Computer-Assisted Design and Synthetic Applications of Chiral Enol Borinates : Novel , Highly Enantioselective Aldol Reagents

Descrevemos recentemente o desenvolvimento de um modelo quantitativo de estados de transição para a previsão da estereosseletividade em condensações aldólicas mediadas por boro. Este modelo fornece percepções qualitativas sobre os fatores, contribuindo para o resultado estereoquímico de uma variedade de reações de importância sintética. O modelo de campo de força foi utilizado para auxiliar na elaboração e preparação de novos ligantes de boro quirais derivados da mentona. Os enolatos de boro quirais foram empregados em vários processos estereosseletivos, incluindo a adição a aldeídos quirais e a síntese total, controlada pelo reagente, da (3S,4S)-estatina. Os enolatos quirais derivados a partir de tioacetatos α-halo e α-oxisubstituídos foram adicionados a aldeídos e iminas. A adição de iminas leva à síntese enantiosseletiva de aziridinas quirais, a síntese total formal da (+)-tioamfenicol, a uma nova e altamente eficiente síntese da cadeia lateral em C-13 do paclitaxel (taxol®) e a semi-síntese do taxol a aprtir da bacatina III. O resultado estereoquímico da adição das iminas foi racionalizado com o auxílio de estudos computacionais. Reações de adição enantiosseletiva de enolatos de boro quirais derivados do tioacetato foram empregados com sucesso a aldeídos ligados à fase sólida, fornecendo produtos aldólicos em rendimentose enantiosseletividades comparáveis às condições usuais em solução.


Transition State Modeling and Design of New Boron Ligands
We recently described a force field model for the aldol reactions of ketone derived enol borinates with aldehydes.This force field is based on MM2, and on new parameters developed from ab initio calculations on the cyclic aldol transition structures (e.g.chair 1 and boats 2, 3; Fig. 1).The model reproduces the aldehyde Si: Re selectivity for the syn selective aldol reactions of a range of chiral Z enol borinates, as well as for the anti selective reactions of E enolates.The force field model suggested that the following factors were important in determining the stereoselectivity of the chiral boron-ligand mediated reactions: (a) the conformational rigidity of the boron-ligand, (b) the relative orientation of the ligands with respect to the transition structure core, and (c) the relative orientation and restrained rotation around the B-C bonds of one ligand relative to the other 1,2 .
Based on this information, it was decided to search for conformationally locked systems.The case of cis-1,2ethylisopropylcyclohexane appeared as an interesting example of conformational lock based on the avoidance of (+/-) double gauche pentane interactions (Fig. 2).There is only one conformation of the chair and of the side chains (4) that does not possess any (+/-) double gauche pentane interactions, while any other rotamer is higher in energy.The terminal methyl group of the ethyl side chain was substituted with a boron atom.For reasons of synthetic accessibility (see below), an extra equatorial methyl group was added to the ligand (5, Fig. 2), which did not alter the computed stereoselectivity.
After running the conformational search of a Si:Re face selection in an E(OB)-enol borinate reaction (for nomenclature see Ref. 3) leading to an anti aldol, we were delighted to discover that the new chiral enolates showed a distinct stereoselectivity in the computational run, surpassing by far Ipc (isopinocampheyl) or any other designed reagent 4 .

The Menthone Derived Boron Reagents
The synthesis of the new reagents 6 and 7 (Fig. 3) took considerable effort to develop due to the need for separation from diastereomeric dialkylboranes formed in the hydroboration step.The minor diastereomeric haloboranes were shown both computationally and experimentally to be lowstereoselective reagents for the aldol reaction.Eventually the borane was purified by crystallization in ethyl ether at low temperature.The reagent is quite stable and is currently prepared uneventfully and stored as a stock solution in methylene chloride in the freezer.
Syn aldols, in boron enolate chemistry, are easily obtained with good enantioselectivity from chiral Z(OB)-enolates because they have only access to a single transition structure, chair 1. High selectivity for anti or unsubstituted aldols is comparably more difficult to achieve because unsubstituted enolates and (partly) E(OB)-enolates may adopt a variety of transition structures, namely chair 1, boat 2, and boat 3 (Fig. 1).This competition among transition structures of similar energy (usually many conformers for each transition structure core-conformation 1, 2, and 3) makes the stereochemical control of the reaction much more difficult to obtain.The chiral E enol borinates derived from the reagents shown in Fig. 3 gave rise to ketone-derived anti-aldols, which had eluded earlier attempts at   effective asymmetric synthesis via direct aldol-type condensation.Although the enantioselectivity was lower than computer-predicted (the aldol force field is not as calibrated with E enolates as it is with Z enolates), the enantiomeric excesses (74-88% e.e.; R = Me; R 1 = alkyl, aryl) were the highest reported for such transformations (Fig. 4).The reagent proved effective also with methyl ketone enolates leading to unsubstituted aldols, although with lower enantiomeric excesses (55-76% e.e.; R = H; R 1 = alkyl, aryl).
Additions to N,N-dibenzylamino aldehydes were also highly diastereoselective: the chiral boron enolate of tbutylthioacetate derived from ent-7 was able to overcome the inherent substrate preference for the Felkin-type product (3,4anti) observed with achiral enolates.It is worth noting that in the ''matched'' cases the 3,4-anti: 3,4-syn diastereomeric ratios are ≥ 98.2:1.8, while in the ''mismatched'' cases the 3,4-syn: 3,4-anti ratios are ≥ 95.4:4.6.These results indicate that it is possible to obtain either the 3,4-anti or the 3,4-syn adduct with very high diastereoselectivity by simple variation of
It is interesting to note that the stereochemistry of the imine (trans) determines the syn stereochemical relationship in the aldol product 10.In fact, the absolute configuration of 10 is consistent with a chair transition structure featuring preferential attack on the imine Re face (Ar axial, Fig. 7).We may also point out that in the aldehyde case, the R group can adopt an equatorial position (aldehyde Si face attack) which eventually leads to the anti relationship between the hydroxy and the halogen groups (Fig. 6).94-97 %), see Fig. 8 9 .The following is noteworthy: a) the enolization preferentially results in the formation of E (OB)-enolates, as implied from the high anti-syn ratios observed in the aldol products; b) the enantiomeric and the anti-syn ratios are independent of the type of R 1 and R 2 substituents (R 1 = TBDMS, Bn; R 2 = Ph, Bu t ); c) the absolute configuration of the aldol products is consistent with chair transition structures featuring preferential attack on the aldehyde Re face [L* derived from (-) menthone].

Semisynthesis of Paclitaxel (Taxol ® )
Paclitaxel ( 12) is considered the most promising cancer chemotherapeutic agent and has recently been approved for treatment of metastatic ovarian and breast cancer 12 .Central to all synthetic strategies for paclitaxel is the synthesis and attachment of the C-13 side chain to the baccatin III nucleous, since the presence of this side chain has proven to be essential for the biological activity of paclitaxel.The chemical complexity of paclitaxel dictates that its commercial production by total synthesis is not likely to be economical, while the naturally derived 10-deacetylbaccatin III (13a, Fig. 9) is readily available in relatively high yield from the needles of the European Yew T. baccata.Preparation of quantities of paclitaxel economically by a semisynthetic approach which involves the condensation of protected 10-deacetylbaccatin III (13b,c) with suitably protected N-benzoyl-(2R,3S)-3-phenylisoserine (14), provides an alternative source of this important natural product and the access to semisynthetic analogs.
We have developed a very simple, new and straightforward approach to the paclitaxel side chain using the imine addition reaction of thioester derived boron enolates bearing chiral ligands. 13,14The side chain is assembled in one single step with the correct relative (syn) and absolute stereochemistry (2R, 3S).The desired compound ( 16) was isolated practically pure by simple solvent extraction without the need for chromatography (Fig. 10).The overall yield is 60% (starting from 15), and the stereochemical control is high (syn:anti ≥ 96:4; e.e. ≥ 96%).Oxazolidine formation occurs using 2-methoxypropene and pyridinium toluene-4-sulfonate in toluene to give (17) (≥ 90%) and the small amount of the unwanted anti diastereomer is removed in this step via chromatography (the anti compound does not cyclize under these conditions).
From the above results, and from many other not reported, it is clear that the stereochemical outcome of the aldol additions to imines is strongly dependent on the type of thioester used (COSPh vs. COSBu t ), contrary to the results using the same boron reagents and aldehydes (Fig. 8) 9 , while the role of the oxygen protecting group is relatively minor.The stereochemical outcome can be rationalized using chair vs. boat transition structures (Fig. 12).Ab initio MO calculations (3-21G basis set) featuring the addition of the BH2 enol borinate derived from acetaldehyde to formaldehyde-imine have recently shown that two competing cyclic transition structures are likely to be important: the chair and the boat 15 .

Enantioselective Aldol Chemistry on Solid Phase
Studies of organic synthesis on a solid support have witnessed an explosive surge of interest in the last few years.Much effort has been expended in the adaptation to the solid phase of the synthetic armoury of organic chemistry.Solid supported strategies leading to the iterative synthesis of the most important biopolymers, namely peptides, oligosaccharides, and oligonucleotides are well established and have also been adapted to automation.However, a solid phase approach to polyketides, a class of biopolymers consisting of a 1, 3, 5, n-polyol chain with defined stereochemistry, has not yet been demonstrated.
Two different approaches, in principle, could be employed for solid phase supported aldol chemistry: formation of the enolate linked to the resin and reaction with an aldehyde in solution; or the immobilization of the aldehyde on the solid support and treatment with an enolate in solution.The second synthetic pathway allows for possible iteration of the aldol process towards a solid phase synthesis of polyketide-type structures, provided a conversion to another aldehyde is accomplished.We were attracted by the possibility of developing a stereoselective aldol protocol on solid phase bound aldehydes using our thioester-derived chiral enolborinates bearing chiral ligands.These boron enolates have been shown to impart a strong reagent control in their reactions with chiral aldehydes (see above), which is required in order to control stereochemistry of the growing chain.Furthermore, the use of thioesters should enable easy conversion to the aldehyde for iteration.
Enantioselective addition reactions of the chiral boron enolate derived from thioacetate to solid phase bound aldehydes have successfully been carried out with a variety of aldehydes and linkers, and giving rise to aldol products in yields and enantioselectivities comparable to the usual solution conditions (Fig. 13) 16 .

Figure 1 .
Figure 1.All-hydrogen substituted ab initio transition structures for boron enolate aldol addition.