Stereodivergent Approach to Both C2,8a-syn and C2,8a-anti Relative Stereochemical Manifolds in the Lepadin Family via a TiCl₄-Promoted Aza-[3+3] Annulation

Abstract

Details in developing a stereodivergent approach to the lepadin family and establishing an entry to both C2,8a-syn and C2,8a-anti relative stereochemical manifolds through a common intermediate are described here. This works paves the foundation for constructing all members of the lepadin family, which consists of three subsets based on an array of interesting relative configurations. These efforts underline the prominence of aza-[3+3] annulation as a unified strategy in alkaloid synthesis.

Key words

titanium(IV) chloride - aza-[3+3] annulation - vinylogous amides - iminium ions - alkaloid synthesis - lepadin alkaloids - stereodivergent approach - episulfide contraction

References

• For reviews, see:
• 1a Harrity JPA. Provoost O. Org. Biomol. Chem.  2005,  3:  1349 
• 1b Hsung RP. Kurdyumov AV. Sydorenko N. Eur. J. Org. Chem.  2005,  23 
• 1c Coverdale HA. Hsung RP. ChemTracts  2003,  16:  238 
• For leading references, see:
• 2a Sklenicka HM. Hsung RP. McLaughlin MJ. Wei L.-L. Gerasyuto AI. Brennessel WW. J. Am. Chem. Soc.  2002,  124:  10435 
• 2b Wei L.-L. Sklenicka HM. Gerasyuto AI. Hsung RP. Angew. Chem. Int. Ed.  2001,  40:  1516 
• For our general work on developing the aza-[3+3]-annula-tion method, see:
• 3a Ghosh SK. Buchanan GS. Long QA. Wei Y. Al-Rashid ZF. Sklenicka HM. Hsung RP. Tetrahedron  2008,  63:  883 
• 3b Sydorenko N. Hsung RP. Vera EL. Org. Lett.  2006,  8:  2611 
• 3c Gerasyuto AI. Hsung RP. Sydorenko N. Slafer BW. J. Org. Chem.  2005,  70:  4248 
• 3d Sydorenko N. Hsung RP. Darwish OS. Hahn JM. Liu J. J. Org. Chem.  2004,  69:  6732 
• 3e Sklenicka HM. Hsung RP. Wei L.-L. McLaughlin MJ. Gerasyuto AI. Degen SJ. Mulder JA. Org. Lett.  2000,  2:  1161 
• 3f Hsung RP. Wei L.-L. Sklenicka HM. Douglas CJ. McLaughlin MJ. Mulder JA. Yao LJ. Org. Lett.  1999,  1:  509 
• For recent studies in this area, see:
• 4a Guo H. Qihai XuQ. Kwon O. J. Am. Chem. Soc.  2009,  131:  6318 
• 4b Alladoum J. Toum V. Hebbe S. Kadouri-Puchot C. Dechoux L. Tetrahedron Lett.  2009,  50:  617 
• 4c Hayashi Y. Gotoh H. Masui R. Ishikawa H. Angew. Chem. Int. Ed.  2008,  47:  4012 
• 4d Zhang R. Zhang D. Guo Y. Zhou G. Jiang Z. Dong D. J. Org. Chem.  2008,  73:  9504 
• 4e Mancey NC. Butlin RJ. Harrity JPA. Synlett  2008,  2647 
• 4f Zhong W. Lin F. Chen R. Su W. Synthesis  2008,  2561 
• 4g Trost BM. Dong G. Org. Lett.  2007,  9:  2357 
• 4h Schmidt A. Gütlein J.-P. Mkrrchyan S. Görls H. Langer P. Synlett  2007,  1305 
• 4i Pattenden LC. Wybrow RAJ. Smith SA. Harrity JPA. Org. Lett.  2006,  8:  3089 
• 4j Shintani R. Hayashi T. J. Am. Chem. Soc.  2006,  128:  6330 
• 4k Halliday JI. Chebib M. Turner P. McLeod MD. Org. Lett.  2006,  8:  3399 
• 4l Katsuyama I. Funabiki K. Matsui M. Muramatsu H. Shibata K. Heterocycles  2006,  68:  2087 
• 4m Bose DS. Kumar RK. Heterocycles  2006,  68:  549 
• 4n Goodenough KM. Raubo P. Harrity JPA. Org. Lett.  2005,  7:  2993 
• 4o Goodenough KM. Moran WJ. Raubo P. Harrity JPA. J. Org. Chem.  2005,  70:  207 
• For leading reviews on the chemistry of iminium ions, see:
• 5a Maryanoff BE. Zhang H.-C. Cohen JH. Turchi IJ. Maryanoff CA. Chem. Rev.  2004,  104:  1431 
• 5b Royer J. Bonin M. Micouin L. Chem. Rev.  2004,  104:  2311 
• 5c Bur SK. Martin SF. Tetrahedron  2001,  57:  3221 
• 5d Speckamp WN. Moolenaar MJ. Tetrahedron  2000,  56:  3817 
• 5e Scholz U. Winterfeldt E. Nat. Prod. Rep.  2000,  17:  349 
• For some reviews see:
• 6a Gademann K. Lawrence AK. Synthesis  2008,  331 
• 6b Stockman RA. Sinclair A. Nat. Prod. Rep.  2007,  24:  298 
• 6c Weintraub PM. Sabol JS. Kane JM. Borcherding DR. Tetrahedron  2003,  59:  2953 
• 6d Mitchinson A. Nadin A. J. Chem. Soc., Perkin Trans. 1  2000,  2862 
• For synthesis of perhydrohistrionicotoxin, see:
• 7a McLaughlin MJ. Hsung RP. Cole KC. Hahn JM. Wang J. Org. Lett.  2002,  4:  2017 
• For synthesis of tangutorine, see:
• 7b Luo S. Zificsak CZ. Hsung RP. Org. Lett.  2003,  5:  4709 
• For synthesis of deplancheine, see:
• 7c Sydorenko N. Zificsak CA. Gerasyuto AI. Hsung RP. Org. Biomol. Chem.  2005,  3:  2140 
• For synthesis of cylindricine C, see:
• 7d Swidorski JJ. Wang J. Hsung RP. Org. Lett.  2006,  8:  777 
• 7e Wang J. Swidorski JJ. Sydorenko N. Hsung RP. Coverdale HA. Kuyava JM. Liu J. Heterocycles  2006,  70:  423 
• For synthesis of aza-phenylene alkaloid family, see:
• 7f Gerasyuto AI. Hsung RP. Org. Lett.  2006,  8:  4899 
• 7g Gerasyuto AI. Hsung RP. J. Org. Chem.  2007,  72:  2476 
• For synthesis of lasubine II, see:
• 7h Zhang Y. Long QA. Gerasyuto AI. Hsung RP. Synlett  2009,  237 
• For isolation of (-)-lepadin A, see:
• 8a Steffan B. Tetrahedron  1991,  47:  8729 
• For isolation of (-)-B and (-)-C, see:
• 8b Kubanek J. Williams DE. de Silva ED. Allen T. Andersen RJ. Tetrahedron Lett.  1995,  36:  6189 
• For isolation of (+)-D, (-)-E, and (-)-F, see:
• 8c Wright AD. Goclik E. König GM. Kaminsky R. J. Med. Chem.  2002,  45:  3067 
• For isolation of (+)-F, (+)-G, and (+)-H, see:
• 8d Davis RA. Carroll AR. Quinn RJ. J. Nat. Prod.  2002,  65:  454 
• For the first total synthesis of a lepadin family member, (-)-lepadin B, see:
• 9a Toyooka N. Okumura M. Takahata H. Nemoto H. Tetrahedron  1999,  55:  10673 
• 9b Toyooka N. Okumura M. Takahata H. J. Org. Chem.  1999,  64:  2182 
• Also see:
• 9c Toyooka N. Nemoto H. Trends Heterocycl. Chem.  2002,  8:  145 
• 9d Toyooka N. Yakugaku Zasshi  2001,  121:  467 
• 10 For total synthesis of (-)-lepadin B, see: Ozawa T. Aoyagi S. Kibayashi C. Org. Lett.  2000,  2:  2955 
• 11 For total syntheses of (-)-lepadin A and (-)-lepadin C, see: Ozawa T. Aoyagi S. Kibayashi C. J. Org. Chem.  2001,  66:  3338 
• 12 For a formal synthesis of (±)-lepadin B: Kalaï C. Tate E. Zard SZ. Chem. Commun.  2002,  1430 
• For an elegant stereodivergent total synthesis of lepadins A-E, and H, see:
• 13a Pu X. Ma D. J. Org. Chem.  2006,  71:  6562 
• 13b Pu X. Ma D. Angew. Chem. Int. Ed.  2004,  43:  4222 
• 14 For total syntheses of (-)-lepadin F and (-)-lepadin G, see: Niethe A. Fischer D. Blechert S. J. Org. Chem.  2008,  73:  3088 
• For other studies, see:
• 15a Mena M. Valls N. Borreg M. Bonjoch J. Tetrahedron  2006,  62:  9166 
• 15b Mena M. Bonjoch J. Pardo DG. Cossy J. J. Org. Chem.  2006,  71:  5930 
• 15c Mena M. Bonjoch J. Tetrahedron  2005,  61:  8264 
• 15d Barbe G. Charette AB. Abstracts of Papers, 232nd National Meeting of the American Chemical Society, San Francisco, CA, Sept 10-14, 2006   American Chemical Society; Washington DC: 2006.  ORGN-747: 
• 16 Zehnder LR. Wei L.-L. Hsung RP. Cole KP. McLaughlin MJ. Shen HC. Sklenicka HM. Wang J. Zificsak CA. Org. Lett.  2001,  3:  2141 
• For related reductions, see:
• 18a Cole KP. Hsung RP. Yang X.-F. Tetrahedron Lett.  2002,  43:  3341 
• 18b Hsung RP. Cole KP. Zehnder LR. Wang J. Wei L.-L. Yang X.-F. Coverdale HA. Tetrahedron  2003,  59:  311 
• 19 For our very first communication of this stereodivergent plan, see: Slafer B. Hsung RP. Sklenicka HM. Abstracts of Papers, 227th National Meeting of the American Chemical Society, Anaheim, CA, Mar 28 to Apr 1, 2004   American Chemical Society; Washington DC: 2004.  ORGN-396: 
• 20a Crabtree RH. Davis MW. J. Org. Chem.  1986,  51:  2655 
• 20b Crabtree RH. Acc. Chem. Res.  1979,  12:  331 
• For the first application of directed hydrogenations employing Crabtree’s catalyst, see:
• 21a Stork G. Kahne DE. J. Am. Chem. Soc.  1983,  105:  1072 
• For a leading application, also see:
• 21b Evans DA. Morrissey MM. J. Am. Chem. Soc.  1984,  106:  3866 
• 22 Ginn JD. Padwa A. Org. Lett.  2002,  4:  1515 
• 24a Shiosaki K. In Comprehensive Organic Synthesis   Vol. 2:  Trost BM. Fleming I. Pergamon; Oxford: 1991.  p.865 
• 24b Roth M. Dubs P. Götchi E. Eschenmoser A. Helv. Chim. Acta  1971,  54:  710 
• 25 Toyooka N. Yoshida Y. Momose T. Tetrahedron Lett.  1995,  36:  3715 
• 27 Li G. Hsung RP. Slafer BW. Sagamanova IK. Org. Lett.  2008,  10:  4991 

17

This particular dihydroxylation was very difficult and required a stoichiometric amount of OsO₄, and Scheme  [4] reveals our best conditions. Other conditions examined were: (i) 5-60 mol% OsO₄ with NMO, or with K₂Fe(CN)₆, or with t-BuOOH; bases were K₂CO₃, MeSO₂NH₂, or DABCO; (ii) cat. to 1.1 equiv of K₂OsO₄˙2 H₂O with K₂Fe(CN)₆; bases were K₂CO₃, or TMEDA, or pyridine; (iii) MCPBA or MMPP or AcOOH; (iv) NBS, DMSO; (v) DMDO or Ozone; (vi) KMnO₄ in H₂O-EtOH or with TEBACl in CH₂Cl₂; (vii) 9-BBN or BH₃˙SMe₂ and then H₂O₂, MeOH; (viii) RuCl₃, NaIO₄; (ix) Hg(OAc)₂, NaBH₄, NaOH; (x) O₂, hν, rose Bengal. However, none of these conditions led to any synthetically useful outcome.

23

Vinylogous amide 18 is again the same as Ma’s mid-stage intermediate. However, in their beautiful studies en route to lepadins A-E and H, hydrogenation of the C4a-8a olefin took place prior to homologation of the C5 carbonyl group via Wittig-type olefinations (see ref. 13).

26

Wittig olefination employing Ph₃P=CHCHO in toluene did not lead to any desired homologation product.