Asymmetric total synthesis of (-)-pironetin employing the SAMP/RAMP hydrazone methodology

Article abstract of DOI:10.1002/chem.200601672

A convergent asymmetric total synthesis of pironetin (1), a polyketide with immunosuppressive, antitumor, and plant-growth regulating activities is described. The synthesis was realized by coupling between the C ₈-C₁₄ 2 and C₇

Full text of DOI:10.1002/chem.200601672

DOI: 10.1002/chem.200601672
Asymmetric Total Synthesis of (ꢀ)-Pironetin Employing the SAMP/RAMP
Hydrazone Methodology**
Dieter Enders,* Sylvie Dhulut, Daniel Steinbusch, and Audrey Herrbach[a]
Dedicated to Professor Alain Krief on the occasion of his 65th birthday
Abstract:
A
convergent asymmetric
SAMP/RAMP hydrazone (SAMP=
(S)-1-amino-2-methoxymethylpyrroli-
dine, RAMP=(R)-1-amino-2-methoxy-
methylpyrrolidine) methodology as a
key step. An asymmetric a-alkylation
of diethyl ketone permitted the intro-
duction of the C10 stereogenic center of
2, whereas the stereocenters C4 and C5
of 15 were installed by an asymmetric
aldol reaction. Finally, the formation of
the a,b-unsaturated d-lactone was ach-
ieved by ring-closing metathesis in the
presence of catalytic amounts of titani-
umtetraisopropoxide.
total synthesis of pironetin (1), a poly-
ketide with immunosuppressive, antitu-
mor, and plant-growth regulating activ-
ities is described. The synthesis was re-
alized by coupling between the C8–C14
2 and C7–C2 15 fragments, respectively,
by using a Mukaiyama-aldol reaction.
The stereogenic centers of each frag-
ment were generated by employing the
Keywords: aldol
reaction
·
asymmetric synthesis · hydrazones ·
metathesis
pironetin
· natural products ·
Introduction
trast to colchicin, vinblastin, or rhizoxin which bind to differ-
ent sites of b-tubulin.[3e] Based on all these characteristics,
pironetin 1 is considered to be a very attractive research
target and several total syntheses have already been de-
scribed in the literature.[4] However, this metabolite suffers
from problems of toxicity and side effects; therefore, some
structural modifications of the natural product have been
studied in order to reduce its toxicity and increase its specif-
icity.[3]
Due to its unique properties and low extraction yields
fromnature, it was our aimto establish an efficient total
synthesis of pironetin 1, which also enabled an easy access
for the preparation of other structural analogues. We envis-
aged its synthesis by employing the SAMP/RAMP hydra-
Pironetin (1) (PA-48153C) was first isolated in 1993 by
Yoshida et al.[1] fromthe fermentation broth of Streptomyces
prunicolor PA-48153, and then in 1994 by Kobayashi and
co-workers[2] from Streptomyces sp. NK10958. This natural
lactone displays very interesting and diverse biological activ-
ities. Pironetin shows a potent immunosuppressive effect on
the responses of both T and B-lymphocytes to mitogens,
whereas immunosuppressants cyclosporin A (CsA) and FK-
506 only antagonize T-cell activation.[1a] Apart frombeing
an immunosuppressive agent with an original mode of
action, pironetin also exhibits a strong regulating activity in
plant growth.[2] More importantly, it has recently been iden-
tified as a strong antitumor agent, which influences the dy-
namic of the tubulin-microtubules system inhibiting the
polymerization of tubulin.[3] Its uniqueness comes from its
ability to bind covalently to the a-subunit of tubulin in con-
zone
(SAMP=(S)-1-amino-2-methoxymethylpyrrolidine,
RAMP=(R)-1-amino-2-methoxymethylpyrrolidine) alkyla-
tion[5] and aldolization[5a,6] methodology developed earlier
by our group.
Our retrosynthetic analysis was initially based on the
asymmetric aldol reaction between the ketone 2 and the lac-
tone-aldehyde 3, in which the stereogenic center C10 could
be introduced by hydrazone a-alkylation, and the C4 and C5
centers by a hydrazone aldol reaction (Scheme 1).
[a] Prof. Dr. D. Enders, Dr. S. Dhulut, Dr. D. Steinbusch,
Dr. A. Herrbach
Institut für Organische Chemie, RWTH Aachen
Landoltweg 1, 52074 Aachen (Germany)
Fax : (+49)241-809-2127
E-mail: Enders@RWTH-Aachen.de
[**] SAMP=(S)-1-amino-2-methoxymethylpyrrolidine
RAMP=(R)-1-amino-2-methoxymethylpyrrolidine
3942
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Chem. Eur. J. 2007, 13, 3942 – 3949

FULL PAPER
thesis of the acrylate ent-11 with Grubbs first-generation
catalyst (0.2 equiv) in the presence of titaniumtetraisoprop-
oxide (0.5 equiv), followed by deprotection of the benzyl
group permitted access to the lactone alcohol ent-12
(Scheme 3).[9]
Scheme 1. Retrosynthetic analysis of pironetin.
Results and Discussion
For the synthesis of ketone 2, the stereogenic center at C10
was generated by asymmetric a-alkylation of 3-pentanone
via its SAMP-hydrazone derivative 4 with (E)-crotylbro-
mide. After removal of the chiral auxiliary from the product
hydrazone 5 by standard acidic conditions in a two-phase
system, ketone 2 was obtained with 98% ee (ee=enantio-
meric excess) and with good yield over two steps
(Scheme 2).
Scheme 3. Attempts to synthesize the aldehyde ent-3: a) TiCl4, DIPEA
(DIPEA=diisopropyl ethyl amine), dichloromethane, ꢀ788C!RT;
b) TBSOTf, lutidine, dichloromethane, ꢀ788C, 80% over two steps,
96% ee, 55% de (deꢁ96% after HPLC); c) MMPP, EtOH, buffer pH 7,
RT, 92%; d) DIBAL-H, THF, 08C!RT, 86 %; e) Ph3P=CH2, THF,
ꢀ788C!RT, 92%; f) TBAF, THF, RT, 97%; g) acrylic acid, DMAP,
DDC, dichloromethane, 08C!RT, 77%; h) Grubbs first-generation cata-
Scheme 2. Synthesis of the a-alkylated ketone 2: a) 1) LiTMP, THF, 08C,
30 min; 2) (E)-crotylbromide, ꢀ1108C; b) pentane/4n HCl, RT, 1 h, 78%
over two steps, 98% ee (CSP GC analysis, Lipodex E).
lyst, TiCAHTREU(GN OiPr)4, dichloromethane, reflux, 96%; i) TiCl4, dichloromethane,
08C!RT, 91 %.
Several oxidation attempts were studied on 12 by using
[10]
To introduce the stereogenic centers C4 and C5 of the lac-
tone aldehyde building block ent-3,[7] we used the syn-selec-
tive asymmetric aldol reaction via titanium azaenolates of
SAMP hydrazones.[5a,7] Butanal SAMP hydrazone 6 was
treated with titaniumtetrachloride and Hünigꢁs base to pro-
vide the titanated hydrazone as a deep-red solution in di-
chloromethane. Subsequent trapping with the aldehyde 7,
followed by protection as a TBS (TBS=tert-butyldimethyl-
silyl) ether, furnished the syn-configured SAMP hydrazone
ent-8 as the major diastereomer (de=55%, deꢁ96% after
HPLC, ee=96%; de=diastereomeric excess) with good
yield. Oxidative cleavage of the chiral auxiliary by using
magnesium monoperoxyphthalate hexahydrate (MMPP)[8]
afforded the corresponding nitrile without racemization in
92% yield. Its reduction with DIBAL-H (DIBAL-H=diiso-
butylaluminum hydride), followed by Wittig olefination of
the corresponding aldehyde ent-9 gave the olefin ent-10 in
good yield. After TBS deprotection and esterification with
acrylic acid, the diene precursor of the metathesis ent-11
was isolated in 75% yield over two steps. Ring-closing meta-
classical conditions, such as pyridiniumchlorochromate,
pyridiniumdichromate,
[11]
DMP (DMP=Dess–Martin peri-
odinane),[12] TPAP/NMO (TPAP=tetra-n-propylammonium
perruthenate, NMP=N-methyl-2-pyrrolidinone)[13] and the
Swern oxidation.[14] Unfortunately, only traces of aldehyde
were observed and were accompanied by decomposition
products of the starting alcohol in all cases. Consequently,
we had to modify our first strategy.
In the new approach, the lactone formation was envisaged
at the end of the synthesis by means of a transition-metal-
catalyzed ring-closing metathesis of the diene 13. We consid-
ered a Mukaiyama-aldol reaction between the alkylated
ꢀ
ketone 2 and the aldehyde 15 to create the C7 C8 bond. The
stereogenic center at C9 may be controlled by a samarium-
iodide-mediated Tishchenko reduction of the b-hydroxyke-
tone 14 (Scheme 4).
For the synthesis of the aldehyde 15, planned to be used
in the aldol reaction with 2, the benzyl group of 10 was re-
moved with calcium in liquid ammonia, and the resulting
primary alcohol was oxidized under Swern conditions to
Chem. Eur. J. 2007, 13, 3942 – 3949
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3943

D. Enders et al.
anti relationship between C9 and C7 was established by
13C NMR spectroscopy (the acetonide methyl group chemi-
cal shifts of 19, d=23.8 and 26.0 ppm). The alcohol on C9
was converted to the methyl ether by using proton sponge
and Meerweinꢁs reagent (Me3OBF4) in dichloromethane.[17]
The cleavage of the TBS ether[18] furnished the alcohol 20,
which was then treated with acryloyl chloride in THF in the
presence of triethylamine to give the ester 13.[19] 13C NMR
spectroscopic analysis of the acetonide methyl group chemi-
cal shifts (d=24.9 and 25.0 ppm) of 21, easily achieved from
20 in two steps, proved the anti relationship between C7 and
C5. The formation of the d-lactone was carried out by em-
ploying the ring-closing metathesis with Grubbs first-genera-
tion catalyst and a catalytic amount of titanium isopropox-
ide.[9] Finally, the removal of the acetate group provided the
title natural product pironetin (1) in 80% yield
(Scheme 6).[4g]
Scheme 4. Retrosynthetic analysis of the new approach.
Scheme 5. Introduction of the stereogenic centers C7, C8, and C9.
a) NH3(liq), Ca, THF, ꢀ788C; b) DMSO, Et3N, SO3–pyridine complex, RT,
83% over two steps; c) 1) diphenyltetramethyldisilazane, nBuLi, THF,
ꢀ788C; 2) TMSCl, Et3N, 5 h, RT; d) BF3·OEt2, dichloromethane, ꢀ788C ,
92% (mixture of diastereomers, 57% of the desired one); e) CH3CHO,
SmI2, THF, ꢀ158C, 90%, 96% de (determined by NMR spectroscopy).
afford the desired aldehyde 15 in 83% yield over two steps.
Deprotonation of the ketone 2 by using diphenyltetrame-
thyldisilazane and n-butyllithiumfollowed by trapping with
a mixture of trimethylsilyl chloride and triethylamine fur-
nished the Z enolate 16, which was used directly in a Mu-
kaiyama-aldol reaction in the presence of BF3·Et2O with the
aldehyde 15 to provide the b-hydroxyketone 14 in 52%
yield.[15] Subsequent samarium-iodide-mediated Tishchenko
reduction introduced the stereogenic center C9 to give 17
with an excellent anti selectivity of 96% de in 90% yield
(Scheme 5).[16]
Scheme 6. Final steps of the pironetin synthesis: a) 1) KOH, MeOH, RT;
2) DMP (DMP=2,2-dimethoxypropane), PPTS (PPTS=pyridinium p-
toluene sulfonate), dichloromethane, 08C!RT, 72% over two steps;
b) Me3OBF4, proton sponge, 408C, 53%, 69% based on the recovered
starting material; c) acetone/6n HCl, RT, 60%, 79% based on the recov-
ered start material; d) 1) KOH, MeOH, RT; 2) DMP, PPTS, dichlorome-
thane, 08C!RT, 60% over two steps; e) acrylic acid chloride, Et3N,
THF, 08C, 48% (not optimized); f) Grubbs first-generation catalyst,
The resulting alcohol 17 was easily converted to the aceto-
nide 19 in two steps by removal of the acetate group and
acetonide formation to determine the configuration. The
ACHTEURNG ACHRET(GNU OiPr)4, dichloromethane, reflux, 32% (not optimized); g) MeOH/3n
3944
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Chem. Eur. J. 2007, 13, 3942 – 3949

Total Synthesis of (ꢀ)-Pironetin
FULL PAPER
tion was quenched with pH 7 buffer solution (330 mL) and then diluted
with Et2O (200 mL). The aqueous phase was extracted with Et2O (3”
150 mL), the combined organic layers were washed with brine, dried
(MgSO4), and concentrated under reduced pressure. The resulting crude
ketone hydrazone 5 was diluted in pentane (140 mL) and cooled to 08C.
An aqueous solution of HCl (4n, 60 mL) was added and the reaction
mixture was vigorously stirred at room temperature for 1 h. The aqueous
layer was separated, extracted with Et2O (3”50 mL), and the organic ex-
tracts were combined, washed with brine (100 mL), dried (MgSO4), fil-
tered, and concentrated under reduced pressure. The crude product was
purified by silica-gel flash chromatography (pentane/Et2O 100:0, 95:5) to
afford the alkylated ketone 2 (7.5 g, 78% over two steps) as a clear
Conclusion
A convergent asymmetric total synthesis of pironetin (1) has
been accomplished. The creation of the stereogenic centers
at C8, C4, and C5 were realized by employing the SAMP/
RAMP hydrazone alkylation and aldolization methodology.
ꢀ
The formation of the C7 C8 bond was carried out by a Mu-
kaiyama-aldol reaction between ketone 2 and aldehyde 15,
which installed the stereogenic centers C4 and C5 simultane-
ously. The last stereogenic center C9 was introduced by
means of a samarium-mediated Tishchenko reduction and
the formation of the a,b-unsaturated d-lactone was achieved
by ring-closing metathesis. Our new approach should permit
easy access to various stereoisomers and structural ana-
logues. Indeed, all the configurations of the stereogenic cen-
ters of pironetin can be simply controlled by auxiliary ex-
change between SAMP and RAMP in the alkylation and
aldol reactions or by modification of the experimental con-
ditions for the aldol reaction between the fragments 2 and
15 as well as for the reduction of the b-hydroxy ketone.
Moreover, as it has already been described by our laborato-
ry, the asymmetric a-alkylation of ketones by means of the
SAMP/RAMP hydrazone methodology allows the introduc-
tion of a large variety of substituents R1 in the C10 posi-
tion.[5] In the same way, different R2 groups may be envis-
aged at the C4 position by employing other aldehydes rather
than butyraldehyde in the aldol reaction.
1
liquid. [a]2D4 =+23.9 (c=1.07 in CHCl3); H NMR (400 MHz, CDCl3): d=
5.49–5.39 (m, 1H), 5.36–5.26 (m, 1H), 2.59–2.50 (m, 1H), 2.43 (dq, 3J-
(H,H)=7.1, 2.2 Hz, 2H), 2.33–2.24 (m, 1H), 2.06–1.97 (m, 1H), 1.62 (dd,
3J
C
ACHTRE(UGN H,H)=7.1 Hz, 3H), 1.02 ppm(t,
3J
127.3, 46.4, 36.3, 34.6, 18.1, 16.3, 7.9 ppm; IR (film, CHCl 3): n˜ =3022,
2970, 2934, 2857, 1714, 1457, 1413, 1376, 1106, 1021, 969 cmꢀ1; MS (EI):
m/z (%): 140 [M]+, 112, 111, 83, 83, 67, 57, 56, 55, 53; elemental analysis
calcd (%) for C9H16O (140.12): C 77.09, H 11.50; found: C 76.83,
H 11.38.
AHCTREUNG
AHCTREUNG
(6.00 mmol, 1.2 equiv) was added dropwise over 15 min at ꢀ788C to a so-
lution of hydrazone 6 (921 mg, 5.00 mmol, 1 equiv) in dichloromethane
(7.5 mL) under argon. The dark-red solution was stirred for 30 min and
then diisopropylethylamine (6.00 mmol, 1.2 equiv) was added over
15 min. The reaction mixture was stirred for 30 min at ꢀ788C, then for
2 h at roomtemperature, and recooled to ꢀ788C. After the addition of
the aldehyde
7 (4.0 mmol, 0.8 equiv) dissolved in dichloromethane
(1.5 mL), the solution was allowed to warm up to room temperature over
16 h and then quenched with a saturated solution of ammonium fluoride
(5 mL) and water (5 mL). The aqueous layer was extracted with dichloro-
methane (3”15 mL). The organic extracts were combined, washed with
brine (30 mL), dried (MgSO4), filtered, and concentrated under reduced
pressure. The crude product (thick-dark-brown oil) was used in the next
step without purification. 2,6-Lutidine (20.0 mmol, 4 equiv) was added to
a stirred solution of crude aldol product (5.0 mmol, 1.0 equiv) in CH2Cl2
(15 mL) under argon, followed by the dropwise addition of TBSOTf
(15.0 mmol, 3 equiv) at ꢀ788C. After stirring for 2 h at the same temper-
ature (TLC control), the mixture was quenched with a saturated solution
of NH4Cl (15 mL) and extracted with dichloromethane (3”10 mL). The
combined organic extracts were dried (MgSO4), filtered, and concentrat-
ed under reduced pressure to give the crude product as a dark-brown
syrup. Purification by flash chromatography on silica gel (pentane/Et2O
90:10, 80:20) gave the TBS-protected product ent-8 as a pale-yellow oil
Experimental Section
General methods: Solvents were dried and purified prior to use. THF
was freshly distilled over sodiumlead alloy under argon. Dichlorome-
thane, dimethyl sulfoxide (DMSO), and triethylamine were distilled over
CaH2 and stored under argon. Acetone was distilled over P2O5 and
stored under argon. Methanol was distilled over magnesium. Et2O, pen-
tane, and EtOAc were distilled over KOH, CaH2, and K2CO3, respective-
ly. Analytical glass-backed TLC plates (silica gel 60 F254) and silica gel
(60, 40–63 mm) were purchased from Merck, Darmstadt. Reagents of
commercial quality were used from freshly opened containers unless oth-
erwise stated. Optical rotations were measured on a Perkin–Elmer P241
polarimeter and with solvents of Merck UVASOL quality. Microanalyses
were obtained with a Heraeus CHN-O-RAPID, Vario EL elemental ana-
lyzer. 1H and 13C NMR spectra were obtained on a Varian VXR 300,
Gemini 300 (both 300 and 75 MHz), Varian Inova 400 (400 MHz and
100 MHz), or Varian Unity 500 (500 and 125 MHz) with TMS as the in-
ternal standard. IR spectra were recorded on a Perkin–Elmer FTIR 1760
spectrometer. Mass spectroscopy was carried out on a Varian MAT 212,
EI 70 eV, 1 mA and a Finnigan MAT SSQ 7000, CI 100 eV (relative in-
tensities are reported in brackets). High-resolution mass spectra were re-
corded on a Finnigan MAT 95.
(1.85 g, 80% over two steps, de=55%, ꢁ96% after HPLC). [a]D28
=
1
ꢀ63.8 (c=1.09 in CHCl3); H NMR (400 MHz, CDCl3): d=7.34–7.23 (m,
3
3
5H), 6.56 (d, J
(d, 3J
(H,H)=12.0 Hz, 1H), 3.93–3.88 (m, 1H), 3.62–3.49 (m, 3H), 3.44–
3.29 (m, 3H), 3.36 (s, 3H), 2.75–2.67 (m, 1H), 2.27–2.20 (m, 1H), 1.98–
1.70 (m, 6H), 1.52–1.42 (m, 2H), 0.88 (s, 9H), 0.89 (t, 3J
(H,H)=7.4 Hz,
ACHRTUNEG(H,H)=6.6 Hz, 1H), 4.50 (d, JACHTRE(UGN H,H)=12.0 Hz, 1H), 4.46
AHCTREUNG
AHCTREUNG
3H), 0.05 (s, 3H), 0.02 ppm(s, 3H); 13C NMR (100 MHz, CDCl3): d=
139.3, 138.4, 128.1, 127.4, 127.3, 74.9, 72.8, 71.7, 67.1, 63.3, 59.1, 50.2, 50.0,
33.8, 26.6, 25.9, 22.02, 21.6, 18.1, 12.2, ꢀ4.4, ꢀ4.5 ppm; IR (film, CHCl 3):
n˜ =3088, 3064, 2956, 2929, 2856, 2727, 1946, 1726, 1692, 1601, 1496, 1461,
1407, 1381, 1362, 1340, 1302, 1254, 1198, 1099, 1056, 1029, 1006, 973, 939,
905, 837, 801, 776, 698, 676, 609, 465 cmꢀ1; MS (EI): m/z (%): 462 [M]+,
420, 418, 286, 280, 269, 204, 185, 175, 173, 139, 117, 115, 114, 101, 1001,
91, 89, 82, 75, 73, 71, 70, 59, 55, 45; HRMS: m/z: calcd for C26H46N2O3Si:
462.3278 [M]+; found: 462.3276.
(E)-(S)-4-Methyloct-6-en-3-one (2): A dry, argon flushed 1 L Schlenk
round-bottomed flask equipped with a magnetic stirring bar was filled
with 2,2,6,6-tetramethylpiperidine (TMP, 114 mmol, 1.5 equiv) and anhy-
drous THF (220 mL). The reaction mixture was cooled to 08C and nBuLi
(114 mmol, 1 equiv) was added dropwise. The orange solution was stirred
for 30 min and a solution of SAMP hydrazone 4 (15 g, 76.0 mmol,
1.0 equiv) in THF (20 mL) was added at 08C. After stirring for 4 h at the
same temperature, the mixture was cooled to ꢀ1108C and (E)-1-bromo-
but-2-ene (68 mmol, 0.9 equiv) was slowly added in order to maintain the
low temperature. After stirring for a further 30 min at ꢀ1108C, the mix-
ture was allowed to warmup to roomtemperature overnight. The reac-
AHCTRE(GNU 2R,3S)-5-Benzyloxy-3-(tert-butyldimethylsilanyloxy)-2-ethylpentanal
(ent-9): SAMP hydrazone ent-8 (7.15 g, 15.45 mmol, 1.0 equiv) in MeOH
(100 mL) was added to a solution of MMPP (32.81 mmol, 2.1 equiv) in a
mixture of MeOH (130 mL) and pH 7 buffer solution (130 mL) at 08C.
The heterogeneous solution was stirred at the same temperature for 6 h,
followed by dilution with Et2O (310 mL) and brine (70 mL). The organic
layer was separated, dried over Na2SO4, filtered, and concentrated under
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3945

D. Enders et al.
reduced pressure. Purification by flash chromatography on silica gel (pen-
tane/Et2O 90:10) afforded the corresponding nitrile (4.95 g, 92%) as a
colorless oil. [a]2D8 =ꢀ10.2 (c=1.09 in CHCl3); 1H NMR (300 MHz,
dition of water (13 mL), followed by extractions with Et2O (3”10 mL).
The combined organic layers were washed with brine (20 mL), dried over
MgSO4, filtered, and concentrated in vacuo. The residue was purified by
chromatography on silica gel (pentane/Et2O 60:40) to give the corre-
sponding alcohol (620 mg, 97%) as a colorless oil. [a]2D3 =+2.0 (c=1.13
in CHCl3); 1H NMR (400 MHz, CDCl3): d=7.37–7.27 (m, 5H), 5.65
CDCl3): d=7.32–7.18 (m, 5H), 4.46 (d, 3J
ACHTREUNG
3J
ACHTREUNG ACHTRENUG
(H,H)=11.8 Hz, 1H), 3.93 (td, 3J
A
ACHTREUNG
A
(ddd, 3J
1H), 5.04 (ddd, 3J
(m, 3H), 1.98 (dtd, 3J
14.8, 6.0, 4.4, 2.0 Hz, 1H), 1.75–1.61 (m, 2H), 1.30–1.19 (m, 1H),
0.80 ppm(t, 3J(H,H)=7.4 Hz, 3H); 13C NMR (100 MHz, CDCl3): d=
G
ACHTRE(UNG H,H)=10.2, 2.0 Hz,
0.04 ppm(s, 6H); 13C NMR (75 MHz, CDCl3): d=138.3, 128.5, 127.7,
120.7, 73.1, 69.0, 65.9, 41.5, 34.1, 25.8, 21.6, 18.0, 12.2, ꢀ4.6 ppm; IR (film,
CHCl3): n˜ =3088, 3065, 3031, 2956, 2931, 2882, 2858, 2801, 2240, 1496,
1463, 1408, 1386, 1363, 1310, 1256, 1208, 1100, 1051, 1029, 1008, 940, 839,
804, 778, 727, 699, 672 cmꢀ1; MS (EI): m/z (%): 347 [M]+, 290, 92, 73; el-
emental analysis calcd (%) for C20H33NO2Si (347.57): C 69.11, H 9.57,
N 4.03; found: C 69.12, H 9.81, N 4.49.
ACHTREUNG
G
ACHTREUNG
AHCTREUNG
139.2, 138.1, 128.6, 127.7, 127.9, 117.2, 74.0, 73.6, 69.8, 52.9, 34.0, 23.3,
12.1 ppm; IR (film, CHCl 3): n˜ =3067, 2960, 2929, 2872, 1639, 1496, 1479,
1454, 1421, 1364, 1310, 1242, 1206, 1029, 1000, 914, 737, 698, 462 cmꢀ1
;
MS (EI): m/z (%): 234 [M]+, 165, 107, 92, 91, 65; elemental analysis
DIBAL-H (1.0m in heptane, 15.5 mmol, 1.35 equiv) was added to a solu-
tion of the nitrile derived from ent-8 (4.0 g, 11.51 mmol, 1.0 equiv) in an-
hydrous THF (23 mL) under argon at 08C. After stirring for 2 h at 08C,
the reaction mixture was quenched with a solution of tartaric acid (1m in
water, 57 mL) and Et2O (23 mL). The heterogeneous solution was stirred
for 1 h. The aqueous layer was extracted with Et2O (3”30 mL) and the
organic solutions were combined, washed with brine (50 mL), dried over
Na2SO4, filtered, and concentrated under reduced pressure. Purification
by flash chromatography on silica gel (pentane/Et2O 90:10) afforded the
aldehyde ent-9 (3.44 g, 86%) as a colorless oil. [a]2D8 =ꢀ23.2 (c=1.21 in
calcd (%) for C15H22O2 (234.33): C 76.88, H 9.46; found: C 76.58, H 9.61.
Dropwise 1,3-dicyclohexylcarbodiimide (DCC, 29.07 mmol, 4.0 equiv)
and the alcohol obtained from ent-10 (1.7 g, 7.26 mmol, 1.0 equiv) were
added successively to a solution of acrylic acid (29.05 mmol, 4.0 equiv)
and 4-dimethylaminopyridine (DMAP, 8.73 mmol, 1.2 equiv) in dichloro-
methane (22 mL) under argon at 08C. The solution was stirred at 08C for
10 min and was then allowed to warm up to room temperature overnight.
The mixture was filtered through Celite, washed with dichloromethane
(15 mL), and concentrated in vacuo. The residue was purified by flash
chromatography on silica gel (pentane/Et2O 80:20) to give the diene ent-
11 (1.55 g, 77%) as a colorless oil. [a]2D3 =ꢀ10.1 (c=1.03 in CHCl3);
CHCl3); 1H NMR (400 MHz, CDCl3): d=9.80 (d, 3J
7.37–7.25 (m, 5H), 4.50 (d, 3J
11.8 Hz, 1H), 4.21 (td, 3J(H,H)=8.8, 4.4 Hz, 1H), 3.52 (t, 3J
5.8 Hz, 2H), 2.34 (ddd, 3J
(H,H)=6.9, 4.7, 2.2 Hz, 1H), 1.91–1.82 (m,
2H), 1.79–1.66 (m, 2H), 0.91 (t, 3J
(H,H)=7.4 Hz, 3H), 0.87 (s, 9H), 0.06
ACHTREUNG
G
ACHTREUNG
G
A
1H NMR (400 MHz, CDCl3): d=7.34–7.24 (m, 5H), 6.38 (dd,
ACHTREUNG ACHTREUNG(H,H)=
3J
(H,H)=17.3, 10.4 Hz, 1H), 5.80 (dd,
(H,H)=10.4, 1.4 Hz, 1H), 5.56 (ddd, 3J
(H,H)=17.0, 10.4, 9.2 Hz, 1H),
5.14–5.06 (m, 1H), 5.04 (dd, 3J
(H,H)=17.0, 0.8 Hz, 1H), 4.46 (s, 2H),
3.53–3.41 (m, 2H), 2.25–2.16 (m, 1H), 2.05–1.75 (m, 2H), 1.59–1.46 (m,
1H), 1.35–1.20 (m, 1H), 0.85 ppm (t, 3J(H,H)=7.4 Hz, 3H); 13C NMR
G
17.3, 1.4 Hz, 1H), 6.10 (dd, 3J
3J
ACHTREUNG
N
N
G
ACHTREUNG
(s, 3H), 0.05 ppm(s, 3H); 13C NMR (100 MHz, CDCl3): d=205.6, 138.5,
128.6, 127.8, 73.2, 69.7, 66.8, 59.5, 34.6, 26.1, 18.4, 18.1, 12.7, ꢀ4.2 ppm;
IR (film, CHCl3): n˜ =3088, 3065, 3031, 2956, 2929, 2857, 2711, 1723, 1496,
1462, 1407, 1383, 1362, 1309, 1256, 1208, 1187, 1101, 1055, 1006, 940, 838,
777, 736, 698, 669, 465 cmꢀ1; MS (EI): m/z (%): 279 [MꢀC5H11]+, 92, 91,
75, 73; elemental analysis calcd (%) for C20H34O3Si (350.57): C 68.52,
H 9.78; found: C 68.43, H 9.90.
ACHTREUNG
AHCTREUNG
(100 MHz, CDCl3): d=166.1, 138.6, 138.0, 130.8, 128.8, 127.8, 127.6,
117.9, 74.0, 73.4, 67.2, 50.2, 32.0, 23.3, 12.0 ppm; IR (film, CHCl 3): n˜ =
2963, 2931, 2874, 1723, 1638, 1619, 1496, 1454, 1405, 1363, 1270, 1195,
1101, 1046, 1029, 985, 918, 866, 809, 737, 698, 461 cmꢀ1; MS (EI): m/z
(%): 288 [M]+, 187, 146, 110, 107, 105, 95, 92, 91, 82, 79, 69, 68, 67, 65,
55; elemental analysis calcd (%) for C18H24O3 (288.38): C 74.97, H 8.39;
found: C 74.72, H 8.83.
ACHTREUNG
ACHTREUNG
pension of Ph3PCH3Br (17.22 mmol, 6 equiv) in anhydrous THF (23 mL)
under argon at ꢀ788C. The orange solution was stirred 30 min at ꢀ788C
and for 30 min at room temperature until it became homogenous. The re-
action mixture was cooled to ꢀ788C and aldehyde ent-9 (1.0 g,
2.87 mmol, 1 equiv) dissolved in THF (8.6 mL) was added. The reaction
was allowed to warmup to roomtemperature overnight and was then
quenched with water (23 mL). The aqueous layer was extracted with
Et2O (3”10 mL). The combined organic phases were washed with brine
(25 mL), dried over MgSO4, filtered, and concentrated in vacuo. Purifica-
tion by flash chromatography on silica gel (pentane/Et2O 100:0, 95:5) af-
forded ent-10 (971 mg, 97%) as a colorless oil. [a]2D8 =ꢀ7.4 (c=1.07 in
CHCl3); 1H NMR (400 MHz, CDCl3): d=7.35–7.25 (m, 5H), 5.65 (ddd,
A
(ent-12):
A
A
ent-11 (1.55 g, 5.37 mmol, 1.0 equiv) in dichloromethane (107 mL) under
argon at roomtemperature. The resulting solution was refluxed at 40 8C
for 2 h and then Grubbs first-generation catalyst (1.09 mmol, 0.2 equiv)
in dichloromethane (50 mL) was added. The reaction mixture was stirred
at reflux for an additional 48 h. The mixture was cooled to room temper-
ature and concentrated under reduced pressure. The residue was purified
by flash chromatography on silica gel (pentane/Et2O 50:50) to provide
the lactone (1.34 g, 96%) as
a
brown oil. [a]2D3 =ꢀ63.3 (c=0.75 in
CHCl3); 1H NMR (400 MHz, CDCl3): d=7.37–7.26 (m, 5H), 6.99 (dd,
3J
4.98 (ddd, 3J
1H), 4.45 (d, 3J
3.85 Hz, 1H), 3.53 (t, J
(m, 2H), 1.56–1.42 (m, 1H), 1.30–1.16 (m, 1H), 0.88 (s, 9H), 0.85 (t,
3J 13C NMR
(H,H)=7.4 Hz, 3H), 0.05 (s, 3H), 0.03 ppm(s, 3H);
(100 MHz, CDCl3): d=139.2, 138.7, 128.4, 127.7, 127.5, 116.1, 72.9, 72.2,
67.1, 51.8, 33.5, 26.0, 22.8, 18.2, 12.1, ꢀ4.2, ꢀ4.5 ppm; IR (film, CHCl 3):
n˜ =3068, 3030, 2957, 2929, 2857, 2800, 1640, 1496, 1462, 1455, 1407, 1379,
1362, 1307, 1255, 1205, 1096, 1058, 1029, 1005, 939, 878, 836, 775, 734,
697, 665 cmꢀ1; MS (EI): m/z (%): 279 [MꢀC5H9]+, 173, 131, 117, 107,
101, 91, 75, 73, 59; elemental analysis calcd (%) for C21H36O2Si (348.59):
C 72.35, H 10.41; found: C 71.84, H 10.84.
C
G
N
3J
3J
3J
(m, 1H), 1.92–1.83 (m, 1H), 1.72–1.60 (m, 1H), 1.56–1.42 (m, 1H),
0.95 ppm(t,
3J(H,H)=7.4 Hz, 3H); 13C NMR (100 MHz, CDCl3): d=
G
ACHTREUNG
N
G
ACHTREUNG
G
N
3
ACHTREUNG
A
A
A
Acrylic
acid
(1S,2S)-1-(2-benzyloxyethyl)-2-ethyl-but-3-enyl
ester
ACHTREUNG(ent-11): A solution of tetrabutylammonium fluoride (TBAF, 1m in THF,
16.4 mmol, 5.9 equiv) was added to
a
solution of ent-10 (970 mg,
2.78 mmol, 1.0 equiv) in THF (13 mL) under argon at room temperature.
The reaction mixture was stirred for 16 h and was then quenched by ad-
3946
www.chemeurj.org
ꢀ 2007 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Chem. Eur. J. 2007, 13, 3942 – 3949

Total Synthesis of (ꢀ)-Pironetin
FULL PAPER
MgSO4, filtered, and concentrated in vacuo. Purification by silica-gel
flash chromatography (Et2O 100%) gave the desired product ent-12
(535 mg, 91%) as a colorless liquid. [a]2D3 =ꢀ79.2 (c=1.00 in CHCl3);
BF3·OEt2 (7.72 mmol, 4.0 equiv) was added to a stirred solution of enolsi-
lane 16 (1.93 mmol, 1 equiv) and aldehyde 15 (1.93 mmol, 1.0 equiv) in
anhydrous dichloromethane
A
1H NMR (400 MHz, CDCl3): d=7.04 (dd, 3J
ACHTREUNG
was stirred at ꢀ788C for 3 h and then partitioned between dichlorome-
thane (100 mL) and saturated aqueous NaHCO3 (50 mL). The aqueous
layer was extracted with dichloromethane (3”30 mL). The combined or-
ganic extracts were dried over Na2SO4, filtered, and concentrated under
reduced pressure. A short purification by flash chromatography (pen-
tane/Et2O 95:5, 90:10) afforded a mixture of diastereoisomers (700 mg,
92% over two steps) as a clear oil, which contained 57% of the desired
diastereoisomer 14 (399 mg).
6.03 (d, 3J(H,H)=9.6 Hz, 1H), 4.71 (dt, 3J
ACHTREUNG ACHTRENUG
AHCTREUNG
CDCl3): d=164.5, 150.7, 120.4, 77.6, 58.5, 38.4, 33.8, 20.7, 10.9 ppm; IR
(film, CHCl3): n˜ =3419, 3016, 2967, 1883, 1711, 1623, 1463, 1387, 1258,
1057, 1016, 922, 826, 755, 667 cmꢀ1; MS (EI): m/z (%): 152 [MꢀH2O]+,
141, 125, 97, 96, 95, 82, 81, 73, 68, 67, 57, 54, 53; elemental analysis calcd
(%) for C9H14O3 (170.21): C 63.51, H 8.29; found: C 63.28, H 8.88.
The mixture of b-hydroxyketone (1.77 mmol, 1.0 equiv) was dissolved in
anhydrous THF (7.1 mL) under argon. To this was added freshly distilled
acetaldehyde (7.08 mmol, 4.0 equiv). The solution was cooled to ꢀ158C
(methanol/ice bath) and a freshly prepared 0.1m solution of SmI2 in THF
(4 mL, 0.4 equiv) was added dropwise (30 min). The initial blue color dis-
appears within 15 s. After stirring for 1 h at ꢀ158C, the reaction mixture
was quenched by the addition of Et2O (20 mL) and saturated aqueous
NaHCO3 (10 mL). The aqueous layer was extracted with Et2O (3”
10 mL) and the combined organic extracts were washed with saturated
aqueous NaHCO3, dried over Na2SO4, filtered and concentrated under
reduced pressure. Purification by silica-gel flash chromatography (pen-
tane/Et2O 95:5, 90:10) gave the desired product 17 (398 mg, 90%) as a
ACHTREUNG(3R,4R)-3-(tert-Butyldimethylsilanyloxy)-4-ethyl-hex-5-enal (15): Benzyl
ether 10 (675 mg, 1.91 mmol, 1.0 equiv) in THF (50 mL) was added to a
dark-blue solution of calcium metal (19.4 mmol, 10 equiv) in liquid am-
monia (10 mL) and anhydrous THF (25 mL) under argon at ꢀ788C. The
reaction mixture was stirred at ꢀ788C for 30 min and was then quenched
by the addition of solid NH4Cl (25 g). The ammonia was allowed to evap-
orate while the reaction was gradually warmed up to room temperature
and then a saturated aqueous solution of NH4Cl was added. The aqueous
phase was extracted with Et2O (3”40 mL) and the organic layers were
washed with brine (80 mL), dried over MgSO4, filtered, and concentrated
in vacuo. After a short filtration on silica gel (pentane/Et2O 80:20), the
corresponding alcohol (500 mg, quantitative, clear oil) was directly used
colorless oil. 1H NMR (400 MHz, CDCl3): d=5.72 (ddd, 3J
ACHTREUNG
10.4, 8.0 Hz, 1H), 5.48–5.33 (m, 3H), 5.10 (dd, 3J
A
in the next step. 1H NMR (400 MHz, CDCl3): d=5.54 (ddd, 3J
17.1, 10.4, 8.7 Hz, 1H), 5.03 (dd, 3J
(H,H)=10.4, 2.2 Hz, 1H), 4.95 (ddd,
3J(H,H)=17.1, 2.2, 1.0 Hz, 1H), 3.77–3.70 (m, 2H), 3.65 (dt, 3J
(H,H)=
11.4, 5.7 Hz, 1H), 2.11–2.00 (m, 1H), 1.70–1.60 (m, 2H), 1.53–1.43 (m,
1H), 1.20–1.06 (m, 1H), 0.83 (s, 9H), 0.80 (t, 3J
(H,H)=7.4 Hz, 3H), 0.03
ACHTRE(UNG H,H)=
3
3
1H), 5.02 (ddd, J
A
ACHTRE(UGN H,H)=8.8,
AHCTREUNG
3.8, 2.5 Hz, 1H), 3.25 (d, 3J
ACHTREUNG
A
ACHTREUNG
A
3J
A
A
ACHTREUNG
AHCTREUNG
ACHTREUNG
(s, 3H), 0.02 ppm(s, 3H); 13C NMR (100 MHz, CDCl3): d=138.6, 116.5,
73.8, 60.1, 51.3, 35.0, 25.9, 23.2, 18.0, 12.0, ꢀ4.5, ꢀ4.4 ppm; IR (film,
CHCl3): n˜ =3343, 3075, 2956, 2860, 1639, 1467, 1418, 1382, 1254, 1082,
914, 838, 775, 668, 490 cmꢀ1; MS (CI): m/z (%): 259 [M+1]+, 243, 189,
173, 131, 127, 109, 83.
A
ACHTREUNG
3H), 0.05 ppm(s, 6H); 13C NMR (100 MHz, CDCl3): d=172.1, 138.2,
130.1, 126.0, 116.0, 73.1, 72.2, 72.0, 51.1, 41.5, 38.0, 36.3, 34.3, 25.9, 22.5,
21.0, 18.1, 17.9, 12.1, 11.4, 9.7, ꢀ4.7, ꢀ4.0 ppm; IR (film, CHCl 3): n˜ =
3529, 2960, 2932, 2858, 1720, 1463, 1374, 1255, 1134, 1071, 966, 948, 914,
837, 776, 667 cmꢀ1; MS (CI): m/z (%): 441 [M+1]+, 381, 363, 323, 309,
250, 249, 231, 213, 199, 179, 137, 113, 83.
DMSO (8 mL) and Et3N (9.69 mmol, 5.0 equiv) were added to a solution
of the alcohol (500 mg, 1.94 mmol, 1.0 equiv) in dichloromethane (8 mL)
under argon. The solution was cooled to 08C and SO3–pyridine complex
(9.69 mmol, 5 equiv) was added. After 30 min of stirring, the reaction
mixture was diluted with Et2O (20 mL) and washed with a saturated solu-
tion of NH4Cl (15 mL). The organic solution was dried over MgSO4, fil-
tered, and concentrated in vacuo. Purification by flash chromatography
on silica gel (pentane/Et2O 95:5, 90:10) afforded the aldehyde 15
(414 mg, 83% over two steps) as a colorless oil. 1H NMR (400 MHz,
Acetic acid (E)-(1R,2R,3S,4S)-1-[(2R,3R)-2-(tert-butyl-dimethylsilanyl-
AHCTREoGNU xy)-3-ethyl-pent-4-enyl]-3-hydroxy-2,4-dimethyl-oct-6-enyl ester (18):
Proton sponge (0.74 mmol, 5 equiv) and Me3OBF4 (0.74 mmol, 5 equiv)
were added to a solution of alcohol 17 (65 mg, 0.148 mmol, 1 equiv) in di-
chloromethane (2 mL) under argon at room temperature. The heteroge-
neous mixture was stirred for 6 h at 408C and then overnight at room
temperature in the dark. The brownish mixture was poured into dichloro-
methane (10 mL) and washed with aqueous HCl (1m, 3”5 mL). The or-
ganic layer was dried over Na2SO4, filtered, and concentrated in vacuo.
Purification by flash chromatography (pentane/Et2O 90:10) afforded 18
(35.6 mg, 53%, 69% based on the recovered start material) as a colorless
CDCl3): d=9.81 (t, 3J
10.4, 8.8 Hz, 1H), 5.13 (dd, 3J
3J
(H,H)=17.3, 1.9, 0.8 Hz, 1H), 4.11 (td, J
(ddd, 3J(H,H)=16.0, 6.3, 2.7 Hz, 1H), 2.48 (ddd, 3J
1.9 Hz, 1H), 2.14–2.06 (m, 1H), 1.62–1.52 (m, 1H), 1.28–1.17 (m, 1H),
0.88 (s, 9H), 0.87 (t, 3J
(H,H)=7.4 Hz, 3H), 0.09 (s, 3H), 0.05 ppm(s,
A
ACHTRE(UGN H,H)=17.3,
AHCTREUNG
3
A
N
ACHTREUNG
A
ACHTREUNG
oil. 1H NMR (400 MHz, CDCl3): d=5.74 (ddd, 3J
8.0 Hz, 1H), 5.48–5.34 (m, 2H), 5.25 (ddd, 3J
(H,H)=6.6, 4.7, 1.9 Hz,
1H), 5.07 (dd, 3J
(H,H)=10.4, 1.9 Hz, 1H), 5.00 (ddd, J
0.8 Hz, 1H), 3.74 (dt, 3J
(H,H)=7.7, 3.8 Hz, 1H), 3.39 (s, 3H), 2.87 (dd,
3J
(H,H)=9.3, 2.2 Hz, 1H), 2.04 (s, 3H), 2.16–1.94 (m, 3H), 1.75 (ddd,
3J
(m, 2H), 1.51 (ddd, 3J
1.37–1.27 (m, 1H), 0.89 (s, 9H), 0.88 (t, 3J
3J(H,H)=6.9 Hz, 3H), 0.80 (d, 3J
(H,H)=6.9 Hz, 3H), 0.10 (s, 3H),
ACHTRE(UNG H,H)=17.3, 10.4,
ACHTREUNG
AHCTREUNG
3H); 13C NMR (100 MHz, CDCl3): d=202.3, 138.2, 117.5, 70.8, 52.5, 48.3,
25.8, 23.0, 18.0, 11.9, ꢀ4.5, ꢀ4.4 ppm; IR (film, CHCl 3): n˜ =3077, 2954,
2862, 2719, 1727, 1466, 1380, 1255, 1091, 1003, 920, 838, 777, 673,
552 cmꢀ1; MS (CI): m/z (%): 257 [M+1]+, 241, 213, 199, 187, 159, 125,
127, 107, 81.
3
A
ACHTRE(UNG H,H)=17.3, 1.9,
AHCTREUNG
AHCTREUNG
3
A
A
ACHTRE(UNG H,H)=4.9 Hz, 3H), 1.72–1.60
AHCTREUNG
AHCTREUNG
(E)-(5S,7S,8R,10R,11R)-10-(tert-Butyldimethylsilanyloxy)-11-ethyl-8-
ACHTREUNG
A
N
ACHTREUNG
0.06 ppm(s, 3H); 13C NMR (100 MHz, CDCl3): d=170.5, 139.0, 130.1,
126.1, 115.6, 85.0, 72.4, 72.2, 60.9, 50.9, 40.3, 38.3, 37.2, 35.7, 25.9, 21.9,
21.3, 18.1, 18.0, 12.3, 12.1, 10.5, ꢀ4.5, ꢀ4.3 ppm; IR (film, CHCl 3): n˜ =
3850, 3745, 3673, 3478, 2939, 2354, 1737, 1643, 1553, 1459, 1374, 1249,
1089, 960, 813, 671 cmꢀ1; MS (CI): m/z (%): 455 [M+1]+, 395, 363, 325,
323, 263, 231, 213, 161, 127, 95.
a
(3.86 mmol, 2 equiv) in THF (7.7 mL) under argon at 08C. After 10 min
of stirring, the solution was cooled to ꢀ788C and a solution of the
ketone 2 (270 mg, 1.93 mmol, 1 equiv) in THF (1 mL) was added. After
stirring for 1 h at ꢀ788C, a solution of TMSCl (7.72 mmol, 4.0 equiv) and
Et3N (1.93 mmol, 1 equiv) in THF (1 mL) was added. The reaction was
stirred for 15 min at ꢀ788C, and then for 5 h at roomtemperature. The
mixture was partitioned between pentane (100 mL) and saturated aque-
ous NaHCO3 (50 mL). The pentane layer was dried (Na2SO4), filtered,
and concentrated under reduced pressure. The crude product was directly
used in the next step without purification.
Acetic acid (E)-(1R,2S,3S,4S)-1-[(2R,3R)-3-ethyl-2-hydroxy-pent-4-enyl]-
3-methoxy-2,4-dimethyl-oct-6-enyl ester (20): A solution of HCl (6n,
600 mL) was added to a stirred solution of 18 (240 mg, 0.528 mmol,
1.0 equiv) in acetone (6 mL) at 08C, and the mixture was stirred for
80 min at room temperature. The reaction was diluted with Et2O
Chem. Eur. J. 2007, 13, 3942 – 3949
ꢀ 2007 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
3947

D. Enders et al.
(10 mL), washed with saturated aqueous NaHCO3, dried over Na2SO4,
filtered, and concentrated under reduced pressure. Purification by flash
chromatography (pentane/Et2O 95:5, 80:20) afforded 20 (108 mg, 60%,
ACHTREUNG
79% based on the recovered start material) as a colorless oil. 1H NMR
3
(400 MHz, CDCl3): d=5.55 (ddd, J
A
5.34 (m, 3H), 5.08 (dd, 3J
17.3, 2.2, 0.8 Hz, 1H), 3.37 (s, 3H), 3.30 (ddd, JAHCTREUNG
1H), 3.27 (s, 1H; OH), 2.82 (dd, JACHTREUNG
(H,H)=10.4, 2.2 Hz, 1H), 5.03 (ddd, 3J
ACHRTEUNG ACHTREUNG
3
3
(pentane/Et2O 90:10) afforded pironetin (1) (5.4 mg, 80%) as a colorless
1
oil. H NMR (400 MHz, CDCl3): d=7.01 (dd, 3J
N
AHCTREUNG
3
3
6.02 (d, J
(H,H)=9.6 Hz, 1H), 5.50–5.30 (m, 2H), 4.74 (dt, J
A
A
4.0 Hz, 1H), 4.24–4.19 (m, 1H), 3.47 (s, 3H), 2.98 (dd, 3J
ACHTREUNG
A
ACHTREUNG
ACHTREUNG
A
ACHTREUNG
129.9, 126.3, 116.5, 85.2, 71.2, 69.5, 61.2, 52.2, 40.5, 38.8, 38.3, 35.7, 23.1,
G
ACHTREUNG
21.1, 18.0, 12.4, 11.7, 10.6 ppm; IR (film, CHCl 3): n˜ =2957, 1727, 1461,
6.8 Hz, 3H); 13C NMR (100 MHz, CDCl3): d=164.8, 150.6, 128.6, 126.8,
120.7, 91.0, 77.6, 67.2, 61.5, 39.0, 38.7, 37.1, 36.6, 36.0, 20.6, 17.8, 15.1,
12.1, 10.8 ppm; HRMS: m/z: C19H32O4: calcd (%) for 292.2038
[MꢀMeOH]+; found: 292.2037.
1375, 1252, 1083, 960, 839, 761, 669 cmꢀ1
; MS (EI): m/z (%): 325
[MꢀCH3]+, 311, 293, 231, 213, 199, 161, 153, 128, 127, 117, 109, 95, 75,
73, 59, 55.
Acrylic
acid
(E)-(1R,3R,4S,5S,6S)-3-acetoxy-1-[(R)-1-ethylallyl]-5-
ACHTREUNGmethoxy-4,6-dimethyldec-8-enyl ester (13): Et3N (0.53 mmol, 5 equiv)
was added to a solution of the alcohol 20 (36 mg, 0.106 mmol, 1 equiv) in
dry THF (1.0 mL) under argon at 08C. A solution of acryloyl acid chlo-
ride (0.53 mmol, 5 equiv) in dry CH2Cl2 (1.0 mL) was added dropwise to
the mixture and stirring was continued for a further 30 min at 08C. Brine
was added and the aqueous phase was quickly extracted with Et2O (3”
5 mL). The combined organic layers were washed with brine, dried
(MgSO4), filtered, and concentrated under reduced pressure. Purification
by flash chromatography (pentane/Et2O 90:10) afforded 13 (20 mg, 48%
not optimized) as a colorless oil. 1H NMR (400 MHz, CDCl3): d=6.39
Acknowledgements
This work was supported by the Deutsche Forschungsgemeinschaft (Son-
derforschungsbereich 380) and the Fonds der Chemischen Industrie. We
thank Degussa AG, BASF AG, Bayer AG and Wacker Chemie for the
donation of chemicals.
(dd, 3J
5.80 (dd, 3J
9.1 Hz, 1H), 5.50–5.32 (m, 2H), 5.25 (ddd, 3J
AHCTREUNG
A
ACHTREUNG
A
ACHTREUNG
1H), 5.12 (dd, 3J
A
ACHTREUNG
[1] a) T. Yoshida, K. Koizumi, Y. Kawamura, K. Matsumoto, H. Itazaki,
Japan Patent Kokai 5–310726, 1993; b) idem. European Patent
560389 A1, 1993.
[2] a) S. Kobayashi, K. Tsuchiya, T. Harada, M. Nishide, T. Kurokawa,
T. Nakagawa, N. Shimada, K. Kobayashi, J. Antibiot. 1994, 47, 697–
702; b) S. Kobayashi, K. Tsuchiya, T. Kurokawa, T. Nakagawa, N.
Shimada, Y. Iitaka, J. Antibiot. 1994, 47, 703–707.
2.0 Hz, 1H), 4.91 (ddd, 3J
G
3
(dd, J
A
(m, 1H), 2.01–1.92 (m, 2H), 1.71 (ddd, 3J
ACHTREUNG
1.68–1.58 (m, 2H), 1.66 (dd, 3J
AHCTREUNG
AHCTREUNG
A
N
ACHTREUNG
[3] a) K. Yasui, Y. Tamura, T. Nakatani, K. Horibe, K. Kawada, K. Koi-
zumi, R. Suzuki, M. Ohtani, J. Antibiot. 1996, 49, 173–180; b) M.
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Biol. 2004, 11, 799–806.
(100 MHz, CDCl3): d=170.3, 165.5, 137.3, 130.2, 129.9, 128.5, 126.2,
117.5, 85.2, 72.9, 70.1, 61.1, 49.5, 40.5, 38.3, 35.7,34.5, 23.0, 21.1, 17.9, 12.3,
11.7, 10.7 ppm; IR (film, CHCl 3): n˜ =2960, 2929, 2875, 1724, 1636, 1620,
1492, 1370, 1261, 1198, 970, 855, 754, 670 cmꢀ1; MS (CI): m/z (%): 395
[M+1]+, 363, 336, 335, 323, 311, 303, 192, 263, 232, 231, 229, 192, 178,
161, 149, 136, 127, 123, 95; HRMS: m/z: calcd for C23H38O5 [MꢀCH2=
CH2, COCH2=CH2]+: 311.1858; found: 311.1858.
Acetic acid (E)-(1R,2S,3S,4S)-1-[(2R,3R)-3-ethyl-6-oxo-3,6-dihydro-2H-
pyran-2-ylmethyl]-3-methoxy-2,4-dimethyloct-6-enyl ester (22): A solu-
tion of TiACHTREUNG(OiPr)4 in dichloromethane (0.1m, 0.0153 mmol, 153 mL) was
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added to a stirred solution of diene 13 (20 mg, 0.051 mmol, 1.0 equiv) in
dichloromethane (17 mL, 0.003m) under argon at roomtemperature. The
resulting solution was refluxed at 408C for 30 min and then Grubbs first-
generation catalyst (0.01 mmol, 0.2 equiv) in dichloromethane (1 mL)
was added. The reaction mixture was stirred at reflux for another 20 h.
The mixture was cooled to room temperature and the solvent was partial-
ly evaporated. The residue was purified by flash chromatography on
silica gel (pentane/Et2O 50:50) to provide the lactone 22 (6.0 mg, 32%
not optimized, 39% based on the recovered start material) as a brown
1
oil. H NMR (400 MHz, CDCl3): d=7.03 (dd, 3J
A
6.12 (d, 3J
4.50–4.43 (m, 1H), 3.39 (s, 3H), 2.88 (dd, J
(s, 3H), 2.30–2.22 (m, 1H), 2.17–1.90 (m, 3H), 1.82–1.70 (m, 2H), 1.67
(d, 3J 3J
(H,H)=5.5 Hz, 3H), 1.64–1.47 (m, 2H), 0.97 (t, (H,H)=7.4 Hz,
3H), 0.89 (d, 3J 3J
(H,H)=6.9 Hz, 3H), 0.82 ppm(d, (H,H)=6.9 Hz, 3H);
ACHTREUNG
3
AHCTRE(UNG H,H)=9.3, 1.6 Hz, 1H), 2.07
A
A
A
A
A
A
13C NMR (100 MHz, CDCl3): d=170.6, 164.0, 150.3, 129.9, 126.4, 120.7,
85.0, 77.4, 70.8, 61.2, 39.0, 38.1, 38.0, 35.6, 33.9, 21.1, 20.3, 17.8, 12.2, 10.8,
10.1 ppm. The data are in accordance with those described in the litera-
ture.[4g]
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Steinbusch, Dissertation, RWTH Aachen (Germany), 2003.
3948
www.chemeurj.org
ꢀ 2007 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Chem. Eur. J. 2007, 13, 3942 – 3949

Total Synthesis of (ꢀ)-Pironetin
FULL PAPER
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Received: November 23, 2006
Published online: February 13, 2007
Chem. Eur. J. 2007, 13, 3942 – 3949
ꢀ 2007 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
3949