Germanium(II)-Mediated Reductive Cross-Aldol Reaction of Aldehydes: Synthesis of Aldols with Diastereocontrolled Quaternary Carbon Centers

Abstract

anti-Selective synthesis of aldols with quaternary carbon centers was achieved by germanium(II)-mediated reductive cross-aldol reaction of tertiary α-bromo aldehydes with both aromatic and aliphatic aldehydes. One-pot direct reduction and reductive amination of the aldol products were performed to give the corresponding 1,3-diol and 1,3-amino alcohol with stereocontrolled quaternary carbon centers.

Key words

aldol reactions - diastereoselectivity - germanium - organometallic reagents - quaternary carbon

References and Notes

• Selected reviews:
• 1a Comprehensive Organic Syntheses   Vol. 2:  Trost BM. Pergamon Press; Oxford: 1991.  p.99-319  
• 1b Mahwald R. Chem. Rev.  1999,  99:  1095 
• 2a Yamago S. Machii D. Nakamura E. J. Org. Chem.  1991,  56:  2098 
• 2b Burke ED. Gleason JL. Org. Lett.  2004,  6:  405 
• 2c Keränen MD. Eilbracht P. Org. Biomol. Chem.  2004,  2:  1688 
• 2d Adhikari S. Caille S. Hanbauer M. Ngo VX. Overman LE. Org. Lett.  2005,  7:  2795 ; and references therein
• For the reactions which involve only one example concerned with the construction of the quaternary carbon center, see:
• 3a Maeda K. Shinokubo H. Oshima K. J. Org. Chem.  1998,  63:  4558 
• 3b Wang W. Li H. Wang J. Tetrahedron Lett.  2005,  46:  5077 ; see also ref. 2a (two examples)
• For the recent reports on the cross-aldol reaction between aldehydes, although they were not concerned with the diastereoselective construction of quaternary carbon centers, see:
• 4a Mahrwald R. Costisella B. Gündogan B. Synthesis  1998,  262 
• 4b Yachi K. Shinokubo H. Oshima K. J. Am. Chem. Soc.  1999,  121:  9465 
• 4c Denmark SE. Ghosh SK. Angew. Chem. Int. Ed.  2001,  40:  4759 
• 4d Northrup AB. MacMillan DWC. J. Am. Chem. Soc.  2002,  124:  6798 
• 4e Córdova A. Tetrahedron Lett.  2004,  45:  3949 
• 4f Denmark SE. Bui T. Proc. Natl. Acad. Sci. U.S.A.  2004,  101:  5439 
• 4g Yasuda M. Tanaka S.-y. Baba A. Org. Lett.  2005,  7:  1845 
• 4h Denmark SE. Bui T. J. Org. Chem.  2005,  70:  10190 
• 4i Denmark SE. Bui T. J. Org. Chem.  2005,  70:  10393 
• 4j Boxer MB. Yamamoto H. J. Am. Chem. Soc.  2006,  128:  48 
• 4k Hayashi Y. Aratake S. Okano T. Takahashi J. Sumiya T. Shoji M. Angew. Chem. Int. Ed.  2006,  45:  5527 
• 5 Mase N. Tanaka F. Barbas CF. Angew. Chem. Int. Ed.  2004,  43:  2420 
• 7 For a pioneering work in low-valent germanium-mediated reductive cross-aldol reaction, see: Kagoshima H. Hashimoto Y. Oguro D. Saigo K. J. Org. Chem.  1998,  63:  691 
• 8 GeCl₂-dioxane complex 3 is easily obtained in good yield by a reduction of GeCl₄, which is not so expensive; see: Lemierre V. Chrostowska A. Dargelos A. Baylère P. Leigh WJ. Harrington CR. Appl. Organomet. Chem.  2004,  18:  676 
• 11 During our investigation, Yamamoto et al. reported useful sequential C-C bond-forming reactions to the aldol products; see: Boxer MB. Yamamoto H. J. Am. Chem. Soc.  2007,  129:  2762 
• 12 Suwa T. Sugiyama E. Shibata I. Baba A. Synthesis  2000,  789 

6

We believe that one of the most serious problems of the cross-aldol reaction using aldehyde enolates is the Lewis acidity of the metal contained. It activates the formyl group of produced metal aldolates to cause undesired overreactions.

9

The anti-stereochemistry of the major isomer of 4aa and 4ab was confirmed by X-ray analysis of their derivatives (6aa and 8ab, respectively).

10

The same transition model was suggested by Nakamura et al. in the TBAF-catalyzed cross-aldol reaction of enol silyl ethers. See ref. 2a.

13

Typical Procedure Bromoaldehyde 1 (0.6 mmol) was added to a stirred solution of 3 (0.6 mmol) and aldehyde 2 (0.6 mmol) in THF (2 mL) at 0 °C. After the mixture was stirred for 4-12 h at 0 °C, MeOH (8 mL) was added and the resulting solution was stirred for additional 1 h at r.t. Then, aq NaHCO₃ (sat., 10 mL) was added. The mixture was extracted with Et₂O-hexane (4:1, three times) and the organic layer was dried over MgSO₄. The solvent was evaporated under reduced pressure and the residue was purified by flash column chromatography on silica gel to give the product.

14

Analytical and Spectroscopic Data of Selected Compounds Compound 4aa (anti, major): ¹H NMR (400 MHz, CDCl₃): δ = 7.90-7.85 (m, 2 H), 7.31-7.20 (m, 5 H), 7.05-7.00 (m, 2 H), 5.46-5.43 (br s, 1 H), 4.71 (s, 1 H), 4.54 (d, J = 0.97 Hz, 1 H, OH), 3.59 (s, 3 H), 3.34 (s, 3 H), 1.30 (s, 3 H). ¹³C NMR (100 MHz, CDCl₃): δ = 147.98, 146.54, 140.46, 128.40, 127.95, 127.55, 126.98, 121.79, 112.74, 77.15, 59.74, 57.49, 51.54, 11.42. HRMS (CI, 200 eV): m/z calcd for C₁₈H₂₂NO₅: 332.1420 [M⁺ + 1]; found: 332.1501. Anal. Calcd for C₁₈H₂₁NO₅: C, 65.24; H, 6.39; N, 4.23. Found: C, 65.28; H, 6.51; N, 4.11.
Compound 4aa (syn, minor): ¹H NMR (400 MHz, CDCl₃): δ = 8.02-7.98 (m, 2 H), 5.15 (d, J = 3.9 Hz, 1 H), 4.71 (s, 1 H), 3.61 (s, 3 H), 3.40 (s, 3 H), 2.76 (d, J = 3.9 Hz, 1 H, OH), 1.28 (s, 3 H). ¹³C NMR (100 MHz, CDCl₃): δ = 122.34, 110.61, 78.10, 58.75, 58.61, 16.14.
Compound 4ab (anti, major): ¹H NMR (400 MHz, CDCl₃): δ = 7.30-7.17 (m, 7 H), 7.16-7.11 (m, 1 H), 7.07-7.03 (m, 2 H), 4.36 (s, 1 H), 4.27-4.22 (br d, J = 10.4 Hz, 1 H), 3.87-3.85 (br s, 1 H, OH), 3.41 (s, 3 H), 3.12 (s, 3 H), 2.84 (ddd, J = 13.8, 9.9, 4.6 Hz, 1 H), 2.53 (ddd, J = 13.8, 9.2, 7.5 Hz, 1 H), 1.55-1.43 (m, 1 H), 1.38 (s, 3 H), 1.29-1.18 (m, 1 H). ¹³C NMR (100 MHz, CDCl₃): δ = 142.39, 142.26, 128.50, 128.06, 128.04, 127.15, 126.36, 125.48, 113.98, 73.86, 59.34, 57.36, 50.61, 32.85, 32.69, 11.12. HRMS (CI, 200 eV): m/z calcd for C₂₀H₂₅O₂: 297.1776 [M⁺ - H₂O + 1]; found: 297.1860. Anal. Calcd for C₂₀H₂₆O₃: C, 76.40; H, 8.33. Found: C, 76.44; H, 8.31.
Compound 4ab (syn, minor): ¹H NMR (400 MHz, CDCl₃): δ = 4.69 (s, 1 H), 3.91 (ddd, J = 10.6, 5.6, 1.7 Hz, 1 H), 3.50 (s, 3 H), 3.26 (s, 3 H), 2.26 (d, J = 5.6 Hz, 1 H, OH). ¹³C NMR (100 MHz, CDCl₃): δ = 111.50, 76.52, 58.92, 58.03, 51.01, 33.89, 33.09, 16.19.
Compound 6aa (anti, major): Mp 139-142 °C. ¹H NMR (400 MHz, CDCl₃): δ = 8.00-7.95 (m, 2 H), 7.36-7.25 (m, 5 H), 7.09-7.04 (m, 2 H), 5.37 (d, J = 2.7 Hz, 1 H), 4.30 (dd, J = 10.9, 5.9 Hz, 1 H), 3.86 (dd, J = 10.9, 5.2 Hz, 1 H), 3.58 (d, J = 2.7 Hz, 1 H, OH), 2.38 (dd, J = 5.9, 5.2 Hz, 1 H, OH), 1.28 (s, 3 H). ¹³C NMR (100 MHz, CDCl₃): δ = 148.20, 146.93, 141.75, 128.57, 128.01, 127.30, 126.81, 122.33, 80.56, 70.94, 47.30, 15.35. HRMS (CI, 200 eV): m/z calcd for C₁₆H₁₈NO₄: 288.1158 [M⁺ + 1]; found: 288.1238. Anal. Calcd for C₁₆H₁₇NO₄: C, 66.89; H, 5.96; N, 4.88. Found: C, 66.73; H, 5.93; N, 4.83.
CCDC-638056 contains the supplementary crystallographic data for this paper. These data can be obtained free of charge from the Cambridge Crystallographic Data Centre via www.ccdc.cam.ac.uk/data_request/cif.
For the determination of the stereochemistry of 4ab, we performed esterification of the diol 6ab according to the procedure given below (Scheme [3] ).
Compound 8ab (anti, major): MgBr₂ (2.62 mmol) was added to a stirred suspension of (2R*,3S*)-2,5-diphenyl-2-methylpentane-1,3-diol (anti-6ab, 0.65 mmol), 4-nitro-benzoic anhydride (2.62 mmol), and Et₃N (3.9 mmol) in CH₂Cl₂ (6 mL) at r.t. After the mixture was stirred for 37 h, it was poured into aq NaHCO₃ (sat., 20 mL) and the mixture was extracted with Et₂O (3 × 20 mL). The collected organic layer was dried over MgSO₄. The solvent was evaporated under reduced pressure and the residue was purified by flash column chromatography on silica gel to give the product.
CCDC-638057 contains the supplementary crystallographic data for this paper. These data can be obtained free of charge from the Cambridge Crystallographic Data Centre via www.ccdc.cam.ac.uk/data_request/cif.
Mp 113-116 °C. ¹H NMR (400 MHz, CDCl₃): δ = 8.31-8.26 (m, 2 H), 8.22-8.16 (m, 4 H), 7.99-7.95 (m, 2 H), 7.41-7.36 (m, 2 H), 7.36-7.31 (m, 2 H), 7.30-7.24 (m, 1 H), 7.21-7.16 (m, 2 H), 7.13-7.08 (m, 1 H), 7.06-7.01 (m, 2 H), 5.98 (dd, J = 10.4, 1.7 Hz, 1 H), 4.56 (d, J = 11.1 Hz, 1 H), 4.41 (d, J = 11.1 Hz, 1 H), 2.67-2.51 (m, 2 H), 2.07-1.96 (m, 1 H), 1.83-1.73 (m, 1 H), 1.66 (s, 3 H). ¹³C NMR (100 MHz, CDCl₃): δ = 164.29, 164.12, 150.53, 150.34, 141.09, 140.56, 135.09, 135.09, 130.67, 130.47, 128.64, 128.32, 128.26, 127.23, 126.40, 125.98, 123.53, 123.37, 77.62, 70.76, 45.94, 32.39, 31.64, 16.79. Anal. Calcd for C₃₂H₂₈N₂O₈: C, 67.60; H, 4.96; N, 4.93. Found: C, 67.56; H, 4.91; N, 4.92.