Scheme 1
Biogenetic pathway proposed for cernupalhine A (1)
Scheme 2
Total synthesis of cernupalhine A (1). Selected reagents and conditions: (a) 3-chloroperbenzoic acid (m-CPBA), NaHCO3, dichloromethane (DCM) (60%, dr 10:1); (b) 1 M HCl, THF (85%); (c) KCN, MeCN/H2O (52%); (d) 6 M HCl, reflux (80%). The carbon atoms that were varied to generate the candidate isomers of 1 for NMR calculations are marked with an asterisk
Figure 1
Plane structure of cryptomoscatone E3
Figure 2
Most likely structure of cryptomoscatone E3 according to NMR calculations. The carbon atoms that were varied to generate the candidate isomers of 11 are marked with an asterisk. The NMR calculations of the resulting eight diastereoisomers were carried out at the B3LYP/6-31G**//MMFF (method A) and B3LYP/6-31G**//B3LYP/6-31G* (method B) levels of theory
Scheme 3
Total synthesis of cryptomoscatone E3. Selected reagents and conditions: (a) Ti(OiPr)4 (10 mol%), (R)-1,1'-bi-2-naphthol (BINOL) (20 mol%), trifluoroacetic acid (TFA), AllylSnBu3, MS 4 Å, dichloromethane (DCM) (79%, ee 90%); (b) 15, BF3⋅OEt2, DCM (dr 61:39); (c) Et2BOMe, LiBH4, tetrahydrofuran (THF), MeOH (71%, two steps); (d) Me2C(OMe)2, pyridinium p-toluene sulfonate (PPTS) (97%); (e) hydrogen fluoride pyridine (HF-Py), Py, THF (72%); (f) Dess-Martin periodinane, DCM; (g) (+)-Ipc2BAllyl, THF (70%, two steps; dr > 95:5); (h) acryloyl chloride, N,N-diisopropylethylamine (DIPEA), DCM, 0 ºC (83%); (i) Grubbs I, DCM (88%); (j) HCl, THF (90%)
Figure 3
Originally proposed structures 20 and 21 for cryptoconcatones H and D, respectively
Figure 4
Most likely structures of cryptoconcatone H according to the NMR calculations. The carbon atoms that were varied to generate the candidate isomers are marked with an asterisk
Scheme 4
Total synthesis of the most likely structure of cryptoconcatone H (22, R = (E)-CH=CH–Ph). Selected reagents and conditions: (a) Grubbs II (3 mol%), DCM (89%, E:Z > 20:1); (b) K2CO3, MeOH; (c) PdCl2(MeCN)2 (10 mol%), THF (78%, two steps; dr > 20:1); (d)tert-butyldimethylsilyl chloride (TBSCl), imidazole, DCM; (e) CAN, acetone/H2O (54%, two steps); (f) [Ir(cod)Cl]2 (2.5 mol%), (R)-BINAP (5 mol%), Cs2CO3, 3-Cl-4-NO2-BzOH, AcOAllyl, THF (59%, dr > 20:1); (g) acryloyl chloride, Et3N, DCM (67%); (h) Grubbs I, DCM; (i) TBAF, AcOH, AcOEt (55%, two steps)
Scheme 5
Total synthesis of the second most likely structure of (+)-cryptoconcatone H (ent-23). Selected reagents and conditions: (a) [Ir(cod)Cl]2 (5 mol%), (S)-BINAP (10 mol%), Cs2CO3, 3-Cl-4-NO2-BzOH, AcOAllyl, THF (93%, dr > 20:1); (b) acryloyl chloride, Et3N, DCM (70%); (c) Grubbs I, DCM; (d) tetra-n-butylammonium fluoride (TBAF), AcOH, AcOEt (38%, two steps)
Figure 5
Planar structure of hemicalide
Figure 6
Isomer that showed the best NMR match for the C-1/C-17 region of hemicalide
Figure 7
Isomer that showed the best NMR match for the C-17/C-25 region of hemicalide
Figure 8
Synthesized structure of one of the possible isomers of the C-1/C-25 subunit of hemicalide
Figure 9
Fragment isomer that showed the best NMR match for the C-36/C-42 region of hemicalide
Figure 10
Virtual fragment used to determine the most likely structure of hemicalide at the C-13/C-27 region. The carbon atoms that were varied to generate the candidate isomers for DP4f calculations are marked with an asterisk
Scheme 6
C-13/C-25 fragment isomer of hemicalide synthesized by Paterson and co-workers3535 MacGregor, C. I.; Han, B. Y.; Goodman, J. M.; Paterson, I.; Chem. Commun.
2016, 52, 4632. following the DP4f predictions. Selected reagents and conditions: (a) (-)-Ipc2BCl, triethylamine (NEt3), Et2O (70%, dr > 20:1); (b)tert-butyldimethylsilyl trifluoromethanesulfonate (TBSOTf), 2,6-lutidine, DCM (95%); (c) AcOEt, lithium diisopropylamide (LDA), THF (97%); (d) HF-pyr, THF (85%); (e) DMAP, Ac2O/pyr/PhH (83%); (f) K2OsO4.2H2O, N-methylmorpholine-N-oxide (NMO), citric acid, tBuOH/H2O/THF (85%); (g) Pd(PPh3)4 (20 mol%), copper(I)-thiophene-2-carboxylate (CuTC), [Ph2PO2][NBu4], dimethylformamide (DMF) (74%)
Figure 11
Virtual fragment used to determine the most likely structure of hemicalide at the C-33/C-44 region. The carbon atoms that were varied to generate the candidate isomers for DP4f calculations are marked with an asterisk
Figure 12
Originally proposed candidates for stolonine A
Figure 13
Originally proposed structures 49 and 50 for glabramycin B and C, respectively, and structure of Sch-642305 (51) verified by X-ray and total synthesis
Figure 14
Most likely structures 52 and 53 for glabramycin B and C, respectively, according to NMR calculations. The carbon atoms that were varied to generate the candidate isomers are marked with an asterisk
Scheme 7
Total synthesis of the most likely structure 52 of glabramycin B. Selected reagents and conditions: (a) diisobutylaluminium hydride (DIBAL), DCM; (b) TBAF, THF; (c) Ag2CO3, Celite, PhH, Δ (65%, three steps); (d) NCCO2Me, lithium bis(trimethylsilyl)amide (LHMDS), THF (99%); (e) HF, MeCN (99%); (f) LiOH.H2O, dioxane, H2O (99%); (g) 2-methyl-6-nitrobenzoic anhydride (MNBA), 4-(dimethylamino)pyridine (DMAP), DCM (64%); (h) H2, Rh/Al2O3, AcOEt (99%); (i) potassium bis(trimethylsilyl)amide (KHMDS), Tf2O, DME;(j) DMP, NaHCO3, DCM; (k) tris(dimethylamino)sulfonium difluorotrimethylsilicate (TAS-F), DMF (69%, two steps)
Figure 15
Originally proposed (61) and most likely (62) structures of nobilisitine A. The carbon atoms that were varied to generate the candidate isomers are marked with an asterisk
Scheme 8
Total synthesis of the most likely structure of nobilisitine A according to NMR calculations. Selected reagents and conditions: (a) NaH, CS2, BrCH2CCH (67%); (b) BzOH, chlorobenzene, reflux (21%); (c) K2CO3, MeOH (91%)
Figure 16
Originally proposed (66) and most likely (67) structures of madeirolide A. The carbon atoms that were varied to generate the candidate isomers are marked with an asterisk
Figure 17
Left: 3D representation of the C-3/C-9 segment of madeirolide A as shown by Wright and Winder
4848 Winder, P. L.; Ph.D. Thesis, Florida Atlantic University, 2009. Available at http://purl.flvc.org/FAU/369392, accessed in February 2018.
http://purl.flvc.org/FAU/369392...
showing the correct
R configuration at C-9. Right: 2D representation of the C-3/C-9 segment of madeirolide A as originally represented by Wright and Winder
4848 Winder, P. L.; Ph.D. Thesis, Florida Atlantic University, 2009. Available at http://purl.flvc.org/FAU/369392, accessed in February 2018.
http://purl.flvc.org/FAU/369392...
with the accidentally inverted configuration at C-9
Scheme 9
Total synthesis of the C-1/C-11 fragment of madeirolide A. Selected reagents and conditions: (a) (-)-(Ipc)2BOTf, i-Pr2NEt, DCM, then TBSOCH2CH2CHO (93%, dr > 95:5); (b) SmI2, EtCHO, THF (dr > 95:5); (c) K2CO3, MeOH; (d) (MeO)2CMe2, PPTS (86%, three steps); (e) TBAF, THF (98%); (f) DMP, NaHCO3, DCM (97%); (g) LiCl, Et3N, THF (95%, E:Z 19:1); (h) TsOH, DCM (dr > 20:1); (i) 2,3-dichloro-5,6-dicyano-p-benzoquinone (DDQ), DCM (61%, two steps); (j) (2,2,6,6-tetramethylpiperidin-1-yl)oxyl (TEMPO), bis(acetoxy)iodobenzene (BAIB), DCM (97%); (k) CrCl2, CHI3, THF (55%); (l) BF3·OEt2, DCM (78%, α:β 19:1)
Figure 18
Originally proposed structure of leiodermatolide
Figure 19
Model fragments used to determine the most likely structure of the C-1/C-15 and C-21/C-33 region of leiodermatolide. The carbon atoms that were varied to generate the candidate isomers for DP4 calculations are marked with an asterisk
Figure 20
Western fragments of leiodermatolide synthesized by Maier and co-workers5252 Rink, C.; Navickas, V.; Maier, M. E.; Org. Lett.
2011, 13, 2334. (78) and Paterson et al.5151 Paterson, I.; Dalby, S. M.; Roberts, J. C.; Naylor, G. J.; Guzmán, E. A.; Isbrucker, R.; Pitts, T. P.; Linley, P.; Divlianska, D.; Reed, J. K.; Wright, A. E.; Angew. Chem., Int. Ed.
2011, 50, 3219. (79)
Scheme 10
Total synthesis of the most likely structure of leiodermatolide. Selected reagents and conditions: (a) Bu2BOTf, NEt3, propanal (97%); (b) SO3-pyridine, DCM, dimethyl sulfoxide (DMSO), Et3N (88%); (c) but-2-ynal, Sn(OTf)2, NEt3, DCM (55%); (d) PBr3, pyridine, Et2O; (e) AcOEt, LDA, CuI, THF (63%, two steps); (f) Me3SiOK, Et2O (100%); (g) EDC.HCl, DMAP, DCM (89%); (h) 89, DCM/PhMe, 100 ºC (72%); (i) 87, Pd(PPh3)4 (20 mol%), Tl(OEt), THF/H2O, tert-butyl methyl ether (TBME) (55%)
Figure 21
Originally proposed structure of elatenyne
Scheme 11
Synthesis of the pyrano[3,2-b]pyran core of the originally proposed structure of elatenyne. Selected reagents and conditions: (a) DIBAL, DCM, then Ac2O, DMAP, pyridine, DCM (83%); (b) MeOH, HCl (90%); (c) Me3SiI, MeCN, then, (Me3Si)2NH; (d) 3,3-dimethyldioxirane, NaHCO3, DCM; (e) Allyl2Mg, Et2O, THF (57%, three steps)
Figure 22
Selected 13C NMR chemical shifts for pyrano[3,2,b]pyran and 2,2'-bifuranyl systems
Figure 23
Most likely structure 99 for elatenyne according to NMR calculations. The carbon atoms that were varied to generate the candidate isomers are marked with an asterisk
Scheme 12
Proposed biosynthesis of elatenyne
Scheme 13
Synthesis of the most likely structure of ent-99 by Burton and co-workers.5959 Dyson, B. S.; Burton, J. W.; Sohn, T.; Kim, B.; Bae, H.; Kim, D.; J. Am. Chem. Soc.
2012, 134, 11781. Selected reagents and conditions: (a) L-(+)-DCT, Ti(OiPr)4, tBuOOH, DCM (38%, ee > 95%); (b) NaH, PMBBr, TBAI, THF; (c) MeMgBr, CuI, THF; (d) TESCl (87%, three steps); (e) p-bromobenzyl-protected 107, Grubbs II, 1,4-benzoquinone, DCM (45%); (f) AD-mix-α, tBuOH/H2O (71%); (g) CSA, DCM (72%); (h) MsCl, Et3N, DCM. (i) TBAF, THF (66%, two steps); (j) TBAI, PhMe (83%); (k) VinylMgBr, PhH/THF (58%); (l) O3, Ph3P, DCM (85%); (m) 114, THF (83%, Z:E > 30:1); (n) TBAF, DCM (80%)
Scheme 14
Synthesis of the most likely structure 99 by Kim and co-workers.5959 Dyson, B. S.; Burton, J. W.; Sohn, T.; Kim, B.; Bae, H.; Kim, D.; J. Am. Chem. Soc.
2012, 134, 11781. Selected reagents and conditions: (a) LiHDMS, CH2=CHCH2Br, THF (85%, anti/syn 9.3:1); (b) ClSO2CH2Cl, 2,6-lutidine, DCM; (c) LiBr, Et2O/THF (72%, two steps); (d) Grubbs I, DCM (94%); (e) BnO(CH2)3MgBr, THF (94%); (f) L-selectride, THF (99%); (g) PhSeBr, SiO2, K2CO3, DCM (70%); (h) NBS, DCM (91%); (i) MeCN, 80 ºC (93%); (j) H2, Pd(OH)2, THF (95%); (k)o-nitrophenylselenocyanide, (Oct)3P, THF, then H2O2 (97%); (l) enyne 126, Grubbs-Hoveyda II, PhH (68%, Z:E 4.6:1); (m) TBAF, THF (98%)
Figure 24
Originally proposed structures 128 and 129 for laurefurenynes A and B, respectively
Figure 25
Structures of notoryne (130) and laurendecumenyne (131)
Figure 26
Most likely structure 132 for laurefurenyne B according to NMR calculations. The carbon atoms that were varied to generate the candidate isomers are marked with an asterisk
Scheme 15
Synthesis of the most likely structure 132 for laurefurenyne B. Selected reagents and conditions: (a) BCl3, DCM (94%); (b) diisopropyl azodicarboxylate (DIAD), PPh3, p-nitrobenzoic acid, THF; (c) K2CO3, MeOH (75%, two steps); (d) crotonaldehyde, Grubbs II, DCM; (e) TMSCH2N2, LDA, THF, then 2 M HCl (45%, two steps)
Figure 27
Originally proposed structure of hexacyclinol
Scheme 16
Rychnovsky's6565 Rychnovsky, S. D.; Org. Lett.
2006, 8, 2895. proposal of structure 138 for hexacyclinol to be obtained from panepophenanthrin (135)
Scheme 17
Synthesis of the revised structure of hexacyclinol (138). Selected reagents and conditions: (a) K10 clay, DCM (98%); (b) Et3SiCl, 2,6-lutidine, DMAP, DCM (83%); (c) Pd2(dba)3, AsPh3, PhMe (96%); (d) Et3N·3HF, MeCN; (e) neat, rt, 72 h (87%, two steps); (f) K10, AcOEt (99%)
Figure 28
Proposed structures for aldingenins A-D
Scheme 18
Synthetic plan by Crimmins and Hughes7272 Crimmins, M. T.; Hughes, C. O.; Org. Lett.
2012, 14, 2168. for structure 140 proposed for aldingenin B
Scheme 19
Synthesis of structure 141 proposed for aldingenin C. Selected reagents and conditions: (a) HOCl, DCM (83%); (b) KOAc, DCM (80%); (c) K2CO3, MeOH (71%); (d) CSA, DCM, 0 ºC, rt; (e) Ac2O, pyr, rt; (f) K2CO3, MeOH; (g) TBSOTf, 2,6-lutidine, DCM, –78 ºC (18%, four steps); (h) OsO4, NaIO4, aq THF, room temperature (rt) (88%); (i) LDA, prenylbromide, THF, HMPA, –78 ºC, 0 ºC; (j) LHMDS, THF, HMPA, then dimethyl D-tartrate, –78 ºC, rt (44%, two steps); (k) MeLi, THF, –78 ºC (94%); (l) TBCO, MeNO2, 0 ºC (25%); (m) TBAF, THF, 0 ºC (85%)
Figure 29
Structures proposed by Kutateladze and co-workers7474 Kutateladze, A. G.; Mukhina, O. A.; J. Org. Chem.
2014, 79, 8397. for aldingenins A and B
Figure 30
Proposed structures for aquatolide by San Feliciano et al.7676 San Feliciano, A.; Medarde, M.; del Corral, J. M. M.; Aramburu, A.; Gordalira, M.; Barreroa, A. F.; Tetrahedron Lett. 1989, 30, 2851. (152) and Tantillo and co-workers7777 Lodewyk, M. W.; Soldi, C.; Jones, P. B.; Olmstead, M. M.; Rita, J.; Shaw, J. T.; Tantillo, D. J.; J. Am. Chem. Soc.
2012, 134, 18550; Liu, Y.; Saurí, J.; Mevers, E.; Peczuh, M. W.; Hiemstra, H.; Clardy, J.; Martin, G. E.; Williamson, R. T.; Science
2017, 356, 5349. (153)
Scheme 20
Total synthesis of the most likely structure 153 for aquatolide. Selected reagents and conditions: (a) Ti(OiPr)4, KOtBn, THF, –10 ºC; (b) HC(OMe)3, pTsOH, MeOH (62%, two steps); (c) BnO(CH2)3CH(CO2H)P(O)Et2, DCC, DMAP, DCM; (d) HCl (aq), acetone (92%, two steps); (e) NaH, THF (76%); (f) (CH2O)n, Cy2NH, CuI, 1,4-dioxane, reflux (79%); (g) hv (300 nm), acetone (77%); (h) BH3, THF, then H2O2, NaOH (36%); (i) DMP, DCM, 0 ºC; (j) EtMgBr, Et2O, 0 ºC; (k) H2, 10% Pd/C, EtOAc; (l) DMP, DCM, 0 ºC, (49%, 4 steps); (m) HC(OMe)3, CeCl3.7H2O, MeOH (82%); (n) LHMDS, THF, -78 ºC, then TMSCl, -78 ºC, rt; (o) BF3·OEt2, DCM, -78 ºC, rt; (p) pTsOH, tol, reflux (59%, three steps)
Figure 31
Structure proposed by Kuono and co-workers8080 Shiraiwa, K.; Yuan, S.; Fujiyama, A.; Matsuo, Y.; Tanaka, T.; Jiang, Z. H.; Kuono, I.; J. Nat. Prod. 2012, 75, 88. for decurrenside D
Scheme 21
(A) Reported synthesis towards decurrenside D according to Sartillo-Piscil and co-workers.8181 González-Márquez, V.; Cruz-Gregorio, S.; Sandoval-Lira, J.; Quintero, L.; Sartillo-Piscil, F.; Tetrahedron Lett. 2015, 56, 5416. (a) BnBr, NaH (90%); (b) H5IO6, EtOAc; (c) NaBH4, EtOH (75%, two steps); (d) BzCl, pyr (85%); (e) AllylTMS (exc.), BF3·OEt2 (exc.), DCM, 0 ºC (80%); (f) 2,2-dimethoxypropane, p-TsOH (cat.) (80%); (g) Br2, CCl4; (h) DBU, DMF (60%, two steps); (i) NBS, AgNO3 (64 %); (j) KMnO4, NaHCO3, MgSO4, MeOH/H2O (65%); (B) structures of the mixture of compounds obtained after acid treatment of 164 by Sartillo-Piscil and co-workers8181 González-Márquez, V.; Cruz-Gregorio, S.; Sandoval-Lira, J.; Quintero, L.; Sartillo-Piscil, F.; Tetrahedron Lett. 2015, 56, 5416. as validated by Kutateladze8282 Kutateladze, A. G.; J. Org. Chem.
2016, 81, 8659. through computed 13C chemical shifts
Figure 32
Structure of decurrenside D proposed by Kutateladze.8282 Kutateladze, A. G.; J. Org. Chem.
2016, 81, 8659.
Figure 33
Originally proposed structures 167 and 168 for ocimicides A1 and B1, and derivatives 169 and 170 for ocimicide A2 and B2, respectively
Scheme 22
Synthesis of advanced intermediate of ocimicide A1. Selected reagents and conditions: (a) Pd(PPh3)4, CuI, CsF (> 99%); (b) (i) OsO4, NMO, 2,6-lutidine, then PIDA; (ii) concentrate, then NaClO2, NaH2PO4, 2-methyl-2-butene; (c) (i) NBS, DMAP; (ii) evaporate, then K2CO3, MeOH (45%, two steps); (d) LHMDS, tol, 103 ºC (44%); (e) (i) MsCl, Et3N, DCM; (ii) concentrate, then NaOMe, MeOH; (iii) concentrate, then 2M H2SO4, THF (96%, two steps)
Figure 34
Originally proposed structures of baulamycins A (177) and B (178)
Scheme 23
Synthesis of the proposed structure of balaumcin A. Selected reagents and conditions: (a) (i) TiCl4, DIPEA, NMP, DCM, 0 ºC, then di-O-(terc-butyldimethylsilyl)-3,5-dihydroxybenzaldehyde (95%); (b) TBSOTOf, 2,6-lutidine (96%); (c) LiBH4, THF, 0 ºC (89%); (d) Swern oxidation; (e) (S)-4-isopropylthiazolidine-2-thione, TiCl4, DIPEA, DCM, -40 to -78 ºC (68%, dr = 5:1); (f) imidazole, MeOH (88%); (g) TESOTf, 2,6-lutidine (94%); (h) (MeO)2P(O)Me, n-BuLi, –78 ºC (83%); (i) 183, Ba(OH)2.8H2O, THF/H2O, 0 ºC (84%); (j) H2, 10% Pd/C, EtOAc (98%); (k) CSA, DCM, MeOH, 0 ºC (79%); (l) DIBAl-H, THF, -78 ºC (77%, dr = 3:1); (m) 2,2-dimethoxypropane, CSA, DCM/MeOH (89%); (n) Dess-Martin oxidation (100%); (o) EtMgBr, THF, 0 ºC (79%, dr = 6:1); (p) Dess-Martin oxidation (78%); (q) 70% HF·py, THF, 0 ºC to rt (90%)
Figure 35
Diasteroisomers 185 and 186 proposed by Goswami and co-workers8787 Guchhait, S.; Chatterjee, S.; Ampapathi, R. S.; Goswami, R. K.; J. Org. Chem. 2017, 82, 2414. for the structure for balaumycin A
Scheme 24
Synthesis of fragment 187. (a) (i) [Rh(cod)Cl]2 (1.5 mol%), catecholborane, iPr3P (6 mol%), Et3N, cyclohexane; (ii) pinacol, cyclohexane (91%, Z:E = 99:1); (b) (i) ICH2Cl, n-BuLi, Et2O, -95 ºC; (ii) MeCN, -95 ºC (85%, Z:E = 99:1); bis-O-methoxymethyl-3,5-dihydroxybenzaldehyde, (R)-TRIP-PA (5 mol%), tol, -30 ºC (89%, dr = 98:2, er = 95:5); (d) bis(pinacolato)diboron (B2Pin2), Cs2CO3, MeOH, THF, 70 ºC; (e) chlorotriethylsilane (TESCl), Et3N, DMAP, DCM (46%, two steps, dr = 98:2)
Scheme 25
Synthesis of fragments 188 and 189. (a) AllylBr, K2CO3, MeCN (100%); (b) RhCl(PPh3)3 (1 mol%), pinBH, DCM (71%); (c) (S)-TIBOCH(Me)SnMe3, n-BuLi, Et2O, -78 ºC; (d) BrCH2Cl, n-BuLi, Et2O; (e) (R)-TIBOCH(Me)SnMe3, n-BuLi, Et2O; (f) BrCH2Cl, n-BuLi, Et2O (64%, four steps, dr > 95:5); (h) MeCH=CH(OMOM) (4:1 Z/E mixture), sec-BuLi, THF, -78 to -30 ºC, then 194, -78 ºC to rt, then I2, THF, -78 ºC, then EtOCH=CH2 and NaOMe, MeOH, -78 ºC to rt (72%); (i) CH2=CH(OMOM), sec-BuLi, THF, -78 to -30 ºC, then 194, -78 ºC to rt, then I2, THF, -78 ºC, then EtOCH=CH2 and NaOMe, MeOH, -78 ºC to rt (86%). TIB = 2,4,6-triisopropyl benzoyl
Scheme 26
Synthesis of the proposed structure of balaumcin A. Selected reagents and conditions: (a) (i) sec-BuLi, (-)-sparteine, Et2O, -78 ºC; (ii)187; (iii) H2O2, NaOH, THF (195, 70%; 196, 48%); (b) HCl, THF/MeOH (177, 83%; 178, 55%)
Scheme 27
Preparation of stereotriad 199. Selected reagents and conditions: (a) CH2=CHMgBr, THF, rt (74%); (b) [Pd(dmba)Cl]2, B2pin2, TsOH (5 mol%), DMSO/MeOH, 50 ºC (67%, E:Z = 97:3); (c) bis(O-methoxymethyl)-3,5-diydroxybenzaldehyde, (R)-TRIP-PA (5 mol%), tol, –30 ºC (95%, dr = 97:3), enantiomeric ratio (e.r.) = 97:3); B2pin2, Cs2CO3, MeOH, THF, 70 ºC; (e) TESCl, Et3N, DMAP, DCM (64%, two steps)
Scheme 28
Preparation of structure 201. Selected reagents and conditions: (a) (i) sec-BuLi, (-)-sparteine, Et2O, -78 ºC, then 199; (ii) H2O2, NaOH, THF (55%); (b) 2 M HCl, THF/MeOH (82%)
Scheme 29
Preparation of baulamycin A and B. Selected reagents and conditions: (a) (i) s-BuLi, ent-200, (+)-sparteine, Et2O, -78 ºC, then ent-199, -78 ºC; (ii) H2O2, NaOH, THF (63%, dr > 95:5); (b) (i) s-BuLi, 202, (+)-sparteine, Et2O, -78 ºC, then ent-199, -78 ºC; (ii) H2O2, NaOH, THF (60%, dr > 95:5); (c) HCl 2 M, THF/MeOH, rt (92% for ent-201; 56% for 203)
Figure 36
Proposed structures of goupiolones A and B (204 and 205, respectively), and revised structure of goupiolone B (206)
Scheme 30
Synthesis of the revised structure of goupiolone B (206). Selected reagents and conditions: (a) 2,2-diphenyl-1-picrylhydrazyl (DPPH), acetone, rt; (b) K3[Fe(CN)6], NaHCO3, MeCH/H2O (4:1), rt (11%); (c) cerium ammonium nitrate (CAN), MeCH/H2O (4:1), rt (22%)
Figure 37
Originally proposed structure for spiroleucettadine
Scheme 31
Different approaches for the synthesis of proposed structure 211 for spiroleucettadine. (a) PhI(OAc)2, aq (CF3)2CHOH, rt, 15 min (8%)
Figure 38
Structures of 220 and 221 considered as possible candidates for spiroleucettadine
Figure 39
Calculated possible structures for spiroleucettadine
Scheme 32
Total synthesis of the most likely structure of spiroleucettadine (223). Selected reagents and conditions: (a) BnCl, K2CO3, tetrabutylammonium iodide (TBAI), acetone, 70 ºC (87%); (b) NaOH, DCM/MeOH (82%); (c) NH(OMe)Me·HCl, EDCI, hydroxybenzotriazole (HOBT), Et3N (87%); (d) 4-MeOBnMgCl, THF, 0 ºC (67%); (e) H2, Pd/C 5%, MeOH/EtOAc (84%); (f) TFA, DCM, 0 ºC (93%); (g) N-methyl carbamoylimidazole, THF; (h) PIDA, TFE, 0 ºC (17%, two steps); (i) DMP, fluoroethanol, 60 ºC (75%); (j) NH2Me·HCl, Et3N, THF (91%)
