Stereoselective synthesis of the C14-C24 degraded fragment of symbiodinolide

Symbiodinolide is a polyol macrolide isolated from the marine dinoflagellate Symbiodinium sp. in 2007. The C14-C24 fragment of symbiodinolide possessing the 17R/18R/21R absolute configuration, which was obtained as one of the degraded products of symbiodinolide, was synthesized stereoselectively from cis-2-butene-1,4-diol. The detailed comparison of the synthetic product with the degraded product in the spectroscopic data confirmed that the stereostructure of the C14-C24 fragment was 17R, 18R, and 21R.     

Determination of absolute configuration of C14−C23 fragment in symbiodinolide

The degradation product C14−C23 2 was obtained using ethenolysis with the 2nd-generation Hoveyda-Grubbs catalyst from 62-membered lactone in symbiodinolide (1). The absolute configurations of three chiral centers in fragment 2 were assigned as 17R, 18R, and 21R by a combination of J-based configuration analysis and the Mosher-Riguera method.     

Stereoselective synthesis and absolute configuration of the C33-C42 fragment of symbiodinolide

Cross-metathesis of methyl ester which was prepared from symbiodinolide with ethylene was performed to give the C33-C42 degraded fragment. This fragment was estimated to be (36S,40S)-diol by the modified Mosher method. Stereoselective synthesis of the (36S,40S)-diol and its diastereomer (36R,40S)-diol was achieved from l-aspartic acid. Synthetic bis-(S)- and (R)-MTPA esters which were derivatized from the (36S,40S)-diol exhibited spectroscopic data identical with those of bis-(S)- and (R)-MTPA esters derived from the degraded product. Thus, the absolute stereochemistry of the C33-C42 fragment was elucidated to be (36S,40S).     

Symbiodinolide, a novel polyol macrolide that activates N-type Ca channel, from the symbiotic marine dinoflagellate Symbiodinium sp.

A 62-membered novel polyol macrolide with a molecular weight of 2859 mu, symbiodinolide, was isolated from the symbiotic dinoflagellate Symbiodinium sp. Symbiodinolide exhibited a potent voltage-dependent N-type Ca²⁺ channel-opening activity at 7 nM and immediately ruptured the tissue surface of the acoel flatworm Amphiscolops sp. at 2.5 μM. The planar structure of symbiodinolide was elucidated by spectroscopic analysis and chemical degradations including hydrolysis and ethenolysis using the second-generation Grubbs' catalyst. Symbiodinolide was found to be a structural congener of zooxanthellatoxins. The relative stereochemistries of C26-C32, C44-C51, and C64-C66 parts, and the absolute stereochemistries of C69-73, C83-C103, and C3′-C18′ parts in symbiodinolide were established.     

Synthesis and structural determination of the C33-C42 fragment of symbiodinolide

Symbiodinolide (1) is a polyol macrolide with a molecular weight of 2859 mu. As one of the degradation reactions, cross-metathesis of 2, which is a methyl ester of 1, with ethylene was performed to give the C33-C42 degraded fragment 4. The absolute configuration of 4 was estimated to be (36S,40S) by Mosher method. Stereoselective synthesis of 4 was achieved in 14 steps from l-aspartic acid. Synthetic bis-(S)- and (R)-MTPA esters exhibited the spectroscopic data identical with those of bis-(S)- and (R)-MTPA esters derived from the degraded fragment 4. Thus, the absolute stereochemistry of 4 was elucidated to be (36S,40S).     

Determination of the absolute stereochemistry of lupane triterpenoids by fucofuranoside method and ORD spectrum

The absolute configurations of the secondary alcohols at C-3 position in betulinic acid and 3-epibetulinic acid have been unambiguously determined as S- and R-configurations, respectively, based on the fucofuranoside method. The absolute stereochemistry of 3α, 27-dihydroxylupen-20(29)-en-28-oic acid methyl ester, a potent topoisomerase II inhibitor, was determined to be 3R, 5R, 8R, 9R, 10R, 13R, 14S, 17S, 18R, and 19R by NMR and ORD spectroscopic studies.     

Highly Oxygenated Triterpenoids and Diterpenoids from Fructus Rubi (Rubus chingii Hu) and Their NF-kappa B Inhibitory Effects

During a phytochemical investigation of the unripe fruits of Rubus chingii Hu (i.e., Fructus Rubi, a traditional Chinese medicine named “Fu-Pen-Zi”), a number of highly oxygenated terpenoids were isolated and characterized. These included nine ursane-type (1, 2, and 4–10), five oleanane-type (3, 11–14), and six cucurbitane-type (15–20) triterpenoids, together with five ent-kaurane-type diterpenoids (21–25). Among them, (4R,5R,8R,9R,10R,14S,17S,18S,19R,20R)-2,19α,23-trihydroxy-3-oxo-urs-1,12-dien-28-oic acid (rubusacid A, 1), (2R*,4S*,5R*,8R*,9R*,10R*,14S*,17S*, 18S*,19R*,20R*)-2α,19α,24-trihydroxy-3-oxo-urs-12-en-28-oic acid (rubusacid B, 2), (5R,8R,9R,10R, 14S,17R,18S,19S)-2,19α-dihydroxy-olean-1,12-dien-28-oic acid (rubusacid C, 3), and (3S,5S,8S,9R, 10S,13R,16R)-3α,16α,17-trihydroxy-ent-kaur-2-one (rubusone, 21) were previously undescribed. Their chemical structures and absolute configurations were elucidated on the basis of spectroscopic data and electronic circular dichroism (ECD) analyses. Compounds 1 and 3 are rare naturally occurring pentacyclic triterpenoids featuring a special α,β-unsaturated keto-enol (diosphenol) unit in ring A. Cucurbitacin B (15), cucurbitacin D (16), and 3α,16α,20(R),25-tetrahydroxy-cucurbita-5,23- dien-2,11,22-trione (17) were found to have remarkable inhibitory effects against NF-κB, with IC₅₀ values of 0.08, 0.61, and 1.60 μM, respectively.     

Stereocontrolled total synthesis of (+)-concanamycin F: the strategic use of boron-mediated aldol reactions of chiral ketones

A highly stereocontrolled total synthesis of the 18-membered macrolide (+)-concanamycin F, a potent inhibitor of vacuolar ATPases, is described that proceeds in 5.8% yield over 26 steps. The three key fragments, C1-C13 vinyl iodide, C14-C22 vinyl stannane and C23-C28 aldehyde, were efficiently constructed using asymmetric boron-mediated aldol reactions of appropriate chiral ketone building blocks. The nature of the silyl protection of the C7/C9 hydroxyls proved to be critical for achieving macrocyclisation, with TES ethers being superior to a cyclic silylene derivative. Following a Liebeskind-Stille cross-coupling reaction between the C1-C13 vinyl iodide and C14-C22 vinyl stannane fragments to assemble the (12E,14E)-diene, a modified Yamaguchi macrolactonisation delivered the requisite 18-membered macrocyclic core. This advanced intermediate was also obtained by an alternative sequence using an esterification step to connect the C1-C13 and C14-C22 fragments followed by a Pd-catalysed intramolecular Stille reaction to install the (12E,14E)-diene. Conversion of the resulting macrocyclic intermediate into a methyl ketone then enabled a highly diastereoselective Mukaiyama aldol coupling of the derived silyl enol ether with the C13-C28 aldehyde fragment to install the fully elaborated side chain, whereby subsequent global deprotection of the resulting β-hydroxyketone under suitable conditions (TASF followed by p-TsOH) afforded (+)-concanamycin F.     

Enantioselective synthesis of aurisides A and B, cytotoxic macrolide glycosides of marine origin

The enantioselective synthesis of aurisides A and B, macrolide glycosides of marine origin, was achieved by a convergent approach. The C1-C9 segment 4 was prepared from (R)-pantolactone, and the C10-C17 segment 14 was synthesized from (R)-glycidyl trityl ether. The Nozaki-Hiyama-Kishi reaction between 4 and 14 and subsequent reactions gave seco acid 10, which was converted into the aglycon (3) of aurisides by construction of the 14-membered lactone and bromine-substituted conjugated diene. The glycosylation reaction of the aglycon provided aurisides A and B.     

Synthesis of brasilibactin A and confirmation of absolute configuration of β-hydroxy acid fragment

A synthesis of brasilibactin A, a cytotoxic siderophore from the actinomycete of Nocardia brasiliensis, and three unnatural diastereomers of the natural product is described. Four possible diastereomers of the β-hydroxy acid fragment were prepared via asymmetric aldol reactions and used to synthesize brasilibactin A and its diastereomers. Careful analysis of ¹H NMR data confirmed that brasilibactin A possesses the 17S,18R absolute stereochemistry.     

Synthesis of the C22-C37 segment of prorocentin

The synthesis of the C22-C37 segment of prorocentin, isolated from the dinoflagellate Prorocentrum lima, was achieved. Because the relative stereochemical relationship between C26 and other stereocenters (C28/C31/C32 established as R*/R*/R*) in the C22-C37 region of natural prorocentin has not yet been determined, both epimers at C26 of the C22-C37 segment were selectively constructed. The synthesis was based on a 5-exo epoxide ring opening reaction to form an oxolane (E-ring), Brown asymmetric methallylation to install the C26-stereocenter, acryloylation of the resulting alcohol, and ring-closing olefin metathesis to establish the Z-olefin at C23/C24.     

Agariblazeispirols A and B, an unprecedented skeleton from the cultured mycelia of the fungus, Agaricus blazei

Agariblazeispirols A and B, which have a unique steroidal skeleton, have been isolated from the cultured mycelia of Agaricus blazei (Agaricaceae). The absolute structure of Agariblazeispirol A was established to be (20S,22R,23R,24S)-13β,22:22,25-diepoxy-5-methoxy-14β-methyl-18-nor-des-A-ergosta-5,7,9,11-tetraen-23-ol by extensive 1D and 2D NMR spectral data, and X-ray analysis. The structure of Agariblazeispirol B was elucidated to be a stereoisomer of agariblazeispirol A at its carbon 22, (20S,22S,23R,24S)-13β,22:22,25-diepoxy-5-methoxy-14β-methyl-18-nor-des-A-ergosta-5,7,9,11-tetraen-23-ol by comparison of extensive 1D and 2D NMR spectral data with those of agariblazeispirol A. Both compounds showed a moderate circumvention of drug resistance on mouse leukemia P388/VCR cells.     

Total synthesis of diastereomeric marine butenolides possessing a syn-aldol subunit at C10 and C11 and the related C11-ketone

Two diastereomeric marine butenolides, (4S,10R,11R)- and (4S,10S,11S)-4,11-dihydroxy-10-methyldodec-2-en-1,4-olide, possessing a syn-aldol subunit at C10 and C11 have been efficiently synthesized by using a three-module coupling strategy. The enantiomeric syn-aldol modules prepared by the syn-selective aldol reaction of the norephedrine-derived chiral propionates were coupled with the chiral C3-C7 module via 1,3-dithiane bisalkylation. The butenolide ring was then installed via a high-yielding ring-closing metathesis (RCM) reaction. Oxidation of the diastereomeric C11-alcohols furnished the corresponding C11-ketones, which are produced by the same marine microorganism.     

2-Cyano-2-indolylpropanoic acid as a chiral derivatizing agent for the absolute configuration assignment of secondary alcohols and primary amines by 1H NMR and VCD

A convenient approach for the absolute configuration assignment of secondary alcohols in the (8R,1′R,2′S,5′R)-15,25, (8S,1′R,2′S,5′R)-15,25, (8R,1′R)-21–24, and (8S,1′R)-21–24 ester series, and of primary amines in the (8R,1′R)-32–37 and (8S,1′R)-32–37 amide series, by means of ¹H NMR and VCD spectroscopy, using 2-cyano-2-indolylpropanoic acid as a chiral derivatizing agent is presented. DFT calculations were carried out to demonstrate the anisotropic effect of the indole skeleton on the chiral alcohol or the amine fragment. Vibrational circular dichroism (VCD) measurements of the above series indicated a VCD bisignated couplet resulting from the interaction of the ester carbonyl group and the CN group. The absolute configuration assignments were further tested by X-ray diffraction analysis.     

Stereoselective synthesis of the C94-C104 fragment of symbiodinolide

Stereoselective synthesis of the C94-C104 fragment of symbiodinolide which is a polyol marine natural product with a molecular weight of 2860 has been accomplished. The synthetic route features Achmatowicz rearrangement and RuO₄-catalyzed dihydroxylation for the construction of the tetrahydropyran moiety and the dithiane addition to the aldehyde for the introduction of the side chain.     

Stereodivergent Synthesis and Stereochemical Reassignment of the C79–C104 Fragment of Symbiodinolide

We have synthesized eight possible diastereoisomers 3 a – h of the C79–C97 fragment of symbiodinolide ( 1 ) in a stereodivergent manner by utilizing a dithiane addition to the aldehyde as a key step. Comparison of the ¹³C NMR chemical shifts of the natural product 1 and the synthetic products 3 a – h indicated that the relative stereostructure of this fragment in symbiodinolide ( 1 ) is that represented in 3 a or f . We have stereodivergently synthesized eight possible diastereoisomers of the C94–C104 fragment 4 a – h , and we have compared their ¹³C NMR chemical shifts with those of the natural product, which established the relative stereochemistry of this fragment to be that described in diastereoisomers 4 a or e . By combining the stereostructural outcomes of the C79–C97 and C94–C104 fragments, we have proposed four candidate compounds of the C79–C104 fragment 2 a – d . We also synthesized diastereoisomers 2 a and b ( 2 a in the preceding article; Chem. Eur. J. 2015 , DOI: 10.1002/chem.201503880) by a Julia–Kocienski olefination and diastereoisomers 2 c and d by a Wittig reaction. By comparing the ¹³C NMR chemical shifts of natural symbiodinolide ( 1 ) with those of the synthetic products 2 a – d , we have reassigned the stereostructure of the C79–C104 fragment of natural product 1 to be that depicted in diastereoisomer 2 b .     

Synthesis of the C1-C12 acid fragment of amphidinolide T marine macrolides via SmI2-mediated enantioselective reductive coupling of aldehydes with a chiral crotonate

A new strategy for enantioselective assembly of the trisubstituted tetrahydrofuran ring has been established for synthesis of the C1-C12 acid fragment of amphidinolide T series marine macrolides. The key steps involve the SmI₂-mediated highly enantioselective reductive coupling of an aldehyde with the (1S,2R)-N-methylephedrine-derived crotonate to form the cis-3,4-disubstituted γ-butyrolactone and the subsequent BF₃-mediated 1,3-anti-selective allylation of the five-membered-ring oxocarbenium ion with allyltrimethylsilane. The desired C1-C12 acid fragment was obtained in >25% overall yield via a 9-step sequence.     

Ipertrofan Revisited—The Proposal of the Complete Stereochemistry of Mepartricin A and B

Being a methyl ester of partricin, the mepartricin complex is the active substance of a drug called Ipertrofan (Tricandil), which was proven to be useful in treatment of benign prostatic hyperplasia and chronic nonbacterial prostatitis/chronic pelvic pain syndrome. Nevertheless, no direct structural evidence on the stereochemistry of its components has been presented to date. In this contribution, we have conducted detailed, NMR-driven stereochemical studies on mepartricins A and B, aided by molecular dynamics simulations. The absolute configuration of all the stereogenic centers of mepartricin A and B was defined as 3R, 7R, 9R, 11S, 13S, 15R, 17S, 18R, 19S, 21R, 36S, 37R, and 38S, and proposed as 41R. The geometry of the heptaenic chromophore of both compounds has been established as 22E, 24E, 26E, 28Z, 30Z, 32E, and 34E. Our studies on mepartricin ultimately proved that partricins A and B are structurally identical to the previously described main components of the aureofacin complex: gedamycin and vacidin, respectively. The knowledge of the stereochemistry of this drug is a fundamental matter not only in terms of studies on its molecular mode of action, but also for potential derivatization, aiming at improvement of its pharmacological properties.     

Stereocontrolled synthesis of the C79-C96 fragment of symbiodinolide

The stereoselective synthesis of the C79-C96 fragment of symbiodinolide is described in which the spiroacetalization and Kotsuki coupling are the key steps.     

Die absolute Konfiguration des Spermin-Alkaloides Aphelandrin

The Absolute Configuration of the Spermine Alkaloid Aphelandrine The relative configuration of aphelandrine ( 1 ) was established by X-ray structure determination. The absolute configuration of the centers 11 and 18 was determined earlier by chiroptic measurements. Therefore, structure 1 with the configurations 11S, 17S, and 18S represents the absolute configuration of aphelandrine. In the presence of base, 1 was converted to (11S, 17R, 18R) orantine ( 2 ). The ¹H-NMR coupling constants between H? C(17) and H? C(18) (part of the dihydrofuran ring) are very much dependent on the substituent pattern of the amino N-atoms N(6) and N(10).