Synthetic approach to wortmannilactone C

Article abstract of DOI:10.1021/ol5036112

A diastereomer of wortmannilactone C has been synthesized according to a convergent and versatile strategy from tert-butyl 3-hydroxypropanoate and ethyl (R)-3-hydroxybutanoate. The key steps are a Liebeskind cross-coupling and a Horner-Wadsworth-Emmons (HWE) reaction to construct the macrolactone. The stereogenic centers at C9, C11, and C21 were controlled by enantioselective allyltitanations, and the C19 stereocenter was controlled by using a Noyori reduction of an acetylenic ketone.

Full text of DOI:10.1021/ol5036112

Letter
pubs.acs.org/OrgLett
Synthetic Approach to Wortmannilactone C
Damien Brandt, Aurelia Dittoo, Veronique Bellosta, and Janine Cossy*
́ ́
Laboratoire de Chimie Organique, Institute of Chemistry, Biology and Innovation (CBI), UMR 8231, ESPCI ParisTech/CNRS/PSL
Research University, 10 rue Vauquelin, 75231 Paris Cedex 05, France
*
S Supporting Information
ABSTRACT: A diastereomer of wortmannilactone C has been
synthesized according to a convergent and versatile strategy from
tert-butyl 3-hydroxypropanoate and ethyl (R)-3-hydroxy-
butanoate. The key steps are a Liebeskind cross-coupling and a
Horner−Wadsworth−Emmons (HWE) reaction to construct
the macrolactone. The stereogenic centers at C9, C11, and C21
were controlled by enantioselective allyltitanations, and the C19
stereocenter was controlled by using a Noyori reduction of an
acetylenic ketone.
iologically active compounds can be of different origins
such as plants, animals, or fungi and particularly soil
B
filamentous fungi which are prolific sources of bioactive natural
1
,2
products. In 2006, it was reported that an isolate of the
fungus Talaromyces wortmannii, which was collected from the
soil in Xishuangbanna in the Yunnan province in China,
contains four novel 22-membered lactones, wortmannilactones
Figure 2. Structures of wortmannilactone C and dolabelide B.
3
A−D. Later on, Talaromyces wortmannii was cultured in
Erlenmeyer flasks, and after 14 days at 27 °C, the solid culture
was extracted with ethyl acetate; the extract was separated to
afford wortmannilactones A−D in a ratio of 71:9:13:7 (Figure
Scheme 1. Retrosynthetic Analysis
1
).
As part of our work on the synthesis and on the
establishment of structure of natural products by total
4
,5
synthesis,
we became interested in the synthesis of
wortmannilactone C which presents cytotoxic activity against
6
a panel of human cancer cell lines. The planar structure of
1
13
wortmannilactone C was established by NMR ( H, C, COSY,
HMQC, HMBC); however, the configuration of the stereo-
genic centers at C9, C11, C19, C21, and C23 was not
established. Arbitrarily, we decided to attribute the R, S, S, R, R
configuration respectively to the C9, C11, C19, C21, and C23
stereogenic centers based on the stereogenic centers at the
same positions of dolabelide B which is also a 22-membered
be assembled using a Liebeskind cross-coupling and by
employing a Horner−Wadsworth−Emmons (HWE) olefina-
tion to construct the macrocycle. The synthesis of Fragment A
was planned from tert-butyl 3-hydroxypropanoate 2, and the
stereogenic centers at C9 and C11 would be controlled using
enantioselective allyltitanations. Fragment B would be
synthesized from ethyl (R)-3-hydroxybutanoate 12. The
stereogenic center present in 12 would correspond to the
C23 stereogenic center of wortmannilactone C, and the
stereogenic centers at C21 and C19 would be respectively
controlled by utilizing an enantioselective allyltitanation and a
Noyori reduction of an acetylenic ketone (Scheme 1).
7
ring lactone (Figure 2).
Here, we would like to report a convergent strategy and a
potential modular access to all the stereoisomers of
wortmannilactone C from Fragments A and B which would
Received: December 15, 2014
Figure 1. Structures of wortmannilactones A−D.
©
XXXX American Chemical Society
A
DOI: 10.1021/ol5036112
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
Scheme 2. Synthesis of Compound 11 (Fragment A)
Scheme 3. Synthesis of Compound 19 (Fragment B)
(
4 equiv), 2,6-lutidine (2 equiv), dioxane/H O] and treatment
2
of the resulting aldehyde with the unsaturated phosphonoester
I (2 equiv) [LiHMDS (1.9 equiv), THF, 2 h]. After a sequence
of reduction by DIBAL-H (3 equiv) in CH Cl , protection of
The synthesis of Fragment A started with the transformation
of tert-butyl 3-hydroxypropanoate 2 to the optically active
homoallylic alcohol 3 in three steps. After protection of the
hydroxyl group [TBDPSCl (1.2 equiv), imidazole (2 equiv),
CH Cl , 0 °C to rt], followed by reduction by DIBAL-H (1.08
2
2
the primary alcohol as a PMB ether [PMBOC(NH)CCl (1.67
3
equiv), CSA (10 mol %), CH Cl , rt, 18 h], and selective
2
2
deprotection of the alcohol protected as a TBDPS ether [NH F
4
10
(15 equiv), MeOH, reflux, 1.5 h], alcohol 7 was isolated and
transformed into the allylic alcohol 8 after an oxidation step, an
HWE olefination with phosphonoester II (1.2 equiv) [LiCl (1.3
2
2
equiv, CH Cl , −78 °C, 2 h), the obtained unstable aldehyde
2
2
was treated with the allyltitanium complex (S,S)-Ti (1.1 equiv,
11
Et O, −78 °C, 12 h) to furnish 3 in 91% yield and with an
equiv), DBU (1.2 equiv), MeCN, rt, 20 h], and a reduction
(55% over the 3 steps). The obtained allylic alcohol 8 was then
converted to iododiene 11 in four steps. After oxidation of 8,
the obtained aldehyde was submitted to the Takai conditions
2
8,9
enantiomeric excess superior to 96%.
This homoallylic
alcohol 3 was then transformed into the protected 1,3-diol 5
in four steps. The first step was the protection of the hydroxyl
group [TBSCl (2.5 equiv), imidazole (4 equiv), CH Cl , 0 °C
12
[CrCl (20 equiv), CHI (2 equiv), THF/dioxane, rt] to
2
2
2
3
to rt] followed by the oxidative cleavage of the unsaturation
OsO (3 mol %), NaIO (4 equiv), 2,6-lutidine (2 equiv),
produce iododiene 9 in 89% yield which, after deprotection/
oxidation of the primary hydroxyl group with DDQ, led to
aldehyde 10 which was reduced by DIBAL-H. The obtained
iododiene 11 corresponds to Fragment A and was formed from
tert-butyl 3-hydroxypropanoate 2 in 19 steps with an overall
yield of 8.7% (Scheme 2).
[
4
4
dioxane/H O]. The resulting aldehyde was treated directly with
2
(
S,S)-Ti (1.1 equiv, Et O, −78 °C, 12 h) to furnish the
2
expected monoprotected syn-1,3-diol 4 (85% over 3 steps)
which was protected [TBSOTf (1.9 equiv), 2,6-lutidine (1.9
equiv), CH Cl , −78 °C, 2 h] as a TBS ether (compound 5)
The synthesis of the second fragment, Fragment B, started
with the transformation of ethyl (R)-3-hydroxybutanoate 12
into the protected diol 13. After a protection step [TBSCl (1.2
equiv), imidazole (2 equiv), CH Cl , 0 °C to rt] followed by a
2
2
(Scheme 2).
To access the C4−C7 diene, the protected 1,3-diol 5 was
transformed into the conjugated dienic ester 6 by oxidative
2
2
cleavage of the terminal double bond [OsO (3 mol %), NaIO4
reduction with DIBAL-H (1.05 equiv), the resulting aldehyde
4
B
DOI: 10.1021/ol5036112
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
Scheme 4. Coupling of Fragments 11 and 19 and End of the
Synthesis
two steps from 18 via an acetylenic bromide intermediate [NBS
(1.2 equiv), AgNO (10 mol %), acetone/H O] which was
3
2
hydrostannylated [Pd(PPh ) (5 mol %), Bu SnH (3 equiv),
3
4
3
THF, −78 °C to rt, 2 h] (Scheme 3).
Having 11 and 19 in hand, these two fragments were coupled
using Liebeskind conditions, i.e. copper thiophencarboxylate
(
CuTC) (2.2 equiv) and tetrabutylammonium diphenylphos-
16
phinate (TBA-DPP) (2.2 equiv) in NMP (0 °C to rt, 5 h),
and the (E,E,E)-triene 20 was isolated in a moderate yield of
4
1%. It is worth noting that other coupling reactions such as a
Heck and a Stille coupling have been tried to access fragment
C3−C24, but were unsuccessful.
After oxidation of the primary allylic alcohol in 20 with
MnO (30 equiv, CH Cl , rt, 18 h), the sensitive aldehyde 21
2
2
2
was directly treated with NaH (100 equiv, THF) to produce
the macrocyclic lactone which was deprotected with HF·Py
1
13
(
64% yield). By comparison of the H and C NMR spectra
17
and the αD described in the literature, the obtained
macrolactone 1 revealed to be a diastereomer of wortmanni-
18
lactone C (Scheme 4).
In summary a diastereomer of wortmannilactone C was
synthesized in 23 steps from 2, with an overall yield of 1.5%,
using a convergent strategy. The key steps were a Liebeskind
coupling and an HWE olefination. In addition as the
allyltitanium complexes and the Noyori ruthenium complexes
are highly face selective reagents, all the diastereomers of
wortmannilactone C should be accessible by the strategy that
has been developed.
ASSOCIATED CONTENT
Supporting Information
■
*
S
Full experimental details and spectroscopic data. This material
is available free of charge via the Internet at http://pubs.acs.org.
AUTHOR INFORMATION
Corresponding Author
■
*
E-mail: janine.cossy@espci.fr.
Notes
The authors declare no competing financial interest.
was directly treated with the allyltitanium complex (R,R)-Ti
(
1.1 equiv, Et O, −78 °C, 12 h) to provide the syn-1,3-diol with
ACKNOWLEDGMENTS
2
■
an excellent dr superior to 98:2. This syn-1,3-diol was then
protected as a TES ether [TESCl (1.5 equiv), DMAP (0.1
equiv), Et N (2 equiv), CH Cl , 0 °C to rt]. To transform diol
We are grateful to S. Sable,
́
F. Herman, and E. Brohan from
Sanofi-Aventis (Vitry-sur-Seine) for their help with the
purification and the characterization of macrolactone 1.
3
2
2
1
3 into the desired protected triol 16, diol 13 was oxidatively
cleaved [OsO (3 mol %), NaIO (4 equiv), 2,6-lutidine (2
4
4
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DOI: 10.1021/ol5036112
Org. Lett. XXXX, XXX, XXX−XXX