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. Author manuscript; available in PMC: 2009 Oct 16.
Published in final edited form as: Org Lett. 2008 Sep 23;10(20):4613–4616. doi: 10.1021/ol8018727

Studies on the Synthesis of Durhamycin A: Stereoselective Synthesis of a Model Aglycone

Rajan Pragani 1, William R Roush 1,*
PMCID: PMC2626543  NIHMSID: NIHMS86362  PMID: 18808128

Abstract

graphic file with name nihms86362u1.jpg

A stereoselective synthesis of the model aglycone corresponding to the anti-HIV aureolic acids durhamycins A (1) and B (2) is described.

The aureolic acids are a family of structually related antitumor antibiotics that include olivomycin A, chromomycin A3, mithramycin, and UCH9.1-7 Several members of this family have been used clinically.1-3 The aglycone of the different family members differs only by the nature of the C(7) substituent. However, considerable structural diversity occurs in the 2,6-dideoxy di-, tri-, and tetrasaccharide units that are appended to the C(2)-hydroxyl and C(6)-phenol of the aglycone. The anticancer properties of the aureolic acids originate from their ability to bind to the minor groove of DNA as 2:1 complexes with Mg2+.8-12 Structural activity relationship data derive primarily from studies of the family of metabolites isolated along with the parent antibiotics, as well as from analogs generated biosynthetically.13-17 Recent efforts especially from the Rohr laboratory have highlighted the importance of the oligosaccharide chains13,14 as well as the C(3)15-17 and C(7)12,14 substituents on biological properties of individual aureolic acids.

The newest members of the aureolic acid family are durhamycins A (1) and B (2),18,19 which were isolated from Actinoplanes durhamensis (Figure 1). In contrast to all other well-studied aureolic acids, which are known for their antitumor properties (vide supra), durhamycins A and B have shown potent inhibition of HIV Tat transactivation (IC50 = 4.8 nM and 48 nM, respectively) and appear to be relatively non-cytotoxic.5,13,18 The unique biological activity of the durhamycins has prompted us to explore new synthetic routes to the aglycone core that is more amenable to analog synthesis than the routes to the aglycone employed20,21 in our total synthesis of olivomycin A.22 Accordingly, we report herein our initial studies on the development of a third-generation synthesis of the aureolic acid aglycones.

Figure 1.

Figure 1

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Durhamycins A and B

We describe herein a highly diastereoselective synthesis of model aglycone 3 which contains the naturally occuring aureolic acid C(3) polyoxygenated sidechain (Scheme 1). We envisioned the acyloin unit of 3 would be installed from diene 4 via a ring-closing metathesis (RCM) and oxidation sequence. A highly diastereoselective allylation of aldehyde 5 with the chiral allylborane 6, to be derived by hydroboration of an allene 7, would afford diene 4.

Scheme 1.

Scheme 1

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Retrosynthetic Analysis of Acyloin 3

Aldehyde 5 was generated in a straightforward manner from commercially available 2-chloro-3-hydroxy-benzaldehyde 8 (Scheme 2). Protection of the phenol unit of 8 as a BOM ether provided 9 in 93% yield. Stille coupling of 9 with vinyl(tributyl)stannane using conditions described by Fu23 then provided aldehyde 5 in 87% yield.

Scheme 2.

Scheme 2

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Synthesis of Aldehyde 5

The synthesis of allene 7 began with the diazotization of L-threonine in water (10, Scheme 3).24 Protection of the crude diol as the cyclopentylidene ketal followed by DCC mediated coupling of the carboxylic acid with N-methoxy-N-methylamine afforded Weinreb amide 11 in 41% yield over the three steps. Amide 11 was then treated with 2-methyl-1-propenylmagnesium bromide.25 Luche reduction26 of the derived enone with NaBH4 and CeCl3 then provided alcohol 12 in 88% yield as an inseparable 7:1 mixture of diastereomers. Fortunately, the two isomers could be separated following protection of the hydroxyl group as a 2,2,2-trichloroethoxymethyl (TCE) ether.27 The olefin of the major TCE ether diastereomer (73% isolated yield) was cleaved by ozonolysis at −78 °C followed by treatment with Me2S and MgSO4 to reduce the ozonide intermediate.28 In this way, aldehyde 13 was obtained in 87% yield (64% from 12). Diastereoselective allenylation of aldehyde 13 was then performed under Corey conditions29 to afford allenol 14 in 65-78% yield with up to 10:1 selectivity.30 O-Methylation of 14 uncontaminated with its epimer, then provided allene 7 as a single isomer in 87% yield.

Scheme 3.

Scheme 3

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Synthesis of Allene 7

The key allylation step was executed as summarized in Scheme 4. Allene 7 was treated with 1Ipc2BH in Et2O31 for 10 min32 to provide a solution of (Z)-allylborane 6, which was cooled to −78 °C and treated with aldehyde 5. This reaction provided diene 4 in 81% yield and with 10:1 diastereoselectivity. The assignment of (Z)-olefin geometry to allylborane 6 derives from the stereochemistry of 4, together with the expectation that the reaction of 5 and 6 proceeds via a chair-like t.s.33

Scheme 4.

Scheme 4

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Synthesis of Diene 4

The stereochemistry of 4 was assigned following conversion to 16 (Scheme 5). Initial attempts to effect the ring-closing metathesis reaction of 4 stalled at less than 10% conversion, owing presumably to formation of a chelate of a ruthenium carbene intermediate with one of the Lewis basic ether units in the substrate.34 However, inclusion of Ti(i-OPr)4 in the metathesis reaction allowed complete conversion of 4 to 15 at 40 °C.35 The stereochemistry of the hydroxyl center [C(4)] in 15 was assigned by Mosher ester analysis (see Supporting Information).36 Further manipulation of 15 via diimide reduction37 to tetrahydronaphthalene 16 (81% yield) allowed assignment of the trans C(3)-C(4) relationship (3JH3,H4 = 8.0 Hz).38 These data require the intermediacy of (Z)-allylborane 6 as the dominant intermediate in the allylboration of 5, assuming that the reaction proceeds via the usual and highly conserved chair-like transition state.33

Scheme 5.

Scheme 5

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Ring Closing Metathesis of Diene 4

The conclusion that the allylboration reaction proceeds via (Z)-allylborane 6 was not expected, since crotyl(diisopinocampheyl)boranes (as well as other dialkylcrotylboranes) are known to undergo rapid olefin isomerization via reversible 1,3-migration of the dialkylboryl unit even at low temperatures.39 We initially assumed that 6 might be stabilized by chelation with the δ-methoxy group (as in 18), shifting the equilibrium away from (E)-allylborane 17. However, the stereocontrol was poor in the analogous hydroboration/allylboration of the simpler allenyl ether 19, thus ruling out this hypothesis (Scheme 6). Therefore, the synthetically useful stereoselectivity of the double diastereoselective allylboration reaction of 5 and 6 could be due to Curtin-Hammett control. However, it is also possible that the steric bulk of the oxygenated side chain in 6 destabilizes the transition state leading to the methallyl tautomer x, thereby slowing the rate of isomerization of 6 to 17.

Scheme 6.

Scheme 6

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Expected Thermal Isomerization of 6

The synthesis of model acyloin 3 was completed as summarized in Scheme 7. Diene 4 was converted into xanthate 21 in 86% yield under standard conditions. The Bu3SnH reduction of 21 was accomplished by using Et3B as the initiator.40,41 The reduction product was then subjected to RCM cyclization using the 2nd generation Grubbs catalyst42 in the presence of Ti(i-OPr)4 to give the dihydronaphthalene, and the TCE protecting group was removed by using activated zinc.43 This three-step sequence furnished alcohol 22 in 34% yield. Oxidation of 22 by using the Dess-Martin reagent44 provided ketone 23, thereby setting the stage for the oxidation of the dihyrohaphthalene unit to the acyloin unit of 3.

Scheme 7.

Scheme 7

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Synthesis of Acyloin 3

Osmium45 and ruthenium46 based keto-hydroxylation reactions were first examined as a means to convert 23 to 3. These reactions yielded the 1,2-diol as the major product. In contrast, a protocol employing KMnO4 and CuSO4•5H2O under phase transfer conditions47 gave only acyloin 3. However, this reaction required a large excess of oxidant and long reaction times, even with sonication.48 It was ultimately found that treatment of ketone 23 in acidic acetone with KMnO449 furnished a 9:1:1 mixture of 3, the hemiketal isomer of 3 and the C(2) diastereomer of 3 (which appears to exist exclusively as a hemiketal). This mixture was separated by column chromatography to afford the major diastereomer, acyloin 3, in 55% yield as an 8:1 mixture of the hydroxy ketone and hemiketal tautomers, respectively, in CDC13.50,51 Coupling constant analysis of the hydroxy ketone tautomer of 3 (3JH2,H3 = 12.0 Hz) indicated that the newly formed C(2) carbinol proton is anti to the C(3) methine proton.

In summary, we have completed the synthesis of an advanced model system for the aglycone of durhamycin A. The highlights of this synthesis include the diastereoselective allylboration of aldehyde 5 and (Z)-δ-(alkoxyallyl)dialkylborane 6 to give 4, the selective Bu3SnH reduction of xanthate 21, the RCM cyclization of the diene derived from 4, and the keto-hydroxylation of the highly functionalized dihydronapththalene 23. Further progress toward the total synthesis of durhamycin A and aureolic acid analogs will be reported in due course.

Supplementary Material

1_si_001. Supporting Information Available.

Experimental procedures and tabulated spectroscopic data for all new compounds. This material is available free of charge via the Internet at http://pubs.acs.org.

2_si_002

Acknowledgments

This work was supported by the National Institutes of Health (GM038436)

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Associated Data

This section collects any data citations, data availability statements, or supplementary materials included in this article.

Supplementary Materials

1_si_001. Supporting Information Available.

Experimental procedures and tabulated spectroscopic data for all new compounds. This material is available free of charge via the Internet at http://pubs.acs.org.

NIHMS86362-supplement-1_si_001.pdf (646KB, pdf)
2_si_002
NIHMS86362-supplement-2_si_002.pdf (3.4MB, pdf)

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