A convergent stereocontrolled synthesis of [3-14C]solanesol

Article abstract of DOI:10.1002/jlcr.3083

In this communication, we report the synthesis of 5 mCi of [3- ¹⁴C]solanesol (1) prepared from ethyl [3-¹⁴C]acetoacetate and (all-E)-octaprenyl bromide (2) in four steps, with a specific radioactivity of 19.83 mCi/mmol and with a chemical/ stereochemical and radiochemical purity of ≥ 95%. (Figure 1). Position 3 of the chain was selected for ¹⁴C labelling because of the metabolic stability of this position. Unlabelled (all-E)-octaprenyl (18) (Scheme 4) necessary for this work was prepared via a convergent iterative 'allyl-allyl' coupling approach of precursors easily derived from readily available inexpensive starting materials. Copyright

Full text of DOI:10.1002/jlcr.3083

Special Issue Article
Received 25 April 2013,
Revised 30 May 2013,
Accepted 3 June 2013
Published online in Wiley Online Library
(wileyonlinelibrary.com) DOI: 10.1002/jlcr.3083
A convergent stereocontrolled synthesis of
†
14
[3- C]solanesol
a
a
a
b
*
Stephen J. Roe, Mark F. Oldfield, Neil Geach, and Andrew Baxter
In this communication, we report the synthesis of ~5 mCi of [3-14C]solanesol (1) prepared from ethyl [3-14C]acetoacetate and
(all-E)-octaprenyl bromide (2) in four steps, with a specific radioactivity of 19.83 mCi/mmol and with a chemical/
stereochemical and radiochemical purity of ≥ 95%. (Figure 1). Position 3 of the chain was selected for 14C labelling because
of the metabolic stability of this position. Unlabelled (all-E)-octaprenyl (18) (Scheme 4) necessary for this work was prepared
via a convergent iterative ‘allyl-allyl’ coupling approach of precursors easily derived from readily available inexpensive
starting materials.1 Copyright © 2013 John Wiley & Sons, Ltd.
Keywords: solanesol; carbon-14; convergent synthesis; stereocontrolled
[3-14C]solanesol. However, solanesol is an isoprene unit shorter
than the side chain of coenzyme Q10 synthesised by Nakamura
et al., and the late stage intermediate required was not
commercially available and thus a synthesis of (all-E)-octaprenyl
Introduction
Solanesol is an acyclic trisesquiterpene alcohol containing nine
(all-E) isoprene units and is one of the major polyprenoids found
in tobacco, and is important as an intermediate to many valuable
bromide (also known as all-trans-farnesylfarnesylgeranyl bromide)
biochemicals, including coenzyme Q10 and Vitamin K analogues.2
(2) was necessary (Figure 1).
The strategies of K. Sato et al.8 and F. Chen et al.1 were applied
As a consequence, the demand for solanesol continues to
escalate because coenzyme Q10 entered the market as a dietary
to develop a convergent synthesis of (all-E)-octaprenyl bromide
supplement, largely because of its perceived health benefits.3
(2). The synthesis started with the selective terminal oxidation
Solanesol is known to possess antibacterial, anti-inflammatory
of geranyl acetate (3) with t-BuOOH in the presence of catalytic
and anti-ulcer activities.4 [14C] labelled solanesol has also been
of interest for studying the chemistry associated with burning
cigarettes and for understanding the contribution it plays with
respect to the flavour and aroma of tobacco smoke.5 Past sources
of [14C] labelled solanesol relied upon laborious isolation from
plants grown in the presence of 14CO2.6 We therefore set about
planning a suitable synthetic [14C] labelling strategy. The
synthesis ideally needed to allow the following: i) incorporation
of the label as late as possible in the synthesis; ii) be
stereoselective with respect to formation of Z/E alkene isomers;
iii) allow separation of any formed isomers by chromatography;
iv) take into account the light, heat and acid sensitivity many
polyprenoids such as solanesol have and v) ideally allow easy
identification of similar intermediates by nuclear magnetic
resonance (NMR) analysis by incorporation of a functionality
which would give characteristic NMR shifts.
amounts of SeO2 and 3-chlorosalicylic acid,9 which after
subsequent reduction with sodium borohydride gave alcohol
(6) in 52% yield over two steps. (Scheme 2). Use of catalytic
3-chlorosalicylic acid was found to result in a faster/cleaner
reaction which consequently made purification of the desired
alcohol (6) easier. Alcohol (6) was then converted to the ‘allyl’
bromide (7) with PBr3 in 80% yield. Bromide (7) was prone to
decomposition and was used immediately. Thus, alkylation of
the known carbanion of sulfone (8)1 with bromide (7) occurred
exclusively at the desired α-position with retention of alkene
configuration, providing the (all-E)-tosyl tetraprenyl acetate (9) in
89% yield.
Preparation of the known (all-E)-tetraprenyl sulfone (14) was
achieved via conversion of readily available (all-E)-farnesol (5)
aSelcia Ltd, Fyfield Business & Research Park, Fyfield Road, Ongar, Essex
CM5 0GS, UK
bBritish American Tobacco Limited, Regents Park Road, Southampton,
Hampshire SO15 8TL, UK
Results and discussion
A paper by T. Nakamura et al. described the synthesis of [3’-14C]-
coenzyme Q10 which contains an (all-E)-decaprenyl side chain
analogous to solanesol being one isoprene unit longer.7 The
key precursors they used for the preparation of the side chain
were ethyl [3-14C]acetoacetate and commercially available
natural solanesol applying an alkylation/Horner–Wadsworth–
Emmons/reduction methodology. (Scheme 1). In our work, we
*Correspondence to: Neil Geach, Selcia Ltd, Fyfield Business & Research Park,
Fyfield Road, Ongar, Essex CM5 0GS, UK
E-mail: neil.geach@selcia.com
† This article is published in Journal of Labelled Compounds and
Radiopharmaceuticals as a special issue on IIS 2012 Heidelberg Conference,
edited by Jens Atzrodt and Volker Derdau, Isotope Chemistry and Metabolite
Synthesis, DSAR-DD, Sanofi-Aventis Deutschland GmbH, Industriepark Höchst
decided to adopt the same approach for the endgame for G876, 65926 Frankfurt am Main, Germany.
J. Label Compd. Radiopharm 2013, 56 485–491
Copyright © 2013 John Wiley & Sons, Ltd.

S. J. Roe et al.
O
O
14C
OEt
3435
14C
27
23
31
OH
27
31
23
OH
i) alkylation
ii) HWE
iii) reduction
7
7
Solanesol
(all-E)-decaprenol
O
3477
14C
OMe
23
31
27
7
OMe
O
[3'-14C]-coenzyme Q10
Scheme 1. Synthesis of [3’-14C] Coenzyme Q10
.
7
via analogous chemistry as reported by T. Nakamura et al.7 (19) in 47% yield over a three-step process (Scheme 5). The
(Scheme 3). Thus, (all-E)-farnesol (5) was quantitatively converted final E-alkene was installed into the chain via a further
to the corresponding bromide with PBr3. Subsequently, ethyl Horner–Wadsworth–Emmons reaction of (all-E)-octaprenyl
acetoacetate was alkylated with the bromide and decarboxylated acetone (19) with triethyl phosphonoacetate forming ethyl (all-
to afford farnesylacetone (10) in 93% yield over two steps. E)-nonaprenoate (20) in 90% yield as a mixture of Z/E isomers in
Horner–Wadsworth–Emmons reaction of (10) with triethyl a ratio of ~(4:1). To complete the synthesis, nonaprenoate (20)
phosphonoacetate gave ethyl (all-E)-tetraprenoate (11) in 76% was reduced with DIBAL yielding [3-14C]solanesol (1) in 63% yield
yield as a mixture of Z/E isomers in a ratio of (2:13) which could as a mixture of isomers. Separation of the desired (all-E) isomer from
be separated by careful silica gel chromatography, although the undesired terminal Z isomer was achieved by three rounds of
separation was more readily achieved after conversion into sulfone preparative reverse phase high-performance liquid chromatography
(14). Thus, ethyl (all-E)-tetraprenoate (11) was then reduced using (HPLC) ultimately giving [3-14C]solanesol (1) with a specific
DIBAL affording the corresponding (all-E)-tetraprenol (12) in 76% radioactivity of 19.83 mCi/mmol and with
a
chemical/
yield which was subsequently converted to the corresponding stereochemical and radiochemical purity of ≥95%. The structure of
unstable bromide (13) and immediately reacted with sodium [3-14C]solanesol was confirmed by comparison with an authentic
p-toluene sulfinate to afford (all-E)-tetraprenyl sulfone (14) in sample.
81% yield over two steps.
With both (all-E)-tetraprenyl sulfones (9) and (14) in hand, we
were set for the coupling of these two fragments to form the Conclusion
required (all-E)-octaprenyl acetate (17) (Scheme 4). To achieve
In conclusion, we have completed the first labelled synthesis of
this, (9) was subjected to the same allylic oxidation protocol we
[3-14C]solanesol (1) starting from [3-14C] acetoacetate and
used previously to prepare (6) resulting in the formation of
(all-E)-octaprenyl bromide (2) easily prepared from readily
alcohol (15) in 42% yield over two steps. Conversion of (15) to
available, inexpensive starting materials. In addition, we have
the corresponding bromide (16) with PBr3 followed by alkylation
of the carbanion of (14) gave the desired (all-E)-octaprenyl
acetate (17) in 57% yield. Subsequent base promoted solvolysis
of the acetate protecting group and removal of the tosyls via
identified conditions for the purification of [3-14C]solanesol,
resulting in the isolation of ~ 5 mCi of material with a chemical/
stereochemical and radiochemical purity of ≥ 95%.
Pd catalysed reduction with Superhydride© afforded the (all-E)-
octaprenyl (18) in 61% yield over two steps. This was then
converted to the corresponding bromide using PBr3 completing
our first objective of synthesising (all-E)-octaprenyl bromide (2)
(All-E)-octaprenyl bromide (2) was found to be light sensitive
and prone to decomposition and therefore needed to be
converted further immediately after formation. Thus, ethyl
[3-14C]acetoacetate was alkylated with (2) and subsequently
decarboxylated affording the desired (all-E)-octaprenyl acetone
O
O
O
a-b
HO
O
O
O
(6)
(3)
c
1
14C
Br
+
OH
S
O
O
(7)
[3-14C]solanesol (1)
(8)
d
O
O
+
14C
Br
EtO
(2)
O
SO2
(9)
O
O
+
+
OH
OH
O
Scheme 2. Synthesis of precursor (9). Conditions: a) cat. 3-chlorosalicylic acid,
SeO2, t-BuOOH, DCM, rt, 24 h; b) NaBH4, EtOH, 0 °C-rt, 3 h, (52% over two steps);
c) PBr3, Et2O, 0 C, 3.5 h, (80%) d) NaH, DMF, À5 C, 16 h, (89%).
(5)
(4)
(3)
Figure 1. Retrosynthetic analysis of [3-14C]Solanesol (1).
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Copyright © 2013 John Wiley & Sons, Ltd.
J. Label Compd. Radiopharm 2013, 56 485–491

S. J. Roe et al.
O
a-c
O
d
O
OH
2
(5)
(11)
(10)
e
g
R = OH (12)
R = Br (13)
f
R
S
O
O
2
2
(14)
Scheme 3. Synthesis of precursor (14). Conditions: a) PBr3, Et2O, 0 C, 2 h; b) ethyl acetoacetate, NaOMe, EtOH, Dioxane, rt, 16 h; c) NaOH, H2O, rt, 64 h then reflux 2 h, (93%
over three steps); d) NaH, Triethyl phosphonoacetate, iso-hexane, rt, 16 h, (76%); e) DIBAL, toluene, À78 C, 1 h (76%); f) PBr3, Et2O, 0 C, 5 h g) p-TolSO2Na, DMF, rt, 16 h, (81%
over two steps).
a-b
O
O
SO2
SO2
HO
O
O
(15)
(9)
c
O
SO2
Br
+
S
O
O
O
(16)
(14)
d
O
SO2
SO2
H
O
3
(17)
e-f
6
R = OH (18)
R = Br (2)
g
R
Scheme 4. Synthesis of precursor (2). Conditions: a) cat. 3-chlorosalicylic acid, SeO2, t-BuOOH, DCM, rt, 30 h; b) NaBH4, EtOH, 0 C-rt, 1 h, (41% over two steps, 56% based on
recovered (9)); c) PBr3, Et2O, 0 C, 2 h; d) NaH, DMF, À5 C, 40 h, (57%, 88% based on recovered (14)); e) NaOMe, MeOH, rt, 4 h; f) Pd(dppp)Cl2, LiEt3BH, 0 C, 3 h then rt 16 h,
(61% over two steps) g) PBr3, Et2O, À5 C-rt, 2 h.
O
a-b
14C
Br
Experimental
6
6
(2)
(19)
General
c
[3-14C]Ethyl acetoacetate was purchased from Perkin Elmer Radiochemicals.
O
14C
(20)
1H NMR spectra were obtained on
a Bruker DPX400 or DPX300
OEt
6
spectrometer with TopSpin v.1.3 (Bruker UK Limited, Banner Lane, Coventry,
CV4 9GH, UK) acquisition and data manipulation software. Activities were
determined by liquid scintillation analysis using a 2100TR liquid scintillation
counter running a standard protocol for [14C] gravimetric analysis. Unless
stated otherwise, all reagents and solvents were purchased from Sigma-
Aldrich, Fisher or Acros and used without further purification. Thin layer
chromatography (TLC) plates were analysed by electronic autoradiography
performed on a Packard Instantimager. HPLC analysis of solanesol was
performed using an Agilent HP1200 system (Agilent Technologies
International sarl, Rue de la Gare 29, CH-1110 Morges, Switzerland) with a
β-RAM radiodetector. The data was acquired using Chemstation and Laura
d
14C
OH
[3-14C]Solanesol (1)
Scheme 5. Radiosynthesis of [3-14C]solanesol (1). Conditions: a) ethyl [3-14C]
acetoacetate, NaOMe, EtOH, Dioxane, rt, 20 h; c) NaOH, H2O, 95 C, 3 h, (47% over
three steps); d) NaH, Triethyl phosphonoacetate, iso-hexane, rt, 16 h, (90%) e)
DIBAL, toluene, À78 C, 0.5 h (63%, 80:20 mixture of E/Z isomers).
J. Label Compd. Radiopharm 2013, 56 485–491
Copyright © 2013 John Wiley & Sons, Ltd.
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S. J. Roe et al.
Lite and acquisition and data manipulation software. An Agilent Zorbax
Eclipse XDB-C18 (Agilent Technologies UK Ltd, 610 Wharfedale Road, IQ
phosphorus tribromide (7.9 mL, 84.0 mmol and 0.44 eq) dropwise over
1 h. The reaction was stirred in the absence of light for 5 h at 0°C. TLC
Winnersh, Wokingham, Berkshire, RG41 5TP, UK), 250 × 4.6 mm, 3.5μ analysis (neat dichloromethane) showed complete consumption of (4).
column was used with isocratic elution comprising of 85% (Methanol/ The reaction mixture was poured into ice cold water (600 mL) and
water, 100/5 v/v): 15% (IPA/water, 100/5 v/v) at a flow rate of 0.8 ml/ extracted with n-pentane (3 × 200 mL). The combined extracts were
min and run-time of 60 min. Ultraviolet detection at 210 nm. Under
these conditions, [3-14C]solanesol elutes at ca. 37 min. Preparative HPLC
purification was performed using a Gilson HPLC system (Gilson, Inc.
3000 Parmenter Street, PO Box 620027, Middleton, WI 53562-0027,
washed with a saturated aqueous sodium bicarbonate solution
(300 mL), brine (300 mL), dried over anhydrous magnesium sulphate,
filtered and concentrated in vacuo at 30°C. The resulting crude oil was
dissolved in dimethylformamide (600 mL), and sodium p-toluene
USA) using unipoint v3.3 acquisition and data manipulation software. sulfinate (44.0 g, 0.25 mol and 1.3 eq) was added. The mixture was stirred
A Phenomenex Gemini C18 (Phenomenex, Queens Avenue, Hurdsfield
Ind. Est., Macclesfield, Cheshire SK10 2BN, UK), 110A, 250 × 21.20 mm,
10μ column was used with isocratic elution comprising of 15%
propan-2-ol in acetonitrile at a flow rate of 20 ml/min and run-time of
65 min. Ultraviolet detection at 210 nm.
at room temperature in the absence of light for 16 h. TLC analysis (neat
dichloromethane) showed complete consumption of the bromide. The
reaction mixture was poured into water (600 mL) and extracted with
diethyl ether (3 × 300 mL). The combined extracts were washed with
water (5 × 250 mL), dried over anhydrous magnesium sulphate, filtered
and concentrated in vacuo yielding a yellow oil. Purification by column
chromatography on silica gel eluting with (neat dichloromethane) gave
the title compound (8) (47.2 g and 83%) as a colourless oil. Rf (neat
dichloromethane) 0.37. 1H NMR (CDCl3, 300 MHz) 7.76 (2H, d, J 8.0),
7.33 (2H, d, J 8.0), 5.19 (1H, t, J 7.7), 5.05 (1H, m), 3.80 (2H, d, J 7.8), 2.46
(3H, s), 1.99–2.06 (4H, m), 1.70 (3H, s), 1.61 (3H, s) and 1.35 (3H, s).
(2E,6E)-8-Hydroxy-3,7-dimethylocta-2,6-dienyl acetate (6)1
A suspension of selenium (IV) oxide (1.70 g, 15.3 mmol and 0.1 eq),
3-chlorosalicylic acid (2.64 g, 15.3 mmol and 0.1 eq) and tert-butyl
hydroperoxide (70% in water, 49.2 g, 38.2 mmol and 2.5 eq) in
dichloromethane (600 mL) was stirred at room temperature for
15 min. Geranyl acetate (3) (30.0 g, 15.3 mmol and 1 eq) was added
dropwise, and the mixture was stirred at room temperature for 24 h.
TLC analysis (neat dichloromethane) showed complete consumption
of (3). The reaction mixture was filtered, and the filtrates were washed with
a 10% aqueous potassium hydroxide solution (300mL), followed by brine
(2× 200mL). The organics were dried over anhydrous magnesium sulphate,
filtered and concentrated in vacuo giving a yellow oil. The yellow oil was
dissolved in ethanol (22mL) and cooled to 0°C. Sodium borohydride
(4.63g, 12.2mmol and 0.8eq) was added slowly over 10min, then the
mixture was allowed to warm to room temperature. After 3 h, TLC analysis
(1:1v/v, iso-hexane: ethyl acetate) showed complete consumption of the
intermediate aldehyde. The reaction mixture was quenched carefully with
a saturated aqueous ammonium chloride solution (100 mL) and extracted
into ethyl acetate (200mL). The aqueous phase was further extracted with
ethyl acetate (3× 100mL), and the combined extracts were dried over
anhydrous magnesium sulphate, filtered and concentrated in vacuo leaving
a yellow oil. Purification by column chromatography on silica gel eluting
with (dichloromethane) (2× 500 mL) then (1:1v/v, iso-hexane: ethyl acetate)
gave the title compound (6) (16.74 g and 52%) as a pale yellow oil. Rf (1:1
iso-hexane: ethyl acetate) 0.32. 1H NMR (CDCl3, 300 MHz) 5.30–5.43 (2H,
m), 4.60 (2H, d, J 7.1), 4.01 (2H, s), 2.18 (2H, m), 2.10 (2H, m), 2.07 (3H, s),
1.73 (3H, s) and 1.68 (3H, s).
(2E,6E,10E)-3,7,11,15-Tetramethyl-9-(toluene-4-sulfonyl)
hexadeca-2,6,10,14-tetraenyl acetate (9)1
To a stirred solution of 1-((E)-3,7-dimethyl-octa-2,6-diene-1-sulfonyl)-4-
methylbenzene (8) (4.30 g, 15.6 mmol and 1.05 eq) and (2E,6E)-8-
bromo-3,7-dimethylocta-2,6-dienyl acetate (7) (4.35 g, 14.9 mmol and
1 eq) in dimethylformamide (44 mL) at –5°C was added a 60% dispersion
of sodium hydride in mineral oil (0.60 g, 14.9 mmol and 1 eq) portion wise
over 10 min. The resulting mixture was stirred at –5°C for 16 h. TLC
analysis (neat dichloromethane) showed almost complete consumption
of (8). The reaction was poured into brine (200 mL) and extracted with
diethyl ether (3 × 50 mL). The combined extracts were washed with water
(10 × 20 mL), dried over anhydrous magnesium sulphate, filtered and
concentrated in vacuo yielding a yellow oil. Purification by column
chromatography on silica gel eluting with neat dichloromethane gave
the title compound (9) (6.41 g and 89%) as a colourless oil. Rf (neat
dichloromethane) 0.11. 1H NMR (CDCl3, 300 MHz) 7.70 (2H, d, J 8.1),
7.28 (2H, d, J 8.1), 5.31 (1H, t, J 7.0), 5.16 (1H, t, J 6.8), 5.04 (1H, m), 4.89
(1H, d, J 10.6), 4.57 (2H, d, J 7.0), 3.87 (1H, m), 2.87 (1H, d, J 13.0), 2.45
(3H, s), 2.22 (1H, dd, J 13.0 and 3.0), 2.06 (3H, s), 1.91–2.10 (8H, m), 1.69
(3H, s), 1.68 (3H, s), 1.60 (3H, s), 1.54 (3H, s) and 1.22 (3H, s).
(2E,6E,10E,14E)-16-Hydroxy-3,7,11,15-tetramethyl-9-(toluene-
(2E,6E)-8-Bromo-3,7-dimethylocta-2,6-dienyl acetate (7)1
4-sulfonyl)hexadeca-2,6,10,14-tetraenyl acetate (15)1
To a stirred solution of (2E,6E)-8-hydroxy-3,7-dimethylocta-2,6-dienyl acetate
(6) (16.7 g, 78.7 mmol and 1 eq) in anhydrous diethyl ether (167 mL) and
pyridine (0.3 mL) at 0°C was added phosphorus tribromide (3.29 mL,
34.6mmol and 0.44 eq) dropwise over 1 h. The reaction was stirred in the
absence of light at 0°C for 3.5 h. TLC analysis (3:1 v/v, iso-hexane: ethyl
acetate) showed complete consumption of (6). The reaction mixture was
poured into ice cold water (300 mL) and extracted with diethyl ether
(3 × 75 mL). The combined extracts were washed with a saturated aqueous
sodium bicarbonate solution (100 mL), brine (100 mL), dried over anhydrous
magnesium sulphate, filtered and concentrated in vacuo at 30°C. Purification
by column chromatography on silica gel eluting with (neat dichloromethane)
gave the title compound (7) (17.32 g and 80%) as a pale yellow oil. Rf
(Dichloromethane) 0.62. 1H NMR (CDCl3, 300 MHz) 5.58 (1H, t, J 7.1), 5.36
(1H, t, J 7.0), 4.60 (2H, d, J 7.1), 3.98 (2H, s), 2.04–2.26 (4H, m), 2.07 (3H, s),
1.77 (3H, s) and 1.72 (3H, s).
To a stirred solution of 70% aqueous tert-butyl hydroperoxide (6.4 g,
49.4 mmol and 3.75 eq) in dichloromethane (128 mL) was added
selenium (IV) oxide (73.1 mg, 0.66 mmol and 0.05 eq) and 3-chlorosalicylic
acid (227.4 mg, 1.32 mmol and 0.1 eq). The reaction mixture was stirred at
room temperature for 15 min then (2E,6E,10E)-3,7,11,15-tetramethyl-9-
(toluene-4-sulfonyl)hexadeca-2,6,10,14-tetraenyl acetate (9) (6.41 g,
13.2 mmol and 1 eq) was added. The resultant reaction mixture was
stirred at room temperature for 14 h. TLC analysis (neat dichloromethane)
showed incomplete consumption of (9). Additional selenium (IV) oxide
(146.2 mg, 1.32 mmol and 0.10 eq) was added and the reaction mixture
was stirred at room temperature for an additional 16 h. LC/MS analysis
showed ~64% conversion to product (15). The reaction mixture was
evaporated under vacuum at 30°C. The resultant crude residue was
dissolved in diethyl ether (250 mL) and was washed with a 10% aqueous
potassium hydroxide solution (4 × 50 mL), water (3 × 50 mL), brine
(50 mL), dried over anhydrous magnesium sulphate, filtered and
concentrated in vacuo yielding a pale yellow oil. Purification by column
chromatography on silica gel eluting with (2:1 v/v, iso-hexane: ethyl
acetate) gave recovered starting material (9) (0.913 g), aldehyde
1-((E)-3,7-Dimethyl-octa-2,6-diene-1-sulfonyl)-4-
methylbenzene (8)1
To a stirred solution of geraniol (4) (33.7 mL, 30.0 g, 0.19 mol and 1 eq) in (0.645 g) and the product (15) (2.328 g) as a colourless oil. The aldehyde
anhydrous diethyl ether (300 mL) and pyridine (0.5 mL) at 0°C was added (0.645 g) was dissolved in ethanol (6 mL) and cooled to 0°C. Sodium
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J. Label Compd. Radiopharm 2013, 56 485–491

S. J. Roe et al.
borohydride (39 mg) was added. The mixture was stirred at room
reflux for 2h. TLC analysis (neat dichloromethane) showed complete
temperature for 1 h. TLC analysis (2:1 v/v, iso-hexane: ethyl acetate) consumption of the intermediate. The reaction mixture was poured into
showed complete consumption of the aldehyde. The reaction mixture water (500 mL) and extracted with n-pentane (3× 150mL). The combined
was quenched by the addition of a saturated aqueous solution of
extracts were washed with water (3× 150mL), dried over anhydrous
ammonium chloride (10 mL) and extracted with dichloromethane magnesium sulphate, filtered and concentrated in vacuo affording title
(3 × 10 mL). The combined extracts were dried over anhydrous compound (10) (27.48g and 93%) as a yellow oil which was used without
magnesium sulphate, filtered and concentrated in vacuo. Purification by further purification. Rf (dichloromethane) 0.40. 1H NMR (CDCl3, 300 MHz)
column chromatography over silica gel eluting with (2:1 v/v, iso-hexane: 5.03–5.17 (3H, m), 2.47 (2H, t, J 7.6), 2.22–2.34 (2H, m), 2.15 (3H, s),
ethyl acetate) gave (15). All title compound (15) were combined giving 1.93–2.14 (8H, m), 1.70 (3H, s), 1.63 (3H, s) and 1.62 (6H, s).
(2.74 g and 41%), (56% based on the recovered starting material (9)) as
a colourless oil. Rf (2:1 iso-hexane: ethyl acetate) 0.11. 1H NMR (CDCl3,
Ethyl (2E,6E,10E)-3,7,11,15-tetramethylhexadeca-2,6,10,14-
300 MHz) 7.73 (2H, d, J 8.3), 7.33 (2H, d, J 8.3), 5.26–5.41 (2H, m), 5.11
(1H, t, J 7.4), 4.90 (1H, d, J 10.7), 4.57 (2H, d, J 7.4), 4.00 (2H, m), 3.89
(1H, m), 2.79 (1H, d, J 13.6), 2.46 (3H, s), 2.24 (1H, m), 1.90–2.15 (8H, m),
2.06 (3H, s), 1.70 (6H, s), 1.51 (3H, s) and 1.30 (3H, s).
tetraenoate (11)12
To a solution of triethylphosphonoacetate (46.9 g, 41.5 mL, 0.209 mol
and 2 eq) in iso-hexane (275 mL) was added a 60% dispersion of
sodium hydride in mineral oil (8.38 g, 0.209 mol and 2 eq). After
30 min, once hydrogen evolution had completely ceased, a solution
of (5E,9E)-6,10,14-trimethylpentadeca-5,9,13-trien-2-one (10) (27.48 g,
0.105 mol and 1 eq) in iso-hexane (275 mL) was added dropwise.
The reaction mixture was stirred at room temperature for 16 h. TLC
analysis (1:1 v/v, iso-hexane: dichloromethane) showed complete
consumption of (10). The reaction mixture was poured into a 50%
saturated brine solution (500 mL) and extracted with iso-hexane
(3 × 300 mL). The combined extracts were washed with water
(3 × 150 mL), dried over anhydrous magnesium sulphate, filtered and
concentrated in vacuo affording a pale yellow oil. Purification by
column chromatography on silica gel eluting with (2:1 v/v, iso-hexane:
dichloromethane) gave the title compound (11) (26.55 g and 76%) as
an inseparable mixture of cis/trans isomers in a ratio of 2:13 as
determined by 1H NMR. Colourless oil. Rf (1:1 v/v, iso-hexane:
dichloromethane) 0.59. 1H NMR (CDCl3, 300 MHz) 5.68 (1H, s), 5.03–5.18
(3H, m), 4.16 (2H, q, J 7.0), 2.17 (3H, s), 1.94–2.15 (12H, m), 1.70 (3H, s),
1.62 (9H, s) and 1.29 (3H, t, J 7.0).
(2E,6E,10E,14E)-16-Bromo-3,7,11,15-tetramethyl-9-(toluene-
4-sulfonyl)hexadeca-2,6,10,14-tetraenyl acetate (16)1
To a stirred solution of (2E,6E,10E,14E)-16-hydroxy-3,7,11,15-tetramethyl-
9-(toluene-4-sulfonyl)hexadeca-2,6,10,14-tetraenyl acetate (15) (9.00 g,
17.90 mmol and 1 eq) in anhydrous diethyl ether (90 mL) and pyridine
(58 μL, 0.72 mmol and 0.44 eq) at 0°C was added phosphorus tribromide
(0.75 mL, 7.88 mmol and 0.44 eq) dropwise over 1 h. The reaction was
stirred in the absence of light for 2 h. TLC analysis (1:1 v/v, iso-hexane:
ethyl acetate) showed complete consumption of (15). The reaction
mixture was poured into ice cold water (100 mL) and extracted with
diethyl ether (3 × 100 mL). The combined extracts were washed with a
saturated aqueous sodium bicarbonate solution (100 mL), brine
(100 mL), dried over anhydrous magnesium sulphate, filtered and
concentrated in vacuo at 30°C giving the title compound (16) (9.01 g
and 89%) as a pale yellow oil. Rf (neat dichloromethane) 0.65. The
1
material was used in the next step without further purification. H NMR
(CDCl3, 300 MHz) 7.71 (2H, d, J 8.0), 7.32 (2H, d, J 8.0), 5.52 (1H, m), 5.32
(1H, t, J 6.7), 5.12 (1H, t, J 6.7), 4.90 (1H, d), 4.57 (2H, d, J 7.0), 3.96 (2H, s),
3.89 (1H, m), 2.85 (1H, d, J 13.2), 2.46 (3H, s), 2.26 (1H, m), 1.94–2.14
(8H, m), 2.06 (3H, s), 1.74 (3H, s), 1.68 (3H, s), 1.53 (3H, s) and 1.25 (3H, s).
(2E,6E,10E)-3,7,11,15-Tetramethylhexadeca-2,6,10,14-tetraen-
1-ol (geranyl geraniol) (12)12
(2E,6E)-1-Bromo-3,7,11-trimethyldodeca-2,6,10-triene10
To a solution of ethyl (2E,6E,10E)-3,7,11,15-tetramethylhexadeca-2,6,10,14-
tetraenoate (11) (26.5g, 0.08 mol and 1 eq) in toluene (265 mL) at À78°C
was added DIBAL (1M in hexane / heptane) (239.1mL, 0.239 mol and
3 eq) slowly over 20min. After 30min of stirring at ‐78°C the reaction was
quenched by careful addition of methanol (30 mL) over 10min. The
reaction mixture was warmed to room temperature and poured into a
mixture of saturated aqueous ammonium chloride solution (350 mL) and
an aqueous 1M solution of hydrochloric acid (350 mL). The mixture was
stirred for 30 min, and then the aqueous layer was separated and extracted
with diethyl ether (3× 300mL). The combined extracts were washed with
water (2× 300mL), brine (300 mL), dried over anhydrous magnesium
sulphate, filtered and concentrated in vacuo affording a pale yellow oil.
Purification by column chromatography on silica gel eluting over a gradient
of (5–20% ethyl acetate in iso-hexane) gave the title compound (12)
(17.56 g and 76%) as a colourless oil. Rf (4:1 iso-hexane: ethyl acetate) 0.25.
1H NMR (CDCl3, 300 MHz) 5.44 (1H, t, J 6.0), 5.12 (3H, m), 4.17 (2H, t, J 6.0),
1.93–2.22 (12H, m), 1.70 (6H, s) and 1.62 (9H, s).
To a stirred solution of E,E-Farnesol (5) (25.0 g, 0.112 mol and 1 eq) in
diethyl ether (250 mL) and pyridine (362 μL, 4.5 mmol and 0.04 eq) at -
5°C was added phosphorus tribromide (4.65 mL, 0.049 mol and 0.44 eq)
dropwise over 1 h. The reaction was stirred in the absence of light
for 2 h. TLC analysis (neat dichloromethane) showed complete
consumption of (5). The reaction mixture was poured into a 10%
aqueous potassium hydroxide solution (300 mL) and extracted with
diethyl ether (3 × 250 mL). The combined extracts were washed with
water (2 × 100 mL), brine (100 mL), dried over anhydrous magnesium
sulphate, filtered and concentrated in vacuo at 30°C affording the title
compound (32 g and 100%) of sufficient purity to use directly in the
next step. Rf (neat dichloromethane) 0.91. 1H NMR (CDCl3, 300 MHz)
5.55 (1H, t, J 8.4), 5.05–5.15 (2H, m), 4.04 (2H, d, J 8.4), 1.94–2.20 (8H, m),
1.75 (3H, s), 1.70 (3H, s) and 1.62 (6H, s).
(5E,9E)-6,10,14-Trimethylpentadeca-5,9,13-trien-2-one (10)11
1-Methyl-4-((2E,6E,10E)-3,7,11,15-tetramethylhexadeca-
2,6,10,14-tetraene-1-sulfonyl)benzene (14)1
To a solution of (2E,6E)-1-bromo-3,7,11-trimethyldodeca-2,6,10-triene
(32.0 g, 0.112 mol and 1 eq) in 1,4-dioxane (128 mL) was added ethyl
acetoacetate (15.68 mL, 0.123 mol and 1.1 eq), followed by a 30% weight To a stirred solution of geranyl geraniol (12) (17.50 g, 0.06 mol and 1 eq)
solution of sodium methoxide in methanol (22.15 g, 0.123 mol and 1.1 eq) in anhydrous diethyl ether (175 mL) and pyridine (300 μL) was added
dissolved in ethanol (50 mL). The resulting reaction mixture was phosphorus tribromide (7.04 g, 2.47 mL, 0.026 mol, 0.44 eq) dropwise
stirred at room temperature for 16 h. TLC analysis (6:1 v/v, iso-hexane: over 1 h. The reaction was stirred in the absence of light for 5 h. TLC
ethyl acetate) showed complete consumption of the starting material.
To the reaction mixture was added a solution of sodium hydroxide (12). The reaction mixture was poured into ice cold water (500 mL) and
(13.44 g, 0.336 mol and 3 eq) in water (128 mL), and the reaction extracted with diethyl ether (2 × 100 mL). The combined extracts were
mixture was stirred at room temperature for 64 h followed by heating to washed with
analysis (neat dichloromethane) showed complete consumption of
a
saturated aqueous sodium bicarbonate solution
J. Label Compd. Radiopharm 2013, 56 485–491
Copyright © 2013 John Wiley & Sons, Ltd. www.jlcr.org

S. J. Roe et al.
(2 × 150 mL), brine (100 mL), dried over anhydrous magnesium sulphate,
filtered and concentrated in vacuo. The resulting crude oil was dissolved
in dimethylformamide (350 mL) and sodium p-toluene sulfinate (13.9 g,
0.078 mol and 1.3 eq) was added. The mixture was stirred at room
temperature in the absence of light for 16 h. TLC analysis (neat
dichloromethane) showed complete consumption of the bromide (13).
The reaction mixture was poured into water (1000 mL) and extracted
with diethyl ether (5 × 200 mL). The combined extracts were washed with
water (5 × 200 mL), brine (200 mL), dried over anhydrous magnesium
sulphate, filtered and concentrated in vacuo to yield a yellow oil.
Purification by column chromatography on silica gel eluting with (neat
dichloromethane) gave the title compound (14) (20.99 g and 81%) as a
colourless oil. Rf (neat dichloromethane) 0.16. 1H NMR (CDCl3, 300 MHz)
7.75 (2H, d, J 8.0), 7.33 (2H, d, J 8.0), 5.20 (1H, t, J 7.3), 5.02–5.16 (3H, m),
3.80 (2H, d, J 8.0), 2.46 (3H, s), 1.93–2.15 (12H, m), 1.70 (3H, s), 1.58–1.65
(9H, m) and 1.36 (3H, s).
mixture was extracted with diethyl ether (3× 100mL), and the combined
extracts were washed with brine (50 mL), dried over anhydrous
magnesium sulphate and concentrated in vacuo affording a pale
yellow oil. Purification by column chromatography on silica gel
eluting with (6:1 v/v, iso-hexane: ethyl acetate) gave the title
compound (18) (2.2557 g and 61%) as a pale yellow oil. Rf (6:1 v/v,
iso-hexane: ethyl acetate) 0.21. 1H NMR (CDCl3, 300 MHz) 5.44 (1H, t,
J 6.9), 5.05–5.21 (7H, m), 4.16 (2H, d, J 6.9), 1.92–2.20 (28H, m), 1.70
(6H, s), 1.62 (21H, s).
(5E,9E,13E,17E,21E,25E,29E)-6,10,14,18,22,26,30,34-
Octamethylpentatriaconta-5,9,13,17,21,25,29,33-
[2-14C]octaen-2-one (19)
To
a solution of (2E,6E,10E,14E,18E,22E,26E)-3,7,11,15,19,23,27,31-
octamethyldotriaconta-2,6,10,14,18,22,26,30-octaen-1-ol (18) (2.64 g,
4.70 mmol and 1eq) in anhydrous diethyl ether (26 mL) and pyridine
(15μL, 0.19 mmol and 0.04 eq) was added phosphorus tribromide
(196.2 μL, 2.07mmol and 0.44 eq) dropwise at ‐5°C. The reaction mixture
was stirred at room temperature for 2 h. TLC analysis (6:1v/v, iso-hexane:
ethyl acetate) showed complete consumption of (18). The reaction mixture
was poured into a saturated aqueous sodium bicarbonate solution (50 mL)
and extracted with diethyl ether (3× 50mL). The combined extracts
were washed with water (50 mL), brine (50mL), dried over anhydrous
magnesium sulphate and evaporated in vacuo to afford a yellow oil. The
yellow oil was dissolved in 1,4-dioxane (11mL) and ethanol (422μL).
Next, ethyl [3-14C]acetoacetate (0.6144g, 4.698 mmol, 93.96mCi and
3476.52MBq) was added followed by a 30% solution of sodium methoxide
in methanol (931 mg, 5.17 mmol and 1.1eq). The reaction mixture was
stirred at room temperature for 20h. TLC analysis (neat dichloromethane)
showed complete consumption of the (all-E)-octaprenyl bromide (2).
Water (7mL) containing sodium hydroxide (564 mg, 14.09 mmol and 3 eq)
was added, and the reaction mixture was heated to 95°C for 3 h. TLC
analysis (neat dichloromethane) showed complete consumption of the
intermediate keto-ester. The reaction mixture was poured into water
(50mL) and extracted with n-pentane (5× 20 mL). The combined extracts
were washed with water (50 mL), dried over anhydrous magnesium
sulphate and concentrated in vacuo to afford a pale yellow oil. Purification
by column chromatography on silica gel eluting with (15:1v/v, iso-hexane:
ethyl acetate) gave the title compound (19) (1.34 g, 44.35 mCi, 1641.0 MBq
and 47%) as a colourless oil. Rf (dichloromethane) 0.54. 1H NMR (CDCl3,
300 MHz) 5.05–5.20 (8H, m), 2.47 (2H, t, J 7.1), 2.28 (2H, m), 2.15 (3H, s),
1.94–2.14 (28H, m), 1.70 (3H, s) and 1.59–1.65 (24H, m).
(2E,6E,10E,14E,18E,22E,26E)-3,7,11,15,19,23,27,31-Octamethyl-
9,17-bis(toluene-4-sulfonyl)-dotriaconta-2,6,10,14,18,22,26,30-
octaenyl acetate (17)1
To a stirred solution of 1-methyl-4-((2E,6E,10E)-3,7,11,15-tetramethylhexadeca-
2,6,10,14-tetraene-1-sulfonyl)benzene (14) (1.62 g, 3.79 mmol and 1.0 eq)
and (2E,6E,10E,14E)-16-bromo-3,7,11,15-tetramethyl-9-(toluene-4-sulfonyl)
hexadeca-2,6,10,14-tetraenyl acetate (16) (2.25 g, 3.98mmol and 1.05 eq)
in dimethylformamide (23 mL) at ‐5°C was added a 60% dispersion of
sodium hydride in mineral oil (151.5mg, 3.79mmol and 1.0eq) portion wise
over 10min. The resulting reaction mixture was stirred at ‐5°C for 16 h. TLC
analysis (neat dichloromethane) showed incomplete consumption of
(14). Additional sodium hydride in mineral oil (15 mg) was added
and the reaction mixture was stirred for an additional 24 h at ‐5°C.
TLC analysis (neat dichloromethane) showed no change. The reaction
mixture was poured into brine (200 mL) and extracted with diethyl
ether (4 × 50 mL). The combined extracts were washed with water
(5 × 50 mL), dried over anhydrous magnesium sulphate, filtered and
concentrated in vacuo yielding a yellow oil. Purification by column
chromatography on silica gel eluting with (neat dichloromethane)
then (10:1–4:1 v/v, iso-hexane: ethyl acetate) gave recovered (14)
(0.51 g and 31%) and title compound (17) (1.96 g and 57%) as a
colourless oil. Rf (10:1 v/v, iso-hexane: ethyl acetate) 0.15. 1H NMR
(CDCl3, 300 MHz) 7.71 (4H, m), 7.31 (4H, d, J 8.0), 5.32 (1H, t, J 6.0),
5.01–5.19 (5H, m), 4.83–4.97 (2H, m), 4.57 (2H, d, J 6.9), 3.79–3.95
(2H, m), 2.87 (2H, m), 2.45 (6H, s), 2.18–2.34 (2H, m), 1.83–2.15
(20H, m), 2.06 (3H, s), 1.73 (3H, s), 1.69 (3H, s), 1.61 (9H, m), 1.52
(6H, s) and 1.22 (6H, m).
Ethyl (2E,6E,10E,14E,18E,22E,26E,30E)-3,7,11,15,19,23,27,31,35-
nonamethylhexatriaconta-2,6,10,14,18,22,26,30,34-[3-14C]
nonaenoate (20)
(2E,6E,10E,14E,18E,22E,26E)-3,7,11,15,19,23,27,31-
Octamethyldotriaconta-2,6,10,14,18,22,26,30-octaen-1-ol (18)1
To a solution of triethylphosphonoacetate (879.2 μL, 4.43 mmol and 2 eq)
in iso-hexane (17 mL) was added a 60% dispersion of sodium hydride in
mineral oil (177.3mg, 4.43 mmol and 2eq). After 30 min, once hydrogen
evolution had completely ceased, a solution of (5E,9E,13E,17E,21E,25E,29E)
-6,10,14,18,22,26,30,34-octamethylpentatriaconta-5,9,13,17,21,25,29,33-
octaen-2-one (19) (1.34 g, 2.22 mmol, 44.35 mCi, 1641.0 MBq and 1 eq) in
iso-hexane (10 mL) was added dropwise. The reaction mixture was
stirred at room temperature for 16 h. TLC/autoradiography (1:1 v/v,
iso-hexane: dichloromethane) showed complete consumption of (19)
and ~77% (20) along with ~17.4% of an isomer. The reaction mixture was
poured into 50% saturated brine (50 mL) and extracted with n-pentane
(3× 50mL). The combined extracts were washed with water (3× 50 mL),
dried over anhydrous magnesium sulphate, filtered and concentrated
in vacuo affording a pale yellow oil. Purification by column chromatography
on silica gel eluting with (2:1v/v, iso-hexane: dichloromethane) gave the
title compound (20) (1.35 g, 40.09 mCi, 1483.3MBq and 90%) as an
inseparable mixture of cis/trans isomers in a ratio of 20:80 by 1H NMR.
To a stirred solution of (2E,6E,10E,14E,18E,22E,26E)-3,7,11,15,19,23,27,31-
octamethyl-9,17-bis(toluene-4-sulfonyl)-dotriaconta-2,6,10,14,18,22,26,30-
octaenyl acetate (17) (6.00 g, 6.57 mmol and 1 eq) in methanol (42 mL)
was added a sodium methoxide solution (25% weight, 284mg, 1.31mmol
and 0.2 eq). The mixture was stirred at room temperature for 4 h. TLC
analysis (1:1 iso-hexane: ethyl acetate) showed complete consumption of
(17). The reaction mixture was concentrated in vacuo, and the resultant
crude residue was dissolved in tetrahydrofuran (120 mL). Next Pd(dppp)
Cl2 (387.5mg, 0.66 mmol and 0.1eq) was added, and the mixture was
cooled to 0°C under nitrogen. Superhydride© (1M in tetrahydrofuran)
(21.7mL, 21.67 mmol and 3.3eq) was added dropwise over 15min, and
the resultant reaction mixture was stirred at 0°C for 3 h then allowed to
warm to room temperature over 16 h. TLC analysis (1:1v/v, iso-hexane: ethyl
acetate) showed complete consumption of the intermediate alcohol. The
reaction mixture was quenched by the addition of a 3 M aqueous sodium
hydroxide solution (50 mL) containing potassium cyanide (100mg). The Colourless oil. Rf (1:1v/v, iso-hexane: dichloromethane) 0.43. 1H NMR (CDCl3,
www.jlcr.org
Copyright © 2013 John Wiley & Sons, Ltd.
J. Label Compd. Radiopharm 2013, 56 485–491

S. J. Roe et al.
300 MHz) 5.68 (1H, m), 5.07–5.22 (8H, m), 4.16 (2H, q, J 7.1), 1.93–2.23 solid. All remaining fractions from all preparative HPLC runs containing (1)
(32H, m), 1.70 (3H, s), 1.57–1.67 (27H, s) and 1.30 (3H, t, J 7.1).
with a purity of >75% were combined (409.0mg, 12.82 mCi and
474.4MBq) giving a white waxy solid. H NMR (CDCl3, 400MHz) 5.44 (1H,
1
[3-14C]solanesol (1)13
t, J 6.9), 5.13 (8H, m), 4.18 (2H, d, J 6.9), 2.00–2.20 (32H, m), 1.71 (6H, s)
and 1.62 (24H, s). The radiochemical purity of the title compound (1)
determined by HPLC was found to be 95.4%. NMR data were fully
consistent with an authentic standard. The specific activity determined by
gravimetric analysis was found to be 19.8mCi/mmol (734 MBq/mmol,
31.4μCi/mg and 1.16MBq/mg).
To a solution of ethyl (2E,6E,10E,14E,18E,22E,26E,30E)-3,7,11,15,19,23,
27,31,35-nonamethylhexatriaconta-2,6,10,14,18,22,26,30,34-nonaenoate
(20) (1.35 g, 2.00 mmol, 40.09 mCi, 1483.3 MBq and 1 eq) in anhydrous
toluene (13.5 mL) at ‐78°C was added 1.5 M DIBAL in toluene (4.0 mL,
6.012 mmol and 3 eq) slowly via a syringe over 20 min. After 30 min,
TLC/autoradiography (2:1 v/v, iso-hexane: dichloromethane) showed
complete consumption of (20). The reaction mixture was quenched by
careful addition of methanol (13.5 mL) over 10 min. The reaction was
allowed to warm to room temperature and then poured into a mixture
of saturated aqueous ammonium chloride solution (12.5 mL) and a 1 M
aqueous solution of hydrochloric acid (12.5 mL). The resultant mixture
was stirred at room temperature for 30 min, and then the organic layer
was separated. The aqueous layer was extracted with diethyl ether
(3 × 30 mL). The combined extracts were washed with water (30 mL),
brine (30 mL), and then dried over anhydrous magnesium sulphate and
concentrated in vacuo. TLC/autoradiography (neat dichloromethane)
showed ~92.4% product as a mixture of cis/trans isomers. Purification
by column chromatography on silica gel eluting with (9:1–6:1 v/v, iso-hexane:
ethyl acetate) gave (1) as an inseparable mixture of cis/trans isomers
(0.801 g, 25.38 mCi, 939.1 MBq and 63%). The mixture was dissolved in
dichloromethane (20 mL) and stirred with water (10 mL) for 30 min.
The aqueous layer was removed, and the organic layer was dried over
anhydrous magnesium sulphate, filtered and concentrated in vacuo.
Purification by preparative HPLC gave a white waxy solid (230.8 mg).
Impure fractions were combined and concentrated giving (362.9mg),
which were re-purified by preparative HPLC. Fractions containing >95%
purity material were combined with the first batch of purified material
and concentrated in vacuo giving a white waxy solid. This material was
re-purified again by preparative HPLC. Fractions containing >95% purity
material were combined and concentrated in vacuo giving the title
Conflict of Interest
The authors did not report any conflict of interest.
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J. Label Compd. Radiopharm 2013, 56 485–491
Copyright © 2013 John Wiley & Sons, Ltd.
www.jlcr.org