An enyne metathesis/(4 + 2)-dimerization route to (±)-differolide

Article abstract of DOI:10.1021/ol9905912

(equation presented) A concise total synthesis of (±)-differolide (1) has been achieved. 2-Vinylbutenolide (2) was prepared by enyne metathesis of allyl propynoate (3) usinq the Grubbs initiator 4. This reaction was examined by ¹H NMR spectroscopy, which led to the hypothesis that low concentration of ruthenium species and high concentration of enyne substrate would be advantageous. Accordingly, slow addition of 4 to solutions of enyne 3 was found to be beneficial. Spontaneous dimerization of 2 gave (±)-differolide (1) and an isomer.

Full text of DOI:10.1021/ol9905912

ORGANIC
LETTERS
1
999
Vol. 1, No. 2
77-279
An Enyne Metathesis/(4 + 2)-
Dimerization Route to (±)-Differolide
2
Thomas R. Hoye,* Scott M. Donaldson, and Tricia J. Vos
Department of Chemistry, UniVersity of Minnesota, Minneapolis, Minnesota 55455
hoye@chem.umn.edu
Received April 14, 1999
ABSTRACT
A concise total synthesis of (±)-differolide (1) has been achieved. 2-Vinylbutenolide (2) was prepared by enyne metathesis of allyl propynoate
1
(
3) using the Grubbs initiator 4. This reaction was examined by H NMR spectroscopy, which led to the hypothesis that low concentration of
ruthenium species and high concentration of enyne substrate would be advantageous. Accordingly, slow addition of 4 to solutions of enyne
was found to be beneficial. Spontaneous dimerization of 2 gave (±)-differolide (1) and an isomer.
3
(()-Differolide (1) was isolated in 1986 from cultures of
the actinomycete Streptomyces aurantiogriseus, strain Tu¨
Scheme 1
1
3
149. The structure was determined by single-crystal X-ray
1
analysis and is supported by the H NMR spectroscopic data.
That this compound is racemic suggested to us that a (perhaps
spontaneous) Diels-Alder reaction of 2-vinylbutenolide (2)
might be a key event in its formation. Indeed, this consid-
eration raises the possibility that (()-1 is not naturally
occurring but could have been first formed during isolation.
We have now synthesized 2 by enyne metathesis of allyl
2
propynoate (3) using the Grubbs initiator carbene complex
3
4
. In fact, 2-vinylbutenolide readily dimerizes to give (()-
istry. The subset of carbene-mediated enyne metathesis
reactions can proceed by either of two pathways (Scheme
2). Initial intermolecular reaction of the metal-carbene
complex can occur either with the alkyne or the alkene.
Subsequent intramolecular involvement of the alkene or
alkyne, respectively, results in formation of the same
conjugated diene product. These two possibilities are por-
trayed specifically for conversion of enyne 3 to 2-vinyl-
butenolide 2 in Scheme 2.
4
differolide (1) as the major product (Scheme 1).
Enyne metathesis (one version of the larger class of enyne
cycloisomerization reactions ) can be promoted by various
metals and may or may not involve metal-carbene chem-
5
6
(
1) Keller-Schierlein, W.; Bahnm u¨ ller, U.; Dobler, M.; Bielecki, J.;
St u¨ mpfel, J.; Z a¨ hner, H. HelV. Chim. Acta 1986, 69, 1833-1836.
2) Balas, L.; Jousseaume, B.; Langwost, B. Tetrahedron Lett. 1989, 30,
525-4526.
3) Schwab, P.; Grubbs, R. H.; Ziller, J. W. J. Am. Chem. Soc. 1996,
18, 100-110.
4) A stereoselective (21 step) synthesis of each enantiomer of differolide
(
4
(
1
We examined the reaction of 3 with 4 by H NMR
1
spectroscopy to look for one or more of the obligatory
intermediates 5-7 and/or 8-10. Thus, substrate 3 (0.025
M) and benzylidenecarbene 4 (∼25 mol %; RudCHPh at δ
(
has been reported. Mori, K.; Tomioka, H.; Fukuyo, E.; Yanagi, K. Liebigs
Ann. Chem. 1993, 671-681.
(
5) Mori, M. J. Synth. Org. Chem. Jpn. 1998, 56, 433-442.
6) Trost, B. M.; Krische, M. J. Synlett 1998, 1-16.
(
2 2
) 20.02 ppm) were combined in CD Cl at room tempera-
1
0.1021/ol9905912 CCC: $18.00 © 1999 American Chemical Society
Published on Web 06/04/1999

Table 1. Reaction Conditions for Metathesis of Enyne 3a
Scheme 2
mol %
Ru
addition
time
[diene 2]:
[styrene]b convnc
%
entry [enyne 3]
1
2
3
4
0.03 M
0.10 M
1.0 M
10
5d
one portion
5 h
2:1
8:1
9:1
9:1
20
50
50
5d
30 h
37 h
0.10 M
10d
100
a
Methylene chloride solvent at ambient temperature. b Measured by
1
integration of the H NMR spectrum of an aliquot of the reaction mixture
(
using solvent suppression of the CH2Cl2 resonance at δ 5.3 ppm).
Measured as the [diene 2]/[enyne 3]. Added as an ∼0.04 M solution in
c
b
d
CH2Cl2.
tion of 3 was increased while the concentration of complex
4
was minimized. It is noteworthy that the progress of these
1
reactions was conveniently monitored by H NMR analysis
of aliquots of the reaction mixtures even when nondeuterated
CH Cl was the reaction solvent. By using a straightforward
2 2
suppression of the solvent resonance at δ 5.3 ppm in these
unlocked samples, we were able to obtain high-quality
spectra for identification of major and minor reaction
components, even when starting substrate concentrations
were as low as 0.01 M. The best overall reaction conditions
we have found use a syringe pump to add slowly a solution
of the initiator 4 to a solution of 3 at relatively high
concentration. When the carbene 4 was added in a single
portion (entry 1), reaction progress stopped at only ∼20%
conversion (i.e., ∼two turnovers per Ru). The effective
concentration of initiator 4 was then reduced by slow addition
of just 5 mol % of the carbene to solutions of higher
concentration of enyne 3 (entries 2 and 3), which resulted
in higher turnover and conversion. Addition of a larger
amount of carbene 4 over a longer time (entry 4) resulted in
complete consumption of enyne 3. On a preparative scale,
these conditions provided 2-vinylbutenolide (2) in 40%
isolated yield (MPLC).
ture. New carbene proton resonances at δ ) 18.91 (t, J ) 4
Hz) and 20.24 (s) ppm, which we attribute to the alkylidene
intermediate 8 and vinylcarbene 10, respectively, quickly
appeared. While these observations do not rule out the “yne-
then-ene” pathway (intermediates 5-7 lack carbene alkyl-
idene protons), they do provide direct evidence that the “ene-
then-yne” pathway is viable. Styrene was also produced,
which is further evidence for the initial generation of 8 from
reaction of 3 with 4.
An important ramification of the “ene-then-yne” pathway
is that substrate concentration is critical; i.e., product 2 is
not released until intermediate 10 encounters another mol-
ecule of enyne 3. This suggests that higher substrate
concentrations should be advantageous. However, we have
elsewhere observed that the autodecomposition of starting
benzylidene initiator 4 occurs faster at higher concentrations.
Taken together, these observations prompted the series of
experiments summarized in Table 1 in which the concentra-
(8) (a) Sydnes, L. K.; Skattebøl, L.; Chapleo, C. B.; Leppard, D. G.;
Svanholt, K. L.; Dreiding, A. S. HelV. Chim. Acta 1975, 58, 2061-2073.
(b) Goldberg, O.; Dreiding, A. S. HelV. Chim. Acta 1976, 59, 1905-1910.
(
c) McIntosh, J. M.; Sieler, R. A. J. Org. Chem. 1978, 43, 4431-4433. (d)
Hoffmann, H. M. R.; Rabe, J. Angew. Chem., Int. Ed. Engl. 1983, 22, 795-
796. (e) Poly, W.; Schomburg, D.; Hoffmann, H. M. R. J. Org. Chem.
1988, 53, 3701-3710. (f) Alanine, A. I. D.; Fishwick, C. W. G.; Jones, A.
D.; Mitchell, M. B. Tetrahedron Lett. 1989, 30, 5653-5654. (g) N a´ jera,
C.; Manche n˜ o, B.; Yus, M. Tetrahedron Lett. 1989, 30, 6085-6088. (h)
Spino, C.; Crawford, J. Can. J. Chem. 1993, 71, 1094-1097. (i) Hoffmann,
R.; Mattay, J.; Banning, A.; Rodewald, U.; M o¨ ller, M. M. J. Prakt. Chem./
Chem.-Ztg. 1994, 336, 343-349. (j) Spino, C.; Pesant, M.; Dory, Y. Angew.
Chem., Int. Ed. Engl. 1998, 37, 3262-3265. (k) Spino, C.; Crawford, J.;
Cui, Y.; Gugelchuk, M. J. Chem. Soc., Perkin Trans. 2 1998, 1499-1506.
(7) 2-Vinylbutenolide (2) was initially prepared (Donaldson, S. M. Ph.D.
Thesis, University of Minnesota, 1990) from (i) 2-bromo-2-butenolide
(
coupling of 3-bromo-2-TBSO-furan with various vinyl-metal species),
(
9) For example, the parent 2-carbomethoxybutadiene (i) dimerizes at
(ii) trimethylsilyl vinyl acetate (aldol addition to 2-bromoacetaldehyde
8
room temperature to give ii (mikanecic acid dimethyl ester), exclusively.
This adduct arises from reaction of the more electron deficient dienophilic
π-bond in i [as does the minor adduct 11 in the dimerization of
followed by lactonization and dehydration), or (iii) ethyl crotonate (aldol
with THPOCH2CHO, and various lactonization/dehydration sequences).
These routes were far less efficient than the enyne metathesis described
2
-vinylbutenolide (2)] and results in para-selectivity (in contrast to the meta-
1
now. H NMR (500 MHz, CDCl3) δ 7.29 (t, J ) 2.5 Hz, 1H), 6.44 (dddd,
orientation of the carbonyl groups observed in the minor isomer 11).
J ) 17.5, 11.5, 1, 1 Hz, 1H), 6.26 (dddd, J ) 17.7, 1, 1, 1 Hz, 1H), 5.48
(
dddd, J ) 10.8, 1, 1, 1 Hz, 1H), and 4.82 (dddd, J ) 2, 1, 1, 1, 1 Hz, 2H);
13
C NMR (75 MHz, CDCl3) δ 173.0, 144.6, 130.2, 125.2, 121.2, and 69.6;
IR (0.008 M in CDCl3) 3010, 2930, 2860, 1755, 1620, 1580, 1440, 1400,
1
7
-
1
340, 1310, 1300, 1210, 1200, 1100, 1060, 1030, and 990 cm ; MS (EI,
+
0 eV, m/z, rel int) 110 (M , 60), 82 (43), 81 (50), and 53 (100).
278
Org. Lett., Vol. 1, No. 2, 1999

Scheme 3
Table 2. Reaction Conditions for Dimerization of
-Vinylbutenolide (2)
2
tem-
entry solvent perature
time
additive % 1a % 11a % 2a
1
2
3
4
5
6
7
8
9
none
none
CDCl3b
CDCl3b
CDCl3b
CDCl3b
CDCl3b
C6D6b
C6D6b
rt
0 °C
rt
rt
rt
50 °C
50 °C
75 °C
75 °C
3 days
10 days
10 days
14 days
14 days
1 day
1 day
12 h
12 h
none
none
none
BHTc
MBd
none
BHTc
none
MBd
9
10
5
31
29
(91)
(88) (12)
(89) (11)
(89) (11)
1
1
27
30
0.6 35
4
4
18
20
(0)
(0)
(0)
(0)
(9)
7
The first sample of 2 we isolated underwent spontaneous
dimerization when stored neat at room temperature. (The
dimerizations of related 2-carbonyl-substituted butadiene
8
derivatives have been studied and are also remarkably
facile. ) Two adducts (from among eight possible racemic
regio- and stereoisomeric 4 + 2 dimers) were observed in
an ∼9:1 ratio (Scheme 3). The major compound was (()-
differolide (1, mp 171-175 °C). The minor component was
a Isolated yields after MPLC on silica gel. Numbers in parentheses
9
1
b
represent product ratios measured directly by H NMR analysis. Solution
c
experiments were performed at a concentration of ∼0.75 M. 2,6-Di-tert-
butyl-4-methylphenol. d Methylene blue.
10
1
the isomeric dimer 11 (colorless oil) in which the butenolide
(
10) The structure assignment of 11 rests principally on H NMR studies.
COSY analysis established the regiochemistry of the adduct. Key NOE
interactions were observed between Ha/He, Hb/Hd, and Hc/Hf (see below).
The proximity of protons Hb and Hd is consistent only with the relative
alkene rather than the vinyl group had participated as the
dienophile.
1
1
1
configuration assigned to 11. H NMR (500 MHz, CDCl3) δ 7.05 (ddd, J
The dimerization of 2 was studied under of a variety of
conditions in order to gain insight into the mechanism of
the reaction. These experiments are summarized in Table 2.
All of the various conditions led to the formation of 1 and
11 in essentially the same ratio (7-10:1). In each case there
was evidence of the generation of intractable, presumably
polymeric material. This was minimized when the dimer-
ization was performed in the presence of the radical inhibitors
BHT or methylene blue. That these products arose from a
Diels-Alder like event is supported by the facts that the
rate of dimerization is insensitive to solvent polarity and is,
qualitatively, second order in [2].
)
5.5, 3.5, 3.5 Hz, 1H), 5.89 (dd, J ) 17.5, 11.0 Hz, 1H), 5.40 (d, J )
1
1.0 Hz, 1H), 5.23 (d, J ) 17.5 Hz, 1H), 4.59 (dd, J ) 9.5, 9.5 Hz, 1H),
.51 (dd, J ) 9.0, 8.0 Hz, 1H), 4.31 (dd, J ) 9.0, 8.0 Hz, 1H), 3.96 (dd,
4
J ) 9.0, 9.0 Hz, 1H), 3.21-3.25 (m, 1H), 2.82 (dddd, J ) 9.5, 8.0, 8.0, 3.5
Hz, 1H) 2.76 (dddd, J ) 19.5, 8.0, 5.5, 2.5 Hz, 1H), and 2.27 (dddd, J )
1
1
3
9.5, 3.5, 3.5, 3.5 Hz, 1H); C NMR (75 MHz, CDCl3) δ 177.0, 168.0,
1
34.4, 132.8, 126.9, 119.7, 70.0, 67.7, 52.8, 39.2, 37.6, and 25.5; IR (0.008
M in CDCl3) 2925, 1770, 1695, 1640, 1430, 1370, 1350, 1310, 1265, 1230,
-
1
1
6
210, 1110, 1090, 1060, and 1020 cm . Anal. Calcd for C12H12O4: C,
5.45; H, 5.45; Found: C, 65.62; H, 5.67.
In summary, the metathesis of enyne 3, which contains
an electron-deficient alkyne, provides a rapid entry to the
parent 2-vinylbutenolide (2) skeleton. Slow addition of the
benzylidene ruthenium carbene 4 permitted maintenance of
high substrate and low ruthenium carbene concentrations.
Optimal reaction conditions were conveniently scouted using
proton NMR analysis of aliquots of reactions run in non-
deuterated solvent. Spontaneous dimerization of 2 to (()-
differolide (1) proceeds in a highly selective manner and
suggests that 1 might be an artifact of isolation.
(
11) (a) The regioselectivity in the formation of (()-differolide (1), in
contrast to its regioisomer 11, is the same as that observed in the
dimerization of the 4-alkylidene-2-vinylbutenolide derivative iii (ligustilide).1
Thus, iii dimerized to (()-levistolide A (iv). It is noteworthy that the
naturally occurring form of iv is also racemic. (b) Ogawa, Y.; Mori, Y.;
Maruno, M.; Wakamatsu, T. Heterocycles 1997, 45, 1869-1872. (c)
Kaouadji, M.; Reutenauer, H.; Chulia, A. J.; Marsura, A. Tetrahedron Lett.
1b
1
1c
1
983, 24, 4677-4678.
Acknowledgment. We thank the National Institutes of
Health (CA-76497) for funding this project.
OL9905912
Org. Lett., Vol. 1, No. 2, 1999
279