All-carbon quaternary centers

The marine alkaloid (-)-norzoanthamine 3 suppresses bone loss in ovariectomized mice, and so is of interest as a lead to antiosteoporotic drugs. A substantial challenge in the assembly of 3 is the stereocontrolled construction of the C ring, with its three all-carbon quaternary centers. In the synthesis of 3 by Masaaki Mayashita of Hokkaido University (Science 2004,305,495), the and C rings were built and two of the three needed quaternary centers were set by the intramolecular Diels-Alder cyclization of 1 to 2. 

The selective constmction of all-carbon quaternary centers is a unique challenge within the realm of organic synthesis that has received significant attention in recent years. Many of the synthetic strategies for chiral oxindole synthesis described within this chapter rely on racemic 3-alkyl or 3-aryl oxindole precursors that are available through a manifold of well established synthetic protocols. Although the synthesis of C3 monosubstituted oxindoles will not be treated in detail within this... 

Chen and coworkers employed the cinchona alkaloid-derived catalyst 26 to direct Mannich additions of 3-methyloxindole 24 to the A-tosylimine 25 to afford the all-carbon quaternary center of oxindole 27 with good enantioselectivity (84% ee) [22]. The outcome of this Mannich reaction is notable in that it provided very good selectivity for the anti diastereomer (anti/syn 94 6). The mechanism of asymmetric induction has been suggested to involve a hydrogen bonding network between the cinchona alkaloid 26, the oxindole enolate of 24, and the imine electrophile 25 (Scheme 7). Asymmetric allylic alkylation of oxindoles with Morita-Baylis-Hillman carbonates has been reported by the same group [23]. 

A unique inversion on the theme of trapping an electrophile with enolate nucleophile has been reported by Krishnan and Stoltz who have installed all-carbon quaternary centers at oxindoles, e.g., 42, in racemic fashion through the treatment of electrophilic 3-halooxindoles with nucleophilic malonates, e.g., 40-41, using DBU (l,8-diazabicyclo[5.4.0]undec-7-ene) for the deprotonation step (Scheme 11) [28]. An asymmetric variation of the chemistry in Scheme 11 has been reported by the same group who constructed enantioeiuiched oxindoles using catalytic Cu(ll)-Lewis acid and a chiral bis(oxazoline) ligand [29]. 

The Kobayashi group has observed the intramolecular diastereoselective spirocyclization of racemic 2-haloindoles bearing a C3-tethered allylic alcohol [71, 72]. For example, CuCl-catalyzed intramolecular Ullmann coupling of 117 followed by spontaneous Claisen rearrangement of the intermediate pyranoindole 118 afforded, in a one-pot synthesis, the all-carbon quaternary center of spiro-oxindole 119 in 95% de (Scheme 31). The methodology has been extended to the synthesis of hexahydropyrroloindoles, e.g., ( )-debromoflustramine B and E. 

As a key intermediate in an approach to the communesins, Weitrreb and co-workers have constructed the all-carbon quaternary center of oxindole 166. The tandem Heck cyclization/carbonylation sequence illustrated in Scheme 41 provided 165 as a single stereoisomer in 79% yield [95]. Further manipulation of 165 revealed the vicinal pair of all-carbon stereocenters housed within 166. An approach to the synthesis of ( )-cotnmrmesin F has been reported by the same group [96]. 

In one approach reported by Nicolaou and colleagues, the CIO quaternary center was constructed via aromatic substitution using an oxindole C3 electrophile (the tosyl derivative of 169) as illustrated in Scheme 42. The all-carbon quaternary center of 170 was set in 47% yield as a 1 1 mixture of oxindole C3 epimers. 

The Williams group has installed the all-carbon quaternary center of notoamide C 178 (28%) along with 3-f77 -notoamide C (48%) via a pinacol rearrangement set forth through oxidation of the indole C2-C3 bond with the Davis oxaziridine 177 (Scheme 43) [107-109]. 

Under the optimal reaction conditions, various a-alkyl styrenes were successfully hydrovinylated to afford the corresponding products bearing an all-carbon quaternary center. However, when the ort/ o-substituted a-alkyl styrenes were tested under the same conditions, no reaction was observed, indicating that the steric hindrance of the substrate has a remarkable negative effect on the reactivity (Scheme 9.6). 

Oxindoles with an all-carbon quaternary center at the C3 position are privileged structural motifs found in many pharmaceuticals and alkaloid natural products [90]. The asymmetric Michael addition of oxindoles proved to be an efficient method for the construction of these structural motifs and a wide range of electrophiles such as a,(3-unsaturated aldehydes [91], ketones [92], sulfones, nitroalkenes [93], and 2-chloroacrylonitrile [94] have been weU studied in recent years (Scheme 5.45). 

In 2009, Glorius and co-workers [47] reported the NHC-catalyzed intramolecular hydroactlation of allylic ether 38 (Scheme 7.27). Importantly, this method could also construct all-carbon quaternary centers, which are very attractive in organic synthesis. 

Feng J, Garza VJ, Krische MJ (2014) Redox-triggered C-C Coupling of alcohols and vinyl epoxides diastereo- and enantioseiective formation of all-carbon quaternary centers via tert-(hydroxy)-prenyiation. J Am Chem Soc 136 8911-8914... 

Smejkal T, Han H, Breit B, Krische Ml (2009) All carbon quaternary centers via ruthenium-catalyzed hydroxymethylation of 2-substituted butadienes mediated by formaldehyde beyond hydroformylation. J Am Chem Soc 131 10366-10367... 

Han H, Krische MI (2010) Direct mthenium-catalyzed C-C coupling of ethanol diene hydro-hydiDxyethylation to form all carbon quaternary centers. Org Lett 12 2844-2846... 

Zbieg JR, Mclnturff EL, Leung JC, Krische MI (2011) Amplification of anri-diastereoselectivity via Curtin-Hammett effects in ruthenium-catalyzed hydrohydroxyalkylation of 1,1-disubstituted allenes diastereoseleetive formation of all-carbon quaternary centers. J Am Chem Soc 133 1141-1144... 

Gao, L. Kang, B. C. Ryu, D. H. Catalytic Asymmetric Insertion of Diazoesters into Aryl-CHO Bonds Highly Enantioselective Construction of Chiral All-Carbon Quaternary Centers. /. Am. Chem. Soc. 2013,135,14556-14559. 

Abstract Synthetically relevant advances in the area of carbon-carbon sigma bond activation have been made possible by 8-acylqumoline directing groups. Stable rhodium metallacycle intermediates have been shown to undergo a variety of transformations, including carboacylation reactions, to produce value-added products containing all-carbon quaternary centers. The kinetic profile of such reactions has been shown to be substrate dependent. 

Keywords 8-Acylquinoline 8-Quinolinyl ketone All-carbon quaternary centers Bond insertion Carboacylation Carbon-carbon bond activation Chelation Cyclometalation Directed metalation Directing group Metallacycle Oxidative addition Rhodium catalyst... 

The [3+2] annulation reaction of a-substituted allenoates with ester-activated a,p-unsaturated imines in the presence of MePPh2 leads to the synthesis of highly functionalized cyclopentenes bearing an all-carbon quaternary center (Scheme 6.8) [10],... 

The highly reactive dianions intermediates in these reactions also enabled the formation of all carbon quaternary centers. Myers used iV,iV -dimethyl-iV,A/ -propylene urea (DMPU) as a less toxic alternative to HMPA in these transformations. These reactions proceeded in high yield and modest-to-excellent diastereoselectivity, ranging from 5.4 1 to 19 1 (Table 7.7). 

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