Selective synthesis of (2Z,4E)-dienyl esters by ene-diene cross metathesis

Article abstract of DOI:10.1021/ol062017d

(Chemical Equation Presented) Cross metathesis of terminal alkenes with methyl (2Z4E)-hexadienoate and related dienyl esters provides substituted (2Z,4E)-dienyl esters in good yields. Small-scale reactions are effectively promoted by the standard second-g

Full text of DOI:10.1021/ol062017d

ORGANIC
LETTERS
2007
Vol. 9, No. 1
5-8
Selective Synthesis of (2Z,4E)-Dienyl
Esters by Ene
Diene Cross Metathesis†
−
Gustavo Moura-Letts and Dennis P. Curran*
Department of Chemistry, UniVersity of Pittsburgh, Pittsburgh, PennsylVania 15260
curran@pitt.edu
Received August 15, 2006
ABSTRACT
Cross metathesis of terminal alkenes with methyl (2Z,4E)-hexadienoate and related dienyl esters provides substituted (2Z,4E)-dienyl esters in
good yields. Small-scale reactions are effectively promoted by the standard second-generation Grubbs Hoveyda catalyst (GH-II), while a new
fluorous GH-II catalyst is used for separation and recovery in gram-scale reactions. The transformation is featured in a rapid synthesis of the
bottom fragments of the potent anticancer agents ( )-dictyostatin and 6-epi-dictyostatin.
−
−
The presence of a (2Z,4E)-dienyl ester (in lactone form) is
one of the key structural features that differentiates the potent
dictyostatin family1 of anticancer agents from its cousins in
the discodermolide family.2 Recent syntheses of dictyostatin
and related molecules3 implement classical approaches to this
functionality, typically involving stepwise olefinations with
attendant oxidation/reduction, protection/deprotection, or
other refunctionalization steps. While reliable, these approaches
are multistep. Toward the end of developing a short, efficient
synthesis of (-)-dictyostatin, we engaged in experiments
directed at a rapid, general approach to substituted (2Z,4E)-
dienyl esters (cis,trans) by ene-diene cross metathesis.
Cross-metatheses reactions of two alkenes have seen
increasing use in synthesis of late,4 and ene-diene cross-
metathesis reactions are also known.4e Our departure point
was a recent report by Grubbs and co-workers on cross
metathesis of alkenes with (2E,4E)-dienyl esters (tran-
s,trans).5 This work showed how to use substituent effects
on the diene to encourage regioselective cross metathesis
and showed that formation of the new double bond at C4-
C5 occurred with modest to good E-selectivity.
We previously developed a traditional cross-metathesis/
Still-Gennari approach to the dictyostatin bottom fragment,
and we wanted to telescope this to a single step by ene-
diene cross metathesis (Figure 1).3i The key open question
for intended use in dictyostatin synthesis and related ap-
plications was the fate of the “spectator” double bond at C2-
C3 of the dienyl ester. Can a less stable (Z)-1,2-disubsituted
† Dedicated to Professor Steven M. Weinreb on the occasion of his 65th
birthday.
(1) (a) Pettit, G. R.; Cichacz, Z. A.; Gao, F.; Boyd, M. R.; Schmidt, J.
M. J. Chem. Soc., Chem. Commun. 1994, 1111-1112. (b) Isbrucker, R.
A.; Cummins, J.; Pomponi, S. A.; Longley, R. E.; Wright, A. E. Biochem.
Pharm. 2003, 66, 75-82. (c) Paterson, I.; Britton, R.; Delgado, O.; Wright,
A. E. Chem. Commun. 2004, 632-633.
(2) (a) Paterson, I.; Anderson, E. A. Science 2005, 310, 451-453. (b)
Gunasekera, S. P.; Wright, A. E. In Anticancer Agents from Natural
Products; Cragg, G. M., Kingston, D. G. I., Newman, D. J., Eds.; CRC
Taylor Francis: New York, NY, 2005; pp 171-189.
(3) (a) Shin, Y.; Choy, N.; Turner, T. R.; Balachandran, R.; Madiraju,
C.; Day, B. W.; Curran, D. P. Org. Lett. 2002, 4, 4443-4446. (b) Paterson,
I.; Britton, R.; Delgado, O.; Meyer, A.; Poullennec, K. G. Angew. Chem.,
Int. Ed. 2004, 43, 4629-4633. (c) Shin, Y.; Fournier, J. H.; Fukui, Y.;
Bruckner, A. M.; Curran, D. P. Angew. Chem., Int. Ed. 2004, 43, 4634-
4637. (d) Shin, Y.; Fournier, J. H.; Balachandran, R.; Madiraju, C.; Raccor,
B. S.; Zhu, G.; Edler, M. C.; Hamel, E.; Day, B. W.; Curran, D. P. Org.
Lett. 2005, 7, 2873-2876. (e) O’Neil, G. W.; Phillips, A. J. J. Am. Chem.
Soc. 2006, 128, 5340-5341. (f) Fukui, Y.; Bru¨ckner, A. M.; Shin, Y.;
Balachandran, R.; Day, B. W.; Curran, D. P. Org. Lett. 2006, 8, 301-304.
(g) Jagel, J.; Maier, M. E. Synlett 2006, 693-696. (h) Shin, Y.; Fournier,
J.-H.; Bru¨ckner, A.; Madiraju, C.; Edler, M. C.; Vogt, A.; Balachandran,
R.; Raccor, B. S.; Zhu, G.; Hamel, E.; Day, B. W.; Curran, D. P. Manuscript
in preparation. (i) Jung, W.-H; Harrison, C.-H.; Shin, Y.; Fournier, J.-H.;
Madiraju, C.; Edler, M. C.; Vogt, A.; Balachandran, R.; Raccor, B. S.; Zhu,
G.; Hamel, E.; Day, B. W.; Curran, D. P. Manuscript in preparation.
(4) (a) Grubbs, R. H.; Trnka, T. M. In Ruthenium in Organic Synthesis;
Murahashi, S.-I., Ed.; Wiley-VCH: Weinheim, 2004; pp 153-178. (b)
Grubbs, R. H. Handbook of Metathesis; Wiley-VCH: Weinheim, 2003.
(c) Fu¨rstner, A. Angew. Chem., Int. Ed. 2000, 39, 3012-3043. (d) Schuster,
M.; Blechert, S. Angew. Chem. Int., Ed. Engl. 1997, 2037-2056. (e) Diver,
S. T.; Giessert, A. J. Chem. ReV. 2004, 104, 1317-1382.
(5) Funk, T. W.; Efskind, J.; Grubbs, R. H. Org. Lett. 2005, 7, 187-190.
10.1021/ol062017d CCC: $37.00
© 2007 American Chemical Society
Published on Web 12/05/2006

C9 of dictyostatin) and methyl (2Z,4E)-hexadienoate 7 (C1-
C4). A mixture of 1 equiv of 6 (0.2 M), 1 equiv of 7, and
Grubbs second-generation catalyst 2 (5 mol %) was refluxed
in dichloromethane for 8 h (Table 1). The solvent was
Table 1. Initial Solvent and Catalyst Surveya
Figure 1. Structure of dictyostatin 1 and ene-diene cross-
metathesis approach to the (2E,4E)-dienyl ester fragment.
catalyst
solvent
T (°C)
conc of 6 and 7 (M)
yieldb (%)
alkene survive the cross metathesis without isomerization?
We are pleased to report that the title cross-metathesis reac-
tion of alkenes with (2Z,4E)-dienyl esters occurs in good
yield, with high E-selectivity at the newly formed alkene
(C4-C5) and with strict retention of the Z geometry at the
spectator alkene (C2-C3). These features align perfectly with
the needs of the dictyostatin synthesis, and a gram-scale
preparation of the dienyl ester fragment of 6-epi-dictyostatin
is reported.
2
2
2
2
2
3
4
CH2Cl2
CH2Cl2
CH2Cl2
toluene
toluene
CH2Cl2
CH2Cl2
40
40
40
110
110
40
0.2
0.15
0.1
0.1
0.2
47
58
43
23
25
62
64
0.15
0.15
40
a Conditions: 1 equiv of alkene 6, 1 equiv of diene 7, 5 mol % of catalyst,
8 h. b Isolated yields.
The structures of the catalysts used in this work are shown
in Figure 2. The second-generation Grubbs catalyst (G-II) 2
removed, and the crude product was purified twice by silica
gel chromatography to provide an encouraging 47% yield of
8. Importantly, this cross-metathesis product was a single com-
pound resulting from metathesis at C4 of 7, and there was
no evidence of metathesis products from the C2-C3 alkene.5
We also obtained a impure fraction containing unreacted
starting material 6 (see below). Diluting the reaction mixture
to 0.15 M increased the yield of 8 to 58%, but the yield
dropped to 43% on further dilution to 0.1 M. Conducting
reactions in toluene at 110 °C provided 8 in only 23% (0.1
M) and 25% (0.2 M) yields. Under the optimum solvent and
concentration conditions (CH2Cl2, 0.15 M), the use of
Hoveyda-Grubbs catalyst 3 provided 8 in 62% isolated
yield, while f-GH catalyst 4 gave a comparable 64% isolated
yield.
Figure 2. Structures of metathesis catalysts.
Table 2. Ene-Diene Stoichiometry Surveya
and the second-generation Grubbs-Hoveyda catalyst (GH-
II) 3 are commercially available. The second-generation
fluorous Grubbs-Hoveyda catalyst6a-c (fGH-II) 4 is new,
but it is closely related to an existing catalyst.6a This was
readily prepared by exchange of fluorous styrene 5 with 2
and was isolated as a bright green solid.7
equiv of ene 9
equiv of diene 6
yield of 10b (%)
1
1
1
1
1.2
1.5
2
2
64
65
68
69
71
76
79
1.5
1.2
1
1
1
Initially, we surveyed catalysts and solvents in the cross-
metathesis reaction of readily available alkene (R,S)-63f (C5-
(6) (a) Light fluorous metathesis catalysts with SPE separation: Matsugi,
M.; Curran, D. P. J. Org. Chem. 2005, 70, 1636-1642. (b) Heavy fluorous
metathesis catalyst with liquid-liquid separation: Yao, Q. W.; Zhang, Y.
L. J. Am. Chem. Soc. 2004, 126, 74-75. (c) Heavy fluorous catalyst with
fluorous silica support: Michalek, F.; Bannwarth, W. HelV. Chim. Acta.
2006, 89, 1030-1037. (d) Catalyst with dissociatable fluorous phosphine:
da Costa, R. C.; Gladysz, J. A. Chem. Commun. 2006, 2619-2621.
1
a Conditions: 5 mol % of catalyst 2, CH2Cl2, 40 °C, 8 h. b Isolated yields
of 10.
6
Org. Lett., Vol. 9, No. 1, 2007

The results of a series of experiments to show the scope
of the reaction with respect to the alkene are summarized in
Table 3. These reactions were run under the standard
conditions with diene 7 and catalyst 2. Changing the
secondary alcohol protecting group on 6 from TBS to MOM
or PMB as well as use of a free primary alcohol provided
cross-metathesis products in comparable isolated yields (58-
65%, entries 1-4). The metathesis yields improved with ene
components that were not branched at the allylic carbon.
p-Allylanisole and allylbenzene provided dienes in 69% and
76% yields (entries 5 and 6), although the allylbenzene
product was contaminated with minor amounts of the (4Z)
isomer (E/Z ) 10/1). Reactions with a pair of symmetrical
1,2-disubstituted alkenes (entries 7 and 8) provided similar
yields (68% and 63%). Ene-diene metathesis with the
complex triene9 in entry 9 provided a single tetraene
regioisomer in 76% yield as an 8/1 E/Z mixture at the C4
alkene. All products were exclusively Z-isomers at the
spectator C2 alkene.
Table 3. Scope of Cross Metathesis: Ene Componenta
The scope with respect to the dienyl ester component was
also briefly investigated with terminal alkenes, and these
results are summarized in Table 4. Standard conditions were
Table 4. Scope of Cross Metathesis: Ene Componenta
entry
R
diene
product
yieldb (%)
1
2
3
4
5
CH2C6H4-p-OMe
CH2Ph
CH2C6H4-p-OMe
CH2Ph
11
11
12
12
12
13a
13b
14a
14b
14c
68
63
71
73
73
a Conditions: 1 equiv of ene, 1 equiv of 7, 5 mol % of 2, 0.15 M, CH2Cl2,
40 °C, 8 h. b Isolated yields as single isomer. c E/Z ratio ) 10:1. d E/Z ratio
) 8:1.
Ph
a Conditions: 1 equiv of ene, 1 equiv of 7, 5 mol % of 2, 0.25 M, CH2Cl2,
40 °C, 8 h. b Isolated yields as single isomer.
To optimize the stoichiometry of the reaction, we ran a
series of individual reactions with excess p-allylanisole 9
(1.2, 1.5, and 2 equiv) and another series of reactions with
excess diene 7 (1.2, 1.5, and 2 equiv). The results of these
experiments are summarized in Table 2.
(Z,E)-Diene 10 was produced as a single stereoisomer, but
the isolated yields of for the series of reactions did not vary
dramatically. The starting point was equimolar stoichiometry,
which produced a 69% yield of 10. When ene 9 was used in
excess (1.2-2 equiv), the yields of 10 increased slightly (71-
79%), while when diene 6 was in excess (1.2-2 equiv), the
yields of 10 decreased slightly (68-64%).
used, except that reactant concentrations were 0.25 M. Cross
metathesis of allylbenzene and p-allylanisole with methyl
(2Z,4E)-4-methylhexadienoate 11 (reacting alkene trisubsti-
tuted) provided the diene products 13a,b in 68 and 63%
yields, while cross metathesis of the same two alkenes and
styrene with ethyl (2Z,4E)-3-methylhexadienoate 12 (specta-
tor alkene trisubstituted) provided the corresponding products
14a-c in 71-73% yields. All of these products were single
stereoisomers at both the reacting (4E) and spectator (2Z)
sites.
These results indicate that competing reactions8 cannot be
completely suppressed by using a modest excess of one
component and, therefore, that a 1/1 stoichiometry is
satisfactory for most applications.
The final goal was to implement a gram-scale process with
catalyst removal and recycle for potential use in the synthesis
(8) In addition to the target product 10, these reaction mixtures exhibited
a second, less polar spot on TLC. The spot contained a mixture of products
resulting from metathesis of alkene 9 (no methyl ester or conjugated alkene
protons in the 1H NMR spectrum). A similar mixture (1H NMR, TLC) was
generated by self-metathesis of 9 in the absence of 7.
(7) Fluorous reagents and FluoroFlash silica products were purchased
from Fluorous Technologies, Inc. D.P.C. holds an equity interest in this
company.
(9) Brummond, K. M.; Mitasev, B. Org. Lett. 2004, 6, 2245-2248.
Org. Lett., Vol. 9, No. 1, 2007
7

of (-)-dictyostatin and analogues. For this we used the
fluorous GH-II catalyst 4 because related catalysts6a have
recently been shown to be readily and reliably separated from
reaction products by fluorous solid-phase extraction.10 The
diene component was 7 as usual, and the alkene component
was (S,S)-15, which is readily available by Brown allylbor-
ation.3f The study is directed toward the synthesis of 6-epi-
dictyostatin, a highly potent isomer of the natural product,3f
and the results of a series of preparative metathesis runs are
summarized in Table 5.
raphy (to remove some 15 and other products11), and the
THF fraction yielded 74% of fGH-II catalyst 4 after
recrystallization. (The crude catalyst recovery was nearly
quantitative; however, NMR spectroscopic analysis showed
small but significant impurities.) Cycles 2 and 3 where run
the same way with the entire sample of recovered catalyst
by scaling 15 accordingly, and yielded 60 and 56% of diene
16. The recovered fGH-II catalyst 4 was returned in 70%
yields after recrystallization from both experiments. In total,
the initial lot of 1.3 g (1.3 mmol) of 4 was used to
metathesize 33.5 g (94 mmol) of 15 into 24.2 g of purified
16 as a single stereoisomer (59% total overall yield). The
recovered catalyst 4 from the last cycle was later used for
other small scale experiments.
Table 5. Three Preparative Cross-Metathesis Cycles with
Fluorous Grubbs-Hoveyda Catalyst 4a
In summary, cross-metathesis reactions of monosubstituted
or symmetrical 1,2-disubstituted alkenes with methyl (2Z,4E)-
hexadienoate and related dienyl esters provides substituted
(2Z,4E)-dienyl esters in good yields and stereoselectivities.
The Z-geometry of the spectator alkene of the dienyl ester
is strictly retained in the product, while the newly formed
alkene is mainly or exclusively the E-isomer. Large scale
reactions are conveniently conducted with 3% of the fluorous
Grubbs-Hoveyda catalyst 4, which can be recovered and
recycled as illustrated by the rapid preparation of 24 g of a
key intermediate for the synthesis of 6-epi-dictyostatin.
scale
cycle (mmol)
weight weight
of 15
of 4 (g)
yield of 16
recovered 4
1
2
3
42
31
21
15.0
11.0
7.5
1.3
1.0
0.7
10.9 g, 59%
8.1 g, 60%
5.2 g, 56%
1.0 g, 74%
0.7 g, 70%
0.4 g, 70%b
Acknowledgment. We thank the National Institutes of
Health (National Cancer Institute) for funding on this work.
We also thank Prof. K. Brummond and Mr. B. Mitasev
(University of Pittsburgh) for a sample of the triene substrate
in Table 1, entry 9.
a Conditions: 1 equiv of 15, 1 equiv of 7, 3 mol % of 4, 0.15 M, CH2Cl2,
40 °C, 8 h, followed by fluorous SPE. b Recrystallized twice.
Supporting Information Available: Complete experi-
In the first cycle, alkene 15 (15 g, 42 mmol), diene 6 (42
mmol), and 3 mol % of fHG-II catalyst 4 were refluxed in
CH2Cl2 for 8 h. After cooling and concentration, the crude
product was loaded onto a 50 g fluorous SPE cartridge7 that
was eluted in a first pass with 9/1 MeOH/H2O followed by
second pass elution with THF. The MeOH/H2O fraction
yielded 10.9 g (59%) of diene 16 after column chromatog-
mental details and compound characterization data, as well
1
as copies of H and 13C NMR spectra. This material is
available free of charge via the Internet at http://pubs.acs.org.
OL062017D
(11) The less polar impurity fraction from the flash chromatography
accounted for 37% of the mass balance and contained a substantial amount
of 15 (∼50%) along with other unidentified products (homodimers?) derived
from 15. (A product with a similar 1H NMR spectrum was generated by
metathesis of 15 in the absence of 7.) The entire mixture fraction was directly
reused in a cross metathesis with 7 to provide an additional 20% of pure
16 after fspe and flash chromatography. Including the reuse of the mixture
fraction raises the overall yield of 16 based on 15 in cycle 1 to 79%.
(10) Reviews on fluorous SPE: (a) Curran, D. P. In The Handbook of
Fluorous Chemistry; Gladysz, J. A., Curran, D. P., Horvath, I. T., Eds.;
Wiley-VCH: Weinheim, 2004; pp 101-127. (b) Curran, D. P. Aldrichim.
Acta 2006, 39, 3-9. (c) Zhang, W.; Curran, D. P. Tetrahedron 2006, in
press.
8
Org. Lett., Vol. 9, No. 1, 2007