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Total Synthesis of (+)-Sorangicin A Amos B. Smith, III,* Shuzhi Dong, Jehrod B. Brenneman, and Richard J. Fox Department of Chemistry, Laboratory for Research.

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Presentation on theme: "Total Synthesis of (+)-Sorangicin A Amos B. Smith, III,* Shuzhi Dong, Jehrod B. Brenneman, and Richard J. Fox Department of Chemistry, Laboratory for Research."— Presentation transcript:

1 Total Synthesis of (+)-Sorangicin A Amos B. Smith, III,* Shuzhi Dong, Jehrod B. Brenneman, and Richard J. Fox Department of Chemistry, Laboratory for Research on the Structure of Matter, and Monell Chemical Senses Center, University of Pennsylvania, Philadelphia, Pennsylvania 19104 Amanda Pester, Lucy Sung, Ben Williams CHEM311/511 – Dr. William M. Malachowski December 8 th, 2009 J. AM. CHEM. SOC. 2009, 131, 12109–12111

2 INTRODUCTION I.Sorangicin A – macrolide antibiotic isolated from myxobacteria Sorangium cellulosum A.Found to be highly effective against a spectrum of both Gram positive and Gram-negative bacteria B.Inhibits bacterial RNA polymerase in both E.coli and S. aureus, while not affecting eukaryotic cells. C.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 (Z,Z,E)-trienoate linkage Instable to reagents such as: Fluoride ion DDQ Dissolving metal sodium amalgam (reducing agent) 31-member macrolactone ring & 15 stereogenic centers Polar elements  hydrophilic region  Sensitive to the solvent and pH environments Signature dioxabicyclo [3.2.1]octane

4 SYNTHETIC PLAN Scheme 1. bicyclic aldehyde (-)-2 tetrahydropyran (-)-3(+) 10 Previously developed (–)-10-epi-6 Alkynyl stannane 4 & Stannyl dienoate 5

5 INVERSION OF C(10) STEROGENIC CENTER Scheme 2. (–)-10-epi-6 (–)-7 (Ley Oxidation/Luche reduction sequence) (–)-7 (+)-8

6 Luche Reduction Mechanism (+)-8

7 (+)-8 (+)-9

8 1 o ALCOHOL TO SULFONE Mitsunobu Mechanism

9 Commercially available, but group chose to prepare in two steps from L-gulonic acid γ- lactone. From supplemental article – Synthesis of 2

10 Oxidization under Parikh-Doering Conditions


12 Takai olefination

13 Sharpless dihydroxylation

14 Scheme 3. 1 st Julia-Kociénski Olefination 65% yield after several recycles **Back to Sorangicin A article

15 Julia-Kociénski Olefination Mechanism (–)-11

16 (–)-11 (–)-12 Scheme 3. continued (Olefinations Galore!) 

17 Testing the efficiency of the olefinations

18 Preparing the aldehyde

19 Julia-Kocienski olefination

20 Deprotection

21 Finishing up the synthesis

22 Stille Reaction

23 Hydrolysis

24 Macrocyclization

25 Evans modified Mukaiyama

26 Deprotection Needed mild deprotection conditions to prevent isomerization and/or decomposition due to the (Z,Z,E) – trienoate Found that TBSOTf, buffered with 2,6 – lutidine, was able to convert the tert-butyl ester to a TBS ester The TBS ester was then treated with 4 N HCl in THF at r.t. for 24 h to obtain (+)- sorangicin A

27 Start of Other Article

28 Iriomoteolide 3a Why do people want to synthesize this molecule? It has potent anti-cancer activity Preliminary physiological properties disclosed show potent cytotoxicity against lymphoma What is it and where does it come from? From the microorganism, species Amphidinum The Amphidinum strain HYA024 was found to produce cytotoxic compounds like iriomoteolides 1a-c and a rare 15-membered macrolide, iriomoteolide 3a (1)

29 How is it synthesized? The retro synthetic approach to 1 involved four major disconections Fragment 6 was planned to be added at the end with a Julia-Kocienski olefination For 3 and 4 an intermolecular esterification was planned The 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)

30 ALKYLATION USING EVAN’S AUXILIARY Scheme 2. Making building block 3 7


32 Sharpless Asymmetric Dihydroxylation Mechanism

33 Heterogeneous catalyst

34 (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 9 10 Scheme 2. continued

35 Synthesis of Reagent 3 Dance of the Protecting Groups

36 Synthesis of Reagent 3 Wittig Reaction Wittig Mechanism

37 Synthesis of Reagent 3 DIPT = diisopropyl tartrate Swern Oxidation

38 Synthesis of Reagent 3 Swern Oxidation Mechanism DMSO Oxalyl chloride (COCl) 2

39 Synthesis of Reagent 3 3

40 Synthetic Scheme

41 Synthesis of Reagent 4 AAC Reaction Catalyzed Asymmetric Acyl Halide- Aldehyde Cyclocondensation (AAC) Nelson et al. J. Org. Chem. 2002, 67, 4680-4683

42 Synthesis of Reagent 4 AAC Mechanism

43 Synthesis of Reagent 4 Boc 2 O = Di-tert- butyldicarbonate

44 Synthesis of Reagent 4

45 Synthetic Scheme


47 Synthesis of Reagent 6 16 BTSH = 2-mercapto- benzothiazole

48 Putting It Together… 20 EDC = 3-(3-dimethylaminopropyl)-1- ethylcarbodiimide

49 Putting It Together… EDC Esterification Mechanism

50 Putting It Together… complex mixture no reaction with 5b 20

51 Putting It Together… INSEPARABLE 20

52 Putting It Together… Products at low yields Ring Closing Metathesis (RCM)




56 76%

57 Putting It Together… Ring Closing Metathesis (RCM) Mechanism catalyst alkylidine

58 Final Product 24 Julia-Kocienski Olefination

59 Final Product

60 Almost Done… Synthesis of 2 7,8-O-isopropylidene Iriomoteolide-2a

61 Hmm, Still Not Done… Structural Editing

62 Structural Editing


64 Antiproliferative Study

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