Quaternary carbon synthesis

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... 

Cyclopropanes are now readily available and have become useful, through hydrogenolysis, for synthesis of compounds containing quaternary carbons, em-dialkyl, r-butyl, and angular-methyl substituents (779), compounds often available only with difficulty otherwise (.77,5i,55,750,756), Cyclopropanes can be formed in good yields by hydrogenation of cyclopropenes (26). 

The unique power of Hoveyda s recyclable ruthenium catalyst D in RCM with electron-deficient and sterically demanding substrates is illustrated in Honda s total synthesis of the simple marine lactone (-)-malyngolide (54), which contains a chiral quaternary carbon center (Scheme 10) [35]. Attempted RCM of diene 52 with 5 mol% of NHC catalyst C for 15 h produced the desired... 

The coupling of carboxylic acids has been profitably used in natural product synthesis. Kolbe electrolysis of 10 is part of a (+) x-onocerin synthesis [120], the dimerization of il leads to a pentacyclosqualene [121], the electrolysis of 12 afforded a dime-with two quaternary carbon atoms [122], and 2,6,10,15,19,23-hexamethyltetracontane has been synthesized from 13 [123]. 

Mermerian AH, Fu GC (2005) Catalytic enantioselective construction of all-carbon quaternary stereocenters synthesis and mechanistic studies of the C-acylation of silyl ketene acetals. J Am Chem Soc 127 5604—5607... 

Entries 10 to 12 illustrate the use of organocopper conjugate addition in the synthesis of relatively complex molecules. The installation of a f-butyl group adjacent to a quaternary carbon in Entry 10 requires somewhat forcing conditions, but proceeds Transition Metals in ooc yie - I 1 Entry 11, the addition is to a vinylogous ester, illustrating the ability... 

Some examples of conjugate addition reactions of allylic silanes are given in Scheme 9.5. Entries 1 to 3 illustrate the synthesis of several (3-allyl ketones. Note that Entry 2 involves the creation of a quaternary carbon. Entry 4 was used in the synthesis of a terpenoid ketone, (+)-nootkatone. Entry 5 illustrates fluoride-mediated addition using tetrabutylammonium fluoride. These conditions were found to be especially effective for unsaturated esters. In Entry 6, the addition is from the convex face of the ring system. Entry 7 illustrates a ring closure by intramolecular conjugate addition. 

For instance, some time ago Newkome et al. reported the synthesis of ruthenium based dendrimers [170]. A dendrimer (80) with twelve peripheral terpyridine ligands was built around a central quaternary carbon-based core. In the final step complexation between the terminal ligand of the dendrimer and a terpyridinyl ruthenium chloride building block afforded the dodecaruthenium cascade molecule 80 (Fig. 35). Thus, preconstructed cores and dendritic fragments were linked by Ru2+ as the connecting unit and this mode of connectivity could be denoted by [—(Ru)—]. 

N-Aziridinylimines are valuable substrates for domino radical cydizations since they are able to serve simultaneously as radical acceptors and donors. They allow a versatile and general construction of quaternary carbon centers from carbonyl compounds [33]. By employing this methodology, an elegant and stereoselective synthesis of ( )-modhephene (3-70), one of the rare naturally occurring [3.3.3]propellanes,... 

They have developed direct asymmetric synthesis of quaternary carbon centers via addition-elimination process. The reactions of chiral nitroenamines with zinc enolates of a-substituted-8-lactones afford a,a-disubstituted-6-lactones with a high ee through addition-elimination process, in which (5)-(+)-2-(methoxy methy l)pyrrolidine (SMP) is used as a chiral leaving group (Eq. 4.96).119 Application of this method to other substrates such as a-substituted ketones, esters, and amides has failed to yield high ee. 

The previous section discussed chelation enforced intra-annular chirality transfer in the asymmetric synthesis of substituted carbonyl compounds. These compounds can be used as building blocks in the asymmetric synthesis of important chiral ligands or biologically active natural compounds. Asymmetric synthesis of chiral quaternary carbon centers has been of significant interest because several types of natural products with bioactivity possess a quaternary stereocenter, so the synthesis of such compounds raises the challenge of enantiomer construction. This applies especially to the asymmetric synthesis of amino group-substituted carboxylic acids with quaternary chiral centers. 

The study of Fuji et al. shows that the addition of lithium enolate 75 to ni-troamine 74 is readily reversible quenching conditions are thus essential for getting a good yield of product 76. An equilibrium mixture of the adducts exists in the reaction mixture, and the elimination of either the prolinol or lactone moiety can take place depending on the workup condition (Scheme 2-34). A feature of this asymmetric synthesis is the direct one pot formation of the enantiomer with a high ee value. One application of this reaction is the asymmetric synthesis of a key intermediate for indole type Aspidosperma and Hun-teria alkaloids.68 Fuji69 has reviewed the asymmetric creation of quaternary carbon atoms. 

For a review of catalytic en-antioselective methods for the synthesis of quaternary carbon stereogenic centers, see a) E. J. Corey, A. Guzman-Perez, Angew. Chem. Int. Ed. 1998, 37, 388-401. For more recent examples, see b) B. M. Trost,... 

Pd-catalyzed Heck reactions are among the most effective methods for the formation of quaternary carbon centers. Considering the significance and the strategic difficulties associated with the synthesis of quaternaiy carbons, particularly in the optically enriched or pure form, it is not a surprise that the development of catalytic asymmetric Heck reactions has held center stage for the past few years. One of the leading labs in this area is that of Shibasaki, who in 1993 reported a concise total synthesis of eptazodne 23 (Scheme 4).141 Thus, treatment of silyl ether 18 with 10 mol% Pd(OAc>2 and 25 mol% (S)-19 leads to the formation of 20 in 90 % yield and 90% ee As illustrated in Scheme 4, once the quaternary carbon center is synthesized efficiently and selectively, the target molecule is accessed in a few steps. 

T. Takemoto, M. Sodeoka, H. Sasai, M. Shibasaki Catalytic Asymmetric Synthesis of Benzylic Quaternary Carbon Centers. An Efficient Synthesis of (-)-Eptazocine , J. Am. Chem. Soc 1993,115, 8477-8478. 

The above method has been applied to a stereoselective synthesis of cyclopenta-nones with quaternary carbon centers (Scheme 16.21) [25],... 

Since the conversion of 235 to 233 requires only heating, it is possible to synthesise the vinylketenimine complex directly from the vinylketene merely by extending the reaction time sufficiently.69,87,89 Note that 233.j and 233.k were obtained as 1 1 mixtures of diastereoisomers. The subsequent reactivity of the vinylketenimine complexes,87,89,135,143 particularly their utility in the asymmetric synthesis of quaternary carbon centers,143 has also been investigated, but is beyond the scope of this review. 

Conjugate addition [2] to Michael acceptors is the most important and useful reaction in organocopper chemistry, and the reaction is often used as the key step in the synthesis of numerous natural and unnatural products. Perhaps one of the most efficient methods for the synthesis of quaternary carbon centers is organo-copper-mediated conjugate addition to /I, yS-disubstituted enones. 

The first synthesis of a semibuckminsterfullerene was accomplished by a procedure analogous to the preparation of corannulene except that 1,2,5,6-tetrake-topyracene served as the starting material (Scheme 5). Flash vacuum pyrolysis of the tetrachloro compound led to a remarkable quadruple ring closure to produce the semi-buckminsterfullerene 27. The NMR shows three methine carbons and five quaternary carbons at 125.5, 126.8, 127.3, 128.6, 136.7, 137.3, 142.0, and 145.4 ppm. The latter signals compare favorably to the single resonance observed at 143 ppm for buckminsterfullerene. 

In another early application to natural product synthesis, Fleming and coworkers utilized this approach in the efficient formation of the gelsemine model (47) from 45 according to Scheme 8. The cyclization step to form the spiro-oxindole (46) proceeded in 85% yield and provided a means of generating the spiro-fused quaternary carbon without the need for carbenium ion or carbanion chemistry. 

The synthesis of [4.4.4.4]fenestrane or windowpane has become an active area of research due to the aesthetic appeal of the hydrocarbon and the nature of its central quaternary carbon atom which is expected to be distorted from normal tetrahedral geometry . Ongoing investigations have generated a number of ring-expanded triquinane and tetraquinane ([5.5.5.5]fenestrane) homologs. These molecules form the subject matter of the discussion which follows. 

Meyers and co-workers recently reported a ketenrmine rearrangement that has been applied to the synthesis of ketones containing a chiral a-quaternary carbon. As... 

Introduction of a quaternary carbon center is readily achieved by PKR. Takano and Zard independently employed this methodology for the synthesis of (—)-dendrobin (Equation (44)). ... 

A number of methods for formation of a quaternary carbon are given below synthesis of ct-cedrene and / -cedrene... 

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