Stereocontrolled additions natural products

Stereocontrolled Additions to Dihydropyridines and Tetrahydropyridines Access to N-Heterocyclic Compounds Related to Natural Products... 

The final chapter in this volume by R. Kumar and R. Chandra (University of Delhi, India) deals with stereocontrolled additions to di- and tetrahydropyridines and particularly their application to natural product synthesis. 

The intramolecular Heck reaction presented in Scheme 8 is also interesting and worthy of comment. Rawal s potentially general strategy for the stereocontrolled synthesis of the Strychnos alkaloids is predicated on the palladium-mediated intramolecular Heck reaction. In a concise synthesis of ( )-dehydrotubifoline [( )-40],22 Rawal et al. accomplished the conversion of compound 36 to the natural product under the conditions of Jeffery.23 In this ring-forming reaction, the a-alkenylpalladium(n) complex formed in the initial oxidative addition step engages the proximate cyclohexene double bond in a Heck cyclization, affording enamine 39 after syn /2-hydride elimination. The latter substance is a participant in a tautomeric equilibrium with imine ( )-40, which happens to be shifted substantially in favor of ( )-40. 

Successful applications of these stereocontrolled conjugate additions have led to asymmetric syntheses of several natural products such as (+ )-cuparenone (39) which involves formation of a quaternary carbon center81, (- )-/ -vetivone (40)8° and steroidal equilenin 4182 the wavy lines in these structures indicate that C—C bond formed stereoselectively under the influence of a temporarily-attached stereogenic sulfoxide auxiliary group. 

Schreiber and his coworkers have published extensively over the past decade on the use of this photocycloaddition for the synthesis of complex molecules730 81. Schreiber was the first to recognize that the bicyclic adducts formed in these reactions could be unmasked under acidic conditions to afford threo aldol products of 1,4-dicarbonyl compounds (175 to 176) (Scheme 40). The c -bicyclic system also offers excellent stereocontrol in the addition of various electrophilic reagents (E—X) to the enol ether of these photoadducts on its convex face (175 to 177). This strategy has been exploited in the synthesis of a variety of architecturally novel natural products. 

When Wacker-type reactions are performed under a CO atmosphere, the (3-H elimination pathway can be suppressed in favor of CO insertion and subsequent nucleophilic cleavage of the acyl metal species.399 This alkoxycarbonylation process has found widespread utility, particularly in the synthesis of five- and six-membered oxacyclic natural products. For example, the THF core of tetronomycin was prepared by the Pd-catalyzed alkoxycarbonylation of 4-alkenol derivatives (Equations (117) and (118)), where stereocontrol was achieved by utilizing either the directing ability of a free hydroxyl or the conformational bias imposed by a bulky silyl ether.420 Additional examples making... 

The silylcuprate conjugate addition reaction has been used for the protection of an enone double bond, which can be regenerated with CuBr2 [22a], and for the strategic introduction of the silyl substituent for stereocontrol and regiocontrol purposes. Enantiopure 5-trimethylsilyl-2-cyclohexenone can be prepared by conjugate addition reaction [44] and the appropriate enantiomer has been converted into a number of natural products (Scheme 3.4) [38]. These synthetic strategies exploit... 

Steroid side chain.1 The key step in a method for stereocontrolled addition of the side chain to 17-kelo steroids is hydroboration of a 17(20)-(Z)-ethylidene steroid (I), which proceeds selectively to give 2, with the desired natural configuration at C,- and C2ft. The product reacts with most alkylating reagents in rather low yield, possibly because of stcric factors however alkylation with the anion of chloroacetonitrile (potassium 2,6-di-r-butyl-4-methylphenoxide) in T1IF gives the nitrile 3 in 60 70% yield. One added attraction of this route is that 9-BBN reacts preferentially with a 17(20)-double bond in the presence of a 5(6 )-double bond. 

Kumar, R. Chandra, R. Stereocontrolled Additions to Dihydropyridines and Tetrahydropyridines Access to N-Heterocyclic Compounds Related to Natural Products. Adv. Heterocycl. Chem. 2001, 78, 269-313. 

Lactones are normally stable compounds, which have found ample application as synthetic intermediates, and, quite recently, have been detected as the central structural unit in physiologically active natural products like obaflorin (123) and lipstatin (124). Characteristic applications of 3-lactones in synthesis are the stereospecific CO2 elimination to form di- and tri-substituted alkenes (e.g. from 125 equation 40) or Grignard addition to the carbonyl group e.g. equation 41). Particularly useful is the formation of 3-lactone enolates (126), which react with a variety of electrophiles (EX) wiA high stereocontrol (equation 42). Organocuprates may be used in chain elongations to form 3-branched carboxylic acids (equation 43). ... 

A different outcome in the presence of an additional vinylic oxygen was observed by Overman s group (Scheme 52). The formation of the five-membered cyclic ether (108) is rationalized in terms of an SnCU-mediated acetal ring opening of (105), subsequent cyclization of (106) to (107), followed by a ring contraction to (108) by a pinacol-type rearrangement. This stereocontrolled reaction proved to be applicable to the synthesis of related natural products. ... 

Stereocontrolled additions to dihydropyridines and tetrahydropyridines as an access to N-heterocycles related to natural products 01AHC(78)269. 

The stereocontrolled synthesis of 1,2-aminols is of interest due to the utility of these substances as efficient synthons for a variety of natural products. A highly stereoselective addition of lithium alkyls or Grignard reagents to the 0-protected a-hydroxy-A-trimethylsi-lylimines generated in situ constitutes the path for the preparation of these 1,2-aminols. Thus, the addition-elimination reaction of lithium hexamethylsilylamide with aldehyde 129, easily obtained in two steps from 103, leads to the a-OTBS-A -TMS-imine 130 (Scheme 30). 

---