Systems diastereoselectivity

The halogen-metal exchange of one of a geminal pair of bromine atoms is readily achieved -a carbenoid is formed which may have sufficient stability to react as an organolithium before decomposing to a carbene by a-elimination.. m in cyclic systems, diastereoselectivity in this process has long been known,114116 though the outcome of reactions such as that of 137 is under a mixture of kinetic and thermodynamic control.117... 

Hydroxy alkenyl and alkynyl nitriles can be subjected to a one-pot addition-alkylation sequence, leading to polysubstituted products. In the case of open-chain systems, diastereoselectivity from 2.3 1 to 6.6 1 was achieved. Cyclic systems may lead to a highly diastereoselective reaction.234,234a 234c iv-Chloroalkenylmagnesium bromides give bicyclic products (Scheme 77 ) 235>236... 

Harada, M., Nakai, T., Tomooka, K. Stevens rearrangement of a cyclic hemiacetal system Diastereoselective approach to chiral -amino ketone. Synlett 2004, 365-367. 

Three of many examples of directed hydrogenation are shown in Equations 15.15-15.17. Equation 15.15 shows the reduction of a homoaUylic alcohol, which was one of the substrates first used to demonstrate this effect. Equation 15.16 shows a more complex substrate in which the diastereoselective reduction by Crabtree s catalyst is directed by the amide function as part of tlie synthesis of pulmitoxins. Equation 15.17 shows that the addition of hydrogen can be directed to a hindered face of a bicyclic system. In this case, the cationic rhodium system qf Brown, as well as Crabtree s catalyst, led to hi selectivity. Many other reactions occur with high selectivity in the presence of Brown s cationic rhodium system. Diastereoselective additions to acyclic systems, along with a rationalization for the selectivity in these types of substrates, can be found in the review by Evans. ... 

The Michael addition to a,/9-unsaturated nitriles has been reviewed. " The addition to cyclic oxo-nitriles is directed either by steric effects or by chelation (Scheme 2-62). y-Hydroxy nitriles such as 161 can be used in a one-pot addition-alkylation sequence, leading to polysubstituted products. For open-chain systems, diastereoselectivities of up to 6.6 1 could be achieved, while cyclic systems afford generally much better ratios (Scheme 2-63). ... 

There has been recent interest in naphtho-fused dithiepines as chiral acyl anion equivalents, particularly since the starting dithiol 128 can be obtained in enan-tiomerically pure form (89TL2575). This is transformed using standard methods into the dithiepine 129, but showed only moderate diastereoselectivity in its addition to carbonyl compounds. On the other hand, as we have seen previously for other systems, formation of the 2-acyl compound 130 and reduction or addition of a Grignard reagent gave the products 131 with much better stereoselectivity (91JOC4467). 

Whereas there are numerous examples of the application of the products from diastereoselective 1,3-dipolar cycloaddition reaction in synthesis [7, 8], there are only very few examples on the application of the products from metal-catalyzed asymmetric 1,3-dipolar cycloaddition reaction in the synthesis of potential target molecules. The reason for this may be due to the fact that most metal-catalyzed asymmetric 1,3-dipolar cycloaddition reaction have been carried out on model systems that have not been optimized for further derivatization. One exception of this is the synthesis of a / -lactam by Kobayashi and Kawamura [84]. The isoxazoli-dine endo-21h, which was obtained in 96% ee from the Yb(OTf)3-BINOL-catalyzed... 

An expedient and stereoselective synthesis of bicyclic ketone 30 exemplifies the utility and elegance of Corey s new catalytic system (see Scheme 8). Reaction of the (R)-tryptophan-derived oxazaboro-lidine 42 (5 mol %), 5-(benzyloxymethyl)-l,3-cyclopentadiene 26, and 2-bromoacrolein (43) at -78 °C in methylene chloride gives, after eight hours, diastereomeric adducts 44 in a yield of 83 % (95 5 exo.endo diastereoselectivity 96 4 enantioselectivity for the exo isomer). After reaction, the /V-tosyltryptophan can be recovered for reuse. The basic premise is that oxazaborolidine 42 induces the Diels-Alder reaction between intermediates 26 and 43 to proceed through a transition state geometry that maximizes attractive donor-acceptor interactions. Coordination of the dienophile at the face of boron that is cis to the 3-indolylmethyl substituent is thus favored.19d f Treatment of the 95 5 mixture of exo/endo diastereo-mers with 5 mol % aqueous AgNC>3 selectively converts the minor, but more reactive, endo aldehyde diastereomer into water-soluble... 

The enol ether double bond contained within the ds-fused dioxa-bicyclo[3.2.0]heptene photoadducts can also be oxidized, in a completely diastereoselective fashion, with mCPBA. Treatment of intermediate XXII, derived in one step from a Patemo-Buchi reaction between 3,4-dimethylfuran and benzaldehyde, with mCPBA results in the formation of intermediate XXIII. Once again, consecutive photocycloaddition and oxidation reactions furnish a highly oxygenated system that possesses five contiguous stereocenters, one of which is quaternary. Intermediate XXIII is particularly interesting because its constitution and its relative stereochemical relationships bear close homology to a portion of a natural product known as asteltoxin. 

Our journey begins with the photo-induced union of 3,4-dimethylfuran (19) and / -(benzyloxy)-propanal (18) (see Scheme 5). Irradiation of a solution of these two simple, achiral compounds in benzene with a 450 W Hanovia lamp equipped with a vycor filter results in the exclusive formation of head-to-head, exo photoadduct 17 in 63% yield. As a cw-fused dioxabicyclo[3.2.0]heptene system, intermediate 17 possesses a folded molecular framework to which access is obstructed on the concave face. In the presence of mCPBA, the less hindered convex face of the enol ether double bond is oxidized in a completely diastereoselective fashion, affording intermediate 16 in 80% yield after regioselective opening of... 

The MT0/H202/pyridine system enjoys a broad substrate scope and has become the method of choice for the epoxidation of di-, tri-, and tetrasubstituted olefins. As an added benefit, it gives high diastereoselectivities for a number of cyclic dienes (Table 12.1). 

The intramolecular Hiyama reaction is excellently suited for the construction of carbocyclic and heterocyclic ring systems of different size. In most examples, problems of induced diastereoselectivity are involved (Sections 1.3.3.3.9.2.2. and D.2.3.). In the total synthesis of the antitumor germacranolide ( )-costunolide from ( ,.E)-farnesol, the correctly substituted ( , )-cyclodecadiene moiety was constructed by an intramolecular Hiyama reaction22. 

For acyclic systems, the anti diastereoselectivity of the (i )-enolates is lower than the syn diastereoselectivity of comparable (Z)-enolates. For example, carboxylic acid esters, which form predominantly ( )-enolates, react with aldehydes with high anti selectivity only in those cases where bulky aromatic substituents are in the alcoholic part of the ester22 25. 

Chiral amide and imide enolates are amongst the most effective reagents providing. yv -3-hy-droxycarboxylic acids in both high simple diastereoselectivity and induced stereoselectivity, e.g., the amides 1 and 2, and especially, the imides 3 and 4 (derived from (S(-valine and (l/ ,2S)-norephedrine, respectively)93 and the C2-symmetric amide 594 are highly effective systems ... 

This 1,2-asymmetric induction has been attributed to stcric and stcrcoclectronic factors. Similarly, the cuprate additions to 4-alkylcyclopentenones l7 -19, and 4-alkylcyclohexcnones16 b-18 proceeded with very high trans diastereoselection. The copper iodide catalyzed addition of propylmagnesium bromide to 4-methyl-2-cyclohexenone gave a trans/cis ratio of 80 20, whereas the addition to 5-methyl-2-cyclohexenone produced a transjcis ratio of 93 72 3-Silyloxy system 3 gave the trans-adduct 4 on treatment with butylcopper-boron trifluoride reagent20. 

This section describes Michael-analogous processes in which, mostly under electrophilic conditions, ally - or alkynylsilanes undergo addition to enones or dienones (Sakurai reactions). The intramolecular addition of allylsilanes is an extremely useful reaction especially for the construction of carbocyclic ring systems, which occurs in a diastereoselective manner, in many cases with complete asymmetric induction. 

If the enone is part of a decalone system, i.e., a / - and an y-substituent are present, on reaction with lithiated areneacetonitriles in THF the exclusive formation of (Tv-substituted decalones is observedl26. The diastereoselectivity at the exocyclic stereogenic center is, however, poor. Applications in the synthesis of anthracyclines are given in the literature127,12S. 

Consecutive Michael additions and alkylations can also be used for the diastereoselective synthesis of 5- and 6-membered ring systems. For instance when 6-iodo-2-hexenoates or 7-iodo-2-heptenoates are employed the enolate of the Michael adduct is stereoselectively quenched in situ to provide the cyclic compound with trans stereochemistry (>94 6 diastereomeric ratio). As the enolate geometry of the Michael donor can be controlled, high stereoselectivity can also be reached towards either the syn or anti configuration at the exocyclic... 

When the cnolate of an enone is brought into reaction with an enone, usually a carbocyclic system is prepared by two consecutive Michael additions (M1MIRC reactions). Due to the lower temperatures employed and the absence of diene polymerization these reactions are useful alternatives for Diels-Alder reactions and proceed in general with high diastereoselectivities. When neither enolate nor enone is cyclic a monocyclic system is formed 338 which can be converted into a bicyclic system when the Michael addition is followed by an aldol reaction339. When, however, the enolate is cyclic a bicyclic or a tricyclic system is formed340 341. 

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