Stereoselective Synthesis of Highly Substituted Annulated Dihydropyrans Based on γ-Lithiation and Homoaldol Reaction of an Enantiopure α-Silylated Vinyl Carbamate

Abstract

The N,N-diisopropylcarbamate of (-)-myrtenol is converted into the corresponding [1-(trimethylsilyl)vinyl] carbamate. Its γ-lithiation by means of sec-butyllithium/TMEDA, titanation, and addition to aldehydes leads with high stereoselectivity to enantiopure anti-homoaldol products. These add, under the influence of boron trifluoride-diethyl ether complex, a second equivalent of aldehyde and form, in an intermolecular silyl-Prins reaction, the title compounds, again with essentially complete stereoselectivity. After desilylation, the reaction takes the regular course with formation of an annulated five-membered ring.

Key words

chiral allyl carbamates - vinyl carbamates - diastereo­selective γ-lithiation - aldehyde addition - annulated dihydropyrans

References

• Reviews:
• 2a Hoppe D. Synthesis  2009,  43 
• 2b Hoppe D. Marr F. Brüggemann M. Top. Organomet. Chem.  2003,  139 
• 2c Christoph G. Hoppe D. In The Chemistry of Organolithium Compounds   Rappoport Z. Marek I. Wiley; Chichester: 2004.  p.1055 
• 3a Hoppe D. Hanko R. Brönneke A. Lichtenberg F. Angew. Chem., Int. Ed. Engl.  1981,  20:  1024 ; Angew. Chem. 1981, 93, 1106
• 3b Becker J. Grimme S. Fröhlich R. Hoppe D. Angew. Chem. Int. Ed.  2007,  46:  1645 ; Angew. Chem. 2007, 119, 1672
• 3c Becker J. Bergander K. Fröhlich R. Hoppe D. Angew. Chem. Int. Ed.  2008,  47:  1654 ; Angew. Chem. 2008, 120, 1678
• 4a Reetz MT. In Organometallics in Synthesis   2nd ed.:  Schlosser M. Wiley-VCH; Chichester: 2002.  p.817 
• 4b Weidmann B. Seebach D. Angew. Chem., Int. Ed. Engl.  1983,  22:  31 ; Angew. Chem. 1983, 95, 12
• 5a Hoppe D. Krämer T. Freire Erdbrügger C. Egert E. Tetrahedron Lett.  1989,  30:  1233 
• 5b Ünaldi S. Özlügedik M. Fröhlich R. Hoppe D. Adv. Synth. Catal.  2005,  347:  1621 
• 5c Becker J. Fröhlich R. Kataeva O. Hoppe D. Eur. J. Org. Chem.  2007,  3349 
• 5d Becker J. Fröhlich R. Salorinne K. Hoppe D. Eur. J. Org. Chem.  2007,  3337 
• 6 Becker J. Dissertation   University of Münster; Germany: 2008. 
• 7a Seppi M. Kalkofen R. Reupohl J. Fröhlich R. Hoppe D. Angew. Chem. Int. Ed.  2004,  43:  1423 ; Angew. Chem. 2004, 116, 1447
• 7b Kalkofen R. Brandau S. Wibbeling B. Hoppe D. Angew. Chem. Int. Ed.  2004,  43:  6667 ; Angew. Chem. 2004, 116, 6836
• 7c Reuber J. Fröhlich R. Hoppe D. Org. Lett.  2004,  6:  783 
• 8 Würthwein E.-U. Hoppe D. J. Org. Chem.  2008,  73:  9055 
• 9 Peschke B. Lüßmann J. Dyrbusch M. Hoppe D. Chem. Ber.  1992,  125:  1421 
• 15 Review: Hoffmann RW. Angew. Chem., Int. Ed. Engl.  1987,  26:  489 ; Angew. Chem. 1987, 99, 503
• 16 Kollmann S. Fröhlich R. Hoppe D. Synthesis  2007,  883 
• 18a Overman LE. Lectures in Heterocyclic Chemistry  1985,  8:  58 
• 18b Fleming I. Chow H.-F. J. Chem. Soc., Perkin Trans. 1  1984,  1815 
• 18c Hoffmann RW. Giesen V. Fuest M. Liebigs Ann. Chem.  1993,  629 
• 18d Blumenkopf T. Overman LE. Chem. Rev.  1986,  86:  857 
• 18e Markó IE. Bayston DJ. Tetrahedron  1994,  50:  7141 
• 19a Semeyn RH. Blaauw RH. Hiemstra H. Speckamp WN. J. Org. Chem.  1997,  62:  3426 
• 19b Dobbs AP. Martinović S. Tetrahedron Lett.  2002,  43:  7055 
• 19c Dobbs AP. Guesné SJ. Martinović S. Coles S. Hursthouse MB. J. Org. Chem.  2003,  68:  7880 
• 19d Lian Y. Hinkle RJ. J. Org. Chem.  2006,  71:  7071 
• 20 Kofron WG. Baclawski LM. J. Org. Chem.  1976,  41:  1879 
• 22 Denzo-SMN: Otwinowski Z. Minor W. Methods Enzymol.  1997,  276:  307 
• 23 Otwinowski Z. Borek D. Majewski W. Minor W. Acta Crystallogr., Sect. A  2003,  59:  228 
• 24 Sheldrick GM. Acta Crystallogr., Sect. A  1990,  46:  467 
• 25 SHELXL-97: Sheldrick GM. Acta Crystallogr., Sect. A  2008,  64:  112 
• 26 Keller E. SCHAKAL   University of Freiburg; Germany: 1997. 
• 27 DIAMOND: Bergerhoff G. Berndt M. Brandenburg K. J. Res. Natl. Inst. Stand. Technol.  1996,  101:  221 

1

X-ray crystal structure analysis.

10

X-ray crystal structure analysis for 12: formula C₂₀H₃₇NO₂Si, M = 351.60, colorless crystal 0.40 × 0.10 × 0.07 mm, a = 10.6208 (3), b = 7.4155 (2), c = 14.7983 (5) Å, β = 108.749 (2)˚, V = 1103.65 (6) Å^³, ρ_calc = 1.058 g cm^-³, µ = 1.010 mm^-¹, empirical absorption correction (0.688 ≤ T ≤ 0.933), Z = 2, monoclinic, space group P2₁ (No. 4), λ = 1.54178 Å, T = 223 K, ω and φ scans, 6133 reflections collected (±h, ±k, ±l), [(sinθ)/λ] = 0.60 Å^-¹, 2594 independent (R _int = 0.041) and 2497 observed reflections [I ≥ 2 σ(I)], 226 refined parameters, R = 0.044, wR ^² = 0.123, Flack parameter 0.01 (4), max. residual electron density 0.16 (-0.16) e Å^-³, hydrogen atoms calculated and refined as riding atoms.

11

Formula 14 depicts the α-(S)-epimer, which is assumed to be the preliminary formed epimer by removal of the pro-S-H (from the rear face). However its configurational stability is unknown, it may be in equilibration with the α-(R)-epimer (not shown).

12

X-ray crystal structure analysis for epi-18a: formula C₂₄H₄₅NO₃Si, M = 423.70, colorless crystal 0.35 × 0.25 × 0.07 mm, a = 10.8529 (5), b = 13.0316 (6), c = 18.5002 (8) Å, V = 2616.5 (2) Å^³, ρ_calc = 1.076 g cm^-³, µ = 0.954 mm^-¹, empirical absorption correction (0.731 ≤ T ≤ 0.936), Z = 4, orthorhombic, space group P2₁2₁2₁ (No. 19), λ = 1.54178 Å, T = 223 K, ω and φ scans, 14181 reflections collected (±h, ±k, ±l), [(sinθ)/λ] = 0.60 Å^-¹, 4588 independent (R _int = 0.050) and 4348 observed reflections [I ≥ 2 σ(I)], 274 refined parameters, R = 0.044, wR ^² = 0.114, Flack parameter -0.01 (3), max. residual electron density 0.21 (-0.17) e Å^-³, hydrogen atoms calculated and refined as riding atoms.

13

X-ray crystal structure analysis for 18a: formula C₂₄H₄₅NO₃Si, M = 423.70, colorless crystal 0.40 × 0.15 × 0.10 mm, a = 10.9427 (4), b = 13.3514 (5), c = 18.4110 (7) Å, V = 2689.9 (2) Å^³, ρ_calc = 1.046 g cm^-³, µ = 0.928 mm^-¹, empirical absorption correction (0.708 ≤ T 0.913), Z = 4, orthorhombic, space group P2₁2₁2₁ (No. 19), λ = 1.54178 Å, T = 223 K, ω and φ scans, 14774 reflections collected (±h, ±k, ±l), [(sinθ)/λ] = 0.60 Å^-¹, 4669 independent (R _int = 0.042) and 4327 observed reflections [I ≥ 2 σ(I)], 274 refined parameters, R = 0.043, wR ^² = 0.111, Flack parameter 0.01 (3), max. residual electron density 0.19 (-0.18) e Å^-³, hydrogen atoms calculated and refined as riding atoms.

14

A six-membered Zimmerman-Traxler transition state of an (E)-allylmetal leads to the anti-diastereomer.^¹5

17

X-ray crystal structure analysis for 23ac: formula C₂₈H₄₁NO₃, M = 439.62, colorless crystal 0.25 × 0.20 × 0.15 mm, a = 9.1840 (2), b = 12.7732 (3), c = 11.7279 (5) Å, β = 102.293 (2)˚, V = 1343.67 (5) Å^³, ρ_calc = 1.087 g cm^-³, µ = 0.540 mm^-¹, empirical absorption correction (0.877 ≤ T ≤ 0.923), Z = 2, monoclinic, space group P2₁ (No. 4), λ = 1.54178 Å, T = 223 K, ω and φ scans, 7668 reflections collected (±h, ±k, ±l), [(sinθ)/λ] = 0.60 Å^-¹, 4270 independent (R _int = 0.038) and 4151 observed reflections
[I ≥ 2 σI)], 297 refined parameters, R = 0.040, wR ^² = 0.112, Flack parameter 0.1 (2), max. residual electron density 0.16 (-0.18) e Å^-³, hydrogen atoms calculated and refined as riding atoms.

21

Data sets were collected with a Nonius KappaCDD diffractometer. Programs used: data collection COLLECT (Nonius B.V., 1998), data reduction Denzo-SMN,^²² absorption correction Denzo^²³ structure solution SHELXS-97,^²4 structure refinement SHELXL-97,^²5 graphics SCHAKAL^²6 and DIAMOND.^²7 CCDC 739288-739291 contain the supplementary crystallographic data for this paper. These data can be obtained free of charge at www.ccdc.cam.ac.uk/conts/retrieving.html [or from the Cambridge Crystallographic Data Centre, 12 Union Road, Cambridge CB2 1EZ, UK; fax: [phone], E-mail: [e-mail]].