Enantioselective Total Synthesis of (−)-Cephalotanin B

Cephalotaxus diterpenoids are attractive natural products with intriguing molecular frameworks and promising biological features. As a structurally unusual member, (−)-cephalotanin B possesses an extraordinarily congested heptacyclic skeleton, three lactone units, and nine consecutive stereocenters. Herein, we report an enantioselective total synthesis of (−)-cephalotanin B based on a divergent asymmetric Michael addition reaction, a novel Pauson–Khand/deacyloxylation process discovered in the development of a second-generation stereoselective Pauson–Khand reaction protocol, and an epoxide-opening/elimination/dual-lactonization cascade to construct the challenging propeller-shaped A–B–C ring system as key transformations.     

A Concise Enantioselective Total Synthesis of (−)-Deoxoapodine

We have established a highly convergent 10-step route for the total synthesis of (−)-deoxoapodine, which is a hexacyclic aspidosperma alkaloid. The quaternary C5 center of the characteristic tetrahydrofuran ring was constructed by a chiral-phosphoric-acid-catalyzed enantioselective bromocycloetherification in a 5-endo fashion and subsequent allylation by using the Keck protocol. Construction of the aspidosperma skeleton features the formation of a nine-membered lactam by a catalytic C−H palladation/alkylation cascade at the indole 2-position and an iron-catalyzed oxidative transannular reaction at a late-stage of the synthesis.     

Enantioselective syntheses of (+)- and (−)-brazilin

Two enantiomers of brazilin were prepared in 9 steps from 7-hydroxychroman-4-one using the AD-mix-α and AD-mix-β-directed enantioselective dihydroxylation of 3-(4-hydroxy-3-methoxyphenyl)-2H-chromen-7-ol as a key step.     

Enantioselective Total Synthesis of (−)-Finerenone Using Asymmetric Transfer Hydrogenation

(−)-Finerenone is a nonsteroidal mineralocorticoid receptor antagonist currently in phase III clinical trials for the treatment of chronic kidney disease in type 2 diabetes. It contains an unusual dihydronaphthyridine core. We report a 6-step synthesis of (−)-finerenone, which features an enantioselective partial transfer hydrogenation of a naphthyridine using a chiral phosphoric acid catalyst with a Hantzsch ester. The process is complicated by the fact that the naphthyridine exists as a mixture of two atropisomers that react at different rates and with different selectivities. The intrinsic kinetic resolution was converted into a kinetic dynamic resolution at elevated temperature, which enabled us to obtain (−)-finerenone in both high yield and high enantioselectivity. DFT calculations have revealed the origin of selectivity.     

Stereospecific Synthesis of (−)-β-Turmerone and (−)-Bisacurol

The structure of (+)-β-turmerone ((+)- 1a ), a constituent of the rhizomes of Curcuma longa Linn. , and Curcuma xanthorriza, is established as (1′R,6S)-2-methyl-6-(4′-methylenecyclohex-2′-en-1′-yl)hept-2-en-4-one by synthesis of its enantiomer (−)- 1a , and of the corresponding (1′S,6S)-diastereoisomer (+)- 1b as well. In a stereospecific seventeen-step procedure, the monoterpene diols 2a and 2b of well-established configuration are converted into the target compounds (−)- 1a and (+)- 1b , respectively. Moreover, (−)-bisacurol (−)- 3a (II), the enantiomer of another bisabolane sesquiterpene derived from Curcuma xanthorriza, is obtained as a single stereoisomer and shown to be (1′S,6R)-2-methyl-6-(4′-methylenecyclohex-2′-en-1′-yl)hept-2-en-4-ol, the relative configuration at the remaining OH-substituted chiral center C(4) still being unknown.     

Synthesis and some transformations of (−)-carveol

Reduction of the oxo group in (?)-carvone with LiAlH₄, NaBH₄, and (i-Bu)₂AlH was performed. It was found that the reduction with the system CeCl₃ · 7 H₂O-NaBH₄ in methanol at 20°C is the most practical procedure for the synthesis of (?)-carveol. Solvolysis of (?)-carvyl methanesulfonate gave products of S_N2 and S_N2′ replacement of the methylsulfonyloxy group, the latter slightly prevailing. Overman rearrangement of (?)-carveol resulted in the formation of the corresponding trichloroacetamide derivative, and intramolecular iodoetherification of the title compound afforded 6-iodomethyl-2,6-dimethyl-7-oxabicyclo[3.2.1]oct-2-ene.     

Synthesis of (−)-Dihydroraputindole D by Enantioselective Benzoylation of a 1,3-Diol Intermediate

The enantioselective synthesis of (−)-dihydroraputindole D is reported. The key step is the desymmetrizing benzoylation of a prochiral 1,3-diol employing Trost′s ProPhenol catalyst system, which has been applied for the first time to a cyclic molecule carrying geminal hydroxymethyl groups. The cyclopenta[f]indoline system was assembled by Au(I)-catalyzed cyclization of an alkynylated indoline precursor. (−)-Dihydroraputindole D was obtained in 17 steps and 8% overall yield starting from dihydroxyacetone. In combination with quantum chemical calculations of the ECD spectra, our synthesis allowed us to determine the absolute configuration (5S,7R) of the natural product (+)-raputindole D from the Rutaceous plant Raputia simulans.     

Total Synthesis of (−)-Rotundone and (−)-epi-Rotundone from Monoterpene Precursors

The first total synthesis of (−)-rotundone has been accomplished from (+)-(R)-limonene and therefore for the first time from an unrelated monoterpene instead of modifying structurally closely related sesquiterpene precursors such as α-guaiene. Challenges such as intermediates with stereocenters prone to epimerization by enolization were overcome by designing a β-methyl-keto route starting from (+)-(R)-limonene which finally gave (−)-rotundone by Nazarov cyclization of a precursor 13a . Diastereomer (−)-epi-rotundone was separated from (−)-rotundone chromatographically. An alternative route from rac-citronellal provided a diastereomer mixture of racemic Nazarov precursor 13 through a TRIP-catalyzed intramolecular aldolization, thus indicating that the Nazarov cyclization precursor 13a is in principle accessible from (−)-(S)-citronellal. The 11-step synthesis from (+)-(R)-limonene with ca. 1 % overall yield confirmed the absolute configuration of (−)-rotundone and provided samples of good olfactory quality.     

Synthesis of (+)- and (−)-Phaselic Acid

The syntheses of both enantiomers of phaselic acid (2-O-caffeoylmalate) are described. The previously unreported acetate-protected caffeic acid anhydride was used with appropriately protected malic acid derivatives as coupling partners to provide fully protected phaselic acid. Sequential unmasking of the protecting groups afforded phaselic acid in an acceptable overall yield.

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Enantioselective synthesis of (−)-γ-jasmolactone

The title compound was prepared in seven steps starting from the commercially available 4-ketopimelic acid. The key step features an enantioselective lactonization promoted by PPL.     

Enantioselective synthesis of the quinolizidine alkaloids (+)-myrtine and (−)-epimyrtine

The enantioselective synthesis of (+)-myrtine 1 and (−)-epimyrtine 2 is described starting from (S)-2-(2-hydroxypropyl)allyltrimethylsilane 4 using an intramolecular allylsilane N-acyliminium ion cyclization.     

First Enantioselective Synthesis of Daphneticin

An enantioselective total synthesis of chiral daphneticin is reported firstly.     

Synthesis of (−)‐Isofagomine

Abstract

1,3‐Dipolar cycloaddition of N‐benzyl nitrone 2 to D‐threo δ‐lactone 15 proceeded with excellent stereoselectivity to provide only one adduct 16. Cycloadduct 16 was subsequently subjected to a sequence of reactions involving rearrangement to γ‐lactone, glycolic cleavage/reduction, protection of the terminal hydroxymethyl group, reduction of the lactone, desilylation/mesylation, and hydrogenolysis of the N‐O bond providing (?)‐isofagomine and its N‐substituted derivatives. The biologic activity of N‐substituted (?)‐isofagomines toward commercially available α‐ and β‐glucosidases, α‐D‐mannosidase, α‐L‐fucosidase, β‐D‐glucuronidase, and β‐D‐galactosidase was tested.     

Total Synthesis and Structural Assignment of (−)-Fusaequisin A

(−)-Fusaequisin A is an irregularly assembled polyketide isolated from the ascomycete Fusarium equiseti. Fusaequisin A shares a carbon backbone with curvicollide C from the ascomycete Podospora curvicolla but its absolute configuration remained hitherto unsettled. Herein, we document the total synthesis of (−)-fusaequisin A and its 4-O-desmethyl derivative following a central-to-lateral building block strategy. Catalytic asymmetric Claisen rearrangement, Julia-Kocienski olefination and olefin cross-metathesis served as key C/C-connecting transformations. The constitution and absolute configuration of (−)-fusaequisin A was deduced and the original structural assignment was adjusted.     

Enantioselective synthesis of γ-lactones from thioglycolic acid: Syntheses of (−)-muricatacin and 5-epi-(−)-muricatacin

An approach for the enantioselective synthesis of functionalized γ-lactones and its application to the syntheses of (−)-muricatacin 1a and 5-epi-(−)-muricatacin 1b is reported. A sequential oxidation of the intermediate 4 with m-chloroperoxybenzoic acid was conducted to realize the reaction mechanism.     

Synthesis of Morpholine-Based Analogues of (−)-Zampanolide and Their Biological Activity

We describe the convergent synthesis of three prototypical examples of a new class of analogues of the complex, cytotoxic marine macrolide (−)-zampanolide that incorporate an embedded N-substituted morpholine moiety in place of the natural tetrahydropyran ring. The final construction of the macrolactone core was based on a high-yielding intramolecular HWE olefination, while the hemiaminal-linked side chain was elaborated through a stereoselective, BINAL-H-mediated addition of (Z,E)-sorbamide to a macrocyclic aldehyde precursor. The synthesis of the common functionalized morpholine building block involved two consecutive epoxide openings with tosylamide and the product of the first opening reaction, respectively, as nucleophiles. Of the three morpholino-zampanolides investigated, the N-acetyl and the N-benzoyl derivatives both exhibited nanomolar antiproliferative activity, thus being essentially equipotent with the natural product. In contrast, the activity of the N-tosyl derivative was significantly reduced.     

Concise Total Synthesis of (−)-Quinocarcin Enabled by Catalytic Enantioselective Reductive 1,3-Dipolar Cycloaddition of Secondary Amides

A concise asymmetric total synthesis of (−)-quinocarcin has been accomplished with high step economy from commercially available starting materials. A catalytic enantioselective reductive 1,3-dipolar cycloaddition reaction of N-heteroaryl secondary amides with reactive dipolarophiles using iridium/copper relay catalysis was developed to prepare the key chiral pyrrolidine intermediate with three stereocenters. This protocol features excellent regio-, exo- and enantioselectivities, broad substrate scope, and good functional group tolerance. The high efficiency was also ensured by a Rh^III-catalyzed C−H activation/cyclization and a tandem diastereoselective hydrogenation/cyclization to construct the tetrahydroisoquinoline-pyrrolidine tetracyclic core unit of quinocarcin.     

Total Synthesis of (−)-Glaucocalyxin A

A practically useful method for the formation of the highly oxygenated bicyclo[3.2.1]octane ring system through Mn(OAc)₃-mediated radical cyclization of alkynyl ketones was developed, which opens up a new avenue for the total synthesis of a number of highly oxidized diterpenoids. Application of this method enabled the first total synthesis of (−)-glaucocalyxin A. Other salient features of the synthesis include a highly enantioselective conjugate addition/acylation cascade reaction, a Yamamoto aldol reaction, and an intramolecular Diels–Alder reaction to assemble the A/B ring system.     

A Stereoselective Synthesis of (−)-Endo-Brevicomin

A stereoselective synthesis of (1S,5R,7R) (-)-endo-brevicomin by employing Sharpless kinetic resolution method has been described.     

Bioinspired Synthesis of (−)-PF-1018

The combination of electrocyclizations and cycloadditions accounts for the formation of a range of fascinating natural products. Cascades consisting of 8π electrocyclizations followed by a 6π electrocyclization and a cycloaddition are relatively common. We now report the synthesis of the tetramic acid PF-1018 through an 8π electrocyclization, the product of which is immediately intercepted by a Diels–Alder cycloaddition. The success of this pericyclic cascade was critically dependent on the substitution pattern of the starting polyene and could be rationalized through DFT calculations. The completion of the synthesis required the instalment of a trisubstituted double bond by radical deoxygenation. An unexpected side product formed through 4-exo-trig radical cyclization could be recycled through an unprecedented triflation/fragmentation.