Highly enantioselective rhodium(I)-catalyzed carbonyl carboacylations initiated by C-C bond activation

Article abstract of DOI:10.1002/anie.201405834

The lactone motif is ubiquitous in natural products and pharmaceuticals. The Tishchenko disproportionation of two aldehydes, a carbonyl hydroacylation, is an efficient and atom-economic access to lactones. However, these reaction types are limited to the transfer of a hydride to the accepting carbonyl group. The transfer of alkyl groups enabling the formation of C-C bonds during the ester formation would be of significant interest. Reported herein is such asymmetric carbonyl carboacylation of aldehydes and ketones, thus affording complex bicyclic lactones in excellent enantioselectivities. The rhodium(I)-catalyzed transformation is induced by an enantiotopic C-C bond activation of a cyclobutanone and the formed rhodacyclic intermediate reacts with aldehyde or ketone groups to give highly functionalized lactones. Delivering the goods: Asymmetric carbonyl carboacylations of aldehydes and ketones provide access to functionalized bicyclic lactones. The rhodium(I)-catalyzed transformation is induced by an enantiotopic C-C bond activation of a cyclobutanone and the transient rhodacyclic adds across an appended carbonyl group to deliver the lactones in excellent enantioselectivities.

Full text of DOI:10.1002/anie.201405834

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Communications
DOI: 10.1002/anie.201405834
Synthetic Methods
Highly Enantioselective Rhodium(I)-Catalyzed Carbonyl
À
Carboacylations Initiated by C C Bond Activation**
Laetitia Souillart and Nicolai Cramer*
Abstract: The lactone motif is ubiquitous in natural products
and pharmaceuticals. The Tishchenko disproportionation of
two aldehydes, a carbonyl hydroacylation, is an efficient and
atom-economic access to lactones. However, these reaction
types are limited to the transfer of a hydride to the accepting
carbonyl group. The transfer of alkyl groups enabling the
Herein, we disclose such an asymmetric carbonyl carbo-
acylation which provides bicyclic lactones induced by a highly
À
enantioselective C C bond activation of cyclobutanones
À
(Scheme 1). The selective catalytic C C bond activation by
transition-metal catalysts is an intriguing strategy to access
À
formation of C C bonds during the ester formation would be
of significant interest. Reported herein is such asymmetric
carbonyl carboacylation of aldehydes and ketones, thus
affording complex bicyclic lactones in excellent enantioselec-
tivities. The rhodium(I)-catalyzed transformation is induced by
À
an enantiotopic C C bond activation of a cyclobutanone and
the formed rhodacyclic intermediate reacts with aldehyde or
ketone groups to give highly functionalized lactones.
L
actones are ubiquitous and very important structural motifs
in natural products and pharmaceuticals.[1] Despite numerous
lactonization methods,[1,2] efficient processes to access lac-
tones from uncommon precursors are highly desirable. Many
methods involve either the stoichiometric activation of the
hydroxy or the carboxy group. An atom-economic strategy is
a crossed intramolecular Tishchenko reaction, thereby dis-
proportionating two aldehyde moieties into a lactone.[3] The
same overall transformation can be achieved by carbonyl
hydroacylations operating by a different mechanism.[4] All the
processes are strictly limited to the transfer of a hydride to the
accepting carbonyl group [Eq. (1)]. However, the transfer of
carbon chains is highly desirable, thus enabling the formation
Scheme 1. Asymmetric carbonyl carboacylation strategy to provide
bicyclic lactones.
organometallic species for uncommon disconnections.[5] The
development of enantioselective variants lags behind and
most reports focus on asymmetric b-carbon-elimination
processes.[6,7] Insertions of rhodium(I) complexes into the
acyl–carbon bond of ketones are mechanistically different,
and strained ketones are a versatile substrate class.[8] Rho-
dium(I)-catalyzed carboacylations of olefins and alkynes for
conversion of a ketone substrate into a structurally more
complex product ketone have been reported,[9] including
recently published enantioselective variants.[10] These reac-
À
of valuable C C bonds during the lactonization event
[Eq. (2)].
À
À
tions involve a C H or C C bond-forming step by reductive
elimination, which is well established with rhodium catalysts.
À
In contrast, related C O bond formations are less common
for rhodium,[4b–f,11] and to the best of our knowledge rhodium-
catalyzed carbonyl carboacylations are elusive. Dong et al.
reported intramolecular asymmetric carbonyl hydroacyla-
tions providing Tishchenko-type lactone products.[4d–f] In this
case the reaction is initiated by an oxidative insertion of the
À
rhodium(I) catalyst into the acyl C H bonds, with subsequent
[*] L. Souillart, Prof. Dr. N. Cramer
Laboratory of Asymmetric Catalysis and Synthesis
EPFL SB ISIC LCSA
addition across the ketone carbonyl group (Scheme 1). In
contrast, our envisioned carbonyl carboacylation process
requires the opposite reaction order. First, an activation of
the acyl–carbon bond of the ketone moiety must proceed,
thus leaving the acyl–hydrogen bond of the aldehyde group
untouched. We hypothesized that the superior reactivity of
the cyclobutanone would enable such reactivity reversal, and
BCH 4305, 1015 Lausanne (Switzerland)
E-mail: Nicolai.cramer@epfl.ch
Homepage: http://isic.epfl.ch/lcsa
[**] This work is supported by the European Research Council under the
European Community’s Seventh Framework Program (FP7 2007–
2013)/ERC Grant agreement no. 257891. We thank Dr. R. Scopelliti
for X-ray crystallographic analysis of compounds 2j and 6.
À
À
overrule the common C H versus C C activation propen-
sity.[12] Moreover, this oxidative insertion reaction must
proceed in an enantioselective manner, thus setting the
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.201405834.
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quaternary stereogenic center of the products. The transient
rhoda(III)cyclopentanone will then add across the carbonyl
group to give, after reductive elimination, the desired lactone.
The investigation of the reaction was performed on the
model cyclobutanone 1a. Submitting 1a to [{Rh(cod)Cl}2] as
a rhodium(I) source in the presence of binap (L1) in 1,4-
dioxane at 1108C gave the desired lactone 2a in a promising
enantiomeric ratio of 93.2:6.8, albeit with poor conversion
and yield (Table 1, entry 1). Segphos-type ligands (L2–L4)
the yield to 25% (entry 11) and an increase of 208C gave the
indenyl acetic acid 4 in high yields (entry 12). This elimination
was not observed in catalytic reactions at 1108C. The bicyclic
lactones 2 were found to eliminate cleanly by simply heating
above 1308C in 1,4-dioxane.
Next, we explored the generality of the process with the
optimized reaction conditions. We first evaluated the influ-
ence of cyclobutanone substitution. Different aliphatic chains,
and aromatic and functional groups such as esters and ethers
are well tolerated, and the lactones 2 are obtained in good
yields and excellent enantioselectivities (Table 2, entries 1–5).
Electronic modifications of the aryl moiety, which influence
the electrophilicity of the aldehyde group, had no impact on
Table 1: Optimization of the asymmetric carbonyl carboacylation.[a]
[a]
À
Table 2: Scope of enantioselective C C activation of aldehydes 1.
Entry
1[d]
1
2
Yield e.r.[c]
[%][b]
Entry
[RhI]
L*
Changes to
conditions
Yield
[%][b]
e.r.[c]
76
80
78
99.3:0.7
1
2
3
4
5
6
7
8
[{Rh(cod)Cl}2]
[{Rh(cod)Cl}2]
[{Rh(cod)Cl}2]
[{Rh(cod)Cl}2]
[{Rh(cod)Cl}2]
[{Rh(cod)Cl}2]
[Rh(cod)(OH)]2
[Rh(cod)2]BF4
[{Rh(cod)I}2]
[{Rh(cod)Cl}2]
[{Rh(cod)Cl}2]
L1
L2
L3
L4
L5
L6
L4
L4
L4
L4
L4
–
–
–
–
–
–
–
–
8
30
93.2:6.8
99.2:0.8
99.5:0.5
99.4:0.6
99.5:0.5
99.8:0.2
n.d.
n.d.
0
n.d.
n.d.
45
94 (89)[d]
2
3
99.4:0.6
99.7:0.3
65
15
0
25
10
11
12
–
81 (3)[d]
25
at 908C
at 1308C
90 (4)[d]
[a] Reaction conditions: 0.05 mmol 1a, 2.50mmol [RhI], 3.00mmol L*,
0.25m in 1,4-dioxane at 1108C for 12 h. [b] Yield of 2a determined by
1H NMR spectroscopy using 1,3,5-trimethoxybenzene as an internal
standard. [c] Determined by HPLC with a chiral stationary phase.
[d] Yield of isolated product. cod=1,5-cyclooctadiene, n.d.=not deter-
mined.
4[d]
5[d]
6[d]
7
89
64
83
83
69
98.9:1.1
97.2:2.8
99.6:0.4
99.5:0.5
99.4:0.6
improved both the yield and enantioselectivity (entries 2–4).
DTBM-Segphos (L4) is the most efficient, thus affording the
lactone 2a in 94% yield with an excellent enantiomeric ratio
of 99.4:0.6 (entry 4). The reaction stalls at 70% conversion
with the related DTBM-MeOBiphep (L5; entry 5). Difluor-
phos (L6) provides outstanding enantioselectivities but low
yields (entry 6). Notably, the reaction is highly sensitive to the
counterion. For instance, other rhodium(I) precursors such as
[{Rh(cod)(OH)}2] or cationic [Rh(cod)2]BF4 do not give
competent catalysts (entries 7 and 8). Intriguingly, the use of
the iodide complex [{Rh(cod)I}2][13,14] totally changed the
reaction pathway, thus inducing formation of the aldol
8[d]
product 3[15] rather than engaging in C C bond cleavage
À
(entry 10). The optimal temperature window for the process is
rather narrow. Lowering the temperature by 208C decreased
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Table 2: (Continued)
Entry
1
2
Yield e.r.[c]
[%][b]
9
86
85
99.5:0.5
10
99.3:0.7
11
80
81
99.7:0.3
99.8:0.2
12[e]
Scheme 2. Mechanistic model for the rhodium-catalyzed asymmetric
carbonyl carboacylation and observed side-reactions.
13[e]
10
–
possible. Reluctant substrates cause extrusion of carbon
monoxide, giving E. Reductive elimination provides cyclo-
propane and an inactive Vaska-type complex.[16] In contrast,
competent substrates undergo insertion of the carbonyl group
into the rhodium(III)–alkyl bond to give the rhodabicycle C.
Reductive elimination forms the ester linkage leading to the
desired lactone 2 and closure of the catalytic cycle.
To illustrate further the complexity-generating potential
of the carbonyl carboacylation, the indenyl acetic acid 4,
formed at higher reaction temperature, was directly exposed
to iodine/sodium bicarbonate at ambient temperature
(Scheme 3). This one-pot iodolactonization provided the
[a] Reaction conditions: 0.10 mmol 1, 2.50 mmol [{Rh(cod)Cl}2],
6.00 mmol L4, 0.25m in 1,4-dioxane at 1108C for 12 h. [b] Yield of
isolated product. [c] Determined by HPLC with a chiral stationary phase.
[d] 2.50 mmol [{Rh(cod)Cl}2], 6.0 mmol L4, 0.25m in 1,4-dioxane at
1108C for 24 h. [e] 5.00 mmol [{Rh(cod)Cl}2], 12.0 mmol L4, 0.25m in
1,4-dioxane at 1108C for 48 h.
the reaction outcome (entries 6–10). We then aimed at
replacing the aldehyde with less reactive and more hindered
ketones. In this respect, activated ketones, such as the a-
ketoester 1l gave 2l, having two quaternary stereogenic
centers at the bridgehead positions, with similar enantiomeric
ratio (entry 11). Unbiased ketones such as the methyl ketone
1m are slightly less reactive and require increased catalyst
loading and prolonged reaction times to provide 2m in good
yield and excellent enantioselectivity (entry 12). In contrast,
the bulkier butyl ketone 1n is not a suitable substrate. While
Scheme 3. One-pot carboacylation/elimination/iodo lactonization for
the synthesis of 6.
À
the C C activation is still proceeding, the addition across the
carbonyl group fails. As a consequence, decarbonylation
occurs to form the cyclopropane 5 (entry 13).[8b,16] As the
concomitantly formed rhodium(I) carbonyl complex is cata-
lytically not competent, a single turnover is observed.
lactone 6 in 81% yield as a single diastereomer and excellent
enantioselectivity. Moreover, X-ray crystallography estab-
lished its absolute configuration.[17] In addition to the X-ray
structure of 2j,[17] it provides evidence for a constant enan-
Mechanistically, the carbonyl carboacylation is induced by
a coordination of the rhodium(I) catalyst to the cyclobuta-
none 1 (Scheme 2). At this stage, too strong of a Lewis-acidic
metal could induce enolization and subsequent intramolecu-
lar aldol addition, thus giving compound 3 as observed with
the [{Rh(cod)I}2] complex. A suitable rhodium complex
oxidatively adds selectively in one of the two enantiotopic
acyl–carbon bonds of the cyclobutanone to give the rhoda-
cyclopentanone B. Depending on the sterics and the electro-
philicity of the appended carbonyl group, two pathways are
À
tiotopicity of the insertion into the acyl C C bond of
cyclobutanones.
In summary, we demonstrated a rhodium-catalyzed car-
bonyl carboacylation process providing efficient access to the
benzo[c]oxepinone scaffold. The transformation is initiated
À
by a highly enantioselective C C bond activation, and
tolerates a broad range of substituents. The reaction is well-
suited for one-pot, complexity-generating downstream reac-
tions. Ongoing research is focused on the exploitation of
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À
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Experimental Section
Cyclobutanone (1a; 18.6 mg, 0.100 mmol), [{Rh(cod)(Cl)}2] (1.14 mg,
2.50 mmol), and (R)-DTBM-Segphos (7.08 mg, 6.00 mmol) were
weighted into an oven-dried vial equipped with a magnetic stir bar,
capped with a septum and purged with nitrogen. Dry 1,4-dioxane
(0.1 mL) was added and the mixture was degassed with three freeze-
pump-thaw cycles. The mixture was stirred for 20 min at 238C and
subsequently heated at 1108C. After 12 h, the reaction mixture was
cooled to 238C and purified by silica gel column chromatography
eluting with pentanes/ethyl acetate (10:1). Lactone 2a was isolated
colorless oil in 94% yield (17.5 mg) and 99.7:0.3 e.r.
Received: June 2, 2014
Published online: July 14, 2014
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À
Keywords: acylation · asymmetric catalysis · C C activation ·
lactones · rhodium
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