Total syntheses of thiocoraline and BE-22179: Establishment of relative and absolute stereochemistry [7]

Full text of DOI:10.1021/ja0001660

2956
J. Am. Chem. Soc. 2000, 122, 2956-2957
Total Syntheses of Thiocoraline and BE-22179:
Establishment of Relative and Absolute
Stereochemistry
Dale L. Boger* and Satoshi Ichikawa
Department of Chemistry and
The Skaggs Institute for Chemical Biology
The Scripps Research Institute
10550 North Torrey Pines Road, La Jolla, California 92037
ReceiVed January 18, 2000
Thiocoraline (1, Figure 1) is a potent antitumor antibiotic1
isolated from Micromonospora sp. L-13-ACM2-092. It constitutes
the newest member of the 2-fold symmetric bicyclic octadep-
sipeptides which include BE-221792 (2), triostin A3 (3), and
echinomycin4 (4), which bind to DNA with bisintercalation.5,6
Unlike BE-22179, thiocoraline does not inhibit DNA topoi-
somerase I or II, but it does inhibit DNA polymerase R at
concentrations that inhibit cell cycle progression and clonoge-
nicity.7 It was found to unwind double-stranded DNA,7 and thus
it may bisintercalate DNA analogous to triostin, echinomycin,
and members of the larger cyclic decadepsipeptides including
sandramycin,8,9 luzopeptins,9,10 and quinoxapeptins.11 Studies on
thiocoraline as well as BE-22179 have established their two-
dimensional structures but not their relative and absolute stereo-
chemistry.1,2 Triostin and echinomycin possess a D-stereochemistry
at the R-position of the amide linkage to the quinoxaline
chromophore (D-Ser) and L-stereochemistry at the remaining
stereogenic centers. We have shown that the analogous centers
of sandramycin8 and the quinoxapeptins,11 like the luzopeptins,10
also incorporate D-Ser. Thus, we anticipated that 1, as well as 2,
might possess a similar stereochemistry with incorporation of an
unusual chromophore bearing D-Cys. Herein, we report the first
total syntheses of thiocoraline and BE-22179, the determination
of their relative and absolute stereochemistry, and the preparation
of sufficient material with which further studies may be conducted.
Key elements of the approach include the late stage introduction
of the chromophore, symmetrical tetrapeptide coupling, macro-
Figure 1.
cyclization of the 26-membered octadepsipeptide conducted at
the single secondary amide site following disulfide formation,
and a convergent assemblage of the tetradepsipeptide with
introduction of the labile thiol ester linkage in the final coupling
reaction under near racemization free conditions. By virtue of
the late stage introduction of the chromophore and despite the
challenges this imposes in the synthesis because of a potential
cleavage of the macrocyclic thiol ester, this approach provides
ready access of a range of chromophore analogues.
The assemblage of tetradepsipeptide 16 from tripeptide 15 and
N-Cbz-D-Cys-OTce (12) along with the preparation of the three
suitably functionalized Cys residues found in 1 are summarized
in Scheme 1. Sequential S- and N-protection of N-Me-Cys-OH
(5)12 with an acetamidomethyl (Acm) group (1.5 equiv of
N-hydroxymethylacetamide, H2SO4, H2O, 25 °C, 12 h) and BOC
group (1.2 equiv of BOC2O, NaOH, THF-H2O, 25 °C, 12 h,
62%) gave 6, the precursor to the bridging disulfide Cys residue.
Selective S-methylation of N-Me-Cys-OH (5,12 1.0 equiv of MeI,
2.0 equiv of NaHCO3, THF-H2O, 25 °C, 3 h) followed by BOC
protection (1.2 equiv of BOC2O, NaOH, THF-H2O, 25 °C, 12
h, 73%) provided 7. Esterification of 7 (1.0 equiv of TMSCHN2,
89%) followed by BOC deprotection of 8 (3 M HCl-AcOEt,
91%) provided 9, the precursor to the second L-Cys residue.
(1) (a) Romeo, F.; Espliego, F.; Baz, J. P.; de Quesada, T. G.; Gravalos,
D.; de la Calle, F.; Fernandez-Puentes, J. L. J. Antibiot. 1997, 50, 734. (b)
Perez Baz, J.; Canedo, L. M.; Fernandez-Puentes, J. L. J. Antibiot. 1997, 50,
738. (c) Perez Baz, J.; Millan, F. R.; De Quesada, T. G.; Gravalos, D. G.
PCT Int. Appl., WO952773, 1995; Chem. Abstr. 1995, 124, 115561.
(2) Okada, H.; Suzuki, H.; Yoshinari, T.; Arakawa, H.; Okura, A.; Suda,
H. J. Antibiot. 1994, 47, 129.
(3) (a) Shoji, J.; Katagiri, K. J. Antibiot. 1961, 14, 335. (b) Shoji, J.; Tori,
K.; Otsuka, H. J. Org. Chem. 1965, 30, 2772. (c) Otsuka, H.; Shoji, J.
Tetrahedron 1967, 23, 1535. (d) Otsuka, H.; Shoji, J.; Kawano, K.; Kyogoku,
Y. J. Antibiot. 1976, 29, 107.
(4) (a) Corbaz, R.; Ettlinger, L.; Graumann, E.; Keller-Schierlein, W.;
Kradolfer, F.; Neipp, L.; Prelog, V.; Reusser, P.; Zahner, H. HelV. Chim. Acta
1957, 40, 199. (b) Keller-Schierlein, W.; Prelog, V. HelV. Chim. Acta 1957,
40, 205. (c) Keller-Schierlein, W.; Mihailovic, M. Lj.; Prelog, V. HelV. Chim.
Acta 1959, 42, 305. (d) Martin, D. G.; Mizsak, S. A.; Biles, C.; Stewart, J.
C.; Baczynskyj, L.; Meulman, P. A. J. Antibiot. 1975, 28, 332. (e) Dell, A.;
Williams, D. H.; Morris, H. R.; Smith, G. A.; Feeney, J.; Roberts, G. C. K.
J. Am. Chem. Soc. 1975, 97, 2497.
(5) (a) Waring, M. J.; Wakelin, L. P. G. Nature 1974, 252, 653. (b) Wang,
A. H.-J.; Ughetto, G.; Quigley, G.; Hakoshima, T.; van der Marel, G. A.; van
Boom, J. H.; Rich, A. Science 1984, 225, 1115. (c) Quigley, G. J.; Ughetto,
G.; van der Marel, G. A.; van Boom, J. H.; Wang, A. H.-J.; Rich, A. Science
1984, 232, 1255.
(6) Yoshinari, T.; Okada, H.; Yamada, A.; Uemura, D.; Oka, H.; Suda,
H.; Okura, A. Jpn. J. Cancer Res. 1994, 85, 550.
(7) (a) Erba, E.; Bergamaschi, D.; Ronzoni, S.; Taverna, S.; Bonfanti, M.;
Catapano, C. V.; Faircloth, G.; Jimeno, J.; D’lncalci, M. Br. J. Cancer 1999,
80, 971. (b) Yoshinari, T.; Okada, H.; Yamada, A.; Uemura, D.; Oka, H.;
Okura, A. Jpn. J. Cancer Res. 1994, 85, 550.
(8) Isolation: Matson, J. A.; Bush, J. A. J. Antibiot. 1989, 42, 1763. Total
synthesis: Boger, D. L.; Chen, J.-H. J. Am. Chem. Soc. 1993, 115, 11624.
Boger, D. L.; Chen, J.-H.; Saionz, K. W. J. Am. Chem. Soc. 1996, 118, 1629.
(9) Boger, D. L.; Chen, J.-H.; Saionz, K. W.; Jin, Q. Bioorg. Med. Chem.
1998, 6, 85.
(10) Isolation: Konishi, M.; Ohkuma, H.; Sakai, F.; Tsuno, T.; Koshiyama,
H.; Naito, T.; Kawaguchi, H. J. Antibiot. 1981, 34, 148. Structure and
stereochemistry: Arnold, E.; Clardy, J. J. Am. Chem. Soc. 1981, 103, 1243.
Total synthesis (luzopeptins A-C): Boger, D. L.; Ledeboer, M. W.; Kume,
M. J. Am. Chem. Soc. 1999, 121, 1098. Boger, D. L.; Ledeboer, M. W.; Kume,
M.; Searcey, M.; Jin, Q. J. Am. Chem. Soc. 1999, 121, 11375.
(11) Isolation: Lingham, R. B.; Hsu, A. H. M.; O’Brien, J. A.; Sigmund,
J. M.; Sanchez, M.; Gagliardi, M. M.; Heimbuch, B. K.; Genilloud, O.; Martin,
I.; Diez, M. T.; Hirsch, C. F.; Zink, D. L.; Liesch, J. M.; Koch, G. E.; Garter,
S. E.; Garrity, G. M.; Tsou, N. N.; Salituro, G. M. J. Antibiot. 1996, 49, 253.
Total synthesis: Boger, D. L.; Ledeboer, M. W.; Kume, M.; Jin, Q. Angew.
Chem., Int. Ed. 1999, 38, 2424.
(12) Blondeau, P.; Berse, C.; Gravel, D. Can. J. Chem. 1967, 45, 49.
10.1021/ja0001660 CCC: $19.00 © 2000 American Chemical Society
Published on Web 03/14/2000

Communications to the Editor
J. Am. Chem. Soc., Vol. 122, No. 12, 2000 2957
Scheme 1
of EDCI, HOAt, DMF, -20 °C, 4 h, 83%) in the absence of
added base to afford 16 (de 95:5). Much lower conversions were
observed using DPPA14 or DEPC14 and Et3N due in part to
competitive base-catalyzed formation of disulfide 10. Analogous
to prior reports,14 near complete racemization was observed (16:
epi-16 ) 58:42) when the nonpolar solvent CH2Cl2 was used.
The use of base in all reactions following formation of the thiol
ester 16 was found to lead to competitive â-elimination or
cleavage of the thiol ester and was avoided. Linear octadepsipep-
tide formation was accomplished by deprotection of the amine
(3 M HCl-AcOEt, 100%) and carboxylic acid (Zn, 90% aqueous
AcOH, 0 °C, 1.5 h, 99%) of 16 to provide 17 and 18, respectively,
which were coupled with formation of the secondary amide in
the absence of added base (1.2 equiv of EDCI, HOAt, CH2Cl2, 0
°C, 4 h, 83%) to obtain 19. Cyclization of 19 to provide the 26-
membered cyclic octadepsipeptide 23 with ring closure conducted
at the single secondary amide site was accomplished by sequential
Tce ester deprotection (Zn, 90% aqueous AcOH, 0 °C, 1.5 h),
disulfide bond formation15 (I2, CH2Cl2-MeOH, 25 °C, 0.001 M,
53% for 2 steps), and BOC deprotection (3 M HCl-dioxane)
followed by treatment with EDCI-HOAt (5.0 equiv of EDCI,
HOAt, 0.001 M CH2Cl2, -20 °C, 6 h, 61% for 2 steps). Reversing
the N-BOC deprotection and disulfide bond formation steps in
this 4-step sequence resulted in lower conversions (13% overall).
To date, all attempts to effect ring closure followed by disulfide
bond formation have not been successful. Even though the 26-
membered-ring macrocyclization reaction proceeds exceptionally
well (>50%), the subsequent disulfide bond formation (I2, CH2-
Cl2-MeOH, 25 °C) fails to occur. Thus, the order of steps enlisted
for formation of 23 was not to improve macrocyclization via the
constrained disulfide, but rather to permit disulfide bond forma-
tion. While it is possible this may be due to constraints within
the macrocycle destabilizing the disulfide, the lack of similar
observations with 3 suggests the origin of the difficulties may lie
with competitive cleavage of the adjacent thiol ester by the
liberated bridging thiol within the 26-membered macrocycle.
Removal of the Cbz protecting group under mild conditions16
(TFA-thioanisole, 25 °C, 4 h) and coupling of 24 with 3-hydroxy-
quinoline-2-carboxylic acid (25,17,18 5.0 equiv of EDCI, DMAP,
CH2Cl2, 25 °C, 24 h, 43%) without protection of the chromophore
Compound 11, the chromophore bearing D-Cys residue, was
prepared by the reduction of its disulfide precursor 10 (1.0 equiv
of Ph3P, 2-mercaptoethanol, H2O, THF, 50 °C, 6 h, 99%) which
in turn was obtained by stepwise Cbz (2.1 equiv of CbzCl, 4.0
equiv of NaHCO3, THF-H2O, 0-25 °C) and Tce (2.5 equiv of
trichloroethanol, 3.0 equiv of DCC,13 HOBt,13 pyridine, -20 °C,
48 h, 76%) protection of D-cystine. Coupling of 6 with 9 (1.0
equiv of EDCI,13 HOAt,13 NaHCO3, CH2Cl2, 0 °C, 12 h, 78%)
provided 12. BOC deprotection of 12 (3 M HCl-AcOEt, 100%),
coupling with N-BOC-Gly-OH (1.5 equiv of EDCI, HOAt,
NaHCO3, CH2Cl2, 0 °C, 12 h, 68%), and methyl ester hydrolysis
of 14 (3 equiv of LiOH, THF-MeOH-H2O, 25 °C, 1.5 h, 100%)
provided 15.
phenol provided (-)-1, [R]25D -180 (c 0.11, CHCl3) [lit.1 [R]25
D
-191 (c 1.1, CHCl3)], identical in all respects with the properties
reported for natural material.1 Under these conditions, a prob-
lematic intramolecular S-N acyl migration to the liberated amine
with cleavage of the thiol ester was minimized.19 Treatment of 1
with NaIO4 (10 equiv, acetone-H2O, 25 °C, 12 h) served to
provide the bis-sulfoxide as a mixture of diastereomers which
was warmed in CH2Cl2 (reflux, 6 h, 66% overall) to promote
elimination and provide BE-22179, identical in all respects with
the properties reported for natural material.2 Thus, the correlations
of synthetic and natural 1 and 2 confirm the two-dimensional
structure assignments and establish the relative and absolute
stereochemisties as those shown in Scheme 1. Sufficient synthetic
material (14 steps, >5% overall for 1) was assembled to permit
further studies on the natural products and their results will be
disclosed in due course.
The key thiol esterification reaction linking the D-cysteine
derivative 11 and the tripeptide 15 was accomplished under near
racemization free conditions with use of EDCI-HOAt (1.2 equiv
(13) DCC ) dicyclohexylcarbodiimide; EDCI ) 1-(3-dimethylaminopro-
pyl)-3-ethylcarbodiimide hydrochloride; HOBt ) 1-hydroxybenzotriazole;
HOAt ) 1-hydroxy-7-azabenzotriazole.
(14) DPPA ) diphenyl phosphorazidate; DEPC ) diethyl phosphorocy-
anidate. (a) Yamada, S.; Yokoyama, Y.; Shioiri, T. J. Org. Chem. 1974, 39,
3302. (b) Yokoyama, Y.; Shioiri, T.; Yamada, S. Chem. Pharm. Bull. 1977,
25, 2423.
(15) Kamber, B.; Hartmann, A.; Eisler, K.; Riniker, B.; Rink, H.; Sieber,
P.; Rittel, W. HelV. Chim. Acta 1980, 63, 899.
Acknowledgment. We gratefully acknowledge the financial support
of the National Institutes of Health (CA41101), The Skaggs Institute for
Chemical Biology, and the Japan Society for Promotion of Sciences (S.I.).
(16) Kiso, Y.; Ukawa, K.; Akita, T. J. Chem. Soc., Chem. Commun. 1980,
101.
(17) Prepared from methyl 3-hydroxyquinoline-2-carboxylate19 by treatment
with LiOH, THF-MeOH-H2O 3/1/1, 25 °C, 2 h (71%).
(18) Boger, D. L.; Chen, J.-H. J. Org. Chem. 1995, 60, 7369.
(19) Preliminary efforts enlisting Fmoc and basic deprotection conditions
vs Cbz protecting groups on 23 failed to provide 24 or 1. In addition, effort
to first form the symmetrical disulfide of 16 followed by simultaneous
formation of both secondary amides of the macrocycle led to a complex
mixture of products.
Supporting Information Available: Full experimentals and charac-
terization of 1, 2, 6-12, 14, 16, 19, and 23 (PDF). This material is
available free of charge via the Internet at http://pubs.acs.org.
JA0001660