A short synthesis of the common dihydropyran segment of the antifungal agents ambruticin and jerangolid A

Article abstract of DOI:10.1016/j.tetlet.2005.06.040

The dihydropyranyl segment common to ambruticin and jerangolid A was prepared in six steps (31.7% yield) from (S)-2-benzyloxypropanal via silyloxydiene cyclocondensation, followed by C-glycosidation, and eventual epimerization at C18.

Full text of DOI:10.1016/j.tetlet.2005.06.040

Tetrahedron
Letters
Tetrahedron Letters 46 (2005) 5529–5531
A short synthesis of the common dihydropyran segment of
the antifungal agents ambruticin and jerangolid A
Julie M. Lukesh and William A. Donaldson*
Department of Chemistry, Marquette University, PO Box 1881, Milwaukee, WI53201-1881, USA
Received 24 May 2005; revised 8 June 2005; accepted 9 June 2005
Available online 1 July 2005
Abstract—The dihydropyranyl segment common to ambruticin and jerangolid A was prepared in six steps (31.7% yield) from (S)-2-
benzyloxypropanal via silyloxydiene cyclocondensation, followed by C-glycosidation, and eventual epimerization at C18.
Ó 2005 Published by Elsevier Ltd.
Ambruticin (1, Scheme 1) is a structurally unique car-
boxylic acid isolated from Polyangium cellulosum var.
fulvum, which exhibits potent oral antifungal activity
against Coccidioides immitis, Histoplasma capsulatum
and Blastomyces dermititidis.1 Extensive spectral ana-
lysis revealed that the structure of 1 consists of a tetra-
biological activity. The complex array of diverse func-
tionality present in 1 has generated considerable syn-
thetic interest,3 including total syntheses by the groups
of Kende et al.,4 Martin and co-workers,5 Lee et al.6
and Liu and Jacobsen.7 To our knowledge, there are
no reported syntheses of the jerangolids. As part of
our interest in the preparation of C-glycosides,8 we here-
in report the enantioselective preparation of the com-
mon dihydropyranyl segment 3, an intermediate in the
Martin synthesis of 1.5
hydropyranyl ring,
a dihydropyranyl ring and a
divinylcyclopropane ring. More recently, the jerangolids
A and D (2a,b), isolated from a strain of Sorangium cell-
ulosum (So ce 307), were found to exhibit antifungal
activity similar to that of 1.2 The structure of 2 from
C6–C18 is identical with the C13–C24 segment of
ambruticin, and similar antibiotic spectrum of 1 and 2
suggests that these segments are responsible for their
Construction and elaboration of the oxane ring was
envisioned by means of a Lewis acid catalyzed diene–
aldehyde cyclocondensation reaction,9 followed by a
C-glycosidation of the derived pseudoglycal. Since C-
glycosidation generally proceeds via axial attack on an
oxonium ion to afford trans-2,6-disubstituted pyrans, it
was anticipated that a subsequent epimerization at
C18 (ambruticin numbering) would be necessary to gen-
erate the desired cis-18,22 relative stereochemistry. To
this end, reaction of 2(S)-benzyloxypropanal (4)10 with
1-methoxy-2-methyl-3-(trimethylsiloxy)-1,3-butadiene
(5)11 in the presence of BF3-etherate, followed by work-
upwith TFA gave an inseparable mixture of diastereo-
meric dihydropyrones 6 and 7 (Scheme 2). The relative
stereochemistry of 6 and 7 was assigned on the basis
1
24
Me
Me
13
CO2H
Me Me
H
H
H
H
H
O
O
O
H
Me
Me
Me
OH
Me
H
H
O
OH
1
O
18
Me
Me Me
H
6
O
R
O
3
Me
1
of their H NMR spectral data.12 In particular, the sig-
OMe
2a, R = OH
2b, R = H
nals for H17 and H19eq (ambruticin numbering) of 6 (d
3.69 and 2.36 ppm, respectively), appear upfield of the
corresponding signals for 7 (d 3.81 and 2.56 ppm,
respectively). These relative chemical shifts are quite
characteristic of diastereomeric dihydropyrones with
an a-alkoxy group.13 Cyclocondensation of 4 with 5 in
the presence of MgBr2, followed by work-upwith
Scheme 1.
Keywords: Hetero-Diels–Alder cycloaddition; C-glycosidation.
*
Corresponding author. Tel.: +1 414 288 7374; fax: +1 414 288
7066; e-mail: willliam.donaldson@marquette.edu
0040-4039/$ - see front matter Ó 2005 Published by Elsevier Ltd.
doi:10.1016/j.tetlet.2005.06.040

5530
J. M. Lukesh, W. A. Donaldson / Tetrahedron Letters 46 (2005) 5529–5531
Acknowledgements
4
i) Lewis
acid
BnO
BnO
BnO
Me
H
H
O
OMe
Me
O
O
O
O
ii) TFA
17
Me
17
Me
Me
Partial financial support for this research was provided
by the Department of Education (P200A000228), and
the Marquette University Graduate School Committee
on Research. High resolution mass spectral data were
obtained at the Washington University Resource for
Mass Spectrometry.
19
19
Me
OTMS
5
(+)-6
7
BF3:OEt2/CH2Cl2/–78oC to 23oC
MgBr2/THF/0oC to 23oC
1 : 1.6 (71%)
1 : 0 (86%)
Scheme 2.
References and notes
TFA gave only dihydropyrone (+)-6. The S configura-
tion at C18 (ambruticin numbering) of 6 is the result
of approach of the diene in an exo sense on the less hin-
dered face of the Mg2+ chelated form of optically active
aldehyde 4.
1. Connor, D. T.; Greenough, R. C.; von Strandtmann,
M. J. Org. Chem. 1977, 42, 3664–3669.
2. Gerth, K.; Washausen, P.; Ho¨ftle, G.; Irschik, H.;
Reichenbach, H. J. Antibiot. 1996, 49, 71–75.
3. For other synthetic studies of ambruticin, see: (a) Barnes,
N. J.; Davidson, A. H.; Hughes, L. R.; Procter, G.;
Rajcoomar, V. Tetrahedron Lett. 1981, 22, 1751–1754; (b)
Barnes, N. J.; Davidson, A. H.; Hughes, L. R.; Procter, G.
J. Chem. Soc., Chem. Commun. 1985, 1292–1294; (c)
Proctor, G.; Russell, A. T.; Murphy, P. J.; Tan, P. J.;
Mather, A. N. Tetrahedron 1988, 44, 3953–3973; (d)
Davidson, A. H.; Eggleton, N.; Wallace, I. H. J. Chem.
Soc., Chem. Commun. 1991, 378–380; (e) Marko, I. E.;
Bayston, D. J. Tetrahedron 1994, 50, 7141–7156; (f)
Marko, I. E.; Bayston, D. J. Synthesis 1996, 297–304; (g)
Wakamatsu, H.; Isono, N.; Mori, M. J. Org. Chem. 1997,
62, 8917–8922; (h) Varelis, P.; Johnson, B. L. Aust. J.
Chem. 1997, 59, 43–51; (i) Michelet, V.; Adiey, K.; Bulic,
B.; Genet, J.-P.; Dujardin, G.; Rossignol, S.; Brown, E.;
Toupet, L. Eur. J. Org. Chem. 1999, 2885–2892; (j) Yin, J.;
Llorente, I.; Villanueva, L. A.; Liebeskind, L. S. J. Am.
Chem. Soc. 2000, 122, 10458–10459; (k) Marko, I. E.;
Kumamoto, T.; Giard, T. Adv. Synth. Catal. 2002, 1063–
1067; (l) Michelet, V.; Adiey, K.; Tanier, S.; Dujardin, G.;
Genet, J.-P. Eur. J. Org. Chem. 2003, 2947–2958.
4. (a) Kende, A. S.; Mendoza, J. S.; Fujii, Y. J. Am. Chem.
Soc. 1990, 112, 9645–9646; (b) Kende, A. S.; Mendoza,
J. S.; Fujii, Y. Tetrahedron 1993, 49, 8015–8038.
Reduction of 6 gave the pseudoglycal (+)-8 as a single
diastereomer (Scheme 3). We8a and others14 have re-
ported that the reaction of glycals with trialkylalumin-
ium reagents is useful for the preparation of C-alkyl
glycosides. To this end, treatment of pseudoglycal 8 with
the weak nucleophile triethylaluminium, in the presence
of boron trifluoride etherate, gave a mixture of trans-
and cis-dihydropyrans (8:1 ratio). The major product
arises via axial attack of the weak nucleophile on the
cyclic oxonium ion generated by ionization of 8. The
pure trans-isomer, (ꢀ)-9, was obtained in good yield
after column chromatography. Removal of the benzyl
protecting group, followed by oxidation gave (ꢀ)-11.15
Base-catalyzed epimerization of the trans-ketone, in
benzene, gave a separable mixture of (ꢀ)-11 and (+)-3
(1:2 ratio).16 Two equilibration/separation cycles gave
pure (+)-3 in 83% combined yield. The NMR spectral
data obtained for 3 was identical with that previously
reported.5
5. (a) Kirkland, T. A.; Colucci, J.; Geraci, L. S.; Marx, M.
A.; Schneider, M.; Kaelin, D. E., Jr.; Martin, S. F. J. Am.
Chem. Soc. 2001, 123, 12432; (b) Beberich, S. M.;
Cherney, R. J.; Colucci, J.; Courillon, C.; Geraci, L. S.;
Kirkland, T. A.; Marx, M. A.; Schneider, M.; Martin, S.
F. Tetrahedron 2003, 59, 6819–6832.
6. Lee, E.; Choi, S. J.; Kim, H.; Han, H. O.; Kim, Y. K.;
Min, S. J.; Son, S. H.; Lim, S. M.; Jang, W. S. Angew.
Chem., Int. Ed. 2002, 41, 176–177.
In summary, the synthesis of the dihydropyranyl seg-
ment (3), common to ambruticin and the jerangolids,
from optically active aldehyde 4, was accomplished in
six steps (31.7% overall yield). The length and yield of
our synthetic route is competitive with that reported
by Martin and co-workers.5
7. Liu, P.; Jacobsen, E. N. J. Am. Chem. Soc. 2001, 123,
10772–10773.
8. (a) Lukesh, J. M.; Donaldson, W. A. Tetrahedron:
Asymmetry 2003, 14, 757–762; (b) Greer, P. B.; Donald-
son, W. A. Tetrahedron 2002, 58, 6009–6018; (c) Liu, L.;
Donaldson, W. A. Synlett 1996, 103–104.
9. (a) Danishefsky, S.; Bilodeau, M. T. Angew. Chem., Int.
Ed. Engl. 1996, 35, 1380–1419; (b) Danishefsky, S. J.
Aldrichim. Acta 1986, 19, 59–69.
BnO
RO
Me
Me
Et3Al
BF3:OEt2
H
H
H
DIBAL
(88%)
O
O
Me
(+)-6
Me
(80%)
Me
Na/NH3
OH
(+)-8
(–)-9, R = Bn
(–)-10, R = H
THF
(79%)
Me
Me
K2CO3
C6H6
10. Enders, D.; von Berg, S.; Jandeleit, B. Org. Synth. 2002,
78, 177–188.
11. Danishefsky, S.; Yan, C. F.; Singh, R. K.; Gammill, R. B.;
McCurry, P. M.; Fritsh, N.; Clardy, J. J. Am. Chem. Soc.
1979, 101, 7001–7008.
Me
Me
PDC
H
H
H
H
DMF
O
O
O
O
+
11
(80%)
Me
Me
(–)-11
(+)-3
12. Compound 6: 1H NMR (300 MHz, CDCl3): d = 7.39–7.28
(m, 6H), 4.70 (d, J = 11.7 Hz, 1H), 4.53 (d, J = 11.7 Hz,
1H), 4.34 (ddd, J = 14.7, 3.8, 3.6 Hz, 1H), 3.69 (qd,
J = 6.5, 4.7 Hz, 1H), 2.79 (dd, J = 16.4, 14.7 Hz, 1H), 2.36
(dd, J = 16.7, 3.2 Hz, 1H), 1.68 (d, J = 1.2 Hz, 3H), 1.30
(11 : 3 = 1 : 2) separable
83% pure 3 after two
equilibration/separation cycles
Scheme 3.

J. M. Lukesh, W. A. Donaldson / Tetrahedron Letters 46 (2005) 5529–5531
5531
(d, J = 6.5 Hz, 3H). Compound 7: 1H NMR (300 MHz,
CDCl3) d 7.39–7.27 (m, 6H), 4.67 (d, J = 11.7 Hz, 1H),
4.59 (d, J = 12.0 Hz, 1H), 4.33 (ddd, J = 14.4, 3.8, 3.8 Hz,
1H), 3.81 (qd, J = 6.5, 4.1 Hz, 1H), 2.68 (dd, J = 16.7,
14.4 Hz, 1H), 2.56 (dd, J = 16.7, 3.5 Hz, 1H), 1.70 (d,
J = 1.2 Hz, 3H), 1.27 (d, J = 6.5 Hz, 3H).
3H), 1.74–1.49 (m, 2H), 1.02 (t, J = 7.3 Hz, 3H); 13C NMR
(75 MHz, CDCl3): d = 209.6, 136.0, 118.1, 78.1, 73.3, 26.8,
26.2, 24.7, 20.1, 10.7; EI-HRMS m/z 168.1150 (calcd for
C10H16O2 m/z 168.1136). Compound 3: ½aꢁ23 +172 (c 0.248,
D
CHCl3); IR (neat): 2966, 2936, 2879, 1721, 1435, 1352,
1229, 1116, 1058, 927 cmꢀ1; 1H NMR (300 MHz, CDCl3):
d = 5.60–5.33 (m, 1H), 4.13–4.05 (m, 1H), 3.92 (dd,
J = 10.4, 4.4 Hz, 1H), 2.25 (s, 3H), 2.21–2.00 (m, 2H),
1.81 (ddq, J = 14.9, 10.9, 3.5 Hz, 1H), 1.60 (ddd, J = 2.4,
2.4, 1.4 Hz, 3H), 1.54 (ddq, J = 14.1, 7.0, 7.0 Hz, 1H), 0.95
(t, J = 7.3 Hz, 3H); 13C NMR (75 MHz, CDCl3):
d = 210.0, 135.7, 119.7, 79.0, 78.5, 27.6, 26.1, 25.9, 19.2,
9.0.
13. Danishefsky, S. J.; Pearson, W. H.; Harvey, D. F.;
Maring, C. J.; Springer, J. P. J. Am. Chem. Soc. 1985,
107, 1256–1268.
14. (a) Maruoka, K.; Nonoshita, K.; Itoh, T.; Yamamoto, H.
Chem. Lett. 1987, 2215–2216; (b) Deshpande, P. P.; Price,
K. N.; Baker, D. C. J. Org. Chem. 1996, 61, 455–458.
23
15. Compound 11: ½aꢁD ꢀ129.2 (c 0.3320, CHCl3); IR (neat):
2967, 2934, 2876, 1717, 1453, 1355, 1120, 1053, 924 cmꢀ1
;
16. Notably, ab initio calculations (6-31G* basis set) of the
two stereoisomers indicated that the cis-isomer (3) is
0.77 kcalmolꢀ1 lower in energy compared to the trans-
isomer (11).
1H NMR (300 MHz, CDCl3): d = 5.49 (ddd, J = 6.2, 3.5,
1.8 Hz, 1H), 4.06 (dd, J = 7.9, 5.9 Hz, 1H), 4.00 (br d,
J = 9.7 Hz, 1H), 2.24 (s, 3H), 2.22–2.14 (m, 2H), 1.70 (s,