CP-263,114/phomoidride B. CP-225,917/phomoidride A. Jamie Tuttle MacMillan Group November 2, 2005

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1 Comparative Syntheses of the CP-molecules: A focus on the Fukuyama and Shair strategies along with a brief look at key bond forming reactions developed by icolaou and Danishefsky C CP-63,114/phomoidride B C CP-,917/phomoidride A Jamie Tuttle MacMillan Group ovember, 00 Lead Material: Spiegel, D. A.; jardarson, J. T.; McDonald, I. M.; Wood, J. L. Chem. ev. 003, 103, 691. Waizumi,.; Itoh, T.; Fukuyama, T. J. Am. Chem. Soc. 000, 1, 78. Chen, C.; Layton, M. E.; Sheehan, S. M.; Shair, M. D. J. Am. Chem. Soc. 000, 1, 744.

2 ! Isolation of the molecules A bit of background - Takushi Kaneko's group at Pfizer originally reported the structure determined via M. - Derived from an unidentified fungus that afflicts the Texas juniper tree. An afflicted twig C 1, CP-,917 C, CP-63,114 - nly small amounts were obtainable using fermentation: 1 L broth produced 31 mg of CP-,917 and 18 mg of CP-63,114 that were isolated by reverse PLC. - Characterization was achieved using M and mass spectrometry.! Therapeutic potential - Molecules found to inhibit as farnesyl transferase: 1 IC0 = 6 µm, IC0 0 µm Importance: Farnesylation of ras protein induces membrane localization that causes cell growth. Farnesylated Protein S Protein - Inhibit squalene synthase: 1 IC0 = 43 µm, IC0 = 160 µm Importance: Disrupts cholestorol biosynthesis starting from farnesyl pyrophosphate. Dabrah, T. T.; Kaneko, T.; Massefski, Jr. Walter; Whipple, E. B. J. Am. Chem. Soc. 1997, 119, 194. Poulter, C. D. Acc. Chem. es. 1990, 3, 70.

3 The big players The following are the only souls to complete total syntheses of CP molecules to date Prof. Tohru Fukuyama J. Am. Chem. Soc. 000, 1, linear steps,.% overall yield Prof. Kyriacos C. icolaou, first to publish the total synthesis review: Angew. Chem. Int. Ed. 00, 41, 678. Angew. Chem. 1999, 111, Angew. Chem. 1999, 111, linear steps, 0.0% overall yield Prof. Matthew D. Shair J. Am. Chem. Soc. 000, 1, linear steps, 0.4% overall yield Prof. Samuel J. Danishefsky Angew. Chem. Int. Ed. 1998, 37, Angew. Chem. Int. Ed. 1998, 37, Angew. Chem. Int. Ed. 1999, 38, 148. Angew. Chem. Int. Ed. 1999, 38, Angew. Chem. Int. Ed. 000, 39, linear steps, 0.003% overall yield

4 A closer look at the unique molecular architecture! A potpourri of complexity C C 1, CP-,917, CP-63,114 - A bridgehead olefin - A quarternary carbon center held in a caged spirolactone - A maleic anhydride moiety - Two pendant olefinic side chains! Similar classes of molecules - Shares structurally homology with glauconic acid and byssochlamic acid Et Et byssochlamic acid carcinogenic Et Et glaucanic acid no known bioactivity Spiegel, D. A.; jardson, J. T.; McDonald, I. M.; Wood, J. L. Chem. ev. 003, 103, 691.

5 Proposed Biosynthesis SEnz S Enz 1 SEnz S Enz 1 SEnz S Enz C [] 1 S Enz 1 S Enz - A series of elegant labelling studies indicated all the carbons for the phomoidrides are derived from succinic acid and an acetyl-coa derivative. SCoA C C Sulikowski, G. A. et al. J. rg. Chem. 000, 6, 337. Sulikowski, G. A. et al. rg. Lett. 00, 4, Spencer, P. et al. J. Am. Chem. Soc. 000, 1, 40.

6 Fukuyama's retrosynthetic analysis X p EtS C 8 1 IMDA X p C 9 EtS C 8 1 C C C C C CP-63,114 * X C C S C 8 1 1,4 addn. S M C 8 1 C C Waizumi,.; Itoh, T.; Fukuyama, T. J. Am. Chem. Soc. 000, 1, 78.

7 ! Preparation of the alkynylester Fukuyama's synthesis: Preparation of starting materials Br EtS, a, EtS BuLi; ClC TF 86% 87% EtS C! Preparation of the vinyl cuprate cat. C C C 3 C(Et) 3 88% Et C 1) LA, Et, 9% ) MsCl, Et 3 3) diethyl malonate aet, Et 4) LiCl, wet DMS heat, 68% 3 steps Et C 1) LA, Et, 94% ) TsCl, pyridine 3) C CLi EDA 78%, steps 1) DIBAL, I, 70% ) t-buli, CuI, MPA, S Cu

8 Fukuyama's synthesis: Preparation of starting materials con't.! Preparation of the protected diol 1) Li TP BF 3 Et Cl ) PhSh, K C 3 cat. KI 84%, steps 3) a, MMCl, 91% TP MM SPh 1) m-cpba ) TFAA, Et 3 3) BrMg 4) CSA,, heat ) C(), CSA 6) PPTS, 1) LA ) Swern 63%, steps C 3% six steps - chanism for trans selectivity LA Al

9 EtS cat. DBU, TF, 0 C Fukuyama's forward synthesis EtS C C C CP-63,114 Cu C 8 1 TMSCl, MPA, S, 78 C to T 80% EtS C 8 1 LiMDS, TF; ClC, 78 C C 84% C EtS C 8 1 C 1) Bu BTf, Et 3, C Cl ; 0 C, 1 h, 80% Bn 8% Bn EtS C 8 1 cat. Cs C 3 ) S 3 -Py, DMS-i-Pr Et C 3 C 1 h 7% X p EtS C 8 1 C C C 9 C C C single diastereomer C 9

10 Fukuyama's forward synthesis! General scheme for boron mediated diastereoselective aldol reaction using Evans' auxiliary Bu B Bu C Bn Bn 141:1 to >00:1 diastereoselectivity Why? Consider the proposed transition states. Bu B Bu Bn B Si-face dipole maximized Bn Bn unfavored Bn Bn B e-face dipole minimized Bn B Bn favored Evans, D. A.; Bartroli, J. A.; Shih, T. L. J. Am. Chem. Soc. 1981, 103, 17.

11 Details of the key step! The key step X p C 9 EtS C 8 1 ZnCl -Et, pyridine C Cl, 1 h X p C 9 EtS C 8 1 C C C C "predominantly desired" - Pyridine acts as a buffer to prevent diene isomerization during the Diels-Alder reaction. - Presumably the C1 stereocenter provides remote stereocontrol. - Yield not given for this step. - First case in literature where acyclic stereocontrol produces a bridgehead adduct. For other information regarding acyclic stereocontrol in Diels-Alder reaction see: Evans, D. A. et al. Angew. Chem. Int. Ed. Engl. 1997, 36, 119. and references therein

12 ! The synthesis continues... Fukuyama's Synthesis Bn C 9 allyl thioglycolate LiMDS, Et, 0 C C 9 EtS C 8 1 3%, steps Allyl C S EtS C 8 1 C C C C DBU, TF, rt, 1. h 93% S C Allyl C 9 EtS C 8 1 1) cat. Pd(Ac), PPh 3 pyrrolidine, C 3 C, T ) Py, AC, 100 C, 1h 87% steps S C 9 EtS C 8 1 C C C C 1) Cl, DBU, C Cl ) IS, C Cl, T 79%, steps S I C 9 EtS C 8 1 1) Ag 3, DMS, 0 C, 74% ) Li-,, T, 1h; Ba() -8, rt, 1h C 9 EtS C 8 1 C C C C

13 ! Concave versus convex ester Fukuyama's synthesis: 3-d analysis of the hydrolysis step S Li, rt 1h Ba() 8, rt 1h EtS EtS C C C C concave ester - This concave face ester is less sterically shielded - The thioalkyl group shields the other ester - Same molecule, different view more accessible

14 ! The last transformations Fukuyama's Synthesis C 9 1) (CCl), C Cl, rt; C, Et, 1 C ) PhC Ag, t-bu, 0 C C 9 EtS C 8 1 4%, 3 steps EtS C 8 1 C C C C t-bu 1) mcpba, C Cl, 0 C ) TFAA, i-pr Et, toluene, 0 C 3) 80% aq. Ac, 70 C 1%, 3 steps C 9 Jones ox., 0 C C, rt C % steps C t-bu - Concluded that this absolute configuration is the same as the natural product. C CP-63,114

15 Shair's retrosynthesis! Shair identifies an anion accelerated oxy-cope rearrangement 1 Dieckmann M 1 C CP-63,114 xy-cope M 1 1 M Chen, C.; Layton, M. E.; Sheehan, S. M.; Shair, M. D. J. Am. Chem. Soc. 000, 1, 744.

16 ! Preparation of starting materials Shair's synthesis 1) Mg 0, TF I(C ) C=CC 3 89% ) PDC, DMF, 94% (C ) CSA, Ph, 80 C 4 % Imidazole, Ts a, TF 9% 1) BF 3 Et TMSCCLi, 8% ) MMCl, ipr Et, 9% TMS MM 1) K C 3,, 88% TMS MM ) CP Zr()Cl, BS, 81% Br MM

17 Shair's Synthesis! Shair's preparation of the rearrangement precursor via kinetic resolution I (E,E)- 3 SnC=C(C) Pd (dba) 3, PPh 3, DMF, 6 C 80% 1) Li (PMBC )Cu(thiophene)C, TMSCl, TF, 78 C ) n-buli, Et, 78 C to 0 C, CC Ph 6%, steps B Ph B 3 TF Ph 3 B C B PMB racemic! chanism and selectivity for CBS reduction Ph (+)--CBS catecholborane, C Cl, rt Ph B Ph B 31% yield, 91% ee more accessible lone pair Ph C C B Ph B PMB less accessible lone pair - Shair's intermediate Ph B Ph B C C PMB C Ph B Ph B C C PMB C Steric interactions disfavor reduction This diastereomer is reduced Corey, E. J.; elal, C. J. Angew. Chem. Int. Ed. 1998, 37, 1986.

18 Shair's Synthesis! The key step: Anion accelerated oxy cope rearrangement/intramolecular Dieckmann condensation Br MM t-buli, Et 78 C to rt, MgBr to rt C PMB 3% MM PMB! The mechanism oxy-cope BrMg PMB MM intramolecular Dieckmann BrMg PMB MM PMB MM MM PMB For Anion xy-cope: Evans, D. A.; Golob, A. M.; J. Am. Chem. Soc. 197, 97, 476.

19 Selectivity for the Shair Grignard Addition! A chelation model explains the approach of the nucleophile TBDPS BrMg Mg Br TBDPS BrMg MgBr TBDPS Dieckmann TBDPS e face addition - Controls four stereochemical facets: 1) C9 stereochemistry ) C10 stereochemistry 3) C1-C16 trisubstituted double bond 4) (Z) enolate geometry to afford transannular Dieckmann cyclization - Interesting the analogous Li and Ce(III) based nucleophiles provided the 9 membered ring but did not effect the subsequent Dieckmann condensation. - The olefin geometry of the alkene grignard reagent dicatates cis/trans relationship of alkyl chains. Chen, C.; Layton, M. E.; Shair, M. D. J. Am Chem. Soc. 1998, 10,

20 ! Further into the synthesis Shair's Synthesis MM PMB KMDS, TF, then CC, 78 C to 0 C 1% C MM PMB 1) BCl 3, 78 C to 30 C ) Dess-Martin, pyr, /C Cl rt 3) acl, a P 4 -methyl--butene, /, rt C MM 1) MMCl, Et 3, C Cl, rt ) KMDS, TF, then CC, 78 C to 0 C C MM TMSTf, C() 3, C Cl, 78 C to 0 C 83 9% over six steps C C

21 ! Another interesting cascade reaction is discovered Shair's Synthesis C MM Fries-like rearrangement TMSTf, C() 3, C Cl, 78 C to 0 C 83 9% over six steps C C C MM deprotection 3 Si C 3 Si Si 3 Fries earrangement AlX 3 AlX 3 AlX 3 AlX 3 Cohen,. et al. J. rg. Chem. 1978, 43, 373.

22 Shair's Synthesis! Arndt-Eistert homologation proceeds inefficiently due to product instability C 1) MsCl, Et 3, TF, 0 C, then C, 0 C ) hv, t-bu-et, 3 C 1%, steps C C t-bu C! Arndt-Eistert homologation mechanism MsCl, Et 3 Ms C Cl uc u Arndt, F.; Eistert, B. rg. eact. 194, 1, 38.

23 ! The final steps of the synthesis Shair's Synthesis C Ki-Pr, Et, then Tf, 78 C to 0 C % C Tf t-bu C t-bu C Pd(Ac), P() 3, C (00 psi), Et 3, TF-C, rt 70% Ac C, 3 C 79% t-bu C C (+)-CP-63,114

24 Comparative analyses of key bond forming reactions! A closer look at some interesting transformations derived from all the total syntheses C The Minotaur/ CP-63,114 The four foci: C7 stereocenter, C1/C16 bridgehead double bond, carbocyclic core, C14 quarternary center reminder: 1) C7 stereocenter ) C1/C16 bridgehead 3) carbocyclic core 4) C14 quarternary carbon center Fukuyama chiral starting materials Diels Alder Diels Alder substrate control Shair chiral starting materials oxy-cope/dieckmann oxy-cope/dieckmann stereoselective acyl transfer/ Arndt Eistert homologation

25 Assembly of the carbocyclic core/bridgehead double bond! icolaou utilizes a type II intramolecular Diels-Alder eaction TBDPS PMB C 8 1 AlCl 90% PMB TBDPS C 8 1 Type I Type II - tether is linked to 4-position - tethered is linked to 3-position trans fused cis fused - fused products generally have 3-4 atom tethers - always gives syn product - bridged fused possible with tether >9 atoms icolaou, K. C. et al. J. Am. Chem. Soc. 00, 14, 183. Shea, K. J. Tet. Lett. 1994, 3, Shea, K. J. J. Am. Chem. Soc. 1988, 110, 860.

26 Assembly of the carbocyclic core/bridgehead double bond! Danishefsky develops a sequential aldol/intramolecular eck reaction I 1) LDA, cyclohexenone 79% ) Tf, 8% 3) Pd(Ac) (PPh 3 ), 9% steps Ms (C ) 6 Bn DBU Ms (C ) 6 Bn (C ) 6 Bn I 1) aldol/protection ) eck syn elim. aldol condensation: anti C4 side chain intramolecular syn carbopalladation PdLx Kwan,. et al. Angew. Chem. Int. Ed. 1998, 37, 1877.

27 Assembly of the maleic anhydride architecture! icolaou develops an interesting multi-step sequence SET PMB C C 8 1 1) MsCl, Et 3 ) K C 3, 60% PMB SET C chanism C SET PMB C 8 1 -exo-dig cyclization/taut. PMB SET C 8 1 +, air PMB TES C 8 1 tautomer. PMB TES deyhdration 3 PMB SET C 8 1 Spiegel, D. A. et al. Chem. ev. 003, 103, 691. icolaou, K. C. et al. J. Am. Chem. Soc. 00, 14, 183. C 8 1

28 Assembly of the maleic anhydride architecture! Danishefsky utilizes singlet oxygen to access the anhydride C 1) hv, ose-bengal ) TPAP 0%, steps C C 8 1 C General mechanism 1 [4+] Kwon,. et al. Angew. Chem. Int. Ed. 1998, 37, 1880 Kernan, M..; Faulkner, D. J. J. rg. Chem. 1988, 3, 773.

29 S S Li Assembly of the C-7 stereocenter! icolaou utilizes a diastereoselective aldehyde alkylation PMB Li PMB Li uc PMB SET S S C 9 C 8 1 C 8 1 e-face addition C % yield, 11:1 desired:undesired! Danishefsky attempted a similar alkylation but undesired diastereomer was favored. ere's route B. C C C C 70% 1:1 mixture diast. C C C C C 8 1 C 4 7 C 8 1 C 4 7 Subsequently, diastereomers are separated Tan, Q.; Danishefsky, S. J. Angew. Chem. Int. Ed. 000, 39, 409

30 Assembly of the C14 quarternary carbon center! Perhaps the most difficult problem! icolaou, along with Fukuyama, rely upon the carbocycle to direct reactions to one diastereotopic center C 8 1 C 9 1) Ac, 8% ) TESTf, 9% TES C 8 1 C 9 3) Dess-Martin, 80 C 49% TES C 8 1 C 9 TES C 8 1 C 9 DMP TES C 8 1 C 9 TES C 8 1 C 9 1) TFA, C 3 S 3, 83% ) Dess-Martin, 8% 0:1 alcohol:anhydride 3) Tf, 0% C 9 1) acl ) MsCl 3) C 4) Ag C 9 C C %, 4 steps C C 8 1 icolaou, K. C. et al. J. Am. Chem. Soc. 00, 14, 0. icolaou, K. C. et al. J. Am. Chem. Soc. 00, 14, 190.

31 Assembly of the C14 quarternary carbon center! Danishefsky utilizes an unusual desymmetrization reaction Cp Ti, 90% 1) trichloroacetyl chloride Zn, Et, ultrasound 8% ) Zn, 4 Cl, ultrasound, 80% 3) TBAF, 70% (C ) 6 PMB [+], reductive de Cl PhSSPh, a/k, 80% hydroxyl group may direct SPh DMP, 90%, 70% sulfanyl group may direct SPh s 4, M, 70% enone alkene is less reactive SPh a 60% SPh C ng, D.; Danishefsky, S. J. Angew. Chem. Int. Ed. 1999, 38, 148.

32 Conclusions! These complex molecules have led to clever and creative methods for overcoming difficult problems.! Persistence is the key success.! Sigmatropic rearrangements provide the most powerful and efficient means of entry into phomoidride systems by generating the carbocycle and alkene in essentially one step.! A good example that model systems, although useful, may not always be a good metric for actual system.