Synthesis of the core structure of cruentaren A

Article abstract of DOI:10.1021/ol0629317

The core structure of the macrolactone cruentaren A (1) was prepared via a ring-closing alkyne metathesis reaction. The corresponding ester 33 was constructed from the benzoic acid derivative 14 and the diol 30. As a key step in the synthesis of acid 14, an aldol reaction resulted in the required anti-OH/Me pattern. The anti-configuration in the stereotetrad of diol 30 was established by a Marshall reaction.

Full text of DOI:10.1021/ol0629317

ORGANIC
LETTERS
2007
Vol. 9, No. 4
655-658
Synthesis of the Core Structure of
Cruentaren A
Viktor V. Vintonyak and Martin E. Maier*
Institut fu¨r Organische Chemie, UniVersita¨t Tu¨bingen, Auf der Morgenstelle 18,
72076 Tu¨bingen, Germany
martin.e.maier@uni-tuebingen.de
Received December 4, 2006
ABSTRACT
The core structure of the macrolactone cruentaren A (1) was prepared via a ring-closing alkyne metathesis reaction. The corresponding ester
33 was constructed from the benzoic acid derivative 14 and the diol 30. As a key step in the synthesis of acid 14, an aldol reaction resulted
in the required anti-OH/Me pattern. The anti-configuration in the stereotetrad of diol 30 was established by a Marshall reaction.
The macrolide cruentaren A (1) is a highly cytotoxic and
antifungal natural product which was isolated by the Ho¨fle
group from the myxobacterium ByssoVorax cruenta (Figure
1).1 With an IC50 value of 1.2 ng mL-1 against the L929
enamides, such as apicularen A2 and salicylihalamide A.3,4
Initially, cruentaren A was patented as a pesticide,5 but in
the meantime it turned out that it is an inhibitor of
mitochondrial F-ATPase from yeast.6 Interestingly, it does
not inhibit V-ATPase, which is the molecular target of the
benzolactone enamides.7 One might speculate that the
allylamine rearranges to an enamide, thus generating a
precursor for an electrophilic acyliminium ion. One should
mention that the allyl amide function is found in other natural
products such as leucascandrolide A8 or ajudazol A.9
(1) Jundt, L.; Steinmetz, H.; Luger, P.; Weber, M.; Kunze, B.; Reichen-
bach, H.; Ho¨fle, G. Eur. J. Org. Chem. 2006, 5036-5044.
(2) (a) Kunze, B.; Jansen, R.; Sasse, F.; Ho¨fle, G.; Reichenbach, H. J.
Antibiot. 1998, 51, 1075-1080. (b) Jansen, R.; Kunze, B.; Reichenbach,
H.; Ho¨fle, G. Eur. J. Org. Chem. 2000, 913-919.
(3) (a) Erickson, K. L.; Beutler, J. A.; Cardellina, J. H., II; Boyd, M. R.
J. Org. Chem. 1997, 62, 8188-8192. (b) Wu, Y.; Esser, L.; De Brabander,
J. K. Angew. Chem. 2000, 112, 4478-4480; Angew. Chem., Int. Ed. 2000,
39, 4308-4310.
(4) For a review, see: Yet, L. Chem. ReV. 2003, 103, 4283-4306.
(5) Molleyres, L.-P.; Ho¨fle, G.; Reichenbach, H.; Kunze, B.; Steinmetz,
H. In PCT Int. Appl. (Syngenta Participations A.-G., Switzerland) WO
2003044005 A1, 2003, 35 pp. CAN 139:2387.
Figure 1. Structure of cruentaren A (1) and key disconnections.
(6) Kunze, B.; Steinmetz, H.; Hoefle, G.; Huss, M.; Wieczorek, H.;
Reichenbach, H. J. Antibiot. 2006, 59, 664-668.
(7) Boyd, M. R.; Farina, C.; Belfiore, P.; Gagliardi, S.; Kim, J. W.;
Hayakawa, Y.; Beutler, J. A.; McKee, T. C.; Bowman, B. J.; Bowman, E.
J. J. Pharmacol. Exp. Ther. 2001, 291, 114-120.
cell line, it is among the most cytotoxic compounds found
in myxobacteria. Structurally, it resembles the benzolactone
10.1021/ol0629317 CCC: $37.00
© 2007 American Chemical Society
Published on Web 01/27/2007

Because of its novel structure and interesting mode of
action, we initiated a program aimed at the synthesis of
cruentaren A and analogues thereof. The synthetic scheme
must address the formation of the stereotetrad that extends
into the side chain.10 In addition, connection of the aryl part
with the aliphatic sector poses a certain challenge. Most
importantly, the propensity of cruentaren A to rearrange to
a less active six-membered lactone (cruentaren B) under
acidic or basic conditions has to be considered. A retrosyn-
thetic analysis is shown in Figure 1. Thus, the Z-configured
allylamine could be fashioned by a Wittig reaction or
reduction of a triple bond. As a key step for macrolactone
formation, a ring-closing alkyne metathesis (RCAM) fol-
lowed by Lindlar reduction was deemed appropriate.11 Of
course, classical macrolactonization strategies (Yamaguchi,
Mitsunobu) might also be considered.12 The stereocenters
at C9 and C10 could be derived from the product of an aldol
reaction. As a key step in the synthesis of a fragment of
type 3 containing the stereotetrad, a Marshall reaction was
envisioned to fashion the anti-configuration at C17/C18. In
this paper, we illustrate the synthesis of the core structure
of cruentaren A based on these key bond-forming reactions.
The synthesis of a benzoic acid building block corre-
sponding to structure 2 was started with 2,4-dimethoxyben-
zoic acid (4), which was allylated13 via the dianion followed
by esterification (Scheme 1). Degradation of the terminal
double bond to an aldehyde function was achieved by a
dihydroxylation/periodate cleavage sequence in good overall
yield.14 Aldehyde 6 was combined with pentynyloxazolidi-
none 7 via an Evans aldol reaction using the standard boron
enolate.15 Protection of the secondary hydroxyl function of
aldol product 8 as a triisopropylsilyl ether using TIPS triflate
and proton sponge as base16 followed by reductive cleavage
of the chiral auxiliary produced the primary alcohol 10.
Conversion of the primary alcohol to the corresponding
methyl group was achieved by tosylation of the alcohol and
treatment of the intermediate tosylate 11 with zinc/sodium
iodide.17 After saponification of the methyl ester 12, the
obtained alkynoic acid 13 was converted to the dianion which
was alkylated at the acetylide using MeI. This way, the acid
14 containing an internal alkyne required for the alkyne
metathesis could be obtained in a concise manner.
Scheme 1. Synthesis of the Functionalized Benzoic Acid 14
propargylic mesylate (S)-17 came to use. This transformation
to alkyne 18 proceeded with excellent diastereoselectivity
(22:1) and good chemical yield (Scheme 2). After silyl
protection of the hydroxyl function, the triple bond of 19
was hydroborated with Cy2BH. The vinylborane intermediate
was in situ oxidized to aldehyde 20.21 Reduction of the
aldehyde gave primary alcohol 21, which was protected using
3,4-dimethoxybenzyltrichloroacetimidate leading to ether 22
in excellent yield.22 Cleavage of the acetonide moiety under
mild conditions (CuCl2‚2H2O, acetonitrile, -5 °C) afforded
diol 23.23 Other attempts to cleave the acetal of 22 (AcOH
in THF at 50 °C, TFA in CH2Cl2, FeCl3/SiO2 in CHCl3) were
As a key step for creation of the stereotetrad of fragment
3, a Marshall reaction18,19 of the known aldehyde20 16 with
(8) D’Ambrosio, M.; Guerriero, A.; Debitus, C.; Pietra, F. HelV. Chim.
Acta 1996, 79, 51-60.
(9) (a) Jansen, R.; Kunze, B.; Reichenbach, H.; Ho¨fle, G. Eur. J. Org.
Chem. 2002, 917-921. (b) Kunze, B.; Jansen, R.; Ho¨fle, G.; Reichenbach,
H. J. Antibiot. 2004, 57, 151-155.
(17) Fujimoto, Y.; Tatsuno, T. Tetrahedron Lett. 1976, 17, 3325-3326.
(18) (a) Marshall, J. A.; Schaaf, G. M. J. Org. Chem. 2001, 66, 7825-
7831. (b) Marshall, J. A.; Yanik, M. M.; Adams, N. D.; Ellis, K. C.;
Chobanian, H. R. Org. Synth. 2005, 81, 157-170.
(19) Prusov, E.; Ro¨hm, H.; Maier, M. E. Org. Lett. 2006, 8, 1025-
1028.
(20) Arai, N.; Chikaraishi, N.; Omura, S.; Kuwajima, I. Org. Lett. 2004,
6, 2845-2848.
(21) Marshall, J. A.; Schaaf, G. M. J. Org. Chem. 2003, 68, 7428-
7432.
(22) (a) Horita, K.; Yoshioka, T.; Tanaka, T.; Oikawa, Y.; Yonemitsu,
O. Tetrahedron 1986, 42, 3021-3028. (b) Dahan, A.; Portnoy, M. J. Org.
Chem. 2001, 66, 6480-6482. (c) Wang, C.; Forsyth, C. J. Org. Lett. 2006,
8, 2997-3000.
(23) Liu, Z.-Y.; Chen, Z.-C.; Yu, C.-Z.; Wang, R.-F.; Zhang, R.-Z.;
Huang, C.-S.; Yan, Z.; Cao, D.-R.; Sun, J.-B.; Li, G. Chem. Eur. J. 2002,
8, 3747-3756.
(10) Koskinen, A. M. P.; Karisalmi, K. Chem. Soc. ReV. 2005, 34, 677-
690.
(11) For a review, see: Fu¨rstner, A.; Davies, P. W. Chem. Commun.
2005, 2307-2320.
(12) Parenty, A.; Moreau, X.; Campagne, J. M. Chem. ReV. 2006, 106,
911-939.
(13) Yang, K.; Blackman, B.; Diederich, W.; Flaherty, P. T.; Mossman,
C. J.; Roy, S.; Ahn, Y. M.; Georg, G. I. J. Org. Chem. 2003, 68, 10030-
10039.
(14) For a recent example, see: Jiang, X.; Fortanet, J. G.; Brabander, J.
K. D. J. Am. Chem. Soc. 2005, 127, 11254-11255.
(15) (a) Gage, J. R.; Evans, D. A. Org. Synth. 1989, 68, 83-91. (b)
Arya, P.; Qin, H. Tetrahedron 2000, 56, 917-947.
(16) Other bases, such as 2,6-lutidine or i-Pr2NEt, gave inferior yields.
656
Org. Lett., Vol. 9, No. 4, 2007

treatment of the bis-silyl ether 29 with TBAF furnished diol
30 in excellent yield.
Scheme 2. Synthesis of the Epoxide Building Block 25a
Formation of an ester bond between acid 14 and diol 30
or a monoprotected derivative thereof turned out to be rather
difficult. Using standard Mitsunobu,25 Yamaguchi,26 or
Trost27 esterification, no trace of product was observed. Also,
attempts to make the desired ester using peptide coupling
reagents like DCC/DMAP or BOP were not successful.
Another option for esterification of sterically hindered acids
and alcohols relies on the reaction of an acid chloride with
a sodium alcoholate. However, attempted conversion of acid
14 to the coresponding acid chloride was not possible.
Instead, formation of the six-membered lactone was ob-
served. Eventually, we found that the desired ester 32 could
be obtained by reaction of the imidazolidine derivative28,29
of acid 14 with the putative disodium alcoholate of diol 30,
prepared by stirring the diol with 2.5 equiv of NaH in DMF
(Scheme 4). This reaction resulted in formation of only one
Scheme 4. Formation of Ester 33 and Its Ring-Closing
Alkyne Metathesis Reaction To Give Macrolactone 37
a DMB ) 3,4-dimethoxybenzyl, PPTS ) pyridinium p-toluene-
sulfonate, Cy ) cyclohexyl, TBS ) tert-butyldimethylsilyl.
unsuccessful. To prepare for the introduction of the alkyne
function, diol 23 was converted to the epoxide 25 using a
one-pot procedure.24
Opening of epoxide 25 with lithium trimethylsilylacetylide
resulted in formation of alcohol 26 (Scheme 3). Cleavage
Scheme 3. Synthesis of Diol 30 from Epoxide 25
regioisomer. The obtained hydroxy ester 32 was protected
as the TBS ether to give 33 in 65% overall yield. At this
stage, the regiochemistry of the ester formation could be
inferred from the COSY spectrum of ester 33. Most revealing
of the carbon-silicon bond and protection of the hydroxyl
function with TBSOTf afforded alkyne 28, which then could
be methylated to give propyne deriviative 29. A final
(25) Hughes, D. L. Org. React. 1992, 42, 335-656.
(26) Takimoto, S.; Inanaga, J.; Katsuki, T.; Yamaguchi, M. Bull. Chem.
Soc. Jpn. 1981, 54, 1470-1473.
(27) Trost, B. M.; Chisholm, J. D. Org. Lett. 2002, 4, 3743-3745.
(28) Stadler, P. A.; Huegi, B. S. HelV. Chim. Acta 1985, 68, 1644-
1646.
(24) (a) Hicks, D. R.; Fraser-Reid, B. Synthesis 1974, 203. (b) Cink, R.
D.; Forsyth, C. J. J. Org. Chem. 1995, 60, 8122-8123. (c) Smith, A. B.,
III; Kim, D.-S. J. Org. Chem. 2006, 71, 2547-2557.
(29) For the reaction of sterically hindered acid chlorides with alcoholates,
see: Moutel, S.; Prandi, J. J. Chem. Soc., Perkin Trans. 1 2001, 305-315.
Org. Lett., Vol. 9, No. 4, 2007
657

in this context were cross-peaks of the ester methine
hydrogen to the vicinal methylene hydrogen atoms. The
crucial RCAM reaction of ester 33 proceeded smoothly and
resulted in the formation of macrolactone 35 in 91% yield.
Thus, addition of the tungsten carbine complex30 34 to a
solution of the diyne 33 (0.009 M in toluene) and stirring
the mixture for 2 h induced an efficient cyclization.11,31
Creation of the Z-double bond was achieved using Lindlar
reduction32 (H2, Pd on CaCO3, poisoned with lead, EtOAc/
quinoline) on the alkyne 35 leading to lactone 36. Under
these conditions, no overreduction was observed. Finally,
deprotection of the DMB group with DDQ led to macro-
lactone 37, the core structure of cruentaren A.
reaction to fashion the anti-OH/Me pattern at C9/C10 and a
Marshall reaction of aldehyde 16 with the allenyl zinc reagent
derived from mesylate 17, which established the stereotetrad
at C15-C18. As a further key reaction a RCAM reaction of
ester 33 was used. The presented strategy should allow for
the synthesis of the natural products as well as analogues
for SAR studies.
Acknowledgment. Financial support by the Deutsche
Forschungsgemeinschaft (Grant No. Ma 1012/20-1) and the
Fonds der Chemischen Industrie is gratefully acknowledged.
We greatly acknowledge important model studies by Frank
Lay (Institute of Organic Chemistry). We also thank Graeme
Nicholson (Institute of Organic Chemistry) for measuring
the HRMS spectra. In addition, a graduate fellowship for
V.V.V. by the state Baden-Wu¨rttemberg (LGFG) is acknowl-
edged.
In summary, we illustrate an efficient route to the
12-membered macrolactone 37 which corresponds to the core
structure of the novel macrolide cruentaren A. Key features
of the synthesis of the building blocks include an aldol
(30) (a) Wengrovius, J. H.; Sancho, J.; Schrock, R. R. J. Am. Chem.
Soc. 1981, 103, 3932-3934. (b) Schrock, R. R.; Clark, D. N.; Sancho, J.;
Wengrovius, J. H.; Rocklage, S. M.; Pedersen, S. F. Organometallics 1982,
1, 1645-1651. (c) Listemann, M. L.; Schrock, R. R. Organometallics 1985,
4, 74-83.
Supporting Information Available: Experimental pro-
cedures and characterization for all new compounds reported
and copies of NMR spectra for important intermediates. This
material is available free of charge via the Internet at
http://pubs.acs.org.
(31) Fu¨rstner, A.; Castanet, A.-S.; Radkowski, K.; Lehmann, C. W. J.
Org. Chem. 2003, 68, 1521-1528.
(32) For a recent example, see: Dakin, L. A.; Langille, N. F.; Panek, J.
S. J. Org. Chem. 2002, 67, 6812-6815.
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