Enantioselective cyclization of 4-alkenoic acids via an oxidative allylic C-H esterification

Article abstract of DOI:10.1021/ol201314m

An enantioselective intramolecular oxidative cyclization of 4-alkenoic acids was developed. The reaction proceeded via a π-allyl Pd intermediate generated by an allylic C-H activation to give γ-lactone derivatives with moderate to good enantioselectivity. Spiro bis(isoxazoline) ligand, SPRIX, was indispensable for this asymmetric transformation.

Full text of DOI:10.1021/ol201314m

ORGANIC
LETTERS
2011
Vol. 13, No. 13
3506–3509
Enantioselective Cyclization of 4-Alkenoic
Acids via an Oxidative Allylic CꢀH
Esterification
Kazuhiro Takenaka, Mitsutoshi Akita, Yugo Tanigaki, Shinobu Takizawa, and
Hiroaki Sasai*
The Institute of Scientific and Industrial Research (ISIR), Osaka University,
Mihogaoka, Ibaraki-shi, Osaka 567-0047, Japan
sasai@sanken.osaka-u.ac.jp
Received May 16, 2011
ABSTRACT
An enantioselective intramolecular oxidative cyclization of 4-alkenoic acids was developed. The reaction proceeded via a π-allyl Pd intermediate
generated by an allylic CꢀH activation to give γ-lactone derivatives with moderate to good enantioselectivity. Spiro bis(isoxazoline) ligand,
SPRIX, was indispensable for this asymmetric transformation.
A Pd-catalyzed allylic substitution, ordinarily referred
to as the TsujiꢀTrost reaction, is known to be one of the
most practical methods in synthetic chemistry due to its
broad applicability.1,2 Installation of a leaving group on
substrates is a prerequisite for the generation of a key
π-allyl Pd intermediate. It has also been realized that a
Pd(II)-catalyzed oxidative allylic CꢀH bond activation
allows an emergence of the π-allyl Pd species without any
leaving groups.3 Hence, such oxidative functionalizations
of allyl compounds have recently been refocused because
of their environmental friendliness.4,5 In this kind of reac-
tion, a carboxy group serves as the nucleophile to afford
allyl esters, which is usually difficult in the conventional
allylic substitution due to the high reactivity of the pro-
ducts toward the catalysts.6 Further expansion of this
(4) (a) Chen, M. S.; White, M. C. J. Am. Chem. Soc. 2004, 126, 1346.
(b) Fraunhoffer, K. J.; Bachovchin, D. A.; White, M. C. Org. Lett. 2005,
7, 223. (c) Chen, M. S.; Prabagaran, N.; Labenz, N. A.; White, M. C. J.
Am. Chem. Soc. 2005, 127, 6970. (d) Fraunhoffer, K. J.; Prabagaran, N.;
Sirois, L. E.; White, M. C. J. Am. Chem. Soc. 2006, 128, 9032. (e)
Delcamp, J. H.; White, M. C. J. Am. Chem. Soc. 2006, 128, 15076. (f)
Fraunhoffer, K. J.; White, M. C. J. Am. Chem. Soc. 2007, 129, 7274. (g)
Reed, S. A.; White, M. C. J. Am. Chem. Soc. 2008, 130, 3316. (h) Liu, G.;
Yin, G.; Wu, L. Angew. Chem., Int. Ed. 2008, 47, 4733. (i) Lin, S.; Song,
C.-X.; Cai, G.-X.; Wang, W.-H.; Shi, Z.-J. J. Am. Chem. Soc. 2008, 130,
12901. (j) Young, A. J.; White, M. C. J. Am. Chem. Soc. 2008, 130,
14090. (k) Wu, L.; Qiu, S.; Liu, G. Org. Lett. 2009, 11, 2707. (l) Reed,
S. A.; Mazzotti, A. R.; White, M. C. J. Am. Chem. Soc. 2009, 131, 11701.
(m) Rice, G. T.; White, M. C. J. Am. Chem. Soc. 2009, 131, 11707. (n)
Luzung, M. R.; Lewis, C. A.; Baran, P. S. Angew. Chem., Int. Ed. 2009,
(1) Tsuji, J. In Handbook of Organopalladium Chemistry in Organic
Synthesis; Negishi, E.-i., Meijere, A., Eds.; Wiley: New York, 2002.
(2) For selected reviews, see: (a) Trost, B. M.; Crawley, M. L. Chem.
Rev. 2003, 104, 2921. (b) Weaver, J. D.; Recio, A., III; Grenning, A. J.;
Tunge, J. A. Chem. Rev. 2011, 111, 1846.
€
ꢀ
48, 7025. (o) Pilarski, L. T.; Selander, N.; Bose, D.; Szabo, K. J. Org.
Lett. 2009, 11, 5518. (p) Thiery, E.; Aouf, C.; Belloy, J.; Harakat, D.; Le
Bras, J.; Muzart, J. J. Org. Chem. 2010, 75, 1771. (q) Shimizu, Y.; Obora,
Y.; Ishii, Y. Org. Lett. 2010, 12, 1372. (r) Yin, G.; Wu, Y.; Liu, G. J. Am.
Chem. Soc. 2010, 132, 11978. (s) Chen, H.; Jiang, H.; Cai, C.; Dong, J.;
Fu, W. Org. Lett. 2011, 13, 992. (t) Stang, E. M.; White, M. C. Angew.
Chem., Int. Ed. 2011, 50, 2094.
(3) For seminal reports, see: (a) Hansson, S.; Heumann, A.; Rein, T.;
Akermark, B. J. Org. Chem. 1990, 55, 975. (b) Grennberg, H.; Simon, V.;
˚
€
Backvall, J.-E. J. Chem. Soc., Chem. Commun. 1994, 265. (c) Jia, C.;
€
Muller, P.; Mimoun, H. J. Mol. Catal. 1995, 101, 127 and references
cited therein.
r
10.1021/ol201314m
Published on Web 06/09/2011
2011 American Chemical Society

catalysis into asymmetric transformations has been re-
ported. White and co-workers have accomplished an en-
antioselective allylic CꢀH acetoxylation using a combination
of Pd(II)-bis(sulfoxide) and optically active Cr(III)-salen
catalysts.7 If enantioselective oxidative allylic substitutions
were governed by only a chiral Pd catalyst, as in Tsujiꢀ
Trost reactions, they might offer a promising and eco-
conscious synthetic protocol for obtention of optically
active allyl esters. We have already discerned that SPRIX,
a chiral ligand possessing isoxazoline coordination
units on a spiro backbone, leads to Pd exhibiting a
unique reactivity in asymmetric oxidative reactions
upon coordination.8 This exceptional property of
SPRIX caused us to develop an enantioselective oxida-
tive allylic substitution. Here, we disclose an enantio-
selective intramolecular oxidative CꢀH esterification
promoted by the PdꢀSPRIX catalyst.
Scheme 1. Oxidative Cyclization of 4-Alkenoic Acids
Table 1. Screening of Chiral Ligands in the Enantioselective
Intramolecular Oxidative Cyclization of 1aa
In 1993, Larock and Annby independently published an
oxidative cyclization of 4-alkenoic acids 1 producing ra-
cemic γ-lactones 2 in good yields (Scheme 1).9 Since they
mentioned the possibility of the π-allyl Pd mechanism,10
weappliedSPRIX tothiscatalyticreaction. To ourdelight,
in the reaction of 5-methyl-2,2-diphenylhex-4-enoic acid
(1a), the desired lactone product 2a was obtained in an
optically active form. Thus, 1a was stirred with 10 mol %
of Pd(OAc)2, 11 mol % of (M,S,S)-i-Pr-SPRIX, and 4
equiv of p-benzoquinone in CH2Cl2 at 25 °C for 10 h to
afford a 70% ee of 3,3-diphenyl-5-(prop-1-en-2-yl)-
dihydrofuran-2(3H)-one (2a) quantitatively (Table 1, en-
try 1). Other chiral ligands were noticeably ineffective under
identical conditions. Reactions using (ꢀ)-sparteine,(S,S)-i-Pr-
BOXAX, and (R)-BINAP produced an enantiomerically
chiral
ligand
convn
(%)b
yield
(%)b
ee
entry
(%)c
1
2
3
4
5
6
7f
(M,S,S)-i-Pr-SPRIX
(ꢀ)-sparteine
(S,S)-i-Pr-BOXAX
(R)-BINAP
(R,R)-Bn-BOX
3e
100
24
27
13
<2
41
11
>98
10
4
70
57
51
40
;
10
;
6
NDd
18
5
none
a All reactions were performed in the presence of 10 mol % of
Pd(OAc)2, 11 mol % of chiral ligand, and 4 equiv of p-benzoquinone
at 25 °C for 10 h in CH2Cl2 (0.1 M) under a nitrogen atmosphere.
b Determined by 1H NMR using p-hydroxyacetophenone as an internal
standard. c Determined by HPLC analysis. d Not determined. e 5 mol %
of complex 3 was used instead of Pd(OAc)2. f 24 h.
(5) For representative recent reports of a catalytic reaction triggered
by CꢀH bond activation, see: (a) Yao, T.; Hirano, K.; Satoh, T.; Miura,
M. Angew. Chem., Int. Ed. 2011, 50, 2990. (b) Stowers, K. J.; Fortner,
K. C.; Sanford, M. S. J. Am. Chem. Soc. 2011, 133, 6541. (c) Yoo, E. J.;
Ma, S.; Mei, T.-S.; Chan, K. S. L.; Yu, J.-Q. J. Am. Chem. Soc. 2011, 133,
7652. (d) Hasegawa, N.; Charra, V.; Inoue, S.; Fukumoto, Y.; Chatani,
N. J. Am. Chem. Soc. 2011, 133, 8070.
(6) A few examples were reported; see: (a) Trost, B. M.; Organ, M. G.
J. Am. Chem. Soc. 1994, 116, 10320. (b) Kirsch, S.; Overman, L. E. J.
Am. Chem. Soc. 2005, 127, 2866. Other metal catalysts can be used. Cu:
(c) Geurts, K.; Fletcher, S. P.; Feringa, B. L. J. Am. Chem. Soc. 2006,
128, 15572. Ru:(d) Kanbayashi, N.; Onitsuka, K. J. Am. Chem. Soc.
2010, 132, 1206.
(7) Covell, D. J.; White, M. C. Angew. Chem., Int. Ed. 2008, 47, 6448.
(8) For a review, see: (a) Bajracharya, G. B.; Arai, M. A.; Koranne,
P. S.; Suzuki, T.; Takizawa, S.; Sasai, H. Bull. Chem. Soc. Jpn. 2009, 82,
285. Forrecentexamples,see:(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. (e) Takenaka, K.; Mohanta, S. C.; Patil, M. L.;
Rao, C. V. L.; Takizawa, S.; Suzuki, T.; Sasai, H. Org. Lett. 2010, 12, 3480.
(f) Bajracharya, G. B.; Koranne, P. S.; Nadaf, R. N.; Gabr, R. K. M.;
Takenaka, K.; Takizawa, S.; Sasai, H. Chem. Commun. 2010, 46, 9064.
(h) Ramalingan, C.; Takenaka, K.; Sasai, H. Tetrahedron 2011, 67, 2889.
(g) Takenaka, K.; Hashimoto, S.; Takizawa, S.; Sasai, H. Adv. Synth. Catal.
2011, 353, 1067.
(9) (a) Larock, R. C.; Hightower, T. R. J. Org. Chem. 1993, 58, 5298.
(b) Annby, U.; Stenkula, M.; Andersson, C.-M. Tetrahedron Lett. 1993,
34, 8545.
(10) A π-allyl Pd intermediate was also postulated for the synthesis of
racemic γ-lactones 2 via a sequential coupling/cyclization reaction; see:
(a) Larock, R. C.; Leuck, D. J.; Harrison, L. W. Tetrahedron Lett. 1987,
28, 4977. (b) Larock, R. C.; Leuck, D. J.; Harrison, L. W. Tetrahedron
Lett. 1988, 29, 6399.
enriched 2a in low conversions and yields (entries 2ꢀ4).
(R,R)-Bn-BOX rendered the consequent complex cataly-
tically inactive in this oxidative cyclization (entry 5). Even
though chiral Pd complex 3, a valuable catalyst for an
aymmetric Wacker-type cyclization of o-allylphenols,11
expedited the reaction moderately, the optical purity of
2a was as low as 10% ee (entry 6). A background reaction,
without any chiral ligands added, was negligible even after
24 h, resulting in only a trace amount of 2a (entry 7). These
(11) Hosokawa, T.; Okuda, C.; Murahashi, S.-I. J. Org. Chem. 1985,
50, 1282 and references cited therein.
Org. Lett., Vol. 13, No. 13, 2011
3507

fluorene ring were also formed satisfactorily (entries 4
and 5). The simple substrate, 5-methylhex-4-enoic acid
(1f), could participate in this cyclization to give the hop
lactone 2f13 quantitatively, albeit with only 18% ee (entry
6). An aromatic group was tolerated on the olefin compo-
nent: products 2gꢀi were obtained in reasonable yields
with moderate enantioselectivities (entries 7ꢀ9). When 1j
bearing a crotyl group was subjected to the reaction
conditions, 2j was produced quantitatively despite the
low enantiopurity (entry 10). This result reflects a con-
siderable relationship between substituents on the olefin
and enantioselectivity. However, the reaction of 1k hardly
proceeded, probably due to the steric hindrance of the
olefin(entry 11). Utilizationofthe benzoicacidsubstrate1l
resulted in a quantitative construction of an isobenzofur-
anone with 40% ee (entry 12).
Table 2. Substrate Scope in the Enantioselective Intramolecular
Oxidative Cyclization of 1a
Scheme 2. Two Possible Pathways for the Enantioselective
Oxidative Cyclization of 1
Itis possiblethatthe reactionisinitiatedbycoordination
of the 4-alkenoic acids 1 to the Pd(II)ꢀSPRIX complex to
give intermediate I (Scheme 2). There are two plausible
pathways to γ-alkenyl-γ-lactone products 2 from I. One is
the traditional Wacker process consisting of an oxypalla-
dation and a subsequent β-H elimination of the resultant II
(pathway a).14 The other includes π-allyl Pd intermediate
III generated by a CꢀH bond activation at the allylic
position (pathway b). To probe whether the latter pathway
was indeed operative, we performed several control experi-
ments. Reaction of 2,2-diphenylhex-5-enoic acid (1j0),
a structural isomer of 1j, furnished the five-membered
γ-lactone 2j quantitatively with 15% ee (Scheme 3a).15
a All reactions were carried out in the presence of 10 mol % of
Pd(OAc)2, 15 mol % of (M,S,S)-i-Pr-SPRIX, and 2 equiv of p-benzo-
quinone in CH2Cl2 (0.1 M) under a nitrogen atmosphere. b Isolated
yield. c Determined by HPLC analysis. d 4 equiv of p-benzoquinone were
used. e The E/Z ratio was 86:14. f No reaction.
observations indubitably indicate a curious character for
SPRIX in the Pd-catalyzed oxidative cyclization.
After optimization of reaction conditions,12 we found an
improvement of the enantioselectivity. Thus, the employ-
ment of 15 mol % of (M,S,S)-i-Pr-SPRIX and 2 equiv of
p-benzoquinone at 0 °C led to a quantitative formation of 2a,
whose enantiomeric excess had now reached 82% (Table 2,
entry 1). The scope of this transformation was next investi-
gated with a variety of 4-alkenoic acids 1. Substituents R1 at
the R-position of the carbonyl group had no significant
influence on the chemical yields. Treatment of 1b (R1 = Bn)
and 1c (R1 = Me) furnished the products 2b and 2c in
quantitative yields and moderate selectivities (48% ee and
55% ee), respectively (entries 2 and 3). Spiro-type lactone
products 2d having a cyclohexane ring and 2e having a
(13) Pai, Y.-C.; Fang, J.-M.; Wu, S.-H. J. Org. Chem. 1994, 59, 6018.
(14) Anti-oxypalladation was proposed for the cyclization of a
cyclohexenyl substrate based on deuterium-labeling studies. See: Trend,
R. M.; Ramtohul, Y. K.; Stoltz, B. M. J. Am. Chem. Soc. 2005, 127,
17778.
(15) No olefin isomer 1j was detected when the reaction was
quenched in advance of its completion (after 2 h). See: ref 9b.
(16) It was reported that the Wacker-type cyclization of 1m gave the
unsaturated γ-lactones 2m. See: Rudler, H.; Harris, P.; Parlier, A.;
Cantagrel, F.; Denise, B.; Bellassoued, M.; Vaissermann, J. J. Organo-
met. Chem. 2001, 624, 186.
(12) See Supporting Information for details.
3508
Org. Lett., Vol. 13, No. 13, 2011

No reaction took place when 2,2-diphenylpent-4-enoic acid
(1m) was employed as a substrate (Scheme 3b).16 These
results suggest a lower possibility for the Wacker mechan-
ism. Additionally, the intermolecular kinetic isotope effect
(KIE) between substrates 1a and 1a-d was evaluated under
the standard conditions (Scheme 3c). The KIE value
(kH/kD) was determined to be 1.8 by comparing the initial
rates in both reactions.17 Interestingly, when the competitive
reaction using a 1:1 mixture of 1a and 1a-d was conducted,
the KIE value was diminished to 1.1 (Scheme 3d). This
phenomenon implies reversible coordination of the sub-
strates to Pd prior to the CꢀH bond activation.18 Prelimin-
ary study of the utility of other nucleophiles clearly shows
the decisive role of the carboxy group in the enantioselective
oxidative cyclization (Scheme 3e and 3f).19 From the above
examination, we infer that the present enantioselective
cyclization catalyzed by PdꢀSPRIX involves the allylic
CꢀH bond activation through a precoordination complex
such as intermediate I (Scheme 2, pathway b).
Scheme 3. Preliminary Mechanistic Study
In summary, we have developed an enantioselective
oxidative cyclization of 4-alkenoic acids 1, where a
π-allyl Pd intermediate is involved. The SPRIX ligand
was pivotal in acquiring optically active γ-alkenyl-γ-
lactone products 2. We believe that this transformation
is the first example of an enantioselective oxidative
allylic CꢀH functionalization directed by only a chiral
Pd catalyst. Careful study on the detailed reaction
mechanism is currently in progress.
Acknowledgment. This work was partly supported by
the JSPS (Grant-in-Aid for Scientific Research (B), No.
22350041). We also thank the technical staff of the
(17) This ratio is quite similar to the reported values for an allylic CꢀH
oxidative alkylation (2.2) and amination (1.64ꢀ1.88), which have been
proposed to proceed via a π-allyl Pd intermediate. See: refs 4i and 4r.
(18) Kakiuchi, F.; Matsuura, Y.; Kan, S.; Chatani, N. J. Am. Chem.
Soc. 2005, 127, 5936 and references cited therein.
(19) Although the reason why 8 was obtained as a sole product has
been uncertain, the Wacker-type cyclizations using a hydroxy nucleo-
phile are disposed to proceed in a 6-endo-trig fashion with SPRIX. See:
Arai, M. A.; Kuraishi, M.; Arai, T.; Sasai, H. J. Am. Chem. Soc. 2001,
123, 2907. Also see: refs 8d and 8e.
Comprehensive Analysis Center of ISIR for their
assistance.
Supporting Information Available. Experimental proce-
dures, details for optimization of the reaction conditions, and
compound characterization data. This material is available
free of charge via the Internet at http://pubs.acs.org.
Org. Lett., Vol. 13, No. 13, 2011
3509