A new diversity-oriented approach to C7-cyclitols, which possess a broad spectrum of biological activities, is developed. The key polyoxygenated intermediates with different O-protecting groups were accessed by an intramolecular aldol-cyclization of a diketone derived from δ-d-gluconolactone. The versatile intermediates can be easily transformed into structurally different carbasugars based on control of deprotection manipulation. The utility of the robust approach is illustrated by the first syntheses of (+)-gabosines P and Q, as well as the syntheses of several other gabosines and related analogues viz. (+)-gabosine E, (−)-gabosine G, (−)-gabosine I, (−)-gabosine K, (+)-streptol, and (−)-uvamalol A. In addition, the absolute configuration of (−)-uvamalol A is assigned by its total synthesis.

A stereoselective synthetic approach was utilized to synthesize enantiopure annuionones A (1b) and B (2b), two ionone-type norsesquiterpenoids that both bear a 6-oxabicyclo[3.2.1]octane framework and possess allelopathic activity. A stereoselective Diels–Alder reaction based on chiral trisubstituted dienophile 20 was employed to obtain the optically active polysubstituted cyclohexane core of both natural products. Using this approach, (+)-annuionone A (1b) and (−)-annuionone B (2b) were synthesized from lactol (+)-15 in 10% overall yield.

•The first synthesis of (+)-botryolide-E.•No expensive reagents and materials is involved.•Short route and high overall yield.The first synthesis of (+)-botryolide-E and its C-7 epimer has been achieved in 8 steps from d-Glucono-δ-lactone, and their antibiotic activities were also investigated preliminarily.Download high-res image (111KB)Download full-size image

(−)-Renieramycin T, an interesting tetrahydroisoquinolinequinone alkaloid with a novel renieramycin–ecteinascidin mixed framework, is synthesized from the known phenol 16 in 22 steps with 6.2% overall yield. In the convergent route, the key cyclocondensation between the isoquinoline moiety 27 and trisubstituted phenylalaninol 14 is achieved with good selectivity to furnish bistetrahydroisoquinoline 29, which permits a rapid construction of the pentacyclic framework having a fully substituted aromatic A ring.

A flexible and practical protocol for the asymmetric synthesis of renieramycin-type antitumor alkaloids is described, in which the stereoselective Pictet–Spengler cyclization of amino ester 16 and aldehyde 15 by regulating temperature and the automatic lactamization after N-deprotection of the cyclization product are exploited to rapidly construct the common pentacyclic framework. (–)-Renieramycin G and (–)-jorunnamycin A, as representative members of the two subgroup renieramycin-type alkaloids, are obtained in 19 steps from L-tyrosine with 15.8% and 14.3% overall yield respectively.

A useful and flexible strategy for synthesis of (−)- and (+)-infectocaryone from commercial sugars is developed. The key step of the synthesis is a new-type Diels–Alder reaction with good chemoselectivity and stereoselectivity, in which a mixture of alkene regioisomers in a dynamic equilibrium is employed as chiral dienophiles for the first time.

Three renieramycin-type antitumor alkaloids, (−)-jorunnamycins A (1) and C (2) and (−)-jorumycin (3), have been synthesized by a new convergent approach, which features a highly regio- and stereoselective Pictet–Spengler cyclization to couple the isoquinoline and the trisubstituted phenylalaninol partners. This synthetic strategy opens an economical access to these important antitumor alkaloids with high yields: (−)-jorunnamycin A, as a common precursor to other renieramycin-type alkaloids and their analogues, is obtained with 18.1% overall yield from l-tyrosine.

Several novel heterocycles have been constructed asymmetrically on the basis of a catalytic Ugi-type condensation of α-isocyanoacetamide and chiral cyclic imine. The combination of phenylphosphilic acid and trifluoroethanol is exploited to promote an Ugi-type reaction with α-isocyanoacetamide for the first time. By means of this reaction, chiral 3-oxazolyl morpholin-2-one/piperazin-2-one derivatives are synthesized with high yields and excellent stereoselectivities. As electron-rich azadienes, these condensation products are further transformed to fused tricyclic frameworks by treatment with appropriate dienophiles such as maleic anhydride and unsaturated acyl chlorides via domino processes. Moreover, a one-pot, three-component synthesis of the chiral tricyclic frameworks from isocyanoacetamide, imine, and maleic anhydride is also feasible.

A series of chiral 5,6-dihydro-1,4-oxazin-2-one substrates, as preformed cyclic aldimines and ketoimines, were employed to develop a new asymmetric Ugi three-component reaction for the first time. The Ugi reaction of the imines, isocyanides, and carboxylic acids opens an efficient access to novel morpholin-2-one-3-carboxamide compounds. The chiral imines showed promising stereoinduction for the new chiral center of the Ugi products, and predominant trans-isomers were obtained in the most cases. Addition of some Lewis acids or proton acids could improve the diastereoselectivity further but usually led to a drop in total yield. The Ugi-3CR could be extended to the stereoselective synthesis of ketopiperazine-2-carboxamide derivatives.

A practical procedure to regioselectively install a methyl group and a phenolic hydroxyl group onto l-tyrosine was developed. By using this approach, protected l-3-hydroxy-4-methoxy-5-methyl-phenylalanine and l-3-hydroxy-4-methoxy-5-methyl-phenylalanol, which are utilized in efficient syntheses of the relevant tetrahydroisoquinoline alkaloids, were prepared conveniently with high yield.l-N-Benzyloxycarbonyl-3-methyl-4-methoxy-phenylalanine methyl esterC20H23NO5[α]D26=+49 (c 0.99, CHCl3)Source of chirality: l-tyrosineAbsolute configuration: (S)l-N-Benzyloxycarbonyl-3-formyl-4-methoxy-5-methyl-phenylalanine methyl esterC21H23NO6[α]D27=+63 (c 1.1, CHCl3)Source of chirality: l-tyrosineAbsolute configuration: (S)l-N-Benzyloxycarbonyl-3-hydroxy-4-methoxy-5-methyl-phenylalanolC19H23NO5[α]D27=-23 (c 1.1, CHCl3)Source of chirality: l-tyrosineAbsolute configuration: (S)l-N-Benzyloxycarbonyl-3-hydroxy-4-methoxy-5-methyl-phenylalanineC19H21NO6[α]D27=+41 (c 1.1, CHCl3)Source of chirality: l-tyrosineAbsolute configuration: (S)l-3-Hydroxy-4-methoxy-5-methyl-phenylalanolC11H17NO3[α]D27=-17 (c 0.99, CHCl3)Source of chirality: l-tyrosineAbsolute configuration: (S)

A useful and flexible strategy for synthesis of (−)- and (+)-infectocaryone from commercial sugars is developed. The key step of the synthesis is a new-type Diels–Alder reaction with good chemoselectivity and stereoselectivity, in which a mixture of alkene regioisomers in a dynamic equilibrium is employed as chiral dienophiles for the first time.

(−)-Renieramycin T, an interesting tetrahydroisoquinolinequinone alkaloid with a novel renieramycin–ecteinascidin mixed framework, is synthesized from the known phenol 16 in 22 steps with 6.2% overall yield. In the convergent route, the key cyclocondensation between the isoquinoline moiety 27 and trisubstituted phenylalaninol 14 is achieved with good selectivity to furnish bistetrahydroisoquinoline 29, which permits a rapid construction of the pentacyclic framework having a fully substituted aromatic A ring.

A flexible and practical protocol for the asymmetric synthesis of renieramycin-type antitumor alkaloids is described, in which the stereoselective Pictet–Spengler cyclization of amino ester 16 and aldehyde 15 by regulating temperature and the automatic lactamization after N-deprotection of the cyclization product are exploited to rapidly construct the common pentacyclic framework. (–)-Renieramycin G and (–)-jorunnamycin A, as representative members of the two subgroup renieramycin-type alkaloids, are obtained in 19 steps from L-tyrosine with 15.8% and 14.3% overall yield respectively.