Accepted Manuscript

Oxazolidinone/enamine ratios in the reactions of α-silyloxy and α-alkoxy alde‐

hydes with proline

Dani Sánchez, Alejandro Castro-Alvarez, Jaume Vilarrasa

PII: S0040-4039(13)01638-9

DOI: http://dx.doi.org/10.1016/j.tetlet.2013.09.073

Reference: TETL 43573

To appear in: Tetrahedron Letters

Received Date: 29 July 2013

Revised Date: 13 September 2013

Accepted Date: 17 September 2013

Please cite this article as: Sánchez, D., Castro-Alvarez, A., Vilarrasa, J., Oxazolidinone/enamine ratios in the

reactions of α-silyloxy and α-alkoxy aldehydes with proline, Tetrahedron Letters (2013), doi: http://dx.doi.org/

10.1016/j.tetlet.2013.09.073

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Graphical Abstract

Oxazolidinone/enamine ratios in the reactions of -silyloxy and -alkoxy aldehydes with proline Dani Sánchez, Alejandro Castro-Alvarez, Jaume Vilarrasa*

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1

Tetrahedron Letters

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Oxazolidinone/enamine ratios in the reactions of -silyloxy and -alkoxy aldehydes with proline

Dani Sánchez, Alejandro Castro-Alvarez, Jaume Vilarrasa*

Departament de Química Orgànica, Facultat de Química, Universitat de Barcelona, Diagonal 645, 08028 Barcelona, Catalonia, Spain

——— * Corresponding author. Tel.: +34 934021258, fax: +34 933397878. E-mail address: jvilarrasa@ub.edu

The reaction of organocatalytically generated enantiopure enamines with a wide variety of electrophiles, as developed over the past decade,1,2 is an excellent tool for the synthesis of chiral building blocks. With notable exceptions, these processes are quite slow due to the very low concentrations of enamine intermediates and to the small rate constants of their reactions with weak electrophiles.

As is well known, linear and -branched aldehydes react with the standard and cheapest aminocatalyst, (S)-proline (Pro), to give several species in equilibrium; not only enamines2 but also oxazolidinones and, under certain conditions, zwitterions have been noted.3 The connection between oxazolidinones and enamines is well established2b,2f and the role of oxazolidinone tautomers in Pro-catalysed reactions has often been discussed.4 In this context, following outstanding pioneering NMR studies on oxazolidinones and/or enamines by the groups of List,3a Seebach,3b Gschwind,2b and Blackmond,2f we examined for the first time the oxazolid-inone/enamine ratios of the adducts of Pro and -substituted aldehydes 1–4 (derivatives of lactic acid or glyceraldehyde, useful chirons or chiroblocks in total synthesis). We compared them to other chiral aldehydes (5, 6,2f 7, and 8) and to additional carbonyl compounds. Our initial objective was to establish, by NMR experiments, whether these chiral -substituted aldehydes react with Pro to give enamines or not. At first sight, if their enamines were quickly formed in situ, the stereogenic centre would be "lost"5 and highly stereoselective cross-aldol reactions (Scheme 1, bottom) were not achieved. A scale of the oxazolidinone/enamine ratios would be very useful not only to rationalize the experimental results6 but also to predict which reactions of (or between) chiral aldehydes were stereoselective.

Scheme 1. Chiral aldehydes examined (reaction with proline in DMSO).

Example of challenging cross-aldol reaction.

The spectra of equimolar mixtures of aldehyde 1 and Pro in DMSO-d6 at room temperature showed that oxazolidinone 1a largely predominated (Scheme 2). Enamines 1b were not observed (they were below the detection limit of 500-MHz NMR instruments). Hemiaminals and zwitterions were not detected either under these conditions. The solution did not change after several days.

Scheme 2. Oxazolidinone 1a largely predominates in the reaction of aldehyde 1 with Pro, in DMSO-d6.

ART ICLE INFO AB ST R ACT

Article history:

Received Received in revised form Accepted Available online

-Silyloxy and -alkoxy aldehydes (propanal derivatives 1–4), when treated with proline in DMSO-d6, give oxazolidinones rather than enamines. In fact, the relative trend is much stronger than that of all other carbonyl compounds examined, including simple aldehydes, -branched aldehydes, -(alkylthio)aldehydes and standard ketones. For 1–4, the high prevalence of oxazolidinones prevents or delays the partial racemization of the -stereocentres.

2013 Elsevier Ltd. All rights reserved. Keywords:

Organocatalysis -Silyloxy and -alkoxy aldehydes Scale of oxazolidinone/enamine ratios Proline as protecting group of aldehydes

Tetrahedron Letters 2

Similarly, equimolar mixtures of Pro with 2, with 3 and with 4 showed only the 1H NMR signals owing to their oxazolidinones (the less crowded exo forms 2a–4a). The DMSO-d6 solutions of 2a did not change after several days. In contrast, those of 3a and 4a showed small amounts of epimers after 1 day and significant amounts after a few days.7 For instance, 52 h later the ratio between 3a and epi-3a (Scheme 3, top) was 1.7:1. To compare, we treated aldehyde 3 with (R)-proline (Scheme 3, bottom); 52 h later, the ratio between epi-ent-

3a and ent-3a was 2.4:1. Thus, the epimerization rate of 3a was slightly higher than that of its epimer. More than fifteen days later both solutions reached the same equilibrium position (nearly 1.2:1 ratio). It is assumed or expected that these epimerizations occur via the enamine forms (although we did not detect them by NMR, in the absence of additives).5,7 Moreover, it is confirmed in practice that -silyloxy aldehydes are less prone than -alkoxy aldehydes to a partial racemization.

Scheme 3. Epimerization of the oxazolidinone obtained from 3 and Pro (3a)

as well as that from 3 and (R)-proline, in DMSO-d6. To establish the relative tendency of aldehydes 1–4 to form

oxazolidinones 1a–4a, we mixed pairs of the aldehydes (1:1 and 1:2) with only 120 mol % of Pro. We observed that the trend to give oxazolidinones (forms a) were 4 > 2 > 1 ≥ 3. We also mixed the four aldehydes together in similar amounts (not exactly equimolar) with only 200 mol % of Pro. When the equilibria were reached (< 1 h), the 1H NMR integrations were compared (Scheme 4). The signal of aldehyde 4 decreased much more than those of the other aldehydes, while 4a grew significantly. In fact, what matters is the order of the relative ratios: [4a]/[4] > [2a]/[2] > [1a]/[1] ≥ [3a]/[3] (3.4:2.0:1.3:1). See Supplementary Data.

Scheme 4. Competition of 1–4 for Pro. Portions of the 1H NMR spectrum (

9.62–9.52 and 5.20–4.85) in DMSO-d6 at 25 ºC.

An equimolar mixture of 5 and Pro in DMSO-d6 gave exo-

oxazolidinone 5a. Unlike 1–4, enamines (Z)-5b (2%) and (E)-5b (1%) were immediately detected. Afterwards, enamines grew and epi-5a appeared. Two days later, (Z)-5b predominated.8 ROESY experiments showed cross peaks of the olefin proton of this enamine with H2 (intense), with H5 (less intense) and with H5 (much less intense) of the pyrrolidine ring. The s-trans conformer predominates, as expected,2 but the rotational barriers are quite low (below 5 kcal/mol according to DFT calculations, see Supplementary Data). An explanation of the above-mentioned epimerization is suggested in Scheme 5 (for 1H NMR spectra at different times also see Supplementary Data). Intermediates such as hemiaminals as well as zwitterions that were not detected under our conditions are not depicted in Scheme 5. Moreover, from ent-5 and Pro we prepared epi-5a in a NMR tube; two days later, the above-mentioned equilibrium, where (Z)-5b predominated, was again obtained.

Scheme 5. Suggested equilibria for the epimerization of 5a. Enamine (Z)-5b

predominated in the equilibrium. Enantiopure 6 and Pro in DMSO-d6 gave two exo-oxazol-

idinones (6a and epi-6a, nearly 1:1 after 30 min) and two enamines,9 which on addition of water afforded racemic 6. In other words, the addition of Pro to 6 caused a partial, rapid inversion of configuration (< 1 h). This did not happen with 1 and 2, took place within several days in the cases of 3 and 4, and required several hours with 5.

For comparison, we also determined the ratios between oxazolidinones (tautomers a) and enamines (forms b) for achiral aldehydes and cyclohexanone. Oxazolidinones largely predominated with -branched aldehydes such as cyclohexanecarboxaldehyde (450+45:1 exo+endo-ox/en) and (CH3)2CHCHO (2-methylpropanal, 90+9:1 exo+endo-ox/en, as reported by Gschwind et al.,2b which we have confirmed).10 -Branched aldehydes and linear aldehydes afforded ox/en ratios lower than cyclohexanone: 3-methylbutanal gave a 4:1 ratio (55+25:20 exo+endo-ox/en) in accord with the report of Gschwind et al.;2b 3-phenylpropanal11 gave a 3:1 ox/en ratio (2.4+0.6:1, exo+endo-ox/en).

(R)-2-(Benzylthio)butanal (7) yielded similar amounts of oxazolidinones and enamines. In fact, 7 gave exo-oxazolidinone 7a, exo-epi-7a (but not endo-oxazolidinones), enamine (E)-7b and enamine (Z)-7b, in 1:1:0.9:0.6 ratio. Comparison of 7 with 1–4 clearly indicates that -SR groups favour enamines much more than -OR groups, which in fact favour oxazolidinones.

On the other hand, there are special cases in which only enamines were noted (< 1:500 ox/en ratio). These enamines, arising from phenylacetaldehyde (benzeneethanal), 2-benzylthio-2-phenylethanal (8) and benzo[c]cyclopentanone (2-indanone),12 have the double bond conjugated with a Ph group or with a Ph group and a thioether. Comparison of 5, 6 and 8 indicates how much -OR substituents favour ox forms (tautomers a) and -SR substituents en forms (tautomers b), with regard to Me groups.

3 The results reported above are collected in Figure 1. In DMSO

the equilibria are greatly shifted to the right, that is, to oxazol-idinones or to enamines or to both (except for the case of cyclohexanone, chosen as a representative ketone, for which both Kox and Ken are very small). The ox/en or a/b experimental ratios are given for each case. In general, these are between the sum of the percentages of oxazolidinones (the ox or a forms), when more than one oxazolidinone tautomer is detected, and the sum of the percentages of Z- and E-enamines (forms en or b). In the cases of 1–4 direct dehydration to enamines (see Ken in Figure 1) was not noted (oxazolidinones are formed preferentially, ratios >> 500:1), while for the last three examples of Figure 1 the route to enamines is preferred, with no trace of oxazolidinones (ratios < 1:500).

Figure 1. Oxazolidinone(s)/enamine(s) ratios (ox/en ratios, or a/b ratios) as determined by 1H NMR in DMSO-d6 at 25 ºC, from Pro and the indicated carbonyl compounds (enantiopure in red).

The trend of 1–4 and Pro to give oxazolidinones is greater

than that of pivalaldehyde (t-BuCHO, which can form oxazolidinones but not enamines, obviously). We found that 2 + tBuCHO + Pro in equimolar amounts gives oxazolidinone 2a and small amounts of the oxazolidinone from tBuCHO, i.e., (2R,5S)-1-aza-2-tert-butyl-3-oxabicyclo[3.3.0]octan-4-one. The ratio of the equilibrium constants that we determined was 12±2.

Finally, we recall that aldehydes 1–4 and secondary amines other than Pro produce enamines readily and completely in DMSO, as do most aldehydes with an enolizable proton.1,2 Indeed, when treated with methyl prolinate and with O-protected prolinols, 1–4 yielded mixtures of Z and E enamines (in 4:1 to 8:1 ratios, with few exceptions, usually within 15 min in the presence of PhCOOH and in 1 h in its absence). One enantiopure aldehyde and its enantiomer gave rise to the same enamine mixture, in the same ratio. Thus, -substituted aldehydes show a "natural" tendency to be converted into enamines (although less so than linear aldehydes, of course). The point is that with Pro the trend to give bicyclic oxazolidinones is much greater.

We should also comment on a competition experiment between Pro and methyl prolinate for 2 in DMSO-d6. One hour after mixing equimolar amounts of the three compounds, despite the fact that Pro is hardly soluble, oxazolidinone 2a predominated (2a and the enamine from methyl prolinate were in a 20:1 ratio). However, the next day the ratio became nearly 1:1.2. When the experiment was repeated in the presence of PhCOOH, the enamine from methyl prolinate appeared immediately, now as rapidly as 2a did, and the equilibrium was reached in 2 h (see Supplementary Data for details). This confirms that -silyloxy aliphatic aldehydes also tend to form enamines, but it is masked when the catalyst is Pro, because

of the COOH group of Pro (since the cyclization to oxazolidinone is favoured) and probably also because of its interaction7 with the N (partially "destabilizing" the enamino group).

In summary, -silyloxy and -alkoxy aldehydes 1–4 do not give detectable percentages of enamines in reacting with Pro. Instead, they show the greatest tendency to yield oxazolidinones of all the carbonyl compounds. However, after a few hours, in the cases of 3 and 4 epimerization of the oxazolidinones begins. In the case of 5, which has a benzylic CH, the enamine forms are immediately noted and, as expected, epimerization is much more rapid. Thus, we disclose here another feature of Pro, viz., by blocking the CHO group it protects aldehydes of type 1–4 "against potential racemization" (for a long time in case of 1 and 2). Last but not least, on attempting to rationalize the reactivity differences among chiral aldehydes in cross-aldol reactions, we have obtained for the first time a scale of the relative trend to afford oxazolidinones or enamines, which besides its academic interest may have practical applications, as we hope to report in the near future.

Acknowledgments

Grants CTQ2009-13590 and 2009SGR-825 are acknowledged. D.S. and A.C.A. hold studentships from the University of Barcelona and the Chile Government, respectively. Thanks are due to Dr. F. Cárdenas and Dr. M. A. Molins for assistance with some 2D NMR experiments.

Supplementary data

Supplementary data associated with this article (copies of 1D and 2D NMR spectra, DFT calculations) can be found, in the online version, at http://dx.doi.org/10.1016/j.tetlett.2013 ..............

References and notes

1. For most recent reviews, see: (a) Science of Synthesis, Asymmetric

Organocatalysis 1; List, B.; Maruoka, K.; Eds.; Thieme: Stuttgart, 2012 (e.g., Yliniemelä-Sipari, S. M.; Piisola, A.; Pihko, P. M. pp 35–72; Mase, N. pp 135–216; Christmann, M. pp 439–454); (b) Melchiorre, P. Angew. Chem. Int. Ed. 2012, 51, 9748–9770; (c) Giacalone, F.; Gruttadauria, M.; Agrigento, P.; Noto, R. Chem. Soc. Rev. 2012, 41, 2406–2447; (d) Jensen, K. L.; Dickmeiss, G.; Jiang, H.; Albrecht, L.; Jørgensen, K. A. Acc. Chem. Res. 2012, 45, 248–264: (e) Nielsen, M.; Worgull, D.; Zweifel, T.; Gschwend, B.; Bertelsen, S.; Jørgensen, K. A. Chem. Commun. 2011, 47, 632–649; (f) Trost, B. M.; Brindle, C. S. Chem.

Soc. Rev. 2010, 39, 1600–1632; (g) Roca-Lopez, D.; Sadaba, D.; Delso, I.; Herrera, R. P.; Tejero, T.; Merino, P. Tetrahedron: Asymmetry 2010, 21, 2561–2601; (h) List, B. Angew. Chem. Int. Ed. 2010, 49, 462–463. (i) Xu, L.-W.; Li, L.; Shi, X.-H. Adv. Synth. Catal. 2010, 352, 243–279.

2. For very recent papers in which chiral enamines from proline derivatives have been characterized, see: (a) Grošelj, U.; Seebach, D.; Badine, D. M.; Schweizer, W. B.; Beck, A. K.; Krossing, I.; Klose, P.; Hayashi, Y.; Uchimaru, T. Helv. Chim. Acta 2009, 1225–1259: (b) Schmid, M. B.; Zeitler, K.; Gschwind, R. M. Angew. Chem. Int. Ed. 2010, 49, 4997–5003; (c) Schmid, M. B.; Zeitler, K.; Gschwind, R. M. Chem. Sci. 2011, 2, 1793–1803; (d) Schmid, M. B.; Zeitler, K.; Gschwind, R. M. J. Am. Chem. Soc. 2011, 133, 7065–7074; (e) Hein, J. E.; Burés, J.; Lam, Y.; Hughes, M.; Houk, K. N.; Armstrong, A.; Blackmond, D. G. Org. Lett. 2011, 13, 5644–5647; (f) Burés, J.; Armstrong, A.; Blackmond, D. G. Chem. Sci. 2012, 3, 1273–1277; (g) Lakhdar, S.; Baidya, M.; Mayr, H. Chem. Comm. 2012, 48, 4504-4506; (h) Sánchez, D.; Bastida, D.; Burés, J.; Isart, C.; Pineda, O.; Vilarrasa, J. Org.

Lett. 2012, 14, 536–539; for histidine and other amino acids, see: (i) Lam, Y.; Houk, K. N.; Scheffler, U.; Mahrwald, R. J. Am. Chem. Soc. 2012, 6286–

6295 and references therein; with Cinchona alkaloids-derived primary amines, see Ref. 1b; with other primary amines, see: (j) Zhang, L.; Luo, S. Synlett 2012, 23, 1575–1589 and references cited therein.

Tetrahedron Letters 4

3. Oxazolidinones from proline and acetone, cyclopentanone or cyclo-hexanone were characterized in DMSO-d6: (a) List, B.; Hoang, L.; Martin, H. J. Proc. Natl. Acad. Sci. (USA) 2004, 101, 5839–5842; for the the effect of solvents, bases, acids and salts on oxazolidinone/-enamine/zwitterion equilibria, see: (b) Seebach, D.; Beck, A. K.; Badine, D. M.; Limbach, M.; Eschenmoser, A.; Treasurywala, A. M.; Hobi, R.; Prikoszovich, W.; Linder, B. Helv. Chim. Acta 2007, 90, 425–471; for exchanges between oxazolidinones, see: (c) Isart, C.; Burés, J.; Vilarrasa, J. Tetrahedron Lett. 2008, 49, 5414–5418; for the role of COO– (instead of COOH), see: (d) Blackmond, D. G.; Moran, A.; Hugues, A.; Armstrong, A. J. Am. Chem. Soc. 2010, 132, 7598–7599; also see Ref. 2e and references therein; for the stabilization of enamine forms by bases, see: (e) Schmid, M. B.; Zeitler, K.; Gschwind, R. M. Chem. Eur. J. 2012, 18, 3362–3370; for the effect of other additives, see: (f) Martínez-Castañeda, A.; Rodríguez-Solla, H.; Concellón, C.; del Amo, V. J. Org. Chem. 2012, 77, 10375–10381 and references therein (guanidinium salts); (g) El-Hamdouni, N.; Companyó, X.; Rios, R.; Moyano, A. Chem. Eur. J. 2010, 16, 1142–1148, and references therein (thioureas).

4. As a dead end, as products of the participation of the carboxyl group of Pro or as nothing other than additional species in the equilibria. More recently, it has been shown that the COO– group may provide anchimeric assistance; see: Kanzian, T.; Lakhdar, S.; Mayr, H. Angew. Chem. Int.

Ed. 2010, 49, 9526–9529. 5. The formation of the (Z/E)-enamines implies a partial loss of the stereo-

chemical purity of the precursors. If these enamine isomers (of a chiral -substituted aldehyde) are in rapid equilibrium, a partial racemization in situ is probable, as is generally assumed. Nevertheless, very interesting exceptions may appear "at short times" (for reactions of quickly formed enamines with strong electrophiles, see Ref. 2f). Since the exceptions to the general rules are always noteworthy, we are searching for further cases in which one out of all the possible configurational and conformational enamine isomers largely predominates and reacts much more rapidly with an electrophile. For classic studies of the equilibria between (Z/E)-enamines of secondary amines, see references cited in: (a) Hudrlik, P. F.; Hudrlik, A. M; Kulkarni, A. K. Tetrahedron Lett. 1985, 26, 139–142; (b) Stradi, R.; Trimarco, P.; Vigevani, A. J. Chem. Soc., Perkin Trans 1 1978, 1–4.

6. Organocatalytic cross-aldol reactions in which -substituted aldehydes related to 1–3 are involved as electrophiles are limited to two pioneering examples: (a) Hanessian, S.; Mi, X. Synlett 2010, 761–764; (b) Enders, D.; David, S.; Deckers, K.; Greb, A.; Raabe, G. Synthesis 2012, 44, 3483–3488 (with 5); on the other hand, there are many cases in which 4 was used as the electrophilic partner: (c) Ref. 2i; (d) Ramasastry, S. S. V.; Albertshofer, K.; Utsumi, N.; Barbas, C. F. Org. Lett. 2008, 10, 1621–1624; (e) Utsumi, N.; Imai, M.; Tanaka, Fujie; Ramasastry, S. S. V.; Barbas, C. F. Org. Lett. 2007, 9, 3445–3448; (f) Enders, D.; Gasperi, T. Chem. Comm. 2007, 88–90; (g) Suri, J. T.; Mitsumori, S.; Albertshofer, K.; Tanaka, F.; Barbas, C. F. J. Org. Chem. 2006, 71, 3822–3828; (h) Ibrahem, I.; Zou, W.; Xu, Y.; Cordova, A. Adv. Synth.

Catal. 2006, 348, 211–222; (i) Suri, J. T.; Ramachary, D. B.; Barbas, C. F. Org. Lett. 2005, 7, 1383–1385; (j) Enders, D.; Grondal, C. Angew.

Chem. Int. Ed. 2005, 44, 1210–1212; (l) Cordova, A.; Notz, W.; Barbas, C. F. Chem. Comm. 2002, 3024–3025; for reviews of reactions of dihydroxyacetone derivatives with aldehydes, with references to the pioneering work of the groups of Barbas, MacMillan, Enders and Cordova, see: (l) Mlynarski, J.; Gut, B. Chem. Soc. Rev. 2012, 41, 587–

596; (m) Enders, D.; Narine, A. A. J. Org. Chem. 2008, 73, 7857–7870; (n) Markert, M.; Mahrwald, R. Chem. Eur. J. 2008, 14, 40–48.

7. In the presence of PhCOOH these epimerizations were more rapid. Since our goal was to obtain a general scale that was useful, it is outside the scope of this communication to re-examine all the equilibria in different media. For instance, the addition of 0.5 equiv of the strong base DBU to the NMR tube of 3a caused the appearance of one main enamine, 3b, H 5.17, C 120.3 (HSQC), and the epimerization of 3a (3a/epi-3a/3b ratio = 1:1.2:0.3), whereas in the case of 2a no enamine of type 2b was detected under the same conditions (but some epimerization took place,

3a/epi-3a ratio = 1:0.06), which suggests that, even though we indicate

in the summary that in the absence of any additive 2a/2b ratio ≈ 3a/3b ratio > 500:1, the true 2a/2b ratio may be much higher than the 3a/3b ratio. Concerning the progress of the epimerizations mentioned in the main text, our tentative explanation is that the process is autocatalytic: in contrast to the proline molecule and N-alkyl prolines (which are zwitterions in the solid state or aqueous media, and may show an internal hydrogen bond in other solvents), oxazolidinones have a basic tertiary N atom (though less basic than that of a standard tertiary amine because of the vicinity of an EWG), whereas enamines have a free COOH, the acidity of which is not fully "compensated" by the R2N-CH=CH group (less basic than its corresponding amine R2NH). Thus, each oxazolidinone molecule, once formed, may play the role of a weak base, favouring the opening of the oxazolidinone rings. Besides, the resulting enamine tautomers (or at least some conformers of them) may increase the rate of all steps that are catalysed by carboxylic acids.

8. This enamine (of Z configuration, according to the NMR spectra) is the most stable species in the equilibrium. The major isomer of a related enamine, obtained from 2 and O-t-butyldiphenylsilyl-(S)-prolinol (see Figure 5 of Ref. 2h), was also of Z configuration (NOESY indicated that the olefin H and Me are cis). Therefore, the drawing shown in Ref. 2h is incorrect.

9. As Burés, Armstrong and Blackmond observed in CDCl3 (Ref. 2f). They studied the kinetics of the oxazolidinone-to-enamine conversions (just after mixing, in the presence of DBU and AcOH) and quick reactions with strong electrophiles. Our NMR spectra in DMSO-d6 and NOESY experiments (EXSY peaks) corroborate their results, but we deal here only with the equilibrium positions (reached after > 30 min). The oxazolidinones we obtained from 6 were identical to those obtained from rac-6. One was the expected exo-oxazolidinone (6a); the other was another exo-oxazolidinone, an epimer of 6a (inverted configuration at the side chain) not its endo-isomer. Thus, in DMSO the stereocentre to the CHO group was inverted quite rapidly (within 1 h), probably through equilibria between the (E)- and (Z)-enamines. Although each oxazolidinone is stereospecifically mainly related with one enamine, in accord with Ref. 2b and 2f, the enamines reach equilibrium rapidly. In DMSO-d6, the 6a/epi-6a/(E)-6b/(Z)-6b ratio was 3.2:3.2:5.5:1. In general, at room temperature the (Z)- and (E)-enamines may be in equilibrium through the reversible equations shown in Schemes 2–5 (via their hemiaminal/N,O-hemiacetal intermediates) and/or through the zwitterions and/or, if an external acid was present, through the C-protonation of the enamine groups (transient iminium salts).

10. As is known,1 enamines from -branched aldehydes, RR’CHCHO, are

destabilized by the steric clash summarized in the drawing below (A1,3-strain between R’ and CH2 to the N):

To avoid this interaction, the relevant dihedral angles are twisted and the

conjugation of the N atom with the double bond diminishes (steric inhibition of the resonance). Oxazolidinones are then indirectly preferred. For a pioneering work on the subject, see: Orsini, F.; Pelizzoni, F.; Forte, M.; Sisti, M.; Bombieri, G.; Benetollo, F. J.

Heterocycl. Chem. 1989, 26, 837–841; for DFT calculations, see Supplementary Data.

11. We used 3-phenylpropanal as a surrogate of linear aldehydes, which are too reactive (aldols, enals); for a relevant study, see: Schmid, M. B.; Zeitler, K.; Gschwind, R. M. J. Org. Chem. 2011, 76, 3005–3015.

12. Working with pairs, we noted that the enamine of phenylacetaldehyde was formed more rapidly and was also thermodynamically more favoured than the other two; both enamine forms of 8 were observed (3.3:1 ratio). In the case of enamines conjugated with carbonyl groups (enaminones), these forms also largely predominated, as expected, and their crystal structures were solved; see: Bock, D. A.; Lehmann, C. W.; List, B. Proc. Natl. Acad. Sci. (USA) 2010, 107, 20636–20641.

TBDPSO

O O

very high % of oxazolidinone(s)

O

O

O

>> 500:1

O

99:1

O

Ph

O

4:1

O O

Ph35:1

very low % of enamine(s)

OO

Ph

O

PhPMBO

O TBS

NO

HOH:OPG

OR +

OPG

NO

O

RH..

–H2O

PGON

O

HO

R

.. 500:1 1.3:133:1

OBnS

Ph

OBnS

O

1:13:1

TBSO

O

< 1:500

high % of enamine(s)

–H2OH2O

Kox Ken

1 2 3 4

*

*

ox/en ratio

O

O-PMB

OPh

O-TBS

OPh

5 6

OR

O-PG

O OHR

O-PG

OS S

via an enamine of thefirst carbonyl compound(without racemization

of 1–4 in situ)

S RSO

O-TBDPS

S

1 3

O

O

R

4

O

O

O-TBS

S

2

+secondary amine*

OSBn

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8

R

1–4

O-TBDPS

O

1

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(Z)-1b

N

1a

O

HOTBDPSO

OTBDPS

NO

O

–H2O OTBDPS

NO

OH

OTBDPS

NO

OH

endo-1a

OTBDPS(E)-1b

NO

HO

4.99 3.88J = 3.9

H 3.77

O-TBDPS

NO

HOOH

hemiaminal(s)OTBDPS

NO

OH2O

3

O

O-PMBOPMB

NO

OH

3a

Pro

H2O

S

S

– H2OH

O-PMB

NO

O

HH

epi-3a

H

3

O

O-PMBO

NO

O

HH

epi-ent-3a

(R)-Pro

H2O

S

S

– H2O

ent-3a

H

PMB

SR

H

RS

H

NO

O

OH

H

R

R

PMB

5.06 J = 3.7

5.10 J = 2.7

5.10 J = 2.7

5.06 J = 3.7

.. ..

.. ..

slow

slow

SR

RS

2

O

O-TBDPS

3

O

O-PMB4

1

O

O-TBS

O

OO

OTBS

NO

OH

OTBDPS

NO

OH

OPMB

NO

OHO

NO

OH

O

1a 2a

4a3a

Pro

H2O

4.99

5.05

4.92

5.16

9.56 9.53

9.619.59

! !

5

OPh

O-TBS

TBS-O

NO

OH

H

5a

Pro

H2O

S

S Ph

– H2O

TBS-O

NO

HO

(E)-5bs-cis

PhHTBS-O

NO

HO

(E)-5bs-trans

Ph H

Ph

N

OO

TBS-O H

HH

(Z)-5bs-trans

Ph

NO

HO

(Z)-5bs-cis

O-TBSHPh

NO

OH

H

epi-5a

R OTBS

H+ or H2O

–H+ or –H2O

H5α H2

H5β

H

quick

TBDPSO

O

O

O

O

O

O

99:1

O

Ph

O

4:1

O O

Ph

35:1

OTBSO

Ph

O

Ph

PMBO

O

500:1 1.3:133:1

OS

Ph

OBnS

OBn

1:1

TBSO

O

2 3 41

3:15 67

>> 500:1

< 1:500

carbonyl + ProKox Ken

oxazolid. enamine(s)ox/en ratio

8

NO

O

RR'

H