Direct catalytic asymmetric aldol reaction of hydroxyketones: asymmetric Zn catalysis with a Et(2)Zn/linked-BINOL complex

Full details of our newly developed catalyses with asymmetric zinc complexes as mimics of class II zinc-containing aldolase are described. A Et(2)Zn/(S,S)-linked-BINOL complex was developed and successfully applied to direct catalytic asymmetric aldol reactions of hydroxyketones. A Et(2)Zn/(S,S)-linked-BINOL 1 = 2/1 system was initially developed, which efficiently promoted the direct aldol reaction of 2-hydroxy-2'-methoxyacetophenone (7d). Using 1 mol % of (S,S)-linked-BINOL 1 and 2 mol % of Et(2)Zn, we obtained 1,2-dihydroxyketones syn-selectively in high yield (up to 95%), good diastereomeric ratio (up to 97/3), and excellent enantiomeric excess (up to 99%). Mechanistic investigation of Et(2)Zn/(S,S)-linked-BINOL 1, including X-ray analysis, NMR analysis, cold spray ionization mass spectrometry (CSI-MS) analysis, and kinetic studies, provided new insight into the active oligomeric Zn/(S,S)-linked-BINOL 1/ketone 7d active species. On the basis of mechanistic investigations, a modified second generation Et(2)Zn/(S,S)-linked-BINOL 1 = 4/1 with molecular sieves 3A (MS 3A) system was developed as a much more effective catalyst system for the direct aldol reaction. As little as 0.1 mol % of (S,S)-linked-BINOL 1 and 0.4 mol % of Et(2)Zn promoted the direct aldol reaction smoothly, using only 1.1 equiv of 7d as a donor (substrate/ligand = 1000). This is the most efficient, in terms of catalyst loading, asymmetric catalyst for the direct catalytic asymmetric aldol reaction. Moreover, the Et(2)Zn/(S,S)-linked-BINOL 1 = 4/1 system was effective in the direct catalytic asymmetric aldol reaction of 2-hydroxy-2'-methoxypropiophenone (12), which afforded a chiral tetrasubstituted carbon center (tert-alcohol) in good yield (up to 97%) and ee (up to 97%), albeit in modest syn-selectivity. Newly developed (S,S)-sulfur-linked-BINOL 2 was also effective in the direct aldol reaction of 12. The Et(2)Zn/(S,S)-sulfur-linked-BINOL 2 = 4/1 system gave aldol adducts anti-selectively in good ee (up to 93%). Transformations of the aldol adducts into synthetically versatile intermediates were also described.     

Benzoimidazole-pyrrolidine (BIP), a highly reactive chiral organocatalyst for aldol process

A new chiral benzoimidazole-pyrrolidine ligand (BIP) was shown to catalyze an aldol process in the presence of an equimolar amount of a Brönsted acid, leading to the aldol adduct in high yield and enantioselectivity. Remarkably, the aldol reaction was still effectively catalyzed when starting from equimolar amounts of aldehyde and ketone in THF.     

Three-component glycolate Michael reactions of enolates, silyl glyoxylates, and α,β-enones

Silyl glyoxylates react with enolates and enones to afford either glycolate aldol or Michael adducts. Product identity is controlled by the countercation associated with the enolate. Reformatsky nucleophiles in the presence of additional Zn(OTf)(2) result in aldol coupling (A), while lithium enolates provide the Michael coupling (B). Deprotonation of the aldol product A with LDA induces equilibration to form the minor diastereomer of Michael product B. This observation suggests that formation of the major diastereomer of Michael product B does not occur via an aldol/retro-aldol/Michael sequence.     

Direct catalytic enantio- and diastereoselective aldol reaction of thioamides

A direct catalytic asymmetric aldol reaction of thioamides using a soft Lewis acid/hard Br?nsted base cooperative catalyst comprising (R,R)-Ph-BPE/[Cu(CH(3)CN)(4)]PF(6)/LiOAr is described. Exclusive enolate generation from thioacetamides through a soft-soft interaction with the soft Lewis acid allowed for a direct aldol reaction to α-nonbranched aliphatic aldehydes, which are usually susceptible to self-condensation under conventional basic conditions. A hard Lewis basic phosphine oxide has emerged as an effective additive to constitute a highly active ternary soft Lewis acid/hard Br?nsted base/hard Lewis base cooperative catalyst, enabling a direct enantio- and diastereoselective aldol reaction of thiopropionamides. Strict control of the amount of the hard Lewis base was essential to drive the catalytic cycle efficiently with a minimized retro-aldol pathway, affording syn-aldol products with high stereoselectivity. Divergent transformation of the thioamide functionality is an obvious merit of the present aldol methodology, allowing for a facile transformation of the aldol product into the corresponding aldehyde, ketone, amide, amine, and ketoester. An aldehyde derived from the direct aldol reaction was subjected to a second direct aldol reaction, which proceeded in a catalyst-controlled manner to provide 1,3-diols with high stereoselectivity.     

Studies on the synthesis of bafilomycin A(1): stereochemical aspects of the fragment assembly aldol reaction for construction of the C(13)-C25) segment

Highly stereoselective syntheses of aldols 8a-c corresponding to the C(13)-C(25) segment of bafilomycin A(1) were developed by routes involving fragment assembly aldol reactions of chiral aldehyde 6a and the chiral methyl ketones 7. A remote chelation effect plays a critical role in determining the stereoselectivity of the key aldol coupling of 6a and the lithium enolate of 7b. The protecting group for C(23)-OH of the chiral aldehyde fragment also influences the selectivity of the lithium enolate aldol reaction. In contrast, the aldol reaction of 6a and the chlorotitanium enolates of 7a,c were much less sensitive to the nature of the C(15)-hydroxyl protecting group. Studies of the reactions of chiral aldehydes with Takai's (gamma-methoxyallyl)chromium reagent 40 are also described. The stereoselectivity of these reactions is also highly dependent on the protecting groups and stereochemistry of the chiral aldehyde substrates.     

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.     

Synthesis of the apoptosis inducing agent apoptolidin. Assembly of the C(16)-C(28) fragment

[reaction--see text] A stereoselective synthesis of the C(16)-C(28) fragment of the apoptosis inducing agent apoptolidin is described. Key steps include two propionate aldol reactions and a stereoselective Mukaiyama aldol addition of enolsilane 19 to beta-methoxy aldehyde 4.     

Zinc-prolinamide complex catalyzed direct asymmetric aldol reactions in the presence of water

An efficient direct asymmetric aldol reaction with zinc triflate and prolinamides as combined catalysts is reported. A series of chiral prolinamides have been designed and used in the direct aldol reaction resulting in the desired products with excellent yields (up to 94% yield) and high enantioselectivities (up to 96% ee). Water was found to play a significant role in the formation of the aldol products, which suggests a new strategy in the design of new organic catalysts.     

The thiopyran route to polypropionates: enantioselective synthesis of membrenone B from racemic fragments

(6S,7S,8S,9R,10S)-(--)-Membrenone B was synthesized in nine steps (9.4% overall yield) beginning with two-directional aldol coupling of tetrahydro-4H-thiopyran-4-one with racemic 1,4-dioxa-8-thiaspiro[4.5]decane-6-carboxaldehyde. The first aldol reaction occurs with dynamic kinetic resolution to give a single adduct (>98% ee). The second aldol reaction is highly diastereoselective (three of eight possible adducts), and both major products are converted to membrenone B. The route also constitutes a formal synthesis of membrenone A.     

Development of a Simple Adjustable Zinc Acid/Base Hybrid Catalyst for C−C and C−O Bond‐Forming and C−C Bond‐Cleavage Reactions

A newly designed zinc Lewis acid/base hybrid catalyst was developed. By adjusting the Lewis acidity of the zinc center, aldol‐type additions of 2‐picolylamine Schiff base to aldehydes proceeded smoothly to afford syn‐aldol adduct equivalents, trans‐N,O‐acetal adducts, in high yields with high selectivities. NMR experiments, including microchanneled cell for synthesis monitoring (MICCS) NMR analysis, revealed that anti‐aldol adducts were formed at the initial stage of the reactions under kinetic control, but the final products were the trans‐(syn)‐N,O‐acetal adducts that were produced through a retro‐aldol process under thermodynamic control. In the whole reaction process, the zinc catalyst played three important roles: i) promotion of the aldol process (C?C bond formation), ii) cyclization process to the N,O‐acetal product (C?O bond formation), and iii) retro‐aldol process from the anti‐aldol adduct to the syn‐aldol adduct (C?C bond cleavage and C?C bond formation).     

Enantioselective Aldol Reactions Catalyzed by Chiral Phosphine Oxides

The development of enantioselective aldol reactions catalyzed by chiral phosphine oxides is described. The aldol reactions presented herein do not require the prior preparation of the masked enol ethers from carbonyl compounds as aldol donors. The reactions proceed through a trichlorosilyl enol ether intermediate, formed in situ from carbonyl compounds, which then acts as the aldol donor. Phosphine oxides activate the trichlorosilyl enol ethers to afford the aldol adducts with high stereoselectivities. This procedure was used to realize a directed cross‐aldol reaction between ketones and two types of double aldol reactions (a reaction at one/two α position(s) of a carbonyl group) with high diastereo‐ and enantioselectivities.     

The Mukaiyama Aldol Reaction: 40 Years of Continuous Development

A directed cross‐aldol reaction of silyl enol ethers with carbonyl compounds, such as aldehydes and ketones, promoted by a Lewis acid, a reaction which is now widely known as the Mukaiyama aldol reaction. It was first reported in 1973, and this year marks the 40th anniversary. The directed cross‐aldol reactions mediated by boron enolates and tin(II) enolates also emerged from the Mukaiyama laboratory. These directed cross‐aldol reactions have become invaluable tools for the construction of stereochemically complex molecules from two carbonyl compounds. This Minireview provides a succinct historical overview of their discoveries and the early stages of their development.     

Total Synthesis of Diterpenoid Steenkrotin A

A concise and diastereoselective total synthesis of the diterpenoid (±)‐steenkrotin A is described for the first time. The strategy mainly features three key ring formations: 1) a rhodium‐catalyzed O? H bond insertion followed by an intramolecular carbonyl‐ene reaction to build up the tetrahydrofuran subunit; 2) sequential SmI₂‐mediated Ueno–Stork and ketyl–olefin cyclizations to construct the [5,7] spirobicyclic skeleton; and 3) an intramolecular aldol condensation/vinylogous retro‐aldol/aldol sequence to form the final six‐membered ring with inversion of the relative configuration at the C7 position.     

Synthetic control leading to chiral compounds

A highly diastereoselective cross aldol reaction is developed using divalent tin enolates formed from stannous trifluoromethanesulfonate and carbonyl compounds. The reaction is extended to a highly enantioselective cross aldol reaction employing chiral diamines derived from (S)-proline as ligands.     

Stereoselective aldol condensations via alkenyloxy dialkoxyboranes: synthetic applications using thioesters

A detailed Investigation of the enolization of phenyl thiopropionate with ethylenechloroboronate (ECB) and diisopropylethylamine (DPEA) and the subsequent aldol condensations of these enolates was conducted. Alkenyloxy dialkoxyboranes derived from thioesters were found to be stereoconvergent: both Z and E enolates give syn aldol condensation products. The thioester additions to chiral aldehydes were studied. Internal selectivity (syn) was usually very high, while the relative stereoselectivity ranged from poor to good, depending on the specific aldehyde used. The aldol products were transformed to known compounds for correlation.     

Selective epimerization of rapamycin via a retroaldol/aldol mechanism mediated by titanium tetraisopropoxide

We describe the efficient and selective epimerization of the immunosuppressant rapamycin to 28-epirapamycin under mild conditions. The mechanism of epimerization involves an equilibrium of the four C28/C29 diastereomers through a two-step retroaldol/aldol (macrocycle ring-opening/ring-closing) sequence. This retroaldol/aldol equilibration is not restricted to rapamycin but is also applicable to acyclic beta-hydroxyketones. A potentially useful extension of the method--the use of beta-hydroxyketones as enolate synthons for effecting inter- or intramolecular aldol reactions under neutral conditions--is demonstrated.     

Carbohydrate-derived alcohols as organocatalysts in enantioselective aldol reactions of isatins with ketones

The catalytic activity of carbohydrate-derived amino alcohols in the enantioselective aldol reaction of ketones with isatin and its derivatives has been examined for the first time. The carbohydrate-derived amino alcohols 5 were found to be efficient organocatalysts for asymmetric aldol reactions. A variety of isatins were used as substrates and the corresponding aldol products were obtained in high yields (up to 99%) and with moderate enantioselectivities (up to 75%).     

Total synthesis of khafrefungin using highly stereoselective vinylogous Mukaiyama aldol reaction

[structure: see text] A convergent total synthesis of khafrefungin was accomplished on the basis of (1) the highly stereoselective TiCl4-mediated vinylogous Mukaiyama aldol reaction using vinylketene silyl N,O-acetal and (2) syn-selective aldol reaction of enal 5a and ethyl ketone 6 followed by anti-dehydration under Mitsunobu conditions.     

Carbene‐Catalyzed Enantioselective Aldol Reaction: Post‐Aldol Stereochemistry Control and Formation of Quaternary Stereogenic Centers

The dominated approaches for asymmetric aldol reactions have primarily focused on the aldol carbon–carbon bond‐forming events. Here we postulate and develop a new catalytic strategy that seeks to modulate the reaction thermodynamics and control the product enantioselectivities via post‐aldol processes. Specifically, an NHC catalyst is used to activate a masked enolate substrate (vinyl carbonate) to promote the aldol reaction in a non‐enantioselective manner. This reversible aldol event is subsequently followed by an enantioselective acylative kinetic resolution that is mediated by the same (chiral) NHC catalyst without introducing any additional substance. This post‐aldol process takes care of the enantioselectivity issues and drives the otherwise reversible aldol reaction toward a complete conversion. The acylated aldol products bearing quaternary/tetrasubstituted carbon stereogenic centers are formed in good yields and high optical purities.     

Réaction pseudo-multicomposants entre le glutaconate de diméthyle et des aldéhydes aromatiques induite par le bromure de phénylzinc : accès domino à des dihydropyranones 2,3,5-trisubstituées

Phenylzinc bromide enables a pseudo three-component reaction of methyl glutaconate and aromatic aldehydes. Unsaturated trisubstituted δ-valerolactones (dihydropyranones) are obtained in fair to good yields by an aldol/aldol/elimination/lactonization domino process that allows the formation of four new bonds in a single step. A putative reaction mechanism is proposed.