A Practical Synthesis of the Ansa Chain of Benzenic Ansamycin Antibiotics: Total Synthesis of an Ansatrienol Derivative

Abstract

A practical and stereocontrolled synthetic approach towards the ansa chain of the benzenic ansamycins (mycotrienins) is described, which can be scaled up to multigram quantities. Key features of the synthesis are the formation of the Z-configured tri­substituted double bond by a one-pot esterification of allyl(diisopropoxy)borane and ring-closing metathesis, formation of the β-keto ester via ethyl diazoacetate addition to an aldehyde, and use of the Duthaler-Hafner acetate aldol reaction for the introduction of the stereocenter at C3. The practicality of this synthesis is demonstrated by the preparation of an ansatrienol derivative, representing­ a formal total synthesis of the ansatrienins.

Key words

aldol reaction - ansamycin antibiotics - macrolactamization - ring-closing metathesis - total synthesis

References

• 2 Funayama S. Cordell GA. Stud. Nat. Prod. Chem.  2000,  23:  51 
• 3a Weber W. Zähner H. Damberg M. Russ P. Zeeck A. Zbl. Bakt. Hyg., I. Abt. Orig. C2  1981,  122 
• 3b Zeeck A. Damberg M. Russ P. Tetrahedron Lett.  1982,  23:  59 
• 4a Sugita M. Furihata K. Seto H. Otake N. Sasaki T. Agric. Biol. Chem.  1982,  46:  1111 
• 4b Sugita M. Sasaki T. Furihata K. Seto H. Otake N. J. Antibiot.  1982,  35:  1467 
• 4c Sugita M. Natori Y. Sueda N. Furihata K. Seto H. Otake N. J. Antibiot.  1982,  35:  1474 
• 4d Sugita M. Hiramato S. Ando C. Sasaki T. Furihata K. Seto H. Otake N. J. Antibiot.  1985,  38:  799 
• 5a Umezawa I. Funayama S. Okada K. Iwasaki K. Satoh J. Masuda K. Komiyama K. J. Antibiot.  1985,  38:  699 
• 5b Funayama S. Okada K. Komiyama K. Umezawa I. J. Antibiot.  1985,  38:  1107 
• 5c Funayama S. Okada K. Iwasaki K. Komiyama K. Umezawa I. J. Antibiot.  1985,  38:  1677 
• 5d Nomoto H. Katsumata S. Takahashi K. Funayama S. Komiyama K. Umezawa I. Omura S. J. Antibiot.  1989,  42:  479 
• 6 Zhang H.-P. Kakeya H. Osada H. Tetrahedron Lett.  1997,  38:  1789 
• 7 Hosokawa N. Naganawa H. Iinuma H. Hamada M. Takeuchi T. J. Antibiot.  1995,  48:  471 
• 8 Smith AB. Barbosa J. Wong W. Wood JL. J. Am. Chem. Soc.  1996,  118:  8316 
• 9a Panek JS. Masse CE. J. Org. Chem.  1997,  62:  8290 
• 9b Masse CE. Yang M. Solomon J. Panek JS. J. Am. Chem. Soc.  1998,  120:  4123 
• 10a Smith AB. Wan Z. Org. Lett.  1999,  1:  1491 
• 10b Smith AB. Wan Z. J. Org. Chem.  2000,  65:  3738 
• 11a Schöning K.-U. Hayashi RK. Powell DR. Kirschning A. Tetrahedron: Asymmetry  1999,  10:  817 
• 11b Schöning K.-U. Wittenberg R. Kirschning A. Synlett  1999,  1624 
• 12 Aldehyde 10 was prepared by ozonolysis of TBS-protected (Z)-but-2-ene-1,4-diol, see: Keck GE. Wager CA. Wager TT. Savin KA. Covel JA. McLaws MD. Krishnamurthy D. Cee VJ. Angew. Chem. Int. Ed.  2001,  40:  231 
• 13 Phosphonate 11 was prepared from dichloroethyl phosphonate (Scheme 9): Patois C. Savignec P. Synth. Commun.  1991,  21:  2391 
• 14 Micalizio GC. Schreiber SL. Angew. Chem. Int. Ed.  2002,  41:  152 
• 15 Nicolas E. Russell KC. Hruby VJ. J. Org. Chem.  1993,  58:  766 
• 16 Evans DA. Fitch DM. J. Org. Chem.  1997,  62:  454 
• 17a Holmquist CR. Roskamp EJ. J. Org. Chem.  1989,  54:  3258 
• 17b Rychnovsky SD. Mickus DE. J. Org. Chem.  1992,  57:  2732 
• 18 Roush WR. Palkowitz AD. J. Org. Chem.  1989,  54:  3009 
• 19 Evans DA. Chapman KT. Carreira EM. J. Am. Chem. Soc.  1988,  110:  3560 
• 21a Hanessian S. Lavallee P. Can. J. Chem.  1975,  53:  2975 
• 21b Ogilvie KK. Iwacha OJ. Tetrahedron Lett.  1973,  14:  317 
• 22 Nicolaou KC. Webber SE. Synthesis  1986,  453 
• 23a Dess DB. Martin JC. J. Org. Chem.  1983,  48:  4155 
• 23b Boeckman RK. Shao P. Mullins JJ. Org. Synth.   Vol. 77:  John Wiley & Sons; London: 1999.  p.141-146  
• 24 Makin SM. Telegina NI. J. Gen. Chem. USSR  1962,  32:  1082 
• 25 Janovskaya LA. Rudenko BA. Kucherov VF. Stepanova RN. Kogan GA. Bull. Acad. USSR, Div. Chem. Sci.  1962,  2093 
• 26a de Koning H. Subramanian-Erhart KEC. Huisman HO. Synth. Commun.  1973,  3:  25 
• 26b de Koning H. Mallo GN. Springer-Fidder A. Subramanian-Erhart KEC. Huisman HO. Recl. Trav. Chim. Pays-Bas  1973,  683 
• 27 Wenkert E. Guo M. Lavilla R. Porter B. Ramachandran K. Sheu J.-H. J. Org. Chem.  1990,  55:  6203 
• 28 Among many different oxidation procedures tested, TPAP (cat.)/NMO was best suited for the oxidation of the highly unsaturated alcohol: Ley SV. Normann J. Griffith WP. Marsden SP. Synthesis  1994,  639 
• 29a Riediker M. Duthaler RO. Angew. Chem., Int. Ed. Engl.  1989,  28:  494 
• 29b Duthaler RO. Herold P. Lottenbach W. Oertle K. Riediker M. Angew. Chem., Int. Ed. Engl.  1989,  28:  495 
• 29c Duthaler RO. Hafner A. Chem. Rev.  1992,  92:  807 
• 29d Duthaler RO. Herold P. Wyler-Helfer S. Riediker M. Helv. Chim. Acta  1990,  73:  659 
• 30 Jaunzems J. Kashin D. Schönberger A. Kirschning A. Eur. J. Org. Chem.  2004,  3435 
• 32 Friedrich-Bochnitschek S. Waldmann H. Kunz H. J. Org. Chem.  1989,  54:  751 
• 33 Bald E. Saigo K. Mukaiyama M. Chem. Lett.  1975,  1163 
• 34 Martin SF. Davidsen SK. J. Am. Chem. Soc.  1984,  106:  6431 
• 35a Still WC. Gennari C. Tetrahedron Lett.  1983,  24:  4405 
• 35b Morimoto Y. Matsuda F. Shirahama H. Tetrahedron  1996,  52:  10609 
• 36 Dias LC. Bau RZ. de Sousa MA. Zukerman-Schpector J. Org. Lett.  2002,  4:  4325 
• 37 Brown HC. Racherla US. Pellechia PJ. J. Org. Chem.  1990,  55:  1868 

1

Rüdiger Wittenberg, current address: DS-Chemie GmbH, Straubinger Straße 12, 28219 Bremen, Germany; Kai-Uwe Schöning, current address: Ciba Speciality Chemicals Inc., R-1059.4.04, 4002 Basel, Switzerland; Stefan Kamlage, current address: Institut für Organische Chemie, Freie Universität Berlin, Takustraße 3, 14195 Berlin, Germany.

20

One major problem that arose during the oxidative cleavage of the boronic ester was the formation of furan 45 which may have originated from over oxidation of diol 26 and formation of the aldehyde 44 (Scheme [10] ). Lactol formation and elimination yields 45. This side reaction was fully suppressed, if H₂O₂ was slowly added to a well cooled solution of the boronate

31

When other alcohols than allyl alcohol were employed we observed exchange of allyl in the alloc group by these alcohols.