Diverse Synthesis of Marine Cyclic Depsipeptide Lagunamide A and Its Analogues

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 <b>10</b>, we synthesized both 1,3-<i>anti</i> and 1,3-<i>syn</i> homoallylic alcohols <b>20a</b> and <b>20b</b> through asymmetric aldol condensation and stereoselective allylation. The following esterification to introduce the l-<i>N</i>-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 (<b>1a</b>), its 39-epimer (<b>1c</b>), and its 2-epimer (<b>1d</b>) were obtained through macrolactamization between alanine and isoleucine moieties

Radical Migration–Addition of <i>N</i>-<i>tert-</i>Butanesulfinyl Imines with Organozinc Reagents

A novel migration–addition sequence was discovered for the reaction of enantioenriched <i>N</i>-<i>tert</i>-butanesulfinyl iminoacetate <b>1a</b> with functionalized benzylzinc bromide reagents, producing <i>tert</i>-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 <i>N</i>-sulfinamine intermediate <b>M6</b> generated by the <i>tert</i>-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

Diastereoconvergent Synthesis of <i>trans</i>-5-Hydroxy-6-Substituted-2-Piperidinones by Addition–Cyclization–Deprotection Process

A diastereoselective one-pot approach to access <i>trans</i>-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

Diastereoconvergent Synthesis of <i>trans</i>-5-Hydroxy-6-Substituted-2-Piperidinones by Addition–Cyclization–Deprotection Process

A diastereoselective one-pot approach to access <i>trans</i>-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

Radical Migration–Addition of <i>N</i>-<i>tert-</i>Butanesulfinyl Imines with Organozinc Reagents

A novel migration–addition sequence was discovered for the reaction of enantioenriched <i>N</i>-<i>tert</i>-butanesulfinyl iminoacetate <b>1a</b> with functionalized benzylzinc bromide reagents, producing <i>tert</i>-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 <i>N</i>-sulfinamine intermediate <b>M6</b> generated by the <i>tert</i>-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

Divergent Synthesis of Revised Apratoxin E, 30-<i>epi-</i>Apratoxin E, and 30<i>S</i>/30<i>R</i>‑Oxoapratoxin E

In this report, originally proposed apratoxin E <b>(30</b><i><b>S</b></i><b>-7)</b>, revised apratoxin E <b>(30</b><i><b>R</b></i><b>-7)</b>, and (30<i>S</i>)/(30<i>R</i>)-oxoapratoxin E <b>(30</b><i><b>S</b></i><b>)-38</b>/<b>(30</b><i><b>R</b></i><b>)-38</b> were efficiently prepared by two synthetic methods. The chiral lactone <b>10</b>, recycled from the degradation of saponin glycosides, was utilized to prepare the key nonpeptide fragment <b>9</b>. 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

Divergent Method to <i>trans</i>-5-Hydroxy-6-alkynyl/alkenyl-2-piperidinones: Syntheses of (−)-Epiquinamide and (+)-Swainsonine

An efficient diastereoselective approach to access <i>trans</i>-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

Asymmetric Synthesis of Apratoxin E

An efficient method for asymmetric synthesis of apratoxin E <b>2</b> is described in this report. The chiral lactone <b>8</b>, recycled from the degradation of saponin glycosides, was utilized to prepare the non-peptide fragment <b>6</b>. In addition to this “<i>from nature to nature</i>” 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

Approach to Chiral 1‑Substituted Isoquinolone and 3‑Substituted Isoindolin-1-one by Addition–Cyclization Process

An approach to access 1-substituted isoquinolones has been developed through the addition–cyclization of imines with Grignard reagents in the presence of 2,2′-dipyridyl. A number of substituted aromatic magnesium reagents were amenable to this process, and the desired products were obtained with excellent yields and outstanding diastereoselectivities (<i>dr</i> > 99:1). The utility of this convenient approach is demonstrated by the formal synthesis of (<i>S</i>)-cryptostyline II. Moreover, <i>N</i>-methylmorpholine (NMM) was found to be an effective additive for the formation of 3-substituted isoindolin-1-ones using one-pot addition–cyclization–deprotection of imine with Grignard reagents

Approach to Chiral 1‑Substituted Isoquinolone and 3‑Substituted Isoindolin-1-one by Addition–Cyclization Process

An approach to access 1-substituted isoquinolones has been developed through the addition–cyclization of imines with Grignard reagents in the presence of 2,2′-dipyridyl. A number of substituted aromatic magnesium reagents were amenable to this process, and the desired products were obtained with excellent yields and outstanding diastereoselectivities (<i>dr</i> > 99:1). The utility of this convenient approach is demonstrated by the formal synthesis of (<i>S</i>)-cryptostyline II. Moreover, <i>N</i>-methylmorpholine (NMM) was found to be an effective additive for the formation of 3-substituted isoindolin-1-ones using one-pot addition–cyclization–deprotection of imine with Grignard reagents