Efficient chiral pool synthesis of the C1-C6 fragment of epothilones

Article abstract of DOI:10.1055/s-2004-834936

An efficient chiral pool synthesis of the C1-C6 fragment of epothilones starting from readily available (-)-pantolactone is described.

Full text of DOI:10.1055/s-2004-834936

PAPER
301
Efficient Chiral Pool Synthesis of the C1–C6 Fragment of Epothilones
S
ynthesis of C1–C
l
6 Fragm
r
ent of
E
i
pothil
c
ones h Klar,* Bodo Röhr, Frank Kuczynski, Wolfgang Schwede, Markus Berger, Werner Skuballa,
Bernd Buchmann
Research Laboratories of Schering AG, Müllerstrasse 170, 13342 Berlin, Germany
Fax +49(30)46892635; E-mail: ulrich.klar@schering.de
Received 7 September 2004; revised 6 October 2004
and C13–C15, respectively.7 As a prerequisite, each chiral
module should offer the potential for flexible synthetic
modifications as well as a large scale production with high
optical purity. Based on this methodology we synthesized
more than 350 epothilone analogs from which our clinical
development candidate ZK-EPO was selected.
Abstract: An efficient chiral pool synthesis of the C1–C6 fragment
of epothilones starting from readily available
(–)-pantolactone is described.
Key words: epothilone, pantolactone, chiral pool synthesis
Herein we describe one of our syntheses of building block
A.8 Even though the synthesis is relatively long we select-
ed it due to its standard and mature chemistry which al-
lowed suitable large scale production of this building
block.9 As a readily available chiral starting material (–)-
pantolactone (1) was chosen which already contains car-
bon atoms C2–C5 including the geminal dimethyl moiety
at C4 (Scheme 1).
The discovery that the natural product class of epothilones
parallels the biological activity of paclitaxel (PT) with re-
spect to its action on the tubulin system stimulated inten-
sive research activities in chemistry, pharmacology, and
medicine. Epothilones, which have been isolated from the
myxobacterial strain sorangium cellulosum were charac-
terized by the groups of Reichenbach and Höfle.1 They
stabilize microtubules similar to PT by inhibiting their de-
polymerization.2 As a consequence, the cell cycle is
blocked in G2/M phase and the cells are driven into apop-
tosis. In contrast to PT, epothilones possess the potential
to overcome multi-drug resistance in vitro and, most im-
portant, in vivo.3–6
In a straightforward manner the hydroxyl group was pro-
tected as tetrahydropyrane ether (2) and the lactone was
reduced to the lactol. The lacking carbon atom C1 was in-
troduced by a Wittig reaction and the primary hydroxyl
group was protected as benzyl ether to yield compound 4.
Interestingly, the THP isomers in 2, which can be separat-
ed very easily, show remarkable differences with respect
to their reactivity in the Wittig reaction. While the reac-
tion is complete within three hours with one isomer, the
use of the other isomer as well as the epimeric mixture
elongates the reaction time to about 20 hours. Analysis at
chiral HPLC columns with racemic reference material re-
vealed that no racemization had occurred.
Epothilone B (Figure 1), which is more potent than PT,
displays significant toxicity at therapeutically relevant
doses.6
Then, olefin 4 was subjected to a hydroboration-oxidation
sequence giving 5a along with a mixture of stereoisomers
5c (8%) resulting from a Markovnikov hydration and 1,3-
diol 5b (7%).10 After separation by chromatography com-
pounds 5a and 5b were transferred directly into acetonide
6 which served as stable key intermediate and was pre-
pared in large scale in the lab by this methodology. Re-
moval of the benzyl ether followed by Swern-oxidation
led to aldehyde 7. The introduction of different substitu-
ents at carbon 5 is achieved by subsequent Grignard reac-
tion or the addition of the corresponding alkyl-lithium
compounds followed by an oxidation of the resulting
epimeric alcohols to yield ketones 8a to 8k. Alternatively,
deprotonation of methyl ketone 8a by LDA followed by
an alkylation with the corresponding alkyl halides is also
suitable. Methyl ketone 8a proved to be a nicely crystal-
line compound from which a X-ray structure was obtained
(Figure 2).
Figure 1 Natural products epothilone B and epothilone D
Therefore, an epothilone analog possessing an improved
therapeutic window would be highly favorable for clinical
applications. Due to the less complex structure,
epothilones can be obtained and modified efficiently by
total syntheses. This offers the opportunity for extensive
structural modifications most of which cannot be
achieved via a partial synthetic approach.
Like other groups we made use of a highly convergent
strategy combining three modular building blocks A, B
and C which represent the ring carbons C1–C6, C7–C12,
SYNTHESIS 2005, No. 2, pp 0301–0305
x
x
.
x
x
.2
0
0
5
Starting from a relatively cheap optically active chiral
pool material we have opened an efficient route to frag-
Advanced online publication: 01.12.2004
DOI: 10.1055/s-2004-834936; Art ID: Z16904SS
© Georg Thieme Verlag Stuttgart · New York

302
U. Klar et al.
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5) There is high flexibility for synthetic modifications at
C6.
All new compounds gave satisfactory analytical and spectral data.
All experiments were conducted under Ar atmosphere. Chromato-
graphic separations were carried out on 63–200 mesh silica gel until
1
otherwise stated. H NMR spectra (300 MHz) were recorded in
CDCl3 on a Bruker Avance 300 spectrometer. IR spectra were re-
corded on a Nicolet 710 spectrometer. CD spectra were recorded in
dioxane on a JASCO J 715 spectrometer. Optical rotations were re-
corded in CHCl3 on a Perkin-Elmer PE 343 spectrometer.
(3R)-4,4-Dimethyl-3-(tetrahydropyran-2-yloxy)dihydrofuran-
2-one (2)
Figure 2 X-ray structure of compound 8a
To a solution of D-(–)-pantolactone (1500 g, 11.52 mol) in CH2Cl2
(8 L) were added 3,4-dihydro-2H-pyran (1.87 L, 20.45 mol) and py-
ridinium p-toluenesulfonate (29 g, 115 mmol). After about 1.5 h the
reaction was exothermic, the solution heated up to 32 °C and was
recooled to 23 °C while stirring was continued for additional 2.5 h.
The solution was added to a sat. aq solution of NaHCO3 and extract-
ed with CH2Cl2. The organic layers were dried over Na2SO4 and
concentrated in vacuo. The crude tetrahydropyranyl isomers 2 were
used without purification (2660 g, max. 11.25 mol, max. 100%).
Samples of each THP-isomer were purified by chromatography for
analytical purposes.
ment A for the synthesis of C6-modified epothilone ana-
logs. There are several advantages to this approach:
1) Both enantiomers are commercially available.
2) No racemisation occurs during the synthesis.
3) All intermediates are stable.
4) Large amounts can be synthesized.
Scheme 1 Preparation of C1–C6 fragment of epothilones
Synthesis 2005, No. 2, 301–305 © Thieme Stuttgart · New York

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Synthesis of C1–C6 Fragment of Epothilones
303
1H NMR (less polar tetrahydropyranyl isomer): d = 5.17 (t, J = 3 Hz,
1 H, O-CH-O), 4.16 (s, 1 H, 3-H), 4.01 (d, J = 9 Hz, 1 H, 4-H), 3.92
(d, J = 9 Hz, 1 H, 4-H), 3.86 (m, 1 H, CH2-O, THP-ether), 3.56 (m,
1 H, CH2-O, THP-ether), 1.91–1.49 [m, 6 H, (CH2)3, THP-ether],
1.22 (s, 3 H, 4-CH3), 1.14 (s, 3 H, 4-CH3).
1H NMR (more polar tetrahydropyranyl isomer): d = 4.87 (t, J = 3
Hz, 1 H, O-CH-O), 4.22 (s, 1 H, 3-H), 4.20 (m, 1 H, CH2-O, THP-
ether), 3.98 (d, J = 10 Hz, 1 H, 4-H), 3.89 (d, J = 10 Hz, 1 H, 4-H),
3.54 (m, 1 H, CH2-O, THP-ether), 1.98–1.50 [m, 6 H, (CH2)3, THP-
ether], 1.20 (s, 3 H, 4-CH3), 1.01 (s, 3 H, 4-CH3).
bromide (910 mL, 7.651 mol) was added over a period of 75 min
(slightly exothermic; 50 °C). The mixture was stirred at 23 °C over-
night, sat. NH4Cl solution and water were added (5 L) and extracted
with EtOAc (30 L). The organic layers were concentrated in vacuo
and the residue filtrated over silica gel (9 L, 0.2–0.5 mesh) with a
mixture of n-hexane–EtOAc (95:5) to give 4 (2076 g, 6.819 mol,
99.1%).
1H NMR: d = 7.38–7.23 (m, 5 H, Ph), 5.88, 5.67 (ddd, 3J1 = 17.2 Hz,
3J2 = 10.5 Hz, 3J3 = 8.0 Hz, 0.4 H, 0.6 H, =CH), 5.28–5.13 (m, 2 H,
=CH2), 4.66, 4.59 (m, 0.6 H, 0.4 H, O-CH-O), 4.53–4.44 (m, 2 H,
3
O-CH2-Ph), 4.03, 3.93 (d, J = 8.0 Hz, 0.6 H, 0.4 H, CH-O), 3.86
(3S)-2,2-Dimethyl-3-(tetrahydropyran-2-yloxy)pent-4-en-1-ol
(3)
(m, 1 H, CH2-O, THP-ether), 3.46 (m, 1 H, CH2-O, THP-ether),
3.38, 3.34 (d, 2J = 8.4 Hz, 0.6 H, 0.4 H, 2-H), 3.25, 3.12 (d, 2J = 8.4
Hz, 0.6 H, 0.4 H, 2-H), 1.87–1.46 [m, 6 H, (CH2)3], 0.99, 0.91 (s,
1.8 H, 1.2 H, 1-CH3), 0.92, 0.89 (s, 1.8 H, 1.2 H, 1-CH3).
To a solution of 2 (448 g, 2091 mmol) in toluene (2 L) at –70 °C was
added a solution of DIBAL (2.4 L, 1.2 M in toluene) over 5 h. The
reaction temperature should not exceed –65 °C, otherwise 1,4-diol
is produced as side product. After 1 h at –70 °C the solution was
added slowly to a mixture of water (1 L) and i-PrOH (500 mL). Due
to a strong exothermic reaction the temperature rose to 60 °C. The
mixture was stirred at 23 °C until a fine crystalline precipitate had
formed which was removed by filtration. The filtrate was concen-
trated in vacuo to yield (2RS,3R)-1-oxa-2-hydroxy-3-[tetrahydro-
pyran-2(RS)-yloxy]-4,4-dimethylcyclopentane (457 g, max. 2091
mmol, max. 100%) as colorless oil which was used without further
purification.
(3S)-5-Benzyloxy-4,4-dimethyl-3-(tetrahydropyran-2-
yloxy)pentan-1-ol (5a) and (3S)-1-Benzyloxy-2,2-dimethylpen-
tane-3,5-diol (5b)
To a solution of 4 (1038 g, 3.41 mol) in THF (13 L) was added bo-
rane–tetrahydrofuran complex (2.1 L, 1 M in THF) at 23 °C over a
period of 20 min. After 2 h (slightly exothermic, temperature → 27
°C) the mixture was cooled to 3 °C and a solution of NaOH (1.7 L,
5% in water) was added over a period of 1 h (→ 7 °C) while a con-
stant N2 flow was used to remove the released H2 gas. After recool-
ing to 0 °C a solution of H2O2 (845 mL, 30% in water) was added
(→ 10 °C) and stirring was continued for 1 h at 4 °C. The mixture
was added portion wise (5 L) to a mixture of a sat. sodium thiosul-
fate solution (2500 g in 8.5 L water; this is absolutely necessary to
decompose all H2O2 before concentration in vacuo is started) and
EtOAc (15 L). After extraction with additional EtOAc (7 L) the or-
ganic layers were concentrated in vacuo. The residue was purified
by flash column chromatography (EtOAc–hexane, 90:10 → 50:50)
to give 5a (572.5 g, 1.775 mol, 52.1%) as a colorless oil along with
5b (59 g, 247.5 mmol, 7.2%) and (3S,4RS)-1-benzyloxy-2,2-di-
methylpentane-3-[tetrahydropyran-2(RS)-yloxy]-4-ol (5c; 86 g,
266.5 mmol, 7.8%).
IR (CHCl3): 3480, 3013, 2950, 2874, 1262, 1133, 1074, 1026, 808
cm–1.
To a mixture of methyltriphenylphosphonium bromide (3000 g, 8.4
mol; dried in circulating air at 120 °C before use) in THF (11 L) at
–60 °C was added the solution of n-BuLi (3.2 L, 8.0 mol, 2.4 M in
hexane). After warming to 20 °C (4 h) the solution of (2RS,3R)-1-
oxa-2-hydroxy-3-[tetrahydropyran-2(RS)-yloxy]-4,4-dimethyl-cy-
clopentane (669 g, 3.1 mmol) in THF (2 L) was added and the mix-
ture stirred for 25 h at 23 °C. To the mixture was added sat.
NaHCO3. After extraction with EtOAc and CH2Cl2 the organic lay-
ers were dried over Na2SO4 and concentrated in vacuo. The residue
was purified by column chromatography (EtAOc–hexane, 0:100 →
50:50) to give 3 (512 g, 2.389 mol, 77.1%) as colorless oil of tet-
rahydropyranyl ether isomers. Samples of each THP-isomer were
separated by chromatography for analytical purposes.
5a
1H NMR: d = 7.37–7.24 (m, 5 H, Ph), 4.67 (m, 1 H, O-CH-O), 4.53
(d, 2J = 12.0 Hz, 1 H, O-CH2-Ph), 4.44 (d, 2J = 12.0 Hz, 1 H, O-CH2-
Ph), 4.02–3.65 (m, 4 H, CH2-O, THP-ether, 1-H), 3.44 (m, 1 H, 3-
H), 3.44, 3.28 (d, 2J = 8.9 Hz, 0.7 H, 0.3 H, 5-H), 3.22, 3.08 (d, 2J =
8.9 Hz, 0.7 H, 0.3 H, 5-H), 2.04 (m, 1 H, OH), 1.91–1.39 [m, 8 H,
(CH2)3, 2-H], 0.97, 0.91 (s, 2.1 H, 0.9 H, 4-CH3), 0.93, 0.88 (s, 2.1
H, 0.9 H, 4-CH3).
Less Polar Tetrahydropyran Isomer
[a]22D +83.5 (c = 0.51).
1H NMR: d = 5.74 (ddd, 3J1 = 17.3 Hz, 3J2 = 10.7 Hz, 3J3 = 7.7 Hz,
1 H, 4-H), 5.26 [m, 1 H, 5-H(Z)], 5.20 [m, 1 H, 5-H(E)], 4.44 (m, 1
H, O-CH-O), 4.40 (d, J = 7.7 Hz, 1 H, 3-H), 3.95 (m, 1 H, CH2-O,
THP-ether), 3.68 (dd, 2J = 11.0 Hz, 3J = 5.1 Hz, 1 H, 1-H), 3.49 (m,
1 H, CH2-O, THP-ether), 3.45 (dd, 3J1 = 8.5 Hz, 3J2 = 5.1 Hz, 1 H,
OH), 3.18 (dd, 2J = 11.0 Hz, 3J = 8.5 Hz, 1 H, 1-H), 1.83–1.45 [m,
6 H, (CH2)3, THP-ether], 0.93 (s, 3 H, 2-CH3), 0.78 (s, 3 H, 2-CH3).
5b
1H NMR: d = 7.39–7.26 (m, 5 H, Ph), 4.51 (s, 2 H, CH2Ph), 3.87–
3.80 (m, 3 H, 5-H, 3-OH), 3.72 (m, 1 H, 3-H), 3.40 (d, 2J = 8.9 Hz,
1 H, 1-H), 3.31 (d, 2J = 8.9 Hz, 1 H, 1-H), 3.20 (t, 3J = 5.1 Hz, 1 H,
1-OH), 1.68–1.61 (m, 2 H, 4-H), 0.93 (s, 3 H, 2-CH3), 0.90 (s, 3 H,
2-CH3).
More Polar Tetrahydropyran Isomer
[a]22D –89.0 (c = 0.50).
(4S)-4-(2-Benzyloxy-1,1-dimethylethyl)-2,2-dimethyl[1,3]diox-
ane (6)
Method 1
1H NMR: d = 5.92 (m, 1 H, 4-H), 5.21 (m, 2 H, 5-H), 4.67 (m, 1 H,
O-CH-O), 3.93 (m, 1 H, CH2-O, THP-ether), 3.84 (d, J = 8.1 Hz, 1
H, 3-H), 3.59 (dd, 2J = 10.7 Hz, 3J = 5.1 Hz, 1 H, 1-H), 3.50 (m, 1
H, CH2-O, THP-ether), 3.31 (dd, 2J = 11.0 Hz, 3J = 6.6 Hz, 1 H, 1-
H), 3.18 (dd, 3J1 = 6.6 Hz, 3J2 = 5.1 Hz, 1 H, OH), 1.83–1.45 [m, 6
H, (CH2)3, THP-ether], 0.94 (s, 3 H, 2-CH3), 0.84 (s, 3 H, 2-CH3).
To a solution of 5a (471 g, 1.46 mol) in acetone (2.3 L) were added
2,2-dimethoxypropane (900 mL, 7.345 mol), p-toluenesulfonic acid
(27.8 g, 146 mmol) and the mixture was stirred at 23 °C for 22 h.
The mixture was then poured into sat. NaHCO3 diluted with water
(1 L) and extracted with CH2Cl2 (5 L). The organic layers were
washed with brine, dried over Na2SO4 and concentrated in vacuo.
The residue was purified by flash column chromatography (EtOAc–
hexane, 0:100 → 40:60) to give 6 (349 g, 1.254 mol, 85.8%) as col-
orless oil along with 2(RS),4(S)-[2-methyl-1-benzyloxyprop-2-yl]-
2-(1-hydroxybut-4-yl)[1,3]dioxane (56 g, 201 mmol, 13.8%).
(1S)-2-[1-(2-Benzyloxy-1,1-dimethylethyl)allyloxy]tetrahydro-
pyran (4)
To a suspension of t-BuOK (1600 g, 14.258 mol) in dioxane (11 L)
was added the solution of 3 (1475 g, 6.883 mol) in dioxane (2 L)
over a period of 2 h (slightly exothermic; 30 °C). After 2 h benzyl
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1H NMR: d = 7.39–7.29 (m, 5 H, Ph), 4.48 (s, 2 H, CH2Ph), 3.94 (dt,
2J = 3J1 = 11.8 Hz, 3J2 = 2.9 Hz, 1 H, 6-H), 3.88–3.81 (m, 2 H, 6-H,
4-H), 3.32 (d, 2J = 8.6 Hz, 1 H, CH2-OBn), 3.14 (d, 2J = 8.6 Hz, 1
H, CH2-OBn), 1.67 (dddd, 2J = 12.6 Hz, 3J1 = 3J2 = 12.0 Hz, 3J3 =
5.5 Hz, 1 H, 5-Hax), 1.41 (s, 3 H, 2-CH3), 1.34 (s, 3 H, 2-CH3), 1.30
(dq, 2J = 12.6 Hz, 3J1 = 3J2 = 3J3 = 2.6 Hz, 1 H, 5-Heq), 0.89 (s, 3 H,
1-CH3), 0.88 (s, 3 H, 1-CH3).
1H NMR: d = 4.03 (dd, 3J1 = 11.8 Hz, 3J2 = 2.6 Hz, 1 H, 4-H), 3.96
(dt, 2J = 11.8 Hz, 3J1 = 11.8 Hz, 3J2 = 2.8 Hz, 1 H, 6-Hax), 3.85 (ddd,
2J = 11.8 Hz, 3J1 = 5.5 Hz, 3J2 = 1.8 Hz, 1 H, 6-Heq), 2.16 (s, 3 H, 4¢-
H), 1.62 (m, 1 H, 5-H), 1.42 (s, 3 H, 2-CH3), 1.34 (m, 1 H, 5-H),
1.33 (s, 3 H, 2-CH3), 1.12 (s, 3 H, 2¢-CH3), 1.07 (s, 3 H, 1¢-H).
CD: [Q] (l) = +0.144 (295 nm).
MS (CI+): m/z [M+] calcd for C11H20O3: 200.27; found: 201 [M +
HRMS (EI+): m/z [M+] calcd for C17H26O3: 278.1882; found:
278.1904.
H+].
Compounds 8b to 8k could be prepared in an analogous manner to
8a.
Method 2
To a solution of 5b (118 g, 495 mmol) in CH2Cl2 (2.5 L) were added
2,2-dimethoxypropane (340 mL, 2.775 mol), ( )-camphor-10-sul-
fonic acid (4.3 g, 18.5 mmol) and the mixture was stirred at 23 °C
for 16 h. The mixture was poured into sat. NaHCO3 and extracted
with CH2Cl2. The organic layers were washed with brine, dried over
Na2SO4 and concentrated in vacuo. The residue was purified by
flash column chromatography (EtOAc–hexane, 20:80) to give 6
(113 g, 406 mmol, 82.0%) as a colorless oil.
(4S)-4-(2-Methyl-3-oxopent-2-yl)-2,2-dimethyl[1,3]dioxane (8b)
[a]22D +13.5 (c = 0.465) {Lit.9k [a]20D = +12.4 (c = 1.0, CHCl3)}.
1H NMR: d = 4.03 (dd, 3J1 = 11.8 Hz, 3J2 = 2.6 Hz, 1 H, 4-H), 3.95
(dt, 2J = 11.8 Hz, 3J1 = 11.8 Hz, 3J2 = 2.6 Hz, 1 H, 6-Hax), 3.84 (ddd,
2J = 11.8 Hz, 3J1 = 5.5 Hz, 3J2 = 1.8 Hz, 1 H, 6-Heq), 2.50 (q, J = 7.3
Hz, 2 H, 4¢-H), 1.61 (m, 1 H, 5-H), 1.40 (s, 3 H, 2-CH3), 1.32 (m, 1
H, 5-H), 1.31 (s, 3 H, 2-CH3), 1.12 (s, 3 H, 2¢-CH3), 1.05 (s, 3 H, 1¢-
H), 1.00 (t, J = 7.3 Hz, 3 H, 5¢-H).
(4S)-2-(2,2-Dimethyl[1,3]dioxan-4-yl)-2-methylpropionalde-
hyde (7)
CD: [Q] (l) = +0.209 (291 nm).
MS (CI+): m/z calcd [M+] for C12H22O3: 214.30; found [M + H+]:
215.
To a solution of 6 (113,5 g, 407.7 mmol) in EtOH (1.9 L) was added
Pd/C (16 g, 10%) and the mixture was shaken under 1 atm of H2 gas
at 23 °C until an uptake of 9.2 L hydrogen was reached (about 2 h).
CH2Cl2 was added, the mixture filtered through celite to remove the
catalyst and the filtrate concentrated in vacuo to give (4S)-4-(2-
methyl-1-hydroxyprop-2-yl)-2,2-dimethyl[1,3]dioxane (73.4 g,
389.9 mmol, 95.6%) as a colorless oil; [a]22D +14.7 (c = 0.645).
(4S)-4-(2-Methyl-3-oxohex-2-yl)-2,2-dimethyl[1,3]dioxane (8c)
1H NMR: d = 4.05 (dd, 3J1 = 11.8 Hz, 3J2 = 2.6 Hz, 1 H, 4-H), 3.96
(dt, 2J = 11.8 Hz, 3J1 = 11.8 Hz, 3J2 = 2.9 Hz, 1 H, 6-Hax), 3.85 (ddd,
2J = 11.8 Hz, 3J1 = 5.5 Hz, 3J2 = 1.8 Hz, 1 H, 6-Heq), 2.47 (t, J = 7.3
Hz, 2 H, 4¢-H), 1.62 (m, 1 H, 5-H), 1.56 (m, 2 H, 5¢-H), 1.41 (s, 3 H,
2-CH3), 1.32 (s, 3 H, 2-CH3), 1.31 (m, 1 H, 5-H), 1.13 (s, 3 H, 2¢-
CH3), 1.05 (s, 3 H, 1¢-H), 0.88 (t, J = 7.3 Hz, 3 H, 5¢-H).
1H NMR: d = 3.96 (ddd, 2J = 3J1 = 11.8 Hz, 3J2 = 2.9 Hz, 1 H, 6-Hax),
3.87 (dd, 2J = 11.8 Hz, 3J = 5.5 Hz, 1 H, 6-Heq), 3.80 (dd, 3J1 = 11.8
Hz, 3J2 = 2.6 Hz, 1 H, 4-Hax), 3.55 (dd, 2J = 11.0 Hz, 3J = 5.9 Hz, 1
3
H, CHHOH), 3.37 (dd, 2J = 11.0 Hz, J = 5.5 Hz, 1 H, CHHOH),
CD: [Q] (l) = +0.224 (292 nm).
MS (CI+): m/z calcd [M+] for C13H24O3: 228.33; found [M + H+];
229.
3
2
3
3
2.99 (t, J = 5.7 Hz, 1 H, OH), 1.77 (dq, J = J1 = J2 = 12.2 Hz,
3J3 = 5.7 Hz, 1 H, 5-Hax), 1.45 (s, 3 H, 2-CH3), 1.38 (s, 3 H, 2-CH3),
1.36 (ddd, 2J = 12.2 Hz, 3J1 = 5.1 Hz, 3J2 = 2.5 Hz, 1 H, 5-Heq), 0.90
(s, 3 H, 2¢-CH3), 0.88 (s, 3 H, 2¢-CH3).
(4S)-4-(2-Methyl-3-oxohept-2-yl)-2,2-dimethyl[1,3]dioxane (8d)
1H NMR: d = 4.04 (dd, 3J1 = 11.8 Hz, 3J2 = 2.6 Hz, 1 H, 4-H), 3.95
(dt, 2J = 11.8 Hz, 3J1 = 11.8 Hz, 3J2 = 2.6 Hz, 1 H, 6-Hax), 3.85 (ddd,
2J = 11.8 Hz, 3J1 = 5.5 Hz, 3J2 = 1.8 Hz, 1 H, 6-Heq), 2.49 (t, J = 7.4
Hz, 2 H, 4¢-H), 1.69–1.47 (m, 3 H), 1.41 (s, 3 H, 2-CH3), 1.35–1.20
(m, 3 H), 1.32 (s, 3 H, 2-CH3), 1.12 (s, 3 H, 2¢-CH3), 1.05 (s, 3 H,
1¢-H), 0.90 (t, J = 7.4 Hz, 3 H, 7¢-H).
To a solution of oxalyl chloride (13.0 mL, 151.6 mmol) in CH2Cl2
(0.5 L) at –70 °C was added DMSO (21.1 mL, 297 mmol) and after
10 min the solution of (4S)-4-(2-methyl-1-hydroxyprop-2-yl)-2,2-
dimethyl[1,3]dioxane (20.0 g, 106.2 mmol) in CH2Cl2 (0.5 L) was
added. After 30 min Et3N (64.8 mL, 467 mmol) was added and the
solution stirred at –35 °C for 1 h. Water was added and the mixture
was extracted with CH2Cl2. The organic layers were washed with
brine, dried over Na2SO4 and concentrated in vacuo. The crude
product 7 (20.9 g) was used without further purification.
CD: [Q] (l) = +0.130 (291 nm).
MS (CI+): m/z [M+] calcd for C14H26O3: 242.36; found: [M + H+]:
243.
(4S)-4-(2-Methyl-3-oxobut-2-yl)-2,2-dimethyl[1,3]dioxane (8a);
General Procedure
(4S)-4-(2-Methyl-3-oxo-4-phenylbut-2-yl)-2,2-dimethyl[1,3]di-
oxane (8e)
To Et2O (350 mL) was added a solution of methylmagnesium bro-
mide (2287 mL, 860 mmol, 3 M in Et2O) at 0 °C, followed by the
solution of crude 7 (103.5 g, 543 mmol) in Et2O (1.7 L) and the mix-
ture was stirred at 0 °C for 0.5 h. The mixture was poured into sat.
NH4Cl solution and extracted with EtOAc. The organic layers were
washed with brine, dried over Na2SO4 and concentrated in vacuo.
The residue was purified by flash column chromatography (EtOAc–
hexane, 15:85) to give epimeric alcohols (4S)-4-(2-methyl-3(RS)-
hydroxybut-2-yl)-2,2-dimethyl[1,3]dioxane (95.1 g, 470 mmol,
86.6%) as a colorless oil.
1H NMR: d = 7.30 (m, 3 H, m,p-Ph), 7.19 (m, 2 H, o-Ph), 4.07 (dd,
3J1 = 11.8 Hz, 3J2 = 2.6 Hz, 1 H, 4-H), 3.97 (dt, 2J = 11.8 Hz, 3J1 =
11.8 Hz, 3J2 = 2.6 Hz, 1 H, 6-Hax), 3.87 (ddd, 2J = 11.8 Hz, 3J1 = 5.1
Hz, 3J2 = 1.5 Hz, 1 H, 6-Heq), 3.85 (s, 2 H, 4¢-H), 1.66 (m, 1 H, 5-
H), 1.43 (s, 3 H, 2-CH3), 1.38 (m, 1 H, 5-H), 1.38 (s, 3 H, 2-CH3),
1.20 (s, 3 H, 2¢-CH3), 1.15 (s, 3 H, 1¢-H).
CD: [Q] (l) = +0.310.
HRMS (EI+): m/z [M+] calcd for C17H24O3: 276.1725; found:
276.1729.
To a solution of (4S)-4-(2-methyl-3(RS)-hydroxybut-2-yl)-2,2-di-
methyl[1,3]dioxane (95.1 g, 470 mmol) in CH2Cl2 (2.5 L) were add-
ed molecular sieves (4 Å, 2.0 g), N-methylmorpholine-N-oxide
(82.8 g, 706.8 mmol) and tetrapropylammonium perruthenate (6.9
g, 19.6 mmol). The mixture was stirred overnight and purified by
flash column chromatography (EtOAc–hexane, 90:10) to give 8a
(89.2 g, 445 mmol, 94.8%) as colorless crystalline solid.
(4S)-4-(2-Methyl-3-oxo-5-phenylpent-2-yl)-2,2-dimethyl[1,3]di-
oxane (8f)
1H NMR: d = 7.27 (m, 3 H, m,p-Ph), 7.14 (m, 2 H, o-Ph), 4.01 (dd,
3J1 = 11.8 Hz, 3J2 = 2.6 Hz, 1 H, 4-H), 3.93 (dt, 2J = 11.8 Hz, 3J1 =
11.8 Hz, 3J2 = 2.6 Hz, 1 H, 6-Hax), 3.83 (ddd, 2J = 11.8 Hz, 3J1 = 5.5
Hz, 3J2 = 1.8 Hz, 1 H, 6-Heq), 2.84 (m, 4 H, 4¢-H, 5¢-H), 1.60 (m, 1
Synthesis 2005, No. 2, 301–305 © Thieme Stuttgart · New York

PAPER
Synthesis of C1–C6 Fragment of Epothilones
305
H, 5-H), 1.36 (s, 3 H, 2-CH3), 1.31 (s, 3 H, 2-CH3), 1.28 (m, 1 H, 5-
H), 1.12 (s, 3 H, 2¢-CH3), 1.03 (s, 3 H, 1¢-H).
Hz, 1 H, 6-Heq), 2.51 (t, J = 7.3 Hz, 2 H, 4¢-H), 2.21 (q, 3J = 7.3 Hz,
2 H, 5¢-H), 1.67 (s, 3 H, 7¢-CH3), 1.63 (m, 1 H, 5-H), 1.62 (s, 3 H,
8¢-H), 1.41 (s, 3 H, 2-CH3), 1.32 (s, 3 H, 2-CH3), 1.31 (m, 1 H, 5-
H), 1.12 (s, 3 H, 2¢-CH3), 1.05 (s, 3 H, 1¢-H).
CD: [Q] (l) = +0.174 (292 nm).
HRMS (EI+): m/z [M+] calcd for C18H26O3: 290.1882; found:
290.1859.
CD: [Q] (l) = +0.225 (291 nm).
HRMS (EI+): m/z [M+] calcd for C16H28O3: 268.2038; found:
(4S)-4-(2-Methyl-3-oxo-7-trimethylsilylhept-6-in-2-yl)-2,2-di-
methyl[1,3]dioxane (8g)
268.2030.
1H NMR: d = 4.02 (dd, 3J1 = 11.8 Hz, 3J2 = 2.6 Hz, 1 H, 4-H), 3.94
(dt, 2J = 11.8 Hz, 3J1 = 11.8 Hz, 3J2 = 2.6 Hz, 1 H, 6-Hax), 3.84 (ddd,
2J = 11.8 Hz, 3J1 = 5.5 Hz, 3J2 = 1.8 Hz, 1 H, 6-Heq), 2.73 (dd, 3J1 =
9.2 Hz, 3J1 = 7.0 Hz, 2 H, 5¢-H), 2.44 (dd, 3J1 = 8.1 Hz, 3J1 = 5.9 Hz,
2 H, 4¢-H), 1.69 (m, 1 H, 5-H), 1.41 (s, 3 H, 2-CH3), 1.33 (s, 3 H, 2-
CH3), 1.31 (m, 1 H, 5-H), 1.13 (s, 3 H, 2¢-CH3), 1.07 (s, 3 H, 1¢-H),
0.12 (s, 9 H, SiCH3).
References
(1) Gerth, K.; Bedorf, N.; Höfle, G.; Irschik, H.; Reichenbach,
H. J. Antibiotics 1996, 49, 560.
(2) Bollag, D. M.; McQueeney, P. A.; Zhu, J.; Hensens, O.;
Koupal, L.; Liesch, J.; Goetz, M.; Lazarides, E.; Woods, C.
M. Cancer Res. 1995, 55, 2325.
(3) Chou, T.-C.; Zhang, X.-G.; Balog, A.; Su, D.-S.; Meng, D.;
Savin, K.; Bertino, J. R.; Danishefsky, S. J. Proc. Natl. Acad.
Sci. U.S.A. 1998, 95, 9642.
(4) Chou, T.-C.; Zhang, X.-G.; Harris, C. R.; Kuduk, S. D.;
Balog, A.; Savin, K.; Bertino, J. R.; Danishefsky, S. J. Proc.
Natl. Acad. Sci. U.S.A. 1998, 95, 15798.
CD: [Q] (l) = +0.170 (290 nm).
(4S)-4-(2-Methyl-3-oxo-8-trimethylsilyloct-7-in-2-yl)-2,2-di-
methyl[1,3]dioxane (8h)
1H NMR: d = 4.05 (dd, 3J1 = 11.8 Hz, 3J2 = 2.6 Hz, 1 H, 4-H), 3.95
(dt, 2J = 11.8 Hz, 3J1 = 11.8 Hz, 3J2 = 2.6 Hz, 1 H, 6-Hax), 3.85 (ddd,
2J = 11.8 Hz, 3J1 = 5.5 Hz, 3J2 = 1.8 Hz, 1 H, 6-Heq), 2.62 (m, 2 H,
4¢-H), 2.23 (m, 2 H, 6¢-H), 1.74 (m, 2 H, 5¢-H), 1.63 (m, 1 H, 5-H),
1.41 (s, 3 H, 2-CH3), 1.33 (s, 3 H, 2-CH3), 1.31 (m, 1 H, 5-H), 1.14
(s, 3 H, 2¢-CH3), 1.06 (s, 3 H, 1¢-H), 0.14 (s, 9 H, SiCH3).
(5) Sepp-Lorenzino, L.; Balog, A.; Su, D.-S.; Meng, D.; Timaul,
N.; Scher, H. I.; Danishefsky, S. J.; Rosen, N. Prostate
Cancer Prostatic Dis. 1999, 2, 41.
(6) Christina, R.; Harris, C. R.; Danishefsky, S. J. J. Org. Chem.
1999, 64, 8434.
CD: [Q] (l) = +0.194 (291 nm).
HRMS (EI+): m/z [M+] calcd for C14H24O3: 240.1725; found:
240.1799.
(7) For reviews on the total syntheses of epothilones see:
(a) Altmann, K.-H. Org. Biomol. Chem. 2004, 2137.
(b) Zhang, R.; Liu, Z. Curr. Org. Chem. 2004, 8, 267.
(c) Wartmann, M.; Altmann, K.-H. Curr. Med. Chem.: Anti-
Cancer Agents 2002, 2, 123. (d) Flörsheimer, A.; Altmann,
K.-H. Expert Opin. Ther. Pat. 2001, 11, 951. (e) Nicolaou,
K. C.; Ritzén, A.; Namoto, K. Chem. Commun. 2001, 1523.
(f) Mulzer, J. Monatsh. Chem. 2000, 131, 205.
(4S)-4-(2-Methyl-3-oxohex-5-en-2-yl)-2,2-dimethyl[1,3]di-
oxane (8i)
3
2
1H NMR: d = 5.93 (m, 1 H, 5¢-H), 5.14 [dq, JZ = 10.3 Hz, J ≈
4J1 ≈ 4J2 ≈ 1.5 Hz, 1 H, 6¢-H(Z)], 5.06 [dq, 3JE = 17.3 Hz, 2J ≈ 4J1 ≈
4J2 ≈ 1.5 Hz, 1 H, 6¢-H(E)], 4.02 (dd, J1 = 11.8 Hz, J2 = 2.6 Hz,
1 H, 4-H), 3.95 (dt, 2J = 11.8 Hz, 3J1 = 11.8 Hz, 3J2 = 2.6 Hz, 1 H,
6-Hax), 3.85 (ddd, 2J = 11.8 Hz, 3J1 = 5.5 Hz, 3J2 = 1.8 Hz, 1 H, 6-
Heq), 3.30 (m, 2 H, 4¢-H), 1.62 (m, 1 H, 5-H), 1.41 (s, 3 H, 2-CH3),
1.34 (s, 3 H, 2-CH3), 1.33 (m, 1 H, 5-H), 1.14 (s, 3 H, 2¢-CH3), 1.09
(s, 3 H, 1¢-H).
3
3
(g) Nicolaou, K. C.; Roschangar, F.; Vourloumis, D. Angew.
Chem. Int. Ed. 1998, 37, 2014.
(8) For another protecting group strategy see: (a) Klar, U.;
Schwede, W.; Skuballa, W.; Buchmann, B.; Schirner, M.
PCT Int. Appl., WO 9907692, 1999. (b) Klar, U.; Skuballa,
W.; Buchmann, B.; Schwede, W.; Bunte, T.; Hoffmann, J.;
Lichtner, R. B. In New Prospects in Anticancer Agents for
the 21st Century, ACS Symposium Series 796; Ojima, I.;
Vite, G. D.; Altmann, K.-H., Eds.; American Chemical
Society: Washington DC, 2001, 131.
CD: [Q] (l) = +0.115 (290 nm).
HRMS (EI+): m/z [M+] calcd for C17H30O3Si: 310.1964; found:
310.1952.
(9) For alternative approaches to the C1–C6 fragment of
epothilones see: (a) Zheng, Y.; Avery, M. A. Tetrahedron
2004, 60, 2091. (b) Ramachandran, P. V.; Prabhudas, B.;
Chandra, J. S.; Reddy, M.; Venkat, R.; Brown, H. C.
Tetrahedron Lett. 2004, 45, 1011. (c) Chandrasekhar, S.;
Raji Reddy, C. Tetrahedron: Asymmetry 2002, 13, 261.
(d) Shioji, K.; Kawaoka, H.; Miura, A.; Okuma, K. Synth.
Commun. 2001, 31, 3569. (e) Panicker, B.; Karle, J. M.;
Avery, M. A. Tetrahedron 2000, 56, 7859. (f) Taylor, R. E.;
Galvin, G. M.; Hilfiker, K. A.; Chen, Y. J. Org. Chem. 1998,
63, 9580. (g) Gabriel, T.; Wessjohann, L. Tetrahedron Lett.
1997, 38, 1363. (h) De Brabander, J.; Rosset, S.;
Bernardinelli, G. Synlett 1997, 824. (i) Erratum 1: De
Brabander, J.; Rosset, S.; Bernardinelli, G. Synlett 1998,
328. (j) Erratum 2: De Brabander, J.; Rosset, S.;
Bernardinelli, G. Synlett 1998, 692. (k) Schinzer, D.;
Limberg, A.; Böhm, O. M. Chem.–Eur. J. 1996, 2, 1477.
(10) A similar observation has been described for 3,4-dialkoxy-1-
alkenes by: Jung, M. E.; Karama, U. Tetrahedron Lett. 1999,
40, 7907.
(4S)-4-(2-Methyl-3-oxohept-6-en-2-yl)-2,2-dimethyl[1,3]di-
oxane (8j)
3
2
1H NMR: d = 5.81 (m, 1 H, 5¢-H), 5.02 [dq, JE = 17.3 Hz, J ≈
4J1 ≈ 4J2 ≈ 1.7 Hz, 1 H, 6¢-H(E)], 4.95 [m, 1 H, 6¢-H(Z)], 4.04 (dd,
3J1 = 11.8 Hz, J2 = 2.6 Hz, 1 H, 4-H), 3.95 (dt, J = 11.8 Hz,
3
2
3J1 = 11.8 Hz, J2 = 2.6 Hz, 1 H, 6-Hax), 3.85 (ddd, J = 11.8 Hz,
3J1 = 5.5 Hz, 3J2 = 1.8 Hz, 1 H, 6-Heq), 2.60 (t, 3J = 7.1 Hz, 2 H, 4¢-
H), 2.29 (m, 2 H, 5¢-H), 1.62 (m, 1 H, 5-H), 1.41 (s, 3 H, 2-CH3),
1.32 (s, 3 H, 2-CH3), 1.31 (m, 1 H, 5-H), 1.13 (s, 3 H, 2¢-CH3), 1.06
(s, 3 H, 1¢-H).
3
2
CD: [Q] (l) = +0.200 (291 nm).
HRMS (EI+): m/z [M+] calcd for C18H32O3Si: 324.2121; found:
324.2134.
(4S)-4-(2,7-Dimethyl-3-oxooct-6-en-2-yl)-2,2-dimethyl[1,3]di-
oxane (8k)
1H NMR: d = 5.06 (t, J = 7.2 Hz, 1 H, 6¢-H), 4.03 (dd, 3J1 = 11.8 Hz,
3J2 = 2.6 Hz, 1 H, 4-H), 3.95 (dt, 2J = 11.8 Hz, 3J1 = 11.8 Hz, 3J2 =
2.6 Hz, 1 H, 6-Hax), 3.84 (ddd, 2J = 11.8 Hz, 3J1 = 5.5 Hz, 3J2 = 1.8
Synthesis 2005, No. 2, 301–305 © Thieme Stuttgart · New York