Intramolecular diastereocontrol

SCHEME 32. Generation of a chiral lithium enolate by intramolecular diastereocontrolled conjugate addition148... 

A key intermediate, 163, which possesses all but one chiral center of (+ )-brefeldin, has been prepared by the enantiocontrolled cycloaddition of the chiral fi,/3-unsaturated ester 162 to 154[107], Synthesis of phyllocladane skeleton 165 has been carried out by the Pd-catalyzed cycloaddition of the unsaturated diester 164 and cobalt-catalyzed cycloaddition of alkynes as key reactions[108]. Intramolecular cycloaddition to the vinylsulfone in 166 proceeds smoothly to give a mixture of the trans and cis isomers in a ratio of 2.4 1[109], Diastereocontrolled cycloaddition of the hindered vinylsulfone 167 affords a single stereoisomeric adduct, 168, which is used for the synthesis of the spirocarbocyclic ring of ginkgolide[l 10],... 

Addition of such a-lithiosulfinyl carbanions to aldehydes could proceed with asymmetric induction at the newly formed carbinol functionality. One study of this process, including variation of solvent, reaction temperature, base used for deprotonation, structure of aldehyde, and various metal salts additives (e.g., MgBrj, AlMej, ZnClj, Cul), has shown only about 20-25% asymmetric induction (equation 22) . Another study, however, has been much more successful Solladie and Moine obtain the highly diastereocontrolled aldol-type condensation as shown in equation 23, in which dias-tereomer 24 is the only observed product, isolated in 75% yield This intermediate is then transformed stereospecifically via a sulfoxide-assisted intramolecular 8, 2 process into formylchromene 25, which is a valuable chiron precursor to enantiomerically pure a-Tocopherol (Vitamin E, 26). 

The preference for the /3-silyl isomer product complements methods available for hydrostannation of alkynes, for which the a-stannyl regioisomer is formed preferentially.70 7011 70c In addition, the /3-silyl products serve as the platform for a tertiary alcohol synthesis (Scheme 15). Upon treatment of vinylsilanes such as B with tetrabutylam-monium fluoride (TBAF) in DMF at 0 °C, a 1,2 carbon-to-silicon migration occurs, affording the tertiary heterosilane E. Oxidation of the C-Si bond then provides the tertiary alcohol. Good 1,2-diastereocontrol has been demonstrated for y-alkoxy substrates, as in the example shown. The studies suggest that the oxidation of the sterically demanding silane intermediate is facilitated by the intramolecular formation of a silyl hemiketal or silyllactone for ketone or ester substrates, respectively.71... 

The skeleton of 47 is a heterocyclic tricyclo[6.2.0.0 ]decane and the similarity to the tricyclic kelsoene is obvious. In the course of the above-mentioned studies we had become curious whether the high facial diastereocontrol in the photocycloaddition reaction could be extended to other bridged 1,6-hexadienes. Kelsoene was an ideal test case. The retrosynthetic strategy for kelsoene along an intramolecular [2+2]-photocycloaddition pathway appeared straightforward. To avoid chemoselectivity problems the precursor to kelsoene should not contain additional double bonds. Alcohol 48, the hydroxy group of which was possibly to be protected, seemed to be a suitable substrate for the photocycloaddition (Scheme 14). Access to the 1,2,3-substi-... 

Use of Rh2(OAc)4 suggested that there was no inherent selectivity attributable to the coordinated carbene or to rhodium(ll). However, modification of dirhodium(ll) ligands to imidazolidinones provided exceptional diastereocontrol, obtained by influencing the conformational energies of the intermediate metal carbene [19, 23], as well as high enantiocontrol. Representative examples of products from these highly selective intramolecular C-H insertion reactions with cyclic systems is given in Scheme 15.6. Additional examples of effective insertions in systems from which diastereomeric products can result are illustrated in processes of the synthesis of 2-deoxyxylolactone (Scheme 15.7) [64, 65]. Here the conformation of the reactant metal carbene that is responsible for product formation is 32 rather than 33. Other examples in non-heteroatom-bound systems (for example, as in Eq. 15) confirm this preference. 

On irradiation, the aldehyde 1 underwent photoenolization to give the quinone methide 9. Intramolecular Diels-Alder cyclization then proceeded with high diastereocontrol to give 2 as a mixture of epimeric esters. 

The intramolecular Michael reaction is also a powerful transformation. In the cyclizations reported by Tetsuaki Tanaka of Osaka University (J. Org. Chem. 2004, 69, 6335), the stereochemical outcome is controlled by the chirality of the sulfoxide. Remarkably, subsequent alkylation or aldol condensation leads to one or two additional off-ring stereocenters with high diastereocontrol. Note that the high stereoselectivity in the cyclization is only observed with the (Z)-unsaturated ester. 

Intramolecular alkylation is an attractive method for ring construction. Helena M.C. Ferraz of the University of Sao Paulo and Marcos N. Eberlin of the State University of Campinas report (J. Org. Chem. 2005, 70, 110) that the intramolecular displacement of the iodide 1 proceeds by way of the tethered enamine 2, delivering the quaternary center of the keto ester 3 with high diastereocontrol. 

Epoxides such as 10 can be prepared in high enantiomeric purity, by, inter alia, kinetic resolution. David Hodgson of Oxford University has demonstrated (J. Am. Chem. Soc. 2004, /26,8664) that on exposure to LTMP, monosubstituted epoxides are smoothly converted into the corresponding alkoxy carbenc or alkoxy carbenoid. When an alkene is available for insertion, the cyclopropane, in this case 11, is formed with high diastereocontrol. This represents a powerful new approach to enantioselective ring construction. It is possible that in the absence of a target alkene, the intermediate alkoxy carbene could divert to intramolecular C-H insertion, which might also proceed with substantial diastereocontrol. 

Scott G. Nelson of the University of Pittsburgh has developed (J. Org. Chem. 2005, 70,4375) a highly diastereocontrolled route to substituted cyclohexanones using the intramolecular Sakurai reaction. The requisite ally silane 12 was prepared by Claisen rearrangement of the allylic alcohol 10, followed by homologation. The Ti enolate from the Sakurai addition was trapped with isobutyraldehyde to give 13. Although 32 diastereomers of 13 are possible, the diastereomer illustrated was the dominant product from the cylization. Note that use of the enantiomerically-pure form of the alcohol 10 would have led to enantiomerically-pure 13. 

Similarly, an intramolecular variant utilizing carbamates 26 derived from allylic alcohols has been developed using an amine like Hunigs base (ethyl diisopropylamine) as additive [21], The products were obtained with complete regio- and diastereocontrol, but surprisingly, only in racemic form when chiral ligands like (DHQ PHAL, being established for the AA, were employed. 

Combination of 26 with pericyclic reaction led to a diastereocontrolled synthesis of anthelmintic (-)-kainic acid and anticholinergic (-)-physostigmine and (-)-physovenine. Thermolysis of 68, obtained from (+)-26 furnished diastereoselectively 69 by intramolecular ene reaction. (-)-Kainic acid was obtained from 69 through a sequence of several steps of reactions (Scheme 19).27... 

A Ti(0-r-Pr)4-mediated intramolecular cyclization of the G( )-C,(i)-anti phenolic aldehyde 575 occurs with total diastereocontrol to afford anti-1,3-dimethyl isochroman 576. Cyclization of the C(l)-C(3)-ry phenolic aldehyde 575 does not occur with the same level of diastereoselectivity and syn-, 3-dimethyl isochroman 577 is formed as an inseparable mixture of diastereomers (Scheme 125) <1999J(P1)3039>. 

Jenkins et al. have reported on diastereocontrol in the intramolecular [3 + 2] cycloaddition. Here, (3R,5S)/(3S,5i )-5-phcnyl-l-hepten-3-ol 114 was irradiated to give a diastereopure [3 + 2] cycloadduct 115 (Scheme 4.58) [88], The other diaste-reomer (3S,5S)/(3R,5R)-114 gave an unresolved mixture. 

Morales, R.C., Lopez-Mosquera, A., Roper, N., Jenkins, P.R., Fawcett, J., and Garcia, M.D. (2006) Diastereocontrol in the intramolecular meta-photocydoaddi-tion of arenes and olefins. Photochemical el Photobiological Sciences, 5 (7), 649-652. 

Intramolecular Carbon-Hydrogen Insertion. The advantages of rhodium(II) catalysts for carbenoid transformations are nowhere more evident than with carbon-hydrogen insertion reactions. Exceptional regio- and diastereocontrol has been observed for Rh2(OAc)4 catalyzed transformations of a broad selection of diazoketones, a-diazo-p-ketoesters, a-diazo-P-keto-sulfones and -phosphonates which yield cyclopentanone derivatives in moderate to good yields (57-54). In contrast, poor yields and low regioselectivities characterize the corresponding copper catalyzed reactions. Applications of dirhodium(II) catalysts for C-H insertion reactions have even been extended to the synthesis of y-lactones (55), 3(2//)-furanones (56,57), P-laetones (58), and P-lactams (59,60). 

The intramolecular C—C bond formation (or cyclization) mediated by (TMS)3SiH has been the subject of numerous publications in the last few years. For example, radical cyclization of bromides 73 was found to be totally regioselective following 5-exo mode ring closure and afforded tetrahydrofuran derivatives (equation 37)89. Furthermore, the chiral auxiliary together with the configuration of the double bond allow for complete diastereocontrol. 

The conjugate addition step can also be intramolecular. For instance, Tanaka and coworkers studied the case of a lithiated vinyl sulfoxide that undergoes intramolecular conjugate addition in high yields and complete diastereocontrols (Scheme 32)148. 

The analogous intramolecular 1,3-dipolar cycloaddition of the cyclic nitrone 155, in an attempt to get to intermediates useful for the synthesis of the cylindricine or lepadiformine natural products, unexpectedly gave by lb/3a bonding the bridged cycloadduct oxazocine 117 in 49% yield with total diastereocontrol. From this reaction, the fused cycloadduct through la/3b bonding (41%) was also isolated (Equation 8) <2000TA2625>. 

Almost at the same time, Pirrung and Johnson " independently described the rearrangement of oxonium ylides prepared by intramolecular rhodium-catalyzed carbene addition. The reaction appears to have a broad scope and gives an easy entry into complex oxygenated polycycles (Scheme 61). When the possibility arises, high levels of diastereocontrol are exercised (Scheme 62). 

Lewis acid catalyzed versions of [4 4- 2] cycloadditions are restricted to functionalized dieno-philes. Nonfunetionalized alkenes and alkynes cannot be activated with Lewis acids and in thermal [4 + 2] cycloadditions these suhstrates usually show low reactivity. It has been reported that intcrmolecular cycloaddition of unactivated alkynes to dienes can be accelerated with low-va-lent titanium, iron or rhodium catalysts via metal-mediated - -complex formation and subsequent reductive elimination39 44. Usually, however, low product selectivities are observed due to side reactions, such as aromatization, isomerization or oligomerization. More effective are nickel-catalyzed intramolecular [4 4- 2]-dienyne cycloadditions which were developed for the synthesis of polycycles containing 1.4-cyclohexadienes45. Thus, treatment of dienyne 1, derived from sorbic acid, with 10mol% of Ni(cod)2 and 30 mol % of tris(o-biphenyl) phosphite in tetrahydrofuran at room temperature affords bicyclic 1,4-dienes 2, via intramolecular [4 + 2] cycloaddition, with excellent yield and moderate to complete diastereocontrol by substituents attached to the substrate. The reaction is sensitive towards variation in the catalyst and the ligand. 

In conclusion, it is now possible to assemble highly functionalized linear triquinanes from acyclic precursors with high diastereocontrol. The sequence mixing intramolecular cyclizations and a [3-f2] radical annulation appears as the strategy of choice. To probe its versatility, this strategy will have to materialize into total syntheses of natural products. 

Scheme 10-129 Intramolecular coupling of silyl bis-enolates occurs with good diastereocontrol.

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