Communication pubs.acs.org/JACS
Total Syntheses of Highly Oxidized ent-Kaurenoids Pharicin A, Pharicinin B, 7‑O‑Acetylpseurata C, and Pseurata C: A [5+2] Cascade Approach Chi He,† Jialei Hu,†,§ Yubing Wu,†,§ and Hanfeng Ding*,†,‡ †
Department of Chemistry, Zhejiang University, Hangzhou 310058, China State Key Laboratory of Elemento-Organic Chemistry, Nankai University, Tianjin 300071, China
‡
S Supporting Information *
For example, excisanin A (1) has been found to induce tumor cell apoptosis and suppress tumor growth,7a and pharicin A (2) represents a novel class of small molecule compounds capable of perturbing mitotic progression and initiating mitotic catastrophe,7b both of which merit further preclinical and clinical investigations for cancer drug development. However, few synthetic achievements toward these molecules have been disclosed,5k presumably ascribed to their densely functionalized tetracyclic skeletons. In addition, to the best of our knowledge, all the existing approaches for constructing the [3.2.1] bicyclic skeleton of ent-kaurenoids required multistep reaction sequences,8 which inevitably increased functional group manipulations and led to lengthier synthetic routes. Therefore, efficient and general strategies for assembling these highly oxidized ent-kaurene diterpenoids remain in urgent demand to accelerate the process of syntheses and biological investigations. Prompted by this problem, we sought to develop a convergent protocol by establishing the [3.2.1] bicyclic motif in a more straightforward manner. Herein, the first asymmetric total syntheses of pharicin A (2), pharicinin B (3), 7-Oacetylpseurata C (4), and pseurata C (5) are reported. Our retrosynthetic analysis is depicted in Scheme 1. We rationalized that pharicin A (2) and related ent-kaurene diterpenoids (3−5) could be synthesized through late-stage stereoselective reduction of diketone 6 followed by installation of the enone moiety. For the construction of 6, an unprecedented cascade cyclization of vinylphenol 8 was devised. Accordingly, intermediate 7 bearing a cedrene-type skeleton was envisaged to be generated in situ through an oxidative dearomatization−induced (ODI) diastereoselective [5+2] cycloaddition,9 which would then undergo a successive pinacol-type C14(12→13) acyl migration10 as promoted by the preinstalled methoxy group at C12 to forge the desired bicyclo[3.2.1]octane ring of the molecules. 1,2-Addition of organolithium reagent 9 to aldehyde 10 would afford 8. Finally, the preparation of 10 could be traced back to [6,6] bicyclic epoxide 11 by taking advantage of an Eschenmoser−Tanabe fragmentation.11 To explore the feasibility of this proposed ODI-[5+2] cycloaddition/pinacol-type 1,2-acyl migration cascade, vinylphenol 12a was chosen as a test substrate (Table 1). Under Wessely conditions,9b the expected bicyclo[3.2.1]octane 13a
ABSTRACT: The unprecedented oxidative dearomatization-induced [5+2] cycloaddition/pinacol-type 1,2-acyl migration cascade efficiently generates a quaternary carbon center and assembles the highly oxygenated bicyclo[3.2.1]octane framework of ent-kaurene diterpenoids. By incorporation of the subsequent retro-aldol/aldol process and singlet oxygen ene reaction, this concise and convergent approach has enabled the first asymmetric total syntheses of pharicin A, pharicinin B, 7-Oacetylpseurata C, and pseurata C.
I
sodon is one of the largest genera in the Labiatae family and is of both economical and medicinal importance.1 Since ancient times, many species of this widely distributed genus have been used in traditional medicine to treat a variety of ailments due to their curative ability.2 The vast majority of the more than a thousand Isodon diterpenoids isolated to date are ent-kaurene diterpenoids, which possess a wide range of bioactivities such as antitumor, antimalarial and antiviral properties.3 In the past 50 years, the intriguing structures as well as important biological activities of ent-kaurenoids have stimulated numerous endeavors from the synthetic community, culminating in elegant syntheses of their core structures and target molecules.4−6 Recently, efforts aiming at identification of novel ent-kaurene diterpenoids as potential medicinal leads resulted in the discovery of several promising congeners embedded with a highly oxygenated bicyclo[3.2.1]octane ring system (Figure 1).7
Figure 1. Representative structures of the highly oxidized entkaurenoids. © 2017 American Chemical Society
Received: March 22, 2017 Published: April 20, 2017 6098
DOI: 10.1021/jacs.7b02746 J. Am. Chem. Soc. 2017, 139, 6098−6101
Communication
Journal of the American Chemical Society Scheme 1. Retrosynthetic Analysis of Pharicin A (2) and Related ent-Kaurenoids (3−5)
Scheme 2. Scope of the Cascade Cyclization
Table 1. Optimization of the ODI-[5+2] Cycloaddition/ Pinacol-Type 1,2-Acyl Migration Cascadea
into the corresponding products in moderate to good yields (60−85%; 13b−i). The relative configuration of the products was unambiguously determined by X-ray crystallographic analysis of 13g (ORTEP drawing, Scheme 2). More importantly, vinylphenols bearing different substitution on the alkyl tether were also found compatible, again resulting in good yields and excellent diastereoselectivities (70−84%, >10:1 dr; 13j, 13m−p). The favored formation of the major or sole diastereomer arises from minimization of the steric interactions between the side-chain substituents and the carbonyl group in an exo transition state. Compared with 13j, the cyclohexyl-fused product 13k was obtained with reduced efficiency and dr, probably due to the lack of the Thorpe−Ingold effect during [5+2] cycloaddition step. Not surprisingly, as a potential quinone methide precursor, subjection of 12l gave a substantially decreased yield. Furthermore, other functionalities on the side chain such as 1,1- and 1,2-disubstituted alkenes, and even alkynes are well tolerated, affording products 13q−t in satisfactory yields. Encouraged by these outcomes, we commenced our synthesis with the construction of tetracyclic diketone C7-epi6 (Scheme 3). The bicyclic ketone 16 with 95% ee was readily prepared on large scale through acetylation of the known chiral alcohol (for a detailed procedure, see SI), which could be obtained from Wieland−Miescher ketone in three steps.14 IBX oxidation of 16 followed by epoxidation of the acquired enone gave 11 in 85% yield over two steps. By employing a modified Eschenmoser fragmentation,15 the acetylene aldehyde 18 was produced in 65% yield. After being converted into 10 through Lindlar hydrogenation, its union with 9 derived from the direct lithiation of bromophenol 19 proceeded smoothly to afford a 2:1 mixture of vinylphenols 8a and 8b in 80% combined yield, setting stage for the key cascade cyclization. The latter isomer could be recycled via an efficient oxidation/reduction sequence, affording a 3:1 mixture of diastereomers favoring 8a. Pleasingly, treatment of 8a with PhI(CF3CO2)2 and K2CO3 in HFIP delivered the anticipated tetracyclic diketone C7-epi-6 as a single diastereomer in 70% yield on gram scale. The relative configuration of C7-epi-6 was unambiguously assigned by X-ray crystallographic analysis (ORTEP drawing, Scheme 3). The single benzylic stereocenter in 8 was found crucial to governing
yield (%)b entry
oxidant
solvent
13a
14
15
1 2 3 4 5
Pb(OAc)4c PhI(OAc)2 PhI(OAc)2 PhI(OAc)2 PhI(CF3CO2)2
CHCl3 CHCl3 TFE HFIP HFIP
7 16 42 63 78
15 30 23
