Regioselective ring-closing metathesis on terpenoid acrylates and acrylamides

Article abstract of DOI:10.1016/S0040-4039(01)01179-0

A series of acrylate esters was prepared by treatment of representative terpenoid aldehydes with allyl or vinyl magnesium bromide followed by reaction with acryloyl chloride. In all cases, ring-closing metathesis (RCM) resulted in regioselective formation

Full text of DOI:10.1016/S0040-4039(01)01179-0

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 42 (2001) 6069–6072
Regioselective ring-closing metathesis on terpenoid
acrylates and acrylamides
Yanming Du and David F. Wiemer*
Department of Chemistry, University of Iowa, Iowa City, IA 52242, USA
Received 21 May 2001; revised 26 June 2001; accepted 27 June 2001
Abstract—A series of acrylate esters was prepared by treatment of representative terpenoid aldehydes with allyl or vinyl
magnesium bromide followed by reaction with acryloyl chloride. In all cases, ring-closing metathesis (RCM) resulted in
regioselective formation of unsaturated lactones through metathesis of the acrylate and terminal olefins. After condensation of
farnesal with a primary amine, a parallel series of reactions led to formation of the corresponding lactam. © 2001 Elsevier Science
Ltd. All rights reserved.
Ring-closing metathesis has become a well-established
strategy for construction of a wide range of cyclic
structures.1 Various studies have shown that the most
popular metathesis reagent, the Grubbs catalyst 1, can
tolerate a number of polar functional groups.2 Its reac-
tivity with any specific substrate is influenced by a
combination of the steric and electronic effects of sub-
stituents on the reacting olefins as well as entropic
factors,3 but most ring-closing metathesis reactions
have been reported on diene substrates that contain no
other alkenes. Some recent studies3a,4 have reported
reaction of the two less-substituted olefins in trienes,
but information on metathesis in systems containing
multiple double bonds with varied substitution patterns
is still limited.
homoallylic alcohols has been used to form unsaturated
five- and six-membered ring lactones.4c,6 However, at
this time there is no literature precedent for such reac-
tions in the presence of the other double bonds typical
of common terpenoids. In this communication, we
describe the construction of conjugated lactones on
terpenoid templates via the regioselective ring-closing
metathesis of acrylate esters.
As shown in Scheme 1, the general approach involved
addition of allyl or vinyl magnesium bromide to a
terpenoid aldehyde. The initial Grignard adduct could
be quenched by addition of acryloyl chloride (Method
A) or isolated as the alcohol and then esterified by
treatment with acryloyl chloride (2 equiv.) and triethyl-
amine (3 equiv.) (Method B).7 In acrylates of the
general structure 3 or 5 without additional olefins in the
R group, treatment with Grubbs catalyst would be
expected to afford an unsaturated lactone. But to test
whether metathesis would be successful in the presence
In connection with our studies of farnesol derivatives,5
a convenient method to append a,b-unsaturated lac-
tones on a terpenoid skeleton was needed. The ring-
closing metathesis of acrylates derived from allylic and
Scheme 1.
* Corresponding author. Fax: 319-335-1270; e-mail: david-wiemer@uiowa.edu
0040-4039/01/$ - see front matter © 2001 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(01)01179-0

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of the olefins typical of different terpenoids, this reac-
tion sequence was applied to a small set of terpene
aldehydes as shown in Table 1.
cyclic product in very good yield despite the abundance
of potential cyclization reactions.
The regioselectivity reflected by the results summarized
in Table 1 can be attributed to the preference of this
catalyst for reaction at the less substituted olefins and
the proximity of two monosubstituted olefins in each
case. Trisubstituted olefins are known to undergo
metathesis as shown by Hoye and Zhao in studies of
linalool-derived dienes containing one tri- and one
monosubstituted olefin.10 However, they suggested that
the trisubstituted olefin reacted with an alkylidene
derived from an initial reaction of the catalyst with the
monosubstituted olefin. By analogy, in the examples
listed in Table 1, it is likely that metathesis is initiated
by reaction of the monosubstituted olefin in a substrate
such as pentaene 17 with the catalyst 1 to afford the
alkylidene 21 followed by cyclization with the acrylate
olefin to afford the lactone 18 (Scheme 2). This reaction
sequence would generate the observed lactones and
methylidene. The tri- and geminally disubstituted dou-
ble bonds of the various terpenoids in Table 1 would
neither initiate the olefin metathesis nor display com-
petitive reactivity for the ruthenium alkylidenes. This is
in agreement with Grubbs observation that the catalyst
(R)-(+)-Citronellal (7), the simplest of the aldehydes
examined with just one remote olefin, undergoes addi-
tion of allyl magnesium bromide and reaction with
acryloyl chloride to give the desired ester 8 in good
yield. Treatment of compound 8 with Grubbs reagent
(1) gave the desired lactone 9 in 86% yield as a 1.1:1
mixture of diastereomers, with no detectable amounts
of either regioisomeric metathesis product. The
sequence worked just as well with aldehydes containing
two olefins. With geranial (10), after allyl addition and
formation of the acrylate ester 11, metathesis gave the
racemic lactone 12 in 73% yield as the only metathesis
product.8 With (S)-(−)-perillaldehyde (13), allyl addi-
tion and reaction with acryloyl chloride gave the ester
14 as the expected mixture of diastereomers. Once
again only a single metathesis product was obtained
(15) albeit as a 1:1 mixture of diastereomers. Finally,
with farnesal (16) as the starting aldehyde, this
sequence gave the pentaenes 17 from reaction with allyl
magnesium bromide and 19 from reaction with vinyl
magnesium bromide. In both cases, treatment with the
Grubbs catalyst followed by DMSO9 gave the desired
Table 1. Synthesis and metathesis of terpenoid acrylates

Y. Du, D. F. Wiemer / Tetrahedron Letters 42 (2001) 6069–6072
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Scheme 2.
Scheme 3.
1 could not initiate metathesis with gem-disubstituted
olefins.3a
References
1. For recent reviews, see: (a) Furstner, A. Angew. Chem.,
Int. Ed. 2000, 39, 3013–3043. (b) Trnka, T. M.; Grubbs,
R H. Acc. Chem. Res. 2001, 34, 18–29.
2. (a) Fu, G. C.; Nguyen, S. T.; Grubbs, R. H. J. Am.
Chem. Soc. 1993, 115, 9856–9857; (b) Grubbs, R. H.;
Miller, S. J.; Fu, G. C. Acc. Chem. Res. 1995, 28,
446–452; (c) Schwab, P.; Grubbs, R. H.; Ziller, J. W. J.
Am. Chem. Soc. 1996, 118, 100–110; (d) Armstrong, S. K.
J. Chem. Soc., Perkin Trans. 1 1998, 371–388.
Given the positive results observed with formation of
the farnesyl derivative 18, we attempted to extend this
approach to preparation of the corresponding lactam.
Because an unprotected acrylamide has been found to
undergo ring-closing metathesis in low yield,11 a p-
methoxybenzyl group was incorporated as a protecting
group. As shown in Scheme 3, condensation of farnesal
(16) with p-methoxybenzylamine afforded the interme-
diate imine 22, which was treated with allyl magnesium
bromide without isolation to afford the secondary
amine 23. After reaction with acryloyl chloride, the
resulting amide 24 was treated with Grubbs catalyst to
afford the lactam 25 in good yield.
3. (a) Kirkland, T. A.; Grubbs, R. H. J. Org. Chem. 1997,
62, 7310–7318; (b) Ulman, M.; Grubbs, R. H.
Organometallics 1998, 17, 2484–2489.
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In conclusion, metathesis of acrylate esters derived
from different terpene aldehydes, as well as an acrylam-
ide derived from farnesal, has been shown to afford
lactone and lactam products in good yield and with
excellent regioselectivity. Further studies on the appli-
cation and biological activity of these terpenoid deriva-
tives will be reported in due course.
Acknowledgements
Financial support from the Roy J. Carver Charitable
6. Ghosh, A. K.; Cappiello, J.; Shin, D. Tetrahedron Lett.
1998, 39, 4651–4654.
Trust is gratefully acknowledged.
.

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7. The acrylate esters 8, 11, 14 were purified by column
3H), 1.68 (d, J=1.0 Hz, 3H), 1.60 (s, 3H); 13C NMR
(CDCl3, 100 MHz) l 164.5, 145.0,142.8, 132.0, 123.5,
121.8, 121.6, 74.9, 39.4, 29.9, 26.2, 25.7, 17.7, 16.8;
HRMS calcd for C14H21O2 (M++H) 221.1542, found
221.1538.
chromatography on an aluminum oxide column. Com-
pound 19 was used in the next step directly without
further purification. All other intermediates and the final
products were purified by column chromatography on
silica gel.
9. Ahn, Y. M.; Yang, K. L.; Georg, G. I. Org. Lett. 2001,
3, 1411–1413.
10. Hoye, T. R.; Zhao, H. Org. Lett. 1999, 1, 1123–1125.
11. Rutjes, F. P. J. T.; Schoemaker, H. E. Tetrahedron Lett.
1997, 38, 677–680.
8. Spectral data for compound 12: 1H NMR (CDCl3, 400
MHz) l 6.89 (ddd, J=9.8, 5.3, 3.1 Hz, 1H), 6.04 (ddd,
J=9.8, 2.3, 1.4 Hz, 1H), 5.35 (dq, J=8.5, 1.2 Hz, 1H),
5.16 (ddd, J=9.8, 8.6, 5.3 Hz, 1H), 5.11–5.04 (m, 1H),
2.46–2.31 (m, 2H), 2.16–2.02 (m, 4H), 1.72 (d, J=1.3 Hz,
.