Enantioselective Cationic Polyene Cyclization vs Enantioselective Intramolecular Carbonyl-Ene Reaction

Article abstract of DOI:10.1021/ja104119j

This paper describes highly efficient catalytic enantioselective cationic polyene cyclization and catalytic enantioselective intramolecular carbonyl-ene reaction in good to high yields with high enantioselectivities. The intimate relationship and mechanistic differences between the two enantioselective reactions were studied in detail. In addition, the cyclization products are versatile and useful building blocks for natural products and pharmaceuticals syntheses.

Full text of DOI:10.1021/ja104119j

Published on Web 07/08/2010
Enantioselective Cationic Polyene Cyclization vs Enantioselective
Intramolecular Carbonyl-Ene Reaction
Yu-Jun Zhao,† Bin Li, Li-Jun Serena Tan, Zhi-Liang Shen, and Teck-Peng Loh*
DiVision of Chemistry and Biological Chemistry, School of Physical and Mathematical Sciences, Nanyang
Technological UniVersity, Singapore 637371
Received May 13, 2010; E-mail: teckpeng@ntu.edu.sg
Table 1. Enantioselective Carbonyl-Ene Reaction of
Abstract: This paper describes highly efficient catalytic enanti-
oselective cationic polyene cyclization and catalytic enantiose-
lective intramolecular carbonyl-ene reaction in good to high yields
with high enantioselectivities. The intimate relationship and
mechanistic differences between the two enantioselective reac-
tions were studied in detail. In addition, the cyclization products
are versatile and useful building blocks for natural products and
pharmaceuticals syntheses.
1,5-Keto-Olefin and Cyclization of Ene Product to Polycylic
Adducta
Both cationic polyene cyclization1 and intramolecular carbonyl-ene
reaction2 are powerful methods for construction of cyclic and poly-
cyclic carbocycles and heterocycles. Recently, Ishihara, MacMillan,
and Jacobsen and their co-workers have elegantly demonstrated
enantioselective polyene cyclization reactions catalyzed by organo-
catalysts.3 On the other hand, despite the pioneering work on metal-
catalyzed enantioselective polyene cyclizations by the groups of
Yamamoto, Yang, Corey, and Gagne´,4 catalytic versions with high
enantioselectivity are still few, as are catalytic intramolecular
carbonyl-ene reactions.5 In addition, the intimate relationship and
mechanistic differences between the intramolecular cationic polyene
cyclization reaction and the carbonyl-ene reaction, as depicted in eq
1, are not well studied.6 Continuing our ongoing interest in enanti-
oselective polyene cyclization,7 in this paper we present our findings
on the interplay between the two reactions of 1,5-keto-olefin substrates
(eq 1), which are prone to cyclize via either polyene cyclization8 or a
carbonyl-ene pathway.6 Both cationic polyene cyclization products
and carbonyl-ene cyclization products could be obtained selectively
in good yields and with high enantioselectivities.
a Standard procedure: Sc(OTf)3 (0.02 mmol), ligand A (0.02 mmol),
MS 4 Å (0.15 g), and (CH2Cl)2 (2 mL) were stirred at room temperature
for
2 h prior to addition of substrate (0.1 mmol in 1 mL of
ClCH2CH2Cl). The reaction was stirred for 36 h before workup. b A
single isomer was isolated. c Isolated yields. d Values of ee were
determined by chiral HPLC analyses (Supporting Information). e TfOH
used instead of TiCl4.
Scheme 1
Our study began with promoting cyclization of keto-olefin 1 using
various conditions (Table 1; see Supporting Information for condition
screening). The best conditions found to effectively catalyze the
enantioselective cyclization of 1 used 0.20 equiv of Sc(OTf)32,9 and
0.20 equiv of Pybox ligand A2,9 with (CH2Cl)2 as solvent. A single
isomer of 6-exo carbonyl-ene cyclization product 2 was obtained in
87% yield and with 95% ee. In addition, 2 was readily converted to
polyene cyclization product 3 in 85% yield without significantly loss
of enantiomeric purity (Table 1, entry 1) with the aid of 4.0 equiv of
TiCl4. Similar results were also obtained with analogous substrates
1a-c (entries 2-4). In all cases, good yields and high enantioselec-
tivities were achieved for both carbonyl-ene products and polyene
cyclization products.
a Ene cyclization product was obtained in 12% yield, 90% ee.
On the other hand, under the optimized reaction conditions,
polyene cyclization products instead of ene products were obtained
when cyclization substrates bore terminators such as furan and
indole rings (Scheme 1, 3d, 95% yield, 91% ee; 3e, 83% yield,
92% ee). Mechanistically, the polyene cyclization prevailed over
the ene cyclization because furan and indole heterocyclic rings are
more nucleophilic than the phenol ether ring in 1 and 1a.10 By the
† Current address: Department of Internal Medicine, University of Michigan.
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C O M M U N I C A T I O N S
Scheme 2
the substrates. For the same reason, cationic polyene cyclization
also favors transition state A and undergoes cascade bicylization
or tricyclization, affording fused polycyclic rings of 3d-f, showing
trans or trans-anti-trans13 conformation (Schemes 1 and 2).
Scheme 4. Determination of Absolute Stereochemistry of
Cyclization Products and Proposed Mechanism
same token, polyene cyclization products were also isolated when
the terminator was a trisubstituted olefin7b (Scheme 2, 1f), although
the product was a mixture of isomers (Supporting Information).
For ease of synthesis and analysis, the cyclization product mixture
of 1f was subjected to TfOH7b to facilitate complete tetracycle
formation. The tetracyclic product 3f was obtained in 62% yield
and with 91% ee over two steps.
This enantioselective cyclization protocol provides an efficient
access to diverse, highly enantiomeric polycyclic terpenoids. To
demonstrate the powerful capability of this method, the cyclization
product 3 was transformed to allylic alcohol 6 in 35% yield and
with 93% ee over four steps (Scheme 3). Alcohol 6 shares the
tricyclic core of 7, which is the key intermediate of van Tamelen’s
total synthesis of (()-triptophenolide 8.11 We believe that this
approach will provide a rapid and enantioselective synthesis of (+)-
triptophenolide 8.
In conclusion, we have demonstrated that both catalytic
enantioselective cationic polyene cyclization and catalytic in-
tramolecular carbonyl-ene reaction were achieved in good to
high yields and with high enantioselectivities by tuning the
substrates or using forcing reaction conditions. To the best of
our knowledge, this is the first time that an R-keto-ester was
demonstrated to initiate enantioselective cationic polyene cy-
clization catalyzed by a Lewis acid. The cyclization products
are versatile and useful building blocks for natural terpenoids
and pharmaceuticals14 syntheses. Efforts focusing on the total
synthesis of (+)-triptophenolide are currently in progress and
will be reported in due course.
Scheme 3. Synthesis of Tricyclic Core of (+)-Triptophenolide
Acknowledgment. We thank Dr. Yong-Xin Li (Nanyang
Technological University) for X-ray analyses. We gratefully
acknowledge the Nanyang Technological University and the
Singapore Ministry of Education Academic Research Fund Tier 2
(Nos. T206B1221 and T207B1220RS) for financial support.
Supporting Information Available: Additional experimental pro-
cedures, spectral data for reactions products, and two CIF files. This
material is available free of charge via the Internet at http://pubs.acs.org.
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