Chemoenzymatic Synthesis and Biological Evaluation of (−)‐Conduramine C‐4

Abstract

Previously unreported (?)‐conduramine C‐4 was synthesized in six steps from a bacterial bromobenzene metabolite in 23% overall yield. The chemoenzymatic route involved toluene dioxygenase dihydroxylation, β‐epoxidation, epoxide ring‐opening, Staudinger reduction, radical debromination, and Amberlite‐ catalyzed hydrolysis. (?)‐Conduramine C‐4 and other related compounds synthesised were assayed for galactosidase‐activity inhibition against β‐D‐galactoside galactohidrolase isolated from Aspergillus oryzae.     

Total Synthesis of (−)-Albocycline

The macrolactone natural product (−)-albocycline is a promising antibiotic candidate for the treatment of both methicillin resistant Staphylococcus aureus (MRSA) and vancomycin-resistant strains. Herein we report a concise total synthesis of (−)-albocycline in 14 steps from commercially available methyl (R)-3-hydroxybutyrate. Novel key steps include the highly regio- and stereoselective reactions of chiral N-sulfinyl metallodienamines (NSMDs) with aldehydes and the Davis oxaziridine, in addition to the Horner–Wadsworth–Emmons olefination of N-sulfinyl imines.     

Microwave‐Promoted Acid‐Catalyzed Rearrangement of Morphinans—A High‐Yield Synthesis of R(−)‐Apomorphine

The microwave‐promoted acid‐catalyzed rearrangement of morphine (1), codeine (2), and thebaine (3) was investigated. In all cases, a significant improvement in the yields were achieved compared to the traditional techniques. R(‐)‐Apomorphine (4), which is a clinically important dopamine agonist, was synthesized from morphine (1) in 75% yield.     

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.     

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.     

Asymmetric Synthesis of (R)‐(−)‐Rhododendrol,the Aglycone of the Hepatoprotective Agent Rhododendrin

Abstract

Starting from 2,3‐O‐isopropylidene‐D‐glyceraldehyde (3) as chiral material, (R)‐(?)‐rhododendrol 2, the aglycone of the naturally occurring rhododendrin 1 was synthesized.     

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.     

Degradation of the Side Chain of (−)‐Sclareol: A Very Short Synthesis of nor‐Ambreinolide and Ambrox

Abstract

The synthesis of nor‐Ambreinolide (8) from (‐)‐sclareol (1) was carried out by treatment with KMnO₄‐Ac₂O and further alkaline hydrolysis. 8 was directly transformed into (‐)‐ambrox (11) by reduction with metal borohydride in the presence of Lewis acids.     

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.     

Enantioselective Synthesis and Racemization of (−)-Sinoracutine

Sinoracutine is a recently isolated alkaloid with unusual stereochemical and biological properties. It features an unprecedented tetracyclic 6/6/5/5 skeleton that bears an N-methylpyrrolidine ring fused to a cyclopentenone. Interestingly, both enantiomers of sinoracutine have been independently isolated from the same plant, yet the molecule does not appear to occur as a racemate. Here, we present a short synthesis of (−)-sinoracutine that relies on a highly diastereoselective Pauson–Khand reaction and a Mandai–Claisen reaction to install the quaternary stereocenter. Our work establishes the absolute configuration of the levorotatory isomer and suggests that the optical purity of sinoracutine varies in nature due to its gradual racemization. Experimental evidence supports this proposal, and a plausible mechanism for the racemization is provided.     

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 Protecting-Group-Free Synthesis of (−)-Salvinorin A

A concise enantioselective total synthesis of the neoclerodane diterpene (−)-salvinorin A is reported. The stereogenic center at C-12 was installed by catalytic asymmetric propargylation with excellent enantioselectivity, and the remaining six stereogenic centers were set up highly diastereoselectively under substrate control. As for our previous synthesis of racemic salvinorin A, two intramolecular Diels-Alder reactions were applied to generate the tricyclic core. A chemoselective Mitsunobu inversion of a syn 1,2-diol allowed for further streamlining of the original reaction sequence by two steps. Overall, (−)-salvinorin A was synthesized in only 16 steps starting from 3-furaldehyde with 1.4 % total yield. Furthermore, an alternative intramolecular Diels-Alder strategy employing a 2-bromo-1,3-diene moiety was investigated.     

Alternative Total Synthesis of (−)-Galanthamine Hydrobromide

Abstract

An alternative total synthesis of (?)-galanthamine (1) hydrobromide, employing ecofriendly amidation, oxidative coupling, and classical resolution strategies is accomplished.     

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 the scalemic form of alkaloid (−)-dipthocarpamine

The scalemic form of active alkaloid (−)-dipthocarpamine was synthesized by asymmetric oxidation ofN-isopropyl-N′-(methylthiohexyl)urea with hydrogen peroxide in the presence of vanadium(IV) complexes with chiral Shiff's bases. Translated fromIzvestiya Akademii Nauk. Seriya Khimicheskaya, No. 3, pp. 564–565, March, 2000.     

Synthesis of Z‐N‐Alkenylformamides

Commercially available difluorinated benzaldehyde was converted to the Z‐N‐alkenylformamides via Horner–Emmons olefination and Curtius rearrangement, followed by reduction with tri‐tert‐butoxy‐aluminohydride.     

Synthesis of 2,3‐Dihydroxy‐1‐Epilupinine

The 1,3‐dipolar cycloaddition of unsaturated D‐threo‐hexaldonolactone 3 and a six‐membered cyclic nitrone 11 led to a single adduct 15, which could be transformed into (1S, 2S, 3S, 9aS)‐2,3‐dihydroxy‐1‐hydroxymethyl‐quinolizidine 28 related to epilupinine via a reaction sequence involving rearrangement of the six‐membered lactone ring into a five‐membered one, removal of the terminal carbon atom from the sugar chain, cleavage of the N‐O bond, and the intramolecular alkylation of the nitrogen atom.      

Total Synthesis of (+)- and (−)-Ononitol

Abstract

A practical, five-step synthetic sequence for conversion of myo-inositol into enantiomerically pure (+)- and (?)-ononitols in 17% and 18% overall yield, respectively, has been developed.