a convergent macrocycle assembly strategy from a tetrapep-
tide fragment and a tripeptide one. Optimization of the
macrocyclization site was achieved through screening of
several different ring closure possibilities. The resultant two
key amide bonds are indicated in Figure 1.
Scheme 2
The various components of cyclomarin C were synthesized
in different fashions. Our synthesis of N-Fmoc 2-amino-3,5-
dimethylhex-4-enoic acid derivative 4 utilized an enantio-
selective [3,3]-Claisen rearrangement5 (Scheme 1). N-TFA
Scheme 1
carried out through a ketalization-reduction sequence to
yield the desired N-Boc O5-Bz derivative 11. An initial
attempt to obtain 11 from L-glutamic acid lacked stereose-
lectivity when introducing a methyl group on its C-4
position.12
N-Boc-â-methoxyphenylalanine methyl ester 20 was pre-
amino acid methyl ester 6 was immediately converted into
N-Phth derivative 9 in an indirect fashion through the N-Boc
derivative 7. It was found that direct transformation of 6 into
9 was accompanied by partial racemization. Ozonolysis6 of
terminal olefin 9 and subsequent Wittig reaction7 afforded
the desired amino acid derivative 10. The amino acid
derivative 4 was finally obtained in three facile steps.
The second noncoded amino acid derivative, N-Boc-N-
methyl 5-benzoyloxyleucine 11, was synthesized with use
of chiral auxiliary strategies (Scheme 2). The first stereogenic
center (12) was introduced through an Evans protocol.8
Following initial protection of alcohol 12 as its benzoic acid
ester, cleavage of the tert-butyl ester was achieved with 10%
TFA in dichloromethane. The resultant acid was then
transformed into its acid chloride, which upon treatment with
the chiral auxiliary lithium salt 14 yielded 15 (85% for 3
steps). Successive treatment of 15 with NaHMDS, then trisyl
azide and quenching with HOAc-KOAc buffer afforded
azide 16.9 Reduction of azide functionality by hydrogenation
and in situ N-Boc protection gave 17. Hydrolysis of the chiral
auxiliary was then done in a routine fashion10 (LiOH, H2O2).
N-Methylation11 of the resulting N-Boc amino acid 18 was
pared from L-phenylalanine13 (Scheme 3). Initially, N-Phth
Scheme 3
phenylalanine 21 was converted into its tert-butyl amide 22.
Subsequently, radical-based bromination13a at the benzyl
position of 22 followed by substitution with hydroxide gave
the syn-â-hydroxyl derivative, which was O-methylated to
23 with Ag2O and MeI. Hydrazine-mediated phthaloyl
deprotection of 23 followed by acid-catalyzed tert-butyl
amide hydrolysis and N-Boc protection provided the amino
acid derivative 20.
(5) (a) Mues, H.; Kazmaier, U. Synthesis 2001, 487. (b) Bakke, M.; Ohta,
H.; Kazmaier, U.; Sugai, T. Synthesis 1999, 1671.
(6) Mooiweer, H. H.; Hiemstra, H.; Spechamp, W. N. Tetrahedron 1991,
47, 3451.
(7) Maryanoff, B. E.; Reitz, A. B. Chem. ReV. 1989, 89, 863.
(8) Evans, D. A.; Ripin, D. H. B.; Halstead, D. P.; Campos, K. R. J.
Am. Chem. Soc. 1999, 121, 6816.
(9) Evans, D. A.; Britton, T. C.; Ellman, J. A.; Dorow, R. L. J. Am.
Chem. Soc. 1990, 112, 4011.
(10) Evans, D. A.; Britton, T. C.; Ellman, J. A. Tetrahedron Lett. 1987
28, 6141.
(11) Aurelio, L.; Brownlee, R. T. C.; Hughes, A. B. Org. Lett. 2002, 4,
3767.
(12) Arda, A.; Jimenez, C.; Rodriguez, J. Tetrahedron Lett. 2004, 45,
3241.
(13) (a) Easton, C. J.; Hutton, C. A.; Roselt, P. D.; Tiekink, E. R. T.
Tetrahedron 1994, 50, 7327. (b) Sheehan, J. C.; Champman, D. W.; Roth,
R. W. J. Am. Chem. Soc. 1952, 74, 3822.
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Org. Lett., Vol. 6, No. 16, 2004