Synthesis of biselyngbyolide B and its c21-c22 z-isomer

In 2009, K suenaga et al Isolated a new 18 membered macrolide, biselyngbyaside (Figure 1, 1), from marine cyanobacteria (org Lett 2009, 11, 2421) Subsequently, several macrolides were isolated, and glycosylated on 3-OH The common structural features of these compounds include conjugated e at C12 and C14, e-diene at C8, trisubstituted E-double bond and m-diene in side chain There are CIS, CIS triol, ene glycol or cis-1,5-diol functional groups in C3-C7 region Biological studies showed that biselyngbyide (1) and biselyngbyide B (2) showed significant growth inhibitory activity, inhibited the production of osteoclasts induced by RANKL and induced the apoptosis of mature osteoclasts In addition, biselyngbyides can also inhibit the activity of SERCA X-ray analysis shows that the interaction of diene and side chain with SERCA is particularly important Recently, the team of Martin E Maier of Eberhard Carls University in Tubingen, Germany reported the total synthesis of biselyngbiolide B and its c21-c22 z-isomer (DOI: 10.1021/acs.job.8b00298) on J org Chem Figure 1 The structures of biselyngbyiades and biselyngbyilides (source: J org Chem.) have attracted the attention of organic chemists due to their interesting structures and potential biological activities The author previously published the synthesis of c1-c13 fragments of these compounds (synlett 2011, 3002), including asymmetric Propargylation of propionic acid derivatives and chain extension under Wittig reaction and brown allylation The Chandrasekhar team then reported the synthesis of c5-c23 segments of biselyngbyide (Tetrahedron lett 2013, 54, 252) Recently, a more concise synthesis route of c1-c13 fragment has been reported (chem Commun 2018, 54, 241-243) The suenaga team completed the full synthesis of biselyngbyolide a (4) (org Lett 2014, 16, 2858), biselyngbyolide B (2) (org Lett 2016, 18, 2047) and biselyngbyolide (1) (J org Chem 2017, 82, 6770) It has been proved that the introduction of glycosyl moiety in the early stage is very important for the synthesis of 1 Goswami et al Also completed the total synthesis of biselyngbyolide B (2) (org Lett 2016, 18, 1908.) The common feature of the synthesis of macrolides is that the c13-c14 bond is constructed by intramolecular cross coupling to form macrolides The reverse synthesis of biselyngbyolide B (2) was analyzed as follows (scheme 1): the conjugated diene was constructed by cross coupling reaction, and the molecular closed-loop was realized by macrolides (Yamaguchi or Mitsunobu lactones) or intramolecular cross coupling The difficulty of synthesis may come from the introduction of allyl hydroxyl groups at C3, C7 and C17 positions and the control of double bond configuration of C18 and C19; in addition, the diene with interval may be isomerized into conjugated diene under harsh conditions Therefore, we hope to construct c14-c23 fragment from cyclic precursor such as 11 The key problem in the previous synthesis of c1-c13 by our group is that the aldehyde [(s) - 2-methyl-5 - (trimethylsilyl) pent-4-alkynaldehyde] which is easy to racemize must be passed In order to avoid this situation, the author attempts to synthesize c1-c13 fragment 8 by cross decomposition of two terminal alkenes 9 and 10 Scheme 1 Inverse synthesis analysis of biselyngbyolide B (2) (source: J org Chem.) for the synthesis of c1-c13 fragment 10, as shown in the figure (scheme 2): the author obtained 14 from the reaction of compound 12 (org Lett 2007, 9, 849) reported in the literature with iodide 13 (org Lett 2006, 8, 3761) After removing the chiral auxiliary group and trimethylsilyl group, the terminal alkyne was hydrogenated with zirconium and iodized to obtain the corresponding vinyl iodine After des Martin oxidation, brown Allylation and alkyne propyl hydroxymethyl ether, the end alkene 10 was obtained, and then the other end alkene 18 was metabolized to 19 3-OH was protected by 2-methoxyethoxymethyl (MEM) Scheme 2 Synthesis of c1-c13 fragment (source: J org Chem.) for the synthesis of c14-c23 fragment, as shown in the figure (scheme 3): the author started from 2-hydroxypropionaldehyde 21 protected by mom, and reacted with 2-methylallylsilane 22 for hosomi Sakurai reaction to obtain alcohol 23 containing vinyl silane Then, the functional dihydropyran 25 was obtained by PRINS reaction of 23 with hydroxypropanal derivative 24 The CIS configuration of C2 and C4 was confirmed by NOESY spectrum After deprotection and oxidation, aldehydes 27 were obtained, and then alkynes 29 were obtained by reaction with dimethyl (1-diazo-2-oxpropyl) phosphonate (28) The removal of Mom gives halogen ether 32 as a single isomer (as opposed to the required configuration) 32 The ring opening was reduced by tert butyl lithium to produce dienol 33, and the vinylstantane 35 was obtained by hydrogenation of tin terminal alkyne under the protection of tbdps Scheme 3 Synthesis of c14-c23 fragment (source: J org Chem.) for the synthesis of compound 40, as shown in the figure below (scheme 4): the obtained vinyl stantane 35 is coupled with iodo olefin 20 through stile coupling, and the intermediate 37 is obtained by removing tervaloyl group, and then the ring opening acid 39 is obtained by oxidation and removing tbdps Macrolide 40 was obtained by intramolecular Mitsunobu reaction The key chemical shifts such as 17-h (about 5.48 ppm) were matched with the natural products, indicating that lactonization occurred at C17 Unfortunately, the mixed acetals at 3-OH can not be cut off after the author has tried various conditions, all of which make 40 decompose Scheme 4 Synthesis of compound 40 (cutC = copper (I) thiophene-2-carboxylate) (source: J org Chem.) for the synthesis of compound 47, as shown in the figure below (scheme 5): the author changes the closed-loop strategy of lactonization and hopes to use the closed-loop coupling reaction instead Firstly, the silicon ether of segment 35 was removed to obtain tributylstannyl triaenol 41, and alcohol 19 was protected by tbdps to obtain acid 44 containing vinyl iodide by dibal-h reduction and oxidation It then reacts with 41 to form ester 45 via Mitsunobu The lactone 46 was obtained by intramolecular still coupling, and the 21 Z isomer biselyngbyolide B (47) was obtained by deprotection By comparing the 13 C NMR data of 47, it is found that the chemical shifts of C23 and other carbon atoms are significantly different from those reported in the literature In particular, C23 of lactones 40, 46 and 47 was found at 12.9 ppm, while biselyngbyolide B (2) was 17.9 ppm Therefore, the author suspects that the pyran route for the synthesis of c14-c23 fragment gives the wrong c21-c22 double bond configuration Scheme 5 Synthesis of compound 47 (source: J org Chem.) in order to obtain the correct double bond isomer of c13-c23 fragment, the author started from the known vinyl stannate 48 (scheme 6), coupled with 4-bromocrotonate 49 to obtain compound 50 Dienol derivative 52 was synthesized by dibal-h reducing ester and toluene sulfonic acid esterification and liet 3bh treatment Tbdps was removed and aldehydes 54 was obtained by DESs Martin oxidation Then brown allylation was carried out to obtain enol 55 Then, under the action of Shiina reagent (2-methyl-6-nitrobenzoic anhydride, mNBA), carboxylic acid 44 was esterified with alcohol 55 to obtain ester 56 Then lactone 57 was obtained by intramolecular Heck reaction, and biselyngbyolide B (2) was obtained by removing the tbdps protecting group 1H and 13C NMR showed that the synthesized products were consistent with the separated natural products The cytotoxicity of L929, kb-3-1 and MCF-7 cell lines was also tested by three macrolides 40, 47 and 2 It was found that 40 (for all cell lines IC 50 > 100 μ mol) had no activity, 47 [IC 50 (μ mol): L929 = 25, kb-3-1 = 50, MCF-7 = 24] had weak activity, and biselyngbyolide (2) [IC 50 (μ mol): L929 = 1, kb-3-1 = 0.2, MCF-7 = 26] did show significant activity These results show that the side chain and molecular configuration are very important to its biological activity Scheme 6 The synthesis of biselyngbyolide B (2) (source: J org Chem.) conclusion: the author realized the intramolecular closed-loop of c1-c13 and c14-c23 fragments by palladium catalyzed intramolecular heck coupling reaction, and completed the synthesis of 18 membered macrolide biselyngbyolide B (2) and its c21-c22 z-isomer The key step is asymmetric allynylation, brown Allylation and cross metathesis of 19 and 44 diallyl equivalents in the synthesis of c1-c13 fragment Preliminary biological studies have shown that the configuration of side chain double bonds is essential for cytotoxicity Corresponding author: Martin E Maier