Synthesis of substituted a-methylene-g-butyrolactones from chloroformates via
palladium catalysed cyclisation–anion capture
Ronald Grigg* and Vladimir Savic
Molecular Innovation, Diversity and Automated Synthesis (MIDAS) Centre, School of Chemistry, Leeds University,
Leeds, UK LS2 9JT
Received (in Cambridge, UK) 17th August 2000, Accepted 5th October 2000
First published as an Advance Article on the web
Cyclisation of chloroformates onto proximate alkyne func-
tionality in the presence of a Pd(0) catalyst followed by anion
capture affords a-methylene-g-butyrolactone derivatives in
moderate to good yields.
moderate to good yields (Table 1, entries a–e) as the only
product. The stereochemistry of all the g-butyrolactones
described in this communication was established from NOE
data. The presence of a terminal substituent on the alkyne
moiety of the chloroformates (Table 1, entries f and g) resulted
in formation of the expected product together with the direct
capture product 4. It is likely that sterically induced slower
cyclisation due to the presence of a terminal substituent caused
the formation of the direct capture products 4.
The (Z-)-lactone isomer formed in the above reactions can be
easily isomerised via Michael addition–retro Michael to
produce the (E)-isomer in almost quantitative yield by heating
in the presence of excess of a secondary amine (Scheme 4). The
opening of the lactone ring was not observed in this reaction.
a-Methylene-g-butyrolactones constitute an important group of
natural products possessing a range of biological activities.1
Their biological profiles are based on the specific reactivity of
the a,b-unsaturated functionality acting, in most cases, as a
Michael acceptor in reactions with biological nucleophiles.2
The importance of this class of compounds has led to a number
of synthetic procedures for the preparation of a-methylene-g-
butyrolactone derivatives.2,3 Our approach is based on our
palladium catalysed cascade cyclisation–anion capture method-
ology, (Scheme 1).4 In the current context cyclisation of
appropriate chloroformates onto the alkyne functionality in the
presence of a Pd-catalyst would produce a vinylpalladium
moiety suitable for further functionalisation by an anion-capture
reagent.
Scheme 1
Compared to the existing Pd-based methodology5 for the
preparation of a-methylene-g-butyrolactones this approach
allows direct access to b-substituted derivatives of this
important class of compounds. In a recent communication we
report similar methodology for the preparation of oxindole
derivatives.6
Scheme 2
The required chloroformates (1) were readily prepared from
homopropargylic alcohols 2 by stirring the alcohol with excess
of COCl2 in toluene at rt for 16 h, (Scheme 2). These alcohols,
if not commercially available, were easily prepared using a
standard propargylation procedure of aldehydes in the presence
of activated zinc (Scheme 2).
The cyclisation reactions (Scheme 3, Table 1) of chloro-
formates in the presence of an equimolar amount of NaBPh4 as
the anion capture reagent were performed in THF at 65–70 °C
(oil bath temperature) in the presence of Pd(OAc)2 (10 mol%)–
PPh3 (20 mol%). In cases of terminally unsubstituted alkyne
functionality the expected g-butyrolactones were isolated in
Scheme 3
Table 1
Entry
Chloroformate (1)
Lactone (3)
Benzoate (4)
Yield (%)a
a
b
c
d
e
f
R1 + H, R2 = H
R1 = H, R2 = H
—
—
—
—
51
51
55
73
49
64b
65c
R1 = H, R2 = CH3
R1 = H, R2 = CH3CH2
R1 = H, R2 = C6H13
R1 = H, R2 = Ph
R1 = H, R2 = CH3
R1 = H, R2 = CH3CH2
R1 = H, R2 = C6H13
R1 = H, R1 = Ph
—
R1 = CH3, R2 = H
R1 = CH3CH2, R1 = H
R1 = CH3, R2 = H
R1 = CH3CH2, R2 = H
R1 = CH3, R2 = H
R1 = CH3CH2, R2 = H
g
a Isolated yields. b Combined yield, ratio 1+1. c Combined yield, ratio 1.3+1.
DOI: 10.1039/b006842j
Chem. Commun., 2000, 2381–2382
This journal is © The Royal Society of Chemistry 2000
2381
Grigg
