Rhodium-catalyzed asymmetric [2+2+2] cyclization of 1,6-enynes and aldehydes

Article abstract of DOI:10.1002/chem.201102418

Asymmetric catalysis: The rhodium-catalyzed asymmetric [2+2+2] cyclization of 1,6-enynes and aldehydes was achieved by using a cationic rhodium(I)/(R)-binap complex as a catalyst (see scheme; cod=1,5-cyclooctadiene). Coordination of the substrate heteroatom to the cationic rhodium plays an important role in this cyclization reaction.

Full text of DOI:10.1002/chem.201102418

DOI: 10.1002/chem.201102418
Rhodium-Catalyzed Asymmetric [2+2+2] Cyclization of 1,6-Enynes and
Aldehydes
Mana Ishida,[a] Yu Shibata,[a] Keiichi Noguchi,[b] and Ken Tanaka*[a]
The transition-metal-catalyzed [2+2+2] cyclization of 1,6-
enynes and alkynes is a valuable method to construct com-
plex cyclic frameworks in a single reaction step.[1,2] Asym-
metric variants of this reaction have been developed by
using cationic rhodium(I)/chiral bisphosphine complexes as
catalysts.[3] However, the successful transition-metal-cata-
lyzed [2+2+2] cyclizations of 1,6-enynes and unsaturated
compounds excluding alkynes are relatively rare.[4–7] In 2008,
two research groups, including ours, independently discov-
ered the transition-metal-catalyzed [2+2+2] cyclization of
1,6-enynes and carbonyl compounds.[4–6,8] Our research
group developed the cationic rhodium(I)/H8-binap complex
catalyzed asymmetric [2+2+2] cyclization of 1,6-enynes and
electron-deficient ketones, which produced bicyclic hetero-
cycles in high yields with high enantiomeric excess (ee;
Scheme 1).[4]
product between 1a and 2a, were generated (Scheme 2). On
the other hand, we have recently reported the asymmetric
cyclization of g-alkynylaldehydes with aldehydes.[9] In this
reaction, chelating alkoxylacetaldehydes are suitable reac-
Scheme 2. Rhodium-catalyzed reactions of 1,6-enyne 1a and aldehydes
2a and 2b; Bn=benzyl.
tion partners, whereas unfunctionalized aldehydes failed to
react with g-alkynylaldehydes. Therefore, the reaction of 1a
and commercially available benzyloxylacetaldehyde (2b)
was examined, which revealed that the desired achiral cross-
reaction product 3ab was obtained in good yield at room
temperature (Scheme 2).
To develop an asymmetric variant of this [2+2+2] cycliza-
tion, the reaction of 1,6-enyne 1b, possessing the monosub-
stituted alkene moiety, and 2b was investigated in the pres-
Scheme 1. Rhodium-catalyzed asymmetric [2+2+2] cyclization of 1,6-
enyne 1a and a-ketoester.
ence of
a
cationic rhodium(I)/(R)-binap complex
(10 mol%). After 16 h at room temperature, the desired
ketone 3bb was obtained in 88% yield with 95% ee
(Table 1, entry 1). The effect of chiral bisphosphine ligands
(Scheme 3) was then examined (Table 1, entries 1–8), which
revealed that biaryl bisphosphines are suitable ligands (en-
tries 1–5), and the use of (R)-binap gives both high product
yield and ee value (entry 1). The catalyst loading could be
reduced to 5 mol% without erosion of the product ee value,
although the product yield decreased within acceptable
levels (Table 1, entry 9).
Thus, the scope of the asymmetric [2+2+2] cyclization of
1,6-enynes with aldehydes was explored by using 5 mol% of
the cationic rhodium(I)/(R)-binap complex at room temper-
ature (Scheme 4). Not only enyne 1b possessing the methyl
group at the alkyne terminus, but also 1,6-enynes 1c and 1d
possessing the aryl group at the alkyne terminus reacted
with 2b in good yields with high ee values, although an
excess of 2b was used. The absolute configuration of ketone
(+)-3db was unambiguously determined to be R by the
anomalous dispersion method (Figure 1).[10] Not only terti-
ary stereocenters but also a quaternary stereocenter could
The Louie group developed the nickel-catalyzed [2+2+2]
cyclization of 1,6-enynes and electron-rich carbonyl com-
pounds.[6] In this reaction, not only ketones, but also alde-
hydes are able to react with 1,6-enynes. We also examined
the reaction of 1,6-enyne 1a and aldehyde 2a in the pres-
ence of a cationic rhodium(I)/rac-binap complex. However,
homo-reaction products of 1a, not the desired cross-reaction
[a] M. Ishida, Y. Shibata, Prof. Dr. K. Tanaka
Department of Applied Chemistry
Graduate School of Engineering
Tokyo University of Agriculture and Technology
Koganei, Tokyo 184-8588 (Japan)
Fax : (+81)42-388-7037
E-mail: tanaka-k@cc.tuat.ac.jp
[b] Prof. Dr. K. Noguchi
Instrumentation Analysis Center
Tokyo University of Agriculture and Technology
Koganei, Tokyo 184-8588 (Japan)
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/chem.201102148.
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Chem. Eur. J. 2011, 17, 12578 – 12581

COMMUNICATION
Table 1. Screening of reaction conditions for rhodium-catalyzed asym-
metric [2+2+2] cyclization of 1,6-enyne 1b and aldehyde 2b.[a]
Entry
Ligand
Catalyst [mol%]
Yield [%][b]
ee [%]
1
2
3
4
5
6
(R)-binap
10
10
10
10
10
10
10
10
5
88
89
72
75
77
55
7
95 (+)
91 (+)
89 (+)
95 (+)
96 (+)
8 (À)
(R)-segphos
(R)-H8-binap
(R)-tol-binap
(R)-xyl-binap
ACHTUNGTRENNUNG
7[c]
8[c]
9[d]
T
9 (+)
A
11
72
21 (À)
95 (+)
[a] [Rh
(cod)2]BF4
(0.010 mmol;
cod=1,5-cyclooctadiene),
ligand
(0.010 mmol), 1b (0.10 mmol), 2b (0.11 mmol), and (CH2Cl)2 (2.0 mL)
were used. [b] Yield of the isolated product. [c] [RhACTHUNTRGNE(UNG nbd)2]BF4 was used.
[d] 1b (0.20 mmol) and 2b (0.22 mmol) were used.
Scheme 3. Structures of chiral bisphosphine ligands.
be constructed, and ketone 3eb was obtained with an excel-
lent ee value. The present asymmetric [2+2+2] cyclization is
not limited to the nitrogen-linked 1,6-enynes. Oxygen- and
carbon-linked 1,6-enynes 1 f–i were also suitable substrates
for this process. Next, we examined the scope of aldehydes.
Unfortunately, 3-(benzyloxy)propionaldehyde (2c) failed to
react with nitrogen- and oxygen-linked 1,6-enynes 1b and
1 f. However, interestingly, carbon-linked 1,6-enyne 1g
Scheme 4. Rhodium-catalyzed asymmetric [2+2+2] cyclization of 1,6-
enynes 1b–i and aldehydes 2a–g. [RhACHTNUGRTNEUNG(cod)2]BF4 (0.010 mmol), (R)-binap
(0.010 mmol), 1b–i (0.20 mmol), 2a–g (0.22–0.60 mmol), and (CH2Cl)2
(2.0 mL) were used. Cited yields are of isolated products. [a] [Rh-
AHCTUNTGREGUN(NN cod)2]BF4 (0.020 mmol), (R)-binap (0.020 mmol), 1g (0.40 mmol), and
2c (0.44 mmol) were used.
smoothly reacted with 4-(benzyloxy)butylaldehyde (2d) as
well as with 2c. Furthermore, unfunctionalized aldehydes 2a
and 2e–g could equally be employed.[11] Another carbon-
linked 1,6-enyne 1h also reacted with unfunctionalized alde-
Figure 1. ORTEP diagram of (R)-(+)-3db with ellipsoids at 30% proba-
bility.
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K. Tanaka et al.
hydes 2e and 2 f to give the corresponding [2+2+2] cycliza-
tion products with good yields and ee values.
um.[13] Intermediate D, which would give cross-reaction
products 3, might be predominantly generated as a result of
the stable five-membered chelation of 2b to rhodium. In
contrast, 1,6-enyne 1 reacts with rhodium in the presence of
2c to generate intermediate C, which would give homo-reac-
tion products, not intermediate E exclusively, presumably
due to the labile six-membered chelation of 2c to rhodium.
In the case of weakly coordinating carbon-linked 1,6-enynes
1g–i, the aldehyde coordination to rhodium followed by in-
sertion to the rhodacyclopentene may not be hampered.
The cyclic compound, obtained from this asymmetric cyc-
lization reaction, may serve as a useful chiral building block
(Scheme 8). Treatment of 3cb with hydrazine afforded spiro
compound 4, with three consecutive stereogenic centers, in
high yield as a single diastereomer.[14]
Scheme 5 depicts our proposed reaction mechanism for
this [2+2+2] cyclization. 1,6-Enyne 1 reacts with rhodium to
generate the rhodacyclopentene intermediate A. Insertion
of aldehyde 2 into intermediate A generates intermediate
B.[12] b-Hydride elimination followed by reductive elimina-
tion of rhodium gives dienone 3.
Scheme 5. Proposed reaction mechanism.
Consistent with the above pathway, the reactions of both
nitrogen- and carbon-linked 1,6-enynes 1b and 1g with deu-
terium-labeled aldehyde [D]2b led to selective and quantita-
tive incorporation of deuterium in the methyl group at-
tached to the chiral center of the products [D]3bb and
[D]3gb (Scheme 6).
Scheme 8. Transformation of reaction product 3cb.
In conclusion, the first asymmetric [2+2+2] cyclization of
1,6-enynes and aldehydes was achieved by using a cationic
rhodium(I)/(R)-binap complex as a catalyst, although this
ring closure generally cannot be applied to the reaction of
heteroatom-linked 1,6-enynes with aldehydes without an
oxygen functionality. Coordination of the substrate heteroa-
tom to the cationic rhodium plays an important role in this
cyclization reaction. Further exploitation of the rhodium-
catalyzed enyne cyclization reactions is underway in our lab-
oratory.
Scheme 6. Deuterium labeling studies.
Experimental Section
A possible explanation for the significant difference of re-
activity between 2b and 2c in the reactions with heteroa-
tom-linked 1,6-enynes 1b and 1 f is shown in Scheme 7. 1,6-
Enyne 1 reacts with rhodium in the presence of 2b to gener-
ate an equilibrium mixture of intermediates C and D
through the bidentate coordination of 1 and 2b to rhodi-
Representative procedure (Scheme 4, (+)-3bb): Under an argon atmos-
phere, (R)-binap (6.2 mg, 0.010 mmol) and [RhACHTUNRGTNEUNG(cod)2]BF4 (4.1 mg,
0.010 mmol) were dissolved in CH2Cl2 (2.0 mL) and the mixture was
stirred at RT for 5 min. H2 was introduced to the resulting solution in a
Schlenk tube. After stirring at RT for 30 min, the resulting mixture was
evaporated to dryness. A solution of 1b (52.6 mg, 0.200 mmol) and 2b
(33.0 mg, 0.220 mmol) in (CH2Cl)2 (2.0 mL) was added to the residue at
RT. The mixture was stirred at RT for 16 h. The resulting solution was
concentrated and purified by
a preparative TLC (hexane/EtOAc/
CH2Cl2 =3:1:1), which gave (+)-3bb as
0.144 mmol, 72% yield, 95% ee).
a colorless oil (59.5 mg,
Acknowledgements
This work was supported partly by Grants-in-Aid for Scientific Research
(Nos. 20675002 and 21·906) from MEXT, Japan. We are grateful to Taka-
sago International Corporation for the gift of H8-binap, segphos, tol-
binap, and xyl-binap, and Umicore for generous support in supplying a
rhodium complex.
Scheme 7. Equilibration between intermediates C–E.
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Rhodium-Catalyzed Asymmetric Cyclization
COMMUNICATION
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Keywords: aldehydes · asymmetric catalysis · cyclization ·
enynes · rhodium
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À
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Received: August 4, 2011
Published online: October 5, 2011
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