Organocatalytic Michael addition, a convenient tool in total synthesis. First asymmetric synthesis of (-)-botryodiplodin

Article abstract of DOI:10.1016/j.tetlet.2003.09.017

The asymmetric Michael addition of propionaldehyde to (2E)-(3-nitro-but-2-enyloxymethyl)-benzene 8, catalyzed by the chiral diamine (S,S)-N-iPr-2,2′-bipyrrolidine, afforded, with 93% ee, a precursor 9 of (-)-botryodiplodin. The nitro functionality of 9 was converted to a ketone via a Nef reaction to give, after a few steps, the enantiomerically enriched (-)-botryodiplodin.

Full text of DOI:10.1016/j.tetlet.2003.09.017

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 44 (2003) 7901–7904
Organocatalytic Michael addition, a convenient tool in total
synthesis. First asymmetric synthesis of (−)-botryodiplodin
Olivier Andrey, Annick Vidonne and Alexandre Alexakis*
University of Geneva, Department of Organic Chemistry, 30 Quai Ernest Ansermet, CH-1211, Geneva, Switzerland
Received 17 July 2003; revised 26 August 2003; accepted 3 September 2003
Abstract—The asymmetric Michael addition of propionaldehyde to (2E)-(3-nitro-but-2-enyloxymethyl)-benzene 8, catalyzed by
the chiral diamine (S,S)-N-iPr-2,2%-bipyrrolidine, afforded, with 93% ee, a precursor 9 of (−)-botryodiplodin. The nitro
functionality of 9 was converted to a ketone via a Nef reaction to give, after a few steps, the enantiomerically enriched
(−)-botryodiplodin.
© 2003 Elsevier Ltd. All rights reserved.
Recently, Barbas et al.1 described the first asymmetric
addition of aldehydes and ketones to nitrostyrene cata-
catalyzed by (R,R)-N-iPr-2,2%-bipyrrolidine ((R,R)-
iPBP) which gave the addition product with 93% ee5
and a diastereomeric ratio (syn/anti ) of 95:5.
lyzed by diamines or
also reported the asymmetric addition of ketones to
nitrostyrene catalyzed by -proline. For our part, we
L
-proline. List2 and Enders3 have
L
The high enantiocontrol and syn diastereocontrol of
this Michael addition led us to consider its application
towards the synthesis of (−)-botryodiplodin 1.6 In 1966,
Sen Gupta et al.7 isolated this antibiotic from Botryo-
diplodia theobromae after which Arsenault8 confirmed
its structure. Furthermore, (−)-botryodiplodin was dis-
covered as a secondary metabolite of Penicillium roque-
forti.9 This mycotoxin exhibits antibiotic and
antileukemic activity10 but is also a mutagen11 and
induces linkage between proteins and DNA.12,13 To
date, only two syntheses of this natural product in
enantiomerically pure form have been described,14,15
both of them using chiral building blocks derived from
have developed new N-substituted derivatives of 2,2%-
bipyrrolidine (Scheme 1) as organocatalysts for the
asymmetric Michael addition to nitroolefins.4 The best
result was obtained for the addition of propionaldehyde
natural products (D-ribose and methylenomycin A).
A retrosynthetic analysis of (−)-botryodiplodin (Scheme
2) leads to nitro compound 3, which is a direct precur-
sor of the open form of 1. Indeed, the nitro group can
Scheme 1. Asymmetric addition of propionaldehyde to
nitrostyrene catalyzed by chiral (R,R)-iPBP.
Scheme 2. Retrosynthetic analysis for (−)-botryodiplodin.
* Corresponding author. Tel.: +41 22 379 65 22; fax: +41 22 379 32 15; e-mail: alexandre.alexakis@chiorg.unige.ch
0040-4039/$ - see front matter © 2003 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2003.09.017

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O. Andrey et al. / Tetrahedron Letters 44 (2003) 7901–7904
be readily transformed to a carbonyl group via the Nef
reaction.16 The nitro compound 3 may arise from a
Michael addition of propionaldehyde to the nitroolefin
2. This last step could be catalyzed by our chiral
diamine (S,S)-iPBP to provide the adduct 3 in an
enantiomerically enriched form.
nitroolefin 2 was protected with a benzyl group.
Nitroolefin 8 was obtained in two steps via a Henry
condensation starting from the commercially available
benzyloxacetaldehyde 7 in 72% yield for the two steps
(Scheme 4). The asymmetric Michael addition of propi-
onaldehyde to nitroolefin 8 was performed with the
chiral (S,S)-iPBP diamine. The adduct 9 was isolated
as a mixture of four diastereomers in 92% yield after
seven days at −10°C. At this stage we were not able to
measure the enantiomeric excess or to separate the
diastereomers.
We started with the preparation of the nitroolefin 2
(Scheme 3), which was readily obtained from the THP-
protected allyl alcohol 5. Aldehyde 6 was prepared by
ozonolysis of 5 and then nitroolefin 2 was obtained via
Henry condensation17 followed by deprotection of the
alcohol. The key step of our synthesis was the
organocatalyzed addition of propionaldehyde to the
nitroolefin 2. Preliminary investigations on a racemic
version, were done using pyrrolidine instead of (S,S)-
iPBP. The first results immediately showed the
difficulties of our approach. Indeed, the addition led to
the simultaneous formation of four stereocentres.
Unfortunately, these centres were not well controlled,
providing a very complex mixture of diastereomers 3,
from which no major isomer could be distinguished.
Acetylation of the crude mixture led to the isolation of
compounds 4 in low yield, along with an equivalent
amount of starting material 3%. After separation, the
nitro functionality of both 3% and 4 was converted to a
carbonyl group using conditions described by Wade.18
Surprisingly, reaction of 4 led predominantly to the
product 11, and compound 3% to the product epi-1,
indicating that the previous acetylation had occurred
more efficiently on the 3,4-cis diastereomer. This direct
approach allowed us to obtain (−)-botryodiplodin but
the yields were low and it was difficult to analyze
clearly each intermediate or to separate the
diastereomers. These considerations forced us to recon-
sider our strategy toward the synthesis of (−)-
botryodiplodin.
We then tested several conditions to transform the nitro
group to the corresponding ketone,19 but all led either
to the decomposition or to the recovery of the starting
material, probably due to the high instability of the
desired 1,4-ketoaldehyde. This was confirmed after pro-
tection of the aldehyde as the corresponding 1,3-diox-
olane, which then allowed the transformation of the
nitro group to the ketone without decomposition. This
transformation was performed using the mild condi-
tions developed by Wade18 with sodium nitrite and
isoamyl nitrite in DMSO. After four days at room
temperature the nitro group had totally disappeared to
give the ketone 10 in 54% yield. In this reaction a
stereocentre was removed and allowed the measurement
of the enantiomeric excess of each diastereomer by
chiral supercritical fluid chromatography (SFC).20 The
diastereomeric ratio, syn/anti was 57:43 and the enan-
tiomeric excesses were 93% for the syn adduct and 74%
for the anti adduct. As predicted the enantiomeric
excess of the syn compound was relatively high but the
diastereocontrol was almost nonexistent. We cannot,
presently, explain this lack of diastereocontrol com-
pared to the addition to nitrostyrene.4 Fortunately, the
two diastereomers were separable by flash chromatog-
raphy on silica gel.
To avoid the direct formation of the lactol form of
(−)-botryodiplodin, the hydroxy group of the
The end of the synthesis consists of only two deprotec-
tion steps, the first one being a H2/Pd/C debenzylation
Scheme 3. Direct approach towards ( )-botryodiplodin. Reagents and conditions: (a) i O3, CH2Cl2, −78°C. ii Me2S, −78°C to
+20°C, 15 h, 65%; (b) 1,1,3,3-tetramethylguanidine 15 mol%, EtNO2, THF, 0°C, 3 h, 90%; (c) TFAA, Et3N, −10°C, 1 h, 47%; (d)
TsOH 10 mol%, MeOH, rt, 1 h, 85%; (e) propionaldehyde 10 equiv., pyrrolidine 15 mol%, CHCl3, 1 d, rt, not isolated; (f) Ac2O,
Py, rt, 15 h, 4 19%+3% 32%; (g) isoamyl nitrite, NaNO2, DMSO, 4 d, rt.

O. Andrey et al. / Tetrahedron Letters 44 (2003) 7901–7904
7903
Scheme 4. Reagents and conditions: (a) EtNO2, 1,1,3,3-tetramethylguanidine 15 mol%, THF, 0°C, 3 h, quant.; (b) TFAA, Et3N,
−10°C, 1 h, 72%; (c) propionaldehyde 10 equiv., (S,S)-iPBP 15%, CHCl3, −10°C, 7 d, 92%; (d) ethylene glycol, PPTS 10 mol%,
C6H6, Dean–Stark, 3 h, 74%; (e) NaNO2, isoamyl nitrite, DMSO, rt, 4 d, 73%; (f) Pd(OH)2/C 15%, H2 1 atm, MeOH, rt, 3 h,
91%; (g) HCl 10−2 M, ether, rt, 3 d, 62%.
Acknowledgements
to provide the crude free alcohol in 91% yield.
Attempts to purify the alcohol led only to a complex
mixture of the desired product, a partially hydrolyzed
product and a new compound resulting from an
intramolecular transacetalization. For this reason the
crude was used without further purification for the
next step. The second deprotection was carried out in
a biphasic mixture of dilute aqueous hydrochloric acid
(10−2 M solution) and ether, and vigorously stirred for
three days at room temperature to give (−)-
botryodiplodin in 62% yield after filtration through
silica gel. Use of a more acidic solution increased the
reaction rate but damaged a large part of product via
b-elimination to the corresponding a,b-unsaturated
ketone.
We thank the Swiss National Science Foundation
(grant no. 20-61891-00) for financial support.
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eight acetylated products.22 The enantiomeric excess of
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11 and 12 had slightly decreased due to the basic
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ated derivative.
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enantioselective synthesis of (−)-botryodiplodin 1 and
have demonstrated the potential of organocatalysis in
asymmetric total synthesis. Moreover, our synthesis
could be applied to the synthesis of a large variety of
analogues by simply changing the starting nitroalkane
or aldehyde.

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O. Andrey et al. / Tetrahedron Letters 44 (2003) 7901–7904
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60°C–1°C/min–100°C–10°C/min–
170°C–10 min, Rt (1a): 48.7, 48.9 min, Rt (1b): 48.2 min.
22. Hydrodex-B-3P, 80°C–1°C/min–170°C, Rt (11a): 36.7, (−)-
isomer 38.4 min, Rt (11b): 35.2, 36.3 min, Rt (12a): 34.2,
34.8 min, Rt (12b): 38.7, 39.3 min.