Total synthesis of (+)-ambruticin [18]

Full text of DOI:10.1021/ja016893s

10772
J. Am. Chem. Soc. 2001, 123, 10772-10773
Total Synthesis of (+)-Ambruticin
Ping Liu and Eric N. Jacobsen*
Department of Chemistry and Chemical Biology
HarVard UniVersity, Cambridge, Massachusetts 02138
ReceiVed August 20, 2001
Ambruticin (1) is a novel antifungal agent that was isolated
from fermentation extracts of the myxobacterium Polyangium
cellulosum by Warner-Lambert scientists in 1977.1 This natural
product exhibits pronounced activity against systemic medical
pathogens such as Coccidioides immitis, Histoplasma capsulatum,
and Blastomyces dermatitidis.1 It also displays potent inhibitory
activity against the yeast strain Hansenula anomala with an MIC
of 0.03 µg/mL.2 Recently, the mechanism of action of ambruticin
has been shown to be analogous to that of pyrrolnitrin, in that its
lethality to cells is achieved through interference with osmoregu-
lation.3 The relative and absolute stereochemistry of 1 have been
established through a combination of spectroscopic studies,4
chemical degradation, and single-crystal X-ray analysis.5 This
structurally intriguing molecule incorporates 10 stereocenters and
3 E-olefins within a relatively small framework bearing a
dihydropyran, a tetrahydropyran diol, and a trisubstituted divi-
nylcyclopropane unit unique to this family of natural products.6
The diverse structural features of ambruticin, in conjunction with
its potentially valuable biological activities, have stimulated
considerable interest in the synthetic community7 and to date two
total syntheses have been documented.8,9 We report herein our
synthetic efforts in this area, which have led to a concise and
highly stereocontrolled total synthesis of 1.
Figure 1. Retrosynthetic analysis (PT ) phenyltetrazolyl).
Scheme 1. Synthesis of the C1-C8 Fragment (2)a
a Conditions: (a) (1S,2R)-6 (10 mol %), room temperature. (b)
BH3‚THF, THF, 0 °C; then 30% H2O2, 3 N NaOH, 0 °C f room
temperature. (c) TBSOTf, 2,6-lutidine, CH2Cl2, -30 °C. (d) Pd/C, H2.
(e) cat. TPAP, NMO, CH2Cl2, room temperature.
From a retrosynthetic standpoint, ambruticin can be viewed as
consisting of four distinct chiral subunits serially linked through
the three double bonds. The strategy underlying our synthetic plan
was to apply efficient, enantioselective reactions to generate each
of the stereochemical elements independently, as this would offer
maximum flexibility for the preparation of stereoisomeric and
structural analogues. Cleavage of the C8-C9 olefin bond revealed
two fragments 2 and 3 (Figure 1), union of which was envisaged
via a Kocien´ski-Julia olefination.10 We anticipated that the two
pyran systems could be fashioned efficiently employing the highly
enantio- and diastereoselective chromium-catalyzed hetero-Diels-
Alder (HDA) methodologies reported recently from our labora-
tories.11 Construction of the central ring would present a
challenging test to state-of-the-art asymmetric cyclopropanation
methodologies. Finally, although it is certainly not obvious, we
envisaged installing the isolated C15 stereocenter by means of
an asymmetric carbonylation reaction on an appropriate conju-
gated diene precursor.
The synthesis of 2 was initiated with a HDA reaction between
diene 412 and aldehyde 5 catalyzed by (1S,2R)-6,11 which provided
dihydropyran 7 in 97% ee (Scheme 1). A highly regio- and
diastereoselective hydroboration/oxidation13 of 7 generated 8 as
a single diastereoisomer, thereby establishing all four stereocenters
in the left-hand pyran of 1. Protection of the secondary hydroxyl
and debenzylation/oxidation of the primary alcohol afforded the
C1-C8 fragment 2 in an overall yield of 53% for the 5-step
sequence.
The carbon framework of the right-hand dihydropyran was
accessed through the asymmetric HDA reaction between diene
12, derived from R,â-unsaturated ketone 11, and aldehyde 13. In
the presence of (1R,2S)-6, 14 was generated in high yield and
greater than 99% ee (Scheme 2). Removal of the triethylsilyloxy
group was effected by hydroboration and acid-catalyzed elimina-
tion,14 and this operation also liberated the primary alcohol.
Oxidation to aldehyde 16 followed by homologation with TMSC-
(1) Ringel, S. M.; Greenough, R. C.; Roemer, S.; Connor, D.; Gutt, A. L.;
Blair, B.; Kanter, G.; von Strandtmann, M. J. Antibiot. 1977, 30, 371-375.
(2) Gerth, K.; Washausen, P.; Ho¨fle, G.; Irschik, H.; Reichenbach, H. J.
Antibiot. 1996, 49, 71-75.
(3) Knauth, P.; Reichenbach, H. J. Antibiot. 2000, 53, 1182-1190.
(4) Connor, D. T.; von Strandtmann, M. J. Org. Chem. 1978, 43, 4606-
4607.
(5) (a) Connor, D. T.; Greenough, R. C.; von Strandtmann, M. J. Org.
Chem. 1977, 42, 3664-3669. (b) Just, G.; Potvin, P. Can. J. Chem. 1980, 58,
2173-2177.
(6) The Ho¨fle group isolated ambruticin and six new analogues bearing an
amino group at the C5 position from myxobacterium Sorangium cellulosum.
See: Ho¨fle, G.; Steinmetz, H.; Gerth, K.; Reichenbach, H. Liebigs Ann. Chem.
1991, 941-945.
(7) For earlier synthetic studies on ambruticin, see: (a) Michelet, V.; Adiey,
K.; Bulic, B.; Geneˆt, J.-P.; Dujardin, G.; Rossignol, S.; Brown, E.; Toupet,
L. Eur. J. Org. Chem. 1999, 64, 2885-2892. (b) Wakamatsu, H.; Isono, N.;
Mori, M. J. Org. Chem. 1997, 62, 8917-8922. (c) Liu, L.; Donaldson, W. A.
Synlett 1996, 103-104. (d) Marko´, I. E.; Bayston, D. J. Synthesis 1996, 297-
304. (e) Marko´, I. E.; Bayston, D. J. Tetrahedron 1994, 50, 7141-7156. (f)
Marko´, I. E.; Bayston, D. J. Tetrahedron Lett. 1993, 34, 6595-6597. (g)
Nagasawa, T.; Handa, Y.; Onoguchi, Y.; Ohba, S.; Suzuki, K. Synlett 1995,
739-741. (h) Davidson, A. H.; Eggleton, N.; Wallace, I. H. J. Chem. Soc.,
Chem. Commun. 1991, 378-380. (i) Burke, S. D.; Armistead, D. M.;
Schoenen, F. J.; Fevig, J. M. Tetrahedron 1986, 42, 2787-2801. (j) Barnes,
N. J.; Davidson, A. H.; Hughes, L. R.; Procter, G. J. Chem. Soc., Chem.
Commun. 1985, 1292-1294. (k) Barnes, N. J.; Davidson, A. H.; Hughes, L.
R.; Procter, G.; Rajcoomar, V. Tetrahedron Lett. 1981, 22, 1751-1754. (l)
Sinay¨, P. In Bioorganic Heterocycles 1986: Synthesis, Mechanism and
BioactiVity; Elsevier: Amsterdam, The Netherlands, 1986; pp 59-70.
(8) (a) Kende, A. S.; Fujii, Y.; Mendoza, J. S. J. Am. Chem. Soc. 1990,
112, 9645-9646. (b) Kende, A. S.; Mendoza, J. S.; Fujii, Y. Tetrahedron
1993, 49, 8015-8038.
(10) (a) Blakemore, P. R.; Cole, W. J.; Kocien´ski, P. J.; Morley, A. Synlett
1998, 26-28. (b) Julia, M.; Paris, J.-M. Tetrahedron Lett. 1973, 14, 4833-
4836.
(11) Dossetter, A. G.; Jamison, T. F.; Jacobsen, E. N. Angew. Chem., Int.
Ed. 1999, 38, 2398-2400.
(12) Li, L.-S.; Wu, Y.; Hu, Y.-J.; Xia, L.-J.; Wu, Y.-L. Tetrahedron:
Asymmetry 1998, 9, 2271-2277.
(9) Martin has presented a total synthesis of ambruticin, see: Kirkland, T.
A.; Martin, S. F.; Colucci, J.; Marx, M.; Geraci, L. Paper Abstracts; 220th
National Meeting of the American Chemical Society, 2000; American
CHemical Society: Washington, DC, 2000; ORGN-126.
(13) Larson, G. L.; Prieto, J. A. Tetrahedron 1983, 39, 855-860.
(14) Larson, G. L.; Hernandez, E.; Alonso, C.; Nieves, I. Tetrahedron Lett.
1975, 16, 4005-4008.
10.1021/ja016893s CCC: $20.00 © 2001 American Chemical Society
Published on Web 10/04/2001

Communications to the Editor
J. Am. Chem. Soc., Vol. 123, No. 43, 2001 10773
Table 1. Fragment Coupling
Scheme 2. Synthesis of the C9-C24 Fragment (3)a
entry
conditionsa,b
E/Z ratioc
1
2
3
4
5
6
7
NaHMDS, THF, -78 °C
1:8
1:6
1:1
1:3
3:1
NaHMDS, THF, -35 °C
KHMDS, DMF, -60 °C
KHMDS, DME, 18-crown-6, -60 °C
LiHMDS, THF/HMPA (4:1 v/v), -60 °C
LiHMDS, DMF/HMPA (4:1 v/v), -35 °C
LiHMDS, DMF/DMPU (1:1 v/v), -35 °C
>30:1
>30:1
a Reactions were set up at the indicated temperatures and then
allowed to warm to room temperature. b In all cases, yields were greater
than 90%. c E/Z ratios were determined by 1H NMR analysis of crude
product mixtures.
Scheme 3. Completion of the Synthesisa
a Conditions: (a) TESOTf, Et3N, Et2O, 0 °C. (b) (1R,2S)-6 (5 mol
%), room temperature. (c) BH3‚THF, THF, 0 °C f room temperature;
then 10% HCl, reflux. (d) (COCl)2, DMSO, Et3N, CH2Cl2, -78 °C f
room temperature. (e) TMSC(Li)N2, THF, -78 °C f room temperature.
(f) Bu3SnCu(Bu)CNLi2, CH3I, THF/DMPU, -78 °C f room temperature.
(g) I2, Et2O, 0 °C. (h) CH2dCHMgBr, Pd(PPh3)4 (5 mol %), PhH, 70
°C. (i) H2/CO (1:1), 20 atm, Rh(acac)(CO)2 (0.5 mol %), (S,R)-22 (2
mol %), PhH, 30-35 °C. (j) CrCl2, CHI3, THF, 0 °C f room temperature.
(k) ethyl acrylate, Pd(OAc)2 (10 mol %), Ag2CO3, CH2Cl2, room
temperature. (l) DIBAL-H, PhMe, -78 °C. (m) Zn(CH3CHI)2‚DME, (R,
R)-26, CH2Cl2, -10 °C. (n) PPh3, PTSH, DEAD, THF, room temperature;
then Mo(VI)/H2O2, EtOH, 0 °C f room temperature.
a Conditions: (a) TBAF, THF, room temperature. (b) Pt, O2, H2O/
acetone, 50 °C.
a one-pot Mitsunobu/oxidation process21 completed the synthesis
of sulfone 3.
With 2 and 3 in hand, a careful survey of conditions for the
crucial fragment coupling was conducted (Table 1). It was found
that high selectivity for either double bond isomer could be
obtained in the Kocien´ski-Julia olefination, with the use of
NaHMDS in THF providing Z alkene (entries 1 and 2) and
LiHMDS in polar solvents affording the desired E isomer almost
exclusively (entries 6 and 7). While similar trends have been
linked previously to solvent effects, the attainment of very high
E selectivity with LiHMDS is unprecedented and potentially of
considerable broader significance.10a
16
(Li)N215 afforded alkyne 17. Addition of Bu3SnCu(Bu)(CN)Li2
to 17 followed by trapping of the intermediate alkenyl cuprate
with MeI and stannane-iodine exchange provided vinyl iodide
18, which was converted to conjugated diene 19 with use of a
Kumada coupling.17
The C15 stereocenter represents one of the most interesting
challenges to the synthesis of 1. While a number of classical
approaches (e.g. [3,3]-sigmatropic rearrangement or a SN2-type
allylic displacement) might be adaptable to this task, such methods
would rely on indirect installation of the C15 center in a multistep
manner. Regioselective hydroformylation of 1,3-dienes affords
â,γ-unsaturated R-methyl-substituted aldehydes directly, and
Nozaki has applied the BINAPHOS catalyst system in an
enantioselective variant with simple model dienes.18 Diene 19 was
subjected to the Nozaki hydroformylation conditions, providing
aldehyde 20 in high diastereoselectivity. This represents the first
application of the Takaya-Nozaki catalytic asymmetric hydro-
formylation in target-oriented synthesis, and it highlights a
powerful and efficient approach to stereochemically defined
R-substituted â,γ-unsaturated aldehydes. Aldehyde 20 was con-
verted to tetraene 24 by a three-step sequence consisting of a
Takai olefination19/Heck reaction/DIBAL-H reduction. Ethylide-
nation of the allylic alcohol of 24 was accomplished by using
the asymmetric Simmons-Smith reaction developed by Charette
and co-workers.20 This transformation afforded the central cy-
clopropane ring with high diastereoselectivity, thereby establishing
the complete carbon framework of the C9-C24 fragment. Finally,
The synthesis was completed by global deprotection and
selective oxidation22 of the primary alcohol to the carboxylic acid
(Scheme 3). The physical and spectroscopic properties of synthetic
1 thus obtained were found to be identical with those of natural
material (1H NMR, 13C NMR, IR, and [R]D).8,23
This total synthesis of ambruticin was accomplished in 16 steps
and 12% yield in the longest linear sequence (21 steps, overall).
Each of the stereochemical challenges was met in a highly
selective manner, with recently developed enantioselective C-C
bond-forming reactions applied to the direct introduction of 8 of
the 10 stereocenters. As such, this route provides a versatile and
flexible route to 1, and a compelling illustration of the impact
modern asymmetric catalysis can have on target-oriented syn-
thesis.
Acknowledgment. The authors are grateful to Prof. G. Ho¨fle for
1
providing H NMR spectra of natural ambruticin and a copy of ref 23
and Prof. K. Nozaki for providing a sample of (S,R)-BINAPHOS. This
work was supported by the NIH (GM-59316).
Supporting Information Available: Experimental procedures, physi-
cal and spectral data; 1H NMR and 13C NMR spectra of synthetic 1; and
comparison of 1H NMR spectra between synthetic 1 and natural 1 (PDF).
This material is available free of charge via the Internet at http://pubs.acs.org.
JA016893S
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