Total Synthesis of Callipeltoside A Denmark Group eting Aaron Bailey September 23, 2008
Callipeltoside A First isolated from Lithistid sponge in 1996 Exhibits moderate cytotoxicity against human bronchopulmonary non-smallcell lung carcinoma Extensive NMR experiments were used to assign the relative stereochemical relationships in macrolactone and sugar regions N Callipetoside A
Synthetic Rationale nly able to isolate from sponge in small quantities (~35 mg total studied since first isolation) Relative stereochemistry of cyclopropyl moiety unclear from NMR experiments SAR studies from diastereomers Four total syntheses reported to date: Evans (02), Trost (02), Patterson (03), Panek (04)
Common Retrons N R Same disconnects proposed in each total synthesis: orner-wadsworth Emmons lefination, and glycosylation to append the sugar X N Each total synthesis demonstrates a unique method of preparing each structure utilizing a variety of different known synthetic transformations
Evans total synthesis Retrosynthetic Analysis for macrolactone a a Ireland-aisen P P 2 P P 3 P R 3 Si N R 3 Si P Bn 5 Ph P P P P 4 Ph
Synthesis of Macrolactone Ph N Bn Cy 2 B, EtN 2-78 to -20 ºC 78 % d.r.= 95:5 N Ph 6 Ph 4 NB(Ac) 3, Ac CN, 0 ºC 98 % N Ph 7 d.r.= >95:5 Ph 1. () 2 C 2, PPTS, acetone, rt. 2. LiSEt, TF, -5 ºC to 0 ºC 3. DIBAL-, Toluene, - 78 ºC 9, BF 3. Et 2, toluene 66 % Ph -78 ºC 86 % 10 d.r.= >95:5 Ph Chan s diene utilized to synthesize 10, under Felkin control 9= TMS TMS
Ireland-aisen Rearrangement 10 Ph 1. TBSTf, 2,6-lutidine C 2 2, -78 ºC 2. PPTS,, rt 67 % TBS Ph 1. Tf, DTBMP, C 2 2, rt 2. 3, C 2 2,, -78 ºC, then 2 S, rt, TBS 12 BrMg TF, -78 ºC 79 % 67 % TBS 11 d.r.= >95:5 1. Li,, TF, 2, rt 2. Cs 2 C 3, allyl bromide, DMF, rt 3. DMBC 2 C, DCC, C 2 2, 0 ºC 69 % TBS DMB 13 LiMDS, TMS. Et 2 N, TF -100 ºC to rt 61 % TBS DMB 14 d.r.= >95:5
Completion of Macrolactone TBS DMB 14 d.r.= >95:5 1. EtS, BP, Et 3 N, C 2 2 0 ºC to rt 2. DDQ,, rt 3. Pd(PPh 3 ) 4, C 2, Et 3 N TF, rt 30 % TBS 15 SEt 1. 2,4,6-3 C 6 2 C, ipr 2 NEt TF, rt then DMAP, toluene 2. PPTS,, rt. 59 % 16 SEt 20 steps to obtain desired macrolactone Abundance of functional group manipulations
Second Synthesis of Macrolactone P P P P P a TMS TMS 9 N Bn 5 P 18 P First route required many functional group manipulations Revised route eliminates requirement of protecting group manipulations
Second Synthesis of Macrolactone TMS Et PMB 1. 21 (5 mol %) Ch 2 2, -78 ºC 2. (aq), TF, rt 99 % Et e.e.= 97 % E:Z= >50:1 PMB 22 1. TBS, imid. DMF, rt 2. LiAl 4, Et 2, 0 ºC to rt 3. S. 3 Py, Et 3 N, DMS, Ch 2 2, 0 ºC 75 % 2 TBS 24 PMB 21= Ph N N Cu N 2 2 Ph SbF 6 Initial reactions conditions provided low yields and poor olefin selectivity (27 % yield, 80 % ee, 11:1 E/Z rapid addition) ptimal reaction conditions were achieved by the slow addition of both reagents.
Stereochemical Complications in Aldol Reaction TBS 24 PMB N Bn 5 Cy 2 B, EtN 2 Et 2, 0 ºC N Bn d.r.= 1.2:1 TBS PMB TBS PMB ent-24 N Bn 5 Cy 2 B, EtN 2 Et 2, 0 ºC TBS N PMB Bn d.r.= 12:1 Using the enantiomer of 24 leads to 10 fold improvement in diastereoselectivity. Different conditions tested determined effects of remote directing groups. -silyl group necessary, but PMB protecting group not required
Completion of Macrolactone TBS PMB ent-24 N Bn 5 1. Cy 2 B, EtN 2, 0 ºC 2. 4 NB(Ac) 3, CN, Ac, 0 ºC 3. N(C 2 C 2 ) 2, EtAc, rt 27 TBS PMB 86 % d.r.= 12:1 1. N()., AI 3, C 2 2, 0 ºC to rt 2. 2 C() 2, PPTS, acetone, rt 3. LA, Et 2, rt 72 % 28 TBS PMB 9, BF 3. Et 2, toluene, -90 ºC 88 % 29 d.r= >20:1 TBS PMB TBSTf, 2,6-lutidene C 2 2, -78 ºC 88 % TBS 30 TBS TBS PMB 31 TBS PMB
Mitsunobu to the Rescue 30 or 31 1. PPTS,, rt 2. Tf, DTBP, C 2 2, rt then PPTS, 57 % TBS TBS PMB 1. TBAF, TF, rt 2. Ms, Et 3 N, DMAP, C 2 2, 0 ºC 3. Li, 2, TF, rt 70 % TBS Ms 34 PMB Cs 2 C 3, 18-crown-6 Toluene, 110 º!C 67 % TBS PMB Modified Mitsunobu conditions afforded desired stereochemistry No isolation of product 35 when starting from alcohol derivative of 34 35
Evans Total Synthesis Retrosynthetic analysis for callipeltose sugar b N N 2 R R CbzN Synthetic challenges: installation of stereocenters Enolate chemistry can be used to obtain high diastereoselectivity
Callipeltose from D-Threonine N 2 1. Na, Cbz, CN, 2 2. I, K 2 C 3, DMF 3. Ts, 2 C() 2, acetone 93 % CbzN 1. iprmg, N. TF 2. MgBr, TF 64 % CbzN 36 Et Et LDA, TF, -78 ºC CbzN 38a 2:1 Et CbzN 38b btained poor d.r. due to formation of undesired enolate Unfortunately, the selectivity could not be improved upon by using alternative bases
Formation of Desired Diastereomer CbzN LDA, TF, -50 ºC CbzN 89 % d.r.= 15:1 Ac 71 % NCbz By utilizing a cyclic ester as the starting material the desired product was obtained in good yield and high selectivity
Completion of the Sugar Ring NCbz 1. 3. BF 4, DTBMP, C 2 2, rt 2. DIBAL-, C 2 2, Ac 2 DMAP, pyridine 76 % Ac NCbz 1. Na, TF 2. DBU, 3 CCN 51 % N N C 3 43 1. BF 3. Et 2, PhS, C 2 2 2. Na, TF 79 % N TBSTf, 2,6-lutidine NTBS PhS C 2 2 92 % PhS 45 Synthesized two different sugar moieties to test in the glycosylation step
Evans Total Synthesis Retrosynthetic Analysis of Side Chain P Michaelis-Arbuzov Coupling reaction M Br Br Corey-Fuchs C Needed to prepare both enantiomers to determine absolute stereochemistry of cyclopropane moiety
Synthesis of Side Chain From D-Mannitol KI 4, KC 3 TF/ 2, rt Cr 2, C 3 TF 70 ºC < 40 % E:Z= 87:13 54 53, K 2 C 3, 94 % 53= P N 2 1. Sia 2 B, TF -15 ºC to 0 ºC 2. Cu 2, 2, MPT, TF 0-70 ºC 70 % E:Z= > 20:1 Takai olefination provided low yields and moderate selectivity Modifying conditions based on Masuda s work the desired product was formed in high yield and selectivity
Synthesis of Side Chain Enantiomer KI 4, KC 3 TF/ 2, rt 53, K 2 C 3,, rt 77 % ent 51 1. Sia 2 B, TF -15 ºC to 0 ºC 2. Cu 2, 2, MPT TF 0-70 ºC 70 % E:Z= > 20:1 53= P N 2 ent 54
Competion of Side Chain C 2 I 2, ZnEt 2 CF 3 C 1. Dowex resin,, rt 2. Pb(Ac) 4, K 2 C 3, C 2 2, rt Br or ent 54 82 % d.r.= > 50:1 3. PPh 3, CBr 4, C 2 2 77 % Br () 2 P () 2 P 59 1. CBr 4, PPh 3, C 2 2, -40 ºC 2. P() 3, 100 ºC 75 % 56, Pd 2 dba 3, P(p-C 6 4 ) 3 ipr 2 NEt DBU, toluene, 100 ºC 80 % 57, Pd(PPh 3 ) 4, TlEt, TF/ 2,rt 93 % Br ent- 59 56= SnBu 3 57= B() 2 Shen s modified Stille conditions could not be applied to the dibromo-olelfin. Instead the coupling reaction was carried out prior to elimination to provide the enyne in good yield
Fragment Assembly TBS TBAF, TF 99 % PMB 35 PMB 45 43 or 44 NIS, Tf, DTBMP 95 % NTBS decomposition Thioether appendage on sugar able to react without decomposition of SM Both anomers can be utilized to provide the desired product Relative stereochemistry determined by NESY 62 PMB N 45= 43= 44= PhS NTBS N C 3 PhS N
Fragment Completion NTBS NTBS PMB 1. DDQ, C 2 2,, 2 2. S 3. Py, Et 3 N DMS, C 2 2 0 ºC to rt 1. 59 (ent 59) LiMDS, - 78 ºC to rt 2. I 2, C 2 2, rt d.r.= 11:1 N NTBS TBAF, Ac, TF, rt 50 % N 1 b 1 a Accomplished in 25 linear steps and a 4 % overall yield. NMR data confirms cyclopropyl moiety too remote for determination ptical rotation confirms natural product to have relative configuration matching that of 1 a
Trost s Total Synthesis Retrosynthetic Analysis from macrolactone 3 3 Ketalization/Aldol 30 PMP asymmetric allylic alkylation P TRC Ru catalyzed Alder-ene TBS 13 16 TRC
Preparation of Macrolactone 1. MgBr 7 1. TBDMS, imid. C 2 2, rt, 2 h 2. N., i-prmg TF, - 20 º C, 15 min 98 % N 9 TF, 0 ºC 2 h TBS 2. 2-methyl (S)-CBS-oxazaborolidine B. 3 S 2, TF, -30 ºC, 1 h d.r.= 10:1, 99 % 11 TBS I, Ag 2 Et 2, rt, 4 h 92 % 13 TBS Reduction required 2.0 equivalents of 2-methyl (S)-CBS-oxazaborolidine for moderate selectivity
Synthesis of Macrolactone-Alder-Ene Reaction 13 TBS R CpRu(C 3 CN) 3 PF 6 acetone, rt TBS R Entry R Mol % Ru Time Yield A 10 2 h 62 % B TRC 5 0.5 h 85 % Product obtained exclusively as linear chain ne of few examples of ruthenium catalyzed Alder-ene reaction to give exclusively linear products Selectivity attributed to coordination of propargylic methyl ether in ruthenacycle and inductive effect of homoallylic oxygen
Proposed chanism of Alder-ene Reaction Trost, B. M., et. al. J. Am. Chem. Soc. 2002, 124, 10396
Asymmetric Allylic Alkylation (AAA) TBS Pd 2 dba 3. CCL 3 p-thoxy phenol nbu 4 N, C 2 2 TBS PMP TRC 19, rt 12 h > 99 %, 2º/1º= 3/1 24 pposite stereocenter observed from expected configuration Selectivity arises from Pd ability to switch from η 1 to η 3 which allows syn to anti interconversion Chloride ion helps facilitate equilibrium by coordinating to Pd
chanism of AAA Trost, B. M., et. al. J. Am. Chem. Soc. 2002, 124, 10396
Aplication of AAA to Macrolactone TBS Pd 2 dba 3. CCL 3 p-thoxy phenol nbu 4 N, C 2 2 TBS PMP 1. TBAF, TF, rt, 12 h TRC ent- 19, rt 12 h > 99 %, d.r.=20:1 28 2. Dess-Martin periodinane NaC 3, Ch 2 2, 0 ºC, 5 h 81 % 30 PMP 1. tert-butylthiopropionate, LDA, TF, -108 ºC 2. TBDMSTf, 2,6-lutidine, C 2 2 0 ºC, 2 h 3. DIBAL-, toluene -78 ºC 56 % d.r.=5:1 TBS PMP 33 TMS BF 3. Et 2, C 2 2-78 ºC 94 % TBS TMS TBSTf, 2,6-di-tert-butylpyridine TBS TBS TMS 36 PMP C 2 2, 0 ºC, 1 h 95 % 37 PMP
Completion of Macrolactone Fragments TBS TBS PMP TMS 1. CAN, acetone/ 2 0 ºC, 5 min 2. toluene, 100 ºC, 1 h 67 % TBS TBS 37 39 1. F. pyridine,, 0 ºC 2. PPT, CN, 2, rt 91 % 3 40 Same steps carried out starting from diasteromer 24 to provide 40 ne studies confirmed stereochemistry of lactones
Appending Cyclopropyl Moiety To determine absolute configuration need to synthesize and append both enantiomers of cyclopropyl moiety menthyl-(+) 2 C C 2 (+)-menthyl LiTMP, BrC 2, TF, -78 ºC, 4h d.r.= 99:1, 87 % menthyl-(+) 2 C C 2 (+)-menthyl 1. Na, IPr, 70 ºC, 12h 2. S 2, rt, 12 h 89 % Na N S menthyl-(+) 2 C menthyl-(+) 2 C N., iprmg C DMAP, C 4, nbu 4 NI, then AIBN 58 TF, -20 ºC, 1h 99 % 60 % Sn(C 4 9 ) 3 N 60 1. DIBAL-, C 2 2-78 ºC, 3 h 2. PPh 3, CBr 4, C 2 2 0 ºC, 4 h 80 % Br Br 62 1. Pd 2 dba. 3 C 3, tris(4-methoxyphenyl)phosphine, DIPEA, DMF 80 ºC, 12 h (Et) 2 P 2. PPh 3, CBr 4, C 2 2-40 ºC, 1h 65 3. P(Et) 3, 100 ºC, 4 h 55 %
Two thods for Appending Dienyne Model studies based on deschlorocallipeltoside Synthesis via lefination (Et) 2 P 65 TBS TBS 39 1. s 4, NM TF/ 2, 0 ºC 4 h 2. NaI 4, TF/ 2 rt, 3h 80 % TBS TBS 46 65, LiMDS, TF, -78 ºC, 3 h E/Z= 4/1 52 % TBS TBS F. pyridine, 0 ºC, 5 h 96 % 66 67
thod 2: tathasis 3 crotonaldehyde, Grubbs II C 2 2, 40 ºC 5 h; then, Cr 2, CI 3, dioxane/tf 0 ºC 3 h, 8:1 (E:Z) 84 % 70 I ent-62, nbuli, 2 Sn Et 2, - 78 ºC to rt, 1h; then 70, 2 Pd(CN) 2, DMF, rt 45 min 70 % 72 Br Br ent-62 s N N Ru P Grubbs II s Ph (Cy-ex) 3
Synthesis of Sugar 1. 2 N., pyridine/et (1:1) N 1. Pt 2, 2, Et 2. benzyl chloroformate DIPEA, C 2 2 87 % N Bn 1. 60 % Ac 2. Na, TF 3. TBSTf, 2,6-lutidine, C 2 2, rt 4. I, Ag 2, DMF, rt 28 % NTBS 1. 2 S 4, PPTS, Ac 2, rt, 2. K 2 C 3,, rt 3. 3 CCN, Na C 2 2, rt 62 % 3 C N NTBS 5
End Game Strategy 3 C N 5 NTBS 1. 67 (72) TMSTf, dichloroethane, 4 Å MS, - 30 ºC 2. TBAF, Ac, TF, rt 69 % N 67 1 or N 72 85 Completion of molecule in 46 total steps (22 linear) for 0.05 % overall yield
Paterson s Synthesis of Macrolactone TMS I (R)-BINL, Ti(i-Pr) 4, TF, Ca 2, -78 ºC 96 % e.e.= 94 % 10 I 1. TBS, imid. C 2 2 2. DIBAL-, C 2 2, -78 ºC TBS 3. Mn 2, C 2 2, rt 76 % 5 I 1. DMB(C 3 )CN, PPTS C 2 2 2. N., i-pr, TF, -20 ºC 3. EtMg, TF, 0 ºC 60 % 6 DMB
Completion of Macrolactone 6 DMB c-ex 2 B, Et 3 N, Et 2-20 ºC; then 5, - 78 ºC to -30 ºC 99 % d.r= 95:5 DMB TBS 11 I 1. SmI 2, EtC, TF, -20 ºC 2. TESTf, 2,6-lutidine, C 2 2, -78 ºC 3. DIBAL-, C 2 2, -78 ºC 4. 3 BF 4, proton sponge C 2 2, 0 ºC 79 % DMB TES TBS I 1. DDQ, C 2 2 p 7 buffer, reflux 2. Dess-Martin periodinane, C 2 281 % TES TBS 14 I 7, BF 3. Et 2, C 2 2, -100 ºC 85 %, d.r. = 95:5 TES TBS 15 I 1. PPTS, () 3 C,. 2. TBSTf, 2,6-lutidine, C 2 2, -78 ºC 3. TBAF, TF 4. Ba() 2. 8 2, 5. 2,4,6-3 (C 6 2 )C, Et 3 N; DMAP, Ph, 80 ºC 57 % TBS 2 I 7= TMS TMS
Completion of Callipeltoside A 2 TBS 1. TFA, aq. TF 2. 4, TMSTf, C 2 2, 4 Å MS, -30 ºC 3. TBAF, Ac, TF 74 % I Pd 2 (PPh 3 ) 2, CuI, ipr 2 N, EtAc, -20 to 0 ºC 83 % N TBS 4= 3 C N N 1 menthyl-(+) 2 C Br n-buli, E 2 C 2 (+)-menthyl Br -78 ºC Synthesized in 4.8 % overall yield (23 steps- longest linear sequence) Sugar and cyclopropyl appendages synthesized by previously reported methods
Panek s Total Synthesis Bn Si 2 Ph C 2 Sn 4, C 2 2-78 ºC, 87 % d.r.= > 30:1 Bn Si 2 Ph C 2 1. Sb 5, C 2 2 2. 3 BF 4, C 2 2 3. 3, 2 S 81 % Bn 11 12, Tf C 2 2, 87 % d.r.= > 30:1 13 Bn C 2 1.mCPBA, C 2 2, rt 2. K 2 C 3,, rt 3. PDC, C 2 2, rt 52 % C 2 14 Bn 1. NaB 4, -78 ºC 2. TBSTf, 2,6-lutidine, -78 ºC 90 % TBS C 2 Bn 1. Li 2. (C) 2, C 2 2 3. C 2 N 2 4. PhC 2 Ag, pyridine, 56 % TBS C 2 Bn 1. CSA, 2. 2, Pd/C, EtAc 3. PDC, C 2 2, rt 85 % TBS C 2 4 12= TMS C 2 Si 2 Ph
Synthesis of Cyclopropyl Dienyne Zn(C 2 I). DME (S,S)-dioxoborolane C 2 2, 82 %, ee= 97 % 1. PDC, C 2 2 2. CBr 4, PPh 3 61 % Br Br SnBu 3 1. CBr 4, PPh 3, C 2 2 (Et) 2 P Pd 2 (dba) 3, (4-Ph) 3 P DIPEA, TF, 68 % 2. P(Et) 3 97 % LiMDS, then 23 TF, 89 % TBDPS Tr 1. TBAF, TF 2. PTS, DIAD, Ph 3 P, TF 3. (N 4 ) 6 Mo 7 24, 2 2 60 % N N PhN N S 2 Tr 1. Ts,,rt 2. EVE, PPTS, rt 90 % 5 23= TBDPS Tr
Completion of Callipeltoside A 5 1. LiMDS, then 4, TF, -78 ºC to rt 2. PPTS, 20 % TBS C 2 1. Li, / 2 /TF 2. 2,4,6-3 PhC, Et 3 N DMAP, toluene, 80 ºC 90 % TBS TBS 28 27 1. TBAF, TF, rt 2. PPTS, 2 /C 3 CN rt 76 % 1.TPB, 2 /C 2 2 2. TBAF, TF, rt 82 % 2
Glycosylation of Macrolactone NTBS N 2 3 C 1. N TMSTf, - 30 ºC 2. TBAF, Ac/TF, rt 73 % Sugar fragment prepared as described by Trost Formal synthesis accomplished with longest linear sequence of 25 steps
Conclusions Four Total Syntheses of Callipeltoside A have been reported to date Trost and Evans both synthesized a diastereomer; changing the configuration about the cyclopropyl moiety The absolute and relative configurations have been assigned based on independent syntheses N R X N
References: Evans, D. A., Burch, J. D., u, E., Jaeschke, G. Tetrahedron, 2008, 64, 4671. Evans, D. A,. u, E., Burch, J. D., Jaeschke, G., J. Am. Chem. Soc. 2002, 124, 5654. Trost, B. M., Gunzner, J. L., Dirat,., Rhee, Y.., J. Am. Chem. Soc. 2002, 124, 10396. Trost, B. M., Dirat,., Gunzner, J. L. Angew. Chem. Int. Ed. 2002, 41, 841. Paterson, I., Davies, R. D. M., eimann, A. C., Marquez, R., yer, A. rg. Lett. 2003, 5, 4477. uang,., Panek, J. S. rg. Lett. 2004, 6, 4383.