Total synthesis of dihydrolysergic acid and dihydrolysergol: development of a divergent synthetic strategy applicable to rapid assembly of D-ring analogs

Article abstract of DOI:10.1016/j.tet.2015.05.093

Abstract The total syntheses of dihydrolysergic acid and dihydrolysergol are detailed based on a Pd(0)-catalyzed intramolecular Larock indole cyclization for the preparation of the embedded tricyclic indole (ABC ring system) and a subsequent powerful inverse electron demand Diels-Alder reaction of 5-carbomethoxy-1,2,3-triazine with a ketone-derived enamine for the introduction of a functionalized pyridine, serving as the precursor for a remarkably diastereoselective reduction to the N-methylpiperidine D-ring. By design, the use of the same ketone-derived enamine and a set of related complementary heterocyclic azadiene [4+2] cycloaddition reactions permitted the late stage divergent preparation of a series of alternative heterocyclic derivatives not readily accessible by more conventional approaches.

Full text of DOI:10.1016/j.tet.2015.05.093

Accepted Manuscript
Total synthesis of dihydrolysergic acid and dihydrolysergol: development of a
divergent synthetic strategy applicable to rapid assembly of D-ring analogs
Kiyoun Lee, Yam B. Poudel, Christopher M. Glinkerman, Dale L. Boger
PII:
S0040-4020(15)00800-5
10.1016/j.tet.2015.05.093
TET 26811
DOI:
Reference:
To appear in: Tetrahedron
Received Date: 14 April 2015
Revised Date: 17 May 2015
Accepted Date: 25 May 2015
Please cite this article as: Lee K, Poudel YB, Glinkerman CM, Boger DL, Total synthesis of
dihydrolysergic acid and dihydrolysergol: development of a divergent synthetic strategy applicable to
rapid assembly of D-ring analogs, Tetrahedron (2015), doi: 10.1016/j.tet.2015.05.093.
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ACCEPTED MANUSCRIPT
Total synthesis of dihydrolysergic acid and dihydrolysergol: development of a divergent synthetic
strategy applicable to rapid assembly of D-ring analogs
Kiyoun Lee, Yam B. Poudel, Christopher M. Glinkerman, and Dale L. Boger*
Department of Chemistry and The Skaggs Institute for Chemical Biology, The Scripps Research
Institute, 10550 North Torrey Pines Road, La Jolla, California 92037, United States
*
Corresponding author: boger@scripps.edu (D. Boger), phone: 858-784-7522, fax: 858-784-7550
Abstract. The total syntheses of dihydrolysergic acid and dihydrolysergol are detailed based on a Pd(0)-
catalyzed intramolecular Larock indole cyclization for the preparation of the embedded tricyclic indole
(ABC ring system) and a subsequent powerful inverse electron demand Diels–Alder reaction of 5-
carbomethoxy-1,2,3-triazine with a ketone-derived enamine for the introduction of a functionalized
pyridine, serving as the precursor for a remarkably diastereoselective reduction to the N-
methylpiperidine D-ring. By design, the use of the same ketone-derived enamine and a set of related
complementary heterocyclic azadiene [4 + 2] cycloaddition reactions permitted the late stage divergent
preparation of a series of alternative heterocyclic derivatives not readily accessible by more
conventional approaches.
Keywords: 1,2,3-triazine cycloaddition, ergot alkaloids, palladium catalyzed indole synthesis, Diels-
Alder cycloaddition
1
. Introduction.
The ergot alkaloids isolated from the fungus Claviceps purpurea comprise a large group of
1
pharmacologically potent indole alkaloids (Figure 1). Among this family of natural products, lysergic
2
acid is the most widely recognized member and several semisynthetic derivatives are clinically used in
3
4
the treatment of a range of neurological diseases. The dopamine agonists, pergolide and bromocriptine,
5
are used for the treatment of Parkinson’s disease and type 2 diabetes, respectively, and ergometrine is
used as a uterotonic agent in combination with oxytocin. Most notorious among the semisynthetic
derivatives is lysergic acid diethylamide (LSD), a powerful psychoactive and psychedelic drug.
Embedded in the structures of the ergot alkaloids are conformationally-restricted variants of the
phenethylamine pharmacophores of both dopamine and related biogenic amines as well as that of
serotonin. Consequently, extensive studies have been conducted to explore not only the biological
1

ACCEPTED MANUSCRIPT
properties of the ergot alkaloids, but to also define the structural features responsible for the activity and
the underlying origin of the pharmacological effects.
Figure 1. Natural products and key semisynthetic analogues.
As a result, the total synthesis of the ergot alkaloids has been the subject of extensive study over
1
a,6
7,8
the last half century.
Herein, we report the total synthesis of dihydrolysergic acid (1) and
9
dihydrolysergol (2) based on two key reactions we recently introduced. Notably, the latter natural
product has only been prepared by semisynthesis from lysergic acid and the work herein discloses the
first total synthesis of this natural product by an alternate route. The first of these reactions is a powerful
1
0,11
intramolecular Larock indole cyclization
for formation of an embedded tricyclic indole isomeric with
1
2
6a
Uhle’s and Kornfeld’s ketones widely used in accessing the ergot alkaloids (Figure 2). The second of
the reactions is a powerful inverse electron demand Diels–Alder reaction of 5-carbomethoxy-1,2,3-
1
3
triazine with a conjugated enamine for the regiospecific introduction of a functionalized pyridine,
serving as the precursor for a subsequent and remarkably diastereoselective reduction to the N-
2

ACCEPTED MANUSCRIPT
methylpiperidine D-ring. An additional and deliberate key feature of the approach is that use of the same
advanced ketone-derived enamine and a series of inverse electron demand [4 + 2] cycloaddition
1
4
15
reactions of heterocyclic azadienes permitted the divergent preparation of isomeric and alternative
heterocyclic derivatives bearing deep-seated structural changes to the ergot skeleton not as readily
accessible by conventional approaches.
Figure 2. Strategic reactions employed.
2
. Results and Discussion.
The synthesis began with the preparation of the tricyclic ketone 12 as illustrated in Scheme 1.
1
0a
Although both the synthesis of 8 (in Supporting Information ) and its participation in the key indole
1
0a
cyclization were detailed in our original studies disclosing the Pd(0)-catalyzed cyclization,
the
synthesis of 8 reported herein is significantly improved and its cyclization has been successfully
1
6
increased to 0.5–1 g scales. Bis-acetylation of the known 2-bromoaniline 3 and subsequent
methanolysis of the O-acetate furnished the free alcohol (83%). This was followed by oxidation (MnO2)
of the benzylic alcohol to provide the aldehyde 4 (92%). Wittig olefination of the resulting aldehyde
1
7
with (methoxymethylene)-triphenylphosphorane afforded the enol ether 5 (86%) as a mixture of olefin
isomers (71% yield over two steps without intermediate purification of 4). Hydrolysis effected by
treatment of 5 with aqueous 6 N HCl/acetone (1:1) furnished aldehyde 6. The substrate for the key
3

ACCEPTED MANUSCRIPT
intramolecular indole annulation was accessed from 6 using an indium variant of a Grignard reagent,
1
8
which was prepared from 1-(trimethylsilyl)propargyl bromide (7). The addition reaction of the in situ
generated indium reagent (3 equiv indium powder, THF, 25 °C to reflux, 2.5 h) proceeded smoothly to
afford the homopropargylic alcohol 8 in excellent yield (82% over two steps from enol ether 5) without
detection of the isomeric allene or competitive reactions derived from enolization of the reactive starting
aldehyde that were observed with the Grignard reagent itself. The key transformation for the preparation
of the tricyclic ketone skeleton was realized with use of the intramolecular Pd(0)-catalyzed Larock
indole annulation of 8, possessing the pendant alkyne and forming the desired tricyclic indole 9 in
excellent yield (90%).
Scheme 1. Preparation of tricyclic ketone 12.
1
0
Our introduction and subsequent investigation of the catalytic indole cyclization indicated that
substrates including 8 were inert towards many candidate palladium catalysts including PdCl
3
PdCl (PhCN) or PdCl (PPh , whereas other readily accessible catalysts including PdCl (PPh )
2
,
,
2
2
2
3
)
2
2
2
Pd(PPh ) and Pd (dba) supported the cyclization reaction. However, significantly improved results
3
4
2
3
4

ACCEPTED MANUSCRIPT
were observed with a Pd
2
(dba)
3
catalyst system that was first found to be remarkably successful in a
challenging Suzuki coupling reaction in our vancomycin synthetic studies, arising from its unusually
1
9
rapid oxidative addition to a hindered, electron-rich aryl bromide. Optimization of this catalyst system
revealed that DtBPF was the best added ligand of those examined, that DMF was the most effective
solvent examined although others were effective, and that soluble organic bases such as Et N were
3
10
found to be superior to insoluble bases like K CO . With the use of 15 mol % of the catalyst and with
2
3
the DtBPF ligand in DMF at 130 °C for 3 h, the reaction provided the indole 9 in yields as high as 90%
now on scales ranging from 0.5–1 g. Despite the expectedly slow oxidative addition with substrates like
8
bearing a hindered, electron-rich ortho disubstituted aryl bromide, they are effective participants in the
cyclization reaction under these conditions. Presumably, this may be attributed to a combination of the
1
9
unique Pd (dba) derived catalyst reactivity and potentially its coordination to the proximal polar
2
3
amide of the substrate.
At this stage, oxidation of the secondary alcohol to the corresponding ketone was examined.
However, all efforts were ineffective under a variety of oxidation conditions. Although clean oxidation
product could be detected (TLC and LCMS), all efforts resulted in competitive benzylic oxidation,
2
naphthalene aromatization, or potential decomposition upon SiO purification. Thus, the reduced
indoline precursor was prepared, which provided two advantages over the candidate indole precursor. In
addition to preventing the competitive over-oxidation, the subsequent requisite enamine now could be
generated regioselectively by virtue of the single stabilizing aryl conjugation. Thus, removal of the
trimethylsilyl group in 9 (Bu NF, THF) followed by methanolysis of the resulting crude N-acetate
4
(
K CO , MeOH) provided 10 (91%). After exploration of several reduction conditions, treatment of 10
2 3
2
0
3
with bis(trifluoroacetoxy)borane generated in situ from BH ·THF in trifluoroacetic acid proved to be
highly effective and afforded the corresponding indoline, which was protected as the benzoyl amide 11
5

ACCEPTED MANUSCRIPT
3 2 2 2
(87% over two steps). Other reduction methods were also successful (Et SiH, TFA/CH Cl , 69%; H ,
PtO , TFA/H O; BH –Py, TFA) but initially afforded 11 in lower conversions. Subsequent oxidation of
2
2
3
2
1
the alcohol by PCC now uneventfully provided the requisite tricyclic ketone 12 in 80% yield.
With the requisite tricyclic ketone 12 in hand, its use in a key inverse electron demand Diels–
1
3a
22
Alder reaction with 5-carbomethoxy-1,2,3-triazine (14, ALD00106) was explored (Scheme 2). The
enamine 13 was prepared by treatment of ketone 12 with pyrrolidine (4Å MS, CHCl , 25 °C, 8 h) and its
3
23
3
Diels–Alder reaction with the 1,2,3-triazine 14 (4 equiv, 0.1 M CHCl , 25 °C, 3 h) proceeded rapidly
to provide the pyridine cycloaddition product 15 (75% from ketone 12) as a single regioisomer without
detection of the intermediates even when conducted at room temperature. The inclusion of 4Å MS in the
reaction mixture or use of higher reaction concentrations (0.3 M) or temperatures (65 °C) even with
prolonged reaction times (15 h) did not further improve the already excellent cycloaddition yield. The
reaction of the 1,2,3-triazine 14 exhibited the now characteristic exclusive N1/C4 cycloaddition
1
3
regioselectivity with the nucleophilic carbon of the electron-rich enamine attached to C4, benefiting
from the complementary azadiene substitution (C5-CO Me). Importantly, the remarkable reactivity of
2
1
4 imparted by the C5 electron-withdrawing substituent provides substantially improved cycloaddition
o
reactivity toward enamine dienophiles such that the reaction with 13 occurred at 25 C, representing a
synthetic scope not observed with 1,2,3-triazine itself.
6

ACCEPTED MANUSCRIPT
Scheme 2. Inverse electron demand Diels–Alder reaction.
The dihydro analogues of lysergic acid comprise an important class of central nervous system
drugs that includes pergolide mesylate, which is produced commercially through the hydrogenation of
lysergic acid. Although the potential reduction of pyridine precursors to the ergot alkaloid D-ring has
6
b
always been an attractive strategy, only one successful implementation has been reported and was
conducted with a precursor lacking the intact ABCD-ring system. In a large measure, this may be
attributed to a problematic pyridine reduction with substrates bearing the core indole, which suffers from
a facile tautomerization to a core naphthalene. Our approach enlists a core indoline incapable of this
competitive reaction and we first examined the use of 15 targeting the fully reduced pyridine ring to
afford saturated derivatives of lysergic acid (Scheme 3).
7

ACCEPTED MANUSCRIPT
Scheme 3. Completion of the total synthesis of dihydrolysergic acid (1) and dihydrolysergol (2).
To this end, pyridine 15 was N-methylated by treatment with MeI (80 °C, 10 h), providing the
pyridinium salt 16 quantitatively. In turn, this crude salt was exposed to a variety of reduction
conditions. After exploration of several methods, a stepwise reduction (NaCNBH , MeOH, 65 °C, 18 h;
3
then NaCNBH , HOAc, 25 °C, 1 h) proved to be highly effective and directly produced near exclusively
3
a single diastereomer 17 (58%, >10:1), whose structure and relative stereochemistry were established by
2
4
a single-crystal X-ray structure determination.
The trans CD ring fusion (C5/C10), the
thermodynamically more stable equatorial disposition of the C8 methyl ester, and the relative C3/C5
trans stereochemistry that places all substituents on the central C-ring in an equatorial disposition,
collectively represent the thermodynamically most stable relative stereochemistry among all
stereocenters. It is remarkable that essentially a single diastereomer emerged from the stepwise
reduction and only a trace of a minor diastereomer(s) was detected (ca. 5%) that likely represents
8

ACCEPTED MANUSCRIPT
predominately the C8 diastereomer. These remarkable results sharply contrast prior efforts where
2
5
reduction of such pyridyl precursors with the imbedded indole intact proved unmanageable or were
2
6
erroneously reported. Removal of the N-benzoyl amide was found to occur under conditions that
promote concomitant oxidation of the indoline to the corresponding indole. This was optimized such
that treatment of 17 with HCl in MeOH (0.5 M, 95 °C, 72 h) provided 18 (55%) directly in a single step
and subsequent hydrolysis of the methyl ester (1 N NaOH/MeOH, 40 °C, 3 h) afforded dihydrolysergic
2
7
acid (1), whose spectroscopic properties perfectly matched those of authentic synthetic material. The
same intermediate 18 was also used to access dihydrolysergol (2) where ester reduction (LiAlH , THF, 0
C, 30 min, 92%) afforded dihydrolysergol (2), whose properties proved identical in all respects with
4
°
2
8,29
those of an authentic sample of the natural product.
A key element of the approach was the use of the enamine 13 derived from ketone 12 in a
cycloaddition reaction with a heterocyclic azadiene for installation of a D-ring pyridine. This strategy
deliberately permits additional cycloaddition reactions of the advanced electron-rich dienophile 13 with
other reactive heterocyclic azadienes (19–24) for the late-stage, divergent preparation of a series of
complementary heterocyclic derivatives (Scheme 4). Representative of this and without individual
1
3d
22
optimization, this included the reaction of 1,2,3-triazine (19, ALD00112), 5-bromo-1,2,3-triazine
1
3a
13b
22
13b
(
20), 4-carbomethoxy-1,2,3-triazine (21, ALD00104), and 4,6-dicarboethoxy-1,2,3-triazine (22,
2
2
ALD00110), each of which displayed the 1,2,3-triazine C4/N1 mode of cycloaddition and provided the
3
0
22
alternatively substituted pyridines 25–28, 1,3,5-triazine (23) that provided the pyrimidine 29, and
3
1
22
3
,6-dicarbomethoxy-1,2,4,5-tetrazine (24, ALD00098) that provided the substituted pyridazine 30
and served further as a precursor to the pyrrole 31 via a unique zinc-mediated reductive ring
3
2
contraction. It is of note that it was the exploration of the ergot alkaloids at Lilly and the preparation of
their simplified ring systems that provided the first synthetic use of such heterocyclic azadiene Diels–
9

ACCEPTED MANUSCRIPT
Alder reactions (use of 30) and the first report of the effective zinc-mediated pyridazine to pyrrole
3
3
reductive ring contraction reaction.
Scheme 4. Divergent synthesis of heterocyclic derivatives.
3
. Conclusions.
Herein, effective total syntheses of dihydrolysergic acid (1) and dihydrolysergol (2) are
disclosed. The approach employed an inverse electron demand Diels–Alder reaction of the tricyclic
ketone 12 derived enamine 13 with 5-carbomethoxy-1,2,3-triazine (14) for the late-stage preparation of
the tetracyclic framework of the ergot alkaloid core structure. Key to the preparation of the tricyclic
ketone 12 was our recently disclosed intramolecular Pd(0)-catalyzed Larock indole annulation of a N-
acetyl 2-bromoaniline derivative substituted with a pendant alkyne to assemble the tricyclic fused indole
found in ergot alkaloids. This strategy deliberately permits the late-stage cycloaddition reaction of the
electron-rich dienophile 13 with additional reactive heterocyclic azadienes for the divergent preparation
of a series of complementary heterocyclic D-ring derivatives not as readily accessible by more
10

ACCEPTED MANUSCRIPT
conventional approaches, including alternatively substituted pyridines, pyrimidines, pyridazines and
pyrroles.
3
4
4
4
. Experimental.
16
.1. (3-Acetylamino-2-bromophenyl)methanol. A stirred solution of 3 (1.81 g, 9.00 mmol) in THF
(90 mL) was treated with pyridine (4.4 mL, 54.0 mmol) and acetic anhydride (3.4 mL, 36.0 mmol) at
2
5 °C. After stirring for 12 h at the same temperature, the resulting mixture was concentrated under
reduced pressure. The mixture was dissolved in MeOH (90 mL) and was treated with potassium
carbonate (1.87 g, 13.5 mmol). After stirring for 3 h at 25 °C, the resulting mixture was quenched with
the addition of H
extracted with EtOAc. The combined organic layers were washed with saturated aqueous NaCl, dried
over anhydrous Na SO , and concentrated under reduced pressure. The residue was purified by flash
2
O and diluted with EtOAc. The layers were separated, and the aqueous layer was
2
4
chromatography (SiO , 70% EtOAc–hexanes) to provide the title compound (1.82 g, 83%) as a white
2
1
solid: H NMR (600 MHz, (CD ) CO) δ 8.50 (br s, 1H), 7.93 (d, J = 8.0 Hz, 1H), 7.39 (d, J = 8.0 Hz,
3
2
1
3
1
H), 7.35 (t, J = 7.8 Hz, 1H), 4.67 (d, J = 6.0 Hz, 2H), 4.50 (t, J = 6.0 Hz, 1H), 2.18 (s, 3H); C NMR
(
150 MHz, CDCl ) δ 169.0, 142.8, 137.3, 128.1, 124.4, 123.6, 115.3, 64.8, 24.1; IR (film) υ 3278,
3
max
–
1
+
1
659, 1592, 1536, 1353, 1300, 1074, 1025, 722 cm ; HRMS (ESI) m/z 243.9968 [(M+H) ,
9 2
C H10BrNO
requires 243.9968].
4
.2. N-(2-Bromo-3-formylphenyl)acetamide (4).
A
solution of N-acetyl 2-bromo-3-
hydroxymethylaniline (1.76 g, 7.24 mmol) in THF (70 mL) was treated with MnO (3.15 g, 36.2 mmol)
2
in a portion at 25 °C. The reaction mixture was stirred for 1 h, followed by another two additions of
MnO (3.15 g, 36.2 mmol) every 1 h. After stirring for an additional 6 h at room temperature, the
2
resulting mixture was filtered through a pad of Celite and concentrated in vacuo to provide crude 4 as a
1
white solid: H NMR (600 MHz, CDCl
3
) δ 10.29 (s, 1H), 8.44 (d, J = 8.2 Hz, 1H), 7.86 (br s, 1H), 7.60
11

ACCEPTED MANUSCRIPT
13
(
d, J = 7.6 Hz, 1H), 7.37 (t, J = 7.9 Hz, 1H), 2.25 (s, 3H); C NMR (150 MHz, CDCl
3
) δ 191.2, 168.4,
1
7
36.4, 133.6, 128.1, 127.8, 125.6, 117.9, 24.6; IR (film) υmax 3253, 2924, 1661, 1521, 1371, 1234, 1024,
–
1
+
92 cm ; HRMS (ESI) m/z 241.9812 [(M+H) , C H BrNO requires 241.9811]. In initial studies, but on
9
8
2
smaller scales (0.94 mmol), the purification of the product provided aldehyde 4 (135 mg) in 92% yield.
4
.3. (E)-N-(2-Bromo-3-(2-methoxyvinyl)phenyl)acetamide (5). A cooled (–78 °C) solution of
(methoxymethyl)triphenylphosphonium chloride (7.45 g, 21.7 mmol) in anhydrous THF (100 mL) was
treated with a solution of potassium tert-butoxide (18.1 mL, 1.0 M in THF, 18.1 mmol) and the mixture
was warmed to 0 °C. The bright red solution was stirred for 10 min and a solution of aldehyde 4 in THF
(45 mL) was added dropwise by syringe. The reaction mixture was allowed to warm to 25 °C and stirred
for 30 min before the resulting mixture was quenched with the addition of saturated aqueous NH Cl and
4
diluted with EtOAc and H O. The layers were separated and the aqueous layer was extracted with
2
EtOAc. The combined organic layers were dried over Na SO , filtered, and concentrated in vacuo. The
2
4
residue was purified by flash chromatography (SiO
2
, 50% EtOAc–hexanes) and provided 5 (1.38 g, 71%
1
over two steps) as a mixture of E/Z (1.4:1) isomers. For major E isomer: H NMR (600 MHz, CDCl
3
) δ
7
.96 (t, J = 8.9 Hz, 1H), 7.79 (s, 1H), 7.11 (t, J = 7.9 Hz, 1H), 7.02 (d, J = 7.7 Hz, 1H), 6.89 (d, J = 12.8
1
Hz, 1H), 6.00 (d, J = 12.8 Hz, 1H), 3.66 (s, 3H), 2.15 (s, 3H). For minor Z isomer: H NMR (600 MHz,
CDCl ) δ 7.96 (t, J = 8.9 Hz, 1H), 7.79 (s, 1H), 7.73 (d, J = 7.9 Hz, 1H), 7.16 (t, J = 8.0 Hz, 1H), 6.19
3
1
3
(
d, J = 7.2 Hz, 1H), 5.50 (d, J = 7.2 Hz, 1H), 3.70 (s, 3H), 2.15 (s, 3H); C NMR (150 MHz, CDCl , a
3
mixture of E/Z isomers) δ 168.13, 168.08, 150.6, 149.3, 136.7, 135.8, 135.4, 135.3, 127.4, 126.9, 125.8,
1
1
21.2, 119.8, 119.6, 114.6, 114.3, 104.5, 103.7, 60.6, 56.4, 24.4; IR (film) υmax 3274, 2931, 2863, 1646,
–
1
+
521, 1210, 1101, 668 cm ; HRMS (ESI) m/z 270.0123 [(M+H) , C11H12BrNO requires 270.0124].
4
.4. N-(2-Bromo-3-(2-hydroxy-5-(trimethylsilyl)pent-4-yn-1-yl)phenyl)acetamide (8). [Hydrolysis]
A cooled (0 °C) solution of 5 (1.79 g, 6.65 mmol) in acetone (50 mL) was treated dropwise with 6 N
12

ACCEPTED MANUSCRIPT
HCl (50 mL). After stirring for 30 min at 0 °C, the reaction mixture was warmed to 25 °C and stirred for
an additional 1 h. The resulting mixture was quenched with the addition of saturated aqueous NaHCO3
and diluted with EtOAc. The layers were separated, and the aqueous layer was extracted with EtOAc.
The combined organic layers were dried over anhydrous Na SO , concentrated in vacuo, and azeotroped
2
4
with toluene to afford the crude 6 as a white solid, which was employed in the next step without further
1
purification: H NMR (600 MHz, CDCl ) δ 9.74 (s, 1H), 8.30 (d, J = 8.3 Hz, 1H), 7.68 (s, 1H), 7.33 (t, J
3
1
3
=
7.9 Hz, 1H), 7.01 (d, J = 7.5 Hz, 1H), 3.89 (s, 2H), 2.26 (s, 3H); C NMR (100 MHz, CDCl
3
) δ 198.0,
1
1
2
68.5, 136.5, 133.3, 128.3, 127.2, 121.8, 116.5, 51.3, 24.8; IR (film) υmax 3274, 2934, 1719, 1657, 1533,
–
1
+
323, 1299, 1101, 1026, 665 cm ; HRMS (ESI) m/z 255.9967 [(M+H) , C10
2
H10BrNO requires
55.9968]. [Indium Grignard Addition] A two neck flask charged with indium powder (2.29 g, 19.96
mmol) in THF (60 mL) was treated with (3-bromoprop-1-ynyl)trimethylsilane (2.2 mL, 13.31 mmol) at
5 °C. After stirring for 15 min, the mixture was subsequently treated dropwise with a solution of the
2
above aldehyde 6 in THF (60 mL). The reaction mixture was allowed to stir for 2.5 h at reflux before the
resulting mixture was cooled to room temperature. The resulting mixture was filtered through a pad of
Celite and diluted with EtOAc and H
2
O. The layers were separated and the aqueous layer was extracted
SO , filtered, and concentrated in vacuo.
with EtOAc. The combined organic layers were dried over Na
2
4
The residue was purified by column chromatography (SiO , gradient elution: 30–50% EtOAc–hexanes)
2
1
and provided 8 (2.00 g, 82% for 2 steps) as a white solid: H NMR (600 MHz, CDCl ) δ 8.19 (d, J = 8.2
3
Hz, 1H), 7.71 (s, 1H), 7.19–7.34 (m, 1H), 7.06 (d, J = 7.5 Hz, 1H), 4.06 (t, J = 6.6 Hz, 1H), 3.12 (dd, J =
1
3.8, 5.1 Hz, 1H), 2.96 (dd, J = 13.8, 7.9 Hz, 1H), 2.52 (dd, J = 16.8, 5.3 Hz, 1H), 2.45 (dd, J = 16.8, 6.1
1
3
Hz, 1H), 2.24 (s, 3H), 0.17 (s, 9H); C NMR (150 MHz, CDCl ) δ 168.2, 138.1, 136.0, 127.8, 127.0,
3
1
1
20.6, 116.2, 102.5, 88.3, 69.1, 43.3, 28.3, 24.9, 0.0; IR (film) υmax 3398, 2957, 1670, 1521, 1404, 1247,
–
1
+
2
022, 839, 733 cm ; HRMS (ESI) m/z 368.0677 [(M+H) , C16H22BrNO Si requires 368.0676].
13

ACCEPTED MANUSCRIPT
4
.5. 1-(4-Hydroxy-2-(trimethylsilyl)-4,5-dihydrobenzo[cd]indol-1(3H)-yl)ethan-1-one (9).
A
solution of 8 (778 mg, 2.12 mmol), Pd (dba) (291 mg, 0.318 mmol) and DtBPF (301 mg, 0.636 mmol)
2
3
in DMF (106 mL, 0.02 M) in a sealed vessel was degassed with argon for 20 min. This solution was
treated with triethylamine (1.5 mL, 10.6 mmol) and the reaction mixture was allowed to stir at 130 ºC
for 3 h. The resulting mixture was cooled to room temperature, filtered through a short pad of silica gel
and diluted with Et O. Excess DMF was removed by washing with H O and extracting with Et O. The
2
2
2
2 4
combined organic layers were dried over Na SO and concentrated in vacuo. The residue was purified
by column chromatography (SiO
2
, gradient elution: 25–40% EtOAc–hexanes) to afford 9 (548 mg,
) δ 7.41 (d, J = 8.3 Hz, 1H), 7.27 (t, J = 7.8 Hz, 1H),
1
9
7
1
9
3
0%) as a light tan oil: H NMR (600 MHz, CDCl
3
.02 (d, J = 7.2 Hz, 1H), 4.39 (d, J = 7.6 Hz, 1H), 3.22 (dd, J = 16.0, 3.9 Hz, 1H), 3.14 (d, J = 14.9 Hz,
H), 3.00 (d, J = 7.4 Hz, 1H), 2.97 (d, J = 7.9 Hz, 1H), 2.77 (s, 3H), 2.07 (d, J = 4.9 Hz, 1H), 0.36 (s,
1
3
H); C NMR (150 MHz, CDCl ) δ 169.1, 135.7, 135.0, 130.4, 129.7, 128.4, 125.8, 121.2, 111.8, 67.8,
3
–
1
5.9, 33.3, 26.0, 2.3; IR (film) υmax 3366, 2897, 1689, 1609, 1376, 1326, 1243, 839, 730 cm ; HRMS
+
(
ESI) m/z 288.1413 [(M+H) , C H NO Si requires 288.1414].
1
6
21
2
4
.6. 1,3,4,5-Tetrahydrobenzo[cd]indol-4-ol (10). [Desilylation] A cooled (0 °C) solution of 9 (435 mg,
1
.52 mmol) in THF (15.2 mL, 0.1 M) was treated with Bu NF (4.55 mL, 1.0 M in THF, 4.55 mmol).
4
After stirring for 2 h at 25 °C, the resulting mixture was quenched with the addition of saturated aqueous
NH Cl and diluted with EtOAc (50 mL). The layers were separated and the aqueous layer was extracted
4
with EtOAc. The combined organic layers were washed with saturated aqueous NaCl, dried over
anhydrous Na SO , and concentrated in vacuo. The crude indole was taken to next step without further
2
4
purification. [Methanolysis] The crude product was dissolved in MeOH (7.6 mL) and was treated with
CO (628 mg, 4.54 mmol). After stirring for 2 h at 25 °C, the resulting mixture was quenched with the
addition of H O and diluted with EtOAc. The layers were separated, and the aqueous layer was extracted
K
2
3
2
14

ACCEPTED MANUSCRIPT
with EtOAc. The combined organic layers were washed with saturated aqueous NaCl, dried over
anhydrous Na SO , and concentrated under reduced pressure. The residue was purified by flash
2
4
1
chromatography (SiO , 70% EtOAc–hexanes) to provide 10 (241 mg, 91%) as a viscous light tan oil: H
2
NMR (600 MHz, CDCl ) δ 8.02 (s, 1H), 7.10–7.22 (m, 2H), 6.90 (dd, J = 5.2, 2.4 Hz, 1H), 6.87–6.89
3
(m, 1H), 4.48 (tt, J = 7.1, 3.8 Hz, 1H), 3.21 (dd, J = 15.8, 3.7 Hz, 1H), 3.15 (dd, J = 15.1, 3.9 Hz, 1H),
1
3
3
.07 (dd, J = 15.7, 6.9 Hz, 1H), 2.96 (dd, J = 15.1, 6.8 Hz, 1H), 2.08 (d, J = 7.9 Hz, 1H); C NMR (150
) δ 133.5, 128.2, 126.3, 123.2, 118.9, 117.0, 110.3, 108.6, 68.2, 36.3, 31.0; IR (film) υmax
MHz, CDCl
388, 2923, 1605, 1442, 1338, 1034, 907, 728 cm ; HRMS (ESI) m/z 174.0913 [(M+H) , C11
requires 174.0913].
3
–
1
+
3
H11NO
4
.7. (4-Hydroxy-2a,3,4,5-tetrahydrobenzo[cd]indol-1(2H)-yl)(phenyl)methanone (11). [Reduction
of Indole] A cooled (0 °C) solution of 10 (302 mg, 1.75 mmol) in THF and TFA (8 mL/8 mL) was
treated dropwise with borane-tetrahydrofuran complex (3.5 mL, 1.0 M in THF, 3.50 mmol). The
reaction mixture was allowed to stir for 10 min at 0 °C at which time an additional portion of borane-
tetrahydrofuran complex (3.5 mL, 1.0 M in THF, 3.50 mmol) was added dropwise. After stirring for an
additional 30 min at the same temperature, the mixture was quenched with the addition of MeOH and
H O. The resulting mixture was neutralized by addition of 1 N NaOH and diluted with EtOAc (40 mL).
2
The layers were separated and the aqueous layer was extracted with EtOAc. The combined organic
layers were washed with saturated aqueous NaCl, dried over anhydrous Na SO , and concentrated in
2
4
vacuo. The residue was purified by flash chromatography (SiO , 70% EtOAc–hexanes) to provide
2
indoline as a colorless oil. [Benzoylation] A cooled (0 °C) solution of the indoline (300 mg, 1.71 mmol)
in CH
benzoyl chloride (289 ꢀL, 2.056 mmol) in CH
resulting mixture was quenched with the addition of saturated aqueous NaHCO and diluted with
2
Cl
2
(15 mL) was treated with Et
3
N (716 ꢀL, 5.14 mmol) followed by dropwise addition of
2
Cl (2 mL). After stirring for 30 min at 25 °C, the
2
3
15

ACCEPTED MANUSCRIPT
CH
2
Cl
2
2 2
. The layers were separated, and the aqueous layer was extracted with CH Cl . The combined
organic layers were washed with saturated aqueous NaCl, dried over anhydrous Na SO , and
2
4
concentrated under reduced pressure. The residue was purified by flash chromatography (SiO , 70%
2
EtOAc–hexanes) to provide a diastereomeric mixture of 11 (423 mg, 87% for 2 steps). For less polar
1
1
6
1
1a: H NMR (500 MHz, CDCl , 50 ºC) δ 7.57 (d, J = 7.3 Hz, 2H), 7.38–7.52 (m, 3H), 6.99 (br s, 1H),
3
.78 (d, J = 7.5 Hz, 1H), 4.47 (s, 1H), 4.36 (br s, 1H), 3.52–3.70 (m, 2H), 2.97 (dd, J = 18.0, 4.8 Hz,
1
3
H), 2.85 (d, J = 18.0 Hz, 1H), 2.21–2.31 (m, 1H), 2.15 (br s, 1H), 1.48 (t, J = 11.6 Hz, 1H); C NMR
, 50 ºC) δ 168.7, 141.3, 136.6, 132.9, 131.8, 130.5, 128.5, 127.7, 127.4, 123.4, 113.7,
(
150 MHz, CDCl
3
–
1
6
5.8, 58.4, 34.9, 33.5, 31.0; IR (film) υmax 3374, 2919, 1625, 1455, 1391, 1228, 770 cm ; HRMS (ESI)
+
1
m/z 280.1333 [(M+H) , C H NO requires 280.1332]. For polar 11b: H NMR (500 MHz, CDCl , 50
18
17
2
3
ºC) δ 7.58 (d, J = 7.4 Hz, 2H), 7.40–7.53 (m, 3H), 7.02 (br s, 1H), 6.80 (d, J = 7.5 Hz, 1H), 4.34 (br s,
1
3
H), 4.23 (dq, J = 10.1, 5.7, 4.3 Hz, 1H), 3.68 (t, J = 11.1 Hz, 1H), 3.36 (dq, J = 18.0, 11.5, 8.2 Hz, 1H),
.24 (dd, J = 16.7, 6.5 Hz, 1H), 2.63 (dd, J = 16.7, 9.6 Hz, 1H), 2.29–2.42 (m, 1H), 1.85 (br s, 1H), 1.52
1
3
(
q, J = 11.3 Hz, 1H); C NMR (150 MHz, CDCl , 50 ºC) δ 168.7, 141.4, 136.6, 132.7, 132.3, 130.6,
3
1
1
28.6, 128.1, 127.5, 123.1, 114.0, 68.6, 58.1, 36.7, 36.3, 36.2; IR (film) υmax 3305, 2922, 1626, 1455,
–
1
+
1
395, 770, 668 cm ; HRMS (ESI) m/z 280.1333 [(M+H) , C18
H17NO
2
requires 280.1332]. The H and
1
3
34
C NMR spectra of 11 in CDCl at 25 ºC exhibit broadened peaks due to Bz rotamers.
3
4
.8. 1-Benzoyl-1,2,2a,5-tetrahydrobenzo[cd]indol-4(3H)-one (12). A cooled (0 °C) solution of 11
(
650 mg, 2.33 mmol) in CH Cl (20 mL, 0.12 M) was treated with PCC (2.51 g, 11.64 mmol, 5 equiv)
2 2
and the mixture was warmed to 25 °C. After stirring for 2 h at the same temperature, the resulting
mixture was diluted with Et O (100 mL) and stirred for 30 min. The solid residue was filtered through a
pad of Celite and washed with Et O. The crude residue was concentrated under reduced pressure and the
residue was purified by flash chromatography (SiO , gradient elution: 30–50% EtOAc–hexanes) to
2
2
2
16

ACCEPTED MANUSCRIPT
1
provide 12 (517 mg, 80%) as a yellow oil: H NMR (500 MHz, CDCl3, 50 ºC) δ 7.58 (d, J = 7.5 Hz, 2H),
7
.43–7.53 (m, 3H), 7.10 (s, 1H), 6.84 (d, J = 7.7 Hz, 1H), 4.49 (s, 1H), 3.78 (q, J = 11.0 Hz, 2H), 3.54
1
3
(
s, 3H), 2.94 (d, J = 15.9, 1H), 2.22–2.40 (m, 1H); C NMR (125 MHz, CDCl , 50 ºC) δ 207.5, 168.8,
3
1
41.3, 136.4, 131.8, 130.9, 130.7, 129.0, 128.7, 127.4, 122.6, 114.8, 58.1, 43.8, 42.0, 34.9; IR (film)
–
1
+
υmax 3365, 2922, 1717, 1600, 1459, 1241, 743, 670 cm ; HRMS (ESI) m/z 278.1174 [(M+H) ,
1
13
C H NO requires 278.1175].
The H and C NMR spectra of 12 in CDCl at 25 ºC
3
18
15
2
3
4
exhibit broadened peaks due to Bz rotamers.
4
.9. Methyl 4-Benzoyl-4,5,5a,6-tetrahydroindolo[4,3-fg]quinoline-9-carboxylate (15). [Enamine
Formation] A solution of 12 (90.2 mg, 0.325 mmol) and 4Å molecular sieves (~450 mg) in CHCl (3.3
3
mL, 0.1 M, passed through basic alumina) was treated dropwise with pyrrolidine (152 ꢀL, 1.63 mmol) at
2
5 °C. After stirring for 8 h at room temperature, the mixture was filtered through a pad of Celite (10%
MeOH–CH Cl + 1% Et N) and the solvent was removed under reduced pressure. The crude enamine
2
2
3
was dried under high vacuum for 5 h. [Inverse Electron Demand Diels–Alder Reaction] A solution of
the enamine 13 in CHCl (2.5 mL, passed through basic alumina) was treated dropwise with 5-
carbomethoxy-1,2,3-triazine (14, 90.5 mg, 0.651 mmol) in CHCl (0.8 mL) during which smooth
3
3
evolution of gas took place. The reaction mixture was stirred for 1 h, followed by another addition of 5-
carbomethoxy-1,2,3-triazine (14, 90.5 mg, 0.651 mmol) in CHCl (0.8 mL). After stirring for additional
3
2
h at 25 °C, the solvent was removed under reduced pressure. The resulting residue was purified by
column chromatography (SiO , 5% MeOH–CH Cl ) to provide 15 (90.2 mg, 75%) as a dark red solid:
2
2
2
1
H NMR (500 MHz, CDCl 50 ºC) δ 9.03 (d, J = 2.0 Hz, 1H), 8.58 (d, J = 2.0 Hz, 1H), 7.61 (d, J = 7.1
3
,
Hz, 2H), 7.45–7.54 (m, 3H), 7.41 (d, J = 7.7 Hz, 1H), 7.24 (s, 1H), 4.53 (s, 1H), 3.99 (s, 3H), 3.92 (t, J =
1
3
1
0.7 Hz, 1H), 3.72–3.86 (m, 1H), 3.46 (dd, J = 15.7, 6.3 Hz, 1H), 3.01 (t, J = 15.1 Hz, 1H); C NMR
(
125 MHz, CDCl , 50 ºC) δ 168.7, 165.5, 160.8, 149.0, 141.7, 136.3, 132.2, 131.0, 130.6, 129.4, 129.2,
3
17

ACCEPTED MANUSCRIPT
–
1
28.6, 128.5, 127.2, 125.1, 117.9, 58.5, 52.2, 37.0, 34.7; IR (film) υmax 3309, 1646, 1428, 1257, 668 cm
1
+
1
13
;
HRMS (ESI) m/z 371.1391 [(M+H) , C H N O requires 371.1390]. The H and C NMR spectra
23 18 2 3
3
4
of 15 in CDCl at 25 ºC exhibit broadened peaks due to Bz rotamers.
3
4
.10. Methyl (5aR,6aR,9R,10aR)-4-Benzoyl-7-methyl-4,5,5a,6,6a,7,8,9,10,10a-decahydroindolo[4,3-
fg]quinoline-9-carboxylate (17). [Formation of Pyridinium Salt] A sealed tube charged with 15 (90.0
mg, 0.243 mmol) in MeI (2.4 mL, 0.1 M) was warmed to 80 ºC and stirred for 10 h, at which point
complete conversion of the starting material to the pyridinium salt had been achieved as monitored by
LCMS. The brown mixture was cooled to room temperature and concentrated in vacuo to provide crude
1
6. [Reduction of Pyridinium Salt] A solution of 16 in anhydrous MeOH (8.1 mL, 0.03 M) was treated
with NaCNBH (153 mg, 2.43 mmol) at 25 ºC under Ar. The reaction mixture was warmed to 65 ºC and
3
stirred for 18 h before it was cooled to 0 ºC and quenched with the addition of saturated aqueous
NaHCO . The organic layers were dried over anhydrous Na SO , and concentrated in vacuo. The
3
2
4
residue was purified by passage through a short pad of silica gel to provide a mixture of partial and full
reduction products and concentrated under reduced pressure. A solution of the mixture of reduction
3
products in acetic acid (8.1 mL, 0.03 M) was treated with NaCNBH (153 mg, 2.43 mmol) at 25 ºC
under Ar. The reaction mixture was allowed to stir for 1 h at 25 ºC before being cooled to 0 ºC. The
resulting mixture was quenched with the addition of saturated aqueous NaHCO and diluted with EtOAc
3
(10 mL). The layers were separated, and the aqueous layer was extracted with EtOAc. The combined
organic layers were further washed with 1 N NaOH, dried over anhydrous Na SO , and concentrated
2
4
under reduced pressure. The residue was purified by preparative thin-layer chromatography (Et N pre-
3
treated SiO
2
, 3% MeOH–CH
2
Cl
2
eluted 3×) to provide 17 (55.3 mg, 58%) and an inseparable mixture of
1
minor reduction products (4.6 mg, 5%): For 17: H NMR (500 MHz, CDCl
3
, 50 ºC) δ 7.55 (d, J = 7.4
Hz, 2H), 7.41–7.50 (m, 3H), 7.09 (br s, 1H), 6.88 (d, J = 7.5 Hz, 1H), 4.48 (s, 1H), 3.73 (s, 3H), 3.68 (t,
18

ACCEPTED MANUSCRIPT
J = 10.8 Hz, 1H), 3.48 (qd, J = 10.2, 6.1 Hz, 1H), 3.17 (dd, J = 11.6, 3.6 Hz, 1H), 2.85 (tt, J = 12.0, 3.7
Hz, 1H), 2.74 (d, J = 13.0 Hz, 1H), 2.45–2.56 (m, 1H), 2.30 (s, 3H), 2.18 (t, J = 11.6 Hz, 1H), 2.05–2.15
1
3
(
m, 1H), 1.86 (dt, J = 13.8, 7.1 Hz, 1H), 1.74 (q, J = 8.8 Hz, 1H), 1.59 (q, J = 12.5 Hz, 1H); C NMR
(
150 MHz, CDCl , 50 ºC) δ 174.0, 168.8, 140.5, 137.6, 136.8, 132.5, 130.4, 128.6, 127.8, 127.3, 118.6,
3
1
1
14.4, 65.5, 60.3, 58.5, 51.7, 43.2, 41.3, 38.6, 32.32, 32.31, 29.9; IR (film) υmax 2924, 1731, 1635, 1456,
–
1
+
1
388, 1254, 732 cm ; HRMS (ESI) m/z 391.2017 [(M+H) , C24
H
26
N
2
O
3
requires 391.2016]. The H and
1
3
34
3
C NMR spectra of 17 in CDCl at 25 ºC exhibit broadened peaks due to Bz rotamers.
The structure and relative stereochemistry of 17 were confirmed upon X-ray (CCDC 1047936) analysis
enlisting a colorless monoclinic plate crystal obtained from MeOH.
4
.11. Methyl (6aR,9R,10aR)-7-Methyl-4,6,6a,7,8,9,10,10a-octahydroindolo[4,3-fg]quinoline-9-
carboxylate (18). A microwave sealed vessel charged with 17 (4.7 mg, 0.012 mmol) was treated with a
solution of HCl (0.5 M in MeOH, 1 mL). The reaction mixture was warmed to 95 °C and stirred for 72
h. The resulting mixture was cooled to room temperature and basified with the addition of 1 N aqueous
2 2
NaOH and diluted with CH Cl . The layers were separated, and the aqueous layer was extracted with
CH Cl . The combined organic layers were dried over anhydrous Na SO , and concentrated in vacuo.
2
2
2
4
The residue was purified by preparative thin-layer chromatography (Et N pre-treated SiO , 5% MeOH–
3
2
1
9

ACCEPTED MANUSCRIPT
1
CH
2
Cl
2
eluted 2×) to afford 18 (1.9 mg, 55%) as an off-white solid: H NMR (600 MHz, CDCl
3
) δ 7.96
(s, 1H), 7.15–7.21 (m, 2H), 6.96 (d, J = 6.6 Hz, 1H), 6.89 (s, 1H), 3.41 (dd, J = 14.6, 4.3 Hz, 1H), 3.26
(dt, J = 11.5, 2.9 Hz, 1H), 2.92–3.01 (m, 3H), 2.69 (dd, J = 14.6, 11.2 Hz, 1H), 2.51 (s, 3H), 2.36 (t, J =
1
3
1
1
1.7 Hz, 1H), 2.16–2.24 (m, 1H), 1.60 (q, J = 13.2 Hz, 1H); C NMR (150 MHz, CDCl ) δ 174.3,
3
33.3, 132.5, 126.1, 123.1, 117.8, 113.3, 111.6, 108.7, 66.7, 58.5, 51.8, 42.9, 41.3, 40.0, 30.5, 26.8, 8.9;
–
1
+
IR (film) υmax 3360, 2922, 2851, 1731, 1456, 749 cm ; HRMS (ESI) m/z 285.1597 [(M+H) ,
requires 285.1597].
17 20 2 2
C H N O
4
.12. Dihydrolysergic Acid (1). A solution of 18 (2.6 mg, 9.1 µmol) in MeOH (600 µL) was treated
with 1 N NaOH (600 µL). After stirring for 3 h at 40 °C, 1 N HCl was added to the mixture to carefully
adjust the pH to 6. The resulting mixture was concentrated in vacuo. The residue was washed with ice
cold water three times and the resulting solid was dried in vacuo to afford dihydrolysergic acid (1, 2.2
2
7 1
mg, 89%) as an off-white solid identical in all respects with authentic material previously reported : H
NMR (600 MHz, DMSO-d ) δ 10.63 (s, 1H), 7.12 (d, J = 8.0 Hz, 1H), 7.01 (t, J = 7.6 Hz, 1H), 6.97 (br
s, 1H), 6.79 (d, J = 7.0 Hz, 1H), 3.29 (d, J = 14.7 Hz, 1H), 3.11 (d, J = 11.3 Hz, 1H), 2.70–2.85 (m, 3H),
.50–2.56 (m, 1H), 2.37 (s, 3H), 2.16 (t, J = 11.5 Hz, 1H), 2.00 (t, J = 11.1 Hz, 1H), 1.34 (q, J = 13.0
6
2
1
3
Hz, 1H); C NMR (150 MHz, DMSO-d ) δ 175.0, 133.1, 132.3, 125.9, 122.1, 118.5, 112.0, 110.0,
6
1
08.7, 66.6, 58.6,. 42.6, 40.9, 30.5, 26.5; IR (film) υmax 3192, 2919, 2851, 1611, 1573, 1259, 1094,. 779
–
1
+
cm ; HRMS (ESI) m/z 271.1440 [(M+H) , C H N O requires 271.1441].
16
18
2
2
1
Table 1. Comparison of H NMR data for 1 (Solvent: DMSO-d
6
; δ in ppm, J in Hz)
chemical shifts (δ)
a
Semi synthetic
Synthetic 1
20

ACCEPTED MANUSCRIPT
(
500 MHz)
0.65 (s, 1H)
.13 (d, J = 8.1 Hz, 1H)
.01 (t, J = 7.6 Hz, 1H)
.98 (bs, 1H)
.79 (d, J = 7.1 Hz, 1H)
(600 MHz)
1
10.63 (s, 1H)
7
7.12 (d, J = 8.0 Hz, 1H)
7.01 (t, J = 7.6 Hz, 1H)
6.97 (br s, 1H)
7
6
6
6.79 (d, J = 7.0 Hz, 1H)
3.29 (d, J = 14.7 Hz, 1H)
3.11 (d, J = 11.3 Hz, 1H)
2.70–2.85 (m, 3H)
3
3
.29 (dd, J = 14.6, 4.1 Hz, 1H)
.12 (dd, J = 11.0, 2.1 Hz, 1H)
2
2
.70–2.85 (m, 3H)
.48–2.55 (m, 1H)
2.50–2.56 (m, 1H)
2
.37 (s, 3H)
.17 (t, J = 11.5 Hz, 1H)
.00 (dt, J = 10.9, 4.1 Hz, 1H)
.34 (q, J = 12.9 Hz, 1H)
Wagger, J.; Požes, A.; Požgan, F. RSC Adv. 2013, 3, 23146.
2.37 (s, 3H)
2
2.16 (t, J = 11.5 Hz, 1H)
2.00 (t, J = 11.1 Hz, 1H)
1.34 (q, J = 13.0 Hz, 1H)
2
1
a
1
3
6
Table 2. Comparison of C NMR data for 1 (Solvent: DMSO-d ; δ in ppm)
chemical shifts (δ)
a
Semi synthetic
Synthetic 1
21

ACCEPTED MANUSCRIPT
(125 MHz)
(150 MHz)
1
1
1
1
1
1
1
1
1
75.1
33.2
32.3
25.9
22.1
18.6
12.0
10.0
08.8
175.0
133.1
132.3
125.9
122.1
118.5
112.0
110.0
108.7
66.6
6
6.6
8.6
2.6
0.9
0.5
6.5
5
58.6
4
4
3
2
42.6
40.9
30.5
26.5
a
Wagger, J.; Požes, A.; Požgan, F. RSC Adv. 2013, 3, 23146.
4
.13. Dihydrolysergol (2). A cooled (0 °C) solution of 18 (3.2 mg, 11.3 µmol) in anhydrous THF (0.2
mL, 0.056 M) was treated dropwise with a solution of LiAlH (56 µL, 1.0 M in THF, 56.3 µmol). After
4
stirring for 30 min at the same temperature, the resulting mixture was quenched with the addition of
MeOH followed by saturated aqueous Rochelle’s salt solution and diluted with CH Cl . The resulting
2
2
biphasic mixture was stirred for 3 h. The layers were separated, and the aqueous layer was extracted
22

ACCEPTED MANUSCRIPT
with CH
2
Cl
2
2 4
. The combined organic layers were dried over anhydrous Na SO , and concentrated in
vacuo. The residue was purified by preparative thin-layer chromatography (Et N pre-treated SiO , 5%
3
2
MeOH–CH Cl ) to provide dihydrolysergol (2, 2.7 mg, 92%) as a white solid identical in all respects
2
2
2
8,29 1
with data reported for authentic material and with a sample of authentic material
: H NMR (600
MHz, CD OD) δ 7.12 (d, J = 8.1 Hz, 1H), 7.04 (t, J = 7.6 Hz, 1H), 6.90 (s, 1H), 6.83 (d, J = 7.1 Hz,
3
1
3
2
1
3
H), 3.58 (dd, J = 10.9, 5.6 Hz, 1H), 3.48 (dd, J = 10.9, 7.0 Hz, 1H), 3.43 (dd, J = 14.5, 4.4 Hz, 1H),
.14 (dt, J = 11.4, 2.8 Hz, 1H), 2.91 (ddd, J = 12.8, 9.9, 3.9 Hz, 1H), 2.48 (s, 3H), 2.07–2.15 (m, 2H),
1
3
.00 (t, J = 11.5 Hz, 1H), 1.10 (q, J = 12.4 Hz, 1H); C NMR (150 MHz, CD
3
OD) δ 135.1, 133.6,
27.4, 123.5, 119.2, 113.4, 111.4, 109.7, 69.1, 66.4, 61.8, 43.6, 41.4, 39.5, 32.0, 27.7; IR (film) υmax
–
1
+
228, 2920, 2849, 1443, 1348, 1226, 1028, 745, 668 cm ; HRMS (ESI) m/z 257.1649 [(M+H) ,
C H N O requires 257.1648].
16
20
2
4
1
.14. Methyl 4-Benzoyl-4,5,5a,6-tetrahydroindolo[4,3-fg]quinoline-9-carboxylate (25). A solution of
2 (7.0 mg, 0.025 mmol) and 4Å molecular sieves (35 mg) in CHCl (0.51 mL, 0.05 M, passed through
3
basic alumina) was treated dropwise with pyrrolidine (10 ꢀL, 0.13 mmol) at 25 °C. After stirring for 10
h at room temperature, the mixture was filtered through a pad of Celite (10% MeOH–CH Cl + 1%
2
2
Et N) and the solvent was removed under reduced pressure. The crude enamine was dried under high
3
vacuum for 5 h. A solution of the enamine 13 in CHCl (0.1 mL, passed through basic alumina) was
3
treated dropwise with 1,2,3-triazine (19, 4.1 mg, 0.12 mmol) in CHCl (0.15 mL). The reaction mixture
3
was stirred for 14 h at 60 °C before the solvent was removed under reduced pressure. The residue was
purified by preparative thin-layer chromatography (SiO , 5% MeOH–CH Cl ) to provide 25 (1.4 mg,
2
2
2
1
1
1
8%) as a white solid: H NMR (500 MHz, CDCl
3
, 50 ºC) δ 8.45 (d, J = 4.9 Hz, 1H), 8.01 (d, J = 7.8 Hz,
H), 7.61 (d, J = 7.3 Hz, 2H), 7.44–7.55 (m, 3H), 7.33 (d, J = 7.6 Hz, 1H), 7.13–7.30 (m, 2H), 4.52 (br
s, 1H), 3.91 (t, J = 10.7 Hz, 1H), 3.73–3.85 (m, 1H), 3.38 (dd, J = 15.2, 6.2 Hz, 1H), 2.98 (t, J = 14.8
23

ACCEPTED MANUSCRIPT
1
3
Hz, 1H); C NMR (150 MHz, CDCl
3
, 50 ºC) δ 168.9, 156.6, 148.3, 141.7, 136.6, 132.4, 130.7, 130.5,
1
29.1, 128.9, 128.7, 127.4, 122.5, 117.8, 116.4, 58.7, 37.1, 35.1; IR (film) υmax 3360, 2921, 2851, 1638,
–1
+
1
470, 1413, 1384, 1085, 779, 698 cm ; HRMS (ESI) m/z 313.1336 [(M+H) , C H N O requires
21 16 2
1
13
3
13.1335]. The H and C NMR spectra of 25 in CDCl at 25 ºC exhibit broadened peaks due to Bz
3
3
4
rotamers.
4
1
.15. (9-Bromo-5a,6-dihydroindolo[4,3-fg]quinolin-4(5H)-yl)(phenyl)methanone (26). A solution of
2 (16.9 mg, 0.0609 mmol) and 4Å molecular sieves (85 mg) in CHCl (1.2 mL, 0.05 M, passed through
3
basic alumina) was treated dropwise with pyrrolidine (22 ꢀL, 0.30 mmol) at 25 °C. After stirring for 10
h at room temperature, the mixture was filtered through a pad of Celite (10% MeOH–CH Cl + 1%
2
2
Et N) and the solvent was removed under reduced pressure. The crude enamine was dried under high
3
vacuum for 5 h. A solution of the enamine 13 in CHCl (0.31 mL, passed through basic alumina) was
3
treated dropwise with 5-bromo-1,2,3-triazine (20, 19.4 mg, 0.122 mmol) in CHCl (0.3 mL). The
3
reaction mixture was stirred for 48 h at 25 °C before the solvent was removed under reduced pressure.
The residue was purified by preparative thin-layer chromatography (SiO
2
2 2
, 5% MeOH–CH Cl ) to
1
provide 26 (3.1 mg, 13%) as a light tan solid: H NMR (500 MHz, CDCl
3
, 50 ºC) δ 8.50 (d, J = 2.2 Hz,
1
H), 8.12 (d, J = 2.2 Hz, 1H), 7.61 (d, J = 7.1 Hz, 2H), 7.44–7.55 (m, 3H), 7.10–7.36 (m, 2H), 4.51 (br
s, 1H), 3.90 (t, J = 10.7 Hz, 1H), 3.70–3.84 (m, 1H), 3.35 (dd, J = 15.4, 6.3 Hz, 1H), 2.90 (t, J = 14.9
1
3
Hz, 1H); C NMR (150 MHz, CDCl , 50 ºC) δ 168.9, 155.0, 149.0, 141.9, 136.4, 133.0, 132.6, 130.7,
3
1
30.6, 129.3, 128.7, 127.4, 119.5, 117.9, 117.2, 58.6, 36.6, 35.0; IR (film) υmax 3345, 2923, 1642, 1419,
–
1
+
1
384, 1077, 787, 667 cm ; HRMS (ESI) m/z 391.0439 [(M+H) , C H BrN O requires 391.0440]. The
21 15 2
1
13
34
3
H and C NMR spectra of 26 in CDCl at 25 ºC exhibit broadened peaks due to Bz rotamers.
4
1
.16. Methyl 4-Benzoyl-4,5,5a,6-tetrahydroindolo[4,3-fg]quinoline-8-carboxylate (27). A solution of
2 (19.3 mg, 0.0696 mmol) and 4Å molecular sieves (~100 mg) in CHCl (1.4 mL, 0.05 M, passed
3
24

ACCEPTED MANUSCRIPT
through basic alumina) was treated dropwise with pyrrolidine (29 ꢀL, 0.35 mmol) at 25 °C. After
stirring for 10 h at room temperature, the mixture was filtered through a pad of Celite (10% MeOH–
CH Cl + 1% Et N) and the solvent was removed under reduced pressure. The crude enamine was dried
2
2
3
under high vacuum for 5 h. A solution of the enamine 13 in CHCl (0.4 mL, passed through basic
3
alumina) was treated dropwise with 4-carbomethoxy-1,2,3-triazine (21, 19.4 mg, 0.139 mmol) in CHCl3
(0.3 mL). The reaction mixture was warmed to 60 °C and stirred for 8 h before the solvent was removed
2
under reduced pressure. The residue was purified by preparative thin-layer chromatography (SiO , 5%
1
MeOH–CH
2
Cl
2
) to provide 27 (9.3 mg, 36%) as a white solid: H NMR (500 MHz, CDCl
3
, 50 ºC) δ 9.03
(d, J = 2.0 Hz, 1H), 8.58 (d, J = 2.0 Hz, 1H), 7.61 (d, J = 7.1 Hz, 2H), 7.45–7.54 (m, 3H), 7.41 (d, J =
7
.7 Hz, 1H), 7.24 (s, 1H), 4.53 (s, 1H), 3.99 (s, 3H), 3.92 (t, J = 10.7 Hz, 1H), 3.72–3.86 (m, 1H), 3.46
1
3
(
dd, J = 15.7, 6.3 Hz, 1H), 3.01 (t, J = 15.1 Hz, 1H); C NMR (125 MHz, CDCl , 50 ºC) δ 168.7, 165.5,
3
1
5
60.8, 149.0, 141.7, 136.3, 132.2, 131.0, 130.6, 129.4, 129.2, 128.6, 128.5, 127.2, 125.1, 117.9, 58.5,
–
1
+
2.2, 37.0, 34.7; IR (film) υmax 3309, 1646, 1428, 1257, 668 cm ; HRMS (ESI) m/z 371.1391 [(M+H) ,
1
13
C H N O requires 371.1390]. The H and C NMR spectra of 27 in CDCl at 25 ºC exhibit
23
18
2
3
3
3
4
broadened peaks due to Bz rotamers.
4
.17. Diethyl 4-Benzoyl-4,5,5a,6-tetrahydroindolo[4,3-fg]quinoline-8,10-dicarboxylate (28). A
solution of 12 (18.1 mg, 0.0653 mmol) and 4Å molecular sieves (~100 mg) in CHCl (1.3 mL, 0.05 M,
3
passed through basic alumina) was treated dropwise with pyrrolidine (27 ꢀL, 0.33 mmol) at 25 °C. After
stirring for 10 h at room temperature, the mixture was filtered through a pad of Celite (10% MeOH–
CH Cl + 1% Et N) and solvent was removed under reduced pressure. The crude enamine was dried
2
2
3
3
under high vacuum for 5 h. A solution of the enamine 13 in CHCl (0.4 mL, passed through basic
alumina) was treated dropwise with 4,6-dicarboethoxy-1,2,3-triazine (22, 29.4 mg, 0.139 mmol) in
CHCl (0.25 mL). The reaction mixture was warmed to 60 °C and stirred for 8 h before the solvent was
3
25

ACCEPTED MANUSCRIPT
removed under reduced pressure. The residue was purified by preparative thin-layer chromatography
1
(
SiO , 5% MeOH–CH Cl ) to provide 28 (7.7 mg, 26%) as a light yellow solid: H NMR (500 MHz,
2
2
2
CDCl 50 ºC) δ 8.12 (s, 1H), 7.61 (d, J = 7.3 Hz, 2H), 7.45–7.55 (m, 3H), 7.10–7.23 (m, 2H), 4.37–4.57
3
,
(m, 5H), 3.91 (t, J = 10.4 Hz, 1H), 3.73–3.85 (m, 1H), 3.58 (dd, J = 15.5, 5.9 Hz, 1H), 2.98 (t, J = 14.8
1
3
Hz, 1H), 1.45 (t, J = 7.1 Hz, 3H), 1.36 (t, J = 7.2 Hz, 3H); C NMR (150 MHz, CDCl , 50 ºC) δ 168.9,
3
1
1
68.0, 164.4, 159.3, 146.4, 141.7, 138.0, 136.3, 134.8, 130.8, 129.5, 128.7, 128.4, 127.4, 123.2, 121.8,
17.8, 62.5, 62.1, 58.0, 38.2, 34.6, 14.3, 13.9; IR (film) υmax 2927, 1723, 1644, 1387, 1244, 1019, 732
–
1
+
1
13
cm ; HRMS (ESI) m/z 457.1759 [(M+H) , C27
24 2 5
H N O requires 457.1758]. The H and C NMR
3
4
spectra of 28 in CDCl at 25 ºC exhibit broadened peaks due to Bz rotamers.
3
4
.18. (5a,6-Dihydroindolo[4,3-fg]quinazolin-4(5H)-yl)(phenyl)methanone (29). A solution of 12 (24
mg, 0.087 mmol) and 4Å molecular sieves (120 mg) in CHCl (1.7 mL, 0.05 M, passed through basic
3
alumina) was treated dropwise with pyrrolidine (36 ꢀL, 0.43 mmol) at 25 °C. After stirring for 10 h at
room temperature, the mixture was filtered through a pad of Celite (10% MeOH–CH
and the solvent was removed under reduced pressure. The crude enamine was dried under high vacuum
for 5 h. A solution of the enamine 13 in CHCl (430 ꢀL, passed through basic alumina) was treated
2 2 3
Cl + 1% Et N)
3
dropwise with 1,3,5-triazine (23, 42 mg, 0.519 mmol) in dioxane (430 ꢀL). The reaction mixture was
stirred for 14 h at 90 °C before the solvent was removed under reduced pressure. The residue was
purified by preparative thin-layer chromatography (SiO , 5% MeOH–CH Cl ) to provide 29 (6.2 mg,
2
2
2
1
2
7
1
3%) as a off white solid: H NMR (500 MHz, CDCl , 50 ºC) δ 9.04 (s, 1H), 9.02 (s, 1H), 7.61 (d, J =
3
.3 Hz, 2H), 7.44–7.55 (m, 3H), 7.39 (d, J = 7.5 Hz, 1H), 7.15–7.30 (m, 1H), 4.53 (br s, 1H), 3.91 (t, J =
1
3
0.7 Hz, 1H), 3.74–3.84 (m, 1H), 3.33 (dd, J = 15.9, 6.4 Hz, 1H), 2.96 (t, J = 15.1 Hz, 1H); C NMR
(
150 MHz, CDCl
3
, 50 ºC) δ 168.9, 164.8, 157.6, 150.8, 142.0, 136.3, 132.1, 130.8, 129.6, 128.7, 127.5,
–
1
1
27.4, 126.8, 117.4, 58.6, 36.2, 34.5; IR (film) υmax 2925, 1723, 1643, 1383, 1247, 787, 667 cm ;
26

ACCEPTED MANUSCRIPT
+
1
13
HRMS (ESI) m/z 314.1287 [(M+H) , C20
H
15
N
3
O requires 314.1288]. The H and C NMR spectra of
3
4
2
4
9 in CDCl at 25 ºC exhibit broadened peaks due to Bz rotamers.
3
.19. Dimethyl 4-Benzoyl-4,5,5a,6-tetrahydroindolo[4,3-fg]phthalazine-7,10-dicarboxylate (30). A
solution of 12 (11.4 mg, 0.0411 mmol) and 4Å molecular sieves (55 mg) in CHCl (0.8 mL, 0.05 M,
3
passed through basic alumina) was treated dropwise with pyrrolidine (17 ꢀL, 0.21 mmol) at 25 °C. After
stirring for 10 h at room temperature, the mixture was filtered through a pad of Celite (10% MeOH–
2 2 3
CH Cl + 1% Et N) and the solvent was removed under reduced pressure. The crude enamine was dried
under high vacuum for 5 h. A solution of the enamine in CHCl (0.4 mL, passed through basic alumina)
3
was treated dropwise with 3,6-dicarbomethoxy-1,2,4,5-tetrazine (24, 16.3 mg, 0.0822 mmol) in CHCl3
(0.41 mL). The reaction mixture was stirred for 3 h at 25 °C before the solvent was removed under
reduced pressure. The residue was purified by preparative thin-layer chromatography (SiO , 5% MeOH–
2
1
CH Cl ) to provide 30 (12.4 mg, 70%) as a white solid: H NMR (600 MHz, CDCl , 25 ºC) δ 7.60 (d, J
2
2
3
=
7.2 Hz, 2H), 7.53 (t, J = 7.4 Hz, 1H), 7.47 (t, J = 7.4 Hz, 2H), 7.03–7.21 (m, 2H), 4.53 (s, 1H), 4.06 (s,
3
1
1
3
H), 4.05 (s, 3H), 3.93 (t, J = 10.6 Hz, 1H), 3.67–3.77 (m, 1H), 3.58–3.67 (m, 1H), 2.73 (dd, J = 16.4,
13
4.4 Hz, 1H); C NMR (150 MHz, CDCl
3
, 50 ºC) δ 168.8, 166.4, 165.1, 152.9, 150.9, 142.1, 135.9,
35.0, 131.1, 131.0, 129.5, 128.8, 127.4, 125.2, 120.3, 118.9, 58.0, 53.4, 53.3, 33.4, 29.0; IR (film) υmax
–
1
+
446, 2953, 1732, 1644, 1455, 1387, 1237, 1155, 730 cm ; HRMS (ESI) m/z 430.1397 [(M+H) ,
1
13
C H N O requires 430.1397]. The H and C NMR spectra of 30 in CDCl at 25 ºC exhibit
24
19
3
5
3
3
4
broadened peaks due to Bz rotamers.
4
.20. Dimethyl 4-Benzoyl-5,5a,6,8-tetrahydro-4H-isoindolo[6,5,4-cd]indole-7,9-dicarboxylate (31).
A solution of 12 (4.5 mg, 0.011 mmol) in acetic acid (0.2 mL, 0.05 M) was treated with zinc dust (34.3
mg, 0.525 mmol) in a portion at 25 °C. After stirring for 22 h at the same temperature, the resulting
mixture was filtered through a short pad of Celite and the solvent was removed under reduced pressure.
27

ACCEPTED MANUSCRIPT
2 2 2
The residue was purified by preparative thin-layer chromatography (SiO , 5% MeOH–CH Cl ) to
1
provide 31 (3.4 mg, 78%) as a white solid: H NMR (500 MHz, CDCl , 50 ºC) δ 9.53 (s, 1H), 8.01 (d, J
3
=
7.8 Hz, 1H), 7.60 (d, J = 7.2 Hz, 2H), 7.48 (dq, J = 14.5, 7.3 Hz, 3H), 7.16 (br s, 1H), 4.48 (br s, 1H),
3
2
1
.97 (s, 3H), 3.93 (s, 3H), 3.85 (t, J = 10.7 Hz, 1H), 3.71 (dd, J = 15.3, 6.7 Hz, 1H), 3.52–3.65 (m, 1H),
13
.46 (t, J = 14.5 Hz, 1H); C NMR (150 MHz, CDCl , 50 ºC) δ 168.7, 160.8, 160.4, 141.1, 136.7, 133.0,
3
30.5, 128.6, 128.4, 128.2, 127.7, 127.4, 125.8, 121.6, 120.8, 120.2, 115.7, 57.8, 52.0, 51.8, 36.3, 26.1;
–
1
IR (film) υmax 3325, 1699, 1635, 1472, 1395, 1256, 1013, 668 cm ; HRMS (ESI) m/z 417.1446
+
1
13
[
20 2 5 3
(M+H) , C24H N O requires 417.1445]. The H and C NMR spectra of 31 in CDCl at 25 ºC exhibit
3
4
broadened peaks due to Bz rotamers.
Acknowledgements
We gratefully acknowledge the financial support of the National Institutes of Health (CA042056 and
CA041101) and wish to thank Curtis Moore (UCSD) for the X-ray structure of 17.
Supplementary data
1
13
Copies of the H and C NMR spectra of all synthetic intermediates and final products are provided.
References and notes
1
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3.
9
28

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1
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1
4. (a) Boger, D. L. Tetrahedron 1983, 39, 2869. (b) Boger, D. L. Chem. Rev. 1986, 86, 781. (c) Boger,
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1
29