Sparteine surrogate

Finding effective chiral ligands is the key to formation of semistabilized chiral lithio-alkanes. Success has been demonstrated from a combination of BuLi and 1C for benzyl trifluoromethyl sulfones and that of t-BuLi and the sparteine surrogate 14 for A-Boc pyrrolidine. ... 

Note added in proof. O Brien has now obtained bispidine ligand 38 (Fig. 3) from (-)-cytisine in 3 steps and demonstrated that it function as a readily accessible (+)-sparteine surrogate in most processes, the stereoselectivity of reactions with ligand 38 are comparable to those with (-)-sparteine as a hgand [92]. Imino Diels-Alder reactions have been investigated as a new route to sparteine analogs, and diamines 38 and epi-38 prepared by this methodology have been examined in the lithiation on hf-Boc-pyrrolidine [93]. 

Strohmann C, Strohfeldt K, Schildbach D, McGrath MJ, O Brien P (2004) Crystal stractures of (-l-)-sparteine surrogate adducts of methyllithium and phenyllithium. Organometallics... 

The use of (+)-sparteine surrogates and the catalytic version of the protocol (now using substoichiometric amounts of chiral diamine) are very exciting extensions that undoubtedly will see further progress, for example in order to decrease the amounts of chiral inductor required for the reaction to work efficiently. Furthermore, the generalisation of this catalytic variant of the method to the synthesis of more phosphines remains to be seen. 

In this chapter, catalytic methods for ligand synthesis are described in detail. In spite of that, the enantioselective deprotonation of tert-butyldimethylpho-sphine borane with a catalytic amount of (—)-sparteine or a (+)-sparteine surrogate, reported by O Brien and co-workers, is included for convenience in Chapter 5, Section 5.4.2, following the discussion on the general strategy of desymmetrisation by enantioselective deprotonation. The coverage of Section 6.2 is mainly limited to systems in which the chiral catalyst acts in the step where the... 

In pursuit of an energy efficient set of conditions suited for process-scale chemistiy, O Brien, Blakemore et al. have also shown that asymmetric alpha-lithiation of N-Boc pyrrolidine as well as other azaheterocycles can he carried out at temperatures up to —20 °C when short reaction times (2-20 min) are maintained/" In the case of N-Boc-pyrrolidine specifically, it vras shown that hy using a (-l-)-sparteine surrogate (+)-2, the asymmetric lithiation and trapping with dimethyl sulfate can he achieved at —30°C providing the alpha-methylated product in 55% yield and 84% ee (Scheme 11.30) when a lithiation time of 2 minutes was used. 

This approach was used for the synthesis of (S)-nicotine (Scheme 16.7). Catalytic asymmetric deprotonation using 1.0 equiv. of s-BuLi, 0.25 equiv. of (+)-sparteine surrogate and 1.0 equiv. of di-i-Pr-bispidine was followed by transmetallation and Negishi eoupling with 3-bromopyridine at 60 °C to give the l -atyl pyrrolidine A in 46% yield. The Boc group was removed using TFA, and Eschweiler-Clarke iV-methylation afforded (S)-nicotine in 96% yield and 92 8 er. 

Morita, Y., Tokuyama. H.. and Fukuyama. T. (2005) Stereocontrolled total synthesis of (-)-kainic add. regio- and stereoselective lithiation of pyrrolidine ring with the (-l-)-sparteine surrogate. Org. Lett., 7, 4337-4340. 

The working hypothesis that guided the design of 134 was that because modelled structures show that the D ring in (+)-sparteine is far away from the coordinated lithium atom, so a simplified version without this ring should not significantly alter the chiral environment around the lithium atom. Therefore, several surrogates 134 were prepared from (-)-cytisine and tested in enantioselective deprotonation of phosphine boranes and sulfides (Scheme 5.53 and Table 5.20). 

Figure 5.1 Chemical structures of (-l-)-sparteine and some of its surrogates.

Table 5.20 shows that this approach allows the synthesis of the other enantiomer to that obtained with (-)-sp. Furthermore, in some cases the surrogate considerably outperformed (-l-)-sparteine (compare entries 6 with 5 or 10 and 11 with 8). A competition experiment with equimolar amounts of (-)-sp and Me-134 in the deprotonation of 4 (R = t-Bu) with 5-BuLi showed that the product was obtained with a 50% ee with the sense of induction of (-l-)-spar-teine, confirming that Me-134 is more reactive than sparteine. The choice of the R group in 134 is crucial. For example, benzyl gives disappointing results probably due to deprotonation at the benzylic position (entries 4 and 12). Up to now, the best surrogate seems to be the diamine Me-134 and this has been used to prepare the enantiomers of some of the phosphine boranes and sulfides discussed earlier in this section. ... 

It is well known that certain diamines increase the reactivity of organolithium compounds by complexation to the Li atom. Consequently, with the appropriate chiral diamines it should be possible to perform catalytic asymmetric deprotonations. In the original report of Evans and co-workers it is mentioned that the enantioselection can be maintained with only 0.7 equivalents of ( )-sparteine, with no further details. These ideas have been recently exploited for t-butyldimethylphosphine borane and the analogous sulfide with sparteine and its surrogates. It can be understood with the catalytic cycle of Scheme 5.54, reported by O Brien and co-workers. 

Finally, the method relies almost exclusively on sparteine or its surrogates, making the exploration of other chiral inductors a worthy effort. 

The chiral bispidine (+)-2, derived from (-)-cytisine, was observed to behave enantiocomplementarily to ( )-sparteine and was applied as a surrogate to the scarcely accessible (-f)-sparteine (Scheme 11.25). Non-sparteine-like chiral diamines and (5,5 )-4, that provide access... 

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