Total Synthesis of Natural (+)‐Lasonolide A

Abstract

The diastereoselective differentiation of two methylene groups of a cyclic acetal is a unique feature of a highly enantioselective total synthesis of natural (+)-lasonolide A (see picture), which is used to create the C22 quaternary asymmetric center. Other key strategies are the use of a sulfone–sulfide as a three-carbon fragment with two latent trans double bonds and macrocyclization through an intramolecular Horner–Emmons reaction. The novel 20-membered macrolide lasonolide A (11 ) was isolated from the Caribbean marine sponge Forcepia sp.1 Lasonolide A displayed antitumor activity by inhibiting the in vitro proliferation of A-549 human lung carcinoma cells and interdicting cell adhesion in a cell assay for the detection of signal-transduction agents.2 The relative stereochemistry of lasonolide A was originally proposed incorrectly based on extensive 2D NMR spectroscopic studies. Its structure was later revised as 1, with the stereochemistry of the hydroxy-substituted epimerizable C28 center and the absolute configuration shown, based on synthetic studies.3, 4 The intriguing structural features and significant biological activity of this natural product led us to undertake its total synthesis. Herein, we describe a highly enantioselective total synthesis of the natural (+)-lasonolide A (1). Retrosynthetically, we envisaged that double bonds could be introduced at C25 by a Wittig olefination of 27, at C2 by an intramolecular Horner–Emmons reaction of the α,β-unsaturated aldehyde derived from 25, and at C14 and C17 by the Julia–Kocieński sulfone-coupling protocol5 (Scheme 3). Formation of the two cis-2,6-disubstituted tetrahydropyran rings by iodoetherification of 7 in the case of the A ring (Scheme 1) and by the intramolecular Michael addition of 19 in the case of the B ring (Scheme 2) was planned, and the choice of protecting groups turned out to be crucial for high stereoselectivity to be observed in these transformations. It was planned to install the C22 quaternary chiral center through the thermodynamic equilibration of 4. To secure subunit 16 with the tetrahydropyran ring A, the known alcohol 26 was oxidized and then allylated with the allylboronate (R,R)-3 of Roush et al.7 to give the homoallylic alcohol 4 with 78 % ee (Scheme 1). The next step was contrived to differentiate the two methylene groups of the 1,3-dioxane ring diastereoselectively and put in place the C22 quaternary stereogenic center. Based on the presumed increased thermodynamic stability caused by hydrogen bonding between the axial hydroxymethyl group and the two oxygen atoms of the acetal as suggested in 6, the tandem conversion of 4 into the benzylidene 5 was explored extensively under a variety of acidic conditions. A remarkable result was observed when 4 was treated with benzaldehyde in the presence of trifluoroacetic acid (4 equiv). This reaction furnished a 5:1 separable mixture of the desired benzylidene 5 and the diastereomeric acetal with the hydroxymethyl group in an equatorial position, in 72 % combined yield. Two other diastereomers in which the benzylidene acetal was formed with the two primary hydroxy groups were produced in 24 % combined yield. After one recycling step with the undesired diastereomeric benzylidenes, compound 5 was produced in a total yield of 82 %. Swern oxidation8 of 5, followed by a second asymmetric allylation, this time with (S,S)-3, gave the alcohol 7 with an enhanced ee value of 91 %. It was found that the cyclic acetal protecting group was beneficial for the stereoselective formation of ring A. Compound 7 underwent cyclization in the presence of iodine to afford a 27:1 mixture of the cis-2,6-disubstituted tetrahydropyran 8 and the corresponding trans isomer. The iodide 8 was subjected to a reaction sequence involving substitution, ozonolysis, a reductive workup, and removal of the benzylidene group by hydrogenolysis. The primary and secondary hydroxy groups of the resulting triol 9 were differentially silylated with TBSCl and TESOTf, respectively, and the benzoate group was then hydrolyzed to provide the alcohol 10. a) (COCl)2, DMSO, CH2Cl2, −78 °C, then Et3N, −78→0 °C; b) (R,R)-3, 4-Å MS, PhMe, −78 °C→RT; 2 n NaOH, 0 °C, 86 % (for steps a and b); c) PhCHO (3 equiv), CF3CO2H (4 equiv), PhMe, −20→0 °C, 82 % (after one recycling step); d) (S,S)-3, 4-Å MS, PhMe, −78 °C→RT; 2 n NaOH, 0 °C, 77 % (for steps a and d); e) I2, K2CO3, MeCN, −30→−20 °C, 95 %; f) BzONa, NMP, 100 °C, 97 %; g) O3, NaHCO3, MeOH, −78 °C; NaBH4, 0 °C, 96 %; h) H2, 10 % Pd/C, HOAc, MeOH, room temperature, 89 %; i) TBSCl, imidazole, DMF, 0 °C, 95 %; j) TESOTf, 2,6-lutidine, CH2Cl2, 0 °C, 98 %; k) K2CO3, MeOH, room temperature, 91 %; l) Dess–Martin periodinane, pyridine, CH2Cl2, room temperature; m) 13, DEAD, Ph3P, THF, 0 °C, 81 %; n) (NH4)6Mo7O24⋅4 H2O, H2O2, phosphate buffer (pH 7.6), THF, EtOH, room temperature; o) 14, DEAD, Ph3P, THF, 0 °C, 75 % (for steps n and o); p) KHMDS, DME, −70 °C→RT, 95 % (for steps l and p); q) p-TsOH⋅H2O, MeOH, room temperature; r) TBSCl, imidazole, DMF, room temperature, 88 % (for steps n, q, and r). DMSO=dimethyl sulfoxide, MS=molecular sieves, Bz=benzoyl, NMP=1-methyl-2-pyrrolidinone, TBS=tert-butyldimethylsilyl, DMF=N,N-dimethylformamide, TES=triethylsilyl, Tf=trifluoromethanesulfonyl, DEAD=diethyl azodicarboxylate, HMDS=bis(trimethylsilyl)amide, DME=1,2-dimethoxyethane, Ts=toluenesulfonyl. We chose the disulfone equivalent 15 as a suitably functionalized substrate for the introduction of the three carbon atoms required in the target fragment in addition to those present in the alcohol 10 and the later introduction of the trans double bonds at C14 and C17. The diol 12 was treated with the tetrazolethiol 13 under Mitsunobu conditions, and the product was oxidized to the corresponding sulfone and then converted into the sulfone–sulfide 15 through a second Mitsunobu reaction with the thiazolethiol 14. The coupling of the aldehyde 11, derived from 10, with 15 was carried out in the presence of KHMDS to give the expected diastereomeric alkenes (trans/cis 31:1), which were separated by chromatography. The synthesis of the subunit 16 was completed by oxidation and protecting-group manipulation of the trans olefinic sulfide. Whereas the heptamolybdate oxidation of the sulfide to the sulfone under normal conditions9 proceeded very slowly with partial desilylation, the reaction in the presence of a phosphate buffer was efficient and reached completion within a few hours. The synthesis of subunit 23, which contains tetrahydropyran B, started with the p-methoxybenzylation of the known alcohol 17,10 followed by oxidative cleavage and asymmetric allylation according to the method of Brown et al.11 to yield the homoallylic alcohol 18, no diastereoisomers of which could be isolated in appreciable amounts (Scheme 2). After oxidative cleavage of the double bond and conversion of the resulting aldehyde into conjugated ethyl esters (trans/cis 24:1), the trans isomer was subjected to silylation of the alcohol functionality and oxidative removal of the PMB protecting group to furnish the hydroxyester 19. The intramolecular Michael addition of 19 produced the cis-2,6-disubstituted tetrahydropyran 20 as a single stereoisomer. Compound 20 was reduced to the corresponding aldehyde and then treated under olefination conditions to give the expected conjugated esters (trans/cis 22:1). The trans isomer was then sequentially reduced, debenzylated, and monosilylated to afford the alcohol 21. Swern oxidation of 21 followed by olefination with the trifluoroethyl phosphonate of Still and Gennari12 provided the conjugated ester 22 (cis/trans 6.6:1). As all attempts at the desilylation of TIPS-protected lasonolide A proved abortive in the last stage of our synthesis, the TIPS group of the cis conjugated ester 22 was exchanged for a TBS group, and the resulting ester was reduced to the aldehyde to yield the tetrahydropyran subunit 23. a) NaH, PMBCl, nBu4NI, DMF, THF, room temperature, 97 %; b) OsO4, NaIO4, H2O, THF, room temperature; c) (−)-Ipc2BCH2CHCH2, Et2O, −78 °C; 3 n NaOH, H2O2, room temperature, 74 % (for steps b and c); d) Ph3PCHCOOEt, PhH, reflux, 87 % (for steps b and d); e) TIPSOTf, 2,6-lutidine, CH2Cl2, 0 °C, 98 %; f) DDQ, H2O, CH2Cl2, room temperature, 87 %; g) NaH, THF, −78→−20 °C, 81 %; h) DIBAL, CH2Cl2, −78 °C; i) EtO2CCH2PO(OEt)2, NaH, THF, −78 °C, 89 % (for steps h and i); j) DIBAL, CH2Cl2, −78 °C, 91 %; k) Li, NH3 (liq), THF, −78 °C, 87 %; l) NaH, TBSCl, THF, 0 °C, 94 %; m) (COCl)2, DMSO, CH2Cl2, −78 °C, then Et3N, −78→0 °C; n) MeO2CCH(Me)PO(OCH2CF3)2, KHMDS, [18]crown-6, THF, −78 °C, 79 % (for steps m and n); o) TBAF, THF, room temperature; p) TBSOTf, 2,6-lutidine, CH2Cl2, 0 °C; q) DIBAL, CH2Cl2, −78 °C, 88 % (for steps o–q). PMB=p-methoxybenzyl, Ipc=isopinocamphenyl, TIPS=triisopropylsilyl, DDQ=2,3-dichloro-5,6-dicyano-1,4-benzoquinone, DIBAL=diisobutylaluminum hydride, TBAF=tetrabutylammonium fluoride. A mixture of the C3–C14 and C15–C25 subunits 16 and 23 was treated with LiHMDS to give a mixture of the coupling product 24 and its cis isomer at the newly formed double bond in a >20:1 ratio (Scheme 3). As the trans,trans-2,4-dienyl carboxylic acid prepared from 24 and substituted with a hydroxy group at C21 was resistant to macrolactonization in our hands, compound 24 was converted into the phosphonoacetate 25 so that a Horner–Emmons olefination could be employed for the macrocyclization. After removal of the two sterically less hindered TBS groups of 25, the resulting diol was subjected to allylic oxidation and cyclization mediated by K2CO3 in the presence of [18]crown-613 to furnish the macrolactone 26 smoothly. Compound 26 was then oxidized to the aldehyde 27. The C26–C35 side chain required for the construction of the complete lasonolide A skeleton was obtained as the phosphonium salt 30 from the known acetonide 2814 and alcohol 2915 by acid-mediated esterification, followed by silylation and nucleophilic substitution with PPh3. The Wittig olefination of 27 and 30 was most effective in the presence of KHMDS, and the protected lasonolide A 31 was desilylated uneventfully to produce the natural (+)-lasonolide A (1), all physical and spectroscopic data of which were identical to those reported in the literature.1, 3 a) LiHMDS, DME, −70 °C→RT, 82 %; b) HO2CCH2PO(OEt)2, DCC, DMAP, CH2Cl2, room temperature, 94 %; c) PPTS, MeOH, room temperature, 91 %; d) MnO2, EtOAc, room temperature; e) K2CO3, [18]crown-6, PhMe, 70→80 °C, 71 % (for steps d and e); f) Dess–Martin periodinane, pyridine, CH2Cl2, room temperature; g) p-TsOH⋅H2O, PhMe, room temperature, 85 %; h) TESOTf, 2,6-lutidine, CH2Cl2, 0 °C; i) Ph3P, MeCN, reflux, 88 % (for steps h and i); j) KHMDS, THF, −60 °C, 86 % (for steps f and j); k) HF⋅py, pyridine, THF, room temperature, 87 %. DCC=1,3-dicyclohexylcarbodiimide, DMAP=4-dimethylaminopyridine, PPTS=pyridinium p-toluenesulfonate, py=pyridine. In summary, we have reported a highly enantioselective total synthesis of natural (+)-lasonolide A. The synthesis is characterized by a diastereoselective differentiation step to create the C22 quaternary asymmetric center, the development of the sulfone–sulfide 15 as a three-carbon fragment with two latent trans double bonds, cyclizations to form the two cis-2,6-disubstituted tetrahydropyrans, and an intramolecular Horner–Emmons reaction to effect macrocyclization. The longest linear synthetic sequence exploited the ready availability of the alcohol 17 in 26 steps and 7.4 % overall yield.