Quaternary centers, asymmetric synthesis

Trost, B. M. Tang, W. Schulte, J. L. Asymmetric synthesis of quaternary centers. Total synthesis of (-J-malyngolide. Org. Lett. 2000, 2, 4013-4015. 

Krische and coworkers [44] developed a Rh-catalyzed asymmetric domino Michael/aldol reaction for the synthesis of substituted cyclopentanols and cyclohex-anols. In this process, three contiguous stereogenic centers, including a quaternary center, are formed with excellent diastereo- and enantioselectivity. Thus, using an enantiopure Rh-BINAP catalyst system and phenyl boronic acid, substrates 2-108 are converted into the correspondding cyclized products 2-109 in 69-88% yield and with 94 and 95% ee, respectively (Scheme 2.24). 

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 asymmetric synthesis of a galanthamine alkaloid relies also on the intramolecular Heck reaction for the preparation of the benzo[h]furan-based key intermediate with a crucial chiral quaternary center, which eventually leads to the synthesis of (-)-galanthamine <00JA11262>. A similar approach towards the construction of galanthamine ring system via an intramolecular Heck reaction has also been investigated <00SL1163>. 

The asymmetric arylation of ketone enolates represents an attractive method for the preparation of optically active carbonyl compounds with a stereogenic quaternary center at the a-position to the carbonyl group. Such types of compounds are important intermediates for natural product synthesis. Replacement of BINAP by 109 provides... 

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. 

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. 

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. 

Deprotonation at an activated 4-position has been employed extensively in asymmetric synthesis, which is the key step in the Seebach protocol for the preparation of a-alkyl amino acids.The existing alkyl group at the 5-position acts as a directing group for the alkylation and is oriented trans to the new alkyl group (Scheme 8.118). This reaction provides an efficient methodology for normally difficult stereoselective construction of a quaternary chiral center. 

In summary, of the many chiral auxiliaries used in the asymmetric synthesis of carbonyl compounds via imines, those able to form a methoxymethyl-chclated azaenolate show the best enantioselectivities (see Tabic 7). The same is true for valine and im-leucine derivatives which form rigid chelates via their carboxyl groups. In particular, quaternary centers (see Table 6) and a-alkvl-/i-oxo esters arc effectively prepared using these chiral auxiliaries. 

One of the severest challenges of asymmetric synthesis is the direct enantioselective construction of quaternary stereogenic centers. Brian Pagenkopof of the University of Texas has reported (Chem. Communications 2003 2592) that alkynyl aluminum reagents will open a trisubstituted epoxide such as 10 at the more substituted center, with inversion of absolute configuration. As the epoxide 10 is available in high from 9 by the method of Yian Shi of Colorado State (J. Am. Chem. Soc. 119 11224, 1997), this opens a direct route to quaternary cyclic stereogenic centers. 

Scheme 82 shows the intramolecular version of the reaction using an alkenyl iodide in the presence of the same Pd system containing silver phosphate (194,195). The reaction can also be used for the asymmetric synthesis of quaternary carbon centers. 

For a recent review on catalytic asymmetric synthesis of quaternary carbon centers, see Corey, E. J. Guzman-Perez, A. Angew. Chem., Int. Ed. 1998, 37, 388. 

Recently, Trost reported an efficient Pd-catalyzed asymmetric allylic alkylation of 1-tetralones [175] and a-arylketone 83 creating a quaternary center as exemplified by the synthesis of 84 (Scheme 7) [176]. Two a-heterocyclic ketones were also alkylated with similar results. Ferrocene-based ligands are effective in pro-... 

Scheme 6. Asymmetric synthesis of a-amino acids bearing a quaternary stereo-genic center...

An efficient asymmetric synthesis of six-membered quinoline derivatives bearing a quaternary carbon center or a spiro-ring by an ene-type cyclization of 1,7-enynes catalyzed by the cationic BINAP-Pd(ll) complex was reported <03JA4704>. 

The efficiency of the palladium-catalyzed asymmetric alkylation of ketone enolates was shown by Trost and coworkers in their synthesis of hamigeran B (50), a potent antiviral agent with low cytotoxicity to host cells (equation 15). The quaternary center... 

Scheme 6-40 Asymmetric Heck reaction to form a quaternary center from a total synthesis of (—)-physostigmine.

Denmark, S. E., Fu, J. Asymmetric Construction of Quaternary Centers by Enantioselective Allylation Application to the Synthesis of the Serotonin Antagonist LY426965. Org. Lett. 2002,4,1951-1953. 

Iserloh, U., Curran, D. P. Catalytic asymmetric synthesis of quaternary carbon centers investigation of intramolecular Heck reactions and... 

Scheme 12.12 shows an example of where asymmetric installation of a quaternary center was a key step in the synthesis of the enantiomer of a chiral natural product, which occurred in 4% overall yield without the use of protecting groups.75... 

Overman s group [67] enlisted an intramolecular Heck reaction to form a quaternary center in their synthesis of gelsemine. When the cyclization precursor 68 was subjected to ligandless conditions [Pd ldbajj, Et N] in the weakly coordinating solvent toluene, the quaternary center was formed with 9 1 diastereoselectivity (70 69 = 89 11). In contrast, use of the coordinating solvent THF and a stoichiometric amount of an added silver salt completely reversed the sense of asymmetric induction in the cyclization reaction (70 69 = 3 97). 

Optically active methyloctalone 3 (or its enantiomer) has been obtained by resolution and by asymmetric synthesis. Both enantiomers are also available commercially. The synthesis described here is by far the most simple and gives the best yield. It is an application of the general method reported for the enantioselective elaboration ol quaternary carbon centers through Michael-type alkylation of chiral imines. ... 

Scheme 5.43 illustrates three applications of this methodology to total synthesis. The first exeunple is taken from Posner s synthesis of estrone and estradiol [211], the second from Posner s synthesis of methyl jasmonate [212], and the third from Holton s synthesis of aphidicolin [213]. The latter is particularly noteworthy in that two contiguous quaternary centers are created in the asymmetric addition with excellent selectivity. In the estrone synthesis, the chirality sense of the product is consistent with the nonchelate model, but the other two examples adhere to a chelate model. Note that the difference is the degree of substitution at the a-position of the enolate. 

The first examples of asymmetric Heck cyclizations that form quaternary carbon centers with high enantioselectivity came from our development of an asymmetric synthesis of the pharmacologically important alkaloid (—)-physosligmine (184) and congeners (Scheme 6-31) [68], In the pivotal reaction, (Z)-2-butenanilide iodide 182 was cyclized with Pd-(S)-BINAP to provide oxindole 183 in 84% yield and 95% ee after hydrolysis of the intermediate silyl enol ether. With substrates of this type, cyclizations in the presence of halide scavengers took place with much low er enantioselectivity [68]. 

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