Convenient synthesis and unusual reactivity of 2-oxo-2H,5H-pyrano[3,2-c]chromenes

The reaction of 4-oxo-4H-chromen-3-carbaldehydes with coumarin-4-acetic acids under the Perkin conditions follows an interesting pathway that involves aldol reaction and subsequent intramolecular lactonization to afford 2-oxo-2H,5H-pyrano[3,2-c]chromene skeleton. In contrast to chromone-3-carbaldehydes, the same reaction with chromone-2-carbaldehydes yielded only the aldol condensation product. The reaction was performed under thermal and microwave conditions. The reactivity of 2-oxo-2H,5H-pyrano[3,2-c]chromenes in water, alcohol and acetic acid was described.     

Diastereoselective aldol reactions of enolates generated from vicinally substituted trimethylsilylmethyl cyclopropyl ketones

[reaction: see text] Vicinally substituted trimethylsilylmethyl cyclopropyl ketones undergo facile desilylative ring opening with Lewis acids under mild conditions. The enolates, thus generated, undergo aldol addition with aldehydes and ketones. The diastereoselectivity of the reaction with aldehydes depends on the nature of the Lewis acid used. The resulting aldol product is easily converted into a substituted tetrahydrofuran derivative.     

Synthesis of

A series of 1,1'-dicinnamoylferrocenes were converted to the corresponding [3]ferrocenophane diols (4a-e) in a stereoselective manner by using samarium diiodide to effect the intramolecular coupling reaction, aldol reaction, and reduction in one-pot operation. The major reaction pathway might be derived from a samarium chelated transition state (I(A)()) having the moieties of s-cis enone and (Z)-enolate. A solid-state structure of such [3]ferrocenophane diol product showed that the cyclopentadienyl groups were in an eclipsed orientation and slightly tilted.     

Highly stereoselective TiCl4-Catalyzed Evans-aldol and Et3Al-mediated Reformatsky reactions. Efficient accesses to optically active syn- or anti-alpha-trifluoromethyl-beta-hydroxy carboxylic acid derivatives

[reaction: see text] The TiCl(4)-catalyzed Evans-aldol reaction of optically active 3,3,3-trifluoropropanoic imide gave the non-Evans syn product stereoselectively, whereas the Reformatsky reaction of 2-bromo-3,3,3-trifluoropropanoic imide in the presence of Et(3)Al led to the Evans anti product. These new approaches enabled us to synthesize all stereoisomers of trifluoromethylated aldol products for the first time.     

Asymmetric aldol reaction catalyzed by the anion of an ionic liquid

Herein we report the synthesis of a chiral imidazolium salt derived from trans-L-hydroxyproline and its applications as a catalyst for the asymmetric aldol reaction. By performing the aldol reaction in [Bmim]NTf(2) as a solvent, we report excellent isolated yields of the aldol product (up to 99%), as well as modest to excellent selectivities (dr superior to 99:1. ee up to 89%). Mechanistic insights and the origins of the selectivity of the aldol reaction are discussed on the basis of the results obtained with two catalytic imidazolium salts having different H-bonding potential.     

Acid/base catalysis by pure water: the aldol reaction

[reaction: see text] The mechanism of aldol reactions in pure water has been studied with density functional calculations (B3LYP/6-311++G(3d,3p)//B3LYP/6-31G(d)). The reaction is a three-step process that involves: (1) water autoionization generates catalytic hydroxide and hydronium ions, (2) hydroxide and hydronium ions rapidly convert donor aldehyde or ketone into enol, and (3) C-C bond formation and proton transfer occur to give the aldol product. This study provides a general basis for understanding acid/base catalysis by pure water.     

Reaction of dimethyl sodio-3-ketoglutarate with glyoxal and substituted glyoxals: First expeditious preparation of bicyclo[3.3.0]octane-3,7-dione; synthesis and crystal structure of 5,7-dihydroxy-4-methoxycarbonyl-3-phenyl-1-indanone

A simple and efficient two-step preparation of bicyclo[3.3.0]octane-3,7-dione starting from the sodium enolate of dimethyl 3-ketoglutarate and glyoxal is described. This is an unprecedented case in which a condensation reaction of glyoxal is more successful under vigorous conditions (refluxing methanol) than under much milder ones (buffered water at ambient temperature). The major product (after hydrolysis-decarboxylation) from the analogous sequence with phenylglyoxal is 5,7-dihydroxy-4-methoxycarbonyl-3-phenyl-1-indanone, the result of a Dieckmann reaction in addition to the Michael and aldol reactions. Only the latter two occur in aqueous buffers, where the product after hydrolysis-decarboxylation is 1-phenylbicyclo[3.3.0]octane-3,7-dione. The X-ray crystal structure of the indanone reveals a novel hydrogen bonding phenomenon.     

Synthesis of 2H-pyrrolo[3,4-C]quinoline via an Aldol/Van Leusen/Staudinger/aza-Wittig sequence

An aldol/van Leusen/Staudinger/aza-Wittig reaction for the preparation of the derivatives of 2H-pyrrolo[3,4-c]quinolines from 2-azidobenzaldehyde, acetyl compounds, and tosylmethyl isocyanide was developed. The process involves an aldol condensation of 2-azidobenzaldehyde with acetyl compound in base, a van Leusen reaction to form the key pyrrole intermediates, and then a Staudinger and intramolecular aza-Wittig reaction occurred with the addition of triphenylphosphine to complete the formation of pyrrolo[3,4-c]quinoline ring in high yields.     

Asymmetric total synthesis of dendrobatid alkaloids: preparation of indolizidine 251F and its 3-desmethyl analogue using an intramolecular Schmidt reaction strategy

Total syntheses of alkaloid 251F (1), a natural product detected from the skin extracts of the dendrobatid frog species Minyobates bombetes, and its racemic 3-desmethyl derivative (2) are reported. A Diels-Alder reaction initiated both syntheses and established four consecutive stereogenic centers. Important to the synthesis of 2 was a first-generation ozonolysis/olefination/aldol strategy to convert a [2.2.1] bicyclic acid to the [3.3.0]bicyclooctane diquinane 4b. Further elaboration to an appropriate keto azide allowed for a key intramolecular Schmidt reaction to deliver the tricyclic core of the target molecule. In a second-generation approach, a tandem ring-opening/ring-closing metathesis reaction effected an overall [2.2.1] --> [3.3.0] skeletal rearrangement to deliver diquinane 4a. In similar fashion, 4a was manipulated to an appropriate keto azide, and an intramolecular Schmidt reaction generated the core cyclic architecture of 251F.     

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.     

Total synthesis and structural elucidation of (-)-maurenone

[reaction: see text] The total synthesis of (2S,3S)-2,3-dihydro-6-[(1'S, 2'R)-2-hydroxy-1-methylbutyl]-3,5-dimethyl-2-[(1'S)-1-methylpropyl]-4H-pyran-4-one (3), the (-)enantiomer of the marine polypropionate, maurenone, was achieved in nine linear steps (13% overall yield) from (R)-2-benzylpentan-3-one ((R)-14) and (R)-2-benzoyloxypentan-3-one ((R)-15). Key fragments were synthesized using highly diastereoselective syn and anti boron aldol reactions and were coupled using a lithium-mediated aldol reaction. Trifluoroacetic acid-promoted cyclization/dehydration was then used to install the gamma-dihydropyrone ring. Eight isomers of one enantiomeric series were synthesized by coupling two ketones with each of four aldehydes. Comparison of the 13C NMR data for the eight isomers with that reported for maurenone established the relative stereochemistry of the natural product.     

Intermolecular asymmetric reductive aldol reaction of ketones as acceptors promoted by chiral Rh(Phebox) catalyst

[reaction: see text] The conjugate reduction of cinnamates with hydrosilane and chiral Rh(Phebox-ip) catalyst in the presence of excess acetone is shown to provide the corresponding intermolecular reductive aldol product in extremely high enantioselectivity (up to 98%). Several cinnamates and crotonate substrates and several ketone acceptors were also examined.     

A telluride-triggered nucleophilic ring opening of monoactivated cyclopropanes

[reaction: see text] Acylcyclopropanemethanol tosylates undergo rapid ring opening at room temperature by the action of lithium telluride to produce the enolate of a homoallylic ketone. The enolate can be protonated to yield the corresponding ketone or treated with benzaldehyde to give the aldol product with good syn or anti diastereoselectivity depending on the conditions.     

A formal total synthesis of dysidiolide

[structure] A formal total synthesis of the natural product dysidiolide is described. Starting from a Diels-Alder reaction between an enoate and a Rawal diene, the cyclohexenone 4 was synthesized. A subsequent stereospecific methyl cuprate addition established the desired trans configuration in the cyclohexane 3. Wacker oxidation of the pentenyl side chain to the diketone 17 followed by an intramolecular aldol condensation led to the bicyclic enone 2, a key intermediate in a recently reported synthesis of dysidiolide.     

Concise strategy to the core structure of the macrolide queenslandon

The fully functionalized core structure of the macrolactone queenslandon was prepared using a novel strategy consisting of a glycolate aldol reaction and hydroboration of the derived enol ether 17 followed by Suzuki cross-coupling with an iodostyrene. After conversion of the cross-coupling product to the seco acid 22, Mitsunobu macrolactonization and protecting group manipulations led to the queenslandon model 5. [structure: see text]     

Synthesis of the C11-C29 fragment of amphidinolide F

[reaction: see text] An efficient synthesis of the C(11)-C(29) fragment 31 of amphidinolide F has been accomplished via a diastereoselective [3 + 2]-annulation reaction of allylsilane 5 and ethyl glyoxylate to prepare the key tetrahydrofuran 15 and a highly stereoselective methyl ketone aldol reaction to generate the C(11)-C(16) segment.     

Enantioselective direct intermolecular aldol reactions with enantiotopic group selectivity and dynamic kinetic resolution

[reaction: see text] Proline-catalyzed aldol reactions of tetrahydro-4H-thipyranone with racemic 1,4-dioxa-8-thia-spiro[4.5]decane-6-carboxaldehyde and with meso/dl 1,4-dioxa-8-thiaspiro[4.5]decane-6,10-dicarboxaldehyde proceed with dynamic kinetic resolution and give single adducts in good yields with excellent ee's. The high enantiotopic group selectivity results from the high intrinsic diastereoface selectivity of the aldehydes. These reactions significantly extend the scope of the enantioselective direct aldol reaction and constitute simple and efficient syntheses of useful tetrapropionate synthons.     

Application of Polyamines and Amino Acid Derivatives Based on 2-Azabicycloalkane Backbone in Enantioselective Aldol Reaction

Carbon–carbon bond forming reactions, such as aldol reaction and condensation, belong to extremely desired transformations as manifested by >25,000 entries in SciFinder. Their stereoselective variant requires the use of an appropriate catalyst with a strictly defined structure. Hence, chiral 2-azabicycloalkane-based catalysts were designed, synthesized and tested in a stereoselective aldol reaction between cyclic/acyclic ketone and p-nitrobenzaldehyde both in organic and aqueous media. Among catalysts containing a chiral bicyclic backbone, amide based on 2-azabicyclo[3.2.1]octane and pyrrolidine units showed the best catalytic activity and afforded aldol product in excellent chemical yields (up to 95%) and good diastereo- and enantioselectivity (dr 22:78, ee up to 63%).     

Synthese von 15-Hydroxy[9]metacyclophan

Synthesis of 15-Hydroxy[9]metacyclophane 3-(1-Nitro-2-oxocyclododecyl)propanal ( 1 ) was converted to 15-hydroxy[9]metacyclophane ( 3 ) on two different routes. In the first case the internal aldol reaction product of 1 was treated with K₂CO₃/THF to give 3 in 29 % yield with regard to cyclododecanone. Alternatively, the aldehyde 1 reacted with a primary amine to form e.g. 4 which gave 3 in the presence of CH₃I/K₂CO₃ in 48 % yield.     

N-heterocyclic carbene-catalyzed [4 + 1] annulation of phthalaldehyde and imines

The diastereoselective synthesis of cis-2-amino-3-hydroxyindanones was realized by the N-heterocyclic carbene-catalyzed [4 + 1] annulation of phthalaldehyde and imines, which may involve a tandem aza-benzoin reaction and aldol reaction.