Formal total synthesis of (+)-lysergic acid via zinc(II)-mediated regioselective ring-opening reduction of 2-alkynyl-3-indolyloxirane

Article abstract of DOI:10.1021/jo2008324

Asymmetric formal synthesis of (+)-lysergic acid was achieved with a reductive ring-opening reaction of chiral 2-alkynyl-3-indolyloxirane with NaBH₃CN as the key step. With Zn(OTf)₂ as an additive, the ring-opening reaction proceeded regioselectively at the 3-position to give the corresponding propargyl alcohol, which was a precursor of the allenic amide for palladium-catalyzed domino cyclization to construct the ergot alkaloid core structure.

Full text of DOI:10.1021/jo2008324

NOTE
pubs.acs.org/joc
Formal Total Synthesis of (þ)-Lysergic Acid via Zinc(II)-Mediated
Regioselective Ring-Opening Reduction of 2-Alkynyl-3-indolyloxirane
Akira Iwata, Shinsuke Inuki, Shinya Oishi, Nobutaka Fujii,* and Hiroaki Ohno*
Graduate School of Pharmaceutical Sciences, Kyoto University, Sakyo-ku, Kyoto 606-8501, Japan
S Supporting Information
b
ABSTRACT: Asymmetric formal synthesis of (þ)-lysergic acid
was achieved with a reductive ring-opening reaction of chiral
2-alkynyl-3-indolyloxirane with NaBH3CN as the key step.
With Zn(OTf)2 as an additive, the ring-opening reaction
proceeded regioselectively at the 3-position to give the corre-
sponding propargyl alcohol, which was a precursor of the allenic
amide for palladium-catalyzed domino cyclization to construct the ergot alkaloid core structure.
he family of ergot alkaloids produced by the fungus Claviceps
purpurea is one of the most intriguing classes of natural
T
products because of their broad biological and pharmacological
activities.1,2 Furthermore, their synthetic derivatives, such as
pergolide or bromocriptine, are used clinically as antiprolactin
and anti-Parkinson’s disease drugs. Ergot alkaloids, particularly
lysergic acid, have a unique tetracyclic skeleton containing a [cd]-
fused indole, Δ9,10-double bond and chiral centers at C5 and C8.
The biological importance and structural features of ergot
alkaloids have stimulated research in the synthetic community,
and a number of total syntheses have been reported to date.3
However, the only enantioselective syntheses of lysergic acid (1)
have been by Szꢀantay in 20044 and Fukuyama in 2009
(Figure 1).5,6
Figure 1. Indole alkaloids of the ergot family and synthetic derivatives.
of indolyl-substituted alkynyloxiranes is unprecedented, no in-
formation was available for appropriate reaction conditions to
control the regio- and stereoselectivities. Herein we describe a
regioselective reductive ring-opening reaction of alkynyloxirane
5 with NaBH3CN in the presence of Zn(OTf)2 and the asym-
metric formal total synthesis of lysergic acid. Mechanistic con-
sideration of the reaction is also presented.
Retrosynthetic analysis of the tetracyclic indole 2 is illustrated
in Scheme 1. The chiral propargyl alcohol 4, which is the
precursor of the allenic amide 3 for stereoselective construction
of 2, will be obtained by regioselective reduction of the oxirane 5
via path A. Oxirane 5 can be prepared by asymmetric/stereo-
selective epoxidation of enyne 6. It is well-known that (E)-enynes
generally show sufficient asymmetric induction in Shi’s asym-
metric epoxidation.13 However, our preliminary investigation
showed that stereoselective preparation of the (E)-enyne was
difficult in this case.14 Therefore, we planned to prepare enyne 6
with a (Z)-configuration by a cross-coupling reaction between
vinyl bromide 7 and the known enantiopure alkyne 8.7 Stereo-
selective preparation of (Z)-vinyl bromide 7 would be achieved
by Uenishi’s method.15
Recently, we reported the enantioselective total syntheses of
(þ)-lysergic acid (1) and related ergot alkaloids using a palla-
dium-catalyzed domino cyclization of chiral allenic tosylamides 3
bearing a bromoindolyl group (Scheme 1).7 This domino
reaction directly provides the tetracyclic indole 2, which is a
common intermediate for ergot alkaloid synthesis. In this
synthetic route, the requisite allenic tosylamide 3 for the domino
cyclization was prepared by method of Myers from the propargyl
alcohol 4,8 which in turn was obtained by the Nozakiꢀ
HiyamaꢀKishi (NHK) reaction of an indolylacetaldehyde deri-
vative with an iodoalkyne. The stereogenic center of 4 at the
propargylic position, which was required for chiral allene forma-
tion, was created by a two-step DessꢀMartin oxidation and (R)-
Alpine-borane reduction.
In this study, a novel synthesis of the allenic tosylamide 3 was
planned by reductive ring-opening reaction of the chiral oxirane 5.
This new synthetic route omits the redundant oxidationꢀ
asymmetric reduction sequence of the previous synthesis. The
challenge was to control the regioselectivity of the ring-opening
reaction because 2-alkynyloxirane 5 bearing an indolyl group at
the 3-position has three reactive carbons, which are A (SN2 at the
indolyl position),9 B (SN2 at the propargylic position),10 and C
(SN20)11 (Scheme 1).12 Because the reductive ring-opening reaction
The synthesis was started from commercially available 4-bro-
moindole 9 (Scheme 2). According to the literature procedure,16
Received: April 23, 2011
Published: May 20, 2011
r
2011 American Chemical Society
5506
dx.doi.org/10.1021/jo2008324 J. Org. Chem. 2011, 76, 5506–5512
|

The Journal of Organic Chemistry
NOTE
Scheme 1. Retrosynthetic Analysis of the Tetracyclic
Indole 2
Scheme 2. Synthesis of 2-Alkynyl-3-indolyloxirane 14
Table 1. Epoxidation of Enyne 12a
VilsmeierꢀHaack reaction of 9 followed by protection of the
indole nitrogen gave aldehyde 10. Treatment of aldehyde 10 with
CBr4 and PPh3 followed by palladium-catalyzed selective hydro-
genolysis of the bromo group at the trans position with Bu3SnH
(Uenishi’s method)15 gave the (Z)-vinyl bromide 7 in good yield.
The existence of the bromo substituent at the indole 4 position
was not problematic. Sonogashira coupling of 7 with the known
alkyne 8 (98% ee), prepared by the same five-step sequence from
(S)-Garner’s aldehyde via palladium/indium-mediated reductive
coupling of an ethynylaziridine with formaldehyde,17 afforded
(Z)-enyne 12, which is the precursor of the alkynyloxirane.
Next, asymmetric epoxidation of enyne 12 was investigated
(Table 1). The reaction of 12 with Shi’s catalyst 15 under the
established conditions18 at 0 °C provided the desired chiral
oxirane 13 in a low yield (35%, dr = 82:18, entry 1). Considering
the poor solubility of enyne 12, the volume of solvent in the
reaction and the amount of the reagents (n-Bu4NHSO4 and
Oxone) were increased to obtain 13 in 77% yield (dr = 82:18,
entry 2). Decreasing the temperature of the reaction (ꢀ10 °C)
slightly decreased the yield (62%, dr = 82:18, entry 3). Unfortu-
nately, Shi’s ketone 16,19 which is widely used as a catalyst for
asymmetric epoxidation of (Z)-alkenes, was not effective in this
case (25% yield, dr = 50:50, entry 4). It should be noted that
epoxidation using m-CPBA was not successful and led to
decomposition of the substrate 12 (entry 5). When the 82:18
diastereomixture 13 obtained in entry 2 (the ratio determined by
1H NMR and HPLC analysis) was used, the oxirane 14 for the
ring-opening reaction was prepared by silylation with TIPSOTf
(Scheme 2).
oxidant
Oxone n-Bu4NHSO4 temp yieldb recov
entry chiral cat. (equiv)
(equiv)
(°C) (%) (%)
drc
1
2
3
4
5
15
15
15
16
2
3
3
3
0.04
0.4
0
0
35
77
62
25
48 82:18
17 82:18
30 82:18
34 50:50
0.4
ꢀ10
0
0.4
m-CPBA (3 equiv)
rt NDd
a The reactions were carried out with a substrate concentration of 100 mM
(entry 1) or 50 mM (entries 2ꢀ4), chiral catalyst 15 or 16 (50 mol %),
Oxone in aqueous Na2(EDTA) (4 ꢁ 10ꢀ4 M), 1.47 M aqueous KOH
and n-Bu4NHSO4 in CH3CNꢀDMM and K2CO3ꢀAcOH buffer.
b Isolated yield. c Determined by 1H NMR analysis. d ND = Not detected.
Oxone = 2KHSO5 KHSO4 K2SO4; DMM = dimethoxymethane.
3
3
recovery of the starting material (Table 1, entry 1). We then
turned our attention to the Lewis acid-mediated reaction based
on the known reductive ring-opening reaction of oxiranes20
including 2,3-diaryl-substituted ones.21 We expected that an
oxophilic Lewis acid would facilitate regioselective ring cleavage
of the oxirane at the 3-position with the assistance of the electron-
donating indole ring and produce the desired product 17
by hydride reduction of the resulting indolium intermediate.
The reductive ring-opening reaction was then investigated
using an 82:18 diastereomixture of 14 because of the difficulty in
separating each of the diastereomers resulting from epoxidation.
Reaction of oxirane 14 with various reducing agents such as
NaBH4 and DIBAL gave a complex mixture of unidentified
products without producing the desired propargyl alcohol 17.
Oxirane 14 was inert to NaBH3CN reduction leading to 79%
5507
dx.doi.org/10.1021/jo2008324 |J. Org. Chem. 2011, 76, 5506–5512

The Journal of Organic Chemistry
NOTE
Among the several Lewis acids investigated, Me2AlCl showed
clean conversion to produce 17 regioselectively in 87% yield.
However, the propargylic position was almost completely epi-
merized (dr = 48:52, entry 4). Fortunately, use of ZnCl2 provided
the desired alcohol 17 in 49% yield with only a slight decrease in
the diastereomeric ratio (78:22, entry 5). Further screening of
other zinc(II) salts (entries 6ꢀ9) revealed that Zn(OTf)2 was
the most effective and produced alcohol 17 in 55% yield without
promoting any epimerization at the propargylic position (dr =
82:18, entry 8). In all cases examined, neither the SN2 product at
the 2-position nor SN20 product was isolated. By contrast,
formation of the double bond isomer 18 and/or the ketone 19
occurred (entries 5ꢀ9).
produced by hydride reduction of 20 at the indole 2 position
(path A), partly supports the intermediacy of 20 in this reaction.
The desired alcohol 17, the major product in the Zn(OTf)2-
mediated reduction, results from hydride reduction at the indolyl
position (path B). Alternatively, a 1,2-hydride shift from 20 (path C)
followed by reduction of the resulting ketone 19 (path D and D0)
under the reductive conditions can explain the formation
of 17 that accompanies complete epimerization when using
Me2AlCl (entry 4). As shown in entry 8 (Table 2), the Zn-
(OTf)2-mediated reaction stereoselectively produced the desired
product 17 and a considerable amount of the ketone 19. This
result suggests that the activation ability of Zn(OTf)2 toward
ketone reduction (path D and D0) is relatively low compared to
that of Me2AlCl.
The above discussions were supported by the following
experiments (Scheme 4). On treatment of ketone 19 under the
Zn(OTf)2-mediated reduction conditions [NaBH3CN, Zn-
(OTf)2 in THF at 60 °C], formation of the alcohols 17 and
epi-17 was not observed (eq 1). The reaction of ketone 19 under
the Me2AlCl-mediated reduction conditions afforded the alco-
hols 17 and epi-17 in an almost 1:1 diastereomixture (eq 2).
Furthermore, reaction of 17 (dr = 78:22) in the presence of 19
(1 equiv) with NaBH3CN and Me2AlCl gave a 62:38 diastereo-
mixture of 17 (eq 3), which was the predicted ratio considering
the reduction of 19. This confirmed that the Meerweinꢀ
PonndorfꢀVerley (MPV)/Oppenauer redox process22 between
17 and 19 was not the major pathway for epimerization in the
presence of Me2AlCl (Table 2, entry 4). In the absence of
NaBH3CN, no epimerization of 17 was observed in the reaction
after 2 h (eq 4).23
A rationale for the observed results of the reductive ring-
opening reaction is depicted in Scheme 3. Lewis acid activation of
the oxirane 14 induces formation of the indolium intermediate
20. Isolation of the double bond isomer 18, which would be
Scheme 3. Pathways for the Reductive Ring-Opening
Reaction
Finally, the asymmetric formal total synthesis of (þ)-lysergic
acid (1) was completed in two steps from the propargyl alcohol
17 (dr = 82:18) (Scheme 5). The alcohol 17 was stereoselec-
tively transformed into the allene 3a using the modified proce-
dure for Myers allene formation.24 Subsequent cleavage of the
silyl group of 3a gave the known allenic tosylamide 3b (dr =
82:18).7 As we previously reported, the tetracyclic indole 2a was
Table 2. Reductive Ring-Opening Reaction of 2-Alkynyl-3-indolyloxirane 14a
yield (%)
entry
Lewis acid
temp (°C)
time (h)
17b (dr)c
18b
19d
recov (%)
79
1
2
none
rt
40
2
28
0.5
0.25
2.5
2
Sm(OTf)3
In(OTf)3
Me2AlCl
ZnCl2
16 (57:43)
13 (79:21)
87 (48:52)
49 (78:22)
22 (80:20)
22 (70:30)
55 (82:18)
45 (78:22)
43
34
3
60
2
4
60
5
60
10
10
7
15
47
20
52
6
ZnBr2
60
52
7
ZnI2
60
2
8
9e
Zn(OTf)2
Zn(OTf)2
60
2
trace
100
0.5
a The reactions were carried out with substrate 14, NaBH3CN (3 equiv), and Lewis acid (3 equiv) in THF. b Calculated from the combined isolated
yields (17 and 18) and HPLC analysis (Chiralcel OD-H). c Determined by HPLC analysis (Chiralcel OD-H). d Isolated yields. e Reaction was carried out
in dioxane.
5508
dx.doi.org/10.1021/jo2008324 |J. Org. Chem. 2011, 76, 5506–5512

The Journal of Organic Chemistry
NOTE
Scheme 4. Supporting Experiments for the Proposed
Reaction Pathways
The compounds 87 and 1025 were synthesized according to the reported
procedures.
4-Bromo-3-(2,2-dibromovinyl)-1-tosyl-1H-indole (11). To
a stirred mixture of PPh3 (25.0 g, 95.4 mmol) in CH2Cl2 (100 mL) was
added CBr4 (15.8 g, 47.7 mmol) at ꢀ20 °C under argon. After the
mixture was stirred for 15 min at this temperature, a solution of aldehyde
10 (6.00 g, 15.9 mmol) in CH2Cl2 (40 mL) was added at ꢀ78 °C. After
being stirred for 10 min at this temperature, the mixture was allowed to
warm to room temperature and stirred for a further 2.5 h at this
temperature. Concentration under reduced pressure gave an oily
residue, which was purified by flash chromatography over silica gel with
n-hexaneꢀEtOAc (4:1) to give 11 as a pale yellow solid (7.66 g, 95%
yield). Recrystallization from n-hexaneꢀEtOAc gave pure 11 as color-
less crystals: mp 152ꢀ153 °C; IR (neat) 1368 (NSO2), 1163 (NSO2);
1H NMR (400 MHz, CDCl3) δ 2.35 (s, 3H), 7.15 (dd, J = 8.0, 8.0 Hz,
1H), 7.25 (d, J = 8.0 Hz, 2H), 7.40 (d, J = 8.0 Hz, 1H), 7.76 (d, J = 8.0 Hz,
2H), 7.96 (d, J = 8.0 Hz, 1H), 8.10 (d, J = 1.0 Hz, 1H), 8.11 (d, J = 1.0 Hz,
1H); 13C NMR (100 MHz, CDCl3) δ 21.6, 90.5, 112.9, 114.2, 117.9,
125.9, 126.9, 127.0 (2C), 127.4, 128.3, 128.8, 130.1 (2C), 134.5, 135.4,
145.7. Anal. Calcd for C17H12Br3NO2S: C, 38.23; H, 2.26; N, 2.62.
Found: C, 38.03; H, 2.17; N, 2.50.
Scheme 5. Formal Total Synthesis of Lysergic Acida
(Z)-4-Bromo-3-(2-bromovinyl)-1-tosyl-1H-indole (7). To a
stirred mixture of 11 (1.50 g, 2.81 mmol) in toluene (28 mL) were added
Pd(PPh3)4 (130 mg, 0.110 mmol; 4 mol %) and Bu3SnH (0.831 mL,
3.09 mmol) at room temperature under argon, and the mixture was
stirred for 8.5 h at this temperature. The mixture was concentrated under
reduced pressure to give a yellow oil, which was purified by flash
chromatography over silica gel with n-hexaneꢀEtOAc (20:1) to give 7
as a white solid. Recrystallization from n-hexaneꢀCHCl3 gave pure 7
(1.05 g, 82%) as colorless crystals: mp 136ꢀ137 °C; IR (neat) 1373
(NSO2), 1172 (NSO2); 1H NMR (500 MHz, CDCl3) δ 2.34 (s, 3H),
6.54 (d, J = 7.4 Hz, 1H), 7.14 (dd, J = 8.0, 8.0 Hz, 1H), 7.24 (d, J = 8.0 Hz,
2H), 7.39 (d, J = 8.0 Hz, 1H), 7.79 (d, J = 8.0 Hz, 2H), 7.87 (d, J = 7.4 Hz,
1H), 7.98 (d, J = 8.0 Hz, 1H), 8.35 (s, 1H); 13C NMR (125 MHz,
CDCl3) δ 21.6, 107.5, 112.8, 114.3, 116.9, 124.1, 125.6, 127.0 (2C),
127.2, 127.8, 128.3, 130.0 (2C), 134.6, 135.5, 145.5. Anal. Calcd for
C17H13Br2NO2S: C, 44.86; H, 2.88; N, 3.08. Found: C, 44.73; H, 3.00;
N, 2.98.
a Abbreviations: IPNBSH = N-isopropylidene-N0-2-nitrobenzenesulfo-
nyl hydrazine; TFE = trifluoroethanol.
obtained from 3b in 87% yield with an 87:13 selectivity via the
palladium-catalyzed domino cyclization of the allenic tosylamide
3b. The reported six-step sequence of reactions, including
separation of the diastereomers after oxidation and esterification,
would provide (þ)-lysergic acid (1).
(S,Z)-N-[6-(4-Bromo-1-tosyl-1H-indol-3-yl)-2-(hydroxyme-
thyl)hex-5-en-3-yn-1-yl]-4-methylbenzenesulfonamide (12).
To a stirred mixture of 7 (800 mg, 1.76 mmol) in a mixed solvent of
(i-Pr)2NH (16 mL) and THF (16 mL) were added 8 (608 mg,
2.40 mmol), PdCl2(CH3CN)2 (22.9 mg, 0.0883 mmol), and CuI (33.6 mg,
0.176 mmol) at room temperature under argon, and the mixture was
stirred for 3 h at this temperature. The mixture was concentrated under
reduced pressure to give a yellow amorphous solid, which was purified by
flash chromatography over silica gel with n-hexaneꢀEtOAc (2:1) to give
In summary, a novel method for regio- and stereoselective
construction of propargyl alcohol was developed based on a
regioselective ring-opening reaction of 2-alkynyl-3-indolyloxir-
ane at the 3-position. Addition of Zn(OTf)2 was important for
promotion of the oxirane cleavage at the 3-position and suppres-
sion of epimerization at the propargylic position. With this
reduction as the key step, asymmetric formal total synthesis of
(þ)-lysergic acid was achieved.
12 as a yellow amorphous solid (913 mg, 83% yield): [R]29 ꢀ41.7
D
(c 0.59, CHCl3); IR (neat) 3323 (OH), 2248 (CtC), 1415 (NSO2),
1372 (NSO2), 1173 (NSO2), 1157 (NSO2); 1H NMR (500 MHz,
CDCl3) δ 2.36 (s, 3H), 2.40 (s, 3H), 2.59 (dd, J = 6.3, 6.3 Hz, 1H),
3.03ꢀ3.09 (m, 1H), 3.25ꢀ3.36 (m, 2H), 3.85ꢀ3.96 (m, 2H), 5.20 (dd,
J = 6.7, 6.7 Hz, 1H), 5.71 (dd, J = 11.7, 2.1 Hz, 1H), 7.14 (dd, J = 8.0, 8.0
Hz, 1H), 7.27 (d, J = 8.0 Hz, 2H), 7.29 (d, J = 8.0 Hz, 2H), 7.42 (d, J = 8.0
Hz, 1H), 7.66 (d, J = 11.7 Hz, 1H), 7.77ꢀ7.81 (m, 4H), 7.94 (d, J = 8.0
Hz, 1H), 8.66 (s, 1H); 13C NMR (125 MHz, CDCl3) δ 21.5, 21.6, 36.4,
43.4, 62.3, 83.2, 95.4, 106.3, 112.7, 114.5, 118.9, 125.5, 126.8, 127.0 (2C),
127.1 (2C), 127.5, 128.5, 129.3, 129.8 (2C), 130.2 (2C), 134.4, 135.5,
136.8, 143.6, 145.8. Anal. Calcd for C29H27BrN2O5S2: C, 55.50; H, 4.34;
N, 4.46. Found: C, 55.37; H, 4.46; N, 4.26.
’ EXPERIMENTAL SECTION
General Methods. All moisture-sensitive reactions were per-
formed using syringe-septum cap techniques under an argon atmo-
sphere, and all glassware was dried in an oven at 80 °C for 2 h prior to
use. Reactions at ꢀ78 °C employed a CO2ꢀMeOH bath. Melting
points were measured by a hot-stage melting point apparatus
(uncorrected). Chemical shifts are reported in δ (ppm) relative to
TMS in CDCl3 as internal standard (1H NMR) or the residual CHCl3
signal (13C NMR). 1H NMR spectra are tabulated as follows: chemical
shift, multiplicity (b = broad, s = singlet, d = doublet, t = triplet, q =
quartet, m = multiplet), number of protons, and coupling constant(s).
N-[(S)-4-[(2S,3R)-(4-Bromo-1-tosyl-1H-indol-3-yl)oxiran-
2-yl]-2-(hydroxymethyl)but-3-yn-1-yl]-4-methylbenzene-
sulfonamide (13). All glassware used for the epoxidation reaction
was carefully washed and coated with 0.1 M potassium hydroxide
5509
dx.doi.org/10.1021/jo2008324 |J. Org. Chem. 2011, 76, 5506–5512

The Journal of Organic Chemistry
NOTE
2-propanolic solution. To a stirred mixture of 12 (50 mg, 0.080 mmol),
the chiral ketone 15 (10.3 mg, 0.040 mmol), and n-Bu4NHSO4 (11 mg,
0.032 mmol) in CH3CN/DMM (1.6 mL, 1:2) was added buffer solution
(0.1 M K2CO3ꢀAcOH in water; 800 μL) at room temperature under
argon. After the mixture was cooled to 0 °C, solutions of Oxone
(147.6 mg, 0.24 mmol) in 4 ꢁ 10ꢀ4 M aqueous Na2(EDTA) (480 μL)
and 1.47 M aqueous KOH (408 μL) were added dropwise to the reaction
mixture separately and simultaneously over a period of 1.5 h. The
mixture was stirred for 22 h at this temperature. The mixture was
concentrated under reduced pressure to give a white residue, which was
dissolved in EtOAc, washed with water and brine, and dried over
MgSO4. The filtrate was concentrated under reduced pressure to give
an oily residue, which was purified by flash chromatography over silica
gel with n-hexaneꢀEtOAc (2:1) to give 13 as a white amorphous solid
NaHCO3. The whole was extracted with EtOAc. The extract was washed
with saturated NaHCO3, water, and brine and dried over MgSO4. The
filtrate was concentrated under reduced pressure to give an oily residue,
which was purified by flash chromatography over silica gel with
n-hexaneꢀEtOAc (4:1) to give 17 (11 mg, 55% yield, dr = 82:18) and
19 (3.9 mg, 20% yield) (entry 8). When the reaction of 14 (20 mg, 0.025
mmol, dr = 82:18) was carried out with ZnCl2 (1.00 M solution in Et2O;
75 μL, 0.075 mmol) in place of Zn(OTf)2, a isomeric mixture of 17 and
18 (11.8 mg, 59% yield, dr = 78:22) and 19 (1.5 mg, 7% yield) were
obtained (entry 5). Compound 18 was isolated by HPLC [a Cosmosil
5C18-ARII column (20 ꢁ 250 mm, Nacalai Tesque, Inc., Kyoto, Japan),
254 nm, MeCN/H2O = 90:10, 10 mL/min; for analytical HPLC: a
Cosmosil 5C18-ARII column (4.6 ꢁ 250 mm, Nacalai Tesque, Inc.,
Kyoto, Japan), 254 nm, MeCN/H2O = 90:10, 1 mL/min, t = 11.05 min].
Compound 17: white amorphous solid; [R]29D ꢀ23.3 [c 0.64 (single
isomer), CHCl3]; IR (neat) 3310 (OH), 1413 (NSO2), 1375 (NSO2),
1173 (NSO2), 1159 (NSO2); 1H NMR (500 MHz, CDCl3) δ
1.00ꢀ1.08 (m, 21H), 1.91ꢀ2.00 (m, 1H), 2.35 (s, 3H), 2.41 (s, 3H),
2.69ꢀ2.75 (m, 1H), 3.11 (ddd, J = 12.0, 6.8, 5.7 Hz, 1H), 3.20 (ddd, J =
12.0, 5.7, 5.7 Hz, 1H), 3.30 (dd, J = 15.2, 6.9 Hz, 1H), 3.33 (dd, J = 15.2,
7.2 Hz, 1H), 3.58 (dd, J = 10.0, 8.6 Hz, 1H), 3.77 (dd, J = 10.0, 4.3 Hz,
1H), 4.65ꢀ4.70 (m, 1H), 5.15 (dd, J = 5.7, 5.7 Hz, 1H), 7.12 (dd, J = 8.0,
8.0 Hz, 1H), 7.24 (d, J = 8.0 Hz, 2H), 7.29 (d, J = 8.0 Hz, 2H), 7.37 (d, J =
8.0 Hz, 1H), 7.57 (s, 1H), 7.74 (d, J = 8.0 Hz, 2H), 7.75 (d, J = 8.0 Hz,
2H), 7.96 (d, J = 8.0 Hz, 1H); 13C NMR (125 MHz, CDCl3) δ 11.8
(3C), 11.9 (6C), 21.5, 21.6, 34.6, 34.9, 45.1, 62.4, 64.8, 83.1, 84.4, 112.9,
114.3, 117.7, 125.4, 126.9 (3C), 127.1 (2C), 127.9, 128.6, 129.7 (2C),
130.0 (2C), 134.9, 136.4, 137.0, 143.4, 145.3; HRMS (FAB) calcd
C38H48BrN2O6S2Si (M ꢀ H)ꢀ 799.1912, found (M ꢀ H)ꢀ 799.1910.
(39.4 mg, 77% yield, dr = 82:18): [R]27 ꢀ17.7 [c 0.44 (dr = 82:18),
D
CHCl3]; IR (neat) 3311 (OH), 2253 (CtC), 1415 (NSO2), 1373
(NSO2), 1173 (NSO2), 1158 (NSO2); 1H NMR (500 MHz, CDCl3) δ
2.16 (dd, J = 6.7, 6.7 Hz, 1H), 2.36 (s, 3H), 2.43 (s, 3H), 2.46ꢀ2.52 (m,
1H), 2.76ꢀ2.82 (m, 1H), 2.95ꢀ3.03 (m, 1H), 3.41ꢀ3.52 (m, 2H), 3.78
(d, J = 3.9 Hz, 1H), 4.63 (dd, J = 6.8, 6.8 Hz, 1H), 4.72 (d, J = 3.9 Hz, 1H),
7.17 (dd, J = 7.9, 7.9 Hz, 1H), 7.25 (d, J = 8.4 Hz, 2H), 7.30 (d, J = 8.4 Hz,
2H), 7.41 (d, J = 7.9 Hz, 1H), 7.66ꢀ7.70 (m, 3H), 7.78 (d, J = 8.4 Hz,
2H), 7.99 (d, J = 7.9 Hz, 1H); 13C NMR (125 MHz, CDCl3) δ 21.5, 21.6,
34.9, 42.9, 48.6, 53.1, 61.8, 78.7, 83.7, 112.9, 113.7, 117.2, 125.8, 126.2,
127.0 (4C), 127.5, 128.6, 129.8 (2C), 130.1 (2C), 134.6, 135.9, 136.8,
143.6, 145.8; HRMS (FAB) calcd C29H26BrN2O6S2 (M ꢀ H)ꢀ
641.0421, found (M ꢀ H)ꢀ 641.0420.
N-[(S)-4-[(2S,3R)-3-(4-Bromo-1-tosyl-1H-indol-3-yl)oxiran-
2-yl]-2-[(triisopropylsilyloxy)methyl]but-3-yn-1-yl]-4-meth-
ylbenzenesulfonamide (14). To a stirred mixture of 13 (50 mg,
0.078 mmol) in CH2Cl2 (218 μL) were added 2,6-lutidine (25.7 μL,
0.234 mmol) and TIPSOTf (31.4 μL, 0.117 mmol) at 0 °C. The mixture
was stirred for 3.5 h at this temperature and quenched by addition of
saturated NaHCO3. The whole was extracted with EtOAc. The extract
was washed with saturated NaHCO3 and brine and dried over MgSO4.
The filtrate was concentrated under reduced pressure to give an oily
residue, which was purified by flash chromatography over silica gel with
n-hexaneꢀEtOAc (4:1) to give 14 as a white amorphous solid (44.5 mg,
73% yield, dr = 82:18): [R]27D ꢀ32.6 [c 0.76 (dr = 82:18), CHCl3]; IR
(neat) 3286 (OH), 1416 (NSO2), 1377 (NSO2), 1175 (NSO2), 1162
Compound 18: yellow amorphous solid; [R]27 ꢀ34.7 (c 0.44,
D
CHCl3); IR (neat) 3297 (OH), 1416 (NSO2), 1362 (NSO2), 1163
1
(NSO2), 1093 (NSO2); H NMR (500 MHz, CDCl3) δ 0.99ꢀ1.08
(m, 21H), 1.57ꢀ1.72 (br m, 1H), 2.37 (s, 3H), 2.41 (s, 3H), 2.73ꢀ2.75
(m, 1H), 3.10ꢀ3.18 (m, 1H), 3.21ꢀ3.29 (m, 1H), 3.64 (dd, J = 9.9, 8.2
Hz, 1H), 3.80 (dd, J = 9.9, 4.4 Hz, 1H), 4.57ꢀ4.68 (m, 2H), 4.94 (d, J =
7.4 Hz, 1H), 5.32 (dd, J = 6.2, 6.2 Hz, 1H), 6.85ꢀ6.86 (m, 1H), 7.07 (dd,
J = 8.0, 8.0 Hz, 1H), 7.17 (d, J = 8.0 Hz, 1H), 7.25 (d, J = 8.0 Hz, 2H),
7.28 (d, J = 8.0 Hz, 2H), 7.67ꢀ7.71 (m, 3H), 7.75 (d, J = 8.0 Hz, 2H);
13C NMR (125 MHz, CDCl3) δ 11.8 (3C), 17.9 (6C), 21.5 (2C), 34.9,
44.9, 52.7, 59.9, 64.6, 82.7, 83.3, 113.3, 118.4, 122.7, 126.5, 127.1 (2C),
127.2 (2C), 128.9, 129.7 (2C), 130.0 (2C), 130.4, 133.6, 134.0, 136.9,
143.5, 144.8, 146.4; HRMS (FAB) calcd C38H48BrN2O6S2Si (M ꢀ H)ꢀ
799.1912, found (M ꢀ H)ꢀ 799.1910.
1
(NSO2); H NMR (500 MHz, CDCl3) δ 0.92ꢀ1.02 (m, 21H), 2.35
(s, 3H), 2.41 (s, 3H), 2.43ꢀ2.48 (m, 1H), 2.86ꢀ2.92 (m, 1H),
2.99ꢀ3.04 (m, 1H), 3.35 (dd, J = 10.0, 10.0 Hz, 1H), 3.55 (dd, J =
10.0, 4.3 Hz, 1H), 3.76 (d, J = 3.9 Hz, 1H), 4.70 (d, J = 3.9 Hz, 1H), 4.94
(dd, J = 6.2, 6.2 Hz, 1H), 7.18 (dd, J = 8.4, 8.4 Hz, 1H), 7.25 (d, J = 8.4
Hz, 2H), 7.27 (d, J = 8.4 Hz, 2H), 7.41 (d, J = 8.4 Hz, 1H), 7.62ꢀ7.68
(m, 3H), 7.76 (d, J = 8.4 Hz, 2H), 8.00 (d, J = 8.4 Hz, 1H); 13C NMR
(125 MHz, CDCl3) δ 11.7 (3C), 17.8 (6C), 21.5, 21.6, 34.7, 44.9, 48.6,
53.2, 64.6, 78.3, 83.6, 112.9, 113.6, 117.3, 125.7, 126.3, 126.9 (2C), 127.0
(2C), 127.4, 128.6, 129.7 (2C), 130.1 (2C), 134.7, 136.0, 136.9, 143.3,
145.6; HRMS (FAB) calcd C38H46BrN2O6S2Si (M ꢀ H)ꢀ 797.1755,
found (M ꢀ H)ꢀ 797.1757.
Compound 19: yellow amorphous solid; [R]27 ꢀ7.68 (c 0.44,
D
CHCl3); IR (neat) 2216 (CtO), 1681 (CdO), 1415 (NSO2), 1377
(NSO2), 1162 (NSO2), 1095 (NSO2); 1H NMR (500 MHz, CDCl3) δ
0.99ꢀ1.08 (m, 21H), 2.36 (s, 3H), 2.42 (s, 3H), 2.73ꢀ2.80 (m, 1H),
3.05 (ddd, J = 12.7, 6.4, 6.4 Hz, 1H), 3.17 (ddd, J = 12.7, 6.4, 6.3 Hz, 1H),
3.57 (dd, J = 9.9, 7.9 Hz, 1H), 3.72 (dd, J = 9.9, 4.4 Hz, 1H), 4.13 (s, 2H),
4.97 (dd, J = 6.4, 6.4 Hz, 1H), 7.13 (dd, J = 8.3, 8.3 Hz, 1H), 7.25 (d, J =
8.0 Hz, 2H), 7.31 (d, J = 8.0 Hz, 2H), 7.36 (d, J = 8.3 Hz, 1H), 7.55 (s,
1H), 7.72 (d, J = 8.0 Hz, 2H), 7.75 (d, J = 8.0 Hz, 2H), 7.96 (d, J = 8.3 Hz,
1H); 13C NMR (125 MHz, CDCl3) δ 11.7 (3C), 17.9 (6C), 21.5, 21.6,
35.1, 42.3, 44.2, 63.8, 82.8, 91.7, 113.0, 114.3, 114.4, 125.7, 126.9 (2C),
127.1 (2C), 127.3, 127.8, 128.4, 129.8 (2C), 130.1 (2C), 134.8, 136.2,
136.8, 143.6, 145.5, 183.9; HRMS (FAB) calcd C38H46BrN2O6S2Si
(M ꢀ H)ꢀ 797.1755, found (M ꢀ H)ꢀ 797.1754.
N-[(2S,5R)-6-(4-Bromo-1-tosyl-1H-indol-3-yl)-5-hydroxy-
2-[(triisopropylsilyloxy)methyl]hex-3-yn-1-yl]-4-methylben-
zenesulfonamide (17), N-[(2S,5R,Z)-6-(4-Bromo-1-tosylindo-
lin-3-ylidene)-5-hydroxy-2-[(triisopropylsilyloxy)methyl]
hex-3-yn-1-yl]-4-methylbenzenesulfonamide (18), and (S)-
N-[6-(4-Bromo-1-tosyl-1H-indol-3-yl)-5-oxo-2-[(triisopropy-
lsilyloxy)methyl]hex-3-yn-1-yl]-4-methylbenzenesulfona-
mide (19) (Table 2). To a stirred mixture of Zn(OTf)2 (27.3 mg,
0.075 mmol) and NaBH3CN (4.7 mg, 0.075 mmol) in THF (1.83 mL)
was added 14 (20 mg, 0.025 mmol, dr = 82:18) at room temperature
under argon. The mixture was allowed to warm to 60 °C and stirred for
2 h at this temperature, followed by quenching by addition of saturated
N-[(2S,4R)-6-(4-Bromo-1-tosyl-1H-indol-3-yl)-2-[(triisopro-
pylsilyloxy)methyl]hexa-3,4-dienyl]-4-methylbenzenesul-
fonamide (3a). To a stirred mixture of IPNBSH (39 mg, 0.150
mmol), PPh3 (39 mg 0.150 mmol), and 17 (30 mg, 0.037 mmol, dr =
82:18) in THF (970 μL) was added diethyl azodicarboxylate (2.2 M
solution in toluene; 68 μL, 0.150 mmol) at 0 °C under argon. The
mixture was allowed to warm to room temperature and stirred for 2 h
5510
dx.doi.org/10.1021/jo2008324 |J. Org. Chem. 2011, 76, 5506–5512

The Journal of Organic Chemistry
NOTE
at this temperature. A mixture of TFE and water (1:1; 480 μL) was
added to the reaction mixture to enable the formation of the
propargylic diazene intermediate. After 16 h, the whole was extracted
with Et2O. The extract was washed with water and brine and dried
over MgSO4. The filtrate was concentrated under reduced pressure to
give an oily residue, which was purified by flash chromatography over
silica gel with n-hexaneꢀEtOAc (8:1) to give 3a as a yellow amor-
phous solid (17 mg, 56% yield, dr = 82:18). Its purity was confirmed
by 1H NMR analysis. All of the spectral data were in agreement with
those reported by us.25
Alkaloids; Cordell, G. A., Ed.; Academic Press: San Diego, 2000; Vol. 54,
pp 191ꢀ257.
(3) For synthesis of (()-lysergic acid, see: (a) Kornfeld, E. C.;
Fornefeld, E. J.; Kline, G. B.; Mann, M. J.; Morrison, D. E.; Jones, R. G.;
Woodward, R. B. J. Am. Chem. Soc. 1956, 78, 3087–3114. (b) Julia,
M.; LeGoffic, F.; Igolen, J.; Baillarge, M. Tetrahedron Lett. 1969, 10,
1569–1571. (c) Armstrong, V. W.; Coulton, S.; Ramage, R. Tetrahedron
Lett. 1976, 17, 4311–4314. (d) Oppolzer, W.; Francotte, E.; B€attig, K.
Helv. Chim. Acta 1981, 64, 478–481. (e) Rebek, J., Jr.; Tai, D. F.
Tetrahedron Lett. 1983, 24, 859–860. (f) Kiguchi, T.; Hashimoto,
C.; Naito, T.; Ninomiya, I. Heterocycles 1982, 19, 2279–2282. (g)
Kurihara, T.; Terada, T.; Yoneda, R. Chem. Pharm. Bull. 1986, 34, 442–
443. (h) Cacchi, S.; Ciattini, P. G.; Morera, E.; Ortar, G. Tetrahedron Lett.
1988, 29, 3117–3120. (i) Hendrickson, J. B.; Wang, J. Org. Lett. 2004,
6, 3–5.
N-[(2S,4R)-6-(4-Bromo-1-tosyl-1H-indol-3-yl)-2-(hydroxy-
methyl)hexa-3,4-dienyl]-4-methylbenzenesulfonamide (3b).
To a stirred solution of 3a (59 mg, 0.075 mmol, dr = 82:18) in THF
(6.8 mL) was added TBAF (1.00 M solution in THF; 150 μL, 0.150
mmol) at 0 °C. The mixture was stirred for 20 min at room temperature
and quenched by addition of saturated NH4Cl. The whole was extracted
with EtOAc. The extract was washed with water and brine and dried over
MgSO4. The filtrate was concentrated under reduced pressure to give an
oily residue, which was purified by flash chromatography over silica gel
with n-hexaneꢀEtOAc (3:2) to give 3b as a white amorphous (43.7 mg,
93% yield, dr = 82:18). Its purity was confirmed by 1H NMR analysis. All
the spectral data were in agreement with those reported by us.7
[(6aR,9S)-4,7-Ditosyl-4,6,6a,7,8,9-hexahydroindolo[4,3-fg]-
quinolin-9-yl]methanol (2a). To a stirred mixture of 3b (20 mg,
0.032 mmol, dr = 82:18) in DMF (0.87 mL) were added Pd(PPh3)4
(3.7 mg, 0.0032 mmol) and K2CO3 (13.3 mg, 0.096 mmol) at room
temperature under argon, and the mixture was stirred for 2.5 h at 100 °C.
The mixture was quenched by addition of saturated NH4Cl. The whole
was extracted with EtOAc. The extract was washed with water and brine
and dried over MgSO4. The filtrate was concentrated under reduced
pressure to give an oily residue, which was purified by flash chromatog-
raphy over silica gel with n-hexaneꢀEtOAc (1:1) to give 2a as a white
amorphous solid (15.2 mg, 87% yield, dr = 87:13). Its purity was
confirmed by 1H NMR analysis. All of the spectral data were in
agreement with those reported by us.7
ꢀ
(4) Moldvai, I.; Temesvꢀari-Major, E.; Incze, M.; Szentirmay, E.;
Gꢀacs-Baitz, E.; Szꢀantay, C. J. Org. Chem. 2004, 69, 5993–6000.
(5) Inoue, T.; Yokoshima, S.; Fukuyama, T. Heterocycles 2009,
79, 373–378.
(6) Kurokawa, T.; Isomura, M.; Tokuyama, H.; Fukuyama, T. Synlett
2009, 775–777.
(7) Inuki, S.; Iwata, A.; Oishi, S.; Fujii, N.; Ohno, H. J. Org. Chem.
2011, 76, 2072–2084.
(8) Myers, A. G.; Zheng, B. J. Am. Chem. Soc. 1996, 118, 4492–4493.
(9) For SN2 reaction of 2-alkynyloxiranes at the 3-position, see:
Ongoka, P.; Mauzꢀe, B.; Miginiac, L. J. Organomet. Chem. 1985, 284,
139–147.
(10) For SN2 reaction of 2-alkynyloxiranes at the 2-position, see: (a)
Krause, N.; Seebach, D. Chem. Ber. 1988, 121, 1315–1320. (b) Bernard,
N.; Chemla, F.; Normant, J. Eur. J. Org. Chem. 1999, 2067–2078.
(11) For SN20 reduction with copper hydride, see: (a) Deutsch, C.;
Lipshutz, B. H.; Krause, N. Angew. Chem., Int. Ed. 2007, 46, 1650–1653.
For SN20 reactionswith carbon nucleophiles, see: (b)Ortizde Montellano,
P. R. J. Chem. Soc., Chem. Commun. 1973, 709–710. (c) Tigchelaar, M.;
Meijer, J.; Kleijn, H.; Bos, H. J. T.; Vermeer, P. J. Organomet. Chem.
1981, 221, 117–221. (d) Doutheau, A.; Sartorelli, J.; Gorꢀe, J.
Tetrahedron 1983, 39, 3059–3065. (e) Alexakis, A.; Marek, I.;
Mangeney, P.; Normant, J. F. Tetrahedron 1991, 47, 1677–1696.
(f) Oehlschlager, A. C.; Czyzewska, E. Tetrahedron Lett. 1983, 24,
5587–5590.
’ ASSOCIATED CONTENT
(12) For a review, see: (a) Chemla, F.; Ferreira, F. Curr. Org.
Chem. 2002, 6, 539–570. For a review on ring-opening reaction of
vinyloxiranes, see: (b) Olofsson, B.; Somfai, P. In Aziridines and
Epoxides in Organic Synthesis; Yudin, A. K., Eds.; Wiley-VCH: Wein-
heim, 2006; pp 315ꢀ347.
Supporting Information. 1H and 13C NMR spectra for
S
b
all new compounds. This material is available free of charge via
the Internet at http://pubs.acs.org.
(13) Wang, Z. X.; Tu, Y.; Frohn, M.; Zhang, J. R.; Shi, Y. J. Am. Chem.
Soc. 1997, 119, 11224–11235.
’ AUTHOR INFORMATION
Corresponding Author
*E-mail: hohno@pharm.kyoto-u.ac.jp; nfujii@pharm.kyoto-u.ac.jp.
(14) We investigated several methods for construction of (E)-vinyl
bromide such as the Hunsdiecker reaction, Takai reaction, and others.
For the Hunsdiecker reaction, see: (a) Hunsdiecker, C. H. Ber. Dtsch.
Chem. Ges. B 1939, 75, 291–297. For the Takai reaction, see: (b) Takai,
K.; Nitta, K.; Utimoto, K. J. Am. Chem. Soc. 1986, 108, 7408–7410.
See also: (c) Bull, J. A.; Mousseau, J. J.; Charette, A. B. Org. Lett. 2008,
10, 5485–5488. (d) Pawluꢀc, P.; Hreczycho, G.; Szudknowska, J.;
Kubicki, M.; Marciniec, B. Org. Lett. 2009, 11, 3390–3393.
(15) Uenishi, J.; Kawahama, R.; Shiga, Y.; Yonemitsu, O.; Tsuji, J.
Tetrahedron Lett. 1996, 37, 6759–6762.
’ ACKNOWLEDGMENT
This work was supported by a Grant-in-Aid for Scientific
Research C (H.O.) and the Targeted Proteins Research Program
from the Ministry of Education, Culture, Sports, Science and
Technology of Japan. S.I. is grateful for Research Fellowships
from the Japan Society for the Promotion of Science (JSPS) for
Young Scientists.
(16) Lauchli, R.; Shea, K. J. Org. Lett. 2006, 8, 5287–5289.
(17) Ohno, H.; Hamaguchi, H.; Tanaka, T. J. Org. Chem. 2001,
66, 1867–1875.
(18) Wang., Z.-X.; Shu, L.; Frohn, M.; Tu, Y.; Shi, Y. Org. Synth.
2003, 80, 9–17.
’ REFERENCES
(19) (a) Shu, L.; Shi, Y. Tetrahedron Lett. 2004, 45, 8115–8117. (b)
Wong, O. A.; Shi, Y. J. Org. Chem. 2006, 71, 3973–3976. (c) Burke, C. P.;
Shi, Y. J. Org. Chem. 2007, 72, 4093–4097.
(1) For isolation of lysergic acid, see: (a) Jacobs, W. A.; Craig, L. C.
J. Biol. Chem. 1934, 104, 547–551. (b) Stoll, A.; Hofmann, A.; Troxler, F.
Helv. Chim. Acta 1949, 32, 506–521.
(2) (a) Ninomiya, I.; Kiguchi, T. In The Alkaloids; Brossi, A., Ed.;
Academic Press: San Diego, 1990; Vol. 38, pp 1ꢀ156. (b) Somei, M.;
Yokoyama, Y.; Murakami, Y.; Ninomiya, I.; Kiguchi, T.; Naito, T. In The
(20) (a) Hutchins, R. O.; Taffer, I. M.; Burgoyne, W. J. Org. Chem.
1981, 46, 5214–5215. (b) Alesso, E. N.; Bianchi, D. E.; Finkielsztein,
L. M.; Moltrasio, G. Y.; Aguirre, J. M. Tetrahedron Lett. 1995,
5511
dx.doi.org/10.1021/jo2008324 |J. Org. Chem. 2011, 76, 5506–5512

The Journal of Organic Chemistry
NOTE
36, 3299–3302. (c) Page, P. B.; Appleby, L. F.; Day, D.; Chan, Y.;
Buckley, B. R.; Allin, S. M.; McKenzie, M. J. Org. Lett. 2009,
11, 1991–1993. (d) Blasio, D. N.; Lopardo, M. T.; Lupattelli, P. Eur. J.
Org. Chem. 2009, 938–944.
(21) For a Lewis acid-mediated regioselective ring-opening and ring-
closure of the 2,3-diaryloxiranes, see: Nicolaou, K. C.; Kang, Q.; Wu,
T. R.; Lim, C. S.; Chen, D. Y.-K. J. Am. Chem. Soc. 2010, 132, 7540–7548.
(22) AlMe3-catalyzed MPV reduction and Oppenauer oxidation in
the presence of secondary alcohol is reported; see: Graves, C. R.; Zeng,
B.-S.; Nguyen, S. T. J. Am. Chem. Soc. 2006, 128, 12596–12597.
(23) The reaction for the prolonged reaction time (16 h) caused
slight epimerization of 17 (72:28).
(24) Movassaghi, M.; Ahmad, O. K. J. Org. Chem. 2007, 72,
1838–1841.
(25) Inuki, S.; Oishi, S.; Fujii, N.; Ohno, H. Org. Lett. 2008, 10,
5239–5242.
5512
dx.doi.org/10.1021/jo2008324 |J. Org. Chem. 2011, 76, 5506–5512