Total synthesis of (±)-cycloclavine and (±)-5-epi- cycloclavine

Article abstract of DOI:10.1021/ja2026882

Novel routes to the naturally occurring indole alkaloid cycloclavine and its unnatural C(5)-epimer are described. Key features include the rapid construction of the heterocyclic core segments by two Diels-Alder reactions. An indole annulation was accompli

Full text of DOI:10.1021/ja2026882

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Total Synthesis of (()-Cycloclavine and (()-5-epi-Cycloclavine
Filip R. Petronijevic and Peter Wipf *
Department of Chemistry and Center for Chemical Methodologies and Library Development, University of Pittsburgh, Pittsburgh,
Pennsylvania 15260, United States
S Supporting Information
b
Scheme 1. First Generation Retrosynthetic Analysis of
Cycloclavine
ABSTRACT: Novel routes to the naturally occurring
indole alkaloid cycloclavine and its unnatural C(5)-epimer
are described. Key features include the rapid construction of
the heterocyclic core segments by two DielsꢀAlder reac-
tions. An indole annulation was accomplished by a late-stage
intramolecular DielsꢀAlder furan cycloaddition, and a
methylenecyclopropane dienophile was used for a stereo-
selective intramolecular [4 þ 2] cycloaddition to give the
cyclopropa[c]indoline building block present in cycloclavine.
rgot alkaloids comprise a notable group of indole alkaloids,
E
whose striking polycyclic molecular architectures and wide
spectrum of physiological activities have attracted organic chem-
ists for decades.1 The lysergic acid and clavine subclasses of ergot
alkaloids differ in the oxidation state of the substituent at C(8).
Cycloclavine (1, Scheme 1) was first isolated in 1969 from the
seeds of the African morning glory (Ipomea hildebrandtii) by
Hoffman and co-workers.2 In spite of its compact size
(C16H18N2, MW = 238), the perimeter of this clavine alkaloid
contains three contiguous stereocenters, two of which are fully
substituted and part of a cyclopropane ring, thus posing a respect-
able synthetic challenge. In 2008, Incze et al. completed the first
synthesis of (()-cycloclavine in 14 steps and 0.2% overall yield.3
We have recently shown that 4-mono- and 3,4-disubstituted
indoles can be synthesized through an intramolecular Dielsꢀ
Alder cycloaddition of furan (IMDAF) reaction.4 We wanted to
demonstrate the utility of this methodology for the construction
of indole natural products, and furthermore, we were attracted to
cycloclavine as a synthetic target due to its unusual molecular
scaffold, featuring the only cyclopropane-containing ergot alka-
loid. Our first generation retrosynthetic plan assumed that the
stability of the cyclopropane moiety in the hydroindole inter-
mediate 2 was sufficient to allow a thermal [4 þ 2] process4 and
that dienone 3 could be obtained by a cascade TBS-deprotection-
intramolecular SN2-displacement.5 Indolinone 4 would be
formed by ortho-alkylation of 3-aminophenol 5. The selective
hydrogenation of cross-conjugated dienone 3 remained a con-
cern, but we hoped that we could effect this conversion by taking
advantage of Lewis acidic reducing agents and the electron-
donating properties of the β-amino substituent.
led to the primary alcohol 4, which was converted to the mesylate
in high overall yield.
Treatment of this mesylate with TBAF in THF (0.1 M)
resulted in a complex mixture of products. In contrast, under
high dilution conditions (0.006 M), TBAF effected silylether
cleavage with concomitant intramolecular alkylation to give 3. In
spite of considerable experimentation, our attempts to regiose-
lectively reduce the trisubstituted alkene in dienone 3 remained
unsuccessful. Alternatively, epoxidation of 3 with tert-butyl
hydroperoxide (TBHP) in THF,8 followed by selective
reduction9 of the intermediate R,β-epoxyketone, furnished β-
hydroxyketone 10, thus masking the disubstituted alkene as a
secondary alcohol. Another round of experiments10 aimed
at the reduction of the vinylogous amide in the presence of the
labile cyclopropane ring identified hydrogenation at high pres-
sure (80 bar) using Raney-Ni as the catalyst as a quantitative
method to access ketone 11 after PCC oxidation.11 While we
were only able to ascertain the configuration at C(5) upon
completion of the synthesis of 14 (vide infra), hydrogenation
occurred exclusively from the R-face, and only the cis-fused
hydroindole was accessible via this route. Exposure of 11 to a
TBAF solution in THF promoted the β-elimination of the aldol
product and furnished the desired R,β-unsaturated ketone in
62% yield. After lithiumꢀtin exchange and 1,2-addition of
stannane 12, a single isomer of the tertiary alcohol 13 was
obtained. Heating in o-dichlorobenzene at 190 °C for 1 h under
microwave irradiation, followed by lactam reduction with LAH,
led to 5-epi-cycloclavine 14, whose analytical data did not match
those of cycloclavine. An X-ray analysis of 14 confirmed the cis-
configuration at the C(5)ꢀC(10) ring fusion of the indoline
O-TBS-protection of 5 and N-acylation with chloroacetyl
chloride provided amide 6 (Scheme 2). Initial efforts to induce
the FriedelꢀCrafts cyclization of 6 proved unsuccessful. How-
ever, after N-methylation of 6 with methyl sulfate, cyclization
under Pd(OAc)2 conditions6 led to the desired indolinone 8 in
77% yield. Stepwise R-methylation and R-hydroxymethylation7
Received: March 24, 2011
Published: April 25, 2011
r
2011 American Chemical Society
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Scheme 2. Synthesis of (()-5-epi-Cycloclavine
Scheme 3. Second Generation Retrosynthetic Analysis
substructure. This was surprising since not only the hydrogena-
tion of the TBS-ether of 10 but also the hydroxyenone 10 and the
deoxygenated 100 consistently provided a sole hydrogenation
isomer, and we had hypothesized based on the Newman projec-
tion of 100 that the cyclopropane group would shield the R-face
from hydrogen delivery (Scheme 2). These substrate prefer-
ences, in addition to the difficulties in reducing the trisubstituted
alkene in dienone 3, required a complete redesign of our retro-
synthetic approach.
The main feature of our second generation retrosynthesis was
an early introduction of the trans-hydroindole stereochemistry
by an intramolecular methylenecyclopropane DielsꢀAlder reac-
tion (Scheme 3). Triene 16 could be derived from alcohol 17 and
vinylogous amide 18.
THP-protection of β-methallyl alcohol 19 and conversion to
dibromocyclopropane 20 under phase transfer conditions was
accomplished in 86% combined yield (Scheme 4).12 Exposure of
20 to n-BuLi (1 equiv) at ꢀ95 °C and subsequent treatment of
the monobromo-monolithiated intermediate with MeI furnished
the tertiary bromide 21.13 Dehydrobromination under thermo-
dynamic conditions followed by THP-deprotection gave cyclo-
propylmethylidene alcohol 17. Conversion of this alcohol to the
mesylate and N-alkylation of the anion of the vinylogous amide
18 provided the coupling product 22 in 67% yield from 17.
Formation of the silyloxy diene from vinylogous amide 22 was
achieved in quantitative yield by treatment with NaHMDS
followed by TBSCl trapping of the enolate.14 Other common
bases such as LiHMDS, LDA, or KHMDS gave either no reaction
or very complex mixtures of products, as evidenced by 1H NMR
analysis.
The crude DielsꢀAlder precursor 16 was smoothly converted
to the indoline by heating under microwave irradiation in
trifluorotoluene at 195 °C for 1 h. The tricyclic ketone 23 was
isolated in 85% yield after removal of the TBS group with TBAF.
Gratifyingly, an X-ray crystallographic analysis of the chloroform
adduct 24 confirmed the desired trans-configuration at the indoline
ring fusion bond as the sole product of the intramolecular
DielsꢀAlder process. A computational analysis suggests that the
energy of the anti-transition state 16‡ leading to 23 is indeed 6.8
kcal/mol lower than the corresponding transition state leading to
the cis-diastereomer.15
The dehydrogenation of β-aminoketone 23 to the corre-
sponding enone 25 was problematic due to competing side
reactions involving the basic amine moiety. We circumvented
this problem by a dealkylative protection of the tertiary amine as
a carbamate with methyl chloroformate in 71% yield.16 Saegusaꢀ
Ito oxidation (LDA, TMSCl, ꢀ78 °C, then Pd(OAc)2) served to
cleanly introduce a double bond at the C(11)ꢀC(16) position of
25.17
Treatment of enone 25 with the tinꢀlithium exchange
product of stannane 12 led to 51% of a tertiary alcohol which
was subjected to the microwave-promoted IMDAF cyclization in
trifluorotoluene at 190 °C to furnish indole 26 in 44% yield.
Finally, reduction of the carbamate with LAH provided (()-
cycloclavine 1 in quantitative yield. The spectroscopic data for 1
were consistent with the previously reported data2,3,18 for the
natural compound.
In summary, we have developed novel synthetic routes to the
ergot alkaloid cycloclavine (1) as well as the unnatural 5-epi-
cycloclavine (14). These total syntheses proceeded in 14 steps
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Scheme 4. Synthesis of (()-Cycloclavine
and 1.2% overall yield for 1 and in 17 steps and 2.3% overall yield
for 14. Noteworthy features of our strategies include the forma-
tion of the indole moieties through the allylic alcohol-IMDAF
reaction, as well as the rapid synthesis of cycloclavine’s indoline
core through a novel and highly stereoselective intramolecular
DielsꢀAlder reaction of a methylenecyclopropane.19,20
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catalysts, hydride reduction (NaBH4, LiAlH4, or NaBH3CN), or single-
electron reduction conditions (SmI2) failed to provide the desired
product, instead favoring cyclopropane ring opening.
S
Supporting Information. Experimental details, charac-
b
terization data, copies of 1H and 13C NMR spectra, and crystal
information files. This material is available free of charge via the
Internet at http://pubs.acs.org.
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’ AUTHOR INFORMATION
Corresponding Author
pwipf@pitt.edu
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’ ACKNOWLEDGMENT
This work was supported by the NIH/NIGMS CMLD
program (GM067082). We thank Dr. Steve Geib (University
of Pittsburgh) for X-ray crystallographic analyses and
Drs. Anthony Cuzzupe and Cody Timmons (University of
Pittsburgh) for preliminary synthetic studies on the synthesis
of cycloclavine.
(17) Ito, Y.; Toshikazu, H.; Saegusa, T. J. Org. Chem. 1978, 43, 1011.
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J = 7.7 Hz), 7.91 (s, 1 H), 6.84 (d, 1 H, J = 7.0 Hz), 3.17 (d, 1 H, J = 9.1
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