Anti Adducts Research Articles

Novel N,O-Cu(OAc)2 complex catalysed diastereo- and enantioselective 1,4-addition of glycine derivatives to alkylidene malonates

Newly developed chiral N,O-Cu(OAc)2 complexes were found to catalyse the diastereo- and enantioselective 1,4-addition of glycine derivatives to alkylidene malonates to afford 3-aryl glutamic acids derivatives in good yields (82–98%) and high stereoselectivities (up to 83% for anti and 90% for syn adducts, respectively). High optical purity anti adducts (up to 99% ee) can be obtained after simple recrystallisation, and their conversion to free 3-aryl glutamic acids was demonstrated by a representative example, chlorpheg, via a one pot process in 72% yield.

Allyl Transfer to Aldehydes and Ketones by Brønsted Acid Activation of Allyl and Crotyl 1,3,2-Dioxazaborolidines

Alkyl dioxazaborolidines are air-stable and often crystalline organoboranes. A variety of Brønsted acids activate allyl dioxazaborolidines to generate reactive allyl-transfer reagents in situ. These reagents add to aldehydes and ketones to generate the corresponding alcohols in good yields under mild conditions. The E- and Z-crotyl reagents react diastereoselectively with aldehydes and ketones to produce anti and syn adducts, respectively, a result consistent with a cyclic transition state (type I mechanism).

ChemInform Abstract: High Stereoselectivity in the Diels—Alder Reaction of Substituted Anthracenes: Reactions of 1‐Succinimidoanthracene and 1‐Phthalimidoanthracene with Maleic Anhydride.

AbstractThe title reaction is influenced by steric factors yielding predominantly the anti adducts (III).

Phthalimide Tricarbonylchromium Complexes: Synthesis, Characterization, Nucleophilic Addition, and Unanticipated syn Adduct Formation upon Addition of Propynyllithium

AbstractThe complexation of phthalimide derivatives with hexacarbonylchromium in dibutyl ether/THF (10:1) afforded the corresponding tricarbonylchromium complexes, which were characterized spectroscopically. Subsequent nucleophilic addition with Grignard or organolithium reagents as well as with sodium tetrahydridoborate gave high yields of the corresponding anti adducts. However, in certain cases, addition of 1‐lithio‐1‐methoxyallene, 1‐propynyllithium, or ethenylmagnesium bromide, the unanticipated formation of the corresponding syn adducts was observed with the relative configuration of the propynyllithium adduct rac‐20 confirmed by a crystal structure analysis. The unusual stereochemistry is explained by the intermediacy of a highly resonance‐stabilized acyliminium ion formed from the original exo adduct. Finally, dehydration of the methyl adduct made available the exo‐methylene derivative rac‐37, bearing another fully sp2‐hybridized ligand system. This compound was also characterized by a crystal structure analysis.

ChemInform Abstract: Diastereofacial Selectivity in 1,3-Dipolar Cycloadditions. Reactions of Diazomethane with endo,cis-5,6-Disubstituted Bicyclo(2.2.2)oct-2- enes.

Abstract The reaction of diazomethane with endo,cis-5,6-diacetoxy, dimesyloxy, bis(methoxycarbonyl) and dihydroxybicyclo[2.2.2]oct-2-ene derivatives, respectively, afforded either only the anti adduct or a mixture of anti and syn adducts wherein the anti diastereoisomer was highly dominant (10:1). The observed facial selectivity provides convincing evidence that direct through space interactions between the attacking 1,3-dipole and acetoxy, hydroxy etc. substituents are, as a whole, repulsive. Steric “non-bonded” repulsions and dipole-dipole interactions override possible stabilizing interactions, e.g. orbital interactions and hydrogen bonding effects.

Structure-Guided Minimalist Redesign of the L-Fuculose-1-Phosphate Aldolase Active Site: Expedient Synthesis of Novel Polyhydroxylated Pyrrolizidines and their Inhibitory Properties Against Glycosidases and Intestinal Disaccharidases

A minimalist active site redesign of the L-fuculose-1-phosphate aldolase from E. coli FucA was envisaged, to extend its tolerance towards bulky and conformationally restricted N-Cbz-amino aldehyde acceptor substrates (Cbz=benzyloxycarbonyl). Various mutants at the active site of the FucA wild type were obtained and screened with seven sterically demanding N-Cbz-amino aldehydes including N-Cbz-prolinal derivatives. FucA F131A showed an aldol activity of 62 μmol h(-1) mg(-1) with (R)-N-Cbz-prolinal, whereas no detectable activity was observed with the FucA wild type. For the other substrates, the F131A mutant gave aldol activities from 4 to about 25 times higher than those observed with the FucA wild type. With regard to the stereochemistry of the reactions, the (R)-amino aldehydes gave exclusively the anti configured aldol adducts whereas their S counterparts gave variable ratios of anti/syn diastereoisomers. Interestingly, the F131A mutant was highly stereoselective both with (R)- and with (S)-N-Cbz-prolinal, exclusively producing the anti and syn aldol adducts, respectively. Molecular models suggest that this improved activity towards bulky and more rigid substrates, such as N-Cbz-prolinal, could arise from a better fit of the substrate into the hydrophobic pocket created by the F131A mutation, due to an additional π-cation interaction with the residue K205' and to efficient contact between the substrate and the mechanistically important Y113' and Y209' residues. An expedient synthesis of novel polyhydroxylated pyrrolizidines related to the hyacinthacine and alexine types was accomplished through aldol additions of dihydroxyacetone phosphate (DHAP) to hydroxyprolinal derivatives with the hyperactive FucA F131A as catalyst. The iminocyclitols obtained were fully characterised and found to be moderate to weak inhibitors (relative to 1,4-dideoxy-1,4-imino-L-arabinitol (LAB) and 1,4-dideoxy-1,4-imino-D-arabinitol (DAB)) against glycosidases and rat intestinal saccharidases.

ChemInform Abstract: Stereoselective Total Synthesis of the Pseudopterolide Kallolide A.

A total synthesis of the pseudopterolides, kallolide A (36) and kallolide A acetate (35), has been achieved. The racemic forms were prepared from the syn adduct 20 of furan 13 and stannane 17 (BF(3).OEt(2)-promoted addition) via the 15-membered propargylic allylic ether 25. [2,3]Wittig ring contraction led to the cis, anti, cis product 26. Alcohol 26 was transformed to butenolide 34 with net retention of configuration by Pd(PPh(3))(4)-catalyzed carbonylation of the mesylate 27 and ensuing AgNO(3)-catalyzed cyclization of the derived allenic acid 29. Solvolysis of the SEM ether (at C2) 34 in acetic acid or aqueous t-BuOH afforded racemic kallolide A acetate (35) and kallolide A (36), respectively, with inversion of stereochemistry by an S(N)1 process. Key elements of stereocontrol, including the steric outcome of the [2,3]Wittig ring contraction, the allenic ester isomerization, and the solvolysis reactions, were predicted from molecular mechanics calculations. The C8 and C2 epimers 45 and 46 of the cis, anti, cis kallolide A SEM ether precursor 34 were also prepared. The synthetic route originated from the anti adduct 19 of aldehyde 13 and the allylic chloride 16 and CuCl (cat), HSiCl(3), and i-Pr(2)NEt. Adduct 19 was subjected to the same sequence as the syn counterpart 20 to produce the trans, anti, cis [2,3]Wittig ring contraction product 42. The derived allenoate 44 afforded a 1:1 mixture of butenolides 45 and 46 upon sequential treatment with TBAF and AgNO(3). Finally, the natural enantiomer (+)-36 of kallolide A was synthesized from the enantioenriched syn adduct (+)-20, prepared by addition of allylic stannane 17 to aldehyde 13 promoted by a modified chiral acyloxyborane Lewis acid.

ChemInform Abstract: A New Method for the Synthesis of β-Amino Acid Derivatives and β-Lactams. Reaction of N-Alkoxycarbonyl-1-methoxyamines with Esters.

The reaction of N-alkoxycarbonyl-1-methoxyamines with esters is an alternative to the reaction of imines with esters for the synthesis of β-amino acid derivatives. In this reaction, N-alkoxycarbonyl-1-methoxyamines corresponding to unstable imines can also be employed. Although anti adducts were obtained preferentially in the absence of Ti complexes, the diastereoselectivity of this reaction was reversed by the addition of Ti(OPr-i)4. The obtained adducts were transformed to the corresponding β-lactams.

ChemInform Abstract: Preparation of Chiral Allenylmetal Reagents from Enantioenriched Allenyl Iodides and Propargylic Mesylates. A Comparison of Indium, Bismuth, and Tin Derivatives.

Chiral allenylmetal halides were prepared starting from enantioenriched ( approximately 95% ee) 1-octyn-3-ol mesylate (1) and 3-butyn-2-ol mesylate (7). Addition of these transient metallo species to aldehydes in situ afforded mainly anti homopropargylic alcohol adducts of varying ee. Three approaches were explored. In the first, the mesylates were converted to allenylstannanes with Bu(3)SnLi.CuBr and the allenylmetal halide was prepared from the resulting enantioenriched allenylstannane by transmetalation with InBr(3), BiBr(3), and SnCl(4) in the presence of cyclohexanecarboxaldehyde. The configurational stability of the transient allenylmetal halide was estimated from the ee of the derived adduct. The second approach involved metalation of the allenyl iodides prepared from mesylates 7 and 1 through S(N)2' displacement with LiCuI(2). From these experiments, it was determined that allenylindium bromides and allenyltin bromides are configurationally stable under the reaction conditions. The adduct obtained from the allenylbismuth bromide was nearly racemic. A superior procedure was developed in which the propargylic mesylates 7 and 1 were converted to allenylindium iodide intermediates through treatment with InI and 5 mol % of a Pd(0) dppf catalyst in THF-HMPA, THF-DMSO, or THF-DMPU. Under these conditions, alpha-branched aldehydes were converted to anti adducts ( approximately 95:5 anti/syn) of >90% ee. Additions to unbranched aldehydes were less diastereoselective, but afforded adducts of high ee. Additions of enantiomeric allenylindium iodide reagents to (R)-beta-ODPS-alpha-methylpropanal (13) afforded diastereomeric adducts (anti,anti and anti,syn) 14, 15 and 18, 19 with excellent diastereoselectivity indicative of a high degree of reagent control. A convenient procedure for the preparation of InI from In and I(2) is also described.

Hydroselenation and Carboselenation of Electron‐Deficient Alkynes with Isolable (Hydrido)(selenolato)platinum(II) Complexes and a Selenaplatinacycle Bearing a Triptycene Skeleton

AbstractThe reaction of [PtH(SeTrip)(PPh3)2] (Trip = 9‐triptycyl) (3) with dimethyl acetylenedicarboxylate (DMAD) or methyl propiolate gave hydroselenation syn adducts. The reaction of [PtH(SeTrip)(dppe)] [dppe = 1,2‐bis(diphenylphosphanyl)ethane], which has a stronger phosphane σ‐donor ligand than 3, with DMAD gave both syn and anti adducts. The reaction of 3 and DMAD in the presence of PPh3 yielded no adducts. These observations indicate that, in the hydroselenation, the dissociation of a PPh3 ligand from 3 is a key step. The selenaplatinacycle 6, which is a thermal reaction product of 3, reacted with DMAD to give the carboselenation product, 1H‐2‐benzoselenin 7, which was also formed by the reaction of TripSeH with DMAD.

Dihydroxyacetone Phosphate Aldolase Catalyzed Synthesis of Structurally Diverse Polyhydroxylated Pyrrolidine Derivatives and Evaluation of their Glycosidase Inhibitory Properties

The chemoenzymatic synthesis of a collection of pyrrolidine-type iminosugars generated by the aldol addition of dihydroxyacetone phosphate (DHAP) to C-alpha-substituted N-Cbz-2-aminoaldehydes derivatives, catalyzed by DHAP aldolases is reported. L-fuculose-1-phosphate aldolase (FucA) and L-rhamnulose-1-phosphate aldolase (RhuA) from E. coli were used as biocatalysts to generate configurational diversity on the iminosugars. Alkyl linear substitutions at C-alpha were well tolerated by FucA catalyst (i.e., 40-70 % conversions to aldol adduct), whereas no product was observed with C-alpha-alkyl branched substitutions, except for dimethyl and benzyl substitutions (20 %). RhuA was the most versatile biocatalyst: C-alpha-alkyl linear groups gave the highest conversions to aldol adducts (60-99 %), while the C-alpha-alkyl branched ones gave moderate to good conversions (50-80 %), with the exception of dimethyl and benzyl substituents (20 %). FucA was the most stereoselective biocatalyst (90-100 % anti (3R,4R) adduct). RhuA was highly stereoselective with (S)-N-Cbz-2-aminoaldehydes (90-100 % syn (i.e., 3R,4S) adduct), whereas those with R configuration gave mixtures of anti/syn adducts. For iPr and iBu substituents, RhuA furnished the anti adduct (i.e., FucA stereochemistry) with high stereoselectivity. Molecular models of aldol products with iPr and iBu substituents and as complexes with the RhuA active site suggest that the anti adducts could be kinetically preferred, while the syn adducts would be the equilibrium products. The polyhydroxylated pyrrolidines generated were tested as inhibitors against seven glycosidases. Among them, good inhibitors of alpha-L-fucosidase (IC50=1-20 microM), moderate of alpha-L-rhamnosidase (IC50=7-150 microM), and weak of alpha-D-mannosidase (IC50=80-400 microM) were identified. The apparent inhibition constant values (Ki) were calculated for the most relevant inhibitors and computational docking studies were performed to understand both their binding capacity and the mode of interaction with the glycosidases.

Anti and Syn Glycolate Aldol Reactions with a Readily Displaced Thiol Auxiliary

The TBDPS protected glycolate derivative of thiol auxiliary 1 is readily prepared (3 steps, 80% overall yield) and has been shown to give excellent anti:syn selectivity (>97:3) and high facial selectivity (88:12 to 97:3) in glycolate aldol reactions with a range of aldehydes (75-87% isolated yield major diastereomer). In contrast, its benzyl protected counterpart displays more versatility with respect to the generation of either anti or syn glycolate aldol adducts, but only modest facial selectivity. The thiol auxiliary has been shown to be readily displaced under mild conditions to give alcohol and ester derivatives of the glycolate aldol adducts.

Pyrrolo[2,1-b]thiazole Derivatives by Asymmetric 1,3-Dipolar Reactions of Thiazolium Azomethine Ylides to Activated Vinyl Sulfoxides

1,3-Dipolar reactions of thiazolium azomethine ylides to enantiopure cyclic and acyclic vinyl sulfoxides provide an efficient access to polyfunctionalized pyrrolo[2,1-b][1,3]thiazoles in a highly regio- and stereoselective manner. Regioselectivity can be inverted by modifying the position of the sulfinyl group at the double bond of the sulfinylfuranones. The sulfoxide is the main controller of the endo selectivity of these processes as well as of the pi-facial selectivity in reactions of (Z)-3-p-tolylsulfinylacrylonitriles. In contrast, the pi-facial selectivity in reactions of 5-alkoxy-3-p-tolylsulfinyl furan-2(5H)-ones is mainly controlled by the configuration at C-5, affording the anti adducts with respect to the alkoxy group as the major or exclusive adducts.

Pd(II)-catalyzed aliphatic Claisen rearrangements of acyclic allyl vinyl ethers

Palladium (II)-catalyzed [3,3] sigmatropic rearrangement of acyclic allyl vinyl ethers delivers 2,3- anti disubstituted pentenal Claisen adducts with high diastereoselectivity. Reaction conditions for circumventing allyl vinyl ether cleavage that had previously plagued catalyzed rearrangement of α-unsubstituted vinyl ether substrates are described. Merging Pd(II) catalysis with the facile access to the Claisen substrates afforded by Ir(I)-catalyzed olefin isomerization provides an expedient procedure for realizing asymmetric anti-selective Claisen rearrangements.

3-Bromozinc Propenyl Esters: An Experimental and Theoretical Study of the Unique Stereocrossover Observed in Their Addition to Aromatic and Aliphatic Aldehydes

We report the results of a combined experimental and theoretical study on the reaction of 3-bromopropenyl acetate in the presence of zinc with three different aldehydes (i.e., benzaldehyde, 2-methylpropanal, and cyclohexanecarboxaldehyde). A 80% de in favor of the anti product has been experimentally observed with both saturated aldehydes, while for benzaldehyde, a 1:1 syn/anti ratio has been found. DFT computations show the existence of three eta1-allylic organozinc complexes [gamma-(Z)-5a, gamma-(E)-5a, and alpha-5a], very close in energy. Only gamma-(Z)-5a and gamma-(E)-5a lead to the observed product. The computational investigation of the reaction of these allylic organozinc complexes with benzaldehyde and 2-methylpropanal demonstrates in both cases the existence of two competitive reaction paths leading to the syn and anti adducts, respectively. An anti preference has been found for 2-methylpropanal with both gamma-(Z)-5a and gamma-(E)-5a species (a diastereoselectivity larger than 80% is predicted), in agreement with the experiment. With benzaldehyde, while the reaction of gamma-(Z)-5a retains an anti-stereopreference (de = 70%), that involving gamma-(E)-5a is characterized by two degenerate transition states. In this case, the agreement between computations and experiments would be satisfactory under the assumption that the initial oxidative addition affords the gamma-(E)-5a zinc complex only. Additional MP2 computations have demonstrated that pi-stacking interactions can play a significant role in determining the relative energy of the transition states leading to the syn and anti products.

Enantioselective Synthesis of Oasomycin A, Part II: Synthesis of the C29–C46 Subunit

Syntheses of the C1–C12 and C13–C28 oasomycin A subunits were described in the preceding Communication. Herein we describe the synthesis and assemblage of the C29–C46 portion of this polyketide natural product. According to the synthesis plan, the C29–C46 fragment targeted as aldehyde I is considered as one of the complex subgoals. Julia disconnection of the D olefin in I affords fragments II and III of comparable complexity (Scheme 1). On the basis of the elegant studies of Wasserman et al., the decision was made to mask the C46 carboxy terminus in sulfone II as its derived 4,5-diphenyloxazole, thus preserving its oxidation state. The singlet-oxygen-mediated liberation of this carboxy moiety could, in principle, be executed at numerous stages in the synthesis because of the compatibility of this transformation with the multitude of other oxygen-protecting groups in the assembled or partially assembled subunits. The C29–C38 fragment III (Scheme 1) is composed of both polyacetate and polypropionate subunits. The latter motif could be introduced by a Sn-mediated syn-selective aldol addition of dipropionyl synthon IV to aldehyde V—a reaction which was developed by us some years ago. The synthesis of aldehyde V began with a chiral Lewis acid catalyzed aldol addition of the Chan diene 1 to benzyloxy acetaldehyde 2 promoted by the Cu complex 3 (5 mol%) that was previously developed by our research group (Scheme 2). The resultant ketoester 4 (95% ee) was reduced with Me4NBH(OAc)3 [7] to afford a 1,3-anti diol (91:9 d.r.). Silylation of the diol (TBSCl, imidazole) followed by a reduction using DIBALH provided aldehyde 5 (77%, 3 steps). The dipropionyl synthon IVwas next introduced by a Sn-mediated aldol addition of b-ketoimide 6 to aldehyde 5 thus providing 7 as a 95:5 mixture of diastereomers. Immediate treatment of 7 with Me4NBH(OAc)3 [7] afforded the anticipated anti diol 8a (90:10 d.r.) which was readily purified by flash chromatography. Selective protection (TBSOTf, lutidine) of the less sterically hindered C33 hydroxy group gave the TBS ether 8b in 75% yield (2 steps). Since we were unable to directly protect the hindered C31 hydroxy group as the PMB ether, the wellprecedented three-step procedure consisting of reductive removal of the chiral auxiliary with LiBH4, protection of the diol as the p-methoxybenzylidene acetal, and selective reduction of the acetal with borane, catalyzed by Sc(OTf)3, [9] was then accomplished (80%, 3 steps). Interestingly, when the aforementioned acetal reduction was attempted with DIBALH, none of the desired product was obtained and the reaction resulted in loss of the TBS group at C37. Alcohol 9 was then silylated (TESOTf, lutidine) and the resulting product was hydrogenated (H2, dry Pd(OH)2/C, EtOAc) to give the alcohol at C38 that was then oxidized with Dess– Martin reagent to afford the desired C29–C38 subunit 10. The construction of sulfone II (Scheme 1) began with the preparation of a,b-unsaturated aldehyde 12 from the known 4,5-diphenyloxazole 11 (Scheme 3). The aldol addition of oxazolidinone 13 to aldehyde 12 catalyzed by magnesium chloride afforded the corresponding anti aldol adduct that Scheme 1. Retrosynthetic analysis of oasomycin A. Bn=benzyl.

Enantioselective Synthesis of Oasomycin A, Part I: Synthesis of the C1–C12 and C13–C28 Subunits

Oasomycin A (I) is a member of the desertomycin family of macrolide natural products and was isolated in 1993 by Thiericke and co-workers during the screening of secondary metabolites of Streptoverticillium baldacii. The overall structure of oasomycin A was established through extensive NMR spectroscopic studies and by direct comparison to other members of the desertomycin family. In 2001, Kishi and coworkers issued a proposal for the relative and absolute stereochemistry of oasomycin A through the use of their “universal NMR database” (Scheme 1). To validate the structural assignment of oasomycin A, we decided to pursue the synthesis of the reported structure, I. Herein, and in the following Communications, we describe our efforts which culminated in the synthesis of oasomycin A (I) and confirm the stereochemical assignment by Kishi and co-workers. First, we describe the synthesis of the C1–C12 and C13–C28 subunits II and III, respectively, which will be united by using the Julia coupling reaction (Scheme 1). Our plan for the synthesis of the C13–C28 fragment III is outlined in Scheme 2. Aldehyde III could be derived from a chelate-controlled reduction of the a,b-unsaturated ketone IV, which in turn can be disconnected at the C21 C22 bond to afford fragments V and VI. We predict successful union of these two fragments because of the greater reactivity of the Weinreb amide VI, which is required to avoid self-condensation of V (M=Li, MgX). This prediction is based on the supposition that the inductive effect of the a-alkoxy substituent should elevate the amide reactivity of VI above that of its reaction partner V. Synthesis of subunit II commenced with the aldol addition of known b-ketoimide 1 to aldehyde 2, which afforded the desired anti,anti aldol adduct as an 84:16 mixture of Scheme 1. Retrosynthetic analysis of oasomycin A (I).

(R)‐ and (S)‐4‐TIPS‐3‐butyn‐2‐ol. Useful Precursors of Chiral Allenylzinc and Indium Reagents.

AbstractChemInform is a weekly Abstracting Service, delivering concise information at a glance that was extracted from about 200 leading journals. To access a ChemInform Abstract, please click on HTML or PDF.

Sterically and Electronically Tunable and Bifunctional Organocatalysts: Design and Application in Asymmetric Aldol Reaction of Cyclic Ketones with Aldehydes

Sterically and electronically tunable and bifunctional organocatalysts have been developed and evaluated in the direct aldol reaction of heterocyclic ketones. Catalysts with different substituents showed variable catalytic efficiency for analogous substrates, indicating the importance of fine-tuning the strength of the hydrogen bonding in the two NH groups. The reactions all proceeded in good to high yield and with excellent enantioselectivities ranging from 90% to >99% ee. In most cases, high diastereoselectivities ranging from 96/4 to 99/1 were obtained for the anti aldol adduct.

(R)- and (S)-4-TIPS-3-butyn-2-ol. Useful Precursors of Chiral Allenylzinc and Indium Reagents

A convenient route to the enantiomers of 4-TIPS-3-butyn-2-ol of >95% enantiomeric purity by reduction of the ynone precursor 4 with the Noyori N-tosyl-1,2-diphenylethylenediamineruthenium cymene catalyst is described. The mesylate derivative of the (S) enantiomer (1c) is converted in situ to an allenylzinc or indium reagent in the presence of a catalyst derived from Pd(OAc)2 and Ph3P and either Et2Zn or InI. A second in situ addition of these reagents to aldehydes leads to anti homopropargylic alcohol adducts. The additions proceed in generally high (60-90%) yield with modest to excellent diastereoselectivity and high enantioselectivity. Only slight mismatching (<5%) is observed with chiral alpha-methyl and alpha-silyloxy aldehydes. Additions to alpha-substituted enals are highly diastereoselective, while beta,beta-disubstituted enals afford ca. 2:1 mixtures of anti and syn adducts.