S. Mosaferi, R.E. Jelley, B. Fedrizzi et al.
Tetrahedron Letters 61 (2020) 152642
It was envisaged that deuterated b-ionone could be prepared
using the inexpensive and readily available deuterated solvent
d6-acetone, which would have the added benefit of introducing
six deuterium atoms. In addition, the use of d6-acetone versus
d3-iodomethane as the source of deuteration is approximately
ten times more cost efficient.
Result and discussion
The proposed synthesis was first investigated using unlabeled
acetone to establish the methodology. Acetone (1) was converted
to unsaturated ester 2 in 88% yield using triethyl phosphonoac-
etate (Scheme 1). Reduction of ester 2 with LiAlH4 gave allylic alco-
hol 3, which was immediately converted to dimethylallyl bromide
4 in 70% yield using HBr. The dianion of ethyl acetoacetate was
formed using NaH and n-BuLi, which was reacted with dimethylal-
lyl bromide 4 to give b-ketoester 5 in 60% yield [28]. Cyclisation of
b-ketoester 5 was achieved easily using tin-(IV) chloride, providing
cyclic b-ketoester 6 in 88% yield [29]. Following formation of the
required cyclohexane ring in cyclic b-ketoester 6, a Wittig reaction,
using methylene(triphenyl)phosphorane, afforded methylenecy-
clohexane ester 7 in 85% yield [30]. Reduction of ester 7 using
DIBAL-H provided primary alcohol 8 in a moderate 62% yield
[31]. LiAlH4 was less effective than DIBAL-H at yielding 7 from 8;
even when excess LiAlH4 was used, starting material consistently
remained. Alcohol 8 was oxidised using Dess-Martin periodinane
(DMP) to give the desired aldehyde 9. Rearrangement of the alkene
in aldehyde 9 using DBU gave conjugated aldehyde 10, which itself
Fig. 1. b-Ionone structure.
approach is based on using isotopically labelled compounds as
analytical standards. In previously reported synthetic methods,
b-ionone has been converted to a deuterated analogue through
the inclusion of three deuterium atoms at the C-10 methyl group
[24]. This approach tends to require long reaction times and/or
results in low yields. However, more importantly, the deuterium
atoms at this position can be readily lost during mass spectrometry
fragmentation, which poses a hindrance to some experimental
designs [23,25]. In another reported method, the toxic and highly
volatile reagent d3-iodomethane is employed as the source of deu-
terium; this reaction results in deuteration of the methyl groups on
the cyclohexene ring [26,27].
Scheme 1. Synthesis of b-cyclocitral and b-ionone. Reagents and conditions: (a) triethyl phosphonoacetate (1.3 equiv.), NaH (1.2 equiv.), THF, 0 °C, 24 h, 88%; (b) LiAlH4 (1.5
equiv.), Et2O, 0 °C, 3 h, 72%; (c) HBr 48% (1.2 equiv.), CH2Cl2, 0 °C, 2 h, 70%; (d) NaH (2 equiv.), ethyl acetoacetate (1 equiv.), 1.6 M n-BuLi (1.6 equiv.), THF, 0 °C, 21 h, 60%; (e)
SnCl4 (1.6 equiv.), CH2Cl2, 0 °C, 24 h, 88%; (f) KOtBu (2.3 equiv.), Ph3P+MeBr- (2.2 equiv.), THF, 60 °C, 23 h, 85%; (g) 1 M DIBAL-H (2.5 equiv.), CH2Cl2, À78 °C, 2 h, 62%; (h) DMP
(1.1 equiv.), CH2Cl2, rt, 2 h, 75%; (i) DBU (3 equiv.), CH2Cl2, 0 °C, 24 h, 60%; (j) 10% aqueous KOH (8 equiv.), acetone, 60 °C, 22 h, 40%.
Scheme 2. Synthesis of d6-b-ionone. Reagents and conditions; (a) triethyl phosphonoacetate (1.3 equiv.), NaH (1.2 equiv.), THF, 0 °C, 24 h, 85%; (b) LiAlH4 (1.5 equiv.), Et2O,
0 °C, 3 h, 77%; (c) HBr 48% (1.2 equiv.), CH2Cl2, 0 °C, 2 h, 69%; (d) NaH (2 equiv.), ethyl acetoacetate (1 equiv.), 1.6 M n-BuLi (1.6 equiv.), THF, 0 °C, 21 h, 58%; (e) SnCl4 (1.6
equiv.), CH2Cl2, 0 °C, 24 h, 86%; (f) KOtBu (2.3 equiv.), Ph3P+MeBr- (2.2 equiv.), THF, 60 °C, 23 h, 82%; (g) 1 M DIBAL-H (2.5 equiv.), CH2Cl2, À78 °C, 2 h, 68%; (h) DMP (1.1
equiv.), CH2Cl2, rt, 2 h, 71%; (i) DBU (3 equiv.), CH2Cl2, 0 °C, 24 h, 65%; (j) 10% aqueous KOH (8 equiv.), acetone, 60 °C, 22 h, 38%.
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