Total Synthesis of (-)-Motuporin

Full text of DOI:10.1021/jo9904617

3000
J . Org. Chem. 1999, 64, 3000-3001
Tota l Syn th esis of (-)-Motu p or in
Tao Hu and J ames S. Panek*
Department of Chemistry, Metcalf Center for Science and
Engineering, 590 Commonwealth Avenue, Boston University,
Boston, Massachusetts 02215
Received March 15, 1999
Motuporin 1a is a cyclic pentapeptide recently identified
through an enzyme assay-guided screening of crude extracts
from the marine sponge Theonella swinhoei Gray (Figure
1).1 Motuporin and the structurally related agent nodularin
1b, isolated from the cyanophyte Nodularin spumogena,2
have displayed potent inhibitory activity against a number
of protein phosphatases. Members of a related family of
hepatotoxic heptapeptides, the mycrocystins, have also
displayed inhibitory activity against protein phosphatases.3
The crucial biochemical role that the protein serine and
threonine phosphatases (PSPs) play in intracellular signal-
ing processes has generated much interest in the ability of
peptides bearing Adda [(2S,3S,8S,9S)-3-amino-9-methoxy-
2,6,8-trimethyl-10-phenyldeca-4,6-dienoic acid] to inhibit the
activity of these phosphatases.4-6 The first total synthesis
of motuporin was reported in 1995 from Schreiber’s group,
and the synthesis of microcystin was recently achieved by
Chamberlin and co-workers.5 This Communication reports
a highly convergent, asymmetric synthesis of 1a and docu-
ments an efficient Pd(0)-mediated cross-coupling reaction for
the construction of the trisubstituted (E,E)-diene in a peptide
system.
Our approach, outlined in Figure 1, utilized asymmetric
crotylation methodology for the introduction of the stereo-
genic centers. Motuporin (1a ) is divided into two principal
fragments, N-Boc-valine-Adda fragment 2 and the remaining
tripeptide fragment 3. Disconnection of 2 at the C5-C6 bond
produces two subunits, the vinyl metal species (4, C6-C10
subunit) and the (E)-vinyl iodide dipeptide 5. Both the right-
hand subunit 5 and the R-azido ester 6 are conveniently
derived from azido alcohol 7. Further retrosynthetic discon-
nection of the individual subunits produced two chiral silane
reagents, of which the anti-azido silane 9 is derived from
the unsubstituted silane reagent (S)-8 through the stereo-
selective azidation of its â-silyl enolate.7
F igu r e 1.
Sch em e 1
Synthesis of 2 required the construction of the right-hand
subunit 5 and the C6-C10 subunit 4 which were joined
together through a Pd(0)-catalyzed cross-coupling reaction
to construct the carbon framework of this valine-Adda
dipeptide fragment. The preparation of the left-hand subunit
4 has been previously reported in our synthesis of Adda
(1) Dilip de Silva, E.; Williams, D. E.; Anderson, R. J .; Klix, H.; Holmes,
C. F. B.; Allen, T. M. Tetrahedron Lett. 1992, 33, 1561-1564.
(2) (a) Rinehart, K. L.; Harada, K.; Namikoshi, M.; Munro, M. H. G.;
Blunt, J . W.; Mulligan, P. E.; Beasley, V. R.; Dahlem, A. M.; Carmichael,
W. W. J . Am. Chem. Soc. 1988, 110, 8557-8558. (b) Namikoshi. M.; Choi,
B. W.; Sakai, R.; Sun, F.; Rinehart, K. L.; Carmichael, W. W.; Evans, W.
R.; Cruz, P.; Munro, M. H. G.; Blunt, J . W. J . Org. Chem. 1994, 59, 2349-
2357.
(3) Goldberg, J .; Huang, H.; Kwon, Y.; Greengard, P.; Nairn, A. C.;
Kuriyan, J . Nature 1995, 376, 745-753 and references therein.
(4) Synthesis of Adda derivatives: (a) Namikoshi, M.; Rinehart, K. L.;
Dahlem, A. M.; Beasley, V. R.; Carmichael, W. W. Tetrahedron Lett. 1989,
30, 4349-4352. (b) Chakraborty, T. K.; J oshi, S. P. Tetrahedron Lett. 1990,
31, 2043-2046. (c) Beatty, M. F.; White, C. J .; Avery, M. A. J . Chem. Soc.,
Perkin Trans. 1 1992, 1637-1641. (d) Kim, H. Y.; Toogood, P. L. Tetrahedron
Lett. 1996, 37, 2349-2352. (e) D’Aniello, F.; Mann, A.; Taddei, M. J . Org.
Chem. 1996, 61, 4870-4871. (f) Sin, N.; Kallmerten, J . Tetrahedron Lett.
1996, 37, 5645-5648. (g) Cundy, D. J .; Donohue, A. C.; McCarthy, T. D.
Tetrahedron Lett. 1998, 39, 5125-5128.
utilizing asymmetric crotylation methodology.6 The 1,3-azido
alcohol 7, obtained via a sequential diastereoselective cro-
tylation and allylic azide isomerization reaction,6 was pro-
tected as its TBDPS ether, at which point the azide group
was subsequently reduced with SnCl2 in anhydrous metha-
nol (0 °C f rt, 4 h). The resulting crude amine was directly
condensed with the pentafluorophenyl ester activated N-Boc-
L-valine in a dioxane/aqueous NaHCO3 biphasic reaction
system at rt to afford dipeptide 10 in high yield (86%, three
steps, Scheme 1). Oxidative cleavage of the (E)-olefin of 10
gave a sensitive aldehyde which was immediately subjected
to Takai’s homologation protocol8 to afford the geometrically
pure (E)-vinyl iodide 5 in 74% yield, completing the synthesis
of the right-hand fragment.
(5) (a) Valentekovich, R. L.; Schreiber, S. L. J . Am. Chem. Soc. 1995,
117, 9069-9070. (b) Humphrey, J . M.; Aggen, J . B.; Chamberlin, A. R. J .
Am. Chem. Soc. 1996, 118, 11759-11770.
(6) Panek, J . S.; Hu, T. J . Org. Chem. 1997, 62, 4914-4915.
(7) Panek, J . S.; Beresis, R.; Xu, F.; Yang, M. J . Org. Chem. 1991, 56,
7342-7344.
(8) Takai, K.; Nitta, K.; Utimoto, K. J . Am. Chem. Soc. 1986, 108, 7408-
7410.
10.1021/jo9904617 CCC: $18.00 © 1999 American Chemical Society
Published on Web 04/14/1999

Communications
J . Org. Chem., Vol. 64, No. 9, 1999 3001
Sch em e 2
Sch em e 3
Coupling of 4 and 5 utilized a modified Negishi protocol,9
catalyzed by Pd(Ph3P)4. Hydrozirconation of alkyne 126 using
Schwartz’s reagent10 [Cp2Zr(H)Cl] (2.0 equiv, THF, 50 °C,
1.0 h) produced the (E)-trisubstituted zirconate as a single
isomer.9a This was followed by an in situ transmetalation
with anhydrous ZnCl2 (3.0 equiv, rt, 2.0 min) to afford the
vinyl zinc species 4. This material was immediately treated
with vinyl iodide 5 (1.0 equiv) and Pd(PPh3)4 (5 mol %),
affording the configurationally pure (E,E)-diene in 81% yield
(Scheme 2).11 This one-pot sequence involving a bimetallic-
mediated transformation gave the fully functionalized va-
line-Adda precursor 13.12 This intermediate was readied for
fragment coupling by conversion to the carboxylic acid via
a two-step sequence: (i) silyl group deprotection with TBAF‚
SiO2 (2.5 equiv, rt, 4 h, 95%) and (ii) oxidation of the derived
primary alcohol with a modified Ley’s oxidation protocol
(TPAP/NMO, CH3CN, 1 h; then H2O, rt, 18 h),13 afforded
the N-Boc-valine-Adda fragment 2 in 87% yield.
The preparation of tripeptide 3 began with the elaboration
of intermediate 7 (Scheme 3). Oxidation of 1,3-azido alcohol
7 followed by protection of the carboxylic acid as a trichloro-
ethyl ester gave 14 in 84% yield (two steps). Olefin oxidation
(RuCl3, NaIO4) of 14, followed by exposure of the resulting
R-azido acid to diazomethane (Et2O, 0 °C), afforded methyl
ester 15. Reduction of the azido group of 15 using SnCl2 (1.5
equiv) produced the free amine, which was coupled with
N-Boc(Me)-D-threonine 1614 (1.1 equiv) under standard
peptide coupling conditions to give dipeptide 17 (89%, two
steps). Deprotection of the Boc group in 17, followed by BOP-
induced amide bond formation with the protected D-
glutamate 18,14 completed the formation of tripeptide 3.
The crucial fragment coupling reaction, [2 + 3], which
provides the cyclization precursor 19, was based on Carpino’s
procedure using HATU.15 Deprotection of tripeptide 3,
followed by treatment with 2 in the presence of HATU/
collidine in DMF, gave the protected pentapeptide 19 in
93.4% yield (Scheme 3). This coupling proceeded without any
detectable level of epimerization.16 Reductive removal of the
trichloroethyl group using zinc/acetic acid (rt, 4 h, 95%) was
followed by N-terminal Boc deprotection to afford the amine
as its TFA salt which was set for macrocyclization. This
intermediate underwent an efficient cyclization in the pres-
ence of HATU and N-ethylmorpholine yielding macrocycle
20 in 79% yield.17 Treatment of 20 with Ba(OH)2 resulted
in the simultaneous hydrolysis of both methyl esters to-
gether with the in situ dehydration of N-methylthreonine.5a
Upon acidification with 1 N HCl to pH 2 and reverse phase
HPLC purification, synthetic motuporin 1a was obtained as
its diacid form in 52% yield. The spectroscopic and analytical
properties of this material were identical in all respects with
the reported data.1,5a,18 Treatment of 1a with NaHCO3/
MeOH provided the disodium salt of motuporin, which
agreed in all respects (1H and 13C NMR, [R]D, IR, FAB-
HRMS, rp-HPLC) with the data reported earlier.1,5a
In closing, the total synthesis of motuporin was completed
in 28 steps, with a longest linear sequence of 16 steps (15.8%
overall). The synthesis emphasized emerging synthetic
methodology: an efficient Pd(0)-catalyzed cross-coupling
reaction of a configurationally well-defined vinyl zinc inter-
mediate with an (E)-vinyl iodide for the construction of the
trisubstituted (E,E)-diene in a peptidic system. Six of the
eight stereogenic centers associated with motuporin were
introduced using asymmetric crotylsilane bond construction
methodology.
(9) (a) Panek, J . S.; Hu, T. J . Org. Chem. 1997, 62, 4912-4913. (b)
Negishi, E.; Okukado, N.; King, A. O.; Van Horn, D. E.; Spiegel, B. I. J .
Am. Chem. Soc. 1978, 100, 2254-2256.
(10) (a) Hart, D. W.; Schwartz, J . J . Am. Chem. Soc. 1974, 96, 8115-
8116. (b) Buchwald, S. L.; La Maire, S. J .; Nielsen, R. B.; Watson, B. T.;
King, S. M. Tetrahedron Lett. 1987, 28, 3895-3898.
(11) More conventional cross-coupling protocols such as the Stille coupling
reaction proved to be less efficient, as only modest yield (20-50%) was
achieved. In addition, considerable levels of double bond isomerization
occurred during the cross-coupling reactions.
(12) To our knowledge, this is the first documentation of a Negishi-type
coupling reaction performed with a peptide system. It is notable that this
strategy may be suitable for the preparation of structurally diverse
cyclicpeptides for the SAR study of the motuporin family.
Ack n ow led gm en t. Financial support was obtained
from NIH/NCI (RO1 CA56304).
Su p p or tin g In for m a tion Ava ila ble: Experimental proce-
dures, spectral data for all new compounds, and copies of proton
and carbon NMR spectra. This material is available free of charge
via the Internet at http://pubs.acs.org.
J O9904617
(13) For a review of Ley’s oxidation, see: Ley, S.; Norman, J .; Griffith,
W.; Marsden, S. Synthesis 1994, 639-666.
(14) For preparation of this compound, see Supporting Information.
(15) (a) Carpino, L. A.; El-Faham, A. J . Org. Chem. 1994, 59, 695. (b)
Carpino, L. A. J . Am. Chem. Soc. 1993, 115, 4397. (c) Carpino, L. A.; El-
Faham, A. J . Org. Chem. 1995, 60, 3561. For an excellent review of peptide
coupling methods, see: Humphrey, J . M.; Chamberlin, R. Chem. Rev. 1997,
97, 2243-2266.
(16) Satisfactory spectroscopic and analytic data (1H and 13C NMR, IR,
[R]D, MS, HRMS) were obtained for all new compounds. Ratios of diaster-
eomers were determined by 1H NMR (400 MHz).
(17) Hale, K. J .; Cai, J .; Williams, G. Synlett 1998, 149-152.
(18) Robert J . Valentekovich, Ph.D. Thesis, Harvard University, J une
1995.