we have accomplished the synthesis of clavicipitic acid,
aurantioclavine, and indolactam V. In order to further
define its application scope in the total synthesis of natural
products, we describe herein the total synthsis of (þ)-
lysergic acid from (R)-4-iodotryptophan derivative 5.
Retrosynthetic analysis of lysergic acid 1 is shown in
Scheme 1. We envisioned that the C ring could be con-
structed by utilizing γ-arylation of R,β-unsaturated ester 3
or intramolecular Heck reaction of olefin 2.3k Both com-
pounds 2 and 3 already have the A/B/D ring system. The
olefin 2 can be accessed from R,β-unsaturated ester 3 via
isomerization of the double bond. The double bond in
intermediate 3 could be formed by an intramolecular ring-
closing metathesis reaction of 4,8 which could be readily
obtained by a series of conversions of functional groups
from (R)-4-iodotryptophan derivative 5. (R)-5, possessing
the C5 stereogenic center of lysergic acid 1, could be
synthesized starting from D-glutamic acid following the
same procedures as described for its enantiomer (S)-5
using the Pd-catalyzed indole synthesis as the key step.5c
Our synthesis of lysergic acid commenced with (R)-5
(Scheme 2). Thus, N-methylation of 5 with MeI and Ag2O
in DMF provided 6 in 83% yield. Reduction of 6 with
Figure 1. Structure of (þ)-lysergic acid.
intermediate,3j (2) Fukuyama’s synthesis in 2009 utilizing a
double-cyclization strategy and an intramolecular Heck
reaction,3k and (3) Ohno’s synthesis in 2011 employing
palladium-catalyzed domino cyclization of allenes.3l
Scheme 1. Retrosynthesis of (þ)-Lysergic Acid
9
LiBH4 followed by Swern oxidation gave aldehyde 7 in
83% overall yield. Wittig reaction of aldehyde 7 with the
reagent derived from methoxymethylene phosphonium chlor-
ide yielded the desired methyl enol ether 8 (trans/cis = 4:5) in
86% yield. Hydrolysis of 8 with Hg(OAc)2/KI provided
the aldehyde 9 in 95% yield.10 Witting reaction of aldehyde
9 afforded the terminal olefin 10 in 92% yield. Deprotec-
tion5a of the Boc group of 10 with TMSOTf followed by N-
alkylation11 with methyl 2-(bromomethyl)acrylate12 afforded
the diene 4 in 76% yield.
Following the synthesis of diene 4, the key RCM reac-
tion was exploited. It is well-known that the presence of
basic amines in the metathesis reaction reduces the catalyst
efficiency due to the interactions of the lone pair of
electrons on nitrogen with the metal center.13 Modifica-
tions of the reactant using the corresponding ammonium
salts or addition of protic14 or Lewis15 acid have been
widely used. Thus, 4 was first treated with Grubbs second-
generation catalyst in the presence of Lewis acid Ti(O-i-Pr)4
Recently, an appealing synthetic method for benzofun-
tionalized indoles, especially for optically pure tryptophan
derivatives, through a Pd-catalyzed reaction of o-haloani-
lines and aldehydes has been developed by Jia and Zhu.4
The method has already been applied in the synthesis of
some natural products.5ꢀ7 Taking advantage of this meth-
odology for the assembly of 4-halotryptophan derivatives,
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