Cross-metathesis approach to a (2E,4E)-dienoic acid intermediate for the synthesis of elaiolide

Article abstract of DOI:10.1016/j.tetlet.2007.03.055

A (2E,4E)-7-hydroxy-2,4-dienoic acid, previously employed as a key intermediate for the total synthesis of the macrodiolide antibiotic elaiolide, was prepared stereoselectively and concisely from (S)-2-methyl-3-trityloxypropanal by a three-step sequence c

Full text of DOI:10.1016/j.tetlet.2007.03.055

Tetrahedron Letters 48 (2007) 3163–3166
Cross-metathesis approach to a (2E,4E)-dienoic acid
intermediate for the synthesis of elaiolide
Akira Morita and Shigefumi Kuwahara*
Laboratory of Applied Bioorganic Chemistry, Graduate School of Agricultural Science, Tohoku University,
Tsutsumidori-Amamiyamachi, Aoba-ku, Sendai 981-8555, Japan
Received 8 February 2007; revised 7 March 2007; accepted 9 March 2007
Available online 12 March 2007
Abstract—A (2E,4E)-7-hydroxy-2,4-dienoic acid, previously employed as a key intermediate for the total synthesis of the macrodio-
lide antibiotic elaiolide, was prepared stereoselectively and concisely from (S)-2-methyl-3-trityloxypropanal by a three-step sequence
consisting of Brown’s asymmetric crotylboration, olefin cross-metathesis, and alkaline treatment. Ethyl 3-pivaloyloxy-4-pentenoate
was used as a masked dienoate in the cross-metathesis step.
ꢀ 2007 Elsevier Ltd. All rights reserved.
Elaiophylin (1), a glycosidic polyketide featuring a 16-
membered macrodiolide core structure, was first isolated
from the culture broth of Streptomyces melanosporus by
Arcamone et al. as a potent antibiotic against Gram-
positive bacteria (Fig. 1).1 After the discovery, 1 was
reisolated from other species of Streptomyces by several
groups as azalomycin B,2 antibiotic 255-E,3 salbomy-
cin,4 and gopalamicin.5 In addition to the antibiotic
activity, 1 is also known to possess a wide range of bio-
activities such as cell cycle inhibitory and apoptosis
inducing activities,6 immunosuppressive activity,7 and
plant growth inhibitory activity.8 The structure of 1,
including its absolute stereochemistry, was determined
on the basis of its X-ray crystallographic analysis9 fol-
lowing the spectroscopic assignment of its gross struc-
ture.10 The attractive biological activities as well as the
complicated C2-symmetric architecture of 1 have stimu-
lated considerable interest in its synthesis,11 which cul-
minated in the total synthesis of 1 by the Kinoshita
group in 1986 after the achievement of the synthesis of
11,110-di-O-methylelaiolide (2) by Seebach and co-work-
ers in the preceding year.12,13 Synthesis of elaiolide (3),
the aglycon of 1, was also reported by Evans et al.14
and Paterson et al.15 Except for the Paterson synthesis,
which utilized a Stille cyclodimerization reaction for
the installation of the macrodiolide core, the other three
syntheses employed the double Yamaguchi esterification
Keywords: Elaiolide; Cross-metathesis; Enantioselective synthesis;
Antibiotic; 2,4-Alkadienoic acid.
*
Figure 1. Structures of elaiophylin and related compounds, and the
Corresponding author. Tel./fax: +81 22 717 8783; e-mail:
retrosynthetic analysis of their cyclodimerization precursors.
skuwahar@biochem.tohoku.ac.jp
0040-4039/$ - see front matter ꢀ 2007 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2007.03.055

3164
A. Morita, S. Kuwahara / Tetrahedron Letters 48 (2007) 3163–3166
pling product of B, while on exposure to the second-
generation Grubbs catalyst (Grubbs-II) afforded a 4:1
mixture of cross-metathesis products, C and D, result-
ing from reactions at either the C4–C5 or the C2–C3
double bonds of dienoate A (Fig. 2).17 Inspired by this
precedent and some related studies,18 we first examined
the feasibility of direct installation of the (2E,4E)-2,4-
alkadienoate system in seco-acid 4 using the cross-
metathesis reaction between ethyl 2,4-pentadieno-
ate (5a) and terminal olefin 6 as a model case (Scheme
1).
As shown in Scheme 1, the cross-metathesis reaction of
5a and 619 proceeded smoothly at room temperature in
the presence of 14 mol % Grubbs-I catalyst, giving 94%
yield of the desired C4–C5 metathesis product 7 as a 4:1
E/Z mixture,20 and the geometrical ratio could be read-
ily improved to 10:1 by equilibration with a catalytic
amount of I2 in refluxing CH2Cl2. With these promising
preliminary results in hand, we set about the cross-
metathesis of 5a with 8a, which was obtainable from
1021 using Brown’s asymmetric crotylboration followed
by acetylation of the resulting homoallylic alcohol 8b.22
Despite scrutiny of various reaction conditions [type and
amount of Grubbs’ catalysts (1st or 2nd, 10–30 mol %),
amount of 5a (3–6 equiv), solvent (CH2Cl2, toluene),
temperature (25–100 ꢁC), use of Lewis acid catalyst
(Ti(OiPr)4),23 and microwave irradiation24], all reaction
conditions tried resulted only in miserably low yields of
the desirable product 9a (<10% yield, as E/Z mixtures).
Similar attempts using 8b to obtain 9b were also unsuc-
cessful, and alteration of the dienoate component from
5a to 5b did not bring any fruitful outcome, giving
mainly a low yield of 11 generated through an undesir-
able metathesis pathway.
Figure 2. A precedent for the cross-metathesis reaction of an E,E-
dienoate with a terminal monoene by Grubbs et al.
of hydroxy acid 4a or 4b for the 16-membered ring for-
mation, and the resulting macrocyclic intermediates
were successfully converted into 1, 2, or 3 in short-step
sequences by taking advantage of their C2-symmetric
nature. The dimerization precursor 4a, in turn, was ob-
tained from D-glucose through a considerably long reac-
tion sequence,12 while the other precursor 4b was
prepared from ethyl (S)-3-hydroxy-2-methylpropanoate
or methacrolein in 13 or 9 steps, respectively, involving a
chiral oxazolidinone-induced asymmetric aldol reaction
as a key step.13,14 Herein, we report an efficient ap-
proach to the monomeric seco-acid (4b or its TBS-pro-
tected congener 4c) by means of olefin cross-metathesis
for the construction of the trans C4–C5 double bond
and asymmetric crotylboration for the C6–C7 bond
formation.
Although cross-metathesis reactions of two monoenes
have been well-studied and applied successfully to total
syntheses of many natural products, the cross-metathe-
sis of a diene with a monoene has not been investigated
so much.16 Especially, investigation of the cross-
metathesis between 2,4-dienoates and monoenes to
form 2,4-alkadienoates has only limited precedents. Re-
cently, Grubbs et al. reported that the cross-metathesis
reaction of ethyl (2E,4E)-2,4-hexadienoate (A) with ter-
minal olefin B in the presence of the first-generation
Grubbs catalyst (Grubbs-I) gave only the homocou-
In order to circumvent this difficulty, we next tried the
use of non-conjugated olefin 12 as a masked dienoate
(Scheme 2).25 After several examinations of reaction
conditions, we found that the cross-metathesis of 8b
with 12 proceeded in the presence of Grubbs-II catalyst
(15–20 mol %) under microwave irradiation condi-
tions,24 giving a mixture containing 13 as the major con-
stituent in about 60% yield.26 Subjection of the mixture
Scheme 1.

A. Morita, S. Kuwahara / Tetrahedron Letters 48 (2007) 3163–3166
3165
aldehyde 15 using a three-step sequence consisting of
Brown’s asymmetric crotylboration, olefin cross-
metathesis, and hydrolysis accompanied by concurrent
elimination.
Acknowledgments
We thank Ms. Yamada (Tohoku University) for mea-
suring NMR and MS spectra. This work was supported,
in part, by a Grant-in-Aid for Scientific Research (B)
from the Ministry of Education, Culture, Sports, Sci-
ence and Technology of Japan (No. 16380075).
Scheme 2.
References and notes
1. Arcamone, F. M.; Bertazzoli, C.; Ghione, M.; Scotti, T.
Giorn. Microbiol. 1959, 7, 207–216.
2. (a) Arai, M. J. Antibiot., Ser. A 1960, 13, 46–50, 51–56; (b)
Takahashi, S.; Arai, M.; Ohki, E. Chem. Pharm. Bull.
1967, 15, 1651–1656.
3. Khlebarova, E. I.; Georgieva-Borisova, I. Kh.; Sheikova,
G. N.; Blinov, N. O. Farmatsiya (Sofia) 1972, 22, 3–7.
4. (a) Hoechst Patent DE 3248-280-A, 1982; (b) Paulus, E.
F.; Vertesy, L.; Scheldrick, G. M. Cryst. Struct. Commun.
1984, C40, 700–703.
5. Nair, M. G.; Chandra, A.; Thorogood, D. L. J. Agric.
Food Chem. 1994, 42, 2308–2310.
Scheme 3.
6. Cui, C.; Wang, H.; Han, B.; Cai, B.; Luo, A.; Song, Y.;
Zhou, P. Zhongguo Kangshengsu Zazhi 2001, 26, 165–170.
7. Lee, S.-Y.; Kim, H.-S.; Kim, Y.-H.; Han, S.-B.; Kim, H.-
M.; Hong, S.-D.; Lee, J.-J. J. Microbiol. Biotechnol. 1997,
7, 272–277.
8. Igarashi, Y.; Yoshida, R.; Furumai, T. Shokubutsu no
Seicho Chosetus 2002, 37, 63–68.
9. (a) Neupert-Laves, K.; Dobler, M. Helv. Chim. Acta 1982,
65, 262–267; (b) Ley, S. V.; Neuhaus, D.; Williams, D. J.
Tetrahedron Lett. 1982, 23, 1207–1210.
to aqueous KOH in methanol brought about b-elimina-
tion of the pivaloyloxy group and concomitant hydroly-
sis of the ethyl ester moiety as expected, but the TBS-
protecting group was also removed under the basic con-
ditions to afford dihydroxy acid 14.27 This result made
us seek another protecting group compatible with the
basic conditions.
10. Kaiser, H.; Keller-Schierlein, W. Helv. Chim. Acta 1981,
64, 407–424.
We eventually selected the trityl protecting group, which
would enable us to lead to the known hydroxy acid 4b
(Scheme 3). Readily available aldehyde 1528 was ex-
posed to Brown’s asymmetric crotylboration conditions
to give 16 (77% isolated yield) and its diastereomer (8%
isolated yield) after chromatographic purification.29 The
desired olefin 16 was then allowed to react with 12 in the
presence of Grubbs-II catalyst (15 mol %) under irradi-
ation of microwave at 90 ꢁC for 1 h (30 min · 2) to fur-
nish 17; the geometry of the newly formed C4–C5
double bond was revealed to be homogeneous and
exclusively E from the 4-H/5-H coupling constant
(15.1 Hz). Metathesis product 17 was then treated with
aqueous KOH in MeOH/THF to give smoothly target
molecule 4b in 46% yield from 16.30 Hydroxy acid 4b
was previously converted into elaiolide (3) in five steps
by Evans et al.,14 and a dimeric dialdehyde obtainable
from 4b via a three-step sequence13,14 was successfully
transformed into elaiophylin (1) in two steps by Kino-
shita et al.12
11. (a) Nakamura, H.; Arata, K.; Wakamatsu, T.; Ban, Y.;
Shibasaki, M. Chem. Pharm. Bull. 1990, 38, 2435–2451; (b)
Ziegler, F. E.; Tung, J. S. J. Org. Chem. 1991, 56, 6530–
6537.
12. (a) Toshima, K.; Tatsuta, K.; Kinoshita, M. Tetrahedron
Lett. 1986, 27, 4741–4744; (b) Toshima, K.; Tatsuta, K.;
Kinoshita, M. Bull. Chem. Soc. Jpn. 1988, 61, 2369–2381.
13. (a) Seebach, D.; Chow, H.-F.; Jackson, R. F. W.; Lawson,
K.; Sutter, M. A.; Thaisrvongs, S.; Zimmermann, J. J.
Am. Chem. Soc. 1985, 107, 5292–5293; (b) Seebach, D.;
Chow, H.-F.; Jackson, R. F. W.; Sutter, M. A.; Thai-
srivongs, S.; Zimmermann, J. Liebigs Ann. Chem. 1986,
1281–1308.
14. Evans, D. A.; Fitch, D. M. J. Org. Chem. 1997, 62, 454–
455.
15. Paterson, I.; Lombart, H.-G.; Allerton, C. Org. Lett. 1999,
1, 19–22.
16. For recent reviews of olefin metathesis, see: (a) Gradillas,
´
A.; Perez-Castells, J. Angew. Chem., Int. Ed. 2006, 45,
6086–6101; (b) Nicolaou, K. C.; Bulger, P. G.; Sarlah, D.
Angew. Chem., Int. Ed. 2005, 44, 4490–4527; (c) Grubbs,
R. H. Tetrahedron 2004, 60, 7117–7140; (d) Connon, S. J.;
Blechert, S. Angew. Chem., Int. Ed. 2003, 42, 1900–1923.
17. Funk, T. W.; Efskind, J.; Grubbs, R. H. Org. Lett. 2005,
7, 187–190. In this study, they also revealed that the
introduction of a bromo substituent at the C2-position of
In conclusion, we accomplished the concise synthesis of
(2E,4E)-7-hydroxy-2,4-dienoic acid 4b, a key intermedi-
ate for the synthesis of 2 and 3, from readily available

3166
A. Morita, S. Kuwahara / Tetrahedron Letters 48 (2007) 3163–3166
22
A enabled regioselective metathesis at its C4–C5 double
bond in the presence of Grubbs-II catalyst.
29. Compound 16: ½aꢁD ꢀ3.2 (c 0.96, CHCl3); IR (film) mmax
1
3507 (br, m), 3058 (m), 1597 (w), 1490 (m), 1448 (s); H
18. (a) Moura-Letts, G.; Curran, D. P. Org. Lett. 2007, 9, 5–8;
(b) Dewi, P.; Randl, S.; Blechert, S. Tetrahedron Lett. 2005,
46, 577–580; (c) Barluenga, S.; Lopez, P.; Moulin, E.;
Winssinger, N. Angew. Chem., Int. Ed. 2004, 43, 3467–3470.
19. Compound 6 was readily obtained from the bis-TBS ether
of (Z)-2-butene-1,4-diol in three steps (O3, CH2Cl2,
ꢀ78 ꢁC, then Me2S; CH2@CHCH2MgBr, ether, 0 ꢁC;
Ac2O, Py, 20 ꢁC).
20. Compound (E)-7: IR (film) mmax 1741 (s), 1717 (s), 1645
(w); 1H NMR (500 MHz, CDCl3) d 0.05 (6H, s), 0.89 (9H,
s), 1.30 (3H, t, J = 7.1 Hz), 2.04 (3H, s), 2.44 (1H, dt,
J = 14.4, 7.4 Hz), 2.54 (1H, dt, J = 14.4, 6.8 Hz), 3.62 (1H,
dd, J = 10.7, 4.9 Hz) 3.65 (1H, dd, J = 10.7, 4.9 Hz), 4.20
(2H, q, J = 7.1 Hz), 4.92–4.97 (1H, m), 5.81 (1H, d,
J = 15.3 Hz), 6.05 (1H, dt, J = 6.9, 15.3 Hz), 6.23 (1H, dd,
J = 11.2, 15.3 Hz), 7.24 (1H, dd, J = 11.2, 15.3 Hz); 13C
NMR (125 MHz, CDCl3) d ꢀ5.5, 14.3, 18.2, 21.1, 25.7,
34.1, 60.2, 63.5, 73.2, 120.3, 131.1, 138.2, 144.2, 167.0,
170.4; HRMS (FAB): m/z calcd for C18H33O5Si, 357.2098;
found, 357.2096 ([M+H]+).
NMR (500 MHz, CDCl3) d 0.93 (3H, d, J = 7.0 Hz), 1.02
(3H, d, J = 7.5 Hz), 1.83–1.91 (1H, m), 2.17–2.25 (1H, m),
2.27 (1H, d, J = 2.5 Hz, OH), 3.11 (1H, dd, J = 5.0,
8.9 Hz), 3.26 (1H, dd, J = 5.8, 8.9 Hz), 3.44–3.48 (1H, m),
5.04 (1H, d, J = 17.1 Hz), 5.05 (1H, d, J = 10.3 Hz), 5.77
(1H, ddd, J = 8.3, 10.3, 17.1 Hz), 7.22 (3H, t, J = 7.4 Hz),
7.27 (6H, t, J = 7.4 Hz), 7.44 (6H, d, J = 7.4 Hz); 13C
NMR (125 MHz, CDCl3) d 10.3, 16.8, 35.4, 41.6, 67.4,
76.2, 86.7, 115.4, 126.9, 127.8, 128.6, 141.7, 144.0; HRMS
(EI) m/z: calcd for C27H30O2, 386.2246; found, 386.2251
(M+).
30. Preparation of 4b: To a stirred solution of 16 (66.5 mg,
0.172 mmol) and 12 (112 mg, 0.491 mmol) in CH2Cl2
(1.3 mL) in a test tube was added Grubbs-II catalyst
(14.7 mg, 17.3 lmol) under a nitrogen atmosphere. The
reaction vessel was capped with a septum and inserted into
the cavity of a Discover Microwave System apparatus
(from CEM) and irradiated at 300 W for 30 min (internal
temperature 90 ꢁC, controlled and monitored with the
standard infrared temperature control system for the
Discover System). After cooling to room temperature, 12
(59.2 mg, 0.259 mmol), Grubbs-II catalyst (8.0 mg,
9.4 lmol) and CH2Cl2 (0.5 mL) were added again, and
the mixture was re-irradiated for additional 30 min under
the same irradiation conditions. The reaction mixture was
filtered through Florisil and the filtrate was concentrated
in vacuo. The residue was chromatographed over SiO2
(hexane/EtOAc, 10:1) to give 153 mg of 17 as a yellow oil,
which was then taken up in MeOH/THF (2:1, 4.5 mL). To
the solution was added dropwise aqueous KOH (1.1 M,
4.5 mL, 5.0 mmol) at room temperature. The mixture was
stirred overnight, and then concentrated in vacuo. The
residue was diluted with water, acidified to pH 3 with
0.5 M aqueous HCl at 0 ꢁC, and extracted EtOAc. The
extract was dried (MgSO4) and concentrated in vacuo.
The residue was chromatographed over SiO2 [hexane/
EtOAc (3:1) containing a trace amount of AcOH] to give
21. Ihara, M.; Takahashi, M.; Fukumoto, K. J. Chem. Soc.,
Perkin Trans. 1 1989, 2215–2221.
22. Brown, H. C.; Bhat, K. S.; Randad, R. S. J. Org. Chem.
1989, 54, 1570–1576.
23. Furstner, A.; Langemann, K. J. Am. Chem. Soc. 1997,
¨
119, 9130–9136.
24. (a) Bargiggia, F.; Murray, W. V. J. Org. Chem. 2005, 70,
´
´
9636–9639; (b) de la Hoz, A.; Dıaz-Ortiz, A.; Moreno, A.
Chem. Soc. Rev. 2005, 34, 164–178.
25. Compound 12 was obtained from ethyl 3-hydroxy-4-
pentenoate in 83% yield by treatment with PivCl in Py in
the presence of a catalytic amount of DMAP. For the
preparation of the hydroxy ester, see: Zibuck, R.; Streiber,
J. M. J. Org. Chem. 1989, 54, 4717–4719.
26. When a mixture of 8b, 12, and Grubbs-II catalyst
(15 mol %) was refluxed in CH2Cl2 without microwave
irradiation, the metathesis reaction was very sluggish,
giving a mixture containing starting material 8b and the
desired product 13 in a ratio of ca. 1:1 even after 2 days (as
judged by the 1H NMR analysis of the crude reaction
mixture). The double bond geometry of 13 could not be
determined by NMR at this stage because of the presence
of overlapping signals due to the olefinic protons of the
contaminating homocoupling product of 12.
22
36.3 mg (46%) of 4b as a white solid. ½aꢁD ꢀ14.3 (c 1.57,
CHCl3); IR (film) mmax 3500–2600 (br), 3058 (m), 3024 (m),
1686 (s), 1637 (m), 1616 (w), 1448 (m), 1274 (m), 1002 (m);
1H NMR (500 MHz, CDCl3) d 0.97 (3H, d, J = 7.0 Hz),
1.06 (3H, d, J = 7.3 Hz), 1.81–1.88 (1H, m), 2.29–2.38
(1H, m), 3.12 (1H, dd, J = 3.8, 9.0 Hz), 3.26 (1H, dd,
J = 5.3, 9.0 Hz), 3.55 (1H, dd, J = 3.0, 8.0 Hz), 5.77 (1H,
d, J = 15.0 Hz), 6.12 (1H, dd, J = 10.3, 15.1 Hz), 6.17 (1H,
dd, J = 7.8, 15.1 Hz), 7.24 (3H, t, J = 7.3 Hz), 7.30
(6H, t, J = 7.3 Hz), 7.32 (1H, dd, J = 15.0, 10.3 Hz),
7.43 (6H, d, J = 7.3 Hz); 13C NMR (125 MHz, CDCl3) d
10.7, 16.8, 35.7, 40.7, 67.3, 77.0, 86.8, 119.0, 127.1, 127.9,
128.4, 128.6, 143.8, 147.1, 148.2, 172.3; HRMS (FAB):
m/z calcd for C30H32O4Na, 479.2198; found, 479.2200
([M+Na]+).
27. Although the exact chemical yield of dihydroxy acid 14
from 13 could not be determined due to the high solubility
of 14 in water, TLC monitoring of the reaction indicated
that 14 was produced almost quantitatively. The E,E-
1
geometry of 14 was assigned from its H NMR coupling
constants (2-H/3-H, 15.1 Hz; 4-H/5-H, 15.1 Hz).
28. Gaunt, M. J.; Jessiman, A. S.; Orsini, P.; Tanner, H. R.;
Hook, D. F.; Ley, S. V. Org. Lett. 2003, 5, 4819–4822.