Esters quaternary stereocenters

Quaternary stereocenters can be obtained with high selectivity with ot-amino acid amides as chiral auxiliaries, which were first converted with P-oxo esters to give enamines such as compounds 58. According to a combinatorial strategy, various enamino esters 58 were screened in Michael additions with MVK (41a) and several metal salts as catalysts. With FeCl3, however, the maximum stereoselectivity achieved was only 77% ee (with enamine 58a derived from L-isoleucine dimethylamide). Cu(0Ac)2H20 turned out be the optimal catalyst for this transformation. With L-valine diethylamide as chiral auxiliary in compound 58b, reaction proceeds with 86% yield and 98% ee after aqueous workup [79]. Importantly, this valuable method for the construction of quaternary stereocenters [80] under ambient conditions seems to be generally applicable to a number of Michael donors [81]. In all cases, the auxiliary can be quantitatively recovered after workup. 

Efficient, highly enantioselective construction of quaternary stereocenter on P-keto esters under phase-transfer conditions has been achieved using N-spiro chiral quaternary ammonium bromide lh as catalyst [32]. This system has a broad generality in terms of the structure of P-keto esters 65 and alkyl halides (Scheme 5.31). 

Access to enantioenriched carbonyl compounds of high value which possess quaternary a-carbon stereocenters containing hetero-functionalities represents one of the most challenging tasks in phase-transfer-catalyzed asymmetric alkylation. In due course, Maruoka and coworkers devised the asymmetric alkylation of cyclic a-amino-P-keto esters 67 with C2-symmetric phase-transfer catalyst lh as a means of obtaining aza-cyclic amino acids with quaternary stereocenters (Scheme 5.32) [33]. 

Asymmetric conjugate addition of a-substituted-oc-cyanoacetates 77 to acetylenic esters under phase-transfer conditions is somewhat of a challenge, because of the difficulty encountered in controlling the stereochemistry of the product. In addition, despite numerous examples of the conjugate additions to alkenoic esters, no successful asymmetric conjugate additions to acetylenic esters have been reported to date. In this context, Maruoka and coworkers recently developed a new morpholine-derived phase-transfer catalyst (S)-76 and applied it to the asymmetric conjugate additions of a-alkyl-a-cyanoacetates 77 to acetylenic esters, as indicated in Table 5.11 [40], In this asymmetric transformation, an all-carbon quaternary stereocenter can be constructed with a high enantiomeric purity. 

The C7 quaternary stereocenter of (+)-gelsemine was established utilizing a Johnson-Claisen rearrangement by S.J. Danishefsky and co-workers.The starting stereoisomeric allylic alcohols were individually subjected to the rearrangement conditions, and each gave rise to the same Y,5-unsaturated ester. 

Sarains A-C are a family of alkaloids isolated from marine sponges. J.K. Cha and co-workers accomplished the synthesis of the western macrocyclic ring of sarain To establish the C3 quaternary stereocenter, they treated the aldehyde substrate with formaldehyde in the presence of sodium carbonate. The aldehyde substrate underwent an aldol reaction followed by a Tishchenko reaction to provide the formate ester of the 1,3-diol product. This ester was hydrolyzed in situ under the reaction conditions and the 1,3-diol was isolated. 

Scheme 11.11 Construction of quaternary stereocenters on P-keto esters by alkylation with the catalysis of 9h.

As in the case of all variations of the Clasien rearrangement, the [3,3]-sigmatropic process is routinely applied for the construction of stereogenicity at quaternary carbon centers. During studies toward the total synthesis of meloscine, orthoester Johnson-Claisen rearrangement was utilized as the key bond formation event when many other attempts to construct the C5 quaternary stereocenter in this sterically-demanding environment failed. Treatment of 351 with trimethyl orthoacetate at elevated temperature readily afforded the ester 352 with moderate diastereoselection." ... 

As a result of the many advantages of the allyl p-ketoesters, we were able to quickly prepare a large number of substrates and demonstrate that the reaction gave yields and enantioselectivities equivalent to the other classes of substrates (Table 9). Additionally, we were able to access a number of products that we had not been able to access previously, such as enantioenriched tertiary fluorides, vinylogous esters and thioesters, nitrogen heterocycles, and compounds containing multiple quaternary stereocenters. These advances comprised the bulk of our secmid paper in the field [25]. 

The construction of a quaternary a-stereocenters was demonstrated in the 117-catalyzed Mannich addition [72] of methylcyclo-pentanone-2-carboxylate to N-Boc-protected aromatic aldimines and furnished the adducts 1-3 in 70-97% yield, with good ee values (85-87%) and diastereoselectivities (Scheme 6.115). The authors exemplified the synthetic utility of the protocol by a simple racemization-free decarboxylation of the Mannich adduct of N-Boc benzaldimine and dimethyl malonate to obtain the respective N-Boc-protected p-amino ester (68% yield/89%... 

Silylene transfer to a -unsaturated esters produces oxasilacyclopentenes and provides a new method for regio- and stereo-selective formation of enolate that can undergo facile and selective Ireland-Claisen rearrangements and aldol addition reactions to provide products with multiple contiguous stereocenters and quaternary carbon centers (Scheme 37). 

Formation of Chiral Quaternary Carbon. Birch reduction-alkylation of benzoic acids and esters establishes quaternary carbon centers. Neighboring stereocenters will influence the stereochemical outcome of the tandem reaction sequence. The following example illustrates how a chiral auxiliary (derived from prolinol) controls the stereoselection in the Birch reduction-alkylation step. ... 

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