Enantioselective Synthesis of Protease Inhibitors and AntiHIV Agents

Part 1: A highly enantio-and diastereoselective Ireland-Claisen rearrangement of chiral C3(acyloxy)-vinyl silanes for the synthesis of anti-disubstituted succinic acid, an important intermediate for matrix metalloprotease inhibitors, has been developed (enantio-and anti/syn selectivities up to 95% and 38/1). The diastereoselectivity of this reaction was found to be sensitive to remote hydroxyl protecting groups, for example, with-OMOM group, the anti/syn ratio was 19/1, while with-OTBDMS, the ratio was 38/1. The resultant Ireland-Claisen rearrangement product was applied to the synthesis of macrocyclic MMP inhibitors, such as SL 422.     

Tandem enyne metathesis and claisen rearrangement: a versatile approach to conjugated dienes of variable substitution patterns

To extend the versatility of the ruthenium carbene-promoted enyne metathesis, it was combined with an Ireland ester enolate Claisen rearrangement. This reaction sequence provided conjugated dienes of higher substitution pattern than that obtained through a cross-enyne metathesis alone. The Ireland-Claisen was conducted across both acyclic and cyclic dienes produced from cross-metathesis and methylene-free enyne metathesis, respectively. In the case of cyclodienes, the Ireland-Claisen rearrangement produced s-trans locked dienes which underwent mode-selective ene reaction. The tandem, sequential use of the Ireland-Claisen rearrangement also proved suitable for chirality transfer originating from chiral propargylic alcohols. Last, the tandem metathesis/Ireland-Claisen was utilized to access 4-substituted-3,5-cyclohexadiene diol derivatives, which are valuable chiral intermediates for natural product synthesis. The combination of this pericyclic reaction with a catalytic metathesis reaction extends the versatility of cross-metathesis since additional diene motifs can be accessed.     

An Ireland-Claisen approach to lignans: synthesis of the putative structure of 5-epi-eupomatilone-6

A novel Ireland-Claisen approach to the putative structure of eupomatilone-6 is described. The rearrangement established the C3 and C4 stereocenters and concomitantly generated a vinyl epoxide. The C5 oxygen was installed by cyclization of the pentenoic acid carboxyl group onto the vinyl epoxide in an S(N)2' fashion to afford the C5-epi stereochemistry. The natural C5 stereochemistry was accessed via a substrate directed dihydroxylation.     

Polycyclic aromatic compounds via radical cyclizations of benzannulated enyne-allenes derived from Ireland-Claisen rearrangement

A new synthetic sequence involving the use of Ireland-Claisen rearrangement of propargylic acetates to form the corresponding benzannulated enyne-allenes followed by Schmittel cyclization to generate benzofulvene biradicals for radical cyclizations leading to polycyclic aromatic compounds was established. Treatment of 9-fluorenone (8) with the lithium acetylide 9 followed by acetic anhydride produced the propargylic acetate 10. A sequence of reactions occurred after 10 was converted to the corresponding silyl ketene acetal 11. An initial Ireland-Claisen rearrangement produced the benzannulated enyne-allene 12, which then underwent a Schmittel cyclization reaction to generate the benzofulvene biradical 13. A subsequent intramolecular radical-radical coupling then produced the formal Diels-Alder adduct 14, which in turn underwent a prototropic rearrangement to give the silyl ester 15 and, after hydrolysis, the carboxylic acid 16 in 57% overall yield from 10 in a single operation. An intramolecular acylation reaction of 16 produced the ketone 17. The carboxylic acids 24-26 were likewise prepared from the diaryl ketones 18-20, respectively. However, the intramolecular [2 + 2] cycloaddition reaction of the benzannulated enyne-allene 33 having a tert-butyl group at the allenic terminus occurred preferentially, producing the 1H-cyclobut[a]indenyl acetic acid 35 as the predominant product.     

A new ring expansion for a chiral hexahydroazulene skeleton possessing an angular methyl group

A new synthetic route for a pseudoguaiane ring system is described. The synthesis features an Ireland-Claisen rearrangement for constructing the trans-fused ring system, followed by a new ring expansion to yield a bicyclo[5.3.0]decane ring system possessing an angular methyl group.     

Ireland-Claisen rearrangement of ynamides: stereocontrolled synthesis of 2-amidodienes

The Ireland-Claisen rearrangement of propargyl ynamido ester substrates is reported. The expected allenamide carboxylic acid products from [3,3]-sigmatropic rearrangement are not isolated, with 2-amidodienes alternatively formed in good yield with high levels of stereocontrol after decarboxylation.     

Synthesis of the B-seco limonoid scaffold

The underlying stereochemically complex and densely functionalized scaffold of the B-seco limonoids was synthesized employing an Ireland-Claisen rearrangement as key transformation.     

A formal total synthesis of Lycopodium alkaloid, (±)-magellanine, by using the intramolecular Pauson Khand reaction

A formal total synthesis of magellanine was accomplished by using the stereoselective Ireland-Claisen rearrangement and the intramolecular Pauson-Khand reaction of exocyclic enynes as key steps.     

Studies toward the total synthesis of armatol F: stereoselective construction of the C6 and C7 stereocenters and formation of the A-ring skeleton

Armatol F, isolated from the red alga Chondria armata as a polyether triterpene, has a solitary oxepane (A-ring) and a fused tricyclic ether moiety (BCD-ring). The A-ring features a rare cis-relationship between the hydroxy group at the quaternary carbon C6 and the carbon chain at C7. As part of our program toward the total synthesis of armatol F, a new stereoselective method for the construction of the C6 and C7 stereocenters has been developed based on chirality-transferring Ireland-Claisen rearrangement. The A-ring skeleton has also been synthesized from the rearrangement product by a process including ring-closing olefin metathesis.     

Diastereoselective ireland-claisen rearrangement of allylic alcohols

The “chelation-controlled” Ireland-Claisen rearrangement of allylic glycolate esters is described in which the stereocontrol of the prochiral sp² sites is achieved by the allylic oxygen substitutent.     

Toward the synthesis of cobyric acid. Enantioselective syntheses of completely differentiated ring D synthons

Alkyne acids 11 were prepared in an enantioselective fashion from allylic ester derivatives 18 or 20 by Ireland-Claisen rearrangement, followed by Si-assisted elimination of HBr. The title compounds are attractive ring D synthons for an ongoing synthesis of cobyric acid.     

Total synthesis of pancratistatin relying on the [3,3]-sigmatropic rearrangement

A new total synthesis of the antitumor alkaloid, pancratistatin (1), has been accomplished from readily available starting materials. Claisen rearrangement of the racemic dihydropyranethylene 17 was employed to construct the A and C rings with the appropriate stereochemistry. In addition, the Ireland-Claisen rearrangement of the enantiomerically pure 9 followed by ring-closing metathesis provided the important intermediate 24, thus implying that our approach could yield the enantioselective synthesis of (+)-pancratistatin. With the appropriately functionalized cyclohexene 24, stereo- and regiocontrolled functional group interchanges, such as iodolactonization, dihydroxylations, and a cyclic sulfate elimination reaction, facilitated the production of the target natural product.     

Enantiospecific synthesis of the phospholipase A2 inhibitor (-)-cinatrin B

The first enantiospecific synthesis of phospholipase A2 (PLA2) inhibitor (-)-cinatrin B (2) from the D-arabinose derivative 9 is described. The spirolactone system was formed by an Ireland-Claisen rearrangement of the allyl ester 8 followed by hydrolysis and stereoselective iodolactonization. The stereoselectivity of the rearrangement was controlled by the asymmetry in the allylic alcohol fragment. Ester (S)-8 gave the desired rearrangement product 7 and the epimer 13 in high yield as a 73:27 ratio, respectively. The final stereocenter at C2 was introduced via a chelation-controlled addition of the Grignard reagent derived from trimethylsilylacetylene to alpha-hydroxy ketone 6. Transformation of the terminal alkyne into the methyl ester 21 followed by acetal hydrolysis and selective lactol oxidation afforded cinatrin B methyl ester (22). Base hydrolysis and acid-induced relactonization then gave (-)-cinatrin B (2).     

Studies toward the synthesis of pinnatoxins: the spiroimine fragment

An enantioselective approach to the spiroimine fragment of pinnatoxins is described. The strategy is based on a recently developed diastereoselective Ireland-Claisen rearrangement to establish the challenging congested quaternary and tertiary stereocenters within the cyclohexene ring.     

Remote stereocontrol in [3,3]-sigmatropic rearrangements: application to the total synthesis of the immunosuppressant mycestericin G

The Ireland-Claisen [3,3]-sigmatropic rearrangement has been used to access biologically important β,β'-dihydroxy α-amino acids. The rearrangement reported is highly stereoselective and offers excellent levels of remote stereocontrol. This strategy has been used to synthesize the natural immunosuppressant mycestericin G and ent-mycestericin G, allowing for a revision of absolute configuration of this natural product.     

Approach to the synthesis of cladiell-11-ene-3,6,7-triol

[reaction: see text] The synthesis of an advanced intermediate in the synthesis of the title compound has been achieved. Key steps include an Ireland-Claisen rearrangement to install the C7 tertiary alcohol stereocenter, an SN2' reaction of an alkoxymethyl Cu reagent, and a diastereoselective Re-catalyzed allylic alcohol transposition.     

Formation of chiral quaternary carbon stereocenters using silylene transfer reactions: enantioselective synthesis of (+)-5-epi-acetomycin

Chiral quaternary carbon stereocenters can be established with high diastereoselectivity by a silylene transfer/Ireland-Claisen rearrangement. The utility of this method was demonstrated by application to a synthesis of (+)-5-epi-acetomycin. [reaction: see text]     

Claisen rearrangements of equilibrating allylic azides

Equilibrating mixtures of allylic azide-containing allylic alcohols or allylic 2-tolylsulfonylacetic esters undergo Johnson-Claisen or Ireland-Claisen rearrangement reactions to give unsaturated γ-azidoesters and -acids, respectively. Decarboxylation of the acids under basic conditions gives azidosulfones, with moderate to high diastereoselectivity.     

Enantioselective syntheses of ring-C precursors of vitamin B12. Substrate control. A novel Si-assisted elimination of vinyl bromides

Homochiral ring-C precursors 34 of Vitamin B(12) have been prepared by Ireland-Claisen rearrangement of allyl esters 32, followed by a novel Si-assisted elimination of HBr. [reaction: see text]     

Enantioselective total synthesis of (-)-dactylolide

[reaction: see text] The enantioselective total synthesis of (-)-dactylolide is reported. The absolute stereochemistry of the tetrahydropyran was established by catalytic asymmetric Jacobsen hetero-Diels-Alder reaction. The remote C19 stereocenter was introduced by a sequence of chelation-controlled Grignard addition and Ireland-Claisen rearrangement.