Total synthesis of (±)-5-deoxystrigol via reductive carbon-carbon bond formation

Article abstract of DOI:10.1021/jo9002085

(Chemical Equation Presented) The total synthesis of 5-deoxystrigol was successfully carried out via the regioselective coupling reaction between the aluminum ate complex of an alkyne and an epoxide and the two reductive carbon-carbon bond formations in t

Full text of DOI:10.1021/jo9002085

SCHEME 1
Total Synthesis of (()-5-Deoxystrigol via
Reductive Carbon-Carbon Bond Formation
Mitsuru Shoji,* Eriko Suzuki, and Minoru Ueda*
Department of Chemistry, Graduate School of Science,
Tohoku UniVersity, Aoba-ku, Sendai 980-8578, Japan
shoji-org@mail.tains.tohoku.ac.jp;
ueda@mail.tains.tohoku.ac.jp
ReceiVed January 30, 2009
The total synthesis of 5-deoxystrigol was successfully carried
out via the regioselective coupling reaction between the
aluminum ate complex of an alkyne and an epoxide and the
two reductive carbon-carbon bond formations in the pres-
ence of transition metals as key steps.
supply of 1 and preparation of its derivatives that could act as
molecular probes are strongly desired for further biological
research.
Although it is well-known that more than 80% of terrestrial
plants utilize symbiotic associations with fungi1 in which plants
provide glucose to fungi and in return fungi provide phosphates
to plants, the concise mechanisms of such mutualism has yet
to be defined. In 2005, Akiyama and co-workers reported that
the roots of Lotus japonicus secrete 5-deoxystrigol (1), a
signaling molecule that induces hyphal branching in arbuscular
mycorrhizal fungi.2 Moreover, 1 was also very recently reported
as a new phytohormone inhibiting shoot branching.3 Thus, the
biological significance of 1 dramatically increases in many fields
such as chemical ecology, chemical biology, and plant biology.
To date, seven naturally occurring strigolactones including 1
have been isolated.4 Unfortunately, because of its low prevalence
in plant materials and the instability of the molecule, very limited
amounts of 1 are available from nature. Thus, the synthetic
The synthesis of 1 has been carried out by Welzel and co-
workers (as a synthetic derivative of strigol)5 and by Akiyama
and co-workers to confirm the structure of the natural product.2
In most cases of the synthesis of strigolactones,5,6 the prepara-
tions of the tricyclic strigolactone framework involved stepwise
construction. In contrast, we envisioned a one-step polycycliza-
tion strategy that was inspired by terpene biosynthesis.7 As
shown in Scheme 1, the retrosynthetic analysis of 1 is described
as follows: (i) the side chain of 1 can be introduced into lactone
2 following reported procedures,5,6 (ii) the tricyclic skeleton of
2 can be formed in one step via transition metal-mediated
reductive carbon-carbon bond formation from acyclic com-
pound 3, (iii) diketoaldehyde 3, which possesses every requisite
(1) Smith, S. E.; Read, D. J. Mycorrhizal Symbiosis; Academic Press: San
Diego, 1997.
(2) Akiyama, K.; Matsuzaki, K.-I.; Hayashi, H. Nature (London, U.K.) 2005,
435, 824–827.
(5) Frischmuth, K.; Samson, E.; Kranz, A.; Welzel, P.; Meuer, H.; Sheldrick,
W. S. Tetrahedron 1991, 47, 9793–9806.
(6) Strigol: (a) MacAlpine, G. A.; Raphael, R. A.; Shaw, A.; Taylor, A. W.;
Wild, H.-J. J. Chem. Soc., Perkin Trans. 1 1976, 410–416. (b) Heather, J. B.;
Mittal, R. S. D.; Sih, C. J. J. Am. Chem. Soc. 1976, 98, 3661–3669. (c) Brooks,
D. W.; Bevinakatti, H. S.; Kennedy, E.; Hathaway, J. J. Org. Chem. 1985, 50,
628–632. (d) Dailey, O. D., Jr. J. Org. Chem. 1987, 52, 1984–1989. (e) Berlage,
U.; Schmidt, J.; Peters, U.; Welzel, P. Tetrahedron Lett. 1987, 28, 3091–3094.
(f) Samson, E.; Frischmuth, K.; Berlage, U.; Heinz, U.; Hobert, K.; Welzel, P.
Tetrahedron 1991, 47, 1411–1416. (g) Hirayama, K; Mori, K. Eur. J. Org. Chem.
1999, 2211–2217. (h) Reizelman, A.; Scheren, M.; Nefkens, G. H. L.;
Zwanenburg, B. Synthesis 2000, 1944–1951Sorgolactone: (i) Sugimoto, Y.;
Wigchert, S. C. M.; Thuring, J. W. J. F.; Zwanenburg, B. J. Org. Chem. 1998,
63, 1259–1267. (j) Matsui, J.; Bando, M.; Kido, M.; Takeuchi, Y.; Mori, K.
Eur. J. Org. Chem. 1999, 2183–2194Orobanchol: (k) Matsui, J.; Yokota, T.;
Bando, M.; Takeuchi, Y.; Mori, K. Eur. J. Org. Chem. 1999, 2201–2210. (l)
Hirayama, K.; Mori, K. Eur. J. Org. Chem. 1999, 2211–2217.
(3) (a) Gomez-Roldan, V.; Fermas, S.; Brewer, P. B.; Puech-Page`s, V.; Dun,
E. A.; Pillot, J.-P.; Letisse, F.; Matusova, R.; Danoun, S.; Portais, J.-C.;
Bouwmeester, H.; Be´card, G.; Beveridge, C. A.; Rameau, C.; Rochange, S. F.
Nature (London, U.K.) 2008, 455, 189–194. (b) Umehara, M.; Hanada, A.;
Yoshida, S.; Akiyama, K.; Arite, T.; Takeda-Kamiya, N.; Magome, H.; Kamiya,
Y.; Shirasu, K.; Yoneyama, K.; Kyozuka, J.; Yamaguchi, S. Nature (London,
U.K.) 2008, 455, 195–200.
(4) Strigol: (a) Cook, C. E.; Whichard, L. P.; Turner, B.; Wall, M. E.; Egley,
G. H. Science 1966, 154, 1189–1190. Strigyl acetate: (b) Cook, C. E.; Whichard,
L. P.; Wall, M. E.; Egley, G. H.; Coggon, P.; Luhan, P. A.; McPhail, A. T.
J. Am. Chem. Soc. 1972, 94, 6198–6199Sorgolactone: (c) Hauck, C.; Muller,
S.; Schildknecht, H. J. Plant Physiol. 1992, 139, 474–478. Alectrol and
orobanchol: (d) Yokota, T.; Sakai, H.; Okuno, K.; Yoneyama, K.; Takeuchi, Y.
Phytochemistry 1998, 49, 1967–1973Solgomol: (e) Xie, X.; Yoneyama, K.;
Kusumoto, D.; Yamada, Y.; Takeuchi, Y.; Sugimoto, Y.; Yoneyama, K.
Tetrahedron Lett. 2008, 49, 2066–2068.
(7) Ogura, K. J. Synth. Org. Chem., Jpn. 1975, 33, 256–269. (a) Biosynthesis
of strigolactones via a C40 carotenoid is also revealed: Akiyama, K.; Hayashi,
H. New Phytol. 2008, 178, 695–698.
3966 J. Org. Chem. 2009, 74, 3966–3969
10.1021/jo9002085 CCC: $40.75 2009 American Chemical Society
Published on Web 04/09/2009

oxidized using Dess-Martin periodinane11 to the corresponding
diketone, which was obtained as a 1:1 equilibrium mixture of
R,ꢀ- and ꢀ,γ-unsaturated esters 13 (as determined by 1H NMR).
Attempts to prepare the desired diketoaldehyde 3, that is,
removal of the TIPS group of 13 followed by Cu(OAc)2/O2
oxidation,12 were hard to attain because of its instability.
Disappointingly, immediate treatment of the crude product after
the oxidation with an excess amount of samarium(II) iodide
did not give the desired tricyclic compound 2. Because the low
reactivity of the cyclization can be attributed to the flexibility
of the acyclic chain structure of the diketoaldehyde, we switched
to the alternative strategy of first constructing the A ring of 1
to fix the conformation before constructing the B and C rings.
As shown in Scheme 3, oxidation of diol 10 followed by
hydrogenation gave diketone 14. Since the pinacol coupling
reaction13,14 of hydroxy-free diketone 14 and corresponding
benzyl or p-methoxybenzyl ether resulted in low yield, the
primary alcohol was protected as pivalate to provide 15. The
intramolecular pinacol coupling reaction under the conditions
of Mukaiyama et al.14c furnished the desired cyclohexanediol
16 in good yield. Removal of the pivaloyl group of 16 followed
byTEMPOoxidationandsubsequentHorner-Wadsworth-Emmons
olefination afforded (E)-R,ꢀ-unsaturated ester 17, selectively.
SCHEME 2
Removal of the TIPS group of 17 followed by TEMPO
oxidation of the resulting alcohol 18 produced cyclization
precursor aldehyde 19. The reductive carbon-carbon bond
formation of aldehyde 19 was carried out in the presence of
samarium(II) iodide15 and subsequent acidic workup to furnish
trans-fused bicyclic ester 20 and cis-fused tricyclic lactone 21
in good yield. For both 20 and 21, the stereochemistry of the
newly formed secondary hydroxy group was syn to the adjacent
tertiary hydroxy group (NOE correlations are illustrated in
Schemes 3 and 4), which can be attributed to the chelation of
the samarium(III) cation to the neighboring hydroxy group.16
As shown in Scheme 4, inversion of the stereochemistry of
the secondary hydroxy group of trans-isomer 20 was ac-
complished via an oxidation-reduction sequence to provide
tricyclic lactone 23. Although oxidation of 20 did not proceed
using TEMPO/NaClO, the use of a catalytic amount of AZADO
(2-azaadamantane-N-oxyl)17 proved to be effective for the
oxidation to afford ketone 22. Diastereoselective reduction of
22 with NaBH4 followed by acidic workup furnished lactone
23.
functional group, can be afforded via regioselective oxidation
and the Wittig reaction of 4, and (iv) triol 4 can be furnished
via regioselective carbon-carbon bond formation of epoxide 6
and alkyne 7, followed by reduction of the resulting alkyne 5.
As shown in Scheme 2, a coupling component, epoxide 8,
was prepared from prenyl alcohol via TIPS protection and
epoxidation. The other coupling component, alcohol 9, was
prepared from 1,3-propanediol via monobenzylation,
SO3-pyridine oxidation,8 and propargylation. Regioselective
carbon-carbon bond formation was accomplished via the
coupling reaction between the epoxide 8 and the aluminum ate
complex of alkyne 9 to give 10.9 Diol 10 was reacted as a
mixture of two diastereomers because the latter oxidation
provided diketone without stereocenters (vide infra). For this
coupling reaction, the hydroxy group of 9 was not protected
because, otherwise, elimination would proceed to give the enyne
derivative of 9.
The remaining transformation involves the reductive olefi-
nation of 1,2-diol 23. After some experimentation, diol 23 was
successfully converted to the desired alkene 2 via treatment with
trimethyl orthoformate and benzoic acid followed by heating
of the resulting cyclic ortho esters to afford tetra-substituted
Next, triol 11 was afforded via hydrogenation of the triple
bond and cleavage of the benzyl ether of 10. Regioselective
TEMPO (2,2,6,6-tetramethyl-1-piperidinyloxy) oxidation10 of
the primary hydroxy group of 11 followed by a Wittig reaction
provided diol 12, which possesses the carbon skeleton of the
tricyclic core of 1. Because the direct oxidation of the desilylated
triol derived from 12 was deemed too difficult, diol 12 was
(11) (a) Dess, D. B.; Martin, J. C. J. Org. Chem. 1983, 48, 4155–4156. (b)
Dess, D. B.; Martin, J. C. J. Am. Chem. Soc. 1991, 113, 7277–7287. (c) Ireland,
R. E.; Liu, L. J. Org. Chem. 1993, 58, 2899.
(12) Arbez-Gindre, C.; Berl, V.; Lepointtevin, J.-P. Steroids 2003, 68, 361–
365.
(13) Lenoir, D. Synthesis 1977, 553–554.
(14) (a) Mukaiyama, T.; Sato, T.; Hanna, J. Chem. Lett. 1973, 1041–1044.
(b) Takeshita, H.; Mori, A.; Nakamura, S. Bull. Chem. Soc. Jpn. 1984, 57, 3152–
3155. (c) Mukaiyama, T.; Kagayama, A.; Shiina, I. Chem. Lett. 1998, 1107–
1108.
(8) Parikh, J. R.; Doering, W. v. E. J. Am. Chem. Soc. 1967, 89, 5505–
5507.
(9) (a) Zhao, H.; Pagenkopf, B. L. Chem. Commun. 2003, 2592–2593. (b)
Zhao, H.; Engers, D. W.; Morales, C. L.; Pagenkopf, B. L. Tetrahedron 2007,
63, 8774–8780.
(15) (a) Hori, N.; Matsukura, H.; Matsuo, G.; Nakata, T. Tetrahedron Lett.
1999, 40, 2811–2814. (b) Hasegawa, E.; Curran, D. P. Tetrahedron Lett. 1993,
34, 1717–1720.
(16) Kawatsura, M.; Matsuda, F.; Shirahama, H. J. Org. Chem. 1994, 59,
6900–6901.
(10) Anelli, P. L.; Montanari, F.; Quici, S. Organic Synthesis; Wiley: New
York, 1993; Coll. Vol. 8, p 367.
(17) Shibuya, M.; Tomizawa, M.; Suzuki, I.; Iwabuchi, Y. J. Am. Chem.
Soc. 2006, 128, 8412–8413.
J. Org. Chem. Vol. 74, No. 10, 2009 3967

SCHEME 3
SCHEME 4
SCHEME 5
followed by a coupling reaction with γ-butenolide 24 in the
presence of potassium carbonate afforded a 1:1 mixture of 1
and its C2′-epimer,6a and this mixture can be easily separated
22
using preparative TLC. All spectra of synthetic 1 including
1H and 13C NMR, IR, and HRMS were identical to the reported
data.2,5
In summary, the total synthesis of 5-deoxystrigol (1) was
successfully carried out. An acyclic precursor that possessed
every requisite functional group of the tricyclic core of 1 was
prepared via the regioselective coupling reaction of epoxide 8
and the aluminum ate complex of alkyne 9. The key steps for
the synthesis of 1 were (1) the transition metal-mediated
reductive carbon-carbon bond formation of six- and five-
membered rings and (2) the introduction of tetra-substituted
carbon-carbon double bond at the ring junction via an ortho
ester.
alkene 2 in a good yield.18,19 In contrast, transformation of 23
to the corresponding 4-trifluoromethyl benzoate and cyclic
sulfate20 followed by reduction with samarium(II) iodide21
resulted in complex mixture of products.
Finally, conventional introduction of the side chain was
performed as shown in Scheme 5. Formylation of lactone 2
Experimental Section
(18) Hiyama, T.; Nozaki, H. Bull. Chem. Soc. Jpn. 1973, 46, 2248–2249.
(19) Olefination of diol 21 under the same reaction condition also provided
2.
(20) (a) Lohray, B. B. Synthesis 1992, 1035–1052. (b) Kolb, H. C.;
VanNieuwenhze, M. S.; Sharpless, K. B. Chem. ReV. 1994, 94, 2483–2515.
(21) (a) Hanessian, S.; Girard, C.; Chiara, J. L. Tetrahedron Lett. 1992, 33,
573–576. (b) Marko´, I. E.; Murphy, F.; Kumps, L.; Ates, A.; Touillaux, R.;
Craig, D.; Carballares, S.; Dolan, S. Tetrahedron 2001, 57, 2609–2619.
Pinacol Coupling Reaction of Diketone 15 to Pinacol 16. To
the solution of zinc (1.20 g, 18.4 mmol), TiCl4 (1.00 mL, 9.12
mmol), and trimethylacetonitrile (3.00 mL, 27.1 mmol) in CH2Cl2
(22) Separation condition: AcOEt/hexane ) 1/1. The Rf value is 0.50 for 1
and 0.45 for its C2′-epimer.
3968 J. Org. Chem. Vol. 74, No. 10, 2009

(40 mL) was added the solution of diketone 15 (424 mg, 0.929
mmol) in CH2Cl2 (6 mL) dropwise at room temperature under argon
atmosphere, and the mixture was stirred for 15 min. The reaction
mixture was quenched with 0.1 M HCl(aq), and the organic
materials were extracted with AcOEt. The organic phase was
washed with sat. NaHCO3(aq) and brine and dried over Na2SO4.
The organic phase was concentrated in vacuo, and the residue was
purified by silica gel column chromatography (AcOEt/hexane )
0/1-1/20) to afford 16 (343 mg, 81%) as a colorless oil. 1H NMR
(400 MHz, CDCl3) δ 0.99 (3H, s), 1.04 (3H, s), 1.05-1.16 (23H,
m), 1.19 (9H, s), 1.36-1.56 (2H, m), 1.60-1.68 (2H, m), 1.76
(1H, td, J ) 13.2, 4.0 Hz), 1.86 (1H, dt, J ) 14.0, 6.8 Hz), 2.23
(1H, dt, J ) 14.0, 7.6 Hz), 3.70 (1H, s), 3.91 (1H, s), 3.91 (1H, d,
gel column chromatography (AcOEt/hexane ) 1/10-1/1) to afford
triol 20 (15.7 mg, 79%) as a colorless solid and lactone 21 (2.7
mg, 16%) as a colorless solid. 20: Rf value 0.47 (AcOEt/hexane )
1
1/1); mp 119.5-120.0 °C (recryst. from hexane); H NMR (400
MHz, CDCl3) δ 0.95 (3H, s), 1.12 (3H, s), 1.20-1.46 (5H, m),
1.28 (3H, t, J ) 7.2 Hz), 1.72-1.84 (2H, m), 2.24-2.39 (2H, m),
2.47-2.62 (3H, m), 3.21 (1H, s), 3.66 (1H, d, J ) 2.8 Hz), 3.96
(1H, dd, J ) 5.6, 2.8 Hz), 4.16 (2H, q, J ) 7.2 Hz); 13C NMR
(100 MHz, CDCl3) δ 14.1, 18.0, 22.8, 27.3, 36.8, 37.6, 38.1, 38.8,
40.2, 44.9, 61.0, 78.3, 79.1, 81.7, 174.5; FT-IR (neat) ν 3483, 2934,
2871, 1719, 1459, 1377, 1299, 1184, 1097, 1031 cm-1. HRMS
(DART-TOF) [M + H]+ calcd for C15H27O5, 287.1859; found,
287.1870. 21: Rf value 0.30 (AcOEt/hexane ) 1/1); mp 166.0-166.7
J ) 10.4 Hz), 4.09 (1H, d, J ) 10.4 Hz), 4.24-4.34 (2H, m); 13
C
1
°C (recryst. from hexane); H NMR (400 MHz, CDCl3) δ 0.97
NMR (100 MHz, CDCl3) δ 11.7, 17.7, 17.86, 17.91, 19.0, 24.8,
27.1, 27.3, 31.8, 34.5, 37.0, 37.5, 61.2, 65.6, 76.7 (2C), 178.5; FT-
IR (neat) ν 3452, 2944, 2868, 1729, 1463, 1159, 1061, 882, 685
cm-1. HRMS (DART-TOF) [M + H]+ calcd for C25H51O5Si,
459.3506; found, 459.3512.
Samarium(II) Iodide-Mediated Cyclization of Aldehyde 19
to Triol 20 and Lactone 21. A solution of aldehyde 19 (19.7 mg,
0.0694 mmol), MeOH (8 µL, 0.2 mmol), and HMPA (72 µL, 0.41
mmol) in THF (2 mL) was degassed by freeze and thaw cycles.
To the mixture was added SmI2 solution (0.1 M in THF, 2.1 mL,
0.21 mmol) dropwise at -80 °C under argon atmosphere. After
2 h, the reaction mixture was quenched with 1 M HCl(aq) and
stirred for 1 h at room temperature. The organic materials were
extracted with AcOEt. The organic phase was washed with sat.
NaHCO3(aq) and brine and dried over Na2SO4. The organic phase
was concentrated in vacuo, and the residue was purified by silica
(3H, s), 1.13 (3H, s), 1.20-1.52 (4H, m), 1.76-1.90 (3H, m), 2.10
(1H, dd J ) 12.4, 9.2 Hz), 2.31 (1H, s), 2.35 (1H, d, J ) 12.4 Hz),
2.51 (1H, d, J ) 2.0 Hz), 2.70-2.84 (2H, m), 4.95 (1H, d, J ) 8.4
Hz), 4.09 (1H, d, J ) 10.4 Hz), 4.24-4.34 (2H, m); 13C NMR
(100 MHz, CDCl3) δ 17.4, 22.0, 26.5, 31.3, 35.1, 35.9, 36.4, 37.8,
47.4, 79.6, 80.8, 83.7, 178.2; FT-IR (neat) ν 3471, 2937, 2871,
1767, 1454, 1369, 1316, 1192, 1048, 1013, 948, 864 cm-1. HRMS
(DART-TOF) [M + H]+ calcd for C13H21O4, 241.1440; found,
241.1451.
Supporting Information Available: Detailed experimental
procedures for the transformations described herein and the
spectroscopic data for all new compounds. This material is
available free of charge via the Internet at http://pubs.acs.org.
JO9002085
J. Org. Chem. Vol. 74, No. 10, 2009 3969