Total synthesis of apratoxin A

Article abstract of DOI:10.1021/ol052907d

We have achieved a total synthesis of apratoxin A in which thiazoline formation was accomplished from the moCys containing amide 4 using PPh ₃(O)/Tf₂O. Deprotection of the Troc and allyl ester in 17, coupling with tripeptide 3, and d

Full text of DOI:10.1021/ol052907d

ORGANIC
LETTERS
2006
Vol. 8, No. 3
531-534
Total Synthesis of Apratoxin A
Takayuki Doi,* Yoshitaka Numajiri, Asami Munakata, and Takashi Takahashi*
Department of Applied Chemistry, Tokyo Institute of Technology, 2-12-1, Ookayama,
Meguro, Tokyo 152-8552, Japan
doit@apc.titech.ac.jp; ttak@apc.titech.ac.jp
Received November 30, 2005
ABSTRACT
We have achieved a total synthesis of apratoxin A in which thiazoline formation was accomplished from the moCys containing amide 4 using
PPh3(O)/Tf2O. Deprotection of the Troc and allyl ester in 17, coupling with tripeptide 3, and deprotection of the allyl ester and the Fmoc,
followed by macrolactamization provided apratoxin A (1).
Apratoxin A (1), isolated from the marine cyanobacterium
Lyngbya majuscula, exhibits potent cytotoxic activity.1
Apratoxin A is a 25-membered cyclic depsipeptide consisting
of a proline, three methylated amino acids (N-methylisoleu-
cine, N-methylalanine, O-methyltyrosine), an R,â-unsaturated
modified cysteine residue (moCys), and a dihydroxylated
fatty acid moiety, 3,7-dihydroxy-2,5,8,8-tetramethylnonanoic
acid (Dtena). An elegant total synthesis of 1 has been
achieved by Forsyth and Chen.2 They prepared the thiazoline
moiety via a unique intramolecular Staudinger reduction/
aza-Wittig process on an R-azido thioester. The synthesis
of an oxazoline analogue has recently been reported by Ma
et al.3,4 Having described a library synthesis of the cyclic
depsipeptide aurilide and a number of analogues using a
polymer support,5 we became interested in the library
synthesis of apratoxin A analogues. As a part of the effort,
we now wish to report a total synthesis of apratoxin A.
Our synthetic strategy is illustrated in Scheme 1. In
principle, apratoxin A (1) can be synthesized from the
coupling of Fmoc-Pro-Dtena-moCys-OH 2 with the
tripeptide, H-Tyr(O-Me)-N-Me-Ala-N-Me-Ile-OAll (3),
if followed by macrolactamization2 between the proline and
N-methylisoleucine residues. The synthesis of 2 is potentially
problematic because the thiazoline ring is labile toward acid
hydrolysis, and there is a risk of epimerization at the chiral
(1) (a) Luesch, H.; Yoshida, W. Y.; Moore, R. E.; Paul, V. J.; Corbett,
T. H. J. Am. Chem. Soc. 2001, 123, 5418-5423. (b) Luesch, H.; Yoshida,
W. Y.; Moore, R. E.; Paul, V. J. Bioorg. Med. Chem. 2002, 10, 1973-
1978.
(2) (a) Chen, J.; Forsyth, C. J. J. Am. Chem. Soc. 2003, 125, 8734-
8735. (b) Chen, J.; Forsyth, C. J. Proc. Natl. Acad. Sci. 2004, 101, 12067-
12072.
(3) Zou, B.; Wei, J.; Cai, G.; Ma, D. Org. Lett. 2003, 5, 3503-3506.
(4) Total synthesis of apratoxin A has been presented in the 2nd Yamada
Symposium on Key Natural Organic Molecules in Biological Systems, 2005,
Hyogo, Japan.
(5) Takahashi, T.; Nagamiya, H.; Doi, T.; Griffiths, P. G.; Bray, A. M.
J. Comb. Chem. 2003, 5, 414-428.
10.1021/ol052907d CCC: $33.50
© 2006 American Chemical Society
Published on Web 01/12/2006

Scheme 1. Retrosynthesis of Apratoxin A (1)
Scheme 2
followed by removal of the acetyl group, provided primary
allylic alcohol 9 in 78% yield after separation by silica gel
column chromatography. Ru(OAc)2[(S)-binap]-catalyzed asym-
metric hydrogenation of 9 under 100 atm of hydrogen12
afforded 10 in quantitative yield (>95% ds).13 Swern
oxidation of 10, followed by a Paterson anti-aldol reaction
with 11,14 and protection of the resultant adduct with TBS
provided 12 in 67% overall yield.15 Removal of the MPM
group from 12 was next accomplished with DDQ, and a
subsequent coupling with N-Boc-Pro-OH by the Yamagu-
chi method16 afforded 13, which was in good accordance
with Forsyth’s intermediate.2 Removal of the benzoate from
13 and oxidative cleavage of the resultant R-hydroxyketone
provided acid 6, as reported previously.2
center attached to the 2-position of a thiazoline.1b,2,6-8 As a
consequence, we therefore planned to effect a dehydrative
thiazoline formation on the moCys-containing amide 4.9,10
Amide 4 could potentially be prepared from the coupling of
the moCys residue 5 with the Dtena moiety 6.
The MPM protection of (S)-5,5-dimethyl-4-hydroxy-2-
hexanone (7), prepared by a proline-catalyzed aldol reaction
of acetone with pivaldehyde,11 was followed by allylation
and acetylation to afford 8 (Scheme 2). Palladium(II)-
catalyzed isomerization of allylic acetate (E/Z ) 9:1),
(6) Wipf, P.; Fritch, P. C. J. Am. Chem. Soc. 1996, 118, 12358-12367.
(7) McKeever, B.; Pattenden, G. Tetrahedron 2003, 50, 2713-2727.
(8) Yu, S.; Pan, X.; Lin, X.; Ma, D. Angew. Chem., Int. Ed. 2005, 44,
135-138.
(9) Forsyth reported that thiazoline formation from the thioester of the
modified cysteine derivative could not avoid elimination of the adjacent
hydroxy group corresponding to the C35 position.
(12) Takaya, H.; Ohta, T.; Sayo, N.; Kumobayashi, H.; Akutagawa, S.;
Inoue, S.; Kasahara, I.; Noyori, R. J. Am. Chem. Soc. 1987, 109, 1596-
1597.
(10) We attempted thioamide formation from N-Boc-Pro-Dtena(O-
TBS)-moSer(O-TBS)-OAll using a Lawesson reagent. However, it failed
because of Michael addition of the formed thioamide to the R,â-unsaturated
ester. The similar result was also recently reported. Xu, Z.; Ye, T.
Tetrahedron: Asymmetry 2005, 16, 1905-1912.
(11) (a) List, B.; Lerner, R. A.; Barbas, C. F., III. J. Am. Chem. Soc.
2000, 122, 2395-2396. (b) List, B. Synlett 2001, 1675-1685. (c) List, B.;
Pojarliev, P.; Castello, C. Org. Lett. 2001, 3, 573-575.
(13) The stereochemistry was determined by nOe observation after
formation of lactone with the secondary alcohol.
(14) Paterson, I.; Wallace, D. J.; Cowden, C. J. Synthesis 1998, 639-
652.
(15) Forsyth did the aldol reaction after attachment with proline
carboxylic acid. See ref 2.
(16) Inanaga, J.; Hirata, K.; Saeki, H.; Katsuki, T.; Yamaguchi, M. Bull.
Chem. Soc. Jpn. 1979, 52, 1989-1993.
532
Org. Lett., Vol. 8, No. 3, 2006

Scheme 3
The key intermediate 4 was prepared from N-Boc-D-Cys-
proceeded cleanly to give the desired thiazoline 17.21
Compound 17 was then immediately treated with Zn-NH4-
OAc22 to remove its Troc group; this did not adversely affect
the thiazoline ring or the adjacent stereogenic center and gave
18 in 90% yield. Treatment of 18 with Pd(PPh3)4/N-
methylaniline3,23 provided 2 in 95% yield.24
Tripeptide 3 was prepared by sequential coupling of
N-methylisoleucine allyl ester with N-Boc-N-methylalanine
and N-Fmoc-O-methyltyrosine by repeated treatment with
HATU-DIEA and then finally Et2NH in CH3CN. Coupling
of 2 and 3 (HATU/DIEA/CH2Cl2) provided 19 in 71% yield
(S-Trt)-OH (14) as follows (Scheme 3): DIBAL reduction
of its Weinreb amide, followed by Wittig olefination,
afforded (E)-15, selectively. Hydrolysis of the ethyl ester,
allyl ester formation, and selective deprotection of the N-Boc
group in the presence of S-Trt (TMSOTf/2,6-lutidine; MeOH)
provided 5.17 Condensation of 5 and 6 (HATU18/DIEA/CH2-
Cl2) gave 16 in 85% yield. Following multistep conversion
of TBS ether 16 into the 2,2,2-trichloroethoxycarbonyl (Troc)
ester 4, the latter was treated with PPh3(O)/Tf2O in CH2Cl2
at 0 °C to induce thiazoline formation.19,20 The reaction
Scheme 4
Org. Lett., Vol. 8, No. 3, 2006
533

(Scheme 4). Cleavage of the O-allyl ester from 19 with Pd-
(PPh3)4/N-methylaniline, followed by removal of the Fmoc
group with Et2NH/CH3CN, afforded the cyclization precursor
20. Finally, the macrolactamization of 20 was performed with
HATU/DIEA. After purification by silica gel chromatogra-
phy, apratoxin A (1) was isolated in 53% yield. The spectral
data of the synthetic 1 were identical to those of the natural
product reported previously.1,2
In summary, a total synthesis of apratoxin A has been
achieved via a convergent strategy involving HATU mac-
rolactamization. Thiazoline formation in 2 was also success-
fully accomplished from the moCys amide 4 using PPh3(O)/
Tf2O. Further refinement of the synthetic scheme for the
synthesis of a combinatorial library of its analogues is
currently underway in our laboratory.
(17) (a) Sakaiani, M.; Ofune, Y. Tetrahedron Lett. 1985, 26, 5543-
5546. (b) Sakaitani, M.; Ofune, Y. J. Org. Chem. 1990, 55, 870-876. (c)
Borgulya, J.; Bernauer, K. Synthesis 1980, 545-547.
(18) HATU ) O-(7-azabenzotriazol-1-yl)-1,1,3,3-tetramethyluronium
hexafluorophosphate: Carpino, L. A. J. Am. Chem. Soc. 1993, 115, 4397-
4398.
(19) You, S.; Razavi, H.; Kelly, J. W. Angew. Chem., Int. Ed. 2003, 42,
83-85.
Acknowledgment. This work was supported by a Grant-
in-Aid from the Ministry of Education, Culture, Sports,
Science, and Technology, Japan (No. 14103013).
(20) Although other methods were evaluated for effecting this transfor-
mation, these proved problematic. (a) Walker, M. A.; Hearthcock, C. H. J.
Org. Chem. 1992, 57, 5566-5568. (b) Parsons, R. L. J.; Heathcock, C. H.
Synlett 1996, 1168-1170. (c) Kuriyama, N.; Akaji, K.; Kiso, Y. Tetrahedron
1997, 53, 8323-8334. (d) Raman, P.; Razavi, H.; Kelly, J. W. Org. Lett.
2000, 2, 3289-3292 and references therein.
Supporting Information Available: Experimental pro-
cedures and 1H and 13C NMR spectra of 1-6, 9, 10, 12, 13,
15, 16, 18, and 19. This material is available free of charge
via the Internet at http://pubs.acs.org.
(21) The â-elimination of the O-Troc group was observed during silica
gel column purification.
(22) The use of acetic acid instead of NH4OAc resulted in hydrolysis of
the thiazoline ring.
(23) Ciommer, M.; Kunz, H. Synlett 1991, 593-595.
(24) The use of morpholine instead of N-methylaniline cleaved the Fmoc
group on the proline ring in 2.
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Org. Lett., Vol. 8, No. 3, 2006