Enantioselective C-C bond activation of allenyl cyclobutanes: Access to cyclohexenones with quaternary stereogenic centers

Article abstract of DOI:10.1002/anie.200804281

(Chemical Equation Presented) Chiral rhodium(I) complexes activate allenyl tert-cyclobutanols efficiently through enantioselective insertion into a C-C σ bond of the cyclobutane (see scheme; cod = 1,5-cyclooctadiene, DTBM = 3,5-di-tert-butyl-4-methoxyphenyl). Ring expansion by this method produced cyclohexenones with quaternary stereogenic centers with excellent enantioselectivity. The catalyst loading can be decreased to just 0.1 mol% in rhodium.

Full text of DOI:10.1002/anie.200804281

Communications
DOI: 10.1002/anie.200804281
Asymmetric Catalysis
À
Enantioselective C C Bond Activation of Allenyl Cyclobutanes:
Access to Cyclohexenones with Quaternary Stereogenic Centers**
Tobias Seiser and Nicolai Cramer*
Dedicated to Professor Duilio Arigoni on the occasion of his 80th birthday
The transition-metal-catalyzed activation of carbon–carbon
s bonds has the potential to change organic synthesis
fundamentally.[1,2] However, the practical implementation of
We report herein a rhodium(I)-catalyzed desymmetriza-
tion of allenyl tert-cyclobutanols. The transformation leads to
highly substituted cyclohexenones with excellent enantiose-
lectivity. We hypothesized that the potential chelating ability
of an allenyl tert-cyclobutyl alcohol 3[8] would favor the
formation of a well-defined adduct 4 with a chiral rhodium
complex, which would ensure efficient transfer of the chiral
information of the ligand to the substrate in the enantiodis-
criminating step. As depicted in Scheme 1, simultaneous
this concept is still a major challenge; in particular, there are
[3]
À
few examples of enantioselective C C activation. Small
À
strained rings occupy a privileged position in C C activation
reactions because of the energy released by strain reduction in
ring-opening reactions.[4] This inherent strain and their
convenient accessibility make symmetric cyclobutane deriv-
atives a promising substrate class.[5] The desymmetrization of
such symmetric molecules is an excellent approach for the
construction of sterically demanding quaternary stereogenic
centers, as the chemical transformation does not take place
directly at a hindered, asymmetrically substituted carbon
atom.[6] The studies of Murakami and co-workers,[3d,e] who
used a highly enantioselective rhodium-catalyzed transfor-
mation to construct benzocyclopentanones and dihydrocou-
marines from cyclobutanones, and Uemura and co-work-
ers,[3a,b] who reported an asymmetric palladium-catalyzed
ring-opening arylation of aryl tert-cyclobutanols, demonstrate
the largely underexplored potential of this concept. For
example, the selective insertion of a suitable metal catalyst
Scheme 1. Mechanistic proposal for the formation of 6 and 7.
À
into one of the two enantiotopic C C bonds (a or b) of a
suitably substituted symmetrical tert-cyclobutanol 1 could
result in an organometallic species, which might subsequently
undergo a cyclization reaction to give the corresponding ring-
expanded cyclohexanone 2 [Eq. (1)].[7]
coordination of the RhI center to both the hydroxy group and
the proximal double bond of the allene should be favored. An
À
enantioselective insertion into the C C s bond of the cyclo-
butane leads to the seven-membered metallacycle 5, and
reductive elimination results in the formation of the methyl-
ene cyclohexanone 6 as the primary product. A metal- or
base-catalyzed isomerization of the exocyclic double bond of
6 can lead in a subsequent step to enone 7.
In a first experiment, the model substrate trans-1-(3,3-
dimethylallenyl)-3-methyl-3-phenylcyclobutanol (3a) was
heated to 808C in toluene in the presence of [{Rh(OH)-
(cod)}2] (2.5 mol%) and (R)-binap (L1; 6 mol%; binap = 2,2’-
bis(diphenylphosphanyl)-1,1’-binaphthyl). Under these con-
ditions, cyclohexanone 6 with an exocyclic double bond was
formed in 79% yield with 76% ee (Table 1, entry 1). How-
ever, during the course of the reaction, 6 isomerized slowly to
enone 7a, and a variable amount also decomposed to
unidentifiable products. The presence of auxiliary bases,
such as cesium carbonate or potassium phosphate, acceler-
ated the isomerization of the double bond and completely
suppressed decomposition pathways, so that the conjugated
product 7a was isolated in virtually quantitative yield without
loss of selectivity (Table 1, entries 5 and 7). Dioxane was also
tested as a solvent, but the use of dry, nonpolar aromatic
solvents (toluene or xylene) resulted in shorter reaction times
[*] T. Seiser, Dr. N. Cramer
Laboratory of Organic Chemistry, ETH Zurich
Wolfgang-Pauli-Strasse 10, HCI H 304, 8093 Zurich (Switzerland)
Fax: (+41)44-632-1328
E-mail: nicolai.cramer@org.chem.ethz.ch
Homepage: http://www.cramer.ethz.ch
[**] We thank the Swiss National Science Foundation (21-119750.01)
and Prof. Dr. E. M. Carreira for generous financial support, Solvias
AG for DTBM-MeObiphep, and Umicore AG & Co. KG for rhodium
salts. N.C. is grateful to the Fonds der Chemischen Industrie for a
Liebig Fellowship.
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.200804281.
9294
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Chemie
[a]
Table 1: Optimization of the reaction conditions.[a]
Table 2: Scope of the rhodium(I)-catalyzed C C activation.
À
Entry L*
3
R1/R2
7
Yield ee [%][c]
[%][b]
1
2
3
4
5
6
7
8
9
10
11[d]
12
13[d]
14[d]
15[d]
16
L3 cis-3a
L3 cis-3b
L5 trans-3b Et/Ph
L3 3c
L5 3d
L5 3e
L3 cis-3 f
L5 trans-3 f Me/iPr
L3 cis-3g tBu/Me
L5 trans-3g Me/tBu
L3 trans-3h Ph/CH2OBn
L5 cis-3h
L3 cis-3i
L5 trans-3i vinyl/Ph
Ph/Me
Ph/Et
7a
7b
7b
7c
97
99
99
88
99
97
80
91
81
80
89
99
85
74
65
94
96 (R)
97 (R)
96 (R)
95 (R)
95 (R)
94 (R)
94 (R)
97 (R)
96 (R)
99 (R)
97 (S)
94 (S)
90 (R)
90 (R)
91 (R)
85 (S)
4-ClC6H4/Me
Me/4-MeC6H4 7d
Me/2-naphthyl 7e
Entry
L* Base
Solvent
Yield [%][b] ee [%][c]
1[d]
2[d]
3
4
5
L1
L1
–
–
toluene
dioxane
79 (6)
<5
28
90
99
71 (6)
79
83
58
99
76 (S)
–
iPr/Me
7 f
7 f
7g
7g
7h
7h
7i
7i
7j
7k
L1 Cs2CO3 dioxane, 5 % H2O
L1 Cs2CO3 dioxane
L1 Cs2CO3 toluene
L1 NEt3
L1 K3PO4
73 (S)
73 (S)
80 (S)
79 (S)
79 (S)
77 (S)
43 (R)
83 (S)
85 (S)
96 (S)
95 (R)
90 (R)
6
7
toluene
toluene
CH2OBn/Ph
Ph/vinyl
8[d,e]
9[d,f]
10
11
12
13
14[d,g]
L6 Cs2CO3 toluene
L7 Cs2CO3 toluene
L2 Cs2CO3 toluene
ent-L4 Cs2CO3 toluene
L3 Cs2CO3 toluene
L5 Cs2CO3 toluene
L5 Cs2CO3 toluene
L5 3j
L5 3k
Ph/2-pyridyl
Ph/H
92
95
92
99
17[d]
18
L3
L5
91
93
93 (R)
92 (R)
[a] Reaction conditions: 3a (0.1 mmol), base (1.5 equiv), [{Rh(OH)-
(cod)}2] (2.5 mol%), L* (6.0 mol%), 0.25m, 808C, 3–24 h. Bn=benzyl,
cod=1,5-cyclooctadiene,
DTBM=3,5-di-tert-butyl-4-methoxyphenyl.
[b] Yield of the isolated product 7a. [c] Enantioselectivities were
determined by HPLC on a chiral stationary phase. [d] The reaction was
carried out at 1008C. [e] L6: 12 mol%. [f] The reaction was carried out
with [{Rh(OAc)(C2H4)2}2] (2.5 mol%). [g] [{Rh(OH)(cod)}2]: 0.05 mol%,
L5: 0.12 mol%.
19[d]
L5
L3
93
57
93 (R)
89 (S)
and higher enantioselectivities (Table 1, entries 2–5). We
screened a range of chiral ligands and observed complete
conversion and moderate to good yields with the phosphor-
amidite ligand (R,R,R)-L6[9] and (À)-dolefine[10] (L7; Table 1,
entries 8 and 9). However, 7a was formed with lower
enantioselectivity (77% ee with L6 and 43% ee with L7)
than that observed with (R)-binap in the best case (80% ee;
Table 1, entry 5). The use of biaryl phosphines with a
narrower dihedral angle[11] than that in binap led to an
increase in enantioselectivity. Thus, enone 7a was formed
with 83% ee with (R)-MeObiphep (L2) and 85% ee with (R)-
segphos (L4; Table 1, entries 10 and 11). A further significant
improvement in selectivity was observed with the sterically
demanding homologues (R)-DTBM-MeObiphep (L3) and
20[d]
[a] Reaction conditions:
3 (0.1 mmol), Cs2CO3 (1.5 equiv), [{Rh-
(cod)(OH)}2] (2.5 mol%), (R)-L3 or (S)-L5 (6.0 mol%), 0.4 mL toluene,
808C, 3 h. [b] Yield of the isolated product 7. [c] Enantioselectivities were
determined by HPLC on a chiral stationary phase. [d] The reaction was
carried out at 1008C for 16 h. Cy=cyclohexyl.
mined by the ligand employed and should therefore be largely
independent of the substitution pattern at the 3-position of
the cyclobutanol substrate.
(S)-DTBM-segphos
(L5;
DTBM = 3,5-di-tert-butyl-4-
We next explored the scope of the rhodium-catalyzed
rearrangement under the optimized reaction conditions
(Table 2). A variety of aromatic substituents are tolerated
(Table 2, entries 1–6), as well as sterically demanding alkyl
substituents (Table 2, entries 7–10). Substrates with function-
alized substituents (Table 2, entries 11 and 12) also react
smoothly with very good selectivities. However, coordinating
groups, such as a 2-pyridyl substituent (Table 2, entry 15) or a
vinyl group (Table 2, entries 13 and 14), slow the reaction
down significantly, so that a higher temperature (1008C) and a
longer reaction time (16 h) are required to ensure complete
conversion. Remarkably, the cyclobutanol derivative 3k,
methoxyphenyl), which afforded 7a with 96 (L3) and
95% ee (L5; Table 1, entries 12 and 13). Remarkably, the
required catalyst amount – starting with 2.5 mol% [{Rh(OH)-
(cod)}2] – could be reduced to 0.1 mol% rhodium without any
loss in yield and only a minor decrease in enantioselectivity
(90 instead of 95% ee, Table 1, entry 14).
The isomeric cyclobutanol cis-3a was transformed into the
opposite enantiomer (R)-7a with excellent enantioselectivity
under the standard conditions with (R)-L3 as the ligand
(Table 2, entry 1; compare Table 1, entry 12). This result
À
shows that the enantiotopic C C bond activated is deter-
Angew. Chem. Int. Ed. 2008, 47, 9294 –9297
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Communications
which has just one substituent in the 3-position (R2 = H;
The cyclohexenone (S)-7a (21.7 mg, 95%, 96% ee) was obtained as a
colorless oil.
Table 2, entry 16), did not undergo potential b-hydride
elimination and was converted smoothly into the correspond-
ing cyclohexenone. However, the resulting enone 7k was
formed with slightly lower enantioselectivity (85% ee).
Allenes cis-3l and trans-3l, which have a cyclic substituent
in place of the geminal methyl groups in substrates 3a–k, also
underwent ring expansion to give the desired cyclohexenone
under these conditions (Table 2, entries 17 and 18). The
terminal allenes 3m and 3n were converted into the
corresponding 3-methylcyclohexenones 7m and 7n in com-
parable yields and selectivities (Table 2, entries 19 and 20).
The absolute configuration of the products was deter-
mined by comparison of the optical rotation of the known
derivative 7o.[12] The ring expansion of cyclobutanol trans-3o
gave cyclohexenone (R)-7o with 97% ee with the ligand (S)-
DTBM-MeObiphep, whereas the treatment of cis-3o under
identical conditions resulted in the formation of (S)-7o
(Scheme 2).
Received: August 29, 2008
Published online: October 29, 2008
À
Keywords: asymmetric catalysis · C C activation · cyclobutanes ·
.
rhodium · ring expansion
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[{Rh(cod)(OH)}2] (2.5 mol%), (S)-L3 (6.0 mol%), 0.4 mL toluene,
1008C, 3 h.
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À
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À
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Experimental Section
The cyclobutanol trans-3a (22.8 mg, 0.100 mmol), cesium carbonate
(49.0 mg, 0.150 mmol), [{Rh(cod)(OH)}2] (1.14 mg, 2.50 mmol), and
(R)-DTBM-MeObiphep (L3; 6.90 mg, 6.00 mmol) were weighed into
an oven-dried vial equipped with a magnetic stir bar. The vial was
then sealed with a rubber septum and flushed with nitrogen. Dry
toluene (0.4 mL) was added, and the reaction mixture was degassed
through three freeze–pump–thaw cycles, stirred at 238C for 10 min,
and then heated for 3 h in an oil bath preheated to 808C. When TLC
analysis indicated complete conversion, the reaction mixture was
cooled to 238C and purified directly on silica gel (CH2Cl2, Rf = 0.29).
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