Synthesis of chaetomellic anhydride A, A potent inhibitor of ras protein farnesyltransferase

Article abstract of DOI:10.3987/COM-08-S(F)16

Chaetomellic anhydride A, a potent inhibitor of Ras protein farnesyltransferase, was synthesized in 61% yield over four steps from methyl propionate. The synthesis features palladium-catalyzed carboxylation reaction under Cacchi conditions, efficiently in

Full text of DOI:10.3987/COM-08-S(F)16

HETEROCYCLES, Vol. 77, No. 1, 2009
179
HETEROCYCLES, Vol. 77, No. 1, 2009, pp. 179 - 186. © The Japan Institute of Heterocyclic Chemistry
Received, 30th April, 2008, Accepted, 23rd June, 2008, Published online, 26th June, 2008.
DOI: 10.3987/COM-08-S(F)16
SYNTHESIS OF CHAETOMELLIC ANHYDRIDE A, A POTENT
INHIBITOR OF RAS PROTEIN FARNESYLTRANSFERASE
Takehiko Yoshimitsu,*,† Yoshimasa Arano,‡ Tomohiro Kaji,† Tatsunori Ino,†
Hiroto Nagaoka,‡ and Tetsuaki Tanaka*,†
†Graduate School of Pharmaceutical Sciences, Osaka University, 1-6 Yamadaoka,
Suita, Osaka 565-0871, Japan, ‡Meiji Pharmaceutical University, 2-522-1 Noshio,
Kiyose, Tokyo 204-8588, Japan
E-mail: yoshimit@phs.osaka-u.ac.jp; t-tanaka@phs.osaka-u.ac.jp
Abstract – Chaetomellic anhydride A, a potent inhibitor of Ras protein
farnesyltransferase, was synthesized in 61% yield over four steps from methyl
propionate. The synthesis features palladium-catalyzed carboxylation reaction
under Cacchi conditions, efficiently incorporating carbon monoxide generated in
situ from acetic formic anhydride into β-carbomethoxyalkenyl triflate, and giving
rise to the maleic anhydride motif of chaetomellic anhydride A. Noteworthy is the
remarkable reactivity of the carboxylation reaction that takes place at room
temperature despite the fact that common palladium-catalyzed carboxylations
generally require rather harsh conditions. The scope of the method is also
presented.
INTRODUCTION
Oncogenic studies have revealed that Ras protein is mutated in approximately 30% of human cancers, the
mutation occurring via farnesylation of the protein catalyzed by a zinc metalloenzyme, protein
farnesyltransferase (PFTase). As a result, PFTase inhibitors have received considerable attention in
cancer chemotherapy due to their potential use as a new chemical substance that blocks oncogenic cell
growth.1,2 Intensive screening of natural and synthetic resources has led to the successful identification of
a number of PFTase inhibitors: chaetomellic acid A (1) is a natural PFTase inhibitor produced by the
coelomycete Chaetomella acutiseta and is obtained as chaetomellic anhydride A (2) that arises from
facile dehydration of the maleic acid motif (Figure 1).3 Because of its significant inhibitory activity
This Paper is dedicated to Professor Emeritus Keiichiro Fukumoto on the occasion of his 75th birthday.

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toward recombinant human PFTase (IC50=55 nM), acid 1 has become an attractive synthetic target in
recent years.4
O
H
HO2C
O
O
O
O
O
1
H
HO2C
O
H
chaetomellic acid A
O
O
O
3
CO2H
2
CP-263,114 (phomoidride B)
chaetomellic anhydride A
Figure 1. Natural farnesyltransferase inhibitors.
The prospect that PFTase inhibitors serve as potential anticancer agents has motivated us to establish an
access to this class of molecules. Our recent efforts in this area have culminated in the synthesis of the
fully functionalized core motif of (-)-CP-263,114 (phomoidride B) (3), which is one of the most
structurally complex natural PFTase inhibitors.5 In this context, we became interested in chaetomellic
anhydride A (2) because it has a simple architecture and can easily be transformed into the bioactive
dianion form of chaetomellic acid A (1) by mild saponification (i.e., pH > 7). We report herein an
expeditious route to anhydride 2 employing a Pd-catalyzed carboxylation technique that would potentially
provide an access to substituted maleic anhydrides, which widely constitute the structural motifs of
bioactive nonadrides (Figure 2).6
O
O
HO
O
O
O
O
O
H
O
O
HO
O
O
O
H
O
O
O
OH
O
O
O
5
O
4
6
byssochlamic acid
glaucanic acid
O
rubratoxin B
Figure 2. Bioactive natural maleic anhydrides.
RESULTS AND DISCUSSION
Various means for synthesizing substituted maleic anhydrides have appeared in the literature, many of
which rely on the transformation of alkynes and alkenes or the condensation of esters.7 Those methods
involve vicinal dialkylations of dimethyl acetylenedicarboxylate via 1,4-nucleophilic addition

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181
reactions,4n,7a double carbonylation of acetylene-cobalt complexes,7b,c condensation of esters with
α-ketoesters followed by dehydration,4r and Ni-catalyzed dicarboxylation of allenes.4c
Palladium-catalyzed carboxylation of β-carboalkoxyalkenyl triflates or halides, followed by cyclization of
resultant maleic acid half-esters, is also particularly useful for this purpose, although it generally requires
the use of highly toxic pressurized carbon monoxide (CO) gas.8
Recently, Cacchi and co-workers reported that aryl and vinyl halides or triflates could be carboxylated in
the presence of palladium(0) catalyst by using acetic anhydride and lithium formate as the condensed
source of CO, giving carboxylic acids in good yields.9,10 Consequently, it occurred to us that the
carboxylation of β-carbomethoxyalkenyl triflates with CO generated in situ under Cacchi conditions
would provide half-esters, which, by subsequent cyclization, could be readily converted into substituted
maleic anhydrides.
CO2H
Br
Ac2O, HCO2Li
iPr2NEt
Pd(OAc)2, LiCl
DMF, 80oC
Scheme 1. Cacchi’s carboxylation reaction.
As an initial investigation of the feasibility of maleic anhydride formation, several cyclic
β-carbomethoxyalkenyl triflates 7a-d were subjected to CO insertion reaction (Table 1). Cyclic triflates
7a-d were each treated with a mixture of acetic anhydride, formic salt,11 LiCl, and iPr2NEt in the presence
of Pd(OAc)2 in DMF at room temperature.12 As expected, enol triflates were consumed within reasonable
reaction times to produce maleic anhydrides and/or half-esters as the major products in various ratios
depending on the ring size of the substrate used. It should be noted, however, that the present reactions
smoothly took place even at room temperature despite the fact that Pd-catalyzed carboxylations generally
require rather harsh conditions (e.g., heating at 80 oC). The progress of the reactions was easily monitored
by TLC, indicating that 5- and 6-membered ring triflates 7a and 7b mainly gave half-esters. Half-ester 9b
produced from triflate 7b could be transformed into corresponding maleic anhydride 8b with azeotropic
dehydration in the presence of TsOH, whereas 5-membered half-ester 9a derived from 7a yielded no
maleic anhydride under the same conditions, resulting in its recovery (entries 1 and 2). In contrast, 7- and
8-membered ring substrates 7c and 7d were found to readily provide maleic anhydrides 8c and 8d,
respectively, along with unstable intermediates (vide infra) that completely disappeared during an acidic
aqueous work-up due to their susceptibility to hydrolysis and high propensity for cyclization (entries 3
and 4). The inefficiency in cyclizing the 5- and 6-ring half-esters derived from 7a and 7b is reasonably

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attributable to the high degree of ring strain of the bicyclic anhydrides compared to that of the larger
carbocycles.
Table 1. Pd-catalyzed carboxylation reaction of β-carbomethoxyalkenyl triflates.
O
Ac2O, HCO2Na
OTf
CO2H
O
iPr2NEt
CO2Me
CO2Me
O
Pd(OAc)2, LiCl
DMF, rt
n
n
n
8
9
7
yield (%)
entry
substrate
time
9a (79)a
8b (86)a
8c (82)b
a
b
c
1
2
3
n=1
n=2
n=3
1.5 h
9.5 h
50 min
8d (90)b
4
d
n=4
55 min
a) overall yield after azeotropic dehydration.
b) after acidic aqueous work-up.
Ac2O HCO2Na
iPr2NEt
PdOTf
CO2Me
TfOPd
CO2Me
TfO
CO2Me
O
Pd(0)
CO
10
7c
11
iPr2NHEt
AcO
PdOAc
O
O
O
CO2Me
O
CO2Me
TfO
12
O
O
O
HO2C
CO2Me
AcO
13
HCO2
or
hydrolysis
14
8c
Scheme 2. Mechanism of maleic anhydride formation.
Quite interestingly, applying a nonaqueous work-up enabled the successful isolation of mixed acetic
anhydride 13 from 7-membered ring substrate 7c:13 after starting triflate 7c had been completely
consumed, the reaction mixture was diluted with dry Et2O and filtered through a short plug of

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Celite/Florisil. Then the filtrate was concentrated in vacuo to give a mixture of two compounds detectable
by TLC, both of which were visualized using UV light and stained with KMnO4 solution. Rapid and
careful chromatography of the mixture afforded highly labile anhydride 13 and cyclized product 8c. The
successful isolation of 13 in this case indicates that the carboxylations proceed through an intermediacy of
the mixed acetic anhydride, which supports Cacchi’s mechanistic proposal.9a A plausible mechanism is
thus reasonably assumed for the present reaction: anhydride 13 generated via acylpalladium intermediate
12 is deacetylated by nucleophilic attack of an acetate and/or a formate anion in the reaction mixture, or
hydrolyzed by moisture, yielding corresponding half-ester 14 that then undergoes rapid cyclization to
afford maleic anhydride 8c (Scheme 2).
The present procedure allowed us to devise an expeditious route to chaetomellic anhydride A (2) (Scheme
3). We initiated the synthesis with β-hydroxy ester 16, which was prepared by aldol condensation of
methyl propionate (15) with pentadecanal. Compound 16 was oxidized with PCC to produce β-keto ester
17 in 93% yield, which, upon treatment with NaH in refluxing toluene followed by the addition of triflic
o
anhydride at 0 C, selectively gave (Z)-β-carbomethoxyalkenyl triflate 18 in 84% yield.14 Although
triflation could be carried out by enolizing 17 with potassium hexamethyldisilazide and subsequent
treatment of the resultant enolate with phenyl triflimide, this procedure led to a somewhat low yield
owing to the production of undesired (E)-triflate isomer (70% yield, Z/E = ca. 3:1). Then, triflate 18 was
subjected to the key anhydride-forming reaction to furnish chaetomellic anhydride A (2) in 87% yield.15
This synthesis enabled a highly efficient four-step access to target 2 in 61% overall yield from
commercially available ester 15.
O
OH
16
O
b
a
C13H27
CO2Me
17
C13H27
CO2Me
OMe
93%
90%
15
dr= ca.1:1
c
84%
O
OTf
18
d
C13H27
CO2Me
O
87%
2
O
(61% total yield from 15)
Reagents and conditions: (a) LDA, C14H29CHO, THF, -78 oC, 90%; (b) PCC, CH2Cl2, rt; (c) NaH, 85 oC,
toluene, then Tf2O, 0 oC, 84%; (d) Ac2O, HCO2Na, i-Pr2NEt, cat. Pd(OAc)2, LiCl, DMF, rt, 87%.
Scheme 3. Synthesis of chaetomellic anhydride A.

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CONCLUSION
In summary, we have established an efficient route to chaetomellic anhydride A (2) via maleic anhydride
formation under Cacchi’s CO insertion conditions. We also found evidence of an intermediacy of the
mixed acetic anhydride in the carboxylation reactions, which supports the mechanistic rationale
previously proposed by Cacchi and co-workers. The expeditiousness of the present synthesis allowed us
to produce chaetomellic anhydride A (2) in a large quantity and thus, the method for elaborating maleic
anhydride motifs established here will provide a foundation for synthesizing various substituted maleic
anhydrides.
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Hayashi, T. Itoh, and T. Fukuyama, Org. Lett., 2003, 5, 2235.
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A. Roig, and A. Vallribera, Tetrahedron, 2007, 63, 2519. Also, see: (c) J.-F. Carpentier, Y. Castanet,
J. Brocard, A. Mortreux, and F. Petit, Tetrahedron Lett., 1991, 32, 4705.
10. For a pertinent review of carbonylation reactions without using CO gas, see: T. Morimoto and K.
Kakiuchi, Angew. Chem. Int. Ed., 2004, 43, 5580.
11. Cacchi has established the superior reactivity of lithium salt (HCO2Li) in carboxylation reactions.
Sodium formate (HCO2Na), however, was used as the formic salt throughout this study because of
ease of availability.
12. A typical procedure for maleic anhydride formation: A mixture of HCO2Na (143 mg, 2.1 mmol),
Ac2O (130 μL, 1.4 mmol), and i-Pr2NEt (245 μL, 1.4 mmol) was stirred at rt for 1 h. To this mixture
were added triflate 7d (221 mg, 0.7 mmol) in DMF (1.0 mL + 0.5 mL x 2 used for rinsing),

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Pd(OAc)2 (7.9 mg, 0.035 mmol), and LiCl (89 mg, 2.1 mmol) sequentially, and the stirring was
continued for another hour. The mixture was poured into a separatory funnel where it was
partitioned between 2 N HCl and Et2O. Then, the organic extracts were combined, dried over
Na2SO4, filtered, and concentrated. The residue was purified by silica gel column chromatography
1
(Et2O/hexane=1:3 v/v) to give maleic anhydride 8d as a colorless oil. IR (neat) ν 1771 cm-1; H
NMR (400 MHz, CDCl3) δ 2.68-2.63 (m, 4H), 1.86-1.79 (m, 4H), 1.60-1.55 (m, 4H); 13C NMR (100
MHz, CDCl3) δ 165.9, 144.3, 25.8, 25.3, 22.9; MS m/z: 180 (M+), 108 (100%); HRMS (EI) calcd for
C10H12O3 (M+): 180.0786, found: 180.0789.
13. NMR data of mixed acetic anhydride 13: 1H NMR (300 MHz, CDCl3) δ 3.56 (s, 3H), 2.63-2.58 (m,
1H), 2.49-2.38 (m, 3H), 2.09 (s, 3H), 1.90-1.59 (m, 6H); 13C NMR (75 MHz, CDCl3) δ 169.0, 167.0,
157.0, 133.0, 116.4, 51.9, 29.9, 26.4, 26.3, 26.0, 24.6, 21.4.
14. (a) R. A. Gibbs, U. Krishnan, J. M. Dolence, and C. D. Poulter, J. Org. Chem., 1995, 60, 7821. (b)
Y. Shao, J. T. Eummer, and R. A. Gibbs, Org. Lett., 1999, 1, 627. (c) H.-O. Kim, C. O. Ogbu, S.
Nelson, and M. Kahn, Synlett, 1998, 1059.
15. Synthesis of chaetomellic anhydride A (2): By applying the same protocol as that described above
(note 12) to triflate 18 (1.59 g, 3.58 mmol), two materials consisting of desired anhydride 2 and its
unstable precursor, a mixed acetic anhydride, were produced. Therefore, the mixture was diluted
with CH2Cl2 followed by adding silica gel (ca. 20 g) to ensure complete cyclization of the precursor,
yielding anhydride 2 as the sole product. Following filtration, concentration and purification by
silica gel column chromatography (CH2Cl2) gave chaetomellic anhydride A (2) (935 mg, 87%) as a
colorless oil, which solidified in a refrigerator (at ~3oC) as a waxy solid. Chaetomellic anhydride
1
A: IR (neat) ν: 1771 cm-1; H NMR (400 MHz, CDCl3) δ 2.45 (t, 2H, J=7 Hz), 2.07 (s, 3H),
1.63-1.54 (m, 2H), 1.34-1.25 (m, 22H), 0.88 (t, 3H, J=7 Hz); 13C NMR (100 MHz, CDCl3) δ 166.1,
165.7, 144.6, 140.3, 31.9, 29.7-29.2 (9 peaks), 27.6, 24.5, 22.7, 14.1, 9.5; MS m/z: 308 (M+), 126
(100%); HRMS (EI) calcd for C19H32O3 (M+) m/z: 308.2351, found: 308.2355. The data are in full
agreement with those reported.4a,f,m Mixed acetic anhydride: 1H NMR (300 MHz, CDCl3) δ 3.57 (s,
3H), 2.25 (t, 2H, J=8 Hz), 2.09 (s, 3H), 1.88 (s, 3H), 1.37-1.16 (m, 24H), 0.88 (t, 3H, J=7 Hz).