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About 100 analogs were synthesized by the route outlined in Scheme 7. These were assayed for their ability to inhibit tubulin polymerization, and several compounds more active than the natural product were discovered.
8.8. LAVENDUSTIN A
One of the first reported solid-phase syntheses of a nonoligomeric natural product was that of lavendustin A.31 This compound is a potent tyrosine kinase inhibitor. Fortunately, the structure of this material is highly amenable to synthesis and elaboration on a solid phase. In fact, the synthesis was reported by a researcher working alone on this project (Green).31
Scheme 8 shows how this synthesis was performed. FMOCprotected methoxy-3-amino-benzoic acid 62 was attached to hydroxymethyl polystyrene resin. The resulting ester 63 was deprotected and then reductively
8.8. LAVENDUSTIN À ÎÀñ
52 THF then cap with CH3CHO
(i) NaOMe (ii) R1COXa
(iv) for 55: oxidation for 56: (PhO)2PON3 then PPh3 , H20
a For 61: R1COX =
or R^NH2 (ii) R3OH, CSA
54 Z = CHoOH 55 Z = COoH 56 Z = CH2NH2
57 Y = CH20(C0)R2 58 Y = C02R2 59 Y = CONHR2 60 Y = CH2NHCOR2
61 (sarcodictyin A)
260 RECENT ADVANCES IN SOLID-PHASE SYNTHESIS OF NATURAL PRODUCTS
aminated with 2,5-dimethoxy-benzaldehyde 64 to give the resin-bound secondary aniline 65. The synthesis was completed by amine alkylation with 2-methoxy-benzyl bromide 66, simultaneous resin cleavage, and de-methylation to yield the natural product 67 in 90% yield from 63. A series of 60 lavendustin analogs were synthesized from three benzoic acids, five benzaldehydes, four benzyl bromides, and three starting resins. Yields varied from 10-83% with purities in the 30-97% range.
8.9. INDOLYL DIKETOPIPERAZINES
The indolyl diketopieprazine family of natural products includes the fu-mitremorgins, verruculogens, and cyclotryprostatins 68. A solid-phase syn-
8.10. BALANOL ANALOGS 261
thesis of analogs of this group of compounds was reported recently.32 It featured Pictet-Spangler cyclizations onto resin-bound (Wang) L-tyrosine derivatives. Several aldehydes (R^CHO) were used to give the compounds 69. Acylation with FMOC-protected amino acids and cyclization/cleavage from the resin formed the diketopiperazine products 70. Forty-two examples were reported, with yields and purities reported in the 50-99% range.
8.10. BALANOL ANALOGS
Several truncated analogs of the natural product balanol 71 were prepared on a solid phase by Nielsen and Lynso.33 Thus, symmetrical di-acids were linked to Wang resin, followed by coupling a number of FMOCprotected
RECENT ADVANCES IN SOLID-PHASE SYNTHESIS OF NATURAL PRODUCTS
Î (³) For (-)-75: ref. 35 q ^
oh For (+)-75: ref. 36 HO^A AJ
(ii) PyBOP, iPr2NEt> H
0H NMP, 25 QC Î
73 (shikimic acid) (±)-75
0- Ó ,
-N (i) Cu(l)/Pd(ll) R—=
R(ii) r2nH2, 'oh
(i) r3co2h, dipc, dmap
(ii) hv- photocleavage
8.11. PSEUDOALKALOIDS FROM SHIKIMIC ACID 263
amino alcohols via O-acylation (FMOC-NH-X-OH). Deprotection and /V-acylation with aromatic acids gave the compounds 72 after cleavage from the resin. Thirty-two analogs were produced in a split-mix format as four pools of eight compounds.
8.11. PSEUDOALKALOIDS FROM SHIKIMIC ACID
The final example described in this chapter is that done by Schriebex and co-workers. They used a scaffold with multivariant sites derived from shikimic acid. However, the end products of their synthesis were compact, highly functionalized structures reminiscent of alkaloids.34 An objective of this study was to produce a very large number of compounds for miniaturized cell-based assays. In fact, about 2 million compounds were made.
The synthetic approach used in this work is shown in Scheme 9. Two known solution pathways were used to convert shikimic acid to an epoxide intermediate. In fact, both the (-)35 and the (+)36 enantiomers were formed. After minor synthetic transformations, these epoxides were linked to Ten-tagel S aminomethyl resin with an o-nitrophenyl-derived photocleavable linker 7437 via amide bond formation to give intermediate 75. The first point of variation was added via various iodo-benzyl nitrone carboxylic acids 76 via 1,3-dipolar addition/esterification reactions. Highly constrained resin-bound tetracyclic hydrooxazoles 77 were thereby produced.