Presentation on theme: "Total Synthesis of (+)-Sorangicin A"— Presentation transcript:
1 Total Synthesis of (+)-Sorangicin A Amos B. Smith, III,* Shuzhi Dong, Jehrod B. Brenneman, and Richard J. FoxDepartment of Chemistry, Laboratory for Research on the Structure of Matter, and Monell Chemical Senses Center,University of Pennsylvania, Philadelphia, Pennsylvania 19104Amanda Pester, Lucy Sung, Ben WilliamsCHEM311/511 – Dr. William M. MalachowskiDecember 8th, 2009J. AM. CHEM. SOC. 2009, 131, 12109–12111
2 INTRODUCTIONSorangicin A – macrolide antibiotic isolated from myxobacteria Sorangium cellulosumFound to be highly effective against a spectrum of both Gram positive and Gram-negative bacteriaInhibits bacterial RNA polymerase in both E.coli and S. aureus, while not affecting eukaryotic cells.Suggested to have increased conformational flexibility leading to better adaption to mutational changes in the binding pocket.Irschik, H; Wray, V.; Irschik,H.; Reichenbach, H, J. Antibiot. 1987, 40, 7
3 STRUCTURE AND CHALLENGES 31-member macrolactone ring & 15 stereogenic centersSignature dioxabicyclo[3.2.1]octane(Z,Z,E)-trienoate linkageInstable to reagents such as:Fluoride ionDDQDissolving metal sodium amalgam (reducing agent)Polar elements hydrophilic regionSensitive to the solvent and pH environments
4 Previously developed (–)-10-epi-6 SYNTHETIC PLANAlkynyl stannane 4 & Stannyl dienoate 5Scheme 1.bicyclic aldehyde (-)-2tetrahydropyran (-)-3(+) 10Previously developed (–)-10-epi-6
5 INVERSION OF C(10) STEROGENIC CENTER Scheme 2.(–)-10-epi (–)-7(Ley Oxidation/Luche reduction sequence)(–) (+)-8
9 From supplemental article – Synthesis of 2 Commercially available, but group chose to prepare in two steps from L-gulonic acid γ-lactone.
10 Oxidization under Parikh-Doering Conditions 18 was oxidized employing Parikh-Doering conditions
11 The first step of the Parikh-Doering oxidation is the reaction of dimethyl sulfoxide (DMSO), 1a & 1b, with sulfur trioxide, 2 at 0 oC or room temperature. Then, the intermediate 3 receives a nucleophilic addition from the alcohol to give the key alkoxysulfonium ion intermediate, 6, where the counterweight of positive charge is sulfate coordinated by pyridine.After that, the addition of at least 2 equivalents of base — typically triethylamine — will deprotonate the alkoxysulfonium ion to give the sulfur ylide 7. The base alse helps the charge counterweight to leave. In the last step, through a five-membered ring transition state, the sulfur ylide 7 decomposes to give the desired ketone or aldehyde 8.
12 Takai olefinationThe resulting sensitive aldehyde 21 was immediately subjected to Takai olefination w/o purificationUsed a mixture of dioxane/THF as a solvent system to improve selectivity as they had problems with their scale-upGot 22 and 23 in 52% and 16% yd respectivelyIn the reaction mechanism proposed by Takai, chromium(II) is oxidized to chromium(III) when replacing both halogen atoms. The geminal carbodianion complex thus formed reacts with the aldehyde in a 1,2-addition along one of the carbon to chromium bonds and in the next step both chromium bearing groups engage in an elimination reaction. In newman projection it can be seen how the steric bulks of chromium groups and the steric bulks of the alkyl and halogen groups drive this reaction towards anti elimination .
13 Sharpless dihydroxylation Lucy will explain mechanism laterGroup needed to differenatiate btw the two different olefins, they reasoned that the electron withdrawing and donating biases of the iodide and phenyl substituents would allow for chemoselective functionalization of the more electron rich olefin.Sharpless dihydroxylation of 22 at r.t. proceded only at the styrene moiety to generate the correspondin diol which was then reacted with NaIO4 getting 2
14 1st Julia-Kociénski Olefination **Back to Sorangicin A article1st Julia-Kociénski OlefinationScheme 3.65% yield after several recycles
16 Scheme 3. continued (Olefinations Galore!) (–) (–)-12
17 Testing the efficiency of the olefinations They tested the efficiency of the olefinations by reversing the coupling partners. Preparing aldehyde 15 from 11 in two steps.10 comes from Scheme 2.With these new conditions the reaction had much better yield (86%) and better stereocontrol giving the E-olefin 16.
19 Julia-Kocienski olefination And deprotection of TBS group with TBAF, THF step.
20 DeprotectionAnd deprotection of TBS group with TBAF, THF step.
21 Finishing up the synthesis To finish the synthesis of 1 the C(38)-C(39) bonds and the C(43)-O sigma bonds had to be formed.Why 4 or 5? Using 4, a alkynyl stannane, meant that the molecule suffered from extensive E/Z isomerization when purified. 5, a stannyl dienoate, was more stable. Used a Stille rxn with excess Ph2PO2NBu4 to suppress E/Z isomerization.
22 Stille ReactionStille Rxn with excess Ph2PO2NBu4 (12 eq) to suppress E/Z isomerization.
24 MacrocyclizationIn the rxns leading up to the macrocyclization there was the possibility of significant isomerization during the activation of the trienoacid, this was prevented by using mild conditions. Group looked at two different versions of mild cond’t.Yonemitsu modification of the Yamaguchi conditions, involving direct introduction at r.t. of DMAP at the outset w/o pre-formation of the mixed anhydrideEvans-modified Mukaiyama protocol, using NaHCO3 sodium bicarbonate at r.t.The problems with (1) is the reversiability of the Michael addition of DMAP or iodide to the activated trienoacid during the lactonization process.Also, halogen exchange which changed 20 to 21 (which is non-reactive as an activation agent for carboxylic acid couplingSo they used 22 which has a non-nucelophilic counterion (ie tetrafluoroborate) mitigating the undesired Michael add’n along with the inactivation pathwayAnd then deprotection.
25 Evans modified Mukaiyama 20-22Reagent 22 delivered macrocycle 19 in 85% yield and with minimum isomerization
26 DeprotectionNeeded to remove MOM, acetonide, and tert-butyl protecting groupsTried TFA in aq. 85 C as show in the Hofle group, the yields were highly substrate dependent 20% to 70%, however application to 19 led only to decompositionLooked at deprotecting the individual fragmentsMOM and acetonide groups could be removed under aq protic acid conditionsHydrolysis of the tert-butyl ester was less efficientTFA in anhydrous CH2Cl2 (dichloromethane) resulted in the destruction of the trienoateLewis acids such as B-bromocatecholboraneGood for MOM and acetonideSlow for tert-butylTMSOTf lead to decomposition on the whole macrolide , too reactiveNeeded mild deprotection conditions to prevent isomerization and/or decomposition due to the (Z,Z,E) – trienoateFound that TBSOTf, buffered with 2,6 – lutidine, was able to convert the tert-butyl ester to a TBS esterThe TBS ester was then treated with 4 N HCl in THF at r.t. for 24 h to obtain (+)-sorangicin A
28 Iriomoteolide 3a Why do people want to synthesize this molecule? It has potent anti-cancer activityPreliminary physiological properties disclosed show potent cytotoxicity against lymphomaWhat is it and where does it come from?From the microorganism, species AmphidinumThe Amphidinum strain HYA024 was found to produce cytotoxic compounds like iriomoteolides 1a-c and a rare 15-membered macrolide, iriomoteolide 3a (1)Nevado Group3a (1) has 8 sterogenic centers, 4 in allylic positionsCmpd 1 is the 1st member of a unique and unprecedented 15 member macrolide class
29 The retro synthetic approach to 1 involved four major disconections How is it synthesized?The retro synthetic approach to 1 involved four major disconectionsFragment 6 was planned to be added at the end with a Julia-Kocienski olefinationFor 3 and 4 an intermolecular esterification was plannedThe group hypothesized that the C2 symmetry of the diol precurser to 5 could be used to make the 1,5-diene by cross-metathesis (CM)/ring closing metathesis (RCM)Expected ring to be EE steroselective.
30 ALKYLATION USING EVAN’S AUXILIARY Scheme 2. Making building block 37
34 Scheme 2. continued910(8) Alternative synthesis of compound 9 starting with a TBS-protected alkyl iodide (8’) gave lower yields and poor diastereomeric ratios. The TBDPS to TBS swap was necessary to allow further functional group manipulations at a later stage of the synthesis.TBDPS -- ~100 times more stable than TBS
35 Synthesis of Reagent 3 Dance of the Protecting Groups
36 Synthesis of Reagent 3Wittig MechanismWittig Reaction
37 Synthesis of Reagent 3DIPT = diisopropyl tartrateSwern Oxidation
38 Synthesis of Reagent 3 Swern Oxidation Mechanism DMSOOxalyl chloride(COCl)2