Stereoselective synthesis from chiral pool

Direct separation of enantiomers by chromatography Use of covalent chiral auxiliaries Stereoselective synthesis of individual enantiomers Separation of diastereoisomers by physical techniques Synthesis from chirality pool materials... 

A review was published covering recent progress in the stereoselective synthesis of piperidines <00S1781>. Routes described in detail include those derived from the chiral-pool, chiral auxiliaries, and catalytic asymmetric methodology. 

One of the fundamental operations in organic synthesis remains the stereoselective reduction of carbonyl groups1241. In a process related to that reported by Hosomi et u/.[25], using hydrosilanes as the stoichiometric oxidant and amino acid anions as the catalytic source of chirality, a variety of ketones were reduced in good to excellent yield and with good stereoselectivity1261. This process reduces the amount of chiral catalyst needed and utilizes catalysts from the chiral pool that can be used directly in their commercially available form. 

At that time, as now, the enantiomers of many chiral amines were obtained as natural products or by synthesis from naturally occurring amines, a-amino acids and alkaloids, while others were only prepared by introduction of an amino group by appropriate reactions into substances from the chiral pool carbohydrates, hydroxy acids, terpenes and alkaloids. In this connection, a recent review10 outlines the preparation of chiral aziridines from enantiomerically pure starting materials from natural or synthetic sources and the use of these aziridines in stereoselective transformations. Another report11 gives the use of the enantiomers of the a-amino acid esters for the asymmetric synthesis of nitrogen heterocyclic compounds. 

In a study which was conducted simultaneously to the work in the Mehta group and which also aimed to prove the absolute configuration of natural kelsoene (1), Schulz et al. used a stereoselective approach starting from the enantiomerically pure chiral pool material (i )-pulegone 17 [9, 10] (see above). The final steps of their synthesis of the unnatural enantiomer of kelsoene (ent-l) were similar to the above-described first total synthesis of natural kelsoene (1) (Scheme 8). Taking into account the steric limitations of the system as communicated by Srinivas and Mehta, diquinane enone ent-6... 

The structurally novel antimitotic agent curacin A (1) was prepared with an overall yield of 2.5 % for the longest linear synthesis. Three of the four stereogenic centers were built up using asymmetric transformations one was derived from a chiral pool substrate. Key steps of the total synthesis are a hydrozirconation - transmetalation protocol, the stereoselective formation of the acyclic triene segment via enol triflate chemistry and another hydrozirconation followed by an isocyanide insertion. For the preparation of the heterocyclic moiety of curacin A (1) the oxazoline - thiazoline conversion provides efficient access to the sensitive marine natural product. 

To date, two total syntheses of myriaporone 4 are known. This chapter is based on the total synthesis of myriaporone 4 published by Taylor et al. in 2004. The synthesis of a chiral precursor, which has also been employed for the total synthesis of related compounds, was published by the same group in 1998. The linear total synthesis starts with an enantiomerically pure molecule from the chiral pool that delivers the stereogenic center at C-12 of the final product, employs Evans aldol reactions as key steps for stereoselective chain elongations and additionally includes reduction/oxidation steps as well as protecting group chemistry. 

A commoner way to make heterocycles by pericyclic reactions is to use 1,3-dipolar cycloadditions. These often occur without catalysis and so are compatible with many other reactions. The starting material 182 for this asymmetric synthesis of swainsonine was derived from a natural sugar (chiral pool strategy, chapter 23). An exceptionally stereoselective Wittig reaction gave the Z-alkene 183 (chapter 15) and the alcohol was converted into the azide 184 with diphenylphos-phoryl azide.24... 

It was imperative that our syntheses of fragments 7 and 8 would allow for their stereoselective generation in either enantiomeric series, and since our plan for the synthesis of the C10-C16 dithiane fragment 7 relied on utilization of readily available substances from the chiral pool (Scheme... 

Solid-phase and combinatorial synthesis of 6-lactams using the Staudinger reaction has widely been studied. Carbohydrates as a chiral pool, however, were not employed except for one report [148]. The polymer supported-imines were employed to prepare several -lactams by enolate/imine condensation and ketene/imine cycloaddition (Scheme 46) [146]. The reactions carried out on the polymer-boimd imines showed a remarkable similarity to those in solution, both in terms of yield and stereoselectivity [54,55]. )S-Lactams were removed from the polymer by CAN oxidation [ 148]. 

When the methodology of stereoselective synthesis was still in its infancy, it was considered advantageous to utilize sequences of stereogenic centers available from enantiomerically pure natural products as building blocks [3, 4] this so-called chiral pool synthesis strategy is exemplified in Scheme 4.2. The bicyclic acetal structure of exo-brevicomin (31) can be ret-rosynthetically linked to the chiral ketodiol 32, which can be derived from (S,S)-(-)-tartaric acid, a readily available chiral starting material. This leads to the building block oriented bond-set depicted in intermediate 32. 

A significant advantage in comparison with selectors derived from the chiral pool is the option of obtaining both enantiomers of the selector through stereoselective synthesis. When one changes the chirality of a selector, e.g. from (R,R) to (S,S), the elution order of the enantiomers of the analyte is changed, which can sometimes be advantageous in the determination of ee. 

A retrosynthetic analysis may well lead to a molecule recognizably derived from the chiral carbon pool. Presumably, the resulting synthesis will then be subject only to the vagaries encountered in the preparation of any target molecule, chiral or not. Unfortunately, the actual situation is not always that simple. If the target molecule contains more than one chiral center, the introduction of the later centers must be highly stereoselective to avoid diastereomer formation. As noted above, though, diastereomers usually are separated fairly readily and the loss of a small amount of... 

---