Stereoselective addition synthesis

Similar results are obtained with the /htetralone derivatives 12, which are useful building blocks in the synthesis of anthracycline antibiotics. Furthermore, the usefulness of the diastereoselec-tive addition to ot-oxo acetals was impressively demonstrated in the synthesis of (-)-7-deoxy-daunomycinone, which uses the completely stereoselective addition of (trimethylsi-lylethynyl)magnesium chloride to the /i-tetraione acetal 12 (R =OMOM R2 = Br) as the key reaction31. 

In a total synthesis of the macrolidc antibiotic cytovaricin, the highly stereoselective addition of (47 ,5iS )-4-methyl-3-(1 -oxopropyl)-5-phenyl-1,3-oxazolidin-2-one to benzyloxyacetaldehyde is one of the key steps giving the adduct which serves as the C, —Cfi unit in the target molecule95 ... 

Lower stereoselectivities arise, however, from the addition of ester enolates to this glyceralde-hyde4. Another highly stereoselective addition is in the synthesis of erythromycin A where a single product results from the addition of lithiated tert-butyl thiopropanoate to the enantiomerically pure aldehyde (2/ ,3/ ,4,S, 6/ ,7/ ,8,S, 9/ ,10.S, 11 / )-7-acetoxy-3,4 9,10-bis(isopropy1-idenedioxy)-11-methoxymethoxy-2,4,6,8,10-pentamethyltridecanal5. 

Due to the reversibility of this nitroaldol reaction, the easy epimerization at the nitro-sub-stituted carbon, and the often low yields in reactions with nitro compounds other than ni-tromethane, few stereoselective additions have been reported. Highly stereoselective reactions are known for the synthesis of cyclic systems (see Section 1.3.5.6.6.). 

Using FmA catalysis and protected 4-hydroxybutanal, compound (97) has been stereoselectively prepared as a synthetic equivalent to the C-3-C-9 fragment of (-F)-aspicillin, a lichen macrolactone (Figure 10.35) [160]. Similarly, FruA mediated stereoselective addition of (25) to a suitably crafted aldehyde precursor (98) served as the key step in the synthesis of the noncarbohydrate , skipped polyol C-9-C-16 chain fragment (99) of the macrolide antibiotic pentamycin [161,162]. 

Although considerable progress has been made in metal-catalyzed preparations of non-racemic cyanohydrins, the HNL-catalyzed reaction is still the most important method for the synthesis of chiral cyanohydrins, especially for large-scale reactions. The usefulness of HNLs as catalysts for the stereoselective addition of HCN to carbonyl compounds has increased substantially because (7 )-PaHNL... 

Except for the syntheses using terpene-derived starting materials (Schemes 13.7, 13.8, and 13.9), the previous juvabione syntheses all gave racemic products. Some of the more recent juvabione syntheses are enantiospecific. The synthesis in Scheme 13.16 relied on a chiral sulfoxide that undergoes stereoselective addition to cyclohexenone to establish the correct relative and absolute configuration at C(4) and C(7). The origin of the stereoselectivity is a chelated TS that leads to the observed product.20... 

The olefin metathesis reaction was also a key feature of the synthesis of epothilone A completed by a group at the Technical University in Braunschweig, Germany (Scheme 13.61). This synthesis employs a series of stereoselective additions to create the correct substituent stereochemistry. Two enantiomerically pure starting materials... 

However, not all nucleophiles show the same bias as shown in Scheme 4.5 on addition to the nitroalkene. The product of the addition of potassium phthalimide has 5 (R) stereochemistry (Eq. 4.38).47 This stereoselective addition is applied for the synthesis of other related antibiotics, such as nikkomycine B.48... 

The reactions of the cycloamyloses may also be useful in achieving stereoselective organic synthesis or they may serve as models for hydrophobic interactions in aqueous solution. As the scope of cycloamylose catalysis is extended to include other reaction types and other cycloamylose derivatives, additional applications will undoubtedly be revealed for the cycloamyloses as catalysts. 

The stereoselective addition of the titanium enolate of A-acetyl-4-phenyl-l,3-thiazolidine-2-thione 153 to the cyclic A-acyl iminium ion 154 is utilized in the synthesis of (-)-stemoamide, a tricyclic alkaloid <06JOC3287>. The iminium ion addition product 155 undergoes magnesium bromide-catalyzed awtz-aldol reaction with cinnamaldehyde 156 to give adduct 157, which possesses the required stereochemistry of all chiral centers for the synthesis of (-)-stemoamide. 

A parallel solution-phase asymmetric synthesis of a-branched amines has been reported by Ellman and coworkers based on stereoselective addition of organomag-nesium reagents to enantiomerically pure tert-butanesulfinyl imines [156]. Micro-wave heating was utilized in two of the steps of this synthesis of asymmetric amines, both for the imine formation and for the resin capture (Scheme 7.128). 

Nucleophilic addition of furan to nitrone occurs upon treatment with trimethyl-silyl triflate (TMSOTf) (586, 587). Catalyzed TMSOTf stereoselective addition of 2-[(trimethylsilyl)oxy]furan to chiral nitrones was carried out in a short synthesis of [IS (la, 2[), 7f>, 8a, 8aa)]-l,2-di(t-butyldiphenylsilyloxy)-indolizidine-7,8-diol (588). Addition to N -gulosyl-C-alkoxymethyl nitrones led to the synthesis of the core intermediate of polyoxin C (218). 

Addition of CN Anion Stereoselective addition of the CN-group to nitrones has received considerable attention for the synthesis of optically active a-hydroxyamino nitriles which can be further transformed into a-hydroxyamino acids and a-amino acids. Me SiCN (TMSCN), Et2AlCN, BU4NCN, and LiCN... 

High stereoselective addition of vinylmagnesium bromide to L-tartaric acid-derived nitrone was used as a key step in the synthesis of (+ )-lentiginosine and its structural analogs (653). 

To complement the above information, a highly enantioselective synthesis of a-amino phosphonate diesters should be mentioned.164 Addition of lithium diethyl phosphite to a variety of chiral imines gives a-amino phosphonate with good to excellent diastereoselectivity (de ranges from 76% to over 98%). The stereoselective addition of the nucleophile can be governed by the preexisting chirality of the chiral auxiliaries (Scheme 2-63). 

Silyltitanation of 1,3-dienes with Cp2Ti(SiMe2Ph) selectively affords 4-silylated r 3-allyl-titanocenes, which can further react with carbonyl compounds, C02, or a proton source [26]. Hydrotitanation of acyclic and cyclic 1,3-dienes functionalized at C-2 with a silyloxy group has been achieved [27]. The complexes formed undergo highly stereoselective addition with aldehydes to produce, after basic work-up, anti diastereomeric (3-hydroxy enol silanes. These compounds have proved to be versatile building blocks for stereocontrolled polypropionate synthesis. Thus, the combination of allyltitanation and Mukayiama aldol or tandem aldol-Tishchenko reactions provides a short access to five- or six-carbon polypropionate stereosequences (Scheme 13.15) [28],... 

The stereospecific reduction of a 2-butyne-l, 4-diol derivative and silver( I)-mediated cyclization of the resulting allene were successively applied to a short total synthesis of (+)-furanomycin 165 (Scheme 4.42) [68], Stereoselective addition of lithium acetylide 161 to Garner s aldehyde in the presence of zinc bromide afforded 162 in 77% yield. The hydroxyl group-directed reduction of 162 with LiAlH4 in Et20 produced the allene 163 stereospecifically. Cyclization followed by subsequent functional group manipulations afforded (+)-furanomycin 165. 

Highly efficient and stereoselective addition of tertiary amines to electron-deficient alkenes is used by Pete et al. for the synthesis of necine bases [26,27], The photoinduced electron transfer of tertiary amines like Af-methylpyrrolidine to aromatic ketone sensitizers yield regiospecifically only one of the possible radical species which then adds diastereospecifically to (5I )-5-menthyloxy-2-(5//)-furanone as an electron-poor alkene. For the synthesis of pyrrazolidine alkaloids in approximately 30% overall yield, the group uses a second PET step for the oxidative demethylation of the pyrrolidine. The resulting secondary amine react spontaneously to the lactam by intramolecular aminolysis of the lactone (Scheme 20) [26,27]. 

SCHEME 21. Synthesis of N-protected a-amino acids and aldehydes by stereoselective addition of bromohthioalkene 5 -41 to sulfonyhmines. Mukaiyama aldol reaction of a-aminoaldehydes... 

Oxynitrilases are enzymes that catalyze the formation and cleavage of cyanohydrins through the stereoselective addition of hydrogen cyanide to aldehydes or methyl ketones giving enantiopure a-hydroxynitriles. The use of (R)-oxynitrilases for the preparation of chiral cyanohydrins has dramatically grown in the last decade because of their possibihties as precursors for the synthesis of many compounds with physiological properties [50]. 

Stereoselective addition of allyl metal reagents to various functionalities is an important reaction in organic synthesis [32, 33]. The allylation of epoxides and aziridines with allyltin reagent is catalyzed by Lewis acids. Even though many Lewis acids have been reported to catalyze this reaction, Bi(OTf)3 is distinct because it avoids the formation of byproducts and is also environmentally more compatible. It catalyzes the reaction of aryl epoxides with tetraallyltin to afford the corresponding homoallyllic alcohol [34]. 

Stereoselective addition to carbonyl groups is a powerful tool in organic synthesis and has received a great deal of attention. Addition to imines can be equally as powerful, but has received much less attention. Denmark and co-workers first introduced the use of bis(oxazoline) ligands in the addition reactions of imines.The most successful ligand has been the modified bu-box ligand 182. This ligand was used both stoichiometrically and catalytically in the reaction between various imines and several alkyllithium species. Selected examples are summarized in Table 9.32 (Fig. 9.54). 

Stereoselective addition of hydrogen to a C=C double bond of an (S)-proline derivation was applied in the total synthesis of gephyrotoxin, a biologically active alkaloid 87). Optically active pyrrolizidine bases have been synthesized by Robins and Sakdarat88) from chiral hydroxyproline derivatives by hydrogenation (ds > 60 %). 

Trost and coworkers employed a magnesate reagent in the formal synthesis of fostriecin (Scheme 18). Stereoselective addition of the corresponding alkenylmagnesium to a-alkoxyketone proceeded smoothly in 75% yield with more than 20 1 diastereoselectivity. 

In this section we refer to types of addition to the carbonyl group, which by their very nature lead to C4-elongation. Examples are found in the addition of furan derivatives and [4+2] cycloaddition. We have recently described [39] the stereoselective addition of 2-furyl-lithium 26 to N,N-diprotected alaninals. For example, the reaction of 26 with alaninal 25 led to a mixture of diastereoisomers syn-21 and anti-28, with predominance of the latter isomer (Scheme 10). A similar method was used in the synthesis of methyl a-D-lincosaminide (see Sec. III.F). 

The stereoselective addition of allylmetal reagents to imines is one of the most important reactions in organic synthesis for carbon-carbon bond formation [118, 129] (Scheme 8.59). 

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