An efficient total synthesis of K-13, a non-competitive inhibitor of ACE I

Article abstract of DOI:10.1016/S0040-4039(00)00695-X

An efficient synthesis of K-13, a non-competitive inhibitor of ACE I, with an endo biaryl ether bond is described. The key cycloetherification reaction of linear tripeptide 10 gave 17-membered macrocycle in quantitative yield. (C) 2000 Elsevier Science Ltd.

Full text of DOI:10.1016/S0040-4039(00)00695-X

Tetrahedron Letters 41 (2000) 4573±4577
An ecient total synthesis of K-13, a non-competitive
inhibitor of ACE I
Antony Bigot, Michele Bois-Choussy and Jieping Zhu*
Institut de Chimie des Substances Naturelles, CNRS, 91198 Gif-sur-Yvette, France
Received 23 March 2000; accepted 21 April 2000
Abstract
An ecient synthesis of K-13, a non-competitive inhibitor of ACE I, with an endo biaryl ether bond is
described. The key cycloetheri®cation reaction of linear tripeptide 10 gave 17-membered macrocycle in
quantitative yield. # 2000 Elsevier Science Ltd. All rights reserved.
K-13 (1, Fig. 1), a 17-membered cyclopeptide with an endo aryl±aryl ether bond, has been isolated
from Micromonospora halophytica ssp. exilisia K-13.1 It is a non-competitive inhibitor of angio-
tensin I converting enzyme and weak inhibitor of aminopeptidase B.2 The characteristic feature
of this cyclopeptide is the presence of the isodityrosine unit (2) which has been found in several
other biologically important natural products such as OF4949 I±IV,3 piperazinomycin4 and a
series of bicyclic hexapeptide antitumor-antibiotics RA I±XIV.5 Total synthesis of K-13 has been
reported by a number of research groups, most of them employing a macrolactamization strategy
through the preparation of a key isodityrosine intermediate (2).6 The synthesis of (2) is never-
theless troublesome and requires linear multistep sequence since direct coupling of two tyrosine
unit proved to be dicult.7 On the other hand, synthesis of K-13 via cycloetheri®cation reaction
has also been developed which appears to be more convergent as the cyclization precursor can be
prepared in only two conventional peptide coupling steps.8 Indeed, three such syntheses have
been accomplished using thallium trinitrate promoted oxidative cyclization and intramolecular
SNAr reaction, respectively.9 11
The nitro group played a pivotal role in our SNAr based cycloetheri®cation methodology.12 Its
dual role as an activator for the cyclization and as a handle for post-manipulation has been fully
demonstrated. In our previous synthesis of K-13 based on this strategy,10 the nitro was used as a
surrogate of hydroxy function (Scheme 1, route a). Although the cyclization worked eciently, its
conversion to hydroxylated derivative via amino intermediate was less than satisfactory in terms
of reproducibility. Based on the consideration that hydro-dediazoniation works better than
* Corresponding author. Fax: 33 1 69 07 72 47; e-mail: zhu@icsn.cnrs-gif.fr
0040-4039/00/$ - see front matter # 2000 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(00)00695-X

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Figure 1.
hydroxylation of diazonium salt,13 an alternative synthesis of K-13 using NO2 as proton surrogate
(Scheme 1, route b) was investigated and is the subject of the present communication.
Coupling of l-methyl 4-methoxyphenyl alanate (5) with l-N-Boc 4-¯uoro-3-nitrophenylalanine
(6)14 gave the dipeptide 7 which after hydrolysis of methyl ester, was reacted with l-methyl
4-methoxy-3-isopropyloxyphenyl alanate (8)13 to a€ord the tripeptide 9 (Scheme 2). Deprotection
of isopropyloxy ether with BCl3 caused partial removal of the N-Boc moiety. However, treatment
Scheme 1.
Scheme 2. Reagents and conditions: (a) EDC, HOBt, 85%; (b) (i) LiOH, THF±H2O; (ii) EDC, HOBt, methyl 3-methoxy-
4-isopropyloxyphenyl alanate (8), 90%; (c) (i) BCl3, (ii) Boc2O, 95%; (d) K2CO3 (3 equiv.), DMSO, 0.01 M, rt, 99%

4575
of the crude product with Boc2O under standard conditions reinstalled the N-Boc function, pro-
viding 10 in excellent yield. Treatment of tripeptide 10 with K2CO3 in DMF at room temperature
for 24 h did not a€ord any cyclic compound and only starting material was recovered. However,
by simply switching to the more polar solvent DMSO,13,15 the cyclization occurred smoothly to
provide the 17-membered macrocycle as a mixture of two atropoisomers 11 and 12 (ratio: 1:1) in
quantitative yield.
Mild acid hydrolysis of the tert-butyloxycarbonyl carbamate (Boc) followed by acetylation and
reduction of the nitro group (Pd/C, H2, MeOH, HBF4) provided the amine 13 (Scheme 3).
Hydrogenolysis must be carried out in an acidic media in order to avoid decomposition of 13
and HBF4 was selected in order to keep the same counterion as in the subsequent diazotization
.
step. The diazonium salt, generated in organic solvent under Cohen's conditions (BF3 OEt2,
tBuONO),16 was then reduced with FeSO4 in DMF17 to a€ord the known compound 146b in 85%
overall yield. Demethylation of 14 with AlBr3 in the presence of EtSH6b,18 a€orded K-13 (1). The
same synthetic sequence applied to compound 12 also a€orded K-13 identical with that obtained
from 11 with equal eciency, thus ®rmly establishing the atropoisomerism of compounds 11 and
12. The physical and spectroscopic data of our synthetic material are identical with those of the
natural product.19
Scheme 3. Reagents and conditions: (a) (i) TFA, rt; (ii) Acꢀ2O, NaHCO3, THF, 100%; (b) Pd/C, H2, MeOH, few drops
t
.
of HBF4, 85%; (c) BuONO, BF3 OEt2, CH2Cl2, ^10 to 0 C; (d) FeSO4, degassed DMF, 85%; (e) AlBr3, EtSH, 65%
Finally, cyclization of 15 containing two potentially nucleophilic hydroxy functions gave only
the 17-membered m,p-cyclophane as a mixture of two atropoisomers without the concomitant
formation of 18-membered p,p-cyclophane (Scheme 4).20 A similar ring size selective cyclization
has been observed in our synthesis of cycloisodityrosine.13 The merit of this approach is that
commercially available l-dopamine can be used instead of a side chain selectively protected
dopamine derivative 8 whose synthesis requires ®ve steps in the, until now, shortest synthesis.21
Scheme 4. aK2CO3 (4 equiv.), DMSO, 0.002 M, rt, molecular seive 3 A, 45%

4576
The total synthesis of K-13 reported herein is one of the most ecient syntheses known to date
in terms of the overall yield and the convergency.
Acknowledgements
A doctoral fellowship from the MRES to A. Bigot is gratefully acknowledged.
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19. Synthetic K-13 (1): mp: 265±270ꢀC dec. (Ref. 2 265±270ꢀC dec.); [ꢀ]D=^6.0ꢀ (c 0.40, MeOH; Ref. 6b [ꢀ]D=^6.5ꢀ,
c 0.46, MeOH; natural:2 [ꢀ]D=^3.4ꢀ, c 0.60, MeOH; MS (FAB thioglycerol): 548 (M+H); H NMR (300 MHz,
1
CD3OD) ꢁ 2.03 (s, 3H), 2.78 (t, J=12.1 Hz, 2H), 2.82±2.98 (m, 2H), 3.01 (dd, J=5.1, 12.3 Hz, 1H), 3.18 (m, 1H),
4.10±4.20 (m, 2H), 4.44 (dd, J=5.0, 11.6 Hz, 1H), 6.35 (d, J=1.9 Hz, 1H), 6.59 (d, J=8.4 Hz, 2H), 6.64 (dd,
J=2.5, 8.3 Hz, 1H), 6.73 (dd, J=1.9, 8.2 Hz, 1H), 6.81 (d, J=8.2 Hz, 1H), 6.95 (m, 3H), 7.03 (dd, J=2.5, 8.3 Hz,

4577
1H), 7.29 (dd, J=2.1, 8.2 Hz, 1H); 13C NMR (75 MHz, CD3OD) ꢁ 22.4, 37.3, 38.7, 39.1, 56.0, 56.1, 57.4, 115.9
(2C), 117.3, 119.1, 121.1, 122.3, 125.5, 128.3, 131.2, 131.4, 132.0 (2C), 132.1, 132.9, 147.2, 147.9, 157.0, 158.1,
171.1, 172.2, 172.9, 178.1.
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