Chelate-controlled addition

Addition of alkynes to a-alkoxy aldehydes is most favorably performed with the corresponding zinc reagents (Table 12)46. As with Grignard reagents, the chelation-controlled addition of zinc alkynes proceeds with higher diastereoselectivity when diethyl ether rather than tetrahydrofuran is used as reaction solvent. 

Allyltrialkoxy- or -tris(dialkylamino)titanium reagents are not capable of chelation-controlled addition reactions with oxy- or amino-substituted carbonyl compounds due to their low Lewis acidity87. To attain chelation control, the application of allylsilanes (Section 1.3.3.3.5.2.2.) and allylstannanes (Section I.3.3.3.6.I.3.2.) in the presence of bidentate Lewis acids like titanium(IV) chloride, tin(lV) chloride or magnesium bromide are the better options. 

Chelation-Controlled Additions of Achiral Enolates to Chiral Aldehydes... 

The chelation-controlled addition of silylketene acetal, 1-phenoxy-l-trimethylsilyloxyethene, to enantiomerically pure (S)-2-dibenzylaminopropanaI is not easily accomplished. Although the predominant formation of one diastcrcomcr is possible (d.r. 95 5), the reaction is plagued by a low chemical yield9. 

With a- and (3-benzyloxyaldehydes, the /-butylthio ketene acetals also gave chelation-controlled addition.91... 

The reactants can be prepared by chelation-controlled addition of organometallic reagents to a-(l-ethoxyethoxy)methyl ketones. Selective sulfonylation occurs at the... 

The key step in the synthesis of A-ring fragment 50 [56] is the chelation-controlled addition of allylstannane 53 to aldehyde 52, which sets the C7 stereocenter and introduces the C8 gem-dimethyl moiety. Aldehyde 52 is itself prepared from 1,3-propanediol using the author s protocol for titanium-catalyzed enantioselective allylstannation [57], which sets the C5 stereocenter, followed by chelation-controlled Mukaiyama aldol addition [58] to establish the C3 stereocenter (Scheme 5.6). 

The efficient addition-cyclization sequence described above could be successfully applied to the preparation of the polyhydroxylated y-amino acid (-)-detoxinine [73], The crucial key step in this fairly short synthesis is the chelate-controlled addition of lithiated benzyloxyallene 120 (R = Bn) to the chiral N-benzyl-substituted imine 121 as shown in Scheme 8.31. The required skeleton of the natural product was generated in good overall yield. 

This chelation-controlled addition generated the homoallylic alcohols 86 with a diastereoselectivity of syn anti=S6ll4 , In contrast to the other syntheses described so far, the ring closing reaction was a 5 2 reaction but not a... 

SCHEME 23. Non-chelate controlled addition of l-bromo-l-hthioalkene 164 to O-protected lac-taldehydes 162. Introduction of an umpoled formyl d synthon CHO... 

SCHEME 8. Schematic representation for the chelate-controlled addition of an organometaUic reagent (M—R) to the carbonyl group of a chiral a-alkoxy carbonyl compound (17). Two diastere-omers 18 with different orientation of R with respect to CH2R can be obtained. The syn diastereomer is obtained when the nucleophihc attack of R takes place on the same face of the plane, defined by the carbonyl group and the R-substituted carbon atom, where CH2R is located in the chelate complex... 

In 2,4-difluorobenzaldehyde and 2,4-difluorophenyl ketones, not only the 4-F but also the 2-F will be replaced by the benzylsulfanyl group, provided the reaction is carried out in dimethyl-formamide using an appropriate amount of phenylmethanethiol.64 However, with tetrahy drofuran as the solvent, the 2-F is predominantly substituted to give 5, independent of the nature of the substituent at the carbonyl group. This selectivity is explained by assuming a chelation-controlled addition as the primary step.64... 

The synthesis of the C20—C26 fragment started with a 4-alkylation of methyl aceto-acetate The first stereocentre was introduced by enantioselecuve catalytic hydrogenation with Noyort s (S)-binap rhodium complex (cf p 102f.) Stereoselective Frater-Seebach alkylation with allyl bromide introduced the second stereocentre in 90% yield (cf p 27) Stereospecifid introduction of the stereocentres C24 and C2 was achieved by a chelation controlled addition of an allylstannane to an aldehyde (see p 66f) After some experimentation with Lewis acid catalysts and reaction conditions a single diastereomer of the desired configuration was ob-... 

Stereoselective chelate-controlled addition of Grignard reagents to tetrahydrooxepine derivatives (Equation 3) involves Zr-catalyzed kinetic resolution with (i )-[EBTHI]Zr-BINOL (BINOL= l,l -bi-2-naphthol) <1996JA4291, 1997JA6205, 1999JOC854>. 

Starting from ethyl (iS )-lactate, rhodinose was prepared in four steps, with 31% overall yield (Scheme 57).272 Chelation-controlled addition of the Grignard... 

Braun, M. Mahler, H. Non-chelate-controlled addition of 1-bromo-l-lifhio-l-alkenes to... 

FIGURE 25.4 Chelation controlled addition of allylzinc bromide to (f )-PGA [(i )-phenylglycine amide] imines. 

Not only does chelation control reverse the stereoselectivity, but it gives a much higher degree of stereoselectivity. Stereoselectivities in chelation-controlled additions to C=0 groups are typically >95 5. But this fits in nicely with the ideas we presented at the end of the last chapter stereoselectivity is likely to be high if a cyclic transition state is involved. Chelation involves just such a transition state, so it should be no surprise that it lets us achieve much higher levels of control than the acyclic Felkin-Anh model does. 

A recent application of the furan-carbonyl photocycloaddition involved the synthesis of the mycotoxin asteltoxin (147)." Scheme 16 shows the synthetic procedure that began with the photoaddition of 3,4-dimethylfuran and p-benzyloxypropanal to furnish photoaldol (148), which was epoxidized with MCPBA to afford the functionalized product (149) in 50% overall yield. Hydrolysis (THF, 3N HCl) provided the monocyclic hemiacetal which was protected as its hydrazone (150). Chelation-controlled addition of ethylmagnesium bromide to the latent a-hydroxy aldehyde (150) and acetonide formation produced compound (151), which was transformed through routine operations to aldehyde (152). Chelation-controlled addition of the lithium salt of pentadienyl sulfoxide (153) followed by double 2,3-sigma-tropic rearrangement provided (154) as a 3 1 mixture of isomers (Scheme 17). Acid-catalyzed cyclization of (154) (CSA/CH2CI2) gave the bicyclic acetal (155), which was transformed in several steps to ( )-asteltoxin (147). ... 

Reasonable diastereofacial selectivity has also been observed in the addition of the allylstannane referred to above to 2-acetoxy-3,4-octanedione (equation 8). Chemoselective Felkin-Anh addition to the more reactive carbonyl carbon located a to the stereocenter is presumed to occur first, followed by an intramolecular chelation-controlled addition of the allylsilane to the second ketone. 

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