Concise total synthesis of (-)-auxofuran by a click Diels-Alder strategy

Article abstract of DOI:10.1021/ol402345x

The first synthesis of auxofuran, a newly discovered auxin-like signaling molecule of streptomycetes, has been achieved in seven steps and 59% overall yield from commercial starting materials. Central to the synthetic route is a click-unclick Diels-Alder

Full text of DOI:10.1021/ol402345x

ORGANIC
LETTERS
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Vol. XX, No. XX
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Concise Total Synthesis of (À)-Auxofuran
by a Click DielsÀAlder Strategy
John Boukouvalas* and Richard P. Loach
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Departement de Chimie, Pavillon Alexandre-Vachon, Universite Laval, 1045 Avenue de
la Medecine, Quebec City, Quebec G1 V 0A6, Canada
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john.boukouvalas@chm.ulaval.ca
Received August 15, 2013
ABSTRACT
The first synthesis of auxofuran, a newly discovered auxin-like signaling molecule of streptomycetes, has been achieved in seven steps and 59%
overall yield from commercial starting materials. Central to the synthetic route is a clickÀunclick DielsÀAlder cycloaddition/cycloreversion
regimen enabling rapid access to an advanced intermediate from an unactivated alkyne.
Soil-dwelling bacteria of the genus Streptomyces produce
a cornucopia of natural products of clinical, agricultural,
and biotechnological value.1 These include over 70% of
commercial antibiotics,2 antibiotic production inducers,3
and some little known signaling molecules whose role can
be surprisingly subtle.4 The first such compound, auxofur-
an, was reported in 2006 by Tarkka, Fiedler, and co-work-
ers as the dominant fungal-growth promoter produced by
the mycorrhiza helper bacterium Streptomyces strain AcH
Figure 1. Structure of auxofuran.
505.5a Remarkably, auxofuran facilitates the mutually ben-
eficial colonization of spruce roots by the fungus Amanita
streptomycetes, produce signaling molecules only in tiny
amounts, it is often difficult to obtain sufficient material
for proper characterization and testing. Initially, the
structure of auxofuran was disclosed as 25a but was soon
muscaria (fly agaric), a process vital to forest ecosystems
whereby plants provide carbohydrates to fungi and in
return fungi provide phosphates to plants.6,7 Because
revised to 1 by Sussmuth5b who also determined its abso-
€
(1) (a) Seipke, R. F.; Kaltenpoth, M.; Hutchings, M. I. FEMS
Microbiol. Rev. 2012, 36, 862–876. (b) van Wezel, G. P.; McDowall,
K. J. Nat. Prod. Rep. 2011, 28, 1311–1333.
lute configuration as S by modified Mosher ester analysis
(Figure 1).
(2) Kitani, S.; Miyamoto, K. T.; Takamatsu, S.; Herawati, E.; Iguchi,
H.; Nishitomi, K.; Uchida, M.; Nagamitsu, T.; Omura, S.; Ikeda, H.;
Nihira, T. Proc. Natl. Acad. Sci. U.S.A. 2011, 108, 16410–16415.
(3) (a) Willey, J. M.; Gaskell, A. A. Chem. Rev. 2011, 111, 174–187.
(b) Davis, J. B.; Bailey, J. D.; Sello, J. K. Org. Lett. 2009, 11, 2984–2987.
(4) Ottmann, C.; van der Hoorn, R. A. L.; Kaiser, M. Chem. Soc.
Rev. 2012, 41, 3168–3178.
Intrigued by the exquisite 4-hydroxy-7-keto-4,5,6,7-tet-
rahydrobenzofuran motif of 1 and the need for meaningful
quantities for biological studies, we were led to undertake
its total synthesis. Reported herein is the first synthesis
of auxofuran, which demonstrates the scaffolding power
of click DielsÀAlder chemistry and certifies the revised
structure assignment.
Retrosynthetically, we envisioned assembly of 1
from chiral carboxylic acid 3 through intramolec-
ular FriedelÀCrafts acylation (Scheme 1). Among pos-
sible approaches to 3, the most expedient entailed
(5) (a) Riedlinger, J.; Schrey, S. D.; Tarkka, M. T.; Hampp, R.;
Kapur, M.; Fiedler, H.-P. Appl. Environ. Microbiol. 2006, 72, 3550–
€
3557. (b) Keller, S.; Schneider, K.; Sussmuth, R. D. J. Antibiot. 2006,
59, 801–803.
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(6) Deveau, A.; Brule, C.; Palin, B.; Champmartin, D.; Rubini, P.;
Garbaye, J.; Sarniguet, A.; Frey-Klett, P. Environ. Microbiol. Rep. 2010,
2, 560–568.
(7) Tarkka, M.; Hampp, R. Soil Biol. 2008, 14, 107–126.
r
10.1021/ol402345x
XXXX American Chemical Society

Scheme 1. Synthesis Strategy for Auxofuran (1)
Scheme 2. Synthesis of Chiral Dienophiles 9À10
a “clickÀunclick” cycloaddition/cycloreversion reac-
tion of oxazole 4 with chiral dienophile 5. Although
variants of this chemistry have found several applications
in natural product synthesis,8À10 the use of unactivated
alkynes as external dienophiles is rare.11 Moreover, the
few known examples pertain to the preparation of fairly
simple, achiral furan reagents.11 Hence, the serviceability
of this process in the context of total synthesis had yet to be
investigated.
Scheme 3. Conversion of Alcohol 9 to (R)-Nonalactone (12)
Toward this end, chiral dienophiles 9À11 were prepared
from commercially available ethyl malonyl chloride 6 as
outlined in Schemes 2À3. Alkynylation12 of 6 with 1-pen-
tynylzinc chloride afforded ynone 7 (92%), which cleanly
underwent Noyori asymmetric transfer hydrogenation13
to deliver propargyl alcohol 9 (99%) with high enantio-
meric purity (>94% ee). Subsequent TBDPS protection
provided silyl ether 10 with an overall efficiency of 87%
(3 steps, Scheme 2). To ensure that the absolute stereo-
chemistry of 9À10 was indeed as we had expected from the
Noyori reduction, 9 was subjected to careful lactonization to
(S)-alkynyllactone 11 (ee 94%) followed by hydrogenation
of the alkyne linkage to provide the known (R)-nonalactone
12 (Scheme 3). Interestingly, the latter is an aroma compo-
nent of Australian wines14 and a worthy target in its own
right, recently synthesized in five steps from L-glutamic
acid14 and by optical resolution of (()-12.15
At this point, the cycloaddition/cycloreversion reaction
of commercially available 4-phenyloxazole 4 with ynone 7
and unactivated alkynes 9À11 was explored (Table 1).
Counterintuitively, the unactivated alkyne 11 turned out
to be more effective than its ynone counterpart 7, affording
furan 14 in essentially quantitative yield (entry 2 vs 1,
Table 1).16 Furthermore, enantiopure14could be obtained
in excellent yield directly from hydroxy ester 9 via in situ
lactonization (95%, entry 3). Even though the bulkier alkyne
10 was less reactive under the same conditions (ca. 40À45%
conversion), a slight modification of the procedure enabled
access to 15 with high efficiency (260À270 °C, 20 h, 84%,
entry 4). It is worthy of note that none of the DielsÀAlder
adducts could be observed in these experiments, presumably
(8) Levin, J. I.; Laakso, L. M. Chapter 3: Oxazole Diels-Alder
Reactions. In Oxazoles: Synthesis, Reactions, and Spectroscopy, Part
A, Vol. 60; Palmer, D. C., Ed.; Wiley-VCH: Weinheim, 2003; pp
417À472.
(9) For intramolecular versions, see: (a) Jacobi, P. A.; Craig, T. A.;
Walker, D. G.; Arrick, D. A.; Frechette, R. F. J. Am. Chem. Soc. 1984,
106, 5585–5594. (b) Liu, B.; Padwa, A. Tetrahedron Lett. 1999, 40, 1645–
1648. (c) Sessions, E. H.; Jacobi, P. A. Org. Lett. 2006, 8, 4125–4128.
(d) Sessions, E. H.; O’Connor, R. T., Jr.; Jacobi, P. A. Org. Lett. 2007, 9,
3221–3224. (e) Onyango, E. O.; Jacobi, P. A. J. Org. Chem. 2012,
77, 7411–7427.
(10) For the use of ynones as external dienophiles, see: (a) Paquette,
L. A.; Efremov, I. J. Am. Chem. Soc. 2001, 123, 4492–4501. (b) Clark,
J. S.; Marlin, F.; Nay, B.; Wilson, C. Org. Lett. 2003, 5, 89–92.
(c) Piggott, M. J.; Wege, D. Tetrahedron 2006, 62, 3550–3556.
(11) (a) Yu, P.; Yang, Y.; Zhang, Z. Y.; Mak, T. C. W.; Wong,
H. N. C. J. Org. Chem. 1997, 62, 6359–6366. (b) Wong, M. K.; Leung,
C. Y.; Wong, H. N. C. Tetrahedron 1997, 53, 3497–3512. See also:
(c) Lopez, F. J.; Jett, M.-F.; Muchowski, J. M.; Dov Nitzan, D.; O’Yang,
C. Heterocycles 2002, 56, 91–95. (d) Dolbier, W. R., Jr.; Mitani, A.; Xu,
W.; Ghiviriga, I. Org. Lett. 2006, 8, 5573–5575.
(14) Cooke, R. C.; van Leeuwen, K. A.; Capone, D. L.; Gawel, R.;
Elsey, G. M.; Sefton, M. A. J. Agric. Food Chem. 2009, 57, 2462–2467.
(15) Yumoto, K.; Hasegawa, M.; Toshima, H. Heterocycles 2010, 81,
421–431.
(16) Conceivably, the cycloaddition of unactivated alkynes to 4 may
proceed through inverse-electron demand; for relevant DFT studies, see:
(a) Jursic, B. S. J. Chem. Soc., Perkin Trans. 2 1996, 1021–1026.
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ꢀ
ꢀ
(12) (a) Carbery, D. R.; Reignier, S.; Myatt, J. W.; Miller, N. D.;
Harrity, J. P. A. Angew. Chem., Int. Ed. 2002, 41, 2584–2587.
(b) Nakayama, A.; Kogure, N.; Kitajima, M.; Takayama, H. Angew.
Chem., Int. Ed. 2011, 50, 8025–8027.
(b) Suarez-Moreno, G. V.; Gonzalez-Zamora, E.; Mendez, F. Org. Lett.
2011, 13, 6358–6561. See also: (c) Boger, D. L. Chem. Rev. 1986, 86, 781–
793.
(17) For similar observations and a discussion on relative rates of
€
€
(13) (a) Matsumura, K.; Hashiguchi, S.; Ikariya, T.; Noyori, R.
J. Am. Chem. Soc. 1997, 119, 8738–8739. (b) Ikariya, T.; Blacker, A. J.
Acc. Chem. Res. 2007, 40, 1300–1308.
cycloaddition/cycloreversion, see: (a) Konig, H.; Graf, F.; Weberndorfer,
V. Liebigs Ann. Chem. 1981, 668–682. (b) Liotta, D.; Saindane, M.; Ott, W.
Tetrahedron Lett. 1983, 24, 2473–2476.
B
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Table 1. Assembly of Disubstituted Furans from Alkynes
Scheme 4. Synthesis of (À)-Auxofuran
HCl-free conditions.19 Pleasingly, we were able to quell
lactonization almost completely by adaptation of the
exceptionally mild method of Tedder and Tatlow.21 Thus,
treatment of acid 16 with 1.2 equiv of trifluoroacetic
anhydride in dichloromethane at 0 °C for 2 h smoothly
promoted cyclization affording 17in 87%yield(Scheme4).
Finally, TBAF desilylation furnished (À)-auxofuran 1
whose NMR spectra were identical to those of the natural
product.5b Although no optical data were reported for
auxofuran, its absolute configuration could be firmly
established as S by conversion of synthetic 1 to Mosher
esters 18 and 19 and NMR comparison with those derived
from a natural sample.5b,22
In conclusion, the first synthesis of auxofuran has been
achieved in seven steps and 59% overall yield from com-
mercially available starting materials. Central to the suc-
cess of this route is a tandem DielsÀAlder/retro-DielsÀ
Alder process enabling rapid assemblage of advanced
intermediate 15 from an unactivated homochiral alkyne.
The wider scope of such “clickÀunclick” regimens in
the context of natural product synthesis is currently under
investigation.
due to rapid collapse into furans under the reaction condi-
tions (g220 °C).17,18
While auxofuran could ultimately be reached from
either 14 or 15, the latter represented a superior starting
point for completing the synthesis. Hydrolysis of the ester
group in 15 provided acid 16 thereby setting the stage
for intramolecular FriedelÀCrafts acylation to ketone 17
(Scheme 4). Initial attempts at generating the acid chloride
of 16 proved utterly unrewarding.19,20 A typical outcome
was the formation of lactone 14, even under essentially
Acknowledgment. We thank the Natural Sciences and
Engineering Research Council of Canada (NSERC) and
the FQRNT-Quebec Centre in Green Chemistry and Cat-
alysis (CGCC) for financial support. We thank NSERC
foradoctoralscholarshiptoR.P.L. Finally, wearegrateful
(18) An isolable DA-adduct arising from the exceptionally fast
reaction of oxazole 4 with benzyne (0 °C, 100%) has been shown to
undergo facile cycloreversion at 40À70 °C: Whitney, S. E.; Winters, M.;
Rickborn, B. J. Org. Chem. 1990, 55, 929–935.
(19) (a) Kangani, C. O.; Day, B. W. Org. Lett. 2008, 10, 2645–2648.
(b) Miles, W. H.; Connell, K. B.; Ulas, G.; Tuson, H. H.; Dethoff, E. A.;
Mehta, V.; Thrall, A. J. J. Org. Chem. 2010, 75, 6820–6829.
€
€
to Prof. Roderich Sussmuth (Technische Universitat Berlin)
for providing to us the NMR spectra of natural auxofuran.
(20) (a) Kanematsu, K.; Soejima, S.; Wang, G. Tetrahedron Lett.
€
1998, 120, 2817–2825.
(21) (a) Tedder, J. M. Chem. Rev. 1955, 55, 787–827. (b) Bourne, E. J.;
Stacey, M.; Tatlow, J. C.; Tedder, J. M. J. Chem. Soc. 1951, 718–720.
(c) Yick, C.-Y.; Tsang, T.-K.; Wong, H. N. C. Tetrahedron 2003, 59,
1991, 36, 4761–4764. (b) Furstner, A.; Weintritt, H. J. Am. Chem. Soc.
Supporting Information Available. Detailed experimental
procedures and characterization data. This material is avail-
able free of charge via the Internet at http://pubs.acs.org.
325–333. (d) de la Torre, M. C.; Garcıa, I.; Sierra, M. A. Chem.;Eur. J.
´
(22) See Table 1 in the Supporting Information for details.
The authors declare no competing financial interest.
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2005, 11, 3659–3667. (e) Tebeka, I. R. M.; Longato, G. B.; Craveiro,
M. V.; de Carvalho, J. E.; Ana, L. T. G.; Ruiz, A. L. T. G.; Silva, L. F.,
Jr. Chem.;Eur. J. 2012, 18, 16890–16901.
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