Access to high levels of molecular complexity by one-pot iridium/enamine asymmetric catalysis

Article abstract of DOI:10.1002/anie.201007001

(Chemical Equation Presented) Independent workers with team spirit: A catalytic sequence that exploits the compatibility of (chiral) cationic iridium catalysts for the isomerization of primary allylic alcohols to aldehydes with organo-catalysts has been d

Full text of DOI:10.1002/anie.201007001

Communications
DOI: 10.1002/anie.201007001
Sequential Catalysis
Access to High Levels of Molecular Complexity by One-Pot
Iridium/Enamine Asymmetric Catalysis**
Adrien Quintard, Alexandre Alexakis,* and Clꢀment Mazet*
The introduction of high levels of molecular complexity in a
minimal number of operations by sustainable approaches is a
contemporary goal in asymmetric catalysis that has recently
attracted much interest in the synthetic community. The
successful combination of at least two organic and/or
organometallic catalysts has enabled remarkable architec-
tural complexity to be created in some cases.[1,2] Acyclic a,b-
chiral aldehydes are particularly attractive targets owing to
their high prevalence as pivotal synthetic building blocks and
to the challenge associated with their preparation with
modular diastereoselectivity and perfect enantioselectivity,
especially when stereolabile aldehydes with a-alkyl substitu-
ents are targeted. The synthesis of a,b-chiral aldehydes by
standard intermolecular enamine catalysis [Eq. (1),
Scheme 1] does not necessarily permit modulation of the
diastereoselectivity and consequently prevents generalization
of this approach.[3] In contrast, the combination of iminium
and enamine catalysis [Eq. (2), Scheme 1] enables valuable
transformations, such as hydrohalogenation, hydrooxidation,
and aminooxidation, to take place with modular diastereose-
lectivity along with virtually perfect enantioselectivity.[4,5]
Nonetheless, the large amount of waste generated and,
more importantly, the limited scope of these reactions are
severe limitations to the development of sustainable and
general processes. From this point of view, the atom-
economical and waste-free asymmetric isomerization of
tetrasubstituted primary allylic alcohols constitutes a valuable
strategy to readily access a,b-chiral aldehydes [Eq. (3),
Scheme 1]. Mazet and co-workers recently reported the
highly enantioselective iridium-catalyzed asymmetric isomer-
ization of 3,3-disubstituted primary allylic alcohols to b-chiral
aldehydes.[6] Preliminary attempts to promote the corre-
sponding isomerization of primary allylic alcohols with a
tetrasubstituted olefin proved unsuccessful.[7] We hypothe-
sized that a combination of the iridium-catalyzed asymmetric
isomerization of 3,3-disubstituted primary allylic alcohols
with enamine catalysis in either a sequential or a tandem
approach would be a viable alternative, provided that
compatibility issues between the organometallic and organic
catalysts could be overcome [Eq. (4), Scheme 1].
To evaluate the feasibility of the overall process, we
conducted preliminary experiments with the isomerization
catalyst 1a (the Crabtree catalyst), (E)-4-methyl-3-phenyl-
pent-2-enol (3a) as a model substrate, the Hayashi–Jørgensen
enamine catalyst 2a, and one equivalent of vinyl sulfone 4 as
the electrophilic partner.[8,9] The reaction was performed in a
sequential manner. First, the organometallic precatalyst was
converted into the highly reactive dihydride intermediate by
applying the standard activation protocol using molecular
hydrogen, followed by degassing and subsequent addition of
the allylic alcohol at room temperature. After completion of
the isomerization reaction, the organic catalyst and the
electrophile were added directly to the same reaction vessel
(Scheme 2). Initially, 5 was obtained in low yield when the
reaction was conducted exclusively in THF. The addition of
CHCl3 and acetic acid had a beneficial effect on the efficiency
of the second step of the sequence.[10] Satisfyingly, under
optimized conditions, the sequential use of the organometallic
and organic catalysts proved to be feasible. As expected from
a parallel kinetic resolution under catalyst control, a 1:1
mixture of two diastereoisomers, syn-5a and anti-5a, was
obtained quantitatively, with 92% ee for syn-5a and 96% ee
for anti-5a (Scheme 2, entry 1).[11] Whereas similar results
were obtained with substrate 3b (syn-5b/anti-5b 1:1; syn-5b:
91% ee, anti-5b: 91% ee), use of the more biased allylic
Scheme 1. Complementary strategies to access acyclic a,b-chiral
aldehydes.
[*] A. Quintard, Prof. Dr. A. Alexakis, Dr. C. Mazet
Dꢀpartement de chimie organique, Universitꢀ de Genꢁve
Quai Ernest Ansermet 30, 1211 Genꢁve 4 (Switzerland)
Fax: (+41)22-379-3215
E-mail: alexandre.alexakis@unige.ch
clement.mazet@unige.ch
[**] This research was supported by the State Secretariat for Education
and Research and the Swiss National Science Foundation.
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.201007001.
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Angew. Chem. Int. Ed. 2011, 50, 2354 –2358

Scheme 2. Parallel kinetic resolution on the basis of an isomerization/a-alkylation sequence. [a] Yield of 5 as determined by 1H NMR spectroscopy.
[b] Determined by supercritical-fluid chromatography (SFC). Absolute configurations as shown. BArF =tetrakis[3,5-bis(trifluoro)phenyl]borate,
Cy =cyclohexyl, TMS=trimethylsilyl.
alcohol 5c (R1 = Me, R2 = tBu) led to an increase in diaste-
reoselectivity (syn-5c/anti-5c 1:4) along with a substantial
erosion in enantioselectivity for both diastereoisomers (syn-
5c: 66% ee, anti-5c: 47% ee). This last result indicates that
catalyst 2a and the transient racemic b-chiral aldehyde act
oppositely in the formation of the Michael adducts 5c
(catalyst control versus substrate control).
This observation prompted us to explore the possibility of
developing a kinetic resolution with the achiral iridium
catalyst 1a in combination with an
aldehydes 5c and the b-chiral aldehyde 6c were obtained in a
similar ratio (58:42) but with an increased diastereoisomeric
ratio (syn-5c/anti-5c 1.0:9.0; syn-5c: 95% ee, anti-5c:
65% ee) as well as an improved level of enantioselectivity
for the enriched aldehyde 6c (80% ee). Catalyst 2b[9f]
displayed similar reactivity and slightly higher selectivity
(Table 1, entry 4) and was subsequently used for all other
substrates surveyed. Not surprisingly, when the less biased
allylic alcohol 3b was employed (R1 = Cy, R2 = Ph), aldehydes
appropriate chiral enamine catalyst
to access enantiomerically enriched
Table 1: Resolution by sequential isomerization/enantioselective a alkylation.
b-chiral and a,b-chiral aldehydes in
a
single operation.[9h,12] Because
examples of kinetic resolution in
enamine catalysis are scarce, we
anticipated that this study might
also provide useful mechanistic
information on the C C bond-for- Entry
5/6
2
R1
R2
5/6
syn-5/anti-5
ee (6)
À
(yield of 5[%])[a]
(ee (syn-5)/
[%][c]
mation step at the a position in the
ee (anti-5) [%])[b]
second part of the sequence.[13]
1[d]
2
5c/6c
5c/6c
5c/6c
5c/6c
5b/6b
5d/6d
5e/6e
2a
2a
2a
2b
2b
2b
2b
Me
Me
Me
Me
Cy
tBu
60:40
(nd)
58:42
(43)
47:53
(31)
54:46
(32)
58:42
(43)
62:38
(38)
63:37
(42)
1.0:4.9
(95/62)
1.0:9.0
(95/65)
1.0:6.1
(50/85)
1.0:9.0
(95/65)
2.0:1.0
(94/90)
1.0:8.7
(nd/66)
1.0:7.3
(91/73)
45
Initial investigations were con-
ducted at room temperature with a
lower stoichiometry of vinyl sulfone
4 (0.5 equiv), with allylic alcohol 3c,
and with catalysts 1a and 2a
(Table 1, entry 1). The correspond-
ing a,b-chiral aldehydes 5c and the
enantiomerically enriched b-chiral
aldehyde 6c were obtained in a
60:40 ratio with anti-5c as the
major diastereoisomer (syn-5c/
anti-5c 1.0:4.9; syn-5c: 95% ee,
anti-5c: 62% ee). An ee value of
45% was measured for 6c. The
reaction was attempted at lower
temperatures, and the best results
were obtained at 08C (compare
tBu
80
3[e]
4
tBu
52
tBu
86
5
Ph
46 (32)[f]
63 (32)[f,g]
63 (15)[f,g]
6
Me
Me
SiMe2Ph
SiMe3
7
[a] The ratio was determined by 1H NMR spectroscopy. The yield given was determined after
chromatography on the basis of 4. [b] The diastereoisomeric ratio was determined by 1H NMR
spectroscopy of the crude reaction mixture. The ee values were determined by SFC or GC. [c] The
ee value was determined by SFC or GC. [d] The reaction was performed at 238C. [e] The reaction was
performed at À208C. [f] In parenthesis is the yield after chromatography. [g] In the reaction mixture, 5–
entries 1–3 in Table 1). a,b-Chiral 10% of desilylated 6 was observed. nd=not determined.
Angew. Chem. Int. Ed. 2011, 50, 2354 –2358
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Communications
5b were isolated in good yield (43% yield, i.e. max. 50%)
systematically with both enantiomers of 2a. Aromatic pri-
mary allylic alcohols 3a,b,f were converted into the desired
a,b-chiral aldehydes 5a,b,f in acceptable yields with con-
stantly high diastereoselectivity (even in the mismatched
case) and with virtually perfect enantioselectivity for the
major isomer (Table 2, entries 2–9). Substrate 3g, with a
combination of primary and secondary alkyl substituents, was
converted into the corresponding adduct 5g in reasonable
yield with excellent enantioselectivity, but with decreased
diastereoselectivity regardless of which enantiomer of cata-
lyst 2a was used (Table 2, entries 8 and 9). For the highly
biased substrates 3c and 3d, the corresponding a,b-chiral
aldehydes 5c,d could only be obtained with high levels of
diastereoselectivity with the matched catalyst 2a. When the
mismatched catalyst ent-2a was employed, the a-alkylation
reaction did not proceed at all. Interestingly, a substantial
erosion in enantioselectivity was observed when the tert-butyl
group was replaced with a much larger (dimethyl)phenylsilyl
or trimethylsilyl substituent (Table 2, entries 10, 12, and
13).[15] The use of catalyst 2b led to slightly diminished
diastereoselectivity along with a net increase in the enantio-
selectivity of the major diastereoisomer (Table 2, entry 14).
These last results provide additional evidence for conflicting
interactions between the enamine catalyst and the large
b substituents of the chiral intermediate during the installa-
tion of the second stereogenic center in the a position.
with reduced diastereoselectivity and increased enantioselec-
tivity (syn-5c/anti-5c 2.0:1.0; syn-5c: 94% ee, anti-5c:
90% ee). Aldehyde 6b was isolated in 32% yield with only
46% ee (Table 1, entry 5). Allylic alcohols with a large silyl
substituent (R2 = SiMe2Ph or SiMe3) exhibited higher levels
of performance, approaching that of 3b (compare entries 4, 6,
and 7 in Table 1). Additional preliminary experiments with
À
other electrophilic sources suggested that C C bond forma-
tion might be both the rate- and enantiodetermining step.[14]
In an effort to access high levels of molecular complexity
with exquisite diastereo- and enantioselectivity, we next
turned our attention to the combination of a chiral isomer-
ization catalyst with a chiral enamine catalyst. In initial
experiments on our model substrate 3a, the serine-derived
chiral isomerization catalyst 1b[6c] was combined with 2a in a
similar procedure to that developed with the achiral catalyst
1a (Table 2). When 1.0 equivalent of electrophile 4 was used,
anti-5c was obtained virtually as the sole product in 46%
yield with 99% ee (Table 2, entry 1). Adjustment of the
stoichiometry of vinyl sulfone 4 to better match the incom-
plete conversion of the iridium-catalyzed isomerization step
facilitated the isolation and purification of product anti-5a
without affecting the outcome of the catalytic sequence
(Table 2, entry 2).[6] This approach was systematically fol-
lowed in subsequent experiments. Under these conditions,
when the mismatched catalyst ent-2b was used, excellent
results were still observed (syn-5c/anti-5c 16:1; syn-5c:
99% ee).
The scope of the sequential reaction was next investigated
placing emphasis on the electrophilic component.[16] Under
À
optimized reaction conditions, a variety of C X bonds could
Next, to probe the general applicability of the method, the
substituents at C3 in the primary allylic alcohols 3 were varied
be formed during the enamine-catalyzed step of the reaction
sequence. The reaction products were obtained in moderate
yields but with constantly high
levels of diastereoselectivity and
remarkable
enantioselectivity
Table 2: Scope of the sequential isomerization/enantioselective a alkylation with a chiral iridium
catalyst in combination with a chiral organocatalyst.[a]
(Scheme 3). For example, a combi-
nation of the iridium-catalyzed iso-
merization step with catalyst 2c
and N-fluorodi(benzenesulfonyl)a-
mine (NFSI) delivered syn-7
smoothly as the major diastereo-
isomer (32:1) with 99% ee in 49%
yield after reduction to the alcohol.
Similarly, through the use of cata-
lyst 2b and N-chlorosuccinimide
(NCS) as a source of electrophilic
chlorine, syn-8 was obtained with
d.r. 24:1 and 99% ee. l-Proline
(2d) was found to be the catalyst
of choice for the reaction of 3a
with diethyl azodicarboxylate
(DEAD): anti-9 was obtained as
the major product with d.r. 24:1
and 99% ee.
Entry
5
R1
R2
4
2
Yield
[%][b]
syn-5/anti-5[c]
ee
[equiv]
[%][d]
1
2
3
4
5
6
7
8
9
10
11
12
13
14
5a
5a
5a
5b
5b
5 f
iPr
iPr
iPr
Cy
Ph
Ph
Ph
Ph
1.0
0.5
0.5
0.7
0.7
0.8
0.8
0.7
0.7
0.6
0.6
0.5
0.7
0.5
2a
2a
ent-2a
2a
ent-2a
2a
ent-2a
2a
ent-2a
2a
ent-2a
2a
2a
46 (46)
32 (63)
34 (68)
66 (94)
61 (87)
64 (80)
55 (69)
54 (78)
45 (60)
30 (49)
nd
1:19
1:49
16:1
1:32
13:1
1:13
9:1
99
99
99
98
98
99
99
99
99
99
nd
75
75
88
Cy
Ph
iPr
iPr
Me
Me
Me
Me
Me
Me
Me
p-OMeC6H4
p-OMeC6H4
Cy
Cy
tBu
5 f
5g
5g
5c
5c
5d
5d
5d
1:5
4:1
1:49
nd
1:24
1:24
1:13
tBu
SiMe2Ph
SiMe2Ph
SiMe2Ph
41 (82)
44 (64)
28 (55)
In conclusion, we have devel-
oped a catalytic reaction sequence
that exploits the compatibility
between recently discovered cat-
ionic iridium catalysts for the iso-
merization of primary allylic alco-
2b
[a] Reactions were carried out with 20 mol% of 2a or 2b with respect to 4. [b] Yield after chromatography
based on 3. The yield based on 4 is given in parenthesis. [c] The diastereoisomeric ratio was determined
by 1H NMR spectroscopy of the crude reaction mixture. [d] The ee value for the major diastereoisomer is
given. Values were determined by SFC or GC.
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Angew. Chem. Int. Ed. 2011, 50, 2354 –2358

Keywords: asymmetric catalysis · iridium ·
.
isomerization · one-pot reactions · organocatalysis
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believe our study will serve as a stepping stone for the design
of improved catalysts in related kinetic resolutions. A chiral
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excellent diastereo- and enantioselectivity. These products
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and the electrophile. We have also shown that the modular
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Received: November 8, 2010
Revised: December 12, 2010
Published online: February 3, 2011
Angew. Chem. Int. Ed. 2011, 50, 2354 –2358
ꢀ 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.angewandte.org
2357

Communications
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[14] When N-chlorosuccinimide or N-fluorodi(benzenesulfonyl)-
amine (0.5 equiv) was used as a source of electrophilic chloride
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nearly racemic form. These observations suggest that in the
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À
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[10] See the Supporting Information for details.
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[17] Preliminary attempts to carry out the catalytic reactions in a
tandem rather than sequential manner were successful with the
achiral catalyst 1a but not with the chiral catalyst 1b. These
studies are ongoing.
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