Synthesis of the C9-C29 fragments of ajudazols A and B

Article abstract of DOI:10.1016/j.tetlet.2007.06.072

The syntheses of both C9-C29 fragments 3 and 4 of the myxobacteria metabolites ajudazols A (1) and B (2) are described. The key steps were a cyclodehydration to form the oxazole, Sonogashira coupling to form the C18-C19 bond and a P-2 Ni mediated partial

Full text of DOI:10.1016/j.tetlet.2007.06.072

Tetrahedron Letters 48 (2007) 5841–5843
Synthesis of the C9–C29 fragments of ajudazols A and B
Danny Ganame, Tim Quach, Charlotte Poole and Mark A. Rizzacasa*
School of Chemistry, The Bio21 Institute, The University of Melbourne, Victoria 3010, Australia
Received 11 May 2007; revised 6 June 2007; accepted 14 June 2007
Available online 20 June 2007
Abstract—The syntheses of both C9–C29 fragments 3 and 4 of the myxobacteria metabolites ajudazols A (1) and B (2) are described.
The key steps were a cyclodehydration to form the oxazole, Sonogashira coupling to form the C18–C19 bond and a P-2 Ni mediated
partial alkyne hydrogenation to install the C17–C18 Z-alkene. The C15 alkene in the ajudazol A fragment 3 was introduced in the
final steps by elimination of the corresponding primary alcohol.
Crown Copyright Ó 2007 Published by Elsevier Ltd. All rights reserved.
Myxobacteria are a life form at the interface between
single and multicellular organisms and are a rich source
of potentially useful secondary metabolites with about
80 different compounds characterized so far.1 The aju-
dazols A (1) and B (2) are novel isochromanone contain-
ing natural products isolated from the myxobacterium
Chondromyces crocatus.2 These molecules also contain
an oxazole moiety connected to a Z,Z,E-triene side-
chain and terminate in an E-3-methoxybutenamide.
Ajudazol A (1) has a methylene group at C15 whilst
the co-metabolite 2 possesses a methyl substituent at
C15 creating an asymmetric center. The relative config-
uration of the isochromanone core and the stereochem-
istry of the Z,Z,E-triene was determined from NOESY
and 1H–1H coupling constant analysis, however, the
absolute stereochemistry remains to be determined. In
addition, the configuration at the isolated stereocenter
at C15 in 2 was also not determined. The ajudazols were
identified as inhibitors of the mitochondrial respiratory
energy metabolism of beef heart sub-mitochondrial par-
ticles (SMP). NADH oxidation in SMP was inhibited at
an IC50 of 13.0 ng/mL (22.0 nM) for ajudazol A (1) and
10.9 ng/mL (18.4 nM) for ajudazol B (2).3
A and B could arise from common late intermediates
and our retrosynthetic approach to both 1 and 2 is
shown in Scheme 1. The key step in the proposed routes
is the formation of the C18–C19 bond by a Sonogashira
cross-coupling reaction5,6 between the oxazole-isochro-
manone fragment alkynes 5 or 6 and common vinyl
iodide 7. Partial hydrogenation should introduce the
C17–C18 Z-alkene in a stereoselective manner. The syn-
thesis of the ajudazol A alkyne fragment 5 would require
amide formation between isochromanone-amine 8 and
acid 9 followed by oxazole formation using the modified
Wipf protocol.7 The C15 primary alcohol could then be
eliminated to introduce the C15 alkene. On the other
hand, the ajudazol B alkyne fragment 6 could be ob-
tained by coupling between the same isochromanone
fragment 8 and either enantiomer of the known chiral
acid 108 followed by cyclodehydration. In this Letter,
we report the synthesis of the model C9–C29 fragments
3 and 4 of ajudazols A (1) and B (2).
The synthesis of the C9–C29 segments of the ajudazols
began with the production of the common vinyl iodide
fragment 7 as outlined in Scheme 2. The known alcohol
119 was oxidized and subjected to Wittig homologation
to give diene 12. Ester reduction followed by bromide
formation and displacement with methylamine gave
the secondary amine 13. Peptide coupling of 13 with
the acid 144,10 then afforded the common vinyl iodide 7.
Taylor and Krebs have reported an approach to the
eastern fragment of ajudazol A (1) in which the C14–
C15 bond was constructed by a Stille cross-coupling
reaction between 2-tributyltin oxazole and a vinyl iodide
triene to afford a model C12–C29 ajudazol A fragment.4
We envisaged a convergent approach in which ajudazols
We next utilized a surrogate for the isochromanone/oxa-
zole fragment and the synthesis of the ajudazol B model
oxazole 15 is shown in Scheme 3. Racemic alcohol 1611
was converted into amine 17 by mesylation, azide dis-
placement, and Staudinger reduction. Peptide coupling
*
Corresponding author. Tel.: +61 3 8344 2397; fax: +61 3 9347
8396; e-mail: masr@unimelb.edu.au
0040-4039/$ - see front matter Crown Copyright Ó 2007 Published by Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2007.06.072

5842
D. Ganame et al. / Tetrahedron Letters 48 (2007) 5841–5843
Me
N
Sonogashira
coupling
Amide formation/
cyclodehydration
Me
OMe
Me
N
OMe
Me
O
OH Me
O
15
N
25
15
O
BnO
29
O
N
18
29
11
3 Ajudazol A fragment; 15-alkene
4 Ajudazol B fragment; 15-Me
Partial
11
hydrogenation
O
Me
1 Ajudazol A; 15-alkene
2 Ajudazol B; 15-Me
OH
O
OTBS
OP Me
O
HO2C
OP Me
O
Me
N
15
+
+
NH2
OMe
Me
N
R
O
Me
I
O
7
R
S
Me
9 R = OTBDPS
10 R = H; or
5 R = OH
6 R = H; 15
OP
O
8
R
S
R
or
OP
O
Scheme 1. Retrosynthetic analysis of ajudazols A (1) and B (2).
OH
1) NaOMe
Br
1) PCC, CH2Cl2
1) NaH
CO2Me
TBDPSCl
HO
11
MeO2C
CO2Me
I
12
2) Ph3P=CHCO2Me
73%
I
2) DMP
3) NaClO2
77%
2) LiAlH4
24% for
2 steps
OH
RO
21
NHMe
1) DiBALH
HO
OMe
Me
+
2) Ph3P, CBr4
3) MeNH2, THF
77% overall
I
O
O
13
HO2C
EDCl•MeI
14
BnO
N
HOBt, DMF
17
9
H
OTBDPS
Me
N
EDCl•MeI
OTBDPS
22 R = TBS
23 R = H
86%
OMe
Me
CSA
HOBt, DMF
79%
MeOH
I
O
7
1) Dess-Martin
reagent
O
N
Scheme 2. Synthesis of vinyl iodide 7.
BnO
2) 2,6-DTBMP
PPh3, (BrCl2C)2
then DBU
24 R = TBDPS
20 R = H; 90%
OR
OTBS
TBAF
THF
HO2C
90% for 3 steps
+
BnO
Me
X
Scheme 4. Synthesis of ajudazol A model oxazole 20.
and R or S 10
16 X = OH
1) MsCl, pyr.
2) NaN3, DMF
3) Ph3P, H2O
17 X = NH2; 96%
was easily separated from the bis-alkylated by-product
by flash chromatography. Monosilylation13 of 21 and
two step oxidation gave acid 9. Peptide coupling between
9 and amine 17 proceeded in high yield and selective re-
moval of the TBS group in 22 was achieved using CSA in
methanol. Dess–Martin oxidation of the resultant alco-
hol 23 gave an intermediate aldehyde, which was
smoothly cyclized to oxazole 24 in a high overall yield.7
Silyl group removal then gave the model ajudazol A oxa-
zole precursor 20. With each of the alkynes in hand, we
next examined the Sonogashira coupling-partial hydro-
genation protocol for the production of 3 and 4.
RO
EDCl•MeI
O
N
BnO
HOBt, DMF
79%
H
Me
18 R = TBS
TBAF
19 R = H; 85%
1) Dess-Martin
reagent
O
2) 2,6-DTBMP
PPh3, (BrCl2C)2
then DBU
BnO
N
Me
( )-15
84%
Scheme 3. Synthesis of ajudazol B model oxazole 15.
of 17 with racemic acid 108 gave amide 18 as a mixture
of diastereoisomers. Silyl group removal afforded
alcohol 19 and Dess–Martin oxidation followed by cyclo-
dehydration using a hindered base7 and dehydrobro-
mination gave the model oxazole ( )-15 in high yield.
Both enantiomers of 15 were also synthesized in homo-
chiral form using either R- or S-108 and chiral HPLC
analysis indicated that no racemisation had occurred
during the oxazole synthesis.
The synthesis of the model C9–C29 ajudazol B fragment
4 is outlined in Scheme 5. Sonogashira coupling between
racemic 15 and iodide 7 gave the enyne 25 in good yield.
Partial hydrogenation of the C17–C18 alkyne in 25
proved challenging. Exposure of 25 to hydrogen gas in
the presence of Lindlar catalyst resulted in no reaction
while prolonged treatment resulted in some formation
of the desired diene 4 in low yield accompanied by a
substantial amount of C17–C18 fully saturated prod-
uct. The use of catalyst poisons did not improve
the yield of 4 and usually resulted in no reaction at
all.
Oxazole 20 required for the production of the ajudazol A
model system 3 was synthesized as shown in Scheme 4.
Preliminary experiments suggested that introduction of
the C15 alkene in the ajudazol A system was best left
until a later stage in the synthesis. The route began with
the alkylation of dimethyl malonate with propargyl bro-
mide.12 Subsequent reduction afforded diol 21, which
At this stage we turned to the P-2 nickel (P-2 Ni) cata-
lyst as reported by Brown.14 This catalyst can be applied
to the partial reduction of alkynes to Z-alkenes in the
presence of ethylenediamine15 and we have successfully

D. Ganame et al. / Tetrahedron Letters 48 (2007) 5841–5843
5843
References and notes
+
( )-15
7
Pd(PPh3)2Cl2
CuI, NEt3
1. Reichenbach, H. J. Ind. Microbiol. Biotechnol. 2001, 27,
149–156.
2. Jansen, R.; Kunze, B.; Reichenbach, H.; Ho¨fle, G. Eur. J.
Org. Chem. 2002, 917–921.
3. Kunze, B.; Jansen, R.; Hofle, G.; Reichenbach, H. J.
Antibiot. 2004, 57, 151–155.
4. Krebs, O.; Taylor, R. J. K. Org. Lett. 2005, 7, 1063–
1066.
79%
Me
N
O
OMe
Me
BnO
N
O
Me
25
H2, P-2 Ni
EDA, EtOH
55%
Me
N
OMe
Me
O
5. Sonogashira, K. In Comprehensive Organic Synthesis;
Trost, B. M., Fleming, I., Eds.; Pergamon Press: Oxford,
1991; Vol. 3, p 521.
18
17
O
BnO
N
( )-4
Me
´
6. Chinchilla, R.; Najera, C. Chem. Rev. 2007, 107, 874–
Scheme 5. Synthesis of the C9–C29 fragment 4 of ajudazol B.
922.
7. Wipf, P.; Lim, S. J. Am. Chem. Soc. 1995, 117, 558–559;
Wipf, P.; Graham, T. J. Org. Chem. 2001, 66, 3242–
3245.
+
20
7
8. Pettigrew, J. D.; Freeman, R. P.; Wilson, B. D. Cancer J.
Chem. 2004, 82, 1640–1648.
9. Yenjai, C.; Isobe, M. Tetrahedron 1998, 54, 2509–
2520.
10. Smissman, E. E.; Voldeng, A. N. J. Org. Chem. 1964, 29,
3161–3165.
11. Aoyagi, Y.; Saitoh, Y.; Ueno, T.; Horiguchi, M.; Takeya,
K.; Williams, R. M. J. Org. Chem. 2003, 68, 6899–6904.
12. Dotz, K. H.; Popall, M. Tetrahedron 1985, 41, 5797–
5802.
Pd(PPh3)2Cl2
CuI, NEt3
O
77%
Me
N
OMe
Me
BnO
N
O
26
OH
2) MsCl, pyr.
3) DBU
1) H2, P-2 Ni
EDA, EtOH
Me
N
OMe
Me
O
15
O
BnO
13. McDougal, P.; Rico, J.; Oh, Y.-I.; Condon, B. J. Org.
Chem. 1986, 51, 3388–3390.
N
3
32% overall
14. Brown, C. A.; Ahuja, V. K. J. Org. Chem. 1973, 38, 2226–
2230.
Scheme 6. Synthesis of the C9–C29 fragment 3 of ajudazol A.
utilized P-2 Ni for the partial hydrogenation of a
skipped diyne to afford a Z,Z-diene.16 The catalyst can
be generated by the NaBH4 mediated reduction of
Ni(OAc)2 in ethanol under a hydrogen atmosphere.14,15
Partial hydrogenation of alkyne 25 proceeded well in the
presence of P-2 Ni and ethylenediamine to afford the de-
sired ajudazol B side-chain 417 in 55% yield along with a
small amount of the C17–C18 fully saturated product.
This produced racemic 4, however, it should be noted
that both enantiomers of the real alkyne fragment 6
could be synthesized as demonstrated in the synthesis
of both R and S-15.
15. Brown, C. A.; Ahuja, V. K. J. Chem. Soc., Chem.
Commun. 1973, 553–554.
16. Feutrill, J. T.; Rizzacasa, M. A. Aust. J. Chem. 2003, 56,
783–785.
17. Data for compound 4: IR mmax (film): 2918, 2851, 1738,
1
1647, 1601, 1459, 1238, 1104 cmÀ1; H NMR (800 MHz,
acetone-d6) d 1.27 (d, J = 7.0 Hz, 3H), 1.88–1.91 (m, 2H),
2.14 (m, 2H) 2.14 (br s, 3H), 2.26 (dt, J = 7.4, 7.4 Hz, 2H),
2.49 (m, 1H), 2.55 (td, J = 7.5, 1.0 Hz, 2H), 2.61 (m, 1H),
2.84 and 2.85 (br s, 3H), 2.99 (m, 1H), 3.51 (t, J = 6.2 Hz,
2H), 3.59 (br s, 3H), 3.92 (dd, J = 6.0, 1.0 Hz, 2H), 4.50 (s,
2H), 5.32 and 5.35 (each br s, 1H), 5.42 (dt, J = 10.0,
7.9 Hz, 1H), 5.48 (dt, J = 9.5, 8.1 Hz, 1H), 5.51 (m, 1H),
5.60 (m, 1H), 6.28 (ddd, J = 11.3, 11.3, 1.0 Hz, 1H), 6.32
(t, J = 11.1 Hz, 1H), 7.26–7.36 (m, 5H), 7.49 (t, J = 1 Hz,
1H); 13C NMR (200 MHz, acetone-d6) d 18.3, 18.7, 23.6,
27.9, 29.3, 32.8, 33.4, 33.5, 34.6, 49.2 and 52.4 (br), 55.3,
70.1, 73.2, 92.2, 124.7, 126.2, 126.9, 128.1, 128.2, 128.9,
129.0, 132.3, 132.7, 134.6, 140.0, 141.0, 167.6, 167.7 and
167.9 (br), 168.81 and 168.83 (br); HRMS (ESI) Calcd for
C31H43N2O4 [M+H+]: 507.3223. Found: 507.3225.
The synthesis of the ajudazol A fragment 3 is outlined in
Scheme 6. Sonogashira coupling between 20 and iodide
7 proceeded smoothly to afford enyne 26 in good yield.
Partial hydrogenation with P-2 Ni as catalyst followed
by mesylation of the primary alcohol and DBU induced
elimination18 afforded the target compound 3.19 At-
tempts at introducing the C15 alkene prior to coupling
and hydrogenation failed to afford 3.
18. Doi, T.; Yoshida, M.; Shin-ya, K.; Takahashi, T. Org.
Lett. 2006, 8, 4165–4167.
19. Data for compound 3: IR mmax (film): 2925, 2856, 1723,
1
1646, 1605, 1455, 1248, 1107 cmÀ1; H NMR (400 MHz,
In conclusion, we have developed a route to the C9–C29
fragments 3 and 4 of ajudazols A (1) and B (2). The key
steps involve a high yielding Sonogashira coupling and
P-2 Ni mediated partial hydrogenation. The synthesis
of the isochromanone fragment of 1 and 2 is currently
underway in our laboratories.
DMSO-d6 85 °C): d 1.83–1.90 (m, 2H), 2.08 (s, 3H), 2.10–
2.13 (m, 2H), 2.22–2.27 (m, 2H), 2.54 (t, J = 7.2 Hz, 2H),
2.84 (s, 3H), 3.33 (d, J = 7.6 Hz, 2H), 3.50 (t, J = 6.4 Hz,
2H), 3.56 (s, 3H), 3.87 (d, J = 5.2 Hz, 2H), 4.47 (s, 2H),
5.28 (s, 1H), 5.37 (s, 1H), 5.35–5.61 (m, 4H), 5.87 (s, 1H),
6.33 (m, 1H), 6.35 (m, 1H), 7.24–7.35 (m, 5H), 7.69 (s,
1H); 13C NMR (200 MHz, DMSO-d6 55 °C): d 18.6, 22.8,
26.8, 27.2, 28.4, 30.4, 31.6, 33.3 and 35.0 (br), 48.5 and
51.8 (br), 55.3, 69.2, 72.2, 92.0, 117.5, 124.1, 125.6, 126.2,
126.3, 127.7, 128.0, 129.0, 132.1, 134.4, 135.3, 139.1, 141.5,
161.2, 166.9, 167.3. HRMS (ESI) Calcd for
C31H40N2O4Na [M+Na+]: 527.2886. Found: 527.2882.
Acknowledgment
We thank the Australian Research Council Discovery
Grants Scheme (DP0556064) for funding.