Chiral lithiated pyrrolidine

Scheme 7-113 Carbocyclization from a chiral lithiated pyrrolidine.

The Sparteine Method 42 was applied successfully to generate chiral a-lithiated pyrrolidine when using the Boc-protected (tcrt-butoxycarbonyl)pyrrolidine and sec-butyllithium/sparteine as an asymmetric deprotonating agent in diethyl ether at — 78 °C. Alkylation, silylation, stanny-lation and methylation occurred with good yield (70-75%) and high selectivity (95% ee)53. 

The enantioselectivity is due to the retention of the chiral sparteine in the lithiated reagent. The adducts have been used to synthesize a number of pyrrolidine and piperidine derivatives. 

We became interested in a disconnection between the pyrrolidine and the aryl group (Approach D) as the most convergent method for enantioselective construction of 12 [10]. Although (-)-sparteine mediated enantioselective lithiation of N-Boc pyrrolidine 19 is well established by Beak [11], arylation of the resulting chiral... 

Pyrrolo[l,2- ][l,2]oxazines are a class of compounds with very few references regarding synthesis and reactivity. An interesting preparation has been described by intramolecular cyclization of IV-hydroxy pyrrolidines carrying a methoxyallene substituent at C-2 (242, Scheme 32). These compounds were obtained by addition of a lithiated allene to chiral cyclic nitrones 241. Cyclization occurred spontaneously after some days at relatively high dilution (0.05 M). Compounds 243 (obtained with excellent diastereoselectivity) can be submitted to further elaboration of the double bond or to hydrogenolysis of the N-O bond to form chiral pyrrolidine derivatives (Section 11.11.6.1) <2003EJ01153>. 

Aminomethylferrocene 338, this time without further methoxy substituents, also lithi-ates diastereoselectively (Scheme 150) , and similar results may be obtained with simple chiral pyrrolidines. Treatment of 322 with the binaphthylamine 337 yields 338. Lithiation generates a 9 1 mixture of diastereoisomeric organoUthiums, which give the phosphine 339 (Scheme 150) Attempts to obtain reversed planar diastereoselectivity by using silylation to block the more reactive lithiation site failed. 

Further progress towards the stereoselective synthesis of chhydrooxazines has also been reported by Reissig and coworkers who exploited the formal [3 + 3] reaction of lithiated methoxyallene with nitrones derived from (R)-glyceraldehyde [97,98]. Subsequent transformations enabled the synthesis of enantiomerically pure pyrrolidine and 2,5-dihydropyrrole derivatives incorporating one asymmetric unit of the chiral template. 

As part of our studies on a-metalated organosilanes, we use (aminomethyl)(lithiomethyl)silanes of the general type A [1]. Systems of types B and C containing defined stereochemical information could be synthesized starting from either chiral amines or from 5i-chiral silanes. A new structural motif (D) arises if the stereogenic center is adjacent to silicon (preferably as part of a rigid system). The goal of these studies was the synthesis of the enantiomerically pure, lithiated 2-silyl-substituted pyrrolidine E. 

For this 1,2-addition Thompson et al. first tested lithiated quinine and quini-dine additives, which were applied successfully in additions to imines [91, 92, 93],but for ketone 24 [Eq. (3)] they obtained only 50-60% ee [90]. Higher enan-tioselectivities were achieved with lithiated ephedrine derivatives with different N-substituents (e.g., NMej, NEtj), among which the pyrrolidine substituent in 26 gave the highest enantioselectivity (82% ee) for the efavirenz precursor 27 [Eq. (3)]. An optimized protocol was developed, whereby the cyclopropylacety-lene (two equivalents) and the chiral amino alcohol (two equivalents) were lithiated with n-BuLi at -15 °C. This mixture of 25 and 26 was then aged for 30min at 0°C. Addition of the ketoaniline 24 (one equivalent) to this mixture at -55°C in THF affords 27 in up to 98% ee ... 

Methylation by MeOTf can also be carried out asymmetrically. Treatment of a-lithio benzyl 2-quinolyl sulfide with MeOTf in the presence of a bis(oxazoline) as an external chiral ligand yielded chiral 1-phenylethanethio quinolyl sulfide (eq 17). Lithiation adjacent to nitrogen of chiral 3,4-substituted piperidines and pyrrolidines followed by diastereoselective substitution with MeOTf offered general routes to 2,4,5- and 2,4,5,6-substituted piperidines as well as 2,3,4- and 2,3,4,5-substituted pyrrolidines. ... 

In the synthesis of amino boronic acid dipeptides 7 (Scheme 11.37) as inhibitors of the serine protease dipeptidyl peptidase IV (DPPIV), Kelly and co-workers have reported an elegant preparation of the optically active proline boronic acid (boroPro) by a direct lithiation of N-Boc-pyrrolidine and a quench with B(OMe)3. The subsequent hydrolysis and resolution with (-1-)-pinanediol provided rapid access to a key chiral intermediate in the synthesis of these dipeptides. The direct a-functionalisation approach avoided a catal5Aic hydrogenation step required in their original synthesis starting from IV-Boc-pyrrole. ... 

In the majority of cases, the deprotonation of carbamates occurs in the presence of diamines (TMEDA, sparteine or like-sparteine diamine). Complex s-BuLi with the chiral (-)-sparteine efficiendy and enantioselectively deprotonates N-Boc-pyrrolidine (127), but the same base complex is less effective with N-Boc-piperidine. So, lithiation of N-t-Boc-piperidine with sec-BuLi-(-)/sparteine requires 16 h for completion of the deprotonation and after subsequent addition of trimethylchlorosilane, the yield of (S)-195 is detected to be only 8% (133). However, the replacement of sparteine by other diamine results in the increased yield of (S)-195 (135). 

---