reactions of elaborate disubstituted alkynes through iodo-
cyclization,4 intramolecular Michael addition,5 or Wacker-
type oxypalladation involving the use of palladium.6 One-pot
transformations, while rare,7 are restricted in substrate scope
and provide low yields and low stereoselectivity. Therefore,
the challenge remains to develop concise one-pot procedures
for the production of highly functionalized alkylidene phtha-
lans with high efficiency and stereoselectivity.
Scheme 1. Stepwise Formation of an Alkylidene Phthalan
In this regard, we became interested in the tertiary
phosphine-assisted nucleophilic Michael addition of alco-
hols onto activated acetylenes to give functionalized β-
benzyloxy acrylates.8,9 With the goal of using these highly
versatile β-benzyloxy acrylate intermediates for further
generation of molecular complexity, we envisioned a sub-
sequent cross-coupling event to take advantage of the
compatibility of phosphines and palladium. Initially, in
the presence of a phosphine, Michael addition of o-iodo-
benzyl alcohol to a propiolate generates a β-(o-iodo-
benzyloxy)acrylate. Then, employing the pre-existing
phosphine as a ligand to promote the reduction of Pd(II)
to Pd(0),10 the β-(o-iodobenzyloxy)acrylate undergoes in-
tramolecular Heck cyclization.11 Joining these two trans-
formations into a one-pot MichaelÀHeck procedure allows
the synthesis of highly functionalized alkylidene phthalans.
We suspected that a tandem MichaelÀHeck approach
would offer rapid access to a group of rare fungal metabo-
lites;isoochracinol (1), isoochracinic acid (2), and 3-deoxy-
isoochracinic acid (3);from the genus Cladosporium.12
Among these compounds, 3-deoxyisoochracinic acid (3) ex-
hibits antibacterial activity, inhibiting the growth of B. subtilis,
a known cause of food poisoning (Figure 1).13
adding methyl propiolate into a solution of o-iodobenzyl
alcohol and PPh3 in MeCN under reflux under Ar pro-
vided methyl β-(o-iodobenzyloxy)acrylate in 99% isolated
yield after purification (Scheme 1). This Michael reaction
produced a 10:1 mixture of E and Z isomers, which we
separated and characterized unambigiously.14 We then
subjected the mixture of β-(o-iodobenzyloxy)acrylates to
Heck conditions, cleanly affording the target annulation
product 7a, isolated as the major (Z) isomer.15
To incorporate this nucleophilic phosphine-catalyzed Mi-
chael addition into a sequential-catalysis process, we ex-
plored the possibility of executing the Pd(0)-catalyzed Heck
cyclization without isolation of the β-(o-iodobenzyloxy)-
acrylate intermediate. First, using PPh3 to catalyze the
Michael addition, we formed the desired Michael adduct
rapidly. Next, we introduced Pd(OAc)2, tetrabutylammo-
nium chloride (TBACl), and K2CO3 to the same flask. After
8 h, we isolated the major cyclic alkylidene phthalan 7a in
76% yield as the Z isomer, with complete consumption of
the β-(o-iodobenzyloxy)acrylate intermediate 6 (Scheme 2).
The one-pot procedure was operationally simpler and more
efficient (76% yield) than the two-pot process (61%).
Scheme 2. Preliminary Investigation of Sequential Catalysis
Figure 1. Rare fungal metabolites.
Before proceeding to the one-pot transformation, we
investigated the efficiency of each reaction step. Slowly
Based on the yields of our two-pot synthesis, we targeted
the Heck reaction to optimize the overall reaction effi-
ciency (Scheme 1). The reaction rate decreased dramatically,
providing only a trace of product, in the absence of TBACl
(Table 1, entries 1 and 2), which is known to improve the
yields of Heck reactions.16 From a screening of palladium
catalysts, Pd(OAc)2 appeared to be the optimal Heck
cyclization catalyst in the presence of PPh3, TBACl, and
K2CO3 in MeCN under Ar (entry 6). To further improve
(4) Mancuso, R.; Mehta, S.; Gabriele, B.; Salerno, G.; Jenks, W. S.;
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(14) We assigned the E and Z isomers based on the coupling
constants of their vinyl protons. See the Supporting Information for
detailed NMR studies, including 1H, 13C, and NOESY NMR spectra.
(15) Subjecting the minor E-phthalan to the reaction conditions led
to its isomerization to the favored Z form, the major product once the
reaction reached equilibrium.
(9) Inanaga, J.; Baba, Y.; Hanamoto, T. Chem. Lett. 1993, 2, 241.
(10) Dieck, H. A.; Heck, R. F. J. Am. Chem. Soc. 1974, 96, 1133.
(11) Heck, R. F. J. Am. Chem. Soc. 1968, 90, 5518.
(12) These fungal metabolites exist as racemates in nature.
€
(13) Holler, U.; Gloer, J. B.;Wicklow, D. T. J. Nat. Prod. 2002, 65, 876.
(16) Jeffery, T. J. Chem. Soc., Chem. Commun. 1984, 1287.
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