Jie
Wang
a,
Wang-Bin
Sun
ab,
Ying-Zi
Li
a,
Xuan
Wang
a,
Bing-Feng
Sun
*a,
Guo-Qiang
Lin
a and
Jian-Ping
Zou
b
aCAS Key Laboratory of Synthetic Chemistry of Natural Substances, Shanghai Institute of Organic Chemistry, 345 Lingling Road, Shanghai 200032, China. E-mail: bfsun@sioc.ac.cn
bKey Laboratory of Organic Synthesis of Jiangsu Province, College of Chemistry and Chemical Engineering, Soochow University, Suzhou, Jiangsu 215123, China
First published on 13th April 2015
A concise formal synthesis of platencin has been realized, featuring an organocatalytic approach to the [2.2.2] bicyclic core, a radical reductive elimination, a Au-catalyzed Meyer–Schuster rearrangement and a Rh-catalyzed chemo- and diastereoselective hydrosilylation.
Tremendous efforts have been exerted from the synthetic community resulting in numerous syntheses of platencin5a–t and its analogues.5u–x From a perspective of target oriented synthesis, Mulzer and Tiefenbacher's work stands out as the most efficient synthesis of platencin so far.5c Nevertheless, synthetic endeavors based on new strategies are still highly desirable. Recently, we successfully developed a convenient approach to bicyclo[2.2.2]octane-1-carboxylates.6 In this paper, we report a formal synthesis of platencin by virtue of this new method.
Our retrosynthesis is depicted in Scheme 1. Nicolaou's intermediate enone 3 was chosen as the direct synthetic target.5a Enone 3 could be reduced to dicarbonyl 4, which in turn could be traced back to 5. Eventually, in light of our methodology, a formal [4 + 2] cycloaddition reaction of nitroethylene (6) with α′-ethoxycarbonyl cyclohexenone (7) was envisaged to access 5.
Our synthesis commenced with the critical [4 + 2] reaction of 6 and 7 (Scheme 2). Surprisingly, by employing the original conditions involving CAT-1 as the catalyst and dichloromethane as the solvent,6 only trace amounts of 8 could be isolated, probably as a result of the high propensity of 6 undergoing polymerization under the reaction conditions. To our delight, when toluene was used as the solvent and 6 was slowly introduced to the reaction mixture, the polymerization of 6 could be significantly suppressed, with 8 being isolated in 74% yield, albeit with an enantioselectivity of only 15% ee which could be ascribed to the absence of any substituent at the β-carbon of 6.
A tandem Michael–Henry reaction was then realized with DBU and formaldehyde, providing 9 as a 1/1 diastereomeric mixture, which without chromatographic purification was brominated with PPh3/CBr4 to furnish 10 in 89% overall yield spanning three steps from 8. The subsequent unprecedented conversion of 10 to 5 was examined with various reducing agents (Table 1). The optimal set of conditions involving n-Bu3SnH/AIBN in heated toluene provided 5 in 91% yield.
Entry | Conditions | Yield (%) |
---|---|---|
1 | Mg, THF, 40 °C | 21 |
2 | Zn, NaI, MeOH, 50 °C | 25 |
3 | Zn, NH4Cl, MeOH, r.t. | — |
4 | SmI2, r.t. | — |
5 | t-BuLi, −78 °C | — |
6 | AIBN, n-Bu3SnH, toluene, 90 °C | 93 |
With a robust protocol established for the synthesis of 5, we proceeded to the next synthetic stage. The Grignard addition of propargylmagnesium bromide to ketone 5 afforded 11 in 87% yield as a 1.5/1 mixture. The subsequent Au-catalyzed Meyer–Schuster rearrangement of 11 proved highly efficient.7 With 2 mol% catalyst in dichloromethane, enone 12 could be obtained in a quantitative yield as a 1.7/1 mixture favouring the (Z)-isomer 12a.8 The chemo- as well as diastereoselective hydrogenation of 12a was investigated (Table 2). A nearly quantitative yield of 4a and its epimer 4b in 1.3/1 ratio could be obtained by rhodium catalyzed hydrosilylation (entry 3).8 Compared to the result obtained with t-BuCu/DIBAL-H (entry 2), the interaction between the exocyclic terminal double bond and the rhodium catalyst probably overrode the adverse inherent steric facial bias, leading to 4a as the major product. Eventually, ketoester 4a was subjected to the reduction–oxidation sequence to provide a ketoaldehyde before undergoing the intramolecular aldol condensation to give enone 3 in 51% yield over three steps.
In view of the fact that the enantioselectivity of the initial key reaction delivering 8 was poor, we continued to improve the reaction by screening more catalysts and conditions, as summarized in Table 3. When 6 was dissolved in toluene and introduced slowly in excess, dichloromethane could be employed as the solvent which resulted in a slightly higher ee of 38% with the reversed sense of enantioselectivity as compared to that obtained with toluene (entries 1 and 2). A lower temperature resulted in significantly decreased reactivity (entry 3). Further investigation of the catalysts revealed CAT-5 to be the optimal one (entries 4–10). The best result was obtained with CAT-5 in nitrobenzene, which furnished 8 in 84% yield and 74% ee (entry 12).
Entry | Catalyst | Conditionsa | Conv.b (%) | eec (%) |
---|---|---|---|---|
a A solution of nitroethylene (6) in toluene (2.0 M) was always employed in excess. b Determined by analysis of the 1H NMR spectra of crude samples. c Determined by chiral HPLC analysis. d 84% isolated yield. | ||||
1 | CAT-1 | Toluene, r.t. | 95 | 15 |
2 | CAT-1 | DCM, r.t. | 72 | −38 |
3 | CAT-1 | DCM, −20 °C | 33 | −42 |
4 | CAT-2 | DCM, r.t. | 55 | −42 |
5 | CAT-3 | DCM, r.t. | 56 | −41 |
6 | CAT-4 | DCM, r.t. | 45 | −52 |
7 | CAT-5 | DCM, r.t. | 88 | −72 |
8 | CAT-6 | DCM, r.t. | 71 | −63 |
9 | CAT-7 | DCM, r.t. | 32 | −68 |
10 | CAT-8 | DCM, r.t. | 50 | −65 |
11 | CAT-5 | PhCN, r.t. | 94 | −73 |
12 | CAT-5 | PhNO2, r.t. | 98d | −74 |
Footnote |
† Electronic supplementary information (ESI) available: Experimental procedures, spectroscopy data, and copies of 1H, 13C and 2D NMR spectra. See DOI: 10.1039/c5qo00065c |
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