Chelation-controlled substitution

The completion of the synthesis of the polyol glycoside subunit 7 requires construction of the fully substituted stereocenter at C-10 and a stereocontrolled dihydroxylation of the C3-C4 geminally-disub-stituted olefin (see Scheme 10). The action of methyllithium on Af-methoxy-Af-methylamide 50) furnishes a methyl ketone which is subsequently converted into intermediate 10 through oxidative removal of the /j-methoxybenzyl protecting group with DDQ. Intermediate 10 is produced in an overall yield of 83 % from 50) , and is a suitable substrate for an a-chelation-controlled carbonyl addition reaction.18 When intermediate 10 is exposed to three equivalents of... 

Exclusive trims attack of the nucleophile is also observed with 2,3-epoxycyclopentanones 1559. In contrast to 2-alkyl- and 2-methoxy-substituted cyclopentanones, preferential trans attack to 2,3-epoxycyclopenlanones occurs with alkyl, ethenyl, and ethynyl nucleophiles. Thus, there is no assistance by the epoxidic oxygen for cis attack. Due to the geometry of the molecule, chelation-controlled cis attack is not possible39 60. 

The addition of dibutylcupratc to the a-substituted /1-formyl esters 1 preferentially affords, via chelation control, the cw-disubstituted y-lactone 241. These results are in agreement with those found with a-unsubstituted /1-esters39-41 (vide supra), assuming a seven-membered chelate as transition state of the addition reaction. The diastercosclectivity is somewhat lower with esters 1 as the stereogenic center is one carbon atom further removed from the reaction center and therefore the steric influence of the substituent R1 is less pronounced. 

The addition of vinylmagnesium bromide to methyl (S)-3-benzyloxy-4-oxobutanoate (5) in tetrahydrofuran proceeded with a slight preference for the nonchelation-controlled reaction product (40 60)5°. A reversal of the diastereoselectivity (80 20) could be observed when the Grignard reagent, as a solution in tetrahydrofuran, was added to a dichloromethane solution of the aldehyde which had been precomplexed with one equivalent of magnesium bromide. The almost exclusive formation of the chelation-controlled reaction product 6 was achieved when tetrahydrofuran was completely substituted by dichloromethane the presence of tetrahydrofuran interferes with the formation of the chelate complex, which is a prerequisite for high chelation-controlled diastereoselection. 

Addition with chelate control to a-hetero-substituted chiral aldehydes ... 

However with j3-methyl-substituted stannanes, the reaction with 2-benzyloxypropanal induced by magnesium bromide, gave predominantly the chelation-controlled cw/i-product91. 

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. 

Microwave-assisted Heck reaction of (hetero)aryl bromides with N,N-dimethyl-2-[(2-phenylvinyl)oxy]ethanamine, using Herrmann s palladacycle as a precatalyst, yielded the corresponding /3-(hetero)arylated Heck products in a good EjZ selectivity (Scheme 79) [90]. The a/yd-regioselectivity can be explained by the chelation control in the insertion step. This selectivity is better than 10/90 when no severe steric hindrance is introduced in the (hetero)aryl bromides. The process does not require an inert atmosphere. There is evidence that a Pd(0)/Pd(II)- and not Pd(II)/Pd(IV)-based catalytic cycle is involved. Similarly, other j6-amino-substituted vinyl ethers such as... 

Reactions through chelated TS Reactions of a- or (3-oxy-substituted aldehydes often show chelation-controlled stereoselectivity with Lewis acids that can accommodate five or six ligands. Chelation with substituents in the allylic reactant can also occur. The overall stereoselectivity depends on steric and stereoelectronic effects in the chelated TS. 

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. 

Further variations of the Claisen rearrangement protocol were also utilized for the synthesis of allenic amino acid derivatives. Whereas the Ireland-Claisen rearrangement led to unsatisfactory results [133b], a number of variously substituted a-allenic a-amino acids were prepared by Kazmaier [135] by chelate-controlled Claisen rearrangement of ester enolates (Scheme 18.47). For example, deprotonation of the propargylic ester 147 with 2 equiv. of lithium diisopropylamide and transmetallation with zinc chloride furnished the chelate complex 148, which underwent a highly syn-stereoselective rearrangement to the amino acid derivative 149. 

Murakami and Taguchi utilized a diastereoselective Grignard addition to a substituted-chiral oxazoline aldehyde 524 (Scheme 8.170) in an improved stereoselective synthesis of D-n7 o-phytosphingosine. The good stereoselectivity observed for 525 can be rationalized by a Felkin-Ahn transition state model although a chelation control mechanism could not be mled out. 

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... 

Intramolecular cyclization of allylsilanes.4 p-Keto esters (or amides) substituted in the a-position by an allylsilane undergo diastereospecific cyclization in the presence of TiCl4 (chelation controlled). Cyclizations induced by F" or BF3 etherate give mixtures of diastereomers. 

A-acetylmannosamine undergoes a chelation-controlled reaction and leads to 90% of the syn-f3-amino alcohol when reacted in a 0.5 M NH4G1 solution. While a dibenzylamino substitutent of a-aminopropionaldehyde is too bulky to enter complexation, a dimethylamino group is not and leads to high levels (99%) of the. sy/z-diastereomer (Table 4).159... 

P-Keto esters and -keto amides, each substituted between the two carbonyl units with a 2-[2-(tri-methylsilyl)methyl] group, also undergo Lewis acid catalyzed, chelation-controlled cyclization. When titanium tetrachloride is used, only the product possessing a cis relationship between the hydroxy and ester (or amide) groups is product yields range from 65 to 88% (Table 8). While loss of stereochemistry in the product and equilibration of diastereomers could have occurred via a Lewis acid promoted retro aldol-aldol sequence, none was observed. Consequently, it is assumed that the reactions occur under kinetic, rather than thermodynamic, control. In contrast to the titanium tetrachloride promoted process, fluoride-induced cyclization produces a 2 1 mixture of diastereomeric products, and the nonchelating Lewis acid BF3-OEt2 leads to a 1 4.8 mixture of diastereomers. 

There are a few reports of hetero-Diels-Alder Reactions promoted by LPDE. Intriguing stereoselectivity is observed for the [4 + 2] cyclization between Danishefsky s diene 77 and a-heteroatom-substituted aldehydes. For example, reaction of 77 with N-Boc-protected a-aminoaldehyde with 76 gave the threo isomer selectively, a result in keeping with a chelation-controUed process. In contrast, the threo diastereoselectivity observed could be reversed by changing the amino protecting group from A-Boc to A,A(-dibenzyl. In this instance, the erythro isomer was generated exclusively via a non-chelation-controlled transition state (Sch. 38) [89]. 

A highly effective catalytic method for alkynylation of epoxides has recently been reported this involves the chelation-controlled alkylation of hetero-substituted epoxides with Mc3A1 and alkynyllithiums via pentacoordinate organoaluminum complexes [82]. For instance, reaction of epoxy ether, (l-benzyloxy)-3-butene oxide (75) in toluene with PhC = CLi under the influence of catalytic MesAl (10 mol%) proceeded smoothly at 0 °C for 5 h to furnish the alkynylation product l-(benzyloxy)-6-phenylhex-5-yn-3-ol (76) in 76 % yield. The yield of the product was very low (3 %) without MeaAl as catalyst under similar conditions. This is the first catalytic procedure for amphiphilic alkylation of epoxides. The participation of pentacoordinate MesAl complexes of epoxy ethers of type 75 is emphasized by comparing the reactivity with the corresponding simple epoxide, 5-phenyl-l-pentene oxide (77), which was not susceptible to nucleophilic attack of PhC s CLi with catalytic Me3Al under similar conditions (Sch. 50). 

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