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

Article abstract of DOI:10.1016/S0040-4039(02)00871-7

The total synthesis of C292 (or LL-Z1640-2) and hypothemycin has been achieved. The 14-membered ring formation was achieved either via an intramolecular Suzuki coupling or much more efficiently via a Mitsunobu macrolactonisation. Reaction conditions were

Full text of DOI:10.1016/S0040-4039(02)00871-7

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 43 (2002) 4627–4631
Convergent stereospecific synthesis of LL-Z1640-2 (or C292),
hypothemycin and related macrolides. Part 2
Patrice Selle`s and Robert Lett*
Unite´ Mixte CNRS-AVENTIS Pharma (UMR 26) 102, route de Noisy, 93235 Romainville, France
Received 16 April 2002; accepted 7 May 2002
Abstract—The total synthesis of C292 (or LL-Z1640-2) and hypothemycin has been achieved. The 14-membered ring formation
was achieved either via an intramolecular Suzuki coupling or much more efficiently via a Mitsunobu macrolactonisation. Reaction
conditions were found to preserve the Z enone; selective epoxidation of C292 afforded hypothemycin. © 2002 Elsevier Science
Ltd. All rights reserved.
We herein report the completion of a total synthesis of
hypothemycin 1 and C292 (or LL-Z1640-2) 2.1 In the
preceding communication,2 we described the stereospe-
cific convergent synthesis of the precursors 3 and 4
which are required for achieving the formation of the
14-membered ring, either via an intramolecular Suzuki
pleted with the two epimers at C-6% in quite comparable
yields throughout all the steps of the sequence.4 Note-
worthy in the present work, unless otherwise specified,
we observed no significant variation (i.e. less than 5%)
of the 60/40 ratio of the two diastereoisomers, epimeric
at C-6%, in the reactions described further.
coupling or via
a Mitsunobu macrolactonisation
(Scheme 1). Another total synthesis of 2, starting from
D
-ribose, has been disclosed in 2001 by Tatsuta and
coworkers.3 In our work, it is worth pointing out that
all the synthesis described here has been achieved with
the 60/40 mixture of the two diastereoisomers, epimeric
at C-6%, starting either from 3 or from 4. We were
confident in that strategy, due to our previous work
showing that the synthesis of radicicol could be com-
1. Intramolecular Suzuki couplings (Scheme 2)
In a previous synthesis of (S)-zearalenone, Hegedus
and coworkers could achieve the intramolecular cou-
pling of an aryliodide and a vinylstannane, in 30–54%
Scheme 1.
Keywords: macrolides; antitumour compounds; coupling reactions; boron and compounds; Suzuki reactions; Mitsunobu reactions.
* 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)00871-7

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P. Selle`s, R. Lett / Tetrahedron Letters 43 (2002) 4627–4631
Scheme 2. Reagents and conditions: Sia2BH (3.9 equiv.), THF, −20°C“rt, 2 h, then addition of acetone (3 equiv.) and afterwards
2 M aq. K3PO4 (2 equiv.) at −10°C“rt, further addition of that mixture via cannula to a solution of 4 mol% [Pd(OAc)2+4TFP]
in DME, i.e. substrate 0.034 M in DME/H2O (ꢀ30/1), reflux, 6 h.
yield depending on the conditions, thus showing for the
first time that the 14-membered macrolide could be
formed via a palladamacrocycle.5 We first examined the
intramolecular Suzuki couplings of vinyldisiamylbo-
ranes, generated in situ, derived from the alkyne 3 and
related compounds 5–7. Hydroboration conditions were
determined on the model compound 5, by following the
disappearance of the starting material by TLC and
further protonolysis (AcOH, 70°C) to yield the corre-
sponding terminal olefin in a quantitative yield, and
were thus optimised when using 3.9 equiv. Sia2BH
(THF, −20°C). Preliminary studies for the coupling
were done in the case of 5 and showed that they were at
best achieved with no protection of the phenol, like in
the parent previous intermolecular couplings (such as
the one affording 4) and model studies.1,2 Best results
were obtained when, after hydroboration completion,
excess Sia2BH was destroyed in situ by addition of
anhydrous acetone (3 equiv.) before achieving the
Suzuki coupling. Thus, in the conditions described in
Scheme 2, the desired macrolides 8 and 9 were isolated
in only 9% and 15% yields, respectively. Noteworthy,
the same reaction conditions applied to 6 and 7 gave no
trace of the corresponding 14-membered macrolides,
although these should be energetically more favoured
by less ring strain and steric interactions than in 8 and
9. All those couplings showed quite complex reactions
and only some by-products could be characterized. One
major difficulty here was to get a good turn-over of the
catalyst, at the minimal dilution (0.03–0.04 M) required
for minimising intermolecular reactions and kinetically
compatible with the time scale required for finding the
conformations allowing the formation of the pal-
ladamacrocycle. Quite significantly, the most flexible
substrates 6 and 7 having a trans-7%,8% double bond
gave no cyclisation at all, moreover 7 affording alone a
significant amount of the product of homocoupling of
the derived vinyldisiamylborane (6%). In all the reac-
tions, even in the described conditions, we isolated the
terminal olefin corresponding to the reduction of the
alkyne in 3 (ꢀ3%), 5 (10%), 5-OTBS (12%), and 7
(8%). It is worth pointing out that, for the macrolides 8
and 9, the ratio of the C-6% epimers was still 60/40, thus
showing that the relative configuration of this centre
had no effect in these cyclisations.
2. Macrolactonisation via Mitsunobu reaction
(Scheme 3)
All the macrolactonisations were achieved in toluene, at
rt, at a concentration of the precursor of 0.007–0.01 M,
affording the desired macrolides in quite comparable
yields (64–70%), and quite remarkably whatever the
privileged conformation, ring strain or steric interac-
tions in the final macrolide, thus showing that these
macrolactonisations do not have a late transition state.
Here again, it is also worth pointing out that there was
no incidence of the configuration at C-6% (60/40 ratio)
and that no significant amount of diolide was formed in
those reactions which were not run in high dilution
conditions, as we already observed in our previous
work concerning radicicol.4,6 The complete inversion of
configuration at C-10% was shown with no ambiguity by
the transformation of 4 (10%R) into 9 (10%S), which was
further converted into hypothemycin (by the compari-
son with the published data); it was also clearly demon-
strated for the conversion of 11 (10%S) into 8 (10%R)
which could be compared with the product of the
intramolecular Suzuki coupling (Scheme 2) by 1H
NMR.

P. Selle`s, R. Lett / Tetrahedron Letters 43 (2002) 4627–4631
4629
Scheme 3. Reagents and conditions: hydroxy-acid 0.007 M in anhydr. toluene, PPh3 (2 equiv.), DEAD (2 equiv.), rt, 15 min.
3. Conversion of macrolide 9 into C292 (LL-Z1640-2)
and hypothemycin (Schemes 4 and 5)
recovered 16m. However, quite fortunately, fast Jones
oxidation of 16m (acetone, 0°C, 10 min) gave the
desired Z-enone 18 (35%) and quite surprisingly the
transposed enone 20 (Dauben-like rearrangement,11 but
here unusually on a secondary alcohol) (Scheme 5).
Thus, with this procedure applied to a millimolar scale
of 16 (60/40 mixture), we isolated the desired Z-enone
in 74% yield, the rearranged enone 20 (10%) and still
recovered 16m (7%).
In a preliminary study, the Z7%,8%-enone 15 could be
isolated in 70% overall yield from 8, after cleavage of
the MPM ether by DDQ7 in buffered conditions (pH 7)
and further oxidation of the mixture of allylic alcohols
(C6%-epimers ꢀ60/40) by active MnO2. No difference of
reactivity of the C6%-epimers and no isomerisation of the
enone were observed in that sequence. The 6%-OMPM
ether of 9 was deprotected by DDQ in buffered condi-
tions to afford the alcohols 16M and 16m (60/40 ratio,
not separable by chromatography) in 94% yield. How-
ever, in contrast with the easy and univoque formation
of 15, the mixture of the two 6%-OH epimers 16M and
16m could not be oxidised into the enone either with a
large excess of active MnO2 (commercial sources,
Attenburrow, Sondheimer, Fatiadi)8 or by DDQ9 (1–5
equiv., toluene, 60°C, 48 h) and only starting material
was recovered. With DDQ, higher temperatures led to
complex mixtures. In order to change the conformation
of the macrolide and modify steric interactions, the triol
17 was prepared but also gave complex mixtures with
active MnO2 at rt. On the other hand, reaction of the
mixture of 6%-OH epimers 16 with PCC in the presence
of 2,5-dimethylpyrazole10 showed now a clear difference
of reactivity between the two diastereoisomers, for the
first time at this level of the sequence: the major epimer
16M was converted quantitatively into the desired Z-
enone 18, isolated in 62% yield in the specified condi-
tions, while the minor one 16m was recovered
unchanged, pure after chromatography (23%). The pure
minor diastereoisomer 16m, thus obtained, reacted very
slowly in the same Parish conditions10 and, after 24 h,
afforded only the E7%,8%-enone 19 in 50% yield and
Noteworthy, oxidation of the triol 17 with PCC/2,5-
dimethylpyrazole was unsatisfactory and gave complex
mixtures. It is worth also mentioning that Swern oxida-
tion of 16M (DMSO 2.2 equiv./oxalyl chloride 1.1
equiv./i-Pr2NEt 5 equiv., CH2Cl2, −78°C to rt, and pH
7 work-up) afforded the desired Z-enone 18 in only
30% yield and recovered 16M (58%) after chromatogra-
phy; Swern oxidation of 16m, in the same conditions,
unexpectedly gave 21 in 50% yield (Scheme 5) and
unreacted 16m (50%).
Acetonide cleavage of 18 could be achieved in carefully
established conditions (0.5 equiv. pTsOH, CH2Cl2/
MeOH 1/1, rt, 3 h 30 min) to afford 2 (C29212 or
LL-Z1640-213) in 76% yield and 20% of recovered 18
after chromatography. These conditions gave us the
best compromise in order to avoid the isomerisation
into the E7%,8%-enone and also the 4%-OH intramolecular
1,4-addition on the enone (adduct stereochemistry not
determined) which occur competitively on longer reac-
tion times. Selective epoxidation of 2 was quite difficult,
due to an unusually unreactive 1%,2%-double bond and
lability of the products, and was at best achieved in
buffered conditions (MCPBA/NaHCO3 (3 equiv.),
CH2Cl2, −20 to 0°C, 4 h) to afford hypothemycin 1 and

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P. Selle`s, R. Lett / Tetrahedron Letters 43 (2002) 4627–4631
Scheme 4. Reagents and conditions: (a) DDQ (1 equiv.), CH2Cl2/pH 7 buffer (9/1) rt, 30 min; (b) pTsOH (0.2 equiv.), MeOH, rt,
4 h; (c) PCC (3 equiv.), 2,5-DMP (10 equiv.), CH2Cl2, 0°C, 6 h; (d) Jones’ reagent, acetone, 0°C, 10 min; (e) pTsOH (0.5 equiv.),
CH2Cl2/MeOH (1/1), rt, 3 h 30 min; (f) MCPBA/NaHCO3 (3 equiv.), −20°C“0°C, 4 h, then pH 7 work-up.
Scheme 5.
unreacted 2 in, respectively, 17 and 30% yield after
chromatography and no other epoxide was isolated.
Noteworthy, dimethyldioxirane (acetone, −20°C), or
Mn(TPP)Cl in the presence of imidazole with 30%
H2O2 (MeCN/CH2Cl2, rt), which were successful in
model studies led only to complex mixtures with 2.1
The epoxide thus obtained with MCPBA was unam-
biguously identified with hypothemycin by comparison
macrolides, related either to zearalenone in the present
work or to radicicol4,6, which are very important tools
for the study of signal transduction.15 Recently,
hypothemycin has also been shown to be a highly
selective inhibitor of some MEK or MAPK kinases,15
and to be a new lead as an inhibitor of T cell activation
with a novel mode of action and a unique modulatory
activity on cytokine production.16
1
of all the data (particularly by comparison of their H
(500 MHz) and 13C NMR (125 MHz) spectra in CDCl3
with those of the natural product.14
Acknowledgements
The synthesis described herein and in the accompany-
ing note is stereospecific, convergent and highly flexible,
allowing modification of the aromatic part. Our synthe-
ses give an access to a whole group of resorcylic
We thank the staff of the Analytical Department of the
Research Center at Romainville, Roussel Uclaf,
Hoechst Marion Roussel and the CNRS for a PhD

P. Selle`s, R. Lett / Tetrahedron Letters 43 (2002) 4627–4631
4631
grant to P. Selle`s, and the Direction des Recherches
Chimiques of Roussel-Uclaf and HMR for support of
this work.
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