Enantioselective, biocatalytic reduction of 3-substituted cyclopentenones: application to the asymmetric synthesis of an hNK-1 receptor antagonist

A convergent and enantioselective route to the hNK-1 receptor antagonist (1) is described, which sets all six stereogenic centers with high diastereoselectivity and delivers 1 in only 11 steps and 23% overall yield. The process was enabled by the development of the enantioselective enzymatic reduction of 3-functionalized cyclopentenones and stereospecific Pd-catalyzed etherification coupling of fragments 6 and 7.     

Enantioselective synthesis of (−)-barrenazines A and B

A short enantioselective synthesis of barrenazines A and B is described. Barrenazines A and B are prepared following a common synthetic route in nine steps (19% overall yield) and eight steps (21% overall yield), respectively, from readily available 4-methoxy-3-(triisopropylsilyl)pyridine. The synthesis relies on a highly diastereoselective nucleophilic addition of a Grignard reagent to a chiral acylpyridinium salt, a radical azidation of a silyl enol ether and the assembly of the pyrazine ring by reductive dimerization of a functionalized 5-azidopiperidin-4-one.     

De novo asymmetric synthesis of anamarine and its analogues

[reaction: see text] The enantioselective synthesis of anamarine has been achieved in 21 steps. The route relies on enantio- and regioselective Sharpless dihydroxylation of dienoate ester and zinc borohydride reduction to establish the C-8-C-11 stereochemistry. A diastereoselective Leighton allylation established the desired C-5 stereochemistry. The route has also been used to prepare two diastereoisomers of anamarine in 14 steps.     

An enantioselective entry to cis-perhydroisoquinolines

An enantioselective route to cis-perhydroisoquinolines, involving a cyclocondensation reaction of (R)-phenylglycinol with a racemic oxoester, a stereoselective conjugate addition to an unsaturated bicyclic lactam, and the closure of the carbocyclic ring by a ring-closing metathesis as the key steps is reported. This route allows the preparation of 3-cyano derivatives as well as cis-octahydroisoquinolines bearing a quaternary center at the C4-position. [reaction: see text]     

De novo asymmetric syntheses of muricatacin and its analogues via dihydroxylation of dienoates

A short and highly efficient route to both enantiomers of muricatacin as well as the C-5-epimer has been developed. The key to the overall transformation is the highly regio- and enantioselective Sharpless asymmetric dihydroxylation of an (E,Z)-dienoate. The highly efficient stereoselective synthesis prepares (-)-muricatacin in seven steps and 66% overall yield.     

Total synthesis of (+)-laurencin: an asymmetric alkylation-ring-closing metathesis approach to medium ring ethers

[formula: see text] The enantioselective total synthesis of (+)-laurencin 1 is achieved in 18 steps from (S)-(+)-4-benzyl-3-benzyloxyacetyl-2-oxazolidinone. The key steps in this synthesis are an asymmetric glycolate alkylation leading to acyl oxazolidinone 2 and a subsequent ring-closing olefin metathesis to construct the oxocene core of 1. The approach to medium ring ethers utilized in this synthesis provides a general and efficient route to the cyclic core of other marine natural products.     

A new strategy for the enantioselective synthesis of carba-prostacyclin analogues based on organocopper conjugate addition to a bicyclic azoene and its application to the synthesis of 13,14-dinor-inter-p-phenylene carbacyclin

An enantioselective synthesis of E/Z-13,14-dinor-inter-p-phenylene carbacyclin (E/Z-2d) by a new strategy has been realized that holds the prospect of serving as a general route for carba-prostacyclin analogues. The key intermediate in this synthesis is the bicyclic azoene Ts-9, and the key step is the regio- and stereoselective conjugate addition of the chiral arylcopper compound Cu-8d/P-n-Bu3 to the azoene with formation of hydrazone 7d. Enantioselective synthesis of azoene Ts-9 of 95% ee from ketone 4 was accomplished in four and five steps, respectively. Thus, enantioselective deprotonation of bicyclic ketone 4 with chiral base Li-10 and trapping of lithium enolate 11 with ClSiMe3 gave enol ether 12, which was chlorinated with N-chlorosuccinimide (NCS) to afford chloro ketone 13. Alternatively, chloro ketone 13 was also prepared upon chlorination of 11 with NCS. Chloro ketone 13 was converted to chloro hydrazone 14, which upon treatment with a mild base furnished azoene Ts-9. Arylcopper compound 8d of 98% ee was obtained in two steps from alcohol 16, which was prepared by enantioselective reduction of ketone 17 with (-)-diisopinocampheylchloroborane. Carbacyclin derivative E/Z-2d was found to be essentially inactive as an inhibitor of ADP induced human platelet aggregation, having an IC50 of >10 micromol/L.     

Enantioselective synthesis of stephacidin B

We describe an enantioselective synthetic route to the antiproliferative alkaloid stephacidin B (1) proceeding in 18 steps and 4.0% yield from 4,4-(ethylenedioxy)-2,2-dimethylcyclohexanone (3). Key features of the synthetic sequence include the use of the Corey-Bakshi-Shibata (CBS) reduction to introduce asymmetry early in the synthetic route, use of the novel electrophile N-(tert-butoxycarbonyl)-5-(isopropylsulfonyloxymethyl)-2,3-dihydropyrrole in a stereoselective enolate alkylation, a diastereoselective Strecker-type addition of hydrogen cyanide to an N-Boc enamine substrate in the solvent hexafluoroisopropanol, platinum-catalyzed nitrile hydrolysis under neutral conditions, cyclization of an acylamino radical intermediate to form the diketopiperazine core of stephacidin B, and implementation of a convergent procedure for introduction of the key 3-alkylidene-3H-indole 1-oxide functional group in the final stage of the route to prepare the structure 2, previously proposed to be the fungal metabolite avrainvillamide (17 steps, 4.2% yield). We observed that synthetic (-)-2 dimerized in the presence of triethylamine to form (+)-stephacidin B (>95%). We also obtained evidence that 2 can form 1 under mild conditions, and that 2 reacts with nucleophiles, such as methanol, by conjugate addition.     

Enantioselective formal total synthesis of the antitumor macrolide bryostatin 7

A new enantioselective synthesis of Masamune's AB fragment (1) for bryostatin 7 is described. Key steps in the new route include a Meerwein-Ponndorf-Verley reduction to set the O(7) stereocenter and an alkylative union between the dithiane 6 and iodide 5 to construct the C(9)-C(10) bond. Because we have previously published a synthesis of Masamune's C-ring phenyl sulfone 2, our new route to 1 constitutes a formal total synthesis of bryostatin 7; it also corrects the previously reported spectral data for 1 in CDCl3.     

Enantioselective synthesis of 10-epi-anamarine via an iterative dihydroxylation sequence

[reaction: see text] The enantioselective syntheses of 10-epi-anamarine and 5,10-epi,epi-anamarine have been achieved in 13 to 14 steps. The route relies upon an enantio- and regioselective Sharpless dihydroxylation of either dienoates or trienoates to establish the C-8 to C-11 stereochemistry. A diastereoselective Leighton allylation established the desired C-5 stereochemistry. The route also relies upon a ring-closing metathesis to establish the alpha,beta-unsaturated lactones.     

Practical and efficient multigram preparation of a camphor-derived diol for the enantioselective Lewis acid catalyzed allylboration of aldehydes

[reaction: see text] Chiral diols are important molecules with widespread use as chiral auxiliaries and ligands in enantioselective synthesis. Therefore, efficient and practical syntheses of highly dissymmetrical nonracemic diols are still a meaningful pursuit. Two new routes to access camphor-derived chiral diol 1 have been developed. One route employs camphorquinone (3) as the starting material, affording in only two steps the desired diol in 55% overall yield. The second route, from camphor (2), leads to the desired diol in an efficient four-step synthesis, with an overall yield of 55%.     

An expedient enantioselective strategy for the oxatetracyclic core of platensimycin

An enantioselective route for the synthesis of oxatetracyclic core of platensimycin is reported for the first time using a 5-exo-trig cyclization followed by intramolecular etherification as key reactions. The requisite dienynone for the radical cyclization is synthesized in eight steps from the Wieland-Miescher ketone employing a Claisen rearrangement.     

An enantioselective approach to (+)-laurencin

A convergent enantioselective route to an advanced intermediate for the synthesis of the marine natural product (+)-laurencin has been developed. The methodology employs ring-opening of an ephedrine-based spiro-epoxide with a chiral secondary alcohol, hemiacetal allylation and ring closing metathesis as the key steps for elaboration of the functionalized medium-ring ether moiety in laurencin.     

Asymmetric Syntheses of 2‐(1‐Aminoethyl)phenols

Three different routes were probed for the synthesis of enantiomerically enriched 2‐(1‐aminoethyl)phenols and their methyl ethers. The first route centers on diastereoselective nucleophile addition to chiral imines. The second route has as key steps the enantioselective reduction of a ketone followed by nucleophilic substitution, and the third route involves a diastereoselective imine reduction. The efficiency of the approach depends on the substrate substitution pattern. All three methods work well for the parent compound 2‐(1‐aminoethyl)phenol ( 1 ) but the third route is the most efficient, providing the compound with >96% enantiomer excess in three steps with an overall yield of 71%. Conversely, for the ortho‐methyl analogue 2 , the first method is best. For the t‐Bu‐substituted analogue 3 , only moderate enantiomeric enrichment was achieved.     

Enantioselective syntheses of colletodiol,colletol, and grahamimycin A

[reaction: see text] The enantioselective synthesis of colletodiol has been achieved in 11 steps from methyl 1,3,5-octatrienoate and 16 total steps from both ethyl sorbate and methyl 1,3,5-octatrienoate. The route relies upon an enantio- and regioselective Sharpless dihydroxylation and a palladium-catalyzed reduction to form a 5-hydroxy-1-enoate and an 7-hydroxy-1,3-dienoate. These esters were further functionalized, coupled, and macrolactonized to provide colletodiol after deprotection. Grahamimycin A and colletol were synthesized in one and two steps, respectively, from colletodiol.     

Enantioselective route to a key intermediate in the total synthesis of forskolin

An enantioselective route for the total synthesis of forskolin, a potent activator of adenylate cyclase, has been developed which is based on reduction of dienone 3 to the (S)-alcohol 4 and conversion in two steps to tricyclic lactone 9, obtained in optically pure form simply by recrystallization.     

An enantioselective enzymatic desymmetrization route to hexahydro-4H-furopyranol,a high-affinity ligand for HIV-1 protease inhibitors

An enantioselective synthesis of (3aS,4S,7aR)-hexahydro-4H-furo[2,3-b]pyran-4-ol, a high-affinity nonpeptide ligand for a variety of potent HIV-1 protease inhibitors is described. The key steps involved a highly enantioselective enzymatic desymmetrization of meso-diacetate, an efficient transacetalization, and a highly diastereoselective reduction of a ketone. This route is amenable to large-scale synthesis using readily available starting materials.     

A short and efficient enantioselective route to a key intermediate for the total synthesis of forskolin

A simple route for the enantioselective synthesis of key intermediates (11 and 12) for the total synthesis of forskolin has been developed starting from acid 6 and (S)-alcohol 5. The latter is prepared by enantioselective catalytic CBS reduction of dienone 3, and is converted by an intramolecular Diels-Alder reaction to tricyclic lactone 9.     

An enantioselective synthesis of tarchonanthuslactone

An enantioselective synthesis of tarchonanthuslactone has been achieved in eight steps from ethyl sorbate. The asymmetry of the route was introduced via a Sharpless asymmetric dihydroxylation allowing access to either enantiomer. The synthesis utilizes a palladium-catalyzed reduction and a diastereoselective base-catalyzed acetal formation as the key steps. The pyran ring of tarchonanthuslactone was established by a Still-olefination/lactonization sequence. DCC-mediated attachment of dihydrocaffeic acid completed the synthesis of tarchonanthuslactone in a 19% overall yield.     

Practical formal total syntheses of the homocamptothecin derivative and anticancer agent diflomotecan via asymmetric acetate aldol additions to pyridine ketone substrates

Two practical, efficient, and scalable asymmetric routes to DE ring fragment 7, a key building block in the synthesis of the homocamptothecin derivative diflomotecan 4, are described. The "acetal route" starts from 2-chloro-4-cyanopyridine 8 and represents an enantioselective and optimized modification of the original racemic discovery chemistry synthesis. The inefficient optical resolution procedure was replaced by an efficient asymmetric acetate aldol addition (dr 87:13) to a ketone substrate as the key step generating the (R)-configured quaternary stereocenter with high stereoselectivity. 7 was finally obtained in 8.9% overall yield (er 99.95:0.05) over nine steps, avoiding chromatographic purifications and comparing favorably with the initial procedure. In the related "amide route" starting from 2-chloroisonicotinic acid 41, a secondary amide directing group was used to facilitate the ortho lithiation of the pyridine 3-position. The key step of this protocol again consists of a practical asymmetric acetate aldol addition (dr = 87:13). The DE ring building block 7 was thus obtained in 11.1% overall yield (er > 99.95:0.05) over nine steps requiring only one chromatographic purification.