A One-Pot Non-Aldol-Aldol Vinylogous Mukaiyama Aldol Tandem Sequence for the Rapid Construction of Polyketide Frameworks

Abstract

The rapid assembly of polyketide segments remains one central task in the field of natural product synthesis. Besides the ­stereoselective assembly of carbon frameworks functional group transformations and protecting group manipulations have to be ­optimized in order to streamline organic synthesis. The activated ­aldehyde derived from Jung’s non aldol-aldol method serves as an intermediate for the subsequent vinylogous Mukaiyama aldol ­reaction.

Key words

semi-pinacol - rearrangement - vinylogous - aldol

References

• First review covering the vinylogous principle:
• 1a Fuson RC. Chem. Rev.  1935,  16:  1 
• 1b For excellent reviews covering the development until 2000, see: Casiraghi G. Zanardi F. Appendino G. Rassu G. Chem. Rev.  2000,  100:  1929 
• 1c See also: Rassu G. Zanardi F. Battistini L. Casiraghi G. Chem. Soc. Rev.  2000,  29:  109 
• 1d For vinylogous Mannich reactions see: Arend M. Westermann B. Risch N. Angew. Chem. Int. Ed.  1998,  37:  1044 ; Angew. Chem. 1998, 110, 1096
• 1e Bur SK. Martin SF. Tetrahedron  2001,  3221 
• 1f For a review covering the vinylogous aldol reaction between 2000 and 2003, see: Kalesse M. In Topics in Current Chemistry   Vol. 244:  Mulzer JH. Springer Verlag; Berlin: 2004.  p.43-76  
• 1g Evans DA. Ng HP. Rieger DL. J. Am. Chem. Soc.  1993,  115:  11446 
• 1h Paterson I. Collet LA. Tetrahedron Lett.  2001,  42:  1187 
• 1i Paterson I. Florence GJ. Gerlach K. Scott JP. Angew. Chem. Int. Ed.  2000,  39:  377 ; Angew. Chem. 2000, 112, 385
• 1j Braun M. Waldmüller D. Synthesis  1989,  856 
• 1k Roush WR. Palkowitz AD. Ando K. J. Am. Chem. Soc.  1990,  112:  6348 
• 1l Christmann M. Bhatt U. Quitschalle M. Claus E. Kalesse M. Angew. Chem. Int. Ed.  2000,  39:  4364 ; Angew. Chem. 2000, 112, 4535
• 1m Christmann M. Bhatt U. Quitschalle M. Claus E. Kalesse M. J. Org. Chem.  2001,  1885 
• 1n Bazán-Tejeda B. Georgy M. Campagne J.-M. Synlett  2004,  720 
• 1o Saito S. Nagahara T. Shiozawa M. Nakadai M. Yamamoto H. J. Am. Chem. Soc.  2003,  125:  6200 
• 1p Denmark SE. Heemstra JR. Synlett  2004,  2411 
• 1q Denmark SE. Beutner GL. J. Am. Chem. Soc.  2004,  125:  7800 
• 1r Takikawa H. Ishihara K. Saito S. Yamamoto H. Synlett  2004,  732 
• 1s Lautens M. Tayama E. Nguyen D. Org. Lett.  2004,  6:  345 
• 1t Lautens M. Ouellet SG. Raeppel S. Angew. Chem. Int. Ed.  2000,  39:  4079 ; Angew. Chem. 2000, 112, 4245
• 2a Hassfeld J. Kalesse M. Tetrahedron Lett.  2002,  5093 
• 2b Hassfeld J. Kalesse M. Synlett  2002,  2007 
• 2c Christmann M. Kalesse M. Tetrahedron Lett.  2001,  42:  1269 
• 2d Hassfeld J. Christmann M. Kalesse M. Org. Lett.  2001,  3561 
• 3a Jung ME. D’Amico DC. J. Am. Chem. Soc.  1993,  115:  12208 
• 3b Jung ME. D’Amico DC. J. Am. Chem. Soc.  1997,  119:  12150 
• 3c Jung ME. Lee WS. Sun D. Org. Lett.  1999,  1:  307 
• 3d Jung ME. Marquez R. Tetrahedron Lett.  1999,  40:  3129 
• 3e Jung ME. van den Heuvel A. Tetrahedron Lett.  2002,  43:  8169 
• 3f Jung ME. van den Heuvel A. Org. Lett.  2003,  5:  4705 
• 3g Jung ME. Hoffmann B. Rausch B. Contreras J.-M. Org. Lett.  2003,  5:  3159 
• 3h Jung ME. van den Heuvel A. Leach AG. Houck KN. Org. Lett.  2003,  5:  3375 
• 4 Katzuki T. Sharpless KB. J. Am. Chem. Soc.  1980,  102:  5974 

5

To a stirred solution of epoxy alcohol 1 (20 mg, 0.172 mmol) and ketene acetal 5 (79 mg, 0.344 mmol) in CH₂Cl₂ (0.6 mL) were added 2,6-lutidine (70 µL, 0.603 mmol) and TBSOTf (79 µL, 0.344 mmol) at -78 °C. The reaction mixture was warmed to r.t. and stirred for 1 h. Then it was poured into a mixture of MTBE (5 mL) and buffer pH 5.5 (3 mL). The organic layer was separated and the aqueous phase was extracted with MTBE (3 × 5 mL). The combined organic layer was washed with 20% aq NaHSO₃ solution (3 × 5 mL), H₂O (3 × 5 mL), buffer pH 7 (3 × 5 mL) and brine (3 × 5 mL), dried and concentrated. The resulting residue was subjected to chromatography on silica gel. Elution with hexane-EtOAc (10:1) furnished the product 8 (Felkin product, 4,5-syn:anti = 3:1) as a colorless oil (55.2 mg, 0.120 mmol, 70%).
Main Product (syn-8): ¹H NMR (400 MHz, CDCl₃): δ = 7.04 (dd, J = 15.6, 7.8 Hz, 1 H), 5.76 (dd, J = 15.6, 1.3 Hz, 1 H), 3.73 (s, 3 H), 3.70 (dd, J = 13.1, 5.3 Hz, 1 H), 3.57 (dt, J = 13.3, 5.9 Hz, 1 H), 2.61 (m, 1 H), 1.69 (ddq, J = 13.3, 5.3, 1.1 Hz, 1 H), 1.53-1.51 (m, 2 H), 1.05 (d, J = 6.8 Hz, 3 H), 0.91 (s, 9 H), 0.89 (s, 9 H), 0.85-0.79 (m, 6 H), 0.07 (s, 6 H), 0.05 (s, 6 H). ¹³C NMR (100 MHz, CDCl₃): δ = 167.6, 153.8, 120.2, 75.9, 74.8, 51.8, 41.3, 40.1, 27.4, 26.67, 26.62, 26.41, 26.39, 18.9, 18.6, 14.2, 11.2, 9.6, -3.1, -3.1, -3.5, -3.8. HRMS: m/z calcd for C₂₀H₄₁O₄Si₂ [8 - t-butyl]: 401.2543; found: 401.2542.