In this report, originally proposed apratoxin E (30S-7), revised apratoxin E (30R-7), and (30S)/(30R)-oxoapratoxin E (30S)-38/(30R)-38 were efficiently prepared by two synthetic methods. The chiral lactone 10, recycled from the degradation of saponin glycosides, was utilized to prepare the key nonpeptide fragment 9. Our alternative convergent assembly strategy was applied to the divergent synthesis of revised apratoxin E and its three analogues. Moreover, ring-closing metathesis (RCM) was for the first time found to be an efficient strategy for the macrocyclization of apratoxins.

In this report, the originally proposed rupestonic acid (5) and pechueloic acid (3) were efficiently synthesized. The chiral lactone 13, recycled from the degradation of saponin glycosides, was utilized to prepare the key chiral fragment 11. During the exploration of this convergent assembly strategy, the ring-closing metathesis (RCM), SmI2-prompted intermolecular addition, and [2,3]-Wittig rearrangement proved to be effective transformations for the synthesis of subunits.

Symplocin A, a linear peptide possessing N-terminal N,N-dimethylisoleucine, statine, and valic acid residues, has been synthesized for the first time employing our previously established ‘one-pot intramolecular tandem protocol’. Moreover, the stereochemistry of natural symplocin A was unambiguously revised through the confirmation by 1D NMR, 2D NMR, and HPLC comparisons with an authentic natural product.

Dolastatin 10, an antineoplastic agent for cancer chemotherapy, is a linear peptide possessing N,N-dimethyl Val-OH, L-valine, (3R,4S,5S)-dolaisoleucine, (2R,3R,4S)-dolaproine and (S)-dolaphenine. Our efficient synthesis includes the following three key features: (1) SmI2-induced cross-coupling was employed to couple aldehyde 11 with (S)-N-tert-butanesulfinyl imine 12 to generate the required stereocenters of Dap (7); (2) asymmetric addition of chiral N-sulfinyl imine 10 provided a straightforward approach to the synthesis of the protected Doe ((S,S)-8); (3) a practical method to the key subunit Val-Dil (24a) has been established as an alternative synthetic route for the synthesis of this challenging chemical structure.

An efficient diastereoselective approach to access trans-5-hydroxy-6-substituted 2-piperidinones skeleton has been developed through one-pot intramolecular tandem process of O-benzyl protected aldimine 11 with Grignard reagents. The diastereoselectivity of substitution at C-6 position of 2-piperidinone was controlled by α-benzyloxy group. In addition, the utility of this straightforward cascade process is demonstrated by the asymmetric syntheses of (+)-L-733, 060 (2) and its 2-substituted analogue 3, as well as (+)-CP-122721 (5).Download high-res image (160KB)Download full-size image

A diastereoselective approach to trans-4-hydroxy-5-substituted 2-pyrrolidinones 1 (P1 = TBS, P2 = H) has been developed through a stereoselective tandem Barbier process of (R,SRS)-8 with alkyl and aryl bromide. The stereochemistry at the C-5 stereogenic center of the trans-4-hydroxy-5-substituted 2-pyrrolidinones was solely controlled by α-alkoxy substitution. This effective approach was successfully used to prepare a variety of substituted (3R,4S)-statines 2. In addition, two bioactive natural products of (+)-preussin 4 and hapalosin 5 were effectively synthesized through this stereoselective tandem Barbier process.

•A high diastereoselective method to key intermediate 5 was developed.•One feature is to form four stereocenters by Oppolzer’s and Paterson’s anti-aldol.•The other feature is the selective addition to form the stereogenic center at C32.A convenient method for diastereoselective synthesis of the key intermediate 5 from triheterocyclic fragment and polyketide 6 for hoiamides A (1) and B (2) was developed. The main feature is the successive construction of four stereogenic centers from C33 to C36 for hoiamides A (1) through the well-established Oppolzer’s anti-aldol and Paterson’s anti-aldol methodology. Furthermore, asymmetric allylation was also utilized as a key step to form the stereogenic center at C32 for hoiamides A (1).

Tubulysin V has been enantioselectively synthesized from the units of dipeptide 23, Tuv and Tup. The features of this synthetic strategy is included three portions, the Tuv fragment 17 was diastereoselectively synthesized from the d-malic acid, the stereocenters of the Tup unit was constructed by the asymmetric reduction as well as methylation, and the epimerization for several known methods was successfully avoided by condensation of fragment 19 with 24, and by deprotection with hydrogenation.

An efficient method for asymmetric synthesis of apratoxin E 2 is described in this report. The chiral lactone 8, recycled from the degradation of saponin glycosides, was utilized to prepare the non-peptide fragment 6. In addition to this “from nature to nature” strategy, olefin cross-metathesis (CM) was applied as an alternative approach for the formation of the double bond. Moreover, pentafluorophenyl diphenylphosphinate was found to be an efficient condensation reagent for the macrocyclization.

An efficient method for asymmetric synthesis of epohelmins A (3), B (4) and their isomer 24 is detailed in this report. The key feature in this divergent synthesis includes the SmI2-induced cross-coupling of N-tert-butanesulfinyl imine 10 with chiral aldehyde 9 derived from d-malic acid. A cascade cyclization to the pyrrolizidine skeleton is achieved in our synthetic route for epohelmins. In addition, an interesting intramolecular oxa-Michael addition was observed for epohelmin A (3).

Asymmetric total synthesis of emericellamide B (9.4%, 17 longest linear steps) is detailed in this report. In this synthetic route, the highly methylated (2R,3R,4S,6S)-3-hydroxy-2,4,6-trimethyldodecanoic acid (HTMD) unit was effectively prepared through the asymmetric methylation, Wittig and Horner–Wadsworth–Emmons reaction. Moreover, pentafluorophenyl diphenylphophinate (FDPP) proved to be an effective condensation reagent for the macrolactamization between C14 and C18.The emericellamide B was asymmetrically synthesis of in 9.4% overall yield. In this synthetic method, the highly methylated (2R,3R,4S,6S)-3-hydroxy-2,4,6-trimethyldodecanoic acid (HTMD) unit was effectively prepared through the asymmetric methylation, Wittig and Horner–Wadsworth–Emmons reaction.

The one-pot tandem process of (2R,4R,SRS)-15 with Grignard reagents for highly diastereoselective synthesis of functionalized 2-piperidinone 1 was developed. Furthermore, the divergent syntheses of L-685,458 3 and its six analogues 20a–f have been conveniently achieved using this effective protocol as the key step.

An efficient diastereoselective approach to access trans-5-hydroxy-6-alkynyl/alkenyl-2-piperidinones has been developed through nucleophilic addition of α-chiral aldimines using alkynyl/alkenyl Grignard reagents. The diastereoselectivity of alkenyl in C-6 position of 2-piperidinone was controlled by α-alkoxy substitution, while the alkynyl was controlled by the coordination of the α-alkoxy substitution and stereochemistry of sulfinamide. The utility of this straightforward cascade process is demonstrated by the asymmetric synthesis of the (−)-epiquinamide and (+)-swainsonine.

A diastereoselective one-pot approach to access trans-5-hydroxy-6-substituted-2-piperidinones by an addition–cyclization–deprotection process has been developed, in which the stereogenic center at the C-6 position was solely controlled by α-OTBS group. The utility of this transformation is demonstrated by the asymmetric synthesis of the enantiomer of (−)-CP-99,994.

The asymmetric total synthesis of lagunamide A (3.0%, 20 steps longest linear sequence) and its five analogues, including the structure dehydrated at the C37 position, are detailed in this report. The key feature in this diverse synthesis includes the elaboration of four consecutive chiral centers at C37–40 and the final macrocyclization. Starting from chiral aldehyde 10, we synthesized both 1,3-anti and 1,3-syn homoallylic alcohols 20a and 20b through asymmetric aldol condensation and stereoselective allylation. The following esterification to introduce the l-N-Me-Ala unit resulted in significant epimerization. This problem was finally overcome by coupling the alcohols with the corresponding acid chloride of the l-alanine derivative. The key α,β-unsaturated carboxylic acid unit was produced by cross-metathesis (CM) of methacrylaldehyde and related olefins. Interestingly, we found that the C7 configuration dramatically affected the ring closure. Natural lagunamide A (1a), its 39-epimer (1c), and its 2-epimer (1d) were obtained through macrolactamization between alanine and isoleucine moieties.

A novel migration–addition sequence was discovered for the reaction of enantioenriched N-tert-butanesulfinyl iminoacetate 1a with functionalized benzylzinc bromide reagents, producing tert-leucine derivatives in excellent diastereoselectivity (dr 98:2). The absolute configurations of two new chiral centers were unambiguously assigned by chemical transformations and X-ray crystallography. In addition, the regio- and diastereoselectivities of this novel reaction were both explained through the key N-sulfinamine intermediate M6 generated by the tert-butyl radical attack on the imine. Computational analysis of this reaction process, which was performed at the B3LYP/6-311++G(3df,2p)//B3LYP/6-31G*-LANL2DZ level, also supported our proposed two-stage mechanism.

An asymmetric approach to key intermediate 17 starting from lactone 7 is described, in which Evan’s alkylation and CBS-catalyzed reduction are used for construction of the chiral centers, respectively. Thus, the synthesis of (E)-dehydroapratoxin A 6 could be accomplished in a general fashion, therein FDPP has been proven as an efficient condensation reagent for the coupling of amine 25 and carboxylic acid 24.An asymmetric approach to key intermediate 17 starting from lactone 7 is described, in which Evan’s alkylation and CBS-catalyzed reduction are used for construction of the chiral centers, respectively. Thus, the synthesis of (E)-dehydroapratoxin A 6 could be accomplished in a general fashion, therein FDPP has been proven as an efficient condensation reagent for the coupling of amine 25 and carboxylic acid 24.

A facile approach to the versatile chiral building block 2 was developed based on glutamic acid, whereby a new method for asymmetric synthesis of sex pheromone 1 was explored from cheap glutamic acid.A convenient method for the preparation of multifunctional chiral building block 2 from d-glutamic acid was described. Cerebroside sphingolipid 1, a sex pheromone of hair crab, was successfully synthesized based on such a readily available building block.

An efficient asymmetric synthesis of the 2-hydroxymethyl 3,6-disubstituted piperidine alkaloid, (−)-deoxoprosophylline, is described. The key step of this route is the SmI2-mediated cross-coupling of chiral N-tert-butanesulfinyl imine 9 with aldehyde 11 to construct hydroxymethyl-β-amino alcohol 12b in 83% yield and high diastereoselectivity (>99%, de).(4R,5S)-Methyl 6-(benzyloxy)-4-hydroxy-5-(2-methylpropane-2-ylsulfinamido)-hexanoateC18H29NO5S[α]D25=-25.5 (c 1.33, CHCl3)Source of chirality: asymmetric synthesisAbsolute configuration: (Rs,4R,5S)(5R,6S)-6-(Benzyloxymethyl)-5-hydroxypiperidin-2-oneC13H17NO3[α]D25=-18.5 (c 0.14, CHCl3)Source of chirality: asymmetric synthesisAbsolute configuration: (5R,6S)(5R,6S)-6-(Benzyloxymethyl)-5-(tert-butyldimethylsilyloxy)piperidin-2-oneC19H31NO3Si[α]D25=-39.7 (c 0.6, CHCl3)Source of chirality: asymmetric synthesisAbsolute configuration: (5R,6S)(2S,3R)-tert-Butyl 2-(benzyloxymethyl)-3-(tert-butyldimethylsilyloxy)-6-oxopiperidine-1-carboxylateC24H39NO5Si[α]D25=+25.2 (c 0.97, CHCl3)Source of chirality: asymmetric synthesisAbsolute configuration: (2R,3S)tert-Butyl (2S,3R)-1-(benzyloxy)-3-(tert-butyldimethylsilyloxy)-6-oxooctadecan-2-ylcarbamateC36H65NO5Si[α]D25=+11.0 (c 1.64, CHCl3)Source of chirality: asymmetric synthesisAbsolute configuration: (2R,3S)(R)-N-((2S,3R)-1-(Benzyloxy)-3-hydroxy-6-oxooctadecan-2-yl)-2-methylpropane-2-sulfinamideC29H51NO4S[α]D25=-13.0 (c 0.64, CHCl3)Source of chirality: asymmetric synthesisAbsolute configuration: (Rs,2R,3S)

A diastereoselective approach to trans-4-hydroxy-5-substituted 2-pyrrolidinones 1 (P1 = TBS, P2 = H) has been developed through a stereoselective tandem Barbier process of (R,SRS)-8 with alkyl and aryl bromide. The stereochemistry at the C-5 stereogenic center of the trans-4-hydroxy-5-substituted 2-pyrrolidinones was solely controlled by α-alkoxy substitution. This effective approach was successfully used to prepare a variety of substituted (3R,4S)-statines 2. In addition, two bioactive natural products of (+)-preussin 4 and hapalosin 5 were effectively synthesized through this stereoselective tandem Barbier process.

A highly diastereoselective approach for the synthesis of trans-4-hydroxy-5-substituted 2-pyrrolidinones has been developed through an intramolecular cascade process of α-chiral aldimines using alkyl, aryl, alkynyl, and alkenyl Grignard reagents. The stereochemistry at the C-5 position of 2-pyrrolidinone after reaction with alkyl, aryl, and alkenyl Grignard reagents was solely controlled by α-alkoxy substitution. For alkynyl Grignard reagents, the stereochemistry was controlled by coordination of the α-alkoxy substitution and the stereochemistry of the sulfinamide. The utility of this one-pot cascade protocol is demonstrated by the asymmetric synthesis of streptopyrrolidine 5 and 3-epi-epohelmin A 3-epi-6.

Dolastatin 10, an antineoplastic agent for cancer chemotherapy, is a linear peptide possessing N,N-dimethyl Val-OH, L-valine, (3R,4S,5S)-dolaisoleucine, (2R,3R,4S)-dolaproine and (S)-dolaphenine. Our efficient synthesis includes the following three key features: (1) SmI2-induced cross-coupling was employed to couple aldehyde 11 with (S)-N-tert-butanesulfinyl imine 12 to generate the required stereocenters of Dap (7); (2) asymmetric addition of chiral N-sulfinyl imine 10 provided a straightforward approach to the synthesis of the protected Doe ((S,S)-8); (3) a practical method to the key subunit Val-Dil (24a) has been established as an alternative synthetic route for the synthesis of this challenging chemical structure.

Symplocin A, a linear peptide possessing N-terminal N,N-dimethylisoleucine, statine, and valic acid residues, has been synthesized for the first time employing our previously established ‘one-pot intramolecular tandem protocol’. Moreover, the stereochemistry of natural symplocin A was unambiguously revised through the confirmation by 1D NMR, 2D NMR, and HPLC comparisons with an authentic natural product.