Stereocenters substituted

Compounds C, D, and F were found to be optically active, each having S absolute configuration at the stereocenter. Substitution reactions of D and F with NaCN in DMF proceeded with inversion of configuration, while treatment of C in the same way proceeded with retention of configuration. 

Recendy, Darzens reaction was investigated for its synthetic applicability to the condensation of substituted cyclohexanes and optically active a-chloroesters (derived from (-)-phenylmenthol). In this report, it was found that reaction between chloroester 44 and cyclohexanone 43 provided an 84% yield with 78 22 selectivity for the axial glycidic ester 45 over equatorial glycidic ester 46 both having the R configuration at the epoxide stereocenter. 

Cleavage of the chiral auxiliary is effected in a three-step procedure commencing with quatemization of the nitrogen with methyl fluorosulfonate, methyl trlfluoromethanesulfonate, or trimethyloxonium tetrafluoroborate. Reduction of the corresponding iminium salt 19 with NaBH4 and acidic hydrolysis of the resulting product affords substituted aldehyde 5 without epimerization of either stereocenter. 

Treatment of an epimeric mixture of 4-substituted 2-(trimethylsilyloxy)-5-phenyl-3-phenylthio-l,4-oxazine 264 with ZnBr2 led to the stereoselective formation of perhydropyrido[2,l-c][l,4]oxazine 266 via the iminium ion 265 by the phenyl bearing stereocenter directed addition of the olefinic double bond from the /S-face of the cyclic moiety (97SL799, 98T10309). Similarly, an epimeric mixture of (45,9aS)-l-trimethylsilyloxy-4-phenyl-3,4,6,7-tetra-hydropyrido[2,l-c][l,4]oxazine was prepared by cyclization of (Z)-5(S)-phenyl-3-phenvlsulfanyl-2-trimethylsilyloxy-4-[4-(trimethylsilyl)but-3-enyll morpholine (OOSC2565). 

The synthetic problem is now reduced to cyclopentanone 16. This substance possesses two stereocenters, one of which is quaternary, and its constitution permits a productive retrosynthetic maneuver. Retrosynthetic disassembly of 16 by cleavage of the indicated bond furnishes compounds 17 and 18 as potential precursors. In the synthetic direction, a diastereoselective alkylation of the thermodynamic (more substituted) enolate derived from 18 with alkyl iodide 17 could afford intermediate 16. While trimethylsilyl enol ether 18 could arise through silylation of the enolate oxygen produced by a Michael addition of a divinyl cuprate reagent to 2-methylcyclopentenone (19), iodide 17 can be traced to the simple and readily available building blocks 7 and 20. The application of this basic plan to a synthesis of racemic estrone [( >1] is described below. 

In this synthesis, we have witnessed the dramatic productivity of the intramolecular enone-olefin [2+2] photocycloaddition reaction. This single reaction creates three contiguous and fully substituted stereocenters and a strained four-membered ring that eventually provides the driving force for a skeletal rearrangement to give isocomene. 

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... 

Chiral, nonracemic allylboron reagents 1-7 with stereocenters at Cl of the allyl or 2-butenyl unit have been described. Although these optically active a-substituted allylboron reagents are generally less convenient to synthesize than those with conventional auxiliaries (Section 1.3.3.3.3.1.4.), this disadvantage is compensated for by the fact that their reactions with aldehydes often occur with almost 100% asymmetric induction. Thus, the enantiomeric purity as well as the ease of preparation of these chiral a-substituted allylboron reagents are important variables that determine their utility in enantioselective allylboration reactions with achiral aldehydes, and in double asymmetric reactions with chiral aldehydes (Section 1.3.3.3.3.2.4.). 

Answer HBr indicates that we will be adding H and Br across the double bond. The presence of peroxides indicates that the regiochemistry will be anti-Markovnikov. To determine whether stereochemistry is relevant in this particular case, we need to look at whether we are creating two new stereocenters. When we place the Br on the less substituted carbon (and the H on the more substituted carbon), we will only be creating one new stereocenter. With only one stereocenter, there are not four possible stereoisomers but just two possible products (a pair of enantiomers). And we will get this pair of enantiomers regardless of whether the reaction was syn or anti ... 

Answer If we compare the starting material and product, we see that we must add H and OH. We look at the regiochemistry, and we see that OH is ending up at the more substituted carbon—so we need a Markovnikov addition. Then, we look at the stereochemistry and we see that we are not creating two stereocenters in this reaction (in fact, we are not even creating one stereocenter). Therefore, the stereochemistry of the reaction will be irrelevant. So we need to choose reagents that will give a Markovnikov addition of H and OH. We can accomplish this with an acid-catalyzed hydration ... 

The high catalytic activity also enabled aza-Claisen rearrangements to form Al-substituted quaternary stereocenters (Fig. 26) [71]. The catalyst does not need to distinguish between differently sized substituents on the double bond of 49 (e.g., R = CDa, R = CHs, ee = 96%), indicating that coordination of the olefin is the stereoselectivity predetermining step. The imidate-N-atom subsequently attacks intermediate 47-1 from the face remote to the Pd-center totally resulting in a... 

Stereochemical Control by the Aldehyde. A chiral center in an aldehyde can influence the direction of approach by an enolate or other nucleophile. This facial selectivity is in addition to the simple syn, anti diastereoselectivity so that if either the aldehyde or enolate contains a stereocenter, four stereoisomers are possible. There are four possible chairlike TSs, of which two lead to syn product from the Z-enolate and two to anti product from the A-enolate. The two members of each pair differ in the facial approach to the aldehyde and give products of opposite configuration at both of the newly formed stereocenters. If the substituted aldehyde is racemic, the enantiomeric products will be formed, making a total of eight stereoisomers possible. 

Entry 6 involves a titanium enolate of an ethyl ketone. The aldehyde has no nearby stereocenters. Systems with this substitution pattern have been shown to lead to a 2,2 syn relationship between the methyl groups flanking the ketone, and in this case, the (3-siloxy substituent has little effect on the stereoselectivity. The configuration (Z) and conformation of the enolate determines the 2,3-vyn stereochemistry.113... 

The only other functional group is the conjugated unsaturated ester. This functionality is remote from the stereocenters and the ketone functionality, and does not play a key role in most of the reported syntheses. Most of the syntheses use cyclic starting materials. Those in Schemes 13.4 and 13.5 lead back to a para-substituted aromatic ether. The syntheses in Schemes 13.7 and 13.8 begin with an accessible terpene intermediate. The syntheses in Schemes 13.10 and 13.11 start with cyclohexenone. Scheme 13.3 presents a retrosynthetic analysis leading to the key intermediates used for the syntheses in... 

As discussed previously, West and coworkers developed a two-step domino process, which is initiated by a Nazarov reaction. This can be extended by an electrophilic substitution. Thus, reaction of 1-179 with TiCl4 led to 1-182 via the intermediate cations 1-180 and 1-181. The final product 1-183 is obtained after aqueous workup in 99% yield (Scheme 1.43) [23]. It is important to mention here that all six stereocenters were built up in a single process with complete diastereoselectivity hence, the procedure was highly efficient. 

The related configurations of stereocenters in substituted cyclic nitronates can be determined by analyzing the spin—spin coupling constants between the vicinal protons in the stereoisomer discussed (Chart 3.7) (276). If needed, the results of this analysis are supplemented by special NOE experiments. 

The reaction of chiral six-membered cyclic nitronates with internal and terminal acetylenes was used with advantage in the synthesis of enantiomerically pure fused substituted aziridines containing several stereocenters (96) (Scheme... 

The approach shown in Scheme 3.235 and Table 3.30 makes it possible to functionalize the methyl group at C-3 in various six-membered cyclic nitronates. 3-Halomethyl-substituted nitronates (439 d,e) are particularly interesting reagents, which cannot be synthesized by known methods. It should be emphasized that the configurations of the stereocenters at the endocyclic carbon atoms are retained in the transformation (438 439). Unfortunately, the diastereose-lectivity of the generation of a new stereocenter in nitronates (439) is low the resulting stereoisomers can be separated by chromatography. 

Another alkyl-bridged PHOX (18, Fig. 29.6) was recently synthesized [17], and used to hydrogenate a series of substituted methylstilbenes in 75-95% ee, and /1-melhylcinnamic esters in 80-99% ee. The hydrogenation results suggest that the selectivity of these catalysts is mainly derived from the substitution at the stereogenic center on the oxazoline ring, with the other stereocenter having a relatively minor effect on the ee-value. 

The previous section discussed chelation enforced intra-annular chirality transfer in the asymmetric synthesis of substituted carbonyl compounds. These compounds can be used as building blocks in the asymmetric synthesis of important chiral ligands or biologically active natural compounds. Asymmetric synthesis of chiral quaternary carbon centers has been of significant interest because several types of natural products with bioactivity possess a quaternary stereocenter, so the synthesis of such compounds raises the challenge of enantiomer construction. This applies especially to the asymmetric synthesis of amino group-substituted carboxylic acids with quaternary chiral centers. 

Besides the methods discussed in Chapter 2, some quaternary stereocenters can also be conveniently constructed through the enantioselective Diels-Alder reaction of the 2-substituted acroleins 75 and 128-130. 

Feringa and coworkers [258] and O Doherty et al. [259] independently reported palladium-catalyzed glycosylations of 2-substituted 6-acyl-2H-pyran-3(6H)-one derivatives and alcohols (Scheme 5.98). This reaction presumably involves electrophilic Pd 7t-allyl complex intermediate, which was generated by the reaction of 2-substituted 6-acyl-2Ff-pyran-3(6H)-one and Pd(0)/PPh3. It is noteworthy that 2-substituted 6-acyl-2H-pyran-3(6H)-one derivatives were stereoselectively converted into 2-substituted 6 - a I k o x y - 2 H - p y r an - 3 (6 H) -o n e derivatives with complete retention of configuration by this reaction. A two-step reduction/oxidation manipulation after the glycosylation can install new stereocenters in the obtained glycosides. 

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