Synthesis of diastereomers of complestatin and chloropeptin I: Substrate-dependent atropstereoselectivity of the intramolecular Suzuki-Miyaura reaction

Article abstract of DOI:10.1002/anie.200800599

See the effect of C: Atropisomers as well as C_C2 epimers of complestatin and chloropeptin I (see picture) are readily synthesized through an intramolecular S_NAr reaction and the Suzuki-Miyaura reaction. The absolute configuration of

Full text of DOI:10.1002/anie.200800599

Angewandte
Chemie
DOI: 10.1002/anie.200800599
Asymmetric Synthesis
Synthesis of Diastereomers of Complestatin and Chloropeptin I:
Substrate-Dependent Atropstereoselectivity of the Intramolecular
Suzuki–Miyaura Reaction**
Yanxing Jia, Mich›le Bois-Choussy, and Jieping Zhu*
Complestatin (1)[1] and chloropeptin I (2),[2] isolated from
Streptomyces lavendulae and Streptomyces sp. WK-3419,
and chloropeptin differ only in the position of the phenyl–
indole ring junction, and it has been demonstrated that the
former is readily isomerized to the latter under mildly acidic
conditions.[6] These compounds belong to a growing family of
vancomycin-type polymacrocyclopeptides with unusual endo
aryl–aryl ether and endo biaryl linkages.[7] The presence of
racemization-prone chlorinated arylglycines and the inherent
difficulties associated with the construction of strained
macrocycles made the synthesis of these natural products
highly challenging. Although a number of groups have been
involved in the total-synthesis exercises,[8] only the group of
Snapper and Hoveyda has accomplished the total synthesis of
chloropeptin I (2)[9] and an atropisomer of complestatin
named isocomplestatin (3; Scheme 1).[10] These total synthe-
ses have also allowed Snapper, Hoveyda, and co-workers to
assign the aR configuration to the axial chirality of natural
products 1 and 2.
We have been interested in this type of natural prod-
uct[11,12] and have recently reported an atropselective syn-
thesis of the DEFG ring of complestatin by way of an
intramolecular Suzuki–Miyaura reaction.[13] As a continua-
tion of this work, we describe herein the syntheses of two
atropisomers of the natural products, isocomplestatin (3) and
isochloropeptin (5), as well as two other CC2 epimers, 4 and 6
(Scheme 1). The intramolecular SNAr[14] and Suzuki–
Miyaura[15] reactions are the two key steps used for the
construction of macrocycles BCD and DEF, respectively. We
observe that the atropselectivity in the formation of the DEF
ring is highly sensitive to both the aryl–aryl bond connectivity
and the stereogenicity of the amino acid constituents. A
change in the absolute configuration of amino acid C
invariably switches the sense of atropselectivity of the
subsequent biaryl-forming process.
The synthesis of the BCD ring is summarized in Scheme 2.
Coupling of (S)-N-methyl-4-fluoro-3-nitrophenylalanine
methyl ester (7)[16] with (R)-N-Boc-3,5-dichloro-4-hydroxy-
phenylglycine (8)[17] turned out to be particularly challenging
due to the low nucleophilicity of 7 and the high sensitivity of 8
towards epimerization. Under optimized conditions (DEPBT,
NaHCO3, 08C to room temperature), the dipeptide (9) was
isolated in 54% yield, together with its CC2 epimer (18%).
Fortuitously, the desired dipeptide 9 can be purified from a
mixture of diastereomers by crystallization in a solution of
CH2Cl2/heptane, and the stereochemical integrity of the
product was confirmed by X-ray analysis (see the Supporting
Information). Removal of the N-Boc function (TFA, CH2Cl2)
afforded the TFA salt of the amine, which was coupled
directly with (R)-N-Boc-3-iodo-4,5-dihydroxyphenylglycine
respectively, display potent activities against HIV-1-induced
cytopathicity and syncyctium formation in CD-4 lymphocytes
and inhibit HIV replication by inhibition of gp120–CD-4
binding at a low-micromolar level (IC50 = 3.3 and 2.0 mm,
respectively).[3] The absolute configurations of the amino acid
constituents of 1[4] and 2[5] were elucidated through detailed
NMR, computational, and degradation studies. Complestatin
[*] Dr. Y. Jia,[+] Dr. M. Bois-Choussy, Dr. J. Zhu
Institut de Chimie des Substances Naturelles, CNRS
91198 Gif-sur-Yvette Cedex (France)
Fax: (+33)1-6907-7247
E-mail: zhu@icsn.cnrs-gif.fr
Homepage: http://www.icsn.cnrs-gif.fr/article.php3?id_arti-
cle=122
[+] Current address:
State Key Laboratory of Natural and Biomimetic Drugs
School of Pharmaceutical Sciences, Peking University
38 Xue Yuan Road, Beijing 100083 (P.R. of China)
[**] Financial support from CNRS and ICSN is gratefully acknowledged.
Y.J. thanks ICSN for a postdoctoral fellowship.
Supporting information for this article (including experimental
procedures, product characterization, and the 1H and 13C NMR
spectra) is available on the WWW under http://www.angewand-
te.org or from the author.
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Scheme 2. Synthesis of the BCD ring and its epimers. a) DEPBT,
NaHCO3, THF, 08C ! RT, 12 h, 54%; b) 1. TFA, CH2Cl2; 2. (R)-10,
HATU, NaHCO3, THF/DMF (3:1), 71%; c) K2CO3, DMSO, RT, 36 h,
72%. Boc: tert-butoxycarbonyl; DEPBT: 3-(diethyloxyphosphoryloxy)-
1,2,3-benzotriazin-4(3H)-one; DMF: N,N-dimethylformamide; DMSO:
dimethylsulfoxide; HATU: O-(7-azabenzotriazol-1-yl)-N,N,N’,N’-tetra-
methyluronium hexafluorophosphate; TFA: trifluoroacetic acid; THF:
tetrahydrofuran.
Scheme 1. Diastereomers of complestatin and chloropeptin I.
(10)[13] to afford the tripeptide 11 in 71% yield. The key
cyclization was realized in a degassed DMSO solution of 11
(c = 0.003m, room temperature) in the presence of potassium
carbonate and 4 Š molecular sieves to provide the desired 16-
membered meta,para-cyclophane 12a (72%) as a single
atropisomer. The cyclization is regioselective since the alter-
native 17-membered and 14-membered para,para-cyclo-
phanes, resulting from nucleophilic attack of the other two
hydroxy groups on the fluoro nitro aromatic system, were not
observed.[18] By following the same synthetic route as that
indicated for (SRR)-12a, the diastereomeric macrocycles
(SRS)-12b, (SSS)-12c, and (SSR)-12d were synthesized
individually by using (S)-8 and/or (S)-10 as coupling partners
of (S)-7. Analysis of the cyclization products indicated
conclusively that no epimerization occurred during the intra-
molecular SNAr reaction. Although of no consequence, the
planar chirality of 12a–12c was determined to be pS, while
that of 12d was assigned as pR on the basis of NOE studies.
Reductive removal of the nitro group from 12a via the
aniline and then diazonium intermediates provided com-
pound 13 in 80% overall yield (Scheme 3). Hydrolysis of the
methyl ester of 13 under basic conditions (LiOH, THF/H2O)
caused extensive epimerization. However, prolonged heating
(3 days) of a 1,2-dichloroethane solution of 13 in the presence
of trimethyltin hydroxide (TMTH) afforded the desired
carboxylic acid 14 in essentially quantitative yield without
epimerization.[19] Coupling of 14 with (R)-4-hydroxyphenyl-
glycine methyl ester (15) furnished the tetrapeptide 16.
Removal of the N-Boc group followed by coupling of the
resulting amine with (R)-8 provided the pentapeptide 17,
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Scheme 3. Elaboration of the BCD ring into the ABCDE fragment. a) SnCl2·2H2O, EtOH, 608C; b) H3PO2, NaNO2, THF/H2O (3:1), 80%;
c) Me3SnOH, 1,2-DCE, 808C; d) 15, EDC, HOAt, NaHCO3, THF, 59% for 16; 70% for 21; e) 7% conc. HCl in MeCN; f) (R)-8, HATU, lutidine,
THF/CH2Cl2 3:1, 73% for 17; 90% for 22; g) TBSCl, imidazole, DMF. 1,2-DCE=1,2-dichloroethane; EDC=N-(3-dimethylaminopropyl)-N’-
ethylcarbodiimide hydrochloride; HOAt=1-hydroxy-7-azabenzotriazole; TBS=tert-butyldimethylsilyl; P=protecting group.
which after N-deprotection afforded the free amine 18, the
spectral data for which are in accord with those described in
the literature.[9]
conformer was detected on the NMR timescale for com-
pounds 16–18 and 21–24.
The completion of the synthesis of bismacrocycle 3 is
depicted in Scheme 4. A HATU-mediated coupling of 23 with
tryptophan derivative 25[20] afforded hexapeptide 26, which
underwent a palladium-promoted intramolecular Suzuki–
Miyaura coupling to furnish the bismacrocycle 27 in 52%
yield. Removal of the TBS protective group then afforded a
compound for which the spectral data were identical in all
respects with those described for isocomplestatin methyl ester
3.[10] Alternatively, cyclization of free phenol 28, obtained by
coupling of 18 with 25, directly furnished macrocycle 3 in 66%
yield. Thus, the Suzuki–Miyaura cyclization afforded the aS
atropisomer regardless the phenol-protecting groups. The
preferential formation of the nonnatural atropisomer in the
Suzuki–Miyaura reaction is in accord with the observations of
Snapper, Hoveyda, and co-workers.[10] The same atropselec-
tivity has also been observed in our synthesis of RP-66453, a
structurally related bismacrocyclic natural product.[21]
Attempted thermal atropisomerization of 3 failed to provide
the natural atropisomer.
Since we have previously shown that the protection of the
phenol group can influence the atropselectivity of the intra-
molecular Suzuki–Miyaura reaction,[13] we decided to intro-
duce a TBS group onto the phenol rings; this was realized
under standard conditions. Hydrolysis of 19 took place rapidly
to afford compound 20 in 89% yield (TMTH, CH2ClCH2Cl,
808C, 12 h). The TBS ether of amino acid C was concurrently
removed, whereas that of ring D survived under these
conditions. Compound 20 was converted into pentapeptide
23 by the same sequence of reactions as that described for the
preparation of 18.
By applying the same synthetic sequence, the pentapep-
tide (RSSRR)-24 was also synthesized from macrocycle
(SSR)-12d. It is worth noting that compounds 18, 23, and 24
have different conformational preferences in solution. The
N-methyl amide bond between amino acids B and C of 18 and
23 adopted the cis conformation, as found in the natural
product (NOE: HB2/HC2). However, that of 24 adopted a trans
conformation, as evidenced by the characteristic NOE cross-
peaks between the NMe and HC2 signals. The downfield shift
of the HB2 signal for compound 24 (d = 5.64 versus 4.91 ppm
for 23) is also in accord with the proposed rotamer structure.
As observed previously, the attachment of amino acid A
locked the conformation of macrocyle BCD, and a single
Smith and co-workers[8e] have demonstrated that the
stereogenicities of amino acids C and D influenced the
conformational preference of the BCD macrocycle. We
surmised that such conformational change should, in turn,
influence the atropselectivity of the subsequent macrocycli-
zation.[22] To verify this hypothesis, we synthesized hexapep-
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Scheme 4. Synthesis of isocomplestatin methyl ester 3. a) HATU, lutidine (1 equiv), THF, 08C to room temperature, 5 h, 84%; b) [PdCl2-
(dppf)]·CH2Cl2 (1 equiv), 1,4-dioxane/H2O (50:3), K2CO3 (10 equiv), 908C, 1 h, 52%; c) KF, HBr in DMF, 1 h, 90%. dppf: 1,1’-bis(diphenylphos-
phino)ferrocene.
tide 29 wherein the R amino acid C of the natural product was
replaced by its S antipode. As shown in Scheme 5, the
intramolecular Suzuki–Miyaura reaction of 29 afforded
bismacrocycle 4, the axial chirality of which was determined
to be aR, in accord with that of the natural product. The
characteristic NOE correlations of NMe/HC2, HC2/HD2’, HD6’
/
HE2, HD6’/HF6’, HD6’/HF5’, HE2/HF5’, HF5’/HF3b, HF2/HF3a, and
HF2’/HF3a were indicative of the stereochemistry of 4. The
chemical shift of the HF2 signal in compounds 3 and 4 (d =
5.58 ppm for 3, d = 4.42 ppm for 4; CD3CN) is also supportive
of the assigned atropisomerism. Molecular models showed
that the HF2 signal for aR atropisomer 4 was located under-
neath that of the indole ring, whereas that for aS atropisomer
3 was in the deshield zone of the indole ring.
To verify whether the terminal a-ketoamide unit can alter
the atopselectivity of the aryl–aryl bond-forming process,[23]
compound 31a was synthesized by coupling of 23 with
tryptophan derivative 30a (Scheme 6). Cyclization of 31a
proceeded smoothly to afford the desired bismacrocycle.
However, the aS atropisomer was once again the only isolable
atropisomer. On the other hand, cyclization of 31b, wherein
the indolyl nitrogen atom was protected as an N-Boc group,
failed to produce the cyclic product.
It has been reported that attempts to convert isocomples-
tatin 3 into isochloropeptin 5 under acidic conditions met with
failure, due probably to the higher ring strain in isocomples-
tatin 3 than in complestatin 1. Since intramolecular Stille
coupling afforded the chloropeptin atropspecifically,[24] the
isochloropeptin 5 is currently inaccessible synthetically. On
the basis that the absence of the terminal a-ketoamide unit in
33 might render it conformationally more flexible than
isocomplestatin, the acid-promoted isomerization of 33 was
carried out. Fortuitously, heating of a TFA solution of 33,
obtained by removal of the TBS protective group from 32, to
508C for 15 min removed the terminal N-Boc function and
triggered a bond reorganization to afford the rearranged
product 34 in quantitative yield. Coupling of 34 with
Scheme 5. Synthesis of epi-AA-CC2-complestatin methyl ester 4.
a) HATU, lutidine (6 equiv), THF/CH2Cl2 (1:1), 58C, overnight, 69%;
b) [PdCl2(dppf)]·CH2Cl2 (1 equiv), 1,4-dioxane/H2O (50:3), K2CO3
(10 equiv), 908C, 1 h, 48%.
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Scheme 6. Synthesis of isochloropeptin I methyl ester 5. a) 23, HATU, lutidine (2.5 equiv), THF, 5 h, 90%; b) [PdCl2(dppf)]·CH2Cl2 (1 equiv), 1,4-
dioxane/H2O (50:3), K2CO3 (10 equiv), 908C, 1 h, 55%; c) KF, HBr in DMF, 0.03m, room temperature, 83%; d) TFA, 508C, 15 min; e) EDC
(2.0 equiv), HOAt (1 equiv), DMF/CH2Cl2 (1:5), 3 h, 83% (over 2 steps).
a-ketoacid 35 then furnished the desired isochloropeptin 5 in
83% yield. In this case, the signal for the FH2 proton in
isochloropeptin appeared in the 1H NMR spectrum at a
higher field (d = 4.46 ppm) than the equivalent signal in
chloropeptin (d = 5.08 ppm).
reverses the atropselectivity of the subsequent macrocycliza-
tion in both the complestatin and chloropeptin series. We
believe that ready accessibility of stereoisomers, including
In Snapper, Hoveyda, and co-workersꢀ synthesis of
chloropeptin, the natural R atropisomer was obtained by an
intramolecular Stille coupling. Since we had demonstrated
that the stereochemistry of amino acid C changed the
atropselectivity of the ring-closure reaction in the comple-
statin series (see the syntheses of 3 and 4), we set out to
examine the cyclization of hexapeptide 37, which should
afford the macrocycle with the phenyl–indole connectivity
found in chloropeptin (Scheme 7). Coupling of 24 with amide
36 proceeded without event to furnish the cyclization
precursor 37. The intramolecular Suzuki–Miyaura coupling
of 37 worked smoothly to provide bismacrocycle 6, the axial
chirality of which was determined to be aS, in 42% yield.
Thus, the atropselectivity switched once again from aR to aS
selective. These results indicated that the absolute config-
uration of amino acid C has a dramatic effect on the
atropselectivity of the DEF-ring-forming reaction regardless
the biaryl ring connectivity.
In conclusion, we have developed a unified strategy for
the synthesis of analogues of complestatin and chloropeptin
by employing intramolecular SNAr and Suzuki–Miyaura
reactions for the closure of the two macrocycles. While
Suzuki–Miyaura reaction was highly atropstereoselective, the
absolute configuration of the axial chirality was found to be
extremely sensitive to both the stereogenicity of the linear
peptide and the aryl–aryl bond connectivity. It is noteworthy
that changing the absolute configuration of amino acid C
Scheme 7. Synthesis of epi-AA-CC2-isochloropeptin methyl ester 6.
a) HATU, lutidine, 67%; b) [PdCl2(dppf)]·CH2Cl2 (1 equiv), 1,4-dioxane/
H2O (50:3), K2CO3 (10 equiv), 908C, 1 h, 42%.
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[11] Selected examples of aryl ether containing macrocycles: a) M.
Bois-Choussy, C. Vergne, L. Neuville, R. Beugelmans, J. Zhu,
Tetrahedron Lett. 1997, 38, 5795 – 5798; b) P. Cristau, J.-P. Vors, J.
Zhu, Org. Lett. 2001, 3, 4079 – 4082; c) T. Temal-Laꢁb, J.
Chastanet, J. Zhu, J. Am. Chem. Soc. 2002, 124, 583 – 590; on
solid support: d) K. Burgess, D. Lim, M. Bois-Choussy, J. Zhu,
Tetrahedron Lett. 1997, 38, 3345 – 3348; e) Y. Feng, Z. Wang, S.
Jin, K. Burgess, J. Am. Chem. Soc. 1998, 120, 10768 – 10769;
f) A. S. Kiselyov, S. Eisenberg, Y. Luo, Tetrahedron 1998, 54,
10635 – 10640; g) P. Cristau, J. P. Vors, J. Zhu, Tetrahedron Lett.
2003, 44, 5575 – 5578.
[12] Biaryl containing macrocycles: a) S. Boisnard, A.-C. Carbon-
nelle, J. Zhu, Org. Lett. 2001, 3, 2061 – 2064; b) S. Boisnard, J.
Zhu, Tetrahedron Lett. 2002, 43, 2577 – 2580; c) A.-C. Carbon-
nelle, J. Zhu, Org. Lett. 2000, 2, 3477 – 3480; d) R. Lꢂpine, J. Zhu,
Org. Lett. 2005, 7, 2981 – 2984.
[13] Y. Jia, M. Bois-Choussy, J. Zhu, Org. Lett. 2007, 9, 2401 – 2404.
[14] a) J. Zhu, Synlett 1997, 133 – 134; b) J. S. Sawyer, Tetrahedron
2000, 56, 5045 – 5065.
[15] N. Miyaura, A. Suzuki, Chem. Rev. 1995, 95, 2457 – 2483.
[16] C. Vergne, M. Bois-Choussy, J. Ouazzani, R. Beugelmans, J. Zhu,
Tetrahedron: Asymmetry 1997, 8, 391 – 398.
[17] A. J. Pearson, M. V. Chelliah, G. C. Bignan, Synthesis 1997, 536 –
541.
[18] A. Bigot, M. E. Tran Huu Dau, J. Zhu, J. Org. Chem. 1999, 64,
6283 – 6296.
[19] a) R. L. E. Furlꢃn, E. G. Mata, O. A. Mascaretti, J. Chem. Soc.
Perkin Trans. 1 1998, 355 – 358; b) K. C. Nicolaou, A. A. Estrada,
M. Zak, S. H. Lee, B. S. Safina, Angew. Chem. 2005, 117, 1402 –
1406; Angew. Chem. Int. Ed. 2005, 44, 1378 – 1382.
[20] a) Y. Jia, J. Zhu, Synlett 2005, 2469 – 2472; b) Y. Jia, J. Zhu, J.
Org. Chem. 2006, 71, 7826 – 7834.
[21] M. Bois-Choussy, P. Cristau, J. Zhu, Angew. Chem. 2003, 115,
4370 – 4373; Angew. Chem. Int. Ed. 2003, 42, 4238 – 4241.
[22] A review on conformation-directed macrocyclization: J. Blan-
kenstein, J. Zhu, Eur. J. Org. Chem. 2005, 1949 – 1964.
[23] In the syntheses of chloropeptin and complestatin by Snapper,
Hoveyda and co-workers,[9,10] cyclization of an ABCDEF
hexapeptide lacking the terminal a-ketoamide unit by an
intramolecular Stille coupling afforded selectively the aR
atropisomer corresponding to natural chloropeptin, whereas
cyclization of a complete ABCDEFG peptide fragment by
intramolecular Suzuki–Miyaura reaction provided the S atrop-
isomer of complestatin. Note that the ring connectivities of these
two natural products are different.
atropisomers, of the natural products should help to define
the structure–activity relationship of these biologically impor-
tant macrocycles.[25]
Received: February 5, 2008
Published online: April 11, 2008
Keywords: chirality · chloropeptin · complestatin · peptides ·
.
Suzuki–Miyaura reaction
[1] a) H. Seto, T. Fujioka, K. Furihata, I. Kaneko, S. Takahashi,
Tetrahedron Lett. 1989, 30, 4987 – 4990; b) I. Kaneko, K.
Kamoshida, S. Takahashi, J. Antibiot. 1989, 42, 236 – 241.
[2] K. Matsuzaki, H. Ikeda, T. Ogino, A. Matsumoto, H. B. Wood-
ruff, H. Tanaka, S. Omura, J. Antibiot. 1994, 47, 1173 – 1174.
[3] a) H. Tanaka, K. Matsuzaki, H. Nakashima, T. Ogino, A.
Matsumoto, H. Ikeda, H. B. Woodruff, S. Omura, J. Antibiot.
1997, 50, 58 – 65; b) K. Matsuzaki, T. Ogino, T. Sunazuka, H.
Tanaka, S. Omura, J. Antibiot. 1997, 50, 66 – 69.
[4] S. B. Singh, H. Jayasuriya, G. M. Salituro, D. L. Zink, A. Shafiee,
B. Heimbuch, K. C. Silverman, R. B. Lingham, O. Genilloud, A.
Teran, D. Vilella, P. Felock, D. Hazuda, J. Nat. Prod. 2001, 64,
874 – 882.
[5] H. Gouda, K. Matsuzaki, H. Tanaka, S. Hirono, S. Omura, J. A.
McCauley, P. A. Sprengeler, G. T. Furst, A. B. Smith, J. Am.
Chem. Soc. 1996, 118, 13087 – 13088.
[6] a) V. R. Hegde, P. Dai, M. Patel, V. P. Gullo, Tetrahedron Lett.
1998, 39, 5683 – 5684; b) H. Jayasuriya, G. M. Salituro, S. K.
Smith, J. V. Heck, S. J. Gould, S. B. Singh, C. F. Homnick, M. K.
Holloway, S. M. Pitzenberger, M. A. Patane, Tetrahedron Lett.
1998, 39, 2247 – 2248.
[7] a) J. Zhu, Expert Opin. Ther. Pat. 1999, 9, 1005 – 1019; b) K. C.
Nicolaou, C. N. C. Boddy, S. Bräse, N. Winssinger, Angew. Chem.
1999, 111, 2230 – 2287; Angew. Chem. Int. Ed. 1999, 38, 2096 –
2152; c) D. H. Williams, B. Bardsley, Angew. Chem. 1999, 111,
1264 – 1286; Angew. Chem. Int. Ed. 1999, 38, 1172 – 1193.
[8] a) M. K. Gurjar, N. K. Tripathy, Tetrahedron Lett. 1997, 38,
2163 – 2166; b) A.-C. Carbonelle, E. G. Zamora, R. Beugelmans,
G. Roussi, Tetrahedron Lett. 1998, 39, 4471 – 4472; c) A. M.
Elder, D. H. Rich, Org. Lett. 1999, 1, 1443 – 1446; d) R. Beugel-
mans, G. Roussi, E. G. Zamora, A.-C. Carbonnelle, Tetrahedron
1999, 55, 5089 – 5112; e) A. B. Smith III, J. J. Chruma, Q. Han, J.
Barbosa, Bioorg. Med. Chem. Lett. 2004, 14, 1697 – 1702; f) Y.
Yamada, A. Akiba, S. Arima, C. Okada, K. Yoshida, F. Itou, T.
Kai, T. Satou, K. Takeda, Y. Harigaya, Chem. Pharm. Bull. 2005,
53, 1277 – 1290; g) Y. Yamada, S. Arima, C. Okada, A. Akiba, T.
Kai, Y. Harigaya, Chem. Pharm. Bull. 2006, 54, 788 – 794.
[9] H. Deng, J.-K. Jung, T. Liu, K. W. Kuntz, M. L. Snapper, A. H.
Hoveyda, J. Am. Chem. Soc. 2003, 125, 9032 – 9034.
[24] Intramolecular Suzuki–Miyaura coupling failed under our
standard conditions in the chloropeptin series.
[25] Selective hydrolysis of chloropeptin: S. B. Singh, H. Jayasuriya,
D. L. Hazuda, P. Felock, C. F. Homnick, M. Sardana, M. A.
Patane, Tetrahedron Lett. 1998, 39, 8769 – 8770. See also
reference [4].
[10] T. Shinohara, H. Deng, M. L. Snapper, A. H. Hoveyda, J. Am.
Chem. Soc. 2005, 127, 7334 – 7336.
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