Total synthesis of (-)-ratjadone.

Article abstract of DOI:10.1021/ol015753k

[reaction in text] A convergent asymmetric synthesis of (-)-ratjadone (1) has been achieved, confirming the assignments of stereochemistry for the naturally occurring antifungal metabolite.

Full text of DOI:10.1021/ol015753k

ORGANIC
LETTERS
2001
Vol. 3, No. 9
1383-1386
Total Synthesis of (−)-Ratjadone
David R. Williams,* David C. Ihle, and Scott V. Plummer
Department of Chemistry, Indiana UniVersity, 800 East Kirkwood AVenue,
Bloomington, Indiana 47405-7102
williamd@indiana.edu
Received February 22, 2001
ABSTRACT
A convergent asymmetric synthesis of (−)-ratjadone (1) has been achieved, confirming the assignments of stereochemistry for the naturally
occurring antifungal metabolite.
Myxobacteria have proven to be a rich resource for biologi-
cally active secondary metabolites exhibiting novel molecular
architecture.1,2 In 1994, the polyketide ratjadone (1) was
isolated from cultures of Sorangium cellulosum strain So
ce360.3 Ho¨fle and co-workers described the structural
connectivity of 1 and determined the relative stereochemistry
for substituents of the tetrahydropyranyl ring. However, the
stereochemical features of 1 at C5, C10, and C16, as well as
the absolute configuration, were not elucidated. Ratjadone
displays potent in vitro antifungal activity with MIC values
in the range from 0.04 to 0.6 µg/mL for Mucor hiemalis,
Phythophthora drechsleri, Ceratocystis ulmi, and Monilia
brunnea.4 Additionally, significant cytotoxicity in mam-
malian L929 cell lines (IC50 ) 0.05 ng/mL) and HeLa cell
line KB3.1 (IC50 ) 0.04 ng/mL) has been demonstrated.4
Structural features of 1, including the 5,6-dihydropyran-
2-one and the arrangement of the C5-C15 bisdiene segment,
suggest similarities with natural products such as callystatin
A,5 leptomycin B,6 anguinomycins,7 and leptofuranins.8
Biological studies of these natural products have indicated
antitumor properties and imply important roles in chemical
transduction of cell morphology and cellular transport
phenomena.
Total syntheses of leptomycin B9 and callystatin A10 have
been reported. Studies directed toward 1 were described in
the course of our investigations,11 and these efforts have
recently culminated in the first total synthesis of (+)-
ratjadone.12 Since the objective of our efforts was also to
address the issues of relative and absolute asymmetry in 1,
(6) (a) Hammamoto, T.; Seto, H.; Beppu, T. J. Antibiot. 1983, 36, 646.
(b) Komiyama, K.; Okada, K.; Tomisaka, S.; Umezawa, I.; Hamamoto, T.;
Beppu, T. J. Antibiot. 1985, 38, 427. (c) Hamamoto, T.; Uozumi, T.; Beppu,
T. J. Antibiot. 1985, 38, 1573. (d) Nishi, K.; Yoshida, M.; Fujiwara, D.;
Nishikawa, M.; Horinouchi, S.; Beppu, T. J. Biol. Chem. 1994, 269, 6320.
(e) Wolff, B.; Sanglier, J.-J.; Wang, Y. Chem. Biol. 1997, 4, 139.
(7) (a) Hayakawa, Y.; Adachi, K.; Komeshima, N. J. Antibiot. 1987,
40, 1349. (b) Hayakawa, Y.; Sohda, K.; Shin-ya, K.; Hidaka, T.; Seto, H.
J. Antibiot. 1995, 48, 954.
(8) Hayakawa, Y.; Sohda, K.-Y.; Seto, H. J. Antibiot. 1996, 49, 980.
(9) Kobayashi, M.; Wang, W.; Tsutsui, Y.; Sugimoto, M.; Murakami,
N. Tetrahedron Lett. 1998, 39, 8291.
(10) (a) Murakami, N.; Wang, W.; Aoki, M.; Tsutsui, Y.; Suimoto, M.;
Kobayashi, M. Tetrahedron Lett. 1998, 39, 2349. (b) Crimmins, M. T.;
King, B. W. J. Am. Chem. Soc. 1998, 120, 9084.
(11) (a) Claus, E.; Kalesse, M. Tetrahedron Lett. 1999, 40, 4157. (b)
Christmann, M.; Kalesse, M. Tetrahedron Lett. 1999, 40, 7201. (c)
Quitschalle, M.; Christmann, M.; Bhatt, U.; Kalesse, M. Tetrahedron Lett.
2001, 42, 1263. (d) Christmann, M.; Kalesse, M. Tetrahedron Lett. 2001,
42, 1269.
(12) (a) Christmann, M.; Bhatt, U.; Quitschalle, M.; Claus, E.; Kalesse,
M. Angew. Chem., Int. Ed. 2000, 39, 4364. (b) Bhatt, U.; Christmann, M.;
Quitschalle, M.; Claus, E.; Kalesse, M. J. Org. Chem. 2001, 66, 1885.
(1) For a review and some recent reports: (a) Reichenbach, H.; Ho¨fle,
G. Drug DiscoVery from Nature; Grabley, S., Thericke, R., Eds.; Springer:
Berlin, 1999; pp 149-179. (b) Sasse, F.; Steinmetz, H.; Heil, J.; Ho¨fle, G.;
Reichenbach, H. J. Antibiot. 2000, 53, 879. (c) Jansen, R.; Kunze, B.;
Reichenbach, H.; Ho¨fle, G. J. Org. Chem. 2000, 6, 913.
(2) For a recent review of synthesis studies, see: Williams, D. R.; Li, J.
J.; Hutchings, R. H. Org. Prep. Proced. Int. 2000, 32, 409.
(3) Schummer, D.; Gerth, K.; Reichenbach, H.; Ho¨fle, G. Liebigs Ann.
1995, 685.
(4) Gerth, K.; Schummer, D.; Ho¨fle, G.; Irschik, H.; Reichenbach, H. J.
Antibiot. 1995, 48, 973.
(5) Kobayashi, M.; Higuchi, K.; Murakami, N.; Tajima, H.; Aoki, S.
Tetrahedron Lett. 1997, 38, 2859.
10.1021/ol015753k CCC: $20.00 © 2001 American Chemical Society
Published on Web 04/03/2001

Scheme 1
we developed a flexible but stereochemically reliable syn-
metric epoxidation18 resulted in pure epoxide 5 (98% yield,
95% de) after flash chromatography.
thesis pathway. Herein we communicate our labors, which
have provided four individual diastereomers of 1 for detailed
spectral comparisons leading to a synthesis of (-)-ratjadone,
the antipode of the natural metabolite.
Synthesis of the tetrahydropyran component was antici-
pated via C-O bond formation from 5 with stereochemical
inversion. Our earlier studies for the stereocontrolled prepa-
ration of 2,3,4-trisubstituted tetrahydrofurans had documented
the stereochemical integrity in similar cases of internal
backside displacements under acidic conditions.19 Hence, we
were gratified to observe the exclusive formation of 6
following protection of 5 as the pivaloate, removal of the
silyl ether, and acid-catalyzed oxirane opening in a 6-exo-
tet fashion.20
Stereochemical assignments were supported by data
obtained from 1H NMR studies of diol 7 following quantita-
tive deprotection of 6 with ceric ammonium nitrate.21 For
example, the irradiation of the signal for HB (δ 4.41) led to
NOE enhancement of HA (δ 3.86), and irradiation of the C20
methyl group (δ 0.88) provided NOE enhancement of HD
(δ 1.83). A series of decoupling experiments indicated an
axial relationship (J ) 11.6 Hz) for HA/HD, and the apparent
quartet for HC (δ 4.00) was attributable to three coupled
hydrogens of similar J values (∼2.7 Hz each) following D2O
exchange.
Utilizing a strategy of acyclic stereocontrol, an unambigu-
ous pathway for construction of the C15-C24 tetrahydropyran
component was deployed (Scheme 1). Aldehyde 3 was
prepared via standard conversions from the known Evans
aldol product 2.13 A crucial element of stereochemistry at
C19 was introduced using the Brown asymmetric allylation
methodology14 via B-allyldiisocampheylborane derived from
(+)-R-pinene affording a syn-homoallylic alcohol (91% yield,
94% de). Purification and protection15 led to 4, which was
subjected to a chemoselective Sharpless dihydroxylation16
of the terminal alkene. Oxidative cleavage of the mixture of
diastereomeric diols (60:40 ratio) with sodium m-periodate
was followed by Wittig olefination with methyl (triph-
enylphosphoranylidene)acetate producing the expected (E)-
R,â-unsaturated ester in 88% yield. No evidence was
observed for elimination of the PMB ether from the
intermediate â-alkoxy aldehyde.17 Reduction of the ester with
diisobutylaluminum hydride and subsequent Sharpless asym-
(18) Gao, Y.; Hanson, R. M.; Klunder, J. M.; Ko, S. Y.; Masamune, H.;
Sharpless, K. B. J. Am. Chem. Soc. 1987, 109, 5765.
(19) Williams, D. R.; Grote, J.; Harigaya, Y. Tetrahedron Lett. 1984,
25, 5231.
(20) Reports of stereo- and regiocontrolled intramolecular openings of
allylic oxiranes have provided an important advance in the synthesis of
cyclic ethers. See: (a) Nicolaou, K. C.; Prasad, C. V. C.; Somers, P. K.;
Huang, C.-K. J. Am. Chem. Soc. 1989, 111, 5330. (b) Nicolaou, K. C.;
Prasad, C. V. C.; Somers, P. K.; Huang, C.-K. J. Am. Chem. Soc. 1989,
111, 5335. For Baldwin’s rules: Baldwin, J. J. Chem. Soc., Chem. Commun.
1976, 734.
(13) Evans, D. A.; Rieger, D. L.; Jones, T. K.; Kaldor, S. W. J. Org.
Chem. 1990, 55, 6260.
(14) (a) Brown, H. C.; Jadhav, P. K. J. Am. Chem. Soc. 1983, 105, 2092.
(b) Brown, H. C.; Bhat, K. S.; Randad, R. S. J. Org. Chem. 1989, 54, 1570.
(15) Nakajima, N.; Horita, K.; Abe, R.; Yonemitsu, O. Tetrahedron Lett.
1988, 29, 4139.
(16) (a) Andrus, M. B.; Lepore, S. D.; Sclafani, J. A. Tetrahedron Lett.
1997, 38, 4043. (b) Xu, D.; Crispino, G. A.; Sharpless, K. B. J. Am. Chem.
Soc. 1992, 114, 7570.
(17) Related experiences in our rhizoxin total synthesis had forced us to
adapt a plan for use of a sterically demanding tert-butyldimethylsilyl ether
to avoid R-hydrogen abstraction. See: Williams, D. R.; Werner, K. M.;
Feng, B. Tetrahedron Lett. 1997, 38, 6825.
(21) (a) These NOE studies were unsuccessful in the presence of the
PMB ether. (b) Johansson, R.; Samuelsson, B. J. Chem. Soc., Perkin Trans.
1 1984, 2371.
1384
Org. Lett., Vol. 3, No. 9, 2001

Scheme 2
Protection of 7 as the corresponding bis-tert-butyldimeth-
°C; then MeI (81%)) provided a mixture (11:1 ratio) of
separable diastereomers favoring the desired 13 (S-config-
uration at C10).25 Standard transformations permitted conver-
sion of 13 to the homochiral aldehyde 14 for chain extension
via the Still modification of the Horner-Emmons reaction.26
Under the usual conditions, reaction of 14 with the bistri-
fluoroethyl phosphonate 15 yielded exclusive formation of
(Z)-R,â-unsaturated ester 16, as confirmed by proton and
carbon NMR data. Hydride reduction to 17 led to Mosher
ester formation27a,b and a direct comparison with the corre-
sponding Mosher ester prepared from the C10 enantiomer of
17.27 These results verified the absence of C10 epimerization
in the preceding Swern oxidation28 or Horner-Emmons
reaction.
ylsilyl (TBS) ether, removal of the pivaloate, and buffered
oxidation with Dess-Martin periodinane22 gave the desired
tetrahydropyranyl aldehyde 8 in high overall yield without
migration of the silyl ether to the less hindered primary
position. During the course of our work, Kalesse et al.
independently illustrated formation of tetrahydropyran system
6 via a similar strategy.11b
The pathway for production of the C1-C14 segment
required careful attention for the incorporation of stereo-
chemical features at C5 and C10. Justifications for these
concerns were amply proven upon syntheses of the three
diastereomers 9, 10, and 11 as well as 1. In fact, the NMR
The Corey-Fuchs procedure29 led to the isolation of the
conjugated enyne 18 (85% overall), and the adaptation of a
hydrozirconation process, described by Wipf and co-work-
ers,30 facilitated a reductive alkylation of the terminal alkyne
via initial transmetalation with dimethylzinc. The resultant
(24) (a) Ple´, P. A.; Hamon, A.; Jones, G. Tetrahedron 1997, 53, 3395.
(b) Kobayashi, M.; Wang, W.; Tsutsui, Y.; Sugimoto, M.; Murakami, M.
Tetrahedron Lett. 1998, 39, 8291.
(25) Evans, D. A.; Ennis, M. D.; Mathre, D. J. J. Am. Chem. Soc. 1982,
104, 1737.
(26) Still, C.; Gennari, C. Tetrahedron Lett. 1983, 24, 4405.
(27) (a) Sullivan, G. R.; Dale, J. A.; Mosher, H. S. J. Org. Chem. 1973,
38, 2143. (b) Ohtani, I.; Kusumi, Y.; Kakisawa, H. J. Am. Chem. Soc. 1991,
113, 4092. (c) Although proton NMR spectra were very similar, diastereo-
meric (R)-esters i and ii were distinguished by different chemical shifts
observed for the diastereotopic C7 methylene hydrogens as indicated below.
spectra of isomers 9 and 10 showed only slight line
variations, absolutely requiring direct comparison with
authentic natural product, whereas isomer 11 was clearly
unique.23 The preparation of this series of ratjadone isomers
utilized a common route as summarized for synthesis of 1.
As shown in Scheme 2, alkylation of the readily available
imide 1224 via the Evans protocol (NaHMDS, THF at -78
(28) Mancuso, A. J.; Huang, S. L.; Swern, D. J. Org. Chem. 1978, 43,
2480.
(29) Corey, E. J.; Fuchs, P. L. Tetrahedron Lett. 1972, 36, 3769.
(30) (a) Wipf, P.; Xu, W. Tetrahedron Lett. 1994, 35, 5197. (b) Wipf,
P.; Ribe, S. J. Org. Chem. 1998, 63, 6454.
(22) Dess, D. B.; Martin, J. C. J. Am. Chem. Soc. 1991, 113, 7277.
(23) Isomer 11 was formed in small quantities from 10 via oxidation of
the allylic alcohol (MnO2) and hydride reduction (NaBH4), providing a
separable mixture of C16 isomers favoring the Cram chelation product 10.
Org. Lett., Vol. 3, No. 9, 2001
1385

Scheme 3
vinylzinc species underwent smooth addition to aldehyde
the basic conditions of the alkylation, but it provided for
facile deprotection in the presence of mild acid during
subsequent oxidations without effecting the premature elimi-
nation of the sulfonyl group.34 In the event, treatment of 28
with buffered Dess-Martin periodinane gave a crude â-phen-
ylsulfonylaldehyde. Removal of the TES ether and oxidation
of the resulting lactol with tetrapropylammonium perruth-
enate (TPAP) and 4-methylmorpholine N-oxide (NMO)35
produced a saturated lactone. Exposure of this species to 1,8-
diazabicyclo[5.4.0]undec-7-ene (DBU) resulted in spontane-
ous elimination. Removal of the silyl ethers using buffered
HF‚pyridine in tetrahydrofuran provided (-)-ratjadone (1).
Our material was identical in all respects except rotation
19,31 providing a separable mixture of alcohols 20 (92%
yield).
We sought the precedence of an established methodology
for introduction of the (S)-C5 stereochemistry. After a survey
of several reactions, the Terashima reduction32 of the unstable
enone 21, using (-)-N-methylephedrine as a chiral modifier,
resulted in a 5:1 mixture of alcohol diastereomers. The major
allylic alcohol 22 was converted to sulfone 23 by careful
oxidation with ammonium molybdate to avoid olefin oxida-
tions, and subsequent protection gave the corresponding
pivaloate.
As shown in Scheme 3, the convergent coupling of
aldehyde 8 and the C3-C14 segment 23 was accomplished
via Wittig olefination. To this end, treatment of 23 with
methanesulfonyl chloride (CH2Cl2; collidine at 0 °C) was
followed by lithium bromide in THF, yielding allylic bromide
24, contaminated with substantial amounts of the analogous
chloride (82% overall from 23). This mixture was efficiently
utilized for nucleophilic displacement to produce the tri-n-
butylphosphonium salt 25 (Scheme 3). Addition of potassium
tert-butoxide in THF into a solution of salt 25 and aldehyde
8 in toluene resulted in a 16:1 E/Z mixture leading to the
purification of E,E-diene 26 in 72% yield.
([R]25 -48 (c 0.12, CHCl3)) with data obtained from a
D
sample of the natural product.36
In summary, our synthesis efforts have provided a flexible
and convergent scheme for the preparation of ratjadone and
various derivatives. These efforts have unambiguously
incorporated key features of relative and absolute stereo-
chemistry, demonstrating 1 as the antipode of (+)-ratjadone.
Acknowledgment. The authors gratefully acknowledge
the National Institute of Health (GM-42897) for the generous
support of our work.
Supporting Information Available: Experimental pro-
cedures and spectral data for all compounds on the synthesis
pathway and a proton NMR spectra for 1, 9, 10, and authentic
(+)-ratjadone. This material is available free of charge via
the Internet at http://pubs.acs.org.
Finally the construction of the sensitive 5,6-dihydropyran-
2-one was undertaken by low-temperature alkylation of the
R-sulfonyl carbanion of 27 with ethylene oxide to yield
primary alcohol 28 (78%).33 Unfortunately attempts to utilize
26 led to internal acyl transfer of the pivaloyl unit upon
deprotonation. However, the triethylsilyl (TES) ether 27
proved to be an ideal choice. Thus, the TES unit did not
undergo O f C migration or nucleophilic cleavage under
OL015753K
(34) Alternative protection schemes led to sulfone elimination yielding
the (E)-unsaturated aldehyde, thus thwarting lactol formation. Unfortunately
the TES ether did not withstand conditions leading to 25.
(31) Ono, N.; Matsumoto, K.; Ogawa, T.; Tani, H.; Uno, H. J. Chem.
Soc., Perkin Trans. 1 1996, 1905.
(32) (a) Terashima, S.; Tanno, N.; Koga, K. J. Chem. Soc., Chem.
Commun. 1980, 1026. (b) Terashima, S.; Tanno, N.; Koga, K. Chem. Lett.
1980, 981.
(33) (a) Kondo, K.; Tunemoto, D. Tetrahedron Lett. 1975, 16, 1007. (b)
Carretero, J. C.; Ghosen, L. Tetrahedron Lett. 1988, 29, 2059.
(35) Griffith, W. P.; Ley, S. V.; Whitecombe, G. P.; White, A. D. J.
Chem. Soc., Chem. Commun. 1987, 1625.
(36) Since our studies had previously led to isomers 9 and 10, which
were not readily distinguished from reported data for the natural product,
we are particularly grateful to Professor Gerhard Ho¨fle (GBF, Braunschweig,
Germany) for generously assisting these efforts by providing a pure sample
of (+)-ratjadone for our direct comparisons.
1386
Org. Lett., Vol. 3, No. 9, 2001