An efficient synthesis of the tamandarin B macrocycle

Article abstract of DOI:10.1016/j.tetlet.2009.12.091

A reliable, high yielding cyclization protocol for the macrocycle of tamandarin B is presented. This strategy will facilitate the synthesis of side chain analogs.

Full text of DOI:10.1016/j.tetlet.2009.12.091

Tetrahedron Letters 51 (2010) 1635–1638
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An efficient synthesis of the tamandarin B macrocycle
*
Kenneth M. Lassen, Jisun Lee, Madeleine M. Joullié
Department of Chemistry, University of Pennsylvania, 231 S. 34th Street, Philadelphia, PA 19104, USA
a r t i c l e i n f o
a b s t r a c t
Article history:
A reliable, high yielding cyclization protocol for the macrocycle of tamandarin B is presented. This strat-
egy will facilitate the synthesis of side chain analogs.
Received 24 November 2009
Revised 15 December 2009
Accepted 16 December 2009
Available online 23 December 2009
Ó 2009 Elsevier Ltd. All rights reserved.
Keywords:
Tamandarin B
Macrolactamization
Peptide coupling
Natural products
1. Introduction
The synthesis commenced with the formation of the Pro-Leu-
Hiv fragment 8 (Scheme 2). Proline benzyl ester (9) was coupled
Since their discovery by Rinehart and co-workers the didem-
nins1 have been of great interest to the synthetic and medicinal
chemistry communities. Didemnin B (1) was the first marine nat-
ural product to reach phase II clinical trials (Fig. 1).2 Didemnin B
and other related analogs have stimulated many total syntheses
to date.3–7 Tamandarins A (2) and B (3) were reported by Vervoort
and Fenical in 2000 and found to possess a very similar structure to
that of the didemnins (Fig. 1).8 The main structural difference is
that the didemnins possess a 23-membered ring containing a more
to Boc-Leu with diethyl cyanophosphonate (DEPC) to yield amide
10 in good yield.6 The Boc group was removed and the resulting
salt was coupled to hydroxyisovaleric acid (11) using BOP (ben-
zotriazol-1-yloxy)tris(dimethylamino)phosphonium hexafluoro-
phosphate) to yield the desired alcohol 8.
The norstatine fragment was synthesized next (Scheme 3). Boc-
D-valine (12) was activated as its pentafluorophenyl ester (14) and
condensed with the lithium enolate of methyl acetate to yield b-
ketoester 15. The ketone was reduced using potassium borohy-
dride to provide alcohol 16. The resulting alcohol was protected
as its TBS ether and the methyl ester was hydrolyzed to yield de-
sired acid 7.10
The last fragment to be synthesized was the N,O-Me2-Tyr-Thr
fragment 6 (Scheme 4). Tyrosine derivative 18 was made by known
procedures.4 A carbodiimide-mediated esterification with alcohol
19 resulted in the desired product (20). Removal of the methyl es-
ter with trimethyltin hydroxide resulted in acid 6 in excellent
yield.14
complex
a(a-isovalerylpropionyl) (Hip) residue while the taman-
darins possess a 21-membered ring containing a simpler hydrox-
yisovaleric (Hiv) acid residue. Macrolactamization at the Pro4-
N,O-Me2-Tyr5 junction has so far provided the highest yields for
the didemnins6,9 and tamandarin macrocyclic analogs.10,11 A reli-
able, high yielding cyclization protocol for tamandarin B would
make the macrocycle more available and facilitate the synthesis
of side chain analogs.
The reaction of acid 7 and alcohol 8 with EDCI (N-(3-dimethyl-
aminopropyl)-N0-ethylcarbodiimide hydrochloride), DCC (dicyclo-
hexyl carbodiimide), or isopropenyl chloroformate did not result
in a high yield of 21 (Scheme 5). As in the first generation synthe-
sis, lactam formation from the activated acid was the major prod-
uct (22) of these reactions.13
In order to decrease the nucleophilicity of the carbamate nitro-
gen, oxazolidine 23 was synthesized from alcohol 16 (Scheme 6).
Methyl ester 23 was then hydrolyzed to acid 24 which was then
subjected to the reaction conditions.
2. Results
The retrosynthetic analysis (Scheme 1) shows the desired cycli-
zation at the Pro4-N,O-Me2-Tyr5 junction. In the previous synthesis,
cyclization occurred at the Thr-Nst position.12,13 The new linear
precursor (5) may be divided into three fragments; N,O-Me2-Tyr-
Thr (6), carboxylic acid (7), and Pro-Leu-Hiv (8) unit.
Oxazolidine acid 24 successfully prevented lactam formation
and provided the desired product 25 in 94% yield (Scheme 7). This
* Corresponding author. Tel.: +1 215 898 3158; fax: +1 215 573 9711.
E-mail address: mjoullie@sas.upenn.edu (M.M. Joullié).
0040-4039/$ - see front matter Ó 2009 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2009.12.091

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K. M. Lassen et al. / Tetrahedron Letters 51 (2010) 1635–1638
Figure 1. Structures of didemnin B (1) and tamandarins A (2) and B (3).
Scheme 1. Retrosynthetic analysis.
Scheme 2. Synthesis of alcohol 8.
Scheme 3. Synthesis of acid 7.

K. M. Lassen et al. / Tetrahedron Letters 51 (2010) 1635–1638
1637
Scheme 4. Synthesis of acid 6.
Scheme 5. Failed reaction conditions.
Scheme 6. Synthesis of oxazolidine acid 24.
Scheme 7. Linear precursor formation and cyclization.
change in the protecting group prevented the undesired side reac-
tion and improved the overall yield significantly. After removal of
the Boc group and oxazolidine fragmentation under acidic condi-
tions, the resulting salt was coupled to acid 6 to form the protected
linear precursor 5. The terminal protecting groups were then re-
moved under hydrogenolysis conditions to afford the linear pre-
cursor. Cyclization with PyAOP ((7-azabenzotriazol-1-yloxy)
tripyrrolidinophosphonium hexafluorophosphate) led to the de-
sired macrocycle (4) in good yield.
3. Conclusion
The tamandarin B macrocycle has been made using a second
generation strategy by cyclization at the Pro4-N,O-Me2-Tyr5 junc-

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tion. This macrocycle synthesis is highly convergent and provides
useful quantities for analog synthesis.
Acknowledgments
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We thank the NIH (CA-40081) for financial support. Financial
support for the departmental instrumentation was provided by
the National Institutes of Health (1S10RR23444-1). We also thank
Dr. George Furst and Dr. Rakesh Kohli for NMR and MS assistance,
respectively.
Supplementary data
Supplementary data associated with this article can be found, in
the online version, at doi:10.1016/j.tetlet.2009.12.091.
13. Liang, B.; Richard, D. J.; Portonovo, P.; Joullié, M. M. J. Am. Chem. Soc. 2001, 123,
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References and notes
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