Asymmetric total synthesis of the immunosuppressant (-)-pironetin

Article abstract of DOI:10.1002/anie.200802423

(Chemical Equation Presented) A short, enantioselective total synthesis of the title compound 1 is described. The 14-step synthesis features a highly stereoselective Brown-type pentenylation and a onepot hydrosilylation/ring- closing metathesis (RCM)/prot

Full text of DOI:10.1002/anie.200802423

Angewandte
Chemie
DOI: 10.1002/anie.200802423
Natural Product Synthesis
Asymmetric Total Synthesis of the Immunosuppressant
(ꢀ)-Pironetin**
Cyril Bressy, Jean-Pierre Vors, Stefan Hillebrand, Stellios Arseniyadis, and Janine Cossy*
Independently isolated by Yoshida et al.[1] and Kobayashi and
co-workers[2] from Streptomyces sp. NK-10958 and the fer-
mentation broths of Streptomyces prunicolor PA-48153,
(ꢀ)-Pironetin (1) was found to display plant-growth-regula-
tory[2a] as well as immunosuppressive activities[1a] similar to
those exhibited by cyclosporin A (CsA) and FK-506.[3] More
recently, (ꢀ)-pironetin has since been identified as a strong
antitumor agent that influences the dynamics of the tubulin–
microtubules system by inhibiting the polymerization of
tubulin.[4] Interestingly, whereas other antitumor agents such
as colchicin, vinblastin, rhizoxin, and epothilone B, bind to b-
tubulin, (ꢀ)-pironetin was shown to bind to the a subunit of
tubulin.[4e]
Scheme 1. Stereoselective boron-mediated pentenylation [Eq. (1)], and
one-pot hydrosilylation/RCM/protodesilylation [Eq. (2)]. Cp*=penta-
methylcyclopentadienyl, Grubbs II=Grubbs second-generation cata-
lyst, Ipc=isopinocampheyl.
Owing to the very limited natural availability of
(ꢀ)-pironetin, as well as its interesting mode of action and
its unique structure, this natural product has been the focus of
considerable synthetic interest, which has resulted in the
development of several total syntheses.[5] Herein we report a
highly stereoselective and straightforward synthesis of
(ꢀ)-pironetin (1) for which we developed two novel and
efficient synthetic methodologies: a stereoselective boron-
mediated pentenylation reaction[6] [Scheme 1, Eq. (1)] and a
one-pot hydrosilylation/ring-closing metathesis (RCM)/pro-
todesilylation reaction [Scheme 1, Eq. (2)].
Our strategy for the synthesis of (ꢀ)-pironetin (1) is
depicted in Scheme 2. Thus, we planned to introduce the
d-lactone moiety and reduce the triple bond stereoselectively
by subjecting compound A to a RCM and a hydrosilylation/
protodesilylation sequence. Compound A was in turn envi-
sioned to arise from aldehyde B through a highly diastereo-
Scheme 2. Retrosynthetic analysis of (ꢀ)-pironetin. PG=protecting
group.
and enantioselective Brown-type pentenylation reaction,
which should establish the syn relationship between the
substituents at C4 and C5. Finally, aldehyde B could be
synthesized from the readily available (S)-Roche ester,
whereby two stereoselective titanium-mediated reactions, a
crotylation and an allylation, would control the configuration
of the three stereogenic centers introduced at C7, C8, and C9.
The synthesis of (ꢀ)-pironetin (1) began with the tosyla-
tion of commercially available (S)-Roche ester, followed by
the reduction of the ester moiety to the corresponding
aldehyde 2 with diisobutylalumninum hydride (DIBAL-H;
Scheme 3). The aldehyde 2 was then subjected to a diastereo-
and enantioselective crotylation using the complex (R,R)-[Ti]-
[*] Dr. C. Bressy, Dr. S. Arseniyadis, Prof. J. Cossy
Laboratoire de Chimie Organique, ESPCI-ParisTech, CNRS
10 rue Vauquelin, 75231 Paris Cedex 05 (France)
Fax: (+33)01-40-79-46-60
E-mail: janine.cossy@espci.fr
Dr. J.-P. Vors
Bayer CropScience, Lyon (France)
Dr. S. Hillebrand
Bayer CropScience, Monheim (Germany)
[**] We thank Bayer CropScience for financial support.
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Scheme 3. Total synthesis of (ꢀ)-pironetin: a) TsCl (1.2 equiv), DIPEA (1.2 equiv), DMAP (0.05 equiv), CH2Cl2, 08C!RT, 2 h; b) DIBAL-H in
toluene (1.2 equiv), toluene, ꢀ788C, 2 h; c) (R,R)-[Ti]-I (1.5 equiv), Et2O, ꢀ788C, 12 h, 60% (3 steps); d) MeOTf (7 equiv), 2,6-di-tert-butylpyridine
(8 equiv), CHCl3, 658C, 12 h, 90%; e) O3, then PPh3 (1.5 equiv), CH2Cl2, ꢀ788C; f) (S,S)-[Ti]-II (1.3 equiv), Et2O, 12 h, ꢀ788C, 56% (2 steps);
ꢁ
g) TBSOTf (1.3 equiv), 2,6-lutidine (1.6 equiv), CH2Cl2, 08C, 2 h; h) HC CLi·EDA (5 equiv), DMSO, RT, 12 h, 80% (2 steps); i) nBuLi (1.2 equiv),
MeI (3 equiv), THF, ꢀ788C; j) OsO4 (0.05 equiv), NMO (1.5 equiv), acetone/H2O, then NaIO4 (1.5 equiv), THF/pH 7 buffer, 82% (2 steps); k) cis-
2-pentene (6 equiv), nBuLi (2 equiv), tBuOK (2 equiv), (ꢀ)-Ipc2BOMe (2.5 equiv), BF3·Et2O (2.5 equiv), THF/Et2O, ꢀ788C, 12 h; l) acryloyl chloride
(1.5 equiv), DIPEA (3 equiv), 08C!RT, 1 h, 65% (2 steps); m) HSi(OEt)3 (1.2 equiv), CH2Cl2, 08C, then [Cp*Ru(MeCN)3]PF6 (1 mol%), 08C!RT,
then Grubbs second-generation catalyst (5 mol%), 408C, then AgF (2.4 equiv), MeOH/H2O/THF, RT; n) aqueous HF, CH3CN/THF, 08C!RT,
64% (2 steps). Cy=cyclohexyl, DIPEA=diisopropylethylamine, DMAP=4-dimethylaminopyridine, EDA=ethylenediamine, TBS=tert-butyldime-
thylsilyl, Tf=trifluoromethanesulfonyl, Ts=para-toluenesulfonyl.
Table 1: Asymmetric Brown-type pentenylation reaction.
I to generate the desired homoallylic alcohol (d.r. > 95:5,
60% yield over three steps), which was subsequently methy-
lated with methyl triflate in the presence of 2,6-di-tert-
butylpyridine in CHCl3 at reflux.[7] This methylation proce-
dure was chosen to avoid basic conditions, which would lead
to the formation of the undesired oxetane. The resulting ether
3 was treated with ozone followed by PPh3 to generate the
corresponding aldehyde, which was treated immediately with
the complex (S,S)-[Ti]-II to afford the homoallylic alcohol 4 in
good yield and with excellent diastereoselectivity (d.r. > 95:5,
50% yield over three steps).
The homoallylic alcohol 4 was protected as a tert-
butyldimethylsilyl ether before the propyne group was
introduced in two steps through displacement of the tosylate
group with lithium acetylide in dimethyl sulfoxide (DMSO)[8]
and subsequent treatment of the terminal alkyne with nBuLi
followed by methyl iodide. Selective oxidative cleavage of the
double bond with OsO4, N-methylmorpholine N-oxide
(NMO), and NaIO4 gave aldehyde 6 (66% yield over
two steps), which was subjected to a highly stereoselective
boron-mediated pentenylation reaction inspired Brownꢀs
asymmetric crotylation protocol[9] (Table 1, entry 2). Thus,
aldehyde 6 was treated with the preformed Z-configured
boron complex resulting from the reaction between
Entry
Method[a]
syn/anti[b]
d.r.[b]
Yield [%][c]
1
2
A
B
>95:5
>95:5
1.8:1
21:1
62
68
[a] Method A: cis-2-pentene, tBuOK, nBuLi, THF, ꢀ788C!ꢀ658C, then
iPrO3B, then 1m HCl, (R,R)-diisopropyl tartrate, then 6, toluene, ꢀ788C.
Method B: cis-2-pentene, tBuOK, nBuLi, THF, ꢀ788C, then
(ꢀ)-Ipc2BOMe, BF3·Et2O, 6, THF, ꢀ788C. [b] Determined by 1H NMR
spectroscopic analysis of the crude reaction mixture. [c] Yield of the
isolated product.
homoallylic alcohol was isolated in good yield and with an
exclusively syn relationship between the two substituents at
C4 and C5. Acylation with acryloyl chloride then afforded the
key intermediate 7 in 65% yield (over two steps). It is
noteworthy that all our attempts to use the conditions
reported by Roush et al.[10] also led to the desired homoallylic
alcohol, however, the observed selectivity was rather poor
(Table 1, entry 1).
(ꢀ)-methoxydiisopinocampheylborane
((ꢀ)-Ipc2BOMe),
This 12-step sequence set the stage for our final one-pot
hydrosilylation/RCM/protodesilylation reaction, which was
cis-2-pentene, and the Schlosser base. The corresponding
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developed after multiple attempts at the RCM of substrate 7
had failed as a result of the presence of the alkyne moiety
(Table 2, entry 1). To circumvent the problem, we decided to
switch the order of our synthetic sequence and performed the
appropriate chiral auxiliary, and as diversity in the olefinic
side chain can be introduced by simple alkylation of the
terminal alkyne, this approach allows straightforward access
to any of the various stereoisomers and a wide array of
structural analogues.
Table 2: One-pot hydrosilylation/RCM/protodesilylation reaction.
Experimental Section
Pentenylation of 6: nBuLi (2 equiv) was added dropwise to a stirred
suspension of tBuOK (2 equiv) and cis-2-pentene (6 equiv) in THF at
ꢀ788C. The reaction mixture was then stirred for 5 min at ꢀ508C.
The resulting orange solution was cooled to ꢀ788C, and a solution of
(ꢀ)-methoxydiisopinocampheylborane in Et2O (0.5m; 2.5 equiv) was
added dropwise. The reaction mixture was stirred for 30 min at
ꢀ788C, and then boron trifluoride diethyl etherate (2.5 equiv) was
added, followed by 6 (1 equiv). The reaction mixture was stirred for a
further 5 h at the same temperature, treated with a 3m solution of
NaOH and H2O2, and heated at reflux for 1 h. The mixture was then
extracted with EtOAc, washed with brine, dried over MgSO4, and
concentrated under reduced pressure. Purification of the crude
residue by flash column chromatography on silica gel afforded the
desired homoallylic alcohol.
Hydrosilylation/RCM/protodesilylation of 7: Triethoxysilane
(1.2 equiv) was added to a solution of 7 (1 equiv) in CH2Cl2 (0.1m
solution) at 08C, followed by [Cp*Ru(MeCN)3]PF6 (0.01 equiv). The
mixture was allowed to warm to room temperature and was stirred
until no starting material remained. The second-generation Grubbs
catalyst was then added (0.05 equiv), and the reaction mixture was
stirred at 408C until complete conversion was observed. The reaction
mixture was allowed to cool to room temperature, and then AgF
(2.4 equiv) was added, followed by MeOH (0.01m), H2O (0.01m), and
THF (0.1m). Stirring was continued in the dark until consumption of
the silylated intermediate was complete. The reaction mixture was
then filtered through Celite, extracted with CH2Cl2, and dried over
MgSO4, and the solvent was evaporated under reduced pressure.
Purification of the crude residue by flash column chromatography on
silica gel afforded the lactone product.
Entry
Method[a]
Product
Yield [%][b]
1
2
3
A
B
C
–
9
1
–
78
64
[a] Method A: Grubbs second-generation catalyst (5 mol%), 408C, then
HSi(OEt)3 (1.2 equiv), CH2Cl2, 08C, then [Cp*Ru(MeCN)3]PF6 (1 mol%),
08C!RT, then AgF (2.4 equiv), MeOH/H2O/THF, RT. Method B: HSi-
(OEt)3 (1.2 equiv), CH2Cl2, 08C, then [Cp*Ru(MeCN)3]PF6 (1 mol%),
08C!RT, then Grubbs second-generation catalyst (5 mol%), 408C, then
AgF (2.4 equiv), MeOH/H2O/THF, RT. Method C: HSi(OEt)3 (1.2 equiv),
CH2Cl2, 08C, then [Cp*Ru(MeCN)3]PF6 (1 mol%), 08C!RT, then Grubbs
second-generation catalyst (5 mol%), 408C, then AgF (2.4 equiv),
MeOH/H2O/THF, RT, then aqueous HF, CH3CN/THF, 08C!RT.
[b] Yield of the isolated product.
ruthenium-catalyzed hydrosilylation reaction prior to the
RCM step. Thus, dienyne 7 was first hydrosilylated under the
conditions developed by Trost and Ball[11] with HSi(OEt)3 in
the presence of [Cp*Ru(MeCN)3]PF6 (1 mol%), and sub-
jected subsequently to RCM with the second-generation
Grubbs catalyst ([Ru]-II; 5 mol%) to afford the correspond-
ing d-lactone. The d-lactone was then treated with AgF to
remove the two silyl groups (Table 2, entry 2). However,
although these conditions enabled the construction of both
the a,b-unsaturated d-lactone moiety and the substituted
alkene with the E configuration in a one-pot process, final
deprotection of the alcohol at C7 with aqueous HF was
necessary to generate the natural product. Thus, 1 was
isolated in 64% yield over two steps (Table 2, entry 3). The
spectroscopic and physical data of 1 were in accordance with
those reported for the natural product ([a]2D0 = ꢀ133.6 (c = 3.5,
CDCl3); lit. [a]2D0 = ꢀ137.5 (c = 3.4 ꢁ 10ꢀ3, CDCl3)).[1,2,5]
Received: May 24, 2008
Published online: November 21, 2008
Keywords: antitumor agents · hydrosilylation · natural products ·
.
pentenylation · ring-closing metathesis
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stereoselective synthesis of (ꢀ)-pironetin (1), which was
obtained in 14 steps and 8.2% overall yield from the
commercially available (S)-Roche ester. The stereogenic
centers at C4 and C5 were generated in the desired config-
uration by use of a stereoselective boron-mediated penteny-
lation, whereas those at C7, C8, and C9 resulted from
stereoselective titanium-mediated crotylation and allylation
reactions. Finally, the a,b-unsaturated d-lactone and the
E alkene were formed in a single step through a one-pot
hydrosilylation/RCM/protodesilylation sequence. This syn-
thesis of (ꢀ)-pironetin is the shortest reported to date.
Furthermore, as the configuration of all stereogenic centers
can be controlled readily through the selection of the
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