Stereocontrol in acyclic systems

Reactions of acyclic molecules can generate diastereomers and the term controlling stereochemistry usually refers to an attempt to generate one diastereomer in preference to another as the major product of a reaction. This section will classify various stereocontrol problems and outline general methodologies that are available to solve each problem. The types of situations where attempts to control stereochemistry are important include  

Reactions where these effects are important were presented in previous chapters. The carbon-carbon bond forming reactions in succeeding chapters contain many additional examples. The purpose of this chapter is 

A typical reaction that illustrates Markovnikov addition is the reaction of HBr with 2-methyl-2-butene to give 2-bromo-2-methylbutane (1, sec. 2.10.A). This reaction proceeds by formation of the more stable carbo-cation, which reacts with the nucleophilic bromide ion. If the anti-Markovnikov bromide (the bromine resides on the less substituted carbon) is desired, a different mechanistic pathway must be followed. A typical anti-Markovnikov addition reaction is addition of borane to the alkene, giving primary alcohol (2) after oxidation of the intermediate alkylborane (sec. 5.4.A). This alcohol can be converted to the anti-Markovnikov bromide, 3, by treatment with PBr3. The key to controlling such reactions is a fundamental 

The hydroboration reaction with alkenes to produce alkylboranes (sec. 5.2) proceeds by a four-center transition state rather than a cationic intermediate. The regiochemistry of the final alkylborane product is controlled by the nonbonded steric interactions of the groups attached to boron (in this case sec-isoamyl from the disiamylborane) and the groups on the alkene. Oxidation with basic hydrogen peroxide converts the borane to the anti-Markovnikov alcohol (2). The difference in regiochemistry between 1 and 2 arose because the mechanism for generating each relied on difference factors. 

Formation of 8 shows that conversion of the OH unit to a leaving group allows an Sn2 reaction to occur. In general, both the hydroxyl and amine units are poor leaving groups. If the alcohol is converted to a 

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While the process works for a great number of conjugated dienes, a few, such as 1,3-cyclopentadiene and those acyclic dienes that have an oxygen substituenl in an allylic position, did not give a chloroacetoxylation product.23 Control of the 1,4-relative stereochemistry and preparation of compounds analogous to the title compounds also work for acyclic dienes,23 5 This process was used to obtain remote stereocontrol in acyclic systems and applied to the synthesis of a pheromone.5... 

The reactions of allylmetal reagents with carbonyl compounds and imines have been extensively investigated during the last two decades [1], These carbon—carbon bondforming reactions possess an important potential for controlling the stereochemistry in acyclic systems. Allylmetal reagents react with aldehydes and ketones to afford homo-allylic alcohols (Scheme 13.1), which are valuable synthetic intermediates. In particular, the reaction offers a complementary approach to the stereocontrolled aldol process, since the newly formed alkenes may be readily transformed into aldehydes and the operation repeated. 

The reaction of allylic organometallics with electrophilic reagents is a very important tool for the formation of carbon-carbon bonds in acyclic systems and for controlling their stereochemistry. Crotyl organometallic (2-butenylmetal) species undergo a 1,3-shift of the metal at room temperature. For the stereocontrolled use of allylmetals in synthesis, it is important to avoid their equilibration. 

Acyclic Substrates. The situation in acyclic systems is much more complicated than in cyclic ones as high stereocontrol for additions to prostereogenic double bonds [reactions (47a,b), Scheme 16] or carbonyl groups [reaction (48), Scheme 16] can only be achieved if the molecule adopts a definite reactive conformation in which one of the two diastereofaces is efficiently shielded by the steric effects of the substituents (Scheme 16) [41]. This means that these substituents have to be of different sizes and may be classified as small (S), medium... 

Aside from the well-documented ability of the Luche reduction to provide stereocontrol in cyclic systems, acyclic stereocontrol is also viable through this process.39-41 A notable example of this was demonstrated in the synthesis of (+)-cannabisativine, a unique natural product found in the common marijuana plant.42 This synthesis necessitated a stereoselective Luche reduction to produce the diol 36 as a single diastereomer. The reaction proceeded in 96% yield and with 95% de. The pronounced diastereoselectivity can be attributed to Cram s rule, in which the hydride ion is delivered from the least sterically hindered side of the intermediate 34. Reduction via the chelated intermediate 35 would also account for the observed stereochemical outcome. 

It is apparent from preceding sections that stereocontrol in cyclic systems is much easier than in acyclic systems, which is due, of course, to the conformational bias inherent in cyclic systems. Synthetic chemists have exploited this fact for many years. A cyclic system can be used to position functional groups, often with control of regio- and stereochemistry. The ring is then opened to give an acyclic system and the regiochemistry and stereochemistry of the substituents has been fixed. There are many examples. 

Six-membered Rings Five-membered Rings Stereocontrol in Cyclic Systems Acyclic Diastereoselection Biomimetic Synthesis... 

The first example of an intermolecular radical addihon/intermolecular trapping domino reactions of an acyclic system in a stereocontrolled fashion to build stereo-genic centers at the a- and 3-carbons was described by Sibi and coworkers [59]. Enantioselective addition of in-sitw-prepared alkyl radical to crotonate or cinnamate,... 

Intramolecular Diels-Alder (IMDA) is a very powerful reaction, which converts an acyclic system into a bicyclic one, often with high stereocontrol. By positioning a good dienophile (typically in the carboxylic component) and a highly... 

The conformational barriers in acyclic radicals are smaller than those in closed-shell acycles, with the barrier to rotation in the ethyl radical on the order of tenths of a kilocalorie per mole. The barriers increase for heteroatom-substituted radicals, such as the hydroxymethyl radical, which has a rotational barrier of 5 kcal/mol. Radicals that are conjugated with a n system, such as allyl, benzyl, and radicals adjacent to a carbonyl group, have barriers to rotation on the order of 10 kcal/mol. Such barriers can lead to rotational rate constants that are smaller than the rate constants of competing radical reactions, as was demonstrated with a-amide radicals, and this type of effect permits acyclic stereocontrol in some cases. "... 

Several recent reviews have included specific types of electrophilic cyclofunctionalization reactions.1 Important areas covered in these reviews are halolactonization u cyclofunctionalization of unsaturated hydroxy compounds to form tetrahydrofurans and tetrahydropyrans lb cyclofunctionalization of unsaturated amino compounds lc cyclofunctionalization of unsaturated sulfur and phosphorus compounds ld lf electrophilic heterocyclization of unconjugated dienes 1 synthesis of y-butyrolactones 1 h synthesis of functionalized dihydro- and tetrahydro-furans lj cyclofunctionalization using selenium reagents lk lm stereocontrol in synthesis of acyclic systems 1" stereoselectivity in cyclofunctionalizations lP and cyclofunctionalizations in the synthesis of a-methylenelactones.lq Previous reference works have also addressed this topic.2... 

Stereocontrolled epoxidation of acyclic systems. Stereoselectivity in the epoxi-dation of homoallylic alcohols is usually low. Nonetheless Kishi etal. have observed... 

Blackburn, B. K., Sharpless, K. B. Rhodium(l) catalyzed hydroboration of olefins. The documentation of regio- and stereocontrol in cyclic and acyclic systems. Chemtracts Org. Chem. 1989, 2, 33-35. 

Further examples of acyclic stereocontrol in related amino acid systems make use of chiral and nonracemic oxaziridine reagents to induce high levels of stereocontrol. In 1992, Davis and coworkers synthesized the methyl ester of the Taxol C13 side chain using this method.30 Following enolization, the dianion of 44 was reacted with the Davis reagent 5 to yield the a-hydroxy (5-amino acid 45 in 49% yield. While the yield was marginal in this particular example, the 86 14 ratio of stereoisomers produced is impressive in this acyclic system. 

Macrocyclic Olefinic Microbial Metabolites Conformational studies based on n.m.r. and c.d. measurements of fourteen-membered ring macrolides have been discussed using diamond lattice conformational models A review on stereocontrol in synthesis of acyclic systems includes the... 

Other aspects of steric control in prostaglandin synthesis have been reviewed by Roberts and Newton, and Bartlett has provided a timely review on stereocontrol in the synthesis of acyclic systems. ... 

P. A. Bartlett, Stereocontrol in the Synthesis of Acyclic Systems Applications to Natural Product Synthesis , Tetrahedron, 1980, 36, 3. 

Most synthetic strategies are aimed toward direct assembly of open-chain systems ( acyclic stereocontrol ). In this manner, individual building blocks containing stereotriads are prepared and then incorporated into the target molecule. This approach mimics polyketide biosynthesis. Many research programs have been dedicated to improve both regio and stereo control, the efficiency of carbon-carbon bonds formation, and then stereoselective reduction of... 

A drawback of the Z enoates is usually lower reactivity, reflected in prolonged reaction times and higher reaction temperatures. This may be overcome by switching to more reactive enone systems. Thus, addition of the functionalized cyano-Gilman cuprate system 67 to Z enone 66 proceeded smoothly at low temperatures, with excellent acyclic stereocontrol at the /i-stereocenter [26, 27]. Stereocontrol upon... 

Some representative examples of the [3+2] annulatlon are listed in Table 1. Both cyclic and acyclic allenophiles participate in the reaction, a-Alkylidene ketones undergo annulation to provide access to spiro-fused systems, and acetylenic allenophiles react to form cyclopentadiene derivatives. The reactions of (E)- and (Z)-3-methy1-3-penten-2-one illustrate the stereochemical course of the annulation, which proceeds with a strong preference for the suprafacial addition of the allene to the two-carbon allenophile. The high stereoselectivity displayed by the reaction permits the stereocontrol led synthesis of a variety of mono- and polycyclic systems. 

The stereocontrol inherent in the totally regiospecific 5-exo-trig isomerizations of substituted 5-hexenyllithiums may be exploited for the stereoselective synthesis of bicyclic systems by tandem cyclization of acyclic diolefinic alkyllithiums. To date, this strategy has not been widely applied, and the first examples were reported by Bailey and Rossi who were able to cyclize the organolithiums derived from iodides 113 and 115 in the presence of TMEDA to afford the polycarbocyclic products 114 and 116 (Scheme 33)61. 

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