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 8th, 2009
J. AM. CHEM. SOC. 2009, 131, 12109–12111

2. INTRODUCTION
Sorangicin A – macrolide antibiotic isolated from myxobacteria Sorangium cellulosum
Found to be highly effective against a spectrum of both Gram positive and Gram-negative bacteria
Inhibits 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 centers
Signature dioxabicyclo
[3.2.1]octane
(Z,Z,E)-trienoate linkage
Instable to reagents such as:
Fluoride ion
DDQ
Dissolving metal sodium amalgam (reducing agent)
Polar elements  hydrophilic region
Sensitive to the solvent and pH environments

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

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

6. Luche Reduction Mechanism
(+)-8
BLOCKED!

7. (+) (+)-9

8. 1o ALCOHOL TO SULFONE
Mitsunobu Mechanism

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 olefination
The resulting sensitive aldehyde 21 was immediately subjected to Takai olefination w/o purification
Used a mixture of dioxane/THF as a solvent system to improve selectivity as they had problems with their scale-up
Got 22 and 23 in 52% and 16% yd respectively
In 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 [2].

13. Sharpless dihydroxylation
Lucy will explain mechanism later
Group 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 article
1st Julia-Kociénski Olefination
Scheme 3.
65% yield after several recycles

15. Julia-Kociénski Olefination Mechanism
(–)-11

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.

18. Preparing the aldehyde
HF/Pyridine (Triethylamine) removes TBS group. DMP Oxidizes.

19. Julia-Kocienski olefination
And deprotection of TBS group with TBAF, THF step.

20. Deprotection
And 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 Reaction
Stille Rxn with excess Ph2PO2NBu4 (12 eq) to suppress E/Z isomerization.

23. Hydrolysis
Hydrolysis.

24. Macrocyclization
In 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 anhydride
Evans-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 coupling
So they used 22 which has a non-nucelophilic counterion (ie tetrafluoroborate) mitigating the undesired Michael add’n along with the inactivation pathway
And then deprotection.

25. Evans modified Mukaiyama
20-22
Reagent 22 delivered macrocycle 19 in 85% yield and with minimum isomerization

26. Deprotection
Needed to remove MOM, acetonide, and tert-butyl protecting groups
Tried 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 decomposition
Looked at deprotecting the individual fragments
MOM and acetonide groups could be removed under aq protic acid conditions
Hydrolysis of the tert-butyl ester was less efficient
TFA in anhydrous CH2Cl2 (dichloromethane) resulted in the destruction of the trienoate
Lewis acids such as B-bromocatecholborane
Good for MOM and acetonide
Slow for tert-butyl
TMSOTf lead to decomposition on the whole macrolide , too reactive
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)
Nevado Group
3a (1) has 8 sterogenic centers, 4 in allylic positions
Cmpd 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 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)
Expected ring to be EE steroselective.

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

31. SHARPLESS ASYMMETRIC DIHYDROXYLATION
Regio/Stereochemistry
AD-mix α

32. Sharpless Asymmetric Dihydroxylation Mechanism

33. Heterogeneous catalyst
3D model?

34. Scheme 2. continued 9 10
(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 3
Wittig Mechanism
Wittig Reaction

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,

42. Synthesis of Reagent 4 AAC Mechanism

43. Synthesis of Reagent 4
Boc2O = Di-tert-butyldicarbonate

44. Synthesis of Reagent 4

45. Synthetic Scheme

46. Synthetic Scheme

47. 2-mercapto-benzothiazole
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… 20
complex
mixture
no reaction with 5b

51. Putting It Together… 20
INSEPARABLE

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

56. Ring Closing Metathesis (RCM)
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

63. Structural Editing

64. Antiproliferative Study