Total synthesis of chloropeptin II (complestatin) and chloropeptin I

Article abstract of DOI:10.1021/ja907193b

(Chemical Equation Presented) The first total synthesis of chloropeptin II (1, complestatin) is disclosed. Key elements of the approach include the use of an intramolecular Larock indole synthesis for the initial macrocyclization, adopting conditions that

Full text of DOI:10.1021/ja907193b

Published on Web 10/19/2009
Total Synthesis of Chloropeptin II (Complestatin) and Chloropeptin I
Joie Garfunkle, F. Scott Kimball, John D. Trzupek, Shinobu Takizawa, Hiroyuki Shimamura,
Masaki Tomishima, and Dale L. Boger*
Department of Chemistry and The Skaggs Institute for Chemical Biology, The Scripps Research Institute, 10550
North Torrey Pines Road, La Jolla, California 92037
Received August 25, 2009; E-mail: boger@scripps.edu
Complestatin (1, chloropeptin II) was first disclosed in 1980 as an
inhibitor of the alternate pathway of human complement,1 Figure 1.
Nine years later, both its original isolation2 from Streptomyces
laVendulae at Sankyo and additional details of its complement activity
were reported along with its structure elucidation by Seto3 that defined
its connectivity and partial stereochemistry. Shortly thereafter, the first
report of its activity against HIV infectivity and its cytopathic effects
were disclosed.4 Five years later, Omura reported the isolation of both
chloropeptin I (2) and chloropeptin II (1) from Streptomyces sp. WK-
3419 as inhibitors of HIV gp120-CD4 binding, determined that
chloropeptin II and complestatin are identical, and established their
partial stereochemistry.5 A more detailed analysis of their NMR data
provided the full structural and stereochemical assignment for chlo-
ropeptin I (2) including the axial atropisomer chirality.6 A remarkable
acid-catalyzed rearrangement (TFA, 50 °C, >90%) of chloropeptin II
(1, complestatin) to the less strained chloropeptin I (2) that proceeds
with retention of the atropisomer stereochemistry subsequently estab-
lished the full stereochemical assignments for 1.1c,7 These later studies
were conducted in the course of the additional isolations of the natural
products at Merck8 and Schering-Plough,9 with the latter establishing
that chloropeptin I (2) is an authentic natural product and not an acid-
catalyzed artifact derived from chloropeptin II (1).
As a result of the challenging structural features and complexity of
1 and 2, rivaling that of the glycopeptide antibiotics (e.g., vancomycin),
combined with their equally important HIV activity derived through
a unique site of action, they have attracted considerable interest.
Although structurally similar to the glycopeptide antibiotics, one of
the characteristic biaryl ether linkages is replaced with a biaryl linkage
to C6 or C7 of a (R)-tryptophan indole embedded in the macrocyclic
core adopting a single atropisomer stereochemistry (R) that is not
capable of thermal interconversion. Snapper and Hoveyda reported
the first, and to date only, total synthesis of a member of this unique
class of natural products, chloropeptin I (2), confirming the structural
and stereochemical assignments.10 Their approach, enlisting a late stage
intramolecular biaryl Stille coupling for closure of the right-hand
macrocyclic ring system (38-42%, three steps) provided exclusively
the natural (R)-atropisomer of 2 as a single diastereomer when
conducted on substrate containing the left-hand macrocycle. Remark-
ably, they later found that extending this approach to chloropeptin II
(1), using an analogous late stage intramolecular biaryl Suzuki coupling,
provided exclusively (63%) the unnatural (S)-atropisomer (isocom-
plestatin).11
Figure 1. Natural products and key retrosynthetic disconnections.
atropdiastereoselectivity (4:1), but it also represents the first reported
example of what may prove to be a useful Larock macrocyclization
strategy. Subsequent introduction of the left-hand ring system by
enlisting an aromatic nucleophilic substitution reaction for ring closure
with biaryl ether formation completed the assemblage of the core
bicyclic structure of 1 and represents a macrocyclization order
complementary to that of Snapper and Hoveyda. Intrinsic in the design
of the approach and by virtue of the single-step acid-catalyzed
conversion of 1 to chloropeptin I (2), the route also provides a total
synthesis of 2.
Although 1 is composed of seven amino acid subunits, each is
extensively modified, four are racemization prone phenylglycines, five
are incorporated with the unnatural D-configuration, and one is
incorporated as a N-methyl derivative. Four of these (A, C, E, and G)
are readily accessible from commercially available precursors,16
whereas the remaining three required more significant synthetic
operations key to implementation of our approach. The B subunit 5,
substituted to accommodate its use in an intramolecular aromatic
nucleophilic substitution reaction for macrocyclic biaryl ether forma-
tion, simply required N-methylation of the Boc derivative of (S)-4-
fluoro-3-nitrophenylalanine prepared by a four-step synthesis previously
utilized to access its enantiomer,17 Scheme 1. The F subunit 6 bearing
the TES-substituted alkyne required for the Larock indole annulation
was accessed by diastereoselective alkylation (dr >99:1) of (S)-8 with
the propargylic diphenylphosphate 715 following a protocol detailed
Complementary to these and related ongoing efforts,12 herein we
report the first total synthesis of chloropeptin II (1, complestatin), the
more strained and challenging of the natural products. Key to the
approach is the use of an intramolecular Larock indole synthesis13 for
the initial macrocyclization, adopting conditions that permit utilization
of a 2-bromoaniline14 and incorporating a removable terminal alkyne
substituent (-SiEt3) that sterically dictates the indole cyclization
regioselectivity,13-15 Figure 1.
Not only did this key reaction provide the fully functionalized right-
hand ring system of 1 in superb conversion (89%) and good
9
16036 J. AM. CHEM. SOC. 2009, 131, 16036–16038
10.1021/ja907193b CCC: $40.75  2009 American Chemical Society

C O M M U N I C A T I O N S
by Cook15 in an approach where the inexpensive (S)-Schollkopf reagent
Scheme 2
derived from L-valine provides the (R)-amino acid derivative 6, Scheme
1.
Scheme 1
The D subunit central to the structure of 1 and 2 was prepared from
commercially available 3-iodo-4,5-dimethoxybenzaldehyde (10), Scheme
2. Asymmetric aminohydroxylation of the corresponding styrene 11
in the presence of (DHQD)2PHAL18 produced 12 in good yield (75%
12), regioselectivity (5:1), and enantioselectivity (>98% ee). The
primary alcohol was protected as its benzyl ether 13 and carried through
the sequence that provided 4 as a protected alcohol avoiding potential
epimerization, but requiring a late stage oxidation. Conversion of the
aryl iodide 13 to the corresponding aryl boronic acid, its selective
Suzuki coupling19 with 2-bromo-5-iodoaniline (14),16 and acetylation
of aniline 15 provided 16.
Boc deprotection of 16 (HCO2H, 23 °C) followed by coupling of
the amine with (R)-FmocHN-3,5-Cl2Hpg-OH16 (17, EDCI, HOAt,
DMF/CH2Cl2 1:6, -20 °C, 16 h, 98%, dr >99:1) and subsequent
protection of the phenol 18 (TMSCHN2, 99%) provided 19. Fmoc
deprotection of 19 (morpholine, DMF/CH3CN 1:2, 23 °C, 16 h)
followed by coupling with 6 (EDCI, HOAt, DMF, 23 °C, 18 h, 83%)
provided the cyclization substrate 20. Following extensive exploration
of the Larock macrocyclization that entailed examination of not only
20 but also the free aniline, the trifluoroacetamide, and their corre-
sponding iodides,20 we found that treatment of 20 with Pd(OAc)2 (1.1
equiv) in the presence of the bidentate ligand DtBPF (1.3 equiv) and
the soluble base Et3N (1.3 equiv) in refluxing toluene/CH3CN (1:1, 1
mM, 110 °C, 1 h) cleanly provided 21 (71%) and its (S)-atropisomer
(not shown) in a superb combined yield (89%) in a reaction that
proceeds with complete cyclization regioselectivity and in good
atropdiastereoselectivity (4:1 R:S) favoring the natural isomer. The
substitution of a soluble base (Et3N vs NaHCO3 > KOAc > K2CO3)
in the conditions reported by Farina and Senanayake, permitting the
use of 2-bromoanilines (DtBPF),14 eliminated competitive aryl chloride
dehalogenation as well as a problematic epimerization observed with
insoluble inorganic bases. The large TES alkyne substituent dictates
the exclusive indole cyclization regioslectivity,13-15 and the aniline
acetamide not only serves to deactivate the strained indole toward
subsequent electrophilic reagents but also favorably influences the
cyclization atropdiastereoselectivity. At present, efforts to reduce the
reaction to one that is catalytic in Pd have been modestly successful
but provide less dependable conversions. Extensive NMR characteriza-
tion of 21 and its unnatural (S)-atropisomer confirmed the stereochem-
ical assignments.16 As noted by Hoveyda,11 the most recognizable
diagnostic distinctions in the atropisomers are the chemical shifts,
multiplicity, and NOEs for the Trp R-CH (acetone-d6: δ 3.59 for R vs
δ 5.05 for S) and diastereotopic Trp ꢀ-CH2 (δ 3.12, d and 3.70, dd for
R vs δ 3.32, dd and 3.51, dd for S).
Liberation of the C-terminus primary alcohol 22 by benzyl ether
hydrogenolysis (H2, Pd(OH)2, THF, 23 °C, 99%) and two-step
oxidation to the carboxylic acid 23 (92%), both of which benefit from
the indole substitution, preceded global deprotection to provide 4 with
BBr3 (25 equiv, CH2Cl2, 23 °C, 17 h) removing the three aryl methyl
ethers, the TES group, and the Boc group that was reinstalled upon
9
J. AM. CHEM. SOC. VOL. 131, NO. 44, 2009 16037

C O M M U N I C A T I O N S
77, 137–142. (c) Tachikawa, K.; Hasumi, K.; Endo, A. Thrombosis Res.
1997, 87, 571–576.
(2) Kaneko, I.; Kamoshida, K.; Takahashi, S. J. Antibiot. 1989, 42, 236–241.
(3) Seto, H.; Fujioka, T.; Furihata, K.; Kaneko, I.; Takahashi, S. Tetrahedron
Lett. 1989, 30, 4987–4990.
treatment with Boc2O providing 4. Notably, the indole N-acetamide
was unaffected by this treatment, and the intrinsically strained ring
system did not undergo rearrangement to the more stable C7 (vs C6)
biaryl indole linkage. The assigned structure and stereochemistry were
reaffirmed, through a full spectroscopic characterization of 4, not only
with observation of key NOEs16 and the diagnostic chemical shifts of
the Trp R-CH (THF-d8: δ 3.86, app t) and the diastereotopic Trp ꢀ-CH2
(δ 2.82, d and 3.43, app t) as well as their multiplicity11 but also simply
through the indole coupling pattern where C7-H remains a singlet (δ
8.30, s) while C4-H and C5-H appear as coupled doublets in 4.
This set the stage for introduction of the left-hand ring system.
Coupling (EDCI, HOAt, DMF/CH2Cl2 1:3, -5 °C, 6 h, 59%) of 4
with the tripeptide 3, prepared by the sequential couplings and
N-terminus deprotections of (R)-H2N-Hpg-OMe (24)16 with 5 (PyBOP,
80%; 4 N HCl, dioxane) and (R)-FmocHN-3,5-Cl2Hpg-OH16 (17,
DEPBT, NaHCO3, THF, 0 °C, 24 h, 83%, 9:1 dr; Bu4NF,21 THF,
0-23 °C, <1 h),16 provided 25. Macrocyclization22 of 25 to provide
26 as predominantly a single atropisomer of an inconsequential mixture
of atropisomers was accomplished upon treatment with K2CO3 in THF
(0.5 mM, 60 °C, 48-64 h) in the presence of 18-c-6 and 4 Å MS in
conversions as high as 81%, provided rigorous anhydrous conditions
were maintained to prevent competitive methyl ester hydrolysis. Two-
step removal of the activating nitro group (H2, Ra-Ni, MeOH, 0-23
°C, 6 h, 87%; t-BuONO, H3PO2, THF, 0 °C, 3 h, 72%)23 afforded 28.
Boc deprotection (4 N HCl, dioxane, 23 °C, 1-3 h) and coupling of
the amine with 2-(3,5-dichloro-4-hydroxyphenyl)-2-oxoacetic acid
(29,10,16 EDCI, HOAt, DMF/CH2Cl2 1:5, 0 °C, 2 h, 55%) provided
the penultimate precursor 30. Deprotection of 30 to provide 1 was
accomplished with LiOH (THF/H2O, 0 °C, 3 h, 60%) in a reaction
where the indole N-acetyl group was removed faster (<30 min) than
the methyl ester hydrolysis. Finally, and although we did not conduct
the reaction on a preparative scale providing an isolated yield, the clean
acid-catalyzed conversion of 1 to 2 was conducted on a small scale
with both synthetic and authentic 1 and monitored by LCMS. The
two samples behaved in the same manner providing only 2 and was
most conveniently conducted with 50% TFA/H2O at 50 °C progressing
at a rate that is easily monitored (5 h, vs <5-15 min with neat TFA
at 50 °C7).24
(4) Momota, K.; Kaneko, I.; Kimura, S.; Mitamura, K.; Shimada, K. Biochem.
Biophys. Res. Commun. 1991, 179, 243–250.
(5) (a) Matsuzaki, K.; Ikeda, H.; Ogino, T.; Matsumoto, A.; Woodruff, H. B.;
Tanaka, H.; Omura, S. J. Antibiot. 1994, 47, 1173–1174. (b) Tanaka, H.;
Matsuzaki, K.; Nakashima, H.; Ogino, T.; Matsumoto, A.; Ikeda, H.;
Woodruff, H. B.; Omura, S. J. Antibiot. 1997, 50, 58–65. (c) Matsuzaki,
K.; Ogino, T.; Sunazuka, T.; Tanaka, H.; Omura, S. J. Antibiot. 1997, 50,
66–69.
(6) Gouda, H.; Matsuzaki, K.; Tanaka, H.; Hirono, S.; Omura, S.; McCauley,
J. A.; Sprengeler, P. A.; Furst, G. T.; Smith, A. B., III. J. Am. Chem. Soc.
1996, 118, 13087–13088.
(7) (a) Jayasuriya, H.; Salituro, G. M.; Smith, S. K.; Heck, J. V.; Gould, S. J.;
Singh, S. B.; Homnick, C. F.; Holloway, M. K.; Pitzenberger, S. M.; Patane,
M. A. Tetrahedron Lett. 1998, 39, 2247–2248. (b) Hegde, V. R.; Dai, P.;
Patel, M.; Gullo, V. P. Tetrahedron Lett. 1998, 39, 5683–5684.
(8) (a) Singh, S. B.; Jayasuriya, H.; Salituro, G. M.; Zink, D. L.; Shafiee, A.;
Heimbuch, B.; Silverman, K. C.; Lingham, R. B.; Genilloud, O.; Teran,
A.; Vilella, D.; Felock, P.; Hazuda, D. J. Nat. Prod. 2001, 64, 874–882.
(b) Singh, S. B.; Jayasuriya, H.; Hazuda, D. L.; Felock, P.; Homnick, C. F.;
Sardana, M.; Patane, M. A. Tetrahedron Lett. 1998, 39, 8769–8770.
(9) (a) Hegde, V. R.; Puar, M. S.; Dai, P. D.; Patel, M.; Gullo, V. P.; Chan,
T.-M.; Silver, J.; Pramanik, B. N.; Jenh, C.-H. Bioorg. Med. Chem. Lett.
2003, 13, 573–575. (b) Hegde, V. R.; Puar, M. S.; Dai, P.; Patel, M.; Gullo,
V. P.; Pramanik, B. N.; Jenh, C.-H. Tetrahedron Lett. 2002, 43, 5339–
5341.
(10) Deng, H.; Jung, J.-K.; Liu, T.; Kuntz, K. W.; Snapper, M. L.; Hoveyda,
A. H. J. Am. Chem. Soc. 2003, 125, 9032–9034.
(11) Shinohara, T.; Deng, H.; Snapper, M. L.; Hoveyda, A. H. J. Am. Chem.
Soc. 2005, 127, 7334–7336.
(12) (a) Jia, Y.; Bois-Choussy, M.; Zhu, J. Angew. Chem., Int. Ed. 2008, 47,
4167–4172. (b) Jia, Y.; Bois-Choussy, M.; Zhu, J. Org. Lett. 2007, 9, 2401–
2404. (c) Yamada, Y.; Akiba, A.; Arima, S.; Okada, C.; Yoshida, K.; Itou,
F.; Kai, T.; Satou, T.; Takeda, K.; Harigaya, Y. Chem. Pharm. Bull. Jpn.
2005, 53, 1277–1290. (d) Smith, A. B., III; Chruma, J. J.; Han, Q.; Barbosa,
J. Bioorg. Med. Chem. Lett. 2004, 14, 1697–1702. (e) Elder, A. M.; Rich,
D. H. Org. Lett. 1999, 1, 1443–1446. (f) Roussi, G.; Zamora, E. G.;
Carbonnelle, A.-C.; Beugelmans, R. Heterocycles 1999, 51, 2041–2063.
(g) Kai, T.; Kajimoto, N.; Konda, Y.; Harigaya, Y.; Takayanagi, H.
Tetrahedron Lett. 1999, 40, 6289–6292. (h) Gurjar, M. K.; Tripathy, N. K.
Tetrahedron Lett. 1997, 38, 2163–2166.
(13) (a) Larock, R. C.; Yum, E. K. J. Am. Chem. Soc. 1991, 113, 6689–6690.
(b) Larock, R. C.; Yum, E. K.; Refvik, M. D. J. Org. Chem. 1998, 63,
7652–7662.
(14) Shen, M.; Li, G.; Lu, B. Z.; Hossain, A.; Roschangar, F.; Farina, V.;
Senanayaka, C. H. Org. Lett. 2004, 6, 4129–4132.
(15) (a) Ma, C.; Liu, X.; Li, X.; Flippen-Anderson, J.; Yu, S.; Cook, J. M. J.
Org. Chem. 2001, 66, 4525–4542. See also: (b) Jeschke, T.; Wensbo, D.;
Annby, U.; Gronowitz, S.; Cohen, L. A. Tetrahedron Lett. 1993, 34, 6471–
6474.
Continued efforts on the optimization and definition of the scope
of the Larock macrocyclization reaction, the examination of the reverse
macrocyclization order, and the extension of the approach to additional
natural products and their key analogues are in progress and will be
disclosed in due course.
(16) Details are provided in Supporting Information.
(17) (a) Boger, D. L.; Kim, S. H.; Mori, Y.; Weng, J.-H.; Rogel, O.; Castle,
S. L.; McAtee, J. J. J. Am. Chem. Soc. 2001, 123, 1862–1871. (b) Boger,
D. L.; Kim, S. H.; Miyazaki, S.; Strittmatter, H.; Weng, J.-H.; Mori, Y.;
Rogel, O.; Castle, S. L.; McAtee, J. J. J. Am. Chem. Soc. 2000, 122, 7416–
7417.
Acknowledgment. In memory of David S. Lewy. We gratefully
acknowledge the financial support of the National Institutes of Health
(CA041101) and the Skaggs Institute for Chemical Biology. We wish
to thank Dr. S. B. Singh (Merck) for authentic samples of 1 and 2.
We wish to especially thank M. Tichenor for introducing improvements
to the Larock macrocyclization and subsequent elaboration to the DEF
ring system; Dr. J. Cottell for initiating studies on the ABCD ring
system; and D. S. Lewy, Drs. A. Pichota, L. Resnick, and W. Han for
exploration of early stage routes to the DEF ring system in which the
syntheses of the amino acid subunits were first developed. J.G. and
J.D.T. were Skaggs fellows.
(18) Reddy, K. L.; Sharpless, K. B. J. Am. Chem. Soc. 1998, 120, 1207–1217.
(19) Miyaura, N.; Suzuki, A. Chem. ReV. 1995, 95, 2457–2483.
(20) Trzupek, J. D. Ph.D. Dissertation, 2006.
(21) Jiang, W.; Wanner, J.; Lee, R. J.; Bounaud, P.-Y.; Boger, D. L. J. Am.
Chem. Soc. 2002, 124, 5288-5290 and 2003, 125, 1877-1887.
(22) (a) Boger, D. L. Med. Res. ReV. 2001, 21, 356–381. (b) Boger, D. L.;
Miyazaki, S.; Kim, S. H.; Wu, J. H.; Loiseleur, O.; Castle, S. L. J. Am.
Chem. Soc. 1999, 121, 3226–3227 and 10004-10011. (c) Boger, D. L.;
Castle, S. L.; Miyazaki, S.; Wu, J. H.; Beresis, R. T.; Loiseleur, O. J. Org.
Chem. 1999, 64, 70–80. (d) Boger, D. L.; Borzilleri, R. M.; Nukui, S.;
Beresis, R. T. J. Org. Chem. 1997, 62, 4721–4736. (e) Boger, D. L.;
Borzilleri, R. M.; Nukui, S. Bioorg. Med. Chem. Lett. 1995, 5, 3091–3096.
(f) Boger, D. L.; Borzilleri, R. M. Bioorg. Med. Chem. Lett. 1995, 5, 1187–
1190. (g) Crowley, B. M.; Boger, D. L. J. Am. Chem. Soc. 2006, 128,
2885–2892.
(23) Crowley, B. M.; Mori, Y.; McComas, C. C.; Tang, D.; Boger, D. L. J. Am.
Supporting Information Available: Full experimental details are
provided. This material is available free of charge via the Internet at http://
pubs.acs.org.
Chem. Soc. 2004, 126, 4310–4317.
(24) Abbreviations: DEPBT, 3-(diethoxyphosphoryloxy)-1,2,3-benzotriazin-4-
one; DtBPT, 1,1′-bis(di-tert-butylphosphino)ferrocene; EDCI, 1-[3-(di-
methyl-amino)propyl]-3-ethylcarbodiimide hydrochloride; HOAt, 1-hydroxy-
7-azabenzotriazole; PyBOP, (benzotriazol-1-yl)tripyrrolidinophosphonium
hexafluorophosphate.
References
(1) (a) Kaneko, I.; Fearon, D. T.; Austen, K. F. J. Immunol. 1980, 124, 1194–
1198. (b) Tachikawa, K.; Hasumi, K.; Endo, A. Thromb. Haemost. 1997,
JA907193B
9
16038 J. AM. CHEM. SOC. VOL. 131, NO. 44, 2009