Synthesis and complete stereochemical assignment of psymberin/irciniastatin A

Article abstract of DOI:10.1021/ja0537068

We describe a concise and flexible synthetic avenue for the preparation of compounds with structures relevant to those proposed for the novel marine-derived differential cytotoxins psymberin and irciniastatin A. Our efforts led to their complete stereoche

Full text of DOI:10.1021/ja0537068

Published on Web 07/21/2005
Synthesis and Complete Stereochemical Assignment of Psymberin/
Irciniastatin A
Xin Jiang, Jorge Garc´ıa-Fortanet, and Jef K. De Brabander*
Department of Biochemistry, The UniVersity of Texas Southwestern Medical Center at Dallas,
5323 Harry Hines BouleVard, Dallas, Texas 75390-9038
Received June 6, 2005; E-mail: jdebra@biochem.swmed.edu
Scheme 1. Synthesis of Fragments 5-7a
In 2004, two groups led by Pettit and Crews independently
disclosed the isolation of constitutionally identical cytotoxins,
irciniastatin A1 and psymberin2 from the marine sponges Ircinia
ramose and Psammocinia sp., respectively. NMR and chiroptical
data substantiated the assigned relative and absolute configuration
for psymberin shown in 1, save for the undefined configuration at
C4.2 The relative stereochemistry of irciniastatin A (2) was only
resolved for the C8-C13 aminal fragment.1 Interestingly, the C8-
aminal configuration in irciniastatin A was opposite to the corre-
sponding center assigned for psymberin.3 Psymberin/irciniastatin
most closely resemble the pederin family of natural products (e.g.,
3 and 4, see Figure 1).4,5 However, a constellation of unique
structural attributes (dihydroisocoumarin and acyclic left half)6 and
unprecedented tumor cell selectivity1,2 indicate that 1/2 might be
functionally distinct from the pederin family of protein synthesis
inhibitors. Herein, we communicate a short, highly convergent
synthesis of 1/2 that (1) resolves the stereochemical ambiguities
and (2) provides material and synthetic avenues for future bio-
chemical and preclinical investigation.
a Reagents and conditions: (a) (-)-(Ipc)2BOMe for the anti-5 series and
(+)-(Ipc)2BOMe for the syn-5 series, CH2CMeCH2Li, Et2O, -78 °C; (b)
NaH, MeI, THF; (c) PPTS, MeOH/H2O, 50 °C; (d) TBSCl, imid, CH2Cl2;
(e) BzCl, py; (f) aq 3 N HCl; (g) Dess-Martin periodinane, CH2Cl2; (h)
NaH2PO4, NaClO2, 2-methyl-2-butene, t-BuOH/H2O; (i) O3, CH2Cl2; Me2S;
(j) TsOH, CH(OMe)3, MeOH; (k) SOCl2, benzene; Et2NH; (l) sec-BuLi,
CuBr‚SMe2, allylBr, THF, -78 °C; (m) BBr3, CH2Cl2, -78f25 °C; (n)
Me3OBF4, CH2Cl2; Na2CO3, MeOH; (o) PMBCl, Bu4NI, K2CO3, DMF,
80 °C; (p) cat. OsO4, NMO, THF/H2O; NaIO4, aq MeOH (q) 15, PhMe,
-15 °C; (r) TBSOTf, 2,6-lutidine, CH2Cl2, 0 °C; (s) O3, CH2Cl2; Ph3P; (t)
Ac2O, Et3N, DMAP, CH2Cl2, 0 °C; (u) N,N′-(1R,2R-cyclohexane-1,2-
diyl)bis(trifluoromethanesulfonamide), Ti(OiPr)4, Et2Zn, PhMe, -15 °C;
(v) TMSCN, ZnI2, MeCN, 0 °C; aq 1 N HCl.
Figure 1. Psymberin, irciniastatins, and related natural products.
(CHO f CONEt2); (2) ortho-metalation/allylation (f 13);10 (3)
BBr3-mediated methyl ether deprotection; (4) methyl ester formation
using a protocol reported by Keck;11 (5) phenol protection; and (6)
oxidative double bond cleavage (f 6).
The synthesis of central fragment 7 commences with the
preparation of C2-symmetrical diol 17 via allylation of monopro-
tected dialdehyde 1412 using Leighton’s silane reagent 15,13
followed by a second allylation of aldehyde 16, which was
unmasked during the workup (Scheme 1C). Monosilylation (18)
and ozonolysis destroys the symmetry and provides a lactol (trapped
as acetate 19) that differentiates the chain termini. Addition of
diethylzinc using conditions reported by Kobayashi14 gave a
secondary alcohol, which was oxidized to ketone 7 after acetate
displacement with TMSCN (8 steps, 30% from 14).5f
Our approach to 1/2 envisioned the coupling of fragments 6-7
via carbon-bond formation to control stereochemistry of the C15-
C17 stereotriad, followed by appending carboxylic acid 5. Given
the unknown stereochemistry at C4, we prepared both anti- and
syn-5 (Scheme 1A).7 Asymmetric methallylation8 of aldehyde 8
followed by methylation and acetonide hydrolysis provided diol 9,
to be converted to benzoate 10 via silylation, benzoylation, and
desilylation. The relative stereochemistry was confirmed through
1H NMR analysis of acetal 11. Finally, a two-step oxidation of
alcohol 10 yielded anti-5 (8 steps, 49% from 8). Syn-5 was prepared
from 8, starting with antipodal methallyl borane reagent.
The aryl fragment 6 was obtained in 7 steps (41% overall yield,
Scheme 1B) from known aldehyde 129 via: (1) oxidation/amidation
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J. AM. CHEM. SOC. 2005, 127, 11254-11255
10.1021/ja0537068 CCC: $30.25 © 2005 American Chemical Society

C O M M U N I C A T I O N S
Scheme 2. Synthesis of 4 Psymberin/Irciniastatin Diastereomersa
rotation of synthetic 28 ([R]D ) +25.2, c 0.11, MeOH) agreed with
those reported for psymberin ([R]D ) +29, c 0.02, MeOH)2 and
irciniastatin A ([R]D ) +24.4, c 0.55, MeOH).1
In summary, we prepared compounds with structures relevant
to those proposed for psymberin/irciniastatin, leading to a complete
stereochemical assignment and the notion that psymberin and
irciniastatin A are identical compounds represented by 28. Starting
from fragments 5-7 (7-8 steps each, 30-49% overall yield) the
synthesis of 28 was completed in an additional 9 steps and 30%
yield (17 steps, 8.9% overall from 14).
Acknowledgment. This work was supported by the National
Institutes of Health (CA 90349), the Robert A. Welch Foundation,
and Merck Research Laboratories. We thank Dr. Radha Akella for
crystallographic analysis of compound 22a. J. G.-F. thanks the
Spanish Ministry of Education and Science for a FPU fellowship.
J. K. De Brabander is a fellow of the Alfred P. Sloan Foundation.
Supporting Information Available: Experimental procedures,
characterization data, copies of NMR spectra, and X-ray crystal structure
data for compound 22a (PDF, CIF). This material is available free of
charge via the Internet at http://pubs.acs.org.
References
(1) Pettit, G. R.; Xu, J. P.; Chapuis, J. C.; Pettit, R. K.; Tackett, L. P.; Doubek,
D. L.; Hooper, J. N. A.; Schmidt, J. M. J. Med. Chem. 2004, 47, 1149. A
C
11-oxo analogue irciniastatin B was also isolated.
(2) Cichewicz, R. H.; Valeriote, F. A.; Crews, P. Org. Lett. 2004, 6, 1951.
a Reagents and conditions: (a) PhBCl2, DIPEA, CH2Cl2, -78 °C; (b)
catecholborane, THF, 0 °C; aq 2 N NaOH; (c) TBAF, THF; (d) cat.
[PtH(PMe2OH)(PMe2O)2H], EtOH/H2O, 80 °C; (e) 10% Pd/C, H2, EtOH;
(f) Ac2O, py; (g) Me3OBF4, polyvinylpyridine, CH2Cl2; filter; (h) anti- or
syn-27, Pr2NEt, PhMe, 40 °C; then add NaBH4, EtOH, 0 °C; (i) LiOH,
MeOH.
(3) The published spectral data, acquired in different NMR solvents, were
insufficient to decisively establish a homomeric or diastereomeric cor-
respondence between the two natural products.
(4) (a) For a review, see: Narquizian, R.; Kocienski, P. J. In The Role of
Natural products in Drug DiscoVery; Mulzer, J., Bohlmann, R., Eds.; Ernst
Schering Research Foundation Workshop 32; Springer: New York, 2000;
pp 25-56. (b) For a complete listing of structures of pederin related natural
products including references, see the Supporting Information of ref 2.
i
(5) For selected examples of total syntheses, see ref 4a and: (a) Kocienski,
P.; Narquizian, R.; Raubo, P.; Smith, C.; Farrugia, L. J.; Muir, K.; Boyle,
F. T. J. Chem. Soc., Perkin Trans. 1 2000, 2357. (b) Roush, W. R.; Pfeifer,
L. A. Org. Lett. 2000, 2, 859. (c) Takemura, T.; Nishii, Y.; Takahashi,
S.; Kobayashi, J.; Nakata, T. Tetrahedron 2002, 58, 6359. (d) Trost, B.
M.; Yang, H.; Probst, G. D. J. Am. Chem. Soc. 2004, 126, 48. (e) Sohn,
J.-H.; Waizumi, N.; Zhong, H. M.; Rawal, V. H. J. Am. Chem. Soc. 2005,
127, 7290. (f) Nakata, T.; Nagao, S.; Mori, N.; Oishi, T. Tetrahedron
Lett. 1985, 26, 6461.
(6) Without exception, all ∼35 members of the pederin family display an
identical cyclic left half pederate side chain; none of them display a
dihydroisocoumarin unit in the bottom half.
(7) During review of this manuscript, the synthesis and configuration of syn
and anti models of the psymberin side chain was reported: Kiren, S.;
Williams, L. J. Org. Lett. 2005, 7, 2905.
(8) Jadhav, P. K.; Bhat, K. S.; Perumal, P. T.; Brown, H. C. J. Org. Chem.
1986, 51, 432.
(9) Lambooy, J. P. J. Am. Chem. Soc. 1956, 78, 771.
(10) (a) Kamila, S.; Mukherjee, C.; Mondal, S. S.; De, A. Tetrahedron 2003,
59, 1339. (b) Casas, R.; Cave´, C.; d’Angelo, J. Tetrahedron Lett. 1995,
36, 1039.
(11) Keck, G. E.; McLaws, M. D.; Wager, T. T. Tetrahedron 2000, 56, 9875.
(12) Johnson, P. R.; White, J. D. J. Org. Chem. 1984, 49, 4424.
(13) Kubota, K.; Leighton, J. L. Angew. Chem., Int. Ed. 2003, 42, 946.
With the three fragments in hand, the foundation was laid to
explore their union via a double convergent coupling strategy
(Scheme 2). Treatment of the (Z)-chlorophenylboryl enolate derived
from 7 with aldehyde 6 yielded one major syn-aldol product 20
predicted from enolate facial bias imposed by the â-alkoxy
substituent.15 Reduction of 20 with catecholborane provided lactone
21 directly after basic workup,16,17 followed by silyl deprotection
to alcohol 22. Crystallographic analysis of crystals obtained from
benzyl ether 22a fully confirmed the assigned structure and relative
stereochemistry.18 Hydrolysis of the nitrile group in 22 with the
platinum(II) catalyst of Ghaffar and Parkins19 yielded amide 23 in
>95% yield. Hydrogenolysis (24) and peracetylation furnished
tetraacetate 25 (>90%, 2 steps).
We had planned to acylate imidate 26 and intercept the incipient
acylimidate with a reducing agent but were unable to prepare and
handle imidates related to and including 26 using Me3OBF4 as
reported.20 Extensive experimentation identified a uniquely ben-
eficial effect of adding polyvinylpyridine during the imidate
formation with Me3OBF4 (soluble pyridine or other amine bases
could not substitute for immobilized pyridine). After TLC analysis
indicated complete conversion, the reaction mixture was filtered
and concentrated, followed by dissolving the crude imidate 26 in
toluene and addition of Hunig’s base and acid chloride 27 (from 5
with (COCl)2). The mixture was heated to 40 °C for 2 h, cooled to
0 °C, and treated with an ethanolic sodium borohydride solution.
After workup, the crude compounds were saponified to afford a
separable mixture of 28 and epi-28 (71:29 ratio) with acid chloride
anti-27 (56% from 25), or an inseparable mixture of 29 and epi-29
(75:25 ratio) with syn-27 (50%). Of the four diastereomers, only
spectral data (1H, 13C) recorded for 28 corresponded exactly with
those of psymberin2 (CD3OD) and irciniastatin A1 (CDCl3). The
(14) Takahashi, H.; Kawakita, T.; Ohno, M.; Yoshioka, M.; Kobayashi, S.
Tetrahedron 1992, 48, 5691.
(15) Evans, D. A.; Calter, M. A. Tetrahedron Lett. 1993, 34, 6871.
(16) Evans, D. A.; Hoveyda, A. H. J. Org. Chem. 1990, 55, 5190.
(17) Workup with aq Na,K-tartrate allowed the diol to be isolated for
derivatization as an acetonide derivative, confirming the relative 1,2-syn,
18
2,3-syn stereochemistry at C15-C17
.
(18) See the Supporting Information.
(19) (a) Ghaffar, T.; Parkins, A. W. Tetrahedron Lett. 1995, 36, 8657. (b)
Ghaffar, T.; Parkins, A. W. J. Mol. Catal. A 2000, 160, 249. (c) For a
nice application, see: Herzon, S. B.; Myers, A. G. J. Am. Chem. Soc.
2005, 127, 5342.
(20) This approach has been used for the synthesis of pederin; see refs 4a and
5c and references therein.
(21) We thank Profs. Cherry Herald and George Pettit for kindly providing
NMR spectra of irciniastatin A.
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