Intramolecular enantioselective synthesis

The catalytic oxidative carbonylation of allene with PdCb and CuCh in MeOH affords methyl a-methoxymethacrylate (559)[499]. The intramolecular oxidative aminocarbonylation of the 6-aminoallene 560 affords the unsaturated J-amino ester 561. The reaction has been applied to the enantioselective synthesis of pumiliotoxin (562)[500]. A similar intramolecular oxycarbonyla-tion of 6-hydroxyallenes affords 2-(2-tetrahydrofuranyl)acrylates[501]. 

Silyl ethers serve as preeursors of nucleophiles and liberate a nucleophilic alkoxide by desilylation with a chloride anion generated from CCI4 under the reaction conditions described before[124]. Rapid intramolecular stereoselective reaction of an alcohol with a vinyloxirane has been observed in dichloro-methane when an alkoxide is generated by desilylation of the silyl ether 340 with TBAF. The cis- and tru/u-pyranopyran systems 341 and 342 can be prepared selectively from the trans- and c/.y-epoxides 340, respectively. The reaction is applicable to the preparation of 1,2-diol systems[209]. The method is useful for the enantioselective synthesis of the AB ring fragment of gambier-toxin[210]. Similarly, tributyltin alkoxides as nucleophiles are used for the preparation of allyl alkyl ethers[211]. 

Diisocyanoadociane, a novel marine-derived diterpenoid, was analyzed retrosynthetically using the intramolecular Diels-Alder transform as T-goal concurrently with topological and stereochemical guidance. The enantioselective synthesis outlined below allowed assignment of absolute configuration. 

N-donor ligand. The reaction appears to proceed via an acyclic iminoplatinum(II) intermediate that undergoes a subsequent intramolecular cyclization. Some mechanistic aspects of this versatile reaction have been elucidated.225,226 A4-l,2,4-oxadiazolines have been prepared by the [2+3] cycloaddition of various nitrones to coordinated benzonitrile in m-[PtCl2( D M SO)(PhCN)] precursors.227,228 Racemic and chiral [PtCl2(PhMeSO)(PhCN)] complexes have also been used in order to introduce a degree of stereoselectivity into the reaction, resulting in the first enantioselective synthesis of A4-l,2,4-oxadiazolines, which can be liberated from the complexes by the addition of excess ethane-1,2-diamine. 

Izquierdo et al. reported the enantioselective synthesis of 5-O-methylthioswainsonine 53 from a derivative a d-glucose as a single stereoisomer. Intramolecular alkylation of the tosylate precursor 52 created the bicyclic system in the final step of the synthesis as outlined in Equation (17) <1996TA2567>. 

Methods for the enantioselective synthesis of 3-substituted indolines by means of the asymmetric intramolecular carbolithiation of 2-bromo-A,-allylanilines in the presence of (-)-sparteine were reported simultaneously by Bailey <00JA6787> and Groth <00JA6789>. Thus, addition of 89 to 2.2 equiv of /BuLi in the presence of the chiral ligand generates the lithium intermediate 90 which upon quenching with methanol affords the chiral indoline 91 in a process that is highly solvent dependent. 

Stereoselective intramolecular oxymercuration of carbohydrate derivatives was proposed as the key reaction for efficient preparation of mono- and dihydroxylated unsymmetrical bis-tetrahydrofuran skeletons present in naturally occurring biologically active acetogenins. The trans- and. mz-selective intramolecular oxymercurations were explored in an enantioselective synthesis of the bis-tetrahydrofuran skeleton of mucoxin (Fig. 57).73... 

An enantioselective synthesis of the Ziegler intermediate 107 of forskolin (108) has been achieved using an intramolecular allenic Diels-Alder reaction (Scheme 19.20) [24], Treatment of propargyl ether 104 with potassium tert-butoxide in tert-butanol affords 106, presumably through the intermediate allene 105. Compound 106 was obtained as a single stereoisomer. 

This approach sets the stage for an enantiotopos-differentiating olefin metathesis which would allow the enantioselective synthesis of 258. However, the realization of such an approach has not yet been successful [132]. The second building block (259) containing the A ring was synthesized diastereoselectively by a diastereoface-differentiating intramolecular Heck-Mizoroki reaction of the enantiomerically enriched furan 260 [120]. 

The proline-mediated intramolecular aldol condensation of dialdehyde substrates was also reported by List in 2003, affording enantioselective synthesis of cyclic p-hydroxy aldehydes via a 6-e ofexo-aldolization reaction (Scheme 11.7d). 

Another enantioselective synthesis of longifolene, shown in Scheme 13.27, uses an intramolecular Diels-Alder reaction as a key step. The alcohol intermediate is resolved in sequence B by formation and separation of a menthyl carbonate. After oxidation, the pyrone ring is introduced by y addition of the ester enolate of methyl 3-methylbutenoate. 

The use of chiral 2-alkylidene-l,3-dithiane 1,3-dioxides in asymmetric cycloaddition reactions has been demonstrated. A highly enantioselective synthesis of (—)-cispentacin by an intramolecular 1,3-dipolar cycloaddition was reported (Scheme 52) <20020L1227, 20030BC684>. 

Cha and co-workers (50) reported a short enantioselective synthesis of the indo-lizidine alkaloid, (—)-swainsonine (247) involving an intramolecular cycloaddition... 

Cha and co-workers (71) reported an enantioselective synthesis of the amylo-glucosidase inhibitor 6,7-diepicastanospermine (376) based on an intramolecular... 

Thus, (2R)-pumiliotoxin C (214) has been prepared from (R)-norvaline (212). The asymmetric center in the triene (213) controls the configuration at three carbon atoms 210). a-Kainic acid, isolated from the algae Digena simplex and Centrocerus clavulatum, was prepared by total synthesis. Its enantioselective synthesis involved a stereocon trolled intramolecular cycloaddition of a (S)-glutamic acid211). Asymmetric cycloadditions also play a decisive role in the synthesis of chiral cytochalasins. In this case 212> the primary chiral information was carried by (S)-alanine and (S)-phenylalanine, respectively. 

It is interesting to note that the oxa-analogous Michael addition was reported for the first time in 1878 by Loydl et al. [19] in their work on the synthesis of artificial malic acid, which was five years ahead of the discovery of the actual Michael reaction described first by Komnenos [20], Claisen [21], and later Michael in 1887 [22] as one of the most important methods for C—C bond formation. In continuation of the early work on the oxa-Michael addition [23], the inter- and intramolecular additions of alkoxides to enantiopure Michael acceptors has been investigated, leading to the diastereo- and enantioselective synthesis of the corresponding Michael adducts [24]. The intramolecular reaction has often been used as a key step in natural product synthesis, for example as by Nicolaou et al. in the synthesis of Brevetoxin B in 1989 [25]. The addition of oxygen nucleophiles to nitro-alkenes was described by Barrett et al. [26], Kamimura et al. [27], and Brade and Vasella [28]. 

Many methods have been developed for the enantioselective synthesis of unnatural a-amino acids. Jeff Johnston of Indiana University reports (J. Am. Chem. Soc. 125 163,2003) coupling the asymmetric alkylation of O Donnell with intramolecular radical cyclization, leading to what appears to be a general method for the enantioselective construction of indolines. 

It is noteworthy that stereochemical control of the two new stereogenic centers at C4a and Cl2b ultimately stems from the stereochemistry at Cl through the intramolecular Diels-Alder reaction. Hence, an optically pure 46 should lead to an enantioselective preparation of a-epoxy lactone 48, thereby ultimately leading to an enantioselective synthesis of arisugacin A [1], LAH reduction of ( )-a-epoxy lactone 48 led to epoxy diol 49 in 78%... 

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