Practical formal total synthesis of (rac)- and (S)-camptothecin

Article abstract of DOI:10.1039/b514147h

A practical, efficient and scalable formal total synthesis of (rac)- and (S)-camptothecin is described, which proceeds via the known DE ring building blocks 19 and (S)-19, respectively. The racemic synthesis starts from diethyl oxalate and uses straightforward carbonyl chemistry in order to generate the pyridone ring system. 19 was formed in 8.4% overall yield over 9 linear steps avoiding any chromatographic purification. The asymmetric version of this approach encompassed a diastereoselective Grignard addition to the enantiomerically pure α-ketoester 30 in order to generate the (S)-configured quaternary stereocenter. The auxiliary could be recycled in high yield and was successfully reused multiple times. The final steps paralleled the racemic approach. (S)-19 was thus prepared in 9.4% overall yield (er = 95: 5) over 10 steps. The Royal Society of Chemistry 2006.

Full text of DOI:10.1039/b514147h

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PAPER
www.rsc.org/obc | Organic & Biomolecular Chemistry
Practical formal total synthesis of (rac)- and (S)-camptothecin
Rene´ Peters,*† Martin Althaus and Anne-Laure Nagy
Received 10th October 2005, Accepted 21st November 2005
First published as an Advance Article on the web 22nd December 2005
DOI: 10.1039/b514147h
A practical, efficient and scalable formal total synthesis of (rac)- and (S)-camptothecin is described,
which proceeds via the known DE ring building blocks 19 and (S)-19, respectively. The racemic
synthesis starts from diethyl oxalate and uses straightforward carbonyl chemistry in order to generate
the pyridone ring system. 19 was formed in 8.4% overall yield over 9 linear steps avoiding any
chromatographic purification. The asymmetric version of this approach encompassed a
diastereoselective Grignard addition to the enantiomerically pure a-ketoester 30 in order to generate
the (S)-configured quaternary stereocenter. The auxiliary could be recycled in high yield and was
successfully reused multiple times. The final steps paralleled the racemic approach. (S)-19 was thus
prepared in 9.4% overall yield (er = 95 : 5) over 10 steps.
step using the tricyclic ketone 3 (CDE ring) had been demonstrated
Introduction
before.3 This concept would have required a chemoselective
lactone reduction of the tricyclic key intermediate 4.
The alkaloid camptothecin (CPT, 1), which was isolated for
the first time in 1958 by Wani and Wall from the Chinese tree
Camptotheca accuminata,1 shows potent antiproliferative activity
and continues to serve as a very attractive and promising lead
structure for the development of new anti-cancer drugs.2
Despite various efforts, all attempts toward this goal remained
fruitless mainly due to preferential reduction of the pyridone
ring system of 4 (Scheme 2) in preference to the lactone moiety.
This unexpected selectivity might be explained by the partial
acyliminium character of 4 expressed by the mesomeric formula
4a shown in Scheme 2.4 However, due to the novelty of the
pyridone formation reaction, this approach will be briefly
described: inexpensive b-ketoester 7 was first hydroxylated at the
a-position by air furnishing tertiary alcohol 6,5 which underwent
a tandem Knoevenagel condensation/lactonization reaction
with diethyl malonate giving access to a,b-unsaturated c-lactone
5. Bromination of the allylic methyl group and subsequent
nucleophilic displacement by thioamide 9 yielded the crystalline
hydrobromide salt 10 serving as starting material for a tandem
vinylogous sulfide contraction reaction/d-lactam formation
providing 11 thus representing a novel reaction for pyridone
formation.
After screening of various bases, phosphines, phosphites,
stoichiometries and solvents for this transformation, the combi-
nation pentamethylpiperidine (1.1 eq.), triethylphosphite (1.1 eq.)
and DMF was found to work very efficiently.6 This step is
practical, since the crude reaction product (ratio of regioisomers:
11/15 = 6.7 : 1) can be easily purified by product precipitation
from EtOAc/hexane (isolated yield of the desired regioisomer 11:
64%) thus removing the undesired regioisomer 15, side products,
Despite exhaustive attempts to develop efficient syntheses of
camptothecin and derivatives thereof, there is from a technical
point of view still no practical synthesis available.2 The currently
known synthetic approaches suffer either from very low yields
(undue waste generation), expensive or commercially not available
reagents (cost and time factor), or highly toxic reagents (health
hazard and environmental problems) and in most cases the
extensive need for column chromatography.
The overall goal of this work was to develop a scalable and
practical synthesis of camptothecin due to the importance of CPT
derivatives in anti-cancer therapy. We will first briefly describe a
route which at the end failed, but which provided important infor-
mation to develop a racemic and finally an asymmetric approach.
Results and discussion
=
unreacted starting material 10, DMF and S P(OEt)3, which is
formed during the desulfurization.
Initial attempts
The mechanism of this reaction is assumed to be related to
the alkylative Eschenmoser sulfide contraction reaction7 and is
initiated by deprotonation of the CH2S carbon atom in 10, which
is triply activated by the ester, the lactone and the iminothioether
moiety (Scheme 3). The carbanion 16 thus formed apparently
attacks the imino group resulting in a subsequent d-lactam
formation. The generated tetracyclic episulfide 17 is desulfurized
by the phosphite reagent giving rise to pyridone 11. The undesired
regioisomer is formed by intramolecular attack of the carbanion
Our initial plan was based on the retrosynthetic analysis shown in
Scheme 1. The utility of the Friedla¨nder condensation in the final
F. Hoffmann-La Roche Ltd, Pharmaceuticals Division, Safety and Technical
Sciences, Synthesis and Process Research, Grenzacherstr. 124, CH-4070
Basel, Switzerland. E-mail: peters@org.chem.ethz.ch
† Current address: ETH Zu¨rich, Laboratory of Organic Chemistry,
Wolfgang-Pauli-Str. 10, Ho¨nggerberg HCI E111, CH-8093 Zu¨rich,
Switzerland.
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Scheme 1
Scheme 2
16 at the imino group and a subsequent nucleophilic attack of the
negatively charged N atom at the sterically more hindered ester
group.
in which the pyridone nitrogen is not alkylated thus allowing for
deprotonation during the treatment with a hydride reducing agent
thereby significantly deactivating the pyridone system toward
reduction. The retrosynthetic strategy is depicted in Scheme 4
and is based on the coupling of DE fragment 19 with quinoline
derivative 18 via a Mitsunobu alkylation and a subsequent Heck
cyclization. This coupling strategy was previously established by
Comins et al. for the total synthesis of (S)-CPT.8
Synthesis of the racemic DE ring building block: a formal total
synthesis of (rac)-CPT
Our synthetic route started from diethyl oxalate 23 used to
prepare a-ketoamide 25 over two steps via a known procedure
In anticipation to overcome the selectivity problem in the reduc-
tion of pyridone 11, we sought access to pyridone intermediate 20,
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dimethyl acetal (DMFMDA) in DMF furnishing enamine 27,
which is a push–pull electron system. The amino residue can thus
be easily replaced by a nucleophile like ammonia. Treatment of
crude 27 with NH4OAc in DMF at 80 ◦C gave direct access to pyri-
done 20, which was obtained from 22 in 53% yield over four steps
after purification by trituration. The chemoselective reduction of
the lactone ring to diol 28 was accomplished by a modification
of a protocol previously reported by Ciufolini et al.12 The NaBH4
reduction of 20 required Lewis acid activation by CeCl3 and the use
of excess NaBH4. Since the reduction did not run to completion
even under these forcing conditions, the remaining 2 to 5% of
both lactol diastereomers still contained in the crude product,
were efficiently removed by trituration with DCM/TBME (2 : 1).
Without CeCl3, the reaction proceeded very sluggishly and
resulted largely in decomposition of starting material 20. Other
reducing reagents such as LiBH4/EuCl3, CaBH4 or K-Selectride
gave complex product mixtures.
While the subsequent acid promoted cyclization giving rise to
the a-hydroxylactone system 19 was remarkably efficient already
at room temperature using various mineral acids like conc. HCl,
HBr or sulfuric acid, product isolation by aqueous workup (acidic,
neutral or basic) was hampered by severe decomposition. Using
acidic ion exchange resins such as amberlyst 15 did not efficiently
solve this problem, since the product was strongly absorbed on
the polymer and large amounts of MeOH were required to elute
19, which was isolated with low purity (1H-NMR). The best
conditions found involved treatment of 28 with 10 eq. concentrated
HCl in DME at room temperature. After disappearance of the
starting material (HPLC monitoring), the mixture was evaporated
to dryness. The diethylammonium chloride salt side product was
finally removed by trituration with MeOH furnishing racemic DE
fragment 19 in nearly quantitative yield and in 8.4% overall yield
from 22 over 9 steps without any chromatographic purification.
Scheme 3
(Scheme 5).9 (E/Z)-1-Methyl-1-propenylmagnesium bromide was
subsequently added to 25 at low temperature in THF. This
Grignard addition suffers from competing enolate formation thus
decreasing the conversion and explaining the low yield of 46% after
high vacuum distillation.10 Oxidative cleavage of the C C double
=
bond of 26 smoothly furnished a-hydroxy-b-keto amide 22.11
Despite steric hindrance, the ketone functionality in 22 is rather re-
active toward nucleophiles due to activation by the a-hydroxy moi-
ety. It was thus possible to apply crude 22 to a tandem Knoevenagel
condensation/lactonization reaction providing a,b-unsaturated c-
lactone 21, representing a vinylogous malonate. The reasonably
acidic allylic b-methyl group therefore allows for a condensation
reaction with tris(dimethylamino)methane or dimethylformamide
Synthesis of the optically active DE ring key building block for the
preparation of (S)-camptothecin
An asymmetric version relying on the racemic approach described
above required the stereoselective access to (S)-22 (Scheme 6) for
Scheme 4
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Scheme 5
which an auxiliary based approach was found. According to the
literature, enantiomerically pure a-ketoester 30 was prepared from
2-oxobutyric acid 29 and (−)-8-phenylmenthol 31.13 The stereo
determining step entailed a diastereoselective Grignard addition to
30 using isopropenylmagnesium bromide (dr = 93 : 7, 1H-NMR).14
Cleavage of the auxiliary using aqueous LiOH in MeOH/THF
required heating in an autoclave to 110 ◦C in order to obtain full
conversion after 24 h resulting in a clean hydrolysis. Separation of
the resulting carboxylic acid 33 and the auxiliary 31 became feasi-
ble by pH-controlled extraction thus allowing a facile recycling of
the rather expensive chiral auxiliary, which was successfully reused
multiple times. The subsequent diethylamide formation procedure
was based on a protocol developed by Merck Process Research
for the formation of related a-hydroxy pyrrolidine amides.15 In
contrast to the Merck procedure, the amide formation required in
our case a deprotonation of the carboxylic acid moiety by a tertiary
amine like ethyldiisopropylamine (Hu¨nig’s base) prior to exposure
to thionyl chloride (er of 34: 93 : 7). To avoid massive decompo-
sition, the secondary amine had to be added slowly by a syringe
pump over 1 h. All attempts to prepare diethylamide 34 directly
from 32 were unsuccessful owing to the low reactivity of ester 32
presumably due to steric hindrance, which also prevented transes-
terification reactions. 34 was purified by column chromatography,
since amide formation resulted in formation of various unidenti-
formation [trituration of crude (S)-20 with TBME, er: 93 : 7]
paralleled the racemic approach described above. The subsequent
reduction furnishing (S)-28 proceeded significantly faster than
in the racemic series. The hydrolysis of the initially formed
product—boron complex—was, however, significantly slower for
the optically active material. Due to the higher purity and also
due to the higher solubility of (S)-28 as compared to (rac)-28, the
crude product was not purified by trituration prior to the d-lactone
formation. The trituration procedure, which was used to purify the
racemic DE fragment, was not directly applicable to (S)-19, since
the racemate is much less soluble in MeOH than the optically
active form.17 The diethylammonium chloride side product was
finally removed by column chromatography (CHCl3/MeOH = 10 :
1). (S)-19 was thus prepared in 9.4% overall yield over 10 steps
(er = 95 : 5) requiring only two chromatographic purifications.
Conclusion
A novel, efficient and scalable approach toward (rac)-19, which is
the DE ring key building block for the synthesis of camptothecin
derivatives, is described. This synthesis uses straightforward
carbonyl chemistry in order to generate the pyridone ring system.
DE fragment 19 was formed in 8.4% overall yield over 9 linear
steps avoiding any chromatographic purification.
The asymmetric version of this approach leading to (S)-
19 encompassed a diastereoselective Grignard addition to the
enantiomerically pure a-ketoester 30 in order to generate the
fied side products.16 Ozonolytic C C double bond cleavage then
=
gave access to optically active a-hydroxy-b-keto amide (S)-22.
The following steps [tandem Knoevenagel condensation/c-lactone
formation (er of (S)-21: 94 : 6], enamine formation and pyridone
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Scheme 6
(S)-configured tetrasubstituted carbon. The final steps paralleled
Syntheses
the racemic approach. (S)-19 was thus prepared in 9.4% overall
yield (er = 95 : 5) over 10 steps including two chromatographic
purifications. This synthesis should provide a good basis for
further process development.
In addition, an unprecedented novel pyridone forming reaction
via a tandem vinylogous sulfide contraction reaction/d-lactam
formation was established.
2-Ethyl-2-hydroxy-3-oxo-butyric acid ethyl ester (6). To a
solution of ethyl 2-ethylacetoacetate (7, 25.00 g, 142.2 mmol) in
DMF (250 mL) was added at room temperature Cs2CO3 (4.656 g,
14.22 mmol, 0.1 eq.). Subsequently, O2 was bubbled through
the solution and the reaction was monitored by HPLC. After
three days, the reaction was quenched by addition of water
(750 mL) and the pH was adjusted to 5 by dropwise addition
of conc. aqueous HCl at 0 ◦C. The mixture was extracted with
ethyl acetate (3 × 500 mL). The combined organic phases were
washed with water (7 × 250 mL), saturated aqueous NaHCO3
(250 mL), brine (250 mL) and were afterwards dried over sodium
sulfate (50 g, 30 min) and filtered. The filter cake was washed
with 100 mL ethyl acetate. After evaporation of the solvent in a
rotary evaporator (50 ◦C, 5 mbar), the crude product (22.08 g,
89% by weight) was obtained as an orange liquid, which was
purified by column chromatography with hexane/ethyl acetate
(9 : 1) furnishing product 6 (12.76 g, 73.25 mmol, 51% by
Experimental
Unless otherwise noted, solvents and reagents were used as is. All
reactions were carried out under an argon atmosphere in oven-
dried glassware. Thin-layer chromatography (TLC) was performed
on silica gel 60 F254 plates, 0.25 mm (Merck). Qualitative HPLC
was performed on a Hewlett-Packard Series 1050 system with UV
detection at a wavelength of 210 nm using Chromolith Perfor-
mance columns (100 × 4.6 mm) with gradient eluent H2O/MeCN
1
weight) as a yellow liquid. H NMR (300 MHz, CDCl3): d 4.26
1
=
containing 10% of a phosphate buffer at pH 3.0. H NMR were
(2H, m, OCH2), 4.13 (1H, s, OH), 2.28 (3H, s, MeC O), 2.35
recorded using CDCl3 as a reference peak. Spectra are given in
ppm (d) and coupling constants J are reported in Hz. Peaks in the
IR spectra are reported in cm−1. Low resolution electron impact
mass spectra (EI-MS) were obtained at an ionization voltage of
70 eV. Data are reported in the form of m/z (intensity relative to
base = 100).
(1H, dq, J = 14.3, J = 7.4, CCHHCH3), 2.00 (1H, dq, J =
14.3, J = 7.4, CCHHCH3), 1.30 (3H, t, J = 7.1, OCH2CH3),
0.88 (3H, t, J = 7.4, CCH2CH3) ppm; 13C NMR (100 MHz,
=
=
CDCl3): d 204.5 (MeC O), 170.4 (OC O), 84.0 (COH), 62.0
=
(OCH2), 27.8 (CCH2CH3), 24.1 (H3CC O), 13.5 (OCH2CH3),
6.8 (CCH2CH3) ppm; IR (MIR) 3475, 2983, 1740, 1720, 1249,
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1198, 1156, 1097 cm−1; MS (EI) m/z (rel. intensity) 175 (8), 157
(5), 132 (100), 104 (32), 89 (16), 57 (66); HRMS (ESI POS) calcd
for C8H14O4Na (MNa+) 197.0790, found 197.0788; Anal. Calcd
for C8H14O4: C, 55.2; H, 8.1. Found: C, 55.0; H, 7.8%.
C13H17BrO6Na (MNa+) 371.0106, found 371.0107; Anal. Calcd
for C13H18BrO6: C, 44.7; H, 4.9. Found: C, 44.7; H, 4.8%.
3-(4,5-Dihydro-3H-pyrrol-2-ylsulfanylmethyl)-2-ethyl-5-oxo-2,5-
dihydro-furan-2,4-dicarboxylic acid diethyl ester hydrogen bromide
salt (10). To a clear yellow solution of 8 (39.85 g, 114.1 mmol)
in toluene (390 mL) was added 9 (11.54 g, 114.1 mmol) at room
temperature. After 5 min, the product started to precipitate.
The suspension was stirred overnight and the solid was finally
collected by filtration. The filter cake was washed with toluene
(50 mL) furnishing product 10 as white crystals (48.29 g, 94%
by weight). Mp: 127 ◦C (decomp., gas evolution); 1H NMR
(300 MHz, CDCl3): d 14.31 (1H, br. s, NH), 5.24 (1H, d, J =
12.8, CHHS), 5.03 (1H, d, J = 12.8, CHHS), 4.39 (2H, q,
J = 7.2, OCH2), 4.24 (4H, m, OCH2 & NCH2), 3.15 (2H, m,
2-Ethyl-3-methyl-5-oxo-2,5-dihydro-furan-2,4-dicarboxylic acid
diethyl ester (5). To a solution of 6 (10.50 g, 60.28 mmol) in
THF (200 mL) was added diethyl malonate (9.63 mL, 61.49 mmol,
1.02 eq.) and subsequently portionwise NaH (2.46 g, 61.49 mmol,
1.02 eq.). The reaction was monitored by HPLC. After 4 h,
the mixture was cooled to 0 ◦C and saturated aqueous NH4Cl
(200 mL) was added. THF (180 mL) was subsequently removed
in a rotary evaporator (50 ◦C, 5 mbar) and ethyl acetate (200 mL)
was added. The organic phase was washed with brine (200 mL)
and was thereafter dried over sodium sulfate (15 g, 30 min) and
filtered. The filter cake was washed with ethyl acetate (30 mL).
After evaporation of solvent in a rotary evaporator (50 ◦C,
5 mbar), the crude product (17.00 g, 104% by weight) was obtained
as a yellow liquid, which was purified by column chromatography
with hexane/ethyl acetate (4 : 1) furnishing product 5 (11.67 g,
43.18 mmol, 72% by weight) as a yellow liquid. 1H NMR
(300 MHz, CDCl3): d 4.36 (2H, q, J = 7.1, OCH2), 4.24 (2H,
m, OCH2), 2.37 (3H, s, Me), 2.34 (1H, dq, J = 14.7, J = 7.4,
CCHHCH3), 1.96 (1H, dq, J = 14.7, J = 7.4, CCHHCH3), 1.38
(3H, t, J = 7.1, OCH2CH3), 1.28 (3H, t, J = 7.0, OCH2CH3),
0.90 (3H, t, J = 7.4, CCH2CH3) ppm; 13C NMR (100 MHz,
=
N CCH2), 2.52 (1H, dq, J = 14.9, J = 7.4, CCHHCH3), 2.37
(3H, m, CCHHCH3 & CH2CH2CH2), 1.39 (3H, t, J = 7.2,
OCH2CH3), 1.31 (3H, t, J = 7.2, OCH2CH3), 0.92 (3H, t, J =
7.4, CCH2CH3) ppm; 13C NMR (100 MHz, CDCl3): d 187.5
=
=
=
=
(N C), 167.4 (C CCH2S), 166.8 (OC O), 165.0 (OC O), 160.3
=
=
(OC O), 124.5 (C CCH3), 89.3 (CCH2CH3), 63.6 (OCH2),
=
=
62.7 (OCH2), 54.3 (NCH2), 38.8 (N CCH2), 30.6 (C CCH2S),
27.8 (CCH2CH3), 21.3 (NCH2CH2), 14.1 (OCH2CH3), 14.1
(OCH2CH3), 7.4 (CCH2CH3) ppm; IR (Nujol) 2923, 2712, 1783,
1757, 1736, 1712, 1606, 1231 cm−1; MS (ESI) m/z 392.2 (MNa+ −
HBr); Anal. Calcd for C17H24BrNO6S: C, 45.3; H, 5.4; N, 3.1.
Found: C, 45.1; H, 5.25; N, 3.4%.
=
=
=
CDCl3): d 173.4 (C CCH3), 167.2 (OC O), 167.1 (OC O), 161.1
=
=
(OC O), 120.5 (C CCH3), 89.6 (CCH2CH3), 63.0 (OCH2), 61.6
(OCH2), 27.4 (CCH2CH3), 14.2 (OCH2CH3), 14.0 (OCH2CH3),
1-Ethyl-3,4-dioxo-4,6,7,8-tetrahydro-1H,3H-furo[3,4-f ]indolizine-
1-carboxylic acid ethyl ester (11). To a solution of 10 (12.00 g,
26.65 mmol) in DMF (240 mL) was rapidly added triethylphos-
phite (5.26 mL, 29.32 mmol, 1.10 eq.) at room temperature.
Subsequently, 1,2,2,6,6-pentamethylpiperidine (5.35 mL,
29.32 mmol, 1.10 eq.) was added dropwise (addition time 5 min).
After the addition of 4 mL, the color of the solution changed
from yellow to orange. The reaction was allowed to stir overnight.
After 18 h, the dark greenish-brown solution was poured onto
dichloromethane (1.5 L) and was washed with aqueous HCl
(750 mL, 0.5 M) and with water (5 × 1 L). The organic phase was
dried over sodium sulfate (50 g, 30 min) and filtered. The filter cake
was washed with dichloromethane (100 mL). The organic phase
was evaporated to dryness in a rotary evaporator (50 ◦C, 1 mbar).
The crude product was obtained as a brown oil (14.02 g, 181%
by weight, regioselectivity: 6.7 : 1). The residue was dissolved in
ethyl acetate (280 mL) at reflux temperature (oil bath temperature
100 ◦C). Hexane (433 mL) was added to the heated solution
resulting in the formation of a few crystals. The mixture was
allowedtoslowly cool toroom temperature overnight andwas then
kept in a freezer at −22 ◦C for 3 days. The crystals were collected
by filtration and washed with 30 mL hexane furnishing product
11 (4.99 g, 17.13 mmol, 64% by weight, regioselectivity >50 :
=
13.4 (C CCH3), 7.2 (CCH2CH3) ppm; IR (MIR) 2981, 1780,
1733, 1718, 1239, 1037 cm−1; MS (EI) m/z (rel. intensity) 271 (6),
214 (18), 197 (15), 168 (18), 152 (100), 151 (57); HRMS (ESI POS)
calcd for C13H18O6Na (MNa+) 293.1001, found 293.1001; Anal.
Calcd for C13H18O6: C, 57.8; H, 6.7. Found: C, 57.5; H, 6.6%.
3-Bromomethyl-2-ethyl-5-oxo-2,5-dihydro-furan-2,4-dicarboxylic
acid diethyl ester (8). To a clear yellow solution of 5 (5.000 g,
18.50 mmol) in tetrachlorocarbon (75 mL) was added bromine
(975 lL, 18.87 mmol, 1.02 eq.) at room temperature. The
solution was heated to reflux and the reaction was monitored
by HPLC. After 37 h, additional bromine (300 lL, 5.809 mmol,
0.314 eq.) was added. After refluxing overnight, the reaction
mixture was cooled to room temperature and was then evaporated
to dryness in a rotary evaporator (40 ◦C, 10 mbar). The crude
product was obtained as an orange oil (7.24 g, 112% by weight),
which was purified by column chromatography with hexane/ethyl
acetate (4 : 1) furnishing product 8 (5.258 g, 15.06 mmol, 81%
by weight as violet crystals. 1H NMR (300 MHz, CDCl3): d 4.54
(1H, d, J = 10.0, CHHBr), 4.51 (1H, d, J = 10.0, CHHBr), 4.42
(2H, q, J = 7.1, OCH2), 4.27 (2H, m, OCH2), 2.45 (1H, dq, J =
14.6, J = 7.2, CCHHCH3), 2.05 (1H, dq, J = 14.6, J = 7.2,
CCHHCH3), 1.41 (3H, t, J = 7.1, OCH2CH3), 1.31 (3H, t, J =
7.1, OCH2CH3), 0.98 (3H, t, J = 7.2, CCH2CH3) ppm; 13C NMR
◦
1
1) as slightly yellow crystals. Mp: 146 C; H NMR (300 MHz,
=
CDCl3): d 6.36 (1H, s, C CH), 4.22 (4H, m, OCH2 & CH2N),
=
=
=
(100 MHz, CDCl3): d 166.8 (C CCH2Br), 164.7 (OC O), 164.1
3.21 (2H, t, J = 7.8, C CCH2), 2.32 (3H, m, CCHHCH3
&
=
=
=
(OC O), 158.0 (OC O), 120.7 (C CCH3), 86.8 (CCH2CH3),
CH2CH2CH2), 2.00 (1H, dq, J = 14.5, J = 7.3, CCHHCH3), 1.28
=
61.4 (OCH2), 60.3 (OCH2), 26.5 (CCH2CH3), 15.9 (C CCH2Br),
(3H, t, J = 7.2, OCH2CH3), 0.92 (3H, t, J = 7.4, CCH2CH3) ppm;
13
=
=
12.1 (OCH2CH3), 12.0 (OCH2CH3), 5.8 (CCH2CH3) ppm; IR
(MIR) 2983, 1784, 1730, 1239, 1041 cm−1; MS (EI) m/z (rel.
intensity) 351 (20), 349 (20), 277 (16), 275 (17), 232 (25), 231 (25),
230 (21), 229 (21), 197 (30), 151 (100); HRMS (ESI POS) calcd for
C NMR (100 MHz, CDCl3): d 168.1 (OC O), 166.4 (OC O),
=
=
=
=
165.6 (O CC C), 159.9 (NC CH), 156.3 (NC O), 110.3
(O CC C), 95.2 (NC CH), 85.9 (CCH2CH3), 62.8 (OCH2),
49.0 (NCH2), 32.9 (NCCH2), 29.8 (CCH2CH3), 21.3 (NCH2CH2),
=
=
=
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14.0 (OCH2CH3), 7.6 (CCH2CH3) ppm; IR (Nujol) 2923, 1776,
1750, 1667, 1586, 1554, 1230 cm−1; MS (EI) m/z (rel. intensity)
291 (6), 218 (100); HRMS (ESI POS) calcd for C15H17NO5Na
(MNa+) 314.1004, found 314.1004; Anal. Calcd for C15H17NO5:
C, 61.85; H, 5.9; N, 4.8. Found: C, 61.6; H, 6.0; N, 4.8%.
10 mbar). The crude product was obtained as a slightly brown solid
(122.5 g, 206% by weight), which was stirred with dichloromethane
(400 mL) at room temperature. The mixture was filtered and the
filter cake was washed with dichloromethane (2 × 60 mL). The
◦
filtrate was evaporated to dryness in a rotary evaporator (40 C,
10 mbar) providing a beige solid (95.0 g, 160% by weight), which
was stirred with toluene (150 mL) under reflux conditions. The hot
mixture was filtered and the filtrate was evaporated to ca. 75 mL in
a rotary evaporator (50 ◦C, 10 mbar) and was then allowed to stand
overnight at 0 ◦C. The mixture was filtered and the crystals were
washed with toluene (2 × 20 mL) furnishing product 9 as white
crystals (28.1 g, 47% by weight). 1H NMR (300 MHz, CHCl3): d
8.43 (1H, br. s, NH), 3.67 (2H, t, J = 10.0, CH2N), 2.92 (2H, t, J =
11-Ethyl-1-(pyrrolidine-1-carbonyl)-7,8-dihydro-1H,6H-furo[3,4-
f ]indolizine-3,4-dione (4). To a solution of pyrrolidine (1.22 mL,
13.90 mmol, 4.05 eq.) in dichloromethane (4.8 mL)
trimethylaluminium (6.95 mL, 14.75 mmol, 4.30 eq.) was added
dropwise at 0 ◦C. The cooling bath was then removed and stirring
was continued for 2.5 h at room temperature. Subsequently,
a solution of 11 (1.000 g, 3.433 mmol) in dichloromethane
(6.4 mL) was added dropwise (addition time 5 min) and the clear
solution was heated for 1.5 h to 50 ◦C and then for 24 h to 55 ◦C
(reaction control by HPLC). The reaction mixture was allowed
to cool to room temperature and was poured on aqueous HCl
(80 mL, 1.0 M). The biphasic system was vigorously stirred for
4 h at room temperature. The aqueous phase was extracted with
dichloromethane (3 × 50 mL). The combined organic phases were
dried over sodium sulfate (15 g, 30 min) and filtered. The filter
cake was washed with dichloromethane (30 mL). The organic
=
10.0, S CCH2), 2.23 (2H, pent, J = 10.0, CH2CH2CH2) ppm.
N,N-Diethyl-oxalamic acid ethyl ester (24)9. To diethyl oxalate
(23, 30.00 g, 203.2 mmol) diethylamine (42.2 mL, 406.4 mmol,
2.0 eq.) was added at room temperature. The colorless clear
solution was heated to reflux (oil bath temperature: 90 ◦C) and
the reaction was monitored by HPLC. After 2.5 h, the resulting
yellow-orange liquid was cooled to room temperature and all
volatile compounds (ethanol, diethylamine) were removed in a
rotary evaporator (50 ◦C, 10 mbar) furnishing the crude product
(35.073 g, 100% by weight) as a yellow liquid. Purification was
achieved using a high vacuum distillation (bp 85 ◦C at 0.08 mbar,
◦
phase was evaporated to dryness in a rotary evaporator (40 C,
10 mbar). The crude product was obtained as a yellow foam
(1.058 g, 97% by weight), which was dissolved in ethyl acetate
(20 mL) at reflux temperature (oil bath temperature 100 ◦C).
Hexane (5 mL) was added to the heated solution. The mixture was
allowed to slowly cool to room temperature overnight. Additional
hexane (16 mL) was added at room temperature and stirring was
continued for 15 min. The crystals were collected by filtration and
washed with hexane (2 mL). The filtrate was afterward filtered
again. Product 4 (823.0 mg, 2.601 mm◦ol, 76% by weight) was
obtained as dark green crystals. Mp: 180 C; 1H NMR (300 MHz,
◦
oil bath temperature 111 C, 40 cm Vigreux column) furnishing
product 24 (30.216 g, 174.4 mmol, 86% by weight) as a colorless
liquid. 1H NMR (300 MHz, CDCl3): d 4.34 (2H, q, J = 7.1, OCH2),
3.43 (2H, q, J = 7.2, NCH2), 3.29 (2H, q, J = 7.2, NCH2), 1.37
(3H, t, J = 7.1, OCH2CH3), 1.23 (3H, t, J = 7.2, NCH2CH3), 1.19
(3H, t, J = 7.2, NCH2CH3) ppm.
N,N-Diethyl-2-oxo butyramide (25)9. A solution of ethyl mag-
nesium bromide in diethyl ether (3.0 M, 63.95 mL 191.8 mmol,
1.10 eq.) was diluted with diethyl ether (183 mL). The solution was
=
=
CDCl3): d 6.64 (1H, s, C CH), 4.22 (2H, m, CH2NC CH),
=
=
3.90 (1H, m, O CNCHH), 3.48 (3H, m, O CNCHH), 3.20
◦
cooled to −15 C and a solution of 24 (30.20 g, 174.4 mmol) in
=
(2H, t, J = 7.8, C CCH2), 2.40 (1H, dq, J = 14.2, J =
diethyl ether (60 mL) was added dropwise (addition time: 30 min).
The resulting viscous suspension was stirred for an additional
75 min at −15 ◦C. Subsequently, the reaction was quenched by
addition of acetic acid (14.96 mL, 261.6 mmol, 1.5 eq.). 5 min
later, water (35 mL) was added to dissolve all salts and the cooling
bath was removed. After 15 min, the mixture was washed with
pH-7-buffer (2 × 200 mL) and the organic phase was dried over
Na2SO4 (20 g, 30 min) and filtered. The filter cake was washed
with diethyl ether (40 mL). After evaporation of solvent in a rotary
evaporator (40 ◦C, 10 mbar), the crude product (26.33 g, 96% by
weight) was obtained as a yellow liquid. Purification was achieved
7.0, CCHHCH3), 2.28 (2H, pent, J = 7.5, NCH2CH2CH2C),
2.01 (1H, dq, J = 14.2, J = 7.0, CCHHCH3), 1.91 (2H, m,
NCH2CH2CH2CH2), 1.78 (2H, m, NCH2CH2CH2CH2), 0.89
(3H, t, J = 7.0, Me) ppm; 13C NMR (100 MHz, CDCl3):
=
=
=
=
d 166.4 (O CC C), 165.3 (OC O), 164.6 (C4H8NC O),
=
=
=
=
=
158.0 (NC CH), 155.1 (NC OC C), 108.7 (O CC C), 96.0
(NC CH), 86.7 (CCH2CH3), 47.5 (NCH2), 47.2 (NCH2), 46.6
=
(NCH2), 31.5 (NCCH2), 30.1 (CCH2CH3), 25.5 (NCH2CH2),
21.7 (NCH2CH2), 20.0 (NCH2CH2), 6.3 (CCH2CH3) ppm; IR
(Nujol) 2925, 2854, 1775, 1662, 1623, 1586, 1557, 1458, 1436,
1404, 1052, 804 cm−1; MS (EI) m/z (rel. intensity) 316 (68), 218
(88), 98 (100); HRMS (ESI POS) calcd for C17H21N2O4 (MH+)
317.1501, found 317.1501; Anal. Calcd for C15H17NO5: C, 64.5; H,
6.4; N, 8.9. Found: C, 64.3; H, 6.1; N, 8.9%.
◦
using a high vacuum distillation (bp 86 C at 2.5 mbar, oil bath
◦
temperature 110 C, 40 cm Vigreux column) furnishing product
25 (18.66 g, 118.7 mmol, 68% by weight) as a colourless liquid.
1H NMR (300 MHz, CDCl3): d 3.40 (2H, q, J = 7.1, NCH2), 3.25
2-Pyrrolidinethione (9). Thioamide 9 was produced according
to a modified literature procedure:18 to a suspension of P2S5
(213.2 g, 959.2 mmol, 1.63 eq.) in THF (3.0 L) Na2CO3 (59.77 g,
563.9 mmol, 0.96 eq.) was added at room temperature. The
mixture was stirred for 40 min at 60 ◦C. 2-Pyrrolidinone (50.00 g,
587.0 mmol) was then added and stirring was continued at 60 ◦C
for 19 h. The solid was removed by filtration and the filter cake was
washed with THF (200 mL) and dichloromethane (200 mL). The
=
(2H, q, J = 7.2, NCH2), 2.78 (2H, q, J = 7.3, O CCH2), 1.18
(3H, t, J = 7.2, Me), 1.16 (3H, t, J = 7.1, Me), 1.18 (3H, t, J =
7.3, Me) ppm.
2-Ethyl-2-hydroxy-3-methyl-pent-3-enoic acid diethylamide (26).
A solution of 1-methyl-1-propenyl magnesium bromide (500 mL,
250.0 mmol, 3.0 eq.) in THF was cooled to −78 ◦C prior to
slow addition of a precooled solution (−78 ◦C) of 25 (13.10 g,
83.2 mmol) in diisopropyl ether (260 mL) via canula (addition
◦
filtrate was evaporated to dryness in a rotary evaporator (40 C,
504 | Org. Biomol. Chem., 2006, 4, 498–509
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time: 10 min). After 60 min, saturated aqueous ammonium
chloride (250 mL) was added and the mixture was extracted with
dichloromethane (3 × 250 mL). The combined organic phases
were dried over sodium sulfate (25 g, 30 min) and filtered. The filter
cake was washed with dichloromethane (50 mL). After removal of
solvent in a rotary evaporator (40 ◦C, 10 mbar), the crude product
(18.05 g, 102% by weight) was obtained as a yellow liquid (E/Z =
5.3 : 1), which was purified by high vacuum distillation (bp 65 ◦C
at 0.28 mbar, oil bath temperature 110 ◦C, 40 cm Vigreux column)
furnishing product 26 (8.145 g, 38.18 mmol, 46%) as a light yellow
liquid in the form of E/Z isomers (E/Z = 5.1 : 1). An analytical
sample of the (E)-isomer was obtained by column chromatography
through the solution for 20 min. Dimethyl sulfide (2.21 mL,
200.7 mmol, 10.0 eq.) was subsequently added and the solution
was allowed to slowly warm to room temperature overnight (16 h
40 min). The mixture was washed with water (3 × 20 mL) and
the organic phase was dried over Na2SO4 (5 g, 30 min) and
filtered. The solid was washed with dichloromethane (10 mL).
After evaporation of solvent in a rotary evaporator (24 ◦C,
10 mbar), the product (S)-22 (587.3 mg, 98% by weight) was
obtained as a yellow oil. An analytical sample was obtained by
column chromatography (pentane/diethyl ether 3 : 1). [a]D20 (c = g
dL−1, CHCl3) = +77.1. The other analytical data are in accordance
with (rac)-22.
1
with hexane/ethyl acetate (4 : 1). H NMR (300 MHz, CDCl3):
=
d 5.68 (1H, q, J = 6.8, C CH), 5.28 (1H, s, OH), 3.40 (4H, m,
5-Diethylcarbamoyl-5-ethyl-4-methyl-2-oxo-2,5-dihydro-furan-3-
carboxylic acid ethyl ester (21). To a solution of 22 (2.500 g,
12.42 mmol) and diethyl malonate (9.73 mL, 62.10 mmol, 5.0 eq.)
in ethanol (100 mL), Cs2CO3 (16.27 g, 49.68 mmol, 4.0 eq.)
was added at room temperature. The reaction was monitored
NCH2), 1.96 (1H, dq, J = 13.8, J = 7.3, CCHHCH3), 1.87 (1H,
dq, J = 13.8, J = 7.3, CCHHCH3), 1.67 (3H, d, J = 6.8, CHCH3),
=
1.57 (3H, br. s, HC CCH3), 1.15 (3H, t, J = 6.8, NCH2CH3), 1.08
(3H, t, J = 6.9, NCH2CH3), 0.86 (3H, t, J = 7.3, CCH2CH3) ppm;
◦
13
=
C NMR (100 MHz, CDCl3) of the (E)-isomer: d 173.0 (NC O),
by HPLC. After 26 h, the yellow suspension was cooled to 0 C
=
=
137.7 (C CH), 120.1 (C CH), 78.5 (COH), 41.4 (NCH2), 41.2
and aqueous HCl (0.5 M, 200 mL, 65.25 mmol, 5.0 eq.) was
added dropwise over 60 min. Ethanol (95 mL) was subsequently
removed in a rotary evaporator (50 ◦C, 5 mbar) and, ethyl acetate
(200 mL) was added. The organic phase was washed with brine
(2 × 150 mL), and was afterwards dried over sodium sulfate
(20 g, 30 min) and then filtered. The filter cake was washed with
ethyl acetate (40 mL). After evaporation of the solvent in a rotary
evaporator (50 ◦C, 5 mbar), volatile components were removed
in a Kugelrohr apparatus (55 ◦C, 0.08 mbar). The crude product
(6.758 g, 183% by weight) was obtained as a yellow liquid. An
analytical sample was obtained by column chromatography
(hexane/ethyl acetate 9 : 1). 1H NMR (300 MHz, CDCl3): d 4.36
(2H, q, J = 7.1, OCH2), 3.58 (1H, m, NCHH), 3.12–3.48 (3H,
m, NCHH), 2.50 (3H, s, CCH3), 2.35 (1H, dq, J = 14.4, J = 7.3,
CCHHCH3), 2.00 (1H, dq, J = 14.4, J = 7.3, CCHHCH3), 1.38
(3H, t, J = 7.1, OCH2CH3), 1.21 (3H, m, NCH2CH3), 1.15 (3H,
m, NCH2CH3), 0.86 (3H, t, J = 7.3, CCH2CH3) ppm; 13C NMR
=
(NCH2), 28.1 (CCH2CH3), 13.5 (C CHCH3), 13.3 (NCH2CH3),
=
12.8 (HC CCH3), 12.4 (NCH2CH3), 8.0 (CCH2CH3) ppm; IR
(MIR) 3353, 2974, 1616, 1380, 1362, 1019 cm−1; MS (EI) m/z (rel.
intensity) 214 (5), 196 (23), 113 (100); HRMS (ESI POS) calcd for
C12H23NO2Na (MNa+) 236.1626, found 236.1629; Anal. Calcd for
C12H23NO2: C, 67.6; H, 10.9; N, 6.6. Found: C, 67.3; H, 10.9; N,
6.55%.
2-N,N -Triethyl-2-hydroxy-3-oxo-butyramide
(22). O3
(150 L h−1) was bubbled through a stirred solution of 26 (8.000 g,
37.50 mmol) in dichloromethane (400 mL) at −78 ◦C until a
blue colour appeared (after 18 min). Subsequently, argon was
bubbled through the solution for 10 min. Dimethyl sulfide (28 mL,
375 mmol, 10.0 eq.) was subsequently added and the solution
was allowed to slowly warm to room temperature overnight. The
mixture was washed with 750 mL water (3 × 250 mL). The organic
phase was dried over Na2SO4 (20 g, 30 min) and filtered. The solid
was washed with dichloromethane (40 mL). After evaporation
of solvent in a rotary evaporator (40 ◦C, 10 mbar), the crude
product (7.85 g, 104% by weight) was obtained as a yellow oil.
An analytical sample was obtained by column chromatography
=
=
(100 MHz, CDCl3): d 177.0 (C CCH3), 166.5 (OC O), 164.8
=
=
=
(NC O), 160.5 (OC O), 119.0 (C CCH3), 90.9 (CCH2CH3),
60.8 (OCH2), 42.2 (NCH2), 42.1 (NCH2), 29.1 (CCH2CH3),
=
14.5 (C CCH3), 13.8 (NCH2CH3), 13.4 (OCH2CH3), 11.8
(NCH2CH3), 6.5 (CCH2CH3) ppm; IR (MIR) 2977, 1777, 1718,
1632, 1320, 1241, 1212, 1035 cm−1; MS (EI) m/z (rel. intensity)
297 (1), 282 (2), 100 (100), 72 (21); HRMS (ESI POS) calcd
for C15H23NO5Na (MNa+) 320.1474, found 320.1472; Anal.
Calcd for C15H23NO5: C, 60.6; H, 7.8; N, 4.7. Found: C, 60.7;
H, 7.7; N, 4.6%.
1
(pentane/diethyl ether 10 : 1). H NMR (300 MHz, CDCl3): d
5.19 (1H, s, OH), 3.41 (2H, m, NCH2), 3.29 (2H, q, J = 7.0,
=
NCH2), 2.19 (3H, s, O CMe), 2.01 (1H, dq, J = 15.0, J = 7.4,
CCHHCH3), 1.96 (1H, dq, J = 15.0, J = 7.4, CCHHCH3), 1.15
(3H, t, J = 7.0, NCH2CH3), 1.12 (3H, t, J = 7.0, NCH2CH3),
0.83 (3H, t, J = 7.4, CCH2CH3) ppm; 13C NMR (100 MHz,
=
=
CDCl3): d 208.2 (MeC O), 170.2 (NC O), 84.8 (COH), 43.1
(S)-5-Diethylcarbamoyl-5-ethyl-4-methyl-2-oxo-2,5-dihydro-furan-
3-carboxylic acid ethyl ester ((S)-21). According to the
preparation of 21, a solution of (S)-22 (587.3 mg, 2.918 mmol)
and diethyl malonate (2.29 mL, 14.59 mmol, 5.0 eq.) in ethanol
(23 mL) was treated with Cs2CO3 (3.822 g, 11.67 mmol, 4.0 eq.)
yielding the crude product (1.224 g, 141% by weight) as a yellow
liquid (er = 94.15 : 5.85, chiral GC Method [carrier gas: H2,
110 kPa (split ratio 1/20), equipment: HP5890_1A, column: BGB-
=
(NCH2), 42.9 (NCH2), 28.9 (CCH2CH3), 26.1 (H3CC O), 15.0
(NCH2CH3), 13.6 (NCH2CH3), 8.6 (CCH2CH3) ppm; IR (film)
3314, 2978, 1719, 1632, 1466, 1384, 1211, 1136, 1084 cm−1; MS
(EI) m/z (rel. intensity) 202 (2), 158 (50), 100 (100); HRMS (ESI
POS) calcd for C10H20NO3 (MH+) 202.1443, found 202.1445%;
Anal. Calcd for C10H19NO3: C, 59.7; H, 9.5; N, 7.0. Found: C,
59.4; H, 9.3; N, 7.0%.
◦
(S)-2-N,N-Triethyl-2-hydroxy-3-oxo-butyramide ((S)-22). O3
(150 L h−1) was bubbled through a stirred solution of 34 (595.0 mg,
2.985 mmol) in dichloromethane (30 mL) at −78 ◦C until a blue
colour appeared (after 6 min). Subsequently, argon was bubbled
175, 30 m × 0.25 mm, temperature: 155 C (isotherm), injector
temperature: 200 ◦C, detector temperature: 220 ◦C, retention
time: 58.16 min (S)-21, 57.02 min (R)-21]). An analytical sample
was obtained by column chromatography (heptane/ethyl acetate
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7 : 3). [a]D (c = 1.025 g dL−1, CHCl3) = −134.8. The other
sulfate (20 g, 30 min) and filtered. The filter cake was washed
with dichloromethane (40 mL). After evaporation of the solvent
in a rotary evaporator (50 ◦C, 5 mbar), the crude product was
obtained as a red-brown liquid (10.632 g, 144% by weight), which
still contains DMF and which was directly used for the preparation
of 20 without further purification.
20
analytical data are in accordance with (rac)-21.
5-Diethylcarbamoyl-4-((E)-2-dimethylamino-vinyl)-5-ethyl-2-oxo-
2,5-dihydro-furan-3-carboxylic acid ethyl ester (27). To
a
solution of 21 (500.0 mg, 22.73 mmol) in DMF (3.0 mL),
tris(dimethylamino)methane (3.0 mL, 17.3 mmol, 10.3 eq.) was
added at room temperature. The color of the reaction mixture
changed from orange to brown to green. The reaction was
monitored by HPLC. After 17 h, the mixture was diluted with
dichloromethane (50 mL) and washed with aqueous HCl (25 mL,
1.0 M) and subsequently with brine (3 × 50 mL). The organic
phase was dried over sodium sulfate (2 g, 30 min) and filtered.
The filter cake was washed with dichloromethane (4 mL). After
evaporation of solvent in a rotary evaporator (50 ◦C, 5 mbar), the
crude product was obtained as an orange oil (627.0 mg, 106% by
weight), which was liberated from residual DMF in a high vacuum
rotary evaporator (50 ◦C, 0.5 mbar) yielding product 27 (536.0 mg,
1-Ethyl-3,4-dioxo-1,3,4,5-tetrahydro-furo[3,4-c]pyridine-1-car-
boxylic acid diethylamide (20). To a solution of crude 27
(10.63 g, 30.17 mmol) in DMF (85 mL), ammonium acetate
(23.7 g, 301.7 mmol, 10.0 eq.) was added at room temperature
resulting in the formation of a shiny red solution, which was
heated to 80 ◦C. The reaction was monitored by HPLC. After
19 h, the mixture was diluted with dichloromethane (150 mL) and
successively washed with water (130 mL), aqueous HCl (130 mL,
0.5 M) and subsequently with brine (3 × 130 mL). The organic
phase was dried over sodium sulfate (20 g, 30 min) and filtered.
The filter cake was washed with dichloromethane (40 mL). After
evaporation of solvent in a rotary evaporator (50 ◦C, 5 mbar),
the crude product was obtained as a red liquid (6.611 g, 79% by
weight). All volatile components were removed in a Kugelrohr
distillation apparatus. The residue was purified by trituration for
18 h at room temperature with heptane/TBME (1 : 1, 12 mL),
then with heptane/TBME (1 : 1, 8 mL) and finally with TBME
(10 mL) furnishing product 20 (1.797 g, 6.46 mmol, 21% by
weight (yield over 4 steps (26 → 20): 53%) as violet crystals.
◦
1
1.517 mmol, 90% by weight) as orange crystals. Mp: 105 C; H
NMR (300 MHz, CDCl3): d 7.97 (1H, br., NCH CH), 6.47 (1H,
=
=
br., NCH CH), 4.32 (2H, m, OCH2), 3.52 (1H, dq, J = 13.2,
J = 7.0, NCHH), 3.18 (3H, s, NCH3), 3.17 (2H, m, NCH2), 3.00
(3H, s, NCH3), 2.99 (1H, m, NCHH), 2.41 (1H, dq, J = 14.3, J =
7.2, CCHHCH3), 2.03 (1H, dq, J = 14.3, J = 7.2, CCHHCH3),
1.39 (3H, t, J = 7.1, OCH2CH3), 1.20 (3H, t, J = 7.0, NCH2CH3),
1.08 (3H, t, J = 7.0, NCH2CH3), 0.84 (3H, t, J = 7.2, CCH2CH3)
◦
1
13
Mp: 177 C; H NMR (300 MHz, CDCl3): d 13.03 (1H, br. s,
=
=
ppm; C NMR (100 MHz, CDCl3): d 171.8 (O CC C), 169.6
=
NH), 7.78 (1H, d, J = 6.6, HNCH CH), 6.93 (1H, d, J = 6.6,
=
=
=
=
(OC O), 168.0 (NC O), 164.4 (OC O), 154.3 (NCH CH),
=
HNCH CH), 3.94 (1H, dq, J = 13.8, J = 6.9, NCH2), 3.50 (1H,
=
=
=
99.3 (O CC C), 91.9 (NCH CH), 87.7 (CCH2CH3), 60.1
(OCH2), 45.7 (NMe), 43.0 (NCH2CH3), 42.4 (NCH2CH3), 36.8
(NMe), 34.6 (CCH2CH3), 14.4 (OCH2CH3), 14.0 (NCH2CH3),
12.3 (NCH2CH3), 7.3 (CCH2CH3) ppm; IR (MIR) 2973, 1745,
1677, 1630, 1613, 1541, 1393, 1177, 1024, 976 cm−1; MS (ESI)
m/z 353.3 (MH+); HRMS (ESI POS) calcd for C18H28N2O5 (M+)
352.1998, found 352.2003; Anal. Calcd for C18H28N2O5: C, 61.3;
H, 8.0; N, 7.95. Found: C, 61.0; H, 8.1; N, 8.0%.
dq, J = 13.8, J = 6.9, NCH2), 3.28 (1H, dq, J = 13.8, J = 6.9,
NCH2), 3.17 (1H, dq, J = 13.8, J = 6.9, NCH2), 2.39 (1H, dq,
J = 14.5, J = 7.3, CCHHCH3), 2.09 (1H, dq, J = 14.5, J =
7.3, CCHHCH3), 1.24 (3H, t, J = 6.9, NCH2CH3), 1.14 (3H, t,
J = 6.9, NCH2CH3), 0.89 (3H, t, J = 7.3, CCH2CH3) ppm; 13C
=
=
=
NMR (100 MHz, CDCl3): d 169.2 (O CC C), 166.6 (OC O),
=
=
=
166.2 (Et2NC O), 160.3 (HNC O), 141.9 (HNCH CH),
=
=
=
112.7 (O CC C), 104.5 (HNCH CH), 89.0 (CCH2CH3), 42.7
(NCH2), 31.7 (CCH2CH3), 14.7 (NCH2CH3), 12.4 (NCH2CH3),
7.6 (CCH2CH3) ppm; IR (Nujol) 3123, 2924, 1776, 1662, 1637,
1609, 1560, 1459, 1247 cm−1; MS (ESI) m/z 279.1 (MH+); HRMS
(ESI POS) calcd for C14H18N2O4Na (MNa+) 301.1164, found
301.1164; Anal. Calcd for C14H18N2O4: C, 60.4; H, 6.5; N, 10.1.
Found: C, 60.4; H, 6.7; N, 9.7%.
(S)-5-Diethylcarbamoyl-4-((E)-2-dimethylamino-vinyl)-5-ethyl-2-
oxo-2,5-dihydro-furan-3-carboxylic acid ethyl ester ((S)-27).
According to the preparation of 27, a solution of (S)-21
(1.220 g, 4.103 mmol) in DMF (7.3 mL) was treated with
tris(dimethylamino)methane (7.55 mL, 42.26 mmol, 10.3 eq.)
yielding the crude product as an orange oil (1.463 mg, 101% by
weight). An analytical sample (yellow oil) was prepared starting
from (S)-21, which had been purified by column chromatography
prior to use. The sample was liberated from residual DMF in
(S)-1-Ethyl-3,4-dioxo-1,3,4,5-tetrahydro-furo[3,4-c]pyridine-1-car-
boxylic acid diethylamide ((S)-20). According to the preparation
of 20, a solution of (S)-27 (1.462 g, 4.148 mmol) in DMF
(11.7 mL) was treated with ammonium acetate (3.263 g,
41.48 mmol, 10.0 eq.) yielding the crude product as a red liquid
(3.175 g, 275% by weight). All volatile components were removed
in a Kugelrohr distillation apparatus (50 ◦C, 0.05 mbar). The
residue (402.8 mg, 35% by weight) was purified by trituration
for 18 h at room temperature with 4.8 mL TBME furnishing
product (S)-20 (329.2 mg, 1.18 mmol, 29% by weight (yield
over 4 steps (34 → (S)-20): 41%), er = 93.3 : 6.7 (chiral HPLC,
sample preparation: ethanol, equipment: Agilent 1100, column:
Chiralpak-ADH, 250 × 4.6 mm, temperature: 25 ◦C, mobile
phase: 90% heptane, 10% ethanol/trifluoroacetic acid (99 : 1),
flow: 0.8 mL min−1, injection volume: 5 lL, detection: UV
326 nm, retention time: 29.78 min (S)-20, 26.01 min (R)-41) as
a high vacuum rotary evaporator (50 ◦C, 0.5 mbar). [a]D (c =
20
1.020 g dL−1, CHCl3) = −238.9. The other analytical data are in
accordance with (rac)-27.
Synthesis of 5-diethylcarbamoyl-4-((E)-2-dimethylamino-vinyl)-
5-ethyl-2-oxo-2,5-dihydro-furan-3-carboxylic acid ethyl ester (27)
using DMFDMA. To a solution of 21 (6.758 g, 22.73 mmol) in
DMF (40 mL), dimethylformamide dimethyl acetal (DMFDMA,
40.0 mL, 285.1 mmol, 12.5 eq.) was added at room temperature.
The color of the reaction mixture changed from orange to brown
to green. The reaction was monitored by HPLC. After 2.5 h,
the mixture was diluted with dichloromethane (150 mL) and
washed with aqueous HCl (150 mL, 1.0 M) and subsequently with
brine (3 × 150 mL). The organic phase was dried over sodium
506 | Org. Biomol. Chem., 2006, 4, 498–509
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◦
yellow crystals. Mp: 199 C; [a]D (c = 0.364 g dL−1, CHCl3) =
reaction was monitored by HPLC. After 4 h, the mixture was
evaporated to dryness in a rotary evaporator (27 ◦C, 1 mbar). The
crude product was obtained as an off-white semisolid (805.4 mg,
194% by weight). 333.3 mg of the crude product were purified by
trituration with 0.7 mL methanol at room temperature for 18 h
furnishing product 19 (168.7 mg, 0.425 mmol, 98% by weight)
20
−67.9. The other analytical data are in accordance with (rac)-20.
N,N-Diethyl-2-hydroxy-2-(3-hydroxymethyl-2-oxo-1,2-dihydro-
pyridin-4-yl)-butyramide (28). To a solution of 20 (1.000 g,
3.595 mmol) in ethanol (40 mL), ground cerium(III) chloride
(2.215 g, 8.99 mmol, 2.5 eq.) was added at room temperature.
The suspension was placed in an ultrasonic bath for 10 min and
◦
1
as white crystals. Mp: 227 C (decomp.). H NMR (300 MHz,
=
CDCl3/MeOH (1 : 1)): d 7.18 (1H, d, J = 6.9, HNCH CH), 6.44
◦
was then cooled to 15 C by a water bath. Sodium borohydride
=
(1H, d, J = 6.9, HNCH CH), 5.31 (1H, d, J = 16.2, OCHH),
(2.40 g, 61.1 mmol, 17 eq.) was added in 6 portions over 3 h. After
each addition, the water bath was removed immediately. After an
additional 2 h at room temperature, the suspension was poured
onto saturated aqueous NaHCO3/brine (1 : 1, 800 mL) and the
mixture was vigorously stirred for 13 h prior to extraction with
dichloromethane/ethanol (4 : 1, 5 × 400 mL). The combined
4.97 (1H, d, J = 16.2, OCHH), 1.65 (2H, m, CH2CH3), 0.76 (3H,
t, J = 7.3, CH2CH3) ppm; 1H NMR (400 MHz, DMSO): d 11.80
=
(1H, s, NH), 7.43 (1H, d, J = 6.8, HNCH CH), 6.36 (1H, d,
=
J = 6.8, HNCH CH), 6.22 (1H, s, OH), 5.24 (1H, d, J = 16.2,
OCHH), 5.19 (1H, d, J = 16.2, OCHH), 1.75 (2H, m, CH2CH3),
0.80 (3H, t, J = 7.4, CH2CH3) ppm; 13C NMR (100 MHz,
◦
organic extracts were evaporated in a rotary evaporator (50 C,
=
=
=
=
DMSO): d 171.9 (OC O), 158.2 (NC O), 149.2 (O CC C),
5 mbar). The crude product was obtained as a purple-red solid
(879.6 mg, 87% by weight), which was purified by trituration
with dichloromethane/TBME (2 : 1, 5.25 mL) yielding product
28 (623.2◦ mg, 2.21 mmol, 61% by weight) as a white solid.
=
=
=
=
134.0 (NCH CH), 118.4 (O CC C), 101.4 (HNCH CH),
71.3 (COH), 64.5 (OCH2), 29.8 (CH2CH3), 7.0 (CH2CH3) ppm;
IR (Nujol) 3308, 3122, 2923, 1751, 1641, 1620, 1556, 1460, 1156,
1031, 842 cm−1; MS (EI) m/z (rel. intensity) 209 (68), 180 (34),
165 (55), 136 (100); HRMS (ESI POS) calcd for C10H12NO4
(MH+) 210.0766, found 210.0765. Anal. Calcd for C10H11NO4: C,
57.4; H, 5.3; N, 6.7. Found: C, 57.5; H, 5.4; N, 6.7%.
1
Mp: 193 C; H NMR (300 MHz, DMSO): d 11.68 (1H, br. s,
=
NH), 7.32 (1H, d, J = 7.1, HNCH CH), 6.41 (1H, d, J = 7.1,
=
HNCH CH), 6.06 (1H, s, COH), 4.68 (1H, br. s, CH2OH), 4.37
(2H, s, CH2OH), 3.05–3.40 (4H, m, NCH2), 2.07 (1H, dq, J =
14.3, J = 7.3, CCHHCH3), 1.86 (1H, dq, J = 14.3, J = 7.3,
CCHHCH3), 1.01 (3H, t, J = 7.0, NCH2CH3), 0.74 (3H, t, J =
7.0, NCH2CH3), 0.68 (3H, t, J = 7.3, CCH2CH3) ppm; 13C NMR
(S)-4-Ethyl-4-hydroxy-1,7-dihydro-4H-pyrano[3,4-c]pyridine-3,8-
dione ((S)-19). According to the preparation of 19, a suspension
of (S)-28 (461.0 mg 1.633 mmol) in DME (9.2 mL) was treated
with conc. aqueous HCl (36.5%, 1.38 mL, 16.33 mmol, 10.0 eq.)
yielding the crude product as an off-white solid (722.8 mg, 212%
by weight, er = 94.1 : 5.9 [chiral HPLC, sample preparation:
ethanol/ethyl acetate solution, equipment: Agilent 1100, column:
Chiralcel-ODH, 250 × 4.6 mm, temperature: 25 ◦C, mobile
phase: 90% heptane, 10% ethanol/trifluoroacetic acid (99 : 1),
flow: 0.8 mL min−1, injection volume: 5 lL, detection: UV
305 nm, retention time: 30.00 min (S)-19, 24.52 min (R)-19],
which was stirred with 2.2 mL methanol at room temperature
overnight. The mixture was filtered and product (S)-19 was
washed with additional methanol (2.2 mL) furnishing white
crystals (117.4 mg, 34% by weight), er = 95.0 : 5.0 (chiral HPLC).
The filtrate was evaporated to dryness furnishing an off-white
solid (564.0 mg, 165% by weight), which was purified by column
chromatography with chloroform/methanol (10 : 1) giving rise to
product (S)-19 (153.7 mg, 0.735 mmol, 45% by weight), er = 95.5 :
=
=
(100 MHz, DMSO): d 171.5 (Et2NC O), 163.3 (HNC O),
=
=
=
=
=
152.5 (O CC C), 132.3 (NCH CH), 126.8 (O CC C), 103.8
(HNCH CH), 77.9 (COH), 55.6 (OCH2), 40.9 (NCH2), 32.8
=
(NCH2), 12.6 (NCH2CH3), 12.2 (NCH2CH3), 7.5 (CCH2CH3)
ppm; IR (Nujol) 3315, 3104, 2922, 2725, 1639, 1596, 1526, 1466,
1376, 1145, 1070, 1021 cm−1; MS (ESI) m/z 283.0 (MH+), 305.3
(MNa+); HRMS (ESI POS) calcd for C14H22N2O4Na (MNa+)
305.1477, found 305.1476; Anal. Calcd for C14H22N2O4: C, 59.5;
H, 7.85; N, 9.9. Found: C, 59.2; H, 8.0; N, 9.6%.
(S)-N,N-Diethyl-2-hydroxy-2-(3-hydroxymethyl-2-oxo-1,2-di-
hydro-pyridin-4-yl)-butyramide ((S)-28). According to the pre-
paration of 28, a solution of (S)-20 (694.0 mg, 2.494 mmol) in
ethanol (28 mL) was treated with ground cerium(III) chloride
(1.537 g, 6.235 mmol, 2.5 eq.) and sodium borohydride (1.081 g,
27.4 mmol, 11 eq., added in 4 portions over 1 h, reaction
time: 4 h 50 min) yielding the crude product as a beige solid
(576.0 mg, 82% by weight), which was redissolved in methanol
(10 mL) at 60 ◦C. The solution was poured on saturated aqueous
NaHCO3/brine (1 : 1, 88 mL) and the resulting suspension
was stirred for an additional 24 h prior to extraction with
dichloromethane/ethanol (4 : 1, 5 × 88 mL). The combined
4.5 (chiral HPLC) as white crystals. Mp: 230 ◦C (decomp.); [a]D
20
(c = 0.168 g dL−1, MeOH) = +102.6 (for a sample with er = 98.1 :
1.9). The other analytical data are in accordance with (rac)-19.
2-Oxo-butyric acid (1R,2S,5R)-5-methyl-2-(1-methyl-1-phenyl-
◦
ethyl)-cyclohexyl ester (30)13. According to the literature,13
a
organic extracts were evaporated in a rotary evaporator (50 C,
solution of 2-oxobutyric acid (2.28 g, 29, 22.11 mmol, 1.3 eq.),
(−)-8-phenylmenthol (31, 4.04 g, 17.02 mmol, 1.0 eq.) and
para-toluenesulfonic acid monohydrate (169.9 mg, 0.884 mmol,
0.52 eq.) in benzene (48 mL) was heated to reflux for 20.5 h
(HPLC control). After cooling down to room temperature, the
solution was washed twice with saturated aqueous NaHCO3 (2 ×
100 mL), and subsequently with water (50 mL) and brine (50 mL).
The organic phase was dried over sodium sulfate (5 g, 30 min) and
filtered. The filter cake was washed with benzene (10 mL). The
organic phase was evaporated to dryness in a rotary evaporator
5 mbar) yielding product (S)-28 (461.5 mg, 1.63 mmol, 66%
by weight) as an off-white solid. Mp: 174 ◦C (decomp.); [a]D
20
(c = 0.253 g dL−1, CHCl3) = −81.8. The other analytical data are
in accordance with (rac)-28.
4-Ethyl-4-hydroxy-1,7-dihydro-4H-pyrano[3,4-c]pyridine-3,8-
dione (19). To a suspension of 28 (560.0 mg, 1.983 mmol) in
DME (11.2 mL), conc. aqueous HCl (36.5%, 1.68 mL 19.83 mmol,
10.0 eq.) was added dropwise at 0 ◦C. The ice bath was removed
after 15 min and the triphasic mixture was vigorously stirred. The
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(40 ◦C, 20 mbar) yielding product 30 as colorless solid (4.98 g,
a yellow solid (931.4 mg, 77% by weight). An analytical sample
was obtained by semipreparative HPLC (Zorbax Extend C18,
21.2 × 150 mm). Despite these efforts, a satisfactory microanalysis
92% by weight). An analytical sample was obtained by column
chromatography (hexane/TBME 96 : 4). [a]D (c = 0.827 g dL−1,
20
1
20
CHCl3) = +1.3; H NMR (300 MHz, CDCl3): d 7.19–7.27 (4H,
could not be not obtained. [a]D (c = 0.251 g dL−1, CHCl3) =
◦
1
m, Ar), 7.09 (1H, m, Ar), 4.95 (1H, td, J = 10.7, J = 4.5, OCH),
2.36 (1H, dq, J = 19.4, J = 7.1, CHHCH3), 2.19 (1H, dq, J =
19.4, J = 7.1, CHHCH3), 2.14 (1H, m, aliphatic), 1.84 (2H, m,
aliphatic), 1.69 (1H, m, aliphatic), 1.50 (1H, m, aliphatic), 1.31
(3H, s, CCH3), 1.22 (3H, s, CCH3), 1.10–1.40 (3H, m, aliphatic),
0.94 (3H, t, J = 7.1, CH2CH3), 0.89 (3H, d, J = 6.4, CHCH3)
ppm. The other analytical data are in accordance with the data
reported in the literature.13
−11.9; mp: 77 C; H NMR (300 MHz, CDCl3): d 5.26 (1H, s,
=
=
C CHH), 5.06 (1H, br. s, C CHH), 2.04 (1H, dq, J = 14.3,
J = 7.4, CHHCH3), 2.04 (1H, dq, J = 14.3, J = 7.4, CHHCH3),
=
1.85 (3H, s, H2C CCH3), 0.94 (3H, t, J = 7.4, CH2CH3) ppm.
13
=
=
C NMR (100 MHz, DMSO): d 179.4 (C O), 144.3 (C CH2),
=
=
113.5 (C CH2), 79.9 (COH), 29.1 (CH2CH3), 19.1 (H3CC CH2),
7.7 (CH2CH3) ppm; IR (film) 3439, 2924, 2627, 1722, 1643, 1295,
1230, 1140 cm−1; MS (EI) m/z (rel. intensity) 126 (4), 119 (9), 99
(100), 43 (26), 41 (9); HRMS (ESI NEG) calcd for C7H11O3 (M −
H)− 143.0708, found 143.0707.
(2S)-2-Ethyl-2-hydroxy-3-methyl-but-3-enoic acid (1R,2S,5R)-
5-methyl-2-(1-methyl-1-phenyl-ethyl)-cyclohexyl ester (32). To a
solution of 30 (4.200 g, 13.27 mmol) in THF (168 mL), isopro-
penylmagnesium bromide (39.8 mL, 19.91 mmol, 1.5 eq.) was
added dropwise at −78 ◦C (addition time: 30 min). After an
additional 50 min (HPLC control), the reaction mixture was
quenched by addition of saturated aqueous NH4Cl (110 mL) and
was extracted with ethyl acetate (2 × 110 mL). The combined
organic phases were washed with brine (110 mL). The organic
phase was dried over sodium sulfate (15 g, 30 min) and filtered.
The filter cake was washed with ethyl acetate (30 mL). The organic
(S)-2-Ethyl-2-hydroxy-3-methyl-but-3-enoic acid diethylamide
(34). o a solution of 33 (1.000 g, 6.95 mmol) in dichloromethane
(30 mL), N-ethyldiisopropylamine (2.50 mL, 14.6 mmol, 2.1 eq.)
and after an additional 8 min thionyl chloride (1.53 mL,
20.85 mmol, 3.0 eq.) were added dropwise at −15 ◦C. After 50 min,
a solution of diethylamine (7.22 mL, 69.5 mmol, 10.0 eq.) in
dichloromethane (20 mL) was added dropwise using a syringe
pump (addition time: 60 min). The reaction mixture was allowed
to slowly warm to room temperature overnight. After dilution
with dichloromethane (50 mL), the solution was washed with
aqueous HCl (50 mL, 1.0 M). The organic phase was dried
over Na2SO4 (5 g, 30 min) and filtered. The solid was washed
with dichloromethane (10 mL). After evaporation of solvent in
a rotary evaporator (40 ◦C, 10 mbar), the crude product (1.36 g,
98% by weight) was obtained as a yellow oil, which was purified
by column chromatography with heptane/ethyl acetate (9 : 1)
yielding product 34 (0.900 g, 4.515 mmol, 65% by weight, er =
93.4 : 6.6, chiral GC [carrier gas: H2, 90 kPa (split ratio 1/20),
equipment: HP6890_2A, column: BGB-176, 30 m × 0.25 mm,
injector temperature: 200 ◦C, detector temperature: 220 ◦C,
retention time: 15.50 min (S)-34, 15.72 min (R)-34]) as yellow oil.
◦
phase was evaporated to dryness in a rotary evaporator (40 C,
8 mbar) yielding product 32 as a yellow oil (4.790 g, 101% by
weight, dr = 93 : 7). An analytical sample was obtained by column
20
chromatography (heptane/ethyl acetate 95 : 1, dr = 94 : 6). [a]D
(c = 0.615 g dL−1, CHCl3) = −44.0; 1H NMR (300 MHz, CDCl3):
=
d 7.15–7.29 (5H, m, Ar), 5.11 (1H, br., C CHH), 4.97 (1H, m,
=
C CHH), 4.84 (1H, td, J = 10.8, J = 4.2, OCH), 2.83 (1H, br. s,
OH), 2.09 (1H, m, Me2CCH), 1.97 (1H, m, OCHCHH), 1.74
=
(3H, s, H2C CCH3), 1.31 (3H, s, PhCCH3), 1.21 (3H, s, PhCCH3),
0.90–1.80 (8H, m, aliphatic), 0.87 (3H, d, J = 6.4, CHCH3), 0.80
(3H, t, J = 7.4, CH2CH3) ppm; 13C NMR (100 MHz, CDCl3):
=
=
d 173.9 (C O), 151.0 (ipso-C6H5), 144.5 (C CH2), 128.2 (meta-
=
C6H5), 125.4 (ortho-C6H5), 125.4 (para-C6H5), 113.1 (C CH2),
[a]D (c = 0.990 g dL−1, CHCl3) = +63.3; H NMR (300 MHz,
CDCl3): d 5.27 (1H, s,), 5.12 (1H, br. s,), 5.03 (1H, m,), 3.42 (4H,
m,), 2.00 (1H, dq, J = 13.9, J = 7.4), 1.91 (1H, dq, J = 14.0,
J = 6.9), 1.71 (3H, s,), 1.16 (3H, t, J = 6.9), 1.12 (3H, t, J =
6.9), 0.88 (3H, t, J = 7.4) ppm; 13C NMR (100 MHz, CDCl3):
20
1
79.7 (COH), 77.8 (OCH), 49.9 (PhCCH), 41.0 (OCHCH2), 39.9
(PhC), 34.5 (MeCHCH2CH2), 31.4 (MeCH), 28.8 (CH2CH3),
27.3 (H3CCCH3), 27.1 (MeCHCH2CH2), 26.4 (H3CCCH3), 21.7
=
(CHCH3), 19.3 (H3CC CH2), 7.8 (CH2CH3) ppm; IR (MIR)
3516, 2961, 1717, 1653, 1457, 1228, 1149, 907, 764, 702 cm−1;
MS (EI) m/z (rel. intensity) 359 (1), 215 (7), 119 (100), 105 (92);
Anal. Calcd for C23H34O3: C, 77.05; H, 9.6. Found: C, 76.8; H,
9.2%.
=
=
=
d 172.3 (NC O), 146.9 (C CH2), 111.5 (C CH2), 77.5 (COH),
41.4 (NCH2), 41.1 (NCH2), 28.2 (CCH2CH3), 18.9 (H2C CCH3),
=
13.1 (NCH2CH3), 12.2 (NCH2CH3), 7.8 (CCH2CH3) ppm; IR
(MIR) 3365, 2973, 1615, 1381, 1363, 1124, 1081, 903 cm−1; MS
(EI) m/z (rel. intensity) 200 (21), 182 (31), 170 (9), 142 (26), 100
(100), 72 (60); Anal. Calcd for C11H21NO2: C, 66.3; H, 10.6; N, 7.0.
Found: C, 66.0; H, 10.75; N, 7.0%.
(S)-2-Ethyl-2-hydroxy-3-methyl-but-3-enoic acid (33). A solu-
tion of 32 (3.025 g, 8.435 mmol) in MeOH/THF (1 : 1, 40 mL)
was treated with aqueous LiOH (1.0 M, 16.9 mL, 16.9 mm◦ol,
2.0 eq). The resulting colorless suspension was heated to 110 C
for 18.5 h providing a slightly brown solution (HPLC control).
After cooling to room temperature, the reaction mixture was
diluted with TBME (150 mL) and aqueous LiOH (150 mL). The
aqueous phase was extracted with TBME (150 mL) to remove the
auxiliary (the combined TBME phases were evaporated to dryness
furnishing 31 in >95% yield). Subsequently, the pH was adjusted
to 2 by addition of 10% aqueous KHSO4. The aqueous phase
was extracted with 400 mL CHCl3/EtOH (4 : 1, 4 × 100 mL).
The combined organic phases were evaporated to dryness in a
rotary evaporator (40 ◦C, 10 mbar). The product was obtained as
Acknowledgements
We would like to thank Dr Milan Soukup and Dr Martin Karpf
for valuable discussions and Mr Thomas Naber, Mrs Se´ve´rine
Baumgartner, Mr Dominik Sta¨mpfli and Mr Anton Cueni for
skillful experimental work. We also thank the members of the
analytical services of F. Hoffmann-La Roche Ltd, Basel, for
efficiently and consistently providing the physical data of all
compounds described.
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8 (a) D. L. Comins, H. Hong, J. K. Saha and G. Jinhua, J. Org. Chem.,
1994, 59, 5120–5121; (b) D. L. Comins, H. Hong and G. Jinhua,
Tetrahedron Lett., 1994, 35, 5331–5334.
9 M. A. Ciufolini and F. Roschangar, Targets Heterocycl. Syst., 2000, 4,
25–55.
10 The use of (E/Z)-1-methyl-1-propenylmagnesium bromide was pre-
ferred over isopropenylmagnesium bromide, since the product, which
is formed from the latter reagent, could not efficiently be separated
by distillation from starting material 25 thus necessitating column
chromatography.
11 Extensive attempts to prepare 22 directly by hydroxylation of the
corresponding b-ketoamide failed. In most instances, a-ketoamide
25 was formed indicating a retro-Claisen condensation of the initial
oxidation product.
References and notes
1 M. E. Wall, in Chronicles of Drug Discovery, ed. D. Lednicer, American
Chemical Society, Washington, D.C., 1993, vol. 3, pp. 327–348.
2 Selected CPT review articles: (a) C. J. Thomas, N. J. Rahier and
S. M. Hecht, Bioorg. Med. Chem., 2004, 12, 1585–1604; (b) W. Du,
Tetrahedron, 2003, 59, 8649–8687; (c) Y. Kawato and H. Terasawa,
Prog. Med. Chem., 1997, 34, 69–109; (d) S.-s. Jew, M. G. Kim, H.-J.
Kim, E.-Y. Roh and H.-g. Park, Korean J. Med. Chem., 1996, 6, 263–
282; (e) C. R. Hutchinson, Tetrahedron, 1981, 37, 1047–1065; (f) A. G.
Schultz, Chem. Rev., 1973, 73, 385–405.
3 W. Shen, C. A. Coburn, W. G. Bornmann and S. J. Danishefsky, J. Org.
Chem., 1993, 58, 611–617.
4 Recently, Yu and co-workers from Bristol-Myers Squibb reported the
reduction of a similar system, in which the ABCDE core had already
been installed: J. Yu, J. DePue and D. Kronenthal, Tetrahedron Lett.,
2004, 45, 7247–7250. Prior to this publication, we had prepared an
analogous system by condensation of 4 with DMFDMA, a subsequent
ozonolysis of the resulting enamine providing the corresponding ketone
(formal allylic oxidation of 4) and a Friedla¨nder condensation with 2.
However, all attempts to efficiently reduce the lactone moiety failed in
our hands.
5 T. Watanabe and T. Ishikawa, Tetrahedron Lett., 1999, 40, 7795–
7798.
6 All attempts to do an intermolecular condensation of lactone 5
with the corresponding methylthioimino ether (5-methylsulfanyl-3,4-
dihydro-2H-pyrrole) or methoxyimino ether (5-methoxy-3,4-dihydro-
2H-pyrrole) derived from 9 were unproductive. For that reason, the
presented intramolecular version was chosen.
12 M. A. Ciufolini and F. Roschangar, Tetrahedron, 1997, 53, 11049–
11060.
13 D. L. Comins, M. F. Baevsky and H. Hong, J. Am. Chem. Soc., 1992,
114, 10971–10972.
14 All attempts to use chiral amines as auxiliaries resulted in disappoint-
ingly low diastereoselectivities.
15 L. Tan, C.-y. Chen, W. Chen, L. Frey, A. O. King, R. D. Tillyer, F. Xu,
D. Zhao, E. J. J. Grabowski, P. J. Reider, P. O’Shea, P. Dagneau and X.
Wang, Tetrahedron, 2002, 58, 7403–7410.
16 On a larger scale, distillation of 34 might be the purification method of
choice.
17 In one single case, treatment of the crude product with MeOH at room
temperature dissolved mainly the (S)-configured DE ring fragment
(er = 98 : 2), while the undissolved material contained the almost
racemic compound (er = 56 : 44). This result could, however, not be
reproduced.
7 M. Roth, P. Dubs, E. Go¨tschi and A. Eschenmoser, Helv. Chim. Acta,
1971, 54, 710–734.
18 D. Brillon, Synth. Commun., 1990, 20, 3085–3095.
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