Enantioselective wacker-type cyclization of 2-alkenyl-1,3-diketones promoted by Pd-SPRIX catalyst

Article abstract of DOI:10.1021/ol1013069

(Equation Presented). An enantioselective intramolecular Wacker-type cyclization of 2-alkenyl-1,3-diketones catalyzed by a Pd(II)-SPRIX complex was developed. The reaction proceeded in a 6-endo-trig mode to give the desired chromene derivatives with moderate to good enantioselectivity. Isomerization of C-C double bonds via a π-allyl Pd intermediate was involved as the key step.

Full text of DOI:10.1021/ol1013069

ORGANIC
LETTERS
2010
Vol. 12, No. 15
3480-3483
Enantioselective Wacker-Type
Cyclization of 2-Alkenyl-1,3-diketones
Promoted by Pd-SPRIX Catalyst
Kazuhiro Takenaka, Suman C. Mohanta, Mahesh L. Patil, C. V. Laxman Rao,
Shinobu Takizawa, Takeyuki Suzuki, and Hiroaki Sasai*
The Institute of Scientific and Industrial Research (ISIR), Osaka UniVersity,
Mihogaoka, Ibaraki, Osaka 567-0047, Japan
sasai@sanken.osaka-u.ac.jp
Received June 7, 2010
ABSTRACT
An enantioselective intramolecular Wacker-type cyclization of 2-alkenyl-1,3-diketones catalyzed by a Pd(II)-SPRIX complex was developed.
The reaction proceeded in a 6-endo-trig mode to give the desired chromene derivatives with moderate to good enantioselectivity. Isomerization
of C-C double bonds via a π-allyl Pd intermediate was involved as the key step.
The intramolecular Wacker-type cyclization using oxygen
nucleophiles is one of the most important processes for the
Scheme 1. Wacker-Type Cyclization of 1,3-Diketones
preparation of O-heterocycles.1 Employment of hydroxy and
carboxy groups as the oxygen functionality is well established
to afford cyclic ethers and lactones, respectively. 1,3-
Diketone moieties, which are equilibrated with the corre-
sponding enol forms, have also proven to take part in the
Wacker-type cyclization: 5-exo-trig cyclization constructs
furan rings,2,3 whereas pyran derivatives are formed in a
6-endo-trig cyclization (Scheme 1).4,5 Since the carbonyl
group is retained in the products, these transformations
efficiently provide valuable synthons.6 To our surprise, no
enantioselective Wacker-type cyclizations of 1,3-diketones
have been published yet. We have reported that spiro
bis(isoxazoline)s (SPRIXs) bearing isoxazoline coordination
units on a spiro backbone are effective chiral ligands in a
variety of asymmetric oxidative reactions.7,8 The high utility
of SPRIXs stimulated us to explore an enantioselective
catalysis using 1,3-diketone nucleophiles. Herein we report
an enantioselective 6-endo-trig Wacker-type cyclization of
(1) For reviews, see: (a) Zeni, G.; Larock, R. C. Chem. ReV. 2004, 104,
2285. (b) Beccalli, E. M.; Broggini, G.; Martinelli, M.; Sottocornola, S.
Chem. ReV. 2007, 107, 5318.
(2) Han, X.; Widenhoefer, R. A. J. Org. Chem. 2004, 69, 1738
.
(3) For related transformations using a Pd catalyst, see: (a) Hosokawa,
T.; Murahashi, S.-I. Heterocycles 1992, 33, 1079. (b) Tenaglia, A.;
Kammerer, F. Synlett 1996, 576
(4) Verotta, L.; Appendino, G.; Belloro, E.; Bianchi, F.; Sterner, O.;
Lovati, M.; Bombardelli, E. J. Nat. Prod. 2002, 65, 433
.
.
10.1021/ol1013069  2010 American Chemical Society
Published on Web 06/25/2010

2-alkenyl-1,3-diketone compounds 1 promoted by a Pd-
SPRIX catalyst.
In oxidative cyclization of 1, it was suspected that initial
products, 7,8-dihydro-2H-chromen-5(6H)-ones 2, were ob-
tained as a racemate due to an electrocyclic ring-opening/
closing sequence (Scheme 2a).9 We conceived that isomer-
Table 1. Screening of Chiral Ligands in the Enantioselective
Intramolecular Wacker-Type Cyclization of (E)-1aa
entry
chiral ligand
convn (%)b yield (%)b ee (%)c
Scheme 2. Working Hypothesis and Initial Attempt
1
2
3
4
5
6
(M,S,S)-i-Pr-SPRIX
(-)-sparteine
(R,R)-Bn-BOX
(S,S)-i-Pr-BOXAX
(R)-BINAP
100
80
50
40
65
10
80
81
rac
traced
NDe
NDe
NDe
trace
none
a All reactions were performed in the presence of 10 mol % Pd(O-
COCF3)2, 12 mol % chiral ligand, and 2 equiv of p-benzoquinone at 25 °C
for 12 h in diglyme (0.2 M) under a nitrogen atmosphere. b Isolated yield.
c Determined by HPLC analysis. d Racemic 2a was obtained in 14% yield.
e Not detected (a complex mixture was obtained).
ization of 2 to 6,7-dihydro-2H-chromen-5(3H)-ones 3 through
a π-allyl Pd intermediate A would suppress such a prob-
lematic racemization. Indeed, reaction of 2-geranylcyclo-
hexane-1,3-dione ((E)-1a) in the presence of a catalytic
amount of Pd-rac-i-Pr-SPRIX complex furnished the desired
3a in 47% yield (Scheme 2b). After extensive optimization
of reaction conditions,10 we succeeded in the isolation of
enantiomerically enriched product. Thus, substrates (E)-1a
were treated with 10 mol % Pd(OCOCF3)3, 12 mol %
(M,S,S)-i-Pr-SPRIX, and 2 equiv of p-benzoquinone in
diglyme at 25 °C to afford 3a in 80% yield with 81% ee,
accompanied by the negligible formation of 2a (Table 1,
entry 1). It should be noted that under identical conditions,
other known chiral ligands such as (-)-sparteine, (R,R)-Bn-
BOX, (S,S)-i-Pr-BOXAX, and (R)-BINAP were ineffective
(entries 2-5). A background reaction scarcely proceeded and
resulted in only a trace amount of 3a (entry 6). These results
evidently demonstrate a great advantage of SPRIX for the
enantioselective Wacker-type cyclization. Presumably, the
Pd-SPRIX complex activates the olefin significantly because
of its strong Lewis acidity.8c
Next, the scope of this enantioselective transformation was
examined with various 2-alkenyl-1,3-diketones 1 (Table 2).
Similar to (E)-1a, the reactions of geranylcyclohexane-1,3-
dione substrates 1b and 1c gave the products 3b and 3c in
moderate yields (58% and 70%) and sufficient selectivities
(84% ee and 78% ee), respectively (entries 2 and 3). The
pyran analog 1d, however, did not afford the desired product
(entry 4). Alkyl and aryl groups were tolerated on the olefin
component (entries 5-7). Substrate 1h bearing a 1,2-
disubstituted alkenyl chain also participated in this 6-endo-
trig cyclization to give 3h in 68% yield with 52% ee (entry
8). No desired products were observed for cyclopentane-
(5) Pd-catalyzed C-C bond-forming reactions have also been reported;
see: (a) Pei, T.; Widenhoefer, R. A. J. Am. Chem. Soc. 2001, 123, 11290.
(b) Pei, T.; Widenhoefer, R. A. Chem. Commun. 2002, 650. (c) Pei, T.;
Wang, X.; Widenhoefer, R. A. J. Am. Chem. Soc. 2003, 125, 648. (d) Qian,
H.; Widenhoefer, R. A. J. Am. Chem. Soc. 2003, 125, 2056. (e) Yip, K.-T.;
Li, J.-H.; Lee, O.-Y.; Yang, D. Org. Lett. 2005, 7, 5717.
(6) For examples, see: (a) Kurdyumov, A. V.; Hsung, R. P.; Ihlen, K.;
Wang, J. Org. Lett. 2003, 5, 3935. (b) Hu, H.; Harrison, T. J.; Wilson,
P. D. J. Org. Chem. 2004, 69, 3782. (c) Wayne Lee, W.-W.; Gan, L.-M.;
Loh, T.-P. Synlett 2005, 2473. (d) Lee, Y. R.; Lee, W. K.; Noh, S. K.;
Lyoo, W. S. Synthesis 2006, 853. (e) Rawat, M.; Prutyanov, V.; Wulff,
W. D. J. Am. Chem. Soc. 2006, 128, 11044.
(7) For a review, see: Bajracharya, G. B.; Arai, M. A.; Koranne, P. S.;
Suzuki, T.; Takizawa, S.; Sasai, H. Bull. Chem. Soc. Jpn. 2009, 82, 285.
(8) For recent examples, see: (a) Bajracharya, G. B.; Koranne, P. S.;
Tsujihara, T.; Takizawa, S.; Onitsuka, K.; Sasai, H. Synlett 2009, 310. (b)
Tsujihara, T.; Takenaka, K.; Onitsuka, K.; Hatanaka, M.; Sasai, H. J. Am.
Chem. Soc. 2009, 131, 3452. (c) Tsujihara, T.; Shinohara, T.; Takenaka,
K.; Takizawa, S.; Onitsuka, K.; Hatanaka, M.; Sasai, H. J. Org. Chem.
2009, 74, 9274. (d) Takenaka, K.; Tanigaki, Y.; Patil, M. L.; Rao, C. V. L.;
Takizawa, S.; Suzuki, T.; Sasai, H. Tetrahedron: Asymmetry 2010, 21, 767.
(9) (a) Gosink, T. A. J. Org. Chem. 1974, 39, 1942. (b) de Groot, A.;
Jansen, B. J. M. Tetrahedron Lett. 1975, 16, 3407. (c) Li, C.; Johnson,
R. P.; Porco, J. A., Jr. J. Am. Chem. Soc. 2003, 125, 5095.
(11) The major enantiomer was opposite to that obtained in the reaction
of (E)-1a.
(12) For selected examples of deuterium labeling studies on mechanism
in the Wacker-type cyclizations, see: (a) Hayashi, T.; Yamasaki, K.; Mimura,
M.; Uozumi, Y. J. Am. Chem. Soc. 2004, 126, 3036. (b) Hay, M. B.; Wolfe,
J. P. J. Am. Chem. Soc. 2005, 127, 16468. (c) Trend, R. M.; Ramtohul,
Y. K.; Stoltz, B. M. J. Am. Chem. Soc. 2005, 127, 17778.
(10) See Supporting Information for details.
Org. Lett., Vol. 12, No. 15, 2010
3481

Table 2. Substrate Scope in the Enantioselective Intramolecular
Wacker-Type Cyclization of 1a
Scheme 3. Reactions of (Z)-1a and 1k
in which one deuterium was shifted to the adjacent carbon,
as a single diastereomer (Scheme 4a). This result clearly
Scheme 4. Deuterium Labeling Experiments
supports the expected ꢀ-H elimination/reinsertion array. The
coupling constant between Ha and Hb in the six-membered
ring (3JHH ) 9.6 Hz), corresponding to a coupling of axial
protons, identified its relative configuration as depicted.
Accordingly, the Pr group and the shifted deuterium were
positioned trans to each other. A crossover experiment
revealed that such a ꢀ-H elimination/reinsertion sequence
occurred intramolecularly. Thus, no crossover products 3f-d
and 3h-d were detected in the reaction of a 1:1 mixture of
1f and 1h-d2 (Scheme 4b).
a All reactions were carried out in the presence of 10 mol %
Pd(OCOCF3)2, 12 mol % (M,S,S)-i-Pr-SPRIX, and 2 equiv of p-benzo-
quinone at 25 °C for 12 h in diglyme (0.2 M) under a nitrogen atmosphere.
The starting material was almost consumed at the end of the reaction in
each case (except for entries 4, 9, and 10). b Isolated yield. c Determined
by HPLC analysis. d The diastereomeric ratio was determined to be 83:17
by 1H NMR spectrum. Data for the major diastereomer are given. e Not
detected (a complex mixture was obtained). f 17 h. g 20 h. h No reaction.
1,3-dione derivative 1i and acetylacetone derivative 1j
(entries 9 and 10). Interestingly, in the reaction of 2-neryl-
cyclohexane-1,3-dione ((Z)-1a), 3a was not the major product
(12% yield, 53% ee).11 Instead, nonisomerized product 2a
was obtained in 72% yield, which was a racemate as we
suspected (Scheme 3a). Dimethylallyl substrate 1k exhibited
the same trend as in the reaction of (Z)-1a, namely, producing
2k in 52% yield (Scheme 3b). These results imply that
substituents on olefin considerably affect the pathway of this
enantioselective cyclization.
A plausible catalytic cycle for this oxidative cyclization
of 1 is illustrated in Scheme 5. As in the conventional
Wacker-type cyclization, this enantioselective catalysis ap-
pears to be commenced by a nucleophilic attack of the enolic
hydroxy group to the tethering alkene activated by the Pd-
SPRIX complex. On the basis of the results in Table 2 and
Scheme 3, we speculated that the steric environment around
Pd in intermediate I would be essential for controlling the
reaction pathway. The R2 substituent bulky enough to interact
with the neighboring Pd atom causes ring flipping (interme-
diate II). The subsequent ꢀ-H elimination produces Pd-H
speicies III, which converts to π-allyl Pd complex IV by
reinsertion. At this stage, the high electrophilicity of Pd-
SPRIX may contribute to the stability of III, from which
To elucidate our working hypothesis shown in Scheme
2a, deuterium labeling experiments were carried out.12 When
substrate 1h-d2 was subjected to the optimal conditions using
rac-i-Pr-SPRIX, we obtained the anticipated product 3h-d2,
3482
Org. Lett., Vol. 12, No. 15, 2010

When R2 is less bulky, i.e., Me groups in both (Z)-1a and
1k, ꢀ-H elimination would happen directly from the inter-
mediate I. The resulting Pd-H moiety in VI seems to be
immediately liberated due to the compelling steric repulsion
with the axial substituent R1, leading to the nonisomerized
product 2.
Scheme 5. Plausible Mechanism
In summary, we have developed an enantioselective
6-endo-trig Wacker-type cyclization of 2-alkenyl-1,3-dike-
tones, where the SPRIX ligand plays a crucial role for
obtaining optically active chromene derivatives. This reaction
is thought to proceed by way of a π-allyl Pd intermediate.
Transformation of products 3 to biologically active com-
pounds and full investigation into the reaction mechanism
are currently ongoing and will be reported in due course.
Acknowledgment. This work was partly supported by the
JSPS(Grant-in-AidforScientificResearch(B),No.22350041).
We also thank the technical staff of the Comprehensive
Analysis Center of ISIR for their assistance.
Supporting Information Available: Experimental pro-
cedures, details for optimization of the reaction conditions,
and compound characterization data. This material is avail-
able free of charge via the Internet at http://pubs.acs.org.
product 2 is not released easily. Finally, ꢀ-H elimination from
V furnishes 3 and Pd0, of which the latter is oxidized by the
action of p-benzoquinone to regenerate the PdII catalyst.
OL1013069
Org. Lett., Vol. 12, No. 15, 2010
3483