Anti-aldol Reaction Research Articles

Chiral Allenylzinc and Indium Reagents for Asymmetric Propargylation

This article describes the further developments of the elegant and synthetically useful methodology designed earlier by the same group, which allows the enantioselective addition of a chiral C-4 synthon to an aldehyde. The authors designed a robust, practical synthesis of the required chiral precursor and described some new applications of their method. This protocol is an excellent alternative to the anti-aldol reaction, which should find a broad application in synthesis of natural products, especially polyketides.

A Stereoselective Anti-Aldol Route to (3R,3aS,6aR)-Hexahydrofuro[2,3-b] furan-3-ol: A Key Ligand for a New Generation of HIV Protease Inhibitors.

A stereoselective synthesis of (3R,3aS,6aR)-hexahydrofuro[2,3-b]furan-3-ol, an important high affinity P2-ligand, in high enantiomeric excess (>99%) is reported. The synthesis features an ester-derived titanium enolate based highly stereoselective anti-aldol reaction as the key step.

Synthesis of (−)-Stemoamide Using a Stereoselective anti-Aldol Step

The synthesis of (-)-stemoamide was achieved in 11 steps from 5-acetoxy-N-crotyl pyrrolidinone. A chiral N-acyl thiazolidinethione was employed in a stereoselective addition to a cyclic N-acyl iminium ion to install the required stereochemistry of carbon C9a. This iminium ion addition product was employed in a stereoselective MgBr2-catalyzed anti-aldol reaction to install the required stereochemistry of carbons C8 and C9. The X-ray crystal analysis of (-)-stemoamide confirmed the structure and the stereochemical outcome of these selective reactions.

Total Synthesis of Piericidin A1 and B1

The first total syntheses of piericidin A1 and B1 are disclosed and unambiguously establish the relative and absolute stereochemistry of the natural products by an approach that will facilitate the synthesis of a series of analogues. Central to the approach is an inverse electron demand Diels-Alder reaction of a N-sulfonyl-1-aza-1,3-butadiene with tetramethoxyethene followed by Lewis acid-promoted aromatization used to assemble the functionalized pyridine core. Additional key elements in the convergent approach include the use of an anti-aldol reaction to install the C9 and C10 relative and absolute stereochemistry, a modified Julia olefination for formation of the C5-C6 trans double bond with convergent assemblage of the side chain, and a penultimate heterobenzylic Stille cross-coupling reaction of the pyridyl core with the fully elaborated side chain.

Synthesis and Confirmation of the Absolute Stereochemistry of the (‐)‐Aflastatin A C9—C27 Degradation Polyol.

The C8−C18 ethyl ketone and C19−C28 aldehyde aflastatin A fragments were synthesized and coupled using a diastereoselective anti aldol reaction. This adduct was successfully converted into the C9−C27 polyol degradation product of (−)-aflastatin A to confirm the relative and absolute stereochemistry of this region of the natural product.

Synthesis and Confirmation of the Absolute Stereochemistry of the (−)-Aflastatin A C9−C27 Degradation Polyol

[reaction: see text]. The C(8)-C(18) ethyl ketone and C(19)-C(28) aldehyde aflastatin A fragments were synthesized and coupled using a diastereoselective anti aldol reaction. This adduct was successfully converted into the C(9)-C(27) polyol degradation product of (-)-aflastatin A to confirm the relative and absolute stereochemistry of this region of the natural product.

Stereoselective Addition of the Titanium Enolate of N-Acetyl (4S)-Isopropyl-1,3-thiazolidine-2-thione to Five-Membered N-Acyl Iminium Ions

[reaction: see text] Addition of the chlorotitanium enolate of N-acetyl 4-isopropyl-1,3-thiazolidine-2-thione to five-membered, N-substituted N-acyl iminium ions furnished the corresponding Mannich-type addition products with good diastereoselectivity and in good yields. The synthetic utility of the addition product 8 was demonstrated in a chemospecific anti-aldol reaction with cinnamaldehyde. By using this strategy, we constructed three contiguous chiral centers with high stereocontrol employing the same chiral auxiliary. X-Ray crystallographic analysis of addition product 2 and aldol product 14 revealed their absolute stereochemistry.

A Second-Generation Total Synthesis of (+)-Discodermolide: The Development of a Practical Route Using Solely Substrate-Based Stereocontrol

A novel total synthesis of the complex polyketide (+)-discodermolide, a promising anticancer agent of sponge origin, has been completed in 7.8% overall yield over 24 linear steps, with 35 steps altogether. This second-generation approach was designed to rely solely on substrate control for introduction of the required stereochemistry, eliminating the use of all chiral reagents or auxiliaries. The common 1,2-anti-2,3-syn stereotriad found in each of three subunits, aldehyde 9 (C(1)-C(5)), ester 40 (C(9)-C(16)), and aldehyde 13 (C(17)-C(24)), was established via a boron-mediated aldol reaction of ethyl ketone 15 and formaldehyde, followed by hydroxyl-directed reduction to give 1,3-diol 14. Alternatively, a surrogate aldehyde 22 was employed for formaldehyde in this aldol reaction, leading to the beta-hydroxy aldehyde 20 as a common building block, corresponding to the discodermolide stereotriad. Key fragment unions were achieved by a lithium-mediated anti aldol reaction of ester 40 and aldehyde 13 under Felkin-Anh control to provide (16S,17S)-adduct 51 and a boron-mediated aldol reaction between enone 10 and aldehyde 9, exploiting unprecedented remote 1,6-stereoinduction, to give the (5S)-adduct 57.

Unified synthesis of C19-C26 subunits of amphidinolides B1, B2, and B3 by exploiting unexpected stereochemical differences in Crimmins' and Evans' aldol reactions.

The efficient synthesis of the C(19)-C(26) subunit of amphidinolide B(1) and B(2) has been completed using a boron-mediated aldol reaction. The synthesis of the C(19)-C(26) subunit of amphidinolide B(3) has also been accomplished through an unexpected anti aldol reaction using a titanium-mediated process. In addition, the first reported examples of a stereochemical discrepancy between the Evans' boron-mediated oxazolidinone and the Crimmins' titanium-mediated oxazolidinethione aldol reactions are disclosed. A working hypothesis is put forth to explain the results.

A short and efficient synthesis of (+)-prelactone B

The asymmetric total synthesis of (+)-prelactone B, a biologically important natural β-hydroxy-δ-lactone derivative that contains a 2,3- trans-dialkylpyran ring system, is described. This approach involves the use of a very efficient oxazolidinone-mediated anti-aldol reaction, and a diastereoselective coupling between a ketene silyl acetal with an aldehyde followed by lactonization.

Highly Diastereoselective anti‐Aldol Reactions Utilizing the Titanium Enolate of cis‐2‐Arylsulfonamido‐1‐acenaphthenyl Propionate.

AbstractFor Abstract see ChemInform Abstract in Full Text.

Synthetic studies directed toward the total synthesis of dolabriferol

Herein we report our results towards the total synthesis of (−)-dolabriferol, describing the synthesis of fragments C1–C9 and C10–C21. This convergent asymmetric approach relies on the use of a common Weinreb amide precursor for the preparation of both fragments, an efficient anti-aldol reaction followed by Zn(BH 4) 2 reduction to give a 1,3- syn diol, a selective oxidation of a triol under Swern conditions with concomitant lactol formation, and a diastereoselective epoxidation of an allylic alcohol with m-CPBA followed by an efficient epoxide opening with Me 2CuCNLi 2.

Asymmetric Total Synthesis of the Gastroprotective Microbial Agent AI‐77‐B.

An enantioselective total synthesis of the pseudopeptide microbial agent AI-77-B, which has shown potent antiulcerogenic properties, is described. The synthesis is convergent and involves the assembly of a dihydroisocoumarin fragment and a hydroxy amino acid. The dihydroisocoumarin derivative was synthesised by means of a Diels-Alder reaction between 1-methoxy-1,3-cyclohexadiene and an alkynyl ester derivative as the dienophile. The alkynyl ester was obtained stereo-selectively by two different synthetic routes: (1) A stereoselective allylation of leucinal, and (2) a titanium enolate-mediated anti-aldol reaction with trichlorobutyraldehyde, a novel homopropargylaldehyde equivalent. The stereocentres of the hydroxy amino acid moiety were generated through a titanium enolate-mediated syn-aldol reaction, Curtius rearrangement, and application of Dondoni's aldehyde homo-logation. Condensation of the dihydroisocoumarin and hydroxy amino acid moieties and subsequent removal of the protecting groups furnished optically active AI-77-B.

A Nucleophilic Addition Ring Closure [NARC]‐Based Synthesis of (+)‐Nonactic Acid.

AbstractFor Abstract see ChemInform Abstract in Full Text.

Highly diastereoselective anti-aldol reactions utilizing the titanium enolate of cis-2-arylsulfonamido-1- acenaphthenyl propionate.

[reaction: see text] anti-Aldol reaction of Ti-enolate derived from cis-2-arylsulfonamido-1-acenaphthenyl propionate with representative aldehydes proceeded in excellent yield with high diastereoselectivity. Both enantiomers of cis-2-amino-1-acenaphthenol were synthesized employing lipase-catalyzed kinetic resolution as the key step.

Asymmetric Total Synthesis of the Gastroprotective Microbial Agent AI-77-B.

An enantioselective total synthesis of the pseudopeptide microbial agent AI-77-B, which has shown potent antiulcerogenic properties, is described. The synthesis is convergent and involves the assembly of a dihydroisocoumarin fragment and a hydroxy amino acid. The dihydroisocoumarin derivative was synthesised by means of a Diels-Alder reaction between 1-methoxy-1,3-cyclohexadiene and an alkynyl ester derivative as the dienophile. The alkynyl ester was obtained stereo-selectively by two different synthetic routes: (1) A stereoselective allylation of leucinal, and (2) a titanium enolate-mediated anti-aldol reaction with trichlorobutyraldehyde, a novel homopropargylaldehyde equivalent. The stereocentres of the hydroxy amino acid moiety were generated through a titanium enolate-mediated syn-aldol reaction, Curtius rearrangement, and application of Dondoni's aldehyde homo-logation. Condensation of the dihydroisocoumarin and hydroxy amino acid moieties and subsequent removal of the protecting groups furnished optically active AI-77-B.

Enantioselective Total Synthesis of (+)‐Testudinariol A Using a New Nickel‐Catalyzed Allenyl Aldehyde Cyclization.

AbstractFor Abstract see ChemInform Abstract in Full Text.

A nucleophilic addition ring closure [NARC]-based synthesis of (+) -nonactic acid

Nonactic acid 1 has been synthesized in 12 steps from readily available (S)-(−)-ethyl lactate in 20% overall yield. The key (“NARC”) sequence in this method involved anti-aldol addition of acylsultam 3 with aldehyde 4 followed by intramolecular oxymercuration. The efficiency and selectivity of the anti-aldol reaction was found to be critically dependent upon the ratio of Lewis acid to base. The intramolecular oxymercuration was also found to be highly diastereoselective and was attributed to allylic control consistent with previous studies in our group.

Enantioselective Total Synthesis of Callipeltoside A.

An asymmetric total synthesis of callipeltoside A has been accomplished highlighted by a catalytic enantioselective vinylogous aldol reaction and a boron-mediated anti-aldol reaction influenced by remote stereocontrol.

Enantioselective total synthesis of (+)-testudinariol a using a new nickel-catalyzed allenyl aldehyde cyclization.

An enantioselective total synthesis of (+)-testudinariol A was completed. A new nickel-catalyzed allenyl aldehyde cyclization was developed in the approach. In addition, an asymmetric anti aldol reaction and a two-directional oxocarbenium ion/vinyl silane condensation were employed as key steps.