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DOI: 10.1055/s-0029-1218389
Protection-, Salt-, and Metal-Free Syntheses of [n]-Shogaols by Use of Dimethylammonium Dimethyl Carbamate (DIMCARB) without Protecting Groups
Publication History
Publication Date:
27 November 2009 (online)

Abstract
Shogaols, the pungent principle of ginger, exhibit interesting bioactivities. Practical preparation of shogaols is highly desired. Here we report the protection/deprotection-, salt-, and metal-free synthesis of shogaol in three steps by use of dimethylammonium dimethyl carbamate (DIMCARB), in which DIMCARB smoothly promoted Mannich-type condensation of the ketone donor with the aldehyde acceptor through the iminium cation intermediate.
Key words
shogaols - protection-free synthesis - salt-free synthesis - metal-free synthesis - cross Mannich-type condensation
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References
Typical Procedure Handling of this class of reaction is very simple. DIMCARB (7, 101 µL, 0.5 mmol) was added to the solution of vanillin (5a, 76.1 mg, 0.5 mmol) in CH2Cl2 (0.5 mL) at 25 ˚C. Gas was evolved. Acetone (12, 36.7 µL, 0.5 mmol) was added in a single portion. Stirring was continued for 48 h. The solvent mixture was acidified with 10% HCl aq (2 mL) and extracted with CH2Cl2 (3 × 3 mL). The combined organic fraction was dried with anhyd Na2SO4, filtrated, and solvent removed in vacuo. Purification with column chromatography (silica gel, hexane-EtOAc) gave the enone 13a (77.8 mg, 81%) as a pale yellow solid. Without extraction, the crude reaction mixture could be directly purified by column chromatog-raphy in decreasing to 56% chemical yield.
8We further investigated decreasing amount of DIMCARB, but chemical yields also decreased in the Mannich-type condensation of vanillin(5a) with acetone(12). Amount of DIMCARB = 1.0 equiv: 81%; 0.5 equiv: 72%; 0.1 equiv: 41%. These results suggested that DIMCARB catalyzed the Mannich-type condensation; however, due to low catalytic ability, a stoichiometric amount of DIMCARB was used for the present reactions.
11Reactions in conventional solvents such as DMSO, DMF, MeCN, 1,4-dioxane, Et2O, THF, MeOH, 2-PrOH, toluene, and CHCl3 resulted in low chemical yields (2a: 0-19%) along with self-Mannich product in 6-42% yields.
13
Typical Procedure
To
a solution of the aldehyde (3a, 58.9 mg,0.3
mmol) in DIMCARB (7, 300 µL, 1.47
mmol) was added dropwise hexanal (15a,
110 µL,0.9 mmol) by use of syringe pump over 10 h at 25 ˚C.
Stirring was continued for 48 h. The solvent mixture was acidified
with 10% HCl aq (2 mL) and extracted with CH2Cl2 (3 × 3
mL). The combined organic fraction was dried with anhyd Na2SO4,
filtrated, and solvent removed in vacuo. Purification with column
chromatog-raphy (silica gel, hexane-EtOAc) gave [6]-shogaol 2a (66.4 mg, 80%) as a pale yellow
liquid; registry number 555-66-8; R
f
= 0.51
(hexane-EtOAc = 70:30). ¹H
NMR (300 MHz, CDCl3): δ = 0.89
(t, J = 6.8
Hz, 3 H, CH3), 1.15-1.57 (m, 6 H, 3 × CH2),
2.10-2.28 (m, 2 H, CH=CHCH
2),
2.75-2.96 (m, 4 H, CH2CH2Ar), 3.87
(s, 3 H, OCH3), 6.09 (dt, J = 15.8, 1.1
Hz, 1 H, COCH=CH), 6.68 (dd, J = 7.9,
1.7 Hz, 1 H, H-6), 6.71 (d, J = 1.7
Hz, 1 H, H-2), 6.82 (dt, J = 15.8,
6.9 Hz, 1 H, COCH=CH), 6.83 (d, J = 7.9
Hz, 1 H, H-5). ¹³C NMR (75 MHz, CDCl3): δ = 200.01
(C), 147.95 (CH), 146.49 (C), 143.95 (C), 133.19 (C), 130.29 (CH),
120.77 (CH), 114.35 (CH), 111.16 (CH), 55.74 (OCH3),
41.80 (CH2), 32.26 (CH2), 31.16 (CH2),
29.72 (CH2), 27.58 (CH2), 22.22 (CH2), 13.72
(CH3). GC (TD-17, Tinj = 250 ˚C,
Tdet = 250 ˚C, He = 0.5
kg/cm², H2 = 0.5
kg/cm², air = 0.5
kg/cm², Ti = 250 ˚C): t
R = 9.410
min; HPLC [Mightysil, hexane-2-PrOH (95:5), flow
rate 1.0 mL/min, λ = 254
nm]: t
R = 13.575
min.