Rhodium-catalyzed enantioselective 1,2-addition of aluminum organyl compounds to cyclic enones

Article abstract of DOI:10.1002/anie.200701087

(Chemical Equation Presented) A question of the ligand: The chemoselectivity of the rhodium-catalyzed addition of AlMe₃ to cyclohex-2-enone is guided by the type of ligand used. Whereas use of an achiral {Rh(cyclooctadiene)} complex leads to a 1,4-addition, use of a {Rh(binap)} species gives highly enantioselective 1,2-additions. This unprecedented reaction can be used for stereoselective 1,2-methylations and arylations of cyclic enones (see scheme).

Full text of DOI:10.1002/anie.200701087

Communications
DOI: 10.1002/anie.200701087
Asymmetric Catalysis
Rhodium-Catalyzed Enantioselective 1,2-Addition of Aluminum
Organyl Compounds to Cyclic Enones
Jürgen Siewert, RenØ Sandmann, and Paultheo von Zezschwitz*
Dedicated to Professor Armin de Meijere
Among carbon–carbon bond-forming processes the 1,2-addi-
tion of metal organyl compounds to carbonyl moieties is one
of the major reactions in organic synthesis. In the last decade
methods based on transition-metal catalysis have been
developed that allow stereoselective reactions with a broad
spectrum of aldehydes.[1] However, ketones and especially
enones still are problematic substrates for which only few
catalyst systems are suitable.[2] In contrast, asymmetric 1,4-
additions of a variety of organometallic compounds to enones
by copper, palladium, and rhodium catalysis are well-estab-
lished.[3] During our studies towards the total synthesis of the
natural product spirodionic acid[4] we envisaged such Rh-
catalyzed enantioselective Michael additions to cyclic enones,
yet employing aluminum organyl compounds, which—to the
best of our knowledge—have hitherto not been used in
combination with Rh catalysts.[5]
The formation of 3 from 2 appears to be the first example
of an enantioselective Rh-catalyzed 1,2-addition to an enone;
thus, the reaction conditions were optimized.[7,8] On lowering
the temperature to 08C or ꢀ208C the enantioselectivity was
only slightly increased to 98% ee, while the reaction was
significantly retarded (Table 1, entries 1–3). Variation of the
Table 1: Variation of reaction temperature and RhI source.[a]
Entry
Catalyst
T [8C]
t [h][b]
Yield [%][c]
ee [%][d]
1
2
[{Rh(cod)Cl}2]
[{Rh(cod)Cl}2]
RT
0
0.5
3.8
26
5.0
5.0
2.0
0.5
2.5
1.5
84
85
47[e]
81
77
97
78
61
4
96
97
98
99
98
>99
97
98
3[{Rh(cod)Cl}
]
2
ꢀ20
4
5
6
7
8
9
[Rh(cod)2]BF4
0
[Rh(cod)(acac)]
[{Rh(cod)OMe}2]
[{Rh(cod)OMe}2]
[{Rh(cod)OMe}2][f]
[{Rh(cod)OMe}2][g]
0
0
RT
RT
RT
Cyclohex-2-enone (2) was treated with [{Rh(cod)Cl}2]
(cod = cyclooctadiene) and an equimolar amount of AlMe3 to
give the desired 3-methylcyclohexanone (1, Scheme 1). To
perform the transformation enantioselectively, in situ pre-
n.d.
[a] 2.5 mol% of dimeric or 5 mol% of monomeric Rh precatalyst,
6 mol% (S)-binap, THF, 0.5 h, RT, then 2, AlMe3 (1.0 equiv). [b] Time
until full consumption of 2. [c] Yield of 3 determined by GC. [d] Deter-
mined by chiral GC. [e] 49% conversion. [f] 0.5 mol% precatalyst and 1
mol% binap. [g] 0.05 mol% precatalyst and 0.1 mol% binap. n.d.=not
determined.
precatalyst led to similar results when starting from com-
plexes with noncoordinating or bidentate counterions
(Table 1, entries 4 and 5), yet significant improvements were
achieved when using [{Rh(cod)OMe}2], thus increasing the
yield to 97% with 99% ee (entry 6). In a second set of
experiments the catalyst loading was reduced, which still gave
good results with 1 mol%, but almost no conversion with
0.1 mol% (Table 1, entries 7–9).
Furthermore, the influence of the solvent was examined,
revealing that THF is the best choice. With other ethers the
yield decreased in the order 1,2-dimethoxyethane > diox-
ane > Et2O; hydrocarbons such as toluene proved unsuitable
owing to significant background reactivity.[9] To gain insight
into the sudden change of the reaction course, various mono-
and bidentate phosphine ligands were tested (PPh3, PnBu3,
dppe, dppb, diop),[10] yet none of them led to the formation of
the 1,4-adduct 1 or the 1,2-adduct 3 in more than 10% yield.
Furthermore, no conversion occurred in the presence of binap
when omitting the Rh precatalyst, thus proving catalysis by a
Rh–binap species.
Scheme 1. Rhodium-catalyzed additions of AlMe3 to 2 (yields deter-
mined by GC analysis).
pared [{Rh[(S)-binap]Cl}2]was used next; yet the use of this
complex led to a dramatic change of the reaction course.
Highly selective 1,2-addition was observed and 1-methylcy-
clohex-2-enol (3) was formed with 96% ee. Since this com-
pound is a known aggregation pheromone of the Douglas-fir
beetle, previously only available in multistep syntheses,[6] the
R configuration could be assigned to the product 3 based on
the reported optical rotation.
[*] J. Siewert, R. Sandmann, Dr. P. von Zezschwitz
Institut für Organische und Biomolekulare Chemie der Georg-
August-Universität Göttingen
Tammannstrasse 2, 37077 Göttingen (Germany)
Fax : (+49)551-39-9475
E-mail: pzezsch@gwdg.de
Only one methyl group of AlMe3 is transferred under
these conditions, as use of less than one equivalent of the
alane resulted in an incomplete conversion (Table 2, entry 1).
Homepage: http://www.org.chemie.uni-goettingen.de/zezschwitz/
Supporting information for this article is available on the WWW
under http://www.angewandte.org or from the author.
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Chemie
Table 2: Variation of the methylaluminum reagent in the synthesis of 3.[a]
cycloheptenone (6) can be transformed into the respective
allyl alcohol in good yield while maintaining the high
enantioselectivity (Table 3, entry 4). On the contrary, cyclic
five-membered enones are problematic substrates since their
1,2-adducts are very prone to dehydration and thus formation
of volatile dienes. With cyclopentenone (7), only a 10% yield
was achieved, and this yield was only slightly increased to
28% by using the geminal-dimethylated cyclopentenone 8
(Table 3, entries 5 and 6). This result is also a consequence of
the formation of oligomeric compounds as verified by GC–
MS analyses. Presumably, small amounts of aluminum
enolates arise from catalyzed or uncatalyzed 1,4-addition
reactions and then undergo oligomerizing Michael additions
with additional amounts of starting material.[5a,d] Moreover,
the catalytic system proved to be less suitable for the
transformation of acyclic enones (9, entry 7) and aryl ketones
(10, entry 8).
Besides methylation, this method can also be used for 1,2-
arylations.[13] The employment of mixed arylalanes, prepared
in situ from AlMe2Cl and the respective Grignard reagents,
gave access to 1-arylcyclohex-2-enols 11 with only trace
amounts of methylated 3 (Scheme 2). Owing to their insta-
bility, the crude allyl alcohols 11 were immediately oxidized to
give diastereomerically pure epoxides 12 in fair yields with
high enantioselectivity.[12]
Entry
Reagent
Equiv
t [h]
Yield [%][b]
1
2
AlMe3
AlMe2Cl
2OMe
AlMeCl2
0.33
1.0
1.0
1.0
1.0
4
2
1
33[c]
60
3AlMe
4
5
47[d]
30
DABCO·2AlMe3
1.75[e]
98
[a] 2.5 mol% [{Rh(cod)OMe}2], 6 mol% (S)-binap, THF, 0.5 h, RT, then
2, alane, RT. [b] Yield of 3 determined by GC. [c] 74% conversion. [d] 50%
conversion. [e] Performed at 08C.
Dimethylaluminum chloride and methoxide could be
employed in this transformation, but these compounds gave
inferior results, while the respective dichloride led to decom-
position (Table 2, entries 2–4). In contrast, the quite air-stable
and easily usable Lewis acid/base pair obtained from 1,4-
diazabicyclo[2.2.2]octane (DABCO) and two equivalents of
[11]
AlMe3 gave an excellent yield of 3 and thus could be used
instead of the pure, pyrophoric AlMe3 (Table 2, entry 5).
Under the optimized conditions the transformation of 2
furnished the natural product 3 in 84% yield of isolated
product with an excellent ee value of 98% (Table 3, entry 1).
Table 3: Variation of substrates.[12]
Entry
Enone
T [8C], t [h]
Yield [%][a]
ee [%][b]
1
2
cyclohex-2-enone (2)
0, 2
60, 3.5
84
86
98
99
1
939RT, 2.5
3
Scheme 2. 1,2-Arylation of cyclohex-2-enone (2) with subsequent epox-
idation (yields refer to amounts of isolated products over the two
steps). m-CPBA=m-chloroperbenzoic acid.
4
5
cyclohept-2-enone (6)
cyclopent-2-enone (7)
0!RT, 374
0!RT, 2
98
10
n.d.
6
RT, 1
28[c]
>95
Regarding the mechanism of these transformations, an
initial transmetalation of the organic residue from aluminum
to rhodium seems likely, which is supported by the observed
higher reactivity of [{Rh(cod)OMe}2]as precatalyst compared
to [{Rh(cod)Cl}2]. A similar transmetalation was proven to be
the first step in the Rh-catalyzed 1,4-addition of arylboronic
acids.[3d] However, the reaction clearly would not just
7
8
RT, 3.5
66, 8
49
7
propiophenone (10)
14[d]
54
[a] Yield of isolated product. [b] Determined by chiral GC. [c] 50%
conversion. [d] Determined by GC analysis, 14% conversion. n.d.=not
determined.
ꢀ
continue by 1,2-addition of an assumed Rh Me species to
the enone, as no adduct 3 was obtained when adding enone 2
to a prestirred mixture of [{Rh(cod)OMe}2], binap, and
AlMe3 in a 0.5:1:1 ratio.
To evaluate the scope of the catalytic system, various
substitution patterns of model substrate 2 were screened.
No 1,2-adduct was formed when starting from 2- or 3-
methylcyclohex-2-enone. Geminal methyl groups at C-4 or C-
5 of the six-membered ring are tolerated, yet the reactivity of
these substrates is significantly lower, thus requiring higher
reaction temperatures to give the 1,2-addition products in
high (from 4) or moderate (from 5) yields with excellent
enantioselectivity (Table 3, entries 2 and 3). Furthermore,
In summary, we have developed the first highly enantio-
selective 1,2-additions to cyclic enones that lack substituents
in the a-position. This transformation was achieved by
combining the readily accessible rhodium/binap catalyst
system with economically attractive alanes. The thus formed
enantiomerically highly enriched allyl alcohols are interesting
intermediates for versatile synthetic applications. Work is
now in progress to precisely elucidate the mechanism of this
reaction, which should provide the key for further enlarge-
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Communications
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Received: March 12, 2007
Published online: August 14, 2007
Keywords: 1,2-addition · alanes · asymmetric catalysis · enones ·
.
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[12]See the Supporting Information for experimental procedures,
determination of the ee values, and analytical data of the new
compounds.
[13]Other trialkyl aluminum reagents turned out to be unsuitable;
no conversion occurred with AliBu3 while the use of AlEt3
mainly afforded cyclohexanone.
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