Eight-Step Enantioselective Total Synthesis of (?)-Cycloclavine

Article abstract of DOI:10.1002/anie.201608820

The first enantioselective total synthesis of (?)-cycloclavine was accomplished in 8 steps and 7.1 % overall yield. Key features include the first catalytic asymmetric cyclopropanation of allene, mediated by the dirhodium catalyst Rh₂(S-TBPTTL)₄, and the enone 1,2-addition of a new TEMPO carbamate methyl carbanion. An intramolecular strain-promoted Diels–Alder methylenecyclopropane (IMDAMC) reaction provided a pivotal tricyclic enone intermediate with more than 99 % ee after crystallization. The synthesis of (?)-1 was completed by a late-stage intramolecular Diels–Alder furan (IMDAF) cycloaddition to install the indole.

Full text of DOI:10.1002/anie.201608820

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International Edition: DOI: 10.1002/anie.201608820
German Edition: DOI: 10.1002/ange.201608820
Natural Product Synthesis
Eight-Step Enantioselective Total Synthesis of (À)-Cycloclavine
Stephanie R. McCabe and Peter Wipf*
Abstract: The first enantioselective total synthesis of (À)-
cycloclavine was accomplished in 8 steps and 7.1% overall
yield. Key features include the first catalytic asymmetric
cyclopropanation of allene, mediated by the dirhodium catalyst
Rh2(S-TBPTTL)4, and the enone 1,2-addition of a new
TEMPO carbamate methyl carbanion. An intramolecular
of three consecutive stereogenic carbons at C(5), C(8), and
C(10), two of them all-carbon quaternary stereocenters,
requires robust synthetic methods and a high degree of
stereochemical control.
To date, three total syntheses and three formal syntheses
of racemic cycloclavine have been reported, including a prior
total synthesis accomplished by our group.[5–9] However, no
enantioselective total synthesis of cycloclavine has been
accomplished. In order to meet this objective and establish
a concise route to either enantiomer, as well as analogues of
the natural product, we fundamentally revised our previous
14-step/1.2% yield approach to racemic product and devel-
oped a streamlined asymmetric total synthesis of the unnatu-
ral enantiomer (À)-cycloclavine [(À)-1; Figure 2)]. Our main
goals were: 1) to introduce the enone moiety in 2 directly
from the ketone product of the methylenecyclopropane
(MCP)-Diels–Alder reaction; 2) to develop an asymmetric
cyclopropanation of unsubstituted allene (5) to install the
quaternary stereocenter that directs the formation of the two
neighboring stereogenic carbons in (À)-1; and 3) to generate
the amide linkage in 3 through direct aminolysis of diazo-
propanoate 6.
strain-promoted
Diels–Alder
methylenecyclopropane
(IMDAMC) reaction provided a pivotal tricyclic enone
intermediate with more than 99% ee after crystallization.
The synthesis of (À)-1 was completed by a late-stage intra-
molecular Diels–Alder furan (IMDAF) cycloaddition to install
the indole.
C
ycloclavine (1) was originally isolated from the seeds of the
African morning glory shrub Ipomoea hildebrandtii, and later
from Aspergillus japonicus, species of filamentous
a
fungus.[1,2] In preliminary biological evaluations, it demon-
strated promising insecticidal and antiparasitic activity.[3]
Cycloclavine belongs to the clavine subset of ergot alkaloids,
a prominent group of natural products that share a fused
indole core (Figure 1). Members of this family have long
served as an inspiration for the design of therapeutic agents
and agrochemicals owing to their potent and diverse biolog-
ical activities.[4] In recent years, major advances in elucidating
the biogenetic origin of ergot alkaloids have been made.[4]
A
unique structural feature of cycloclavine is a pyrrolidine-fused
cyclopropane in place of the piperidine that is typical for
other clavine and lysergic acid alkaloids.
While its biological properties remain largely unexplored,
the unusual pentacyclic scaffold of cycloclavine has attracted
the interest of synthetic chemists. In particular, the assembly
Figure 2. A retrosynthetic strategy to enantiomerically enriched cyclo-
clavine.
Diazopropanoates are difficult substrates for transition-
metal-mediated cyclopropanations owing to their propensity
to undergo b-hydride elimination.[10] However, we hoped that
dirhodium complexes with hindered carboxylate ligands
would be amenable to our strategy and also enable the
unprecedented use of volatile allene in this reaction.[11,12] The
coupling of vinylogous amide 4 to the activated ester
eliminates several linear steps. A conventional approach
would have required conversion of the ester into a more
reactive acid chloride or anhydride for N-acylation of the
vinylogous amide. The successful implementation of this two-
step approach to 3 would represent a major improvement
Figure 1. Structures of natural ergot alkaloids of the clavine and
lysergic acid subclasses and cycloclavine in its unnatural configuration
[(À)-1].
[*] S. R. McCabe, Prof. Dr. P. Wipf
Department of Chemistry, University of Pittsburgh
Pittsburgh, PA 15260 (USA)
E-mail: pwipf@pitt.edu
Supporting information (including experimental details) and the
ORCID identification number(s) for the author(s) of this article can
be found under http://dx.doi.org/10.1002/anie.201608820.
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compared to our previous[6] synthesis, which required seven
steps to access an analogous intermediate.
Table 1: Optimization of catalytic asymmetric allene cyclopropanation.
We first explored an experimental validation of the key
cyclopropanation. Allene (5) represents an ideal, atom-
economical precursor to MCPs. However, little is known
about the fundamental behavior of unsubstituted allene in
transition-metal-catalyzed cyclopropanations.[13] In addition,
allene is well known to oligomerize in the presence of certain
metals, and therefore its successful use in an enantioselective
metal carbenoid cyclopropanation remained speculative.[14,15]
We were thus pleased to see that the reaction proceeded
smoothly in the presence of 1 mol% of dirhodium catalyst 8
(Table 1, Entry 1). After screening several chiral variants of 8,
we identified complex 9[12] as the most promising catalyst for
enantioselective conversions. The degree of enantioinduction
depended on the nature of the ester, with the sterically
hindered tert-butyl diazopropanoate providing the best e.r. at
low temperatures (entries 2 and 3). However, MCPs bearing
an activated ester facilitated direct aminolysis and were
therefore strategically more appealing (entries 4–6). While
the succinimide and pentachlorophenyl diazopropanoates
provided only moderate enantioinduction (entries 4 and 5),
the pentafluorophenyl diazopropanoate provided the desired
cyclopropane in high yield with a good e.r. of 87:13, which
could be further improved to an excellent e.r. through
crystallization (see below).
Entry
R
Catalyst
T [8C]
Yield [%]
e.r.
1
2
3
4
5
6
Et
8
9
9
9
9
9
À78
88
51
47
27
50:50[a]
91:9[a]
t-Bu
t-Bu
Su[b]
Pcp[c]
Pfp[d]
À78
À98 to À80
À78 to RT
À78
93:7[a]
77:23[a]
77:23[a,e]
87:13
74[f](84)[g]
86
À78
[a] Determined by 1H NMR analysis of diastereomeric Mosher ester
derivatives (see the Supporting Information); [b] succinimide; [c] pen-
tachlorophenyl; [d] pentafluorophenyl; [e] crystallization provided
enrichment of the mother liquor up to 90:10 e.r.; [f] reaction on
0.2 mmol scale; [g] reaction on 2 mmol scale.
inconsequential, since both starting isomers provided the E-
alkene product 3, probably owing to rapid isomerization of
the enamine upon deprotonation and preferential trapping of
the E enamide. Chiral supercritical fluid chromatography
(SFC) analysis of amide 3 revealed an e.r. of 87:13, which
reflects the enantiomeric enrichment obtained in the prior
cyclopropanation step. Treatment of amide 3 with NaHMDS
triggered enolization to the corresponding enolate, which was
trapped in situ with TBSCl to deliver the highly reactive
amino silyloxy diene 12. This diene underwent an anti-
selective intramolecular [4+2] cycloaddition with the pendant
After confirming the feasibility of the first key reaction,
our focus shifted to the elaboration of enone 2 (Scheme 1).
The pivotal cyclopropanation with 10 proceeded well on
a gram scale and afforded the enantiomerically enriched 11 in
86% yield. The vinylogous amide 4 was deprotonated with
nBuLi at À788C in THF, then acylated with activated ester 11
to afford amide 3. The E/Z ratio of 4 proved to be
Scheme 1. Our eight-step total synthesis of (À)-cycloclavine. DMAP=4-dimethylaminopyridine, HDMS=hexamethyldisilazane, TBS=tert-butyldi-
methylsilyl, THF=tetrahydrofuran, TBAF=tetra-n-butylammonium fluoride, TFA=trifluoroacetic acid, DMSO=dimethyl sulfoxide, mw=micro-
wave irradiation.
2
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methylenecyclopropane upon microwave irradiation at 958C.
nitrogen-protecting group that can be cleaved in situ by
The crude enol ether products were directly subjected to
TBAF cleavage to afford separable diastereomers of ketone
14 in 4.8:1 d.r. at C(5).
thermolysis.
The relative configuration at the new ring junction in the
major diastereomer was assigned as trans through a combina-
tion of NMR and X-ray analyses.[16] An ab initio calculation at
the MP6-31 + G* level of the two transition states leading to
the trans- and cis-ring fusion products in the intramolecular
Acknowledgements
The authors thank Dr. Steven Geib (University of Pittsburgh)
for X-ray structure analyses and gratefully acknowledge
funding from the NIH (GM067082) and NSF (CHE-0910560).
SRM also acknowledges support from the Mary E. Warga and
the University of Pittsburgh School of Arts and Sciences
Predoctoral Fellowships.
strain-promoted
Diels–Alder
methylenecyclopropane
(IMDAMC)[17] reaction revealed that the trans stereochem-
istry in 13° is only slightly favored (< 0.5 kcalmolÀ1), thus
rationalizing the relatively modest diastereoselectivity (4.8:1
d.r.) observed for this process.
Keywords: allene · clavine alkaloids · cycloaddition ·
Next, a Pd(DMSO)2(TFA)2-catalyzed direct dehydrogen-
ation of ketone 14 was achieved by using a modification of the
method originally reported by Diao and Stahl for the aerobic
dehydrogenation of ketones.[18] Under optimized conditions,
the reaction proceeded with excellent regioselectivity, form-
ing the less-substituted enone 2 exclusively. This one-step
method is particularly appealing because it uses molecular O2
and catalytic PdII. In prior work, this transformation required
two steps and the use of stoichiometric transition metal.[6]
Enone 2 was obtained as a crystalline solid and provided 2 in
more than 99% ee after recrystallization.
cyclopropanation · enantioselectivity
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The final challenge of the synthesis was the introduction
of the indole core through an IMDAF reaction.[19–22] A Boc-
carbamate-stabilized furylamine methyllithium suffered
stereo- and chemoselectivity problems in the 1,2-addition on
enone 2; that is, lactam addition was competitive with ketone
addition. Therefore, we developed a new 2,2,6,6-tetramethyl-
1-piperidinyloxy (TEMPO) carbamate that led to a more
thermodynamically stable and chemoselective furyl lithium
species 15. This reagent underwent 1,2-addition to enone 2 at
low temperatures in Et2O to afford the tertiary allylic alcohol
16 as a separable 1.5:1 mixture of diastereomers at C(3). The
relative configuration of the major diastereomer was assigned
based on a combination of 1D NOE/2D ROESY correlations
and X-ray analysis. Alcohol 16 was subjected to the IMDAF
reaction in toluene at 1358C. This cyclization/aromatization
sequence was accompanied by concurrent thermolysis[23] of
the TEMPO carbamate protecting group to deliver the
desired, protecting-group-free indole. Reduction of the
lactam with LiAlH4 yielded (À)-cycloclavine [(À)-1], in
48% yield.
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give racemic product:
In conclusion, we report the first enantioselective syn-
thesis of (À)-cycloclavine. In terms of efficiency, this 8-step/
7.1% overall yield route from allene is a significant improve-
ment on previous syntheses. Key features include the first use
of unsubstituted allene in a transition-metal-mediated enan-
tioselective cyclopropanation to deliver a methylenecyclopro-
pane adorned with an active ester handle for immediate
further derivatization. This transformation represents a direct
and atom-economical method to access MCPs and could be
further expanded for the synthesis of diverse “spring-loaded”
reagents in organic synthesis.[24] Additional noteworthy fea-
tures include the application of a regioselective aerobic
dehydrogenation to form bicyclic enone 2 and the develop-
ment of a TEMPO carbamate as a new carbanion-stabilizing
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[16] The configuration of 14 was assigned through analysis of vicinal
coupling constants. A single-crystal X-ray structure of Æ-(14)
confirmed this assignment (see the Supporting Information).
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Received: September 9, 2016
Published online: && &&, &&&&
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Communications
Natural Product Synthesis
S. R. McCabe, P. Wipf*
&&&& — &&&&
Eight-Step Enantioselective Total
Synthesis of (À)-Cycloclavine
Ringing the changes: An enantioselective
total synthesis of (À)-cycloclavine was
accomplished in 8 steps and 7.1% overall
yield. Key features include the use of
unsubstituted allene in a transition-
metal-mediated enantioselective cyclo-
propanation to deliver a methylenecyclo-
propane (MCP). This transformation
gives direct and atom-economical access
to MCPs and could be further expanded
for the synthesis of diverse “spring-
loaded” reagents in organic synthesis.
Angew. Chem. Int. Ed. 2016, 55, 1 – 5
ꢀ 2016 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.angewandte.org
5
These are not the final page numbers!