Convergent stereospecific synthesis of C292 (or LL-Z1640-2), and hypothemycin. Part 1

Article abstract of DOI:10.1016/S0040-4039(02)00870-5

The stereospecific synthesis of the precursors required for the 14-membered ring formation either via an intramolecular Suzuki coupling or via an intermolecular Suzuki coupling followed by a macrolactonisation is herein reported. One-pot Suzuki couplings were here achieved with vinyldisiamylboranes which were generated in situ from the related chiral precursor. The present convergent approach of C292 (or LL-Z1640-2) and hypothemycin gives a flexible access to related macrolides.

Full text of DOI:10.1016/S0040-4039(02)00870-5

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 43 (2002) 4621–4625
Convergent stereospecific synthesis of C292 (or LL-Z1640-2),
and hypothemycin. Part 1
Patrice Selle`s and Robert Lett*
Unite´ Mixte CNRS-AVENTIS Pharma (UMR 26) 102, route de Noisy, 93235 Romainville, France
Received 16 April 2002; revised 2 May 2002; accepted 7 May 2002
Abstract—The stereospecific synthesis of the precursors required for the 14-membered ring formation either via an intramolecular
Suzuki coupling or via an intermolecular Suzuki coupling followed by a macrolactonisation is herein reported. One-pot Suzuki
couplings were here achieved with vinyldisiamylboranes which were generated in situ from the related chiral precursor. The
present convergent approach of C292 (or LL-Z1640-2) and hypothemycin gives a flexible access to related macrolides. © 2002
Elsevier Science Ltd. All rights reserved.
Due to our interest in radicicol 1,1,2 we were quite
intrigued by a Sandoz patent3 which appeared in 1994
concerning the biological properties of the macrolide
87-250904-F1 2 and later on, in 1996, by patents on
LL-Z1640-2 (Takeda)4 or C292 (Cor Therapeutics)5 3.
Those patents showed that these molecules were
inhibitors of the release of some cytokines (IL-1b,
IL-1a, IL-6, TNFa) and thus had properties which
appeared quite similar to those of radicicol. The mecha-
nism of action of all these molecules was then
unknown. Moreover, identity of LL-Z1640-2 (first dis-
covered at Lederle Laboratories6) and C292 was not
discussed. Quite remarkably, C292 was shown to be a
specific inhibitor of PTK, not inhibiting PKA or PKC,
and moreover a highly selective inhibitor among some
tyrosine kinases (receptor or non receptor).5 Since 1992,
radicicol was known to be a specific inhibitor of some
tyrosine kinases such as p60v-src.7 Later on, radicicol8
and 87-250904-F19 were also shown to be specific
inhibitors of the expression of COX-2 (not of COX-1)
and of some cytokines (via an accelerated degradation
of their mRNA). Indeed, these apparent similarities
were puzzling since radicicol and the other macrolides
differed by the chiral center at 10% and by the function-
alities, these compounds being necessarily in quite dif-
ferent conformations. On the other hand, the structure
of hypothemycin had just been corrected in 1993 by an
X-ray structure10 and appeared thus to be the epoxide
of 3. Therefore we were interested in achieving a
flexible convergent stereospecific synthesis of these
resorcylic macrolides which appeared then to be impor-
tant tools for biochemistry, especially for the study of
signal transduction, and could be considered as new
leads.
The total synthesis of LL-Z1640-2 3 from
D-ribose has
been reported in 2001 by Tatsuta and co-workers.11 We
wish now to disclose our stereospecific convergent syn-
thesis.12 Macrolides 2–4 are related to zearalenone
which is produced very efficiently industrially by fer-
mentation. Therefore, in a preliminary work, we first
studied a hemisynthesis of 3 starting from zearalenone,
but were unable to obtain the required intermediates.12
Concerning the synthesis of 2–4, one difficult problem
is to preserve the Z enone in the intermediates and the
final macrolide, due to previous results showing that
these 14-membered macrolides having the Z7%,8% keto-6%
enone are highly disfavoured energetically and give the
corresponding E7%,8% enone as the only product under
basic or acidic conditions.3,5,12 According to our prelim-
inary work on epoxidation of zearalenone derivatives,
we chose to introduce the highly sensitive 1%,2%-epoxide
in the last steps, even if we were aware that the E1%,2%
double bond was unexpectedly unreactive towards
many epoxidation reagents,12 as already pointed out in
the early work of the Merck group on zearalenone
derivatives.13 However, based on the X-ray structure of
hypothemycin 4, we expected the highly stereoselective
formation of the desired epoxide for steric reasons,
assuming that the precursor might have such an
analogous conformation.
Keywords: macrolides; antitumour compounds; coupling reactions;
boron and compounds; Suzuki reactions; zirconium and compounds;
epoxides.
* Corresponding author. Tel.: 33 1 49 91 52 80; fax: 33 1 49 91 38 00;
e-mail: robert.lett@aventis.com
0040-4039/02/$ - see front matter © 2002 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(02)00870-5

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P. Selle`s, R. Lett / Tetrahedron Letters 43 (2002) 4621–4625
Our synthesis is based on the retrosynthetic analysis
described in Scheme 1, which leads to three subunits:
the aromatic part A, the C1%–C6% and C7%–C10% enantio-
pure subunits B and C. This approach is quite flexible
and allows examination of the formation of the 14-
membered macrocycle either via an intramolecular
Suzuki coupling or via a macrolactonisation (via an
acyl activation or a Mitsunobu reaction). Hence, the
enantiopure subunits B and C derive from easily avail-
able starting materials. We decided to generate the
required 4%,5%-diol by the regio- and stereospecific open-
ing of the epoxide by a carbamate derived from D in
the presence of BF3·Et2O:14 this route has also some
flexibility since the same carbamate can also set up an
amino alcohol15 in a regio- and stereospecific reaction
under different conditions, and moreover, an epoxy
alcohol such as D can generally be obtained in high
yield and enantiomeric purity by a Sharpless asymmet-
ric epoxidation of a trans-disubstituted allylic alcohol.
We preferred such a route to a Sharpless asymmetric
dihydroxylation of a Z disubstituted olefin.
that the OTBS protective group here allows avoidance
of o-metalation at position 3 of 6 by its steric effect.
The 2-OTBS group also allows conversion of the amide
7 into the methyl ester 8 in good yield, this is probably
because the preliminary easy cleavage of the phenol
OTBS group leads to a conformation of the intermedi-
ate imidate salt favouring the desired cleavage of the
tetrahedral intermediate; when the same phenol was
protected as a methyl ether, the initial amide was the
only product after hydrolysis of the corresponding imi-
date salt. The acid 9 was finally obtained in a quasi-
quantitative yield, under conditions avoiding the
decarboxylation which occurs at higher temperatures or
with longer heating, or also very easily at the reacidifi-
cation when the o-phenol is deprotected.16
2. Enantiopure C7%–C10% subunit synthesis (Scheme 3)
The alkyne 11 was obtained via the opening of enan-
tiopure (R) or (S) propylene oxide by the lithio deriva-
tive of 10 at −78°C, in the presence of BF3·Et2O, under
stoichiometric conditions. Further protection of the
alcohol as a TBS ether and specific deprotection of the
TMS-alkyne under mild conditions gave 12 in 76%
overall yield (three steps). The enantiopure, (R) or (S),
E and Z vinyl iodides 13 and 15 were obtained from 12,
1. Synthesis of the aromatic part (Scheme 2)
The methyl ester 8 was obtained in 48% overall yield
from 4-methoxysalicylic acid 5. It is worth pointing out
Scheme 1.
Scheme 2. Reagents and conditions: (a) TBSCl (2.5 equiv.), iPr2NEt (3.6 equiv.), DMF, rt, 2 h; (b) oxalyl chloride (1.1 equiv.),
DMF cat., CH2Cl2, −10°C“rt, overnight, then Et2NH (2.0 equiv.), 1 h, rt; (c) Et2NAlMe2 from Me3Al (4 equiv.) and Et2NH (4
equiv.), toluene, −6°C“rt, 45 min, then bis-OTBS from 5, reflux, overnight; (d) tBuLi/pentane (1.08 equiv.), Et2O, −78°C, 10 min,
then Br2 (1.06 equiv.); (e) Me3O+, BF4 (1.3 equiv.), CH2Cl2, rt, overnight, then evaporation; (f) aq. satd Na2CO3/MeOH (1/1),
−
rt, 6 h; (g) conc. NaOH/DME (1/1), reflux, overnight; (h) TMSOK (2 equiv.), DME, reflux, overnight.

P. Selle`s, R. Lett / Tetrahedron Letters 43 (2002) 4621–4625
4623
Scheme 3. Reagents and conditions: (a) 10 (1.05 equiv.), Et2O, −78°C, nBuLi (1.05 equiv.), 30 min, then (R) or (S) propylene oxide
(1.0 equiv.), and further addition of BF3·Et2O (1.0 equiv.) in 50 min, −78°C; (b) TBSCl/imidazole/DMF, rt; (c) K2CO3 (1.1
equiv.)/MeOH, rt, 5 h; (d) Cp2ZrCl2 (2 equiv.), LiBHEt3 (2 equiv.), THF, rt, then 12, rt, 15 min and I2 (1.1 equiv.) in THF; (e)
nBuLi (1.1 equiv.), THF/hexane, −78°C, 15 min, then I2 (1.1 equiv.) in THF; (f) Sia2BH (2 equiv.), THF, −20“0°C, 3 h and then
AcOH, 65°C, 3 h.
4. C1%–C10% fragment (Scheme 4)
respectively, by hydrozirconation with Schwartz’
reagent17a (generated in situ under Lipshutz
conditions17b), or by hydroboration of the derived
iodoalkyne 14 with Sia2BH and further protonolysis by
acetic acid.18
The condensation of the two enantiopure fragments was
optimized with 1.5 equiv. of 15 to afford a 60/40 mixture
of the two diastereoisomers 28 (10%S) or 30 (10%R),
epimeric at 6%, in 77% yield and recovered unreacted
aldehyde 27 (13%) after chromatography. After depro-
tection of the TMS–alkyne, the 6%-OH was protected as
an OMPM ether by reaction of the mixture of the two
diastereoisomers with the trichloroacetimidate 32 and
triflic acid catalysis21 to afford a 60/40 mixture of the
corresponding 6%-OMPM ethers. At this level, we decided
to complete the synthesis with this 60/40 mixture of 6%
epimers, since the two diastereoisomers were not easily
separable either as 6%-OH (28 or 30) or as 6%-OMPM (29
or 31); we were also confident in that strategy, due to our
previous work in which the synthesis of radicicol could
be completed with the two epimers at 6% in comparable
yields throughout all the steps of the sequence.2
3. Enantiopure C1%–C6% subunit synthesis (Scheme 4)
Compound 20 was obtained in 34% overall yield from
2-butyne-1,4-diol 16 (six steps). The highly selective
deprotection of the TBS ether of 19 was best achieved
with DDQ (5 mol%) in CH3CN/H2O (9/1)19 at rt, thus
affording 20 in 74% yield and reisolated 19 (17%) after
chromatography; other deprotection conditions
(AcOH/THF/H2O/rt or TBAF/AcOH/THF/rt) led to
competitive deprotection of the TMS-alkyne. Sharpless
asymmetric epoxidation of 20 with (+)-DET gave the
epoxyalcohol 21 in 85% yield and high enantiomeric
excess since no trace of the other enantiomer could be
1
detected by careful H NMR analysis (300 MHz) of the
corresponding (+)- and (−)-MTPA esters.20 The carba-
mate assisted epoxide opening of 22, in the presence of
BF3·Et2O,14 was regio- and stereospecific to afford 23 in
91% yield. Simultaneous hydrolysis of the carbonate
and TMS deprotection of the alkyne was achieved
under mild conditions (MeONa/MeOH, rt) and the
triol 24 was isolated in 93% yield after purification over
a Dowex-H+ column. Specific protection of the primary
alcohol and further acetonide formation gave 25 (73%
overall). The terminal alkyne had to be reprotected as a
TMS derivative in order to avoid proton abstraction in
the presence of the more basic vinyllithio reagent to be
used for the condensation with the C1%–C6% aldehyde.
5. Macrocyclisation precursors (Schemes 5 and 6)
The precursor 34 (10%S) required for an intramolecular
Suzuki coupling was obtained in 74% overall yield from
29. The ester was prepared under stoichiometric condi-
tions via an acyl activation (DCC/DMAP, rt) of the acid
9 (1 equiv.) (Scheme 5). The other precursor 36 (10%R)
required for a macrolactonisation via a Mitsunobu
reaction was obtained in 47% overall yield from 31, via
an intermolecular Suzuki coupling of the vinyldisiamyl-
borane prepared in situ2 (Scheme 6). This coupling was
optimized with 8 (1.2 equiv.), and results were less
satisfactory with the corresponding 2-phenol TBS or
methyl ethers. The best results were obtained under the
conditions described in Scheme 6, with tri-2-furylphos-
phine.12 Cleavage of the methyl ester of 35 here was quite
difficult, but nevertheless afforded the acid 36 under
optimized conditions in 65–70% yield.
The highly selective deprotection of the TBS ether was
again best achieved with DDQ (8 mol%) in CH3CN/H2O
(9/1), at rt, in order to minimize the cleavage of the
acetonide and that of the TMS–alkyne, and thus afford
26 (73%) and recovered TMS–alkyne derivative of 25
(15%) after chromatography. Swern oxidation of 26 gave
the pure aldehyde 27 in quantitative yield after chro-
matography.
The completion of our synthesis of C292 (or LL-Z1640-2)
and hypothemycin is described in the accompanying
note.22

4624
P. Selle`s, R. Lett / Tetrahedron Letters 43 (2002) 4621–4625
Scheme 4. Reagents and conditions: (a) Red-AlR (1.5 equiv.)/toluene, THF, 0°C“rt, overnight, 81%; (b) NaH (1.03 equiv.), THF,
rt, 1 h, then −78°C, TBSCl (1.03 equiv.), 36 h, 74%; (c) MsCl (1.1 equiv.), NEt3 (1.1 equiv.), CH2Cl2, −10°C“rt, 30 min; (d) NaI
(1.5 equiv.), acetone, rt, 1 h; (e) 10 (1.5 equiv.), THF, nBuLi (1.5 equiv.), −78°C, 30 min, then 18 and HMPA (THF/HMPA=10/
1), rt, 4 h; (f) DDQ (5 mol%), MeCN/H2O (9/1), rt, 2 h; (g) Ti(OiPr)4 (1 equiv.), (+)-DET (1.24 equiv.), anhydr. CH2Cl2, tBuOOH
(ꢀ3 M in isooctane) (2.1 equiv.), −25°C, overnight; (h) PhNCO (2.5 equiv.), CH2Cl2/pyridine, rt, 1 h; (i) BF3·Et2O (1.1 equiv.),
Et2O, −20°C, 2 h, then 1N H2SO4, rt, overnight; (j) MeONa (0.35 equiv.), MeOH, rt, 8 h, then Dowex 50 WX8 column eluted
by MeOH; (k) TBSCl (1.05 equiv.), imidazole (1.05 equiv.), DMF, rt, 1 h; (l) 2-methoxypropene (2 equiv.), TsOH cat., CH2Cl2,
rt, 1 h; (m) nBuLi/hexane (1.1 equiv.), Et2O, −30°C, 30 min, then TMSCl (1.1 equiv.), −30“−10°C, 98%; (n) DDQ (8 mol%),
MeCN/H2O (9/1), rt, 2 h, 73%; (o) oxalyl chloride (1.1 equiv.), DMSO (2.2 equiv.), CH2Cl2, −78°C, 30 min, then 26, 30 min and
NEt3 (5.0 equiv.), −78“0°C; (p) 15 (n equiv.), Et2O, −78°C, then tBuLi/pentane (2n equiv.), 15 min, and further addition of 27
in pentane, −78“0°C; (q) K2CO3 (1.4 equiv.), MeOH, rt, 5 h; (r) 32 (2 equiv.), Et2O, CF3SO3H (0.004 equiv.), rt, 4 h.
Scheme 5. Reagents and conditions: (a) TBAF 1 M/THF (1.1 equiv.), rt, 10 h; (b) DCC (2.2 equiv.), DMAP (1.2 equiv.), CH2Cl2,
rt, 5 h.
Acknowledgements
Hoechst Marion Roussel and the CNRS for a PhD
grant to P.S., and the Direction des Recherches
Chimiques of Roussel-Uclaf and HMR for support of
this work.
We thank the staff of the Analytical Department of the
Research Center at Romainville, Roussel Uclaf,

P. Selle`s, R. Lett / Tetrahedron Letters 43 (2002) 4621–4625
4625
Scheme 6. Reagents and conditions: (a) Sia2BH (2 equiv.), THF, −25°C“rt, 2 h and then aq. 2 M K3PO4 (2 equiv.), further
addition of that mixture via cannula at rt to a solution of 8 (1.2 equiv.) and 15 mol% [Pd(OAc)2+4TFP] in DME; DME/H2O
ꢀ7/1, reflux, 8 h; (b) TBAF 1 M/THF (3.5 equiv.), rt, 6 h, 93%; (c) 2N aq. NaOH (13 equiv.)/MeOH (1/3), reflux, overnight, 71%.
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