Diastereoselectivity remote

The boron-zinc exchange is an unique way for preparing chiral secondary alkylzinc reagents which are configurationally stable over a wide temperature scale. Coupled with the thermal rearrangement of tertiary organoboranes, a broad range of open-chain and cyclic polyfunctional molecules have been prepared. In addition, several examples of a diastereoselective remote C-H activation have been studied. 

A cursory inspection of key intermediate 8 (see Scheme 1) reveals that it possesses both vicinal and remote stereochemical relationships. To cope with the stereochemical challenge posed by this intermediate and to enhance overall efficiency, a convergent approach featuring the union of optically active intermediates 18 and 19 was adopted. Scheme 5a illustrates the synthesis of intermediate 18. Thus, oxidative cleavage of the trisubstituted olefin of (/ )-citronellic acid benzyl ester (28) with ozone, followed by oxidative workup with Jones reagent, affords a carboxylic acid which can be oxidatively decarboxylated to 29 with lead tetraacetate and copper(n) acetate. Saponification of the benzyl ester in 29 with potassium hydroxide provides an unsaturated carboxylic acid which undergoes smooth conversion to trans iodolactone 30 on treatment with iodine in acetonitrile at -15 °C (89% yield from 29).24 The diastereoselectivity of the thermodynamically controlled iodolacto-nization reaction is approximately 20 1 in favor of the more stable trans iodolactone 30. 

With chiral auxiliaries1,41 a remote chiral moiety is temporarily introduced into the substrate in order to direct the nucleophilic addition diastereoselectively. The chiral auxiliary can be removed from the initial addition product with complete conservation of the chirality of the desired product and also of the chiral auxiliary. The recovered chiral auxiliary can then be reused in further reactions. Therefore, chiral auxiliaries are used to chiralize an a priori achiral carbonyl substrate by the introduction of a covalently bound, but nevertheless easily removable, chiral source. 

On the basis of this analysis, it may be anticipated that the extent of aldehyde diastereofa-cial selectivity will depend on the difference in size of the R3 aldehyde substituent relative to that of the methyl group. The examples summarized in Table 2 are generally supportive of this thesis, particularly the reactions of (F)-2-butenylboronntc. The data cited for reactions of 3-methoxymethoxy-2-methylbutanal with (Z)-2-butenylboronate and 2-propenylboronate, however, also show that diastereoselectivity depends on the stereochemistry at C-3 of the chiral aldehydes. These data imply that simple diastereoselectivity depends not simply on reduced mass considerations, but rather on the stereochemistry and conformation of the R3 substituent in the family of potentially competing transition states21,60. The dependence of aldehyde diastcrcofacial selectivity on the stereochemistry of remote positions of chiral aldehydes has also been documented for reactions involving the ( )-2-butenylchromium reagent62. 

Recently, silicon-tethered diastereoselective ISOC reactions have been reported, in which effective control of remote acyclic asymmetry can be achieved (Eq. 8.91).144 Whereas ISOC occur stereoselectively, INOC proceeds with significantly lower levels of diastereoselection. The reaction pathways presented in Scheme 8.28 suggest a plausible hypo thesis for the observed difference of stereocontrol. The enhanced selectivity in reactions of silyl nitronates may he due to 1,3-allylie strain. The near-linear geometry of nitrile oxides precludes such differentiating elements (Scheme 8.28). 

The simplest nitroalkene, nitroethene, undergoes Lewis acid-promoted [4+2] cycloaddition with chiral vinyl ethers to give cyclic nitronates with high diastereoselectivity. The resulting cyclic nitronates react with deficient alkenes to effect a face-selective [3+2] cycloaddition. A remote acetal center controls the stereochemistry of [3+2] cycloaddition. This strategy is applied to synthesis of the pyrrolizidine alkaloids (+)-macronecine and (+)-petasinecine (Scheme 8.33).165... 

With the Mo-catalyzed macrolactamization secured, we turned our attention to the problem of C2-C6 remote stereochemical control. Catalytic hydrogenation of unsaturated cyclic amide 76, in the presence of 10% Pd(C), resulted in the formation of 78 in 84% yield and with >98% diastereoselectivity. 

Stratakis, M., Sofikiti, N., Baskakis, C. and Raptis, C. (2004). Dye-sensitized intrazeolite photooxygenation of 4-substituted cyclohexenes. Remote substituent effects in regioselectivity and diastereoselectivity. Tetrahedron Lett. 45, 5433-5436... 

In entry 15 of Table 21.10, it is noted that even a remote hydroxyl group directed hydrogenation by the cationic [Rh(diphos-4)(nbd)]+ catalyst to afford a moderate diastereoselectivity (80 20) [23]. This is an interesting example of long-range 1,5-asymmetric induction. 

Almost 50 years ago, Cram outlined a rule (Cram s rule), which proved to be fruitful in understanding, predicting, and controlling diastereoselectivity induced by a remote stereocenter [258,259], Numerous examples of 1,2 induction have confirmed over the time the predictive character of this rule [260], Afterwards, other important contributions of Felkin and coworkers and Anh... 

For the photooxygenation of chiral alkenes in solution bearing a stereogenic centre at the or more remote position with respect to the double bond, low or negligible diastereoselection is expected. The photooxygenation of 2-methyl-5-phenyl-2-hexene 156, a chiral alkene that bears a stereogenic centre at the /3-position with respect to the double bond, gave in solution low diastereoselectivity ca 10% By Na-Y... 

SCHEME 55. Changes in the regiochemistiy and diastereoselection by zeohte confinement due to a remote substituent... 

Chiral aziridines having the chiral moiety attached to the nitrogen atom have also been applied for diastereoselective formation of optically active pyrrolidine derivatives. In the first example, aziridines were used as precursors for azomethine ylides (90-95). Photolysis of the aziridine 57 produced the azomethine ylide 58, which was found to add smoothly to methyl acrylate (Scheme 12.20) (91,93-95). The 1,3-dipolar cycloaddition proceeded with little or no de, but this was not surprising, as the chiral center in 58 is somewhat remote from the reacting centers... 

Substrate-induced diastereoselection is the most common principle in alkylations of enolates derived from ketones. There are numerous successful applications reported in the literature (for extensive reviews, see refs 1, 3, and 79). The following account does not cover this extensive field with all its applications in detail, but rather presents representative examples which provide a general overview of the different synthetic methods available for alkylations of ketone enolates of various structural types, as well as demonstrating that remote asymmetric induction can be efficient and predictable. 

Finally, a homoallylic THP ether may be involved in directing the cyclopropanation reaction of a trimethylsilyl enol ether (equation 54) . The lower diastereoselectivity may be a consequence of the remote position of the directing group (homoallylic position). 

Interestingly, in the mismatched manifold, the diastereoselectivity seemed to be controlled by the more remote homoallylic stereocenter. The allyl moiety was apparently delivered syn to the allylic substituent, as illustrated for the allylzincation of the organo-lithium derived from 234 which led to 235 with high diastereoselectivity (equation 114). 

Desymmetrization of an achiral, symmetrical molecule through a catalytic process is a potentially powerful but relatively unexplored concept for asymmetric synthesis. Whereas the ability of enzymes to differentiate enantiotopic functional groups is well-known [27], little has been explored on a similar ability of non-enzymatic catalysts, particularly for C-C bond-forming processes. The asymmetric desymmetrization through the catalytic glyoxylate-ene reaction of prochiral ene substrates with planar symmetry provides an efficient access to remote [28] and internal [29] asymmetric induction (Scheme 8C.10) [30]. The (2/ ,5S)-s> i-product is obtained with >99% ee and >99% diastereoselectivity. The diene thus obtained can be transformed to a more functionalized compound in a regioselective and diastereoselective manner. 

Use of remote allylic silyl ethers, such as 72b,c, rather than of allylic alcohol 72a in intramolecular oxymercurations leads to a higher 1,3-syM-diastereoselectivity (equation 34)47. The overall yields for syn-Ti and anti-14 range between 85-93%. The best selectivity reaches 7 1 involving the (t-BujPl Si group (entry 36 of Table 1). 

Hydrogen bonding and steric effects have been investigated in a theoretical study of the origin of the diastereoselectivity in the remote 1,5-stereoinduction of boron aldol (g) reactions of /3-alkoxy methyl ketones 125 high levels of 1,5-anti-stereocontrol have been achieved in such reactions of tf-methyl-a-alkoxy methyl ketones, giving both Felkin and anti-Felkin products.126 (g)... 

The hydroxyl group at the allylic position has a significant effect on the syn/anti methyl stereoselectivity [67,68] and the diastereoselectivity [63,64] of the photo-oxygenation ene reaction (see Sec. II.B). To assess the effect of the hydroxyl at the more remote homoallylic position, the reaction of O with the geminal dimethyl trisubstituted homoallylic alcohols (85, 86, 89) and the cis dis-ubstituted 90 was examined in nonpolar solvents [116], The regioselectivity trend was compared with that of the structurally similar trisubstituted alkenes (87, 88, 91) [105], The results are summarized in Table 12. 

The diastereoselective influences of remote substituents on enolate alkylations. Tetrahedron Lett. 1990, 31, 4569 4572. 

The spiro carbon is a stereogenic center in spiropyrans, but because of the achiral structure of the open merocyanine form, the photochromic process will always lead to racemization unless additional chiral moieties are present. When a chiral substituent was introduced, remote from the spiro center, it was possible to isolate diastereo-isomers of the spiropyrans, but rapid epimerization at the spiro center occurred.1441 Diastereoselective switching was successful with 28, in which a stereogenic center was present close to the spiro carbon (Scheme 15).[45] Distinct changes in CD absorption at 250 nm were monitored upon irradiation with UV (250 nm) and with visible light (>530 nm) and a diastereomeric ratio of 1.6 1.0 was calculated for the closed form 28. Furthermore, a temperature-dependent CD effect was observed with this system it was attributed to an inversion of the diastereomeric composition at low temperatures. It might be possible to exploit such effects in dual-mode chiral response systems. A diastereoselective ring-closure was also recently observed in a photochromic N6-spirobenzopyran tricarbonyl chromium complex. 451 ... 

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