1,3-stereocontrol

The initiator and monomer control not only the rates and degrees of addition and insertion polymerizations, but also the overall configuration of the macromolecule produced. Stereoregular polymers, that is, those with a regular tactic structure, can be produced only under quite specific conditions. Polymerizations that lead to stereoregular polymers are called stereospecific. 

Stereospecific polymerizations can be divided into three groups according to whether they proceed from prochiral or chiral monomer molecules and whether they have chiral or achiral monomeric units. Those polymerizations classified according to the property of the groups can be further subdivided into classes according to the properties of the molecules produced and the molecular systems produced. 

Achiral monomers are converted to dissymmetric polymer molecules in achiral stereospecific polymerizations. An example of this is the polymerization of propylene to isotactic or syndiotactic poly(propylene). These kinds of polymerizations are commonly called stereospecific, although the two following classes are also stereospecific. 

A prochiral monomer molecule is converted to a polymer with chiral groups in prochiral stereospecific or chirality-producing stereospecific polymerizations. An example of this is the polymerization converting benzo-furan to optically active polymers with the catalyst RAlCl2/optically active phenyl alanine. 

---

Supression of olefin isomerization is critical for acyclic stereocontrol ... 

It is possible to prepare 1-acetoxy-4-chloro-2-alkenes from conjugated dienes with high selectivity. In the presence of stoichiometric amounts of LiOAc and LiCl, l-acetoxy-4-chloro-2-hutene (358) is obtained from butadiene[307], and cw-l-acetoxy-4-chloro-2-cyclohexene (360) is obtained from 1.3-cyclohexa-diene with 99% selectivity[308]. Neither the 1.4-dichloride nor 1.4-diacetate is formed. Good stereocontrol is also observed with acyclic diene.s[309]. The chloride and acetoxy groups have different reactivities. The Pd-catalyzed selective displacement of the chloride in 358 with diethylamine gives 359 without attacking allylic acetate, and the chloride in 360 is displaced with malonate with retention of the stereochemistry to give 361, while the uncatalyzed reaction affords the inversion product 362. 

In MeOH, l,4-dimethoxy-2-cyclohexene (379) is obtainejl from 1,3-cydo-hexadiene[315]. Acetoxylation and the intramolecular alkoxylation took place in the synthesis of the naturally occurring tetrahydrofuran derivative 380 and is another example of the selective introduction of different nucleo-philes[316]. In intramolecular 1,4-oxyacetoxylation to form the fused tetrahy-drofurans and tetrahydropyrans 381, cis addition takes place in the presence of a catalytic amount of LiCI, whereas the trans product is obtained in its absence[317]. The stereocontrolled oxaspirocyclization proceeds to afford the Irons product 382 in the presence of Li2C03 and the cis product in the presence of LiCl[ 318,319]. 

Disconnections which leave stereocenters on newly created appendages are not strategic unless the stereocenters can be removed with stereocontrol prior to the disconnection (see section 4.3). 

If the disconnection of a bond found to be strategic by criteria 1-3 produces a new ring appendage bearing stereocenters, those centers should be removed if possible (by stereocontrolled transforms) before the disconnection is made. 

There is also a category of intramolecular reactions/transforms which involves total mechanistic stereocontrol with conformationally restricted structures, for example the halolactonization transform 149 150 and the internal cycloaddition 151 152. These... 

Examples were given above of stereocontrol due to substrate bias of a steric nature. Substrate bias can also result from coordinative or chelate effects. Some instances of coordinative (or chelate) substrate bias are shown retrosynthetically in Chart 18. 

There are a number of powerful synthetic reactions which join two trigonal carbons to form a CC single bond in a stereocontrolled way under proper reaction conditions. Included in this group are the aldol, Michael, Claisen rearrangement, ene and metalloallyl-carbonyl addition reactions. The corresponding transforms are powerfully stereosimplifying, especially when rendered enantioselective as well as diastereoselective by the use of chiral controller groups. Some examples are listed in Chart 20. 

Apply stereoselective transforms to reduce the number of reactive functional groups, especially those of sufficient reactivity to cause interference with stereocontrolled C-C disconnective transforms. 

Clearable Stereocenter(s). Stereocenter(s) which can be eliminated retrosynthetically by application of a transform with stereocontrol (stereoselectivity). 

Mechanism-Control of Stereochemistry. Stereocontrol in a reaction or transform as a result of mechanistic factors rather than substrate structure alone. 

Erythronolide B, the biosynthetic progenitor of the erythromycin antibiotics, was synthesized for the first time, using as a key step a new method for macrolactone ring closure (double activation) which had been devised specifically for this problem. Retrosynthetic simplification included the clearance of the stereocenters at carbons 10 and 11 and the disconnection of the 9,10-bond, leading to precursors A and B. Cyclic stereocontrol and especially the Baeyer-Villiger and halolactonization transforms played a major role in the retrosynthetic simplification of B which was synthesized starting from 2,4,6-trimethylphenol. 

The intermediate A was also made by an alternative route using interesting new methodology for stereocontrol (Ref. 2). 

Atractyligenin and its sulfated glucoside (actractyloside) are toxins which block the transport of ADP into mitochondria and which occur in the coffee bean. Atractyligenin was synthesized following a multistrategic retrosynthetic plan in which the disconnection of ring B was a major objective. Novel stereocontrolled processes were employed for the critical cyclization to form the tetracarbocyclic network and for introduction of the carboxylic substituent. 

The synthesis of the tricyclic intermediate A was further improved by the development of a short and stereocontrolled synthesis of compound B (Ref. 9) ... 

Forskolin is an activator of the enzyme adenylate cyclase which has therapeutic utility. Outlined below are stereocontrolled routes to racemic and natural chiral forms of forskolin derived by multistrategic retrosynthedc analysis. 

The necessity for producing large amounts of synthetic prostaglandins and analogs provided the impetus for a number of improvements in the bicyclo[2.2.1]heptene approach. Especially important was the development of an enantioselective modification for the synthesis of chiral prostanoids without resolution (1975) and the invention of a chiral catalyst for the stereocontrolled conversion of 15-keto prostanoids to either 15(5)- or 15(7 )- alcohols. 

Compound A was also made by a direct, stereocontrolled total synthesis (Ref. 4). 

A stereocontrolled route to the native form of thromboxane B2 was carried out starting with a-methyl-D-glucoside (Ref. 3). 

TTie condensation of fluormated carbonyl compounds is a versatile approach to the stereo- and regioselective construction of specifically tluonnated materials It is possible to use fluormated reactants in vanous oxidation states and to utilize them either as the nucleophilic or electrophilic reaction partners Stereocontrol in those processes using the fluormated carbonyl compounds m a nucleophilic fashion has lagged behind the achievement of higher yields... 

This reaction has received especial attention for the stereocontrolled synthesis of polyfluorinated artrfieial pyrethroids [65, 66] (equation 52). 

These zinc reagents are useful precursors for stereocontrolled palladium-catalyzed cross-coupling reactions, as illustrated in equations 73-80 [100, 101, 102, 103, 104, 105, 106, 107, 108] This methodology has been used to prepare new fluorinated analogues of codlemone [I09. ... 

The most valuable characteristic of the Patemo-Buchi reaction is the ability to set multiple stereocenters in one reaction and the development of diastereocontrolled reactions has been a major theme of research concerning this reaction. Stereocontrol can be envisioned to spring from either the carbonyl or the alkene and be controlled by either the substrate directly or by a chiral auxiliary. Little success has been achieved in substrate-induced selection by the carbonyl the most successful results were produced by... 

Stereocontrolled Additions to Dihydropyridines and Tetrahydropyridines Access to N-Heterocyclic Compounds Related to Natural Products... 

Lavilla et al. have reported several stereocontrolled oxidative electrophilic additions to A-alkyl-l,4-dihydropyridines 34 leading to the synthesis of 3-halo-2-substituted-l,2,3,4-tetrahydropyridines 67 (98JOC2728). Adding a stoichiometric amount of iodine or NIS (A-iodosuccinimide) to a methanolic solution of 1 -methy 1-... 

---