Complementary chemoenzymatic routes to both enantiomers of febrifugine

Article abstract of DOI:10.1039/b901670h

Two complementary strategies for the synthesis of febrifugine are detailed based on previously developed chemoenzymatic approaches to the 3-hydroxypiperidine skeleton. The introduction of the quinazolone-containing side chain in both strategies was based

Full text of DOI:10.1039/b901670h

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PAPER
www.rsc.org/obc | Organic & Biomolecular Chemistry
Complementary chemoenzymatic routes to both enantiomers of febrifugine†
Marloes A. Wijdeven,a Rutger J. F. van den Berg,a Roel Wijtmans,a Peter N. M. Botman,b Richard H. Blaauw,b
Hans E. Schoemaker,c Floris L. van Delfta and Floris P. J. T. Rutjes*a
Received 26th January 2009, Accepted 30th April 2009
First published as an Advance Article on the web 4th June 2009
DOI: 10.1039/b901670h
Two complementary strategies for the synthesis of febrifugine are detailed based on previously
developed chemoenzymatic approaches to the 3-hydroxypiperidine skeleton. The introduction of the
quinazolone-containing side chain in both strategies was based on an N-acyliminium ion-mediated
coupling reaction.
Introduction
Febrifugine (1) (Fig. 1) was first isolated in 1946 from Dichroa
febrifuga1 and later also from the more common Hydrangea
umbellate.2 Due to facile epimerization of febrifugine into isomeric
isofebrifugine (2), the relative and absolute stereochemistry were
corrected on several occasions.3–5 In 1999, Kobayashi and co-
workers published the first asymmetric synthesis thereby also
establishing the absolute stereochemistry.6 The latter result has
spurred renewed synthetic and medicinal interest in febrifugine
and derivatives.7 The interest mainly stems from the fact that
febrifugine shows powerful antimalarial activity—it is more potent
than chloroquine8—although severe side effects have precluded
clinical use so far. In recent years, we have developed complemen-
Scheme 1 Retrosynthesis.
tary chemoenzymatic approaches for the rapid construction of
of febrifugine. It was shown previously in our group,10b that lactam
3-hydroxypiperidine scaffolds, either starting from the amino acid
3 can be readily obtained from the chemoenzymatically generated
cyanohydrin 4 using N-acyliminium ion chemistry.
allysine ethylene acetal,9 or from an enantiopure cyanohydrin.10 It
was envisaged that these pathways would also be well suited for
the synthesis of febrifugine and potentially useful derivatives. In
The second approach, in this case leading to ent-1 was thought
to proceed via the known hydroxypipecolic acid 5,9a involving in-
this contribution, we detail two chemoenzymatic strategies which
troduction of the quinazolone-containing side chain and removal
have resulted in enantioselective syntheses of either enantiomer of
of the ester function. The latter compound in turn can be readily
febrifugine.
obtained from L-allysine ethylene acetal 6.
Results
Our studies commenced with reductive cyclization of cyanohydrin
4 (Scheme 2), followed by conversion of the resulting N,N-acetal
into the N,O-acetal 7 via diazotation.10b In initial approaches,
we focused on introducing the side chain as a whole via the
corresponding stannyl enol ether 9 (M = SnOTf) as previously
described by Kobayashi et al. for exocyclic N-acyliminium ions.7d
Fig. 1 Febrifugine and isofebrifugine.
A retrosynthesis of the first approach is shown in Scheme 1,
where it was anticipated that the allyl function of lactam 3 could be
converted in a number of steps into the desired quinazolone moiety
However, this strategy appeared unsuccessful in our hands using
the endocyclic N-acyliminium precursor 7 despite trying a variety
of conditions and Lewis acids, also in combination with the
corresponding silyl enol ether (M = TMS).
Due to these unsuccessful results, we anticipated that the
side chain could be built up in two steps, first by introducing
a 2-(chloromethyl)allyl moiety, followed by nucleophilic dis-
placement of the chloride by a quinazolone nucleophile. Thus,
N-acyliminium ion precursor 7 was reacted with allylsilane 8
under the influence of BF3·OEt2 to give the corresponding adduct
10 in good yield (74%) as a 1:1 mixture of cis/trans-isomers.
Both isomers could be successfully reacted with quinazolone
aInstitute for Molecules and Materials, Radboud University Nijmegen,
Heyendaalseweg 135, NL-6525 AJ Nijmegen, The Netherlands. E-mail:
F.Rutjes@science.ru.nl; Fax: +31 24 365 3393; Tel: +31 24 365 3202
bChiralix B.V., P.O. Box 31070, NL-6503 CB Nijmegen, The Netherlands
cDSM Pharma Products, P.O. Box 18, NL-6160 MD Geleen, The
Netherlands
† Electronic supplementary information (ESI) available: Experimental
procedures of compounds 4, 16–20, 22 and 1H and 13C spectra of all
new compounds. See DOI: 10.1039/b901670h
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Scheme 2 Initial approaches to febrifugine.
11 in the presence of NaH to give the substitution product 12
in 81% yield. At this stage, selective reduction of the lactam
carbonyl was in order, which was attempted in a variety of ways.
However, none of our approaches (e.g. Boc-protection followed
by reduction, Boc-protection followed by enol triflate forma-
tion and subsequent reduction, selective thionolactam formation
followed by reduction) led to successful selective reduction to
the corresponding piperidine system, so this pathway was also
abandoned.
We then chose to build-up the side chain more gradually,
which we anticipated would also be advantageous for preparing
derivatives of febrifugine. In this case, precursor 7 was reacted
with allyltrimethylsilane and BF3·OEt2 to give lactam 3 as a 4.2:1
mixture of cis/trans-isomers (Scheme 3).10b After chromatographic
separation of both diastereoisomers, we continued with the
cis-isomer. Reduction with LiAlH4 resulted in the formation of
13 in good yield, which at this stage represents a formal synthesis
of febrifugine, since literature describes its further conversion into
the natural product.7f However, we chose to develop a synthetically
more versatile route offering opportunities to synthesize analogues
at a later stage. To this end, the amine and hydroxyl were
protected with a Boc and a MOM group, respectively. Subsequent
mCPBA-mediated epoxidation afforded 15 as a 2.5:1 mixture
of diastereoisomers in 52% yield over two steps. The epoxide
was then regioselectively opened with sodium azide to give 16
(70%), followed by Staudinger reduction to form amine 17 in
86% yield. The amine function was intended to serve as a handle
for introduction of the aromatic part. Thus, treatment with
isatoic anhydride (Et3N, EtOAc, 40 ◦C) led to introduction of
anthranilic acid at the amine and hydroxy function. Subsequent
hydrolysis of the ester then afforded the desired amide 18 in a
satisfactory 74% yield. The quinazolinone moiety was then formed
via condensation under the influence of triethyl orthoformate
in toluene at elevated temperatures, providing 19 in 82% yield.
The final steps involved Dess Martin periodinane oxidation to
give ketone 20 (83%), followed by protecting group removal with
HCl in EtOAc to afford isofebrifugine (2), which was isomerized
Scheme 3 Synthesis of (+)-febrifugine.
in refluxing water into (+)-febrifugine (1). Analytical data of
both natural products were in accordance with those reported
in literature.6
The second approach commenced with the earlier reported
strategy to convert allysine ethylene acetal 6 into the corresponding
N,O-acetal 5 in a four step sequence.9 At this stage, we also
attempted to introduce the side chain as a whole applying similar
conditions as mentioned before, but we did not observe any
product formation either. Then, we switched to the two-step
sequence described in Scheme 4. This pathway proceeded via
the introduction of the (chloromethyl)allyl moiety by reacting
N,O-acetal 5 with 2-(chloromethyl)allylsilane 8 in the presence
of BF3·OEt2 yielding 21 in 95% yield as sole diastereoisomer.
Next, the skeleton of febrifugine was completed via a successful
reaction of 21 with the deprotonated quinazolone 11 to afford 22 in
80% yield. Subsequent quantitative ester saponification (NaOH,
THF/H2O), followed by a Barton decarboxylation, involving
mixed anhydride formation, coupling with thiolactam 23 and
tBuSH-mediated radical removal of the carboxylate, provided
24 in a satisfactory yield of 59%. Finally, ent-febrifugine was
obtained in 76% yield via oxidative cleavage of the allylic double
bond with osmium tetroxide and sodium periodate, followed by
hydrogenolysis of the Cbz-protection group.
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20
Major-16: [a]D -15.7 (c 0.31, CH2Cl2). IR (film) 3434, 2967,
1
2933, 2881, 2094, 1679, 1649, 1419, 1161, 1031 cm-1. H-NMR
(400 MHz, CDCl3, rotamers) d 4.69–4.690 (m, 3H), 4.35–4.34 (m,
1H), 3.90–3.86 (m, 1H), 3.73 (m, 1H), 3.57–3.56 (m, 1H), 3.38–
3.35 (m, 3H), 3.23–3.19 (m, 2H), 2.65–2.59 (m, 2H), 1.87–1.86 (m,
2H), 1.71 (m, 3H), 1.69 (m, 9H). 13C-NMR (75 MHz, CHCl3) d
156.5, 95.0, 80.9, 73.4, 66.8, 56.1, 55.6, 49.4, 38.6, 28.6, 28.3, 25.7,
24.0. HRMS (ESI+): calcd for C15H28N4NaO5 (M+Na+): 367.1957,
found: 367.1944.
20
Minor-16: [a]D +25.3 (c 0.20, CH2Cl2). IR (film) 3438,
1
2933, 2872, 2107, 1684, 1666, 1416, 1148, 1040 cm-1. H-NMR
(400 MHz, CDCl3, rotamers) d 4.67 (m, 2H), 4.44–4.39 (m, 1H),
3.89 (m, 2H), 3.62 (m, 2H), 3.37–3.32 (m, 5H), 2.77–2.70 (m,
1H), 1.94–1.91 (m, 3H), 1.62 (m, 2H), 1.46 (m, 10H). 13C-NMR
(75 MHz, CHCl3) d 155.9, 95.2, 80.6, 74.5, 70.4, 56.3, 55.6, 51.7,
38.8, 29.8, 28.4, 25.7, 24.0. HRMS (ESI+): calcd for C15H28N4NaO5
(M+Na+): 367.1957, found: 367.1932.
(2S,3S)-2-[3-(2-Aminobenzoylamine)-2-hydroxypropyl]-3-
methoxymethoxypiperidine-1-carboxylic acid tert-butyl ester (18)
To a solution of 17major (239 mg, 0.75 mmol) in dry EtOAc (70 mL)
were added isatoic anhydride (429 mg, 2.63 mmol) and triethyl
amine (151 ml, 1.125 mmol) and the mixture was stirred overnight
at 40 ◦C. The reaction was quenched by the addition of saturated
aqueous NaHCO3 (50 mL) and extracted with EtOAc (4 ¥ 75 mL).
The combined organic layers were washed with brine (150 mL),
dried over Na2SO4, filtrated and concentrated in vacuo. The crude
product was dissolved in a mixture of THF (20 mL), methanol
(20 mL) and aqueous 1 M NaOH (20 mL). After stirring for
2 h, the reaction was quenched by adding saturated aqueous
NaHCO3 (70 mL) and extracted with EtOAc (4 ¥ 100 mL).
The combined organic layers were washed with brine (100 mL),
dried over Na2SO4, filtrated and concentrated in vacuo. Flash
chromatography (1:2–3:1 EtOAc:heptane) afforded product 18major
Scheme 4 Synthesis of ent-febrifugine.
Conclusions
We successfully applied our previously developed strategies for
the synthesis of 3-hydroxypiperidines to the total synthesis of
febrifugine, providing access to both enantiomers. The first
approach proceeds in 15 steps with an overall yield of 2.5%
starting from cheap materials and offering various possibilities for
the synthesis of analogues. Using the second strategy, febrifugine
is obtained in 10 steps with 32% overall yield. One of the
reasons for the higher efficiency is the higher selectivity in the
N-acyliminium ion reaction, which renders the epimerization of
isofebrifugine into febrifugine superfluous. Access to the starting
material is somewhat more limited, however, and there are also
fewer possibilities for the synthesis of analogues as compared
to the first route. The synthesis of series of analogues and their
biological evaluation are currently under investigation in our
laboratory.
20
(222 mg, 0.51 mmol, 67%) as a colorless oil. [a]D +8.8 (c 0.19,
CH2Cl2). IR (film) 3443, 3339, 2971, 2928, 2889, 1649, 1416, 1152,
1
1031 cm-1. H-NMR (400 MHz, CDCl3, rotamers) d 7.35–7.50
(m, 1H), 7.33 (m, 1H), 6.71–6.63 (m, 3H), 5.50 (m, 2H), 4.67–
4.66 (m, 2H), 4.65–4.59 (m, 1H), 3.88–3.81 (m, 2H), 3.76–3.70 (m,
1H), 3.55–3.54 (m, 1H), 3.38 (m, 3H), 3.20–3.14 (m, 1H), 1.88–
1.68 (m, 5H), 1.60–1.45 (m, 12H). 13C-NMR (75 MHz, CHCl3)
d169.2, 156.6, 148.6, 132.1, 127.3, 117.1, 116.6, 116.3, 95.0, 80.8,
73.6, 66.4, 55.6, 49.6, 44.6, 38.7, 28.7, 28.3, 25.7, 24.0. HRMS
(ESI+): calcd for C22H35N3NaO6 (M+Na+): 460.2424, found:
460.2381.
Experimental section
(2S,3S)-2-(3-Azido-2-hydroxypropyl)-3-methoxymethoxy-
piperidine-1-carboxylic acid tert-butyl ester (16)
(2S,3S)-2-[2-Hydroxy-3-(4-oxo-4H-quinazolin-3-yl)propyl]-3-
methoxymethoxypiperidine-1-carboxylic acid tert-butyl ester (19)
Epoxide 15 (20 mg, 0.066 mmol) was dissolved in a mixture of
methanol (4 mL) and H2O (0.5 mL), and sodium azide (22 mg,
0.33 mmol) and ammonium chloride (11 mg, 0.2 mmo◦l) were
added. The reaction mixture was stirred overnight at 70 C and
then quenched with saturated aqueous NaHCO3 (5 mL) and
EtOAc (5 mL). The aqueous layer was extracted with EtOAc
(3 ¥ 10 mL), the combined organic layers were washed with brine
(20 mL), dried over Na2SO4, filtrated and concentrated in vacuo.
Flash chromatography (1:5 EtOAc:heptane) afforded the two pure
diastereoisomers 16major (11 mg, 0.032 mmol, 50%) and 16minor
(4 mg, 0.012 mmol, 20%) as colorless oils.
To a solution of 18major (232 mg, 0.52 mmol) in toluene (10 mL)
were added p-TsOH (20 mg, 0.11 mmol) and triethyl orthoformate
(260 mg, 1.56 mmol) and the mixture was stirred overnight
at 40 ◦C. The reaction was quenched with saturated aqueous
NaHCO3 (10 mL) and extracted with EtOAc (4 ¥ 15 mL).
The combined organic layers were washed with brine (40 mL),
dried over Na2SO4, filtrated and concentrated in vacuo. Flash
chromatography (1:2–2:1 EtOAc:heptane) afforded product 19major
20
(197 mg, 0.44 mmol, 85%) as a colorless oil. [a]D +59.8 (c 0.28,
2978 | Org. Biomol. Chem., 2009, 7, 2976–2980
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CH2Cl2). IR (film) 2971, 2941, 2876, 2353, 2340, 1684, 1645, 1558,
1152, 1035 cm-1. 1H-NMR (400 MHz, CDCl3, rotamers) d 8.29–
8.22 (m, 2H), 7.73 (m, 2H), 7.48 (m, 1H), 4.68 (m, 3H), 4.48–
4.38 (m, 2H), 3.86 (m, 1H), 3.73 (m, 2H), 3.60–3.57 (m, 1H),
3.37 (m, 3H), 2.70 (m, 1H), 1.88 (m, 2H), 1.70 (m, 2H), 1.53–
1.41 (m, 2H), 1.37 (m, 9H). 13C-NMR (75 MHz, CHCl3) d 161.3,
156.5, 148.3, 148.0, 134.1, 127.5, 126.8, 126.5, 122.0, 95.0, 80.9,
73.4, 65.3, 55.6, 51.8, 49.5, 38.7, 28.7, 28.2, 25.7, 24.0. HRMS
(ESI+): calcd for C23H33N3NaO6 (M+Na+): 470.2267, found:
470.2267.
(2S,5R,6S)-6-(2-Chloromethylallyl)-5-hydroxypiperdine-1,2-
dicarboxylic acid 1-benzyl ester 2-methyl ester (21)
To a solution of 5 (400 mg, 1.24 mmol) in CH2Cl2 (10 mL) were
added 2-chloromethylallyltrimethylsilane (720 mL, 3.96 mmol)
◦
and BF3·OEt2 (462 mL, 2.46 mmol) at -30 C. The reaction was
warmed to rt, stirred for 3 h and quenched with saturated aqueous
NaHCO3 (10 mL) and extracted with CH2Cl2 (2 ¥ 10 mL). The
combined organic layers were dried over Na2SO4 and concentrated
in vacuo. Flash chromatography (2:1–5:1 EtOAc-heptane) afforded
20
product 21 as a colorless oil (449 mg, 1.18 mmol, 95%). [a]D -40 (c
1.19, CH2Cl2). IR (film) 3444, 2949, 1753, 1694, 1408, 1292, 1207,
1011 cm-1. 1H-NMR (300 MHz, CDCl3, rotamers) d 7.31–7.29 (m,
5H), 5.18–4.81 (m, 5H), 4.34–4.26 (m, 2H), 3.86–3.80 (m, 2H),
3.68-.365 (m, 3H), 2.60–2.51 (m, 2H), 2.23–2.13 (m, 2H), 1.75–
1.61 (m, 2H). No clear 13C-NMR due to rotamers. HRMS (ESI+):
calcd for C19H24ClNNaO5 (M+Na+): 404.1241, found: 404.1241.
(2S,3S)-2-[2-Oxo-3-(4-oxo-4H-quinazolin-3-yl)propyl]-3-
methoxymethoxypiperidine-1-carboxylic acid tert-butyl ester (20)
Both diastereoisomers of 19 (14 mg, 0.035 mmol) were dissolved in
CH2Cl2 (5 mL) and Dess-Martin periodinane (39 mg, 0.091 mmol)
was added. After stirring overnight, the reaction was quenched
with saturated aqueous NaHCO3 (5 mL) and extracted with
dichloromethane (4 ¥ 5 mL). The combined organic layers
were washed with brine (15 mL), dried over Na2SO4, filtrated
and the solvent was removed under reduced pressure. Flash
chromatography (1:2–2:1 EtOAc:heptane) afforded product 20
(2S,5R,6S)-5-Hydroxy-6-[2-(4-oxo-4H-quinazolin-3-ylmethyl)-
allyl]piperdine-1-carboxylic acid benzyl ester (24)
To a solution of 22 (123 mg, 0.25 mmol) in THF (1 mL) was
added 1 M aqueous NaOH (1.84 mL) in 4 portions over 3 h.
The solution was neutralized with 1 M aqueous HCl to pH = 7,
concentrated in vacuo and acidified to pH = 2 with 1M aqueous
HCl. The mixture was extracted with CH2Cl2 (3 ¥ 10 mL) and the
combined organic phases are dried over Na2SO4 and concentrated
in vacuo. The crude acid (120 mg, 0.25 mmol) was dissolved in
THF (4 mL) and cooled to -15 ◦C. Isobutyl chloroformate (34 mL,
0.25 mmol) and N-methylmorpholine (28 mL, 0.25 mmol) were
added subsequently and the mixture was stirred for 5 minutes,
followed by the addition of a solution of 2-mercaptopyridine
N-oxide (40 mg, 0.30 mmol) and Et3N (44 mL, 0.30 mmol) in
THF (8 mL). The reaction mixture was stirred for 1 h with the
exclusion of light, where after 2-methyl-2-propanethiol (86 mL,
0.75 mmol) was added and the mixture was exposed to a sunlamp
for 3 h. The reaction was quenched with H2O (20 mL) and
extracted with CH2Cl2 (3 ¥ 30 mL). The combined organic
phases were washed with brine (20 mL), dried over Na2SO4
and concentrated in vacuo. Flash chromatography (100:0–95:5
EtOAc:MeOH) afforded product 24 as a colorless oil (64 mg,
20
(10 mg, 0.022 mmol, 83%). [a]D +41.3 (c 0.20, CH2Cl2). IR
(film) 2976, 2937, 2885, 1675, 1606, 1351, 1148, 1031 cm-1.
1H-NMR (400 MHz, CDCl3, rotamers) d 8.29–8.27 (m, 1H), 8.04
(m, 1H), 7.76–7.71 (m, 2H), 7.51–7.47 (m, 1H), 5.24–5.20 (m,
1H), 5.00–4.98 (m, 2H), 4.69 (m, 2H), 3.86–3.84 (m, 1H), 3.75–
3.73 (m, 1H), 3.40 (m, 3H), 3.07–04 (m, 1H), 2.85–2.65 (m, 2H),
2.07–2.04 (m, 1H), 1.90 (m, 1H), 1.72 (m, 1H), 1.44 (m, 10H).
13C-NMR (75 MHz, CHCl3) d 201.1, 160.9, 155.3, 148.2, 146.9,
134.2, 127.5, 127.1, 126.6, 121.8, 95.5, 80.5, 74.1, 55.7, 53.4, 51.2,
38.4, 36.5, 28.3, 25.4, 23.7. HRMS (ESI+): calcd for C23H31N3NaO6
(M+Na+): 468.2111, found: 468.2148.
(+)-Febrifugine·2HCl (1)
A solution of 20 (76 mg, 0,17 mmol) in methanol (10 mL)
and concentrated HCl (1 mL) was stirred for 2 h and then
concentrated in vacuo to yield isofebrifugine·2HCl (2, 59 mg,
0.16 mmol, 92%). Isofebrifugine·2HCl (59 mg, 0.16 mmol) was
dissolved in 1M NaOH (2 mL) and EtOAc (2 mL) and after
stirring for 10 min extracted with EtOAc (4 ¥ 5 mL). The
combined organic layers were washed with brine (10 mL), dried
over Na2SO4, filtrated and concentrated in vacuo. The free amine
was dissolved in H2O (20 mL) and heated to 80 ◦C for 20 min.
Concentrated HCl (4 mL) was added and the solvent was removed
under reduced pressure. Crystallization from ethanol afforded
20
0.148 mmol, 59%). [a]D +64 (c 0.19, CH2Cl2). IR (film) 3417,
1674, 1609, 1255, 774, 733, 696 cm-1. 1H-NMR (200 MHz, CDCl3,
rotamers) d 8.39–8.28 + 8.11 (2 x m, 2H), 7.77–7.70 (m, 2H), 7.55–
7.47 (m, 1H), 7.32–7.30 (m, 5H), 5.14 (m, 2H), 4.93 (m, 1H), 4.63
(m, 3H), 4.14 (m, 1H), 3.88 (m, 1H), 2.97–2.85 (m, 1H), 2.22–2.05
(m, 3H), 1.97–1.71 (m, 3H), 1.49–1.37 (m, 1H). No clear 13C-
NMR due to rotamers. HRMS (ESI+): calcd for C25H27N3NaO4
(M+Na+): 456.1893, found: 456.1899.
(+)-febrifugine·2HCl (1). mp = 209 ◦C. [a]D +13.2 (c 0.07,
20
1
D2O). H-NMR (400 MHz, CD3OD) d 8.79 (s, 1H), 8.29–8.27
(5R,6S)-3-[3-(3-Hydroxy-piperdin-2-yl)-2-oxo-propyl]-3H-
quinolizin-4-one·2HCl (ent-febrifugine·2HCl) ((-)-1)
(m, 1H), 7.98–7.95 (m, 1H), 7.78–7.76 (m, 1H), 7.72–7.68 (m,
1H), 5.23–5.12 (m, 2H), 3.64–3.60 (m, 1H), 3.45–3.40 (m, 2H),
3.35–3.37 (m, 1H), 3.10–2.88 (m, 2H), 2.10–1.99 (m, 2H), 1.78–
1.74 (m, 1H), 1.60–1.57 (m, 1H). 13C-NMR (75 MHz, CD3OD)
d 201.5, 160.6, 151.3, 143.4, 137.3, 130.3, 128.4, 124.4, 121.9,
68.3, 58.1, 56.3, 45.0, 40.1, 31.7, 21.5. HRMS (ESI+): calcd for
C16H20N3O3 (M+H+): 302.1504, found: 302.1505. Analytical data
of both natural products were in accordance with those reported in
literature.6
To a solution of 24 (59 mg, 0.14 mmol) in a mixture of THF
(0.9 mL) and H2O (1.7 mL) were added OsO4 (2 mol%, 17 mL of a
solution of 4 wt% in H2O) and NaIO4 (73 mg, 0.34 mmol). After
stirring for 2 h, the reaction was quenched with saturated aqueous
NaHCO3 (4 mL), and extracted with CH2Cl2 (3 ¥ 10 mL). The
combined organic layers were dried over Na2SO4, concentrated
in vacuo and dissolved in methanol. Pd/C (7.5 mg, 0.07 mmol)
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and 1M aqueous HCl (154 mL) were added and the solution was
stirred under H2 (1 atm) for 2 h. The reaction mixture was filtered
over Celite and the solvent was evaporated under reduced pressure
and F. J. McEvoy, J. Org. Chem., 1955, 20, 136; (d) B. R. Baker, F. J.
McEvoy, R. E. Schaub, J. P. Joseph and J. H. Williams, J. Org. Chem.,
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5 (a) D. F. Barringer, G. Berkelhammer, S. D. Carter, L. Goldman and
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Berkelhammer and R. S. Wayne, J. Org. Chem., 1973, 38, 1937.
6 S. Kobayashi, M. Ueno, R. Suzuki, H. Ishitani, H. S. Kim and Y.
Wataya, J. Org. Chem., 1999, 64, 6833.
7 For examples of synthesis of febrifugine and analogues, see: (a) Y.
Takeuchi, H. Abe and T. Harayama, Synthesis, 1999, 1814; (b) Y.
Taniguchi and K. Ogasawara, Org. Lett., 2000, 2, 3193; (c) H. Ooi, A.
Urushibara, T. Esumi, Y. Iwauchi and S. Hatakeyama, Org. Lett., 2001,
3, 953; (d) O. Okitsu, R. Suzuki and S. Kobayashi, J. Org. Chem., 2001,
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Synthesis, 2008, 3081–3087.
20
to afford product (-)-1·2HCl (32 mg, 0.11 mmol, 76%). [a]D -11
(c 0.31, H2O). 1H-NMR (400 MHz, CD3OD) d 8.92 (s, 1H), 8.31–
8.29 (m, 1H), 7.99–7.97 (m, 1H), 7.79–7.77 (m, 1H), 7.74–7.71 (m,
1H), 5.25–5.14 (m, 2H), 3.67–3.62 (m, 1H), 3.49–3.40 (m, 2H),
3.35–3.37 (m, 1H), 3.11–2.97 (m, 2H), 2.10–1.99 (m, 2H), 1.78–
1.74 (m, 1H), 1.60–1.57 (m, 1H). 13C-NMR (75 MHz, D2O) d
202.4, 161.7, 149.3, 143.5, 136.9, 129.7, 127.2, 124.5, 120.6, 67.8,
56.7, 56.0, 44.4, 39.3, 30.5, 20.5 Spectral data are in accordance
with (+)-febrifugine (1).6
Acknowledgements
This research was performed as part of the Program Integration
of Biosynthesis & Organic Synthesis (IBOS) of ACTS–NWO. C.
van den Broek (DSM Pharma Chemicals) is kindly acknowledged
for assistance with the large scale HNL experiments.
8 (a) Y. Takaya, H. Tasaka, T. Chiba, K. Uwai, M. A. Tanitsu, H. S.
Kim, Y. Wataya, M. Miura, M. Takeshita and Y. J. Oshima, J. Med.
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2980 | Org. Biomol. Chem., 2009, 7, 2976–2980
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