Synthesis and conformational analysis of macrocycles related to 10-oxa-epothilone

Article abstract of DOI:10.1002/ejoc.200400212

A short and convergent synthesis of macrocyclic lactones related to 10-oxa-epothilone is based on aldolisation of a 3-(2′-methylallyloxy) aldehyde derived from methyl (2S)-3-hydroxy-2-methylpropionate followed by ring-closing metathesis. Wiley-VCH Verlag

Full text of DOI:10.1002/ejoc.200400212

FULL PAPER
Synthesis and Conformational Analysis of Macrocycles Related to
10-Oxa-epothilone
Delphine Quintard,[a] Philippe Bertrand,[a] Christian Bachmann,[b] and
Jean-Pierre Gesson*[a]
Keywords: Aldolisation / Epothilone / Macrocycles / Ring-closing metathesis
A short and convergent synthesis of macrocyclic lactones re-
lated to 10-oxa-epothilone is based on aldolisation of a 3-(2Ј-
methylallyloxy) aldehyde derived from methyl (2S)-3-hy-
droxy-2-methylpropionate followed by ring-closing meta-
thesis.
(© Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim,
Germany, 2004)
Introduction
dently synthesized by White[21Ϫ23] and by Ermolenko and
Potier,[24] appears to be much less active. Few attempts to
modify the C1ϪC3 part have been made. Initial synthetic
studies by Nicolaou on 2,3-dehydro epoA (6a) have shown
that this compound retains tubulin affinity.[9] Recently,
Vite[25] has demonstrated that 2,3-dehydro epoB (6b), pre-
pared by dehydration of epoB (2),[26] is almost as active
(IC50 3.4 nM) as epoB (0.8 nM) against HCT-116 human
colon carcinoma cells [6a being 10 times less potent than
epoA (1) against the same cell line]. Moreover, the (3R)-
cyano derivative 7 obtained by cyanide addition to 6b is
also very active against tubulin polymerisation and cancer
cell lines in vitro, in contrast to the (3S) diastereoisomer.[23]
These results, together with those obtained by ring en-
largement or ring contraction of the macrocycle in the
epoA[27] or epoB series,[28] can be interpreted in terms of the
different conformations, the crucial importance of which Ϫ
particularly for the aldol moiety (vide infra) Ϫ has been
elegantly demonstrated by Taylor.[29,30] The more stable
conformer, in solution, for EpoA, EpoB and EpoD, de-
duced from computational studies (MM2 force field) and
NOE measurements, is similar to the solid-state structure
found by X-ray for EpoB.[1] Conformational flexibility of
these macrocycles is important. however, and numerous 3D
models of tubulin-bound epoA or B were proposed[31Ϫ38]
before the very recent high-resolution NMR structure of
epoA bound to tubulin.[39] This shows two main confor-
mational switches between the 3D structures of free and
tubulin-bound epoA: the C16ϪC17ϪC18ϪC19 dihedral
angle changes from anti-periplanar to syn-periplanar, prob-
ably to allow hydrogen bonding of the nitrogen atom of
the thiazole ring with the protein, and the C2ϪC3ϪC4ϪC5
dihedral angle changes from a gaucheϩ to a gaucheϪ con-
formation to allow the C3 hydroxy group to point outwards
from the macrocycle ring. No change occurs in the import-
Epothilones A (EpoA, 1 ) and B (EpoB, 2), isolated by
Höfle from the myxobacterium Sorangium cellulosum,[1] are
potent antitumour agents (Figure 1).[2Ϫ4] These compounds
act by microtubule stabilization, being able to displace pa-
clitaxel from its tubulin complex. They are also character-
ised by improved properties (high potency, activity against
MDR cell lines, better water solubility) with respect to this
widely used clinical drug. Their 16-membered macrocyclic
structure and side chain are reminiscent of other microtub-
ule stabilisers such as sarcodictyn A,[5] eleutherobin,[6] lauli-
malide[7] and peloruside A.[8] The ongoing interest in epo-
thilones has prompted numerous synthetic studies,[9Ϫ12]
a
large number of analogues having already been prepared by
several groups and interesting structure-activity relation-
ships (SARs) pointed out: desoxy EpoB (EpoD, 3), for ex-
ample, shows a better therapeutic index and is now in phase
I clinical trials,[13] the presence of a hydroxy group at C21
(EpoF) affords better water solubility associated with im-
proved efficacy,[14] different side chains are allowed at
C15,[15] and a lactam function may be present instead of
the lactone.[16,17] At the beginning of these SAR studies, few
attempts to modify the unfunctionalised C9-C11 part were
made. Recently, though, (E)-10,11-dehydro EpoB (Epo490,
4) (as well as its analogue in the EpoA series) has been
isolated and shown to be highly cytotoxic,[18,19] together
with synthetic (E)-9,10-dehydro-12,13-desoxy EpoB (5a).[20]
On the other hand, (Z)-9,10-dehydro EpoB (5b), indepen-
[a]
´
UMR 6514, Universite de Poitiers et CNRS,
40, Avenue du Recteur Pineau, 86022 Poitiers, France
Fax: (internat.) ϩ 33-5-49453501
E-mail: jean-pierre.gesson@univ-poitiers.fr
[b]
´
UMR 6503, Universite de Poitiers et CNRS,
40, Avenue du Recteur Pineau, 86022 Poitiers, France
4762
© 2004 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
DOI: 10.1002/ejoc.200400212
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Synthesis and Conformational Analysis of Macrocycles Related to 10-Oxa-epothilone
FULL PAPER
the presence of an unsaturated ester, an analogue of epoA
bearing a phenyl group in place of the thiazole moiety was
first prepared by use of β-allyloxy aldehyde 9a and a
racemic homoallylic alcohol.
Results and Discussion
Preparation of the key aldehydes 9a and 9b started from
the commercially available methyl (2S)-3-hydroxy-2-methyl-
propionate (10). Etherification with allyl or 2-methylallyl
bromide afforded 11a (70%) or 11b (85%), which were then
reduced with LAH to give 12a and 12b (54 and 58%). An
alternative route starting from the commercially available
(2R)-3-bromo-2-methylpropan-1-ol (13) was less efficient;
protection as a THP ether 14 (or alternatively as a TBDMS
ether) was carried out first, but all conditions used to pre-
pare allyl ether 15 were limited due to competitive elimin-
ation of HBr from 14. The best conditions turned out to
be under phase-transfer catalysis, but only a limited (31%)
isolated yield of 15a was obtained, together with a 49%
yield of the THP ether of 2-methyl-prop-2-en-1-ol. Depro-
tection afforded alcohol 12a (91%), which was converted
into aldehyde 9a with PCC (70%) or under Swern con-
ditions (73%). Swern oxidation of 12b afforded 9b (76%)
(Scheme 1).
Esterification of racemic alcohol 16 with the known acid
17[42] (DCC, DMAP, CH2Cl2) afforded 18 in only 25% iso-
lated yield with use of 1 equiv. of 17 and DCC with respect
to 16, but the yield was increased to 75% with use of 2
equiv. of acid and DCC (Scheme 2). Ester 18 was converted
into the corresponding (Z) enolate (LDA, THF).[13] Upon
addition of 9a (Ϫ78 °C, 30 min), a 5:1 mixture of two aldols
was obtained in 58% yield. Only the major aldol 19 could
be isolated in pure form (23%) after flash chromatography,
together with mixed fractions that could be recycled. The
syn-anti configuration is consistent with similar aldolisation
reactions in the epothilone series, as deduced from compari-
son of NMR spectroscopic data (JH7,H8 ϭ 8.3 Hz and
JH6,H7 ϭ 2.5 Hz) with literature data.[40,43,44] It may be
noted that, as would be expected, the ratio in favour of the
anti isomer is increased from ca. 2:1 to 5:1 upon replace-
Figure 1. Epothilone structures and target analogue 8
ant aldol part (C5ϪC8), in agreement with previous obser- ment of a methylene by an oxygen atom at the β position
vations made by Taylor. of the aldehyde. In the former case the anti selectivity is
In a search for new epothilone analogues, it seems pro- best explained by the Roush model[45] (due to the presence
mising to replace one of the methylene groups at C9 or C10 of the alkene moiety) while in our case chelation (affording
by a heteroatom such as oxygen or sulfur (thereby further the same isomer) may be more important. The final RCM
enhancing water solubility). Furthermore, a short route of 19 (3 ϫ 10Ϫ3 m) was carried out at room temp. in CH2Cl2
should be achievable if a C2ϪC3 double bond is present in the presence of 0.1 equiv. of the second generation
instead of the C3 hydroxy group, and this double bond Grubbs catalyst 20.[46] After chromatography, the macro-
should be amenable for further modifications to prepare a cycles 21 (30%) and 22 (18%), differing only in their side
new set of analogues, as shown by Vite. Indeed, multistep chain configurations, were isolated. The (E) configurations
syntheses of 9-oxa-[40] and 10-oxa-epothilones,[41] using of the newly created alkenes were confirmed by NMR (J ϭ
ring-closing metathesis (RCM) as the final step, have re- 14.9 and 15.2 Hz, respectively). Comparison of the H3
cently been patented by the Schering group. In our case the chemical shifts in 21/22 and compounds 23/24[40] (as well
retrosynthetic strategy toward 8 is based on the preparation as with the methyl analogue 28, vide infra) was used to
of the 3-(2Ј-methylallyloxy) aldehyde 9b, followed by aldoli- determine the C15 configuration, since this proton is more
sation and RCM. To test the feasibility of such a strategy in shielded in the natural (15S) isomer (Table 1).
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D. Quintard, P. Bertrand, C. Bachmann, J.-P. Gesson
FULL PAPER
Scheme 1
Table 1. Comparison of 1H chemical shifts (ppm) of protons H3
and H15 in 21/22/28 and 23/24
Compound
21
22
23
24
28
δ H3
δ H15
6.82
5.65
7.17
5.51
6.78
5.16Ϫ5.22
7.02
5.21Ϫ5.26
6.77
5.62
nesium bromide and DIP-Cl[49] (under these conditions no
filtration of magnesium salts is needed). Compound 25
{[α]D ϭ Ϫ18.6 (c ϭ 0.6, CHCl3) (ref.: [α]D ϭ Ϫ15.9 (c ϭ
4.9, CHCl3)[40] and [α]D ϭ Ϫ20.2 (c ϭ 1, CHCl3)[41]} was
obtained in 70% yield and 96% ee (chiral HPLC). As before,
esterification of 17[40] with 25 (DCC, DMAP, CH2Cl2) af-
forded 26 (78%). Aldolisation with 9b afforded a 5:1 mix-
ture of two aldols (49%), the major of which could be iso-
lated in pure form after flash chromatography (27, 19%).
The observed NMR spectroscopic data (JH7,H8 ϭ 8.5 Hz
and JH6,H7 ϭ 2.8 Hz) are similar to those of 19. The final
RCM was carried out as before with 20 (0.15 equiv.,
CH2Cl2, room temp., 72 h), to give a 46% yield of 28 and
8 (1.3:1 ratio), which were readily separated by flash chro-
matography. It is interesting to point out that such RCMs
have previously been reported with the Schrock Mo cata-
lyst[50,51] while the use of the Grubbs ruthenium carbene
[RuCl2(PCy3)2CHPh] was unsuccessful, the formation of a
lactone by metathesis between the C13ϪC14 and the
C2ϪC3 alkenes not having been observed under such con-
ditions. The (E) configuration in 28 is in agreement with
13C chemical shifts and with NOE experiments.
Conformational Analysis
As mentioned earlier, the epothilone macrocycle is fairly
flexible but the configuration of the aldol moiety (C5ϪC8)
is critical for bioactivity. Conformation I exists in equilib-
Scheme 2
Alcohol 25 was prepared from the corresponding alde- rium with conformation II and their relative contributions
hyde by a slight modification of the reported pro- in solution may be deduced from JH6,H7. According to
cedure:[47,48] (Ϫ)-Ipc2Ballyl was generated from allylmag- Taylor, in the case of EpoA, the computationally predicted
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Synthesis and Conformational Analysis of Macrocycles Related to 10-Oxa-epothilone
FULL PAPER
Examination of the 1H NMR spectra reveals that the
H6,H7 coupling constants for the two isomers are different:
9.5 Hz for 28 and 2.7 Hz for 8. The observed coupling con-
stant for 28 is thus similar to the value reported for EpoA
(J ϭ 8.5 Hz, CD2Cl2), in agreement with a 9:1 ratio for
conformers I and II (ratio 4:1 for EpoA). A reversal of sta-
bility between the two conformers is found for 8, the ob-
served coupling constant being in agreement with a 1:4 ra-
tio between conformers I and II. In addition, in the case of
8, a NOE is clearly observed between H6 and Me8, and
this is only possible for conformer II. Similarly, it was found
in the phenyl series that the (15S) isomer 21 exhibits a larger
JH6,H7 value (9.1 Hz) than the (15R) isomer 22. The confor-
mation of the epothilone macrocycle is thus modified by
inversion of configuration at C15.
Furthermore, for epothilones C and D, Taylor[52] has
found two stable conformers for the C11ϪC15 part, con-
former III being the more stable. For the compound trans-
28, NOEs are observed between H15 and H13, and the
coupling constant between H15 and H14b is 10.3 Hz while
that with H14a is Ͻ1 Hz. Those data fit better with model
III. For the cis compound 8, NOEs cannot be observed
between H13 and H15, since their NMR signals are col-
lapsed. The coupling constants between H15 and H14a/
H14b are 6.8 and 6.9 Hz, respectively. This indicates that
conformer IV is predominant in this case (Figure 3).
Scheme 3
value of JH6,H7 is 10.5 Hz for the more stable conformer I
and 1 Hz for conformer II (Figure 2).
Molecular modelling at the RHF/3.21G level (Gaussian
98[53]) was then carried out and, as expected, large sets of
possible conformations were found both for 8 and for 28.
As indicated above, important aspects are the position of
the C12 methyl group, which may be found either ‘‘up’’ or
‘‘down’’ with respect to the median plane of macrocycle,
and the C5ϪC6ϪC7ϪC8 torsion angle. The most interest-
ing result is the presence, in the more stable conformers,
of a hydrogen bond between the OH aldol and O10, thus
producing conformations of type I (Figure 2). Hence, for
the more stable conformers of 28 (Erel ϭ Ϫ12.8 kcal/mol,
total energy ϭ Ϫ1822.42555 au), the H bonding is charac-
˚
terised by a 1.78 A distance and by a 144° bond angle, while
˚
values of 1.78 A and 148.5° are observed for 8 (Erel ϭ Ϫ8.2
kcal/mol). The C5ϪC6ϪC7ϪC8 torsion angles in these
conformers are Ϫ59.3° and Ϫ63.1°, respectively (Figure 4).
For (E) isomer 28, these calculations are in agreement with
NMR spectroscopic data corresponding to conformer I.
The more stable conformer II was found at a much higher
energy (Erel ϭ 0 kcal/mol) with an s-cis ester configuration.
Figure 2. Taylor models of the C5ϪC8 region (left) and oxa com-
pounds (right) showing possible hydrogen bonding
Figure 3. Taylor models of the C1ϪC13 region showing possible NOEs
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D. Quintard, P. Bertrand, C. Bachmann, J.-P. Gesson
FULL PAPER
1
with TMS as internal standard. Assignment of H NMR and 13C
NMR spectra was achieved by COSY 1H-1H, NOE and DEPT
(Multiplicity by DEPT: s ϭ C, d ϭ CH, t ϭ CH2, q ϭ CH3).
High-resolution MS were performed by the ‘‘Service Central de
Microanalyse’’ (CNRS, Lyon). All reactions were run under an in-
ert atmosphere. THF was dried with and distilled from sodium/
benzophenone, and CH2Cl2 was distilled from CaCl2. Organic ex-
tract mixtures were dried with anhydrous Na2SO4 and filtered, and
the solvent was then removed under reduced pressure. All separ-
ations were performed under flash chromatography (MPLC) con-
ditions on silica gel (25Ϫ40 mµ), completed, if necessary, by pre-
parative thin-layer chromatography (TLC) performed on silica gel
plates (60 GF254).
Methyl (2R)-3-Allyloxy-2-methylpropanoate (11a): In
a flask
wrapped with aluminium foil and under N2, methyl (ϩ)-l-β-
hydroxyisobutyrate (2 mL, 18.05 mmol) was added to a suspension
of MgSO4 (435 mg, 18 mmol) and Ag2O (5.4 g, 23.5 mmol) in
petroleum ether (80 mL). After the system had been stirred for 1 h
at room temp., the flask was cooled in an ice bath, and allyl bro-
mide (2.34 mL, 27.07 mmol) was slowly added. After 30 min, a se-
cond fraction of Ag2O was added (5.9 g, 25.3 mmol), and the mix-
ture was stirred at room temp. overnight. Filtration through Celite
and magnesium sulfate, concentration in vacuo and chromatogra-
phy on silica gel (eluent: petroleum ether/EtOAc, 90:10) afforded
1.8 g of 11a (70%) as a colourless oil. [α]2D0 ϭ ϩ13 (c ϭ 1.7, CHCl3).
3
1H NMR (CDCl3): δ ϭ 1.17 (d, J1H ϭ 7.1 Hz, 3 H, 2-CH3), 2.75
3
3
2
(qt, J3H ϭ 7.1, J2H ϭ 6.9 Hz, 1 H, 2-H), 3.63 (dd, J1H ϭ 9.2,
3J1H ϭ 7.3 Hz, 2 H, 3-H2), 3.70 (s, 3 H, CH3 ester), 3.98 (dt, 3J1H ϭ
4
3
2
5.5, J2H ϭ 1.4 Hz, 2 H, 1Ј-H2), 5.16 (dd, J1Hcis ϭ 10.3, J1H
ϭ
3
4
1.4 Hz, 1 H, 3Ј-Hcis), 5.25 (ddd, J1Htrans ϭ 17.2, J1H ϭ 1.4,
2J1H ϭ 0.6 Hz, 1 H, 3Ј-Htrans), 5.90 (ddt, 3J1Htrans ϭ 17.2, 3J1Hcis
ϭ
10.3, 3J2H ϭ 5.5 Hz, 1 H, 2Ј-H) ppm.13C NMR (CDCl3): δ ϭ 15.2,
41.4, 53.0, 73.1, 73.3, 118.3, 135.8, 176.5 ppm. IR (cmϪ1): ν˜ ϭ
3082, 1736, 1647, 1459, 1394, 992, 927.
Figure 4. Conformation of 28 and 8 obtained from calculations
(C atoms black, H atoms light grey, other atoms as indicated)
Methyl (R)-2-Methyl-3-(2Ј-methylallyloxy)propanoate (11b): Use of
the same procedure as above with 10 (1 mL, 9 mmol) and 3-bromo-
2-methylpropene (1.36 mL, 13.54 mmol) (except for stirring at
room temp. for 3 d) gave 11b (1.33 g, 85%) as a colourless oil.
[α]2D0 ϭ ϩ14 (c ϭ 0.5, CHCl3). 1H NMR (CDCl3): δ ϭ 1.17 (d,
3J1H ϭ 8.5 Hz, 3 H, 2-CH3), 1.71 (br. s, 3 H, 2Ј-CH3), 2.75 (m, 1
H, 2-H), 3.43 (dd, 2J1H ϭ 9.2, 3J1H ϭ 5.9 Hz, 1 H, 3-Ha), 3.59 (dd,
For the (Z) isomer, the more stable conformer does not fit
with NMR spectroscopic data, but conformer II is closer in
energy (Erel ϭ Ϫ2.6 kcal/mol). It is characterised by an s-cis
ester configuration and an intermolecular hydrogen bond
between the OH aldol and the ester carbonyl.
3
2J1H ϭ 9.2, J1H ϭ 7.3 Hz, 1 H, 3-Hb), 3.70 (s, 3 H, CH3 ester),
3.88 (t, 4J2H ϭ 0.7 Hz, 2 H, 1Ј-H2), 4.88 (t, 4J2H ϭ 0.6 Hz, 1 H, 3Ј-
Ha), 4.93 (t, 4J2H ϭ 0.9 Hz, 1 H, 3Ј-Hb) ppm. 13C NMR (CDCl3):
δ ϭ 13.2, 19.3, 40.1, 50.2, 71.7, 75.1, 112.3, 142.1, 175.4 ppm. IR
(cmϪ1): ν˜ ϭ 3077, 1736, 1657, 1455, 1375, 1251, 1199, 1095, 991,
901.
Conclusion
In conclusion, 10-oxa-epothilone analogues have been
prepared in only 14 operations (7 steps in the longer linear
sequence) by aldolisation of a chiral 3-(2Ј-methylallyloxy)-
propanal, followed by ring-closing metathesis. These macro-
cycles are amenable to further transformations such as
epoxidation at C12, C13 or Michael addition at C3. No
significant cytotoxic activity against L1210 leukemia was
observed for 8, 21, 22 and 28 (IC50 Ͼ 10 µm). Whether the
observed lack of activity is or is not due to the introduction
of the oxygen atom at C10 remains to be studied.
(2R)-3-Allyloxy-2-methylpropanol (12a): A solution of 11a (2.76 g,
19.3 mmol) in anhydrous diethyl ether (30 mL) was added dropwise
under N2 to a suspension of lithium aluminium hydride (293 mg,
7.7 mmol) in diethyl ether (50 mL). The mixture was heated at re-
flux for 1 h, stirred at room temp. overnight and cooled to 0 °C,
and ethyl acetate (1.32 mL, 13.5 mmol) followed by ethanol
(5.1 mL, 86.8 mmol) were then slowly added to quench excess Li-
AlH4. The salts were precipitated by acidification with HCl (1 n,
6 mL). Water was added, and the aqueous phase was extracted with
diethyl ether (3 ϫ 20 mL). The organic extracts were then washed
with brine, dried (MgSO4) and concentrated under vacuo to pro-
vide a yellow oil (1.95 g), which was chromatographed on silica gel
(petroleum ether/EtOAc, 80:20 to 60:40 as eluent) to afford 12a
(1.1 g, 44%, 54% based on recovered starting material). [α]2D0 ϭ ϩ16
(c ϭ 0.46, CHCl3). 1H NMR (CDCl3): δ ϭ 0.87 (d, 3J1H ϭ 6.9 Hz,
Experimental Section
Melting points are uncorrected. H NMR and 13C NMR were re-
corded on a Bruker 300 MHz spectrometer, in CDCl3 as solvent
1
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Synthesis and Conformational Analysis of Macrocycles Related to 10-Oxa-epothilone
FULL PAPER
3 H, 2-CH3), 2.07 (m, 1 H, 2-H), 2.64 (s, 1 H, OH), 3.45 (dd, tration and washing with diethyl ether (200 mL), the aqueous phase
2J1H ϭ 9.5, 3J1H ϭ 6.5 Hz, 2 H, 1-H2), 3.62 (dd, 2J1H ϭ 9.5, 3J1H ϭ
of the filtrate was extracted with diethyl ether (3 ϫ 40 mL). The
6.2 Hz, 2 H, 3-H2), 3.99 (dd, J1H ϭ 5.5, J1H ϭ 1.2 Hz, 2 H, 1Ј- organic extracts were combined, dried (MgSO4) and concentrated
3
4
3
2
4
H2), 5.22 (dq, J1Hcis ϭ 10.0, J1H ϭ J2H ϭ 1.5 Hz, 1 H, 3Ј-Hcis), in vacuo. Chromatography on silica gel (eluent:petroleum ether/
3
4
5.29 (dq, J1Htrans ϭ 17.2, J2H
ϭ
2J1H ϭ 1.6 Hz, 1 H, 3Ј-Htrans), EtOAc, 90:10) afforded 16 in quantitative yield. 1H NMR (CDCl3):
3
3
3
5.90 (ddt, J1Htrans ϭ 17.2, J1Hcis ϭ 10.0, J2H ϭ 5.5 Hz, 1 H, 2Ј-
δ ϭ 1.88 (br. s, 3 H, 16-CH3), 2.42 (m, 2 H, 14-H2), 4.24 (t, 3J2H ϭ
H) ppm. 13C NMR (CDCl3): δ ϭ 13.4, 35.4, 67.9, 72.2, 75.6, 117.1, 6.0 Hz, 15-H), 5.14 (d, J1Hcis ϭ 8.2 Hz, 1 H, 12-Hcis), 5.17 (d,
3
134.4) ppm. IR (cmϪ1): ν˜ ϭ 3391, 3081, 1647, 1455, 1266, 1197,
3J1Htrans ϭ 15.3 Hz, 1 H, 12-Htrans), 5.83 (m, 1 H, 13-H), 6.52 (br.
s, 1 H, 17-H), 7.3 (m, 5 H, Ph) ppm. 13C NMR (CDCl3): δ ϭ 14.0,
40.2, 77.1, 118.1, 126.2, 126.8, 128.5, 128.6, 129.0, 129.4, 135.0,
137.5, 140.0 ppm. MS: m/z ϭ 188 (12), 147 (100), 129 (94), 115
(47), 91 (91), 77 (39), 69 (37), 65 (23), 55 (15), 51 (28). IR (cmϪ1):
ν˜ ϭ 3432, 3064, 3028, 1659, 1642, 1600, 1584, 1495.
1093, 993, 926.
(2R)-2-Methyl-3-(2Ј-methylallyloxy)propanol (12b): This compound
was produced by the same procedure as used for 12a, starting from
11b (1.3 g, 7.5 mmol) and giving 12b (0.41 g, 38%). [α]2D0 ϭ ϩ15
(c ϭ 0.23, CHCl3). 1H NMR (CDCl3): δ ϭ 1.17 (d, 3J1H ϭ 8.5 Hz,
3 H, 2-CH3), 1.71 (br. s, 3 H, 2Ј-CH3), 2.75 (m, 1 H, 2-H), 3.42
Keto Ester 18: 4-(Dimethylamino)pyridine (1.435 g, 11.75 mmol)
and dicyclohexylcarbodiimide (2.42 g, 11.75 mmol) were added un-
2
3
2
(dd, J1H ϭ 9.4, J1H ϭ 3.5 Hz, 1 H, 3-Ha), 3.46 (dd, J1H ϭ 9.4,
3J1H ϭ 4.9 Hz, 1 H, 3-Hb), 3.69 (d, J1H ϭ 7.0 Hz, 2 H, 1-H2),
3
der N2 to
a solution of 2-methyl-1-phenylhexa-1,5-dien-1-ol
3.88 (t, 4J2H ϭ 0.7 Hz, 2 H, 1Ј-H2), 4.89 (t, 4J2H ϭ 0.5 Hz, 1 H, 3Ј-
Ha), 4.94 (t, 4J2H ϭ 0.7 Hz, 1 H, 3Ј-Hb) ppm. 13C NMR (CDCl3):
δ ϭ 13.2, 19.3, 40.1, 67.7, 71.7, 75.1, 112.3, 142.1 ppm. IR (cmϪ1):
ν˜ ϭ 3436, 3077, 1258, 1200, 1095, 984, 899.
(2.21 g, 11.75 mmol) and 4,4-dimethyl-5-oxohept-2-enoic acid
(2.0 g, 11.75 mmol) in dichloromethane (80 mL). After stirring
overnight at room temp., the mixture was washed with water
(50 mL). The aqueous phases were combined and extracted with
dichloromethane (3 ϫ 20 mL). The combined organic phases were
washed with brine, dried (MgSO4) and concentrated on a rota-
(2R)-3-Allyloxy-2-methylpropanal
(9a):
DMSO
(1.20 mL,
16.9 mmol) in solution in CH2Cl2 was slowly added under N2 to a
cooled (Ϫ50 °C) solution of oxalyl chloride (0.74 mL, 8.46 mmol)
in freshly distilled CH2Cl2 (25 mL). After the mixture had been
stirred at Ϫ 60 °C for 15 min, 12a (1 g, 7.69 mmol) in solution in
CH2Cl2 (7.5 mL) was slowly added (1 mL/min). The reaction was
stirred at Ϫ 60 °C for 1 h 30, Et3N (5.34 mL, 38.4 mmol) was ad-
ded, and the reaction flask was allowed to warm to room temp.
The mixture was then washed with water and with satd. NH4Cl
solution and the combined aqueous phases were extracted with
CH2Cl2 (3 ϫ 15 mL), dried (MgSO4) and concentrated in vacuo to
afford 9a as a yellow oil (719 mg, 76%) after chromatography on
silica gel (eluent: petroleum ether/EtOAc, 90:10). [α]2D0 ϭ ϩ3.6 (c ϭ
vapor. Chromatography on silica gel (petroleum ether/EtOAc, 95:5)
3
afforded 18 (1.0 g, 25%). 1H NMR (CDCl3): δ ϭ 1.01 (t, J2H
ϭ
4
7.0 Hz, 3 H, 6-CH3), 1.32 (s, 6 H, CH3,gem), 1.89 (d, J1H ϭ 1.4
Hz, 3 H, 16-CH3), 2.50 (q, J3H ϭ 7.0 Hz, 2 H, 6-H2), 2.59 (m, 2
H, 14-H2), 5.07 (dd, J1Hcis ϭ 10.1, J1H ϭ 1.8 Hz, 1 H, 12-Hcis),
5.13 (dd, J1Htrans ϭ 15.6, J1H ϭ 1.8 Hz, 1 H, 12-Htrans), 5.42 (t,
3
3
2
3
2
3J2H ϭ 7.6 Hz, 1 H, 15-H), 5.76 (ddt, J1Htrans ϭ 17.1, J1Hcis
ϭ
3
3
3
3
10.1, J2H ϭ 7.0 Hz, 1 H, 13-H), 5.90 (d, J1Htrans ϭ 15.8 Hz, 1 H,
3
2-H], 6.54 (s, 1 H, 17-H), 7.07 (d, J1Htrans ϭ 15.8 Hz, 1 H, 3-H),
7.25Ϫ7.30 (m, 5 H, Ph) ppm. 13C NMR (CDCl3): δ ϭ 8.4, 13.8,
23.6, 31.5, 37.5, 50.5, 78.7, 117.7, 120.7, 126.7, 128.1, 129.0, 133.4,
135.3, 137.0, 151.2, 165.5, 211.7 ppm.
1
3
0.4, CHCl3). H NMR (CDCl3): δ ϭ 1.13 (d, J1H ϭ 7.1 Hz, 3 H,
2
3
2-CH3), 2.63 (m, 1 H, 2-H), 3.60 (dd, J1H ϭ 9.5, J1H ϭ 5.3 Hz,
Aldol 19:
A solution of freshly distilled diisopropylamine
2
3
1 H, 3-Ha), 3.66 (dd, J1H ϭ 9.5, J1H ϭ 6.7 Hz, 1 H, 3-Hb), 3.99
(0.380 mL, 2.71 mmol) was added dropwise at Ϫ30 °C under N2 to
a solution of nBuLi in hexanes (1.70 mL, 2.71 mmol) in THF
(7 mL). After stirring for 15 min at Ϫ30 °C, the resulting LDA was
diluted with THF (7 mL) and was then cooled to Ϫ78 °C. Keto
ester 18 (840 mg, 2.47 mmol) in solution in THF (3.5 mL) was then
added. After the mixture had been stirred for one hour at Ϫ78 °C,
aldehyde 9a (316.2 mg, 2.47 mmol) in THF (3.5 mL) was added
dropwise over 5 min. After 30 minutes at Ϫ78 °C, the reaction mix-
ture was allowed to warm to room temperature and was then
quenched by addition of a saturated NH4Cl solution (10 mL).
After extraction of the aqueous phase with diethyl ether (3 ϫ
15 mL), the combined organic extracts were washed with brine
(25 mL), dried (MgSO4) and concentrated. Separation by flash
3
4
(dt, J1H ϭ 5.6, J1H
ϭ
2J1H ϭ 1.4 Hz, 2 H, 1Ј-H2), 5.19 (dt,
ϭ
4J1H ϭ 1.4 Hz, 1 H, 3Ј-Hcis), 5.27 (dt,
3J1Hcis ϭ 10.3, J1H
2
3J1Htrans ϭ 17.2, J1H ϭ J1H ϭ 1.4 Hz, 1 H, 3Ј-Htrans), 5.80 (ddt,
4
2
3J1Htrans ϭ 17.2, J1Hcis ϭ 10.3, J2H ϭ 5.6 Hz, 1 H, 2Ј-H), 9.7 (d,
3J1H ϭ 1.5 Hz, 1 H, CHO) ppm.13C NMR (CDCl3): δ ϭ 10.7, 29.7,
70.1, 72.2, 117.2, 134.4, 203.9. IR (cmϪ1) ϭ 3080, 2851, 1731, 1645,
1189, 1096, 926, 798 ppm.
3
3
(2R)-2-Methyl-3-[2Ј-methylallyloxy]propanal (9b): This compound
was produced by the same procedure as used for 12a, starting from
12b (400 mg, 2.77 mmol) and affording 9b (299 mg, 76%) as a yel-
low oil. [α]2D0 ϭ Ϫ0.2 (c ϭ 1.4, CHCl3). 1H NMR (CDCl3): δ ϭ
1.17 (d, 3J1H ϭ 8.5 Hz, 3 H, 2-CH3), 1.71 (br. s, 3 H, 2Ј-CH3), 2.75
chromatography on silica gel (petroleum ether/EtOAc, 95:5) af-
2
3
(m, 1 H, 2-H), 3.42 (dd, J1H ϭ 9.4, J1H ϭ 3.5 Hz, 1 H, 3-Ha),
3
forded pure aldol 19 (23%). 1H NMR (CDCl3): δ ϭ 0.9 (d, J1H
ϭ
2
3
4
3.48 (dd, J1H ϭ 9.4, J1H ϭ 4.9 Hz, 1 H, 3-Hb), 3.88 (t, J2H
ϭ
3
6.9 Hz, 3 H, 8-CH3), 1.06 (d, J1H ϭ 6.9 Hz, 3 H, 6-CH3), 1.32 (s,
4
0.7 Hz, 2 H, 1Ј-H2), 4.91 (t, J2H ϭ 0.5 Hz, 1 H, 3Ј-Ha), 4.94 (t,
4J2H ϭ 0.7 Hz, 1 H, 3Ј-Hb), 9.74 (br. s, 1 H, 1-H) ppm. 13C NMR
(CDCl3): δ ϭ 10.9, 19.3, 46.7, 69.8, 75.2, 112.2, 142.1, 203 ppm.
IR (cmϪ1): ν˜ ϭ 3077, 2856, 2726, 1725, 1656, 1254, 1097, 1057,
982, 902.
6 H, CH3,gem), 1.89 (3 H, s, 16-CH3), 2.55 (m, 2 H, 14-H2), 3.10
3
3
3
(qd, J3H ϭ 6.9, J1H ϭ 2.8 Hz, 1 H, 6-H), 3.41 (tqd, J2H ϭ 7.8,
3J3H ϭ 5.5, 3J1H ϭ 4.2 Hz, 1 H, 8-H), 3.49 (dd, 2J1H ϭ 9.1, 3J1H ϭ
4.2 Hz, 1 H, 9-Ha), 3.50 (dd, J1H ϭ 9.1, J1H ϭ 4.7 Hz, 1 H, 9-
2
3
3
3
Hb), 3.56 (dt, J1H ϭ 8.3, J2H ϭ 2.5 Hz, 1 H, 7-H), 3.94 (dt,
4
(؎)-3-Hydroxy-2-methyl-1-phenylhexa-1,5-diene (16): 2-(Methyl)-
cinnamaldehyde (10 mL, 71.6 mmol) was dissolved in THF CH2), 5.43 (t, J2H ϭ 6.7 Hz, 1 H, 15-H), 5.81 (m, 2 H, CϭCH2),
3J1H ϭ 5.4, J2H ϭ 1.5 Hz, 2 H, 11-H2), 5.06Ϫ5.27 (m, 4 H, Cϭ
3
3
(70 mL), and zinc in powder form (9.36 g, 143 mmol) was then ad-
ded portionwise and allyl bromide dropwise (13 mL, 143 mmol).
5.95 (d, J1Htrans ϭ 15.9 Hz, 1 H, 2-H), 6.54 (s, 1 H, 17-H), 7.10
3
(d, J1Htrans ϭ 15.9 Hz, 1 H, 3-H), 7.24Ϫ7.30 (m, 5 H, Ph) ppm.
The reaction mixture was stirred overnight at room temperature 13C NMR (CDCl3): δ ϭ 9.8, 12.9, 13.3, 22.51, 22.55, 35.1, 36.6,
and quenched with saturated NH4Cl solution (50 mL). After fil-
41.7, 50.5, 71.2, 72.1, 72.6, 77.8, 115.9, 116.9, 120.5, 125.0, 125.8,
Eur. J. Org. Chem. 2004, 4762Ϫ4770
www.eurjoc.org
© 2004 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
4767

D. Quintard, P. Bertrand, C. Bachmann, J.-P. Gesson
FULL PAPER
127.2, 128.1, 132.3, 132.4, 133.7, 134.2, 134.3, 136.0, 149.9, 164.3,
tection 256 nm). 1H NMR (CDCl3): δ ϭ 1.96 (s, 3 H, 16-CH3),
214.9 ppm. IR (cmϪ1): ν˜ ϭ 3507,3079, 1715, 1644, 1600, 1492, 2.30Ϫ2.40 (m, 2 H and 1 H, 14-H2, OH), 2.63 (s, 3 H, 21-H3), 4.13
3
3
3
1417, 1366, 1294, 1021. HRMS: calcd. 469.2954; found 469.2960.
(dd, J1H ϭ 6.0, J1H ϭ 6.1 Hz, 1 H, 15-H), 5.03 (dd, J1Hcis
ϭ
10.0, 2J1H ϭ 1.5 Hz, 1 H, 12-Hcis), 5.08 (dd, 3J1Htrans ϭ 17.0, 2J1H ϭ
Macrocycles 21 and 22: Grubbs catalyst 20 (0.1 equiv.) was added
to a solution of diene 19 (as a mixture of (6R,7S,8S) and
(6S,7R,8R) diastereoisomers, 39 mg, 0.083 mmol) in CH2Cl2 and
the resulting mixture was stirred at room temp. under N2 for 3
days. Removal of solvent in vacuo afforded a crude mixture, which
was directly purified by preparative TLC on silica (petroleum ether/
EtOAc, 85:15, as eluent) to give 21 (10.8 mg, 30%) and then 22
(6.8 mg, 18%).
3
3
1.5 Hz, 1 H, 12-Htrans), 5.75 (ddt, J1Htrans ϭ 17.0, J1Hcis ϭ 10.0,
3J2H ϭ 7.1 Hz, 1 H, 13-H), 6.48 (br. s, 1 H, 17-H), 6.85 (s, 1 H, 20-
H) ppm. 13C NMR (CDCl3): δ ϭ 14.2, 18.9, 39.8, 76.4, 115.6,
117.5, 118.8, 134.6, 141.6, 152.5, 164.5) ppm.
Keto Ester 26: 4-(Dimethylamino)pyridine (1.22 g, 10 mmol) and
dicyclohexylcarbodiimide (2.06 g, 10 mmol) were added under ni-
trogen to a solution of 25 (1.05 g, 5 mmol) and 17 (1.7 g, 10 mmol)
in dichloromethane (40 mL). After stirring for 7 days at room
temp., the mixture was washed with water (4 ϫ 15 mL). The aque-
ous phases were combined and extracted with dichloromethane (3
ϫ 20 mL). The combined organic phases were washed with brine,
dried (MgSO4) and concentrated in vacuo. Chromatography on sil-
ica gel (petroleum ether/EtOAc, 90:10) afforded 26 (1.40 g, 77.5%).
3
Compound 21: 1H NMR (CDCl3): δ ϭ 0.93 (d, J1H ϭ 7.1 Hz, 3
3
H, 8-H3), 1.07 (d, J1H ϭ 6.8 Hz, 3 H, 6-CH3), 1.27 (s, 3 H,
CH3,gem), 1.36 (s, 3 H, CH3,gem), 1.89 (m, 1 H, 8-H), 1.95 (s, 3 H,
16-CH3), 2.52 (m, 2 H, 14-H2), 2.90 (br. s, 1 H, OH), 3.11 (dq,
3J3H ϭ 6.7, 3J1H ϭ 3.3 Hz, 1 H, 6-H), 3.28 (dd, 3J1H ϭ 9.3, 3J1H ϭ
2
4.6 Hz, 1 H, 7-H), 3.72 (br. m, 1 H, 9-H), 3.83 (dd, J1H ϭ 12.7,
[α]2D0 ϭ Ϫ15.8 (c ϭ 0.12, CHCl3). H NMR (CDCl3): δ ϭ 1.02 (t,
1
2
3
3J1H ϭ 5.5 Hz, 1 H, 11-Ha), 3.97 (dd, J1H ϭ 12.7, J1H ϭ 4.5 Hz,
1 H, 11-Hb), 5.53 (dd, 3J1H ϭ 9.4, 3J1H ϭ 4.0 Hz, 1 H, 15-H), 5.63
(dt, 3J1Htrans ϭ 15.3, 3J2H ϭ 4.8 Hz, 1 H, 12-H), 5.71 (dt, 3J1Htrans ϭ
3J2H ϭ 7.2 Hz, 3 H, 6-CH3), 1.29 (s, 6 H, CH3,gem), 2.09 (s, 3 H,
16-CH3), 2.48 (q, 3J3H ϭ 7.2 Hz, 2 H, 6-H2), 2.54 (m, 2 H, 14-H2),
3
2
2.70 (s, 3 H, 21-H3), 5.06 (dd, J1Hcis ϭ 10.0, J1H ϭ 1.7 Hz, 1 H,
3
3
15.3, J2H ϭ 6.3 Hz, 1 H, 13-H), 6.09 (d, J1Htrans ϭ 15.9 Hz, 1 H,
3
2
12-Hcis), 5.10 (dd, J1Htrans ϭ 17.2, J1H ϭ 1.7 Hz, 1 H, 12-Htrans),
3
2-H), 6.57 (br. s, 1 H, 17-H), 7.17 (d, J1Htrans ϭ 15.9 Hz, 1 H, 3-
3
3
5.38 (t, J2H ϭ 6.5 Hz, 1 H, 15-H), 5.74 (ddt, J1Htrans ϭ 17.2,
H), 7.20Ϫ7.35 (m, 5 H, Ph) ppm. 13C NMR (CDCl3): δ ϭ 10.7,
14.6, 14.8, 23.3, 24.7, 36.9, 37.2, 44.3, 51.5, 71.4, 72.9, 73.2, 76.6,
78.1, 122.1, 127.1, 127.2, 128.5, 128.6, 129.0, 129.4, 129.7, 136.3,
137.4, 151.5, 165.6, 214.8 ppm. HRMS: calcd. 463.2460; found
463.2464.
3J1Hcis ϭ 10.0, J2H ϭ 6.9 Hz, 1 H, 13-H), 5.90 (d, J1Htrans
ϭ
3
3
15.9 Hz, 1 H, 2-H), 6.54 (s, 1 H, 17-H), 6.95 (s, 1 H, 20-H), 7.05
3
(d, J1Htrans ϭ 15.9 Hz, 1 H, 3-H) ppm. 13C NMR (CDCl3): δ ϭ
8.3, 10.8, 16.2, 20.5, 20.5, 29.0, 35.4, 50.4, 82.6, 115.1, 116.6, 119.0,
120.2, 137.3, 141.9, 142.0, 149.0, 165.9, 166.1, 212.0 ppm. HRMS:
calcd. 384.1609; found 384.1607. MS: m/z ϭ 361 (2), 320 (9), 208
(53), 192 (65), 176 (11), 168 (55), 151 (61), 134 (8), 125 (72), 112
(27), 96 (48), 81 (37), 67 (42), 57 (100). IR (cmϪ1): ν˜ ϭ 3106, 3077,
1714, 1644, 1505, 1099, 1040, 990.
3
Compound 22: 1H NMR (CDCl3): δ ϭ 1.13 (d, J1H ϭ 7.0 Hz, 3
3
H, 8-H3), 1.20 (s, 3 H, CH3,gem), 1.26 (d, J1H ϭ 6.8 Hz, 3 H, 6-
4
CH3), 1.41 (s, 3 H, CH3,gem), 1.89 (m, 1 H, 8-H), 1.95 (d, J1H
ϭ
2
1.4 Hz, 3 H, 16-CH3), 2.52 (m, 2 H, 14-H2), 2.93 (dd, J1H ϭ 9.5,
3J1H ϭ 3.1 Hz, 9-Ha), 3.04 (dq, 3J1H ϭ 9.1, 3J3H ϭ 6.7 Hz, 1 H, 6-
Aldol 27: A solution of nBuLi in hexanes (0.98 mL, 1.57 mmol) was
added at Ϫ30 °C to a solution of freshly distilled diisopropylamine
(0.219 mL, 1.57 mmol) in THF (1.4 mL). After stirring at Ϫ30 °C
for 15 min, the resulting LDA was cooled to Ϫ78 °C, and 26
(524 mg, 1.445 mmol) dissolved in THF (1.4 mL) was then added.
After the system had been stirred at Ϫ78 °C for one hour, 9b
(11.5 mg, 0.784 mmol) was added dropwise, and after 30 min at the
same temperature the reaction mixture was quenched with glacial
acetic acid (0.215 mL, 3.76 mmol). The reaction mixture was then
allowed to warm to room temp., and saturated NH4Cl was added.
After extraction of the aqueous phase with diethyl ether (3 ϫ
15 mL), the combined organic extracts were washed with brine
(25 mL), dried (MgSO4) and concentrated in vacuo. Flash chroma-
tography on silica gel (petroleum ether/EtOAc, 85:15) afforded 27
(74.3 mg, 19%) as the major product. [α]2D0 ϭ Ϫ1.3 (c ϭ 1.3,
2
3
H), 3.28 (br. s, 1 H, OH), 3.55 (dd, J1H ϭ 12.4, J1H ϭ 9.6 Hz, 1
H, 11-Ha), 3.65 (dd, J1H ϭ 9.1, J1H ϭ 4.0 Hz, 1 H, 7-H), 3.79
3
3
2
3
2
(dd, J1H ϭ 9.5, J1H ϭ 2.8 Hz, 9-Hb), 4.26 (dd, J1H ϭ 12.4,
3J1H ϭ 3.7 Hz, 1 H, 11-Hb), 5.53Ϫ5.77 (m, 3 H, 12-H, 13-H, 15-
3
H), 6.09 (d, J1Htrans ϭ 15.8 Hz, 1 H, 2-H), 6.61 (s, 1 H, 17-H),
6.83 (d, J1Htrans ϭ 15.8 Hz, 1 H, 3-H), 7.23Ϫ7.37 (m, 5 H, Ph)
3
ppm. 13C NMR (CDCl3): δ ϭ 14.4, 16.4, 16.7, 23.0, 23.3, 35.2,
37.7, 46.1, 52.4, 71.2, 72.7, 76.9, 78.0, 122.2, 126.8, 127.4, 128.2,
128.98, 129.0, 129.6, 132.1, 135.7, 136.9, 151.4, 165.0, 213.7 ppm.
HRMS: calcd. 463.2460; found 463.2462.
(3S)-3-Hydroxy-2-methyl-1-[2Ј-methyl-4Ј-thiazolyl]hexa-1,5-diene
(25): (Ϫ)-Diisopinocampheylborane chloride (1.44 g, 4.5 mmol)
was dissolved in anhydrous diethyl ether (5 mL) under nitrogen in
a Schlenk flask. Then, after the mixture had been cooled to Ϫ40
°C, a solution of allylmagnesium bromide in diethyl ether (1 m, 3.75
mL, 3.75 mmol) was added dropwise and the mixture was warmed
to room temperature over about one hour. The resulting solution
of (allyl)diisopinocampheylborane was then cooled to Ϫ78 °C, and
3
CHCl3). 1H NMR (CDCl3): δ ϭ 0.9 (d, J1H ϭ 6.9 Hz, 3 H, 8-
CH3), 1.06 (d, 3J1H ϭ 7.15 Hz, 3 H, 6-CH3), 1.32 (s, 6 H, CH3,gem),
1.70 (br. s, 3 H, 12Ј-CH3), 1.75 (m, 1 H, 8-H), 2.08 (3 H, s, 16-
3
CH3), 2.54 (m, 2 H, 14-H2), 2.71 (s, 3 H, 21-H3), 3.1 (qd, J3H
ϭ
3
2-methyl-3-[2Ј-methylthiazol-4Ј-yl]propenal (502 mg, 6.66 mmol) in 7.15, J1H ϭ 2.9 Hz, 1 H, 6-H), 3.47 (m, 2 H and 1 H, 9-H2, OH),
diethyl ether (2 mL) was very slowly added. After stirring for 3.5
hours at Ϫ78 °C, the reaction mixture was allowed to warm to 0 H2), 4.86 (s, 1 H, CϭCH), 4.92 (q, J3H ϭ 0.9 Hz, 1 H, CϭCH),
3
3
3.57 (dd, J1H ϭ 8.2, J1H ϭ 2.9 Hz, 1 H, 7-H), 3.81 (s, 2 H, 11-
4
3
2
°C and was then quenched by addition of acetaldehyde (1.01 mL,
18 mmol). The mixture was then oxidised with sodium acetate solu-
tion (3 m, 3 mL, 9 mmol) and hydrogen peroxide in water (35%,
5.06 (dd, J1Hcis ϭ 10.1, J1H ϭ 1.2 Hz, 1 H, CϭCH), 5.11 (dd,
3J1Htrans ϭ 17.2, J1H ϭ 1.2 Hz, 1 H, CϭCH), 5.40 (t, J2H
6.9 Hz, 1 H, 15-H), 5.74 (ddt, J1Htrans ϭ 17.2, J1Hcis ϭ 10.1,
ϭ
2
3
3
3
1.5 mL) followed by a conventional workup to provide a yellow oil 3J2H ϭ 6.9 Hz, 1 H, CϭCH), 5.95 (d, J1Htrans ϭ 15.7 Hz, 1 H, 2-
3
3
(1.70 g). Chromatography over silica gel (eluent: petroleum ether/ H), 6.54 (s, 1 H, 17-H), 6.95 (s, 1 H, 20-H), 7.05 (d, J1Htrans
ϭ
EtOAc, 70:30) afforded 25 (441.3 mg, 70%). [α]2D0 ϭ Ϫ18.6 (c ϭ
0.58, CHCl3), ee: 96.1%, {ref.: [α]D ϭ Ϫ15.9}, (Chiralcel OD-H,
15.7 Hz, 1 H, 3-H) ppm. 13C NMR (CDCl3): δ ϭ 10.7, 14.2, 14.7,
19.1, 29.7, 29.7, 36.1, 37.6, 42.7, 51.4, 72.8, 73.6, 75.2, 78.5, 116.3,
0.46 ϫ 25 cm, eluent: hexane/2-propanol, 90:10, 1 mL/min, UV de- 116.4, 117.8, 120.9, 121.0, 133.3, 136.8, 137.4, 142.1, 152.4, 164.6,
4768 © 2004 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim www.eurjoc.org
Eur. J. Org. Chem. 2004, 4762Ϫ4770

Synthesis and Conformational Analysis of Macrocycles Related to 10-Oxa-epothilone
FULL PAPER
[11] [11a]
´
K. C. Nicolaou, A. Ritzen, K. Namoto, Chem. Commun.
165.1, 215.9 ppm. HRMS: calcd. 526.2603; found 526.2601. IR
[11b]
(cmϪ1): ν˜ ϭ 3490, 3078, 1714, 1643, 1503.
´
R. M. Buey, J. F. Dıaz, J. M. Andreu,
2001, 1523Ϫ1535.
A. OЈBrate, P. Giannakakou, K. C. Nicolaou, P. K. Sasmal, A.
Ritzen, K. Namoto, Chem. Biol. 2004, 11, 225Ϫ236.
[11c]
´
K.-
2,3-Dehydro-10-oxa-epothilone B (8) and Macrocycle 28: Grubbs
catalyst 20 (14.2 mg, 0.0165 mmol) was added under N2 to a solu-
tion of 27 (56 mg, 0.111 mmol) in dichloromethane (37 mL). After
the mixture had been stirred for 5 days at room temp., conversion
of 27 was complete and the reaction mixture was concentrated in
vacuo and purified by preparative TLC (petroleum ether/EtOAc,
75:25). Two compounds were isolated: 8 (Rf: 0.50, 26%) and 26 (Rf:
0.35, 20%).
H. Altmann, G. Bold, G. Caravatti, D. Denni, A. Flörsheimer,
A. Schmidt, G. Rihs, M. Wartmann, Helv. Chim. Acta 2002,
85, 4086Ϫ4110.
[12]
[13]
J. Mulzer, Chem. Mon. 2000, 131, 205.
T. C. Chou, O. A. O’Connor, W. P. Tong, Y. Guan, Z.-G.
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[14]
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[16]
Compound 28: Oil; [α]2D0 ϭ ϩ82 (c ϭ 0.2; CHCl3). 1H NMR
(CDCl3): δ ϭ 7.00 (s, 1 H), 6.77 (d, J ϭ 15.8 Hz, 1 H), 6.64 (s, 1
H), 6.09 (d, J ϭ 15.8 Hz, 1 H), 5.62 (d, J ϭ 10.5 Hz, 1 H), 5.48
(dd, J ϭ 10.7, 5.0 Hz, 1 H), 4.18 (d, J ϭ 12.2 Hz, 1 H), 3.70 (ddd,
J ϭ 9.5, 2.4, 1.9 Hz, 1 H), 3.70 (m, 1 H), 3.56 (d, J ϭ 12.2 Hz, 1
H), 3.48 (m, 1 H, OH), 2.97 (qd, J ϭ 6.7, 9.5 Hz, 1 H), 2.90 (dd,
J ϭ 9.8, 2.4 Hz, 1 H), 2.72 (s, 3 H), 2.70 (dd, J ϭ 10.5, 11.6 Hz, 1
H), 2.40 (dd, J ϭ 3.4, 11.6 Hz, 1 H), 2.16 (s, 3 H), 1.70 (s, 3 H),
1.40 (s, 3 H), 1.28 (d, J ϭ 6.7 Hz, 3 H), 1.28 (s, 3 H) and 1.18 (d,
J ϭ 7.2 Hz, 3 H) ppm. 13C NMR (75 M Hz, CDCl3): δ ϭ 13.2,
15.5, 16.7, 17.5, 19.2, 22.8, 23.2, 29.6, 34.9, 46.3, 52.5, 70.1, 76.3,
77.4, 78.4, 116.3, 120.0, 122.4, 125.6, 135.1, 137.5, 151.4, 152.3,
164.8, 164.9, 213.7 ppm. HRMS: [M ϩ Na]ϩ calcd. 476.2471;
found 476.2470.
[17]
[18]
[19]
[20]
Compound 8: Oil; [α]2D0 ϭ Ϫ44 (c ϭ 0.2; CHCl3). 1H NMR (CDCl3):
δ ϭ 7.12 (d, J ϭ 15.8 Hz, 1 H), 6.98 (s, 1 H), 6.58 (s, 1 H), 6.00 (d,
J ϭ 15.8 Hz, 1 H), 5.47 (m, 2 H), 3.82 (d, J ϭ 12.1 Hz, 1 H), 3.78
(d, J ϭ 12.1 Hz, 1 H), 3.74 (dd, J ϭ 8.9, 2.8 Hz, 1 H), 3.72 (dd,
J ϭ 7.1, 2.7 Hz, 1 H), 3.29 (dd, J ϭ 9.1, 4.1 Hz, 1 H), 3.10 (qd,
J ϭ 6.9, 2.7 Hz, 1 H), 2.95 (br. s, 1 H), 2.71 (s, 3 H), 2.51 (dd, J ϭ
6.9, 6.8 Hz, 2 H), 2.16 (s, 3 H), 1.74 (m, 1 H), 1.60 (s, 3 H), 1.37
(s, 3 H), 1.27 (s, 3 H), 1.08 (d, J ϭ 6.9 Hz, 3 H) and 0.94 (d, J ϭ
7.2 Hz, 3 H) ppm. 13C NMR (CDCl3): δ ϭ 10.6, 14.3 (2 ϫ), 15.4,
19.2, 22.5, 24.0, 31.6, 36.9, 43.2, 51.2, 72.0, 72.1, 75.3, 78.0, 116.1,
119.6 120.1, 122.1, 134.1, 137.8, 150.7, 152.4, 164.7, 165.2, 214.8
ppm. HRMS: [M ϩ Na]ϩ calcd. 476.2471; found 476.2474.
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