The
À
N H···O interaction to the sulfonate group than in the
mismatched case (1.96 ꢀ vs. 2.11 ꢀ)—the greater stability
reflected by an increase in DDG° to 2.8 from 1.2 kcalmolÀ1
with achiral 4d. The low efficiency of ligand 4b, with an N-Me
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À
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effect
between
the
chirality
of
the
2-bis-
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Conflict of interest
The authors declare no conflict of interest.
Keywords: aminocatalysis · asymmetric catalysis ·
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Manuscript received: December 11, 2016
Revised: March 2, 2017
Final Article published: && &&, &&&&
Angew. Chem. Int. Ed. 2017, 56, 1 – 6
ꢀ 2017 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.angewandte.org
5
These are not the final page numbers!

Angewandte
Communications
Chemie
Communications
Asymmetric Catalysis
R. Manzano, S. Datta, R. S. Paton,*
D. J. Dixon*
&&&& — &&&&
Enantioselective Silver and Amine Co-
catalyzed Desymmetrizing
Cycloisomerization of Alkyne-linked
Cyclohexanones
A matching effect between a chiral
aminocatalyst and a chiral ligand for
silver is exploited in the title reaction of 4-
propargylamino cyclohexanones for the
direct enantioselective synthesis of 2-
azabicyclo[3.3.1]nonanes. The reaction is
efficient, broad in scope and proceeds
with high enantioselectivity.
6
www.angewandte.org
ꢀ 2017 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Angew. Chem. Int. Ed. 2017, 56, 1 – 6
These are not the final page numbers!