Enantioselective intramolecular aldehyde α-alkylation with simple olefins: Direct access to homo-ene products

Article abstract of DOI:10.1021/ja4047312

A highly selective method for the synthesis of asymmetrically substituted carbocycles and heterocycles from unactivated aldehyde-olefin precursors has been achieved via enantioselective SOMO-catalysis. Addition of a catalytically generated enamine radical cation across a pendent olefin serves to establish a general asymmetric strategy toward the production of a wide range of formyl-substituted rings with alkene transposition. Conceptually, this novel mechanism allows direct access to "homo-ene"-type products.

Full text of DOI:10.1021/ja4047312

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Communication
Enantioselective Intramolecular Aldehyde #-Alkylation
with Simple Olefins: Direct Access to Homo-Ene Products
Robert J. Comito, Fernanda Gadini Finelli, and David W. C. MacMillan
J. Am. Chem. Soc., Just Accepted Manuscript • Publication Date (Web): 07 Jun 2013
Downloaded from http://pubs.acs.org on June 7, 2013
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Journal of the American Chemical Society
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Enantioselective Intramolecular Aldehyde α-Alkylation with Simple Olefins:
Direct Access to Homo-Ene Products
Robert J. Comito, Fernanda G. Finelli, and David W. C. MacMillan*
Merck Center for Catalysis at Princeton University, Princeton, New Jersey 08544
dmacmill@princeton.edu
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Abstract: A highly selective method for the synthesis of
asymmetrically substituted carbocycles and heterocycles from
unactivated aldehyde–olefin precursors has been achieved via
enantioselective SOMO-catalysis. Addition of a catalytically
generated enamine radical cation across a pendent olefin serves
Lewis Acid (LA) Catalyzed Intramolecular Carbonyl-Ene Cyclization
O
OH
Me
LA
O
LA
Me
Me
1-ene
Me
Me
to establish
a general asymmetric strategy towards the
production of a wide range of formyl-substituted rings with
alkene transposition. Conceptually, this novel mechanism
allows direct access to “homo-ene” type products.
Lewis acid
ring closure
aldehyde-olefin
Organocatalytic Aldehyde-Olefin Alkylation: α-Carbonyl Cyclization
O
Me
Me
O
Carbocyclic and heterocyclic ring systems bearing
asymmetric substitution patterns are widely distributed among
medicinal agents and bioactive natural products.1 A preeminent
goal of organic synthesis is the development of technologies to
enable the rapid and enantioselective construction of these high–
value cyclic substructures from simple starting materials.2 Along
these lines, the powerful carbonyl-ene cyclization delivers
stereochemically complex small ring systems from achiral
aldehyde–olefin precursors in a routine and predictable fashion
through a mechanism that does not require pre-functionalization
of the olefin component.3 This fundamental transformation has
been widely studied and a number of catalytic enantioselective
carbonyl-ene protocols have been developed.4,5 Expanding upon
this general concept, we sought to invent a one-carbon extended,
“homo-ene” variant, wherein unactivated substrates undergo
asymmetric α-carbonyl cyclization through a SOMO-activation
mechanism, to stereoselectively generate cyclic adducts bearing
synthetically useful aldehyde and olefin functional handles. We
describe herein the development of the first asymmetric “homo-
ene” cyclization, a transformation we anticipate will be of
significant value to the chemical synthesis community.
N
−2e−
−2H+
O
Me
Me
N
H
Me
Ph
Me
Me
aldehyde-olefin
amine catalyst
α-C=O ring closure
−1e−, −H2O
H2O, −H+
O
O
2
1-he
Ph
Me
Ph
−1e−
N
N
Me
N
Me
Me
N
tBu
tBu
Me
Me
Figure 1. Impetus and design elements of home-ene reaction
strategy was our expectation that cyclization would proceed via a
highly ordered chair-E transition state15 (1-he) to deliver the
product with trans diastereoselectivity in a fashion that is highly
analogous to the venerable ene 2π-electron pathway (1-ene).
Notably, this study would require only simple olefins as the
tethered SOMO-phile component, a substantial expansion of the
scope and utility of this enantioselective oxidation pathway.16
Design Plan. In 2007, our laboratory introduced a mode of
asymmetric activation termed SOMO (singly occupied
molecular orbital) organocatalysis.6 Subsequent to our initial
discovery, we have established SOMO organocatalysis as a
remarkably robust and versatile activation platform, capable of
Table 1. Effect of catalyst structure and counterion on cyclization
CHO
Me
CHO
facilitating
a range of previously elusive transformations,
O
Me
20 mol% cat.
Fe(phen)3X3
including direct enantioselective α-allylic alkylation,7 α-
enolation,8 α-vinylation,9 α-chlorination,10 and α-arylation,11 as
well as polycyclization12 and cycloaddition13 to generate
cyclohexyl rings and pyrrolidines. Recently, we questioned
whether the SOMO platform might be leveraged for the
development of an asymmetric α-carbonyl “homo-ene”
cyclization of unactivated aldehyde-olefin substrates. While the
traditional carbonyl-ene cyclization proceeds through a LUMO-
lowered 2π-electron pathway, the SOMO activation mode is
distinguished by an electrophilic 3π-electron species (1-he).
Based on precedent from our lab,6-13 we anticipated that this
enamine radical cation would add stereoselectively from the
unshielded Re-face to the pendent olefin, thus generating a
transient alkyl radical. Operation of a radical-polar crossover
mechanism14 would serve to oxidize the radical to the
corresponding carbocation (2). Finally, deprotonation and
hydrolysis would regenerate the amine catalyst and deliver the
enantioenriched cyclized product. Central to the proposed
N
Me
Me
Me
Me
N
H
DME, Na2HPO4
–30 °C, 12 h
N
N
R
Me
Ts
Ts
formyl-olefin (3)
catalyst•TFA
ring adduct (4)
catalyst (R)
X-
yield (%)a
ee (%)b
entry
-
-
-
-
SbF6
SbF6
SbF6
ClO4
5 (H)
6 (Ph)
41%
41%
43%
12%
73%
95%c
89%
97%
99%
99%
99%
99%
1
2
3
7 (1-naphthyl)
7 (1-naphthyl)
7 (1-naphthyl)
7 (1-naphthyl)
4
5
6
-
PF6
Tf2N-
aDetermined by 1H NMR using internal standard. Diastereoselectivity
>20:1 in all cases. bDetermined by chiral SFC analysis of the
corresponding alcohol, absolute configuration determined by chemical
correlation. cIsolated in 93% yield.
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Table 3. Scope of π-nucleophile, selectivity of olefin transposition
Table 2. Scope of the enantioselective homo-ene ring products
1
2
3
4
5
6
7
8
Z
CHO
Z
CHO
O
Me
Me
CHO
CHO
O
Me
Fe(phen)3(Tf2N)3
Fe(phen)3(Tf2N)3
N
•TFA
tBu
N
Y
Me
Me
DME, Na2HPO4
–30 °C, 12h
DME, Na2HPO4
N
H
tBu
N
H
N
N
−30 °C, 12 h
X
X
R
R
Ts
Ts
20 mol% 7a
20 mol% 7 (R = 1-naphthyl)
homo-ene adduct
yield / % eeb
substrate
product
entry
1
substrate
yield / % eea
entry
product
Me
CHO
CHO
CHO
CHO
9
82% yield
97% ee
>20:1 drb
1
2
99% yield
98% ee
>20:1 drc
Me
Me
Me
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
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45
46
47
48
49
50
51
52
53
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56
57
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60
O
O
N
N
Ts
Ts
Me
CHO
Me
CHO
CHO
CHO
77% yield
86% ee
>20:1 drb
2
3
4
87% yield
97% ee
>20:1 drc
N
N
Ts
Ts
N
N
Ts
Ts
Me
CHO
Me
75% yieldc
95% ee
>20:1 drb
CHO
CHO
CHO
Me
3
90% yield
97% ee
>20:1 drc
O
O
N
N
Me
Me
CHO
CHO
Ts
Ts
76% yieldc
96% ee
>20:1 drb
4
5
Me
Me
Me
Ph
CHO
Ph
CHO
79% yield
96% ee
>20:1 drc
Me
CHO
62% yieldc
85% ee
>20:1 drb
N
N
Me
CHO
Ts
Ts
TMS
CHO
CHO
Me
CHO
CHO
5
6
78% yield
92% ee
>20:1 drc
84% yield
99% ee
>20:1 drb
Me
6
Me
N
N
Ts
Ts
tBuO2C CO2tBu
tBuO2C CO2tBu
CHO
aDetermined by chiral HPLC analysis of the alcohol or aryl ester.
bDetermined by 1H-NMR analysis. cDetermined by 1H-NMR analysis
using an internal standard.
77% yield
98% ee
>20:1 drc
Me OHC
N
N
Ts
Ts
Results. The proposed transformation was first evaluated in
the context of the amine-tethered prenyl aldehyde substrate 3.
As presented in Table 1, treatment of this aldehyde with base
and Fe(III)trisphenanthroline in the presence of an
imidazolidinone catalyst (5, 6, or 7) led to the stereoselective
formation of piperidine 4 with high levels of trans diastereo-
selectivity and enantiocontrol. Optimal selectivities were
obtained with the naphthyl-bearing amine catalyst 7, presumably
due to enhanced facial shielding of the SOMO intermediate (1-
aR = 1-naphthyl. Determined by chiral HPLC analysis of the alcohol or
aryl ester. Diastereoselectivities determined by 1H-NMR analysis.
cDetermined by 1H-NMR analysis using an internal standard.
b
precursors (entries 2 and 3), demonstrating the mild conditions
employed in generating the 3π-electron activated intermediate.
The products depicted in Table 2 represent important structural
motifs that are widely encountered throughout natural product
synthesis and drug discovery.1
he).
Variation
of
the
counterion
(X–)
in
the
Fe(III)trisphenanthroline salt revealed the soluble tris-
bistriflamide salt to be most effective (entry 6).
The reaction is also tolerant of a broad array of olefin systems
as suitable π-nucleophiles for this homo-ene type cyclization. As
highlighted in Table 3, alkylidene cycloalkanes of various ring
sizes readily undergo enantioselective C–C bond formation to
generate the corresponding bicyclic products in good yield and
with excellent stereocontrol (entries 1–3). In addition, α-
carbonyl cyclization using styrenyl olefins is readily
accomplished (entry 4). Importantly, non-symmetrical 1,2,2-
trisubstituted alkenes, e.g. bearing methyl and cyclohexyl
groups, can generate the purported carbocation intermediate (2)
before undergoing selective deprotonation to generate single
olefin-transposition regioisomers (entry 6, >98:2 rr). We note
that, at this stage, unfunctionalized 1,2-disubstituted olefins are
not effective substrates for this transformation, presumably due
Having identified optimal conditions for the organocatalytic
“homo-ene” reaction, we next explored the scope of the reaction
with respect to the tethering moiety. As shown in Table 2, the
method was found to readily accommodate significant structural
diversity in the linker, offering enantioselective access to a wide
range of 5- and 6-membered carbocyclic and heterocyclic ring
systems. Under our conditions, achiral substrates were cyclized
to
generate
piperidine,
pyrrolidine,
tetrahydropyran,
tetrahydrofuran, cyclopentane, and cyclohexane motifs with
good to excellent diastereoselectivity (>20:1), enantioselectivity
(85–99%) and yield (62–95%). Notably, the formation of
tetrahydrofuran and pyrrolidine adducts was achieved without β-
oxy or β-amino elimination from the corresponding aldehyde
2
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Table 4. Production of rings with three contiguous stereocentersa
Scheme 1. Sequential organocatalytic hydrogenation-cyclizationa
1
2
3
4
5
6
7
Me
CHO
CHO
cat. 7 (20 mol%)
O
Me
O
Me
O
Me
•TCA
•TFA
•TFA
N
N
N
Me
Fe(phen)3(Tf2N)3
Me
Me
Me
Me
Me
Me
Me
Me
Me
DME, Na2HPO4
N
H
N
H
N
X
H
X
−30 °C, 12 h
R
Me
R
Me
Me
optically pure
trisubstituted ring
12
S,S-7 (R = 1-naphthyl)
R,R-7 (R = 1-naphthyl)
substrate
With S,S-7 as catalyst With R,R-7 as catalyst
CHO
8
9
Me
Me
CHO
CHO
CHO
1
2
Me
CHO
Me
Me
Me
Me
Im
So
Me
Me
Me
Me
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
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Me
N
S-12
S,S-7
Ts
N
N
N
68% yield
N
10
Ts
Ts
Ts
Ts
>20:1 dr, >99% ee
99% ee
94% yield, >20:1 dr
91% yield, >20:1 dra
CHO
Im
So
Me
tBuO2C
Me
CO2tBu
Me
Me
CHO
CHO
CHO
3
4
Me
Me
Me
Me
S-12
R,R-7
Me
Me
Me
N
N
H
Ts
O
O
O
68% yield
99% ee
77% yield, 13:1 dr
13 Hantzsch ester
>20:1 dr, >99% ee
52% yield, 14:1 dr
5
6
Me
CHO
CHO
CHO
Me
Me
CHO
Me
Me
Me
Me
CHO
O
Me
Im
So
Me
Me
Me
Me
O
S-12
S,S-7
99% ee
62% yield,b 16:1 dr
65% yield,b 17:1 dr
81% yield
11
11:1 dr, >99% ee
8
7
Me
CHO
Me
CHO
Me
CHO
Me
CHO
Me
Im
So
tBuO2C
Me
CO2tBu
Me
Me
Me
Me
Me
O
O
O
S-12
R,R-7
N
H
O
99% ee
67% yield, >20:1 dr
75% yield, >20:1 dr
60% yield
13 Hantzsch ester
5:1 dr, >99% ee
O
Me
tBu
Me
TsN
Me
Ar
Me
Conditions: Step 1) 2.5 equiv. 13, 20 mol% 12, CHCl3, –50 °C, 24 hours.
Step 2) 2.5 equiv. Fe(phen)3(Tf2N)3, 2.5 equiv. Na2HPO4, 20 mol % 7, –
30 °C, DME, 12 hours. aDiastereoselectivities determined by 1H-NMR
analysis. Enantiomeric excess determined by chiral HPLC analysis of the
corresponding alcohol or terephthalic acid monomethyl diester.
N
Me
N
Me
N
Me
N
Me
Ar
TsN
tBu
O
8 favored for S,S-cat 7
9 favored for R,R-cat 7
aDiastereoselectivities determined by H-NMR analysis. Determined by
1H-NMR analysis using an internal standard.
1
b
stereochemical relationship across the newly forming bond. In
each case, the amine catalyst strongly dictated the
diastereochemical outcome, effectively overriding the influence
of the substrate β-methyl stereocenter with either catalyst
antipode. Presumably, the steric demand of the amine catalyst
provides a major conformational lock, enforcing a chair-E
transition state (see 8 and 9) and thereby matching or overriding
the inherent substrate bias.
Finally, in an extension of the findings shown in Table 4, we
have developed a simple two-step organocatalytic protocol by
which to achieve the overall conversion of simple achiral
aldehydes to stereochemically complex cyclic adducts. As
shown in Scheme 1, substrates 10 and 11 were subjected to
to the higher oxidation potential for conversion of secondary
radicals to secondary cations in comparison to their tertiary
radical counterparts.17 Despite this current limitation in scope,
cycloadducts bearing monosubstituted olefin substituents are
nonetheless readily accessible from allyl silane precursors (entry
5).
We next sought to examine the ability of the amine catalyst to
override the influence of stereochemical information already
present on the intramolecular cyclization substrate. We
recognized that if catalyst-controlled stereodifferentiation could
be achieved, it should be possible to selectively generate a
diverse array of highly complex cyclic systems bearing three or
more contiguous stereocenters. As shown in Table 4,
enantioenriched aldehyde substrates incorporating β-methyl
substitution (99% ee) were subjected to our ring-closing
conditions with either the S,S-7 or R,R-7 catalyst. Remarkably,
catalyst-mediated cyclization in both enantiomeric series
successfully delivered ring systems bearing three contiguous
stereocenters, with excellent selectivity for the trans-
sequential
enantioselective
organocatalytic
transfer
hydrogenation (using catalyst 12) followed directly by
asymmetric homo-ene cyclization (using either enantiomer of
catalyst 7) to generate the observed products in good overall
yield and with excellent selectivity. The transformations
depicted in Scheme 1 serve to highlight the ability of the
SOMO-mediated homo-ene technology to effect the rapid
production of stereochemical complexity in cyclic architectures.
3
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In summary, enantioselective SOMO-organocatalysis has
1
2
3
4
5
6
7
8
been leveraged for the development of a potentially general
approach toward the synthesis of stereochemically rich
carbocycles and heterocycles from achiral precursors. This
protocol bears analogy to the venerable carbonyl-ene cyclization,
yet provides access to a differentiated array of complex cyclic
scaffolds incorporating valuable aldehyde and olefin functional
handles. We anticipate that this method will find broad
application among practitioners of organic synthesis.
9
Acknowledgement. Financial support was provided by the
NIHGMS (R01 GM103558-01) and kind gifts from Merck,
Amgen and Abbvie.
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Supporting Information Available. Experimental procedures
and spectral data are provided. This material is available free of
charge via the Internet at http://pubs.acs.org.
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298-316.
(15) a) Curran, D. P.; Porter, N. A.; Giese, B. Stereochemistry of Radical
Reactions: Concepts, Guidelines, and Synthetic Applications. VCH: New
York, 1995. b) Renaud, P. Stereoselectivity of Radical Reactions: Cyclic
Systems. In Radicals in Organic Synthesis; Renaud, P.; Sibi, M. P. Eds.;
Wiley-VCH: Weinheim, 2001; pp 298-316.
(16) Intramolecular cyclizations using SOMO catalysis have previously been
accomplished using π-rich activated olefins such as allylsilanes. This study
expands the scope and utility of the enantioselective SOMO oxidation
pathway via the use of simple olefins.
(17) Unpublished results from our lab have indicated that the initial radical
coupling step is reversible when oxidation of the resulting radical to a cation is
relatively slow.
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Journal of the American Chemical Society
Enantioselective Aldehyde-Olefin Alkylation: Direct Access to Homo-Ene Adducts
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amine
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catalyst
−2e−
tBu
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aldehyde-olefin
"homo-ene" adduct
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