Asymmetric Total Synthesis and Biological Evaluation of (+)-Cycloclavine

Article abstract of DOI:10.1055/s-0037-1610395

The first total synthesis of natural (+)-cycloclavine uses a catalytic asymmetric cyclopropanation of allene, a regiospecific Pd-catalyzed enone formation, and two intramolecular Diels-Alder reactions for indole/indoline annulations. The binding properties of natural (+)- and unnatural (-)-cycloclavine on 16 CNS receptors revealed significant stereospecificity and unique binding profiles in comparison to LSD, psilocin, and DMT. Differential 5-HT affinities, as well as novel sigma1 receptor properties bode well for potential therapeutic developments of clavine alkaloid scaffolds.

Full text of DOI:10.1055/s-0037-1610395

SYNTHESIS
0
0
3
9
-
7
8
8
1
1
4
3
7
-
2
1
0
X
Georg Thieme Verlag Stuttgart · New York
2018, 50, A–L
feature
A
en
S. R. McCabe, P. Wipf
Feature
Synthesis
Asymmetric Total Synthesis and Biological Evaluation of
(+)-Cycloclavine
Stephanie R. McCabe
Peter Wipf*
0
0
0
0-0
0
0
1-
7
6
9
3-5
8
6
3
Department of Chemistry, University of Pittsburgh, Pittsburgh, PA
15260, USA
pwipf@pitt.edu
Published as part of the 50 Years SYNTHESIS – Golden Anniversary Issue
Received: 29.10.2018
Accepted: 31.10.2018
Published online: 20.11.2018
Peptide ergot alkaloids
H
H
O
O
H
H
DOI: 10.1055/s-0037-1610395; Art ID: ss-2018-z0728-fa
O
O
N
N
N
N
License terms:
O
O
HO
HN
O
H
HO
HN
H
O
Abstract The first total synthesis of natural (+)-cycloclavine uses a
catalytic asymmetric cyclopropanation of allene, a regiospecific Pd-
catalyzed enone formation, and two intramolecular Diels–Alder reac-
tions for indole/indoline annulations. The binding properties of natural
(+)- and unnatural (–)-cycloclavine on 16 CNS receptors revealed signif-
icant stereospecificity and unique binding profiles in comparison to
LSD, psilocin, and DMT. Differential 5-HT affinities, as well as novel
sigma-1 receptor properties bode well for potential therapeutic devel-
opments of clavine alkaloid scaffolds.
N
N
H
H
N
N
(–)-ergotamine
α-ergocryptine
H
H
Lysergic acid ergot alkaloids
Clavine ergot alkaloids
HO
HN
HO
H
N
H
O
H
H
O
H
N
N
N
H
N
H
H
N
H
N
H
H
N
H
(+)-lysergic acid
(+)-ergonovine
(–)-agroclavine
(+)-costaclavine
Key words clavine ergot alkaloids, enantioselective allene cyclopro-
panation, psychedelics, stereospecific GPCR binding, LSD, psilocin,
DMT, 5-HTA, sigma-1 receptors
Figure 1 Examples of naturally occurring ergot alkaloids
novative synthetic approaches. In pioneering studies from
the group of Szántay, 4-bromo-Uhle’s ketone was subjected
to an alkylation and intramolecular aldol reaction with 3-
methylaminopropanoate, and the first synthesis of (±)-cy-
cloclavine was completed in 2008 by a cyclopropanation of
a tetrasubstituted alkene with CH2N2 (Scheme 1).5 Motivat-
ed by our interests in the synthetic and medicinal chemis-
try of indoles,6 the structurally unique indoline-indole scaf-
fold of cycloclavine served as our first ergot alkaloid target.
In 2011, we developed an intramolecular SN2-displacement
and furan Diels–Alder reaction for the formation of the
fused pentacyclic ring system and the synthesis of (±)-5-
epi-cycloclavine.7 Subsequently, we modified this approach
and used an intramolecular Diels–Alder reaction to a strain-
activated methylenecyclopropane for the construction of
the indoline segment and the total synthesis of (±)-cyclo-
clavine (Scheme 1).7
While the unique properties of naturally occurring
compounds have always fascinated researchers from all
branches of Science, the total synthesis of alkaloids current-
ly experiences a remarkable renaissance, motivated by the
complex architectures, diverse functionalities, and pro-
found biological and cultural impact of this large family of
natural products.1 Indole alkaloids, in particular, are at-
tracting significant attention in Chemistry and Medicine.2
With the goal to explore both innovative synthetic strate-
gies and new biological applications, we have recently es-
tablished a program in the total synthesis of ergot alkaloids
of the clavine and lysergic acid subclasses (Figure 1).3
In 1969, A. Hofmann and co-workers at Sandoz in Basel,
Switzerland, reported the isolation of a novel, cyclo-
propane-containing ergot alkaloid, (+)-cycloclavine, from
the seeds of the morning glory Ipomoea hildebrandtii VAT-
KE, collected in Nairobi, Kenya.4 After a latency of almost 40
years, cycloclavine has now become a popular target for or-
ganic synthesis, and a number of groups have reported in-
In 2014, Brewer and co-workers used a fragmentation
and an azomethine ylide 1,3-dipolar cycloaddition to con-
struct racemic cycloclavine (Scheme 2).8 Cao’s group devel-
Georg Thieme Verlag Stuttgart · New York — Synthesis 2018, 50, A–L

B
S. R. McCabe, P. Wipf
Feature
Synthesis
catalytic asymmetric cyclopropanation of allene, an intra-
molecular Diels–Alder reaction to methylenecyclopropane
(IMDAMC), and an intramolecular Diels–Alder reaction to
furan (IMDAF). Subsequently, a formal synthesis of both en-
antiomers of cycloclavine was realized by Bisai and co-
workers based on a D- or L-proline catalyzed -aminoxyl-
ation and a Heck coupling (Scheme 2).12 Most recently,
Dong and co-workers developed a benzyne cycloaddi-
tion/alkene carboacylation route to both (–)-5-epi-cyclo-
clavine and (–)-cycloclavine, utilizing a ring-enlargement of
a benzocyclobutenone intermediate as a key reaction.13 The
impressive publication surge and the diverse strategies of
these synthetic approaches illustrate the high level of cur-
rent interest in architecturally novel alkaloid natural prod-
ucts. We now report the details of the first enantioselective
total synthesis of (+)-cycloclavine.
Szántay et al., 2008
alkylation and intramolecular aldol
H
N
Br
O
N
O
H
H
N
O
EtO
N
HO
N
EtO
H
H
(
)-cycloclavine
N
N
N
H
H
H
intramolecular
Diels–Alder
Petronijevic & Wipf, 2011
intramolecular SN
2
OH
O
N
1. MsCl
BocN
HO
2. TBAF
N
H
O
O
N
H
O
N
O
N
(
)-5-epi-cycloclavine
O
H
TBS
intramolecular
Diels–Alder
intramolecular
Diels–Alder
H
1. NaHMDS
TBSCl
2. µW
N
H
O
HO
O
N
N
H
(
)-cycloclavine
N
O
CO2Me
N
N
3. TBAF
Boc
H
Our retrosynthetic analysis is summarized in Scheme 3.
In analogy to our route to (–)-cycloclavine,11 we selected an
asymmetric rhodium-catalyzed cyclopropanation of allene
with a diazopropanoate active ester, followed by an amino-
lysis with 4-(methylamino)but-3-en-2-one, for the assem-
bly of the key precursor for the IMDAMC reaction. After in-
stalling the enone in the six-membered ring by a Diao–
Stahl ketone dehydrogenation,14 the thermally removable
Tempoc group for amine protection15 would be used to sta-
bilize an aminomethyllithium reagent and favor enone 1,2-
addition versus lactam ring opening. The final indole ring
fusion was envisioned to be accomplished by the IMDAF cy-
cloaddition.6b,d,f,7,16
Scheme 1 Early synthetic strategies in the total synthesis of cyclo-
clavines
oped two formal syntheses of racemic cycloclavine and a
formal synthesis of (+)-cycloclavine starting from substitut-
ed indoles and intersecting with the late stage alkene in
Szántay’s synthesis.9
Another formal synthesis of (±)-cycloclavine that con-
verged with Szántay’s approach was accomplished by Netz
and Opatz in 2016, utilizing a -alkylation of a pyrrolinone
followed by a Heck coupling.10
The first asymmetric synthesis of (–)-cycloclavine, the
enantiomer of the natural alkaloid, was accomplished by
our group in 2017.11 Key features of this synthesis were a
Biographical Sketches
Stephanie R. McCabe re-
ceived her B.Sc. (Honours) in
2012 from the Australian Na-
tional University, conducting re-
search under the supervision of
Professor Martin Banwell. In
2018, she obtained her Ph.D. in
the Wipf group at the University
of Pittsburgh. Her research in-
terests centered on natural
product total synthesis.
Peter Wipf received his Ph.D.
in 1987 from the University of
Zürich under the direction of
Professor Heinz Heimgartner.
He then joined the laboratory of
Professor Robert E. Ireland at
the University of Virginia as a
Swiss NSF postdoctoral fellow,
and, in 1990, the University of
Pittsburgh as an Assistant Pro-
fessor. Since 2004, he is the Dis-
tinguished University Professor
of Chemistry at the University
of Pittsburgh. Wipf’s research
focuses on the total synthesis of
natural products, organometal-
lic, heterocyclic and medicinal
chemistry.
Georg Thieme Verlag Stuttgart · New York — Synthesis 2018, 50, A–L

C
S. R. McCabe, P. Wipf
Feature
Synthesis
Jabre, Watanabe & Brewer, 2014
Stahl dehydrogenation
reduction
azomethine ylide cycloaddition
IMDAF
1,2-addition
H
H
N
H
H
O
O
O
CO2Et
HO
H
OTBS
OH
O
O
N
EtO2C
EtO2C
N2
N
N
N
SnCl4
N
H
N
N
H
N
O
H
(
)-cycloclavine
O
(+)-cycloclavine
N
NH
N
N
1,2-addition
Piv
Piv
N
N
Piv
Piv
CO2TMS
Cao et al., 2014, 2017, 2018
Rh2L*4-cat. asymmetric
cyclopropanation
O
O
OH
aza-Cope
Mannich
N
NTs
O
Br
N2
H
NHTs
H
IMDAMC
•
O
Br
H
N
Li
O
O
N
RO
+
+
O
O
N
R
O
N
N
O
N
Heck coupling
O
N
R = Ts, Boc
NH
TBS
H
Ts
or radical
aminolysis
cyclization
imine addition/lactamization
Scheme 3 Retrosynthetic analysis of (+)-cycloclavine
O
O
O
S
H
N
N
N
H
N
Br
H
Br
N
For the realization of this retrosynthetic plan, two build-
ing blocks and a chiral ligand needed to be prepared and
optimized at the onset of the synthesis. The condensation
of pyruvic acid (2) with tosyl hydrazide (1) under acidic
conditions provided hydrazone 3 in 93% yield (Scheme 4).
Treatment with oxalyl chloride and esterification of the re-
sulting acid chloride with pentafluorophenol (PfOH) deliv-
ered an active ester intermediate suitable for rapid segment
assembly. Base-mediated diazo formation produced the
first building block 4 in 21% yield.
H
CO2Me
(+)-cycloclavine
N
Boc
N
R
N
Br
Heck
Boc
coupling R = Boc, Bn
NO2
MeO2C
MeO2C
Domino Friedel–Crafts
nitro-Michael
CHO
N
Bn
N
Bn
Netz & Opatz, 2016
N
Br
Br
H
enolate alkylation
O
N
+
O
N
F
Heck
Boc
HO2C
1. (COCl)2
DMF, CH2Cl2
2. PfOH, CH2Cl2
coupling
N
F
F
F
OH
O
Boc
O
O
N
O
2
O
intramolecular
Diels–Alder
HN
S
S
NH2
McCabe & Wipf, 2017
N
O
asymmetric allene cyclopropanation
HCl, H2O
100 °C; 93%
3. NEt3, CH2Cl2
21%
H
N2
F
O
H
N2
1
3
4
Rh2(S-TBPTTL)4
•
O
O
O
N
+
F
O
F
N
Scheme 4 Preparation of pentafluorophenyl diazoester 4
N
H
O
HN
F
F
(–)-cycloclavine
F
Next, we focused on the selection of an appropriate
transition metal catalyst and chiral ligand for the asymmet-
ric allene cyclopropanation step. Diazopropanoates 5 are
challenging reagents for use in metal-mediated cyclopro-
panations because of the propensity of the metal carbenoid
6 to undergo competing -hydride migration to form an
acrylic ester 7 (Scheme 5). In the past decade, several meth-
ods have emerged that address this limitation. Fox et al.
found that dirhodium complexes with sterically hindered
carboxylate ligands in conjunction with low reaction tem-
peratures effectively promoted intermolecular cyclopro-
panations over the competing -H migration pathway.17
N
H
Bisai et al., 2018
EtO2C
Br
Wittig
ONHPh
CHO
Br
N
Heck
H
coupling
proline-cat.
N
N
H
N
asymmetric
Ts
Ts
α-aminoxylation
N
H
red.
amination
Dong et al., 2018
Rh-cat.
H
N
cyclopropanation
carboacylation
[2+2]-cycloaddition
N3
O
O
N
OH
H
O
N2
I
(–)-cycloclavine
O
O
O
MLn N2
H
H
β-H migration
H
H
OR
OR
OR
N
OH
Boc
N2
MLn
H
N
N
Boc
Boc
5
6
7
N
Scheme 5 Competing -hydride migration pathway
N
H
H
(–)-5-epi-cycloclavine
Scheme 2 Recent formal and total syntheses of cycloclavines
Among the enantioselective variants, bulky carboxyl-
ates derived from L-tert-leucine, such as Rh2(S-PTTL)4 (8),
were found to be particularly effective. More recently,
Georg Thieme Verlag Stuttgart · New York — Synthesis 2018, 50, A–L

D
S. R. McCabe, P. Wipf
Feature
Synthesis
Hashimoto et al. showed that the substrate scope could
be further expanded when the dirhodium complex
Rh2(S-TBPTTL)4 (9) was used as the catalyst (Figure 2).18 We
also prepared the enantiomer of 9, Rh2(R-TBPTTL)4 (10),
from D-tert-leucine [(R)-18] and anhydride 17 in toluene at
reflux, followed by a ligand exchange reaction with
Rh2(OAc)4 in a chlorobenzene/MeCN mixture at 130 °C
(Scheme 6). Furthermore, we reasoned that the 4,7-diphe-
nyl substitution pattern on the phthalimide ring of the nov-
el, sterically demanding dirhodium catalyst 11 would im-
pose even greater steric discrimination than the corre-
sponding bromide substituents in 9 and 10, hopefully
leading to greater differentiation between the enantiotopic
faces of the allene. This catalyst was prepared in a Diels–
Alder reaction of diphenylbutadiene (19) and maleic anhy-
dride (20), followed by DDQ oxidation to afford anhydride
21, which was reacted with (S)-18 in the presence of tri-
ethylamine to give 22 and subjected to a ligand exchange
reaction to yield 11 (Scheme 7).
NH2
(S)
H
O
1. xylenes
140 °C
78%
Ph
Ph
Ph
Ph
O
O
OH
O
Ph
+
(S)-18
O
N
O
2. DDQ
PhMe
reflux
84%
NEt3, PhMe
reflux; 31%
CO2H
O
Ph
O
O
19
20
21
22
Rh2(OAc)4, PhCl
reflux; 48%
11
Scheme 7 Preparation of chiral dirhodium catalyst 11
stituted allenes with succinimidyl diazoacetate.20 Finally,
the (salen)cobalt(II) catalyst 16 was also screened since
Katsuki et al. showed that it was an excellent catalyst for the
enantioselective cyclopropanation of styrenes with -alkyl-
diazoacetates.21
The results of the cyclopropanation of allene (23) with
pentafluorophenyl diazopropanoate (4) to give methy-
lenecyclopropane 24 in the presence of the chiral catalysts
8–16 are summarized in Table 1. Rh(II)-Catalysts with steri-
cally hindered amino acid ligands but lacking phthalimide
substituents, such as 8 and 12, provided a low e.r. of ap-
proximately 7:3 (Table 1, entries 1 and 5). Hashimoto’s
tetrabromophthaloyl tert-leucine dirhodium catalyst 9 re-
sulted in a notable improvement, giving the cyclopropane
(R)-24 in a high yield with an e.r. of 87:13 (entry 2). As ex-
pected, the (R)-tert-leucine derived 10 gave the enantio-
meric product (S)-24 in identical yield and e.r. (entry 3).
Disappointingly, however, virtually no enantioinduction
was observed when allene was reacted with 4 in the pres-
ence of the sterically more demanding dirhodium catalyst
11 (product e.r. = 55:45, entry 4). With this catalyst, no re-
action occurred at –78 °C and the mixture had to be
warmed to –40 °C before conversion was observed. The chi-
ral cyclopropane catalyst 13 delivered the desired product
24 in moderate yields and with poor enantioinduction (en-
try 6). Davies’ proline-based catalyst 14 also provided only
a moderate yield of 61%, and negligible asymmetric induc-
tion (entry 7). The reaction of Ru(II)-catalyst 15 did not de-
liver any of the desired product. Instead, upon warming the
reaction mixture from –78 °C to room temperature, full
conversion into the undesired -H migration product 25
was observed (entry 8). Similarly, the (salen)cobalt(II) cata-
lyst 16 showed no catalytic activity even at room tempera-
ture (entry 9).
Br
Br
Br
Br
O
O
O
Br
Br
N
N
N
Br
Br
O
O
O
O
O
O
O
O
O
4
Rh Rh
Rh Rh
4
Rh Rh
Rh2(R-TBPTTL)4 (10)
4
Rh2(S-PTTL)4 (8)
Rh2(S-TBPTTL)4 (9)
Ph
O
Ph
O
Ph
O
O
Br
N
O
N
Ph
O
O
O
O
O
4
4
Rh Rh
13
Rh Rh
Rh Rh
4
Rh2(S-DPPTTL)4 (11)
Rh2(S-PTAD)4 (12)
N
N
O
Co
RO2S
N
PF6
(NCMe)4
Ru
O
H
PhPh
Ph
N
O
O
Rh Rh
O
4
14 (R = p-C12H25C6H4)
16
15
Figure 2 Cyclopropanation catalysts
NH2
(R)
Br
H
O
(R)-18
1.
O
Br
Br
OH
O
10
In our synthetic route, the cyclopropanation of allene
(23) with diazopropanoate 4 in the presence of 1 mol% of
the dirhodium catalyst Rh2(R-TBPTTL)4 (10) provided the
enantiomerically enriched methylenecyclopropane (S)-24
on multi-gram scale. Ester aminolysis with the lithium salt
of 26 gave the vinylogous imide 27 in 80% yield and 87:13
e.r. (Scheme 8). Deprotonation of 27 with NaHMDS in THF
at –78 to –50 °C formed the corresponding sodium enolate,
which was trapped with TBSCl to give the silyl enol ether
intermediate 28. When heated at 95 °C in THF in the micro-
NEt3, PhMe, reflux; 97%
2. Rh2(OAc)4, PhCl/MeCN
reflux; 75%
O
Br
17
Scheme 6 Preparation of chiral dirhodium catalyst 10
For further comparisons of ligand chemotypes, we de-
cided to include an evaluation of the known dirhodium cat-
alysts 12–14 (Figure 2).19 The ruthenium(II) complex 15
was added to this list because 15 was highly effective in re-
lated asymmetric cyclopropanations of mono- and disub-
Georg Thieme Verlag Stuttgart · New York — Synthesis 2018, 50, A–L

E
S. R. McCabe, P. Wipf
Feature
Synthesis
Table 1 Catalytic Asymmetric Cyclopropanation of Allene: Catalyst Screen
O
O
catalyst
O
(1 mol%)
OPfp
•
+
OPfp
OPfp
25
solvent
temperature
N2
4
23
24
Entry
Catalyst
Temperature
Solvent
Major product
Yield (%)
e.r.a
Major
enantiomer
1
2
3
4
5
6
7
8
9
8
–78 °C
–78 °C
–78 °C
hexanes
CH2Cl2
CH2Cl2
CH2Cl2
hexanes
CH2Cl2
hexanes
CH2Cl2
THF
24
24
24
24
24
24
24
25
–
83
86
86
78
84
59
61
NDb
–
72:28
R
R
S
9
87:13
87:13
55:45
73:27
59:41
53:47
–
10
11
12
13
14
15
16c
–78 °C to –40 °C
–78 °C
R
R
R
R
–
–
–78 °C
–78 °C
–78 °C to r.t.
–78 °C to r.t.
–
a Enantiomeric ratios were determined by chiral SFC analysis of the corresponding imide 27.
b ND: Not determined.
c 10 mol% N-methylimidazole was added.
NHMe
wave reactor, this diene underwent the intramolecular
strain-promoted Diels–Alder (IMDAMC) reaction, and TBAF
O
26
O
NaHMDS
n-BuLi, THF
OPfp
TBSCl, THF
O
N
–78 to –50 °C
O
O
O
N
cleavage of the product silyl enol ether formed the desired
trans-adduct 30 in 66% yield along with the cis-adduct 29 in
15% yield. These two diastereomers were readily separated
chromatographically. Dehydrogenation of 30 under modi-
fied Diao–Stahl conditions14 with Pd(TFA)2 and DMSO in
AcOH under an atmosphere of oxygen at 55 °C gave the cor-
responding enone 31 in 66% yield as a single regioisomer.
Interestingly, dehydrogenation of the epimer 29 under
these conditions provided the opposite enone regioisomer
32 stereospecifically in 56% yield. This complete switch in
regioselectivity for the cis- and trans-diastereomers 29 and
30 parallels results obtained for the enolization of cis- and
trans-2-decalones.22 The configuration at the decalin ring
junction governs the regioselectivity of enolization process
due to torsional strain effects. The torsional strain that was
proposed to govern the regiochemistry of enolization in cis-
and trans-decalones has also been investigated in greater
detail in relevant cis- and trans-octalins.22b,23
Enone 31 was obtained as a crystalline solid, and its en-
antiomeric ratio could be further enriched by recrystalliza-
tion from 87:13 to yield product with >99% e.r. Chiral SFC
analysis was used to evaluate each batch for enantiomeric
purity.
For the completion of the total synthesis, stannane 34
was treated with n-BuLi at low temperature and converted
into the corresponding lithium carbanion (Scheme 9). Addi-
tion of enone 31 to the reaction mixture delivered two dias-
tereomeric allylic alcohols, which could be separated by
chromatography on silica gel to give -alcohol -35 and -
DMAP, –78 °C
to rt; 80%
TBS
28
(S)-24
27 (e.r. 87:13)
Pd(TFA)2
DMSO, O2
H
H
O
O
N
O
N
N
+
AcOH, 55 °C, 4 d
O
O
O
30 (66%)
31
66%
32
THF, 95 °C
µw, 30 min
(not observed)
+
then TBAF
THF, 30 min
O
N
Pd(TFA)2
DMSO, O2
O
N
O
N
+
AcOH, 55 °C, 4 d
O
O
H
O
H
29 (15%)
32
56%
33
(not observed)
Scheme 8 Segment condensation, IMDAMC reaction, and dehydroge-
nation
alcohol -35 in 41% and 32% yield, respectively. The intra-
molecular Diels–Alder (IMDAF) reaction of -35 (bearing a
pseudo-equatorial hydroxy group) at 135 °C in a sealed
tube was followed by spontaneous aromatization and cleav-
age of the Tempoc protecting group under the reaction con-
ditions to form indole 36. The stereoisomeric alcohol -35
was inert under these conditions, quite likely due to steric
strain in the transition state that requires a pseudo-axial
position of the substituent bearing the furan ring. Finally,
lactam reduction led to (+)-cycloclavine in 34% yield over
two steps from -35. Overall, the synthesis of the natural
enantiomer was accomplished in 8 steps and 4% yield. The
specific rotation of the synthetic material was determined
Georg Thieme Verlag Stuttgart · New York — Synthesis 2018, 50, A–L

F
S. R. McCabe, P. Wipf
Feature
Synthesis
to be +61.4 (c 0.2, CHCl3), which was consistent with the
literature value +63 (c 1, CHCl3).4 Mass spectra, IR, 1H, and
13 C NMR data were also consistent with the previously re-
ported data for the natural product as well as its enantio-
mer.4,11
room metabolite psilocybin, and even LSD, are now moving
to the forefront of clinical research on the management of
mental health, anxiety, neurodegeneration, and substance-
use disorders.24 It would appear that more fundamental re-
search on efficacy, tolerability, and safety of serotonergic
psychedelics is highly warranted.
It is well known that binding of lysergic acid derivatives
to brain membrane receptors is stereospecific, since L-LSD,
the psychotropically inactive enantiomer of LSD, is ca. 1000
times weaker as a brain membrane receptor radioligand
displacing agent,25 and L-LSD as well as the other diastereo-
mers, D-iso-lysergic acid diethylamide (iso-LSD) and L-iso-
lysergic acid diethylamide (L-iso-LSD), show no psychic ef-
fects in humans up to a dose of 0.5 mg, which corresponds
to a 20-fold increase over a still distinctly active D-LSD
dose.26 Having gained ready synthetic access to both natural
(+)-cycloclavine and its unnatural enantiomer (–)-cyclo-
clavine,11 we were therefore interested to determine the re-
ceptor profiles of both compounds, and compare them to
other serotonergic agents.
H
O
HO
n-BuLi, Et2O
–67 to –75 °C, 10 min
O
N
O
N
O
N
O
N
O
then 31, Et2O
–86 to –93 °C, 0.5 h
O
Bu3Sn
N
34
α-35 (41%)
β-35 (32%)
H
H
PhMe, 135 °C
sealed tube, 68 h
LiAlH4, THF
reflux
O
N
N
34% (2 steps)
N
N
H
H
36
(+)-cycloclavine
Scheme 9 Completion of total synthesis of (+)-cycloclavine
In contrast to the vast literature on lysergic acid deriva-
tives, relatively little is known about the pharmaceutical
potential of clavine ergot alkaloids.2b Lysergic acid deriva-
tives, most notably lysergic acid diethylamide (LSD) have
significant hallucinogenic properties that can interfere with
their therapeutic potential. Most of these effects are
thought to be mediated through agonist action at the 5-hy-
droxytryptamine receptor 2A, 5-HT2A. In the tailwind of the
rapidly expanding medical uses of cannabinoids, the mush-
For an initial survey, we selected 13 pertinent CNS re-
ceptors and profiled both enantiomers at 10 M concentra-
tion (Table 2). Compound binding was calculated as a per-
cent inhibition of a radioactively labeled ligand specific for
each target. As a group, the cycloclavines were more selec-
tive in this receptor panel than D-LSD,27,28 the bioactive LSD
stereoisomer. D-LSD was active at the adrenergic 1 and his-
tamine H1 receptors (Table 2, entries 1 and 6), whereas both
Table 2 Effects of Cycloclavines and D-LSD Expressed as Percent Inhibition (% Inh.) of Specific Binding of a Radioligand Standard to Selected CNS
Receptorsa
Entry
Receptor
(+)-Cycloclavine [10 M] (+)-Cycloclavine [1 M] (–)-Cycloclavine [10 M] (–)-Cycloclavine [1 M] D-LSD [10 M]b
1c
2
Adrenergic 1
Dopamine D1
Dopamine D2L
Dopamine D3
GABAA
57
91
81
93
9
59
30
14
64
0
100d
93
85
78
0
3
4
75
32
5c
6
Histamine H1
Muscarinic M2
Muscarinic M5
Nicotinic acetylcholine 42
Opiate 
17
0
27
0
85c
2
7
8
11
9
15
11
75
6
15
0
9
10
11
12
13
73
23
97
100
29
NDe
100
93
Orexin OX1
Serotonin 5-HT1A
Serotonin 5-HT2A
97
91
89
73
51
100
a Biochemical assays were performed in duplicate at human receptors at Eurofins Cerep Panlabs and are presented as the percent inhibition of specific binding or
activity of a radioligand, unless otherwise indicated.
b Data from ref. 27.
c Rat receptor data.
d Data from ref. 28.
e ND: Not determined.
Georg Thieme Verlag Stuttgart · New York — Synthesis 2018, 50, A–L

G
S. R. McCabe, P. Wipf
Feature
Synthesis
cycloclavines were moderately active at the opiate  recep-
tor (entry 10). Neither ergot chemotype showed significant
activity at GABAA, muscarinic M2 and M5, and nicotinic ace-
tyl-choline 42 receptors (entries 5, 7, 8, and 9). We were
unable to find LSD data on orexin OX1, but cycloclavine did
not perturb radioligand binding at this site at a 10 M con-
centration (entry 11).
selected N,N-dimethyltryptamine (DMT) and psilocin as
two relevant reference compounds.31,32 DMT is the only
known endogenous N,N-dimethylated trace amine in mam-
mals, and a prominent component in the sacramental tea
ayahuasca.33 Its psychopharmacology has recently been
compared to so-called ‘near-death experiences’.34 Psilocin is
the pharmacologically active agent after ingestion of the
prodrug psilocybin present in some species of psychedelic
mushrooms. Psilocybin is currently clinically investigated
as a treatment for anxiety and depression in cancer care, as
well as for enhancement of cognitive flexibility and creativ-
ity.35
As suggested by the preliminary assays, (+)-cycloclavine
provided considerably more potent at the 5-HT1A receptor
than (–)-cycloclavine with an activation potency EC50 = 0.14
M versus ~5 M for (–)-cycloclavine (Table 3, entry 1).
Both stereoisomers are poor activators at 5-HT2A, suggest-
ing that hallucinogenic or strongly euphoric effects in hu-
mans might be limited in comparison to D-LSD, even
though (+)-cycloclavine displays its most potent activation
potential EC50 = 16 nM at 5-HT2C, a receptor that is thought
to contribute to the observed mental effects of psychedelic
drugs (entries 2 and 4). With the exception of DMT, which
has only moderate potency, none of the tested agents acti-
vated 5-HT2B, a 5-HT receptor subtype that has been associ-
ated with cardiotoxicity. Overall, the 5-HT profile of (+)-cy-
cloclavine closely mirrors that of psilocin, and to a lesser ex-
tent, that of DMT. It is substantially different from D-LSD, a
property that we believe bodes well for future therapeutic
investigations of this compound class.
Significant differences between (+)- and (–)-cyclo-
clavine revealed themselves in the dopamine D1, D2L, and D3
monoamine receptor family (Table 2, entries 2–4). In close
analogy to D-LSD, natural (+)-cycloclavine maintained
strong affinity to these receptors, which stimulate cognitive
and motor functions. (–)-Cycloclavine showed compara-
tively moderate activity at the dopamine D3 receptor at 10
M concentration, but fell below the threshold of 50% inhi-
bition at 1 M, whereas (+)-cycloclavine still maintained
significant binding at this concentration (entry 4). A less
prominent but still distinctive stereospecificity was ob-
served at the serotonin 5-HT1A and 5-HT2A receptors (en-
tries 12 and 13). Natural (+)-cycloclavine had very potent
binding properties at both 10 and 1 M, whereas (–)-cyclo-
clavine tailed off at 1 M. Serotonin receptors regulate a
plethora of behavioral responses, from aggression, anxiety,
appetite, to learning, memory, sleep, and even aging.29 D-
LSD is one of the most potent agonists at 5-HTA, and the af-
finity at the 5-HTA2 and possibly the 5-HT2C receptors ver-
sus the 5-HT1A receptor correlates with the mental effects
of psychedelics in humans.30 In view of this interesting ste-
reospecificity, and the significance of 5-HT receptors to hu-
man behavior, we decided to pursue additional studies on
5-HT subtypes (Table 3).
The unusual activity on the opioid  receptor, and the
relative similarity to psilocin and DMT in the 5-HT panel in-
spired us to also evaluate the activity of cycloclavines in the
sigma-1 assay, a receptor that was originally mischaracter-
ized as an opioid receptor and has now been implicated in
neuroinflammation and neuroprotection.36 DMT was iden-
tified as an endogenous sigma-1 receptor regulator.33,37 Sur-
prisingly, while (+)-cycloclavine was inactive, the unnatural
(–)-cycloclavine was determined to have a Ki = 8.3 M for
The purpose of our second generation functional assays
on human 5-HT receptors was to determine effective con-
centrations EC50 or inhibitory constants (Ki) for (+)-cyclo-
clavine and (–)-cycloclavine. Cellular agonist effects were
calculated as a percentage of a control response to a validat-
ed reference for each target, and cellular antagonist effect
was calculated as percent inhibition of a validated control
agonist response for each target. In addition to D-LSD, we
Table 3 Effects of Cycloclavines, DMT, Psilocin, and D-LSD on 5-HT Subtypes and Sigma-1 Receptorsa,b
Entry
Receptor
(+)-Cycloclavine [M]
(–)-Cycloclavine [M]
DMTc [M]
Psilocinc [M]
D-LSDc [M]
1
Serotonin 5-HT1A
Serotonin 5-HT2A
Serotonin 5-HT2B
Serotonin 5-HT2C
Sigma-1
0.14
~10
>20
~5
0.075d
0.076
3.4
0.123d
0.721
>20
0.003d
0.261
12
2
>50
>20
3.2
8.3
3
4
0.016
~50
0.424d
5.2e
0.094d
>10e
0.015d
NDf
5d
a Biochemical assays were performed in duplicate at human receptors at Eurofins Cerep Panlabs and results are based on 5-point concentration response curves,
unless otherwise indicated.
b Activation potency EC50 values are shown, unless otherwise specified.
c Data from ref. 31, unless otherwise specified.
d Inhibition constants Ki.
e Data from ref. 32.
f ND: Not determined.
Georg Thieme Verlag Stuttgart · New York — Synthesis 2018, 50, A–L

H
S. R. McCabe, P. Wipf
Feature
Synthesis
the inhibition of the binding of the radiolabeled agonist hal-
operidol to sigma-1, and therefore found to be very similar
to DMT (Ki = 5.2 M) (Table 3, entry 5). To the best of our
knowledge, this is the first time that stereospecific binding
of ergot alkaloids to a sigma receptor has been observed,
and, accordingly, it is feasible to consider (–)-cycloclavine as
a potential lead structure for sigma receptor modulator de-
sign.
tions were monitored by TLC analysis (pre-coated silica gel 60 F254
plates, 250 m layer thickness) and visualization was accomplished
with a KMnO4 solution (1.50 g of KMnO4, 10 g of K2CO3, and 1.25 mL
of 10% NaOH in 200 mL of H2O), when needed. Flash chromatography
was performed using SiO2 (40–63 m). Specific rotations were mea-
sured on a polarimeter equipped with a sodium lamp. Pentafluoro-
phenyl 2-diazopropanoate (4)11 and stannane 3411 were prepared as
reported previously.
In conclusion, we have successfully completed a total
synthesis of natural (+)-cycloclavine, featuring an optimiza-
tion of the catalyst for the asymmetric cyclopropanation of
allene with an active ester diazopropanoate, a regiospecific
Pd-catalyzed ketone dehydrogenation to the enone, and
two intramolecular Diels–Alder reactions for indole/indo-
line annulations. Furthermore, we have characterized the
binding effects of (+)- and (–)-cycloclavine against 16 CNS
receptors, and discovered significant stereospecificity prop-
erties. (+)-Cycloclavine has at least 10-fold higher potency
at the serotonin 5-HT2C receptor than at any of the other
tested receptors, making it one of the most selective trypt-
amines discovered to date. Furthermore, the receptor sub-
type profile of (+)-cycloclavine resembles that of the clini-
cally validated mushroom metabolite psilocin more closely
than the related psychedelics LSD and DMT. Finally, we de-
termined that the unnatural (–)-cycloclavine has consider-
ably lower affinities at all 5-HT receptors than (+)-cyclo-
clavine, but is quite active at the sigma-1 receptor, a proper-
ty that it shares with the endogenous sigma-1 ligand DMT.
We suggest that these results, in combination with the ex-
cellent synthetic tractability of the cycloclavine scaffold,
encourage future research on the medicinal chemistry of
clavine alkaloids.
N-Tetrabromophthaloyl-(R)-tert-leucine
An oven-dried flask topped with a Dean–Stark apparatus and con-
denser was charged sequentially with (R)-tert-leucine [(R)-18; 0.500
g, 3.77 mmol), tetrabromophthalic anhydride (17; 1.79 g, 3.77 mmol),
anhyd toluene (10 mL), and NEt3 (0.0536 mL, 0.377 mmol). The re-
sulting heterogeneous mixture was heated at reflux while the solvent
was removed at a rate of ca. 1 mL/h. The solution was cooled to r.t.
and treated with aq 5% HCl (6 mL) and EtOAc (15 mL). The aqueous
layer was extracted with EtOAc (6 mL) and the combined organic lay-
ers were dried (Na2SO4) and concentrated to give N-tetrabromoph-
20
thaloyl-(R)-tert-leucine as a white solid; yield: 2.11 g (97%); []D
+22.3 (c 0.40, EtOH).
1H NMR (300 MHz, acetone-d6):  = 4.68 (s, 1 H), 1.19 (s, 9 H).
The experimental data were consistent with the literature-reported
data for the enantiomer.18
Dirhodium(II) Tetrakis[N-tetrabromophthaloyl-(R)-tert-leuci-
nate] [Rh2(R-TBPTTL)4, 10]
An oven dried flask topped with a Dean–Stark apparatus and con-
denser was charged with Rh2(OAc)4 (0.130 g, 0.294 mmol), N-tetra-
bromophthaloyl-(R)-tert-leucine (0.933 g, 1.62 mmol), and a mixture
of chlorobenzene and MeCN (9:1, 13 mL). The resulting dark purple
solution was heated at reflux while the solvent was removed at a rate
of ca. 1 mL/ h over 5 h, during which time the solution turned emer-
ald green. After 5 h, the reaction mixture was cooled to r.t. and treated
sequentially with toluene (40 mL) and sat. aq NaHCO3 (40 mL). The
organic layer was washed with NaHCO3 (40 mL), brine (40 mL), fil-
tered, and dried (Na2SO4) to provide 10 (0.555 g, 75%) as a green solid,
which was used directly without further purification.
All glassware were dried in an oven at 140 °C for at least 2 h prior to
use. All air and moisture-sensitive reactions were performed under a
dry N2 atmosphere. Reactions carried out at 0 °C employed an ice bath
and reactions carried out at –78 °C employed a dry ice/acetone bath.
THF and Et2O were distilled over Na/benzophenone ketyl; Et3N,
CH2Cl2, and toluene were distilled from CaH2. All other materials were
obtained from commercial sources and used as received. Microwave
reactions were performed using a Biotage Initiator or an Anton Paar
Monowave 300 reactor in glass microwave vials (cap sealed) with
continuous magnetic stirring and internal ruby thermometer and/or
external infrared surface temperature sensor. IR spectra were ob-
tained from neat solids or oils on ATR FT-IR spectrophotometers.
Melting points were determined in open capillary tubes and are un-
corrected. High-resolution mass spectra were obtained on a Q-TOF
1H NMR (300 MHz, benzene-d6):  = 5.37 (s, 4 H), 1.45 (s, 36 H).
The experimental data were consistent with the literature-reported
data for the enantiomer.38
4,7-Diphenyl-3a,4,7,7a-tetrahydroisobenzofuran-1,3-dione
A clear, yellow solution of butadiene 19 (2.0 g, 9.6 mmol) and maleic
anhydride 20 (1.1 g, 11 mmol) in xylenes (25 mL) was heated at 140
°C for 16 h. After this time, the reaction was cooled to 0 °C and the
resulting precipitate was filtered to afford the Diels–Alder adduct as a
white solid; yield: 2.29 g (78%).
1H NMR (500 MHz, CDCl3):  = 7.43 (app t, J = 7.3 Hz, 4 H), 7.39–7.36
(m, 6 H), 6.56 (s, 2 H), 3.84 (d, J = 4.0 Hz, 2 H), 3.74 (dd, J = 4.5, 2.0 Hz,
2 H).
1
MS or a Thermo Scientific Exactive Orbitrap LC-MS. H and 13C NMR
The experimental data were consistent with the literature-reported
data.39
spectra were obtained at 300, 400, 500, 600, or 700 MHz NMR in
CDCl3, unless otherwise specified. 13C NMR spectra were obtained at
100, 125, or 150 MHz with proton-decoupling. Chemical shifts () are
reported in parts per million with the residual solvent peak used as
4,7-Diphenylisobenzofuran-1,3-dione (21)
an internal standard: 1H/13
C (Solvent)  = 7.26/77.16 (CDCl3);
A red solution of 4,7-diphenyl-3a,4,7,7a-tetrahydroisobenzofuran-
1,3-dione (1.0 g, 3.3 mmol) and DDQ (1.5 g, 6.6 mmol) in toluene (10
mL) was heated at 110 °C for 17 h. The reaction mixture was concen-
7.16/128.06 (C6D6), 5.32/54.00 (CD2Cl2), and 2.08/20.43 (toluene-d8)
and are tabulated as follows: chemical shift, multiplicity (standard
abbreviations), and coupling constant(s), number of protons. Reac-
Georg Thieme Verlag Stuttgart · New York — Synthesis 2018, 50, A–L

I
S. R. McCabe, P. Wipf
Feature
Synthesis
trated and filtered, and the solid was washed with EtOH to provide
crude 21 (0.832 g, 84%) as a light pink solid that was used without
further purification.
Asymmetric Cyclopropanation of Allene; General Procedure
(Table 1)
1H NMR (300 MHz, CDCl3):  = 7.85 (s, 2 H), 7.61–7.57 (m, 4 H), 7.54–
7.51 (m, 6 H).
Pentafluorophenyl (R)-1-Methyl-2-methylenecyclopropane-1-
carboxylate [(R)-24)]11
An oven-dried three-necked flask was charged with the respective
catalyst (0.0056 mmol) and hexanes or CH2Cl2 (2.8 mL), and the re-
sulting green solution was cooled to –78 °C and treated dropwise
with an excess of condensed gaseous allene (23; ca. 14 mmol). The
reaction mixture was then treated with a solution of pentafluorophe-
nyl 2-diazopropanoate (4; 0.56 mmol) in hexanes or CH2Cl2 (1.7 mL)
via syringe pump at a rate of 1 mL/h. After the addition was complete,
the mixture was allowed to warm to r.t. The solution was concentrat-
ed under reduced pressure and the resulting residue was purified by
chromatography on SiO2 (0–2% Et2O/hexanes) to provide methy-
lenecyclopropane (R)-24.
The experimental data were consistent with the literature-reported
data.39
(S)-2-(1,3-Dioxo-4,7-diphenylisoindolin-2-yl)-3,3-dimethylbuta-
noic Acid (22)
An oven-dried microwave vial was charged sequentially with 4,7-di-
phenylisobenzofuran-1,3-dione (21; 0.300 g, 1.00 mmol), (S)-tert-
leucine (0.199 g, 1.50 mmol), and NEt3 (0.0283 mL, 0.200 mmol), and
the resulting heterogeneous brown solution was heated at reflux for
19 h. The solution was cooled to r.t., and extracted with aq 5% HCl and
EtOAc. The aqueous layer was back-extracted with EtOAc (3 ×), and
the combined organic layers were dried (Na2SO4), filtered, and con-
centrated. The resulting residue was purified by chromatography on
SiO2 (0–20% acetone/CH2Cl2) to provide the carboxylic acid 22 as a
1H NMR (400 MHz, CD2Cl2):  = 5.64 (t, J = 2.8 Hz, 1 H), 5.56 (t, J = 2.2
Hz, 1 H), 2.30 (dt, J = 9.2, 2.5 Hz, 1 H), 1.63 (dt, J = 9.2, 2.4 Hz, 1 H),
1.51 (s, 3 H).
19
white foam; yield: 0.128 g (31%); mp 142.7–145 °C; []D –10.6 (c
(R,E)-N,1-Dimethyl-2-methylene-N-(3-oxobut-1-en-1-yl)cyclopro-
pane-1-carboxamide [(R)-27]11
0.17, CHCl3).
IR (ATR): 2963, 1770, 1710, 1603, 1475, 1382, 1122, 903, 752, 698 cm–1
.
An oven-dried flask charged with vinylogous amide 267 (0.0178 g,
0.18 mmol, 1.0 equiv) was evacuated and backfilled with N2 (3 ×).
Freshly distilled THF (0.6 mL) was added and the resulting solution
was cooled to –78 °C and treated dropwise with n-BuLi (2.29 M solu-
tion in hexanes, 0.082 mL, 0.19 mmol, 1.05 equiv). The resulting clear,
pale yellow solution was stirred for 5 min at –78 °C, then treated with
a solution of ester (R)-24 (0.053 g, 0.19 mmol, 1.05 equiv) in THF (1
mL). The resulting bright yellow solution was treated with DMAP
(0.023 g, 0.19 mmol, 0.1 equiv) and stirred for 10 min at –78 °C. The
cold bath was removed and the reaction mixture was allowed to
warm to r.t. The reaction was quenched with sat. aq NaHCO3. After
addition of EtOAc, the aqueous layer was extracted with EtOAc (3 ×)
and the combined organic layers were dried (Na2SO4) and concentrat-
ed. The crude product was purified by chromatography on SiO2 (10–
15% EtOAc/hexanes) to provide vinylogous imide (R)-27 as a clear,
pale yellow oil; yield: 28 mg (80%).
1H NMR (300 MHz, CDCl3):  = 7.67 (s, 2 H), 7.56 (app dd, J = 7.6, 1.9
Hz, 4 H), 7.52–7.45 (m, 6 H), 4.68 (s, 1 H), 1.14 (s, 9 H).
13C NMR (100 MHz, CDCl3):  = 172.3, 167.3, 140.4, 136.5, 136.3,
129.6, 128.9, 128.3, 128.1, 60.0, 35.8, 28.2.
HRMS (LCMS ESI+): m/z calcd for C26H24NO4 (M + H)+: 414.1700;
found: 414.1698.
Tetrakis-(S)-2-(1,3-dioxo-4,7-diphenylisoindolin-2-yl)-3,3-di-
methylbutanoic Acid Dirhodium(II) Complex (11)
A microwave vial was charged with (S)-2-(1,3-dioxo-4,7-diphenyliso-
indolin-2-yl)-3,3-dimethylbutanoic acid (22; 0.090 g, 0.22 mmol),
Rh2(OAc)4 (0.016 g, 0.036 mmol), and chlorobenzene (0.5 mL), and the
resulting green solution was heated overnight at 145 °C (external
temperature, oil bath). The reaction mixture was cooled and concen-
trated. The resulting green residue was purified by chromatography
on SiO2 (0–2% acetone/CH2Cl2) to deliver a green residue, which was
dissolved in EtOAc and concentrated to provide the bis-EtOAc adduct
of 11 as an emerald green crystalline solid; yield: 36 mg (48%); mp
280–282.9 °C (dec.); []D20 +217 (c 0.03, CHCl3).
1H NMR (300 MHz, CDCl3):  = 8.36 (d, J = 13.8 Hz, 1 H), 5.71 (d, J =
13.8 Hz, 1 H), 5.69 (app t, J = 3.0 Hz, 1 H), 5.53 (app s, 1 H), 3.15 (s, 3
H), 2.29 (s, 3 H), 1.79 (dt, J = 9.6, 2.2 Hz, 1 H), 1.49 (s, 3 H), 1.32 (dt, J =
9.6, 2.2 Hz, 1 H).
IR (ATR): 2944, 1716, 1606, 1509, 1353, 1226, 1046, 737 cm–1
.
SFC conditions for e.r. analysis: Chiralpak-IC semi-prep column (250 ×
10 mm), gradient elution: 5-15% i-PrOH, 7 mL/min, 254 nm detection,
P = 100 bar.
1H NMR (500 MHz, CDCl3):  = 7.52 (br s, 8 H), 7.44–7.33 (m, 40 H),
4.20 (s, 4 H), 4.12 (q, J = 7.3 Hz, 4 H, EtOAc), 2.04 (s, 6 H, EtOAc), 1.23
(t, J = 7.0 Hz, 6 H, EtOAc), 0.84 (s, 36 H).
13C NMR (125 MHz, CDCl3):  =187.4 (8 C), 171.9 (4 C), 166.3 (4 C),
166.1 (4 C), 140.0 (4 C), 139.3 (4 C), 136.8 (8 C), 136.3 (4 C), 135.3 (4
C), 129.9 (8 C), 128.2 (16 C), 127.8 (16 C), 60.7 (EtOAc), 60.6 (4 C), 35.6
(4 C), 28.2 (12 C), 21.2 (EtOAc), 14.3 (EtOAc).
Pentafluorophenyl (S)-1-Methyl-2-methylenecyclopropane-1-car-
boxylate [(S)-24] (Table1, entry 3)
An oven-dried three-necked flask fitted with a N2 inlet, a dry-ice con-
denser, and a septum was charged with Rh2(R-TBPTTL)4 (10; 0.566 g,
0.226 mmol) and CH2Cl2 (141 mL), and the green solution was cooled
to –78 °C (dry ice/acetone bath) and treated dropwise with an excess
of condensed gaseous allene (23; ca. 65 drops, 5.14 g, 5.52 mmol).
The resulting solution was then treated with a solution of perfluoro-
phenyl 2-diazopropanoate (4; 6.00 g, 22.6 mmol) in CH2Cl2 (12 mL)
via syringe pump at a rate of ca. 2 mL/h. The reaction mixture was
allowed to stir at –78 °C for 1 h before warming to r.t. The resulting
green residue was purified by chromatography on SiO2 (0–1%
Et2O/hexanes) to afford methylenecyclopropane (S)-24 as a clear and
pale yellow oil; yield: 5.41 g (86%); []D19 +2.8 (c 7.6, CHCl3).
HRMS (ESI+): m/z calcd for C104H89N4O16Rh2 (M + H)+: 1855.4378;
found: 1855.4318.
Georg Thieme Verlag Stuttgart · New York — Synthesis 2018, 50, A–L

J
S. R. McCabe, P. Wipf
Feature
Synthesis
1H NMR (500 MHz, CD2Cl2):  = 5.64 (app t, J = 2.8 Hz, 1 H), 5.56 (app
t, J = 2.3 Hz, 1 H), 2.30 (dt, J = 9.5, 2.5 Hz, 1 H), 1.63 (dt, J = 9.2, 2.4 Hz,
1 H), 1.51 (s, 3 H).
HRMS (ESI+): m/z calcd for C12H8F5O2 (M + H)+: 279.0439; found:
279.0450.
an orange oil that was used directly in the next conversion. The crude
enol ether adducts (assumed 3.98 g, 12.9 mmol) were immediately
dissolved in THF (130 mL), treated dropwise with TBAF (12.9 mL, 1 M
solution in THF, 12.9 mmol) and stirred at r.t. for 30 min. The reaction
mixture was filtered through a pad of Florisil (washed with EtOAc)
and concentrated. The resulting residue was purified by chromatogra-
phy on SiO2 (20% EtOAc/hexanes to elute recovered starting material,
then 50–70% EtOAc/hexanes to elute the trans-diastereomer 30, then
90–100% EtOAc/hexanes to elute the cis-diastereomer 29) to provide
trans-ketone 30 as a pale yellow solid (1.64 g, 66%) and cis-ketone 29
as a yellow oil (0.371 g, 15%).
All other experimental data were consistent with the reported data
for the enantiomer.11
(S,E)-N,1-Dimethyl-2-methylene-N-(3-oxobut-1-en-1-yl)cyclopro-
pane-1-carboxamide [(S)-27]
An oven-dried round bottomed flask was charged with vinylogous
amide 267 (2.77 g, 27.9 mmol) and evacuated and backfilled with N2
(3 ×). Distilled THF (93 mL) was added and the resulting solution was
cooled to –78 °C and treated dropwise with n-BuLi (11.7 mL, 2.5 M
solution in hexanes, 29.3 mmol). The mixture was stirred for 5 min at
–78 °C, then treated dropwise with a solution of pentafluorophenyl
(S)-1-methyl-2-methylenecyclopropane-1-carboxylate [(S)-24; 8.15
g, 29.3 mmol] in THF (15 mL). The reaction mixture was treated with
DMAP (0.0341 g, 0.279 mmol) and stirred for 10 min at –78 °C. The
cold bath was removed and the solution was allowed to warm to r.t.,
and quenched with sat. aq NaHCO3 and EtOAc. The aqueous layer was
extracted with EtOAc (3 ×) and the combined organic layers were
dried (Na2SO4) and concentrated. The crude product was purified by
chromatography on SiO2 (10–15% EtOAc/hexanes) to afford [(S)-27];
yield: 4.30 g (80%); e.r. 87:13 by SFC analysis) as a clear and pale yel-
low oil; []D19 –243.2 (c 2.24, CHCl3).
1H NMR (500 MHz, CDCl3):  = 8.37 (d, J = 14.0 Hz, 1 H), 5.73 (d, J =
13.5 Hz, 1 H), 5.71 (app t, J = 2.8 Hz, 1 H), 5.53 (s, 1 H), 3.15 (s, 3 H),
2.29 (s, 3 H), 1.80 (dt, J = 9.8, 2.4 Hz, 1 H), 1.50 (s, 3 H), 1.33 (dt, J = 9.7,
2.4 Hz, 1 H).
HRMS (ESI+): m/z calcd for C11H16NO2 (M + H)+: 194.1176; found:
194.1175.
30
[]D19 –104.3 (c 0.93 CHCl3).
1H NMR (400 MHz, CDCl3):  = 3.41 (dd, J = 12.8, 4.0 Hz, 1 H), 2.80
(ddd, J = 13.6, 4.0, 1.6 Hz, 1 H), 2.69 (ddt, J = 15.5, 4.8, 1.6 Hz, 1 H), 2.66
(s, 3 H), 2.54 (ddd, J = 15.4, 12.2, 7.2 Hz, 1 H), 2.35 (app t, J = 13.4 Hz, 1
H), 2.13 (tdd, J = 12.6, 5.0, 1.4 Hz, 1 H), 1.72 (ddd, J = 13.1, 7.3, 1.9 Hz,
1 H), 1.38 (s, 3 H), 0.95 (d, J = 3.6 Hz, 1 H), 0.66 (d, J = 4.0 Hz, 1 H).
HRMS (ESI+): m/z calcd for C11H16NO2 (M + H)+: 194.1176; found:
194.1179.
All other experimental data were consistent with the reported data
for the enantiomer.11
29
[]D19 +11.0 (c 0.15 CHCl3).
1H NMR (300 MHz, CDCl3):  = 3.73 (app t, J = 6.5 Hz, 1 H), 2.84 (dd, J =
15.0, 6.0 Hz, 1 H), 2.72 (s, 3 H), 2.53–2.25 (m, 4 H), 1.83 (dt, J = 14.2,
5.2 Hz, 1 H), 1.34 (s, 3 H), 0.93 (d, J = 4.5 Hz, 1 H), 0.84 (d, J = 4.5 Hz, 1
H).
HRMS (ESI+): m/z calcd for C11H16NO2 (M + H)+: 194.1176; found
194.1178.
(1aS,3aR,7aR)-1a,3-Dimethylhexahydro-2H-cyclopropa[c]indole-
2,5(3H)-dione (30) and (1aS,3aS,7aR)-1a,3-Dimethylhexahydro-
2H-cyclopropa[c]indole-2,5(3H)-dione (29)
(1aS,3aR,7aS)-1a,3-Dimethyl-1,1a,3a,4-tetrahydro-2H-cyclopro-
pa[c]indole-2,5(3H)-dione (31)
A solution of Pd(TFA)2 (0.044 g, 0.129 mmol) and DMSO (0.018 mL,
0.259 mmol) in AcOH (13 mL) was heated at 55 °C under an atmo-
sphere of O2 (balloon). After stirring at 55 °C overnight, ketone 30
(0.500 g, 2.59 mmol) was added and the reaction mixture was al-
lowed to stir at 55 °C for 4 days. Additional Pd(TFA)2 (2 × 0.11 g) was
added after 24 and 48 h to drive the reaction to completion. The mix-
ture was concentrated and purified by chromatography on SiO2 (50–
70% EtOAc/hexanes) to deliver enone 31 as a pale yellow solid; yield:
0.32 g (66%).
An oven-dried flask was charged with NaHMDS (2.50 g, 12.9 mmol)
and anhyd THF (150 mL) under an atmosphere of N2. The resulting
clear and colorless solution was stirred for 15 min at r.t., then cooled
to –78 °C, and stirred for a further 15 min at this temperature prior to
treatment with a solution of 27 (2.75 g, 14.2 mmol) in THF (20 mL)
slowly at a rate of ca. 4 mL/h, maintaining the temperature of the ace-
tone/dry ice bath below –50 °C. During the slow addition of the am-
ide, the solution changed color from clear and pale yellow to clear and
orange. The resulting clear, orange solution was allowed to warm to
–50 °C over 1 h, cooled to –78 °C and treated dropwise with a solution
of TBSCl (2.36 g, 15.5 mmol) in THF (52 mL). The reaction mixture
was allowed to stir for a further 5 min at –78 °C before the cold bath
was removed, and the solution allowed to reach r.t.
1H NMR analysis of an aliquot (CDCl3) indicated conversion into enol
ether 28.
1H NMR (300 MHz, CDCl3):  = 7.65 (d, J = 13.5 Hz, 1 H), 5.67 (app s, 1
H), 5.52 (d, J = 13.8 Hz, 1 H), 5.45 (app s, 1 H), 4.23 (s, 2 H), 3.13 (br s,
3 H), 1.73 (dt, J = 9.6, 2.1 Hz, 1 H), 1.47 (s, 3 H), 1.25 (dt, J = 9.4, 2.2 Hz,
1 H), 1.00 (s, 9 H), 0.25 (s, 3 H), 0.24 (s, 3 H).
Enantiomeric Enrichment by Recrystallization of Enone 31; Typi-
cal Procedure
Enone 31 (0.110 g, 0.573 mmol) was dissolved in boiling MTBE (9.5
mL) and 1,2-dichloroethane (0.4 mL) and the solution was allowed to
cool to r.t., and kept overnight at –20 °C. The mother liquor was re-
moved via pipette transfer and the white needle-shaped crystals were
washed with MTBE (2 ×) and placed under vacuum to remove trace
solvents. The first recrystallization provided compound of >99.5:0.5
e.r. by chiral SFC analysis; a 95.4:4.6 e.r. was achieved in the second
recrystallization, and the third recrystallization led to 98:2 e.r. to de-
liver a combined yield of enone 31 (0.0654 g, 60%, 69% of theoretical
The mixture was concentrated and directly subjected without purifi-
cation to the next reaction. A solution of crude amide 28 (assumed
3.98 g, 12.9 mmol) in THF (28 mL, 3.5 mL × 8 batches) was heated un-
der microwave irradiation at 95 °C for 30 min, then concentrated to
deliver the crude Diels–Alder adducts (assumed 3.98 g, 12.9 mmol) as
maximum) as a white crystalline solid. Only combined samples with
17
e.r. >97.5:2.5 were carried on in the subsequent reaction; []D
111.1 (c 0.484, CHCl3).
+
Georg Thieme Verlag Stuttgart · New York — Synthesis 2018, 50, A–L

K
S. R. McCabe, P. Wipf
Feature
Synthesis
1H NMR (400 MHz, CDCl3):  = 6.98 (d, J = 9.6 Hz, 1 H), 6.15 (d, J = 9.6
Hz, 1 H), 3.82 (dd, J = 14.2. 3.8 Hz, 1 H), 2.91 (dd, J = 15.9, 3.6 Hz, 1 H),
2.72 (s, 3 H), 2.44 (dd, J = 15.6, 14.0 Hz, 1 H), 1.47 (s, 3 H), 1.34 (d, J =
4.0 Hz, 1 H), 0.86 (d, J = 4.0 Hz, 1 H).
HRMS (ESI+): m/z calcd for C11H14NO2 (M + H)+: 192.1019; found:
192.1018.
-35
[]D18 +30.1 (c 0.2, CHCl3).
1H NMR (500 MHz, C6D6):  = 6.81 (d, J = 1.0 Hz, 1 H), 5.98 (dd, J = 3.3,
2.3 Hz, 1 H), 5.89 (d, J = 2.5 Hz, 1 H), 5.43 (d, J = 9.5 Hz, 1 H), 5.36 (d, J =
9.5 Hz, 1 H), 3.74 (d, J = 14.5 Hz, 1 H), 3.54 (d, J = 15.0 Hz, 1 H), 3.30 (s,
1 H), 2.97 (dd, J = 13.3, 2.3 Hz, 1 H), 2.53 (s, 3 H), 2.40 (app t, J = 10.8
Hz, 1 H), 1.67 (app t, J = 12.3 Hz, 1 H), 1.54 (app t, J = 13.0 Hz, 2 H),
1.31 (s, 3 H), 1.27–1.23 (m, 9 H), 1.06 (dt, J = 13.5, 2.8 Hz, 1 H), 0.93 (s,
3 H), 0.92 (s, 3 H), 0.75 (d J = 3.5 Hz, 1 H), 0.23 (d, J = 3.5 Hz, 1 H).
All other experimental data were consistent with the reported data
for the enantiomer.11
SFC analysis: Chiralpak-IC semiprep column (250 × 10 mm), gradient
elution: 1–30% i-PrOH, 5.5 mL/min, 254 nm detection, P = 100 bar.
HRMS (ESI+): m/z calcd for C26H38N3O5 (M + H)+: 472.2806; found:
472.2810.
(1aS,7aR)-1a,3-Dimethyl-1,1a,6,7-tetrahydro-2H-cyclopropa[c]in-
dole-2,5(3H)-dione (32)7
-35
[]D18 +2.0 (c 0.3, CHCl3).
A microwave flask was charged with Pd(TFA)2 (0.0092 g, 0.027 mmol).
The flask was purged and filled with O2, followed by the addition of
DMSO (1.9 L) and AcOH (1.3 mL). The resulting brown solution was
stirred at 55 °C under an atmosphere of O2 (balloon) for 20 h then
treated with ketone 29 (0.052 g, 0.27 mmol). After 3 days, 1H NMR
analysis of an aliquot (CDCl3) indicated exclusive formation of a single
regioisomer. The reaction mixture was concentrated and purified by
chromatography on SiO2 (50% EtOAc/hexanes) to deliver vinylogous
amide 32 as a white solid; yield: 0.029 g (56%).
1H NMR (300 MHz, C6D6):  = 6.84 (dd, J =1.8, 0.9 Hz, 1 H), 6.02 (dd, J =
3.2, 2.0 Hz, 1 H), 5.86 (dd, J = 3.2, 0.8 Hz, 1 H), 5.60 (d, J = 9.6 Hz, 1 H),
5.45 (d, J = 9.6 Hz, 1 H), 3.74 (app s, 2 H), 3.45 (d, J = 13.2 Hz, 1 H), 3.12
(app d, J = 9.4 Hz, 1 H), 2.46 (s, 3 H), 2.08 (d, J = 13.8 Hz, 1 H), 1.58 (t,
J = 13.0 Hz, 3 H), 1.30–1.23 (m, 12 H), 1.08 (app dd, J = 11.5, 3.4 Hz, 1
H), 0.93 (app s, 6 H), 0.76 (d, J = 3.3 Hz, 1 H), 0.21 (d, J = 3.6 Hz, 1 H).
HRMS (ESI+): m/z calcd for C26H38N3O5 (M + H)+: 472.2806; found:
472.2815.
IR (ATR): 2956, 1732, 1607, 1458, 1241, 1074 cm–1
.
1H NMR (300 MHz, CDCl3):  = 5.49 (s, 1 H), 2.93 (s, 3 H), 2.68–2.65
(m, 1 H), 2.63 (d, J = 5.0 Hz, 1 H), 2.35 (td, J = 12.4, 6.8 Hz, 1 H), 1.73
(ddd, J = 13.0, 4.7, 2.8 Hz, 1 H), 1.41 (s, 3 H), 1.33 (d, J = 4.2 Hz, 1 H),
1.17 (d, J = 4.2 Hz, 1 H).
13C NMR (100 MHz, CDCl3):  = 197.2, 177.1, 164.4, 101.4, 36.9, 30.1,
29.9, 29.2, 26.2, 24.5, 10.4.
(+)-Cycloclavine
A solution of -35 (0.128 g, 0.272 mmol) in anhyd degassed toluene
(10 mL) was heated to 135 °C in a sealed tube for 90 h. The reaction
mixture was concentrated and filtered through a pad of SiO2, washing
with 2–5% acetone/CH2Cl2 to provide crude 36 (27 mg, 39%), which
was used directly in the next step.
HRMS (LCMS ESI+): m/z calcd for C11H14NO2 (M + H): 192.1019;
found: 192.1020.
All data were consistent with the literature-reported data.7
1H NMR (400 MHz, CD2Cl2):  = 8.14 (br s, 1 H), 7.21 (d, J = 8.0 Hz, 1 H),
7.09 (dd, J = 8.0, 7.2 Hz, 1 H), 7.02 (app s, 1 H), 6.80 (d, J = 6.8 Hz, 1 H),
3.78 (dd, J = 11.8, 4.2 Hz, 1 H), 3.29 (dd, J = 13.6, 4.0 Hz, 1 H), 2.79 (s, 3
H), 2.71–2.64 (m, 1 H), 1.80 (s, 3 H), 1.14 (d, J = 3.6 Hz, 1 H), 0.84 (d, J =
3.2 Hz, 1 H).
Allylic Alcohols -35 and -35
A microwave vial was charged with a solution of crude 36 (0.0270 g,
0.107 mmol) in anhyd THF (1.2 mL) under an atmosphere of N2. The
solution was cooled to 0 °C and treated dropwise with LiAlH4 (0.535
mL, 1 M solution in Et2O, 0.535 mmol). The reaction mixture was
stirred at reflux in a sealed tube for 16 h, diluted with Et2O, cooled to
0 °C and treated sequentially with H2O (0.020 mL), aq 15% NaOH
(0.020 mL) and H2O (0.061 mL), warmed to r.t. and stirred for 15 min.
Anhyd MgSO4 was then added and the solution was stirred rigorously
for 15 min, and filtered through a pad of Celite. The crude residue was
purified by chromatography on SiO2 (pre-washed column with 0.1%
NEt3/CH2Cl2, then gradient elution 0–2% MeOH/CH2Cl2 with 0.1% NEt3
added to each eluent) to deliver (+)-cycloclavine as a white solid;
yield: 22.0 mg (86%, or 34% over 2 steps); mp 161.1–163.8 °C (dec.);
[]D18 +61.4 (c 0.2, CHCl3); {Lit.4 []D20 +63 (c 1, CHCl3)}
An oven-dried 3-necked 25 mL flask fitted with two stoppers and N2
inlet was charged with stannane 3411 (0.893 g, 1.57 mmol) and evacu-
ated under high vacuum, then backfilled with N2 (3 ×). A stopper was
exchanged for an internal thermocouple thermometer and anhyd
Et2O (5 mL) was added. The clear, pale yellow solution was cooled to
–70.5 °C (Et2O/dry ice) and stirred for 10 min, then treated dropwise
with n-BuLi (0.628 mL, 2.5 M solution in hexanes, 1.57 mmol), during
which time the temperature rose to –67.4 °C. The resulting clear, yel-
low solution was stirred for 15 min while the internal temperature
was maintained between –67.4 and –74.5 °C, then cooled to –93.1 °C
using a liquid N2/Et2O bath, and treated with a solution of enone 31
(0.250 g, 1.31 mmol) in anhyd THF/Et2O 1:1 (3.5 mL) slowly over 10
min in 0.4 mL portions. The temperature rose to –86 °C during the ad-
dition, and the reaction mixture was subsequently stirred for 30 min
below –90 °C, then for I h at –76 °C. The solution was diluted with
EtOAc and quenched with aq 2 M NH4Cl, maintaining the internal
temperature below –50 °C. The aqueous layer was extracted with
EtOAc (5 ×), and the combined organic layers were dried (Na2SO4),
and concentrated. The residue was purified by chromatography on
SiO2 (gradient elution 5% acetone/CH2Cl2 to elute recovered starting
material enone 31 (3 mg), then alcohol -35, then 10% acetone/CH2Cl2
was used to elute alcohol -35) to deliver equatorial alcohol -35
(0.250 g, 41%) and axial alcohol -35 (0.196 g, 32%) as white foams.
IR (ATR): 3409, 3166, 3103, 3062, 2942, 2885, 2843, 2788, 1617, 1590,
1442, 1322, 1165, 1095, 922, 749 cm–1
.
1H NMR (500 MHz, CDCl3):  = 7.89 (br s, 1 H), 7.13 (dd, J = 8.0, 0.5 Hz,
1 H), 7.09 (app t, J = 7.8 Hz, 1 H), 6.90 (app t, J = 1.8 Hz, 1 H), 6.82 (dd,
J = 7.0, 0.5 Hz, 1 H), 3.15 (d, J = 9.0 Hz, 1 H), 3.13 (dd, J = 13.8, 3.8 Hz, 1
H), 2.78 (dd, J = 11.5, 4.0 Hz, 1 H), 2.63–2.57 (m, 1 H), 2.40 (d, J = 8.5
Hz, 1 H), 2.36 (s, 3 H), 1.69 (s, 3 H), 1.60 (d, J = 3.5 Hz, 1 H), 0.45 (d, J =
3.5 Hz, 1 H).
13C NMR (150 MHz, CDCl3):  = 135.6, 133.7, 128.8, 123.1, 118.2,
113.5, 110.5, 108.1, 69.8, 65.7, 40.1, 34.5, 27.9, 25.1, 24.4, 16.6.
Georg Thieme Verlag Stuttgart · New York — Synthesis 2018, 50, A–L

L
S. R. McCabe, P. Wipf
Feature
Synthesis
DEPT-135 (100 MHz, CDCl3):  = 123.1 (CH), 118.2 (CH), 110.5 (CH),
108.1 (CH), 69.8 (CH), 65.8 (CH2), 40.1 (NCH3), 25.1 (CH2), 24.4 (CH2),
16.6 (CH3).
HRMS (LCMS ESI+): m/z calcd for C16H19N2 (M + H)+: 239.1543; found:
(9) (a) Wang, W.; Lu, J.-T.; Zhang, H.-L.; Shi, Z.-F.; Wen, J.; Cao, X.-P.
J. Org. Chem. 2014, 79, 122. (b) Chen, J.-Q.; Song, L.-L.; Li, F.-X.;
Shi, Z.-F.; Cao, X.-P. Chem. Commun. 2017, 53, 12902. (c) Chen,
J.-Q.; Mi, Y.; Shi, Z.-F.; Cao, X.-P. Org. Biomol. Chem. 2018, 16,
3801.
(10) Netz, N.; Opatz, T. J. Org. Chem. 2016, 81, 1723.
(11) McCabe, S. R.; Wipf, P. Angew. Chem. Int. Ed. 2017, 56, 324.
(12) Chaudhuri, S.; Ghosh, S.; Bhunia, S.; Bisai, A. Chem. Commun.
2018, 54, 940.
239.1544.
All relevant data were consistent with the literature-reported data for
the natural product4 and the enantiomer.11
(13) Deng, L.; Chen, M.; Dong, G. J. Am. Chem. Soc. 2018, 140, 9652.
(14) Diao, T.; Stahl, S. S. J. Am. Chem. Soc. 2011, 133, 14566.
(15) Lizza, J. R.; Bremerich, M.; McCabe, S. R.; Wipf, P. Org. Lett. 2018,
20, 6760.
(16) Padwa, A.; Flick, A. C. Adv. Heterocycl. Chem. 2013, 110, 1.
(17) Panne, P.; DeAngelis, A.; Fox, J. M. Org. Lett. 2008, 10, 2987.
(18) Goto, T.; Takeda, K.; Anada, M.; Ando, K.; Hashimoto, S. Tetrahe-
dron Lett. 2011, 52, 4200.
Funding Information
The authors are grateful to Boehringer-Ingelheim Pharmaceuticals
Inc., Ridgefield CT, for partial financial support of this work. SRM also
acknowledges support from the Mary E. Warga and the University of
Pittsburgh Arts and Sciences Mellon Fellowships.()
(19) (a) Davies, H. M. L.; Stafford, D. G.; Doan, B. D.; Houser, J. H.
J. Am. Chem. Soc. 1998, 120, 3326. (b) Qin, C.; Boyarskikh, V.;
Hansen, J. H.; Hardcastle, K. I.; Musaev, D. G.; Davies, H. M. L.
J. Am. Chem. Soc. 2011, 133, 19198. (c) DeAngelis, A.; Dmitrenko,
O.; Yap, G. P. A.; Fox, J. M. J. Am. Chem. Soc. 2009, 131, 7230.
(20) Lindsay, V. N. G.; Fiset, D.; Gritsch, P. J.; Azzi, S.; Charette, A. B.
J. Am. Chem. Soc. 2013, 135, 1463.
Acknowledgment
The authors thank M. K. Wipf for graphical support.
Supporting Information
(21) Uchida, T.; Katsuki, T. Synthesis 2006, 1715.
Supporting information for this article is available online at
https://doi.org/10.1055/s-0037-1610395. Spectral data (1H and 13C
(22) (a) House, H. O.; Trost, B. M. J. Org. Chem. 1965, 30, 1341.
(b) Velluz, L.; Valls, J.; Nominé, G. Angew. Chem., Int. Ed. Engl.
1965, 4, 181.
NMR for selected new compounds and (+)-cycloclavine).
S
u
p
p
orit
n
gInformati
o
n
S
u
p
p
orit
n
gInformati
o
n
(23) Nasipuri, D. Stereochemistry of Organic Compounds: Principles
and Applications; New Age International: New Delhi, 1994.
(24) dos Santos, R. G.; Bouso, J. C.; Alcazar-Corcoles, M. A.; Hallak, J.
E. C. Exp. Rev. Clin. Pharm. 2018, 11, 889.
(25) Bennett, J. P. Jr.; Snyder, S. H. Brain Res. 1975, 94, 523.
(26) Hofmann, A. LSD – My Problem Child; McGraw-Hill Book Com-
pany: New York, 1980.
(27) Roth, B. L.; Baner, K.; Westkaemper, R.; Siebert, D.; Rice, K. C.;
Steinberg, S.; Ernsberger, P.; Rothman, R. B. Proc. Natl. Acad. Sci.
U.S.A. 2002, 99, 11934.
(28) Rickli, A.; Luethi, D.; Reinisch, J.; Buchy, D.; Hoener, M. C.;
Liechti, M. E. Neuropharmacology 2015, 99, 546.
References
(1) (a) Hager, A.; Vrielink, N.; Hager, D.; Lefranc, J.; Trauner, D. Nat.
Prod. Rep. 2016, 33, 491. (b) Susick, R. B.; Morrill, L. A.; Picazo,
E.; Garg, N. K. Synlett 2017, 28, 1. (c) Wang, Y.; Xie, F.; Lin, B.;
Cheng, M.; Liu, Y. Chem. Eur. J. 2018, 24, 14302. (d) Xie, X.; Zu, L.
Synlett 2018, 29, 1008. (e) Liu, H.; Jia, Y. Nat. Prod. Rep. 2017, 34,
411.
(2) (a) Chadha, N.; Silakari, O. Eur. J. Med. Chem. 2017, 134, 159.
(b) Bharate, S. S.; Mignani, S.; Vishwakarma, R. A. J. Med. Chem.
2018, 61, in press; doi.org/10.1021/acs.jmedchem.7b01922.
(c) Homer, J. A.; Sperry, J. J. Nat. Prod. 2017, 80, 2178.
(29) Nichols, D. E.; Nichols, C. D. Chem. Rev. 2008, 108, 1614.
(30) (a) Glennon, R. A.; Titeler, M.; McKenney, J. D. Life Sci. 1984, 35,
2505. (b) Nichols, C. D.; Sanders-Bush, E. Heffter Rev. Psychedel.
Res. 2001, 2, 73. (c) Ref. 24
(3) McCabe, S. R.; Wipf, P. Org. Biomol. Chem. 2016, 14, 5894.
(4) Stauffacher, D.; Niklaus, P.; Tscherter, H.; Weber, H. P.;
Hofmann, A. Tetrahedron 1969, 25, 5879.
(5) Incze, M.; Doernyei, G.; Moldvai, I.; Temesvari-Major, E.; Egyed,
O.; Szantay, C. Tetrahedron 2008, 64, 2924.
(31) Rickli, A.; Moning, O. D.; Hoener, M. C.; Liechti, M. E. Eur. Neuro-
psychopharmacol. 2016, 26, 1327.
(6) (a) Pierce, J. G.; Kasi, D.; Fushimi, M.; Cuzzupe, A.; Wipf, P. J. Org.
Chem. 2008, 73, 7807. (b) Petronijevic, F.; Timmons, C.;
Cuzzupe, A.; Wipf, P. Chem. Commun. 2009, 104. (c) Wang, C.;
Widom, J.; Petronijevic, F.; Burnett, J. C.; Nuss, J. E.; Bavari, S.;
Gussio, R.; Wipf, P. Heterocycles 2009, 79, 487. (d) LaPorte, M.;
Hong, K. B.; Xu, J.; Wipf, P. J. Org. Chem. 2013, 78, 167.
(e) Alverez, C.; Arkin, M. R.; Bulfer, S. L.; Colombo, R.; Kovaliov,
M.; LaPorte, M. G.; Lim, C.; Liang, M.; Moore, W. J.; Neitz, R. J.;
Yan, Y.; Yue, Z.; Huryn, D. M.; Wipf, P. ACS Med. Chem. Lett. 2015,
6, 1225. (f) Xu, J.; Wipf, P. Org. Biomol. Chem. 2017, 15, 7093.
(7) Petronijevic, F. R.; Wipf, P. J. Am. Chem. Soc. 2011, 133, 7704.
(8) Jabre, N. D.; Watanabe, T.; Brewer, M. Tetrahedron Lett. 2014, 55,
197.
(32) Ray, T. S. PLoS One 2010, 5, e9019.
(33) Fontanilla, D.; Johannessen, M.; Hajipour, A. R.; Cozzi, N. V.;
Jackson, M. B.; Ruoho, A. E. Science 2009, 323, 934.
(34) Timmermann, C.; Roseman, L.; Williams, L.; Erritzoe, D.;
Martial, C.; Cassol, H.; Laureys, S.; Nutt, D.; Carhart-Harris, R.
Front. Psych. 2018, 9, 1424.
(35) (a) Nutt, D. J. Psychopharm. 2016, 30, 1163. (b) Prochazkova, L.;
Lippelt, D. P.; Colzato, L. S.; Sjoerds, Z.; Kuchar, M.; Hommel, B.
Psychopharmacology
(Berl)
2018,
in
press;
doi.org/10.1007/s00213–018-5049-7.
(36) Chu, U. B.; Ruoho, A. E. Mol. Pharmacol. 2016, 89, 142.
(37) Szabo, A.; Frecska, E. Neural Regen. Res. 2016, 11, 396.
(38) Goto, T.; Takeda, K.; Shimada, N.; Nambu, H.; Anada, M.; Shiro,
M.; Ando, K.; Hashimoto, S. Angew. Chem. Int. Ed. 2011, 50, 6803.
(39) Rainbolt, J. E.; Miller, G. P. J. Org. Chem. 2007, 72, 3020.
Georg Thieme Verlag Stuttgart · New York — Synthesis 2018, 50, A–L