LETTER
Synthesis of Aldols with Stereocontrolled Quaternary Carbons
1723
(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, W. J.; Harrington, C. R. Appl. Organomet. Chem.
2004, 18, 676.
(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).
In summary, we reported a novel germanium-mediated
cross-aldol reaction between aldehydes to construct qua-
ternary carbon centers. We achieved a highly anti-selec-
tive cross-aldol reaction of aldehyde-enolates with both
aromatic and aliphatic aldehydes. The produced germani-
um aldolates were directly converted to other functional-
ized products in a single pot. Detailed mechanistic studies
and further application of the system are ongoing.
(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.
Acknowledgment
(11) During our investigation, Yamamoto et al. reported useful
sequential C–C bond-forming reactions to the aldol
products; see: Boxer, M. B.; Yamamoto, H. J. Am. Chem.
Soc. 2007, 129, 2762.
(12) Suwa, T.; Sugiyama, E.; Shibata, I.; Baba, A. Synthesis
2000, 789.
This work was supported by a Grant-in-Aid for Scientific Research
from the Ministry of Education, Culture, Sports, Science and Tech-
nology of the Japanese Government. We also acknowledge financi-
al support from the Tokuyama Science Foundation and Mitsubishi
Chemical Corporation Fund. S.T. expresses his special thanks for
the Center of Excellence (21COE) program ‘Creation of Integrated
EcoChemistry’ of Osaka University.
(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
References and Notes
(1) Selected reviews: (a) Comprehensive Organic Syntheses,
Vol. 2; Trost, B. M., Ed.; Pergamon Press: Oxford, 1991,
99–319. (b) Mahwald, R. Chem. Rev. 1999, 99, 1095.
(2) (a) Yamago, S.; Machii, D.; Nakamura, E. J. Org. Chem.
1991, 56, 2098. (b) Burke, E. D.; Gleason, J. L. Org. Lett.
2004, 6, 405. (c) Keränen, M. D.; Eilbracht, P. Org. Biomol.
Chem. 2004, 2, 1688. (d) Adhikari, S.; Caille, S.; Hanbauer,
M.; Ngo, V. X.; Overman, L. E. Org. Lett. 2005, 7, 2795; and
references therein.
Compound 4aa (anti, major): 1H NMR (400 MHz, CDCl3):
d = 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): d = 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.
(3) For the reactions which involve only one example concerned
with the construction of the quaternary carbon center, see:
(a) Maeda, K.; Shinokubo, H.; Oshima, K. J. Org. Chem.
1998, 63, 4558. (b) Wang, W.; Li, H.; Wang, J. Tetrahedron
Lett. 2005, 46, 5077; see also ref. 2a (two examples).
(4) 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: (a) Mahrwald, R.; Costisella, B.; Gündogan, B.
Synthesis 1998, 262. (b) Yachi, K.; Shinokubo, H.; Oshima,
K. J. Am. Chem. Soc. 1999, 121, 9465. (c) Denmark, S. E.;
Ghosh, S. K. Angew. Chem. Int. Ed. 2001, 40, 4759.
(d) Northrup, A. B.; MacMillan, D. W. C. J. Am. Chem. Soc.
2002, 124, 6798. (e) Córdova, A. Tetrahedron Lett. 2004,
45, 3949. (f) Denmark, S. E.; Bui, T. Proc. Natl. Acad. Sci.
U.S.A. 2004, 101, 5439. (g) Yasuda, M.; Tanaka, S.-y.;
Baba, A. Org. Lett. 2005, 7, 1845. (h) Denmark, S. E.; Bui,
T. J. Org. Chem. 2005, 70, 10190. (i) Denmark, S. E.; Bui,
T. J. Org. Chem. 2005, 70, 10393. (j) Boxer, M. B.;
Yamamoto, H. J. Am. Chem. Soc. 2006, 128, 48.
(k) 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, C. F. III Angew. Chem. Int.
Ed. 2004, 43, 2420.
Compound 4aa (syn, minor): 1H NMR (400 MHz, CDCl3):
d = 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): d = 122.34,
110.61, 78.10, 58.75, 58.61, 16.14.
Compound 4ab (anti, major): 1H NMR (400 MHz, CDCl3):
d = 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): d = 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.
(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
Compound 4ab (syn, minor): 1H NMR (400 MHz, CDCl3):
d = 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). 13
C
NMR (100 MHz, CDCl3): d = 111.50, 76.52, 58.92, 58.03,
overreactions.
51.01, 33.89, 33.09, 16.19.
(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.
Compound 6aa (anti, major):
Mp 139–142 °C. 1H NMR (400 MHz, CDCl3): d = 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
Synlett 2007, No. 11, 1720–1724 © Thieme Stuttgart · New York