Synthesis of Bicyclic Hemiacetals Catalyzed by Unnatural Densely Substituted γ-Dipeptides

The asymmetric synthesis of bicyclic highly substituted tetrahydropyrans is described. The reaction is catalyzed by unnatural γ-dipeptides based on densely substituted l- and d-proline derivatives. This organocatalytic one-pot reaction takes place among a ketone, a nitroalkene, and an aldehyde to yield an octahydro-2H-chromene scaffold. Monomeric species, from which the corresponding γ-dipeptides are synthesized, cannot catalyze the reaction, thus confirming the emergent nature of the catalytic behavior of these dimeric species.

Optical rotations were measured at 589 nm (Sodium line) in a digital polarimeter with a thermally jacketed 5 cm cell at approximately 20 °C. Concentrations are given in g/100 mL.
Infrared spectra were recorded on an Alpha-Bruker FT-IR spectrometer with a single reflection ATR module. Wavenumbers are given in cm -1 .
High Resolution Mass Spectra (HRMS) analyses were carried out by SGIker services (Central Service of Alava and Bizkaia, University of the Basque Country) and performed on a LC/QTOF, Agilent mass spectrometer using electrospray ionization (ESI) mode.
NMR spectra were recorded at 400 or 500 MHz for 1 H NMR, 101 or 126 MHz for 13 C NMR and 376 MHz for 19 F NMR using CDCl3, acetone-d6 and methanol-d4 as solvents and TMS as internal standard. The data are reported as s = singlet, d = doublet, t = triplet, q = quartet, m = multiplet or unresolved, bs = broad signal, coupling constant(s) (J) in Hz, integration. 13 C NMR spectra were recorded with 1 H decoupling. Structural assignments were made with additional information from gCOSY, gHSQC, and gHMBC experiments Enantioselectivities were measured by HPLC using chiral stationary phases (Daicel Chiralpak IA/IB/IC/ID). In these experiments the racemic mixtures were analysed in order to establish the enantiomeric parameters of each enantiomer.
For X-Ray diffraction analyses, Agilent Technologies Super-Nova diffractometer was employed, equipped with monochromated Cu kα radiation (λ = 1.54184 Å) and Atlas CCD detector. Measurements were accomplished at 100 K with the aid of an Oxford Cryostream 700 PLUS temperature device. Data frames were processed (united cell determination, analytical absorption correction with face indexing, intensity data integration and correction for Lorentz and polarization effects) utilizing the Crysalis software package. 7 The structure was solved by Superflip 8 and refined by full-matrix least-squares with SHELXL-97 9 . Final

S5
Under these conditions, L-proline 11 was not very efficient and a low conversion was observed after one day of reaction (Table S1, entry 1). It is interesting to note that Enders and Seki 13 observed, under different conditions, medium-low ee's in the Michael reaction between 6a and 7a (18-57%). Similarly, D-prolinol derivative 12 showed low catalytic activity (Table S1, entry 2). Pro-Gly dimer 13 was moderately efficient in the presence of benzoic acid (Table S1, entry 4). However, no noticeable ee was observed. The −dipeptide XL-Gly-OH 14 also showed moderate catalytic activity and a modest ee (Table S1,

Screening of different chiral organocatalysts based on primary amines
The catalytic activities of quinidine derivative 15 and bifunctional amine-thiourea 16 were investigated. In both cases, the Michael step required 10 days to achieve less than 30% conversion. Then, ethyl glyoxylate (2 eq.) and triethylamine (0.2 eq) were added and the resulting reaction mixture was allowed to stir at room temperature for 1 day. The final product 10aaa could not be distinguished in the reaction crude and the enantiomeric excess could not be determined in any case (Scheme S1).
This step could be monitored by NMR analysis of reaction mixtures, according to our previously described characterization of Michael adducts obtained via monomeric and dimeric species (see refs. 17 and 18 of the main text). Then triethylamine (140 μL, 1.0 mmol, 0.2 eq.) and the freshly distilled ethyl glyoxylate 8a (10.0 mmol, 2.0 eq.) were successively added and the resulting reaction mixture was allowed to stir at room temperature 1 day.

Studies with Other Cyclic Ketones
After optimizing the reaction conditions, the scope of this process was investigated employing other cyclic ketones. Unfortunately, the reaction presented some restrictions regarding the nature of the nucleophiles. For instance, when tetrahydro-4H-pyran-4-one 6d and cyclohexane-1,3-dione 6e were selected as starting materials, no formation of the

X-Ray diffraction structures
Compounds 10aaa and 10aaa' were recrystallized in a mixture of hexane and ethyl acetate. Crystal growth was performed by slow evaporation at room temperature of the solvent mixture.

Isomerization Reaction
This process is mediated by a suitable base such as DBU via nitronate INTaad shown in