Synthesis of apicidin

Article abstract of DOI:10.3987/com-00-9014

Tetrapeptide containing L-2-amino-8-protected hydroxydecanoic acid, L-N-O-methyltryptophan, L-isoleucine and D-pipecolinic acid was cyclized with pentafluorophenyl diphenylphosphinate. The cyclic tetrapeptide was deprotected and oxidized to apicidin [cyclo-(N-O-methyl-L-Trp-L-Ile-D-Pip-L-2-amino-8-oxo-decanoyl)].

Full text of DOI:10.3987/com-00-9014

HETEROCYCLES, Vol. 55, No. 1, 2001, pp. 1 - 4, Received, 19th July, 2000
SYNTHESIS OFAPICIDIN
Wataru Kuriyama and Takeshi Kitahara*
Department of Applied Biological Chemistry, Graduate School of Agricultural and Life
Sciences, The University of Tokyo, 1-1-1 Yayoi, Bunkyo-ku, Tokyo 113-8657, Japan
Abstract – Tetrapeptide containing L-2-amino-8-protected hydroxydecanoic acid, L-N-O-
methyltryptophan, L-isoleucine and D-pipecolinic acid was cyclized with pentafluorophenyl
diphenylphosphinate. The cyclic tetrapeptide was deprotected and oxidized to apicidin
[cyclo-(N-O-methyl-L-Trp-L-Ile-D-Pip-L-2-amino-8-oxodecanoyl)].
Apicidin (1) was first isolated from Fusarium pallidoroseum by the Merck Research Group.1,2 It shows in vitro
antiapicomplexan and in vivo antimalarial activity.1,2 Its apicomplexan activity appears to be due to the mechanism of
the apicomplexan histone deacetylase (HDA) inhibiting activity.1,2 The known mammalian histone deacetylase
inhibitor, trichostatin3 (2) and structually related compound, HC toxin,4 (3) also have apicomplexan activity.1 (Figure)
Figure
O
O
O
O
O
N
H
H
N
O
N
H
NH
N
NHOH
N
NH
H
N
O
N
N
O
OMe
O
O
O
O
2 Trichostatin
3 HC toxin
1 Apicidin
O
Some cyclic tetrapeptides with (2S,9S)-2-amino-8-oxo-9,10-epoxydecanoic acid and its analogues which have
mammalian histone deacetylase inhibiting activity have been synthesized5-8 and the histone deacetylase function was
explored.8 We are interested in the synthesis of apicidin and related analogues because apicidin possesses the same
inhibiting activity as HC toxin without epoxide linkage in the side chain. Herein, we report the synthesis of apicidin.
The cyclization site was determined by hydrogen bond analysis.2 The carbonyl groups of pipecolinic acid and
2-amino-8-oxodecanoic acid and the amino group of the latter play an important role in the apicidin conformation. N-O-
Methyl-L-tryptophan (6) was synthesized as follows. (Scheme 1)
Scheme 1
CO H
CO Me
CO Me
2
2
H N
2
2
FmocHN
H N
2
1) MeOH, S(O)Cl2 (q. y.)
2) FmocCl (q. y.)
1) Et3SiH, TFA (83%)
2) H2O2, cat.Na2WO4
then NaHCO3, Me2SO4
(25%)
N
H
N
N
H
5
OMe
6
3) Et2NH (60%)
4

When the Fmoc protected amino group is substituted with other alkyl groups (in the case of methyl), the yield of each
step is good.9 But in our case, perhaps due to overoxidation of the amino group, the yield of the oxidation step was poor.
In the case of MeReO3 and urea・H2O2 , the yield was up to 40%.
Synthesis of 2-amino-8-oxodecanoic acid [2-amino-8-protected hydroxydecanoic acid (11)] is outlined in Scheme 2.
During the Grignard reaction in the presence of cuprous bromide, the racemization rate is very low between 2-amino-
β-lactone and alkylmagnesium bromide.10 2-Boc-amino-β-lactone (8) was synthesized from L-serine (7) via
cyclization step under modified Mitsunobu conditions using dimethyl azodicarboxylate,10,11 and alkylbromide(10)was
obtained from 1,5-pentanediol (9) via a monoprotection procedure.12
Scheme 2
NH
2
NHBoc
O
1) Boc2O (q. y.)
OH
HO C
2
O
2) PPh3, DMAD
(68%)
7
Mg, CuBr・SMe2
NHBoc
8
OTBDPS
(35%)
1) NaH, TBSCl (68%)
2) PCC (70%)
HO C
2
3) EtMgBr (100%)
Br
11
HO
OH
4) TBDPSCl (89%)
5) TBAF (79%)
OTBDPS
9
6) PPh3, CBr4 (59%)
10
Each amino acid [(6), (11) and (13), (14)] was condensed to give dipeptides (12) and (15), which were condensed
again to give open-chained tetrapeptide (16). (Scheme 3)
NHBoc
Scheme 3
NHBoc
OTBDPS
OTBDPS
H
N
H
N
CO H
CO Me
2
2
EDC, HOBt
NEM (63%)
LiOH
+
6
11
O
O
N
N
EDC, HOBt
13
HCl・H N
OMe
OMe
12
NEM
(61% from 12)
NHBoc
2
1) EDC, HOBt, NEM (91%)
2) 4N HCl - AcOEt (66%)
N
+
HO C
2
N
CO Me
2
O
CO Me
H
2
16
14
OTBDPS
15
NHBoc
O
H
N
N
N
H
O
CO Me
2
O
N
OMe
17
The ring closure was successfully achieved with the use of FDPP (pentefluorophenyl diphenylphosphinate).13 (Scheme
4) Under normal conditions such as using some carbodiimide and base, ring closure did not proceed. Deprotection
of TBDPS proceeded very slowly (with 50 eq. TBAF・H2O, for one week, the starting material was still remained).

However, in the presence of powdered molecular sieves 4A to remove water in the reaction mixture, TBDPS was easily
cleaved over one day. Each diastereomer of 11, 12, 17, and 18 was inseparable.
Scheme 4
O
O
1) LiOH
2) 4N HCl - AcOEt
N
H
N
NH
17
H
N
N
3) FDPP, NEM, DMF
4) TBAF, MS4A, THF
(44% in 4 steps)
OMe
O
O
18
OH
Finally, oxidation was achieved with TPAP and NMO.14Moffat oxidation15 or Dess-Martin periodinane16 did not effect
the oxidation and only the starting material was recovered. (Scheme 5)
Scheme 5
O
O
N
TPAP, NMO,MS4A, CH2Cl2
H
N
NH
18
H
N
N
(88%)
OMe
O
O
O
Apicidin 1
The synthetic compound was identical to the natural product in all respects. (1HNMR, IR, [α]D and Rf value).17
In conclusion, the synthesis of apicidin, a cyclic tetrapeptide containing an abnormal amino acid, was achieved.
Syntheses of apicidin analogues, histone deacethylase inhibitors are now in progress, and will be discussed precisely in a
full account.
ACKNOWLEDGEMENTS
This work is supported by Ajinomoto Co. Ltd. We thank Dr. T. Tsuji for the generous gift of spectral data and authentic
sample.
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17. Apicidin
mp 186-188oC; 1H NMR (300 MHz, CDCl3): 7.56 (1H, d, J = 7.8 Hz), 7.39 (1H, d, J = 8.1 Hz), 7.00 - 7.30 (4H,
m), 6.46 (1H, d, J = 10.2 Hz), 6.42 (1H, d, J = 6 Hz), 5.06 (1H, d, J = 4.5 Hz), 4.73 (1H, t, J = 10.5 Hz), 4.18 (1H,
dt, J = 7.5, 10.0 Hz), 3.90 - 4.10 (2H, m), 4.03 (3H, s), 3.79 (1H, dd, J = 10.5, 10 Hz), 3.45 (1H, dd, J = 6.0, 15.0
Hz), 3.05 (1H, dt, J = 2.4, 13.0 Hz), 2.39 ( 2H, q, J = 7.5 Hz), 2.36 (2H, t, J = 7.5 Hz), 1.05 - 2.20 (17H, m), 1.04
(3H, t, J = 7.5 Hz), 0.92 (3H, t, J = 7.5 Hz), 0.86 (3H, d, J = 6.6 Hz); IR (film) 3271, 1713, 1694, 1667, 1616 cm-1;
HRMS (FAB, NBA) MH+ calcd for C34H50 N5O6 624.3761, found 624.3718; [α]D28 -82.6o (c0.25, CHCl3)