Tetrasubstituted carbon centers

The cyclization to form very congested quaternary carbon centers involving the intramolecular insertion of di-, tri-, and tetrasubstituted alkenes is particularly useful for natural products synthesis[l36-138], In the total synthesis of gelsemine, the cyclization of 166 has been carried out, in which very severe steric hindrance is e.xpected. Interestingly, one stereoisomer 167... 

The Heck reaction of 1,3 -diene systems via 7r-allylpalladium is also useful. This cyclization, which forms very congested quaternary carbon centers involving the intramolecular insertion of di-, tri- and tetrasubstituted alkenes, is particularly useful for natural products synthesis. In the synthesis of morphine, bis-cyclization of the octahydroisoquninoline precursor 112 by the intramolecular Heck reaction proceeded using palladium trifluoroacetate and 1,2,2,6,6-pentamethylpiperidine (PMP). The insertion of the diene system forms the 7i-allylpalladium intermediate 113, which attacks the phenol intramolecularly to form the benzofuran ring 114. Based on this method, the elegant total syntheses of (—)- and (+)-dihydrocodeinone, and (—)- and (+)-morphine (115) have been achieved [50],... 

This rearrangement can be also performed with acyclic tetrasubstituted olefins, enabling control of two adjacent carbon centers. Thus, hydroboration of Z- and E-2,3-dimethylstilbene (43) with BH3.THF and subsequent heating at 70 °C for 12 h furnishes stereo selectively the syn and anti organoboranes 44, which after oxidative workup provide the corresponding alcohols syn-45 and anti-45 in 90 % yield and dr > 99.5 % (Scheme 7) [7-9]. 

Although Heck reactions with tetrasubstituted alkenes are known, their examples are rare (Scheme 3-3) [50-52]. One trendsetting observation was that tetrasubstituted alkenes with a conjugated carbonyl group have a sufficiently increased reactivity. The application of such coupling reactions gave a rapid entry to systems with quaternary carbon centers. 

Scheme 11.45 Rh(OAc)2 and chiral Lewis acid-catalyzed reaction to produce y-hydroxyketone with a tetrasubstituted carbon center [66b].

Hydroxy acids having a tetrasubstituted carbon center can be synthesized via organocatalytic reactions between an aioUzable ketone and aryl or alkyl a-keto acid. This type of reaction was performed with the catalyst based on molecular recognition... 

Use of a zipper molecule with aryl iodide and double-bond functionaHties [77] leads to a significant increase in molecular complexity, the overall sequence resulting in the formation of five bonds, five stereocenters, two rings, and a tetrasubstituted carbon center. 

In the niid-1980 s indacranone (17) came to the group, and we faced the challenge of enantiospecifically preparing a tetrasubstituted carbon center. Initially, we established the stereogenic center in intermediate 18 via an achiral phase-transfer reaction employing methyl iodide, aliquat 336, toluene and 50%... 

For the diazoacetates, Mamoka and coworkers reported on the chiral titanium BINOLate-catalyzed highly enantioselective 1,3-dipolar cycloaddition reactions between diazoacetates and monodentate a-substituted acroleins, which give 2-pyrazolines with an asymmetric tetrasubstituted carbon center in 2006 (Table 7.6) [23], The titanium BINOLates, such as (5)-BlNOL/Ti(OPr )4 (2 1 molar ratio) complex (TB-b) and bis (5)-binaphthoxy)(isopropoxy)titanium oxide (TB-c), showed good results in terms of yields and enantiose-lectivities compared with simple (5)-BINOL/Ti(OPr )4 (1 1 molar ratio) complex (TB-a). The synthetic utility of the present reaction was further demonstrated by the total synthesis of a bromopyrrole alkaloid manzacidin A (Scheme 7.13), which was isolated firom the Okinawan sponge Hymeniacidon sp. [24],... 

Chiral separations are concerned with separating molecules that can exist as nonsupetimposable mirror images. Examples of these types of molecules, called enantiomers or optical isomers are illustrated in Figure 1. Although chirahty is often associated with compounds containing a tetrahedral carbon with four different substituents, other atoms, such as phosphoms or sulfur, may also be chiral. In addition, molecules containing a center of asymmetry, such as hexahehcene, tetrasubstituted adamantanes, and substituted aHenes or molecules with hindered rotation, such as some 2,2 disubstituted binaphthyls, may also be chiral. Compounds exhibiting a center of asymmetry are called atropisomers. An extensive review of stereochemistry may be found under Pharmaceuticals, Chiral. 

Mastery of tetrasubstituted olefins greatly expands the tools available for the synthesis of chiral carbon skeletons and tetrasubstituted olefins have the added value of possibly creating two stereogenic centers simultaneously. 

The carbon-carbon double bond of alkenylboronic esters was easily hydrogenated in the presence of palladium on charcoal to give the corresponding saturated species. With a tetrasubstituted substrate, the stereochemistry of two new adjacent centers was controlled (Scheme 9.54) [112], Likewise, 1-alkynyldiisopropoxyboranes cleanly furnished (Z)-l-alkenylboronates over Lindlar catalyst in high stereoselectivity [113]. Asymmetric hydrogenation of 1-phenylethenylboronic ester has been carried out in the presence of [Rh(cod)2]BF4-(R)-BINAP. After oxidation, 1-phenylethanol was obtained with 80% ee [114]. 

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