Elsevier

Tetrahedron

Volume 60, Issue 41, 4 October 2004, Pages 9199-9204
Tetrahedron

An expedient synthesis of spiroketals: model studies for the calyculin C16–C25 fragment

https://doi.org/10.1016/j.tet.2004.07.059Get rights and content

Abstract

A new short strategy to prepare the spiroketal fragment of calyculins is presented. A novel Seyferth–Gilbert type homologation of hindered lactols to the corresponding alkynes has been achieved for the first time. The spirocyclization was achieved efficiently via a DIHMA (double intramolecular hetero-Michael addition) process of this hindered ynone. The spirocyclization rate is not dependent on the stereochemistry of the alkoxy substituent in the oxolane ring.

Introduction

The 1,6-dioxaspiro[4.5]decane ring system is a common motif, occurring in nearly 100 natural products.1 It is noteworthy that in most of these structures, the configuration of the stereogenic carbon atom is dictated by double anomeric effect, placing the oxygen in the oxolane ring axial with respect to the oxane ring (Fig. 1).2 Due to the wide occurrence of such structures, a rapid and reliable entry into the spirocyclic structure is highly desirable. This was of special interest to us because of our ongoing efforts towards the total synthesis of calyculin C, a potent protein phosphatase inhibitor.3, 4 In this paper we report our recent results on a highly convergent strategy to achieve this goal.5

Our retrosynthetic strategy for the model spiroketal is based on a convergent strategy (Scheme 1). The actual spiroketal formation is based on the DIHMA (double intramolecular hetero-Michael addition) process of a suitably derived ynone.6 Thus, our penultimate goal became the ynone 13, which would be available through a nucleophilic addition of the alkyne 8 onto the Weinreb amide 12, in turn available via Evans aldol methodology from propionyloxazolidinone 9 and benzyloxypropanal. The alkyne was envisioned to arise through a Seyferth–Gilbert-type homologation7 of the aldehyde (or lactol) corresponding to lactone 4.

Although seemingly well precedented, several questions remained to be answered. First, the electrophilic end of the ynone 13a,b is highly sterically crowded, which might affect the cyclization rate. Secondly, the formation of the highly substituted alkyne 8 is not trivial. Thirdly, the existence of the requisite alkoxy group in the oxolane ring might affect the cyclization rate and/or the stability of the ensuing spirocycle. To shed light on this latter question, we decided to enter the spirocyclization with enantiopure 12 and racemic 8. Rate differences between the diastereomers would thus become evident experimentally.

Section snippets

Results

The alkyne 8 was prepared as shown in Scheme 2, beginning with an addition of the ester enolate of ethyl isobutyrate to 2-benzoyloxyacetaldehyde 2 affording the hydroxy ester 3 in 63% yield. Protection of the hydroxy group (NaH, BnCl, 75%) and DIBAL-H reduction of the lactone gave lactol 5 in near quantitative yield, ready for the Seyferth–Gilbert type homologation to the alkyne without further purification. If the initial ester aldol reaction was allowed to warm to higher temperatures, the

Conclusions

We have presented a new strategy to prepare the spiroketal fragment of calyculins. A novel Seyferth–Gilbert type homologation of hindered lactols to the corresponding alkynes has been achieved for the first time. The spirocyclization was achieved efficiently via a DIHMA (double intramolecular hetero-Michael addition) process. The spirocyclization rate is not dependent on the stereochemistry of the alkoxy substituents in the oxolane ring. Application of this protocol in the total synthesis of

General

All reactions were conducted under a positive pressure of argon. THF was distilled prior to use from sodium-benzophenone, MeOH from Mg(OMe)2 and toluene from sodium. Other solvents were pro analysis grade.

Melting points were determined on a Gallenkamp melting point apparatus MFB-595 and are uncorrected. TLC was conducted on Merck 0.25 mm silica gel 60 F plates and samples were visualized with UV light, anisaldehyde, PMA or ninhydrin staining. Flash chromatography was performed using Merck silica

Acknowledgements

Funding and financial support provided by the Finnish Academy, the Ministry of Education, Jenny and Antti Wihuri Foundation and Emil Aaltonen Foundation are gratefully acknowledged. We would like to thank Mr. Y. Masuda for the valuable work with the lactone fragment and Päivi Joensuu at the University of Oulu for providing the high resolution mass spectroscopy data.

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