Diastereoselection Reformatsky reactions

Kagoshima, H., Hashimoto, Y., Oguro, D., Saigo, K. An Activated Germanium Metal-Promoted, Highly Diastereoselective Reformatsky Reaction. J. Org. Chem. 1998, 63, 691-697. 

In more recent work, germanium catalysts such as GeClq gave a highly diastereoselective Reformatsky reaction favoring the syn diastereomer.228 Another syn selective reaction was reported using TiCl2 and Cu.229 Enantioselective Reformatsky reactions have also used chiral amino alcohols as additives.220... 

Yang and coworkers used the a-bromo propionic imide 328 for a diastereoselective Reformatsky reaction that was mediated by diethyl zinc under catalysis of Ni(acac)2 and permitted to use aryl alkyl ketones as the carbonyl components. The... 

Stereoselective Reformatsky reaction. The Reformatsky reaction of the chiral 2-azetidinone 1 with 3-(2-bromopropionyl)-2-oxazolidone (2a) gives essentially a 1 1 mixture of the diastereomers 3a(3 and 3aa. However, introduction of two methyl groups at C4 in 2 markedly improves the (i-diastereoselectivity, as does an increase in the temperature from 0 to 67° (reflux, THF). The highest diastereoselectivity (95 5) is observed with the derivative of 4,4-dibutyl-5,5-pentamethylene-2-oxa-zolidone. The 3p-diastereomer is a useful intermediate to lp-methylcarbapenems.1... 

The Reformatsky reagent from 2a shows only slight diastereoselectivity in reactions with aldehydes but reactions with 2b give 2,3-vyn-aldols as the major prod-... 

Reformatsky reactions of Af-(2-bromoalkanoyl)-l,3-benzoxazin-4-ones 267 and 272 and imines derived from aniline or /)-substituted anilines gave fra j -/3-lactams 273 with complete diastereoselectivity, and the l,3-benzoxazin-4-one auxiliary 269 could also be recycled. However, in the similar transformations of imines containing an o-methoxyphenyl substituent on the nitrogen, no cyclization to azetidinone occurred and /r -/3-aminocarboxamide derivatives 274 were the only products formed (Scheme 51) <2005S725>. 

A main drawback of the Reformatsky reaction resides in the poor control of simple diastereoselectivity, resulting in variable ratios of syn and anti /3-hydroxyesters (equation... 

Conversely, acceptable or excellent levels of tt-facial diastereoselectivity are obtained in Reformatsky reactions involving a chiral non racemic haloderivative. 

A synthesis of a higher sugar, 2-deoxy-4-octulose, has been carried out using, as the key step, the Reformatsky reaction of methyl bromoacetate (la) with the /i-D-arabino-hexos-2-ulopyranose derivative 36, which affords the manno-derivative 37 in good d.e. (equation 26)102. The same authors developed analogous diastereoselective syntheses of... 

When 191a was used in a vinylogous Reformatsky reaction with the 3-ulose derivative 192 in refluxing ether, a 2 1 a/ adduct ratio was obtained (equation 99). The facial selectivity ensured by the rigid bicyclic framework of 192 was accompanied by a complete simple diastereoselectivity in the formation of the a-adduct193. 

Electron-withdrawing fluorine atoms are introduced on the methylenic a-carbon by the Reformatsky reaction of Boc-leucinal with ethyl bromodifluoroacetate in the presence of activated zinc dust with no diastereoselection. Under thermodynamic control, the y -isomer is obtained almost exclusively (Scheme 16)J15 The use of additives such as diethylaluminium chloride-silver(II) acetate enhances the chemical yield of the reaction, but also presents the disadvantage of being nonstereoselectiveJ78 ... 

The 1,4-conjugate addition of ester enolates to a, 3-enones was first reported by Kohler in 1910,138a c as an anomalous Reformatsky reaction, but chemoselectivity was dependent on the structure of the a,(3-enone and restricted to bromozinc enolates obtained from either a-bromoisobutyrate or bromomalonate esters (Scheme 66).138d,e Further evaluation, with lithio ester enolates and lithio amide enolate additions, has resulted in identification of four factors that affect the chemoselectivity and diastereoselectivity of additions to a, 3-enones.139 These factors are (a) enolate geometry, (b) acceptor geometry, (c) steric bulk of the -substituent on the acceptor enone and (d) reaction conditions. In general, under kinetic reaction conditions (-78 °C), ( )-ester enolates afford preferential 1,2-addition products while (Z)-ester enolates afford substantial amounts of 1,4-addition products however, 1,2 to 1,4 equilibration occurs at 25 C in the presence of HMPA. The stereostructure of the 1,4-adducts is dependent on the initial enolate structure for example, with ( )-enones, (Z)-ester enolates afford anti adducts, while (E)-ester enolates afford syn adducts (Scheme 54). In contrast, amide enolates show a modest preference for anti diastereomer formation. 

The Sml2-mediated Reformatsky reaction provides a useful alternative to traditional versions of the reaction as it proceeds under mild, homogeneous conditions, with high chemo- and diastereoselectivity. Although a-halo esters are the most common substrates for the reaction, in principle any a-halo carbonyl compound can be employed in the reaction. The reactions are most often carried out by the addition of Sml2 to a 1 1 mixture of the a-halocarbonyl compound and the coupling partner. These are often referred to as Barbier conditions (see Section 5.4). 

Analogous asymmetric, samarium Reformatsky reactions of chiral 3-bro-moacetyl-2-oxazolidinones have been described by Fukuzawa.140 For example, reduction of 124 with Sml2 generates a samarium enolate that then reacts with pivalaldehyde to give the a-unbranched (I-hydroxycarboximide 125 in 87% yield and in high diastereoisomeric excess (Scheme 5.89). The reaction is synthetically noteworthy as highly diastereoselective acetate aldol processes are difficult to achieve. Sm(III) ions are likely to play an important role in the... 

In most cases, the Reformatsky reaction is not very stereospecific and mixtures of erythro- and threo-p-hydroxyesters are obtained when asymmetric a-haloesters are used as reagents (equation 79). The erythro threo ratio appears to depend on the solvent polarity and the reaction time. However, it is of current interest to develop highly stereocontrolled asymmetric Reformatsky reactions. To date, high diastereoselectivities could be achieved only in a few cases either by substitution of zinc with other metal... 

Yields in the Sml2-promoted intramolecular Reformatsky reaction are typically higher for ketones than for aldehyde substrates, but in both series diastereoselectivity is virtually complete. It has been suggested that reaction of Smh with the 3-bromoacetoxy initially generates a Sm ester enolate, with cyclization taking place through a rigid cyclic transition structure enforced by chelation (Scheme 4). ... 

Seven-membered ring lactones can be accessed in excellent yields by the Smia-mediated intramolecular Reformatsky reaction as well. Although several substitution patterns provide exceptional relative asymmetric induction in this process (equation 62), it is clear that high diastereoselectivity cannot be achieved for all substitution patterns in the formation of seven-membered ring lactones. ... 

Meanwhile, Reformatsky reaction of sulfinimines 178 with bromodifluoroacetate provides the adducts in excellent diastereoselectivities (see Scheme 9.40) [68]. The ste-... 

The Reformatsky reaction with activated germanium metal proceeds highly diastereoselectively to give aldol adducts in high yields (Scheme 11.64) [90]. 

Organozinc reactions. Barbier alkylation of aldehydes with 2-arenesulfinylallyl halides is highly diastereoselective. Practical conditions for the Reformatsky reaction of aldehydes are further defined. ... 

The unusual chiral (3-methoxy-y-amino acid dolaproine (Dap) is the most complex unit of dolastatin 52, which has a remarkable antineoplastic activity and is now in Phase II human cancer clinical trials. Many synthetic strategies such as aldol condensation and a cobalt-catalyzed Reformatsky reaction have been employed in its synthesis. Almeida and Coelho have demonstrated a stereoselective synthetic method for A-Boc-dolaproine (53) through a sequence of MBH reaction, a diastereoselective double bond hydrogenation and hydrolysis of the ester functional group (Scheme 5.8). ... 

Advances (since 2004) in the diastereoselective Reformatsky-type reaction 13CSR937. 

A short review covers recent advances in the catalytic enantioselective Reformatsky reaction, while highlighting significant current challenges, and the diastereoselective 0 Reformatsky has also been reviewed (61 references). NHC s catalyse Reformatsky 0 reaction of aldehydes with -TMS-carbonyls, to give -hydroxycarbonyl compounds. ... 

An actual synthesis corresponding to this pattern is shown in Scheme 11.4. It relies on well-known reaction types. Steps I, J, K correspond to the disconnection leading to intermediate I. The bond connection at C-9, C-10, corresponding to conversion of intermediate II to I, is done using a Grignard reagent in step E. This results in an alcohol oxidation level at C-9 which is adjusted to the required carbonyl much later in the synthesis (step J). The conversion of IV to III in the retrosynthetic scheme corresponds to step A in the synthesis. A Reformatsky reaction is employed. The overall synthesis is not stereocontrolled. The relative stereochemistry at C-4 and C-7 is established by the catalytic hydrogenation in step H of the synthesis. In principle, this reaction could be diastereoselective since the adjacent chiral center... 

Guided by the success of the Evans and related auxiliaries, several attempts were made to use enantiomerically pure a-bromoacyl oxazolidinones for stereoselective Reformatsky reactions. Fukuzawa and coworkers developed the reaction of various bromoacetyl oxazolidinones 323 as an alternative to an asymmetric acetate aldol addition. The conversion was mediated by samarium iodide and yielded P-hydroxy carbonyl compounds 325 with high diastereoselectivity in optimal combinations of auxiliary group and aldehyde. Among the different auxiliaries, the geminal dimethyl- and diphenyl-substituted ones performed better than the original Evans oxazolidinones. The stereochemical outcome was rationalized by assuming that an O-bound samarium(III) enolate reacts via a chair-like... 

Later, different amino alcohols were used for the same type of difluoro Refor-matsky reactions [158], and the extension to prochiral ketones was reported recently [171]. In addition, protocols for monofluoro Reformatsky reactions were disclosed that lead to products with moderate diastereoselectivity but remarkable enantioselectivity for the individual diastereomers [172]. All these protocols have in common that they are not catalytic and the chiral additive needs to be applied at least in stoichiometric amounts. Thus, it seems that protocols for an enantioselective catalytic difluoro Reformatsky as well as difluoro aldol reaction are still missing. 

The reaction of an a-halo carbonyl compound with zinc, tin, or indium together with an aldehyde in water gave a direct cross-aldol reaction product (Eq. 8.90).226,227 A direct Reformatsky-type reaction occurred when an aromatic aldehyde reacted with an a-bromo ester in water mediated by zinc in low yields. Recently, it was found that such a reaction mediated by indium was successful and was promoted by son-ication (Eq. 8.91).228 The combination of BiCl3-Al,229 CdCl2-Sm,230 and Zn-Et3B-Eb0231 is also an effective mediator. Bismuth metal, upon activation by zinc fluoride, effected the crossed aldol reaction between a-bromo carbonyl compounds and aldehydes in aqueous media. The reaction was found to be regiospecific and syn-diastereoselective (Eq. 8.92).232... 

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