Scheme 1. Synthesis of Sansalvamide A Fragmentsa
Figure 1. Retrosynthetic approach.
Herein we describe the synthesis of 14 novel Sansalvamide
A derivatives using the amino acids shown (Figure 2). The
significant aspects of our work include the consecutive
a Conditions: (a) coupling agent [TBTU and/or HATU (1.25
equiv ea)], DIPEA (3 equiv), CH3CN; (b)TFA, anisole (2 equiv),
CH2Cl2; (c)LiOH (4 equiv), MeOH.
monomer 3a-d gave the desired tripeptide (Fragment 1) in
good yields (80-95%).6
The synthesis of Fragment 2 was completed by coupling
residue 4a,b to residue 5a-d to give the dipeptide 4-5-Boc
(90-95% yield) (Scheme 1). The amine was deprotected in
Fragment 1 using TFA, and the acid was deprotected in
Fragment 2 using lithium hydroxide. Fragments 1 and 2 were
coupled using multiple coupling agents,7 yielding 14 ex-
amples of linear pentapeptides (50-74% yield) (Scheme 2).6
The linear pentapeptides were amine deprotected using
HCl (pH < 2). Upon completion, the reaction was concen-
trated in vacuo, and the acid was deprotected by neutralizing
the reaction with lithium hydroxide and then adding an
additional 4 equiv of lithium hydroxide in methanol to give
pH ) ∼11.8 Following acid deprotection, the reaction was
concentrated in vacuo and subjected to HATU, TBTU,
PyAOP, PyBrop, and/or DEPBT coupling reagents (∼0.5
(6) All dipeptide and tripeptide structures were confirmed using 1H NMR.
All linear hexameric peptides were confirmed using LCMS and 1H NMR,
and cyclized peptides were all confirmed using LCMS. (Note: 1H NMR
was also used for cyclized peptides, but because of their complexity, they
were not seen as the primary confirmation for cyclized compounds).
(7) (a) Bolla, M. L.; Azevedo, E. V.; Smith, J. M.; Taylor, R. E.; Ranjit,
D. K.; Segall, A. M.; McAlpine, S. R. Org. Lett. 2003, 5, 109. (b) Robinson,
J. L.; Taylor, R. E.; Liotta, L. A.; Bolla, M. L.; Azevedo, E. V.; Medina,
I.; McAlpine, S. R. Tetrahedron Lett. 2004, 45, 2147 (c) Liotta, L. A.;
Medina, I.; Robinson, J. L.; Carroll, C. L.; Pan, P.-S.; Corral, R.; Johnston,
J. V. C.; Cook, K. M.; Curtis, F. A.; Sharples, G. J.; McAlpine, S. R.
Tetrahedron Lett. 2004, 45, 8447 (d) Ring-closing reactions are slow and
typically low yielding. Unpublished results from the Guy lab at UCSF and
recently our lab have found that the use of several coupling reagents
facilitates ring-closing reactions by providing a choice of reagents for the
specific substrate.
Figure 2. Monomers used in the synthesis of derivatives.
placement of N-methyl amino acids within the macrocycles
and comparison of their cytotoxicity to those containing NH
amino acids. This resulted in the discovery of two derivatives
that exhibited cytotoxicity against colon cancer cell lines
(HCT-116). In addition, we synthesized derivatives utilizing
all L-amino acids and all D-amino acids. Furthermore, the
synthesis of the peptide derivatives (as opposed to depsipep-
tide derivatives) provided macrocycles biologically more
stable than those containing a labile lactone. The peptide
derivatives demonstrate higher potency in the colon cancer
assays (presumably due to their greater stability in cells).5
Our synthesis utilized a convergent approach (Figure 1).
Using 2(1-H-benzotriazole-1-yl)-1,1,3-tetramethyl-uronium
tetrafluoroborate (TBTU) as a coupling reagent and diiso-
propylethylamine (DIPEA), acid-protected residue 1a,b and
N-Boc-protected residue 2a-f (Scheme 1) were coupled to
give the dipeptide 1-2-Boc (80-94% yield). Deprotection
of the amine on residue 2 using TFA gave the free amine
1-2 (∼quantitative yields). Coupling of this dipeptide to
(8) All linear protected pentamers were amine deprotected and then
confirmed via LCMS. Upon confirmation that the linear amine deprotections
were completed, the acid deprotections were undertaken, and confirmation
of the fully amine and acid deprotected pentamers were determined via
LCMS.
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Org. Lett., Vol. 7, No. 16, 2005