Enantioenrichment carbamates

Employing this method, enantioenriched phenol esters 68, amides 69, and carbamates 70 (after Curtius rearrangement of the intermediate acyl azide) were prepared in yields often greater than 90% with ee-values reaching up to 97% (generally 80-95%, see Fig. 37). 

Jacobsen et al. [48], in 1997 for the first time demonstrated KR of racemic terminal epoxides with water as nucleophile for the production of optically pure epoxides and corresponding 1,2-diols. Since then, various other nucleophiles viz., carboxylic acids, phenols, thiols, amines, carbamates and indols were used in KR to produce optically pure epoxides with concomitant production of corresponding enantioenriched l,2-bifimctional moieties [49-52]. 

The chiral base i-BuLi/(—)-sparteine enantioselectively deprotonates the benzylic position of Ai-Boc-3-chloropropyl carbamates, which then cyclize to yield 2-substituted pyrrolidines with enantiomeric ratios greater than 90 10 (Scheme 63). Beak and coworkers showed that enantioselectivity is achieved through an asymmetric deprotonation to give an enantioenriched organolithium intermediate, which undergoes cyclization faster than epimerization. 

The regioselectivity in the reaction of enantioenriched lithioallyl carbamates with chlorotributyl- or chlorotrimethyltin depends largely on the substitution pattern of the alkenyl residue. Those derived from primary 2-alkenyl carbamates 302 provide exclusively or with large excess the 1-substitution products 313 with inversion of the configuration (equation No (E)-ent-314 was observed. 

Homoaldol reaction with enantioenriched l-metatto-2-atkenyi carbamates... 

When employing enantioenriched l-titano-2-alkenyl carbamates 334 in carbonyl addition, the selectivity depends on the enantiomeric purity that was achieved in its preparation (see Section IV.C.l). The (ii)-crotyl derivative (R)-334a has been employed several times (equation 92)224,252,253 optically active homoaldol products 346 are easily converted into y-lactones 347 by four different pathways, which require an oxidation step (see Section IV.C.6). Appfications in target synthesis include the natural products (-b)-quercus... 

Generation of Enantioenriched, Configurationally Stable Organolithium Reagents. (1 S,2E)-1 -(N.Af-Diisopropyl-carbamoyloxy)-l-methyl-2-butenyllithium-(—)-sparteine is configurationally stable in solution and is obtained by kinetic resolution of the racemic 2-alkenyl carbamate by n-butyllithium-(—)-sparteine with >80% de (eq 4). The enantioenriched allylstan-nane, obtained on y-stannylation, was used as chiral homoenolate reagent. The methoxycarbonylation (a, inversion) yields enantioenriched 3-alkenoates. ... 

Enantioenriched a-carbamoyloxy allylic stannanes can be prepared by lithiation of allylic carbamates in the presence of (-)-sparteine (Eq. 42) [62]. Ilie resulting lithiated sparteine complex reacts with BuaSnLi at the a-position to afford the substitution product. The crotyl derivative of 80% ee is thus prepared. This stannane undergoes thermal addition to benzaldehyde at 160 °C to afford the anti- S) adduct of 79% ee in 79% yield. 

The use of substrate control in rhodium catalyzed C H aminations is covered in detail in Espino and Du Bois recent review of rhodium catalyzed oxidative amina tion [51]. A brief summary of relevant material is provided here, leading to a discussion of recent advances in the synthesis of chiral amines from achiral substrates. Rhodium catalyzed C H amination proceeds via a concerted insertion process rendering it a stereospecific transformation. Thus, the appropriate choice of an enantioenriched starting material can facilitate the synthesis of enantioenriched amines, which would often be particularly difficult to access in any other manner. As exemplified in Scheme 12.9, the C H insertion reaction of enantiomerically pure carbamate 9 was accomplished with complete retention of configuration providing the chiral oxazolidinone 10 in greater than 98% ee [13]. 

Although early studies by Nozaki examined (-)-sparteine 2 in the asymmetric lithiation of isopropylferrocene (as noted in Sect. 1.1 above), the first enantioselective generation of planar chirality in good ees using an organolithium (Clay-don, in this volume) was reported by Uemura in 1994 in the lithiation of tricar-bonyl(q -phenyl carbamate)chromium complexes using chiral diamines. After quenching with electrophiles, enantioenriched (o-substituted phenyl car-bamate)chromium complexes were obtained in up to 82% ee (Scheme 19) [61]. 

Similar features are observed when the homologous M-benzyl-2-piperid-inemethanol carbamate rac-105 was treated with achiral base [Eq. (30)] [73]. Again, one diastereomer rac-108, formed by an wZ-process in the deprotonation step, was highly favored. In the presence of TMEDA, the yield is increased but the d.r. decreased. The intermediate rac-106 arises from the abstraction of the pro-S proton in (i )-105, and the pro-R proton in (S)-105. Deprotonation under the influence of (-)-sparteine with concomitant kinetic resolution is a convenient access to enantioenriched material 108 was produced with 94% ee (Sect. 2.5.4) [73,74]. 

Methylations with methyl iodide were observed to proceed with high yields and stereoselectivities. Longer-chain alkyl iodides failed in most attempts. Allyl bromide reacts smoothly - however, products of low enantioenrichment (see 146g) result. We explain the fact by a single electron transfer (SET) during the alkylation. The intermediate formation of a mesomerically stabilized allyl radical supports the SET pathway [89]. A solution to this problem was most recently published by Taylor and Papillon who converted a lithio carbamate into the corresponding zinc cuprate prior to allylation [90]. Studies on the stereochemistry in a few metal-exchange reactions have been published by Nakai et al. [91]. 

Similar trends were recorded for further secondary benzyl carbamates. During these investigations it turned out that an extended mesomeric system in the aromatic substituent leads to a decreased configurational stability, and thus, to products with lower enantioenrichment. Some of the results are summarized in the following Eq. (62). 

As it is seen from Eq. (62b) and (62e), the method allowed for the synthesis of moderately enantioenriched methyl esters of the commercially available drugs ibuprofen (224), 60% ee [136] or naproxen (230), 47% ee [136], from optically active carbamates 222 or 228, respectively. The final step is a reductive removal of the carbamoyloxy group by Pd-catalyzed hydrogenolysis, which proceeds with inversion [138-140] but some erosion of the enantiomeric purity results. 

The first configurationally stable l-oxy-2-alkenyllithium 253 was reported in 1986 by Hoppe and Kramer [Eq. (70)] [8]. It was generated by deprotonation of the enantioenriched allyl carbamate 252, obtained fi om the corresponding alcohol via kinetic resolution through Sharpless epoxidation. More conveniently accessible are the 1-methyl derivatives 254 and analogues either from (R)- or (S)-lactaldehydes via Wittig olefination [154]. Kinetic resolution of rac-254 during deprotonation is also possible [155-157]. 

This section focuses on metallated, enantioenriched 2-alkenyl carbamates, their stereochemical features, and their use in homoaldol reactions. Much of the chemistry, often developed for racemates, has been summarized in previous reviews [6, 7,64,142,159-165], and it can be easily applied to enantioenriched compounds. 

Enantioenriched 3-(trialkylstannyl)alkenyl carbamates are accessible from the lithium compound (S)-265a in both enantiomeric forms [ 173]. These can be kept for several days in the refrigerator. Metal exchange with titanium tetrachloride in the presence of an aldehyde or ketone generates the highly reactive a-trichlorotitanium intermediate 312, leading to homoaldol adducts 314 or ent-314, respectively. From the configuration of these adducts it is concluded that the... 

The racemic imidates 35 and carbamates 36, which were obtained from an MBH adduct, can be transformed into enantioenriched amides 37 and amines 38 via the regio- and enantioselective [l,3]-sigmatropic O- to A-rearrangement directly or through a decarboxylation catalyzed by cinchona alkaloids. 

Backvall and coworkers have also developed a practical method for the chemo-enz3unatic DKR of primary amines using dibenzyl carbonate as acyl donor, combining the use of CAL-B and the ruthenium complex mentioned above in toluene at 90 °C for the production of enantioenriched (R)-carbamates (60-95% )deld, 90-99% ee Table 9.6) [243]. The main advantage of this method is that the benzyloxycarbonyl group (Cbz) can be easily removed by hydrogenolytic cleavage without any loss of the carbamate optical purity (compoimd in entry 1 of Table 9.6) [244]. 

Schultz-Fademrecht C, Tius MA, Grimme S, Wibbeling B, Hoppe D. Synthesis of enantioenriched 5-alkylidene-2-cyclopentenones from chiral allenyl carbamates generation of a chiral lithium allenolate and allylic activation for a con-rotatory 4jt-electrocyclization. Angew. Chem. Int. Ed. 2002 41 1532-1535. 

Good enantioselectivity has been demonstrated in the transmetallation of the enantioenriched a-lithio carbamates to configurationally stable a-(N-carbamoyl)allq l cuprates and their subsequent reactions with electrophiles such as vinyl iodides, vinyl triflates, a-iodo-a,p-enoates, propargyl mesylates and allyl bromide (Scheme 11.27). ... 

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