Given the biological activity, the extreme rarity of 14-
membered cyclic tetrapeptides8 with multiple stereocenters
and the desire to secure the complete identity of the natural
product, for which no samples remain, we undertook the
preparation of the two diastereomers of 1 that have not yet
been synthesized, namely 1a and 1b. Herein we describe
our results which, when coupled with the analytical ex-
pertise of the original cyclocinamide A isolation team, lead
us to the conclusion that a reexamination of the natural
product stereostructure is necessary.
Although much research on R/β peptides, particularly
R/β3 peptides, has appeared in recent years,9 cyclic R/β
peptides have been little explored. Nonetheless, it seemed
reasonable to assume that the cyclization of a linear
precursor to 1a would be challenging,10 particularly given
that there are no N-alkyl amides to help sample the s-cis
amide conformation. The synthetic plan relied on the use
of (cyclo)Asn (3, Scheme 1, blue), a protected asparagine
residue11 that acts as a turn inducer.12 Our previous work
with (cyclo)Asn indicated that this residue would both
aid in the organic solubility of late-stage synthetic inter-
mediates and protect the asparagine chiral center from
epimerization in the key cyclization step, i.e., 1À2 amide
bond formation.13,14 Thus, the site of ring closure was
dictated more by key precursor availability and less by
predicted ease of cyclization.15 Conversely, this approach
would allow for another exploration of a previously
unsuccessful closure site.
The retrosynthesis for 1a and 1b is depicted in Scheme 1
and was envisioned to arise from three dipeptide segments.
Addition of the glycine-pyrrole side chain would be a
late-stage event, as would liberation of the asparagine
residue. Thus, the proposed product of cyclization would
be tetrapeptide 3. Fission of the bonds indicated affords
two suitably protected dipeptides of roughly equivalent
size and complexity: isoseryl-5-bromotryptophan (Ise-5-
Br-Trp) 4 and diaminopropionyl(cyclo)asparagine [Dap-
(cyclo)Asn] 5. Compound 5 can be accessed from known
asparagine imine 616 and the appropriate diaminopropio-
nic acid chloride 7a or 7b.
Synthesis of dipeptide 4 (Scheme 2) began with known
oxazolidinone 8,17 which underwent selective ring opening
with cesium carbonate18 to give the corresponding alcohol
prior to treatment with tert-butyldiphenylchlorosilane to
afford fully protected isoserine 9 in 66% yield over two
steps. Due to protection group lability of R-silyloxy-β-
amino acids,19 the methyl ester deprotection was per-
formed with only 1 equiv of NaOH. The resulting crude
acid was immediately activated with HOAt and EDCI
hydrochloride before introduction of (S)-5-bromotrypto-
phan methyl ester;20 the desired dipeptide was isolated in
85% yield. For further use the methyl ester was reacted as
needed with excess lithium hydroxide to give the desired
free acid dipeptide 4, which was taken on crude to the
coupling reaction with Dap-(cyclo)Asn dipeptide 5.
Scheme 2. Synthesis of Dipeptide 4
Scheme 1. Retrosynthesis of Cyclocinamides
Syntheses of the two Dap-(cyclo)Asn dipeptide diaster-
eomers 5a and 5b (Scheme 3) began with construction of a
(11) Postema and Liu experienced problems with asparagine free
amide, which would suggest protection would be useful. See ref 5 for
details.
(12) Konopelski, J. P.; Wei, Y.; Olmstead, M. M. J. Org. Chem. 1999,
64, 5148–5151.
(13) We have previously employed a (cyclo)Asn derivative in a “self-
reproduction of chirality” approach to enantiomerically pure R-methyl-
asparagine derivatives. See: Hopkins, S. A.; Ritsema, T. A.; Konopelski,
J. P. J. Org. Chem. 1999, 64, 7885–7889.
(14) Epimerization at the C-terminal amino acid in the cyclization
event of small peptides bearing pseudoproline turn inducers has been
documented. See ref 10a.
ꢀ
(15) Cavelier-Frontin, F.; Pepe, G.; Verducci, J.; Siri, D.; Jacquier, R.
J. Am. Chem. Soc. 1992, 114, 8885–8890.
(16) Konopelski, J. P.; Filonova, L. K.; Olmstead, M. M. J. Am.
Chem. Soc. 1997, 119, 4305–4306.
(8) (a) Karle, I. L.; Handa, B. K.; Hassall, C. H. Acta Crystallogr.
1975, B31, 555–560. (b) Hassall, C. H.; Sanger, D. G.; Handa, B. K.
J. Chem. Soc. C 1971, 2814–2818.
(17) Andruszkiewicz, R.; Wyszogrodzka, M. Synlett 2002, 12, 2101–
2103.
(18) Ishizuka, T.; Kunieda, T. Tetrahedron Lett. 1987, 28, 4185–4188.
(19) Greco, M. N.; Zhong, H. M.; Maryanoff, B. E. Tetrahedron
Lett. 1998, 39, 4959–4962.
(9) Boersma, M. D.; Haase, H. S.; Peterson-Kaufman, K. J.; Lee,
E. F.; Clarke, O. B.; Colman, P. M.; Smith, B. J.; Horne, W. S.; Fairlie,
W. D.; Gellman, S. H. J. Am. Chem. Soc. 2012, 134, 315–323.
(10) (a) Skropeta, D.; Jolliffe, K.; Turner, P. J. Org. Chem. 2004, 69,
8804–8809. (b) Cyclization of an all-S linear tetrapeptide precursor to
cyclocinamide A void of any turn-inducing element failed. See ref 5 for
details.
(20) See Supporting Information for detailed synthesis, characteriza-
tion, and full spectroscopic details.
Org. Lett., Vol. 14, No. 8, 2012
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