Studies on the total synthesis of RP 66453: synthesis of fully functionalized 15-membered biaryl-containing macrocycle.

Article abstract of DOI:10.1021/ol016021v

[structure: see text] Palladium-catalyzed Suzuki cross-coupling, Corey's enantioselective alkylation of glycine template, and macrolactamization are key steps in an efficient synthesis of the 15-membered macrocycle 2.

Full text of DOI:10.1021/ol016021v

ORGANIC
LETTERS
2001
Vol. 3, No. 13
2061-2064
Studies on the Total Synthesis of RP
66453: Synthesis of Fully
Functionalized 15-Membered
Biaryl-Containing Macrocycle
Sabine Boisnard, Anny-Claude Carbonnelle, and Jieping Zhu*
Institut de Chimie des Substances Naturelles, CNRS,
91198 Gif-sur-YVette Cedex, France
zhu@icsn.cnrs-gif.fr
Received April 23, 2001
ABSTRACT
Palladium-catalyzed Suzuki cross-coupling, Corey’s enantioselective alkylation of glycine template, and macrolactamization are key steps in
an efficient synthesis of the 15-membered macrocycle 2.
RP-66453 (1, Figure 1)), a novel secondary metabolite, has
been isolated from an Actinomycetes strain by Helynck and
centers as well as the possible atropisomerism of the biaryl
axis remains unknown at the present time. This new bicyclic
compound binds very specifically to the neurotensine recep-
tor from guine-pig (IC50 ) 30 µg/mL). Subsequent structural
modification has led to the discovery of potent neurotensin
antagonists, claimed to be useful for treating psychose,
Alzheimer’s, and Parkinson’s disease, etc.2
Structurally RP 66453 belongs to a growing family of
complex macrocycles that includes the vancomycin class
antibiotics,3 chloropeptin4 and kistamine5 to name a few. The
characteristic structural feature of these natural products is
the presence of macrocycles with both endo aryl-aryl and
endo aryl-aryl ether bonds. The complex molecular archi-
tecture and important bioactivities have made them attractive
yet challenging synthetic targets. Indeed, these molecules
Figure 1.
(2) Clerc, F. F.; Dubroeucq, M. C.; Helynck, G.; Leboul, J.; Martin, J.
P. FR 2720066, November 24, 1995.
co-wokers at Rhoˆne-Poulenc Rorer.1 The plane structure has
been deduced from detailed spectroscopic studies. However,
the absolute configuration of the five asymmetric carbon
(3) (a) Williams, D. H.; Bardsley, B. Angew. Chem., Int. Ed. 1999, 38,
1173-1193. (b) Zhu, J. Exp. Opin. Ther. Pat. 1999, 9, 1005-1019.
(4) Matsuzaki, K.; Ikeda, H.; Ogino, T.; Matsumoto, A.; Woodruff, H.
B.; Tanaka, H.; Omura, S. J. Antibiot. 1994, 47, 1173-1174.
(5) Naruse, N.; Oka, M.; Konishi, M.; Oki, T. J. Antibiot. 1993, 46,
1812-1818.
(1) Helynck, G.; Dubertret, C.; Frechet, D.; Leboul, J. J. Antibiot. 1998,
51, 512-514.
10.1021/ol016021v CCC: $20.00 © 2001 American Chemical Society
Published on Web 05/24/2001

have provided impetus for the development of numerous new
synthetic methodologies.6
To the best of our knowledge, no synthetic work on RP
66453 has been reported.7 Scheme 1 summarizes one of the
Scheme 2a
Scheme 1. Retrosynthetic Analysis
a Reaction conditions: (a) Br2, acetic acid, 90%; (b) AlCl3, Py,
CH2Cl2, 98%; (c) K2CO3, iPrBr, DMSO, 83%; (d) ethylene glycol,
benzene, pTsOH, Dean-Stark, 91%; (e) (i) BuLi, B(OMe)3, THF,
-78 °C; (ii) 3 N HCl, 67%.
as an isopropyl ether was based on our previous observation
that it can be easily removed from the complex molecular
structure under mild conditions.11 Lithium-bromide ex-
change followed by addition of trimethyl borate provided,
after acidic workup and flash chromatography, the pure
arylboric acid 6 in 67% yield.
A palladium-catalyzed Suzuki cross-coupling reaction12
between methyl L-N-Boc-3-iodo-4-methoxyphenyl alanate
1113 and 6 under standard conditions gave the biaryl 12 in
higher than 85% yield. The cross-coupling of in situ
generated aryl borate with 11 also produced the same
compound, but with less efficiency.14 Reduction of the
aldehyde, mesylation of the resulting benzyl alcohol, and
Finkelstein bromination gave the benzyl bromide 13 in 56%
overall yield (Scheme 3). It was observed that the amino
ester function of 12 was unusually prone to reduction. Thus,
treatment of 12 with NaBH4 in MeOH led to the formation
of a diol as a major byproduct even at -78 °C. However,
this side reaction was avoided by simply changing the solvent
from MeOH to THF. Following Corey’s procedure,15 alky-
lation of N-(diphenylmethylene)glycine tert-butyl ester with
bromide 13 in the presence of a catalytic amount of O(9)-
allyl-N-(9-anthracenylmethyl)cinchonidinium bromide (14,
0.1 equiv) produced, after chemoselective hydrolysis of the
imine function (THF, aqueous citric acid, SiO2), the orthogo-
nally protected biaryl bisamino acid derivative 4 in 65%
yield. Only one diastereomer was detectable from NMR
synthetic strategies being pursued in our laboratory. In a
forward sense, a sequence of macrolactamization8 and
intramolecular SNAr reaction9 is projected for the assemblage
of A-B and B-O-C macrocycles, respectively. To proceed
with the synthesis, all asymmetric carbon centers are
arbitrarily assigned as S configuration, keeping in mind that
the convergent approach would allow one to easily modulate
the stereochemical issue.
One of the building blocks, arylboric acid 6, was synthe-
sized as shown in Scheme 2. Bromination of vanillin in acetic
acid gave regioselectively 5-bromovanillin in excellent
yield.10 Two-step protective group interchange gave, after
acetal formation, the bromide 10. The protection of phenol
(10) Bromination of 3,4-dihydroxybenzaldehyde gave the wrong regioi-
somer. Anhoury, M. L.; Crooy, P.; De Neys, R.; Eliaers, J. J. Chem. Soc.,
Perkin Trans. I 1974, 1015-1017.
(6) For a review on vancomycin synthesis, see: Nicolaou, K. C.; Boddy,
C. N. C.; Bra¨se, S.; Winssinger, N. Angew. Chem., Int. Ed. 1999, 38, 2096-
2152.
(7) For an approach to the total synthesis of Chloropeptin, see: (a)
Carbonnelle, A.; Gonzalez-Zamora, G.; Beugelmans, R.; Roussi, G.
Tetrahedron Lett. 1998, 39, 4471-4472. (b) Elder, A. M.; Rich, D. H. Org.
Lett. 1999, 1, 1443-1446.
(8) For an alternative strategy involving the formation of an aryl-aryl
bond as a key cyclizaion step, see refs 6, 7, and the following. (a) Li, W.;
Burgess, K. Tetrahedron Lett. 1999, 40, 6527-6530. (b) Carbonnelle, A.-
C.; Zhu, J. Org. Lett. 2000, 2, 3477-3480.
(9) (a) Zhu, J. Synlett 1997, 133-144. (b) Burgess, K.; Lim, D.; Martinez,
C. I. Angew. Chem., Int. Ed. 1996, 35, 1077-1078. (c) Sawyer, J. S.
Tetrahedron 2000, 56, 5045-5065.
(11) Bois-Choussy, M.; Vergne, C.; Neuville, L.; Beugelmans, R.; Zhu,
J. Tetrahedron Lett. 1997, 38, 5795-5798.
(12) Suzuki, A. In Metal-catalyzed cross-coupling reactions; Diederich,
F., Stang, P. J., Eds.; Wiley-VCH: Weinheim, 1998; pp 49-97.
(13) Prepared in four conventional steps from L-tyrosine; for iodination
procedure, see: Chiarello, J.; Joullie´, M. M. Synth. Commun. 1988, 18,
2211-2223.
(14) Maddaford, S. P.; Keay, B. A. J. Org. Chem. 1994, 59, 6501-
6503.
(15) Corey, E. J.; Xu, F.; Noe, M. C. J. Am. Chem. Soc. 1997, 119,
12414-12415. See also: Lygo, B.; Wainwright, P. G. Tetrahedron Lett.
1997, 38, 8595-8598.
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Org. Lett., Vol. 3, No. 13, 2001

With compound 3 in hand, we next turned our efforts to
the elaboration of the 14-membered macrocycle with an endo
aryl-aryl ether bond. Treatment of compound 3 with TFA
followed by Boc2O under standard conditions furnished the
acid 20, which was coupled with methyl L-4-fluoro-3-
nitrophenylalanine19 to provide tetrapeptide 21 in 92% yield
(Scheme 4). Selective hydrolysis of tert-butyl ester in the
Scheme 3a
Scheme 4a
a Reaction conditions: (a) TFA; (b) Boc2O, dioxane, aqueous
NaHCO3, 98%; (c) EDC, HOBt, L-methyl 4-fluoro-3-nitrophenyl
alanate, 92%; (d) BCl3, CH2Cl2, 82%.
a Reaction conditions: (a) Pd(PPh3)4, aqueous Na2CO3, DME,
90 °C, 85%; (b) NaBH4, THF, -78 °C, 80%; (c) MsCl, Et3N,
CH2Cl2; (d) LiBr, Me2CO, 69%; (e) CsOH‚H2O 14, Ph2CdNCH2-
COOBut; (f) 15% aqueous citric acid, THF, SiO2, 65%; (g) EDC,
HOBt 15, 90%; (h) LiOH, THF-H2O; (i) EDC, C6F5OH, CH2Cl2;
(j) Pd/C, cyclohexene, tert-butyl alcohol, Hunig’s base, 95 °C, 70%.
presence of the N-Boc function using ZnBr2 was found to
be sluggish.20 Finally, removal of the isopropyl ether with
BCl3 provided compound 2, a precursor for investigating the
intramolecular SNAr reaction. While the 1H NMR spectrum
of compound 21 showed two sets of peaks at room
temperature that coalesced when it was recorded at 333 K
in DMSO-d6, that of compound 2 displayed only one set of
peaks at room temperature. This result indicated that the
energy barrier of atropisomerism in such a ring system is
relatively low in accord with our previous observation.8b
The cyclization of 2 was performed by varying the base
(NaH, K2CO3, K2CO3/crown ether 18-C-6, CsF, K2CO3/
CaCO3, DBU], the solvent (THF, DMF, DMSO), and the
temperature (0 to 40 °C). Unfortunately, none of these
conditions allowed us to isolate the desired bicyclic com-
pound. A degradation of starting material was observed in
most of the reaction conditions examined. The B-O-C
macrocycle is structurally reminiscent of the cycloisodi-
tyrosine unit found in the RA series whose synthesis has
been a subject of many recent efforts.21,22 A total synthesis
spectroscopy. Since the existing chiral center is far away
from the reaction site, it is reasonable to assume that the
newly created asymmetric carbon is S configured according
to Corey’s empiric model. Coupling of 4 with (2S,3S) N-Cbz
isoleucine (15)16 mediated by EDC and HOBt provided
compound 16 in 90% yield. The methyl ester on the A ring
was selectively converted into the activated ester 18 via
saponification and esterification with pentafluorophenol. One-
pot hydrogenolysis of the N-Cbz function and macrolactam-
ization were best realized under transfer hydrogenation
conditions. Thus, heating a solution of 18 in tert-BuOH in
the presence of Pd/C, cyclohexene, and Hunig’s base
provided the 15-membered biaryl macrocycle 3 in 70% yield
(three steps from 16).17 Using tert-BuOH instead of MeOH
or EtOH as the solvent is essential in order to avoid the
competitive trans-esterification. Cyclization of seco-acid 19
mediated by HATU18 has also been examined, leading to
macrocycle 3 in only 27% yield.
(18) Carpino, L. A. J. Am. Chem. Soc. 1993, 115, 4397-4398.
(19) Vergne, C.; Bois-Choussy, M.; Ouazzani, J.; Beugelmans, R.; Zhu,
J. Tetrahedron: Asymmetry 1997, 8, 391-398
(20) Wu, Y. Q.; Limburg, D. C.; Wilkinson, D. E.; Vaal, M. J.; Hamilton,
G. S. Tetrahedron Lett. 2000, 41, 2847-2849.
(16) (2S,3S) isoleucine is commercially available.
(17) (a) Shcmidt, U.; Za¨h, M.; Lieberknecht, A. J. Chem. Soc., Chem.
Commun. 1991, 1002-1004. (b) Heffner, R. J.; Jiang, J.; Joullie´, M. M. J.
Am. Chem. Soc. 1992, 114, 10181-10189.
(21) For reviews, see: (a) Rama, R. A. V.; Gurjar, M. K.; Reddy, K. L.;
Rao, A. S. Chem. ReV. 1995, 95, 2135-2167. (b) Yamamura, S.; Nishiyama,
S. J. Synth. Org. Chem. Jpn. 1997, 55, 1029-1039.
Org. Lett., Vol. 3, No. 13, 2001
2063

functionalized A-B biaryl macrocycle 2 of RP-66453
featuring a key macrolactamization step. An alternative ring
construction sequence, i.e., C-O-B and then C-O-B-
A-A, is being actively pursued in our group.
Scheme 5
Acknowledgment. Financial support from this institute
in the form of doctoral fellowships to S. Boisnard is
gratefully acknowledged. We thank Professor P. Potier for
his interest in this work.
Supporting Information Available: Full experimental
details and characterization data for compounds 2-4, 6,
8-10, 12, 13, 16-18, 20, and 21. This material is available
free of charge via the Intenet at http://pubs.acs.org.
OL016021V
of RA-VII featuring a key cyclization of dipeptide 22 to
cycloisodityrosine 23 has been reported by our laboratory
(Scheme 5).23 In view of this result, we tentatively attributed
the failure of the present cyclization to the unfavorable
conformational property of the compound 2.
(22) (a) Boger, D. L.; Yohannes, D.; Zhou, J. Patane, M. A. J. Am. Chem.
Soc. 1993, 115, 3420-3430. (b) Boger, D. L.; Zhou, J. Borzilleri, R. M.;
Nukui, S.; Castle, S. L. J. Org. Chem. 1997, 62, 2054-2069. (c) 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.
(23) Bigot, A.; Tran Huu Dau, M. E.; Zhu, J. J. Org. Chem. 1999, 64,
6283-6296.
In conclusion, we have reported a synthesis of the fully
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Org. Lett., Vol. 3, No. 13, 2001