Article

pubs.acs.org/joc

Total Synthesis of (+)-Lysergic Acid

Qiang Liu,†,§ Yu-An Zhang,†,§ Ping Xu,† and Yanxing Jia*,†,‡
†
State Key Laboratory of Natural and Biomimetic Drugs, School of Pharmaceutical Sciences, Peking University, 38 Xueyuan Road,
Beijing 100191, China
‡
State Key Laboratory of Applied Organic Chemistry, Lanzhou University, Lanzhou 730000, China
*
S Supporting Information

ABSTRACT: We report the enantioselective total synthesis

of (+)-lysergic acid using two different strategies, which
featured three metal-catalyzed reactions for the construction of
the BCD three rings, involving Pd-catalyzed indole synthesis
for the construction of the B ring, a ring-closing metathesis
reaction for the formation of the D ring, and an intramolecular
Heck reaction to forge the C ring. In synthetic strategy I, the
synthesis was achieved in 20 steps following the ring
construction sequence of BDC. In synthetic strategy II, the synthetic route was shortened to only 12 steps by following the
ring construction sequence of DBC and using a 4-chlorotryptophan derivative for the intramolecular Heck reaction. Moreover,
we also discussed an unsuccessful synthetic strategy.

■ INTRODUCTION
Lysergic acid (1) is a representative natural product of the ergot
structural features of ergot alkaloids, a number of total
syntheses of lysergic acid (1) have been reported to date.2
alkaloid family, which are particularly important because they The first synthesis of racemic lysergic acid was achieved by
possess a wide spectrum of biological activities (Figure 1).1 Woodward and Kornfeld in 1956.2a So far, its total synthesis
has been achieved by 13 groups.2a−u Most previous syntheses
have relied on a stepwise linear approach using Kornfeld’s
ketone, except for Oppolzer’s intramolecular imino-Diels−
Alder strategy.2e In recent years, palladium-catalyzed reactions
of 3,4-disubstitued indole derivatives provide an attractive
approach for the construction of the C ring of lysergic acid.
However, only four asymmetric syntheses are recently reported:
Szántay’s synthesis in 2004 involved optical resolution of the
tetracyclic indole intermediate;2n Fukuyama, Ohno, and our
group employed palladium-catalyzed methodologies for the
construction of the key C ring.2o−u
4-Halotryptophan derivatives containing a chiral center are
useful intermediates for the synthesis of 3,4-disubstituted indole
alkaloids. However, their synthesis is arduous.3 Recently, Zhu
and Jia have developed a useful method for the synthesis of 4-
halotryptophan derivatives via a Pd-catalyzed annulation
reaction.4 In our previous work, we validated the efficiency of
this methodology by successfully accomplishing the asymmetric
synthesis of clavicipitic acid, aurantioclavine, indolactam V,
Figure 1. Structures of (+)-lysergic acid and other ergot alkaloids.
lysergic acid, and rugulovasine A.2u,5 Herein, we describe
another successful example toward the total synthesis of
(+)-lysergic acid (1) from an (R)-4-halotryptophan derivative.

■
One of the most biologically important ergot alkaloids is α-
ergocryptine (2). Its semisynthetic derivative bromocryptine RESULTS AND DISCUSSION
(3) is clinically used as a prolactin inhibitor. The lysergic acid
diethylamide (LSD) (4), another representative ergot alkaloid, Unsuccessful Attempts for the Synthesis of (+)-Lyser-
is strongly and notoriously psychoactive. From a structural gic Acid. As shown in the retrosynthetic analysis outlined in
perspective, lysergic acid (1) possesses a unique tetracyclic
ergoline skeleton that contains the Δ9,10-double bond and two Received: August 23, 2013
chiral centers. Intrigued by the biological activities and unique

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The Journal of Organic Chemistry Article

Scheme 1, we envisioned that (+)-lysergic acid (1) could be aldehyde 7 could be obtained by hydrolysis of methyl enol
obtained by simple transformation of compound 5. The ether 11 had failed.
Next, we planned to synthesize the aldehyde 7 by utilizing
Scheme 1. Initial Retrosynthetic Analysis of (+)-Lysergic the Nef reaction of a nitro compound (Scheme 3).8 Reduction
Acid (1)
Scheme 3. Attempted Synthesis of Tricyclic Aldehyde 7 by
Nef Reaction

piperidine ring of 5 could be constructed by means of an

intramolecular SN2′ displacement of alcohol 6, which could be
readily accessed by Morita−Baylis−Hillman reaction of tricyclic
aldehyde 7 with methyl acrylate.6 The tricyclic aldehyde 7
could be obtained starting from (R)-4-iodotryptophan
derivative 8. For the synthesis of 8, the same procedures
could be used as its enantiomer (S)-8 including the Pd-
catalyzed annulation reaction as the key step.5b
Our synthesis of compound 7 commenced with (R)-4-
iodotryptophan derivative 8 as shown in Scheme 2. Thus, N-

Scheme 2. Attempted Synthesis of Tricyclic Aldehyde 7 by

Hydrolysis of Methyl Enol Ether 11

of 9 with LiBH4, followed by Swern oxidation, gave aldehyde

12 in 83% overall yield. Henry reaction of aldehyde 12 with
nitromethane provided a diastereomeric mixture of the
expected β-nitro alcohol 13, which was subsequently
dehydrated to afford nitroalkene 14 in 82% overall yield solely
as the E isomer.9 With the nitroalkene 14 in hand, we next
explored the intramolecular Heck reactions. Surprisingly, an
extensive literature search showed that there are only a few
reported intramolecular Heck reactions of nitroalkenes. Den-
mark reported that intramolecular Heck reaction of iodoaryl
nitroalkene needed 1.0 equiv of Pd(OAc)2.10 Gratefully, when
nitroalkene 14 was treated with 0.1 equiv of Pd(OAc)2, 0.2
equiv of Ph3P, and 2 equiv of Ag2CO3 in benzene at 25 °C, the
intramolecular Heck reaction proceeded smoothly and gave Z/
E isomers of 15 in 80% yield. The isomers of 15 were unstable,
and Z/E isomerization of the double bond would occur on
silica gel. Attempts were made to transform the mixture of 15
to the tricyclic aldehyde 7 by Nef reaction using oxidative,
methylation of (R)-8 with MeI and Ag2O in DMF provided 9 reductive, and neutral conditions.8 Unfortunately, either the
in 83% yield. Treatment of compound 9 with t-BuLi afforded reaction was inert or complex products were formed, and no
the desired tricyclic ketone 10 in 80% yield, which was desired product 7 was found.
described recently in the synthesis of Rugulovasine A by us.5d We next examined the construction of the skeleton of the
However, Wittig reaction of ketone 10 was unsuccessful. A tricyclic aldehyde 7 via the palladium-catalyzed α-arylation of
variety of reaction conditions were screened, including using aldehyde 17 directly (Scheme 4). Wittig reaction of aldehyde
Ph2POCH2OCH3 and ylide Ph3PCH2OCH3Cl as olefin 12 yielded the desired methyl enol ether 16 (trans:cis = 5:4) in
reagents.7 The reaction proceeded poorly, and no desired 86% yield. Hydrolysis of 16 with Hg(OAc)2/KI gave the
product 11 was found. Therefore, our original idea that tricyclic aldehyde 17 in 95% yield.6,11 According to the reported
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The Journal of Organic Chemistry Article

Scheme 4. Attempted Synthesis of Tricyclic Aldehyde 7 by Starting from Wittig reaction of aldehyde 17, the terminal
Pd-Catalyzed α-Arylation of Aldehyde 17 olefin 21 was obtained in 92% yield (Scheme 6).
Deprotection5a of the Boc group of 21 with TMSOTf, followed
by N-alkylation14 with methyl 2-(bromomethyl)acrylate,15
afforded the diene 20 in 76% overall yield. The ring-closing
metathesis reaction of the diene 20 proceeded smoothly when
using Grubbs II catalyst in the presence of protic acid p-TsOH
(1.1 equiv) in toluene at 50 °C.16 The desired product 19 was
obtained in 88% yield. It was presumed that the presence of
protic acid inhibited the interactions of the lone pair of
electrons on nitrogen with the metal center.17 With the crucial
intermediate 19 in hand, the γ-arylation reaction of α,β-
unsaturated ester 19 was examined first. To the best of our
knowledge, there is no literature report on the intramolecular γ-
arylation reaction of α,β-unsaturated esters. Indeed, a variety of
conditions screening failed to give the desired product 22.18
Alternatively, the α,β-unsaturated ester 19 was subjected to
isomerization of the double bond according to Fukuyama’s
procedure.2o An inseparable mixture of epimers of 18 (trans/cis
= 1:1) was afforded in 84% yield. For the intramolecular Heck
reaction of 18, a variety of reaction conditions were examined.
protocol, a variety of intramolecular α-arylation conditions were We found that Ag2CO3 was necessary as the base and halide
investigated.12 However, the reaction normally formed several scavenger to suppress alkene isomerization in the reaction.19
unidentified side products and no desired product 7 was When 18 was treated with 0.1 equiv of Pd(OAc)2, 0.3 equiv of
obtained. In addition, the intramolecular Heck reaction of Ph3P, and 2 equiv of Ag2CO3 in CH3CN at refluxing for 2 h,
methyl enol ether 16 was also investigated, and no desired the desired Heck product 22 was obtained in 84% yield (brsm)
product was observed. and 34% of the starting material 18 was recovered. Surprisingly,
Strategy I for the Successful Synthesis of (+)-Lysergic the ratio of trans versus cis of the recovered 18 was still 1:1.
Acid. Having realized that the tricyclic aldehyde 7 was difficult Because the D ring of 18 should be a trans-2,5-disubstituted
to prepare, we turned our attention to the development of an 1,2,5,6-tetrahydropyridine for smooth β-H elimination, 18 was
efficient alternative strategy for the synthesis of (+)-lysergic probably epimerized under basic conditions. Finally, the
acid (1) (Scheme 5). Instead of constructing C ring first, we deprotection of Boc and hydrolysis of methyl ester of 22
with KOH, accompanied with the isomerization of the double
Scheme 5. Retrosynthetic Analysis of (+)-Lysergic Acid (1) bond, furnished (+)-lysergic acid (1) in 52% yield.2e Thus, our
of Strategy I first-generation enantioselective total synthesis of (+)-lysergic
acid (1) was achieved in 12 steps and 12.7% overall yield
starting from (R)-4-iodotryptophan derivative 8, or 20 steps
and 4.5% overall yield starting from readily available glutamic
acid.
Strategy II for the Successful Synthesis of (+)-Lysergic
Acid. Although we have accomplished the total synthesis of
(+)-lysergic acid (1), the synthetic route was not convergent
due to several redundant conversions of functional groups. For
instance, conversion of the 4-nitro-tryptophan derivative to the
4-iodotryptophan derivative 8 required two more steps and
carbon chain extension from ester 9 to olefin 21 needed five
steps. To overcome these shortcomings effectively, we
postulated that (1) the stereocenter of the D ring could be
generated by the enantioselective addition of chiral imine and
(2) using 3-chloro-2-iodoaniline instead of 3-nitro-2-iodoani-
line to undergo Pd-catalyzed indole synthesis; the product
could be subjected to the subsequent intramolecular Heck
reaction directly. The retrosynthetic analysis of common
intermediate 22 is illustrated in Scheme 7. The C ring could
be constructed by utilizing intramolecular Heck reaction of 4-
proceeded to investigate a new ring-closing sequence. The D chlorotryptophan derivative 23, which was regarded as an inert
ring of 18 would be first synthesized via ring-closing metathesis substrate and rarely used in the intramolecular Heck reaction.
reaction of 20, followed by isomerization of the double bond of Compound 23 can be accessed from α,β-unsaturated ester 24
19.13 The C ring could be sequentially constructed by utilizing via isomerization of the double bond. The ester 24 containing
intramolecular Heck reaction of β,γ-unsaturated ester 18 or γ- the A/B/D ring system could be synthesized by the Pd-
arylation of α,β-unsaturated ester 19.2o The diene 20 should be catalyzed indole synthesis from 3-chloro-2-iodoaniline (25) and
readily accessible from aldehyde 17 through a sequence of aldehyde 26, which already contains the D ring of (+)-lysergic
conversions of functional groups. acid (1). The tetrahydropyridine in aldehyde 26 could be
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Scheme 6. Total Synthesis of (+)-Lysergic Acid (1) by Strategy I

Scheme 7. Retrosynthetic Analysis of Common Intermediate 22

formed by ring-closing metathesis reaction of diene 27, which was found that the yield could be improved by shortening the
could be prepared by N-alkylation of 28. The chiral allylamine reaction time. The optimized conditions were 40 mol % of
28 could be readily obtained by one-pot reaction of aldehyde Pd(OAc)2 and 3 equiv of DABCO·6H2O at 80 °C for 6 h.
29, allylic bromide, and tert-butanesulfinamide in the presence Since compound 32 was difficult to be purified by flash column
of indium metal and titanium tetraethoxide.20 chromatography, it was subjected to Boc protection without
Preparation of the precursor 23 for intramolecular Heck further purification, affording the product 33 in 39% overall
reaction is outlined in Scheme 8. When a mixture of aldehyde yield for two steps. Removal of the tert-butanesulfinyl group
29, (SR)-N-tert-butanesulfinamide, allyl bromide, indium and subsequent reductive methylation gave 24 in 72% overall
powder, and Ti(OEt)4 was heated in THF at 60 °C for 5 h, yield.23,24 Isomerization of the double bond of 24 with lithium
a mixture of two inseparable diastereoisomers of 28 (dr = 7:1) 2,2,6,6-tetramethylpiperidide (LTMP), followed by quenching
was obtained in 79% yield.20 N-Alkylation of 28 with methyl 2- with saturated aqueous NH4Cl solution, provided a mixture of
(bromomethyl)acrylate afforded the major diene product 27 in epimers 23 (2:1).2o
74% yield together with its diastereoisomer in 10% yield.21 The Having succeeded in the preparation of the key intermediate
diastereoisomers could be separated by careful column 23, we explored the intramolecular Heck reaction. Unexpect-
chromatography in this step. The ring-closing metathesis edly, the intramolecular Heck reaction of 4-chlorotryptophan
reaction of 27 proceeded smoothly in refluxing CH2Cl2 for derivative 23 was a formidable task. A variety of reaction
12 h, and the desired product 30 was isolated in 90% yield.21 conditions (palladium sources, ligands, bases, and solvents)
Subsequent deprotection of the TBS group with TBAF, were examined, and some of the representative ones are shown
followed by Dess−Martin oxidation, gave aldehyde 26 in 78% in Table 1. All the catalyzed conditions did not give any desired
overall yield.22 cyclized product (Table 1, entries 1−2).25a However, under
With the key chiral aldehyde 26 in hand, the stage was set for Fu’s reaction conditions, the starting material was recovered in
the Pd-catalyzed indole synthesis to construct B ring. Direct 52% yield (Table 1, entry 2).25b When the reaction was
annulation of 3-chloro-2-iodoaniline (25) and aldehyde 26 conducted with 0.5 equiv of Pd2(dba)3CHCl3, the desired
under standard conditions provided the desired product in product 22 was obtained in 20% yield with recovery of 35% of
around 20% yield.4 After screening a variety of conditions, it the starting material (Table 1, entry 3). Therefore, further
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Scheme 8. Synthesis of Intermediate 23

Table 1. Optimization of the Reaction Conditions for the Intramolecular Heck Reaction

yield (%)
entry catalyst ligand base solvent T (°C) t (h) 23a product 22b
c
1 Pd(OAc)2 (0.2 equiv) dppp (0.2 equiv) Cs2CO3 (1.5 equiv) EG 140 2 0 0
2 Pd2(dba)3CHCl3 (0.1 equiv) P(t-Bu)3HBF4 (0.2 equiv) Cy2MeN (3 equiv) dioxane 80 1.5 52 0
3 Pd2(dba)3CHCl3 (0.5 equiv) P(t-Bu)3HBF4 (1 equiv) Cy2MeN (3 equiv) dioxane 80 1.5 35 20
4 Pd2(dba)3CHCl3 (0.5 equiv) P(t-Bu)3HBF4 (1 equiv) Cy2MeN (3 equiv) dioxane 80 (MW) 0.25 59 0
5 Pd2(dba)3CHCl3 (0.5 equiv) P(t-Bu)3HBF4 (1 equiv) Cy2MeN (3 equiv) dioxane 100 1.5 27 25
6 Pd2(dba)3CHCl3 (0.5 equiv) P(t-Bu)3HBF4 (1 equiv) Cy2MeN (3 equiv) Cs2CO3 (1.5 equiv) dioxane 80 1.5 65 22
7 Pd2(dba)3CHCl3 (0.5 equiv) John-Phos (1 equiv) Cy2MeN (5 equiv) dioxane 80 1.5 43 0
8 Pd2(dba)3CHCl3 (0.5 equiv) Dave-Phos (1 equiv) Cy2MeN (3 equiv) dioxane 80 1.5 79 0
9 Pd2(dba)3CHCl3 (0.5 equiv) X-Phos (1 equiv) Cy2MeN (3 equiv) dioxane 80 1.5 0 0
a
Isolated yield. bYield based on recovered starting material. cEG = ethylene glycol.

optimization of the reaction conditions was carried out in the the presence of 0.5 equiv of Pd2(dba)3CHCl3, 1.0 equiv of P(t-
presence of 0.5 equiv of Pd2(dba)3CHCl3. The microwave Bu)3HBF4, and 3.0 equiv of Cy2MeN in dioxane at 100 °C.
treatment could not improve the reaction efficiency (Table 1, Finally, following the same above procedure for 22 furnished
entry 4). When the reaction was conducted at a higher (+)-lysergic acid (1).2e Thus, our second-generation enantio-
temperature, more starting material 23 was converted to the selective total synthesis of (+)-lysergic acid (1) was achieved in
desired product 22 without the loss of yield (Table 1, entry 5). only 12 steps and 1% overall yield starting from readily available
When Cs2CO3 was used as the co-base, the conversion of the and known aldehyde 29. Although the overall yield was not
starting material was significantly inhibited (Table 1, entry satisfactory, which was mainly due to the challenge of the
6).25c Further optimization of the reaction conditions was intramolecular Heck reaction of chlorosubstituted substrate, the
carried out in the presence of different ligands. Unfortunately, present synthesis represented the shortest sequence for the
no desired product 22 was found under these conditions asymmetric total synthesis of (+)-lysergic acid (1). In addition,
(Table 1, entries 7−9). Therefore, the intramolecular Heck the challenge of the Heck reaction using aryl chloride as the
reaction of 4-chlorotryptophan derivative 23 was performed in reaction partner underscores the need to develop more
E dx.doi.org/10.1021/jo4018777 | J. Org. Chem. XXXX, XXX, XXX−XXX
The Journal of Organic Chemistry Article

powerful catalytic systems for the Heck reaction with complex were washed with brine and dried over Na2SO4. Purification by FCC
aryl chlorides. (PE-EtOAc, 10:1) afforded the isomers 15 (68 mg, 80% yield, ratio =

■
1.8:1): major isomer 1H NMR (400 MHz, CDCl3) δ 8.06 (br s, 1 H),
7.75 (s, 1 H), 7.45 (d, J = 7.6 Hz, 1 H), 7.39 (d, J = 7.6 Hz, 1 H), 7.29
CONCLUSIONS (t, J = 7.5 Hz, 1 H), 6.41 (d, J = 4.6 Hz, 1 H), 5.22 (m, 1 H), 3.07−
In summary, we have achieved the enantioselective total 3.25 (m, 2 H), 2.33 (s, 3 H), 1.68 (s, 9 H), 1.51 (s, 9 H); minor isomer
synthesis of (+)-lysergic acid (1) by utilizing two different
1
H NMR (400 MHz, CDCl3) δ 7.98 (br s, 1 H), 7.48 (d, J = 7.8 Hz, 1
strategies, which both featured three metal-catalyzed reactions H), 7.44 (s, 1 H), 7.37 (d, J = 7.8 Hz, 1 H), 7.31 (t, J = 7.8 Hz, 1 H),
for the construction of three key rings, involving Pd-catalyzed 6.91 (d, J = 1.4 Hz, 1 H), 5.22 (m, 1 H), 3.07−3.25 (m, 2 H), 2.89 (s,
indole synthesis for the construction of the B ring, a ring- 3 H), 1.66 (s, 9 H), 1.48 (s, 9 H); mixture of isomers 13C NMR (100
MHz, CDCl3) δ 155.2, 149.5, 140.6, 139.1, 135.1, 132.9, 130.5, 129.7,
closing metathesis (RCM) reaction for the formation of the D 126.0, 125.2, 123.9, 122.0, 121.8, 120.9, 118.1, 117.6, 117.0, 114.3,
ring, and an intramolecular Heck reaction to forge the C ring. 113.7, 84.2, 84.1, 81.0, 80.5, 47.8, 36.6, 30.6, 30.4, 28.3, 28.1, 26.5; IR
In strategy I, the synthesis of (+)-lysergic acid (1) has been (KBr) 2977, 2930, 1734, 1695, 1523, 1442, 1392, 1366, 1331, 1301,
achieved in 20 steps starting from D-glutamic acid as the chiral 1282, 1255, 1147, 1122, 1049, 851, 767 cm−1; HRMS (ESI) m/z calcd
pool and the ring construction order was BDC. In strategy II, for C23H29N3O6Na (M + Na)+ 466.1954; found 466.1952.
the synthetic route was shortened to only 12 steps by adjusting Compound 28. A mixture of indium powder (1.48 g, 12.9 mmol),
the ring construction order to DBC and using 4-chlorotrypto- (SR)-N-tert-butanesulfinamide (1.04 g, 8.6 mmol), compound 29 (2.00
phan derivative 23 as the intramolecular Heck reaction partner. g, 9.9 mmol), and Ti(OEt)4 (3.6 mL, 17.2 mmol) in THF (18 mL)

■
was stirred under argon for 1 h at 23 °C. At this time, allylic bromide
(2.08 g, 17.2 mmol) was added and the reaction mixture was heated
EXPERIMENTAL SECTION for 5 h at 60 °C. The mixture was cooled to room temperature,
General Methods. Unless otherwise noted, all experiments were quenched with brine (18 mL), and diluted with EtOAc. The resulting
carried out under an Ar atmosphere. Dichloromethane was distilled suspension was filtered through a short pad of Celite and concentrated
over CaH2. Toluene was distilled over sodium, and tetrahydrofuran in vacuo. The residue was purified by FCC (PE-EtOAc, 4:1) to afford
was distilled over Na−K alloy. The other reagents and solvents were the epimers 28 (2.36 g, 79% yield, dr = 7:1) as a colorless liquid: 1H
directly used from the supplier without further purification unless NMR (400 MHz, CDCl3) mixture of epimers δ 5.79−5.69 (m, 1 H),
noted. Reactions at −78 °C employed a dry ice−acetone bath. 5.13−5.09 (m, 1.75 H), 5.06−5.02 (m, 0.25 H), 3.60−3.55 (m, 2 H),
Chemical shifts were reported in δ (ppm) relative to TMS in CDCl3 as 3.30−3.28 (m, 1 H), 3.21−3.12 (m, 1 H), 2.40−2.24 (m, 2 H), 1.56−
internal standard (1H NMR) or the residual CHCl3 signal (13C NMR). 1.50 (m, 4 H), 1.15 (s, 9 H), 0.84 (s, 9 H), −0.01 (s, 6 H); 13C NMR
1
H NMR spectra were tabulated as follows: chemical shift, multiplicity (100 MHz, CDCl3) mixture of epimers δ 134.3, 134.0, 118.8, 117.7,
(br s = broad singlet, s = singlet, d = doublet, dd = doublet of doublets, 62.8, 62.6, 55.6, 55.6, 54.7, 40.4, 39.9, 31.7, 31.3, 28.8, 28.6, 25.8, 22.6,
t = triplet, q = quartet, m = multiplet), number of protons, and 18.2, −5.4; HRMS (ESI) m/z calcd for C34H74N2O4S2Si2Na (2M +
coupling constant (Hz). Infrared spectra were recorded with a thin Na)+ 717.4527; found 717.4498.
layer of the product on a KBr disk and reported in frequency of Compound 27. Epimers 28 (2.04 g, 5.9 mmol) and ethyl α-
absorption (cm−1). High-resolution mass spectra (HRMS) were (bromomethyl)acrylate (4.55 g, 25.7 mmol) were dissolved in
acquired on an FT-MS (7.0 T) equipped with an ESI source in anhydride THF (60 mL) and HMPA (6 mL) with stirring under
positive mode. argon at 0 °C. NaH (0.62 g, 25.7 mmol) was added in 1 h. Then the
Compound 14. To an ice-cooled solution of compound 12 (300 mixture was stirred at room temperature for another 1 h. The mixture
mg, 0.57 mmol) in CH3NO2 (3.8 mL) was added Et3N (103 μL, 0.74 was cooled to 0 °C and quenched with brine carefully. The aqueous
mmol), and the mixture was stirred for 12 h at room temperature, and phase was extracted with EtOAc (3 × 50 mL). The organic layer was
then the mixture was concentrated in vacuo. To a solution of the combined, washed with brine and dried over Na2SO4, filtered, and
residue 13 in CH2Cl2 (3.8 mL) was added SOCl2 (61 μL, 0.85 mmol) evaporated. The residue was purified by FCC (PE-EtOAc, 7:1) to
at −78 °C, and the mixture was stirred for 1 h at the same affored compound 27 as a colorless liquid (1.93 g, 74% yield): [α]20 D +
temperature. After Et3N (285 μL, 2.05 mmol) was added, the reaction 18.5 (c 0.4, MeOH); 1H NMR (400 MHz, CDCl3) δ 6.35 (d, J = 1.2
mixture was allowed to warm to 0 °C and quenched with saturated Hz, 1 H), 5.90 (d, J = 1.2 Hz, 1 H), 5.78 (m, 1 H), 5.08−5.03 (m, 2
aqueous NH4Cl, followed by addition of CH2Cl2 (5 mL). The organic H), 4.25 (d, J = 18.4 Hz, 1 H), 3.75 (s, 3 H), 3.58 (m, 2 H), 3.41 (d, J
layer was separated, and the aqueous phase was further extracted with = 18.4 Hz, 1 H), 2.94 (m, 1 H), 2.39 (m, 2 H), 1.82 (m, 1 H), 1.73
CH2Cl2 (2 × 15 mL). The combined organic phases were washed with (m, 1 H), 1.59 (m, 2 H), 1.17 (s, 9 H), 0.87 (s, 9 H), 0.02 (s, 6 H);
brine and dried over Na2SO4. Purification by FCC (PE-EtOAc, 10:1)
13
C NMR (100 MHz, CDCl3) δ 166.6, 137.6, 136.0, 126.3, 117.2, 62.9,
afforded the product 14 (266 mg, 82% yield) as a colorless oil: 1H 57.9, 51.9, 44.1, 39.4, 30.6, 29.2, 25.9, 23.5, 18.3, −5.3, −5.4; IR (KBr)
NMR (400 MHz, CDCl3) δ 8.23 (d, J = 7.5 Hz, 1 H), 7.69 (d, J = 7.5 2953, 2928, 2857, 1724, 1639, 1472, 1438, 1388, 1361, 1296, 1258,
Hz, 1 H), 7.48 (s, 0.4 H), 7.40 (s, 0.6 H), 7.34 (d, J = 12.0 Hz, 1 H), 1195, 1155, 1095, 835, 776 cm−1; HRMS (ESI) m/z calcd for
7.08 (d, J = 12.0 Hz, 1 H), 6.98 (t, J = 7.5 Hz, 1 H), 5.25−5.38 (m, 1 C22H44NO4SSi (M + H)+ 446.2755; found 446.2753.
H), 3.54−3.57 (m, 1 H), 3.34 (m, 0.4 H), 2.94 (m, 0.6 H), 2.81 (s, 1.8 Compound 30. To a degassed solution of compound 27 (800 mg,
H), 2.73 (s, 1.2 H), 1.64 (s, 9 H), 1.40 (s, 4 H), 1.05 (s, 5 H); 13C 1.79 mmol) in DCM (600 mL) was added Grubbs II catalyst (76 mg,
NMR (100 MHz, CDCl3) δ 155.3, 154.9, 148.6, 140.4, 136.5, 134.4, 0.09 mmol). The mixture was heated to reflux and stirred for 12 h.
130.3, 126.6, 126.3, 125.7, 115.5, 84.5, 84.3, 80.4, 55.3, 55.0, 31.7, 30.0, The solution was concentrated in vacuo, and the residue was purified
28.0, 27.7, 26.8; IR (KBr) 2978, 2931, 1738, 1696, 1530, 1416, 1369, by FCC (PE-EtOAc, 4:1) to afford compound 30 (674 mg, 90% yield)
1282, 1254, 1157, 1092, 1052, 964, 861, 845, 775, 747 cm−1; HRMS as a brown liquid: [α]20D − 12.1 (c 0.5, MeOH); H NMR (400 MHz,
1

(ESI) m/z calcd for C23H30IN3O6Na (M + Na)+ 594.1077; found CDCl3) δ 6.97 (d, J = 4.4 Hz, 1 H), 4.13 (d, J = 18.4 Hz, 1 H), 3.70 (s,
594.1074. 3 H), 3.59 (t, J = 5.6 Hz, 2 H), 3.48 (d, J = 18.4 Hz, 1 H), 3.42 (m, 1
Compound 15. Compound 14 (110 mg, 0.19 mmol) and Ag2CO3 H), 2.66 (d, J = 16.4 Hz, 1 H), 2.10 (dd, J = 3.6, 16.4 Hz, 1 H), 1.69−
(106 mg, 0.38 mmol) were suspended in freshly distilled benzene (10 1.46 (m, 4 H), 1.17 (s, 9 H), 0.86 (s, 9 H), 0.01 (s, 6 H); 13C NMR
mL). Pd(OAc)2 (4.3 mg, 0.019 mmol) was added to the solution, (100 MHz, CDCl3) δ 165.6, 136.5, 128.1, 62.6, 58.7, 55.7, 51.5, 35.6,
followed by the addition of triphenylphosphine (10 mg, 0.038 mmol). 30.0, 28.8, 28.7, 25.8, 23.3, 18.2, −5.4; IR (KBr) 3510, 2922, 2855,
The mixture was stirred at rt for 24 h and quenched with saturated 1638, 1431, 1375, 1321, 1161, 1062 cm−1; HRMS (ESI) m/z calcd for
aqueous NH4Cl, followed by the addition of EtOAc (5 mL). The C40H79N2O8S2Si2 (2M + H)+ 835.4811; found 835.4789.
organic layer was separated, and the aqueous phase was further Compound 31. To a solution of compound 30 (1.36 g, 3.3 mmol)
extracted with EtOAc (2 × 15 mL). The combined organic phases in anhydrous THF (33 mL) was added the TBAF·3H2O (2.05 g, 6.5

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The Journal of Organic Chemistry Article

mmol). The solution was stirred for 2 h at room temperature, (dd, J = 8.0, 14.4 Hz, 1 H), 2.37 (dd, J = 4.0, 19.2 Hz, 1 H), 2.17−2.10
quenched with brine, and concentrated in vacuo, and the residue was (m, 1 H), 1.66 (s, 9 H); 13C NMR (100 MHz, CDCl3) δ 166.3, 149.1,
dissolved in EtOAc (150 mL). The organic layer was washed with 137.9, 137.3, 129.6, 126.8, 126.2, 125.5, 125.0, 123.8, 116.9, 114.0,
brine (3 × 50 mL), dried over Na2SO4, filtered, and evaporated. The 84.2, 51.9, 51.5, 44.4, 32.8, 32.4, 28.1; IR (KBr) 3307, 2979, 2947,
residue was purified by FCC (DCM-MeOH, 30:1) to afford 2818, 1733, 1656, 1424, 1372, 1283, 1256, 1155, 1102, 1042 cm−1;
compound 31 as a colorless liquid (935 mg, 95% yield): [α]20 D − HRMS (ESI) m/z calcd for C21H26ClN2O4 (M + H)+ 405.1576; found
24.4 (c 0.5, MeOH); 1H NMR (400 MHz, CDCl3) δ 6.99 (d, J = 4.8 405.1563.
Hz, 1 H), 4.07 (d, J = 18.0 Hz, 1 H), 3.71 (s, 3 H), 3.64 (br s, 2 H), Compound 24. To a stirred mixture of compound 34 (180 mg,
3.57 (d, J = 18.8 Hz, 1 H), 3.54 (m, 1 H), 2.65 (dd, J = 3.2, 19.6 Hz, 1 0.45 mmol) and aqueous formaldehyde (0.18 mL, 2.25 mmol, 37%) in
H), 2.19−2.09 (m, 2 H), 1.72−1.49 (m, 4 H), 1.17 (s, 9 H); 13C NMR acetonitrile (11 mL) was added sodium cyanoborohydride (56 mg,
(100 MHz, CDCl3) δ 165.5, 136.6, 128.1, 62.3, 58.8, 54.1, 51.6, 37.2, 0.90 mmol). After being stirred for 20 min, the reaction was quenched
29.5, 28.9, 28.8, 23.2; IR (KBr) 3411, 2949, 2870, 1712, 1658, 1436, with saturated aqueous NH4Cl solution and extracted with EtOAc.
1384, 1362, 1265, 1186, 1061, 926 cm−1; HRMS (ESI) m/z calcd for The aqueous layer was basified by addition of saturated aqueous
C28H50N2O8S2Na (2M + Na)+ 629.2901; found 629.2918. Na2CO3. The aqueous solution was extracted with EtOAc. The
Compound 26. To a solution of compound 31 (765 mg, 2.5 organic layer was then dried over Na2SO4 and concentrated under
mmol) in anhydrous DCM (50 mL) was added the Dess−Martin reduced pressure. The residue was purified by FCC (PE-EtOAc, 1:1)
periodinane (1.14 g, 2.7 mmol). The solution was stirred for 1 h at to afford compound 24 (152 mg, 81% yield) as a yellow liquid: [α]20 D +
room temperature and quenched with saturated aqueous Na2CO3 4.3 (c 0.5, MeOH); 1H NMR (400 MHz, CDCl3) δ 8.09 (br s, 1 H),
solution. The aqueous phase was extracted with DCM. The organic 7.39 (s, 1 H), 7.20−7.19 (m, 2 H), 7.00−6.98 (m, 1 H), 3.76 (s, 3 H),
layer was combined, dried over Na2SO4, filtered, and evaporated. The 3.52−3.35 (m, 3 H), 3.17 (m, 1 H), 2.70 (dd, J = 10.0, 14.0 Hz, 1 H),
residue was purified by FCC (DCM-EtOAc, 3:1) to afford compound 2.58 (s, 3 H), 2.24 (br s, 2 H), 1.67 (s, 9 H); 13C NMR (100 MHz,
26 (628 mg, 82% yield) as a pale yellow liquid: [α]20 D − 11.6 (c 0.5, CDCl3) δ 166.4, 149.2, 137.2, 137.1, 128.1, 127.1, 126.2, 125.4, 124.8,
MeOH); 1H NMR (400 MHz, CDCl3) δ 9.78 (s, 1 H), 6.98 (dd, J = 123.7, 117.6, 114.0, 84.2, 56.8, 51.6, 50.8, 41.0, 28.6, 28.2, 25.7; IR
1.6, 6.0 Hz, 1 H), 4.11 (d, J = 18.4 Hz, 1 H), 3.71 (s, 3 H), 3.52−3.47 (KBr) 2959, 2931, 2792, 2343, 2178, 1738, 1704, 1424, 1369, 1354,
(m, 2 H), 2.70 (dd, J = 3.2, 19.6 Hz, 1 H), 2.57 (t, J = 7.6 Hz, 2 H), 1279, 1262, 1145, 1095 cm−1; HRMS (ESI) m/z calcd for
2.11 (m, 1 H), 1.92 (m, 1 H), 1.75 (m, 1 H), 1.17 (s, 9 H); 13C NMR C22H28ClN2O4 (M + H)+ 419.1732; found 419.1719.
(100 MHz, CDCl3) δ 201.1, 165.4, 136.1, 128.0, 58.8, 54.0, 51.6, 40.9, Compound 23. To a stirred solution of 2,2,6,6-tetramethylpiper-
36.4, 28.9, 24.5, 23.3; IR (KBr) 3401, 2952, 2927, 1714, 1658, 1435, idine (123 μL, 0.72 mmol) in THF (1 mL) was added n-BuLi (425 μL,
1385, 1361, 1266, 1075, 1023, 918 cm−1; HRMS (ESI) m/z calcd for 0.68 mmol, 1.6 M in hexanes) at 0 °C. After stirring for 30 min at
C28H47N2O8S2 (2M + H)+ 603.2768; found 603.2779. room temperature, the mixture was cooled to −78 °C. Compound 24
Compound 33. To a solution of compound 26 (400 mg, 1.3 (56.7 mg, 0.14 mmol) was dissolved in dried THF (1.5 mL), and
mmol) in anhydrous DMF (4.8 mL) were added the 3-chloro-2- added dropwise to the former mixture solution via syringe. After
iodoaniline (25) (676 mg, 2.66 mmol) and DABCO·6H2O (876 mg, stirring for 40 min, saturated aqueous NH4Cl solution was added. The
4.0 mmol) successively under an argon atmosphere. After oxygen was reaction mixture was then allowed to warm to 0 °C and stirred for 20
discharged with argon for 0.5 h, Pd(OAc)2 (119.4 mg, 0.52 mmol) was min. The organic layer was separated, and the aqueous phase was
added, and then the solution was heated at 80 °C for 6 h. The mixture further extracted with EtOAc (2 × 15 mL). The combined organic
was then filtered through a pad of Celite, extracted with EtOAc, phases were dried over Na2SO4. Purification by FCC (PE-EtOAc, 3:1)
washed with brine, dried over anhydrous Na2SO4, filtered, and afforded the mixed epimers 23 (42 mg, 74% yield, ratio = 2:1) as a
evaporated. The residue was purified by FCC (DCM-EtOAc, 3:1) to yellow oil: 1H NMR (400 MHz, CDCl3) δ 8.09 (br s, 1 H), 7.48 (s, 0.7
afford crude compound 32 (267 mg) as a yellow liquid. H), 7.44 (s, 0.3 H), 7.18−7.17 (m, 2 H), 5.90−5.87 (m, 1 H), 5.78−
The yellow liquid 32 mentioned above was dissolved in anhydrous 5.70 (m, 1 H), 3.74 (s, 0.9 H), 3.70 (s, 2.1 H), 3.58−3.53 (m, 0.7 H),
CH3CN. To the solution were added Boc2O (170 mg, 0.78 mmol) and 3.47−3.41 (m, 1 H), 3.26−3.16 (m, 2.3 H), 2.84−2.76 (m, 1.3 H),
DMAP (16 mg, 0.13 mmol), and the mixture was stirred for 6 h. The 2.67−2.62 (m, 0.7 H), 2.54−2.52 (m, 3 H), 1.66 (s, 9 H); 13C NMR
solution was concentrated in vacuo, and the residue was purified by (100 MHz, CDCl3) δ 173.5, 172.9, 149.2, 136.9, 130.6, 130.4, 127.3,
FCC (PE-EtOAc, 3:1) to afford compound 33 (272 mg, 39% yield two 127.2, 126.1, 125.8, 125.8, 124.7, 124.6, 123.7, 123.6, 122.9, 122.3,
steps) as a white foam: [α]20 1
D + 20.0 (c 0.5, MeOH); H NMR (400 117.2, 116.7, 113.9, 84.0, 84.0, 61.2, 60.5, 54.0, 52.0, 51.9, 50.7, 43.0,
MHz, CDCl3) δ 8.09 (d, J = 2.4 Hz, 1 H), 7.36 (s, 1 H), 7.21−7.19 42.7, 41.6, 38.8, 29.6, 29.5, 28.1; HRMS (ESI) m/z calcd for
(m, 2 H), 7.08 (d, J = 4.4 Hz, 1 H), 4.28 (d, J = 18.4 Hz, 1 H), 3.96 C22H28ClN2O4 (M + H)+ 419.1732; found 419.1721.
(dd, J = 7.2, 14.0 Hz, 1 H), 3.77 (s, 3 H), 3.64 (d, J = 18.4 Hz, 1 H), Compound 22. Compound 23 (30 mg, 0.072 mmol) dissolved in
3.18 (dd, J = 7.2, 14.4 Hz, 1 H), 3.04 (dd, J = 8.0, 14.0 Hz, 1 H), 2.61 dry dioxane (3.6 mL) was degassed for 30 min. P(t-Bu)3·HBF4 (21
(dd, J = 2.8, 18.8 Hz, 1 H), 2.24 (dd, J = 4.0, 18.8 Hz, 1 H), 1.67 (s, 9 mg, 0.072 mmol), Pd2(dba)3·CHCl3 (37 mg, 0.036 mmol), and
H), 1.02 (s, 9 H); 13C NMR (100 MHz, CDCl3) δ 165.6, 149.0, 137.1, Cy2MeN (42 mg, 0.22 mmol) were added to the reaction, and the
136.4, 128.0, 126.7, 125.9, 125.7, 125.0, 123.8, 117.0, 114.0, 84.4, 58.4, resulting reaction mixture was heated at 100 °C under an argon
56.7, 51.6, 35.3, 29.0, 28.1, 27.2, 23.0; IR (KBr) 2980, 2951, 1737, atmosphere for 1.5 h. After cooling, the reaction was quenched with
1660, 1424, 1372, 1355, 1255, 1153, 1101, 1080 cm−1; HRMS (ESI) saturated aqueous NH4Cl, followed by addition of EtOAc (5 mL). The
m/z calcd for C25H34ClN2O5S (M + H)+ 509.1877; found 509.1881. organic layer was separated, and the aqueous phase was further
Compound 34. Compound 33 (360 mg, 0.71 mmol) was extracted with EtOAc (2 × 30 mL). The combined organic phases
dissolved in a 1:1 mixture of anhydrous 1,4-dioxane and anhydrous were washed with brine and dried over Na2SO4. Purification by FCC
MeOH (4.3 mL), and anhydrous HCl in dioxane (4 M solution in (PE-EtOAc, 3:1) afforded the starting material 23 (8.1 mg, 27% yield)
dioxane, 0.7 mL) was added. After the mixture was stirred at room and the product 22 (5.0 mg, 25% yield brsm) as a yellow solid: [α]20 D −
temperature for 1 h, all volatiles were removed in vacuo, and the 163 (c 1.23, CHCl3); 1H NMR (400 MHz, CDCl3) δ 7.80 (s, 1 H),
residue was dissolved in water and extracted with EtOAc. The water 7.29−7.33 (m, 2 H), 7.13 (d, J = 7.28 Hz, 1 H), 7.05 (s, 1 H), 4.06 (s,
layer was basified to pH 8 with aqueous saturated NaHCO3 and 1 H), 3.71 (s, 3 H), 3.50 (d, J = 17.4 Hz, 1 H), 3.35−3.39 (m, 2 H),
extracted with EtOAc. Combined organic extracts were washed with 2.95 (m, 1 H), 2.70 (m, 1 H), 2.60 (s, 3 H), 1.66 (s, 9 H); 13C NMR
brine, dried over Na2SO4, and concentrated in vacuo. The residue was (100 MHz, CDCl3) δ 166.0, 150.1, 140.4, 133.5, 131.6, 129.0, 127.1,
purified by FCC (EtOAc) to afford compound 34 as a yellow liquid 125.6, 120.0, 119.8, 115.4, 113.5, 83.4, 57.3, 51.6, 48.8, 42.3, 39.3, 37.4,
(255 mg, 89% yield): [α]20 D − 45.0 (c 0.5, MeOH); H NMR (400
1
28.2; IR (KBr) 3434, 2922, 1730, 1257, 1116, 802 cm−1; HRMS (ESI)
MHz, CDCl3) δ 8.13 (d, J = 6.4 Hz, 1 H), 7.47 (s, 1 H), 7.23−7.18 m/z calcd for C44H53N4O8 (2M + H)+ 765.3858; found 765.3856.
(m, 2 H), 7.02 (bs, 1 H), 3.72−3.69 (m, 4 H), 3.47 (dd, J = 2.4, 16.8 (+)-Lysergic Acid (1). To a solution of compound 22 (31 mg, 0.08
Hz, 1 H), 3.24 (dd, J = 4.4, 14.4 Hz, 1 H), 3.15−3.08 (m, 1 H), 2.82 mmol) in ethanol (1 mL) was added 1 N KOH (1 mL). The reaction

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was heated at 70 °C for 3 h. The hot solution was treated with Baitz, E.; Szántay, C. J. Org. Chem. 2004, 69, 5993−6000. (o) Inoue,
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found 269.1285.

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* Supporting Information
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1
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(8) (a) Noland, W. E. Chem. Rev. 1955, 55, 137−155. (b) Ballini, R.;
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AUTHOR INFORMATION (9) Ohtake, N.; Yamada, K.; Mano, E.; Okamoto, O.; Ushijima, R.;
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The authors declare no competing financial interest. 2358. (b) Terao, Y.; Fukuoka, Y.; Satoh, T.; Miura, M.; Nomura, M.

■ ACKNOWLEDGMENTS
This research was supported by the National Natural Science
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