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An efficient approach to functionalized (

The Cu(OTf)2 catalyzed Ugi-type reactions of N,O-acetals with isocyanides have been described for the synthesis of pyrrolidinyl and piperidinyl 2-carboxamides. 4-Hydroxy-5-substituted-prolinamides can be obtained in high diastereoselectivities (2,4-cis/trans > 19 : 1) and a stereoselective model was proposed for 2,4-cis selectivity. Moreover, 4-F-VH 032, a novel analog of the VHL ligand, was conveniently obtained by utilizing the present method.

A highly regioselective approach to access amide enol carbamates and carbonates 5a-5c', 7a-7h, and 9 was developed through Cu(OTf)2-catalyzed reactions of ynamides 4 with t-butyl carbamates 2 and 8 and t-butyl carbonates 6. Moreover, this strategy was successfully applied to generate amide enol carbamates 11a-11s and 14a-14f from imides 10 and 13 with ynamides through an N-Boc cleavage-addition ring-opening process. A range of substituents was amenable to this transformation, and the desired amide enol carbamates and carbonates were obtained in moderate to good yields.

Regioselective C-H alkenylation of

The Cu(OTf)

A diastereoselective approach to obtain amino alcohols 10 through SmI2-induced radical addition of chiral imine 8 with 2-(benzyloxymethylsulfonyl)pyridine 9 is described. This approach was easily used for the synthesis of non-natural amino acid 15, a flexible key fragment whose utility was demonstrated in the divergent synthesis of dolastatin 10 (1) and its nine analogues 31a, 31c, 31d, 31e, 31f, 31g, 40a, 40b and 40c were obtained.

An efficient approach to access functionalized tertiary-type β-hydroxyl carboxamides has been developed through Sc(OTf)3-catalyzed addition of ynamides and substituted ketones. Water was found to be an important reaction substrate, and the solvent was not needed in this process. A broad range of substituted ynamides and ketones was well applicable to the reaction with excellent chemical selectivities. Moreover, several chiral β-hydroxyl carboxamides 3j–3r were prepared with excellent regioselectivities and outstanding diastereoselectivities.

An efficient approach to a functionalized bicyclo[2.2.2]octan-2-one scaffold has been developed through a one-pot cascade process including amino acid involved successive Michael addition and decarboxylative-Mannich sequence. Starting from α,β-unsaturated ketones and amino acids, a series of desired products 7a-7m and 8a-8o were obtained with moderate yields. In addition, the tandem process was reasonably explained by the results of DFT calculations.

A zinc-catalyzed decarboxylative A3 reaction of cyclic amino acids, α,β-unsaturated aldehydes and terminal alkynes has been developed. A series of functionalized N-heterocyclic 1,6-enynes have been successfully obtained with excellent regioselectivities through this novel approach. In addition, the utility of this straightforward process is demonstrated by the preparation of a polycyclic nitrogen-containing heterocyclic compound.

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).

An efficient approach to access functionalized tertiary-type β-hydroxyl carboxamides has been developed through Sc(OTf)

A zinc-catalyzed decarboxylative A

An effective approach to access dyadic 1,3-oxazinan-2-ones 8a-8c and 4,4a,5,6-tetrahydro-[1,3]oxazino[3,4-a]quinolin-1(3H)-ones 8d-8h was developed through Sc(OTf)3-catalyzed intramolecular cyclization from tert-butoxycarbonyl to acyliminium ion 7a-7j. A variety of substituted N,O-acetals, with different ring size, proved to be suitable substrates for this transformation, and a series of (4aS,6S,7R)-6-OTBS-7-substituted-hexahydropyrrolo[1,2-c][1,3]oxazin-1-ones 11a-11j and other chiral dyadic 1,3-oxazinan-2-ones 8i, 8j, 11k were synthesized in moderate yields with excellent diastereoselectivities (dr > 99:1). Moreover, 2,5-trans-products 11a-11j were obtained through this interesting Lewis acid-catalyzed intramolecular cyclization process.

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.

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).

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).

An efficient asymmetric approach to access functionalized pyrido- and pyrrolo[1,2- c][1,3]oxazin-1-ones has been developed through a nucleophilic addition-cyclization process of N, O-acetal with ynamides. A number of substituted ynamides 8a-8o and 3-silyloxypyrrolidine or piperidine N, O-acetals 6a, 7 were amenable to this transformation, and the desired products 9a-9o, 10a-10m were obtained with excellent regioselectivities and outstanding diastereoselectivities. Moreover, chiral ynamides 14a-14f could also experience this addition-cyclization process to afford products 15a-15f in excellent yields.

An efficient approach for asymmetric synthesis of (+)-spicigerine, (+)-cassine and their 3-epimers has been developed through the intramolecular diastereoselective tandem addition/cyclisation process of α-chiral aldimine 9 with methylmagnesium bromide and the asymmetric addition of nucleophilic reagents to aminal 14. Moreover, the first asymmetric synthesis of (+)-spicigerine has been achieved in this manuscript. In this synthetic strategy, the asymmetric syntheses of (+)-spicigerine and (+)-cassine was achieved in a 14% overall yield and nine steps and an 18% overall yield and seven steps from cheap α-chiral aldimine 9, respectively.

A diastereoselective new approach for the synthesis of trans-4-hydroxy-5-allyl-2-pyrrolidinone 9 has been developed through In-mediated allylation of α-chiral aldimine 8 with allyl bromide. The stereochemistry at the C-2 stereogenic center of 9 was controlled by both the α-OTBS substitution and the sulfinamide moiety. The utility of this asymmetric allylation is demonstrated by the asymmetric syntheses of epohelmins A (4) and B (10).

The one-pot tandem process of ( 2R,4R,S RS )- 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.

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.

An efficient and step-economical approach to access functionalized pyrrolizidine derivatives by a one-pot tandem sequence, including an aldol condensation and subsequent 1,3-dipolar cycloaddition process, has been developed, starting from acetone, aldehyde, and proline. A number of substituted aromatic aldehydes were amenable to this transformation, and the desired products, racemic 7a–7w and chiral 9a–9m, were obtained with excellent regioselectivities and outstanding diastereoselectivities. Moreover, in situ NMR studies revealed MgSO4 could effectively promote the aldol condensation pathway in this tandem 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.

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.

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.

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.

An enantioselective route for oxazoline 4, a key fragment toward the asymmetric synthesis of leiodelide A, is described. We synthesized northern subunit 6 through a Julia–Lythgoe olefination and subsequent Sharpless asymmetric dihydroxylation. Moreover, a highly diastereoselective method using well-established Evans’ asymmetric aldol condensation was developed for preparation of southern fragment 5. The additional feature of this synthetic route is the formation of oxazoline 4 through DAST-promoted cyclization of the amidation product from subunits 5 and 6.

The diastereoselective nucleophilic addition of organic boronic ester to 3-hydroxy-2-substituted N -acyliminium ions 9 led to the formation of 2,5- cis -pyrrolidine 10 , from which a convenient synthesis of (−)-7a- epi - 1 was developed. In addition, an efficient asymmetric synthesis of (−)-hyacinthacine A1 1 was achieved through the reduction/ring-opening process.

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.

A novel one-pot method for the diastereoselective synthesis of trans-4-hydroxy-5-substituted 2-pyrrolidinones via intramolecular cascade reaction of a series of Grignard reagents is presented.

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.

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.

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.

The diastereoselective nucleophilic addition of organic boronic ester to 3-hydroxy-2-substituted N -acyliminium ions 9 led to the formation of 2,5- cis -pyrrolidine 10 , from which a convenient synthesis of (−)-7a- epi - 1 was developed. In addition, an efficient asymmetric synthesis of (−)-hyacinthacine A1 1 was achieved through the reduction/ring-opening process.