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

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

Practical Asymmetric Synthesis of Amathaspiramides B, D, and F

The practical asymmetric synthesis of amathaspiramides B, D, and F has been accomplished by utilizing an aza-Barbier allylation as the key step to construct the common intermediate with two adjacent stereocenters. A kinetically controlled cyclization to build the challenging thermodynamically less stable 8<i>R</i>-hemiaminal moiety is also important in the synthesis of amathaspiramide D. The route is readily scalable, and gram quantity of the final product D has been prepared

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

Practical Asymmetric Synthesis of Amathaspiramides B, D, and F

The practical asymmetric synthesis of amathaspiramides B, D, and F has been accomplished by utilizing an aza-Barbier allylation as the key step to construct the common intermediate with two adjacent stereocenters. A kinetically controlled cyclization to build the challenging thermodynamically less stable 8<i>R</i>-hemiaminal moiety is also important in the synthesis of amathaspiramide D. The route is readily scalable, and gram quantity of the final product D has been prepared

Copper-Catalyzed Asymmetric Hydroboration of α‑Dehydroamino Acid Derivatives: Facile Synthesis of Chiral β‑Hydroxy-α-amino Acids

The Cu-catalyzed asymmetric conjugate hydroboration reaction of β-substituted α-dehydroamino acid derivatives has been established, affording enantioenriched <i>syn</i>- and <i>anti</i>-β-boronate-α-amino acid derivatives with excellent combined yields (83–99%, dr ≈ 1:1) and excellent enantioselectivities (92–98% ee). The hydroboration products were expediently converted into valuable β-hydroxy-α-amino acid derivatives, which were widely used in the preparation of chiral drugs and bioactive molecules

Regio- and Stereoselective Cascades via Aldol Condensation and 1,3-Dipolar Cycloaddition for Construction of Functional Pyrrolizidine Derivatives

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 <b>7a</b>–<b>7w</b> and chiral <b>9a</b>–<b>9m</b>, 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

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