Enantioselective total synthesis of callipeltoside A: two approaches to the macrolactone fragment

doi:10.1016/j.tet.2008.02.001

Tetrahedron

Volume 64, Issue 21, 19 May 2008, Pages 4671-4699

https://doi.org/10.1016/j.tet.2008.02.001 Get rights and content

Abstract

The enantioselective total synthesis of callipeltoside A is described. Two syntheses of the macrolactone subunit are included: the first relies upon an Ireland–Claisen rearrangement to generate the trisubstituted olefin geometry and the second utilizes an enantioselective vinylogous aldol reaction for this purpose. Enantioselective syntheses of the sugar and chlorocyclopropane side chain fragments are also disclosed. The relative and absolute stereochemistry of this natural product was determined by fragment coupling with the two enantiomers of the side chain fragment.

Graphical abstract

Introduction

In 1996, Minale and co-workers isolated minute quantities of callipeltoside A (1, Fig. 1) from the lithistid sponge Callipelta sp.1, 1(a) This macrolide was the first reported member of a new class of marine natural products, characterized by several unique structural features. Appended to the 14-membered macrolactone, which contains a 6-membered hemiketal, are a highly functionalized deoxyamino sugar (callipeltose) and a dienyne-trans-chlorocyclopropane side chain. Additional analysis of the sponge extracts revealed the presence of two further members of this family: callipeltosides B and C (Fig. 1).^1b All three macrolides possess the macrolactone and side chain portions, but differ in their sugar subunits and glycoside linkages. Extensive NMR experiments were used to assign the relative stereochemical relationships in the macrolactone and sugar regions, however, the relative stereochemistry of the side chain remained unresolved; moreover, the absolute stereochemistry was not assigned. These stereochemical ambiguities coupled with promising biological activity and lack of natural material (vide infra) make this molecule an attractive candidate for total synthesis. To date, four total syntheses and numerous approaches to the synthesis of various subunits have been reported.2, 2(b), 2(c), 2(d), 2(e), 2(f), 2(g), 2(h), 2(i), 2(j), 2(k), 2(l), 2(m), 2(n), 2(o), 2(p), 2(q), 2(r), 2(s), 2(t)

Preliminary biological assays indicated that callipeltoside A exhibits moderate cytotoxicity against human bronchopulmonary non-small-cell lung carcinoma NSCLC-N6 and P388 cell lines (IC₅₀ values of 11.26 and 15.26 μg/mL, respectively).^1a Flow cytometry assays of NSCLC-N6 cell line treated with callipeltoside A revealed in vitro inhibition of cell proliferation of the G1 phase. This cell cycle dependent effect may be induced by enzyme inhibition or terminal cell differentation. No further biological investigations have been disclosed, perhaps due to the lack of an abundant source of the natural product.

In 1986, Celmer compared published structures of macrolactone antibiotics and found that a majority of macrolides share two common characteristics: (1) they possess a d-configuration at the lactone-containing alkoxy stereocenter, and (2) the C₇ carbon is either unsubstituted (‘classical macrolides’) or has an l-OH substitution (‘unusual macrolides’),3, 3(a), 3(b) although exceptions do exist. Since the proposed relative stereochemistry of callipeltoside did not follow both trends, we decided to pursue the stereoisomer that possesses the C₇ l-OH configuration, a more conserved trait amongst the ‘unusual macrolides’. Based on the original NOESY data,^1a selection of this enantiomer of the macrolide dictates the stereochemistry of the sugar to be as illustrated in Figure 1. Synthesis of the two possible diastereomers 1a and 1b, that differ only in the configuration of the cyclopropyl group, would allow the absolute and relative stereochemistry of callipeltoside A to be unequivocally determined.

Our strategy involved disconnecting callipeltoside into three principal fragments: macrolactone A, callipeltose derivative B, and chlorocyclopropane side chain C (Scheme 1). A late-stage glycosylation would allow some flexibility should the stereochemical assignment of the sugar moiety prove to be incorrect. The final fragment coupling was planned to be a Horner–Wadsworth–Emmons olefination of each enantiomer of phosphonate C to an appropriate aldehyde, a strategy that would allow a late-stage divergence of the synthesis to the two possible diastereomers.

Section snippets

Synthesis of the macrolactone fragment: first generation

Our initial approach to the synthesis of macrolactone fragment A focused on the construction of the trisubstituted olefin by an Ireland–Claisen rearrangement of an oxygenated enolate (Scheme 2). Rearrangment precursor 2 would be prepared from aldehyde 3, which is available from β-ketoester 4. The stereochemical array of substrate 4 can be derived from the stereochemistry of β-ketoimide 5 through a series of diastereoselective aldol reactions.

The synthesis began with the anti-selective aldol

Conclusions

The enantioselective total synthesis of callipeltoside A has been accomplished in 25 steps (longest linear sequence) and 4% overall yield. A series of key methodologies were developed during the course of this synthesis: (1) a diastereoselective addition of an oxygenated enolate to a methyl ketone to prepare the densely functionalized callipeltose in a rapid and convergent manner; (2) a diastereoselective cyclopropanation of an electron-poor vinyl chloride using Shi's modified Simmons–Smith

General information

All non-aqueous reactions and distillations were carried out under an atmosphere of dry nitrogen in glassware that had been flame-dried under a stream of nitrogen. THF, CH₂Cl₂, toluene, and Et₂O were purified by passage through a bed of activated alumina. All other reaction solvents were distilled from calcium hydride. Solvents used for extraction and chromatography were of HPLC grade. Analytical thin layer chromatography was performed on EM Reagent 0.25 mm silica gel 60-F plates. Visualization

Acknowledgements

Financial support was provided by NIH (GM33328-18), NSF, and Merck Research Laboratories. The authors also wish to thank Professor Andre Charette for suggesting the investigation of the Shi Simmons–Smith modification.

References and notes (50)

Total...B.M. Trost et al.
Angew. Chem., Int. Ed.
(2002)
D.A. Evans et al.
J. Am. Chem. Soc.
(2002)
B.M. Trost et al.
J. Am. Chem. Soc.
(2002)
I. Paterson et al.
Org. Lett.
(2003)
H. Huang et al.
Org. Lett.
(2004)
Macrolactone...T.R. Hoye et al.
Org. Lett.
(1999)
F. Velázquez et al.
Org. Lett.
(2000)
I. Paterson et al.
Angew. Chem., Int. Ed.
(2001)
M. Romero-Ortega et al.
Tetrahedron Lett.
(2002)
H.F. Sneddon et al.
Org. Lett.
(2003)
J.A. Marshal et al.
Org. Lett.
(2004)
L. Boulard et al.
Synlett
(2007)
...G.R. Smith et al.
Carbohydr. Res.
(1998)
M.K. Gurjar et al.
Carbohydr. Lett.
(1998)
A.J. Pihko et al.
Tetrahedron: Asymmetry
(2001)
D.A. Evans et al.
Org. Lett.
(2001)
H. Huang et al.
Org. Lett.
(2003)
Side...H.F. Olivo et al.
Org. Lett.
(2000)
D.A. Evans et al.
Org. Lett.
(2001)
M.N. Masuno et al.
J. Org. Chem.
(2005)
Allison, B. Ph.D. Thesis, Harvard University: Cambridge, MA, USA,...
D.A. Evans et al.
J. Am. Chem. Soc.
(1995)
A.B. Charette et al.
J. Am. Chem. Soc.
(1998)
(b)This reaction has been applied to a synthesis of the callipeltoside side chain (see...
Z. Yang et al.
Tetrahedron Lett.
(1998)
A. Zampella et al.
J. Am. Chem. Soc.
(1996)
A. Zampella et al.
Tetrahedron
(1997)
W.D. Celmer
Ann. N.Y. Acad. Sci.
(1986)
W.D. Celmer
J. Am. Chem. Soc.
(1965)
D.A. Evans et al.
Tetrahedron
(1992)
D.A. Evans et al.
J. Am. Chem. Soc.
(1988)

T.-H. Chan et al.

J. Am. Chem. Soc.

(1980)

D.A. Evans et al.

J. Am. Chem. Soc.

(1996)

K. Fujiwara et al.

J. Am. Chem. Soc.

(1998)

D.A. Evans et al.

J. Am. Chem. Soc.

(1999)

tol-BINAPCuF has been shown to catalyze vinylogous aldol reactions with excellent olefin selectivity and moderate...G. Bluet et al.

Tetrahedron Lett.

(1999)

G. Bluet et al.

J. Org. Chem.

(2001)

D.N. Butler et al.

J. Am. Chem. Soc.

(1964)

H.E. Zimmerman et al.

J. Am. Chem. Soc.

(1957)

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Enantioselective total synthesis of callipeltoside A: two approaches to the macrolactone fragment

Abstract

Graphical abstract

Introduction

Section snippets

Synthesis of the macrolactone fragment: first generation

Conclusions

General information

Acknowledgements

Angew. Chem., Int. Ed.

J. Am. Chem. Soc.

J. Am. Chem. Soc.

Org. Lett.

Org. Lett.

Org. Lett.

Org. Lett.

Angew. Chem., Int. Ed.

Tetrahedron Lett.

Org. Lett.

Org. Lett.

Synlett

Carbohydr. Res.

Carbohydr. Lett.

Tetrahedron: Asymmetry

Org. Lett.

Org. Lett.

Org. Lett.

Org. Lett.

J. Org. Chem.

J. Am. Chem. Soc.

J. Am. Chem. Soc.

Tetrahedron Lett.

J. Am. Chem. Soc.

Tetrahedron

Ann. N.Y. Acad. Sci.

J. Am. Chem. Soc.

Tetrahedron

J. Am. Chem. Soc.

J. Am. Chem. Soc.

J. Am. Chem. Soc.

J. Am. Chem. Soc.

J. Am. Chem. Soc.

Tetrahedron Lett.

J. Org. Chem.

J. Am. Chem. Soc.

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