cells.4 The San B natural product contains two thiazoles and
one oxazole, and is a modified octapeptide macrocycle.
Unlike other natural products isolated from this sponge,
San B contains two proline residues that are presumed to
control the conformation of the macrocycle5 and thus
influence its biological activity.6,7 It has also been established
that although the inclusion of proline residues within a
macrocycle increases the number of conformational states
by decreasing the energy difference between the trans- and
cis-isomers, it also limits the number of available low energy
conformations because of allylic 1,3-interactions. As noted
by Taunton and Deng in their synthesis of trans,trans- and
cis,cis-Ceratospongamide,5 two different conformations
were stable and did not interconvert. Gerwick et al. showed
that these two isomers also had distinct biological activity;
indeed, trans,trans-Ceratospongamide inhibits transcrip-
tional activation of IL-1β (IC50 = 32 nM), whereas the cis,
cis- rotamer is inactive.8
Scheme 1. Retrosynthetic Strategy for San B Conformers
The potent cytotoxic and antibiotic properties of other
macrolides isolated from the nudibranch H. sanguineus
sponge, and the small microgram quantities of the com-
pound that are available from the natural source, mean
that alternative methods for evaluating biological activity
are required. Herein we report the first total synthesis of
the natural product, San B (1), which exists as the trans,
trans- configuration about each proline residue and con-
firm its structure. In addition, we report the synthesis of
two other San B conformers: trans,cis-Sanguinamide B (2,
San B*, Scheme 1), which maintains trans- configuration
about Pro-1 and is cis- about Pro-2, and cis,cis-Sanguina-
mide B (3, San B**, Scheme 1), which adopts the cis-
configuration about both proline residues.
The San B conformers (1ꢀ3) were synthesized via the
coupling of two fragments; Fragment I and Fragment II
(Scheme 1). Fragment I was derived from a Hantzsch
thiazole reaction between Ala thioamide derivative 5 and
(R)-bromoketone6, followed byN-terminalextensionwith
Val. Fragment II was also obtained via a Hantzsch reac-
tion between oxazole (R)-bromoketone 12 and Pro thioa-
mide derivative 13 to form oxazole-thiazole moiety 11.
Oxazole (R)-bromoketone 12 was obtained from the cycli-
zation and oxidation of a Ser residue. Subsequent exten-
sion of the core oxazole-thiazole moiety 11 via peptide
coupling to Pro and Leu furnished Fragment II.
The synthesis of Fragment I began with the protection
of commercially available Boc-Ala-OH 14 using (trim-
ethylsilyl) diazomethane (TMSD) in methanol, converting
the acid to an ester (Scheme 2). The ester was transformed
into an amide using ammonium hydroxide, which was
subsequently converted to the desired thioamide 5 using
Lawesson’s Reagent. The thioamide was subjected to
modified Hantzsch thiazole synthesis conditions that
preserved stereochemical integrity at CR of the Ala
residue.9 Specifically, thioamide 5 was treated with ethyl
bromopyruvate 6 and potassium bicarbonate to generate a
hydroxyl thiazoline intermediate. This intermediate was
subsequently dehydrated tothiazole15withtrifluoroacetic
anhydride (TFAA), pyridine, and triethylamine (TEA).
Removal of the Boc protecting group with trifluoroacetic
acid (TFA), followed by peptide coupling to Boc-Val-OH
4 with O-(Benzotriazol-1-yl)-N,N,N0,N0-tetramethyluro-
nium tetrafluoroborate (TBTU) and N,N-diisopropy-
lethylamine (DIPEA), and subsequent amine deprotec-
tion with TFA furnished the desired Fragment I (7).
Fragment II, comprised of two consecutive heterocycles
and three amino acids, was synthesized by constructing the
heterocycles first in order to optimize the overall yield for
this fragment.10 Using standard peptide coupling condi-
tions, H2N-Ser(Bzl)-OMe 16 was coupled to dimethoxy
acetal bromopyruvic acid 17, and the benzyl protecting
(7) (a) Chatterjee, J.; Mierke, D.; Kessler, H. J. Am. Chem. Soc. 2006,
128, 15164–15172. (b) Heller, M.; Sukopp, M.; Tsomaia, N.; John, M.;
Mierke, D. F.; Reif, B.; Kessler, H. J. Am. Chem. Soc. 2006, 128, 13806–
13814.
(8) Tan, L. T.; Williamson, R. T.; Gerwick, W. H.; Watts, K. S.;
McGough, K.; Jacobs, R. J. Org. Chem. 2000, 65, 419–425.
(9) Aguilar, E.; Meyers, A. I. Tetrahedron Lett. 1994, 35, 2473–2476.
(10) (a) Davis, M. R.; Singh, E. K.; Wayyudi, H.; Kunicki, J.;
Alexander, L. D.; Nazarova, L. A.; Fairweather, K.; Giltrap, A.; Jolliffe,
K. A.; McAlpine, S. R. Tetrahedron 2011, 68, 1029–1051.
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