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. Author manuscript; available in PMC: 2009 Apr 13.
Published in final edited form as: Org Lett. 2006 Apr 27;8(9):1759–1762. doi: 10.1021/ol060206q

TESOTf-Induced Rearrangement of Quinols. Efficient Construction of the Fully Functionalized Carbon Skeleton of the Griseusins by a Divergent-Reconvergent Approach

Kathlyn A Parker 1,*,†, Thomas L Mindt 1,#, Yung-hyo Koh 1,‡
PMCID: PMC2668545  NIHMSID: NIHMS60982  PMID: 16623544

Abstract

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The “reverse polarity” or “umpolung” strategy for the total synthesis of aryl C-glycosides was developed in the context of the antibiotic (−)-griseusin B. Although a key reaction in a model sequence for the total synthesis produced two structurally divergent products, both were converted to the same advanced model intermediate that contains the complete carbon skeleton and (except for the extraneous oxygen substituent in the model series) the functional group pattern of the griseusins.

(−)-Griseusin A (1a) and B (2a),1,2 their more recently isolated 4′-deacetyl derivatives 1b and 2b,3 and the more complex 3′-O-α-D-forosaminyl-(+)-griseusin A (3)4 are aromatic, polyketide derived antibiotics produced by the actinomycete strain Streptomyces griseus (Figure 1).

Figure 1.

Figure 1

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(−)-Griseusin A and B, the 4′-Deacetyl Griseusins and 3′-O-α-D-Forosaminyl-(+)-Griseusin A.

The griseusins belong to the growing family of pyrano naphthoquinones that includes the well-known kalafungin, nanaomycins, medermycin, and granaticin.5 Members of this class display a variety of interesting biological activities. Moore and Czerniak proposed that the pyrano naphthoquinones including the griseusins act as bioreductive alkylation agents via quinone methide intermediates in a manner similar to that of the anticancer agent mitomycin C.6 The griseusins are active against gram-positive bacteria; the deacetyl griseusins 1b and 2b and the forosaminyl griseusin A 3 have demonstrated activity against methicillin-resistant Staphylococcus aureus (MRSA), a growing health problem.7

The pyrano naphthoquinones have attracted interest in both the biosynthesis/bioengineering8,9,10 and organic synthesis11 communities. Total syntheses of (+)-griseusin A2a and (+)-9-deoxy griseusin B2b and a synthesis of a mixture of protected (−)-griseusin A isomers have been reported.12

Our own work on the synthesis of the griseusins is one component of a broad program focused on the synthesis of naturally occurring aryl C- glycosides with a variety of substitution patterns on the aromatic aglycone.13 The oxidation pattern of the naphthyl C-glycoside moiety in the griseusins is the same as that in the mederrhodins,8b an arrangement that we have designated the group IV substitution pattern.14 The synthesis of one of these compounds by the “reverse polarity” or “umpolung” strategy would provide a demonstration of its power for the preparation of members of the group IV aryl C-glycosides.

Our retrosynthetic analysis of (−)-grieusin B (2a) suggested the elaboration of quinone glycal 4, envisioned as the Stille coupling product of bromo quinone glycal 5 with an appropriate stannane compound (Scheme 1). On the basis of our previous work, we anticipated that key intermediate 5 would be available from a dienone-phenol type rearrangement15 of quinol intermediate 6. Quinol 6, in turn, should be the product of regioselective addition16 of the lithiated reagent from a 4-deoxy glycal 817 to 2-bromo juglone derivative 7.

Scheme 1.

Scheme 1

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Retrosynthesis of (−)-Griseusin B (2a).

To test what appeared to be a reasonable but not directly precedented dienone-phenol rearrangement, we examined the behavior of the model quinol 9 (Scheme 2).16 In experiments intended to effect the protection of the tertiary hydroxyl group of this compound (TBDMSOTf, DIPEA, 0 °C, 4.5 hr),18 we had noticed that extended reaction times or higher temperatures led to the appearance of aromatized product 11. Indeed, when the intermediate silyl ether 10 was subjected to the silyl triflate reagent for 2 days at room temperature, the protected, rearranged naphthalenehydroquinone was isolated in 45% yield (not optimized).

Scheme 2.

Scheme 2

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Dienone-Phenol Rearrangement to the Group 4 Substitution Pattern of Aryl C-Glycosides.

Next, we investigated the 1,2-addition reaction that is the foundation of the “umpolung strategy” with 2-bromo juglone methyl ether (12).19 For these feasibility studies (Scheme 3), we used readily available rhamnal derivative 1320 as a model for the less accessible deoxy glycal 8. Thus, lithiated rhamnal 1421 was added to quinone 12. Quenching of the reaction with water at room temperature22 led to the isolation of an approximately 1:1 mixture23 of the expected diastereomeric mixture of quinol glycal 15 and the surprising but attractive quinone glycal 16. In the context of a synthesis of griseusins, the appearance of this functionalized quinone was potentially advantageous.

Scheme 3.

Scheme 3

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Lithiated Glycal Addition to 2-Bromo Juglone Methyl Ether.

The mechanism of formation of quinone 16 is not clear. It is presumably the result of air oxidation of the corresponding hydroquinone, formed by quenching the product of conjugate addition or of coupling of a radical anion/radical cation pair.24 In any case, attempts to convert adduct 15 to the rearranged and oxidized 16 under the conditions of the addition reaction were unsucessful.23 Although we were unable to alter the ratio of these two adducts in the product mixture, we found that this 1:1 mixture was consistently produced in combined yields of >80 %. Therefore we set out to discover the chemistry that would convert each of the products to the same advanced (model) intermediate.

We first examined the elaboration of quinone glycal 16. Stille coupling with vinyl stannane 1825 as proposed in our retrosynthetic analysis did not afford the desired compund 19 but, instead, a complex mixture of inseparable products (Scheme 4). This result is not surprising in light of the ease by which vinyl quinones undergo cyclization reactions under thermal and photochemical conditions and the inherent instability of the products of these conversions.26,27

Scheme 4.

Scheme 4

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Transformation of Quinone Glycal 16 to Advanced Intermediate 22.

Focusing again on progress toward the griseusins, we resorted to an indirect strategy that utilizes protected bromo hydroquinone substrates for the Stille coupling with vinyl stannanes.26 Thus, reduction of quinone glycal 16 yielded hydroquinone 20, which was directly protected as hydroquinone 21. Stille coupling of intermediate 21 with vinyl stannane 18 yielded protected vinyl hydroquinone glycal 22 in good yield. This readily available compound contains the complete carbon skeleton of the griseusins and, except for the extra hydroxyl equivalent on the dihydropyran ring, it is appropriately functionalized for completion of a total synthesis.

Next we turned our attention to the potential of quinol glycal 15 as a precursor for this same advanced model intermediate 22 (Scheme 5). In an attempt to effect the conversion of quinol 15 to intermediate 23, we subjected it to the TESOTf rearrangement conditions (Hunig’s base at room temperature, Scheme 2). However, this experiment yielded only the TES-protected quinol glycal 24. Next, we attempted the silica gel-promoted rearrangement of quinols as reported by Wigal.28 However, substrate 15 proved to be stable under the applied conditions and no rearranged product 25 was observed. These results are consistent with related observations that suggest that a bromo substituent retards a dienol-phenol rearrangement.29

Scheme 5.

Scheme 5

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Elaboration of Advanced Intermediate 22 from Quinol Glycal 15 by a Dienone-Phenol-Type Rearrangement.

In order to access a suitable and useful substrate for the dienone-phenol-type rearrangement, we converted TES-protected quinol 24 to protected quinol 26 by Stille coupling with vinyl stannane 18 (Scheme 5). When protected quinol 26 was treated with excess TESOTf and Hunig’s base at room temperature, it was cleanly converted to quinone 22, identical in all respects to the product derived from bromoquinone 16.

With this achievement, both quinol glycal 15 and quinone glycal 16 have been converted to advanced model intermediate 22, each in only three steps and each in good overall yield (approximately 70 %). This result provides an unusual example of the utility of two regioisomeric products, obtained from a single reaction mixture, for the preparation of the same, desired compound.

Despite the additional manipulations associated with processing two intermediates, only seven steps total are required to prepare a complex structure that contains the complete carbon skeleton and (except for the extraneous C-oxygen substituent in the model 22) the functional group pattern of the griseusins from a bromoquinone and a protected glycal.

Application of the divergent reconvergent approach to the total synthesis of (−)-griseusin B (2a) is currently being investigated. The modular assembly nature of the synthetic scheme suggests that it might be efficiently applied to the preparation of griseusin analogs for structure-activity-relationship (SAR) studies.

Supplementary Material

si20060323_051. Supporting Information Available.

Detailed descriptions of the experimental procedures and complete analytical data for all new compounds. This material is available free of charge via the Internet at http://pubs.acs.org.

Acknowledgments

The work described in this communication was supported by the National Institutes of Health (CA-87503). For a part of his graduate school career, T.L.M. was a Fellow of the Graduate Assistance in Areas of National Need program of the U.S. Department of Education. We thank Dr. Tun-Li Shen for the mass spectroscopic measurements.

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Associated Data

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

Supplementary Materials

si20060323_051. Supporting Information Available.

Detailed descriptions of the experimental procedures and complete analytical data for all new compounds. This material is available free of charge via the Internet at http://pubs.acs.org.

NIHMS60982-supplement-si20060323_051.pdf (1.7MB, pdf)

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