Synthesis diastereoselective additions

An analogous solvent effect was observed upon treatment of the chiral a-alkoxy aldehyde 11 with 2-lithio-4-methylfuran in the presence of zinc bromide. This highly diastereoselective addition reaction was the key step in a synthesis of the enantiomcrically pure C-10-C-20 fragment of the immunosuppressant KK 506139. 

One of the first examples of this type of reaction, using a chiral alcohol as an auxiliary, was the asymmetric synthesis of 2-hydroxy-2-phenylpropanoic acid (atrolactic acid, 3, R1 =C6H5 R3 = CH3) by diastereoselective addition of methyl magnesium iodide to the men-thyl ester of phcnylglyoxylie acid4,5 (Table 22). 

Besides simple alkyl-substituted sulfoxides, (a-chloroalkyl)sulfoxides have been used as reagents for diastereoselective addition reactions. Thus, a synthesis of enantiomerically pure 2-hydroxy carboxylates is based on the addition of (-)-l-[(l-chlorobutyl)sulfinyl]-4-methyl-benzene (10) to aldehydes433. The sulfoxide, optically pure with respect to the sulfoxide chirality but a mixture of diastereomers with respect to the a-sulfinyl carbon, can be readily deprotonated at — 55 °C. Subsequent addition to aldehydes afforded a mixture of the diastereomers 11A and 11B. Although the diastereoselectivity of the addition reaction is very low, the diastereomers are easily separated by flash chromatography. Thermal elimination of the sulfinyl group in refluxing xylene cleanly afforded the vinyl chlorides 12 A/12B in high chemical yield as a mixture of E- and Z-isomers. After ozonolysis in ethanol, followed by reductive workup, enantiomerically pure ethyl a-hydroxycarboxylates were obtained. 

The quantitative and diastereoselective addition of the sodium enolate of te/7-buty] 5-methyl-3-oxohexanoate to the Michael acceptor 2 was used in the synthesis of 0-methyl pisiferic acid280. 

The diastereoselective addition of [(S)-3-alkoxy-l-octenyl]lithium to an enantiomerically pure cyclic y-(rer/-butyldimethylsilyloxy)-o(,/S-unsaturated sulfone was employed in the synthesis of ( )-prostaglandin E219, with addition occurring exclusively anti to the sterically demand-... 

Although there are some examples of diastereoselective addition of allylic stannanes to substituted 1,3-oxazolidi-nones (Scheme 52),141 these reactions have still not been applied to asymmetric synthesis. 

Rhodium complexes catalyze 1,2-addition of main group metal compounds to aldimines as well. Table 5 summarizes the reported methods. Electron-withdrawing substituents such as sulfonyl and acyl groups on the imino nitrogen atom are important to obtain sufficiently high reactivity. Asymmetric synthesis (diastereoselective and enantioselective) has also been accomplished. 

The bromoallene (-)-kumausallene (62) was isolated in 1983 from the red alga Laurencia nipponica Yamada [64a], The synthesis of the racemic natural product by Overman and co-workers once again employed the SN2 -substitution of a propargyl mesylate with lithium dibromocuprate (Scheme 18.22) [79]. Thus, starting from the unsymmetrically substituted 2,6-dioxabicyclo[3.3.0]octane derivative 69, the first side chain was introduced by Swern oxidation and subsequent Sakurai reaction with the allylsilane 70. The resulting alcohol 71 was protected and the second side chain was attached via diastereoselective addition of a titanium acetylide. The synthesis was concluded by the introduction of two bromine atoms anti-selective S -substitution of the bulky propargyl mesylate 72 was followed by Appel bromination (tetrabromo-methane-triphenylphosphine) of the alcohol derived from deprotection of the bromoallene 73. 

Scheme 6.2. Diastereoselective addition of a functionalized cuprate to cyclopentenone 14 in the synthesis of prostaglandin E2 (PGE2) (TBS = t-butyidimethylsilyl,...

The Corey allylation system based on a chiral bis(sulfonamide) auxiliary was put to use with success in a number of synthetic efforts, including the total synthesis of the anticancer agent leucascandrolide (Scheme 13). Chiral reagent 152 is added to an achiral aldehyde, 3-(/ -methoxybenzyloxy)propanal, affording intermediate 153 in high stereoselectivity. The latter is transformed into a pyranyl aldehyde, which is subjected to a second allylation (this time, a doubly diastereoselective addition) en route to the completion of leucascandrolide. 

Several allylic boron reagents have been recently employed in a series of doubly diastereoselective additions toward a synthesis of mycalamide. " Thus,... 

As demonstrated in the course of a total synthesis of the macrolide bafilo-mycin, double diastereoselective additions can be useful even in the mismatched manifold. For example, the crotylation of chiral a-substituted aldehyde 167 with (E)- affords an 85 15 ratio of diastereomers favoring the desired anti-anti product (Scheme 17). Without a chiral tartrate reagent, the undesired anti-syn diastereomer would be intrinsically favored from aldehyde 167. The use of the appropriate tartrate reagent, the (R,R) unit in this instance, overturns this preference to afford an acceptable ratio of the two separable dias-teomers. 

G. Casiraghi, L. Colombo, G. Rassu, and P. Spanu, Synthesis of enantiomerically pure 2,3-dideoxy-hept-2-enono-1,4-lactone derivatives via diastereoselective addition of 2-(trimethyl-siloxy)furan to D-glyceraldehyde and D-serinal-based three-carbon synthons, Tetrahedron Lett. 30 5325 (1989). 

The use of stoichiometric amounts of sulfur ylides in the diastereoselective addition to imines has been recognized for a long time as a means of efficient synthesis... 

Several reports have employed a more traditional approach where the use of enantio-pure chiral amino auxiliaries, that, after the successful Strecker reaction, can be chemically modified to yield the free amino acids. For example, Chakraborty and co-workers have reported the highly diastereoselective addition of trimethylsilyl cyanide to a variety of a-phenylglycinol-derived benzaldimines [16]. (S)-a-Methylbenzylamine has been used as a chiral auxiliary for the asymmetric Strecker reaction [17]. (R)-Phenylglycinol has been utilized as a chiral auxiliary from the asymmetric Strecker reaction products of aldehydes in the synthesis of a,a-disubstituted amino acids [18]. (R)- and (S)-2-Amino-2-phenylethanol were used as chiral auxiliaries in the synthesis of optically pure a-arylglycines [19]. 

McDonald performed an asymmetric synthesis of D-desosamine, with high selectivity, by diastereoselective addition of TMS-acetylene to an a-unbranched aldehyde obtaining the propargylic alcohol [23]. The reaction proceeded in nearly 100 % diastereoselectivity albeit in moderate (60 %) yield (Eq. 19). 

However, two factors are likely to lead to the further exploitation of this reaction in synthesis (a) the addition may proceed with a useful degree of stereoselectivity, and (b) the initial adducts may be readily converted into amines (for example by acylation followed by reduction [41] or by reaction with carbon disulfide [42]). An example of a diastereoselective addition is shown in the following equation [41] others have been described [41,43,44] ... 

The addition of lithium azide to ferr-butyldimethylsilyloxy-2-penten-4-olides during the synthesis of a 3 -azido-3 -deoxythymidine derivative66 and the diastereoselective addition of benzy-lamine to (R)-4-0-benzyl-4-hydroxy-2-penten-5-olide giving substituted /9-amino acid derivatives67 have also been reported. 

A simple and efficient stereoselective synthesis of aziridine-2-phosphonate 781 and phosphine oxide 782 was achieved by diastereoselective addition of Grignard reagents to 277-azirine phosphonate 779 and phosphine oxide 780. Addition of benzenethiol and heterocyclic amines proceeded in an analogous manner to yield functionalized aziridines 783 and 784 (Scheme 188). 

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