Total Synthesis of Amphidinolide X and Its 12Z-Isomer by Formation of the C12-C13 Trisubstituted Double Bond via Ring-Closing Metathesis

Abstract

Amphidinolide X, a 16-membered cytotoxic macro­diolide, and its 12Z-isomer have been synthesized via ring-closing metathesis (RCM) for assembling the C12-C13 trisubstituted double bond. A 29:71 E/Z mixture was obtained from the seco substrate appended with a bulky C8-ODPS group in 50-65% combined yields by using 20 mol% of the second-generation Grubbs initiator and the corresponding indenylidene ruthenium complex. Amphidinolide X and 12Z-isomer exhibit similar cytotoxicity (IC₅₀: 7.6-13.9 µg/mL) against A549, KB, and HL60 cell lines.

anti-selective aldehyde crotylation - macrodiolide - ring-closing metathesis - microwave - trisubstituted olefin

References and Notes

1 Tsuda M. Izui N. Shimbo K. Sato M. Fukushi E. Kawabata J. Katsumata K. Horiguchi T. Kobayashi J.
J. Org. Chem.  2003,  68:  5339 

2a Kobayashi J. Tsuda M. Nat. Prod. Rep.  2004,  21:  77 

2b Kobayashi J. Kubata M. J. Nat. Prod.  2007,  70:  451 

3 Tsuda M. Izui N. Shimbo K. Sato M. Fukushi E. Kawabata J. Kobayashi J. J. Org. Chem.  2003,  68:  9109 

For the first total syntheses of amphidinolide X and Y, see:

4a Lepage O. Kattnig E. Fürstner A. J. Am. Chem. Soc.  2004,  126:  15970 

4b Fürstner A. Kattnig E. Lepage O. J. Am. Chem. Soc.  2006,  128:  9194 

5 For a review, see: Parenty A. Moreau X. Campagne J.-M. Chem. Rev.  2006,  106:  911 

For reviews, see:

6a Grubbs RH. Chang S. Tetrahedron  1998,  54:  4413 

6b Fürstner A. Angew. Chem. Int. Ed.  2000,  39:  3012 

6c Trnka TM. Grubbs RH. Acc. Chem. Res.  2001,  34:  18 

6d Schrock RR. Hoveyda AH. Angew. Chem. Int. Ed.  2003,  42:  4592 

6e Deiters A. Martin SF. Chem. Rev.  2004,  104:  2199 

6f Grubbs RH. Tetrahedron  2004,  60:  7117 

6g Nicolaou KC. Bulger PG. Sarlah D. Angew. Chem. Int. Ed.  2005,  44:  4490 

6h Gradillas A. Pérez-Castells J. Angew. Chem. Int. Ed.  2006,  45:  6086 

6i Schrodi Y. Pederson RL. Aldrichimica Acta  2007,  40:  45 

6j Hoveyda AH. Zhugralin AR. Nature (London)  2007,  450:  243 

6k See also: Handbook of Metathesis   Vol. 1-3:  Grubbs RH. Wiley-VCH; Weinheim: 2003. 

7 For the second total synthesis of amphidinolide Y, see: Jin J. Chen Y. Li Y. Wu J. Dai W.-M. Org. Lett.  2007,  9:  2585 

For Ru-mediated RCM to macrocyclic trisubstituted E-alkenes, see:

8a Fürstner A. Thiel OR. Ackermann L. Org. Lett.  2001,  3:  449 

8b Nicolaou KC. Vassilikogiannakis G. Montagnon T. Angew. Chem. Int. Ed.  2002,  41:  3276 

8c Nicolaou KC. Montagnon T. Vassilikogiannakis G. Mathison CJN. J. Am. Chem. Soc.  2005,  127:  8872 

8d Ichige T. Kamimura S. Mayumi K. Sakamoto Y. Terashita S. Ohteki E. Kanoh N. Nakata M. Tetrahedron Lett.  2005,  46:  1263 

8e Alexander MD. Fontaine SD. La Clair JJ. DiPasquale AG. Rheingold AL. Burkart MD. Chem. Commun.  2006,  4602 

8f Trost BM. Dong G. Vance JA. J. Am. Chem. Soc.  2007,  129:  4540 

8g Feyen F. Jantsch A. Altmann K.-H. Synlett  2007,  415 

8h For Ru-mediated RCM to macrocyclic trisubstituted Z-alkenes or E/Z mixtures, see: Vassilikogiannakis G. Margaros I. Tofi M. Org. Lett.  2004,  6:  205 

8i Nicolaou KC. Xu H. Chem. Commun.  2006,  600 

8j Park PK. O’Malley SJ. Schmidt DR. Leighton JL. J. Am. Chem. Soc.  2006,  128:  2796 

8k Smith AB. Mesaros EF. Meyer EA. J. Am. Chem. Soc.  2006,  128:  5292 

8l Larrosa I. Da Silva MI. Gómez PM. Hannen P. Ko E. Lenger SR. Linke SR. White AJP. Wilton D. Barrett AGM. J. Am. Chem. Soc.  2006,  128:  14042 

8m Alhamadsheh MM. Gupta S. Hudson RA. Perera L. Tillekeratne LMV. Chem. Eur. J.  2008,  14:  570 

8n For Mo-mediated RCM to macrocyclic trisubstituted Z-alkenes or E/Z mixtures, see: Xu Z. Johannes CW. Houri AF. La DS. Cogan DA. Hofilena GE. Hoveyda AH. J. Am. Chem. Soc.  1997,  119:  10302 ; and references cited therein

8o May SA. Grieco PA. Chem. Commun.  1998,  1597 

8p Content S. Dutton CJ. Roberts L. Bioorg. Med. Chem. Lett.  2003,  13:  321 

9a Chen Y. Jin J. Wu J. Dai W.-M. Synlett  2006,  1177 

9b For an alternative synthesis, see: Rodríguez-Escrich C. Olivella A. Urpí F. Vilarrasa J. Org. Lett.  2007,  9:  989 

10a Brown HC. Bhat K. J. Am. Chem. Soc.  1986,  108:  293 

10b Roush WR. Halterman RL. J. Am. Chem. Soc.  1986,  108:  294 

10c Roush WR. Ando K. Powers DB. Palkowitz AD. Halterman RL. J. Am. Chem. Soc.  1990,  112:  6339 

10d Benowitz AB. Fidanze S. Small PLC. Kishi Y. J. Am. Chem. Soc.  2001,  123:  5128 

11 Hackman BM. Lombardi PJ. Leighton JL. Org. Lett.  2004,  6:  4375 

12 Garbaccio RM. Stachel SJ. Baeschlin DK. Danishefsky SJ. J. Am. Chem. Soc.  2001,  123:  10903 

13

We used noncrystallized form of the reagent. An 85:15 mixture of (S,S)-9 and its Z-isomer was prepared from an 85:15 mixture of E- and Z-crotyl chloride obtained from Aldrich according to the literature procedure (ref. 11). The Z-isomer of (S,S)-9 reacted with (R)-8 to produce a syn-homoallyl alcohol which is different from 3′. The diaste-
reomeric ratio of >99:1 was estimated according to the ¹H NMR spectrum of the product mixture.

14a Heckrodt TJ. Mulzer J. Synthesis  2002,  1857 

14b Bailey WF. Punzalan ER. J. Org. Chem.  1990,  55:  5404 

15 Inanaga J. Hirata K. Saeki H. Katsuki T. Yamaguchi M. Bull. Chem. Soc. Jpn.  1979,  52:  1989 

16a McMurry JE. Wong GB. Synth. Commun.  1972,  2:  389 ; and references cited therein

16b For microwave-assisted cleavage of aromatic methyl esters, see: Sheppard GS. Wang J. Kawai M. Fidanze SD. BaMaung NY. Erickson SA. Barnes DM. Tedrow JS. Kolaczkowski L. Vasudevan A. Park DC. Wang GT. Sanders WJ. Mantei RA. Palazzo F. Tucker-Garcia L. Lou P. Zhang Q. Park CH. Kim KH. Petros A. Olejniczak E. Nettesheim D. Hajduk P. Henkin J. Lesniewski R. Davidsen SK. Bell RL. J. Med. Chem.  2006,  49:  3832 

17a Fürstner A. Langemann K. J. Am. Chem. Soc.  1997,  119:  9130 

17b Nevalainen M. Koskinen AMP. Angew. Chem. Int. Ed.  2001,  40:  4060 

18a Jafarpour L. Schanz H.-J. Stevens ED. Nolan SP. Organometallics  1999,  18:  5416 

18b Fürstner A. Hill AF. Liebl M. Wilton-Ely JDET. Chem. Commun.  1999,  601 

18c For use of an analogous indenylidene ruthenium complex of 24 in the synthesis of the ADE-ring system of Nakadomarin A, see: Fürstner A. Guth O. Düffels A. Seidel G. Liebl M. Gabor B. Mynott R. Chem. Eur. J.  2001,  7:  4811 

18d For recent studies on comprehensive comparison of RCM initiators, see: Clavier H. Nolan SP. Chem Eur. J.  2007,  13:  8029 

18e Bieniek M. Michrowska A. Usanov DL. Grela K. Chem. Eur. J.  2008,  14:  806 

19

Procedure for Synthesis of (12 Z )-Amphidinolide X via Ring-Closing Metathesis of the seco Ketone 19 Using Second-Generation Grubbs Initiator 23 To a degassed, refluxing solution of the seco ketone 19 (30.0 mg, 6.3×10^-2 mmol) in anhyd CH₂Cl₂ (100 mL) under a nitrogen atmosphere was added the second-generation Grubbs initiator 23 (2.7 mg, 0.3×10^-2 mmol). The resulting clear, pale pink solution changed to a clear yellow color after refluxing for 24 h. Three additional portions of 23 (2.7 mg, 0.3×10^-2 mmol; a total of 1.2×10^-2 mmol) were added after 24, 48, and 72 h, respectively. After refluxing for a total of 4 d, the reaction mixture was concentrated to <1 mL on a rotary evaporator, and the remaining mixture was purified directly by flash column chromatography over SiO₂ [eluting with 3% EtOAc in PE (bp 60-90 °C)] to give (12Z)-amphidinolide X [(12Z)-1, 24.0 mg, 85%]. (12Z)-Amphidinolide X [(12Z)-1]: colorless oil; [α]_D ¹⁷ -16.0 (c 1.00, CHCl₃). IR (film): 2964, 1731, 1655, 1454, 1377, 1315, 1269, 1215, 1167, 1049 cm^-1. ¹H NMR (400 MHz, CDCl₃): δ = 6.92 (dd, J = 16.0, 6.4 Hz, 1 H), 5.81 (dd, J = 16.0, 1.6 Hz, 1 H), 5.18 (dt, J = 8.8, 4.0 Hz, 1 H), 4.88 (d, J = 10.4 Hz, 1 H), 4.82 (dt, J = 8.8, 7.2 Hz, 1 H), 3.74 (ddd, J = 10.0, 7.6, 2.8 Hz, 1 H), 2.96-2.89 (m, 1 H), 2.85-2.80 (m, 1 H), 2.66-2.58 (m, 2 H), 2.53 (dd, J = 14.8, 4.8 Hz, 1 H), 2.42-2.33 (m, 2 H), 2.26-2.19 (m, 1 H), 2.16 (s, 3 H), 1.89-1.82 (m, 2 H), 1.70 (s, 3 H), 1.64 (dd, J = 13.2, 7.2 Hz, 1 H), 1.49-1.47 (m, 2 H), 1.36-1.30 (m, 2 H), 1.26 (s, 3 H), 1.15 (d, J = 7.6 Hz, 3 H), 1.05 (d, J = 6.8 Hz, 3 H), 0.91 (t, J = 7.6 Hz, 3 H). ¹³C NMR (125 MHz, CDCl₃): δ = 206.4, 171.3, 166.0, 151.7, 137.3, 126.3, 120.0, 81.9, 79.5, 78.0, 72.8, 44.8, 43.8, 43.1, 40.0, 35.9, 33.9, 31.4, 30.1, 27.3, 26.7, 23.5, 19.6, 17.8, 14.7, 14.6. MS (+ESI): m/z (rel. int.) = 471 (100) [M + Na⁺]. HRMS (+ESI): m/z calcd for C₂₆H₄₀O₆Na⁺ [M + Na⁺], 471.2717; found: 471.2719.

20

Procedure for the Synthesis of Amphidinolide X via Ring-Closing Metathesis of 17 Using Second-Generation Grubbs Initiator 23 as the Key Step To a degassed, refluxing solution of 17 (150.0 mg, 0.21 mmol) in anhyd CH₂Cl₂ (150 mL) under a nitrogen atmosphere was added the second-generation Grubbs initiator 23 (8.9 mg, 1.1×10^-2 mmol). The resulting clear, pale pink solution changed to a clear yellow color after refluxing for 24 h. Three additional portions of 23 (8.9 mg, 1.1×10^-2 mmol; a total of 4.4×10^-2 mmol) were added after 24, 48, and 72 h, respectively. After refluxing for a total of 6 d, the reaction mixture was concentrated to <1 mL on a rotary evaporator and the remaining mixture was purified directly by flash column chromatography over SiO₂ [eluting with 3% EtOAc in PE (bp 60-90 °C)] to give a 71:29 mixture of the Z and E RCM products 20 and 21 (70.0 mg, 50%) as a colorless oil. The Z/E ratio was determined by the integration of the corresponding signals in the ¹H NMR spectrum. An pure sample of isomer 20 was obtained by flash column chromatography [eluting with 3% EtOAc in PE (bp 60-90 °C)] of the product mixture.
Compound 20: colorless oil; [α]_D ¹⁷ -35.9 (c 2.0, CHCl₃).
IR (film): 2929, 1733, 1653, 1456, 1428, 1379, 1268, 1167, 1112, 1086 cm^-1. ¹H NMR (400 MHz, CDCl₃): δ = 7.68-7.65 (m, 4 H), 7.42-7.32 (m, 6 H), 6.93 (dd, J = 16.0, 6.0 Hz, 1 H), 5.75 (dd, J = 16.0, 1.6 Hz, 1 H), 5.02-5.00 (m, 1 H), 4.86 (d, J = 10.8 Hz, 1 H), 4.78 (dt, J = 8.4, 7.2 Hz, 1 H), 3.82-3.78 (m, 1 H), 3.74-3.70 (m, 1 H), 2.97-2.89 (m, 1 H), 2.74-2.67 (m, 1 H), 2.43-2.36 (m, 2 H), 2.30-2.22 (m, 2 H), 1.91-1.71 (m, 4 H), 1.67 (s, 3 H), 1.64-1.61 (m, 2 H), 1.48-1.44 (m, 2 H), 1.36-1.30 (m, 2 H), 1.25 (s, 3 H), 1.14 (d, J = 6.8 Hz, 3 H), 1.02 (d, J = 6.0 Hz, 3 H), 1.00 (s, 9 H), 0.96 (d, J = 7.2 Hz, 3 H), 0.91 (t, J = 7.2 Hz, 3 H). ¹³C NMR (125 MHz, CDCl₃): δ = 171.3, 166.2, 151.8, 136.3 (2), 136.1 (2), 135.7, 135.3, 134.2, 129.7, 129.6, 127.7 (2), 127.6 (2), 127.4, 119.9, 81.7, 79.8, 77.8, 74.3, 67.6, 44.8, 44.0, 40.1, 38.5, 36.1, 33.4, 31.3, 27.2 (3), 27.1, 26.8, 24.2, 23.3, 19.5, 19.3, 17.9, 14.8, 14.4. MS (+ESI): m/z (rel. int.) = 711 (100) [M + Na⁺]. HRMS (+ESI): m/z calcd for C₄₂H₆₀O₆SiNa⁺ [M + Na⁺], 711.4051; found: 711.4054.
A plastic tube was charged with the 71:29 mixture of 20 and 21 (50.0 mg) in THF (2 mL) followed by adding 70% hydrogen fluoride pyridine (2 mL) at r.t. The resultant mixture was stirred for 24 h at r.t. and the reaction was quenched carefully with sat. aq Na₂CO₃. The reaction mixture was extracted with Et₂O and the combined organic layer was dried over anhyd Na₂SO₄, filtered, and concentrated under reduced pressure. The residue was purified by flash column chromatography over SiO₂ [eluting with 20% EtOAc in PE (bp 60-90 °C)] to give a mixture of the alcohol (34.0 mg, 75%) as a colorless oil. The structure of the alcohol was confirmed by mass spectrometry data. MS (+ESI): m/z (rel. int.) = 473 (100) [M + Na⁺]. HRMS (+ESI): m/z calcd for C₂₆H₄₂O₆Na⁺ [M + Na⁺]: 473.2874; found: 473.2880.
To a solution of the above mixture (34.0 mg, 7.5×10^-2 mmol) in CH₂Cl₂ (1 mL) at r.t. was added NaHCO₃ (19 mg, 0.225 mmol) followed by carefully adding a solution of Dess-Martin periodinane in CH₂Cl₂ (0.3 M, 0.5 mL, 0.15 mmol). The resultant mixture was stirred at r.t. for 4 h followed by treating with sat. aq Na₂S₂O₃. The reaction mixture was extracted with CH₂Cl₂. The organic layer was washed with brine, dried over anhyd Na₂SO₄, filtered, and concentrated under reduced pressure. The residue was purified by flash column chromatography over SiO₂ [eluting with 15% EtOAc in PE (bp 60-90 °C)] to give amphidinolide X (1, 8.0 mg, 23%) and (12Z)-amphidinolide X [(12Z)-1, 21.0 mg, 62%].
Amphidinolide X (1): colorless oil; [α]_D ¹⁷ -26.8 (c 1.00, CHCl₃). IR (film): 2963, 1717, 1654, 1453, 1377, 1265, 1186, 1039 cm^-1. ¹H NMR (500 MHz, CDCl₃): δ = 7.12 (dd, J = 15.8, 7.2 Hz, 1 H), 5.79 (dd, J = 15.8, 1.6 Hz, 1 H), 5.20 (m, 2 H), 4.95 (d, J = 10.3 Hz, 1 H), 3.96 (dt, J = 11.2, 3.6 Hz, 1 H), 2.78 (m, 1 H), 2.69 (dd, J = 16.6, 6.1 Hz, 1 H), 2.69 (m, 1 H), 2.58 (dd, J = 13.6, 3.9 Hz, 1 H), 2.58 (dd, J = 16.5, 7.5 Hz, 1 H), 2.41 (dd, J = 13.3, 6.3 Hz, 1 H), 2.18 (m, 1 H), 2.17 (m, 1 H), 2.14 (s, 3 H), 2.12 (m, 1 H), 1.94 (tt, J = 13.5, 3.3 Hz, 1 H), 1.75 (dd, J = 13.9, 2.4 Hz, 1 H), 1.55 (s, 3 H), 1.54 (m, 1 H), 1.50 (m, 2 H), 1.35 (m, 2 H), 1.30 (s, 3 H), 1.14 (d, J = 6.9 Hz, 3 H), 0.92 (t, J = 7.5 Hz, 3 H), 0.91 (d, J = 7.1 Hz, 3 H). ¹³C NMR (125 MHz, CDCl₃): δ = 205.5, 170.7, 165.8, 153.2, 135.6, 126.1, 120.3, 83.0, 80.6, 78.5, 74.3, 47.2, 44.3, 43.6, 41.5, 35.6, 35.4, 33.1, 30.5, 30.5, 24.7, 18.2, 17.9, 17.6, 15.5, 14.7. MS (+ESI): m/z (rel. int.) = 471 (100) [M + Na⁺]. HRMS (+ESI): m/z calcd for C₂₆H₄₀O₆Na⁺ [M + Na⁺]: 471.2717; found: 471.2699.

Remote control of alkene geometry by endocyclic groups in ring-closing metathesis has been reported. For examples of formation of disubstituted macrocyclic alkenes, see:

21a Meng D. Su D.-S. Balog A. Bertinato P. Sorensen EJ. Danishefsky SJ. Zheng Y.-H. Chou T.-C. He L. Horwitz SB. J. Am. Chem. Soc.  1997,  119:  2733 

21b Fürstner A. Thiel OR. Blanda G. Org. Lett.  2000,  2:  3731 

21c Fürstner A. Dierkes T. Thiel OR. Blanda G. Chem. Eur. J.  2001,  7:  5286 

21d Aïssa C. Riveiros R. Ragot J. Fürstner A. J. Am. Chem. Soc.  2003,  125:  15512 

21e Couladouros EA. Mihou AP. Bouzas EA. Org. Lett.  2004,  6:  977 

21f Castoldi D. Caggiano L. Panigada L. Sharon O. Costa AM. Gennari C. Angew. Chem. Int. Ed.  2005,  44:  588 

21g Matsumura T. Akiba M. Arai S. Nakagawa M. Nishida A. Tetrahedron Lett.  2007,  48:  1265 

21h Mohapatra DK. Ramesh DK. Giardello MA. Chorghade MS. Gurjara MK. Grubbs RH. Tetrahedron Lett.  2007,  48:  2621 

21i For examples of formation of trisubstituted macrocyclic alkenes, see: Meng D. Bertinato P. Balog A. Su D.-S. Kamenecka T. Sorensen EJ. Danishefsky SJ. J. Am. Chem. Soc.  1997,  119:  10073 

21j Nicolaou KC. Vassilikogiannakis G. Montagnon T. Angew. Chem. Int. Ed.  2002,  41:  3276 

21k Nicolaou KC. Montagnon T. Vassilikogiannakis G. Mathison CJN. J. Am. Chem. Soc.  2005,  127:  8872 

21l Vassilikogiannakis G. Margaros I. Tofi M. Org. Lett.  2004,  6:  205 

21m Alhamadsheh MM. Gupta S. Hudson RA. Perera L. Tillekeratne LMV. Chem. Eur. J.  2008,  14:  570 

21n Trost BM. Dong G. Vance JA. J. Am. Chem. Soc.  2007,  129:  4540 

21o Ramírez-Fernández J. Collado IG. Hernández-Galán R. Synlett  2008,  339 ; see also ref. 7