Structure-activity investigations of analogues of the C15-C26 phorboxazoles segment

Article abstract of DOI:10.1055/s-1999-2922

A variety of analogues of phorboxazole C15-C26 segment have been prepared via three different reaction sequences. Structure activity investigations of the oxazole substitution pattern point to a pharmacophoric lead structure.

Full text of DOI:10.1055/s-1999-2922

1808
LETTER
Structure-Activity Investigations of Analogues of the C15-C26 Phorboxazoles
Segment
P. Wolbers,a H. M. R. Hoffmann,*,a F. Sasseb
aDepartment of Organic Chemistry, University of Hannover, Schneiderberg 1 B, D-30167 Hannover, Germany
bGBF, Gesellschaft für Biotechnologische Forschung mbH, Abt. Naturstoffbiologie, Mascheroder Weg 1, D-38124 Braunschweig,
Germany
Fax +49 (0)511 762 3011; E-mail: hoffmann@mbox.oci.uni-hannover.de
Received 31 August 1999
Asymmetric syntheses of the esters (-)-36 and (+)-67 in
Abstract: A variety of analogues of phorboxazole C15-C26 seg-
multigram quantities have been described by us starting
from the oxabicyclic ketones meso-2 and rac-5. Under
ment have been prepared via three different reaction sequences.
Structure activity investigations of the oxazole substitution pattern
typical reaction conditions (DIBAH reduction and subse-
quent PCC oxidation) the corresponding aldehydes (-)-4
and (+)-77b were obtained in good yield (Scheme 1).
point to a pharmacophoric lead structure.
Key words: oxazole synthesis, drug discovery, natural products,
SAR-studies
During the last decade a wide variety of 2,4-disubstituted
oxazoles and thiazoles have been found in biologically ac-
tive natural products.1 The biosynthetic origin of 2,4-di-
substituted oxazoles has been investigated on the disora-
zoles by Höfle, Reichenbach and their coworkers who
have shown that serine is the nitrogen source for oxazoles
in nature.2 Thus oxazoles are masked amino acids. Unlike
conventional zwitterionic α-amino acids the covalent ox-
azoles are capable of crossing the blood brain barrier. In-
tensive synthetic and pharmacological studies have also
been carried out on the epothilones, containing a 2,4-
disubstituted thiazole in their side chain.3
Reaction conditions: a) 1. DIBAH, THF, rt, 4 h; 2. PCC, DCM, rt, 15
h, 73% over 2 steps; b) DIBAH, toluene, -78 °C, 1 h. 68% (ref. 7b).
Scheme 1
Using the reaction conditions developed earlier5 aldehyde
(-)-4 was converted into 5-methoxy oxazole ester (-)-8.
The ester group and the heteroaromatic methoxy group
were reduced in one step using LiAlH4 to give oxazolyl
methanol (-)-9. In contrast, aldehyde (+)-7 was trans-
formed into the unsaturated nitrile. Rhodium(II) catalyzed
cycloaddition with dimethyl diazomalonate gave oxazolyl
ester (+)-10, which was reduced to the corresponding ox-
azole methanol (+)-11 in reasonable yield.
Figure 1
A third pathway towards analogues of the C15-C26 phor-
boxazole segment is shown in Scheme 3. Starting from al-
dehydes (-)-4 and (-)-12 we prepared a,b-unsaturated
esters in excellent yield and with good stereocontrol
(>90%; E:Z > 20:1) using the protocol of Masamune and
Roush.8 Basic hydrolysis afforded the corresponding a,b-
unsaturated acids (-)-13 and (-)-14 quantitatively.
The phorboxazoles A and B 1a and 1b are two new highly
cytotoxic macrolides with two 2,4-disubstituted oxazole
rings.4 Starting from the corresponding C20-C26 alde-
hyde we have described two new synthetic routes to the
C15-C26 segment of the phorboxazoles.5 Since we were
interested in the discovery and design of potential
pharmacophores, we synthesized a variety of analogues of
the C15-C26 segment of the phorboxazoles. As starting
material we required enantiopure tetrahydropyranyl ace-
taldehydes.
The oxazole ring was formed biomimetically using serine
as nitrogen source:9 a peptide coupling of the a,b-unsatur-
ated acids (-)-13 and (-)-14 with serine methyl ester using
isobutyl chloroformate (IBCF) and N-methyl morpholine
(NMM) gave the two corresponding amides, which were
Synlett 1999, No. 11, 1808–1810 ISSN 0936-5214 © Thieme Stuttgart · New York

LETTER
Structure-Activity Investigations of Analogues of the C15-C26 Phorboxazoles Segment
1809
Reaction conditions: a) NaH, DCM, rt, 2 h, 83% (E:Z = 2.7:1); b)
LiAlH4, THF, -78 °C, 3 h, 45%; c) 1. Ph3PCHCN, toluene, LiCl, rt,
18 h, 94% (E:Z > 20:1); 2. (CO2Me)2CN2, Rh2(OAc)4, CHCl3, 15 h,
reflux, 65%.
Reaction conditions: a) 1. (EtO)2P(O)CH2CO2Et, LiCl, DBU,
MeCN, rt, 2 h, 91%; 2. LiOH, THF, H2O, rt, 15 h, 100%; b) 1. isobu-
tyl chloroformate, NMM, -25 °C, 15 min, then L-serine methylester
hydrochloride, rt, 3 h, 75%; 2. Et3N+SO2N-CO2Me, THF, reflux, 2 h,
71%; 3. CuBr2, DBU, HMTA, DCM, rt, 30 min, 75%; c) 1.
(EtO)2P(O)CH2CO2Et, LiCl, DBU, MeCN, rt, 2 h, 86%; 2. LiOH,
THF, H2O, rt, 15 h, 100%; d) 1. isobutyl chloroformate, NMM, -25
°C, 15 min, then L-serine methylester hydrochloride, rt, 3 h, 72%; 2.
Et3N+SO2N-CO2Me, THF, reflux, 2 h, 71%; 3. CuBr2, DBU, HMTA,
DCM, rt, 75%.
Scheme 2
subsequently cyclodehydrated to the oxazoline esters with
Burgess reagent.10 The oxidation procedure developed at
Bristol-Myers Squibb (Cu(II)/DBU/HMTA in DCM)11
afforded oxazole esters (-)-15 and (-)-16. The three-step
reaction sequence (a,b-unsaturated acids → a,b-unsatur-
Scheme 3
ated oxazole ester) proceeded in good overall yield (> • 2,4-disubstituted oxazole esters (-)-15 and (-)-16 are less
20%). active than 2,4,5-trisubstituted oxazole ester.
The oxazole containing compounds were tested against • less complex 2,4,5-trisubstituted oxazole esters (17 - 19)
pathogenic yeast Candida albicans and phytopathogenic are less cytotoxic than the oxazole esters with tetrahydro-
fungus Ustilago zeae. No antifungal activity was ob- pyran side chain (+)-10 and (-)-20.
served. However, some interesting observations were
While the biological activity of the most potent substances
(+)-10 and (+)-21 is considerably lower than that of well
made with regard to cytotoxic activity (Table 1).12
Discussion of structure-activity relationship (SAR). All known cytotoxic molecules such as the epothilones A and
substances show cytotoxic activity. However, the potency B (IC50 = 4 and 1 ng/ml for L929 cells) our compounds are
of the molecules is significantly dependent on the substi- structurally more simple. We think that 5-methoxy ox-
tution pattern of the oxazole ring. In the search for a po- azole esters containing modified side chains at carbon C2
tential lead optimization, the following points should be and C4 are molecules of interest in the area of cancer re-
borne in mind:
search.
• 2,4,5-trisubstituted oxazole esters are potent down to
submicromolar concentrations [(+)-10 and (-)-20 with
IC50 = 0.1 mg/ml and IC50 = 0.5 µg/ml).
Acknowledgement
We thank Professors G. Höfle and H. Reichenbach for a helpful dis-
cussion, the Deutsche Forschungsgemeinschaft for a PhD fel-
lowship (P.W., Graduiertenkolleg Chemische und Technische
Grundlagen der Naturstofftransformation) and the Fonds der Che-
mischen Industrie for support of our work.
• 2,4-disubstituted oxazole methanols (+)-11 and (+)-21
are one hundred times less cytotoxic than 2,4,5-trisubsti-
tuted oxazole esters (+)-10 and (-)-20.
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P. Wolbers et al.
LETTER
1996, 49, 560; c) An excellent review on the epothilones is
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Lett. 1999, 40, 4527; see also Misske, A. M.; Hoffmann, H. M.
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(6) Wolbers, P.; Hoffmann, H. M. R. Tetrahedron 1999, 55, 1905.
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1997, 8, 3913; b) Weiss, J. M. PhD thesis, Universität
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synthetic studies: Williams, D. R.; Clark, M. P. Tetrahedron
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Article Identifier:
1437-2096,E;1999,0,11,1808,1810,ftx,en;G13699ST.pdf
Synlett 1999, No. 11, 1808–1810 ISSN 0936-5214 © Thieme Stuttgart · New York