Total synthesis of (-)-tamandarin B

Article abstract of DOI:10.1016/S0040-4039(00)01409-X

The synthesis of tamandarin B is described. Key steps in the synthesis of the macrocycle component include a diastereoselective ketone reduction, linear precursor formation via an activated pentafluorophenyl ester, and HATU-promoted cyclization. Side-chain coupling was achieved in excellent yield with the newly developed coupling reagent DEPBT. (C) 2000 Published by Elsevier Science Ltd.

Full text of DOI:10.1016/S0040-4039(00)01409-X

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 41 (2000) 9373–9376
Total synthesis of (−)-tamandarin B†
Madeleine M. Joullie´,* Padma Portonovo, Bo Liang and David J. Richard
Department of Chemistry, University of Pennsylvania, Philadelphia, PA 19104-6323, USA
Received 10 August 2000; accepted 21 August 2000
Abstract
The synthesis of tamandarin B is described. Key steps in the synthesis of the macrocycle component
include a diastereoselective ketone reduction, linear precursor formation via an activated pen-
tafluorophenyl ester, and HATU-promoted cyclization. Side-chain coupling was achieved in excellent
yield with the newly developed coupling reagent DEPBT. © 2000 Published by Elsevier Science Ltd.
As a continuation of our investigation1 of the metabolites of an unidentified didemnid
ascidian found on a shallow-water reef near the Brazilian village of Tamandare´,2 we now report
the synthesis of a minor metabolite, tamandarin B or [Nst1-(2S)Hiv2]didemnin B (1, Fig. 1).
Figure 1. Structures of three didemnid ascidian metabolites
Tamandarin B was isolated as an amorphous white solid, whose mass was decreased by 14
units as compared with tamandarin A, indicating the absence of a methylene group. The 13C
* Corresponding author.
†
Dedicated with affection and thanks to Professor Harry Wasserman for being an exceptional role model and for his
service to the profession.
0040-4039/00/$ - see front matter © 2000 Published by Elsevier Science Ltd.
PII: S0040-4039(00)01409-X

9374
NMR confirmed the absence of a methylene signal and further experiments established the
presence of a Nst1 (norstatine) residue instead of the Ist1 (isostatine) residue in tamandarin A.2
The structural similarity of tamandarins A and B to didemnin B suggests that they might be
simplified didemnin mimics (Fig. 1). Indeed, modification of the linear side-chain resulted in an
increase of potency as observed for the didemnins.3
Whether the didemnin class of cyclopeptides will ever afford a clinically useful drug is not
clear. The real interest of these natural products lies in the investigation of the distinct
mechanisms that mediate their different types of bioactivity. Many naturally occurring small
molecules inhibit the progression of the cell cycle by binding to a protein required for cell
division. Understanding this process helps to determine the function of the protein and may be
useful in cell-cycle regulation.4 Since the tamandarins are more synthetically accessible than the
didemnins, they will be useful in enhancing the still-unfolding research directed toward untan-
gling the molecular mechanisms by which these compounds exert their multifaceted biological
activity.
Formation of the required macrocycle was achieved by stepwise coupling of the common
tetrapeptide, an advanced intermediate used in our previous didemnin synthesis,5 with Hiv-
norstatine. Subsequent addition of the side-chain dipeptide produced the desired depsipeptide.
Synthesis of acid 4 began with protection of the amino function of -valine as its benzyloxy-
D
carbonyl (Cbz) derivative (Scheme 1). Activation of the carboxylic functionality as a pen-
tafluorophenyl ester,6 followed by condensation with the lithium enolate of methyl acetate,
provided the desired b-ketoester.7 Stereoselective reduction with KBH4 followed by recrystalliza-
tion gave only the desired alcohol in good yield. Conversion of the secondary hydroxyl group
to the silyl ether, followed by hydrolysis of the methyl ester, provided acid 4.
Scheme 1. (a) CbzꢀCl, sat. NaHCO3, 93%; (b) C6F5OH, EDAC·HCl, DMAP, CH2Cl2, 95%; (c) LiCH2CO2Me, THF,
83%; (d) KBH4, MeOH, −30°C, 77% desired diastereomer after recrystallization; (e) TIPSOTf, 2,6-lutidine, CH2Cl2,
82%; (f) 1N NaOH, MeOH, THF, H2O (1:1:1), 81%
Hydroxyisovaline, which was obtained from -valine via diazotization and displacement by
L
water under acidic conditions,5 was protected as its allyl ester (Scheme 2). Coupling to the
norstatine acid subunit using EDAC provided the elongated ester. Subsequent deprotection of
the carboxylic acid moiety with Pd(PPh3)4 produced the required compound in nearly quantita-
tive yield,8 which was then converted to its activated pentafluorophenyl ester 5.

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Scheme 2. (a) 1N H2SO4, NaNO2, 80%; (b) allyl bromide, DMF, K2CO3, Bu4NI, 89%; (c) 4, EDAC·HCl, DMAP,
CH2Cl2, 60%; (d) Pd(PPh3)4, morpholine, THF; (e) pentafluorophenyl triflate, pyr., CH2Cl2, 64%, two steps
Hydrogenolysis of the Cbz group of the fully protected tetrapeptide led to formation of the
free amine coupling partner (Scheme 3).
Scheme 3. (a) H2, Pd/C, EtOAc/MeOH (1:1), 94%; (b) 5, DIEA, DMAP, CH2Cl2, 79%; (c) MgBr2·Et2O, CH2Cl2, −15
to 0°C; (d) H2, Pd/C, EtOAc/MeOH (1:1); (e) HATU, DIEA, DMF, 23%, three steps; (f) HCl(g), EtOAc, −30 to 0°C;
(g) (R)-MeLeu(OH)-(S)-Pro-(S)Lac, DEPBT, DIEA, CH2Cl2, 85%, two steps
Reaction of the two components provided the fully protected linear precursor. Mild cleavage
of the SEM ester with MgBr2·Et2O9 was selective in the presence of two carbamates, a silyl
ether, and two ester functionalities, as previously reported.10 Removal of the benzyloxycarbonyl
protecting group proceeded smoothly to yield the corresponding amino-alcohol. HATU-pro-
moted cyclization produced the Boc-protected macrocycle. The two remaining protecting groups
were then simultaneously removed by treatment with hydrogen chloride gas in anhydrous ethyl
acetate. Subsequent coupling of the hydrogen chloride amine salt with the side-chain provided
1
tamandarin B whose H and 13C NMR were identical to those of the natural product;2 IR
(KBr): 3468, 3334, 2957, 2934, 2869, 1737, 1658, 1632, 1574, 1533, 1514, 1467, 1452, 1385, 1247,

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1179, 1075, 1032 cm−1; HRMS: m/z=1064.5897 (M+Na+), calcd for C58H87N7O14: 1064.5896
(l=0.1 ppm); [h]2D0=−43°, MeOH, 589 nm, c=0.12.
In the course of our investigations as to the effectiveness of various coupling reagents for this
transformation, we noted the development of a novel coupling reagent, 3-(diethoxyphosphoryl-
oxy)-1,2,3-benzotriazin-4(3H)-one (DEPBT).11 This reagent was notable both for its resistance
to racemization of sensitive substrates and its high yields of amide bond formation. Use of this
compound, with slight modification from the conditions which have previously been reported11
provided tamandarin B in excellent yield. The reaction demonstrated the high efficiency of this
coupling reagent and its utility in complex natural product synthesis.
Acknowledgements
We gratefully acknowledge the NIH (CA-40081), NSF (Che-9901449) and the University of
Pennsylvania for financial support. We thank Professor William Fenical and Dr. He´le`ne
1
Vervoort for providing the H and 13C spectra of the natural product and a preprint of their
manuscript.
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