Synlett 2006(16): 2670-2672  
DOI: 10.1055/s-2006-950435
LETTER
© Georg Thieme Verlag Stuttgart · New York

Construction of the Key Amino Alcohol Moiety of the Cinchona Alkaloids

Yuichi Kobayashi, Yuuya Motoyama
Department of Biomolecular Engineering, Tokyo Institute of Technology, B52, Nagatsuta-cho 4259, Midori-ku, Yokohama 226-8501,Japan
Fax: +81(45)9245789; e-Mail: ykobayas@bio.titech.ac.jp;
Further Information

Publication History

Received 3 June 2006
Publication Date:
22 September 2006 (online)

Abstract

An N-Teoc [CO2(CH2)2TMS] protected form of the amino alcohol moiety found in the cinchona alkaloids was constructed by Curtius rearrangement followed by reaction of the isocyanate ­intermediate with TMS(CH2)2OH in one pot. Deprotection of the N-Teoc protective group and subsequent piperidine ring formation were easily accomplished with CsF in DMF at 110 °C in one pot to afford model compounds of the alkaloids.

8

Synthesis of 4b in racemic form: see ref. 7a,b.

12

Aldol reaction of a simpler compound i with PhCHO was preliminarily studied by using the protocols developed by Evans13 (Bu2BOTf and 9-BBNOTf with Et3N and i-Pr2NEt) and Crimmins10 (TiCl4 with sparteine). The former was unsuccessful, while the latter produced aldol ii (syn:anti = 84:16) in 79% yield (J Ha-Hb = 5 Hz for the syn isomer; J Ha-Hb = 8 Hz for the anti isomer; Figure [2] ).

Figure 2

14

A TBS ether was also synthesized from aldol 10 and hydrolyzed to acid, in 64% yield for the two steps. However, subsequent Curtius rearrangement did not take place, even under more forcing conditions than those used for 11, and instead gave a mixture of the starting acid and other unidentified products.

16

Probably due to steric hindrance, the hydrolysis with H2O2 and LiOH in aqueous THF required a higher temperature of 70 °C.

18

Clean formation of the isocyanate 12 was detectable by TLC.

19

To a solution of acid 11 (408 mg, 0.728 mmol) and Et3N (0.21 mL, 1.49 mmol) in benzene (1.5 mL) were added DPPA (0.19 mL, 0.891 mmol) and 2-trimethylsilylethanol (0.21 mL, 1.47 mmol). The solution was heated to reflux for 12 h, cooled to r.t., and diluted with sat. NaHCO3. The resulting mixture was extracted with EtOAc four times. The combined extracts were dried over MgSO4 and concentrated to afford an oil, which was purified by chromatography on silica gel (hexane-EtOAc) to afford 13 (381 mg, 77%).

20

The 1H NMR spectral data of selected compounds (300 MHz, CDCl3).Compound 4a: δ = 1.10-1.90 (m, 8 H), 2.61 (dt, J = 3, 12 Hz, 1 H), 2.71-2.79 (m, 1 H), 3.03 (d, J = 11 Hz, 1 H), 4.55 (d, J = 5.4 Hz, 1 H), 7.19-7.48 (m, 5 H).Compound 4b: δ = 1.10-1.80 (m, 8 H), 2.71 (dt, J = 3, 12 Hz, 1 H), 3.04-3.19 (m, 2 H), 5.46 (d, J = 4.5 Hz, 1 H), 7.42-7.56 (m, 4 H), 7.73 (d, J = 7 Hz, 1 H), 7.79 (d, J = 8 Hz, 1 H), 7.88 (d, J = 7 Hz, 1 H), 8.08 (d, J = 7 Hz, 1 H).Compound 10: δ = 1.01 (s, 9 H), 1.20-2.10 (m, 6 H), 2.52-2.62 (m, 2 H), 3.24 (dd, J = 13, 3 Hz, 1 H), 3.61 (t, J = 6 Hz, 2 H), 3.76 (t, J = 9 Hz, 1 H), 3.99 (dd, J = 9, 2 Hz, 1 H), 4.32-4.43 (m, 2 H), 4.91 (dd, J = 6, 3 Hz, 1 H), 7.14-7.48 (m, 16 H), 7.62-7.75 (m, 4 H).Compound 14: δ = 0.05 (s, 9 H), 0.99 (t, J = 8 Hz, 2 H), 1.10-1.70 (m, 7 H), 2.95 (br s, 1 H), 3.56 (t, J = 6 Hz, 2 H), 3.87-4.00 (m, 1 H), 4.17 (t, J = 8 Hz, 2 H), 4.71 (d, J = 8 Hz, 1 H), 4.88 (br s, 1 H), 7.22-7.45 (m, 5 H).Compound 15: δ = 0.05 (s, 9 H), 0.99 (t, J = 8 Hz, 2 H), 1.10-1.70 (m, 6 H), 2.45 (s, 3 H), 2.88 (s, 1 H), 3.60-4.30 (m, 5 H), 4.71 (d, J = 8 Hz, 1 H), 4.85 (br s, 1 H), 7.20-7.46 (m, 7 H), 7.66 (d, J = 7 Hz, 2 H).Compound 16: δ = 1.00 (s, 9 H), 1.10-2.10 (m, 6 H), 2.51 (dd, J = 13, 10 Hz, 1 H), 3.01 (d, J = 3 Hz, 1 H), 3.23 (dd, J = 13, 3 Hz, 1 H), 3.54-3.65 (m, 3 H), 3.92 (dd, J = 9, 2 Hz, 1 H), 4.05-4.22 (m, 1 H), 4.57-4.68 (m, 1 H), 5.74 (dd, J = 6, 3 Hz, 1 H), 7.06-8.14 (m, 22 H).Compound 19: δ = 0.05 (s, 9 H), 0.80-1.70 (m, 8 H), 2.53 (br s, 1 H), 3.45 (t, J = 6 Hz, 2 H), 3.95-4.16 (m, 1 H), 4.23 (t, J = 8 Hz, 2 H), 5.11 (d, J = 8 Hz, 1 H), 5.78 (s, 1 H), 7.30-8.30 (m, 7 H).Compound 20: δ = 0.05 (s, 9 H), 1.05 (t, J = 8 Hz, 2 H), 1.10-1.60 (m, 6 H), 2.39 (br s, 1 H), 2.42 (s, 3 H), 3.84 (t, J = 8 Hz, 2 H), 3.96-4.07 (m, 1 H), 4.23 (t, J = 8 Hz, 2 H), 5.02 (d, J = 8 Hz, 1 H), 5.76 (br s, 1 H), 7.20-8.30 (m, 11 H).