Contiguous asymmetric centers

The 1,3-dipolar cycloaddition reaction of nitrones with alkenes gives isoxazolidines is a fundamental reaction in organic chemistry and the available literature on this topic of organic chemistry is vast. In this reaction until three contiguous asymmetric centers can be formed in the isoxazolidine 17 as outlined for the reaction between a nitrone and an 1,2-disubstituted alkene. The relative stereochemistry at C-4 and C-5 is always controlled by the geometric relationship of the substituents on the alkene (Scheme 8.6). 

The mechanism of 1,3-dipolar cycloaddition can be found in Ref. 63 and the references within. The reaction of nitrone with 1,2-disubstituted alkenes creates three contiguous asymmetric centers, in which the geometric relationship of the substituents of alkenes is retained. The synthetic utility of nitrone adducts is mainly due to their conversion into various important compounds. For instance, P-amino alcohols can be obtained from isoxazolidines by reduction with H2-Pd or Raney Ni with retention of configuration at the chiral center (Eq. 8.44). 

Substituted 4,5-dihydro-5-vinylisoxazoles (40), obtained by regio- and stereospecific cycloaddition of nitrile oxides to dienes, undergo smooth osmium-catalyzed c/s-hydro-xylation to give amino-polyol precursors (equation 28)45. The reaction is anti selective, the diastereomeric ratios ranging from 73 27 up to 99 1. Highest stereoselectivities were observed when R3 was methyl. Thus, whereas osmylation of 40a afforded a 78 22 mixture of 41a and 42a, respectively, in 80% overall yield, similar treatment of 40b resulted in a 92 8 mixture of 41b and 42b, respectively, in 70% overall yield. The cycloaddition-osmylation sequence allows control of the relative configuration of up to 4 contiguous asymmetric centers. 

Treatment of 6-lithio-3,4-dihydro-2H-pyran (660) with the epoxy iodide (661) afforded the epoxydihydropyran (662). Compound (662) cyclized on exposure to basic A1203 to a single hydroxydihydropyran (663) which was oxidized with Collins reagent to the keto aldehyde (664) containing three contiguous asymmetric centers of fixed stereochemistry (Scheme 153). The metallated dihydropyrans have also found use in the construction of keto lactones (78JA7101). 

Addition of an organocuprate to the chiral ester (5) followed by similar a-acetoxylation results in generation of two contiguous asymmetric centers to give 7 with high optical purity. 

The diastereoselective alkylation and aldol reactions possible with the propionimide 7 were used to obtain the three contiguous asymmetric centers in a stereoselective synthesis3 of (+ )-Prelog-Djerassi lactone (8), a degradation product of methymycin. 

In the 3-lactam area, Grieco et al. have applied their development of substituted bicyclo[2.2.1]hep-tanes to a synthesis of the thienamycin precursor (188a), embedded in which are three contiguous asymmetric centers corresponding to C-5, C-6 and C-8 in the natural product (190). Readily obtained bromo aldehyde (187), upon treatment with the MeLi-derived higher order cuprate Me2Cu(CN)Li2 in... 

Thiazolines activated with an equivalent of BF3 readily react with a wide range of organometals, giving tranj-4,5-disubstituted thiazoles stereoselectively. Alkyllithiums, Grignard reagents, lidiium alkynides, nitronates, ester and ketone enolates have been employed as the nucleophile. Stereocontrolled construction of three contiguous asymmetric centers is performed with a lithiated isothiocyanatoacetate, and the product is successfully transformed to (+)-biotin (Scheme 27), ° ... 

Sulfide has also been involved in a new two-step annulation method which featured stereospecific formation of three contiguous asymmetric centers. It was found that the lithium dienolate of the vinyl-ogous ester (6a) reacts rapidly with the a-thiophenyl butenolide (6b) to provide the corresponding adduct as a single diastereoisomer. Subsequent addition of vinyllithium, acidification and cyclization gave the tricyclic lactone (Scheme 30). 

The synthesis of lycorine-type alkaloids has received the attention of chemists as a target for exploration of new synthetic methods, because the stereoselective construction of the contiguous asymmetric centers reported until now is not always efficient. Since the previously published review (S), two investigations of the total synthesis of ( )-lycorine (1) (118), and the first total syntheses of optically active (+)-lycorine (1) and (+)-l-deoxylcorine (84) (119), the unnatural enantiomer of lycorine (1), were reported. Both of the synthetic strategies involve the construction of highly functionalized hexahydroindoline derivatives, followed by cyclization to form ring B. 

The synthesis of antimycin A3 (676), a potent antifungal agent, makes use of lactaldehyde 658 to establish the stereochemistry of the three contiguous asymmetric centers in the eastern half of the dilactone skeleton via intermediate 678. Strategically, the 4,5-diphenyl-oxazole heterocycle is used as a template for protection of the latent activated carboxylate group, which is unmasked by photooxygenation [120,200]. The chiral western half of the dilactone framework is derived from the differentially protected L-threonine derivative 677. 

Lee synthesized 2,6-czs-disubstituted tetrahydropyrans via radical cychzation in the total synthesis of lasonolide A (Sect. 3.1.1). hi this synthesis, Lee also achieved the 6-endo, 6-exo tandem radical cychzation constructing two contiguous asymmetric centers containing a quaternary carbon (Scheme 7). 

Under Br0nsted acidic condition, the transformation was slower but furnished exclusively the desired spiro compound 152 in an excellent yield. The two reactions under Au(l) or Brpnsted acid catalysis proceeded under very mild conditions in a stereoselective manner and two new contiguous asymmetric centers were formed. 

Especially when combining two or more pericyclic reactions with each other, the outcome is highly efficient and could be almost qualified as miraculous, as each cycloaddition event could introduce a new ring, two new covalent bonds, and up to four new contiguous asymmetric centers in one step. Moreover, great progress has been achieved in the intramolecular and asymmetric pericyclic reactions recently, which provide highly effective approaches for the rapid elaboration of complex polycyclic systems. Some prominent total syntheses achieved based on pericyclic MBFTs will be exemplified below. 

Carpanone 58 is a lignan isolated from the bark of the Carpano tree it possesses no element of symmetry by having five contiguous asymmetric centers. Its biomimetic synthesis, first reported by Chapman et al., was accomplished by diastereoselective oxidative homocoupling of an electron-rich o-hydroxystyrene followed by rapid CKi/o-selective inverse-electron demanding Diels-Alder... 

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