A facile synthesis of 5,5-dideutero-4-dimethyl(phenyl)silyl-6-undecyl- tetrahydropyran-2-one as a deuterium labeled synthon for (-)-tetrahydrolipstatin and (+)-δ-hexadecanolide

Article abstract of DOI:10.1002/jlcr.3081

Deuterium-labeled biologically active compounds are gaining importance because they can be utilized as tracers or surrogate compounds to understand the mechanism of action, absorption, distribution, metabolism, and excretion. Deuterated drug molecules (heavy drugs) become novel as well as popular because of better stability and bioavailability compared with their hydrogen analogs. Labeling of organic molecules with deuterium at specific positions is thus gaining popularity. In this work, we have exploited a highly regioselective and enantioselective direct Michael addition of methyl-d₃ alkyl ketones to dimethyl(phenyl)silylmethylene malonate that was catalyzed by (S)-N-(2-pyrrolidinylmethyl)pyrrolidine/trifluoroacetic acid/ D₂O combination with high yield and isotopic purity. The 5,5-dideutero-4- dimethyl(phenyl)silyl-6-undecyl-tetrahydropyran-2-one was obtained from the adduct of methyl-d₃ undecanyl ketone and dimethyl(phenyl) silylmethylene malonate by a silicon controlled diastereoselective ketone reduction, lactonization, and deethoxycarbonylation. The dideuterated silylated tetrahydropyran-2-one is the precursor for geminal ²H ₂-labeled (+)-4-hydroxy-6-undecyl-tetrahydropyran-2-one, an advanced intermediate for gem-dideutero (-)-tetrahydrolipstatin and (+)-δ- hexadecanolide syntheses. Copyright

Full text of DOI:10.1002/jlcr.3081

Research Article
Received 22 March 2013,
Revised 17 May 2013,
Accepted 28 May 2013
Published online 9 July 2013 in Wiley Online Library
(wileyonlinelibrary.com) DOI: 10.1002/jlcr.3081
A facile synthesis of 5,5-dideutero-4-dimethyl
(phenyl)silyl-6-undecyl-tetrahydropyran-2-one
as a deuterium labeled synthon for (ꢀ)-
tetrahydrolipstatin and (+)-δ-hexadecanolide†
Sandip J. Wagh,a Raghunath Chowdhury,a Sulekha Mukhopadhyay,b
a
*
and Sunil K. Ghosh
Deuterium-labeled biologically active compounds are gaining importance because they can be utilized as tracers or surrogate
compounds to understand the mechanism of action, absorption, distribution, metabolism, and excretion. Deuterated drug
molecules (heavy drugs) become novel as well as popular because of better stability and bioavailability compared with their
hydrogen analogs. Labeling of organic molecules with deuterium at specific positions is thus gaining popularity. In this work, we
have exploited a highly regioselective and enantioselective direct Michael addition of methyl-d3 alkyl ketones to dimethyl
(phenyl)silylmethylene malonate that was catalyzed by (S)-N-(2-pyrrolidinylmethyl)pyrrolidine/trifluoroacetic acid/ D2O
combination with high yield and isotopic purity. The 5,5-dideutero-4-dimethyl(phenyl)silyl-6-undecyl-tetrahydropyran-2-one was
obtained from the adduct of methyl-d3 undecanyl ketone and dimethyl(phenyl)silylmethylene malonate by a silicon controlled
diastereoselective ketone reduction, lactonization, and deethoxycarbonylation. The dideuterated silylated tetrahydropyran-2-one
is the precursor for geminal 2H2-labeled (+)-4-hydroxy-6-undecyl-tetrahydropyran-2-one, an advanced intermediate for
gem-dideutero (–)-tetrahydrolipstatin and (+)-δ-hexadecanolide syntheses.
Keywords: deuterium labeling; organocatalysis; Michael addition; 5,5-dideutero-4-dimethyl(phenyl)silyl-6-undecyl-tetrahydropyran-2-one;
methyl-d3 alkyl ketones, dimethyl(phenyl)silylmethylene malonate; 4,4-dideuterated 3-silyl-5-keto ester
Recently, deuterated drug molecules (heavy drugs) become
Introduction
novel as well as popular drugs that exhibit better stability and
There are significant advancements in the analytical techniques for
bioavailability compared with their hydrogen analogs.12,13
the detection of stable isotopes (e.g., 2H and 13C) attached to
Deuterated paroxetine,14,15 an antidepressant (Figure 1) altered
organic molecules by NMR or mass spectrometry. Therefore, there
the drug’s metabolism and prolonged its activity in vivo. The
is a surge of interest in applications of stable isotope-labeled
metabolism rate of deuterated analog of venlafaxine,16 dual
compounds in general and deuterium (2H or D)-labeled
serotonin/norepinephrine reuptake inhibitor dropped to 50%.
compounds, in particular, in a variety of scientific fields.
The nephrotoxicity of efavirenz (Figure 1), an HIV-1 non-nucleoside
Deuterium-labeled biologically active compounds are utilized as
reverse transcriptase inhibitor got reduced to a good extent.17 The
tracers or surrogate compounds to understand the mechanism
of action, absorption, distribution, metabolism, and excretion.1–3
Compounds labeled with deuterium at specific positions are used
chiral center next to α-ketoamide (S-configuration) in telaprevir
(Figure 1) tends to epimerize (R-configuration), which was
suppressed through the deuteration at the specified position of
in the investigation of chemical and enzymatic reaction
telaprevir.18
mechanisms,4,5 kinetics,6–10 and the structural elucidation of
biological macromolecules.11
The 4-hydroxytetrahydropyran-2-one (commonly known as
β-hydroxy-δ-lactone) subunit is present in a large number of
The difference in physical and chemical properties between H
and D is very small but measurable. Deuteration increases
lipophilicity of organic molecules. A C–D bond is shorter than a
C–H bond. There is a slight increase in basicity of deuterated
amines and a slight decrease in acidity of deuterated phenols
and carboxylic acids. The primary use of D substitution in place of
H in drug discovery is to use the kinetic isotope effect (KIE), which
usually ranges from onefold to sevenfold, with exceptions. Thus,
site specific substitution of hydrogen with D where H atom
abstraction is the rate determining step that can impede
metabolism and also can reduce toxicity. Because of KIE, deuterium
slows epimerization thus enhances stereochemical stability.
aBio-Organic Division, Bhabha Atomic Research Centre, Trombay, Mumbai
400085, India
bChemical Engineering Division, Bhabha Atomic Research Centre, Trombay,
Mumbai 400085, India
*Correspondence to: Sunil K. Ghosh, Bio-Organic Division, Bhabha Atomic
Research Centre, Trombay, Mumbai 400085, India.
E-mail: ghsunil@barc.gov.in
†Supporting information may be found in the online version of this article.
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S. J. Wagh et al.
biologically important molecules19–21 (Figure 2) and it has been (phenyl)silyl group to a hydroxyl group with retention of
shown22 from structure activity relationship (SAR) studies that the configuration. Labeled 4-dimethyl(phenyl)silyltetrahydropyran-2-
lactone moiety is essential for the biological activity. The synthesis ones with deuterium at specific positions would therefore be
of 4-hydroxytetrahydropyran-2-ones can be achieved from the useful for detailed biological studies for such kind of molecules.
corresponding
4-dimethyl(phenyl)silyl-tetrahydropyran-2-ones The H–D exchange reactions are often carried out at C–Hs α to a
by a stereospecific Fleming–Tamao23,24 oxidation of dimethyl carbonyl or OH groups, aryl-C–Hs and benzylic C–Hs because of
the reactivity of these positions.25–27 Inactivated positions do not
undergo H–D exchange so easily, although some efforts have been
made for perdeuteration of alkanes.28–30 We propose a selective
deuterium labeling strategy at the unreactive 5-position of the
tetrahyropyran-2-one as shown in Scheme 1. The 5,5-dideutero-
4-dimethyl(phenyl)silyl-tetrahydropyran-2-ones 1-d2 could be
obtained from the 4,4-dideuterated 3-silyl-5-keto ester 2-d2 which
in turn could be prepared by a regioselective and enantioselective
Michael addition of methyl-d3 alkyl ketones 3 to a silylmethylene
malonate 4. Herein, we report enantioselective organo-catalyzed
Michael addition of methyl-d3 alkyl ketones 3 to silylmethylene
malonate 4 and conversion of one of the adducts to 5,5-
Figure 1. Some D-labeled pharmaceuticals.
Scheme 1. Retro synthetic analysis of 6-alkyl-5,5-dideutero-4-dimethyl(phenyl)
silyl-tetrahydropyran-2-ones.
Scheme 2. Synthesis of 4-hydroxy-6-undecyl-tetrahydropyran-2-one 5, the
known intermediate for (–)-tetrahydrolipstatin 6 and (+)-δ-hexadecanolide 7.
Figure 2. Some biologically active β-hydroxy-δ-lactones.
Scheme 3. Michael addition of methyl ketones to malonate 4.
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S. J. Wagh et al.
dideuterated 4-silyl-tetrahydropyran-2-one 1-d2 via a Si-directed
carbonyl reduction,31 lactonization, and deethoxycarbonylation
as the key steps. The corresponding proteo analog 1 (R¼C11H23ꢀ)
is the precursor32 for 4-hydroxy-6-undecyl-tetrahydropyran-2-one
5, the known intermediate for (–)-tetrahydrolipstatin 633 and (+)-
δ-hexadecanolide 734 syntheses (Scheme 2).
Scheme 4. Michael addition of acetone-d6 to malonate 4.
Result and discussion
Recently, we have shown35 a highly regioselective Michael
addition of alkyl methyl ketones to silylmethylene malonate 4
using N-(2-pyrrolidinylmethyl)pyrrolidine 836 (Scheme 3) and
Trifluoroacetic acid combination as the catalyst system of choice
and N-methyl-2-pyrrolidone (NMP) as the solvent. A large
number of alkyl methyl ketones with varying steric or electronic
nature were reacted with malonate 4 to give exclusively the
adducts 2 with high yield, regioselectivity and enantioselectivity
(Scheme 3). The optimized conditions were to use 4–12 equiv of
alkyl methyl ketone with respect to silylmethylene malonate 4
and 30 mol% of catalyst 8 in combination with 10 mol% of TFA
in NMP (0.25 M) at –10 °C for 3–7 days providing the adducts 2
in very good yield (>76%) and with high enantiomeric excess
(>90%). The formation of the regioisomeric addition product
could not be detected in any of the cases.
Scheme 5. Prototropy of the enamines.
When we replaced ordinary acetone with acetone-d6 3a
(99.5 atom% D) in the aforementioned optimized conditions,
we obtain our desired product 2a-d5 (Scheme 4) in 64% yield
but with deteriorated deuterium content (CD2:71 atom% D,
CD3:61 atom% D).
Although, the result was slightly disappointing, it was not
totally unexpected. Barbas III37 has suggested that these
reactions proceeded through enamine intermediates38,39 of the
Scheme 6. Synthesis of methyl-d3 alkyl ketones.
Table 1. Conjugate addition of methyl-d3 ketones 3a-e to silyl malonate 4
Entry
Ketone (equiv)
Time (d)/ Temp (°C)
Product
Yielda
%eeb
atom% D (CD2)c
1
2
3
4
5
3a (10)
3b (5)
3c (4)
3d (5)
3e (5)
4/ꢀ10
2/ꢀ10
4/ꢀ10
3/ꢀ10
3/4
2a-d5
2b-d2
2c-d2
2d-d2
2e-d2
64
82
80
88
95
77
99
86
96
90
>95
93
82
93
82
Ee, enantiomeric excess.
aYield of chromatographically homogeneous product.
bDetermined by HPLC.
1
cFrom H NMR spectra by comparing integration of the scrambled CD2 peaks with terminal Me or ester Me groups.
J. Label Compd. Radiopharm 2013, 56 649–654
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S. J. Wagh et al.
is also the first successful attempt to engage unsymmetrical alkyl
methyl-d3 ketones to add via methyl terminal of acetyl group in
such reactions. One of the ketone adducts thus obtained
has already been converted to gem-dideutero substituted
tetrahydropyran-2-one, the precursor for deuterated analog of 4-
hydroxy-6-undecyl-tetrahydropyran-2-one, an advanced intermediate
for (–)-tetrahydrolipstatin and (+)-δ-hexadecanolide syntheses.
The 4-silyl-6-alkyl-tetrahydropyran-2-ones hold promise for O-and
N-heterocyclic natural/pharmaceutical products with deuterium
labeling at specific positions.
Scheme 7. Synthesis of 5,5-dideutero substituted tetrahydropyran-2-one 1-d2.
Experimental
carbonyl donors. It is well-established40,41 that in the presence of
acid, the prototropy of the reactive enamine is more favorable,
and the equilibration between the more and less substituted
enamines 9 and 10 (Scheme 5) could occur. Thus, the moisture
content of the solvent and the use of non-deuterated TFA might
have scrambled the D–H in donor acetone-d6 or in the product
resulting in the lowering of deuterium content in the product.
The deuterium content of the product 2a-d5 could be improved
to a good extent (CD2:>95 atom% D, CD3:>95 atom% D) by
using dry NMP and adding a small amount of D2O in to the
reaction mixture.
To see the generality of this process, a few methyl-d3 alkyl ketones
viz. 2-heptanone 3b, 2-octanone 3c, 2-undecanone 3d, and 2-
tridecanone 3e were synthesized from commercially available
starting materials as depicted in Scheme 6. An addition of an
ethereal solution of methyl magnesium iodide-d3 (99 atom% D)
to Weinreb’s amides 11b–e42 directly gave methyl-d3 ketones
3b–e in very good yield and isotopic purity (Scheme 6).
When this methyl alkyl ketones 3a–d were reacted with the
silyl malonate 4 under optimal conditions, we obtained only
one regioisomeric product in very good yield and with good to
excellent enantioselectivity as depicted in Table 1. The
deuterium content at the specified site was also very high
(82–>95% atom% D) in all cases. The reaction requires excess
amount of ketones (4–10 equiv) to obtain appreciable rate of
reaction and completion within a period mentioned in Table 1.
Valuable ketones that have been used in excess can be
recovered partially during isolation of products.
General experimental
High-performance liquid chromatography grade acetone and NMP were
used as received. Dimethyl(phenyl)silyl chloride, CD3MgBr (1 M solution
in ether) and (S)-N-(benzyloxycarbonyl)proline were obtained from
Aldrich (MO, USA). Silylmethylene malonate 4 was prepared following a
procedure reported by us.43 The catalyst 8 was prepared following the
literature procedures.36
Solvent removal was carried out using a rotary evaporator connected
to a dry ice condenser. TLC (0.5 mm) was carried out using homemade
silica plates with fluorescence indicator. Column chromatography was
performed on silca gel (230–400 mesh).
1H and 13C NMR spectra were recorded in a 200 MHz (1H: 200 MHz, 13C:
50MHz) or 500 MHz (1H: 500MHz, 13C: 125 MHz) or 600 MHz (1H: 600 MHz,
13C: 150 MHz) or 700 MHz (1H: 700MHz, 13C: 175 MHz) spectrometers. 1H
and 13C shifts are given in ppm, δ scale and are measured relative to internal
CHCl3 and CDCl3 as standards, respectively. Enantiomeric excess
determinations were carried out by HPLC using a JASCO PU-2080
instrument (Japan) fitted with a Daicel chiralpak AD-H column and
UV-2075 detector with λ fixed at 254 nm. Optical rotations were
measured in a JASCO DIP Polarimeter (Japan).
General procedure I: preparation of N-methoxy-N-
methylamides 11b–e
In
a typical procedure, an acyl chloride (10 mmol) and N,O-
dimethylhydroxylamine hydrochloride (1.1g, 11mmol) was dissolved in
dichloromethane (100 mL) at room temperature. The solution was cooled
to 0°C, and pyridine (1.9mL, 22 mmol) was added to it. The reaction mixture
was stirred at room temperature for 1h and evaporated under reduced
pressure. The residue was partitioned between brine and dichloromethane.
The organic extract was dried over MgSO4 and evaporated under reduced
pressure to afford the amides 11b–e in 93–96% yield which were
sufficiently pure and used directly for the next step.
We next carried out a Si-directed reduction31 of the carbonyl
group in 2e-d2 to intermediate alcohol that could not be isolated
but provided directly the lactone 12-d2 without any loss of D
(Scheme 7). The ester group in 12-d2 was hydrolyzed with lithium
hydroxide to give the intermediate acid, which on refluxing in
toluene gave 5,5-dideutero analog of the 4-silyl-6-undecyl-
tetrahydropyran-2-one 1-d2. The relative and absolute
stereochemistry of the silyl and the alkyl groups in 1-d2 were
assigned from the 1H and 13C chemical shift values32 and
comparing the specific rotation value [α]2D5 = –30.8 (c 2.6, CHCl3);
lit.32 [α] D 25 = ꢀ39.9, c 1.93, CHCl3). The proteo analog 1 has already
been converted32 to 4-hydroxy-6-undecyl-tetrahydropyran-2-one
5, an advanced intermediate for (–)-tetrahydrolipstatin 633 and
(+)-δ-hexadecanolide 734 syntheses.
N-Methoxy-N-methylhexanamide 11b
Yield: 94%; IR (neat): 3433, 2959, 1653, 1463, 1416 cmꢀ1 1H NMR
;
(200 MHz, CDCl3): δ 0.88 (t, J = 6.6 Hz, 3H, CH3CH2), 1.24–1.37 (m, 4H,
2 × CH2), 1.53–1.68 (m, 2H, CH2), 2.39 (t, J = 7.5 Hz, 2H, CH2CH2CO), 3.16
(s, 3 H, N-CH3), 3.66 (s, 3H, O-CH3); 13C NMR (50 MHz, CDCl3): δ 13.7,
22.3, 24.1, 31.4, 31.7, 32.0, 61.0, 174.5; EI-MS: m/z 160 (2%, M + 1), 99
(44), 71 (52), 61 (100).
N-Methoxy-N-methylheptanamide 11c
Conclusions
Yield: 93%; IR (neat): 3453, 2949, 1656, 1468, 1418 cmꢀ1 1H NMR
;
In conclusion, we have developed a directly organocatalytic
asymmetric Michael addition of alkyl methyl-d3 ketones to a
silylmethylene malonate in good yields and with high
regioselectivity and enantioselectivity. The deuterium content
(200 MHz, CDCl3): δ 0.86 (t, J = 6.6 Hz, 3H, CH3CH2), 1.20–1.40 (m, 6H,
3 × CH2), 1.53–1.67 (m, 2H, CH2), 2.39 (t, J = 7.2 Hz, 2H, CH2CH2CO), 3.16
(s, 3H, N-CH3), 3.66 (s, 3H, O-CH3); 13C NMR (50 MHz, CDCl3): δ 13.8,
22.3, 24.4, 28.9, 31.4, 31.7, 32.0, 61.0, 174.5; EI-MS: m/z 113 (30%), 103
of the products at the specified position is appreciably high. This (8), 85 (35), 73 (5), 61 (100).
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J. Label Compd. Radiopharm 2013, 56 649–654

S. J. Wagh et al.
diluted with water and extracted with EtOAc/hexane (1/1). The organic
extract was washed with brine, dried (MgSO4), and evaporated. The
residue was purified by column chromatography on silica using
hexane/EtOAc (95/5) as eluent to give either 2a-d5 (64%) or 2b-e-d2
(80–95%).
N-Methoxy-N-methyldecanamide 11d
Yield: 95%; IR (neat): 3443, 2958, 1653, 1478, 1412 cmꢀ1 1H NMR
;
(200 MHz, CDCl3): δ 0.85 (t, J = 6.2 Hz, H, CH3CH2), 1.24 (s, broad, 12H,
6 × CH2), 1.57–1.66 (m, 2H, CH2), 2.39 (t, J = 7.4 Hz, 2H, CH2CH2CO), 3.16
(s, 3H, N-CH3), 3.66 (s, 3H, O-CH3); 13C NMR (50 MHz, CDCl3): δ 13.9,
22.5, 24.4, 29.1, 29.3 (3C), 31.7 (2C), 32.0, 61.0, 174.5.
Ethyl (3S)-3-dimethyl(phenyl)silyl-4,4-dideutero-2-
ethoxycarbonyl-5-oxohexanoate 2a-d5
N-Methoxy-N-methyldodecanamide 11e
Yield: 119 mg, 64%; HPLC: Daicel chiralpak AD-H, 2-propanol/hexane (1/99),
flow rate= 1.0mL/min, tR(3S)-2a-d5 14.5min (88.3%), tR(3R)-2a-d5 21.05 min
(11.7%); Opt. Rot.: [α]2D4 = + 1.3 (c 1.55, CHCl3), lit.35 for preteo analog [α]
Yield: 96%; IR (neat): 3443, 2959, 1654, 1478, 1408 cmꢀ1 1H NMR
;
(200 MHz, CDCl3): δ 0.83 (t, J = 6.6 Hz, 3H, CH3CH2), 1.21 (s, broad, 18H,
9 × CH2), 1.50–1.61 (m, 2H, CH2), 2.36 (t, J = 7.4 Hz, 2H, CH2CH2CO), 3.13
(s, 3H, N-CH3), 3.63 (s, 3H, O-CH3); 13C NMR (50 MHz, CDCl3): δ 13.8,
22.4, 24.4, 29.0, 29.1 (2C), 29.2, 29.3 (2C), 31.6, 31.9, 61.8, 174.4; EI-MS:
m/z 244 (0.5%, M + 1), 183 (8), 109 (8), 85 (15), 71 (35), 61 (100).
25 = +4.78 (c = 2.31, MeOH); IR (film): 3070, 3029, 2957, 2931, 2855, 1747,
D
1729, 1465, 1427, 1370, 1301, 1250, 1152, 1032, 817 cmꢀ1
;
1H NMR
(200MHz, CDCl3): δ 0.31 (s, 3H, CH3Si), 0.32 (s, 3H, CH3Si), 1.20 (t, J = 7.2Hz,
6H, 2 × CH3CH2OCO), 2.28 (d, J = 5.6Hz, 1H, SiCH), 3.47 (d, J = 5.6Hz, 1H,
CHCHSi), 3.95–4.11 (m, 4H, 2× CH3CH2OCO), 7.30–7.35 (m, 3H, Ph), 7.47–
7.52 (m, 2H, Ph); 13C NMR (50 MHz, CDCl3): δ ꢀ3.6, ꢀ3.4, 13.8 (2C), 20.0,
51.5, 61.0, 61.1, 127.6 (2C), 129.0, 134.0 (2C), 137.0, 169.3, 169.7, 207.6.
General procedure II: preparation of alkyl methyl-d3 ketones
3b–3e
An ethereal solution of CD3MgI (1 M, 11 mL, 11 mmol) was added drop
Ethyl (3S)-3-dimethyl(phenyl)silyl-4,4-dideutero-2-
ethoxycarbonyl-5-oxodecanoate 2b-d2
wise to
a stirred solution of N-methoxy-N-methylamides 11b–e
(10 mmol) in ether (15 mL) at 0 °C. After 1.5 h, the reaction mixture were
poured into ice-cold 0.5 M aqueous HCl (25 mL) and extracted with
dichloromethane. The organic extract was dried over MgSO4 and
evaporated under reduced pressure. The residue was distilled to give
the respective ketones 3b–e in 70–87% yield.
Yield: 174 mg, 82%; HPLC: Daicel chiralpak AD-H, 2-propanol/ hexane
(0.7/99.3), flow rate = 1.0 mL/min, tR(3S)-2b-d2 14.0 min (99.51%), tR(3R)-2b-d2
23.5 min (0.49%); Opt. Rot.: [α]D25 = +1.94 (c 3.1, CHCl3), lit.35 for preteo analog
[α]2D5 = +1.92 (c = 2.61, MeOH); IR (neat): 3070, 3028, 2956, 2930, 2853, 1746,
1729, 1465, 1426, 1370, 1301, 1249, 1151, 1032, 817 cmꢀ1 1H NMR
;
(200MHz, CDCl3): δ 0.32 (s, 3H, CH3Si), 0.33 (s, 3H, CH3Si), 0.85 (t, J = 6.6Hz,
3H, CH2CH3), 1.16–1.26 (m, 10H, 2 × CH2 and 2 × CH3CH2OCO), 1.35–1.46
(m, 2H, CH2), 2.08–2.22 (m, 2H, COCH2), 2.26–2.31 (m, 1H, SiCH), 3.49
(d, J = 5.8 Hz, 1H, CHCHSi), 4.00–4.11 (q, J = 7.2 Hz, 4H, 2 × CH3CH2OCO),
7.30–7.34 (m, 3H, Ph), 7.47–7.52 (m, 2H, Ph); 13C NMR (50 MHz, CDCl3):
δ ꢀ3.5, ꢀ3.2, 13.8 13.9 (2C), 20.0, 22.4, 23.4, 31.3, 42.4, 51.8, 61.0, 61.3,
127.6 (2C), 129.1, 134.2 (2C), 137.0, 169.5, 169.9, 210.0; EI-MS: m/z 407
(M+-CH3, 12%), 345 (18), 246 (14), 135 (100), 75 (35).
1,1,1,-Trideuterioheptan-2-one 3b
Yield: 75%; IR (neat): 2925, 2855, 2253, 1714, 1465, 1410 cmꢀ1 1H NMR
;
(200 MHz, CDCl3): δ 0.86 (t, J = 6.6 Hz, 3H, CH3CH2), 1.21–1.34 (m, 4H,
2 × CH2), 1.47–1.62 ( 2H, CH2), 2.39 (t, J = 7.2 Hz, 2H, CH2CH2CO); 13C
NMR (50 MHz, CDCl3): δ 13.8, 22.3, 23.4, 31.2, 43.6, 209.3; EI-MS: m/z 117
(2%, M+), 99 (40), 71 (68), 61 (100).
1,1,1,-Trideuteriooctan-2-one 3c
Ethyl (3S)-3-dimethylphenylsilyl-4,4-dideutero-2-
ethoxycarbonyl-5-oxoundecanoate 2c-d2
Yield: 82%; IR (neat): 2926, 2855, 2253, 1714, 1465, 1411 cmꢀ1 1H NMR
;
(200 MHz, CDCl3): δ 0.85 (t, J = 6.6 Hz, 3H, CH3CH2), 1.25–1.28 (m, 6H,
3 × CH2), 1.46–1.57 (m, 2H, CH2CH2CH2CO), 2.35–2.42 (t, J = 7.5 Hz, 2H,
CH2CH2CO); 13C NMR (50 MHz, CDCl3): δ 13.9, 22.4, 23.7, 28.7, 31.5, 43.6,
209.4; EI-MS: m/z 131 (8%, M+), 113 (5), 88 (6) 74 (20), 61 (100).
Yield: 175 mg, 80%; HPLC: Daicel chiralpak AD-H, 2-propanol/ hexane
(0.7/99.3), flow rate = 1.0 mL/min, tR(3S)-2c-d2 7.41 min (92.91%), tR(3R)-2c-d2
11.4 min (7.09%); Opt. Rot.: [α]2D5 = +1.92 (c 2.61, CHCl3); IR (neat): 3070, 3029,
2957, 2931, 2855, 1747, 1729, 1465, 1427, 1370, 1301, 1250, 1152, 1032,
817 cmꢀ1; 1H NMR (200 MHz, CDCl3): δ 0.31 (s, 3H, CH3Si), 0.33 (s, 3H, CH3Si),
0.85 (t, J=6.4Hz, 3H, CH2CH3), 1.16–1.23 (m, 12H, 3 × CH2 and
2×CH3CH2OCO), 1.31–1.45 (m, 2H, CH2), 2.08–2.23 (m, 2H, COCH2), 2.26–
2.31 (m, 1H, SiCH), 3.50 (d, J= 5.6 Hz, 1H, CHCHSi), 4.00–4.11 (m, 4H,
2×CH3CH2OCO), 7.28–7.33 (m, 3H, Ph), 7.47–7.52 (2H, m, Ph); 13C NMR
(50 MHz, CDCl3): δ ꢀ3.5, ꢀ3.2, 13.9 (2C), 20.0, 20.1, 22.4, 23.6, 28.8, 31.5, 42.5,
51.8, 61.1, 61.2, 127.6 (2C), 129.1, 134.2 (2C), 137.3, 169.5, 169.8, 209.9; EI-MS:
m/z 421 (M+-CH3, 12%), 359 (17), 261 (12), 199(18) 135 (100), 144(24) 75 (35).
1,1,1,-Trideuterioundecan-2-one 3d
Yield: 70%; IR (neat): 2925, 2855, 2253, 1714, 1465, 1410 cmꢀ1 1H
;
NMR (600 MHz, CDCl3): δ 0.89 (t, J= 6Hz, 3H, CH3CH2), 1.28–1.32 (m, 14H,
7 × CH2), 1.57–1.60 (m, 2H, CH2CH2CH2CO), 2.42 (t, J= 6.6 Hz, 2H,
CH2CH2CO); 13C NMR (50MHz, CDCl3): δ 13.9, 22.0, 22.5, 23.8, 29.1, 29.2
(2C), 29.3, 31.7, 43.6, 208.8; EI-MS: m/z 173 (5%, M+), 112 (5), 74 (26), 61 (100)
1,1,1,-Trideuteriotridecan-2-one 3e
Ethyl (3S)-3-dimethylphenylsilyl-4,4-dideutero-2-
ethoxycarbonyl-5-oxotetradecanoate 2d-d2
Yield: 87%; IR (neat): 2926, 2855, 2253, 1714, 1465, 1410 cmꢀ1 1H NMR
;
(200 MHz, CDCl3): δ 0.87 (t, J = 6 Hz, 3H, CH3CH2), 1.25 (s, broad, 16H,
8 × CH2), 1.52–1.64 (m, 2H, CH2CH2CH2CO), 2.4 (t, J = 7.2 Hz, 2H,
CH2CH2CO); 13C NMR (50 MHz, CDCl3): δ 13.6, 22.3, 23.4, 28.8, 29.0, 29.1
(2C), 29.3 (2C), 31.5, 43.2, 208.1; EI-MS: m/z 201 (2%, M+), 74 (20), 61 (100).
Yield: 210 mg, 88%; HPLC: Daicel chiralpak AD-H, 2-propanol/ hexane
(0.7/99.3), flow rate = 1.0 mL/min, tR(3S)-2d-d2 9.1 min (98.11%), tR(3R)-2d-d2
15.5 min (1.89%); Opt. Rot.: [α]D24 = +2.0 (c 1.49, CHCl3), lit.35 for preteo analog
[α]2D8 = +4.81 (c = 2.91, MeOH); IR (neat): 3070, 3028, 2956, 2930, 2853, 1746,
1729, 1465, 1426, 1370, 1301, 1249, 1151, 1032, 817 cmꢀ1 ; H NMR
(500MHz, CDCl3): δ 0.41 (s, 3H, CH3Si), 0.42 (s, 3H, CH3Si), 0.96 (t, J = 7 Hz,
3H, CH2[CH2]3CH3), 1.25–1.36 (m, 18H, [CH2]6CH3 and 2 × CH3CH2OCO),
General procedure III. Michael addition of methyl-d3 ketones
3a–e to silylmethylene malonate 4 using organocatalyst 8
Acetone-d6 or respective alkyl methyl-d3 ketone (2–5 mmol, 4–10 equiv) 1.49–1.52 (m, 2H, CH2CH2[CH2]6CH3) 2.21–2.34 (m, 2H, COCH2[CH2]4CH3),
was added to a stirred mixture of silylmethylene malonate 4 (153 mg, 2.37 (d, J = 5.5Hz, 1H, SiCH), 3.57 (d, J= 5.5 Hz,1H, CHCHSi), 4.13–4.17
0.5 mmole, 1 equiv), pyrrolidine 8 (23 mg, 0.15 mmol, 0.3 equiv), TFA (m, 4H, 2 × CH3CH2OCO), 7.34–7.42 (m, 3H, Ph), 7.59–7.60 (2H, m, Ph);
(4 μL, 0.05 mmol, 0.1 equiv), and D2O (20 μL, 1 mmol, 2 equiv) in dry 13C NMR (125 MHz, CDCl3): δ ꢀ3.4, ꢀ3.1, 13.9 (2C), 14.0, 20.1, 22.6,
NMP (1 mL) at ꢀ10 °C. After 2–4 d at ꢀ10 °C, the reaction mixture was 23.7, 29.1, 29.2, 29.3 29.4, 31.8, 42.5, 51.8, 61.1, 61.3, 127.6 (2C), 129.1,
J. Label Compd. Radiopharm 2013, 56 649–654
Copyright © 2013 John Wiley & Sons, Ltd.
www.jlcr.org

S. J. Wagh et al.
134.2 (2C), 137.3, 169.4, 169.8, 209.9; EI-MS: m/z 343 (M+-SiMe2Ph, 13%),
327 (19), 249 (17), 181 (20) 135 (100), 75 (34).
Acknowledgement
Mr. Sandip J. Wagh is thankful to Council of Scientific and Industrial
Research (CSIR), New Delhi for a fellowship.
Ethyl (3S)-3-dimethylphenylsilyl-4,4-dideutero-2-
ethoxycarbonyl-5-oxohexadecanoate 2e-d2
References
Yield: 240 mg, 95%; HPLC: Daicel chiralpak AD-H, 2-propanol/ hexane
(0.7/99.3), flow rate = 1.0 mL/min, tR(3S)-2e-d2 19.7 min (94.99%), tR(3R)-2e-d2
26.19 min (5.01%); Opt. Rot.: [α]D22 = +1.67 (c 1.9, CHCl3), lit.32 for preteo analog
[α]2D3 +4.67 (c 1.07, MeOH); IR (neat): 3070, 3028, 2956, 2930, 2853, 1746,
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;
(200MHz, CDCl3): δ 0.32 (s, 3H, CH3Si), 0.33 (s, 3H, CH3Si), 0.87 (t, J= 6Hz,
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1.38–1.54 (m, 2H, CH2), 1.92–2.02 (m, 1H, SiCH), 3.34 (d, J = 11.4 Hz, 1H,
CHCO2CH2CH3), 3.79–3.81 (m, 1H, CHOCO), 4.00–4.17 (m, 2H,
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29,5, 29.6 (2C), 31.8, 34.7, 47.3, 61.6, 78.6, 128.1 (2C), 129.8, 134.0 (2C),
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(4S,6S)-5,5-Dideutero-4-dimethyl(phenyl)silyl-6-undecyl-
tetrahydro-2H-pyran-2-one 1-d2
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IR (film): 2960, 2931, 2859, 2250, 1740, 1427, 1256, 1113, 1064, 834,
812, 701 cm–1; Opt. Rot.: [α]2D5 = –30.8 (c 2.6, CHCl3), lit.32 for preteo analog
[α] 25 = ꢀ39.9 (c 1.93, CHCl3); 1H NMR (200 MHz, CDCl3): δ 0.32 (s, 6H,
D
[CH3]2Si), 0.87 (t, J = 6.4 Hz, 3H, CH2CH3), 1.24 (s, broad, 18H, 9 × CH2),
1.38–1.48 (m, 3H, CH2 and SiCH), 2.21 (dd, J = 13.2, 15.8 Hz, 1H,
CHAHBCO2-), 2.42 (dd, J = 5.7, 15.8 Hz, 1H, CHAHBCO2-), 3.97–4.09 (m, 1H,
CHOCO), 7.35–7.39 (m, 3H, Ph), 7.44–7.49 (m, 2H, Ph); 13C NMR (50 MHz,
CDCl3): δ –5.5, –5.4, 14.2, 14.8, 22.7, 25.2, 29.4 (2C), 29.5, 29.6, 29.7 (2C),
30.1, 31.9, 35.0, 78.3, 128.2 (2C), 129.7, 133.9 (2C), 135.8, 173.9; EI-MS:
m/z 390 (M+ 2), 235 (5), 135 (100), 116 (25), 75 (18).
Conflict of Interest
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The authors did not report any conflict of interest.
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Copyright © 2013 John Wiley & Sons, Ltd.
J. Label Compd. Radiopharm 2013, 56 649–654