Studies toward the total synthesis of RP-66453

Article abstract of DOI:10.1016/S0040-4039(02)00307-6

Synthesis of a bicyclic A-B-O-C ring system of RP-66453, an neurotensine receptor antagonist, with an endo aryl-aryl and an endo aryl-aryl ether bond is described. An alternative synthetic strategy starting from the construction of functionalized B-O-C cycloisodityrosine unit is also detailed.

Full text of DOI:10.1016/S0040-4039(02)00307-6

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 43 (2002) 2577–2580
Studies toward the total synthesis of RP-66453
Sabine Boisnard and Jieping Zhu*
Institut de Chimie des Substances Naturelles, CNRS, 91198 Gif-sur-Yvette, France
Received 23 January 2002; revised 11 February 2002; accepted 13 February 2002
Abstract—Synthesis of a bicyclic A-B-O-C ring system of RP-66453, an neurotensine receptor antagonist, with an endo aryl–aryl
and an endo aryl–aryl ether bond is described. An alternative synthetic strategy starting from the construction of functionalized
B-O-C cycloisodityrosine unit is also detailed. © 2002 Elsevier Science Ltd. All rights reserved.
Isolated from an Actinomycetes strain, RP-66453 (1)
OH HO
O
C
(Fig. 1) and its semi-synthetic derivatives bind specifi-
cally to the neurotensine receptor and are claimed to be
useful for treating psychosis, Alzheimer’s and Parkin-
son’s diseases.1 Structurally, it is characterized by the
presence of (a) a 15-membered macrocycle with an endo
aryl–aryl bond (A-B), reminiscent of biphenomycin
antibiotics (2);2,3 and (b) a strained 14-membered biaryl
ether containing meta,para-cyclophane (B-O-D). Nota-
bly, the similar cycloisodityrosine unit with reversed
peptide coupling sequence has been found in the family
of anti-tumor agent, named RA series (e.g. RA-VII,
3).4,5 Although the gross structure of RP-66453 has
been determined from detailed spectroscopic studies by
Helynck and co-workers at Rhoˆne-Poulenc Rorer,6 the
absolute configuration of the five stereocenters as well
as the possible atropisomerism of the biaryl axis
remained unknown.
A
B
COOH
NH
O
H
N
N
H
H2N
O
O
1 RP 66453
HO
OH
R
O
H
N
COOH
H2N
N
H
O
OH
NH2
From a synthetic perspective, RP-66453 is a challenging
molecule because of the inherent ring strain associated
with its two-bridged macrocyclic ring systems. We have
been engaged in a program aiming at the total synthesis
and stereo-structural elucidation of RP-66453 and have
reported a synthesis of a fully functionalized AB
macrocycle.7 A recent report from Boger’s group8 deal-
ing with the preparation of cycloisodityrosine unit of
the same natural product prompted us to detail in this
letter our approaches to the A-B-O-C bicycle (4) as well
as the appropriately functionalized B-O-C macrocycle
(5).
2a biphenomycin A, R = OH
2b biphenomycin B, R = H
OMe
O
Me
O
N
NMe
O
NH
O
O
HN
Me
N
HN
O
OMe
O
Keywords: neurotensine receptor antagonist; RP 66453; macrocycle;
biaryl; biaryl ether; intramolecular SNAr reaction.
* Corresponding author. Fax: 33 1 69 07 72 47; e-mail: zhu@
icsn.cnrs-gif.fr
3 RA-VII
Figure 1.
0040-4039/02/$ - see front matter © 2002 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(02)00307-6

2578
S. Boisnard, J. Zhu / Tetrahedron Letters 43 (2002) 2577–2580
The intramolecular SNAr reaction developed in our group
has been demonstrated to be very efficient in construction
of the biaryl ether containing macrocycles.9 A number of
complex natural products have since been synthesized
using this cycloetherification methodology as a key ring
closure step.10 Therefore, we initially planned to access
the skeleton of RP-66453 by constructing A-B, then
A-B-O-C bicycle. For this purpose, the biphenyl ring
system was synthesized by a key macrolactamization
OMe HO
OH
O2N
F
A
B
C
O
H
H
N
N
BocHN
N
H
H
O
O
COOMe
6
strategy. Subsequent introduction of (L)-4-fluoro-3-nitro
K2CO3 (10 euiv.),
THF (0.002M),
molecular sieves,
50°C, 4 days
phenyl alanine methyl ester11 and functional group
manipulation led to the compound 6 ready for the second
macrocyclization studies.12 However, the cyclization of
6 was found to be particularly difficult. Dozens of reaction
conditions varying bases (K2CO3, CsF, DBU, NaH),
solvents (DMF, DMSO, MeCN, THF), additives (18-
crown ether, molecular sieves) and temperature were
examined. The only conditions that allowed us to isolate
the desired bicyclic system 4 (Scheme 1) [yield: about 15%,
MS (ESI), m/z=812 (M+Na)+, 828 (M+K)+] consist of
performing the cycloetherification of 6 in THF at 50°C
in the presence of potassium carbonate and molecular
sieves.13
O2N
OMe HO
O
COOMe
NH
O
H
N
N
H
BocHN
O
H
H
O
4
The low yield of the cycloetherification reaction made
the overall sequence via biphenyl A-B macrocycle inad-
Scheme 1.
BocHN
BocHN
PrOi
OiPr
PrOi
OiPr
MeOOC
d
b,c
MeOOC
A
B
A
9
B
OMe
OMe
AllocHN
COOBut
RHN
7 R = H
8 R = Alloc
COOH
a
BocHN
PrOi
OiPr
BocHN
F
HO
OH
3
MeOOC
4
F
NO2
MeOOC
A
B
NO2
C
e
A
B
C
OMe
H
N
OMe
H
N
AllocHN
AllocHN
O
CONHMe
11
O
CONHMe
12
BocHN
COOMe
RO
f
NO2
Y
F
O
X
O
OMe
H2N
CONHMe
N
H
CONHMe
10
AllocHN
13a R = Y = H, X = NO2; 13b R = X = H, Y = NO2,
5a R = Me, X = NO2, Y = H; 5b R = Me, X = H, Y = NO2
Scheme 2. Reagents and conditions: (a) Alloc, K2CO3, dioxane–H2O, room temperature, 96%; (b) TFA, room temperature; (c)
Boc2O, aqueous NaHCO3, dioxane, 91%; (d) EDC (1.3 equiv.), HOBt (1.3 equiv.), 10 (1.2 equiv.), Et3N (1.4 equiv.), 85%; (e) BCl3
(5 equiv.), CH2Cl2, −78°C, then Boc2O, THF, NaHCO3, room temperature, 70%; (f) K2CO3, DMF, then MeI, 60%.

S. Boisnard, J. Zhu / Tetrahedron Letters 43 (2002) 2577–2580
2579
equate for the total synthesis of this natural product.
Consequently, an alternative synthetic sequence, i.e.
construction of B-O-C cyclophane followed by forma-
tion of the biphenyl macrocycle A-B was investigated.
The synthesis started from the known biaryl bisamino
acid 7,7 synthesized by a key Suzuki coupling14 and a
chiral quaternary ammonium salt catalyzed enantio-
selective alkylation of glycine template15 (Scheme 2).
The N-allyloxycarbamate protection of the amine
under standard conditions provided 8. Removal of a
tert-butyl ester without touching the N-tert butyloxy-
carbamate under the recently described conditions
(ZnBr2, CH2Cl2) met with marginal success.16 On the
other hand, a two-step sequence involving the mild
acidic treatment of 8 followed by reintroduction of
N-Boc function produced acid 9 in excellent overall
yield. Coupling of this acid with methyl amide 10
mediated by EDC–HOBt furnished 11, which was
then transformed to phenol 12 upon selective removal
of isopropyl ether (BCl3, CH2Cl2).
24, 1995. Chem. Abstr. 1996, 124: 233154x and
124:233155y.
2. (a) Ezaki, M.; Iwami, M.; Yamashita, M.; Kohsaka,
M.; Aoiki, H.; Imanaka, H. J. Antibiot. 1985, 38, 1453–
1461; (b) Uchida, I.; Shigematsu, N.; Ezaki, M.; Hashi-
moto, M. J. Antibiot. 1985, 38, 1462–1468; (c) Uchida,
I.; Ezaki, M.; Shigematsu, N.; Hashimoto, M. J. Org.
Chem. 1985, 50, 1341–1342; (d) Kannan, J. C.;
Williams, D. H. J. Org. Chem. 1987, 52, 5435–5437; (e)
Hempel, J. C.; Brown, F. K. J. Am. Chem. Soc. 1989,
111, 7323–7327; (f) Brown, F. K.; Hempel, J. C.;
Dixon, J. S.; Amato, S.; Mueller, L.; Jeffs, P. W. J.
Am. Chem. Soc. 1989, 111, 7328–7333.
3. For synthetic studies, see: (a) Schmidt, U.; Meyer, R.;
Leitenberger, V.; Lieberknecht, A.; Griesser, H. J.
Chem. Soc., Chem. Commun. 1991, 275–277; (b) Carl-
stro¨m, A. S.; Frejd, T. J. Chem. Soc., Chem. Commun.
1991, 1216–1217; (c) Schmidt, U.; Meyer, R.; Leiten-
berger, V. Griesser, H.; Lieberknecht, A. Synthesis
1992, 1025–1030; (d) Brown, A. G.; Edwards, P. D.
Tetrahedron Lett. 1990, 31, 6581–6584; (e) Brown, A.
G.; Crimmin, M. J.; Edwards, P. D. J. Chem. Soc., PT
1 1992, 123–130; (f) Carbonnelle, A.-C.; Zhu, J. Org.
Lett. 2000, 2, 3477–3480.
In sharp contrast to the cyclization of 6, the key
size-selective ring-forming process based on the
intramolecular SNAr reaction proceeded smoothly.5,17
Thus, treatment of 12 in DMF (0.002 M) in the pres-
ence of potassium carbonate furnished the 14-member
cyclophane as a mixture of two atropisomers in a 3/1
ratio. The 15-membered para,para cyclophane resulting
from the nucleophilic attack of the ring B 4-hydroxy
function was not formed because of its inherent higher
ring strain. The instability of cyclophane 13 towards
flash chromatography purification prompted us to
examine the one-pot tandem cyclization/methylation
processes. Thus, when the cycloetherifcation of 12
under defined conditions (K2CO3, 0.002 M in DMF)
deemed complete by TLC analysis, an excess of methyl
iodide was introduced to the reaction mixture to pro-
mote the methylation of the remaining free hydroxy
function. Under these conditions, the desired
cycloisodityrosine 5 was reproducibly isolated in greater
than 60% yield.
4. For a review, see: Itokawa, H.; Takeya, K.; Hitot-
suyanagi, Y.; Morita, H. The Alkaloids; Cordell, G. A.,
Ed.; Academic Press, 1997; Vol. 49, 301–387.
5. For synthetic studies, see: (a) Inaba, T.; Umezawa, I.;
Yuasa, M.; Inoue, T.; Mihashi, S.; Itokawa, H.; Ogura,
K. J. Org. Chem. 1987, 53, 2957–2958; (b) Inoue, T.;
Inaba, T.; Umezawa, I.; Yuasa, M.; Itokawa, H.;
Ogura, K.; Komatsu, K.; Hara, H.; Hoshino, O. Chem.
Pharm. Bull. 1995, 43, 1325–1335; (c) Boger, D. L.;
Patane, M. A.; Zhou, J. J. Am. Chem. Soc. 1994, 116,
8544–8556; (d) Boger, D. L. Zhou, J.; Borzilleri, R. M.;
Nukui, S.; Castle, S. L. J. Org. Chem. 1997, 62, 2054–
2069; (e) Bigot, A.; Tran Huu Dau, E.; Zhu, J. J. Org.
Chem. 1999, 64, 6283–6296 and references cited therein.
6. Helynck, G.; Dubertret, C.; Frechet, D.; Leboul, J. J.
Antibiot. 1998, 51, 512–514.
In conclusion, we reported two synthetic approaches
to the bicyclic ring system of RP-66453. The higher
yield obtained in the cyclization of 12 relative to that
of 6 clearly indicated the appropriate direction to be
pursued. Further work is in progress and will be
reported in due course.
7. Boisnard, S.; Carbonnelle, A.-C.; Zhu, J. Org. Lett.
2001, 3, 2061–2064.
8. Krenitsky, P. J.; Boger, D. L. Tetrahedron Lett. 2002,
43, 407–410.
9. Zhu, J. Synlett 1997, 133–144.
10. (a) Rama, R. A. V.; Gurjar, M. K.; Reddy, K. L.;
Rao, A. S. Chem. Rev. 1995, 95, 2135–2167; (b)
Burgess, K.; Lim, D.; Martinez, C. I. Angew. Chem.,
Int. Ed. Engl. 1996, 35, 1077–1078; (c) Nicolaou, K. C.;
Boddy, C. N. C.; Bra¨se, S.; Winssinger, N. Angew.
Chem., Int. Ed. Engl. 1999, 38, 2096–2152; (d) Sawyer,
J. S. Tetrahedron 2000, 56, 5045–5065.
11. Vergne, C.; Bois-Choussy, M.; Ouazzani, J.; Beugel-
mans, R.; Zhu, J. Tetrahedron: Asymmetry 1997, 8,
391–398.
Acknowledgements
We thank CNRS for financial support. A doctoral
fellowship from this institute to S. Boisnard is grate-
fully acknowledged. We thank Professor Potier for his
interest in this work.
12. To proceed with the synthesis, all asymmetric carbon
centers were arbitrarily assigned as S configuration.
13. Using molecular sieves as additive is essential to the
success of this cyclization; Boisnard, S. Ph.D. disserta-
tion, Universite´ Paris Sud, December 2001.
References
1. Clerc, F. F.; Dubroeucq, M. C.; Helynck, G.; Leboul,
J.; Martin, J. P. FR 2720066 (WO 9532218) novembre

2580
S. Boisnard, J. Zhu / Tetrahedron Letters 43 (2002) 2577–2580
Tetrahedron Lett. 1997, 38, 8595–8598.
16. Wu, Y.-Q.; Limburg, D. C.; Wilkinson, D. E.; Vaal, M.
J.; Hamilton, G. S. Tetrahedron Lett. 2000, 41, 2847–
2849.
14. Suzuki, A. In Metal-catalyzed cross-coupling reactions;
Diederich, F.; Stang, P. J., Eds.; Wiley-VCH: Weinheim,
1998; pp. 49–97.
15. (a) Corey, E. J.; Xu, F.; Noe, M. C. J. Am. Chem. Soc.
1997, 119, 12414–12415; (b) Lygo, B.; Wainwright, P. G.
17. Bigot, A.; Zhu, J. Tetrahedron Lett. 1998, 39, 551–554.