Enantioselective total synthesis of callipeltoside A: two approaches to the macrolactone 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... et al.
Angew. Chem., Int. Ed.
(2002)et al.J. Am. Chem. Soc.
(2002)et al.J. Am. Chem. Soc.
(2002)et al.Org. Lett.
(2003)et al.Org. Lett.
(2004)Macrolactone... et al.Org. Lett.
(1999)et al.Org. Lett.
(2000)et al.Angew. Chem., Int. Ed.
(2001)et al.Tetrahedron Lett.
(2002)et al.Org. Lett.
(2003)et al.Org. Lett.
(2004)et al.Synlett
(2007)... et al.Carbohydr. Res.
(1998)et al.Carbohydr. Lett.
(1998)et al.Tetrahedron: Asymmetry
(2001)et al.Org. Lett.
(2001)et al.Org. Lett.
(2003)Side... et al.Org. Lett.
(2000)et al.Org. Lett.
(2001)et al.J. Org. Chem.
(2005) - Allison, B. Ph.D. Thesis, Harvard University: Cambridge, MA, USA,...
- et al.
J. Am. Chem. Soc.
(1995) - et al.
J. Am. Chem. Soc.
(1998)(b)This reaction has been applied to a synthesis of the callipeltoside side chain (see... - et al.
Tetrahedron Lett.
(1998) - et al.
J. Am. Chem. Soc.
(1996)et al.Tetrahedron
(1997) Ann. N.Y. Acad. Sci.
(1986)J. Am. Chem. Soc.
(1965)- et al.
Tetrahedron
(1992) - et al.
J. Am. Chem. Soc.
(1988)
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.
J. Am. Chem. Soc.
Cited by (47)
Progress in catalytic asymmetric α-functionalization of vinylogous nucleophilic species
2023, Organic Chemistry FrontiersRecent applications of Stille reaction in total synthesis of natural products: An update
2018, Journal of Organometallic ChemistryCitation Excerpt :Next, the latter was converted into intermediate 315 in several steps. For preparing callipeltoside A 309, callipeltoside aglycon 315 reacted with thioglycoside donor 316 under standard conditions according to Evans's method [62] (CH2Cl2, DTBMP, r. t., and then, −15 °C to r. t., NIS, TfOH). The resulting TIPS-protected compound upon reaction with TBAF in THF provided callipeltoside A 309 in 83% yield (over two steps).
(−)-Lyngbyaloside B, a Marine Macrolide Glycoside: Total Synthesis and Stereochemical Revision
2016, Strategies and Tactics in Organic SynthesisCitation Excerpt :Thus, it was conceived that the macrolactone 36 would be available from the tertiary alcohol 37 and the carboxylic acids 9a,b. The synthesis of the tertiary alcohol 37 started with reduction of known ester 38,55 followed by silylation of the resultant alcohol, and subsequent removal of the MPM group to give the alcohol 39 (Scheme 8). Sharpless asymmetric epoxidation of 39 successfully installed the C-13 stereogenic center with high enantiomeric purity (e.r. = 96:4).
Oxazolidinones as chiral auxiliaries in asymmetric aldol reactions applied to total synthesis
2013, Tetrahedron AsymmetryCitation Excerpt :This reaction was used for the formation of aldol adduct 260 with excellent diastereoselectivity (de: 95: 5), which followed the construction of aldehyde 261. In the reaction sequences the chiral auxiliary was removed with DIBAl-H.133 The synthesis of paraconic acids 263–270 were completed by Park et al.
2.12 Selected Diastereoselective Reactions: Additions of Achiral Carbanions to Chiral Aldehydes and Ketones
2012, Comprehensive ChiralityFirst example of an atropselective dehydro-Diels-Alder (ADDA) reaction
2011, Tetrahedron Letters