ORGANIC LETTERS
Palladium-Catalyzed Sequential Arylation and Allylic Alkylation of Highly Functionalized Ketones: A Concise Synthesis of Mesembrine
2009 Vol. 11, No. 3 555-558
Yuanhong Zhao, Yongyun Zhou, Leilei Liang, Xiaodong Yang, Fengxiang Du, Liang Li, and Hongbin Zhang* Key Laboratory of Medicinal Chemistry for Natural Resource, Ministry of Education, School of Chemical Science and Technology, Yunnan UniVersity, Kunming, Yunnan 650091, P. R. China
[email protected];
[email protected] Received November 12, 2008
ABSTRACT
An unprecedented palladium-catalyzed sequential procedure toward arylation and allylic alkylation of highly functionalized cyclohexenones was developed. This new protocol leads to useful building blocks containing a benzylic quaternary carbon in only one step. A concise total synthesis of mesembrine based on this procedure was achieved in only five steps with 22% overall yield.
Benzylic quaternary carbon centers are widely presented in bioactive natural products1 (Figure 1). Efficient methodologies leading to the construction of such a quaternary carbon center represents one of the most synthetic challenge as well as powerful entry into the structurally diverse family of natural alkaloids.2 Although synthetic efforts toward those units have generated a number of strategies or tactics over the years, many unfortunately fail to meet adequate measures of flexibility in terms of diversity-oriented synthesis. (1) For recent reviews, see: (a) Kornienko, A.; Evidente, A. Chem. ReV. 2008, 108, 1982–2014. (b) Somei, M.; Yamada, F. Nat. Prod. Rep. 2005, 22, 73–103. (c) Jin, Z. Nat. Prod. Rep. 2005, 22, 111–126. (d) Zezula, J.; Hudlicky, T. Synlett 2005, 388–405. (e) Somei, M.; Yamada, F. Nat. Prod. Rep. 2004, 21, 278–311. (2) For recent reviews, see: (a) Trost, B. M.; Jiang, C. Synthesis 2006, 369–396. (b) Christoffers, J.; Baro, A. AdV. Synth. Catal. 2005, 347, 1473– 1482. (c) Peterson, E. A.; Overman, L. E. Proc. Natl. Acad. Sci. U.S.A. 2004, 101, 11934–11948. Douglas, C. J.; Overman, L. E. Proc. Natl. Acad. Sci. U.S.A. 2004, 101, 5363–5367. Denissova, I.; Barriault, L. Tetrahedron 2003, 59, 10105–10146. 10.1021/ol802608r CCC: $40.75 Published on Web 12/31/2008
2009 American Chemical Society
Carefully analysis of the alkaloids shown in Figure 1, a common motif is characteristic and might be derived from synthetically valuable building blocks as shown in Scheme 1.
Figure 1. Important bioactive alkaloids and common unit presented in those structures.
We envisaged that an arylation reaction followed by an allyl alkylation of a highly functionalized ketone, namely 3-ethoxy-
Scheme 1. Retrosynthetic Analysis of Representative Alkaloids
2-cyclohexenone, would provide the versatile building blocks for the synthesis of alkaloids as indicated in Figure 1. Although palladium-mediated arylation of ketones has been well documented in the literature, mainly simple ketones being utilized as substrates.3 Few attempts4 have been made toward ketones in high functionality that is of importance for further synthetic manipulation. In this paper, we wish to report the preliminary results concerning construction of the benzylic quaternary carbon centers with a single-pot catalysis of different transformation strategy5 and a concise route toward the total synthesis of (()mesembrine based on our new protocol. With palladium acetate being a palladium source and racemic BINAP as a ligand, we initiated our studies on the arylation of 3-ethoxy-2-cyclohexenone, a commercially available starting material with rich functionality for further transformation. Our first arylation with 4-bromoveratrole in the presence of cesium carbonate in toluene ended in failure. After a few unsuccessful attempts, the desired arylation occurred when sodium bis(trimethylsilyl)amide being employed as a base in 1,4-dioxane at 90 °C (see Table 1).
Table 1. Arylation of Highly Functionalized Cyclohexanonea
entry
time (h)
1 2 3 4 5 6
24 24 24 24 24 48
base
solvent
yieldb (%)
Cs2CO3 BuOK NaN(SiMe3)2 t BuOK NaN(SiMe3)2 NaN(SiMe3)2
toluene toluene toluene 1,4-dioxane 1,4-dioxane 1,4-dioxane
0 trace
