Enantioselective Synthesis of Bicarbocyclic Structures with an All-Carbon Quaternary Stereocenter Through Sequential Cross Metathesis and Intramolecular Rauhut-Currier Reaction

A new extension of the Birch-Cope sequence is described which allows the efficient enantioselective construction of highly functionalized, fused bicarbocyclic structures with an all-carbon quaternary stereocenter in two steps. The two step sequence includes a cross metathesis between a terminal alkene and a polarized alkene followed by an intramolecular Rauhut-Currier reaction with a trialkylphosphine catalyst. The enantioselective synthesis of fused bicarbocyclic structures containing all-carbon quaternary stereocenters is an important activity in organic synthesis. Due to their intriguing complex chemical architecture and their potential therapeutic applications, these structures have attracted the attention of synthetic chemists for many decades. Recent examples of bicarbocyclic structures with all-carbon quaternary stereogenic centers that have fomented synthetic activity include the cyanthiwigins, 1-6 the guanacastapenes, 7-10 and platensimycin 11-16 . One of the most common tools to enantioselectively generate these structures is the Hajos-Parrish-Eder-Sauer-Weichert reaction. 17-19 In fact, the popularity of this reaction in natural product synthesis is another indication of the demand for bicarbocyclic architectures, which can serve as key intermediates in complex molecule construction. In the interest of developing new tools to create enantiomerically pure bicarbocyclic structures with all-carbon quaternary stereocenters in an angular position, we have extended our Birch-Cope sequence (Scheme 1) 20,21 to rapidly create several such structures, with the hydrindane skeleton. The procedure selectively functionalizes the terminal alkene of the Birch-Cope sequence product 2 with a Grubbs cross metathesis reaction 22 and then performs an intramolecular Rauhut-Currier reaction with trialkylphosphine to afford 4 (Scheme 1). One pot tandem reactions, such as the RauhutCurrier reaction, are important for the efficient construction of complex chemical structures and therefore are an active research area in the synthetic community. 23-31 The intramolecular Rauhut-Currier reaction 32 has experienced a resurgence based on * Corresponding author. Tel.: +1 610 526 5016; fax: +1 610 526 5086; e-mail: [email protected]. groundbreaking studies by Krische, 33 Murphy, 34,35 and Roush. 36 Under the influence of catalytic phosphine, conjugated systems can be merged to form a new ring while retaining one conjugated system for subsequent functionalization. Application of the intramolecular Rauhut-Currier reaction to the cross metathesis product 3 should afford valuable intermediates 4 on the path to a range of complex chemical architectures. Details of the successful transformation of 2 to 4 are presented herein. Scheme 1. Olefin cross metathesis and Rauhut-Currier reaction to bicarbocyclic structures with an all-carbon quaternary stereocenter in an angular position. The Birch-Cope sequence product 2 was subjected to cross metathesis in the presence of an alkene (3-20 eq.) and the second generation Hoveyda-Grubbs (HG2, 2.5 mol%) catalyst. Initially, the Grubbs second generation (G2) catalyst was tested, but the reaction proved more efficient with HG2. Previous reports 37,38 have described similar reactivity differences in Grubbs catalysts used for related cross metathesis examples. In all cases, an excess of alkene was essential for maximizing the conversion of 2. 39 As has been previously reported 22 , the cross metathesis was amenable to a variety of alkenes (Table 1). Alkenes functionalized with a ketone, 1,3-dioxolane, ester, acid and sulfone were all successful, although the sulfone was markedly less efficient. The cross metathesis reactions predominantly or exclusively formed the E alkene isomer. Table 1. Olefin cross metathesis and Rauhut-Currier reaction. EWG: yield (%): E/Z ratio conditions: yield (%): a -C(=O)CH3 87 ~8.5:1 PBu3(0.3 eq.), CH2Cl2, 81