An approach to the enantiocontrolled synthesis of pseudomonic acids via a novel mono—claisen rearrangement

A short, efficient approach to a key chiral intermediate for the synthesis of pseudomonic acids A and C is delineated.Pseudomonic acids A($\text{1a}$), B($\text{1b}$), and C($\text{2}$) are members of a novel of “C-glycopyranoside” antimicrobial agents which have recently attracted synthetic attetion.² Presently, we wish to report a short efficient stratedy towards the total synthesis of opticaly active pseudomonic acids. The sequence is highlighted by a novel controlled mono-Claisen rearrangement and a highly regioselective π-allylpalladium mediated displacement.Diacetyl-(L)-arabinal ($\text{3}$)³ was converted to the bis-ketenesilylacetal $\text{4}$ and warmed to 60°C according to the Ireland ester-enolate Claisen rearrangement method.⁴ Over a period of ≈5h, smooth conversion to a major rearranged product $\text{5}$ was observed by 300 MHz NMR. The identity of $\text{5}$ was confirmed by direct desilylation and methylation (KF, KHCO₃, H₂O, HMPA, CH₃I). After flash chromatography, compound $\text{7}$ was isolated in 55% overall yield from $\text{3}$. Careful inspection of the crude methylation product revealed the presence of ≈5% doubly rearranged product $\text{6}$.The rearrangement of $\text{4}$ to $\text{5}$ is a unique example of a selective mono-Claisen rearrangement in which the rate of a second similar Claisen rearrangement ($\text{5}$ → $\text{6}$) is much slower under the reaction conditions. Although the reasons for this interesting selectivity are unclear at this time,⁵ in practice, the mono-Claisen rearrangement obviates the need for selective differentiation of the two hydroxyl groups, a difficult task at best, in this case.Palladium mediated allylic acetate displacement provided an ideal method for introduction of a second chemodifferentiated side chain with allylic retention and retention of stereochemistry. Alkylation of $\text{7}$ with sodiothylmalonate using 5 mole % Pd(O)dppe₂⁶ was unusually facile (<45 min, 25°C, THF). After semi-preparative HPLC, essentially a single regio- and stereoisomer was isolated in 96% yield.⁷ Structure $\text{8}$ was confirmed by extensive ¹H-NMR decoupling, as well as an off-resonance ¹³C-NMR experiment. In particular, H₁ (δ 4.53) was coupled vicinally to H₆ and H₆′ (5 Hz, 8 Hz) and H₂ (1.5 Hz), and allylically to H₃ (2 Hz). In contrast, H₄ (δ 2.78) was coupled to H₇ (10 Hz), H_5e and H_5a (1.8 Hz, 4 Hz), H₃ (5 Hz), and H₂ (<1 Hz). In addition, H₁ and H₄ exhibited a small long range coupling constant (J = <1 Hz). The coupling constants rule out

regioisomer $\text{9}$ and are fully consistent with the indicated conformation, which minimizes 1,3-diaxial-like interactions.Finally, catalytic osmylation of $\text{8}{}^8$ gave a single cis-diol $\text{10}$ in nearly quantitative yield. Appending of suitably functionalized side chains to provide an enantiocontrolled synthesis of pseudomonic acids A($\text{1a}$) and C($\text{2}$) is in progress.^9,10     

Enantiospecific syntheses of intermediates in the total synthesis of pseudomonic acids

Enantiospecific syntheses of 1S,6S-3,7-dioxabicyclo[4.3.0]non-4-en-8-one (1) and of the enantiomer (2) from D- and L-arabinose respectively have been achieved by two different routes. The conversion of (1) to 6S-(3R-acetanilido)-3,6-dihydro-2H-pyranyl-N,N-dimethylacetamide (3), a key intermediate in the synthesis of pseudomonic acids, is described.     

Model studies on the synthesis of pseudomonic acids

The efficient synthesis of racemic 4α-acetonyl-2?,3?-dihydroxycyclohexane-1α-acetanilide (1) from cyclohex-2-enol demonstrates a potential strategy for the control of the stereochemistry of the four contiguous chiral carbon atoms in the pyran ring of pseudomonic acids. An intermediate containing both a secondary amide and a tertiary amide reacted with methyl lithium to give a product derived from exclusive nucleophilic attack at the tertiary amide.     

An approach to the synthesis of pseudomonic acids

The synthesis of the cis-fused γ-lactone 2,7-dioxabicyclo-[4,3,0]non-4-en-8-one (3) by two routes is reported. Its stereoselective conversion to a key intermediate for pseudomonic acid synthesis is described.     

Microwave‐assisted claisen rearrangement. Application to the synthesis of angelicin derivatives

4′‐(Hydroxy, chloro, amino, acetoxy and methoxy)‐methyl‐4,5′‐dimethylangelicins were efficiently and rapidly synthesized via Claisen rearrangement of 4‐methyl‐7‐[4‐(hydroxy, chloro, amino, acetoxy and methoxy)‐but‐2‐ynyloxy]‐coumarins respectively under microwave irradiation. Prominent among the advantages of this new method are operational simplicity, good yields in short reaction times and easy work‐up procedures employed.     

Acyclic stereocontrol via the claisen rearrangement: a formal synthesis of (+) tirandamycic acid

The optically active lactone 1a, prepared previously by the claisen rearrangement, serves as a starting material for the synthesis of (?) alcohol 7b which has been ultilized by Ireland in the synthesis of tirandamycic acid 8a.     

Use of the ketel claisen rearrangement for the synthesis of cyclic sesquiterpenes containing quaternary centers. A formal synthesis of cuparene

We have shown that the ketal based Claisen rearrangement can be useful for generating vicinal quaternary and tertiary-quaternary centers by suitable substitution on the reacting 2-cyclohexenols and cycloalkanone ketal. A rapid and efficient method for preparing hindered cycloalkanone ketals in very pure form is presented, as well as a useful modification for synthesizing the required 2-cyclohexenols from alkyl anisoles with a minimum number of undesired side products.     

Preparation of advanced intermediates for the synthesis of both methyllycaconitine and racemulsonine via a common intermediate

Polycyclic precursors to 1 and 2 have been prepared via a common intermediate. The key steps include the intramolecular alkylation of a phenol and a selective metal-ammonia reduction.     

Ketoreductases in the synthesis of valuable chiral intermediates: application in the synthesis of α-hydroxy β-amino and β-hydroxy γ-amino acids

A general method for the synthesis of β-alkyl α-hydroxy β-amino and α- and γ-alkyl substituted β-hydroxy-γ-amino acids is described. The synthesis of all three classes of amino acids proceeds through a common chiral alcohol intermediate that is generated from a pro-chiral ketone diester via the action of a nicotinamide-dependent ketoreductase. Regioselective chemical or enzymatic hydrolysis followed by rearrangement under Hofmann or Curtius conditions gives the final amino acid products. High yields of single diastereomers of the final amino acids are obtained. Amino acids with both natural and unnatural alkyl substituents can be accessed using this methodology.     

The efficient synthesis of chiral key intermediates for monobactam antibiotics

Chemical asymmetric syntheses of the key intermediates (4,6,8) for the synthesis of monobactam antibiotics (SQ 26776 (azthreonam), sulfazecin, and SQ 26180) are accomplished from (±)-4-phenylsulfonyl-2-azetidinone.     

Non-carbonyl-stabilized metallocarbenoids in synthesis: the development of a tandem rhodium-catalyzed bamford-stevens/thermal aliphatic claisen rearrangement sequence

A tandem rhodium-catalyzed Bamford-Stevens/Claisen rearrangement is presented. The tandem reaction uses Eschenmoser hydrazones for the in situ generation of non-carbonyl-stabilized diazo alkanes, which are presumably intercepted by Rh(II) catalysts to induce a 1,2-hydride migration. This sequence provides high levels of stereocontrol for the generation of simple acyclic (Z)-enol ethers. These enol ethers undergo either thermal or Lewis acid accelerated Claisen rearrangements to provide products of high diastereopurity. Also presented are cascade reactions, wherein a third chemical step occurs after the initial tandem sequence (i.e., Bamford-Stevens/Claisen/ene and Bamford-Stevens/Claisen/Cope).     

Synthetic and mechanistic studies of the retro-Claisen rearrangement. 4. An application to the total synthesis of (+)-Laurenyne

[formula: see text] A novel asymmetric total synthesis of marine natural product (+)-Laurenyne has been achieved. The key elements of the strategy are the sequential metal ion-templated SN2' cyclization affording a highly functionalized chiral vinyl cyclobutane and a retro-Claisen rearrangement for the construction of an eight-membered ring ether.     

Imide-amide rearrangement of oxazaphosphorimidates: studies towards the application to the synthesis of chiral Lewis bases

The Lewis acid catalysed imide-amide rearrangement of oxazaphosphorimides to diazaphoshoramides is reported for the first time. In spite of the similarity to the previously reported Lewis acid catalysed imide-amide rearrangement of dioxaphosphorimides to oxazaphosphoramides we show that this rearrangement proceeds by a different mechanism, not involving the formation of an oligomeric intermediate. The oxazaphosphorimides are prepared in situ by the Staudinger reaction of the appropriate trivalent phosphorus compound with an azide and after the addition of BF₃·OEt₂, undergo rearrangement to the corresponding diazaphosphoramides. We have found that the rearrangement occurs with retention of configuration at the phosphorus atom and inversion of configuration at the rearranged carbon atom. When starting from chiral 1,2-aminoalcohol, substituted at the carbon atom that undergoes rearrangement, a mixture of diastereomers is obtained, but the diastereomeric ratio, initially obtained in the formation of the trivalent phosphorus compounds is maintained during the whole transformation. This implies that if the rearrangement is to be used for the preparation of chiral phosphoramides with defined stereochemistry at the phosphorus atom, a high diastereoselectivity during the preparation of the trivalent phosphorus precursors should be obtained.     

The carbonyl epoxide rearrangement. A chiral synthesis of the mus musculus pheromone

The carbonyl-epoxide rearrangement in conjunction with the Sharpless asymmetric epoxidation procedure has been applied to an efficient synthesis of both enantiomers corresponding to the Mus musculus pheromone.     

Alkylation epoxide rearrangement. Application to stereoselective synthesis of chiral pheromone epoxides.

An approach is described for the stereospecific conversion of threo and erythro 1,2-epoxy-3-alkanol tosylates to cis and trans internal epoxides, respectively. The method is illustrated by the synthesis of chiral epoxides, including insect pheromones.     

Concise synthesis of two advanced intermediates for the asymmetric synthesis of polyhydroxylated indolizidine alkaloids

A concise five-step approach to indolizidinones 10 and 11, two advanced intermediates for the asymmetric synthesis of polyhydroxylated indolizidine alkaloids, has been developed by using N-Cbz pyrrolidin-2-yl pyridin-2-yl sulfide 13 as the chiral building block. The method features a SmI₂-mediated coupling of sulfide 13 with functionalized aldehyde 14 and a tandem N-deprotection-lactamization, which constitutes a stepwise “2 + 4” annulation method for the construction of the indolizidinone ring system of 12a.