Enol Phosphates Research Articles

Synthesis of Vinylogous Amides by Gold(I)-Catalyzed Cyclization of N-Boc-Protected 6-Alkynyl-3,4-dihydro-2H-pyridines

The gold(I)-catalyzed cyclization of N-Boc-protected 6-alkynyl-3,4-dihydro-2H-pyridines, prepared by the Sonogashira coupling of lactam-derived enol triflates or phosphates, provides vinylogous amides, which are useful intermediates in the synthesis of natural compounds. The Au(I)-catalyzed reaction is carried out with Ph3PAuOTf as a catalyst and proceeds via a 6-endo-dig cyclization to form a vinylgold species that after protodeauration generates a cyclic carbamate intermediate. This intermediate is in most cases not isolated, but the addition of a base to the reaction mixture rapidly and quantitatively delivers the target vinylogous amide. The first synthesis of a natural compound from Sonneratia hainanensis has been accomplished by this approach.

Convenient Syntheses of Enantiopure 1,2-Oxazin-4-yl Nonaflates and Phosphates and Their Palladium-Catalyzed Cross-Couplings

Efficient methods to prepare enantiopure 1,2-oxazin-4-yl nonaflates and phosphates were elaborated. The corresponding 1,2-oxazin-4-ones were transformed into their enolates and then quenched with nonafluorobutanesulfonyl fluoride or diphenyl chlorophosphate to provide the title compounds. Alternatively, the corresponding α-bromo ketones were subjected to Perkow reactions efficiently leading to the respective enol phosphates. A variety of palladium-catalyzed cross-couplings such as Kumada–Corriu, Sonogashira, Heck reactions or borylation reactions were studied, which delivered the expected new 4-substituted 1,2-oxazine derivatives generally in satisfactory yields. A few typical subsequent transformations were studied including a copper-catalyzed [3+2] cycloaddition with a galactose-derived azide. They demonstrate the synthetic potential of the newly prepared enantiopure 4-substituted 1,2-oxazines.

ChemInform Abstract: General Synthetic Approach to Functionalized Dihydrooxepines.

AbstractA three step reaction sequence consisting of an initial Baeyer—Villiger oxidation followed by enol phosphate ester formation and reduction is described.

General synthetic approach to functionalized dihydrooxepines.

A three-step sequence to access functionalized 4,5-dihydrooxepines from cyclohexenones has been developed. This approach features a regioselective Baeyer-Villiger oxidation and subsequent functionalization via the corresponding enol phosphate intermediate.

Total Synthesis and Biological Evaluation of (+)‐Gambieric Acid A and Its Analogues

In this study, we report the first total synthesis and complete stereostructure of gambieric acid A, a potent antifungal polycyclic ether metabolite, in detail. The A/B-ring exocyclic enol ether 32 was prepared through a Suzuki-Miyaura coupling of the B-ring vinyl iodide 18 and the alkylborate 33 and subsequent closure of the A-ring by using diastereoselective bromoetherification as the key transformation. Suzuki-Miyaura coupling of 32 with acetate-derived enol phosphate 49, followed by ring-closing metathesis of the derived diene, produced the D-ring. Subsequent closure of the C-ring through a mixed thioacetalization completed the synthesis of the A/BCD-ring fragment 8. The A/BCD- and F'GHIJ-ring fragments (i.e., 8 and 9) were assembled through Suzuki-Miyaura coupling. The C25 stereogenic center was elaborated by exploiting the intrinsic conformational property of the seven-membered F'-ring. After the oxidative cleavage of the F'-ring, the E-ring was formed as a cyclic mixed thioacetal (i.e., 70) and then stereoselectively allylated by using glycosylation chemistry. Ring-closing metathesis of the diene 3 thus obtained closed the F-ring and completed the polycyclic ether skeleton. Finally, the J-ring side chain was introduced by using a Julia-Kocienski olefination in the presence of CeCl3 to complete the total synthesis of gambieric acid A (1), thereby unambiguously establishing its complete stereostructure. The present total synthesis enabled us to evaluate the antifungal and antiproliferative activities of 1 and several synthetic analogues.

One‐Pot Preparation of Arylethynyl Sulfides and Bis(arylethynyl) Sulfides

AbstractAn efficient preparation for arylethynyl sulfides 1 and bis(arylethynyl) sulfides 2 has been accomplished through a one‐pot, three‐step strategy that starts from arylethanonyl sulfides and bis(arylethanonyl) sulfides, respectively, without the use of various terminal arylacetylenes as substrates. When lithium hexamethyldisilazane (LHMDS), ClP(O)(OEt)2, and LHMDS were sequentially added to a tetrahydrofuran solution of different substrates [arylethanonyl sulfides or bis(arylethanonyl) sulfides], 1 or 2 were obtained in moderate to good yields. The reaction procedure involves the formation of an enol phosphate and a subsequent base‐induced elimination.

Complementary and Stereodivergent Approaches to the Synthesis of 5‐Hydroxy‐ and 4,5‐Dihydroxypipecolic Acids from Enantiopure Hydroxylated Lactams

AbstractWe describe two complementary and stereodivergent routes, from commercially available and inexpensive starting materials, for the synthesis of 4,5‐dihydroxy‐ and 5‐hydroxypipecolic acids based on the chemistry of lactam‐derived enol phosphates. The synthesis of the 4,5‐cis‐4,5‐dihydroxypipecolic acids required the preparation from 2‐deoxy‐D‐ and ‐L‐ribose of the enantiopure cis‐(4S,5R)‐ and ‐(4R,5S)‐4,5‐dihydroxy‐δ‐valerolactam, respectively. These new chiral synthons are potentially useful for the synthesis of other natural products. The key step is the Pd‐catalyzed methoxycarbonylation reaction of the enol phosphates generated from these lactams. This reaction provided enecarbamate esters that were easily converted by stereoselective reduction to the target compounds. The synthesis of the 4,5‐trans‐4,5‐dihydroxypipecolic acid, as well as of 5‐hydroxypipecolic acids, was realized from a known (S)‐5‐hydroxy‐δ‐valerolactam derivative and, for the dihydroxylated compound, required a highly stereoselective allylic bromination reaction of the enecarbamate ester obtained by methoxycarbonylation of the enol phosphate. The preparation of the (4R,5S) enantiomer of the cis‐4,5‐dihydroxy‐δ‐valerolactam from 2‐deoxy‐L‐ribose, alongside the fact that (R)‐5‐hydroxy‐δ‐valerolactam can be prepared from (R)‐(–)‐γ‐hydroxymethyl‐γ‐butyrolactone, means our approach allows for the synthesis of all stereoisomers of these compounds, which can be employed as conformationally constrained scaffolds in drug discovery.

Asymmetric oxidation of enol phosphates to α-hydroxy ketones using Sharpless reagents and a fructose derived dioxirane

The asymmetric oxidation of a variety of differently substituted, acyclic and cyclic enol phosphates using the Sharpless AD-reagents AD-mix-α and AD-mix-β, and a fructose derived chiral ketone as a catalyst, afforded the corresponding α-hydroxy ketones in high enantioselectivity and good yield. The influence of steric and electronic factors of the substrates on the facial stereoselectivity in the reported oxidations was studied.

Synthesis of Both Enantiomers of the Streptomyces Alkaloid 4-epi-SS20846A

The enantiodivergent synthesis of the Streptomyces alkaloid 4- epi -SS20846A was based on a Takai olefination/Suzuki–Miyaura­ coupling sequence for the highly stereoselective introduction of the E , E -pentadienyl side chain on the piperidine skeleton. Optical separation of a key hydroxylated enamide ester, prepared by palladium-catalyzed methoxycarbonylation of a lactam-derived enol phosphate, was successfully achieved by both lipase-catalyzed kinetic resolution and semipreparative HPLC. This approach allowed us to obtain the enantiopure target alkaloid in 35–38% yield over six steps.

ChemInform Abstract: Base‐Mediated Tandem Reaction of α‐Aryloxyacetophenones with Phosphonates: Selective Synthesis of Enol Phosphates.

AbstractA novel, simple method is developed for the synthesis of enol phosphates.

ChemInform Abstract: P—C Cross‐Coupling onto Enamides: Versatile Synthesis of α‐Enamido Phosphane Derivatives.

AbstractSecondary phosphane—borane derivatives and phosphane oxide (VI) react with α‐amido enol phosphate reagents to afford new chiral or achiral tertiary α‐enamido phosphane derivatives.

An efficient synthesis of enol phosphates via organic base-promoted addition of phosphites to 4-oxo-enoates

A TMG catalyzed, practical and efficient hydrophosphorylation of 4-oxo-enoates by diethyl or diphenyl phosphite has been described. This protocol allows a convenient access to a variety of enol phosphates under mild conditions in good yield with excellent stereoselectivity.

ChemInform Abstract: Gold(I)‐Catalyzed Stereoselective Synthesis of Alkenyl Phosphates by Hydrophosphoryloxylation.

AbstractTitle hydrophosphoryloxylation of alkynes proceeds smoothly in the presence of low amounts of gold catalyst (0.01—1 mol%) to selectively afford the kinetic enol phosphates (III), (V), (VII).

Photochemically Induced Synthesis of the Topoisomerase I Inhibitors Indeno[1,2-c]isoquinoline-5,11-diones

A convenient synthesis of indeno[1,2- c ]isoquinoline-5,11-diones has been achieved using combinational photochemical and carbocationic cyclization tactics. The synthetic route involved first the construction of adequately functionalized N -styryl benz­amides via Suzuki–Miyaura cross-coupling reaction with enol phosphate combined with a six-π-electron photocyclization process. The assembling of the title compounds was readily ensured through sequential carbocationic annulation reaction and ultimate oxidation of a latent hydroxy functionality.

A Concise Synthesis of 3-Arylated Di- and Tetrahydro-2H-2-benzazepin-1-ones; A New Synthetic Approach to the Homoprotoberberine Framework

A variety of 3-arylated di- and tetrahydro-2H-2-benz­azepin-1-ones were efficiently assembled through a sequence involving a Suzuki–Miyaura cross-coupling reaction with enol phosphates derived from the corresponding benzazepine-1,3-di­ones. This technique has been further exploited for the construction of the homoprotoberberine skeleton, which was readily accessed by intramolecular carbocationic annulation reaction applied to a suitably substituted precursor.

ChemInform Abstract: Recent Applications of the Suzuki—Miyaura Cross—Coupling to Complex Polycyclic Ether Synthesis

AbstractReview: ca. 100 refs.

Expeditious Racemic and Enantiodivergent Synthesis of 1‐Deoxymannojirimycin and 1,4‐Dideoxymannojirimycin

AbstractThe racemic and enantiodivergent syntheses of 1‐deoxymannojirimycin (DMJ) and 1,4‐dideoxymannojirimycin have been realized through key enamide ester intermediates obtained by converting cis‐4,5‐dihydroxylated δ‐valerolactam derivatives into the corresponding enol phosphates and subjecting them to Pd‐catalyzed methoxycarbonylation. Further elaborations of these intermediates included stereocontrolled catalytic hydrogenation, for the synthesis of racemic 1,4‐dideoxymannojirimycin, and hydroboration/oxidation, for the synthesis of DMJ. Enantiodivergency was attained by optical resolution before exhaustive functional group deprotection, through the formation of diastereomeric camphanic esters. As the key racemic intermediate esters were easily prepared in a few steps on a large scale, and the final chromatographic separation of the camphanic esters was straightforward, this approach represents a convenient way to obtain both enantiomers of DMJ for medicinal chemistry studies.

Base-Mediated Tandem Reaction of α-Aryloxyacetophenones with Phosphonates: Selective Synthesis of Enol Phosphates

A new, simple method for the synthesis of enol phosphates by base-mediated tandem reaction of α-aryloxyacetophenones with phosphonates is described. In the presence of Cs2CO3, a variety of α-aryloxyacetophenones smoothly underwent the sequential O-P bond-forming/C-O bond cleavage/isomerization tandem reaction with phosphonates at room temperature, providing the corresponding enol phosphates in moderate to excellent yields.

P–C Cross‐Coupling Onto Enamides: Versatile Synthesis of α‐Enamido Phosphane Derivatives

AbstractWe report herein the Pd‐catalyzed P–C cross‐coupling reaction between enol phosphates and secondary phosphane–borane complexes or phosphane oxides. The reaction was performed under mild conditions, owing to Pd activation of the P–H bonds of the phosphane–boranes (or phosphane oxides) and to the powerful enol phosphate coupling reagents. New useful chiral and achiral α‐β‐alkenylphosphane derivatives bearing an amido group in the α‐position to the P center were obtained in yields up to 70 %.

Total Synthesis of (−)‐Brevenal: A Streamlined Strategy for Practical Synthesis of Polycyclic Ethers

We describe a streamlined strategy for the practical synthesis of trans-fused polycyclic ethers and its application to a concise total synthesis of (-)-brevenal, a new pentacyclic polyether natural product with intriguing biological activities. The B-, D-, and E-rings were constructed by TEMPO/PhI(OAc)(2)-mediated oxidative lactonization of the corresponding 1,6-diols, with minimal need for manipulation of oxygen functionalities. The B- and E-ring lactones were appropriately functionalized by Suzuki-Miyaura coupling of lactone-derived enol phosphates and subsequent stereoselective hydroboration. The A-ring was formed by our mixed thioacetalization methodology. The AB- and DE-ring fragments were assembled through Suzuki-Miyaura coupling, and the C-ring was forged in the same manner as that for the A-ring. More than two grams of the pentacyclic polyether core of (-)-brevenal have been synthesized by the synthetic route developed in this study.