Total synthesis of Amaryllidaceae alkaloids, (+)-vittatine and (+)-haemanthamine, starting from d-glucose

The stereoselective total synthesis of (+)-vittatine 1 and (+)-haemanthamine 2 starting from d-glucose is described. The cyclohexene ring in 1 was prepared in an optically active form from d-glucose using Ferrier's carbocyclization reaction, and the critical quaternary carbon was stereoselectively generated via chirality transfer by the Claisen rearrangement of cyclohexenol 6. The hexahydroindole skeleton was effectively constructed by the intramolecular aminomercuration-demercuration of 14, followed by Chugaev reaction to provide 16. Finally, Pictet-Spengler reaction completed the first chiral synthesis of (+)-vittatine 1. On the other hand, the α-hydroxylation of the ester 5 stereoselectively proceeded to give α-hydroxy ester 19, to which was introduced an amino function to provide 4. A similar transformation of 4, as employed in the synthesis of vittatine, furnished (+)-haemanthamine 2.     

An expedient total synthesis of optically active piperidine and indolizidine alkaloids (−)-β-conhydrine and (−)-lentiginosine

Attempts directed toward the stereocontroled total synthesis of piperidine and indolizidine alkaloids resulted in the synthesis of (−)-β-conhydrine 1 and (−)-lentiginosine 3. The synthesis of 1 and 3 were developed from protected d-mannitol as the chiral precursor, which involved nucleophilic addition and azide nucleophilic substitution, Barbier allylation, ring closing metathesis, and Sharpless asymmetric dihydroxylation as the key steps.     

New derivatives of trifluoroacetyl acetaldehyde and trifluoroaldol

The reaction of β-ethoxyvinyl trifluoromethyl ketone 1 with O-nucleophiles such as alcohols and diols leads to various derivatives of trifluoroacetyl acetaldehyde, such as β-alkoxyvinyl trifluoromethyl ketones 3 and cyclic keto acetals 4. Several derivatives synthesized contain chiral auxiliaries. Reduction of the compounds 1, 3, 4 under various reaction conditions leads to the trifluoroaldol derivatives 6, 7, 9, 10 containing a protected aldehyde group. The compounds obtained are useful building blocks in fluoroorganic synthesis.     

Asymmetric synthetic study of macrolactin analogues

We designed two aromatic analogues 1a and 1b of macrolactin A with expectation of enhancing biological activity and metabolical stability. As a result of retrosynthetic analysis of these compounds 1a-b, two synthetic strategies have been examined. The first strategy includes the enantioselective addition of nonadienyl anion, derived from 3, to aldehyde 4 as a key step. The second one includes epimerization of ynone 7 to (E,E)-conjugated dienone 31 and subsequent diastereoselective hydride-reduction of 31. Although the former route furnished no desired target, the latter one was revealed to work well for the synthesis of 1. Unfortunately, the aimed (2Z,4E)-analogue 1a could not be synthesized due to an epimerization of the (2Z)-olefin into the (2E)-olefin. However, these methods could be applied to the total asymmetric synthesis of the (2E,4E)-analogue 1b. Overall, control of all of the four stereocenters was achieved by means of asymmetric and diastereoselective reactions without using any chiral natural sources.     

Determination of the absolute stereochemistry and asymmetric total synthesis of madindolines A and B: a practical improvement to a second-generation approach from the first-generation

In this report, we describe an efficient, highly convergent, stereocontrolled first total synthesis and a second-generation synthesis of madindolines A 1 and B 2, potent selective inhibitors of interleukin 6. The key steps include (1) asymmetric oxidative ring-closure reaction of tryptophol 3 to construct a chiral 3a-hydroxyfuroindoline 4 using the modified Sharpless asymmetric epoxidation condition, (2) highly diastereoselective acylation to build up the quaternary carbon center, and (3) intramolecular acylation of ester 32 with allylsilanes to produce the full substituted cyclopentenedione units. Our first synthetic route defines for the first time both their relative and absolute configurations. Moreover, a more efficient second-generation synthesis was designed, which is suitable for gram-scale preparation of these compounds.     

Stereoselective synthesis of (6S) and (6R)-5,6-dihydro-6-[(2R)-2-hydroxy-6-phenylhexyl]-2H-pyran-2-one and their cytotoxic activity against cancer cell lines

Stereoselective total synthesis of α,β-unsaturated lactone (1a), isolated from Ravensara crassifolia, has been achieved efficiently starting from chiral 2,3-O-isopropylidene-d-glyceraldehyde (3) followed by asymmetric allylation and ring-closing metathesis. The antiproliferative activities of compounds 1a, 1b and the unusual bicyclic compound 2 were evaluated against three-cancer cell lines, THP-1 and U-937 (leukemia) and A-375 (melanoma).     

Diastereoselective synthesis of aziridine esters via amino selanyl esters

A synthesis of aziridine esters based on the cyclisation of amino selanyl esters induced by the selanyl group activation was developed with either the Meerwein salt or NBS. Two asymmetric approaches are proposed: the diastereoselective reductions of α-selanyl β-iminoesters derived from α-oxoesters, which lead to cis chiral aziridine esters 6 and 6′; and the diastereoselective conjugate additions of a chiral amide to α,β-unsaturated esters providing trans chiral aziridine esters 6 and 6″.     

Total synthesis of aspergillide B and structural discrepancy of aspergillide A

Fourteen-membered cytotoxic macrolides 1 and 2 were synthesized from alcohol 10 in 15 steps utilizing stereospecific Pd(II)-catalyzed cyclization of ζ-hydroxy chiral allylic alcohol 7. Aspergillides A and B were isolated from marine fungus, and their structures were proposed as 1 and 2, respectively. The synthetic 1 was not matched with aspergillide A but matched with aspergillide B. The chiral center at C-13 position of aspergillide B was revised to be (S)-configuration. The key steps of the stereoselective synthesis include the Sharpless asymmetric dihydroxylation, cross-metathesis, stereospecific construction of tetrahydropyran ring of 16 using Pd^II catalyst, and the Yamaguchi macrolactonization.     

Gold and platinum catalyzed cascade reaction of propargyl acetates bearing terminal alkynes or methyl ketones

A gold (III)-catalyzed cascade reaction of propargyl acetates bearing an extra terminal alkyne (1) afforded γ-keto esters 3 and lactones 4. These products should be generated through allenyl ketone intermediate B via a 1,2-acyloxy cyclization/fragmentation/cycloisomerization/hydrolysis sequence. On the other hand, the cascade reaction of α-acetoxy ketones bearing terminal alkynes 5 afforded lactone 6 via allenyl ketone intermediate A. This reaction involves a [3,3]-sigmatropic acyloxy rearrangement/cycloisomerization/hydrolysis sequence.     

Optically active imidazoles derived from enantiomerically pure trans-1,2-diaminocyclohexane

A new exploration of monoprotected derivatives of trans-1,2-diaminocyclohexane as a platform for the synthesis of enantiomerically pure imidazole derivatives is described. The primary amino group (-NH₂), present in the mono-imine derivative of salicylic aldehyde (hemi-salen derivative) 5 was used for sequential reactions with formaldehyde and the corresponding α-(hydroxyimino)ketone. (S)-(−)-1-Phenylethylamine was also used as starting material for the preparation of new imidazole N-oxides 7c and 10a-c, bearing a chiral N-(1-phenylethyl)carboxamido function at C(4). Imidazole N-oxides 10a,b possessing either a Me or i-Pr group at N(1), respectively, follow the known sulfur-transfer pathway to afford the corresponding imidazole-2-thiones 13a,b. However, in the case of imidazole N-oxide 10c with a bulky adamantan-1-yl substituent at N(1), the attempted ‘sulfur-transfer reaction’ led to the deoxygenated imidazole derivative 14. Finally, the same reaction with 7c, which bears an electron-withdrawing N-(1-phenylethyl)carboxamide residue at C(4) of the imidazole ring, yielded a mixture of deoxygenated imidazole 16 and imidazole-2-thione 15c.     

Stereoselective synthesis of iriomoteolide-1a hemiketal core

A stereoselective synthesis of the cyclic hemiketal core of iriometeolide-1a (1) is described. The key step involves a Sakurai reaction of allylsilane 4 and aldehyde 5, which bears a chiral α-tertiary center. Mild TES deprotection of β,γ-unsaturated ketone 23 led to concomitant cyclization to produce the fully intact hemiketal core 2.     

Enantioselective intramolecular cyclopropanation of α-diazo-β-keto sulfones: asymmetric synthesis of bicyclo[4.1.0]heptanes and tricyclo[4.4.0.0]decenes

Catalytic asymmetric synthesis of some new chiral building blocks useful for natural product synthesis is described. The intramolecular cyclopropanation (IMCP) reaction of α-diazo-β-keto sulfones affording bicyclo[4.1.0]heptanes such as 9a-d is found to proceed with high enantioselectivity (93-98% ee). The yield is moderate due to the competing intramolecular C-H insertion reaction. As intramolecular C-H insertion reaction is not observed in the reaction of the substrates possessing a quaternary carbon at the allylic position, the reactions of 19a and 19b proceed with high enantioselectivity (95% ee) and yield. It was also found that the substrates possessing an ether group, such as 19a and 19b, could be used in this enantioselective IMCP reaction.     

Development of novel LpxC inhibitors: chiral-pool synthesis of C-triazolyl glycosides

The Zn²⁺-dependent deacetylase LpxC plays an important role in the biosynthesis of the cell wall of Gram-negative bacteria and therefore represents an interesting target for the development of novel antibiotics. In a 10-step, chiral pool synthesis starting from d-mannose (3), a series of C-aryl furanosidic hydroxamic acids bearing a 1,4-disubstituted triazole ring in α-configuration at the furanose moiety was stereoselectively synthesized and tested for inhibitory activity against LpxC. The key step of the synthesis comprises a Cu(I) catalyzed Huisgen cycloaddition of terminal alkyne 10 with various azides to introduce diversity to the potential LpxC inhibitors. The X-ray crystal structure of the click product 11e proves the stereochemistry at the anomeric center and the substitution pattern of the triazole ring. The synthesized compounds did not inhibit LpxC.     

Chiral N-phosphonyl imine chemistry: new reagents and their applications for asymmetric reactions

Novel chiral N-phosphonyl imines 2 have been designed and synthesized using chiral N-phosphoramide 1. These N-phosphonyl imines have been successfully utilized for asymmetric aza-Darzens reaction and asymmetric aza-Henry reaction. The C₂-symmetric chiral auxiliary tolerates oxidation, is not sensitive to racemization and can be recycled for large scale synthesis.     

Lipase-catalyzed kinetic resolution of thiotetronic acid derivatives bearing a chiral quaternary carbon: total synthesis of (R)-thiolactomycin and its O-analogue

We have developed a chemoenzymatic synthesis of (R)-thiolactomycin (1) having a chiral quaternary carbon atom at C5. In the kinetic resolution of the thiotetronic acid precursor 4, both enantiomers were obtained with high enantiomeric excess by use of Chirazyme^® L-2. Chemical transformations of the (R)-alcohol 4 provided the chiral (R)-thiolactomycin (1) in 36% yield in five steps.     

Unusual sulfanylation through ring transformation of arene-tethered 2H-pyran-2-ones by in situ built Michael adduct

A novel synthesis of highly functionalized alkylsulfanylmethyl arenes 8a-m through the ring transformation of 6-aryl-4-methyl/ethylsulfanyl-2H-pyran-2-one-3-carbonitriles 1a-j, by reaction with methyl vinyl ketone 2, is delineated and illustrated. To ascertain the course of reaction, 3-arylsulfanylmethyl-2-methyl-6-methylsulfanyl-4-phenylbenzonitriles 8k-m were also prepared from the reaction of 1 with 4-arylsulfanyl-butan-2-ones 7c,d.     

Stereoselective synthesis of C15C24 and C25C30 fragments of dolabelides

The stereocontrolled synthesis of a C15C24 fragment of dolabelides is reported. The C19 and C21 hydroxyl-bearing stereocenters were installed using ruthenium-mediated asymmetric hydrogenations of cyclic hemiketal 4 and β-keto ester 7. The C25C30 portion of dolabelides was prepared as well by ring opening of chiral epoxy alcohol 12 to set up the C27 stereogenic center.     

Asymmetric synthesis of the tricyclic core of cyathin diterpenoids via intramolecular Heck reaction

The enantioselective synthesis of the ketones 3 which displays the carbon core of NGF-inducing cyathane diterpenes is described. The key tricyclic trienone 22 was assembled in 13 steps from Michael adduct (R)-8a via intramolecular Heck cyclization of the chiral triflate 21. The trienone 22 was further elaborated into ketone 3 through trimethylaluminum-promoted expansion of the C-ring with trimethylsilyldiazomethane.     

A new synthesis of spiropyrrolidine-tetralones via an unexpected formal ring-contraction of 4-disubstituted piperidine to 3-disubstituted pyrrolidine

We have developed an efficient synthesis of novel racemic spiropyrrolidine-tetralones via an unexpected ring-contraction reaction of a 4-disubstituted piperidine to 3-disubstituted pyrrolidine. We suggest that intramolecular quaternization of the piperidine nitrogen of compound 7 occurs to form a bridged bicyclic quaternary ammonium salt intermediate 10. The ring opening of 10 with cyanide resulted in pyrrolidine 9. The synthesis of racemic spiropyrrolidine-tetralone 15 is described as well as the related spiropiperidine-indanone, 1b.     

Regioselective synthesis of 4- and 5-oxazole-phosphine oxides and -phosphonates from 2H-azirines and acyl chlorides

A simple and efficient regioselective synthesis of 4-oxazole-phosphine oxides 11 and -phosphonates 12 from 2H-azirine-phosphine oxides 1 and -phosphonates 6 is described. The key step for the synthesis of oxazoles 11 is a base-mediated ring closure of vinylogous α-aminophosphorus compounds derived from phosphine oxides 4 and from phosphonates 8. These derivatives 4 and 8 are obtained by reaction of functionalized azirines 1 and 6 with acyl chlorides 2 and subsequent acid-catalyzed ring opening of N-acylaziridine-phosphine oxides 3 and -phosphonates 7. Regioselective thermal ring cleavage of N-acylaziridine-phosphine oxides 3 leads α-chloro-β-(N-acylamido)-phosphine oxides 13 and their treatment with bases gives 5-oxazole-phosphine oxides 16.