Synthesis of the eastern portion of ajudazol a based on stille coupling and double acetylene carbocupration

Article abstract of DOI:10.1021/ol047313+

(Chemical Equation Presented) A strategy for the synthesis of ajudazol A, an unusual, pharmacologically active metabolite from myxobacteria, based on the Stille cross-coupling of a 2-stannyl-oxazole with a vinyl iodide unit is described; the vinyl halide unit containing a (Z,Z)-diene was prepared in one pot by the double acetylene carbocupration of a functionalized alkyl cuprate followed by trapping with 2,3-dibromopropene.

Full text of DOI:10.1021/ol047313+

ORGANIC
LETTERS
2
005
Vol. 7, No. 6
063-1066
Synthesis of the Eastern Portion of
Ajudazol A Based on Stille Coupling
and Double Acetylene Carbocupration
1
Oliver Krebs and Richard J. K. Taylor*
Department of Chemistry, UniVersity of York, Heslington, York, YO10 5DD, UK
rjkt1@york.ac.uk
Received December 30, 2004
ABSTRACT
A strategy for the synthesis of ajudazol A, an unusual, pharmacologically active metabolite from myxobacteria, based on the Stille cross-
coupling of a 2-stannyl-oxazole with a vinyl iodide unit is described; the vinyl halide unit containing a (Z,Z)-diene was prepared in one pot by
the double acetylene carbocupration of a functionalized alkyl cuprate followed by trapping with 2,3-dibromopropene.
There is increasing interest in novel, bioactive natural
products produced by myxobacteria. Myxobacteria are
In addition to the unusual isochromanone moiety, the
terminal N-methyl amide of 3-methoxybutenoic acid is
apparently unprecedented, as is the oxazole-linked polyene
fragment. The internal (Z,Z)-diene unit is also an unusual
feature in myxobacterial natural products, although examples
are known from other natural sources (see below). In later
studies, the ajudazols were shown to be antimicrobial agents
“
social bacteria” often found in animal dung and organic-
rich soils, some of which secrete antibiotics to kill other
1
bacteria that are then digested. The myxobacteria Chon-
dromyces crocatus has proved to be a rich source of bioactive
2
natural products that include the cytostatic chondramides
3
and the crocacins, which inhibit the growth of fungi and
yeasts by interfering with electron flow within cytochromes
in the respiratory chain. More recent studies by Jansen et al.
have resulted in the isolation of two additional, novel natural
products from C. crocatus, which were named ajudazol A
4
and ajudazol B. Extensive spectroscopic studies (HRMS,
IR, and UV but mainly two-dimensional NMR) resulted in
the assignment of the novel dihydroxylated methyliso-
chromanone structures 1a and 1b as shown in Figure 1.
(
1) (a) Reichenbach, H.; H o¨ fle, G. In Drug DiscoVery from Nature;
Grabley, S., Thiericke R., Eds.; Springer-Verlag: Berlin, 1999; pp 149-
87. (b) H o¨ fle, G.; Reichenbach, H. The Biosynthetic Potential of
1
Myxobacteria. In Sekund a¨ rmetabolismus bei Mikroorganismen; Kuhn, W.,
Fiedler, H.-P., Eds.; Attempto Verlag: T u¨ bingen, 1995; pp 61-78.
(
2) Jansen, R.; Kunze, B.; Reichenbach, H.; H o¨ fle, G. Liebigs Ann. 1996,
Figure 1. Ajudazols A (1a) and B (1b) [only one enantiomer is
shown, although their absolute configuration is not known (nor is
the configuration at C-15 in ajudazol B)] and synthetic analogue
2.
2
85-290.
3) Sasse, F.; Kunze, B.; Gronewold, T. M. A.; Reichenbach, H. J. Natl.
Cancer Inst. 1998, 90, 1559-2563 and references therein.
4) Jansen, R.; Kunze, B.; Reichenbach, H.; H o¨ fle, G. Eur. J. Org. Chem.
002, 917-921.
(
(
2
1
0.1021/ol047313+ CCC: $30.25
© 2005 American Chemical Society
Published on Web 02/23/2005

5
that also inhibit mitochondrial electron transport. Thus, the
therefore became the first target for this study. (Z,Z)-Diene
units are increasingly common in natural products, and some
6
ajudazols are interesting synthetic targets, and substructure
bioassay should shed light on their mode of action. In this
Letter, we outline our synthetic approach to ajudazol A and
illustrate the viability of this approach by describing the
successful preparation of analogue 2, which possesses the
oxazole ring and the complete eastern side chain.
time ago we developed a double acetylene carbocupration
7
procedure for their stereocontrolled synthesis. This meth-
odology was utilized to prepare the Navel orangeworm
7
pheromone and has subsequently been employed by other
8
groups to prepare insect pheromones, the myxobacteria-
9
The retrosynthetic analysis, shown in Figure 2, is based
on the key Stille disconnection, which generates the substi-
tuted 2-stannyl-oxazole 3 and an eastern side chain unit 4,
terminated by a vinylic halide function. This convergent route
involving the introduction of the complete eastern side chain
at a late stage of the synthesis was devised to minimize the
chances of intramolecular reactions between the oxazole or
chromanone portions of the molecule and reactive intermedi-
ates needed during the construction of the polyene side chain.
derived apicularens, and salicylihalamide A, isolated from
9
,10
a marine sponge.
Double acetylene carbocupration is a
1
1
variant of the Normant reaction in which organocuprates
react with four molecules of acetylene to give the corre-
sponding four-carbon homologated (Z,Z)-dienyl cuprates,
which can be trapped to produce (Z,Z)-dienes via a one-pot
7
process with excellent stereocontrol.
To date, the double acetylene carbocupration procedure
has always been carried out with unfunctionalized di(alkyl)-
cuprates. The synthesis of target molecule 7 (Scheme 1) is
Scheme 1
therefore noteworthy in that it employs the tetrahydro-
pyranyloxypropylcuprate 8 derived from the readily avail-
12
able THP-protected 3-iodopropanol 9. Treatment of 9 with
equiv of t-BuLi at -78 °C followed by addition of CuBr‚
SMe produced the functionalized dialkylcuprate 8 as a clear
solution. Addition of 6 equiv of acetylene (gas buret) at -15
C over 1 h generated a dark-green solution of the presumed
2
2
°
vinyl cuprate, and an additional 7 equiv of acetylene was
then added at -5 °C over 20 min to produce the desired
(
Z,Z)-dienyl cuprate 10. The solution was immediately cooled
to -40 °C, and 2,3-dibromopropene in HMPA was added,
giving, after workup and chromatography (SiO -AgNO
2
3
;
Figure 2. Retrosynthesis of ajudazol A (1a); in practice, a
measured excess of acetylene gas is required in the final step
depicted.
(6) (a) Sirirath, S.; Tanaka, J.; Ohtani, I. I.; Ichiba, T.; Rachmat, R.;
Ueda, K.; Usui, T.; Osada, H.; Higa, T. J. Nat. Prod. 2002, 65, 1820-
1
2
2
823. (b) Shimada, K.; Kaburagi, Y.; Fukuyama, T. J. Am. Chem. Soc.
003, 125, 4048-4049. (c) Wipf, P.; Graham, T. H. J. Am. Chem. Soc.
004, 126, 15346-15347 and references therein.
We decided to test the viability of this Stille coupling
approach using 2-tributylstannyloxazole (as a model for 3)
and vinyl halide 4. Retrosynthetic analysis of side chain 4
suggested an amide coupling with 3-methoxybutenoic acid
(7) (a) Furber, M.; Taylor, R. J. K.; Burford, S. C. J. Chem. Soc., Perkin
Trans. 1 1986, 1809-1815. (b) Taylor, R. J. K.; Casy, G. In Organocopper
Reagents: A Practical Approach; Taylor, R. J. K., Ed.; Oxford University
Press: Oxford, 1994; Chapter 2.
(8) Millar, J. G. Tetrahedron Lett. 1997, 38, 7971-7972.
(
9) (a) Snider, B. B.; Song, F. Org. Lett. 2000, 2, 407-408. (b) Snider,
6
in the final step and an (E)-stereoselective Wittig reaction
B. B.; Song, F. Org. Lett. 2001, 3, 1817-1820.
on aldehyde 5 to produce a suitable precursor. The (Z,Z)-
dienyl aldehyde 5 would be available from alcohol 7, which
(10) Smith, A. B.; Zheng. J. Tetrahedron 2002, 58, 6455-6471.
(11) Normant, J.-F.; Alexakis, A. Synthesis 1981, 841-870. (b) Normant,
J.-F. In Organocopper Reagents: A Practical Approach; Taylor, R. J. K.,
Ed.; Oxford University Press: Oxford, 1994; Chapter 11.
(12) Cox, G. G.; Moody, C. J.; Austin, D. J.; Padwa, A. Tetrahedron
1993, 49, 5109-5126.
(
5) Jansen, R.; Kunze, B.; Reichenbach, H.; H o¨ fle, G. J. Antibiot. 2004,
5
7, 151-155.
1064
Org. Lett., Vol. 7, No. 6, 2005

to remove the (Z)-alkene resulting from simple carbocupra-
tion, 16%), the desired diene 11 in 54% yield on a 4 mmol
scale. The (Z,Z)-configuration of the diene portion in 11 was
confirmed by NMR spectroscopy of the internal diene
protons (J ) ca. 11 Hz). It should be noted that the
corresponding sequence was also studied using other protect-
ing groups for the 3-iodopropanol (TBDMS, TBDPS, TIPS,
and MOM), as well as with 1,1-diethoxy-3-iodopropane, but
without success. The THP-derived organocopper reagent was
also less reactive in the carbocupration process than the
corresponding unfunctionalized dialkylcuprates, but the
acetylene insertions could be achieved by adding more
acetylene gas at higher temperatures over a longer period
according to the procedure mentioned above and described
in detail in Supporting Information. The best solvent mixture
for this double carbocupration was diethyl ether/hexane (ca.
Scheme 2
4:1). With more polar solvents, acetylene deprotonation
(formation of copper acetylide, CuCtCR) occurred; in less
polar mixtures, the vinyl/dienyl cuprate completely decom-
posed at the temperature of the second insertion step (-5
1
1,13
°
C).
2 3
Stabilizing additives such as Me S or P(OEt)
prevented acetylene insertion. The resulting THP-protected
diene 10 was deprotected to give the free alcohol 7 in 83%
1
4
yield by stirring with Montmorillonite K10 in methanol.
The alcohol 7 was oxidized using the Dess-Martin
periodinane to give the corresponding aldehyde 5, which was
used immediately in a Wittig reaction with ethyl (triphenyl-
phosphoranylidene)acetate to give the desired (E)-configured
(
J ) 15.6 Hz) R,â-unsaturated ester 12 in 92% yield over
described gives the acid exclusively as the (E)-isomer
the two steps (Scheme 2). The ester 12 was reduced with
diisobutylaluminum hydride to the corresponding alcohol
(
quantitative yield. Subsequent studies revealed that the vinyl
bromide (4, X) Br) was insufficiently reactive as a Stille
coupling partner. We therefore carried out a halogen
exchange by treating vinyl bromide 13 with t-BuLi and
quenching the resulting organolithium reagent with iodine
to produce vinyl iodide 14. Compound 14 was then depro-
tected and the resulting alcohol converted into the corre-
(confirmed by NOESY) in high purity.
The Stille coupling of side chain 4 (X ) I) with
-(tributylstannyl)oxazole (16) was investigated next (Scheme
85%), which was protected as the THP derivative 13 in
19
2
3
). It should be noted that no success was achieved in the
Scheme 3
15
sponding bromide by treatment with dimethyl sulfide/NBS.
The use of PPh /CBr occasionally gave higher yields but
was unreliable. The bromide was then transformed into amine
5 by treatment with excess methylamine; all three reactions
3
4
1
coupling of 16 with the vinyl bromide 4 (X ) Br):
temperatures of ca. 100 °C were required before any reaction
was observed, but at these temperatures the diene system
proved to be unstable. A range of palladium catalysts,
including Pd(PPh ) and PdCl (NCMe) , were employed for
3 4 2 2
the Stille coupling of 4 (X ) I) with 2-(tributylstannyl)-
oxazole (16), but the best yields were obtained using
proceeded in yields of >80%. Amine 15 was then coupled
with 3-methoxybutenoic acid to give the requisite Stille
coupling partner 4 (X ) I) in 95% yield.
3
-Methoxybutenoic acid (6) was prepared from methyl
acetoacetate in 50% overall yield by treatment with trimethyl
orthoformate according to a literature procedure16 followed
by hydrolysis of the intermediate ester with lithium hydrox-
17
18
ide. Other syntheses of 6 are available, but the procedure
(17) Preparation of (E)-3-methoxybutenoic acid (6):
(
13) Normant, J.-F.; Cahiez, G.; Bourgain, M.; Chuit, C.; Villieras, J.
Bull. Soc. Chim. Fr. 1974, 1656-1660.
14) Gautier, E. C. L.; Graham, A. E.; McKillop, A.; Standen, S. P.;
Taylor, R. J. K.; Tetrahedron Lett. 1997, 38, 1881-1884.
15) Grdina, M. B.; Orfanopoulos, M.; Stephenson, L. M. J. Org. Chem.
979, 44, 2936-2937.
16) Smissman, E. E.; Voldeng, A. N. J. Org. Chem. 1964, 29, 3161-
165.
(
(18) Kresge, A. J.; Ubysz, D. J. Phys. Org. Chem. 1994, 32, 316-322.
Zanatta, N.; de Cortelli, M. F. M.; Carpes, M. J. S.; Bonacorso, H. G.;
Martins, M. A. P. J. Heterocycl. Chem. 1997, 34, 509-514.
(19) Dondoni, A.; Fogagnolo, M.; Medici, A.; Negrini, E. Synthesis 1987,
185-187.
(
1
(
3
Org. Lett., Vol. 7, No. 6, 2005
1065

PdCl
2 3 2
(PPh ) in DMF at 50 °C, which gave the required
adduct 2 in 60% yield. Compound 2 was fully characterized
Table 1. Comparison of the NMR Data of Ajudazol A (1a)
and Analogue 2
4
(including HRMS). Unlike ajudazol A, compound 6 appears
to be stable during silica gel chromatography and at higher
temperatures (80 °C). The thermal and acid sensitivity of
1a therefore appears to be associated with the hydroxy-
isochromanone portion.
Compound 2 is a close analogue of ajudazol A (1a) but
lacks the isochromanone side chain at the oxazole C-12 site.
The NMR data for 2 were therefore compared with those
4
reported for ajudazol A (1a) as shown in Table 1.
synthetic 2
ajudazol A (1a)4
As can be seen, the H and 13C NMR data of both
compounds are in good accord, providing strong support for
the proposed structure, particularly for the unusual structural
features of ajudazol A such as the (Z,Z)-diene functionality,
the exo-methylene group, and the N-methyl methoxybutenoic
acid amide. In addition, both compounds ajudazol A and
analogue 2 show a distinct UV absorption at 320 nm in
methanol.
1
Ca
1Hb
13Cb
1Hb
13Cb
1
4
15
15′
161.0
134.0
161.0
134.4
117.4
30.0
127.6
125.2
123.6
132.0
26.8
5.44/5.95 (2 × bs) 117.0 5.85/5.35 (2 × bs)
1
1
1
1
2
2
6
7
8
9
0
1
3.39 (d, 7.6 Hz)
29.7 3.27 (d, J ) 7.8 Hz)
127.6 5.52 (m)
5.39-5.61 (m)
c,d
c,d
6.33 (dd, 10.7 Hz) 124.8 6.29 (dd, ∼11 Hz)
6.40 (dd, 10.7 Hz) 123.2 6.37 (dd, ∼11 Hz)
In summary, double acetylene carbocupration using a
functionalized alkylcuprate and 2,3-dibromopropene as the
trapping reagent was employed as the cornerstone of a
synthesis of the polyene side chain of ajudazol A, an
antimicrobial agent isolated from the myxobacteria Chon-
dromyces crocatus. This new methodology (using function-
alized cuprates) could be useful for the preparation of other
5.39-5.61 (m)
2.15 (dt, 7.0 Hz)
2.28 (dt, 7.3 Hz)
5.39-5.61 (m)
5.39-5.61 (m)
3.90 (d, 6.0 Hz)
2.87 (s)
131.5 5.45 (m)
26.4 2.19 (m)
31.0 2.08 (m)
131.4 5.54 (ddt)
125.5 5.39 (m)
49.6 3.84 (d, 5.7 Hz)
33.2 2.82 (s)
168.1
91.4 5.24 (s)
166.4
17.7 2.04 (s)
54.3 3.53 (s)
d
d
22
23
31.4
132.0
125.7
50.1
35.0
168.0
91.8
167.0
18.1
54.8
2
2
4
5
e
e
NMe
e
2
2
2
6
7
8
(
Z,Z)-diene-containing natural products such as the bi-
e
5.17 (s)
6a
6b
6c
tungolides A-F, leustroducsin B, or disorazole C. In
addition, a Stille coupling procedure has been developed to
link the polyene side chain vinyl iodide and 2-(tributyl-
stannyl)oxazole to produce the novel ajudazol A analogue
29
OMe
2.11 (s)
3.60 (s)
e
a
b
Data for carbons 1-13 are given in ref 4. In DMSO-d6 at 80 °C, if
c
d
e
2, which lacks only the isochromanone side chain at the
3 1 2
not stated otherwise. In CDCl at 50/55 °C. J ) J . Doubling of the
1 13
H and C NMR signals at room temperature is observed for both
oxazole C-12 site. We are currently utilizing the methodology
described herein to complete a synthesis of ajudazol A itself.
compounds.
Supporting Information Available: Experimental pro-
Acknowledgment. The Deutsche Forschungs-gemein-
schaft (German Research Foundation) and the Alexander von
Humboldt Foundation are thanked for postdoctoral support
1
13
cedures and H and C NMR spectra for all compounds.
This material is available free of charge via the Internet at
http://pubs.acs.org.
(O.K.). We also thank Gail Young (University of York) for
many helpful discussions.
OL047313+
1066
Org. Lett., Vol. 7, No. 6, 2005