Synthesis of DEFG ring of complestatin and chloropeptin I: Highly atropdiastereoselective macrocyclization by intramolecular Suzuki-Miyaura reaction

Article abstract of DOI:10.1021/ol070889p

Palladium-catalyzed intramolecular Suzuki-Miyaura reaction of linear tripeptide (23) afforded the 16-membered DEFG ring of complestatin (3) in good yield with an excellent atropdiastereoselectivity. Acidic treatment of 3 triggers a stereospecific rearrang

Full text of DOI:10.1021/ol070889p

ORGANIC
LETTERS
2007
Vol. 9, No. 12
2401-2404
Synthesis of DEFG Ring of
Complestatin and Chloropeptin I: Highly
Atropdiastereoselective Macrocyclization
by Intramolecular Suzuki-Miyaura
Reaction
Yanxing Jia, Miche`le Bois-Choussy, and Jieping Zhu*
Institut de Chimie des Substances Naturelles, CNRS,
91198 Gif-sur-YVette Cedex, France
zhu@icsn.cnrs-gif.fr
Received April 17, 2007
ABSTRACT
Palladium-catalyzed intramolecular Suzuki-Miyaura reaction of linear tripeptide (23) afforded the 16-membered DEFG ring of complestatin (3)
in good yield with an excellent atropdiastereoselectivity. Acidic treatment of 3 triggers a stereospecific rearrangement leading to the corresponding
DEFG ring 4 of chloropeptin I.
A number of biologically important natural products contain
strained macrocycle(s) with a specific atropisomeric con-
figuration(s). The vancomycin family of glycopeptide anti-
biotics that contain both planary and axially chiral cyclophane
subunits are notable examples.1 Recent additions to this class
of compounds include chloropeptin (1)2 and complestatin
(2),3 isolated from Streptomyces sp. WK-3419 and Strepto-
myces laVendulae, respectively. Both bicyclic natural cyclo-
phanes display potent activities against HIV-1 induced
cytopathicity and syncyctium formation in CD-4 lymphocytes
and inhibit HIV replication by inhibition of gp 120-CD4
binding at a low-micromolar level (IC50 ) 2.0 and 3.3 µM,
respectively).4 The absolute configurations of the amino acid
constituents of 15 and 26 were elucidated through detailed
NMR, computational, as well as degradation studies. Com-
plestatin is readily isomerized to chloropeptin I under mild
acidic conditions.7 The presence of highly racemization-prone
(4) (a) Tanaka, H.; Matsuzaki, K.; Nakashima, H.; Ogino, T.; Matsumoto,
A.; Ikeda, H.; Woodruff, H. B.; Omura, S. J. Antibiot. 1997, 50, 58-65.
(b) Matsuzaki, K.; Ogino, T.; Sunazuka, T.; Tanaka, H.; Omura, S. J.
Antibiot. 1997, 50, 66-69.
(5) Gouda, H.; Matsuzaki, K.; Tanaka, H.; Hirono, S.; Omura, S.;
McCauley, J. A.; Sprengeler, P. A.; Furst, G. T.; Smith, A. B. J. Am. Chem.
Soc. 1996, 118, 13087-13088.
(6) 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.
(7) (a) Hegde, V. R.; Dai, P.; Patel, M.; Gullo, V. P. Tetrahedron Lett.
1998, 39, 5683-5684. (b) 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.
(1) (a) Zhu, J. Expert. Opin. Ther. Pat. 1999, 9, 1005-1019. (b) Nicolaou,
K. C.; Boddy, C. N. C.; Bra¨se, S.; Winssinger, N. Angew. Chem., Int. Ed.
1999, 38, 2096-2152. (c) Williams, D. H.; Bardsley, B. Angew. Chem.,
Int. Ed. 1999, 38, 1172-1193.
(2) Matsuzaki, K.; Ikeda, H.; Ogino, T.; Matsumoto, A.; Woodruff, H.
B.; Tanaka, H.; Omura, S. J. Antibiot. 1994, 47, 1173-1174.
(3) (a) Seto, H.; Fujjioka, T.; Furihata, K.; Kaneko, I.; Takahashi, S.
Tetrahedron Lett. 1989, 30, 4987-4990. (b) Kaneko, I.; Kamoshida, K.;
Takahashi, S. J. Antibiot. 1989, 42, 236-241.
10.1021/ol070889p CCC: $37.00
© 2007 American Chemical Society
Published on Web 05/12/2007

chlorinated arylglycines and inherent difficulties associated
with the construction of strained macrocycles with defined
atropisomerism 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 Snapper
and Hoveyda group accomplished the total syntheses of
chloropeptin I (1)9 and an atropisomer of complestatin (2)
(Figure 1).10 These total syntheses have also allowed them
of this research program, we report herein the first completely
atropdiastereoselective synthesis of fully functionalized
DEFG ring (3) and (4) of complestatin and chloropeptin I,
respectively (Figure 2). The syntheses feature a key atrop-
Figure 2. DEFG fragments of chloropeptin I and complestatin.
diastereoselective intramolecular Suzuki-Miyaura reaction.
We document also that the presence of free-hydroxy group
is not required for the stereospecific isomerization of 3 to 4
under acidic conditions.
Figure 1. Structures of chloropeptin I (1) and complestatin (2).
To begin our synthesis, the tryptophane derivative 13 is
prepared as summarized in Scheme 1. Palladium-catalyzed
annulation of 2-iodo-5-nitroaniline 5 with (R)-2-N,N-di-tert-
butoxycarbonyl-5-oxopentane 6 according to our recently
developed conditions afforded the protected 6-nitro tryp-
tophane 714-16 that was subsequently converted to the
6-amino derivative (8) under standard conditions. Diazoti-
zation of aniline followed by iodination provided iodo
derivative 9, which underwent palladium-catalyzed cross
coupling with bis(pinacolato) diboron under Miyaura’s
conditions to provide the corresponding arylboronate (10).17,18
Removal of N-Boc protective groups under mild conditions
to assign the (R)-configuration to the axial chirality of both
natural products and highlighted the dependence of atrop-
selectivity on the structure of the linear precursor. Indeed,
they documented that cyclization of a model peptidic
precursor is non-atropselective leading to two atropisomers
in a 1/1 ratio.
We have a long interest in the synthesis of this type of
macrocyclic natural products11,12 and have recently ac-
complished the first total synthesis of an atropstereomer of
RP-66453,13 structurally related to 1 and 2. As a continuation
(8) 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) Beugelmans, R.; Roussi, G.; Zamora, E. G.;
Carbonnelle, A.-C. Tetrahedron 1999, 55, 5089-5112. (e) Smith, A. B.;
Chruma, J. J.; Han, Q.; Barbosa, J. Bioorg. Med. Chem. Lett. 2004, 14,
1697-1702. (f) Yamada, Y.; Akiba, A.; Arima, S.; Okada, C.; Yoshida,
K.; Itou, F.; Kai, T.; Satou, T.; Takeda, K.; Harigaya, Y. Chem. Pharm.
Bull. 2005, 53, 1277-1290; g) Yamada, Y.; Arima, S.; Okada, C.; Akiba,
A.; Kai, T.; Harigaya, Y. Chem. Pharm. Bull. 2006, 54, 788-794.
(9) Deng, H.; Jung, J.-K.; Liu, T.; Kuntz, K. W.; Snapper, M. L.;
Hoveyda, A. H. J. Am. Chem. Soc. 2003, 125, 9032-9034.
(12) Biaryl ether containing macrocycles, see: (a) Carbonnelle, A.-C.;
Zhu, J. Org. Lett. 2000, 2, 3477-3480. (b) Boisnard, S.; Carbonnelle, A.-
C.; Zhu, J. Org. Lett. 2001, 3, 2061-2064. Total synthesis of biphenomycin
B: (c) Le´pine, R.; Zhu, J. Org. Lett. 2005, 7, 2981-2984.
(13) Bois-Choussy, M.; Cristau, P.; Zhu, J. Angew. Chem., Int. Ed. 2003,
42, 4238-4241.
(14) (a) Jia, Y.; Zhu, J. Synlett 2005, 2469-2472. (b) Jia, Y.; Zhu, J. J.
Org. Chem. 2006, 71, 7826-7834.
(15) The annulation reaction has been independantly developed by the
group of Baran, see: (a) Baran, P. S.; Guerrero, C. A.; Ambhaikar, N. B.;
Hafensteiner, B. D. Angew. Chem., Int. Ed. 2005, 44, 606-609. (b) Baran,
P. S.; Hafensteiner, B. D.; Ambhaikar, N. B.; Guerrero, C. A.; Gallagher,
J. D. J. Am. Chem. Soc. 2006, 128, 8678-8693.
(10) Shinohara, T.; Deng, H.; Snapper, M. L.; Hoveyda, A. H. J. Am.
Chem. Soc. 2005, 127, 7334-7336.
(11) Aryl ether containing macrocycles, see: (a) Zhu, J. Synlett 1997,
133-144. (b) Bois-Choussy, M.; Vergne, C.; Neuville, L.; Beugelmans,
R.; Zhu, J. Tetrahedron Lett. 1997, 38, 5795-5798. (c) Bigot, A.; Tran
Huu Dau, M. E.; Zhu, J. J. Org. Chem. 1999, 64, 6283-6296. (d) Cristau,
P.; Vors, J.-P.; Zhu, J. Org. Lett. 2001, 3, 4079-4082. (e) Temal-La¨ıb, T.;
Chastanet, J.; Zhu, J. J. Am. Chem. Soc. 2002, 124, 583-590. (f)
Enantioselective cycloetherification: Islas-Gonzalez, G.; Bois-Choussy, M.;
Zhu, J. Org. Biomol. Chem. 2003, 1, 30-32.
(16) The annulation between ketone and aniline has been reported earlier
from the group of Chen, see: Chen, C.-Y.; Lieberman, D. R.; Larsen, R.
D.; Verhoeven, T. R.; Reider, P. J. J. Org. Chem. 1997, 62, 2676-2677.
(17) Ishiyama, T.; Murata, M.; Miyaura, N. J. Org. Chem. 1995, 60,
7508-7510.
(18) This substituted tryptophane has been synthesized independently
by the group of J. M. Campagne, private communication.
2402
Org. Lett., Vol. 9, No. 12, 2007

Scheme 1. Synthesis of Tryptophane Derivative 13
Scheme 2. Synthesis of
N-Boc-D-3-iodo-4,5-diisopropyloxyphenyl Glycine Methyl Ester
20
directly the amino ester 20.22 The Sharpless AA of styrene
14 with (DHQ)PHAL afforded (S)-15 in 33% yield (88%
ee). Chiral HPLC analysis indicated that the enantiomeric
excess (ee) of the (R)-15 synthesized by the Sharpless AD
method is higher than 92%.
The synthesis of linear tripeptide and subsequent macro-
cyclization via formation of the endo aryl-aryl bond is
depicted in Scheme 3. Coupling of the amino ester 20 with
D-N-Boc-3,5-dichloro-4-hydroxyphenyl glycine 21 afforded
the dipeptide 22 in 80% yield. Removal of N-Boc group from
22 (TFA, CH2Cl2) followed by coupling with tryptophane
derivative 13 (HATU, 2,5-lutidine) afforded the tripeptide
23 in 78% overall yield.
The macrocyclization via intramolecular Suzuki-Miyaura
reaction turned out to be extremely difficult to realize.12,23
After extensive optimization of reaction conditions varying
the palladium sources, the ligands, the solvents, and the
reaction temperatures, the best conditions found consist of
performing the reaction in dioxane-H2O in the presence of
1 equiv of PdCl2(dppf) and 10 equiv of K2CO3. Under these
conditions, cyclization of 23 afforded cyclophane 3 in 66%
yield as a single atropdiastereomer. The distinguishing feature
of the cyclic structure is the upfield shift of proton Ha from
δ ) 7.3 ppm in 23 to δ ) 5.7 ppm in 3, presumably due to
the anisotropic effect of indole ring. The axial chirality of 3
was determined to be R by the observation of the charac-
teristic NOE correlations as shown in Scheme 3. The
chemical shift of the proton Hb (δ ) 4.10 ppm) is also in
accord with Snapper and Hoveyda’s assignment.10
(TMSI, CHCl3, then MeOH) followed by coupling with
2-(3,5-dichloro-4-hydroxyphenyl)-2-oxoethanoic acid (11)10
furnished the keto amide (12), which was hydrolyzed to the
corresponding acid 13 under mild basic conditions.
Synthesis of D-3-iodo-4,5-diisopropyloxyphenyl glycine
methyl ester 20 is summarized in Scheme 2. Sharpless
aminohydroxylation of styrene 1419 under a variety of
conditions afforded the desired amino alcohol (15) in only
33% yield (76% ee), together with the wrong regioisomer
(16).20 The low-regioselectivity and moderate enantioselec-
tivity of this transformation prompted us to examine an
alternative, albeit longer reaction sequence using Sharpless
asymmetric dihydroxylation as a key step.21 Treatment of
14 with AD-mix-R afforded the desired (S)-diol (17) in an
excellent yield and enantiomerical purity (95% ee). The so-
obtained diol was converted to amino alcohol 18 via a
conventional three-step sequence involving (a) selective
protection of the primary alcohol; (b) Mitsunobu reaction;
and (c) reduction of azide under Staudinger conditions.
Protecting group manipulation of 18 afforded 15, which was
oxidized to the acid 19 without event. The N-Boc deprotec-
tion and esterification of carboxylic acid of 19 was realized
in methanol in the presence of thionyl chloride to afford
(19) Synthesized from known 3,4-dihydroxy-5-iodobenzaldehyde in two
steps: (a) i-PrBr, K2CO3, DMF, 55°C, 91%; (b) Ph3PCH3Br, n-BuLi, THF,
-20-0 °C, 84%.
It is interesting to note that cyclization of model tripeptide
24 lacking an OH group in the amino acid residue D gave
(20) (a) Reddy, K. L.; Sharpless, K. B. J. Am. Chem. Soc. 1998, 120,
1207-1217. (b) Liu, Z.; Ma, N.; Jia, Y.; Bois-Choussy, M.; Malabarba,
A.; Zhu, J. J. Org. Chem. 2005, 70, 2847-2850.
(22) Jia, Y.; Ma, N.; Liu, Z.; Bois-Choussy, M.; Gonzalez-Zamora, E.;
Malabarba, A.; Brunati, C.; Zhu, J. Chem.-Eur. J. 2006, 12, 5334-5351.
(23) Miyaura, N.; Suzuki, A. Chem. ReV. 1995, 95, 2457-2483.
(21) Kolb, H. C.; VanNieuwenhze, M. S.; Sharpless, K. B. Chem. ReV.
1994, 94, 2483-2547.
Org. Lett., Vol. 9, No. 12, 2007
2403

of 3 to 60 °C for 30 min, a smooth isomerization occurred
to give the corresponding DEFG ring (4) of chloropeptin I.
The proton Hc appeared as a doublet in 3 became a triplet
(J ) 8.0 Hz) in cyclophane 4 that is indicative of the ring
connectivity. This experiment showed that the presence of
a free hydroxy group is not a prerequisite to this type of
rearrangement. However, it is reasonable to assume that the
same mechanism might be operating in the isomerization of
3 to 4 (Scheme 4).
Scheme 3. Synthesis of Macrocycle 3
Scheme 4. Isomerization of 3 to 4
In summary, we have developed an efficient synthesis of
strained DEFG ring 3 of complestatin featuring a key
atropdiastereoselective intramolecular Suzuki-Miyaura reac-
tion. The palladium-catalyzed heteroannulation and the
Sharpless asymmetric dihydroxylation have been used as key
steps for the syntheses of non-proteinogenic amino acids 10
and 20, respectively. We also documented that the presence
of free phenol group is not compulsory for the stereospecific
rearrangement of 3 to the corresponding chloropeptin I
subunits 4. We are exploiting these results for the atrop-
stereoselective total syntheses of both complestatin and
chloropeptin I.
the two atropstereoisomers in a one to one ratio under similar
reaction conditions.10 The atropstereoselectivity of this
intramolecular Suzuki-Miyaura reaction is thus highly sub-
strate-dependent.24
Acknowledgment. The financial supports from CNRS
and the Institut de Chimie des Substances Naturelles are
gratefully acknowledged.
Stereospecific rearrangement of complestatin to chloropep-
tin I has been reported that involved the participation of free
hydroxy group.7 We found that upon heating a TFA solution
Supporting Information Available: Experimental de-
tails, physical data for compounds 5-10, 12-19, 22, 23, 3,
4, and copies of 1H NMR specrtra. This material is available
free of charge via the Internet at http://pubs.acs.org.
(24) For a review on conformation-directed macrocyclizaiton, see:
Blankenstein, J.; Zhu, J. Eur. J. Org. Chem. 2005, 1949-1964
OL070889P
2404
Org. Lett., Vol. 9, No. 12, 2007