Synthesis of Polyoxygenated Heterocycles by Diastereoselective Functionalization of a Bio-Based Chiral Aldehyde Exploiting the Passerini Reaction

Abstract

A chiral bio-based building block, prepared by the lipase-mediated desymmetrization of an erythritol derivative, was further functionalized and then submitted to stereoselective Passerini reactions, allowing the synthesis of a small library of new molecules. Thanks to the presence of different functional groups, further cyclizations were performed providing bicyclic polyoxygenated heterocycles.

1. Introduction

Over the last 50 years, a tremendous progress in methodologies and techniques of organic synthesis has made possible the preparation of nearly any molecule. However, not all the total syntheses reported over the years can be scaled up into cost-effective and environmentally sustainable industrial processes. According to the principles of Green Chemistry, issues such as step economy, atom economy, and operational simplicity are becoming more and more important.

Consequently, also the synthesis of libraries of compounds profits from the development of new environmentally benign, short, selective, and atom and step economic synthetic pathways.

However, the sustainability of a synthesis not only relies on the employed methodology, and the availability of the starting materials plays a very important role as well. In the last few decades, building blocks extracted from oil or other fossil materials have been the starting point for many syntheses, including polymerizations. In order to preserve these resources, in recent years, great attention within the scientific community and the governments as well has been given to the alternative exploitation of renewable sources or waste [1]. The most readily accessible biomass is undoubtedly lignocellulosic feedstock, which is a powerful precursor of many bio-based chemicals and polymers [2]. This very complex matrix is characterized by three main components: lignin, cellulose, and hemicelluloses. They can be separated and submitted to degradation processes, allowing the isolation of high added-value molecules, which can be further elaborated by synthetic methodologies or by fermentation processes.

In this context, multicomponent reactions (MCRs) can improve sustainability in both target- and diversity-oriented syntheses [3]. MCRs are still underexploited because of some limitations that hamper their full utilization. For example, they usually rely mostly on commercially available inputs. A possible solution is offered by the development of efficient pre-MCR sequences, converting simple bio-based building blocks into more complex (chiral) components. Chiral inputs may be very useful, making it possible the control of diastereoselection during the MCR and in the post-condensation transformations as well, although this goal is not easily achieved [4].

In recent years we synthesized enantiopure chiral building blocks by a chemoenzymatic [5,6,7,8,9,10] and/or organocatalytic [7,11,12] approach, often using bio-based starting materials [5,6,9,10], and used them for controlling the diastereoselectivity in different isocyanide-based MCRs (Ugi-Joullié [5,7], Passerini [6,8,9,10], or Ugi [11,12] reactions).

A bio-based building block readily available from lignocellulosic biomass is erythritol 1, which is produced from glycerol [13] or from waste cooking oil [14] by means of osmophilic yeasts, such as Yarrowia lipolytica. This molecule is used as artificial sweetener [15], but it has found many applications in polymer chemistry, such as biodegradable polyurethanes [16,17] or polyesters [18], or in the synthesis of plant derived phthalates [19]. Erythritol, a meso compound, can be efficiently desymmetrized by means of Amano PS lipase [5] to give chiral monoesters, such as 2. An appropriate functional group manipulation allowed us to obtain different chiral building blocks, namely pyrroline 3 and aldehyde 4 which were used in diastereoselective Ugi-Joullié [5,9] or a Passerini reaction [9], affording 5 and 6 respectively (Scheme 1).

Herein, we present a different elaboration of 2, aiming to introduce a double bond. We planned to submit the resulting aldehyde 7 to a diastereoselective Passerini reaction affording 8, followed by a series of new post-condensation transformations [20] ending up with the synthesis of polyoxygenated heterocycles.

2. Results and Discussion

2.1. Synthesis of the Bio-Based Precursor of Chiral Aldehyde to Be Used in the Passerini Reaction

Chiral building block 2 (Scheme 1) can be prepared by the chemoenzymatic desymmetrization of diol 11, which, in turn, was prepared from erythritol 1, as previously described (Scheme 2) [5,21]. However, we also developed an efficient alternative synthesis starting from D-isoascorbic acid 9, an antioxidant readily accessible from simple sugars. Actually, lactone 10, prepared through a known procedure [22], can be efficiently reduced with LiAlH₄, affording 11 in high overall yield and avoiding the difficult chromatographic purification that was needed in our previous synthesis. Even if the chirality of 9 is destroyed during the transformation into meso-11 and reintroduced during the following lipase-mediated desymmetrization, this is compensated by the high overall yield and by the possibility to obtain both enantiomeric series, thanks to the complementary enzymatic acylation and hydrolysis [5]. Moreover, direct conversion of lactone 10 into aldehyde 4 is not feasible. The starting building block 9 is cheap and renewable.

Initially we planned to synthesize aldehyde 7 (Scheme 1) bearing a terminal double bond (R³ = H) [23] and for this purpose we submitted 2 to Swern oxidation followed by Wittig olefination, but, under a variety of conditions, we never succeeded to get 12 (Scheme 3).

Then we switched to the carbethoxymethylenation which has the advantage of introducing two functional groups at once (a double bond conjugated with an ester), which could have enabled exploring different post-condensation transformations after the multicomponent reaction.

However, this reaction turned out to be not so trivial as expected. A Wittig olefination was first performed with (carbethoxymethylene)triphenylphosporane on aldehyde 4: when the aldehyde was prepared by Swern oxidation of 2, compound 13 was isolated in a good (73%) overall yield, but in a 41:59 E:Z ratio. Also, a partial epimerization (2%) at the stereogenic center α to the aldehyde was detected, as demonstrated by GC-MS. Switching to TEMPO/(diacetoxyiodo)benzene oxidation and performing the olefination in the presence of triethylamine, the yield increased to 89% and the diastereomeric ratio reverted to 70:30 (E:Z), but again a partial epimerization (6%) occurred.

Thus, we turned to Horner–Wadsworth–Emmons olefination. After careful optimization, the reaction in the presence of lithium chloride and Hünig’s base [24] afforded 13 in good overall yield (86%) and high stereoselectivity (95:5 E:Z), without any trace of epimerization. The minor Z isomer was readily removed by chromatography.

Then we planned to selectively hydrolyze the acetyl ester moiety on E-13 to release 14, the precursor of aldehyde 15. Initially we tried basic conditions (1 M KOH in MeOH, Et₃N/H₂O/MeOH 1:1:5). In all cases, even employing a mild base like Et₃N, which was successfully used for an analogous of 13 [9], we never identified expected 14, isolating instead the Michael product 16 in good yield [79% (KOH) or 88% (Et₃N)]. Moreover, we observed a total or a partial transesterification to give the methyl ester analogue of 16. With KOH transesterification was complete, whereas with Et₃N we obtained a Me/Et ratio of 66:34. The substitution of MeOH with EtOH (Et₃N/H₂O/EtOH 1:1:5) prevented transesterification but afforded a slower and complete conversion into 16 in a moderate, unoptimized, 62% overall yield. 16 was obtained as an inseparable diastereomeric mixture (d.r. 74:26, cis:trans, determined by GC-MS).

To avoid basic conditions, we switched to the enzymatic hydrolysis of the acetate. We tried several enzymes, working at pH 7 (phosphate buffer) in the presence of different cosolvents (about 15% of THF or iPr₂O) [25] and at different concentrations (0.07–0.15 M). The hydrolysis turned out to be very slow and, only using lipase from Candida antarctica (Novozym 435) we isolated, after 7–8 days, just a moderate amount (around 50%, depending on the concentration of 13) of 14. Lipase from porcine pancreas, either the commercial one or the one supported on Celite following our protocol [26], was ineffective. On the contrary, lipase from Pseudomonas cepacia from Amano promoted a slow hydrolysis of the acetyl but, after 6 days, only the Michael product 16 was isolated in 54% yield.

In order to suppress the Michael cyclization, we decided to substitute the acetyl with a protecting group that could be cleaved under acidic conditions, such as the t-butyldimethylsilyl ether. It was easily introduced through a high-yield, epimerization-free protection–deprotection sequence affording 17 [23]. Of course, this sequence produces ent-14. However, starting from the pseudoenantiomeric monobutyrate of 2, obtained by enzymatic monohydrolysis of the corresponding dibutyrate [5], 14 could be synthesized as well. In this case, the olefination gave best results simply treating the aldehyde with the anion of triethyl phosphonoacetate, affording E-18 in almost diastereomerically pure form [23].

Silyl ether removal was not as simple as expected. Under basic conditions, using nBu₄NF, TBDMS removal was rapidly followed by the intramolecular Michael reaction to give ent-16. Employing 40% HF in MeCN we also observed, as side reaction, the hydrolysis of the acetonide, although this problem was never observed on very similar substrates [5]. 25% H₂SiF₆ in MeCN afforded ent-14 in only 30% yield, again for the partial cleavage of the acetonide [27].

Finally, we tried hydrogen fluoride pyridine complex (Olah’s reagent) in pyridine/THF [28]. After a careful optimization of the reaction conditions, with the aim of reducing the amount of Olah’s reagent, we found that lowering from 125 to 35 the equivalents, ent-14 can be isolated in almost quantitative yield, even if a longer time is required (3 days vs 30 h).

2.2. Stereoselective Passerini Reaction

Ent-14 is the precursor of the chiral aldehyde ent-15 that we wanted to use in the diastereoselective Passerini reaction (Scheme 4). Initially, we decided to oxidize the alcohol with TEMPO/(diacetoxyiodo)benzene in methylene chloride, followed by t-butyl isocyanide addition, in a one-pot procedure. The third component, the carboxylic acid (AcOH), is already present, being a by-product of the oxidation. The classic Passerini conditions (entry 1,

Table 1. Preliminary experiments using ent-15, obtained by TEMPO/PhI(OAc)₂ oxidation of ent-14.

Entry 1	Solvent	Additive (equiv.)	Temperature (°C)	Yield (%)	anti-20a:syn-20a 2
1 3	CH2Cl2	none	r.t.	67	61:39
2 3	CH2Cl2/THF	ZnBr2 (0.4)	r.t.	51	76:24
3 4	CH2Cl2/THF	ZnBr2 (0.4)	r.t.	55	71:29

Notes: ¹ 1.1 equivalents of isocyanide. ² Determined by ¹H-NMR; the relative configuration of compounds 20a was determined as reported in the Supplementary Materials; ³ no drying procedure of the aldehyde. ⁴ In the presence of 3 Å MS.

) afforded an acceptable overall yield, but only a fair diastereoselectivity (61:39) with anti-20a prevailing.

In order to increase the d.r., we added ZnBr₂, a Lewis acid that proved to be very efficient in Passerini reactions of similar erythritol-derived aldehydes [9]. Moreover, according to our optimized procedure, we diluted the CH₂Cl₂ solution of the oxidation step with THF to improve the solubility of the Lewis acid (entry 2). We observed an increased stereoselectivity, but the overall yield was still unsatisfactory. The main problem seems to be the overoxidation of the intermediate aldehyde to carboxylic acid 21, which of course can compete with acetic acid in the multicomponent reaction, affording 22. This overoxidation is likely due to the easy formation, in the presence of humidity, of the hydrated form 19, stabilized by an intramolecular H-bond.

Working under strictly anhydrous conditions (3 Å MS), we suppressed the overoxidation and the yield increased to some extent but diastereoselectivity slightly decreased (entry 3).

For these reasons, we decided to perform the oxidation under Swern conditions (Scheme 5), which are known to completely suppress overoxidation. Although this protocol does not permit a one-pot procedure, it has the advantage to allow the use of different carboxylic acids in the Passerini reaction. Taking care of the work-up conditions, performed under slightly acidic conditions, we were able to completely avoid the epimerization of aldehyde ent-15, which was used as such, avoiding chromatography, because of its instability over silica gel. When ent-15 was submitted to a traditional Passerini reaction in methylene chloride, we isolated a mixture of anti- and syn-20a in excellent 92% overall yield from ent-14 but with a poor diastereomeric ratio (59:41) (entry 1,

Table 2. Optimization of the stereoselective Passerini reaction.

Entry 1	Product	R 1	Solvent	Additive (equiv.)	Temperature (°C)	Time	Yield (%) 2	anti-20:syn-20 3
1	20a	Me	CH2Cl2	none	20	1.5 h	92	59:41
2	20a	Me	THF	none	20	42 h	97	51:49 4
3	20a	Me	THF	ZnBr2 (0.4)	20	4 h	78	80:20
4	20a	Me	THF	Zn(OAc)2 (1.1) 5	20	19 h	79	56:44
5	20b	Ph	THF	none	20	23 h	97	45:55
6	20b	Ph	THF	ZnBr2 (0.4)	20	17 h	59	76:24
7	20b	Ph	THF	ZnBr2 (0.4)	0	16 h	54	74:26
8	20b	Ph	THF	ZnBr2 (0.4)	−30	6 d	39	65:35
9	20b	Ph	THF	Zn(OBz)2 (1.1) 5	20	5 h	36	64:36

Notes: ¹ The crude aldehyde was thoroughly dried by azeotropic water removal with toluene and 1.1 equivalents of isocyanide and carboxylic acid were used. ² Overall yield of all stereoisomers over two steps. ³ Determined by ¹H-NMR in all cases and by HPLC as well (entries 5–9); the relative configuration of compounds 20 was determined as reported in the Supplementary Materials. ⁴ Also minor amounts of trans isomers were detected. ⁵ In these cases, no carboxylic acid was added in the MCR.

). The use of THF further increased the yield, but not the diastereoselectivity, which was even worse (entry 2).

Moreover, the reaction turned out to be very slow (42 h vs. 1.5 h), which also favored a partial epimerization of the aldehyde.

The addition of a substoichiometric amount of ZnBr₂ had a beneficial effect on the d.r. and an accelerating effect on the rate (4 h vs. 31 h), but the overall yield decreased (entry 3).

A problem we observed only in the ZnBr₂ promoted Passerini is the formation of small amounts (usually less than 10%) of a diastereomeric mixture of the so called ‘truncated Passerini products’ 23, which are not separable by chromatography from 20a, but can be acetylated in situ maintaining the overall d.r.. The formation of ‘truncated’ products in the presence of Lewis acids is not completely unexpected and is well documented [29].

Unfortunately, the separation of anti- and syn-20a is possible, but troublesome, and therefore we decided to use benzoic acid, instead of acetic acid, because the two epimers of 20b can be separated more easily by chromatography and by HPLC. The Passerini with no additives gave results like the one with acetic acid (entry 5). In the presence of ZnBr₂, the rate increase was lower, compared to acetic acid (cfr. entries 3 and 6). We also studied the influence of the temperature: the reaction done at 0 °C resulted almost comparable to the one at 20 °C (entries 7 and 6), while at −30 °C the rate dramatically decreased and a lower yield and d.r. were observed (entry 8).

Based on our recent results on another chiral bio-based aldehyde [10], we also tried a modification of the Passerini reaction using zinc dicarboxylates. Using Zn(OAc)₂, the diastereoselectivity diminished considerably and the reaction became very slow, most likely because the Zn salt is poorly soluble (entry 4). Switching to zinc benzoate, the reaction rate increased noticeably but the yield was only modest and the d.r. was not satisfactory (entry 9). The unsatisfactory overall yield is most likely because recovery of 20 is incomplete. In our previous work, to liberate the Passerini product from zinc, a strongly acidic work-up was used, but here this acidic work-up is not possible, because of the presence of the very labile isopropylidene moiety.

After all, since the conditions using substoichiometric ZnBr₂ (entries 6) were the best performing ones, we decided to study the scope of the reaction (Scheme 6) as summarized in

Table 3. Scope of the ZnBr₂ promoted Passerini.

Entry 1	Compd	R 1	R 2	Yield (%) 2	anti-20: syn-20
1	20a	Me	t-Bu	78	80:20 3
2	20b	Ph	t-Bu	59	75:25 4,5
3	20c	CH2 = CH(CH2)2	t-Bu	53	78:22 5
4	20d	Me	2,3-(Me)2C6H3	51	93:7 3,4
5	20e	Me	−C(CH2CH=CH2)(CO2Et)2	64	98:2 3,4
6	20f	Ph	2,3-(Me)2C6H3	57	90:10 3
7	20g	Ph	4-OBn-C6H4(CH2)2	63	85:15 3
8	20h	2-Me-C6H4	Bn	56	88:12 3
9	20i	MeOCH2	c-Hex	64	84:16 3

Notes: ¹ The crude aldehyde, obtained by Swern oxidation of ent-14, was thoroughly dried by azeotropic water removal with toluene and all reactions are performed at 20 °C in THF, using 1.1 equivalents of carboxylic acid and isocyanide and 0.4 equivalents of ZnBr_2; the average duration is around 20 h. ² Yields over two steps. ³ By ¹H-NMR. ⁴ Only in these cases we observed the formation of a considerable amount of truncated Passerini products which were acylated in situ. ⁵ By HPLC.

.

We used diverse isocyanides (primary, secondary, and tertiary aliphatic or aromatic) and carboxylic acids (aliphatic and aromatic). The overall yield over two steps (oxidation and Passerini) was good in all cases. The stereoselectivity ranges from moderate to excellent. We noticed that the stereoselectivity depends only marginally on the structure of the carboxylic acid. The structure of the isocyanide on the contrary influences more the stereoselectivity. In some cases we observed excellent d.r.s (>10:1), which are uncommon in intermolecular Passerini reactions of chiral aldehydes [4].

The role of ZnBr₂ in promoting the stereoselectivity is not completely clear. On the previously described similar aldehyde 24 [9], we reported a model for explaining the stereoselectivity, based on the chelation of the metal by the carbonyl oxygen and the oxygen on carbon β to the aldehyde (I, Scheme 7) [30]. On the other hand, the outcome of chiral aldehyde 26 [10] led us to revise our rationale, also because in that case a β-chelation is clearly not possible. In the light of the observation that, performing the Passerini reaction in iPr₂O, the initially unsoluble ZnBr₂ is partially dissolved upon addition of the isocyanide, we supposed a zinc coordination by it to give intermediate 28. Therefore, in our previous paper, we proposed a concerted transition state, where 28 is also coordinated by the carbonyl oxygen. The formation of anti-27 was then rationalized through a preferred transition state II.

If a similar mechanism is working on aldehyde ent-14, a possible transition state explaining the prevailing formation of anti-20 would be III.

2.3. Elaboration of Passerini Products

The presence of additional functional groups on the Passerini products allowed us to study different post-condensation transformations thus increasing the scaffold diversity. Aware of the easy intramolecular 5-exo-trig cyclization of 14 to give 16, we expected that basic solvolysis of 20a and 20b, would afford fast cyclization of the resulting secondary alcohol. The sequence was studied on both anti and syn diastereoisomers (Scheme 8), changing the reaction conditions to optimize yield and d.r. (

Table 4. Michael cyclization of compounds 20a and 20b.

Entry 1	Compd	Conditions 1	Time (h)	Temperature	Yield (%)	24:25 (from anti) 3,4 26:27 (from syn) 3,4
1	anti-20a	KOH (1 M)	1	r.t.	33	91:9
2	anti-20a	EtONa (0.1 M) 2	4	r.t.	58	90:10
3	anti-20b	EtONa (0.1 M) 2	4	r.t.	73	92:8
4	anti-20b	EtONa (0.1 M) 2	22	0 °C	83	89:11
5	anti-20b	EtOH:Et3N 5:1:1	94	r.t. (67 h), 60 °C (24 h)	74	82:18
6	syn-20a	KOH (1 M)	1	r.t.	16	84:16
7	syn-20a	EtONa (0.1 M) 2	5.5	r.t.	73	82:18
8	syn-20b	EtONa (0.1 M) 2	6	r.t.	65	83:17

Notes: ¹ All reactions were performed in EtOH as solvent. ² Prepared in situ from EtOH and Na. ³ By ¹H-NMR. ⁴ The reported relative configurations have been determined as reported in the Supplementary Materials.

).

The reaction was performed independently on the separated diastereoisomers of two Passerini products, differing by the acyl substituent (R¹ = Me, 20a; R¹ = Ph, 20b), which of course afford the same tetrahydrofuran. All reactions turned out to be stereoselective, whatever the base employed. KOH was not satisfying (entries 1 and 6): despite the high reaction rate and the d.r.s which are among the best (entries 1 and 6), the isolated yield was rather poor.

Switching to sodium ethoxide [31], the reaction was slower and the d.r.s were comparable, but the yield increased significantly (entries 2 and 7). We texted the influence of the temperature as well: working a t 0 °C the reaction was slower, as expected, and we isolated the mixture of 24 and 25 in higher yield but no beneficial effect on the d.r. was observed (entry 4). As far as it concerns the starting acyl derivative, the cyclization of anti-20b affording 24 turned out to be more efficient than that of anti-20a (entries 3 and 2), while syn-20a provided 26 in higher yield but with the same d.r. as syn-20b (entries 7 and 8). Milder conditions employing Et₃N as base in EtOH required very long time and higher temperature which negatively affects either the yield and the d.r. We also performed a one-pot, three-step sequence: Swern oxidation/Passerini reaction/cyclization. The overall yield is almost comparable, but the purification is really complex because both the Passerini and the Michael reaction are not completely stereoselective, which renders this procedure unpractical.

The relative configuration of compounds 24–27 was determined by NMR studies as described in the Supplementary Materials.

The structure of 24 suggested the possibility to transform it into a bicyclic lactone, structurally correlated with styryllactones, such as (+)-goniofufurone 29a [32] and its diastereoisomer 29b [33] (Scheme 9), characterized by cytotoxic activity against several tumor cell lines [34].

For this purpose, we cleaved the isopropylidene moiety by means of trifluoroacetic acid using the previously reported conditions (MeOH:TFA:H₂O 1.6:1:1, 87%) [5] and then further increased the yield substituting MeOH with THF (THF:TFA:H₂O 2:1:1, 97%) although the reaction required more time (8 days vs. 3) [33] (Scheme 9).

The structure of 31 is partially rigid and, coupling MM2 calculations with NMR data, we were able to unambiguously establish the cis junction between the two O-heterocycles, and the relative trans relationship between the substituents on C₂ and C₃ (more details are reported in the Supplementary Materials). This assignment is also corroborated, especially for the relative configuration of ring junction, by comparison with the NMR spectra of 29a and 29b.

This confirmed the configuration of compound 24 and hence of 25–27 as well. Moreover, since the configuration of the stereogenic center generated during the Passerini reaction is not affected during the intramolecular Michael cyclization, we were able to assign the anti relative configuration to the prevailing stereoisomer in compounds 20, which is also supported by spectroscopic analogies with similar compounds.

Finally, we decided to exploit the two double bonds of 20c to perform a ring closing metathesis expecting to obtain 32 presumably as the Z stereoisomer. Although the cyclization of medium size rings is expected to be difficult, there are already several reports in the literature on the formation of 9- [35] or 10-membered lactones [36] through this strategy, but all of them used only terminal double bonds. We attempted the RCM reaction on the major anti stereoisomer and performed different experiments using either first (33) or second-generation Grubbs catalysts (34), and working under high dilution conditions (Scheme 10). Unfortunately, we only recovered unreacted starting material.

Reasoning that the presence of the ester conjugated with the double bond could be a problem, we decided to reduce ester 18 to the allylic alcohol 35 [37], which was selectively protected as anisyl ether (36) and finally desilylated to afford 37, the precursor of the aldehyde to be involved in a Passerini reaction under the optimized conditions of Table 3. The MCR was only moderately stereoselective (77:13) and on anti-38 we tried again the RCM with both catalysts, working in high dilution (1 mM). Again, the expected product was not obtained, and we only isolated in low yield (15%) the product of an intermolecular metathesis. One of the possible reasons of the failed cyclization is probably the presence of a substituted double bond which in many instances can hamper the RCM, though in the literature successful cyclizations involving a substituted double bond are well documented [38].

3. Materials and Methods

3.1. General Information

NMR spectra (see Supplementary Materials) were recorded on a Gemini 300 MHz instrument (Varian, Palo Alto, CA, USA) at r.t. in CDCl₃ at 300 MHz (¹H), and 75 MHz (¹³C), using, as internal standard, TMS (¹H-NMR in CDCl₃, 0.000 ppm) or the central peak of CDCl₃ (¹³C in CDCl₃, 77.02 ppm). Chemical shifts are reported in ppm (δ scale). Peak assignments were made with the aid of gCOSY and gHSQC experiments. In ABX system, the proton A is considered upfield and B downfield. IR spectra were recorded as solid, oil, or foamy samples, with the ATR (attenuated total reflectance) technique. TLC analyses were carried out on silica gel plates and viewed at UV (λ = 254 nm or 360 nm) and developed with Hanessian stain (dipping into a solution of (NH₄)₄MoO₄·4H₂O (21 g) and Ce(SO₄)₂·4H₂O (1 g) in H₂SO₄ (31 mL) and H₂O (469 mL) and warming). R_f values were measured after an elution of 5–7 cm. Column chromatography was done with the ‘flash’ methodology by using 220–400 mesh silica. Petroleum ether (40–60 °C) is abbreviated as PE. All reactions employing dry solvents were carried out under nitrogen. After extractions, the aqueous phases were always re-extracted two times with the appropriate organic solvent, and the organic extracts were always dried over Na₂SO₄ and filtered before evaporation to dryness. HRMS: samples were analyzed with a Synapt G2 QToF mass spectrometer (Waters, Milford, MA, USA). MS signals were acquired from 50 to 1200 m/z in either ESI positive or negative ionization mode. GC-MS were carried out using an HP-1 column (12 m long, 0.2 mm wide), electron impact at 70 eV, and a mass temperature of about 170 °C. Only m/z > 33 were detected. All analyses were performed (unless otherwise stated) with a constant He flow of 1.0 mL min⁻¹ with initial temp. 70 °C, init. time 2 min, rate 20 °C min⁻¹, final temp. 260 °C, inj. temp. 250 °C, det. temp. 280 °C. HPLC analyses were carried out on a HP-1100 system (Agilent, Santa Clara, CA, USA) equipped with a HYDRO RP column (150 × 3 mm, 4 μ) at 25 °C with flow = 0.5 mL/min and isocratic elution (CH₃CN/H₂O 50:50). Detection was done with UV at 220 nm; b) C6 PHENYLIC RP column (150 × 3 mm, 4 μ) at 25 °C with flow = 0.34 mL/min and gradient H₂O/MeOH 35:65 for 20 min, then up to 30:70 until min 25. Then H₂O:MeOH 30:70. Detection was done with UV at 220 nm.

3.2. Syntheses

((4R,5S)-2,2-dimethyl-1,3-dioxolane-4,5-diyl)dimethanol (11). Method A: from erythritol through a known procedure [21]. Method B: D-isoascorbic acid 9 was transformed into lactone 10, as previously reported [22]. Then, to a suspension of LiAlH₄ (1.756 g, 46.50 mmol) in THF dry (45 mL) at 0 °C, a solution of 10 (3.659 g, 23.15 mmol) in dry THF (32 mL) was added dropwise (40 min). The mixture was allowed to reach room temperature and stirred for 3 h. Then it was cooled to 0 °C and carefully quenched with Fieser method: deionized water (1.7 mL), NaOH (15%, 1.7 mL) and deionized water (5.1 mL) were sequentially added dropwise. The mixture was stirred until a white suspension was obtained, which was filtered through a Celite cake. The Celite was washed several times with boiling THF and the filtrate was concentrated. The residue was triturated with Et₂O to afford 11 (3.082 g, 82% yield) as a white solid, which analytical data are agree with the reported ones [21].

Ethyl 3-((4S,5R)-5-(acetoxymethyl)-2,2-dimethyl-1,3-dioxolan-4-yl)acrylate (13). (a) Swern oxidation: to a solution of dry DMSO (87 μL, 1.22 mmol) in dry CH₂Cl₂ (2.9 mL), a solution of oxalyl chloride in dry CH₂Cl₂ (2.0 M, 515 μL) was added at −78 °C. After 10 min stirring a solution of alcohol 2 (100 mg, 0.49 mmol) in dry CH₂Cl₂ (2 mL) was added dropwise, and the solution was stirred for 10 min. Then Et₃N (320 μL, 2.30 mmol) was added and the solution was stirred for 1 h at −78 °C. The reaction was quenched by addition of 5% aq. (NH₄)H₂PO₄ (10 mL, added with 1 N HCl solution to reach a final pH = 4) and extracted with Et₂O (3 × 10 mL). The combined organic layers were washed with 5% aq. NaHCO₃ (10 mL) and brine (10 mL), dried (Na₂SO₄), and concentrated to afford the expected aldehyde as a yellow oil, which was used as such for the next reaction. (b) Horner-Wadsworth- Emmons reaction: to a suspension of LiCl (31 mg, 0.73 mmol) and 3 Å molecular sieves (10 mg/0.1 mmol aldehyde) in dry MeCN (5.4 mL) triethyl phosphonoacetate (165 μL, 0.73 mmol), diisopropylethylamine (85 μL, 0.49 mmol) and the crude aldehyde were added. The reaction was stirred at room temperature for 28 h, then it was filtered on a Celite cake. The solution was diluted with saturated aq. NH₄Cl (10 mL) and extracted with Et₂O (3 × 10 mL). The combined organic layers were washed with brine (10 mL), dried, and concentrated to afford a 95:5 E:Z mixture (¹H-NMR). The residue was purified by chromatography (PE:Et₂O 7:3) to afford E-13 (108 mg, 81% yield from 11) and Z-13 (4.9 mg, 5% yield from 11) as pale yellow oils. E-13: R_f = 0.22 (PE:Et₂O 7:3). ¹H-NMR (CDCl₃): δ 6.85 (dd, J = 15.6, 5.5 Hz, 1H, CH=CHCO₂Et), 6.15 (dd, J = 15.6, 1.6 Hz, 1H, CHCO₂Et), 4.83 (ddd, J = 6.8, 5.5, 1.6 Hz, 1H, H-4), 4.46 (dt, J = 6.8, 5.3 Hz, 1H, H-5), 4.21 (q, J = 7.1 Hz, 2H, CH₂CH₃), 4.09, 3.95 (AB part of an ABX syst., J_AB = 10.0 Hz, J_AX = 4.1 Hz, J_BX = 4.9 Hz, 2H, CH₂OAc), 2.07 (s, 3H, CH₃CO), 1.53, 1.40 (2 s, 2 × 3H, (CH₃)₂C), 1.30 (t, J = 7.1 Hz, 3H, CH₃CH₂). Z-13: R_f = 0.38 (PE:Et₂O 7:3). ¹H-NMR (CDCl₃): δ 6.29 (dd, J = 11.6, 7.0 Hz, 1H, CH=CHCO₂Et), 5.94 (dd, J = 11.6, 1.7 Hz, 1H, CHCO₂Et), 5.65 (td, J = 7.2, 1.7 Hz, 1H, H-4), 4.69 (td, J = 7.2, 3.3 Hz, 1H, H-5), 4.18 (q, J = 7.2 Hz, 2H, CH₂CH₃), 4.12 (dd, J = 11.7, 3.4 Hz, 1H, CHHOAc), 3.87 (dd, J = 11.7, 6.9 Hz, 1H, CHHOAc), 2.07 (s, 3 H, CH₃CO), 1.53, 1.40 (2 s, 2 × 3H, (CH₃)₂C), 1.30 (t, J = 7.2 Hz, 3H, CH₃CH₂).

Ethyl 2-((3aS,4S,6aR)-2,2-dimethyltetrahydrofuro[3,4-d][1,3]dioxol-4-yl)acetate (anti-16) and Ethyl 2-((3aS,4R,6aR)-2,2-dimethyltetrahydrofuro[3,4-d][1,3]dioxol-4-yl)acetate (syn-16). A solution of 13 (50 mg, 0.18 mmol) in EtOH (1 mL) was treated with H₂O (200 μL) and Et₃N (200 μL) and stirred for 6 days at room temperature. The reaction was quenched with saturated aq. NH₄Cl (10 mL) and extracted with Et₂O (3 × 10 mL). The combined organic layers were washed with brine (10 mL), dried, and concentrated. The residue was purified by chromatography (PE: Et₂O 6:4 to Et₂O + 1% EtOH) to give 16 (26 mg, 62% yield, colorless oil)) as an inseparable mixture of syn and anti stereoisomers (74:26 by GC-MS). R_f = 0.30 (PE:Et₂O 1:1). The individual NMR spectra were extrapolated from the NMR spectra of a 74:26 (syn:anti) mixture and are in agreement with the previously reported [31], where however the complete NMR spectra of syn-16 are not available. Syn-16: ¹H-NMR (CDCl₃): δ 4.78 (dd, J = 6.1, 3.4 Hz, 1H, H-6a), 4.71 (dd, J = 6.1, 3.7 Hz, 1H, H-3a), 4.17 (q, J = 7.1 Hz, 2H, CH₂CH₃), 4.01 (d, J = 10.7 Hz, 1H, H-6), 3.86 (td, J = 7.2, 3.7 Hz, 1H, H-4), 3.49 (dd, J = 10.7, 3.6 Hz, 1H, H-6); 2.77, 2.75 (AB part of an ABX system, J_AB = 16.7 Hz, J_AX = 7.0 Hz, J_BX = 6.4 Hz, 2H, CH₂CO₂Et), 1.47, 1.33 (2 s, 2 × 3H, (CH₃)₂C), 1.27 (t, J = 7.0 Hz, 3H, CH₃CH₂). ¹³C-NMR (CDCl₃): δ 171.2 (C=O), 112.2 (C-2), 81.1 (C-6a), 80.8 (C-3a), 78.3 (C-4), 72.7 (C-6), 60.8 (CH₂CH₃), 33.8 (CH₂CO₂Et), 26.0, 24.9 ((CH₃)₂C), 14.2 (CH₃CH₂). Anti-16: ¹H-NMR: δ 4.82 (ddd, J = 6.0, 4.2, 1.2 Hz, 1H, H-6a), 4.57 (dd, J = 6.0, 1.6 Hz, 1H, H-3a), 4.45 (td, J = 7.1, 1.6 Hz, 1H, H-4); 4.17 (q, J = 7.1 Hz, 2H, CH₂CH₃), 3.99 (dd, J = 10.7, 1.5 Hz, 1 H, H-6); 3.49–3.43 (m, 1H, H-6), 2.48 (d, J = 7.1 Hz, 2H, CH₂CO₂Et), 1.52, 1.33 (2 s, 2 × 3H, (CH₃)₂C), 1.27 (t, J = 7.0 Hz, 3H, CH₃CH₂). ¹³C-NMR (CDCl₃): δ 170.4 (C=O), 113.0 (C-2), 84.5 (C-3a), 81.1 (C-4), 81.0 (C-6a), 72.3 (C-6), 60.6 (CH₂CH₃), 36.4 (CH₂CO₂Et), 26.6, 25.0 ((CH₃)₂C), 14.2 (CH₃CH₂).

((4R,5S)-5-(((tert-butyldimethylsilyl)oxy)methyl)-2,2-dimethyl-1,3-dioxolan-4-yl)methanol (17). It was prepared in two steps from 2, as previously described, as a pale yellow oil in 98% overall yield [23]. R_f = 0.60 (PE:Et₂O 1:1). [α]²³_D = +3.73 (c = 1.03, CHCl₃). HRMS (ESI+): m/z 299.1661 (M + Na⁺). C₁₃H₂₈O₄SiNa requires: 299.1649. The other analytical data agree with the reported ones.

(E)-Ethyl 3-((4R,5S)-5-(((tert-butyldimethylsilyl)oxy)methyl)-2,2-dimethyl-1,3-dioxolan-4-yl)acrylate (18). It was prepared in two steps from 17, as previously described, as a colorless oil in 94% overall yield and a 97:3 E:Z ratio [23]. R_f = 0.76 (PE:Et₂O 6:4). [α]²³_D = +12.03 (c = 0.97, CHCl₃). The analytical data agree with the reported ones.

(E)-ethyl 3-((4R,5S)-5-(hydroxymethyl)-2,2-dimethyl-1,3-dioxolan-4-yl)acrylate (ent-14). A solution of 18 (803 mg, 2.33 mmol) was dissolved in THF/pyridine (24.6 mL, 65:35) and cooled to 0 °C. Then Olah’s reagent (hydrogen fluoride pyridine complex) (~70% HF, 2.1 mL, ~81 mmol) was added and the reaction was stirred at the same temperature for 3 days. The reaction was quenched with saturated aq. NH₄Cl (20 mL) and extracted with Et₂O (3 × 20 mL). The combined organic layers were washed with water (4 × 25 mL) and brine (20 mL), dried and concentrated. The residue was purified by chromatography (PE:Et₂O 3:7) to give ent-14 (532 mg, 99% yield) as a colorless oil The analytical data are in agreement with the reported ones [39]. R_f = 0.25 (PE/Et₂O 3:7). [α]²⁴_D = −33.32 (c = 1.14, CHCl₃).

General procedure for the synthesis of Passerini products (20a–i, 38). (a) Swern oxidation: the same procedure described above for the oxidation of 2 was followed, starting from ent-14. The crude yellow oil was thoroughly dried by azeotropic water removal and then it was directly employed in the next Passerini reaction. (b) General procedure the for the Passerini reaction under classic conditions (method A): a solution of crude aldehyde ent-15 in dry CH₂Cl₂ (20a) or THF (20a, 20b, 20c, 38) (1 M) at 20 °C was treated with the appropriate carboxylic acid (1.1 eq) and isocyanide (1.1 eq) and stirred until complete. The solution was concentrated and purified by chromatography. (c) General procedure for the Passerini reaction with ZnBr₂ (20a–i, 38) (method B): a solution of crude ent-14 (2 M in THF), carboxylic acid (1.1 equiv.) and isocyanide (1.1 equiv.) were added to a solution of ZnBr₂ (0.4 equiv.) in dry THF (1 M) at 20 °C. The resulting solution was stirred at 20 °C until complete. After quenching with saturated aq. NH₄Cl, an extraction with ethyl acetate was performed. The combined organic layers were washed with 5% aq. NaHCO₃, dried and concentrated. The residue was purified by chromatography.

Ethyl (E)-3-((4R,5R)-5-((R)-1-acetoxy-2-(tert-butylamino)-2-oxoethyl)-2,2-dimethyl-1,3-dioxolan-4-yl)acrylate (20a). It was prepared by method A in CH₂Cl₂ (overall yield anti + syn: 92% from ent-14, d.r. 59:41) or in THF (overall yield anti + syn: 97% from ent-14, d.r. 51:49), and by method B (overall yield anti + syn: 78% from ent-14, d.r. 80:20). Chromatography was performed with PE:CH₂Cl₂:Et₂O 3:1:1. The separation of the two diastereoisomers was possible only after repeated chromatographies. Anti-20a: colorless oil. R_f = 0.68 (PE:Et₂O 2:8). [α]²⁴_D = −50.26 (c = 0.815, CHCl₃). IR (ATR): ν_max 3355, 2981, 2938, 1751, 1719, 1682, 1525, 1456, 1368, 1303, 1253, 1210, 1179, 1161, 1122, 1060, 1033, 982, 938, 883, 861, 795. GC-MS: R_t 9.89 min: m/z 356 (M⁺ − 15, 0.2), 198 (5.1), 172 (6.8), 171 (8.6), 170 (12), 154 (7.3), 152 (8.6), 151 (7.0), 143 (11), 131 (5.3), 130 (17), 129 (6.7), 126 (14), 125 (13), 113 (6.1), 112 (30), 109 (7.9), 108 (5.5), 101 (8.1), 97 (24), 85 (15), 84 (43), 83 (5.6), 81 (10), 69 (6.0), 59 (17), 58 (43), 57 (52), 56 (5.1), 55 (10), 43 (100), 42 (6.3), 41 (23), 39 (9.9). ¹H-NMR (CDCl₃): δ 6.89 (dd, J = 15.6, 5.4 Hz, 1H, CHCH=CH), 6.12 (dd, J = 15.6, 1.6 Hz, 1H, O=CCH=CH), 5.82 (broad s, 1H, NH), 4.87 (ddd, J = 6.7, 5.4, 1.6 Hz, 1H, H-4), 4.85 (d, J = 7.9 Hz, 1H, CHOAc), 4.66 (dd, J = 7.9, 6.5 Hz, 1H, H-5), 4.19 (q, J = 7.1 Hz, 2H, CH₂CH₃), 2.10 (s, 3 H, CH₃CO), 1.51, 1.38 (2 s, 2 × 3H, C(CH₃)₂), 1.32 (s, 9H, C(CH₃)₃), 1.27 (t, J = 7.1 Hz, 3H, CH₂CH₃). ¹³C-NMR (CDCl₃): δ 169.4, 166.0, 165.8 (C=O), 141.3 (CHCH=C), 122.5 (CHCH=CH), 109.6 (C-2), 76.4 (C-5), 76.1 (C-4), 71.3 (CHOAc), 60.6 (CH₂CH₃), 51.7 (C(CH₃)₃), 28.6 (C(CH₃)₃), 27.6, 25.0 (CH₃CCH₃), 20.6 (CH₃CO), 14.2 (CH₃CH₂). HRMS (ESI+): m/z 394.1835 (M + Na⁺). C₁₈H₂₉NNaO₇ requires: 394.1836. Syn-20a: colorless oil. R_f = 0.79 (PE:Et₂O 2:8). [α]²⁴_D = −62.52 (c = 0.90, CHCl₃). IR (ATR): ν_max 3361, 2981, 2937, 2875, 1751, 1719, 1682, 1525, 1456, 1368, 1303, 1254, 1210, 1178, 1161, 1121, 1060, 1033, 983, 938, 883, 862, 795, 661. GC-MS: R_t 9.79 min: m/z 356 (M⁺ − 15, 0.8), 198 (12), 172 (6.0), 171 (8.3), 170 (9.1), 154 (5.1), 152 (9.9), 151 (5.2), 143 (8.6), 198 (12), 172 (6.0), 171 (8.3), 170 (9.1), 154 (5.1), 152 (9.9), 151 (5.2), 143 (8.6), 131 (6.8), 130 (19), 129 (7.2), 126 (12), 125 (11), 113 (5.7), 112 (27), 109 (6.0), 108 (5.3), 101 (8.5), 97 (22), 85 (15), 84 (36), 83 (5.4), 81 (9.0), 69 (6.3), 59 (16), 58 (44), 57 (49), 55 (11), 43 (100), 42 (6.3), 41 (22), 39 (9.1). ¹H-NMR (CDCl₃): δ 6.81 (dd, J = 15.6, 5.6 Hz, 1 H, CH=CHCO), 6.10 (dd, J = 15.6, 1.5 Hz, 1H, CH=CHCO), 5.86 (broad s, 1H, NH), 4.94 (d, J = 5.7 Hz, 1H, CHOAc), 4.89 (ddd, J = 7.0, 5.6, 1.5 Hz, H-4), 4.75 (dd, J = 7.0, 5.7 Hz, H-5), 4.20 (q, J = 7.1 Hz, 2 H, CH₂CH₃), 2.15 (s, 3 H, CH₃CO), 1.53, 1.39 (2 s, 2 × 3H, (CH₃)₂C), 1.32 (s, 9 H, C(CH₃)₃), 1.29 (t, J = 7.1 Hz, CH₃CH₂). ¹³C-NMR (CDCl₃): δ 170.1, 166.2, 165.6 (C=O), 141.8 (CHCH=C), 123.5 (CHCH=CH), 109.7 (C-2), 76.7 (C-5), 75.9 (C-4), 72.8 (CHOAc), 60.6 (CH₂CH₃), 51.6 (C(CH₃)₃), 28.5 (C(CH₃)₃), 27.2, 25.2 (CH₃CCH₃), 21.0 (CH₃CO), 14.2 (CH₃CH₂). HRMS (ESI+): m/z 394.1830 (M + Na⁺). C₁₈H₂₉NNaO₇ requires: 394.1836.

Ethyl (E)-3-((4R,5R)-5-((R)-1-benzoyloxy-2-(tert-butylamino)-2-oxoethyl)-2,2-dimethyl-1,3-dioxolan-4-yl)acrylate (20b). It was prepared by method A in THF (overall yield anti + syn: 97% from ent-14, d.r. 45:55), and by method B (overall yield anti + syn: 59% from ent-14, d.r. 75:25). Chromatography was performed with PE:CH₂Cl₂:Et₂O 3:1:1. Anti-20b: white solid. M.p. 103.5–107.1 °C (CH₂Cl₂). R_f = 0.64 (PE:Et₂O 4:6). R_f = 0.25 (PE/Et₂O 3:7), [α]²⁴_D= −53.53 (c = 0.97, CHCl₃). IR (ATR): ν_max 3338, 3077, 2977, 1712, 1669, 1602, 1535, 1453, 1368, 1294, 1253, 1238, 1218, 1179, 1161, 1114, 1068, 1047, 1029, 1001, 989, 881, 819, 804, 787, 760, 709, 686, 671, 626. GC-MS: R_t 11.91 min: m/z 418 (M⁺ − 15, 2.2), 130 (5.2), 112 (8.9), 106 (7.0), 105 (100), 84 (12), 77 (16), 58 (6.7), 57 (16), 43 (7.8), 41 (7.1). ¹H-NMR (CDCl₃): δ 6.89 (dd, J = 15.6, 5.4 Hz, 1H, CHCH=CH), 6.12 (dd, J = 15.6, 1.6 Hz, 1H, O=CCH=CH), 5.82 (broad s, 1H, NH), 4.87 (ddd, J = 6.7, 5.4, 1.6 Hz, 1H, H-4), 4.85 (d, J = 7.9 Hz, 1H, CHOAc), 4.66 (dd, J = 7.9, 6.5 Hz, 1H, H-5), 4.19 (q, J = 7.1 Hz, 2H, CH₂CH₃), 2.10 (s, 3H, CH₃CO), 1.51, 1.38 (2 s, 2 × 3H, C(CH₃)₂), 1.32 (s, 9H, C(CH₃)₃), 1.27 (t, J = 7.1 Hz, 3H, CH₂CH₃). ¹³C-NMR (CDCl₃): δ 169.4, 166.0, 165.8 (C=O), 141.3 (CHCH=C), 122.5 (CHCH=CH), 109.6 (C-2), 76.4 (C-5), 76.1 (C-4), 71.3 (CHOAc), 60.6 (CH₂CH₃), 51.7 (C(CH₃)₃), 28.6 (C(CH₃)₃), 27.6, 25.0 (CH₃CCH₃), 20.6 (CH₃CO), 14.2 (CH₃CH₂). ¹H-NMR (CDCl₃): δ 8.09–8.02 (m, 2 H), 7.62 (tt, J = 7.5, 1.4 Hz, 1H), 7.53–7.44 (m, 2H), 7.05–6.95 (m, 1H, CH=CHCO), 6.16 (dd, J = 15.6, 1.0 Hz, 1H, CH=CHCO), 5.90 (broad s, 1H, NH), 5.55–5.48 (m, 1H, CHOBz), 4.99–4.91 (m, 2H, H-4, H-5), 4.16–4.04 (m, 2H, CH₂CH₃), 1.39 (s, 6H, (CH₃)₂C), 1.34 (s, 9H, C(CH₃)₃), 1.19 (t, J = 7.1 Hz, CH₃CH₂). ¹³C-NMR (CDCl₃): δ 166.0, 165.6, 165.1 (C=O), 142.2 (CHCH=C), 133.7, 129.9 (×2), 128.6 (×2) (aromatic CH), 128.8 (aromatic quat.), 123.0 (CHCH=CH), 109.5 (C-2), 77.0 (covered by CDCl₃), 76.0 (C-5, C-4), 71.8 (CHOBz), 60.5 (CH₂CH₃), 51.7 (C(CH₃)₃), 28.5 (C(CH₃)₃), 27.2, 24.8 (CH₃CCH₃), 14.1 (CH₃CH₂). HRMS (ESI+): m/z 456.1995 (M + Na⁺). C₂₃H₃₁NNaO₇ requires: 456.1993. Syn-20b: white solid. M.p. 99.6–103.8 (CH₂Cl₂). R_f = 0.59 (PE:Et₂O 4:6). [α]²⁴_D= −69.80 (c =1.00, CHCl₃). IR (ATR): ν_max 3362, 2981, 2965, 2937, 1730, 1713, 1688, 1603, 1586, 1543, 1495, 1454, 1381, 1364, 1317, 1296, 1256, 1213, 1181, 1161, 1134, 1099, 1060, 1039, 987, 947, 914, 885, 851, 798, 765, 716, 688, 676, 633, 610. GC-MS: R_t 12.23 min: m/z 418 (M⁺ − 15, 0.9), 171 (9.4), 130 (5.9), 112 (8.8), 106 (8.8), 105 (100), 84 (12), 77 (15), 58 (6.6), 57 (14), 43 (6.2), 41 (5.3). ¹H-NMR (CDCl₃): δ 8.14–8.04 (m, 2H), 7.66–7.56 (m, 1H), 7.53–7.43 (m, 2H), 6.83 (dd, J = 15.7, 4.9 Hz, 1H, CH=CHCO), 6.06 (dd, J = 15.6, 1.4 Hz, 1H, CH=CHCO), 5.96 (broad s, 1H, NH), 5.22 (d, J = 4.7 Hz, 1H, CHOBz), 5.01–4.88 (m, 2H, H-4, H-5), 4.03 (q, J = 7.1 Hz, 2H, CH₂CH₃), 1.59, 1.42 (2 s, 2 × 3H, (CH₃)₂C), 1.31 (s, 9H, C(CH₃)₃), 1.14 (t, J = 7.1 Hz, CH₃CH₂). ¹³C-NMR (CDCl₃): δ 166.3, 165.6, 165.3 (C=O), 141.6 (CHCH=C), 133.7, 129.9 (×2), 128.6 (×2) (aromatic CH), 129.0 (aromatic quat.), 123.4 (CHCH=CH), 109.6 (C-2), 77.0 (partially covered by CDCl₃), 75.8 (C-5, C-4), 73.3 (CHOBz), 60.4 (CH₂CH₃), 51.6 (C(CH₃)₃), 28.5 (C(CH₃)₃), 27.2, 25.0 (CH₃CCH₃), 14.0 (CH₃CH₂). HRMS (ESI+): m/z 456.1995 (M + Na⁺). C₂₃H₃₁NNaO₇ requires: 456.1993.

Ethyl (E)-3-((4R,5R)-5-((R)-2-(tert-butylamino)-2-oxoethyl-1-(4-pentenoyloxy))-2,2-dimethyl-1,3-dioxolan-4-yl)acrylate (20c). It was prepared by method A in THF (overall yield anti + syn: 66% from ent-14, d.r. 47:53), and by method B (overall yield anti + syn: 53% from ent-14, d.r. 78:22). Chromatography was performed with PE:CH₂Cl₂:Et₂O 3:1:1. Anti-20c: colorless oil. R_f = 0.70 (PE:Et₂O 4:6). R_f = 0.25 (PE/Et₂O 3:7), [α]²⁴_D= −22.22 (c = 0.99, CHCl₃). IR (ATR): ν_max 3385, 2987, 2966, 2940, 1732, 1714, 1687, 1534, 1454, 1380, 1367, 1300, 1255, 1222, 1160, 1128, 1108, 1070, 1043, 1003, 984, 957, 931, 914, 881, 810, 790, 762, 744, 691, 666, 631, 603. GC-MS: R_t 10.75 min: m/z 396 (M⁺ − 15, 0.1), 170 (7.4), 154 (6.1), 152 (5.4), 151 (5.9), 130 (11), 129 (5.8), 126 (7.4), 125 (10), 112 (25), 97 (15), 85 (7.9), 84 (40), 83 (58), 81 (8.8), 69 (5.3), 59 (13), 58 (33), 57 (51), 56 (8.9), 55 (100), 54 (6.6), 53 (7.1), 43 (25), 42 (6.2), 41 (27), 39 (15). ¹H-NMR (CDCl₃): δ 6.90 (dd, J = 15.6, 5.6 Hz, 1H, CH=CHCO), 6.11 (dd, J = 15.6, 1.5 Hz, 1H, CH=CHCO), 5.81 (ddt, J = 17.1, 10.2, 6.1 Hz, 1H, CH=CH₂), 5.79 (broad s, 1H, NH), 5.13–4.98 (m, 2H, CH=CH₂), 5.03 (d, J = 7.2 Hz, 1H, CHOCO), 4.87 (ddd, J = 7.1, 5.6, 1.5 Hz, H-4), 4.72 (t, J = 7.1 Hz, H-5), 4.20 (q, J = 7.1 Hz, 2H, CH₂CH₃), 2.55–2.33 (m, 2H, CH₂CH₂), 1.51, 1.39 (2 s, 2 × 3H, (CH₃)₂C), 1.32 (s, 9H, C(CH₃)₃), 1.29 (t, J = 7.1 Hz, CH₃CH₂). ¹³C-NMR (CDCl₃): δ 171.4, 165.9, 165.8 (C=O), 141.8 (CHCH=C), 136.3 (CH=CH₂), 122.6 (CHCH=CH), 115.8 (CH=CH₂), 109.5 (C-2), 76.5, 76.0 (C-5, C-4), 71.3 (CHOCO), 60.5 (CH₂CH₃), 51.7 (C(CH₃)₃), 33.0, 28.3 (CH₂CH₂C=C), 28.5 (C(CH₃)₃), 27.5, 24.9 (CH₃CCH₃), 14.2 (CH₃CH₂). HRMS (ESI+): m/z 434.2154 (M + Na⁺). C₂₃H₃₁NNaO₇ requires: 434.2149. Syn-20c: colorless oil. R_f = 0.67 (PE:Et₂O 4:6). [α]²⁰_D = −62.20 (c = 0.54, CHCl₃). IR (ATR): ν_max 3376, 2980, 2936, 1752, 1720, 1684, 1524, 1455, 1367, 1303, 1254, 1215, 1160, 1116, 1060, 1033, 984, 916, 883, 862, 796. GC-MS: R_t 10.66 min: m/z 396 (M⁺-15, 0.8), 311 (5.7), 254 (5.2), 198 (9.3), 197 (6.4), 181 (5.5), 172 (6.8), 171 (9.1), 170 (11), 154 (8.9), 153 (5.1), 152 (9.7), 151 (7.5), 143 (5.5), 131 (9.7), 130 (21), 129 (12), 126 (11), 125 (15), 113 (6.1), 112 (29), 108 (6.0), 101 (7.0), 97 (18), 85 (8.6), 84 (41), 83 (81), 82 (5.4), 81 (11), 69 (6.0), 59 (14), 58 (36), 57 (54), 56 (9.6), 55 (100), 54 (6.8), 53 (6.0), 43 (26), 42 (6.3), 41 (26), 39 (13). ¹H-NMR (CDCl₃): δ 6.81 (dd, J = 15.6, 5.5 Hz, 1H, CH=CHCO), 6.09 (dd, J = 15.6, 1.6 Hz, 1H, CH=CHCO), 5.84 (broad s, 1H, NH), 5.81 (ddt, J = 17.1, 10.2, 6.1 Hz, 1H, CH=CH₂), 5.10 (dq, J = 17.1, 1.6 Hz, 1H, CHCHH), 5.04 (dq, J = 10.2, 1.5 Hz, 1H, CHCHH), 4.95 (d, J = 5.8 Hz, 1H, CHOCO), 4.89 (ddd, J = 7.1, 5.6, 1.6 Hz, H-4), 4.75 (dd, J = 7.0, 5.8 Hz, H-5), 4.19 (q, J = 7.2 Hz, 2H, CH₂CH₃), 2.55–2.35 (m, 2H, CH₂CH₂), 1.52, 1.38 (2 s, 2 × 3H, (CH₃)₂C), 1.31 (s, 9H, C(CH₃)₃), 1.28 (t, J = 7.2 Hz, CH₃CH₂). ¹³C-NMR (CDCl₃): δ 172.2, 166.2, 165.6 (C=O), 141.9 (CHCH=C), 136.2 (CH=CH₂), 123.5 (CHCH=CH), 116.0 (CH=CH₂), 109.7 (C-2), 76.7, 75.9 (C-5, C-4), 72.8 (CHOCO), 60.6 (CH₂CH₃), 51.6 (C(CH₃)₃), 33.4, 28.5 (CH₂CH₂C=C), 28.5 (C(CH₃)₃), 27.2, 25.2 (CH₃CCH₃), 14.2 (CH₃CH₂). HRMS (ESI+): m/z 434.2150 (M + Na⁺). C₂₃H₃₁NNaO₇ requires: 434.2149.

Ethyl (E)-3-((4R,5R)-5-((R)-1-acetoxy-2-((2,6-dimethylphenyl)amino)-2-oxoethyl)-2,2-dimethyl-1,3-dioxolan-4-yl)acrylate (20d). It was prepared by method B in THF (overall yield anti + syn: 51% from ent-14, d.r. 93:7). Chromatography was performed with PE:CH₂Cl₂:Et₂O 3:1:1. Anti-20d: white solid. M.p. 124.8–127.1 °C (CH₂Cl₂). R_f = 0.37 (PE:CH₂Cl₂:Et₂O 3:2:2). [α]²⁰_D= −48.78 (c = 0.98, CHCl₃). IR (ATR): ν_max 3239, 2985, 2928, 2855, 1747, 1717, 1660, 1540, 1472, 1371, 1304, 1259, 1227, 1161, 1120, 1069, 1041, 982, 928, 880, 800, 766, 708, 685. GC-MS: R_t 12.64 min: m/z 419 (M⁺, 8.7), 419 (8.7), 404 (8.3), 361 (11), 219 (30), 199 (5.8), 190 (6.3), 179 (6.7), 178 (15), 177 (100), 176 (33), 172 (5.7), 160 (7.7), 148 (47), 147 (12), 143 (6.1), 126 (15), 125 (6.0), 122 (6.7), 121 (27), 120 (13), 112 (12), 109 (6.2), 106 (5.8), 105 (11), 101 (6.7), 97 (18), 91 (5.0), 85 (9.1), 84 (20), 81 (5.0), 77 (6.6), 59 (8.2), 55 (6.6), 43 (66), 39 (5.6). ¹H-NMR (CDCl₃): δ 7.27 (broad s, 1H, NH), 7.14–7.02 (m, 3H), 6.93 (dd, J = 15.6, 5.1 Hz, 1H, CHCH=CH), 6.19 (dd, J = 15.6, 1.2 Hz, 1H, O=CCH=CH), 4.96 (ddd, J = 6.3, 5.1, 1.2 Hz, 1H, H-4), 4.87 (d, J = 9.6 Hz, 1H, CHOAc), 4.70 (dd, J = 9.6, 6.3 Hz, 1H, H-5), 4.19 (q, J = 7.2 Hz, 2H, CH₂CH₃), 2.21 (s, 6H, CH₃Ar), 2.13 (s, 3H, CH₃CO), 1.59, 1.43 (2 s, 2 × 3H, C(CH₃)₂), 1.29 (t, J = 7.2 Hz, 3H, CH₂CH₃). ¹³C-NMR (CDCl₃): δ 169.6, 165.7, 165.5 (C=O), 140.8 (CHCH=C), 135.4 (×2), 133.0 (aromatic quat.), 128.1 (×2), 127.4 (aromatic CH), 122.5 (CHCH=CH), 110.1(C-2), 76.2 (C-4), 75.9 (C-5), 71.2 (CHOAc), 60.6 (CH₂CH₃), 27.8, 25.1 (CH₃CCH₃), 20.3 (CH₃CO), 18.3 (CH₃Ar), 14.2 (CH₃CH₂). HRMS (ESI+): m/z 442.1846 (M + Na⁺). CH₂₉NNaO₇ requires: 442.1836.

Ethyl (E)-3-((4R,5R)-5-((R)-1-acetoxy-2-(1,1-bis-(ethoxycarbonyl)-3-butenylamino)-2-oxoethyl)-2,2-dimethyl-1,3-dioxolan-4-yl)acrylate (20e). It was prepared by method B in THF (overall yield anti + syn: 64% from ent-14, d.r. 98:2). Chromatography was performed with PE:CH₂Cl₂:Et₂O 3:1:1. Anti-20e: pale yellow oil. R_f = 0.45 (PE:CH₂Cl₂:Et₂O 3:1:1). [α]²⁰_D= −39.19 (c = 1.04, CHCl₃). IR (ATR): ν_max 3410, 2984, 2925, 2855, 1740, 1720, 1695, 1505, 1466, 1370, 1305, 1259, 1213, 1178, 1160, 1096, 1060, 1014, 987, 928, 882, 857, 795, 756, 665. GC-MS: R_t 12.29 min: m/z 498 (M⁺ − 15, 11), 498 (11), 455 (9.6), 440 (11), 410 (5.8), 396 (5.9), 383 (6.7), 382 (35), 344 (15), 313 (7.5), 272 (5.5), 271 (19), 241 (10), 239 (8.9), 229 (7.7), 216 (7.5), 214 (10), 213 (6.3), 199 (34), 198 (13), 181 (12), 174 (13), 172 (6.0), 171 (25), 170 (27), 168 (7.1), 153 (12), 143 (20), 142 (51), 141 (9.1), 126 (7.3), 125 (17), 124 (10), 114 (5.4), 113 (8.5), 112 (58), 111 (6.0), 109 (6.6), 101 (14), 97 (37), 96 (16), 87 (6.7), 85 (17), 84 (41), 83 (7.1), 81 (7.5), 73 (5.2), 71 (5.8), 69 (11), 68 (26), 59 (12), 55 (9.4), 44 (8.6), 43 (100), 41 (14), 39 (6.9). ¹H-NMR (CDCl₃): δ 7.44 (broad s, 1 H, NH), 6.89 (dd, J = 15.6, 4.9 Hz, 1 H, CH=CHCO), 6.15 (dd, J = 15.6, 1.4 Hz, 1H, CH=CHCO), 5.58 (ddt, J = 17.8, 10.2, 7.4 Hz, 1H, CH=CH₂), 5.17–5.05 (m, 2H, CH=CH₂), 4.29–4.14 (m, 6H, CH₂CH₃), 3,07, 3.03 (AB part of an ABX syst., J_AB = 14.2 Hz, J_AX = 7.9 Hz, J_BX = 7.1 Hz, 2H, CH₂CH=CH₂), 2.09 (CH₃CO), 1.60, 1.41 (2 s, 2 × 3H, (CH₃)₂C), 1.28 (t, J = 7.2 Hz, CH₃CH₂), 1.25 (t, J = 7.2 Hz, CH₃CH₂), 1.24 (t, J = 7.2 Hz, CH₃CH₂). ¹³C-NMR (CDCl₃): δ 168.9, 167.13, 167.08, 165.8, 165.7 (C=O), 140.5 (CHCH=C), 131.0 (CH=CH₂), 122.2 (CHCH=CH), 119.9 (CH=CH₂), 110.1 (C-2), 76.2 (C-4), 75.8 (C-5), 70.1 (CHOAc), 66.2 (C(CO₂Et)₂), 62.6 (×2), 60.6 (CH₂CH₃), 36.8 (CH₂CH=CH₂), 27.7, 25.2 (CH₃CCH₃), 20.3 (CH₃CO), 14.2, 13.9 (×2) (CH₃CH₂). HRMS (ESI+): m/z 536.2091 (M + Na⁺). C₂₄H₃₅NNaO₁₁ requires: 536.2102.

Ethyl (E)-3-((4R,5R)-5-((R)-1-benzoyloxy-2-((2,6-dimethylphenyl)amino)-2-oxoethyl)-2,2-dimethyl-1,3-dioxolan-4-yl)acrylate (20f). It was prepared by method B in THF (overall yield anti + syn: 57% from ent-14, d.r. 90:10). Chromatography was performed with PE:CH₂Cl₂:Et₂O 3:1:1. Anti-20f: white solid. M.p. 152.7–153.2 °C (CH₂Cl₂). R_f = 0.31 (PE:Et₂O 4:6). [α]²⁰_D= +25.16 (c = 1.03, CHCl₃₄). IR (ATR): ν_max 3247, 2987, 2935, 1726, 1671, 1602, 1515, 1475, 1452, 1371, 1263, 1223, 1176, 1161, 1110, 1071, 1030, 983, 880, 864, 766, 708, 682, 654, 619. ¹H-NMR (CDCl₃): δ 8.08–8.02 (m, 2H), 7.60 (tt, J = 7.5, 1.4 Hz, 1H), 7.46 (t, J = 7.5 Hz, 2H), 7.37 (broad s, 1H, NH), 7.14–7.02 (m, 3H), 6.96 (dd, J = 15.6, 5.4 Hz, 1H, CHCH=CH), 6.16 (dd, J = 15.6, 1.6 Hz, 1H, O=CCH=CH), 5.36 (d, J = 8.5 Hz, 1H, CHOBz), 5.03 (ddd, J = 6.4, 5.4, 1.5 Hz, 1H, H-4), 4.94 (dd, J = 8.5, 6.4 Hz, 1H, H-5), 3.99, 3.96 (AB part of an ABX₃ syst., J_AB = 11.0 Hz, J_AX = J_BX = 7.2 Hz, 2H, CH₂CH₃), 2.23 (s, 6H, CH₃Ar), 1.58, 1.46 (2 s, 2 × 3H, C(CH₃)₂), 1.08 (t, J = 7.2 Hz, 3H, CH₂CH₃). ¹³C-NMR (CDCl₃): δ 165.4 (×2), 165.3 (C=O), 141.2 (CHCH=C), 135.4 (×2), 133.0, 128.6 (aromatic quat.), 133.7 (×2), 130.0 (×2), 128.5, 128.2 (×2), 127.5 (aromatic CH), 123.3 (CHCH=CH), 110.2 (C-2), 76.4 (C-4, C-5), 71.7 (CHOBz), 60.4 (CH₂CH₃), 27.8, 25.2 (CH₃CCH₃), 18.4 (CH₃Ar), 14.0 (CH₃CH₂). HRMS (ESI+): m/z 504.2008 (M + Na⁺). C₂₇H₃₁NNaO₇ requires: 504.1993.

Ethyl (E)-3-((4R,5R)-5-((R)-1-benzoyloxy-2-(2-(4-benzyloxyphenyl)ethylamino)-2-oxoethyl)-2,2-dimethyl-1,3-dioxolan-4-yl)acrylate (20g). It was prepared by method B in THF (overall yield anti + syn: 63% from ent-14, d.r. 85:15). Chromatography was performed with PE:CH₂Cl₂:Et₂O 3:1:1. Anti-20g: pale yellow solid. M.p. 119.5–122.3 °C (CH₂Cl₂). R_f = 0.64 (PE:Et₂O 4:6). [α]²⁴_D= −43.85 (c = 1.00, CHCl₃). IR (ATR): ν_max 3409, 2983, 2937, 1714, 1683, 1611, 1583, 1530, 1511, 1453, 1379, 1241, 1177, 1162, 1111, 1070, 1026, 991, 878, 858, 806, 736, 711, 695. ¹H-NMR (CDCl₃): δ 8.02 (d, J = 8.2 Hz, 2H), 7.60 (t, J = 7.3 Hz, 1H), 7.46 (t, J = 7.8 Hz, 2H), 7.43–7.28 (m, 5H), 7.04 (d, J = 8.2 Hz, 2H), 6.96 (dd, J = 15.6, 5.4 Hz, 1H, CHCH=CH), 6.76 (d, J = 8.2 Hz, 2H), 6.16 (t, J = 6.0 Hz, 1H, NH), 6.12 (d, J = 15.6 Hz, 1H, O=CCH=CH), 5.49 (d, J = 5.2 Hz, 1H, CHOBz), 4.93 (s, 4H, CH₂Ph, H-4, H-5), 4.04, 4.01 (AB part of an ABX₃ syst., J_AB = 11.0 Hz, J_AX = J_BX = 7.2 Hz, 2H, CH₂CH₃), 3.58–3.36 (m, 2H, NHCH₂), 2.72 (t, J = 6.9 Hz, 2H, NHCH₂CH₂), 1.37 (s, 6 H, C(CH₃)₂), 1.13 (t, J = 7.1 Hz, 3H, CH₂CH₃). ¹³C-NMR (CDCl₃): δ 166.7, 165.5, 164.9 (C=O), 157.4, 137.0, 130.6, 128.6 (aromatic quat.), 141.9 (CHCH=C), 133.7, 129.9 (×2), 129.6 (×2), 128.54 (×2), 128.51 (×2), 127.9, 127.3 (×2), 114.9 (×2) (aromatic CH), 123.0 (CHCH=CH), 109.7 (C-2), 76.8, 76.0 (C-4, C-5), 71.5 (CHOBz), 69.8 (PhCH₂O), 60.4 (CH₂CH₃), 40.5 (NHCH₂), 34.3 (NHCH₂CH₂), 27.2, 24.8 (CH₃CCH₃), 14.0 (CH₃CH₂). HRMS (ESI+): m/z 610,2427 (M + Na⁺). C₃₄H₃₇NNaO₈ requires: 610.2411.

Ethyl (E)-3-((4R,5R)-5-(2-benzylamino-(R)-1-((2-methylbenzoyl)oxy)-2-oxoethyl)-2,2-dimethyl-1,3-dioxolan-4-yl)acrylate (20h). It was prepared by method B in THF (overall yield anti + syn: 56% from ent-14, d.r. 88:12). Chromatography was performed with PE:CH₂Cl₂:Et₂O 3:1:1. Anti-20h: white solid. M.p. 83.8–85.9 °C (CH₂Cl₂). R_f = 0.64 (PE:Et₂O 4:6). [α]²⁴_D= −33.33 (c = 1.01, CHCl₃). IR (ATR): ν_max 3331, 2984, 2931, 1723, 1664, 1601, 1551, 1494, 1455, 1434, 1387, 1367, 1307, 1235, 1208, 1173, 1157, 1141, 1071, 1029, 972, 922, 880, 858, 802, 737, 696, 668, 639. ¹H-NMR (CDCl₃): δ 7.96 (dd, J = 8.1, 1.5 Hz, 1H), 7.43 (td, J = 7.5, 1.2 Hz, 1H), 7.35–7.21 (m, 7H), 6.93 (dd, J = 15.6, 5.4 Hz, 1H, CHCH=CH), 6.46 (t, J = 6.0 Hz, 1 H, NH), 6.12 (dd, J = 15.6, 1.3 Hz, 1 H, O=CCH=CH), 5.38 (d, J = 7.0 Hz, 1H, CHOCO), 4.98–4.87 (m, 2H, H-4, H-5), 4.61 (dd, J = 15.1, 6.5 Hz, 1H, CHHPh), 4.33 (dd, J = 15.1, 5.1 Hz, 1H, CHHPh), 4.05, 4.02 (AB part of an ABX₃ syst., J_AB = 11.0 Hz, J_AX = J_BX = 7.1 Hz, 2H, CH₂CH₃), 2.57 (s, 3H, CH₃Ar), 1.46, 1.41 (2 s, 2 × 3H, C(CH₃)₂), 1.13 (t, J = 7.1 Hz, 3H, CH₂CH₃). ¹³C-NMR (CDCl₃): δ 167.2, 165.41, 165.38 (C=O), 141.5 (CHCH=C), 141.3, 137.5, 127.6 (aromatic quat.), 132.7, 131.8, 130.8, 128.6 (×2), 127.5 (×2), 127.4, 125.8 (aromatic CH), 123.2 (CHCH=CH), 109.9 (C-2), 76.7, 76.1 (C-4, C-5), 71.3 (CHOCO), 60.4 (CH₂CH₃), 43.4 (NHCH₂), 27.3, 24.9 (CH₃CCH₃), 21.7 (CH₃Ar), 14.0 (CH₃CH₂). HRMS (ESI+): m/z 504.1990 (M + Na⁺). C₂₇H₃₁NNaO₇ requires: 504.1993.

Ethyl (E)-3-((4R,5R)-5-(2-cyclohexylamino-(R)-1-((2-methoxyacetoxy)-2-oxoethyl)-2,2-dimethyl-1,3-dioxolan-4-yl)acrylate (20i). It was prepared by method B in THF (overall yield anti + syn: 64% from ent-14, d.r. 84:16). Chromatography was performed with PE:CH₂Cl₂:Et₂O 3:2:2. Anti-20i: white solid. M.p. 146.2–148.7 °C (CH₂Cl₂). R_f = 0.20 (PE:CH₂Cl₂:Et₂O 3:2:2). [α]²⁴_D= −43.13 (c = 1.03, CHCl₃). IR (ATR): ν_max 3314, 2989, 2938, 2856, 1758, 1716, 1661, 1550, 1452, 1420, 1384, 1356, 1303, 1259, 1245, 1225, 1183, 1161, 1122, 1096, 1077, 1031, 978, 929, 889, 879, 853, 804, 760, 734, 720, 694, 665, 645. ¹H-NMR (CDCl₃): δ 6.87 (dd, J = 15.6, 5.4 Hz, 1H, CHCH=CH), 6.12 (dd, J = 15.6, 1.6 Hz, 1H, O=CCH=CH), 5.92 (t, J = 8.4 Hz, 1H, NH), 4.98 (d, J = 8.1 Hz, 1H, CHOCO), 4.89 (ddd, J = 6.6, 5.4, 1.6 Hz, H-4), 4.69 (dd, J = 8.1, 6.6 Hz, H-5), 4.18 (q, J = 7.1 Hz, 2H, CH₂CH₃), 4.13, 4.07 (AB syst., J = 16.8 Hz, CH₂OMe), 3.84–3.69 (m, 1H, CHNH), 3.44 (s, 3H, CH₃O), 1.94–1.82 (m, 2H), 1.75–1.54 (m, 4H), 1.52, 1.39 (2 s, 2 × 3H, C(CH₃)₂), 1.40–1.27 (m, 1H), 1.28 (t, J = 7.2 Hz, 3H, CH₂CH₃), 1.25–1.05 (m, 3H). ¹³C-NMR (CDCl₃): δ 168.9, 165.7, 165.4 (C=O), 141.0 (CHCH=C), 122.6 (CHCH=CH), 109.7 (C-2), 76.1, 76.0 (C-4, C-5), 71.0 (CHOCO), 69.3 (CH₃OCH₂), 60.6 (CH₂CH₃), 59.4 (OCH₃), 48.3 (NHCH), 32.7, 32.5, 25.4, 24.5 (×2) (CH₂ of cyclohexyl), 27.5, 24.9 (CH₃CCH₃), 14.1 (CH₃CH₂). HRMS (ESI+): m/z 450.2101 (M + Na⁺). C₂₁H₃₃NNaO₈ requires: 450.2098.

(R)-2-(tert-Butylamino)-1-((4R,5R)-5-((E)-3-(4-methoxyphenoxy)prop-1-en-1-yl)-2,2-dimethyl-1,3-dioxolan-4-yl)-2-oxoethyl pent-4-enoate (38). It was prepared by method A in THF (overall yield anti + syn: 74% from 37, d.r. 62:38) and by method B (overall yield anti + syn: 45% from 37, d.r. 77:23). Chromatography was performed with PE:CH₂Cl₂:Et₂O 3:1:1. Anti-38: colorless oil6. R_f = 0.47 (PE:Et₂O 1:1). [α]²⁰_D= −22.70 (c = 0.45, CHCl₃). IR (ATR): ν_max 3391, 2977, 2935, 1745, 1689, 1507, 1455, 1367, 1216, 1163, 1107, 1063, 1035, 973, 916, 877, 824, 798, 744, 711. GC-MS: R_t 13.03 min: m/z 475 (M⁺, 5.1), 475 (5.1), 353 (21), 352 (100), 270 (13), 252 (11), 238 (5.8), 214 (14), 196 (9.2), 165 (5.1), 156 (7.9), 144 (8.8), 138 (14), 125 (8.1), 124 (54), 123 (20), 113 (5.5), 111 (33), 109 (11), 95 (13), 88 (11), 83 (31), 81 (7.1), 69 (8.9), 59 (7.9), 58 (17), 57 (32), 55 (54), 53 (13), 43 (13), 41 (15). ¹H-NMR (CDCl₃): δ 6.82 (s, 4 H, aromatic H), 6.02 (dtd, J = 15.6, 4.8, 0.6 Hz, 1H, CH-CH₂OPMP), 5.91 (ddt, J = 15.6, 6.6, 1.3 Hz, 1H, CH=CHCH₂OPMP), 5.86 (s, 1H, NH), 5.77 (ddt, J = 17.1, 10.2, 6.1 Hz, 1H, CH=CH₂), 5.06–4.95 (m, 2H, CH=CH₂), 4.99 (d, J = 7.8 Hz, 1H, CHOCO), 4.77 (t, J = 6.6 Hz, 1H, H-5), 4.56 (dd, J = 7.6, 6.4 Hz, 1H, H-4), 4.45 (d, J = 4.7 Hz, 2H, CH₂OPMP), 3.77 (OCH₃), 2.56–2.30 (m, 4H, CH₂CH₂CO), 1.50, 1.38 (2 s, 2 × 3H, (CH₃)₂C), 1.33 (s, 9H, (CH₃)₃C). ¹³C-NMR (CDCl₃): δ 171.5, 166.2 (C=O), 154.0, 152.6 (aromatic quat.), 136.4 (CH=CH₂), 129.3, 127.0 (CH=CH), 115.8 (CH=CH₂), 115.5, 114.7 (aromatic CH), 109.1 (C-2), 77.5 (C-5), 76.4 (C-4), 71.5 (CHOCO), 68.0 (CH₂OPMP), 55.7 (OCH₃), 51.6 (C(CH₃)₃), 33.2 (CH₂), 28.6 (C(CH₃)₃), 28.4 (CH₂), 27.6, 25.1 ((CH₃)₂C). HRMS (ESI+): m/z 498,2443 (M + Na⁺). C₂₆H₃₇NNaO₇ requires: 498,2462.

Ethyl 2-((3aR,4S,6R,6aR)-6-(tert-butylcarbamoyl)-2,2-dimethyltetrahydrofuro[3,4-d][1,3]dioxol-4-yl)acetate (24) and Ethyl 2-((3aR,4R,6R,6aR)-6-(tert-butylcarbamoyl)-2,2-dimethyltetrahydrofuro[3,4-d][1,3]dioxol-4-yl)acetate (25). A solution of sodium ethoxide (1.6 mL, 0.1 M, prepared in situ by addition of sodium to EtOH) was added to a solution of anti-20a (100 mg, 0,23 mmol) and the reaction was stirred at room temperature for 5 h. The mixture was poured into saturated aq. NH₄Cl (10 mL) and extracted with CH₂Cl₂. The organic layers were washed with brine, dried, and concentrated. Chromatography with PE:Et₂O afforded 24 (45 mg, 41%) and a mixture of 24 and 25 (18 mg, 17% yield), which was purified again to afford an analytical sample of 25. The d.r. of the reaction is 90:10). The same reaction was performed under the same conditions starting from anti-20b and afforded the same product with an overall 73% and a 89:11 d.r. 24: white solid. M.p. 61.1–62.4 °C (PE/Et₂O)). R_f = 0.48 (PE:Et₂O 1:1). [α]²¹_D= −2.94 (c = 1.00, CHCl₃). IR (ATR): ν_max 3389, 2988, 2964, 2936, 1729, 1683, 1524, 1480, 1457, 1403, 1395, 1375, 1364, 1308, 1280, 1268, 1251, 1237, 1205, 1179, 1159, 1106, 1072, 1057, 1038, 1024, 992, 973, 927, 897, 866, 839, 825, 809, 763, 698, 648, 616. GC-MS: R_t 9.14 min: m/z 314 (M⁺ − 15, 0.8), 226 (14), 186 (18), 185 (12), 184 (100), 172 (17), 171 (30), 170 (16), 155 (20), 154 (5.4), 143 (8.5), 129 (9.3), 128 (26), 127 (14), 126 (27), 125 (11), 109 (5.1), 101 (27), 100 (6.3), 99 (11), 98 (14), 97 (18), 88 (18), 87 (30), 85 (41), 84 (17), 83 (7.8), 82 (7.0), 81 (37), 74 (7.0), 73 (7.7), 71 (11), 70 (8.2), 69 (8.6), 59 (18), 58 (33), 57 (79), 56 (7.1), 55 (15), 43 (39), 42 (9.0), 41 (32), 39 (7.0). ¹H-NMR (CDCl₃): δ 6.72 (s, 1H, NH), 5.18 (dd, J = 6.0, 0.3 Hz, 1H, H-6a), 4.63 (dd, J = 6.0, 3.6 Hz, 1H, H-3a), 4.32 (s, 1H, H-6), 4.21, 4.18 (AB part of an ABX₃ syst., J_AB = 10.5 Hz, J_AX = J_BX = 7.2 Hz, 2H, CH₂CH₃), 4.08 (dtd, J = 9.0, 3.8, 0.3 Hz, 1H, H-4), 2.81, 2.70 (AB part of an ABX syst., J_AB = 17.4 Hz, J_AX = 3.8 Hz, J_BX = 9.0 Hz., 2 H, CH₂CO₂Et), 1.47, 1.32 (2 s, 2 × 3H, C(CH₃)₂), 1.37 (s, 9H, C(CH₃)₃), 1.29 (t, J = 7.2 Hz, 3H, CH₂CH₃). ¹³C-NMR (CDCl₃): δ 171.1, 167.9 (C=O), 112.7 (C-2), 83.9 (C-6), 83.6 (C-6a), 80.7 (C-3a), 77.6 (C-4), 60.8 (CH₂CH₃), 51.0 (C(CH₃)₃), 33.8 (CH₂CO₂Et), 28.7 (C(CH₃)₃), 26.1, 25.0 (CH₃CCH₃), 14.2 (CH₃CH₂). HRMS (ESI+): m/z 352.1728 (M + Na⁺). C₁₆H₂₇NNaO₆ requires: 352.1736. 25: colorless oil. R_f = 0.36 (PE:Et₂O 1:1). GC-MS: R_t 9.40 min: m/z 314 (M⁺-15, 0.7), 271 (16), 254 (6.3), 229 (17), 215 (32), 198 (7.7), 184 (16), 173 (5.2), 172 (46), 171 (21), 170 (9.3), 155 (11), 152 (13), 143 (11), 135 (5.4), 129 (7.2), 128 (6.4), 127 (14), 126 (19), 125 (14), 109 (9.9), 101 (18), 100 (6.0), 99 (8.8), 98 (10), 97 (32), 88 (33), 86 (6.7), 85 (100), 84 (17), 83 (7.7), 81 (18), 74 (6.5), 73 (7.8), 71 (12), 70 (9.9), 69 (10), 61 (6.8), 60 (6.2), 59 (24), 58 (35), 57 (82), 56 (8.3), 55 (15), 43 (52), 42 (13), 41 (40), 39 (9.5). ¹H-NMR (CDCl₃): δ 6.57 (s, 1H, NH), 4.94 (dd, J = 6.4, 2.8 Hz, 1H, H-6a), 4.52 (dd, J = 6.4, 3.8 Hz, 1H, H-3a), 4.22 (dt, J = 8.2, 4.1 Hz, 1H, H-4), 4.36 (d, J = 2.8 Hz, 1H, H-6), 4.19 (q, J = 7.2 Hz, 2H, CH₂CH₃), 2.66, 2.54 (AB part of an ABX syst., J_AB = 15.5 Hz, J_AX = 8.1 Hz, J_BX = 4.5 Hz., 2H, CH₂CO₂Et), 1.54, 1.34 (2 s, 2 × 3H, C(CH₃)₂), 1.36 (s, 9H, C(CH₃)₃), 1.29 (t, J = 7.2 Hz, 3H, CH₂CH₃). ¹³C-NMR (CDCl₃): δ 170.2, 169.1 (C=O), 114.1 (C-2), 84.5 (C-6), 83.8 (C-6a), 83.4 (C-3a), 82.3 (C-4), 61.0 (CH₂CH₃), 51.1 (C(CH₃)₃), 38.0 (CH₂CO₂Et), 28.6 (C(CH₃)₃), 27.2, 25.3 (CH₃CCH₃), 14.2 (CH₃CH₂). HRMS (ESI+): m/z 352.1728 (M + Na⁺). C₁₆H₂₇NNaO₆ requires: 352.1730.

Ethyl 2-((3aR,4S,6S,6aR)-6-(tert-butylcarbamoyl)-2,2-dimethyltetrahydrofuro[3,4-d][1,3]dioxol-4-yl)acetate (26) and Ethyl 2-((3aR,4R,6S,6aR)-6-(tert-butylcarbamoyl)-2,2-dimethyltetrahydrofuro[3,4-d][1,3]dioxol-4-yl)acetate (27). Compounds 26 and 27 were obtained under the same conditions described for compounds 24 and 25, starting either from syn-20a or syn-20b in 73% and 65% yield respectively, and a 82:18 or 83:17 d.r. As the two diastereomers could not be separated the 82:18 mixture of them was characterized. 26,27: colorless oil. R_f = 0.34 (PE:Et₂O 1:1). IR (ATR): ν_max 3417, 2976, 2936, 2908, 2876, 1734, 1681, 1525, 1456, 1366, 1332, 1288, 1266, 1229, 1209, 1181, 1163, 1101, 1045, 1028, 983, 951, 921, 895, 861, 800, 723. GC-MS: R_t1 9.33 min: m/z 314 (M⁺ − 15, 21), 314 (21), 284 (15), 229 (6.1), 228 (5.5), 184 (9.3), 173 (8.4), 172 (100), 171 (14), 170 (9.3), 155 (16), 154 (11), 152 (10), 143 (6.8), 128 (10), 127 (11), 126 (55), 125 (7.8), 101 (15), 100 (6.0), 99 (11), 98 (22), 97 (11), 88 (12), 87 (22), 85 (26), 84 (13), 83 (6.4), 82 (5.7), 81 (29), 71 (7.2), 70 (5.2), 59 (12), 58 (22), 57 (30), 55 (7.8), 43 (18), 41 (14); R_t2 9.42 min: m/z 314 (M⁺ − 15, 7.1), 314 (7.1), 284 (5.2), 242 (5.8), 229 (15), 215 (16), 212 (8.0), 186 (6.6), 184 (14), 173 (5.7), 172 (47), 171 (69), 170 (18), 155 (15), 154 (16), 146 (8.0), 143 (11), 129 (6.1), 128 (8.1), 127 (11), 126 (29), 125 (29), 115 (5.8), 101 (17), 100 (6.1), 99 (11), 98 (16), 97 (31), 89 (6.7), 88 (47), 87 (5.2), 86 (7.2), 85 (100), 84 (28), 83 (8.2), 82 (6.6), 81 (34), 73 (8.2), 72 (6.0), 71 (14), 70 (13), 69 (11), 61 (7.6), 60 (6.3), 59 (31), 58 (41), 57 (63), 56 (8.4), 55 (15), 44 (5.3), 43 (47), 42 (13), 41 (35), 39 (7.7). From NMR spectra of an 82:18 mixture we could extrapolate the spectra of 26 and 27. ¹H-NMR (26) (CDCl₃): δ 6.23 (s, 1H, NH), 4.98 (dd, J = 6.0, 4.2 Hz, 1H, H-6a), 4.72 (dd, J = 6.0, 3.6 Hz, 1H, H-3a), 4.25–4.12 (m, 2H, CH₂CH₃), 4.04 (td, J = 6.6, 3.6 Hz, 1H, H-4), 4.01 (d, J = 4.2 Hz, 1H, H-6), 2.83, 2.78 (AB part of an ABX syst., J_AB = 15.2 Hz, J_AX = 5.4 Hz, J_BX = 4.9 Hz., 2H, CH₂CO₂Et), 1.43, 1.30 (2 s, 2 × 3H, C(CH₃)₂), 1.38 (s, 9H, C(CH₃)₃), 1.29 (t, J = 7.2 Hz, 3H, CH₂CH₃). ¹H-NMR (27) (CDCl₃): δ 6.35 (s, 1H, NH), 5.02 (dd, J = 5.4, 4.5 Hz, 1H, H-6a), 4.66–4.59 (m, 2H, H-3a, H-4), 4.28 (d, J = 4.5 Hz, 1H, H-6), 4.25–4.12 (m, 2H, CH₂CH₃), 2.51, 2.46 (AB part of an ABX syst., J_AB = 14.3 Hz, J_AX = 5.5 Hz, J_BX = 6.3 Hz., 2H, CH₂CO₂Et), 1.47, 1.31 (2 s, 2 × 3 H, (CCH₃)₂), 1.38 (s, 9H, C(CH₃)₃), 1.27 (t, J = 7.2 Hz, 3H, CH₂CH₃). ¹³C-NMR (27) (CDCl₃): δ 170.7, 166.3 (C=O), 112.6 (C-2), 81.8 (C-6), 81.6 (C-6a), 80.3 (C-3a), 77.7 (C-4), 60.8 (CH₂CH₃), 51.0 (C(CH₃)₃), 33.8 (CH₂CO₂Et), 28.7 (C(CH₃)₃), 26.1, 25.0 (CH₃CCH₃), 14.2 (CH₃CH₂). ¹³C-NMR (27) (CDCl₃): δ 170.0, 166.6 (C=O), 112.9 (C-2), 83.9 (C-3a), 81.2 (C-6), (the peaks of C-6a and C-4 are covered by the signals of 26), 60.4 (CH₂CH₃), 51.1 (C(CH₃)₃), 36.3 (CH₂CO₂Et), 28.8 (C(CH₃)₃), 26.2, 24.4 (CH₃CCH₃), 14.2 (CH₃CH₂). HRMS (ESI+): m/z 352.1720 (M + Na⁺). C₁₆H₂₇NNaO₆ requires: 352.1730.

(2R,3R,3aS,6aS)-N-(tert-Butyl)-3-hydroxy-5-oxohexahydrofuro[3,2-b]furan-2-carboxamide (31). A solution of 24 (25 mg, 13.2 μmol) in THF (759 μL) and water (379 μL) was treated with CF₃COOH (379 μL). The reaction was stirred at r.t. for 48 h and then refluxed for 6 days. The crude product was evaporated and chromatographed (AcOEt) to afford 31 (17 mg, 92%) as a white solid. M.p. 153.3–156.1 °C (ACOET). R_f = 0.31 (AcOEt). [α]²³_D= −20.88 (c = 1.08, CHCl₃). IR (ATR): ν_max 3379, 1812, 1665, 1526,1362, 1310, 1256, 1230, 1199, 1188, 1155, 1141, 1084,1066, 1043 1025, 1005, 939, 908, 861, 845,707, 675, 613. ¹H-NMR (CDCl₃): δ 6.19 (s, 1H, NH), 5.01 (t, J = 4.4, 1H, H-3a), 4.92 (ddd, J = 6.0, 4.4, 1.5 Hz, 1H, H-6a), 4.30 (dt, J = 8.1, 4.4 Hz, 1H, H-3), 4.11 (d, J = 8.1 Hz, 1H, H-2), 3.24 (d, J = 4.8 Hz, 1H, OH), 2.82, 2.74 (AB part of an ABX syst., J_AB = 18.8 Hz., J_AX = 1.5 Hz, J_BX = 6.0 Hz, 2H, H-6), 1.38 (s, 9H, C(CH₃)₃). ¹³C-NMR (CDCl₃): δ 174.4, 169.2 (C=O), 82.3 (C-3a), 79.3 (C-2), 76.8 (C-6a), 75.3 (C-3), 51.4 (C(CH₃)₃), 36.6 (C-6), 28.7 (C(CH₃)₃). HRMS (ESI+): m/z 244.1165 (M + H⁺). C₁₁H₁₈NO₅ requires: 244.1177.

(E)-3-((4R,5S)-5-(((tert-butyldimethylsilyl)oxy)methyl)-2,2-dimethyl-1,3-dioxolan-4-yl)prop-2-en-1-ol (35). It was prepared by reduction of 18, as previously described, to afford a colorless oil in 96% overall yield [37]. R_f = 0.36 (PE:Et₂O 75:25). The analytical data agree with the reported ones.

(E)-((4R,5S)-5-(((tert-Butyldimethylsilyl)oxy)methyl)-2,2-dimethyl-4-(3-((4-methoxyphenyl)oxy)prop-2-en-1-yl)-1,3-dioxolane (36). A solution of 35 (116 mg, 0.38 mmol) in dry CH₂Cl₂ (3.8 mL) was treated with p-methoxyphenol (143 mg, 1.15 mmol), and triphenylphosphine (151 mg, 0.58 mmol). Then diethyl azodicarboxylate (97%, 93 µL, 0.58 mmol) was slowly added at 0 °C. The reaction mixture was then stirred for 4 days at room temperature. The solvent was evaporated under reduced pressure and the residue was purified by column chromatography on silica gel (PE:Et₂O, 8:2) to afford 36 (138 mg, 88%) as a colorless oil. R_f = 0.89 (PE:AcOEt 6:4). [α]³⁴_D= +2.46 (c = 0.95, CHCl₃). IR (ATR): ν_max 2930, 2857, 1507, 1463, 1379, 1228, 1212, 1168, 1096, 1040, 972, 939, 834, 824, 775, 745, 714, 666. GC-MS: R_t 11.58 min: m/z 408 (M⁺, 2.7), 293 (20), 285 (6.0), 227 (5.4), 211 (12), 201 (11), 181 (19), 169 (17), 165 (9.6), 131 (9.3), 125 (16), 124 (37), 123 (37), 117 (8.4), 116 (9.9), 115 (11), 112 (8.0), 111 (100), 109 (8.0), 101 (7.2), 95 (25), 93 (6.0), 89 (29), 83 (5.9), 81 (6.0), 77 (8.8), 75 (39), 74 (8.7), 73 (90), 69 (52), 67 (8.6), 59 (25), 57 (7.8), 55 (8.4), 53 (18), 45 (6.1), 43 (31), 41 (34), 39 (5.8). ¹H-NMR (CDCl₃): δ 6.83 (s, 4H, aromatic H), 5.99 (dt, J = 15.6, 4.8 Hz, 1H, CH-CH₂OPMP), 5.91 (dd, J = 15.6, 6.5 Hz, 1H, CH=CHCH₂OPMP), 4.69 (t, J = 6.5 Hz, 1H, H-4), 4.49 (d, J = 4.8 Hz, 2H, CH₂OPMP), 4.20 (q, J = 6.1 Hz, 1H, H-5), 3.76 (OCH₃), 1.47, 1.37 (2 s, 2 × 3H, (CH₃)₂C), 0.88 (s, 9 H, (CH₃)₃C), 0.05, 0.04 (2 s, 2 × 3H, CH₃Si). ¹³C-NMR (CDCl₃): δ 153.9, 152.7 (aromatic quat.), 128.9, 128.3 (CH=CH), 115.6, 114.6 (aromatic CH), 108.6 (C-2), 78.5 (C-5), 77.7 (C-4), 68.4 (CH₂OPMP), 62.2 (CH₂OSi), 55.7 (OCH₃), 27.8, 25.4 ((CH₃)₂C), 25.9 (C(CH₃)₃), 18.2 (SiC(CH₃)₂), −5.4 (Si(CH₃)₂. HRMS (ESI+): m/z 431.2221 (M + Na⁺). C₂₂H₃₆NaO₅Si requires: 431.2230.

((4S,5R)-5-((E)-3-(4-Methoxyphenoxy)prop-1-en-1-yl)-2,2-dimethyl-1,3-dioxolan-4-yl)methanol (37). It was synthesized following the same procedure used for ent-14, starting from 36 (138 mg, 0.34 mmol). Chromatography with PE:Et₂O 3:7 afforded 37 as a colorless oil (98 mg, 99%). R_f = 0.605(PE:Et₂O 7:3).

[α]²³_D= −33.74 (c = 0.74, CHCl₃). IR (ATR): ν_max 3544, 3496, 2983, 2927, 2872, 1592, 1504, 1463, 1408, 1385, 1339, 1309, 1292, 1235, 1211, 1184, 1162, 1136, 1109, 1075, 1061, 1028, 1014, 977, 945, 897, 870, 851, 828, 800, 744, 649. GC-MS: R_t 9.89 min: m/z 294 (M⁺, 2.6), 125 (9.1), 124 (100), 123 (15), 111 (5.3), 109 (14), 95 (5.7), 81 (8.4), 69 (6.6), 59 (21), 57 (5.7), 55 (6.6), 53 (8.8), 44 (7.2), 43 (21), 41 (9.9). ¹H-NMR (CDCl₃): δ 6.83 (s, 4H, aromatic H), 6.04 (dt, J = 15.6, 5.1 Hz, 1H, CH-CH₂OPMP), 5.86 (dd, J = 15.6, 7.2 Hz, 1H, CH=CHCH₂OPMP), 4.70 (t, J = 7.0 Hz, 1H, H-5), 4.51 (d, J = 5.0 Hz, 2H, CH₂OPMP), 4.26 (q, J = 6.0 Hz, 1H, H-4), 3.77 (OCH₃), 3.55 (t, J = 5.6 Hz, 1H, OH), 1.51, 1.39 (2 s, 2 × 3H, (CH₃)₂C). ¹³C-NMR (CDCl₃): δ 154.0, 152.5 (aromatic quat.), 130.1, 127.6 (CH=CH), 115.8, 114.6 (aromatic CH), 108.9 (C-2), 78.3 (C-4), 77.2 (C-5), 68.1 (CH₂OPMP), 62.0 (CH₂OH), 55.7 (OCH₃), 27.8, 25.2 ((CH₃)₂C). HRMS (ESI+): m/z 317.2473 (M + Na⁺). C₁₆H₂₂ NaO₅ requires: 317.2462.

4. Conclusions

In conclusion, we have presented another insight into diastereoselective Passerini reaction were a bio-based chiral aldehyde is involved. Moreover, we exploited the additional functional groups for expanding scaffold diversity, leading to the formation of different oxygenated heterocycles.