Total synthesis of anti-HIV agent chloropeptin I

Article abstract of DOI:10.1021/ja030249r

A convergent diastereo- and enantioselective total synthesis of anti-HIV agent chloropeptin I is reported. Important features of the total synthesis include: (1) the use of Ti-catalyzed cyanide addition to imines to prepare a requisite amino acid moiety,

Full text of DOI:10.1021/ja030249r

Published on Web 07/02/2003
Total Synthesis of Anti-HIV Agent Chloropeptin I
Hongbo Deng, Jae-Kyung Jung, Tao Liu, Kevin W. Kuntz, Marc L. Snapper,* and Amir H. Hoveyda*
Department of Chemistry, Merkert Chemistry Center, Boston College, Chestnut Hill, Massachusetts 02467
Received April 23, 2003; E-mail: amir.hoveyda@bc.edu
Scheme 1
Chloropeptin I (1) was obtained from Streptomyces sp. WK-
3419 in 1994, and its structure was elucidated through NMR
spectroscopy.1 Five years earlier, chloropeptin II (or complestatin)
had been isolated from a fermentation broth of Streptomyces
laVendulae.2 Complestatin isomerizes to 1 under acidic conditions.3,4
Both natural products exhibit notable activity against HIV-1-induced
cytopathicity and syncyctium formation in CD-4+ lymphocytes.1,2
They inhibit HIV replication by disruption of HIV gp-120 glyco-
protein binding to the CD4 receptor of T-lymphocytes (IC50 values
of 2.0 and 3.3 µM for 1 and 2, respectively).1a,d More recently,
researchers at Merck isolated two additional derivatives and an
atropisomer of 2 (isocomplestatin), which demonstrate anti-HIV
integrase property.5,6 Structural complexity and potent biological
activity of 1 and 2, which carry racemization-prone electron-
deficient chlorinated amino acids, and the requirement for stereo-
selective biaryl macrocycle formation render these natural products
important targets for total synthesis. The first stereoselective total
synthesis of the more active member of this family, chloropeptin I
(1), is reported herein.7
formation) with optically pure 6, which can be prepared by Ti-
catalyzed asymmetric cyanide addition (Scheme 3),14,15 delivered
7 (86% overall). Treatment of 7 with a dilute solution (0.01 M) of
NaIO416 led to the derived boronic acid; higher concentrations gave
rise to the formation of unidentified byproducts and a low yield of
the desired compound.
The resulting boronic acid was subjected to conditions reported
previously for Cu-mediated formation of biaryl ethers.17 These
As indicated by the retrosynthesis plan in Scheme 1, the success
of the proposed route depends on the availability of effective and
stereoselective methods for biaryl ether formation (IV f III) and
biaryl cross coupling (II f I) as well as efficient protocols for
preparation of the required arylglycine units. Accordingly, our first
objective became the selective synthesis of tripeptide 7 (Scheme
2) and the study of its conversion to biaryl ether 8.
As depicted in Scheme 2, boronic ester 3, prepared8 in 90-95%
yield from the corresponding Boc-protected amino acid,9 was
coupled with 410 in the presence of DEPBT11,12 and methylated
with TMSCHN2 to afford dipeptide 5 in 74% overall yield. A
variety of protocols were investigated to identify the conditions
shown in Scheme 2, such that peptide coupling could be effected
in high yield with minimal epimerization at the sensitive site of
the dichlorophenylglycine moiety.13 Removal of the Boc group and
union of the resulting amine salt (to avoid diketopiperizine
procedures provide 8 but in low yields (15-20%), particularly when
the reaction was carried out on gram scale. Extensive experimenta-
tion led us to determine that the presence of 10 equiv of MeOH
(vs substrate) is crucial for efficient biaryl ether formation; reactions
proved to be significantly more sluggish without MeOH (>24 h
vs 3-6 h for >98% conv). The positive influence of MeOH may
be linked to the in situ formation of the boron dimethyl ester or
the increased solubility of the Cu salt.18 We also determined that
use of Et3N leads to notably more facile transformations (vs
pyridine). As illustrated in Scheme 2, biaryl ether 8 was converted
to tetrapeptide 10 in four steps (75% overall). It is noteworthy that
installment of the phenylglycine terminus was performed after the
two phenols were unmasked along with conversion of the methyl
ester to the desired carboxylic acid (AlBr3, EtSH); thus, peptide
coupling was effected with excellent site-selectivity without the
need for hydroxyl group differentiation. It should also be noted
9
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10.1021/ja030249r CCC: $25.00 © 2003 American Chemical Society

C O M M U N I C A T I O N S
Scheme 2. Enantioselective Synthesis of the Macrocyclic Biaryl Ether Segment of Chloropeptinsa
a (a) 1.5 equiv of 4, 1.6 equiv of DEPBT, 1 equiv of NaHCO3, THF, 0 °C f 22 °C, 12 h; 74%. (b) 1.5 equiv of TMSCHN2, CH2Cl2/MeOH, 22 °C, 1.5
h; >98%. (c) HCl (g), MeOH, -78 °C f 22 °C, 1 h. (d) 1.5 equiv of HOAt, 1.5 equiv of EDC, 1.5 equiv of NaHCO3, 1 equiv of 6, THF/DMF, 0 °C f
22 °C, 12 h; 86% from 5. (e) 3 equiv of NaIO4, 3 equiv of NH4OAc, acetone/water (0.01 M), 22 °C, 12 h. (f) 2 equiv of Cu(OAc)2, 10 equiv of Et3N, 4
Å MS, 10 equiv of MeOH, CH2Cl2 (0.01 M), 22 °C, 5 h, 50% from 7. (g) HCl (g), MeOH, -78 °C f 22 °C, 1. 5 h; NaHCO3. (h) 1.5 equiv of TFAA, 3
equiv of 2,6-lutidine, CH2Cl2, 0 °C f 22 °C, 2 h; 94% for two steps. (i) 20 equiv of AlBr3, EtSH, 0 °C, 1.5 h. (j) 1.1 equiv of 9, 1.5 equiv of HOAt, 1.5
equiv of EDC, 1.5 equiv of NaHCO3, THF, 0 °C f 22 °C, 12 h, 80% for two steps.
Scheme 3 a
was prepared20 in the manner illustrated in eq 1 (Scheme 5). (3)
Amino acid 12 was introduced as its Na salt, because the corres-
ponding carboxylic acid proved to be unstable (labile C-Sn bond).
(4) The biaryl coupling conditions are based on those reported pre-
viously.21 However, after extensive studies, we established that this
critical C-C bond forming reaction (13 f 14) is significantly more
efficient in the presence of collidine. The positive effect of added
base might be related to stabilization of the active Pd complex; in
the absence of this additive, the reaction turns black (vs light
brown), and no further conversion is detected after 30 min.13
The total synthesis of chloropeptin I was completed from 14 in
three steps. Removal of the Boc group of 14 under acidic conditions,
coupling of the resulting amine terminus with R-ketoacid 15,
prepared as illustrated in eq 2 (Scheme 5), and conversion of the
methyl ester to the desired carboxylic acid delivered 1 in 60%
overall yield without complications due to epimerization or hydrate
formation. The synthetic sample proved to be identical to authentic
a (a) 10 mol % chiral ligand, 10 mol % Ti(Oi-Pr)4, 2 equiv of TMSCN,
2 equiv of i-PrOH (over 12 h), tol., 4 °C; 93% ee, >98%. (b) HCl (g),
MeOH/HOAc, -78 °C (30 min) f 22 °C (2 h). (c) 10 equiv of Et3SiH,
TFA, 72 °C, 2 h. (d) HCl (g), MeOH, -78 °C (10 min) f 65 °C (2 h). (e)
1 equiv of Boc2O, aqueous NaOH, dioxane, 22 °C, 1 h; >98% ee, 50%
overall for four steps.
that, although 10 was isolated as a single conformational isomer,
until amino acid unit 98 was installed, all intermediates existed as
a mixture of rotamers (ratios depending on solvent and substrate);13
such observations are consistent with the results of previous
degradation studies.5,6
1
material by extensive H NMR analysis, as well as by HRMS,
analytical HPLC, and optical rotation.22
In summary, we have completed the first stereoselective total
synthesis of anti-HIV agent chloropeptin I. Salient features of the
total synthesis include the discovery of two critical positive effects
exerted by additives: MeOH in the Cu-mediated biaryl ether
formation and collidine in the Pd-mediated cross-coupling, resulting
in efficient formation of the two macrocycles of the target molecule.
Future studies include optimization and a detailed study of several
key steps in the total synthesis, and application of the protocols
outlined above to the synthesis of other members of this important
class of natural products.
With tetrapeptide 10 in hand, we began to outfit this advanced
intermediate in preparation for performing the second key macro-
cyclization. Toward this end, as outlined in Scheme 4, subjection
of 10 to NIS led to selective formation of the desired o-iodide.
Subsequent removal of the TBS and TFA protecting groups under
meticulously controlled acidic conditions19 and installment of the
second dichlorophenylglycine module (4) afforded 11 in nearly 70%
overall yield. Following the cleavage of the Boc group, the depro-
tected amine terminus derived from 11 was coupled with Na salt
12 to afford 13, which was directly subjected to 1 equiv of Pd(Pt-
Bu3)2, 5 equiv of CsF, and 10 equiv of collidine (dioxane, 50 °C,
5 h) to afford 14, isolated as a single diastereomer (38-42% overall
yield from 11). Several issues regarding the sequence transforming
from 10 to 14 are noteworthy: (1) Removal of the Boc and TFA
groups had to be performed under <2 M acidic conditions; other-
wise, significant decomposition would ensue due to cleavage of the
terminal phenylglycine methyl ester. (2) Stannyl tryptophane 12
Acknowledgment. This work was funded by the NIH (GM-
57212 to A.H.H. and M.L.S.), Schering-Plough, and Novartis (to
A.H.H.). We thank the Korean Science & Engineering Foundation
and AstraZeneca for postdoctoral fellowships to J.-K.J. and T.L.,
respectively. We are grateful to Drs. V. Hegde (Schering-Plough)
and S. Singh (Merck) for providing us with authentic samples of
1. We thank Mr. C. Kowalcyk (Boston College) for his invaluable
assistance with mass spectrometry, and we acknowledge C. Krueger
and J. Porter for experimental assistance.
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C O M M U N I C A T I O N S
Scheme 4. Synthesis of the Bicyclic Core and Completion of Total Synthesis of Chloropeptin Ia
a (a) 1.5 equiv of NIS, MeCN, 22 °C, 1 h; 60% (82% based on recovered 10). (b) HCl, MeOH, 45 °C, 4 h; NaHCO3. (c) 1.5 equiv of HATU, 3 equiv
of collidine, 1.1 equiv of 4, CH2Cl2/THF, 0 °C f 22 °C, 3 h; 85% for two steps. (d) HCl, MeOH, 22 °C, 3 h. (e) 1.1 equiv of 12, 1.1 equiv of HATU, 5
equiv of collidine, CH2Cl2/THF, 0 °C f 22 °C, 4 h. (f) 1 equiv of Pd(Pt-Bu3)2, 10 equiv of collidine, 5 equiv of CsF, dioxane (0.002 M), 50 °C, 5 h; ∼40%
from 11. (g) HCl, MeOH, 22 °C, 1.5 h. (h) 1.5 equiv of 15, 1.5 equiv of HOAt, 3 equiv of EDC, CH2Cl2/DMF, 0 °C f 22 °C, 3 h; 60% for two steps. (i)
10 equiv of LiOH, H2O/THF (1/5), 0 °C, 2 h; 98%.
Scheme 5 a
(5) Singh, S. B.; Jayasuriya, H.; Hazuda, D. L.; Felock, P.; Homnick, C. F.;
Sardana, M.; Patane, M. A. Tetrahedron Lett. 1998, 39, 8769-8770.
(6) Singh, S. B.; Jayasuriya, H.; Salituro, G. M.; Zink, D. L.; Shafiee, A.;
Heimbuch, B.; Silverman, K. C.; Lingham, R. B.; Genilloud, R. O.; Teran,
A.; Vilella, D.; Felock, P.; Hazuda, D. J. Nat. Prod. 2001, 64, 874-882.
(7) For selected previous synthetic studies, see: (a) Gurjar, M. K.; Tripathy,
N. K. Tetrahedron Lett. 1997, 38, 2163-2166. (b) Carbonelle, A.-C.;
Zamora, E. G.; Beugelmans, R.; Roussi, G. Tetrahedron Lett. 1998, 39,
4471-4472. (c) Elder, A. M.; Rich, D. H. Org. Lett. 1999, 1, 1443-
1446. (d) Kai, T.; Kajimoto, N.; Konda, Y.; Harigaya, Y.; Takayanagi,
H. Tetrahedron 1999, 55, 5089-5112.
(8) See the Supporting Information for details.
(9) Firooznia, F.; Gude, C.; Chan, K.; Marcopulos, N.; Satoh, Y. Tetrahedron
Lett. 1999, 40, 213-216.
(10) Pearson, A. J.; Chelliah, M. V.; Bignan, G. C. Synthesis 1997, 536-541.
(11) Li, H.; Jiang, X.; Ye, H.; Fan, C.; Romoff, T.; Goodman, M. Org. Lett.
1999, 1, 91-93.
(12) Abbreviations: DEPBT ) 3-(diethyloxyphosphoryloxy)-1,2,3-benzotri-
azin-4(3H)-one, EDC ) 1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide,
HATU ) 2-(1-H-7-azabenzotriazol)-1,1,3,3-methyluronium hexafluoro-
phosphate, HOAt ) 1-hydroxy-7-azabenzotriazole.
(13) Details will be disclosed later in the full account of this work.
(14) (a) Krueger, C. A.; Kuntz, K. W.; Dzierba, C. D.; Wirschun, W. G.;
Gleason, J. D.; Snapper, M. L.; Hoveyda, A. H. J. Am. Chem. Soc. 1999,
121, 4284-4285. (b) Porter, J. R.; Wirschun, W. G.; Kuntz, K. W.;
Snapper, M. L.; Hoveyda, A. H. J. Am. Chem. Soc. 2000, 122, 2657-
2658. (c) Josephsohn, N. S.; Kuntz, K. W.; Snapper, M. L.; Hoveyda, A.
H. J. Am. Chem. Soc. 2001, 123, 11594-11599.
(15) For an alternative synthesis of 6, see: Evans, D. A.; Katz, J. L.; Peterson,
G. S.; Hinterman, T. J. Am. Chem. Soc. 2001, 123, 12411-12413.
(16) (a) Coutts, S. J.; Adams, J.; Krolikowski, D.; Snow, R. J. Tetrahedron
Lett. 1994, 35, 5109-5112. (b) Nakamura, H.; Fujiwara, M.; Yamamoto,
Y. Bull. Chem. Soc. Jpn. 2000, 73, 231-235.
(17) (a) Evans, D. A.; Katz, J. L.; West, T. R. Tetrahedron Lett. 1998, 39,
2937-2940. (b) Chan, D. M. T.; Monaco, K. L.; Wang, R.-P.; Winters,
M. P. Tetrahedron Lett. 1998, 39, 2933-2936. For studies related to
macrocyclizations, see: (c) Decicco, C. P.; Song, Y.; Evans, D. A. Org.
Lett. 2001, 3, 1029-1032.
(18) A significant byproduct in the Cu-mediated reaction relates to formation
of phenol derived from the boronic acid; none of the corresponding methyl
ether is detected, however. This observation is in contrast to a previous
hypothesis (ref 17a) that phenol formation arises from reaction of
adventitious water.
a 1.1 equiv of Tf2O, 1.2 equiv of Et3N, -78 °C, 2 h; >98%. (b) 3 equiv
of TMSI, CHCl3, 65 °C, 3 h. (c) 1.1 equiv of (Boc)2O, THF, 22 °C, 12 h. (d)
1 equiv of (Me3Sn)2, 3 equiv of LiCl, 0.5 mol % BHT, 5 mol % Pd(PPh3)4,
dioxane, 85 °C, 7 h; 80% for two steps. (e) aqueous NaOH, MeOH, 0 °C
f 22 °C, 1 h; >98%. (f) 1.5 equiv of NIS, THF, 22 °C, 2 h. (g) 2.5 equiv
of n-BuLi, 5 equiv of MeO(CO)2OMe, THF, -78 °C, 1 h; 47% for two
steps. (h) 10 equiv of aqueous NaOH, MeOH, 0 °C f 22 °C, 1 h; >98%.
Note Added after ASAP. In the version posted ASAP on 7/2/03,
the description of the synthesis of 12 shown in Scheme 5 was
incorrect. The version posted 7/2/03 and the print version are correct.
Supporting Information Available: Experimental procedures and
spectral and analytical data for select intermediates and 1 (PDF). This
material is available free of charge via the Internet at http://pubs.acs.org.
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