Intermediate (–)-2.53 OTBS OTBS OHC 1. NaClO2, NaH2PO4 2-methyl-2-butene t-BuOH, H2O 2. TMSCHN2 MeOH, benzene (87% for 2 steps) H OTBS OTBS MeO2C 1. O3, CH2Cl2; Me2S 2. DBU, THF (50% for 2 steps) H 1. Wittig Olefination 2. DIBAL-H 3. DMP, NaHCO3 (57%, 3 steps) OTBS OTBS OHC H OTBS OTBS N XC MgBr 1. (4 equiv.) THF, -15 °C 2. MeI, HMPA –10 °C to 23 °C 3. 10% oxalic acid (60% for 3 steps) H OTBS OTBS OHC H OTBS OTBS MeO2C H 1. CuBr·S(CH3)2 HMPA, TMSCl THF, –78 °C 2. BTAF 4Å mol. sieves MeI, THF (37%, two steps) MgBr t-BuO2C NH2 t-Bu cat. HCl, toluene azeotrope (87%) C-12 Inversion 7 Steps (+)-2.21 (!)-2.53 (+)-2.50 (+)-2.48 (+)-2.47 (+)-2.45 O
2.8.2. PROPOSED ENDGAME EMPLOYING EASTERN HEMISPHERE IN TANDEM BUCHWALD-HARTWIG/HECK CASCADE
One possible endgame scenario for the total synthesis of (+)-nodulisporic acid is shown in Scheme 2.31. A strategy in which the sidechain is attached to the eastern
Scheme 2.31. Proposed Endgame for the Total Synthesis of (+)-Nodulipsoric Acid A Employing the Tandem Buchwald-Hartwig/Heck-type Process
NH TIPSO O PGO Cl N O O OH HO CO2H H (+)-Nodulisporic Acid A N O OPG PGO CO2Me H TIPSO 1. TIPS Removal 2. TPAP, NMO 3. Deprotect OH 4. Ti(iPrO)4, allyl alcohol
5. Pd(PPh3)2Cl2, (nBu)3SnH, CH2Cl2 OPG Br H H H H H OMe O Pd-RuPhos RuPhos NaOt-Bu, PhMe H
2.139 2.161
hemisphere prior to the fragment coupling is preferred over any strategy in which the sidechain would need to be attached after the fragment coupling, owing to increased convergency and the avoidance of manipulating the sensitive ring system of NsAA. Thus,
2.139 and a western hemisphere typified by 2.161 will be joined using the RuPhos71 pre- catalyst developed by the Buchwald group. The resulting intermediate 2.162, possessing the carbon skeleton of NsAA, will be de-protected on the D-ring oxygen, and the resulting
alcohol will be oxidized using Ley’s conditions.72 (+)-Nodulisporic acid A will then be
revealed following removal of the protecting groups from the hydroxyls at C-24 and C-7, and subsequent transesterification of the methyl ester to an allyl ester to enable palladium- catalyzed transformation to the acid, a sequence Merck has employed for the synthesis of NsAA analogs.73 The exact protecting groups that will be employed for the protection of the C-24 and C-7 hydroxyls have not yet been determined. The choices available for this task are of course limited due to the highly sensitive nature of NsAA’s ring system (see Chapter 1 of this work).
2.4. REFERENCES FOR CHAPTER 2
1. Smith III, A. B.; Visnick, M.; Haseltine, J. N.; Sprengeler, P. A., Organometallic reagents in synthesis : A new protocol for construction of the indole nucleus. Tetrahedron
1986, 42, (11), 2957-2969.
2. Smith, A. B.; Davulcu, A. H.; Cho, Y. S.; Ohmoto, K.; Kurti, L.; Ishiyama, H., Indole Diterpene Synthetic Studies. Total Synthesis of (+)-Nodulisporic Acid F and Construction of the Heptacyclic Cores of (+)-Nodulisporic Acids A and B and (-)-Nodulisporic Acid D. J. Org. Chem. 2007, 72, (13), 4596-4610.
3. Smith, A. B.; Davulcu, A. H.; Kurti, L., Indole Diterpenoid Synthetic Studies.
Construction of the Heptacyclic Core of (-)-Nodulisporic Acid D. Org. Lett. 2006, 8, (8), 1669- 1672.
4. Kurti, L. Indole Diterpenoid Synthetic Studies. Part 1. Optimization of the Synthetic Sequence Leading to the Eastern Hemisphere Sub-Target of Nodulisporic Acids A, D, and F. Part 2. Construction of the Highly Strained CDEF Parent Tetracycle of Nodulisporic Acids A and B. University of Pennsylvania, Philadelphia, 2006.
5. Erian, A. W.; Sherif, S. M.; Gaber, H. M., The Chemistry of a-haloketones and their Utility in Heterocyclic Synthesis. Molecules 2003, 8, 793-865.
6. Gibe, R.; Kerr, M. A., Convenient Preparation of Indolyl Malonates via Carbenoid Insertion. J. Org. Chem. 2002, 67, (17), 6247-6249.
7. Sheffy, F. K.; Godschalx, J. P.; Stille, J. K., Palladium-catalyzed cross coupling of allyl halides with organotin reagents: a method of joining highly functionalized partners regioselectively and stereospecifically. J. Am. Chem. Soc. 1984, 106, (17), 4833-4840.
8. Smith, A. B.; Kurti, L.; Davulcu, A. H., A New Modular Indole Synthesis. Construction of the Highly Strained CDEF Parent Tetracycle of Nodulisporic Acids A and B. Org. Lett.
9. Smith, A. B.; Kurti, L.; Davulcu, A. H.; Cho, Y. S.; Ohmoto, K., Indole Diterpene Synthetic Studies: Development of a Second-Generation Synthetic Strategy for (+)- Nodulisporic Acids A and B. J. Org. Chem. 2007, 72, (13), 4611-4620.
10. Grubbs, R. H.; Trnka, T. M., The development of L2X2Ru=CHR olefin metathesis
catalyst: an organometallic success story. Acc. Chem. Res. 2001, 34, 18.
11. Grubbs, R. H.; Trnka, T. M., Ruthenium-Catalyzed Olefin Metathesis. In Ruthenium in Organic Synthesis, Wiley-VCH Verlag GmbH & Co. KGaA: 2005; pp 153-177.
12. Wieland, P.; Miescher, K., Über die Herstellung mehrkerniger Ketone. Helv. Chim. Acta 1950, 33, (7), 2215-2228.
13. Smith, A. B.; Fukui, M., Total synthesis of (+)-phyllanthocin. J. Am. Chem. Soc.
1987, 109, (4), 1269-1272.
14. Hajos, Z. G.; Parrish, D. R., Asymmetric synthesis of bicyclic intermediates of natural product chemistry. J. Org. Chem. 1974, 39, (12), 1615-1621.
15. Hagiwara, H.; Uda, H., Optically pure (4aS)-(+)- or (4aR)-(-)-1,4a-dimethyl-4,4a,7,8- tetrahydronaphthalene-2,5(3H,6H)-dione and its use in the synthesis of an inhibitor of steroid biosynthesis. J. Org. Chem. 1988, 53, (10), 2308-2311.
16. Shigehisa, H.; Mizutani, T.; Tosaki, S.-y.; Ohshima, T.; Shibasaki, M., Formal total synthesis of (+)-wortmannin using catalytic asymmetric intramolecular aldol condensation reaction. Tetrahedron 2005, 61, (21), 5057-5065.
17. Kirk, D. N.; Petrow, V., Modified steroid hormones. Part XXVII. A new route to 4- methyl-3-oxo-!-4-steroids. J. Chem. Soc. 1962, 1091-1096.
18. Smith, A. B.; Kurti, L.; Davulcu, A. H.; Cho, Y. S., Development of a Scalable Synthesis of a Common Eastern Tricyclic Lactone for Construction of the Nodulisporic Acids. Org. Process Res. Dev. 2007, 11, (1), 19-24.
19. Evans, D. A.; Chapman, K. T.; Carreira, E. M., Directed reduction of .beta.-hydroxy ketones employing tetramethylammonium triacetoxyborohydride. J. Am. Chem. Soc. 1988,
110, (11), 3560-3578.
20. Hashimoto, S.-i.; Kogen, H.; Tomioka, K.; Koga, K., Asymmetric synthesis of 2- substituted cycloalkanecarboxaldehydes. Tetrahedron Lett. 1979, 20, (32), 3009-3012.
21. Smith, A. B.; Cho, Y. S.; Ishiyama, H., Nodulisporic Acid A Synthetic Studies. 2. Construction of an Eastern Hemisphere Subtarget. Org. Lett. 2001, 3, (24), 3971-3974.
22. Wu, Y. D.; Houk, K. N.; Trost, B. M., Origin of enhanced axial attack by sterically undemanding nucleophiles on cyclohexenones. J. Am. Chem. Soc. 1987, 109, (18), 5560- 5561.
23. Smith, A. B.; Leenay, T. L., Indole diterpene synthetic studies. 5. Development of a
unified synthetic strategy; a stereocontrolled, second-generation synthesis of (-)-paspaline.
J. Am. Chem. Soc. 1989, 111, (15), 5761-5768.
24. Mewshaw, R. E.; Taylor, M. D.; Smith, A. B., Indole diterpene synthetic studies. 2.
First-generation total synthesis of (-)-paspaline. J. Org. Chem. 1989, 54, (14), 3449-3462.
25. Trost, B. M.; Nishimura, Y.; Yamamoto, K., A total synthesis of aphidicolin. J. Am.
Chem. Soc. 1979, 101, (5), 1328-1330.
26. Smith, A. B.; Kingery-Wood, J.; Leenay, T. L.; Nolen, E. G.; Sunazuka, T., Indole
diterpene synthetic studies. 8. The total synthesis of (+)-paspalicine and (+)-paspalinine. J.
Am. Chem. Soc. 1992, 114, (4), 1438-1449.
27. Suzuki, M.; Suzuki, T.; Kawagishi, T.; Noyori, R., Organocopper conjugate addition
revisited. Tetrahedron Lett. 1980, 21, (13), 1247-1250.
28. Lipshutz, B. H.; Wilhelm, R. S.; Kozlowski, J., Chemistry of higher order, mixed
organocuprates. reactions of α,β-unsaturated ketones. Tetrahedron Lett. 1982, 23, (37), 3755-3758.
29. Nagata, W.; Yoshioka, M., Alkylaluminum cyanides as potent reagents for
30. Greene, A. E.; Lansard, J. P.; Luche, J. L.; Petrier, C., Efficient syntheses of (.+-.)-!- cuparenone. Conjugate addition of organozinc reagents. J. Org. Chem. 1984, 49, (5), 931- 932.
31. Luche, J.-L.; Petrier, C.; Lansard, J. P.; Greene, A. E., Ultrasound in organic
synthesis. 4. A simplified preparation of diarylzinc reagents and their conjugate addition to "- enones. J. Org. Chem. 1983, 48, (21), 3837-3839.
32. Flemming, S.; Kabbara, J.; Nickisch, K.; Neh, H.; Westermann, J. r., Nickel-
Catalysed Conjugate Addition of Trimethylaluminum to Sterically Hindered ",!-Unsaturated Ketones. Synthesis 1995, (03), 317-320.
33. Frisch, M. J.; Trucks, G. W.; Schlegel, H. B.; Scuseria, G. E.; Robb, M. A.;
Cheeseman, J. R.; Scalmani, G.; Barone, V.; Mennucci, B.; Petersson, G. A.; Nakatsuji, H.; Caricato, M.; Li, X.; Hratchian, H. P.; Izmaylov, A. F.; Bloino, J.; Zheng, G.; Sonnenberg, J. L.; Hada, M.; Ehara, M.; Toyota, K.; Fukuda, R.; Hasegawa, J.; Ishida, M.; Nakajima, T.; Honda, Y.; Kitao, O.; Nakai, H.; Vreven, T.; Montgomery, J. A.; Peralta, J. E. J.; Ogliaro, F.; Bearpark, M.; Heyd, J. J.; Brothers, E.; Kudin, K. N.; Staroverov, V. N.; Kobayashi, R.; Normand, J.; Raghavachari, K.; Rendell, A.; Burant, J. C.; Iyengar, S. S.; Tomasi, J.; Cossi, M.; Rega, N.; Millam, J. M.; Klene, M.; Knox, J. E.; Cross, J. B.; Bakken, V.; Adamo, C.; Jaramillo, J.; Gomperts, R.; Stratmann, R. E.; Yazyev, O.; Austin, A. J.; Cammi, R.; Pomelli, C.; Ochterski, J. W.; Martin, R. L.; Mororkuma, K.; Zakrzewski, V. G.; Voth, G. A.; Salvador, P.; Dannenberg, J. J.; Dapprich, S.; Daniels, A. D.; Farkas, Ö.; Foresman, J. B.; Ortiz, J. V.; Cioslowski, J.; Fox, D. J. Gaussian 09, Revision A.1, Wallingford, CT, 2009.
34. Bourgain-Commerçon, M.; Foulon, J.-P.; Normant, J. F., Regioselectivite de la
reaction des dialkyl cuprates de magnesium sur des aldehydes !,"-ethyleniques. J.
Organomet. Chem. 1982, 228, (3), 321-326.
35. Chuit, C.; Foulon, J. P.; Normant, J. F., Réactivité des dérivés organocuivreux vis-a-
vis des aldéhydes !,"-éthyléniques. Tetrahedron 1981, 37, (7), 1385-1389.
36. Chuit, C.; Foulon, J. P.; Normant, J. F., Action des dialkylcuprates de lithium sur les
aldéhydes !," -éthylénioues. Tetrahedron 1980, 36, (16), 2305-2310.
37. Matsuzawa, S.; Horiguchi, Y.; Nakamura, E.; Kuwajima, I., Chlorosilane-accelerated
conjugate addition of catalytic and stoichiometric organocopper reagents. Tetrahedron 1989,
45, (2), 349-362.
38. Snider, B. B.; Vo, N. H.; O'Nei, S. V.; Foxman, B. M., Synthesis of (±)-Allocyathin B2
and (+)-Erinacine A. J. Am. Chem. Soc. 1996, 118, (32), 7644-7645.
39. Ireland, R. E.; Mander, L. N., Experiments directed toward the total synthesis of
terpenes. XI. The total synthesis of (.+-.)-rimuene and (.+-.)-13-epi-rimuene. J. Org. Chem.
1967, 32, (3), 689-696.
40. Boeckman, R. K.; Silver, S. M., Total synthesis of (+-)-.beta.-gorgonene. J. Org.
41. Ziegler, F. E.; Wallace, O. B., The Total Synthesis of (.+-.)-Scopadulcic Acids A and B and (.+-.)-Scopadulciol. J. Org. Chem. 1995, 60, (12), 3626-3636.
42. Corey, E. J.; Boaz, N. W., d-orbital stereoelectronic control of the stereochemistry of SN2' displacements by organocuprate reagents. Tetrahedron Lett. 1984, 25, (29), 3063- 3066.
43. Corey, E. J.; Boaz, N. W., Evidence for a reversible d, [pi]-complexation, [beta]- cupration sequence in the conjugate addition reaction of Gilman reagents with [alpha],[beta]- enones. Tetrahedron Lett. 1985, 26, (49), 6015-6018.
44. Stork, G.; Hudrlik, P. F., Generation, nuclear magnetic resonance spectra, and alkylation of enolates from trialkylsilyl enol ethers. J. Am. Chem. Soc. 1968, 90, (16), 4464- 4465.
45. Duhamel, P.; Cahard, D.; Poirier, J.-M., Unprecedented route to enolates from silyl enol ethers and enol acetates: reaction with hard and soft electrophiles. J. Chem. Soc., Perkin Trans. 1 1993, (21), 2509-2511.
46. Yu, W.; Jin, Z., A facile generation of enolates from silyl enol ethers by potassium ethoxide. Tetrahedron Lett. 2001, 42, (3), 369-372.
47. Kuwajima, I.; Nakamura, E.; Shimizu, M., Fluoride-mediated reactions of enol silyl ethers. Regiospecific monoalkylation of ketones. J. Am. Chem. Soc. 1982, 104, (4), 1025- 1030.
48. Johnson, C. R.; Adams, J. P.; Braun, M. P.; Senanayake, C. B. W.; Wovkulich, P. M.;
Uskokovic, M. R., Direct !-iodination of cycloalkenones. Tetrahedron Lett. 1992, 33, (7),
917-918.
49. Simov, V. Part 1. Total Synthesis of (-)-Clavosolide A; Part 2. Synthesis of the
Western Hemisphere of (+)-Nodulisporic Acid A. University of Pennsylvania, Philadelphia,
2009.
50. Smith III, A. B.; Jeon, J., In University of Pennsylvania: Philadelphia, 2010.
51. Hynes, J.; Nasser, T.; Overman, L. E.; Watson, D. A., Preparation of !-Sulfenyl
Enones by Thermal Fragmentation of "-Sulfenyl Enol Triflates. Org. Lett. 2002, 4, (6), 929-
931.
52. Ye, S.; Ding, Q.; Wang, Z.; Zhou, H.; Wu, J., Tandem addition-cyclization reactions
of 2-alkynylbenzenamines with isocyanates catalyzed by PdCl2. Org. Biomol. Chem. 2008,
6, (23), 4406-4412.
53. Fu, W.; Xu, C.; Zou, G.; Hong, D.; Deng, D.; Wang, Z.; Ji, B., AuCl3-Catalyzed
Tandem Reaction of N-(o-Alkynylphenyl)imines: A Modular Entry to Polycyclic Frameworks
Containing an Indole Unit. Synlett 2009, 2009, (EFirst), 763,766.
54. Suzuki, Y.; Ohta, Y.; Oishi, S.; Fujii, N.; Ohno, H., Efficient Synthesis of
Domino Multicomponent Coupling and Bis-cyclization. J. Org. Chem. 2009, 74, (11), 4246- 4251.
55. Barluenga, J.; Fernandez, M. A.; Aznar, F.; Valdes, C., Cascade Alkenyl
Amination/Heck Reaction Promoted by a Bifunctional Palladium Catalyst: A Novel One-Pot Synthesis of Indoles from o-Haloanilines and Alkenyl Halides. Chem. Eur. J. 2005, 11, (8), 2276-2283.
56. Harris, M. C.; Huang, X.; Buchwald, S. L., Improved Functional Group Compatibility in the Palladium-Catalyzed Synthesis of Aryl Amines. Org. Lett. 2002, 4, (17), 2885-2888.
57. Surry, D. S.; Buchwald, S. L., Biaryl Phosphane Ligands in Palladium-Catalyzed Amination. Angew. Chem. Int. Ed. 2008, 47, (34), 6338-6361.
58. Shen, X.; Hyde, A. M.; Buchwald, S. L., Palladium-Catalyzed Conversion of Aryl and Vinyl Triflates to Bromides and Chlorides. J. Am. Chem. Soc. 2010, 132, (40), 14076-14078.
59. Furrow, M. E.; Myers, A. G., Practical Procedures for the Preparation of N-tert- Butyldimethylsilylhydrazones and Their Use in Modified Wolff-Kishner Reductions and in the Synthesis of Vinyl Halides and gem-Dihalides. J. Am. Chem. Soc. 2004, 126, (17), 5436- 5445.
60. Iwao, M.; Kuraishi, T., Directed Lithiation of 1-(tert-Butoxycarbonyl)indolines. A Convenient Route to 7-Substituted Indolines. Heterocycles 1992, 34, (5), 1031-1038.
61. Huang, X.; Anderson, K. W.; Zim, D.; Jiang, L.; Klapars, A.; Buchwald, S. L., Expanding Pd-Catalyzed C‚N Bond-Forming Processes: The First Amidation of Aryl
Sulfonates, Aqueous Amination, and Complementarity with Cu-Catalyzed Reactions. J. Am. Chem. Soc. 2003, 125, (22), 6653-6655.
62. Kranenburg, M.; van der Burgt, Y. E. M.; Kamer, P. C. J.; van Leeuwen, P. W. N. M.; Goubitz, K.; Fraanje, J., New Diphosphine Ligands Based on Heterocyclic Aromatics
Inducing Very High Regioselectivity in Rhodium-Catalyzed Hydroformylation: Effect of the Bite Angle. Organometallics 1995, 14, (6), 3081-3089.
63. Wittig, G.; Schöllkopf, U., Über Triphenyl-phosphin-methylene als olefinbildende Reagenzien I. Mitteil. Chem. Ber. 1954, 87, (9), 1318-1330.
64. Horner, L.; Hoffmann, H. M. R.; Wippel, H. G.; Klahre, G., Chem. Ber. 1959, 92, 2499-2505.
65. Wadsworth, W. S., Synthetic Applications of Phosphoryl-Stabilized Anions. In Organic Reactions, John Wiley & Sons, Inc.: 2004.
66. Oh-e, T.; Miyaura, N.; Suzuki, A., Palladium-Catalyzed Cross-Coupling Reaction of Aryl or Vinylic Triflates with Organoboron Compounds. Synlett 1990, 1990, (04), 221,223.
67. Löffler, A.; Pratt, R. J.; Rüesch, H. P.; Dreiding, A. S., Die Wohl-Ziegler-Bromierung von Tiglin- und Angelika-säureestern. Helv. Chim. Acta 1970, 53, (2), 383-403.
68. Murelli, R. P.; Cheung, A. K.; Snapper, M. L., Conformationally Restricted (+)- Cacospongionolide B Analogues. Influence on Secretory Phospholipase A2 Inhibition. J. Org. Chem. 2006, 72, (5), 1545-1552.
69. Müller, S.; Liepold, B.; Roth, G. J.; Bestmann, H. J., An Improved One-pot Procedure for the Synthesis of Alkynes from Aldehydes. Synlett 1996, 1996, (06), 521,522.
70. Hart, D. W.; Schwartz, J., Hydrozirconation. Organic synthesis via organozirconium intermediates. Synthesis and rearrangement of alkylzirconium(IV) complexes and their reaction with electrophiles. J. Am. Chem. Soc. 1974, 96, (26), 8115-8116.
71. Biscoe, M. R.; Fors, B. P.; Buchwald, S. L., A New Class of Easily Activated
Palladium Precatalysts for Facile C‚N Cross-Coupling Reactions and the Low Temperature Oxidative Addition of Aryl Chlorides. J. Am. Chem. Soc. 2008, 130, (21), 6686-6687.
72. Ley, S. V.; Norman, J.; Griffith, W. P.; Marsden, S. P., Tetrapropylammonium Perruthenate, Pr4N+RuO4-, TPAP: A Catalytic Oxidant for Organic Synthesis. Synthesis 1994, 1994, (07), 639,666.
73. Chakravarty, P. K.; Shih, T. L.; Colletti, S. L.; Ayer, M. B.; Snedden, C.; Kuo, H.; Tyagarajan, S.; Gregory, L.; Zakson-Aiken, M.; Shoop, W. L.; Schmatz, D. M.; Wyvratt, M.; Fisher, M. H.; Meinke, P. T., Nodulisporic acid side-Chain modifications: access to the 2'', 3'', 4'', and 6'' registers. Bioorg. Med. Chem. Lett. 2003, 13, (1), 147-150.
CHAPTER 3. EXPERIMENTAL SECTION
3.1 MATERIALS AND METHODS
All solvents used were reagent grade. Diethyl ether (Et2O), tetrahydrofuran (THF),
methylene chloride, and toluene were obtained from a PurSolv™ PS-400. TMEDA and tert- butanol were freshly distilled over CaH2 prior to use. All reagents were purchased from
Aldrich or Acros and used as received, except for benzyltrimethylammonium fluoride, which was dried under vacuum at 70 °C overnight prior to use. Reactions were magnetically stirred in oven-dried glassware under an argon atmosphere and monitored by thin layer chromatography (TLC) with 0.25 mm E. Merck pre-coated silica gel plates. All starting materials were azeotroped with benzene (3x) and dried under vacuum prior to use. Flash chromatography was performed with silica gel 60 (particle size 0.040 – 0.062 mm) supplied by Silicycle and Sorbent Technologies. Yields refer to chromatographically and spectroscopically pure compounds, unless otherwise stated. Infrared spectra were recorded on a Jasco Model FT/IR-480 Plus spectrometer. Proton and carbon NMR spectra were recorded on a Bruker AMX-500 and Bruker Avance III 500 MHz spectrometer. Chemical shifts are reported relative to either chloroform (!!7.27) or benzene (! 7.16) for 1H NMR and
either chloroform (! 77.2) or benzene (! 128.4) for 13C NMR. Optical rotations were
measured on a Perkin-Elmer model 241 polarimeter or a Jasco polarimeter. High resolution mass spectra were measured at the University of Pennsylvania Mass Spectrometry Service Center.
3.2 EXPERIMENTAL PROCEDURES
O
O
Diketone (+)-2.30, (+)-C-4-Methyl Wieland-Miescher Ketone: The triketone substrate 2.29
for the catalytic Robinson Annulation was synthesized by the procedure of Zeigler (J. Org. Chem. 1986, 51, 4573). To a solution of 2-methylcyclohexane-1,3-dione (60 g, 476 mmol) and ethyl vinyl ketone (freshly distilled, 52 ml, in 1,2-dimethoxyethane (240 ml) stirring under argon in a round-bottomed flask was added DABCO (60 g, 535 mmol, recrystallized from ethyl ether) in one portion. The resulting mixture was stirred at room temperature for 16 h, cooled to 0 °C, and treated with 20% HCl (aq, 400 ml) dropwise (NOTE: this step must be performed slowly and cautiously, as side-products can form resulting from intramolecular aldol reactions if the acid is added too fast). The mixture was stirred for 15 min at 0 °C, then extracted with ethyl ether (3 X 300 ml). The organic layers were combined, dried (MgSO4),
filtered, and concentrated under vacuum to give an amber oil (98 g, >95%). The 1H NMR was consistent with that of the published data: m.p.: 48-50 °C; 1H NMR (500 MHz, CDCl3) !
2.76 - 2.70 (m, 4H), 2.65 - 2.59 (m, 4H), 2.38 (q, 2H, J = 14.6, 7.3 Hz), 2.32 (t, 2H, J = 7.2 Hz), 2.08 – 2.00 (m, 3H), 1.94 – 1.85 (m, 1H), 1.24 (s, 3H), 1.02 (t, J = 7.3 Hz).
Organocatalytic Sonication-Mediated Robinson Annulation: The procedure of Shibasaki (Tetrahedron 2005, 61, 5057) was employed: The crude Michael addition product was placed in a round-bottomed flask equipped with a stir bar. The flask was further charged with L-Phenylalanine (23.1 g, 140 mmol), PPTS (58.6 g, 233 mmol), and anhydrous DMSO
(33 ml, 466 mmol). The mixture was briefly pumped and back-filled with argon, then the flask was sealed and placed in a sonicator water bath. The mixture was sonicated for 16 h. Note: water should be continuously and slowly dripped into the water bath to offset
evaporation, or the bath will go dry. The bath attained a temperature of ca. 50 °C during this time. Sonication was ceased and the mixture was cooled to room temperature, diluted with ethyl acetate (300 ml), and poured into saturated sodium bicarbonate (500 ml). The layers were separated, and the aqueous layer back-extracted with ethyl acetate. The combined organic layer was washed with brine, dried (MgSO4), filtered and concentrated in vacuo to an orange oil (45.8 g). The crude product was purified by flash chromatography (silica gel, 25% ethyl acetate/hexanes, 15 X 9 cm) to give 36.9 g of an oil. The oil was dissolved in hexanes with ethyl ether added to assist in dissolution (approx. 15:1 hexanes/ether, ~ 10 ml/g of enone). The optical rotation of the purified product was found to be [!]25D =+ 122 ° (c 1.0, CHCl3), corresponding to approximately 90% ee (literature: [!]25D =+ 136 ° (c 1.0,
CHCl3) (Hagiwara and Uda, J. Org. Chem.1988, 53, 2308). The resulting solution was placed in a -20 °C freezer for 16 h, and the crystalline product was harvested via filtration. The crystals were washed with a small amount of cold hexanes to give the desired product as a crystalline solid (55 g in the first crop ([!]25D =+ 144.6 ° (c 1.18, CHCl3)), 7.5 g in the
second crop). The mother liquors could be purified by silica chromatography as describe above and the resulting product recrystallized to give another 4.7 g of product for a total yield of 67.2 g, 75%. The spectroscopic data for this material was in agreement with published data: 1H NMR (500 MHz, CDCl
3) " 2.86 (dddd, J = 11.17, 4.99, 4.99, 1.12 Hz, 1H),
2.67 (ddd, J = 16.07, 10.45, 6.04 Hz, 1H), 2.53-2.45 (m, 3H), 2.42 (dddd, J = 12.16, 5.55, 1.18 Hz, 1H), 2.17-2.02 (m, 3H), 1.80 (d, J = 1.35, 3H), 1.75 (m, 1H), 1.41 (s, 3H).
OTMS O
O H
Silyl Enol Ether 2.34, Modified Procedure for the Dissolving Metal Reduction of C-4- methyl Wieland-Meischer Ketone Monoketal: While the dissolving metal reduction of C-4-