Letter Cite This: Org. Lett. XXXX, XXX, XXX−XXX
pubs.acs.org/OrgLett
Asymmetric Formal Synthesis of (−)-Cephalotaxine via PalladiumCatalyzed Enantioselective Tsuji Allylation Zhi-Wei Zhang,*,† Cui-Cui Wang,† Hong Xue,† Yu Dong,† Jian-Hua Yang,† Shouxin Liu,*,† Wen-Qing Liu,† and Wei-Dong Z. Li‡ †
State Key Laboratory Breeding Base-Hebei Province Key Laboratory of Molecular Chemistry for Drug, College of Chemical & Pharmaceutical Engineering, Hebei University of Science & Technology, Shijiazhuang 050018, P. R. China ‡ School of Life Science and Engineering, Southwest Jiaotong University, Chengdu 610031, P. R. China S Supporting Information *
ABSTRACT: Asymmetric synthesis of the pentacyclic alkaloid (−)-cephalotaxine was accomplished via palladiumcatalyzed enantioselective Tsuji allylation for construction of the aza-containing tetrasubstituted stereogenic center (95% yield, 93% ee). The allyl enol carbonate precursor was prepared from Hanaoka’s ketone intermediate, which was formed by a novel formic acid promoted ring-expansion reaction.
C
synthesis of CET reported by the Weinreb and Semmelhack groups in 1972,4 more than a dozen asymmetric and 20 racemic syntheses have been developed.1,5 More recently, three comprehensive overviews about the chemical syntheses and bioactivities of Cephalotaxus alkaloids have been published,1e−g and Hong’s group,5c Chandrasekhar’s group,5f and Fan’s group,5g respectively, disclosed their achievements in the total synthesis of (±)-CET. For the enantioselective synthesis of (−)-CET,1 a commonly employed strategy was the formation of the seven-membered benzazepine ring from a chiral spirocyclic compound (Figure 1) via acid-promoted cyclization6 or palladium-catalyzed Heck reaction.7 In addition to these practical methods, Gin8 reported the synthesis of (−)-CET via strain-release rearrangement of Nvinyl-2-arylaziridines as the key step. The Ishibashi group9 described a radical cascade in their asymmetric synthesis. However, despite tremendous efforts to develop more efficient synthesis,1,5 most of the asymmetric approaches employed chiral compounds to synthesize the key optically active intermediates.6−9 Efficient catalytic enantioselective syntheses of CET were, respectively, reported by Tietze,7b Tu,6e and Renaud.7g A straightforward strategy using catalytic asymmetric transformations from readily available compounds remains highly desirable. The Dolby−Weinreb enamine4a,c,e,10 is also a classic intermediate in the total synthesis of CET (Figure 1). Hanaoka’s ketone compound 2,11 a related pyrrolobenzazepine, was recently the support of an efficient preparation of the skeleton of (±)-CET using conventional reactions as key
ephalotaxine (CET, Figure 1) is parent to a large family of related natural alkaloid esters that show clinically
Figure 1. Cephalotaxus alkaloids and asymmetric synthetic approaches.
important bioactivity.1 Homoharringtonine, as the most effective anticancer compound among the family, was approved by the FDA as an adult orphan-drug for the treatment of chronic myeloid leukemia in 2012.2 Structurally, CET has a pentacyclic ring system with three contiguous stereogenic centers. Its absolute configuration was determined by X-ray analysis of the corresponding p-bromobenzoate by Powell in 1974.3 The interesting structure and biological activities of its naturally occurring ester derivatives made this group of alkaloids attractive synthetic targets. Since the first total © XXXX American Chemical Society
Received: December 25, 2017
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DOI: 10.1021/acs.orglett.7b04008 Org. Lett. XXXX, XXX, XXX−XXX
Letter
Organic Letters transformations.12 A retrosynthetic analysis toward asymmetric construction of the pentacyclic frame revealed that direct installation of an allyl substituent at the α-position of ketone 2 by catalytic asymmetric allylic alkylation (AAA) would be an ideal approach. The palladium-catalyzed AAA reactions have been well-studied as one of the most powerful tools for asymmetric carbon−carbon bond formations.13 The sevenmembered cyclic ketone 2 as a prochiral nucleophile14 provides a perfect testing ground to explore the AAA reactions for establishing the aza-containing tetrasubstituted stereogenic center (C5 in Figure 1). As a continuation of our study toward synthesis of Cephalotaxus alkaloids12 and application of AAA reactions,15 we report herein the asymmetric synthesis of (−)-CET using palladium-catalyzed enantioselective Tsuji allylation16 as the key transformation. Furthermore, a new approach to Hanaoka’s intermediate 2 via formic acid promoted ring expansion of aldehyde 1 is established (Scheme 1).
Scheme 2. Intermolecular AAA Reaction of 2 and Synthesis of Allyl Enol Carbonate 5
Table 1. Ligand Screen
Scheme 1. Ring Expansion of Aldehyde 1 for Synthesis of 2
entry
ligand
time (h)
yielda (%)
eeb (%)
1 2 3 4 5 6 7c
L1 L2 L3 L4 L5 L6 L4
1 1 1 1 1 1 5
95 91 94 95 0 80 90
80 16 81 93
