Synthesis of the C10-C24-bis-spiroacetal core of 13-desmethyl spirolide C based on a sila-stetter-acetalization process

Article abstract of DOI:10.1002/chem.201402894

Synthesis of the bis-spiroacetal core of 13-desmethyl spirolide C has been completed based on a sila-Stetter-acetalization process. The acylsilane and enone partners in the Stetter reaction were prepared in 7 and 11 steps, respectively, from (S) and (R)-a

Full text of DOI:10.1002/chem.201402894

DOI: 10.1002/chem.201402894
Full Paper
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Organic Synthesis
Synthesis of the C10–C24-Bis-Spiroacetal Core of 13-Desmethyl
Spirolide C, Based on a Sila-Stetter-Acetalization Process
Jessica Labarre-Lainꢀ, Ignacio PeriÇan, Valꢀrie Desvergnes,* and Yannick Landais*[a]
Dedicated to Professor Max Malacria for his 65th birthday and his contribution to radical and organometallic chemistry.
Abstract: Synthesis of the bis-spiroacetal core of 13-des-
methyl spirolide C has been completed based on a sila-Stet-
ter-acetalization process. The acylsilane and enone partners
in the Stetter reaction were prepared in 7 and 11 steps, re-
spectively, from (S) and (R)-aspartic acid. The quaternary
center at C19 in the enone moiety was controlled by relying
on the Seebach’s chiral self-reproduction method using an
enantiopure (S)-lactic acid based dioxolanone. The final acid-
catalyzed spiroacetalization provided the desired spiroacetal
as a mixture of diastereoisomers in 13 linear steps. Whatever
the conditions used, the non-natural transoid isomer was
formed preferentially. However, both cisoid and transoid iso-
mers were isolated pure and their structure assigned unam-
biguously through NMR spectroscopic studies.
Introduction
Spirolides 1a–f and their congeners (gymnodimine 2, pinna-
toxins 3, pteriatoxines (not shown)) are macrocylic imine phy-
cotoxins isolated from the digestive glands of mussels and
scallops. The spirolides are metabolites of the dinoflagellate
Alexandrium ostenfeldii and Alexandrium peruvianum
(Figure 1).[1] These toxins are transferred and concentrated in
shellfish edible tissues and can finally reach marine animals
and humans by vectorial transport.[2] Shellfish poisoning thus
constitutes a potent threat to human health but also to the
shellfish industry. Oysters and mussels are thus regularly
banned from harvesting and consumption due to this potent
toxicity.[3a] Toxicological studies have mainly been carried out
on macrocycles 2 and 3, which have recently succumbed to
total synthesis.[4,5] Spirolides were shown to induce fast lethal
toxicity when administrated through intraperitoneal injection
to mice and rats but were also found to be less toxic when in-
gested by oral administration.[3b] Recent reports have shown
that 13-desmethyl spirolide C is a potent antagonist of nicotin-
ic acetylcholine receptors in the subnanomolar range.[3c,d] It
was also shown to be neuroprotective and to reduce simulta-
neously intracellular Ab and hyperphosphorylated Tau in
vitro.[6] Consequences of these effects on the treatment of Alz-
heimer’s disease were recently demonstrated in transgenic
mouse models.[7] Nevertheless, no toxicological studies have
Figure 1. Spirolides 1a–f, gymnodimine 2 and pinnatoxin 3, macrocylic
imine phycotoxins.
been carried out to evaluate the long-term impact of spirolides
on human health. Unfortunately, spirolides are only available in
a small amount, thus preventing thorough biological studies.
This has led several research groups around the world to study
the synthesis of spirolide fragments, but to date,[2a,8] no total
synthesis of a member of the spirolide family has ever been
completed.
We recently embarked on the study of the total synthesis of
13-desmethyl spirolide C 1e, the most potent member of this
family by following the strategy depicted in Figure 2, which in-
volves the disconnection of 1e into three main fragments, that
is, a 5,5,6-bis-spiroacetal 4, a spiroimine 5, and a furan 6. While
several approaches to the 6,5,6-bis-spiroacetal skeleton have
been devised, notably in the context of the pinnatoxin synthe-
sis,[5] less effort has been devoted to the preparation of 5,5,6-
analogues.[9] Amongst the previous strategies to access the
[a] J. Labarre-Lainꢀ, Dr. I. PeriÇan, Dr. V. Desvergnes, Prof. Dr. Y. Landais
University of Bordeaux
351, Cours de la libꢀration, 33405 Talence Cedex (France)
Fax: (+33)5-40-00-62-86
E-mail: v.desvergnes@ism.u-bordeaux1.fr
y.landais@ism.u-bordeaux1.fr
Supporting information for this article is available on the WWW under
http://dx.doi.org/10.1002/chem.201402894.
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Results and Discussion
Synthesis of acylsilane 9
Preliminary studies showed unambiguously that the acylsilanes
were superior to aldehydes in the Stetter coupling with
enones.[13,14] The required acylsilane 9 was thus prepared by
starting from morpholine amide 11 by following the Scheidt
procedure (Scheme 1).[15] Amide 11 was itself available through
the coupling of the amide enolate of 12 and epoxide 13
issued from the chiral pool. After all our attempts to prepare
13 with high enantioselectivity had failed, the latter was ob-
tained through a three-step synthesis starting from (S)-aspartic
acid, using a literature protocol[16] (see the Supporting Informa-
tion). Addition of PhMe2SiLi onto 11, finally led to gram quanti-
ties of acylsilane 9 in 51% overall yield and in seven steps
from (S)-aspartic acid.
Figure 2. Retrosynthetic analysis of spirolide 1e and bis-spiroacetal fragment
4.
bis-spiroacetal core of spirolides, Ishihara et al. used as a key
step the acetalization of a triketone fragment,[10] the formation
of the quaternary center at C19 being controlled in a late-
stage through addition of a methyl Grignard reagent onto the
remaining ketone. Brimble and co-workers also proposed an
elegant access to the 5,5,6-bis-spiroacetal by using an iterative
hypervalent iodine mediated radical oxidative cyclization.[11]
This approach, although straightforward, also led to the non-
natural diastereoisomer.[11a] We describe here our own efforts
to access the bis-spiroacetal fragment 4 of spirolide 1e, by
using a novel sila-Stetter-acetalization process (Figure 2).
Such spiroacetalizations starting from readily available 1,4-di-
ketones have been used on purpose in the synthesis of pinna-
toxin 3.[5] In the search for a convergent and rapid assembly of
1,4-diketones, the Stetter[12] and sila-Stetter[13] reactions ap-
peared as convenient processes, the conditions of which
would be compatible with many functional groups. The elabo-
ration of the bis-spiroacetal 4 would thus start with the cou-
pling between enone 8 and acylsilane 9, and the formation of
the C15ÀC16 bond of diketone 7, the protecting groups of
which would be removed under acidic conditions, thus trigger-
ing the acetalization. Protection of the alcohol functional
groups at C12, C19, and C22 would be carried out by using
tert-butyldimethylsilyl (TBS) groups as these should be easily
removable under acidic catalysis, while a more stable tert-bu-
tyldiphenylsilyl (TBDPS) group would be introduced at C10.
Preliminary studies in this direction effectively demonstrated
that spiro- and bis-spiroacetals could be efficiently assembled
in a limited number of steps, giving rise to 5,5,6- as well as
6,5,6-bis-spiroacetal skeletons.[14] We also showed that the two
steps could be carried out in a single-pot operation. Applica-
tion of this strategy to the elaboration of the C10–C24 bis-spi-
roacetal skeleton of spirolide 1e has been carried out and is
discussed in full detail below.
Scheme 1. Synthesis of acylsilane 9. LDA=lithium diisopropylamide.
Synthesis of enone 8
With 9 in hand, we then turned our attention to fragment 8
and toward the introduction of a tertiary alcohol at C19. In
contrast with Ishihara’s and Brimble’s strategies,[2a,10,11] it was
decided to set up the stereochemistry of the C19 center prior
to the acetalization. The stereoselective introduction of the
quaternary center was carried out by relying on Seebach’s
chiral self-reproduction method using enantiopure 2-tert-butyl-
5-substituted-1,3-dioxolanone 18, which was easily prepared
by condensation of (S)-lactic acid with pivalaldehyde.[17] The al-
kylation of 18 by using 17 (X=I or OTs) should allow the for-
mation of the C19–C20 bond, while controlling the stereo-
chemistry at C19. Precedents from the literature showed that
functionalized electrophiles could effectively be introduced in
this way with high yield and diastereocontrol.[18] Hydrolysis of
the dioxolanone and amidification would then afford the Wein-
reb amide 15, precursor of the enone 8 (Scheme 2). Tosylate
20 was initially prepared from epoxide 16a, which, as above,
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Scheme 3. Sila-Stetter reaction between enone 8 and acylsilane 9.
DBU=1,8-diazabicyclo[5.4.0]undec-7-ene.
The sila-Stetter reaction was then carried out using an equi-
molar amount of enone 8 and acylsilane 9 in THF at 758C,
with thiazolium salt 24 (30 mol%) as a precatalyst,[13,14] DBU as
a base, and iPrOH as the desilylating agent (Scheme 3). These
conditions afforded the 1,4-diketone 7 along with the unreact-
ed acylsilane 9, which could not be separated by chromatogra-
phy, the mixture being used as such in the acetalization step.
1
Yields estimated through H NMR spectroscopy indicated that
7 was obtained in a satisfying 70% yield when one equivalent
of 9 was used. Increasing the amount of 9 to 1.3 and then
1.5 equivalents led to 7 in 73 and 85% NMR yield, respectively.
The coupling was finally found to be highly reproducible as
shown by the reaction carried out with 8 on a 2.4 mmol scale,
in which diketone 7 was obtained in 90% yield (1H NMR spec-
troscopy).
Scheme 2. Synthesis of enone 8. CDI=1,1’-carbonyldiimidazole; DMAP=4-
dimethylaminopyridine.
Spiroacetalization was first carried out by using camphorsul-
fonic acid (CSA) in CH3CN (Scheme 4, Table 1, entry 1). Disilylat-
ed bis-spiroacetals were obtained in a 73% isolated yield as
a 2.5:1.5:1 inseparable mixture of three diastereoisomers 25a–
c (25c not shown). Another compound 26a, which had lost its
silyl group at C19 was also isolated pure in 25% yield. The ste-
reochemistry of 26a was assigned unambiguously, revealing
a non-natural transoid stereochemistry by two-dimensional
was obtained from (R)-aspartic acid through a high-yielding
three-step sequence.[16] Silyl-protected epoxide 16a was react-
ed with a TMS-vinyl Grignard reagent[19] and the protecting
group was removed under acidic conditions to afford diol 19.
Tosylation of the primary alcohol group, followed by protec-
tion of the secondary one led to 20 in 81% yield. Compound
20 was also obtained through a shorter route (two steps from
16b, 69% yield), involving an epoxide ring opening of tosylate
16b with the TMS-vinyl Grignard reagent,[20] followed by silyla-
tion with TBSCl, thus avoiding the previous protection–depro-
tection sequence.
Direct alkylation of dioxolanone 18 with tosylate 20 met
with failure, but better results were obtained when starting
from the corresponding iodide 21.[18] The alkylation occurred
with high diastereocontrol, leading to 22 in 82% yield as
a
single stereoisomer with the relative configuration as
shown.[17] Dioxolanone ring-opening under basic conditions,[21]
followed by coupling of the resulting carboxylic acid with the
N-methyl-N-methoxy amine led to the Weinreb amide 23.[22]
Protection of the tertiary hydroxy group in 23 followed by ad-
dition of a vinyl Grignard reagent finally led to the desired
enone 8 in 11 steps (longest linear sequence) and 21% overall
yield from (R)-aspartic acid.
Scheme 4. Spiroacetalization of 1,4-diketone 7 in CH3CN. CSA=camphorsul-
fonic acid.
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When the reaction was carried
out using HCl as an acid (gener-
ated through treatment of AcCl
with MeOH), similar results were
obtained with diol 28a as the
major compound (entry 3). As
mentioned above, hydrogen
bonding between OH at C19
and the acetal oxygen atoms
likely favors the undesired trans-
oid isomer. Hexafluoro-2-propa-
nol (HFIP), known to exhibit
strong hydrogen-bonding prop-
Table 1. Spiroacetalization of 1,4-diketone 7.
Entry
Conditions
25a/25b[e]
26a/26b[e]
27a/27b[e]
28a/28b[e]
Yield[f]
1
2
3
4
5[g]
CH3CN/CSA[a,b]
MeOH/CSA[a,c]
MeOH/AcCl[c]
MeOH[d]/CSA
CH3CN/HF-Pyr
36:22
25:0
–
–
–
39:0
–
–
98
95
84
34
49
–
–
–
–
39:31
27:21
–
16:2
28:3
26:8
4:6
–
[a] 0.5 equivalents of CSA were added. [b] A third isomer 25c was detected but not identified. [c] A third
isomer 27c was detected but not identified. [d] With HFIP (MeOH/HFIP 10:1). [e] Isolated yields in %. [f] Overall
isolated yields in % including non-identified isomers. [g] 258C, 72 h.
NMR NOESY experiments.[23] For 26a, correlations between OH
and H12 and complementary selective NOESY experiment es-
tablished the stereochemistry to be transoid as depicted in the
Supporting Information. As previously reported in the literature
for spirolides B and D,[10,11] the transoid stereochemistry adopt-
ed by 26a represents the thermodynamically favored isomer.
Stabilization of 26a can be explained through hydrogen bond-
ing between the free hydroxyl group and the spiroacetal
oxygen atoms. Based on the respective NMR spectroscopic
shifts of various isomers, 25b was deduced to exhibit the natu-
ral cisoid-configuration. Under the conditions used, the cisoid-
isomer 26b was never detected.
DFT calculations at the MO62x-31+G(d,p) level have also
been performed with a TMS protecting groups instead of the
TBDPS used experimentally. For both isomers, the more stable
conformation exhibits distances between H12 and OH that are
in good agreement with connectivities observed in NOESY ex-
periments (see the Supporting Information).[24]
erties,[25] was thus added to MeOH. Under these conditions,
diastereoisomers 28a and 28b were obtained in a 3:1 ratio,
albeit in modest yield (entry 4). For the same purpose, treat-
ment of the acetal mixture 26a–b with acetic anhydride or
acetyl chloride led to the desired tertiary acetate at C19, but in
low yield and with no improvement in stereoselectivity . Treat-
ment of 7 with a large excess of HF-pyridine (entry 5) led to
the diastereomerically pure transoid isomer 26a, along with
a mixture of fully deprotected 28a–b and degradation prod-
ucts. Finally, alternative conditions, such as pyridinium p-tolue-
nesulfonate (PPTS) in CH3CN, were also studied, but no conver-
sion was observed, whereas degradation of 7 occurred with tri-
fluoroacetic acid (TFA) or ZnCl2 in CH2Cl2.
As previously noticed by Ishihara[10] and Brimble,[8a,11] on re-
lated compounds, the non-natural transoid- isomer is formed
preferentially in all cases. All our efforts to reverse the stereo-
control upon acetalization failed whatever the conditions used.
Both cisoid and transoid isomers were, however, isolated pure
1
A different result was obtained when treating diketone 7
with CSA in MeOH (Scheme 5, Table 1, entry 2). Under these
conditions, the tert-butyldiphenylsilyl group at C10 was re-
moved which lead to two sets of compounds. The major com-
pound was obtained in 70% yield as a separable 1.25:1 mix-
ture of isomers 27a–b along with a smaller amount (18%) of
the totally desilylated and separable bis-spiroacetals 28a–b in
a 8:1 ratio. A third isomer 27c (not shown), for which the ste-
reochemistry could not be determined, was also present (7%).
and their structure assigned through H NMR spectroscopy. All
transoid isomers exhibiting the same range of chemical shifts,
some NMR spectroscopic shifts tables were listed and com-
pared to the supposed cisoid isomers. These data are discussed
in the Supporting Information.
As a final experiment, we performed a one-pot sila-Stetter-
acetalization cascade by starting from enone 8 and acylsilane
9 (Scheme 3). CSA was added at room temperature after com-
pletion of the sila-Stetter process in THF. Under these condi-
tions (24 h, RT), we were pleased to observe that the fully pro-
tected bis-spiroacetal stereoisomeric mixture 25a–c was
formed in high yield (95%) in a 2.5:1.5:1 ratio. Deprotection of
25a–c by using nBu4NF (TBAF) in THF led to deprotected bis-
spiroacetals 26a–c with the same diastereoisomeric ratio.
Conclusion
We report here the synthesis of the C10–C24 bis-spiroacetal
fragment of 13-desmethyl spirolide C 1e by using, as a key-
step, a sila-Stetter-acetalization cascade. The spiroacetal motif
was obtained as a mixture of diastereomers in 13 steps (lon-
gest linear sequence) and 18% overall yield from (R)-aspartic
acid. As observed by Ishihara, Brimble, and co-workers,[10,11] the
spiroacetalization led to a mixture of the non-natural transoid
and natural cisoid isomers, in the favor of the former. Our at-
tempts to reverse the selectivity by using various conditions
Scheme 5. Spiroacetalization of 1,4-diketone 7 in MeOH.
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however, obtained pure through chromatography. As pointed
out by Brimble,[2a,11a] the incorporation of the thermodynami-
cally more stable transoid isomer into the macrocyclic core of
the spirolide should, however, allow the re-equilibration and
the control of the spiroacetal stereochemistry. Efforts are now
underway to access the spiroimine moiety and to connect the
different fragments en route to the total synthesis of 13-des-
methyl spirolide C 1e.
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Experimental Section
One-pot sila-Stetter-acetalization reaction
DBU was freshly distilled in a Kugelrohr apparatus and iPrOH was
dried over molecular sieves. In a Schlenk tube, 3-ethyl-5-(2-hydrox-
yethyl)-4-methylthiazolium bromide 24 (10.4 mg, 0.04 mmol,
35 mol%) was dried overnight under vacuum at 458C. The tube
was placed under an argon atmosphere and a solution of acylsi-
lane 9 (96.5 mg, 0.16 mmol, 1.5 equiv) in THF (0.3 mL) was added,
followed by DBU (5 mL, 0.03 mmol, 30 mol%). The reaction mixture
turned orange and a solution of enone 8 (55.8 mg, 0.11 mmol,
1 equiv) in THF (0.3 mL) was added, followed by iPrOH (26 mL,
0.30 mmol, 2.7 equiv). The mixture was stirred for 2 h at 758C and
then cooled to room temperature. CSA was then introduced in
portions (of 12 mg, 0.06 mmol, 0.5 equiv) until completion of the
reaction (24 h at RT). The solvent was then removed under reduced
pressure and the residue purified by flash chromatography over
silica gel (pentane/EtOAc) to afford a mixture of three diastereoiso-
mers 25a–c (79.3 mg, 98%). Further treatment with TBAF (1m in
THF, 0.12 mL, 0.12 mmol, 1.1 equiv) in THF (1 mL) provided prod-
ucts 27a–c in a 2.5:1.5:1 ratio. Spectroscopic data (see the Sup-
porting Information) were in good agreement with those obtained
from spiroacetals prepared through the 2-step sequence.
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Acknowledgements
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We thank CNRS, MNERT, ANR (Blanc N811-BS07–006–02), and
EU (Marie Curie PIEF-GA-2011–298063) for generous support.
We also thank Dr. C. Guillou, Dr. L. Chabaud (ICSN, Gif s/
Yvette), and Dr. F. Robert (ISM, Bordeaux) for fruitful discus-
sions. We are grateful to N. Pinaud, I. Pianet and J.M. Lasnier
(CESAMO, ISM, Bordeaux) for NMR experiments and to
CESAMO (ISM, Bordeaux) and CRMPO (Rennes) for HRMS analy-
ses.
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Keywords: acetalization · bis-spiroacetal · organic synthesis ·
sila-Stetter reaction · silicon
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Received: April 1, 2014
Published online on && &&, 0000
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FULL PAPER
Phycotoxins: Synthesis of the bis-spi-
roacetal core of 13-desmethyl spirolide
C by using a sila-Stetter-acetalization
cascade is described (see scheme;
&
Organic Synthesis
J. Labarre-Lainꢀ, I. PeriÇan,
V. Desvergnes,* Y. Landais*
TBS=tert-butyldimethylsilyl, TMS=trime-
thylsilyl). The acylsilane and enone frag-
ments were prepared in 7 and 11 steps
from (S)- and (R)-aspartic acid. Spiroace-
talization of the 1,4-diketone was car-
ried out under acidic conditions deliver-
ing the desired spiroacetal as a mixture
of diastereoisomers in 18% overall yield.
&& – &&
Synthesis of the C10–C24-Bis-
Spiroacetal Core of 13-Desmethyl
Spirolide C, Based on a Sila-Stetter-
Acetalization Process
Chem. Eur. J. 2014, 20, 1 – 7
www.chemeurj.org
7
ꢁ 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
&
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These are not the final page numbers! ÞÞ