A case study of the MAC (masked acyl cyanide) oxyhomologation of N,N-dibenzyl-L-phenylalaninal with anti diastereoselectivity: preparation of (2S,3S)-allophenylnorstatin esters

Abstract

The three-component reaction between a protected α-amino aldehyde, an alcohol and an α-silyloxymalononitrile provides an expedient access to protected α-hydroxy-β-amino acid derivatives. The prototypical process, performed on N-Cbz-phenylalaninal, is known to proceed with syn diastereoselectivity. The present study demonstrates that the diastereoselectivity of the reaction can be inverted, using the rationale of a Felkin-Anh interaction model. Reactions performed on N,N-dibenzyl-L-phenylalaninal proceed with a high anti diastereoselectivity, providing a panel of synthetically useful ester derivatives of (2S,3S)-allophenylnorstatin. The procedure is exploited to accomplish one of the most efficient syntheses of the title compound to date, in 3 steps (66% yield) from N,N-dibenzyl-L-phenylalaninal.

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Introduction

Since its first advocacy several decades ago,¹ the umpolung concept has fructified to provide powerful tools for conducting organic synthesis.² Particular attention has been paid to the development and application of acyl anion equivalents, such as 1,3-dithianes,³ dialkylhydrazones,⁴ cyanohydrins⁵ and α-aminonitriles.⁶ A significant family of umpolung reagents are constituted by O-functionalized α-hydroxymalononitriles, known as masked acyl cyanide (MAC) reagents, first introduced by Yamamoto and Nemoto.⁷ The deprotonated form of a MAC reagent is nucleophilic and it reacts with an electrophile; subsequent unmasking reveals an acyl cyanide which can be further transformed into a carboxylic acid derivative by reaction with a nucleophile. This reactivity profile has been widely exploited in multi-step syntheses of biologically active molecules⁸ and in other synthetic applications.⁹

When the electrophilic partner is a chiral α-amino aldehyde and the MAC reagent is a silyl ether—hereafter referred to generically as H-MAC-[Si]—the one-pot reaction constitutes an oxyhomologation, presumably proceeding via a [1,4]-silyl transfer mechanism, to provide access to an α-hydroxy-β-amino acid derivative in which the alcohol function is protected as a silyl ether (Fig. 1). Despite the importance of α-hydroxy-β-amino acids,¹⁰ few applications of MAC methodology have been made thereto and they have, for the most part, been characterized by a syn diastereoselectivity (syn : anti ratio around 4 : 1).¹¹ Recently, however, we discovered that when Garner's aldehyde is used as the electrophilic partner the oxyhomologation gives the corresponding MAC reaction product with an anti diastereoselectivity.¹²

Fig. 1 The proposed mechanism for the reaction of an H-MAC-[Si] reagent with a protected chiral α-amino aldehyde, highlighting two models that may govern the diastereoselectivity in the first step. Once unmasked, the acyl cyanide intermediate reacts with a nucleophile.

One of the appealing features of MAC methodology is that the mild reaction conditions ensure that no erosion of the inherent enantiomeric composition of a chiral substrate is observed;^7m,8c this means that the oxyhomologation of a single enantiomer of an α-amino aldehyde substrate will furnish the oxyhomologation product as a single enantiomer.

While the mechanism of the MAC reaction has not been studied in detail, it seems plausible that the syn selectivity observed with unrestricted α-amino aldehydes might arise via an anti-Felkin–Anh model implicating a hydrogen bond between the carbamate-protected amine and the aldehyde during the first step, whereas Garner's aldehyde, devoid of an NH motif, reacts via a Felkin–Anh model (Fig. 1). If this reasoning is valid, it should be possible to perform an anti stereoselective MAC oxyhomologation reaction on an unrestricted α-amino aldehyde on the condition that the protecting group suite does not contain an NH motif. To probe this hypothesis, an N,N-dibenzyl-protected amino aldehyde appeared to us to be an appropriate substrate, since compounds of this type are known to react with nucleophiles^13,14 with good Felkin–Anh selectivity and without loss of enantiomeric enrichment. In order to provide direct comparison with Nemoto's reference work using N-Cbz-phenylalaninal,^7m the present study focuses on the MAC reaction of N,N-dibenzyl-L-phenylalaninal with alcohols. We describe herein the successful anti oxyhomologation of this substrate to prepare ester derivatives of the 2S,3S stereoisomer of allophenylnorstatin.¹⁵

Results and discussion

We began this study with a consideration of H-MAC-[Si] reagents. Almost all of the work described previously in the literature has employed 2-(tert-butyldimethylsilyloxy)malononitrile 1a (H-MAC-TBS);^{7j–r,8c–g,9a–d} the related triisopropylsilyl and tert-butyldiphenylsilyl derivatives 1b (H-MAC-TIPS)^7m and 1c (H-MAC-TBDPS)¹² have each been alluded to on only one occasion. All three of these reagents are appealing since they possess significant steric bulk, which might have an advantageous impact on the diastereoselectivity of the oxyhomologation reaction. However, an important factor for the synthetic utility of any H-MAC-[Si] reagent is a convenient and reliable access to the reagent itself. No syntheses of the derivatives 1b and 1c have been described to date. The earliest synthesis of 1a required a rather inefficient five-step sequence starting from diethyl 2-bromomalonate.^7a Subsequently, a three-step procedure was proposed starting from malononitrile, requiring acetylation, oxidative cleavage, then silyl ether formation;¹⁶ this is the basis of the approach that we have adopted for our preparative procedures (Scheme 1).

Scheme 1 Reaction conditions. Reactions carried out on 4.6 mmol scale unless stated. a: R₃SiCl (1.5 equiv.), imidazole (2 equiv.), DMF; R₃Si = TBS or TBDPS, 30 min at 0 °C then 30 min at rt; R₃Si = TIPS, 16 h, 0 °C slowly to rt. b: R₃SiOTf (1.5 equiv.), 2,6-lutidine (2 equiv.), CH₂Cl₂; R₃Si = TBS, 30 min at 0 °C then 30 min at rt; R₃Si = TIPS or TBDPS, 16 h, 0 °C slowly to rt. c: Conducted on 20 mmol scale.

Acetylation of malononitrile¹⁷ proceeded smoothly to provide 2 essentially in its enol tautomer form in 94% yield. Oxidative cleavage was performed using peracetic acid and, in our experience, the quality of the resulting 2-hydroxymalononitrile 3 was critical; its use immediately after preparation led to the best yields in the subsequent silylation step. For this latter, we compared the efficacy of silyl triflates with that of silyl chlorides on a 4.6 mmol scale. In all three cases the silylation was noticeably more efficient and reproducible with the triflate (yields 78–87%) than with the corresponding chloride (yields 60–65%) (Scheme 1). Using this adaptation and extension of the original procedure, the three MAC reagents 1a-c were prepared conveniently on around gram scale. Gratifyingly, when the H-MAC-TBS 1a synthesis was conducted at a preparative 20 mmol scale, the isolated yield of 1a from 2 improved to 97%.

Each H-MAC-[Si] reagent 1a–c was evaluated in the oxyhomologation of N,N-dibenzyl-L-phenylalaninal using methanol as the standard alcohol component. On the basis of previous work, DMAP was used as the mild base and reactions were run overnight in ether at 0 °C. The number of equivalents of MAC reagent and base were screened, invariably in the presence of a sufficient excess of methanol. Results are presented in Table 1. For H-MAC-TBS 1a, use of a slight excess of the reagent gave good yields of products 4a/4a′ (entries 1 and 2), and this improved when a larger excess of the reagent was employed (entries 3 and 4), reaching 83% in the presence of 2 equivalents of base. Running the reaction at room temperature (entry 5) was slightly deleterious to the yield. For H-MAC-TIPS 1b, a very similar reactivity profile was observed. With one equivalent of reagent and base the yield of 4b/4b′ was moderate 56% (entry 6) but improved when the quantity of either the reagent or the base was increased (entries 7 and 8) and reached a satisfying 80% in the presence of two equivalents of each (entry 9). Running the reaction at room temperature had a marginally negative effect on the yield (entry 10). For H-MAC-TBDPS 1c, a comparable reactivity profile was once again observed, with yields of 4c/4c′ ranging from 51 to 74% depending on the number of reagent equivalents (entries 11–14). Running the reaction at room temperature had no perceptible effect on the yield (entry 15).

Table 1 Investigation of the reaction conditions^a

entry	H-MAC-[Si] (equiv.)		DMAP (equiv.)	Yield^b4/4′ (%)	dr (anti : syn)^c
a Reaction conditions: N,N-dibenzyl-L-phenylalaninal (0.5 mmol; 1 equiv.), stated amounts of H-MAC-[Si] and DMAP, methanol (3 equiv.) in Et2O (5 mL), 16 h, 0 °C, under argon. b Isolated yields are given. c Determined by ^1H NMR; see text for details. d Reaction run at room temperature.
1	1a	1.2	1	68	94 : 6
2	1a	1.2	2	77	92 : 8
3	1a	2.4	1	80	92 : 8
4	1a	2.4	2	83	92 : 8
5^d	1a	2.4	2	78	91 : 9
6	1b	1.2	1	56	93 : 7
7	1b	1.2	2	65	93 : 7
8	1b	2.4	1	71	94 : 6
9	1b	2.4	2	80	91 : 9
10^d	1b	2.4	2	70	91 : 9
11	1c	1.2	1	51	92 : 8
12	1c	1.2	2	51	92 : 8
13	1c	2.4	1	71	93 : 7
14	1c	2.4	2	74	93 : 7
15^d	1c	2.4	2	74	91 : 9

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The diastereomeric ratios (dr) were established by inspecting the ¹H NMR spectra of the product mixtures and integrating the signals for protons whose chemical shifts were most conveniently differentiated between diastereomer pairs. In the event, this turned out to be the TBS methyl groups signals for 4a/4a′, the CHOTIPS signals for 4b/4b′ and the methyl ester signals for 4c/4c′. Within the precision limits of this method, the dr was uniformly high in all three cases, regardless of the reaction conditions involved, and was always greater than 10 : 1. The major diastereomer 4c crystallized and an X-ray diffraction study revealed that it had the 2S,3S configuration (Fig. 2),¹⁸ which confirmed that the MAC reaction had indeed proceeded with the desired anti diastereoselectivity. Intuitively we felt that the major diastereomers 4a and 4b should also be anti, and this was confirmed by subjecting each of the three samples 4a/4a′, 4b/4b′ and 4c/4c′ to selective desilylation using TBAF in THF to provide, in good yield after chromatography, a single product 5 (Scheme 2), whose spectroscopic and optical rotation data were the same as those published for the anti 2S,3S stereoisomer.^15f In these transformations, the ¹H NMR spectra of the crude reaction products indicated the presence of the minor syn diastereomers in silylated form, suggesting that the deprotection process may be diastereoselective, although we did not pursue this matter further.

Fig. 2 X-ray diffraction structure of compound 4c showing the 2S,3S configuration. For clarity, hydrogen atoms have been removed, with the exception of those at the stereogenic centres.

Scheme 2 Reaction conditions. For 4a/4a′ and 4b/4b′: 1 h, 0 °C. For 4c/4c′: 16 h, rt.

The results collected in Table 1 show that all three H-MAC-[Si] reagents performed in a satisfactory manner, with all products 4a/4a′–4c/4c′ being obtained with high anti diastereoselectivity. Comparison of best yields (entries 4, 9 and 14) gave a marginal advantage to 1a over 1b which was in turn better than 1c (83%, 80% and 74% yields, respectively). As mentioned above, H-MAC-TBS is the most studied reagent so far and its synthesis was the most efficient in our hands so we continued our studies with this reagent and retained the conditions of entry 4 as standard.

The scope of the MAC oxyhomologation of N,N-dibenzyl-L-phenylalaninal was evaluated using a panel of alcohols. Results are presented in Scheme 3. As before, dr values were determined by integration of the ¹H NMR signals of the TBS methyl groups and we considered it plausible that the anti diastereomer predominated in each case. Support for this contention was provided by the ¹H NMR data, which invariably showed the diagnostic TBS methyl groups signals at lower field for the major anti isomer than for the minor syn isomer (see ESI†).

Scheme 3 Reaction conditions. N,N-dibenzyl-L-phenylalaninal (0.5 mmol; 1 equiv.), 1a (2.4 equiv.), DMAP (2 equiv.) and ROH (3 equiv.) in Et₂O (5 mL), 16 h, 0 °C, under argon. Isolated yields are indicated. The dr was determined by ¹H NMR; see text for details. Only the major anti diastereomer is illustrated.

Ethanol and benzyl alcohol gave good yields of products 6/6′ and 7/7′ with high diastereoselectivity. With three other uncongested primary alcohols—allyl alcohol, propargyl alcohol and phenylethanol—the products (8/8′–10/10′ respectively) were likewise obtained in very good yields and high dr, reaching 95 : 5 for compound 10/10′. When the reaction was carried out with branched chain primary alcohols—isoamyl alcohol, isobutanol and (S)-2-methylbutanol—the yield of the oxyhomologation products (11/11′–13/13′ respectively) was more modest (46–64%), although the dr values remained consistently high. The presence of the chiral center in 2-methylbutanol had no perceptible effect on the dr value. With two representative secondary alcohols—isopropanol and cyclopentanol—the reactions were much less efficient; the desired products 14/14′ and 15/15′ were isolated only in low yields (11% and 14%, respectively), although the dr values were still just as high as those observed for primary alcohol substrates. Notwithstanding the limitations arising from the steric bulk of the alcohol, these oxyhomologation reactions provided rapid access to a selection of ester derivatives of N,O-protected (2S,3S)-allophenylnorstatin, some of which (e.g. allyl and propargyl) appear amenable to subsequent functionalization.

The methyl ester of (2S,3S)-allophenylnorstatin, itself a LTA₄ hydrolase inhibitor,¹⁹ has been used as a building block for the preparation of BACE1 inhibitors,²⁰ photobiological switches,²¹ and symmetrical peptidomimetic scaffolds;²² it has also served as an intermediate for the preparation of a variety of other biologically active compounds,²³ as has the corresponding ethyl ester.²⁴ These two ester derivatives were prepared readily as follows (Scheme 4). Catalytic hydrogenolysis of the single stereoisomer 5 (obtained viaScheme 2) gave the methyl ester 16 in high yield (88%). In a similar fashion, compound 17 was first obtained as a single anti isomer in 91% yield by selective desilylation of 6/6′ (dr 92 : 8) using TBAF in THF; taking the diastereomeric composition of the substrate into account, this equates to a near quantitative yield of the available anti component. Compound 17 was subjected to catalytic hydrogenolysis to provide ethyl ester 18 in good yield (73%). These procedures provide a convenient access to esters 16 and 18 as an alternative to the classical approach involving acid-mediated esterification of the parent amino acid.

Scheme 4 Preparation of (2S,3S)-allophenylnorstatin esters.

To complete this study we prepared (2S,3S)-allophenylnorstatin in its free amino acid form (Scheme 5). The benzyl ester derivative 7/7′ (dr 92 : 8) was desilylated using TBAF to furnish exclusively the anti derivative 19 in 84% yield; on the basis of the diastereomeric composition of the substrate, this equates to a 91% yield of the available anti component. For the final step, catalytic hydrogenolysis of all three benzyl groups was envisaged in the presence of a palladium catalyst. Initial experiments carried out in methanol were hampered by the formation of mixtures of products resulting from partial N-debenzylation and the unwanted formation of N- and/or O-methylated derivatives.²⁵ To circumvent this problem we performed the hydrogenation in ethyl acetate; mutatits mutandis, complete debenzylation was achieved cleanly to provide the target hydroxy amino acid 20 in 95% yield. Spectroscopic and optical rotation data were in full agreement with the literature data for the (2S,3S) stereoisomer. This 3-step synthesis of (2S,3S)-allophenylnorstatin in 66% overall yield from N,N-dibenzyl-L-phenylalaninal is one of the shortest and most efficient to date.²⁶

Scheme 5 Preparation of (2S,3S)-allophenylnorstatin.

Conclusions

This study reveals that MAC reactions between N,N-dibenzyl-L-phenylalaninal and alcohols proceed with high anti diastereoselectivity. These results contrast significantly with Nemoto's work on MAC reactions involving N-Cbz-phenylalaninal, which gave products with syn diastereoselectivity.^7m The combined observations provide the first example of the MAC oxyhomologation of an α-amino aldehyde in a directed diastereoselective manner, through judicious choice of the amine protecting group suite. Using the new anti-directed formulation, a panel of ester derivatives of orthogonally N,O-protected (2S,3S)-allophenylnorstatins has been prepared. While the reactions were sensitive to the steric bulk of the alcohol, a number of synthetically useful esters were prepared in this way and an expedient new synthesis of the title amino acid in single-enantiomer form was achieved in only 3 steps.

Experimental

General experimental methods

N,N-Dibenzyl-L-phenylalaninal {[α]²⁴_D = −91.2 (c 1.0, CHCl₃), lit.²⁷ [α]²⁰_D = −90.0 (c 1.0, CHCl₃)} was prepared from commercial (S)-phenylalaninol according to literature procedure.²⁸ Peracetic acid solution (35 wt% in acetic acid) was purchased from Acros. Solvents and reagents were purified under argon as follows: Et₂O and THF were distilled from Na/benzophenone; DMF and 2,6-lutidine were distilled from CaH₂; CH₂Cl₂ was passed through an activated alumina column immediately before use; methanol and ethanol were distilled from Mg/I₂; benzyl alcohol, isopropanol, isobutanol, isoamyl alcohol and (S)-2-methylbutan-1-ol were distilled from CaO; allyl alcohol, propargyl alcohol and phenylethyl alcohol were dried over CaSO₄, K₂CO₃ and Na₂SO₄ respectively, followed by distillation. All other reagents were obtained commercially and were used directly as supplied. Preparative flash chromatography was performed using columns packed with SDS (35–70 μm) or Macherey–Nagel (40–63 μm) silica gel. Analytical thin-layer chromatography, used to monitor preparative flash chromatography and to provide characteristic retention factors (R_f), was performed on 0.25 mm commercial silica gel plates (Merck 60F-254); plates were visualized by UV fluorescence at 254 nm and then revealed by heating after dipping in a ninhydrin solution (1.5% in n-BuOH) or a potassium permanganate solution (7.5% in water). ¹H and ¹³C NMR spectra were recorded on Bruker DPX250 (250 and 62.9 MHz, respectively), Bruker AV300 (300 and 75.5 MHz, respectively), Bruker AV360 (360 and 90.6 MHz, respectively), Bruker Avance I 400 and Bruker Avance III 400 spectrometers (400 and 100.6 MHz, respectively). Chemical shifts (δ) are given in parts per million, using solvent signals as internal standards (CDCl₃: δ_H = 7.26 ppm, δ_C = 77.0 ppm; DMSO-d₆: δ_H = 2.50 ppm, δ_C = 39.5 ppm; CD₃OD: δ_H = 3.31 ppm, δ_C = 49.0 ppm; D₂O: δ_H = 4.79 ppm). Assignments were aided by JMOD pulse sequences and 2D experiments (HSQC, HMBC, COSY). Splitting patterns for ¹H signals are designated as s (singlet), d (doublet), t (triplet), q (quartet), br s (broad singlet), or m (multiplet). Coupling constants (J) are reported in Hz. Positive and negative electrospray (ES⁺, ES⁻) high resolution mass spectra (HRMS) were recorded with a Bruker Daltonics micrOTOF-Q instrument. Infrared spectroscopy (IR) analyses were recorded on a FT-IR PerkinElmer Spectrum Two spectrophotometer using an ATR diamond accessory; maximum absorbances (ν) are given in cm⁻¹. Elemental analyses were performed by the Microanalysis Service of the I.C.S.N. (Gif-sur-Yvette, France). Melting points (Mp) were determined with a Büchi M-560 apparatus in open capillary tubes and are uncorrected. Optical rotations were measured on a Jasco P-1010 polarimeter using a 10 cm quartz cell; values for [α]^T_D were obtained with the D-line of sodium at the indicated temperature T, using solutions of concentration (c) in units of g 100 mL⁻¹.

Preparation of MAC reagents: H-MAC-[Si]

2-(1-Hydroxyethylidene)malononitrile (2). Malononitrile (3.00 g, 45.4 mmol) was dissolved in ether (50 mL). Potassium carbonate (7.50 g, 54.3 mmol) was added in one portion and the reaction mixture was stirred vigorously for 1 h at room temperature under argon. After cooling at 0 °C, acetic anhydride (6.9 mL, 73.0 mmol) diluted in Et₂O (25 mL) was added dropwise over 20 min and the reaction mixture was stirred for 4 h at room temperature. Water (30 mL) was introduced and the mixture was acidified at 0 °C with concentrated HCl until pH ∼1. The aqueous phase was extracted with Et₂O (3 × 20 mL) and the combined organic layers were washed with brine (30 mL), dried over Na₂SO₄ and concentrated under reduced pressure to give 2 (4.60 g, 94%) as a yellow-orange solid. Mp 141 °C. Crude 2-(1-hydroxyethylidene)malononitrile obtained in this way showed a very satisfactory ¹H NMR spectrum and could be used in the subsequent reaction without further purification. An analytically pure sample was obtained by recrystallization from Et₂O/n-hexane to furnish 2 (4.22 g, 86%) as a light yellow-orange solid. Mp 141 °C (lit.¹⁷ 140.5 °C). R_f 0.25 (EtOAc/MeOH, 9 : 1). IR (ATR): ν 3045, 2610, 2238, 2225, 1600, 1574, 1507, 1402, 1359, 1227 cm⁻¹. HRMS (ES⁻): calcd for C₅H₃N₂O [M − H]⁻ 107.0251; found 107.0250. ¹H NMR (360 MHz, DMSO-d₆), δ 2.21 (s, 3H, =C–CH₃), 12.1 (br s, 1H, =C–OH). ¹³C NMR (62.9 MHz, DMSO-d₆), δ 21.2 (=C–CH₃), 59.2 (C(CN)₂), 113.8 (C(CN)CN), 115.7 (C(CN)CN), 189.3 (=C–OH). Anal. calcd for C₅H₄N₂O: C, 55.56; H, 3.73; N, 25.91. Found: C, 55.54; H, 3.53; N, 25.97.

2-Hydroxymalononitrile (3). To a solution of crude 2-(1-hydroxyethylidene)malononitrile 2 (1.00 g, 9.26 mmol) in water (24 mL) was added dropwise over 10 min at 0 °C a peracetic acid solution (35 wt% in acetic acid, 6.2 mL, 32.3 mmol) diluted with glacial acetic acid (20 mL). After complete addition, the resulting clear yellow solution was stirred at room temperature for 2 h. The reaction mixture was gradually concentrated on a rotary evaporator (water bath below 35 °C) until 10 mbar and traces of acetic acid were removed by three co-evaporations with water. (NOTE: Although we have never observed any complications, a Plexiglas protective shield around the rotary evaporator was used during concentration of peracetic acid). The residual yellowish oil was dried under high vacuum (10⁻² mbar) until no more traces of water or acetic acid were observed by ¹H NMR (around 2 h). Unstable 2-hydroxymalononitrile 3 (∼760 mg, 9.26 mmol, quant.), isolated as a milky yellowish oil, was quickly analyzed by NMR. It was then engaged directly in the next reaction without any purification. ¹H NMR (300 MHz, DMSO-d₆), δ 6.08 (s, 1H, CH(CN)₂), 8.22 (br s, 1H, OH). ¹³C NMR (62.9 MHz, DMSO-d₆), δ 49.9 (CH(CN)₂), 114.6 (CH(CN)₂).

General procedure for 2-hydroxymalononitrile silylation

Method A (using a silyl chloride). Crude 2-hydroxymalononitrile 3 (4.63 mmol, 1 equiv.) was dissolved in DMF (10 mL) under argon and the solution was cooled at 0 °C. Silyl chloride reagent (1.5 equiv.) was added in one portion, followed by imidazole (630 mg, 9.26 mmol, 2.0 equiv.) in several portions. The reaction mixture was then stirred for the specified time and at the indicated temperature (see below). After addition of a saturated aqueous Na₂CO₃ solution (10 mL), the aqueous phase was extracted with Et₂O (6 × 10 mL). The combined organic layers were washed with 1 M HCl (50 mL), brine (50 mL), dried over Na₂SO₄ and concentrated on a rotary evaporator (water bath at 40 °C) until the appropriate pressure depending of the nature of the H-MAC-[Si]. The crude residue was then purified by flash chromatography to afford pure O-silylated hydroxymalononitrile.

Method B (using a silyl triflate). To an ice-cooled mixture of crude 2-hydroxymalononitrile 3 (4.63 mmol, 1 equiv.) in CH₂Cl₂ (5 mL) under argon was added the silyl triflate reagent (1.5 equiv.) in a single portion followed by dropwise addition of 2,6-lutidine (1.08 mL, 9.26 mmol, 2.0 equiv.) and the reaction mixture was then stirred for the specified time and at the indicated temperature (see below). After addition of a saturated aqueous Na₂CO₃ solution (10 mL), the aqueous layer was extracted with Et₂O (6 × 10 mL) and the combined organic phases were washed with 1 M HCl (50 mL), brine (50 mL), dried over Na₂SO₄ and concentrated on a rotary evaporator (water bath at 40 °C) until the appropriate pressure depending of the nature of the H-MAC-[Si]. The crude residue was then purified by flash chromatography to afford pure O-silylated hydroxymalononitrile.

2-(tert-Butyldimethylsilyloxy)malononitrile, H-MAC-TBS (1a). According to method A: silylation of 2-hydroxymalononitrile 3 (380 mg, 4.63 mmol) was performed with tert-butyldimethylsilyl chloride (1.05 g, 7.00 mmol) and imidazole in DMF for 30 min at 0 °C followed by 30 min at room temperature. After work-up and concentration under reduced pressure (until 450 mbar), the brown liquid residue was purified by flash chromatography (pentane then pentane/Et₂O, 20 : 1; then concentration of fractions on a rotary evaporator with a water bath at 40 °C until 450 mbar) to give H-MAC-TBS 1a (583 mg, 65% over 2 steps) as a colorless liquid. According to method B: silylation of 2-hydroxymalononitrile 3 (380 mg, 4.63 mmol) was carried out with tert-butyldimethylsilyl triflate (1.6 mL, 6.97 mmol) and 2,6-lutidine in CH₂Cl₂ for 30 min at 0 °C followed by 30 min at room temperature. After work-up and concentration under reduced pressure (until 450 mbar), the pale brown liquid residue was purified by flash chromatography (pentane then pentane/Et₂O, 20 : 1; then concentration of fractions on a rotary evaporator with a water bath at 40 °C until 450 mbar) to furnish compound 1a (790 mg, 87% over 2 steps) as a colorless liquid. H-MAC-TBS 1a can be stored under argon for several months at −18 °C. R_f 0.18 (pentane/Et₂O, 20 : 1). IR (ATR): ν 2957, 2934, 2862, 2252, 1473, 1259, 1115 cm⁻¹. ¹H NMR (300 MHz, CDCl₃), δ 0.28 (s, 6H, Si(CH₃)₂), 0.94 (s, 9H, SiC(CH₃)₃), 5.33 (s, 1H, CH(CN)₂). ¹³C NMR (75.5 MHz, CDCl₃), δ −5.5 (Si(CH₃)₂), 17.9 (SiC(CH₃)₃), 25.0 (SiC(CH₃)₃), 50.8 (CH(CN)₂), 112.3 (CH(CN)₂). Anal. calcd for C₉H₁₆N₂OSi: C, 55.06; H, 8.21; N, 14.27. Found: C, 54.81; H, 8.12; N, 14.13. ¹H and ¹³C NMR data were in agreement with those described in literature.^7a

Larger scale synthesis of H-MAC-TBS (1a). To a solution of crude 2-(1-hydroxyethylidene)malononitrile 2 (2.15 g, 19.9 mmol) in water (25 mL) was added dropwise over 20 min at 0 °C a peracetic acid solution (35 wt% in acetic acid, 13.4 mL, 69.8 mmol) diluted with glacial acetic acid (42 mL). After complete addition, the resulting clear yellow solution was stirred at room temperature for 2 h. The reaction mixture was gradually concentrated on a rotary evaporator (water bath below 35 °C) until 10 mbar and traces of acetic acid were removed by three co-evaporations with water. (NOTE: Although we have never observed any complications, a Plexiglas protective shield around the rotary evaporator was used during concentration of peracetic acid). The residual yellowish oil was dried under high vacuum (10⁻² mbar) until no more trace of water and acetic acid was observed by ¹H NMR (around 2 h). To the crude 2-hydroxymalononitrile 3 (1.66 g, 19.91 mmol) in solution in CH₂Cl₂ (8 mL), were slowly introduced tert-butyldimethylsilyl triflate (7.1 mL, 31.0 mmol), followed by 2,6-lutidine (4.8 mL, 41.5 mmol). The resulting solution was stirred for 30 min at 0 °C and for an additional 30 min at room temperature. After addition of a saturated aqueous Na₂CO₃ solution (40 mL), the aqueous layer was extracted with Et₂O (6 × 20 mL) and the combined organic phases were washed with 1 M HCl (100 mL), brine (100 mL), dried over Na₂SO₄ and concentrated on a rotary evaporator (water bath at 40 °C) until 450 mbar. The crude residue was then purified by flash chromatography (pentane then pentane/Et₂O, 20 : 1; then concentration of fractions on a rotary evaporator with a water bath at 40 °C until 450 mbar) to furnish compound 1a (3.79 g, 97% over 2 steps) as a colorless liquid.

2-(Triisopropylsilyloxy)malononitrile, H-MAC-TIPS (1b). According to method A: silylation of 2-hydroxymalononitrile 3 (380 mg, 4.63 mmol) was performed with triisopropylsilyl chloride (1.5 mL, 7.01 mmol) and imidazole in DMF overnight from 0 °C to room temperature. After work-up and concentration under reduced pressure, the brown liquid residue was purified by two successive flash chromatographies (pentane then pentane/Et₂O, 50 : 1; pentane then pentane/Et₂O, 20 : 1) to separate H-MAC-TIPS from triisopropylsilanol. H-MAC-TIPS 1b (665 mg, 60% over 2 steps) was isolated as a colorless viscous liquid. According to method B: silylation of 2-hydroxymalononitrile 3 (380 mg, 4.63 mmol) was carried out with triisopropylsilyl triflate (1.9 mL, 7.05 mmol) and 2,6-lutidine in CH₂Cl₂ overnight from 0 °C to room temperature. After work-up and concentration under reduced pressure, the brown liquid residue was purified by two successive flash chromatographies (pentane then pentane/Et₂O, 50 : 1; pentane then pentane/Et₂O, 20 : 1) to separate H-MAC-TIPS from triisopropylsilanol. H-MAC-TIPS 1b (862 mg, 78% over 2 steps) was obtained as a colorless liquid. H-MAC-TIPS 1b can be stored under argon for several months at −18 °C. R_f 0.23 (pentane/Et₂O, 20 : 1). IR (ATR): ν 2948, 2870, 2252, 1463, 1114 cm⁻¹. ¹H NMR (300 MHz, CDCl₃), δ 1.07–1.14 (m, 18H, SiCH(CH₃)₂), 1.16–1.24 (m, 3H, SiCH(CH₃)₂), 5.40 (s, 1H, CH(CN)₂). ¹³C NMR (75.5 MHz, CDCl₃), δ 11.5 (SiCH(CH₃)₂), 17.3 (SiCH(CH₃)₂), 51.3 (CH(CN)₂), 112.3 (CH(CN)₂). Anal. Calcd for C₁₂H₂₂N₂OSi: C, 60.46; H, 9.30; N, 11.75. Found: C, 60.20; H, 9.08; N, 11.67.

2-(tert-Butyldiphenylsilyloxy)malononitrile, H-MAC-TBDPS (1c). According to method A: silylation of 2-hydroxymalononitrile 3 (380 mg, 4.63 mmol) was performed with tert-butyldiphenylsilyl chloride (1.8 mL, 7.03 mmol) and imidazole in DMF for 30 min at 0 °C followed by 30 min at room temperature. After work-up and concentration under reduced pressure, the orange viscous oil was purified by flash chromatography (pentane/Et₂O, 9 : 1) to give H-MAC-TBDPS 1c (965 mg, 65% over 2 steps) as a colorless viscous oil, which crystallized as a white solid after standing for 24 h at −18 °C. According to method B: silylation of 2-hydroxymalononitrile 3 (380 mg, 4.63 mmol) was carried out with tert-butyldiphenylsilyl triflate²⁹ (1.43 M in CHCl₃, 5.0 mL, 7.15 mmol) and 2,6-lutidine in CH₂Cl₂ overnight from 0 °C to room temperature. After work-up and concentration under reduced pressure, the brown liquid residue was purified by flash chromatography (pentane then pentane/Et₂O: 20 : 1) to furnish H-MAC-TBDPS 1c (1.18 g, 80% over 2 steps) as a colorless viscous oil, which crystallized as a white solid after standing for 16 h under high vacuum (10⁻² mbar). H-MAC-TBDPS 1c can be stored under argon for several months at −18 °C. Mp 48 °C. R_f 0.25 (pentane/Et₂O, 20 : 1). IR (ATR): ν 3074, 2962, 2933, 2890, 2860, 2253, 1590, 1472, 1428, 1112 cm⁻¹. HRMS (ES⁺): calcd for C₁₉H₂₀N₂NaOSi [M + Na]⁺ 343.1237; found 343.1228. ¹H NMR (300 MHz, CDCl₃), δ 1.15 (s, 9H, SiC(CH₃)₃), 5.08 (s, 1H, CH(CN)₂), 7.46–7.59 (m, 6H, SiPh), 7.69–7.73 (m, 4H, SiPh). ¹³C NMR (75.5 MHz, CDCl₃), δ 19.3 (SiC(CH₃)₃), 26.3 (SiC(CH₃)₃), 51.5 (CH(CN)₂), 111.9 (CH(CN)₂), 128.5 (CH_Ph), 129.3 (C_Ph), 131.2 (CH_Ph), 135.5 (CH_Ph). Anal. calcd for C₁₉H₂₀N₂OSi: C, 71.21; H, 6.29; N, 8.74. Found: C, 71.22; H, 6.33; N, 8.55.

MAC reactions with alcohols as nucleophiles

General procedure for MAC reactions. To freshly prepared N,N-dibenzyl-L-phenylalaninal (c. 0.5 mmol, 1 equiv.) and H-MAC-[Si] 1a–c (2.4 equiv.) under argon, were added dry Et₂O (5 mL) followed by the alcohol (3 equiv.). After cooling at 0 °C, DMAP (2 equiv.) was added in one portion and the reaction mixture was stirred overnight under argon at this temperature. A saturated aqueous Na₂CO₃ solution (10 mL) was introduced at 0 °C. After addition of water (10 mL) to dissolve the salts, the aqueous phase was extracted with Et₂O (6 × 10 mL). The combined organic phases were washed with 1 M HCl (50 mL), brine (50 mL), dried over Na₂SO₄ and concentrated under reduced pressure. The crude residue was purified by flash chromatography (pentane/Et₂O, 20 : 1) to give the corresponding ester MAC reaction products.

The diastereoisomeric ratio (dr) was determined by ¹H NMR analysis (CDCl₃ at 293 K) on crude products either before or (in the cases of 14/14′, 15/15′, 4b/4b′ and 4c/4c′) after chromatography. For product samples obtained from H-MAC-TBS, dr was determined by integration of the TBS methyl groups signals. For product samples obtained from H-MAC-TIPS, dr was determined by integration of the CHOTIPS signals. For product samples obtained from H-MAC-TBDPS, dr was determined by integration of the OMe signals.

Methyl (2S,3S)-2-(tert-butyldimethylsilyloxy)-3-(dibenzylamino)-4-phenylbutanoate (4a). According to the general procedure, the MAC reaction was performed with N,N-dibenzyl-L-phenylalaninal (155 mg, 0.47 mmol), H-MAC-TBS 1a (223 mg, 1.14 mmol), methanol (58 μL, 1.43 mmol) and DMAP (115 mg, 0.94 mmol) in Et₂O. Flash chromatography gave inseparable MAC reaction products 4a/4a′ (dr 92 : 8, 196 mg, 83%), as a colorless oil. R_f 0.39 (pentane/Et₂O, 20 : 1). IR (ATR): ν 3022, 2951, 2925, 2858, 1752, 1738, 1605, 1494, 1454, 1250, 1125 cm⁻¹. HRMS (ES⁺): calcd for C₃₁H₄₂NO₃Si [M + H]⁺ 504.2928; found 504.2904. Spectroscopic data for the major anti (2S,3S)-diastereomer (4a): ¹H NMR (360 MHz, CDCl₃), δ 0.08 (s, 3H, SiCH₃), 0.13 (s, 3H, SiCH₃), 0.96 (s, 9H, SiC(CH₃)₃), 2.91–3.05 (m, 2H, PhCH₂CH), 3.37–3.44 (m, 1H, CHN), 3.53 (s, 3H, OCH₃), 3.61 (d, J = 13.9 Hz, 2H) and 3.78 (d, J = 13.9 Hz, 2H) (AB syst., N(CH₂Ph)₂), 4.60 (d, J = 4.3 Hz, 1H, CHOTBS), 7.08–7.14 (m, 6H, Ph), 7.17–7.31 (m, 9H, Ph). ¹³C NMR (90.6 MHz, CDCl₃), δ −4.8 (Si(CH₃)₂), 18.2 (SiC(CH₃)₃), 25.8 (SiC(CH₃)₃), 32.6 (PhCH₂CH), 51.5 (OCH₃), 54.4 (N(CH₂Ph)₂), 62.7 (CHN), 71.9 (CHOTBS), 125.8 (CH_Ph), 126.7 (CH_Ph), 127.9 (CH_Ph), 128.0 (CH_Ph), 128.7 (CH_Ph), 129.6 (CH_Ph), 139.5 (C_Ph), 140.3 (C_Ph), 173.4 (COOCH₃).

Methyl (2S,3S)-3-(dibenzylamino)-2-(triisopropylsilyloxy)-4-phenylbutanoate (4b). According to the general procedure, the MAC reaction was performed with N,N-dibenzyl-L-phenylalaninal (164 mg, 0.50 mmol), H-MAC-TIPS 1b (290 mg, 1.22 mmol), methanol (62 μL, 1.53 mmol) and DMAP (122 mg, 1.00 mmol) in Et₂O. Flash chromatography gave inseparable MAC reaction products 4b/4b′ (dr 91 : 9, 217 mg, 80%), as a colorless oil. R_f 0.36 (pentane/Et₂O, 20 : 1). IR (ATR): ν 3028, 2946, 2864, 2804, 1755, 1738, 1604, 1495, 1455, 1256, 1122 cm⁻¹. HRMS (ES⁺): calcd for C₃₄H₄₈NO₃Si [M + H]⁺ 546.3398; found 546.3375. Spectroscopic data for the major anti (2S,3S)-diastereomer (4b): ¹H NMR (250 MHz, CDCl₃), δ 0.96–1.10 (m, 21H, Si(CH(CH₃)₂)₃), 2.99 (dd, J = 14.8, 9.5 Hz, 1H) and 3.08 (dd, J = 14.8, 5.0 Hz, 1H) (AB part of ABX syst., PhCH₂CH), 3.35–3.44 (m, 1H, CHN), 3.55 (s, 3H, OCH₃), 3.60 (d, J = 13.8 Hz, 2H) and 3.69 (d, J = 13.8 Hz, 2H) (AB syst., N(CH₂Ph)₂), 4.62 (d, J = 5.8 Hz, 1H, CHOTIPS), 7.04–7.10 (m, 4H, Ph), 7.14–7.29 (m, 11H, Ph). ¹³C NMR (62.9 MHz, CDCl₃), δ 12.7 (Si(CH(CH₃)₂)₃), 18.1 (Si(CH(CH₃)₂)₃), 32.8 (PhCH₂CH), 51.4 (OCH₃), 54.6 (N(CH₂Ph)₂), 63.8 (CHN), 73.2 (CHOTIPS), 125.9 (CH_Ph), 126.7 (CH_Ph), 127.9 (CH_Ph), 128.1 (CH_Ph), 128.9 (CH_Ph), 129.6 (CH_Ph), 139.5 (C_Ph), 140.8 (C_Ph), 173.4 (COOCH₃).

Methyl (2S,3S)-2-(tert-butyldiphenylsilyloxy)-3-(dibenzylamino)-4-phenylbutanoate (4c). According to the general procedure, the MAC reaction was performed with N,N-dibenzyl-L-phenylalaninal (146 mg, 0.44 mmol), H-MAC-TBDPS 1c (340 mg, 1.06 mmol), methanol (54 μL, 1.33 mmol) and DMAP (108 mg, 0.88 mmol) in Et₂O. The resulting reaction mixture was concentrated under reduced pressure to destroy excess of H-MAC-TBDPS and purified directly. Flash chromatography gave inseparable MAC reaction products 4c/4c′ (dr 93 : 7, 203 mg, 74%), as a colorless oil. R_f 0.20 (pentane/Et₂O, 20 : 1). IR (ATR): ν 3027, 2950, 2929, 2855, 2800, 1748, 1601, 1496, 1451, 1428, 1360, 1257, 1106 cm⁻¹. HRMS (ES⁺): calcd for C₄₁H₄₆NO₃Si [M + H]⁺ 628.3241; found 628.3210. Spectroscopic data for the major anti (2S,3S)-diastereomer (4c): ¹H NMR (360 MHz, CDCl₃), δ 1.09 (s, 9H, SiC(CH₃)₃), 2.98 (dd, J = 14.8, 9.7 Hz, 1H) and 3.14 (dd, J = 14.8, 4.0 Hz, 1H) (AB part of ABX syst., PhCH₂CH), 3.19 (s, 3H, OCH₃), 3.38–3.44 (m, 1H, CHN), 3.45 (d, J = 13.7 Hz, 2H) and 3.62 (d, J = 13.7 Hz, 2H) (AB syst., N(CH₂Ph)₂), 4.54 (d, J = 5.4 Hz, 1H, CHOTBDPS), 6.96–7.02 (m, 4H, Ph), 7.11–7.17 (m, 7H, Ph), 7.20–7.27 (m, 4H, Ph), 7.32–7.43 (m, 6H, Ph), 7.62–7.67 (m, 4H, Ph). ¹³C NMR (100.6 MHz, CDCl₃), δ 19.5 (SiC(CH₃)₃), 27.1 (SiC(CH₃)₃), 33.1 (PhCH₂CH), 51.1 (OCH₃), 54.4 (N(CH₂Ph)₂), 63.4 (CHN), 73.2 (CHOTBDPS), 125.9 (CH_Ph), 126.6 (CH_Ph), 127.4 (CH_Ph), 127.6 (CH_Ph), 127.8 (CH_Ph), 128.1 (CH_Ph), 128.8 (CH_Ph), 129.6 (CH_Ph), 129.7 (CH_Ph), 129.8 (CH_Ph), 132.9 (C_Ph), 133.0 (C_Ph), 136.0 (CH_Ph), 136.1 (CH_Ph), 139.4 (C_Ph), 140.6 (C_Ph), 172.5 (COOCH₃).

Methyl (2S,3S)-3-(dibenzylamino)-2-hydroxy-4-phenylbutanoate (5). From 4a /4a′: To a stirred solution of methyl (2SR,3S)-2-(tert-butyldimethylsilyloxy)-3-(dibenzylamino)-4-phenylbutanoate 4a/4a′ (dr 92 : 8; 161 mg, 0.32 mmol) in dry THF (10 mL) at 0 °C under argon, was added dropwise tetrabutylammonium fluoride (1 M in THF, 480 μL, 0.48 mmol). After stirring for 1 h at 0 °C, the reaction mixture was quenched by addition of a saturated aqueous NH₄Cl solution (10 mL) and extracted with EtOAc (3 × 10 mL). The combined organic phases were washed with brine (20 mL), dried over Na₂SO₄ and concentrated under reduced pressure. The crude product was purified by flash chromatography (pentane/EtOAc, 5 : 1) to furnish the anti alcohol 5 (100 mg, 80%), as a colorless oil. From4b/4b′: Following the above procedure using (2SR,3S)-3-(dibenzylamino)-2-(triisopropylsilyloxy)-4-phenylbutanoate 4b/4b′ (dr 91 : 9; 169 mg, 0.31 mmol), anti alcohol 5 (104 mg, 86%) was obtained after flash chromatography (pentane/EtOAc, 3 : 1). From4c/4c′: Following a minor modification of the above procedure (reaction performed at rt for 16 h) using methyl (2SR,3S)-2-(tert-butyldiphenylsilyloxy)-3-(dibenzylamino)-4-phenylbutanoate 4c/4c′ (dr 93 : 7; 200 mg, 0.32 mmol), anti alcohol 5 (88 mg, 71%) was obtained after flash chromatography (pentane/EtOAc, 5 : 1). R_f 0.20 (pentane/EtOAc, 5 : 1). [α]²²_D = +35.9 (c 1.0, CHCl₃) [lit.^14e [α]²⁰_D = + 35.8 (c 1.0, CHCl₃)]. IR (ATR): ν 3513, 3062, 3026, 2952, 2803, 1729, 1602, 1494, 1453, 1252, 1220, 1105 cm⁻¹. HRMS (ES⁺): calcd for C₂₅H₂₈NO₃ [M + H]⁺ 390.2064; found 390.2051. ¹H NMR (360 MHz, CDCl₃), δ 2.82 (dd, J = 14.0, 7.6 Hz, 1H) and 3.04 (dd, J = 14.0, 7.2 Hz, 1H) (AB part of ABX syst., PhCH₂CH), 3.14 (br s, 1H, CHOH), 3.43 (ddd, J = 7.6, 7.2, 1.8 Hz, 1H, CHN), 3.53 (s, 3H, OCH₃), 3.67 (d, J = 13.7 Hz, 2H) and 3.83 (d, J = 13.7 Hz, 2H) (AB syst., N(CH₂Ph)₂), 4.50 (br s, 1H, CHOH), 7.04–7.10 (m, 2H, Ph), 7.19–7.32 (m, 13H, Ph). ¹³C NMR (90.6 MHz, CDCl₃), δ 31.9 (PhCH₂CH), 52.3 (OCH₃), 54.5 (N(CH₂Ph)₂), 62.1 (CHN), 69.6 (CHOH), 126.1 (CH_Ph), 126.9 (CH_Ph), 128.0 (CH_Ph), 128.1 (CH_Ph), 128.8 (CH_Ph), 129.5 (CH_Ph), 139.0 (C_Ph), 139.5 (C_Ph), 174.9 (COOCH₃).

Ethyl (2S,3S)-2-(tert-butyldimethylsilyloxy)-3-(dibenzylamino)-4-phenylbutanoate (6). According to the general procedure, the MAC reaction was performed with N,N-dibenzyl-L-phenylalaninal (151 mg, 0.46 mmol), H-MAC-TBS 1a (215 mg, 1.10 mmol), ethanol (82 μL, 1.40 mmol) and DMAP (112 mg, 0.92 mmol) in Et₂O. Flash chromatography gave inseparable MAC reaction products 6/6′ (dr 91 : 9, 174 mg, 73%), as a viscous colorless oil. R_f 0.29 (pentane/Et₂O, 20 : 1). IR (ATR): ν 3027, 2956, 2929, 2854, 2796, 1747, 1730, 1601, 1494, 1454, 1365, 1254, 1130 cm⁻¹. HRMS (ES⁺): calcd for C₃₂H₄₄NO₃Si [M + H]⁺ 518.3085; found 518.3062. Spectroscopic data for the major anti (2S,3S)-diastereomer (6): ¹H NMR (360 MHz, CDCl₃), δ 0.09 (s, 3H, SiCH₃), 0.13 (s, 3H, SiCH₃), 0.96 (s, 9H, SiC(CH₃)₃), 1.10 (t, J = 7.0 Hz, 3H, OCH₂CH₃), 2.90 (dd, J = 14.4, 5.0 Hz, 1H) and 2.98 (dd, J = 14.4, 8.8 Hz, 1H) (AB part of ABX syst., PhCH₂CH), 3.34–3.41 (m, 1H, CHN), 3.57 (d, J = 13.7 Hz, 2H) and 3.83 (d, J = 13.7 Hz, 2H) (AB syst., N(CH₂Ph)₂), 3.87–4.05 (m, 2H, OCH₂CH₃), 4.62 (d, J = 3.6 Hz, 1H, CHOTBS), 7.02–7.07 (m, 2H, Ph), 7.08–7.13 (m, 4H, Ph), 7.15–7.23 (m, 9H, Ph). ¹³C NMR (90.6 MHz, CDCl₃), δ −4.7 (SiCH₃), −4.6 (SiCH₃), 14.0 (OCH₂CH₃), 18.2 (SiC(CH₃)₃), 25.8 (SiC(CH₃)₃), 32.6 (PhCH₂CH), 54.4 (N(CH₂Ph)₂), 60.6 (OCH₂CH₃), 62.7 (CHN), 71.4 (CHOTBS), 125.7 (CH_Ph), 126.7 (CH_Ph), 127.9 (CH_Ph), 128.8 (CH_Ph), 129.6 (CH_Ph), 139.6 (C_Ph), 140.2 (C_Ph), 173.1 (COOEt).

Benzyl (2S,3S)-2-(tert-butyldimethylsilyloxy)-3-(dibenzylamino)-4-phenylbutanoate (7). According to the general procedure, the MAC reaction was performed with N,N-dibenzyl-L-phenylalaninal (147 mg, 0.45 mmol), H-MAC-TBS 1a (212 mg, 1.08 mmol), benzyl alcohol (140 μL, 1.35 mmol) and DMAP (110 mg, 0.90 mmol) in Et₂O. Flash chromatography gave inseparable MAC reaction products 7/7′ (dr 92 : 8, 215 mg, 83%), as a colorless oil. R_f 0.34 (pentane/Et₂O, 20 : 1). IR (ATR): ν 3031, 2956, 2929, 2858, 2801, 1752, 1730, 1601, 1494, 1454, 1363, 1253, 1123 cm⁻¹. HRMS (ES⁺): calcd for C₃₇H₄₆NO₃Si [M + H]⁺ 580.3241; found 580.3217. Spectroscopic data for the major anti (2S,3S)-diastereomer (7): ¹H NMR (360 MHz, CDCl₃), δ 0.05 (s, 3H, SiCH₃), 0.13 (s, 3H, SiCH₃), 0.95 (s, 9H, SiC(CH₃)₃), 2.80 (dd, J = 14.4, 4.3 Hz, 1H) and 2.95 (dd, J = 14.4, 9.7 Hz, 1H) (AB part of ABX syst., PhCH₂CH), 3.31–3.38 (m, 1H, CHN), 3.55 (d, J = 14.6 Hz, 2H) and 3.87 (d, J = 14.6 Hz, 2H) (AB syst., N(CH₂Ph)₂), 4.71 (d, J = 2.9 Hz, 1H, CHOTBS), 4.85 (d, J = 12.2 Hz, 1H) and 5.03 (d, J = 12.2 Hz, 1H) (AB syst., OCH₂Ph), 6.82–6.91 (m, 2H, Ph), 7.03–7.11 (m, 6H, Ph), 7.12–7.19 (m, 9H, Ph), 7.27–7.31 (m, 3H, Ph). ¹³C NMR (90.6 MHz, CDCl₃), δ −4.7 (SiCH₃), −4.6 (SiCH₃), 18.2 (SiC(CH₃)₃), 25.8 (SiC(CH₃)₃), 32.4 (PhCH₂CH), 54.4 (N(CH₂Ph)₂), 62.6 (CHN), 66.3 (OCH₂Ph), 70.9 (CHOTBS), 125.7 (CH_Ph), 126.6 (CH_Ph), 127.8 (CH_Ph), 128.0 (CH_Ph), 128.1 (CH_Ph), 128.4 (CH_Ph), 128.6 (CH_Ph), 129.7 (CH_Ph), 135.4 (C_Ph), 139.6 (C_Ph), 140.1 (C_Ph), 172.9 (COOBn).

Allyl (2S,3S)-2-(tert-butyldimethylsilyloxy)-3-(dibenzylamino)-4-phenylbutanoate (8). According to the general procedure, the MAC reaction was performed with N,N-dibenzyl-L-phenylalaninal (143 mg, 0.43 mmol), H-MAC-TBS 1a (203 mg, 1.03 mmol), allyl alcohol (88 μL, 1.29 mmol) and DMAP (105 mg, 0.86 mmol) in Et₂O. Flash chromatography gave inseparable MAC reaction products 8/8′ (dr 91 : 9, 188 mg, 82%), as a colorless oil. R_f 0.35 (pentane/Et₂O, 20 : 1). IR (ATR): ν 3027, 2956, 2929, 2858, 2800, 1751, 1730, 1602, 1494 1453, 1362, 1252, 1126 cm⁻¹. HRMS (ES⁺): calcd for C₃₃H₄₄NO₃Si [M + H]⁺ 530.3085; found 530.3060. Spectroscopic data for the major anti (2S,3S)-diastereomer (8): ¹H NMR (360 MHz, CDCl₃), δ 0.08 (s, 3H, SiCH₃), 0.13 (s, 3H, SiCH₃), 0.96 (s, 9H, SiC(CH₃)₃), 2.91 (dd, J = 14.4, 5.0 Hz, 1H) and 2.99 (dd, J = 14.4, 9.0 Hz, 1H) (AB part of ABX syst., PhCH₂CH), 3.37–3.45 (m, 1H, CHN), 3.58 (d, J = 14.0 Hz, 2H) and 3.83 (d, J = 14.0 Hz, 2H) (AB syst., N(CH₂Ph)₂), 4.35 (ddt, J = 13.0, 5.8, 1.1 Hz, 1H) and 4.43 (ddt, J = 13.0, 6.1, 1.1 Hz, 1H) (AB part of ABXM syst., OCH₂CH=CH₂), 4.66 (d, J = 3.6 Hz, 1H, CHOTBS), 5.11–5.21 (m, 2H, OCH₂CH=CH₂), 5.74 (dddd, J = 16.9, 10.4, 6.1, 5.8 Hz, 1H, OCH₂CH=CH₂), 7.01–7.08 (m, 2H, Ph), 7.08–7.13 (m, 4H, Ph), 7.15–7.23 (m, 9H, Ph). ¹³C NMR (90.6 MHz, CDCl₃), δ −4.7 (SiCH₃), −4.6 (SiCH₃), 18.2 (SiC(CH₃)₃), 25.9 (SiC(CH₃)₃), 32.5 (PhCH₂CH), 54.5 (N(CH₂Ph)₂), 62.7 (CHN), 65.3 (OCH₂CH=CH₂), 71.4 (CHOTBS), 118.6 (OCH₂CH=CH₂), 125.8 (CH_Ph), 126.7 (CH_Ph), 127.9 (CH_Ph), 128.0 (CH_Ph), 128.7 (CH_Ph), 129.7 (CH_Ph), 131.7 (OCH₂CH=CH₂), 139.5 (C_Ph), 140.1 (C_Ph), 172.7 (COOAll).

Propargyl (2S,3S)-2-(tert-butyldimethylsilyloxy)-3-(dibenzylamino)-4-phenylbutanoate (9). According to the general procedure, the MAC reaction was performed with N,N-dibenzyl-L-phenylalaninal (143 mg, 0.43 mmol), H-MAC-TBS 1a (202 mg, 1.03 mmol), propargyl alcohol (80 μL, 1.29 mmol) and DMAP (105 mg, 0.86 mmol) in Et₂O. Flash chromatography gave inseparable MAC reaction products 9/9′ (dr 93 : 7, 217 mg, 95%), as a colorless oil. R_f 0.15 (pentane/Et₂O, 20 : 1). IR (ATR): ν 3311, 3027, 2951, 2929, 2856, 2802, 2134, 1757, 1740, 1602, 1493, 1452, 1363, 1250, 1124 cm⁻¹. HRMS (ES⁺): calcd for C₃₃H₄₂NO₃Si [M + H]⁺ 528.2928; found 528.2906. Spectroscopic data for the major anti (2S,3S)-diastereomer (9): ¹H NMR (300 MHz, CDCl₃), δ 0.09 (s, 3H, SiCH₃), 0.13 (s, 3H, SiCH₃), 0.95 (s, 9H, SiC(CH₃)₃), 2.42 (t, J = 2.7 Hz, 1H, OCH₂C≡CH), 2.89–3.03 (m, 2H, PhCH₂CH), 3.36–3.45 (m, 1H, CHN), 3.58 (d, J = 14.0 Hz, 2H) and 3.79 (d, J = 14.0 Hz, 2H) (AB syst., N(CH₂Ph)₂), 4.40 (dd, J = 15.6, 2.7 Hz, 1H) and 4.56 (dd, J = 15.6, 2.7 Hz, 1H) (AB syst., OCH₂C≡CH), 4.63 (d, J = 3.9 Hz, 1H, CHOTBS), 7.05–7.13 (m, 6H, Ph), 7.16–7.25 (m, 9H, Ph). ¹³C NMR (90.6 MHz, CDCl₃), δ −4.8 (SiCH₃), −4.7 (SiCH₃), 18.1 (SiC(CH₃)₃), 25.8 (SiC(CH₃)₃), 32.6 (PhCH₂CH), 51.9 (OCH₂C≡CH), 54.4 (N(CH₂Ph)₂), 62.6 (CHN), 71.5 (CHOTBS), 75.0 (OCH₂C≡CH), 77.3 (OCH₂C≡CH), 125.8 (CH_Ph), 126.7 (CH_Ph), 128.0 (CH_Ph), 128.8 (CH_Ph), 129.6 (CH_Ph), 139.4 (C_Ph), 140.1 (C_Ph), 172.2 (COOCH₂C≡CH).

2-Phenylethyl (2S,3S)-2-(tert-butyldimethylsilyloxy)-3-(dibenzylamino)-4-phenylbutanoate (10). According to the general procedure, the MAC reaction was performed with N,N-dibenzyl-L-phenylalaninal (145 mg, 0.44 mmol), H-MAC-TBS 1a (208 mg, 1.06 mmol), 2-phényléthanol (160 μL, 1.33 mmol) and DMAP (108 mg, 0.88 mmol) in Et₂O. Flash chromatography gave inseparable MAC reaction products 10/10′ (dr 95 : 5, 210 mg, 80%), as a colorless oil. R_f 0.05 (pentane/Et₂O, 20 : 1). IR (ATR): ν 3027, 2953, 2929, 2857, 2801, 1751, 1729, 1601, 1495, 1453, 1361, 1254, 1130 cm⁻¹. HRMS (ES⁺): calcd for C₃₈H₄₈NO₃Si [M + H]⁺ 594.3398; found 594.3372. Spectroscopic data for the major anti (2S,3S)-diastereomer (10): ¹H NMR (300 MHz, CDCl₃), δ 0.05 (s, 3H, SiCH₃), 0.11 (s, 3H, SiCH₃), 0.95 (s, 9H, SiC(CH₃)₃), 2.75 (t, J = 7.2 Hz, 2H, OCH₂CH₂Ph), 2.84 (dd, J = 14.4, 4.8 Hz, 1H) and 2.98 (dd, J = 14.4, 9.0 Hz, 1H) (AB part of ABX syst., PhCH₂CH), 3.32–3.43 (m, 1H, CHN), 3.57 (d, J = 14.2 Hz, 2H) and 3.83 (d, J = 14.2 Hz, 2H) (AB syst., N(CH₂Ph)₂), 4.12 (t, J = 7.2 Hz, 2H, OCH₂CH₂Ph), 4.63 (d, J = 3.3 Hz, 1H, CHOTBS), 6.97–7.04 (m, 2H, Ph), 7.06–7.13 (m, 6H, Ph), 7.16–7.35 (m, 12H, Ph). ¹³C NMR (90.6 MHz, CDCl₃), δ −4.8 (SiCH₃), −4.6 (SiCH₃), 18.2 (SiC(CH₃)₃), 25.9 (SiC(CH₃)₃), 32.5 (PhCH₂CH), 34.8 (OCH₂CH₂Ph), 54.4 (N(CH₂Ph)₂), 62.5 (CHN), 65.1 (OCH₂CH₂Ph), 71.3 (CHOTBS), 125.7 (CH_Ph), 126.5 (CH_Ph), 126.7 (CH_Ph), 127.9 (CH_Ph), 128.0 (CH_Ph), 128.4 (CH_Ph), 128.6 (CH_Ph), 128.7 (CH_Ph), 129.7 (CH_Ph), 137.4 (C_Ph), 139.6 (C_Ph), 140.0 (C_Ph), 173.0 (COOCH₂CH₂Ph).

3-Methylbutyl (2S,3S)-2-(tert-butyldimethylsilyloxy)-3-(dibenzylamino)-4-phenylbutanoate (11). According to the general procedure, the MAC reaction was performed with N,N-dibenzyl-L-phenylalaninal (141 mg, 0.43 mmol), H-MAC-TBS 1a (202 mg, 1.03 mmol), isoamyl alcohol (140 μL, 1.29 mmol) and DMAP (105 mg, 0.86 mmol) in Et₂O. Flash chromatography gave inseparable MAC reaction products 11/11′ (dr 91 : 9, 154 mg, 64%), as a colorless oil. R_f 0.44 (pentane/Et₂O, 20 : 1). IR (ATR): ν 3031, 2956, 2928, 2857, 2801, 1750, 1726, 1603, 1494, 1455, 1362, 1253, 1126 cm⁻¹. HRMS (ES⁺): calcd for C₃₅H₅₀NO₃Si [M + H]⁺ 560.3554; found 560.3531. Spectroscopic data for the major anti (2S,3S)-diastereomer (11): ¹H NMR (400 MHz, CDCl₃), δ 0.10 (s, 3H, SiCH₃), 0.14 (s, 3H, SiCH₃), 0.83 (d, J = 6.8 Hz, 6H, OCH₂CH₂CH(CH₃)₂), 0.97 (s, 9H, SiC(CH₃)₃), 1.34 (q, J = 6.8 Hz, 2H, OCH₂CH₂CH(CH₃)₂), 1.44–1.52 (m, 1H, OCH₂CH₂CH(CH₃)₂), 2.88 (dd, J = 14.8, 4.8 Hz, 1H) and 3.00 (dd, J = 14.8, 9.2 Hz, 1H) (AB part of ABX syst., PhCH₂CH), 3.34–3.41 (m, 1H, CHN), 3.57 (d, J = 13.6 Hz, 2H) and 3.87 (d, J = 13.6 Hz, 2H) (AB syst., N(CH₂Ph)₂), 3.90–4.02 (m, 2H, OCH₂CH₂CH(CH₃)₂), 4.66 (d, J = 2.8 Hz, 1H, CHOTBS), 7.01–7.05 (m, 2H, Ph), 7.06–7.11 (m, 4H, Ph), 7.14–7.23 (m, 9H, Ph). ¹³C NMR (100.6 MHz, CDCl₃), δ −4.6 (SiCH₃), −4.5 (SiCH₃), 18.2 (SiC(CH₃)₃), 22.3 (OCH₂CH₂CHCH₃), 22.4 (OCH₂CH₂CHCH₃), 24.7 (OCH₂CH₂CH(CH₃)₂), 25.9 (SiC(CH₃)₃), 32.5 (PhCH₂CH), 37.1 (OCH₂CH₂CH(CH₃)₂), 54.4 (N(CH₂Ph)₂), 62.6 (CHN), 63.2 (OCH₂CH₂CH(CH₃)₂), 71.1 (CHOTBS), 125.8 (CH_Ph), 126.7 (CH_Ph), 127.9 (CH_Ph), 128.0 (CH_Ph), 128.7 (CH_Ph), 129.7 (CH_Ph), 139.6 (C_Ph), 140.1 (C_Ph), 173.2 (COOCH₂).

Isobutyl (2S,3S)-2-(tert-butyldimethylsilyloxy)-3-(dibenzylamino)-4-phenylbutanoate (12). According to the general procedure, the MAC reaction was performed with N,N-dibenzyl-L-phenylalaninal (138 mg, 0.42 mmol), H-MAC-TBS 1a (196 mg, 1.00 mmol), isobutanol (118 μL, 1.27 mmol) and DMAP (103 mg, 0.84 mmol) in Et₂O. Flash chromatography gave inseparable MAC reaction products 12/12′ (dr 91 : 9, 105 mg, 46%), as a colorless oil. R_f 0.39 (pentane/Et₂O, 20 : 1). IR (ATR): ν 3026, 2957, 2931, 2857, 2800, 1750, 1730, 1603, 1495, 1453, 1363, 1251, 1129 cm⁻¹. HRMS (ES⁺): calcd for C₃₄H₄₈NO₃Si [M + H]⁺ 546.3398; found 546.3375. Spectroscopic data for the major anti (2S,3S)-diastereomer (12): ¹H NMR (250 MHz, CDCl₃), δ 0.10 (s, 3H, SiCH₃), 0.15 (s, 3H, SiCH₃), 0.76 (d, J = 6.7 Hz, 3H, OCH₂CHCH₃), 0.79 (d, J = 6.7 Hz, 3H, OCH₂CHCH₃), 0.98 (s, 9H, SiC(CH₃)₃), 1.73 (nonuplet, J = 6.7 Hz, 1H, OCH₂CH(CH₃)₂), 2.87 (dd, J = 14.5, 5.0 Hz, 1H) and 3.01 (dd, J = 14.5, 9.0 Hz, 1H) (AB part of ABX syst., PhCH₂CH), 3.34–3.44 (m, 1H, CHN), 3.57 (d, J = 14.0 Hz, 2H) and 3.89 (d, J = 14.0 Hz, 2H) (AB syst., N(CH₂Ph)₂), 3.65 (dd, J = 10.5, 6.7 Hz, 1H) and 3.70 (dd, J = 10.5, 6.7 Hz, 1H) (AB part of ABX syst., OCH₂CH(CH₃)₂), 4.70 (d, J = 2.8 Hz, 1H, CHOTBS), 6.97–7.06 (m, 2H, Ph), 7.06–7.12 (m, 4H, Ph), 7.14–7.24 (m, 9H, Ph). ¹³C NMR (90.6 MHz, CDCl₃), δ −4.6 (SiCH₃), −4.5 (SiCH₃), 18.2 (SiC(CH₃)₃), 19.1 (OCH₂CH(CH₃)₂), 25.9 (SiC(CH₃)₃), 27.5 (OCH₂CH(CH₃)₂), 32.4 (PhCH₂CH), 54.4 (N(CH₂Ph)₂), 62.5 (CHN), 70.9 (OCH₂CH(CH₃)₂), 71.0 (CHOTBS), 125.8 (CH_Ph), 126.7 (CH_Ph), 127.9 (CH_Ph), 128.0 (CH_Ph), 128.6 (CH_Ph), 129.7 (CH_Ph), 139.6 (C_Ph), 140.0 (C_Ph), 173.2 (COOi-Bu).

(S)-2-Methylbutyl (2S,3S)-2-(tert-butyldimethylsilyloxy)-3-(dibenzylamino)-4-phenylbutanoate (13). According to the general procedure, the MAC reaction was performed with N,N-dibenzyl-L-phenylalaninal (131 mg, 0.40 mmol), H-MAC-TBS 1a (188 mg, 0.96 mmol), (S)-2-methylbutan-1-ol (135 μL, 1.20 mmol) and DMAP (98 mg, 0.80 mmol) in Et₂O. Flash chromatography gave inseparable MAC reaction products 13/13′ (dr 90 : 10, 107 mg, 48%), as a colorless oil. R_f 0.27 (pentane/Et₂O, 20 : 1). IR (ATR): ν 3027, 2957, 2929, 2858, 2800, 1747, 1726, 1603, 1496, 1453, 1361, 1254, 1128 cm⁻¹. HRMS (ES⁺): calcd for C₃₅H₅₀NO₃Si [M + H]⁺ 560.3554; found 560.3534. Spectroscopic data for the major anti (2S,3S)-diastereomer (13): ¹H NMR (400 MHz, CDCl₃), δ 0.10 (s, 3H, SiCH₃), 0.14 (s, 3H, SiCH₃), 0.74 (d, J = 6.8 Hz, 3H, OCH₂CH(CH₃)CH₂CH₃), 0.81 (t, J = 7.4 Hz, 3H, OCH₂CH(CH₃)CH₂CH₃), 0.97 (s, 9H, SiC(CH₃)₃), 1.18–1.28 (m, 2H, OCH₂CH(CH₃)CH₂CH₃), 1.46–1.56 (m, 1H, OCH₂CH(CH₃)CH₂CH₃), 2.86 (dd, J = 14.6, 4.8 Hz, 1H) and 3.01 (dd, J = 14.6, 9.6 Hz, 1H) (AB part of ABX syst., PhCH₂CH), 3.35–3.42 (m, 1H, CHN), 3.57 (d, J = 14.0 Hz, 2H) and 3.90 (d, J = 14.0 Hz, 2H) (AB syst., N(CH₂Ph)₂), 3.69 (dd, J = 10.6, 6.6 Hz, 1H) and 3.78 (dd, J = 10.6, 6.2 Hz, 1H) (AB part of ABX syst., OCH₂CH(CH₃)CH₂CH₃), 4.69 (d, J = 2.4 Hz, 1H, CHOTBS), 7.00–7.04 (m, 2H, Ph), 7.06–7.11 (m, 4H, Ph), 7.13–7.24 (m, 9H, Ph). ¹³C NMR (100.6 MHz, CDCl₃), δ −4.6 (SiCH₃), −4.5 (SiCH₃), 11.1 (OCH₂CH(CH₃)CH₂CH₃), 16.2 (OCH₂CH(CH₃)CH₂CH₃), 18.2 (SiC(CH₃)₃), 25.8 (OCH₂CH(CH₃)CH₂CH₃), 25.9 (SiC(CH₃)₃), 32.4 (PhCH₂CH), 33.9 (OCH₂CH(CH₃)CH₂CH₃), 54.4 (N(CH₂Ph)₂), 62.5 (CHN), 69.4 (OCH₂CH(CH₃)CH₂CH₃), 70.9 (CHOTBS), 125.8 (CH_Ph), 126.7 (CH_Ph), 127.9 (CH_Ph), 128.0 (CH_Ph), 128.6 (CH_Ph), 129.7 (CH_Ph), 139.6 (C_Ph), 140.0 (C_Ph), 173.3 (COOCH₂).

Isopropyl (2S,3S)-2-(tert-butyldimethylsilyloxy)-3-(dibenzylamino)-4-phenylbutanoate (14). According to the general procedure, the MAC reaction was performed with N,N-dibenzyl-L-phenylalaninal (121 mg, 0.37 mmol), H-MAC-TBS 1a (175 mg, 0.89 mmol), isopropanol (85 μL, 1.11 mmol) and DMAP (90 mg, 0.74 mmol) in Et₂O (4 mL). Flash chromatography gave inseparable MAC reaction products 14/14′ (dr 93 : 7, 21 mg, 11%), as a colorless oil. R_f 0.40 (pentane/Et₂O, 20 : 1). IR (ATR): ν 3028, 2952, 2930, 2855, 2800, 1749, 1721, 1604, 1495, 1454, 1373, 1258, 1141, 1105 cm⁻¹. HRMS (ES⁺): calcd for C₃₃H₄₆NO₃Si [M + H]⁺ 532.3241; found 532.3217. Spectroscopic data for the major anti (2S,3S)-diastereomer (14): ¹H NMR (360 MHz, CDCl₃), δ 0.12 (s, 3H, SiCH₃), 0.16 (s, 3H, SiCH₃), 0.99 (s, 9H, SiC(CH₃)₃), 1.03 (d, J = 6.3 Hz, 3H, OCHCH₃), 1.18 (d, J = 6.3 Hz, 3H, OCHCH₃), 2.82 (dd, J = 14.8, 4.7 Hz, 1H) and 2.98 (dd, J = 14.8, 9.7 Hz, 1H) (AB part of ABX syst., PhCH₂CH), 3.32 (ddd, J = 6.8, 4.7, 2.5 Hz, 1H, CHN), 3.52 (d, J = 14.0 Hz, 2H) and 3.93 (d, J = 14.0 Hz, 2H) (AB syst., N(CH₂Ph)₂), 4.68 (d, J = 2.5 Hz, 1H, CHOTBS), 4.86 (septuplet, J = 6.3 Hz, 1H, OCH(CH₃)₂), 6.94–7.02 (m, 2H, Ph), 7.05–7.12 (m, 4H, Ph), 7.15–7.23 (m, 9H, Ph). ¹³C NMR (90.6 MHz, CDCl₃), δ −4.6 (SiCH₃), −4.4 (SiCH₃), 18.2 (SiC(CH₃)₃), 21.5 (OCHCH₃), 21.8 (OCHCH₃), 25.9 (SiC(CH₃)₃), 32.4 (PhCH₂CH), 54.3 (N(CH₂Ph)₂), 62.4 (CHN), 68.2 (OCH(CH₃)₂), 70.4 (CHOTBS), 125.7 (CH_Ph), 126.7 (CH_Ph), 127.8 (CH_Ph), 127.9 (CH_Ph), 128.7 (CH_Ph), 129.7 (CH_Ph), 139.6 (C_Ph), 140.1 (C_Ph), 172.9 (COOi-Pr).

Cyclopentyl (2S,3S)-2-(tert-butyldimethylsilyloxy)-3-(dibenzylamino)-4-phenylbutanoate (15). A minor adaptation of the general procedure was used. To freshly prepared N,N-dibenzyl-L-phenylalaninal (161 mg, 0.49 mmol) and H-MAC-TBS 1a (231 mg, 1.18 mmol) under argon, was added dry Et₂O (5 mL). After cooling at 0 °C, DMAP (120 mg, 0.98 mmol) was introduced and the reaction mixture was stirred for 10 min at 0 °C then cyclopentanol (95 μL, 1.47 mmol) was added. The reaction mixture was stirred overnight under argon at 0 °C. A saturated aqueous Na₂CO₃ solution (10 mL) was introduced at 0 °C. After addition of water (10 mL) to dissolve the salts, the aqueous phase was extracted with Et₂O (6 × 10 mL). Followed by the addition of water (10 mL) to dissolve the salts. The combined organic phases were washed with 1 M HCl (50 mL), brine (50 mL), dried over Na₂SO₄ and concentrated under reduced pressure. Flash chromatography (pentane/Et₂O, 30 : 1) gave inseparable MAC reaction products 15/15′ (dr 90 : 10, 38 mg, 14%), as a viscous colorless oil. R_f 0.43 (pentane/Et₂O, 10 : 1). IR (ATR): ν 3025, 2956, 2929, 2860, 2800, 1758, 1728, 1604, 1494, 1462, 1379, 1268, 1121 cm⁻¹. HRMS (ES⁺): calcd for C₃₅H₄₈NO₃Si [M + H]⁺ 558.3398; found 558.3371. Spectroscopic data for the major anti (2S,3S)-diastereomer (15): ¹H NMR (300 MHz, CDCl₃), δ 0.13 (s, 3H, SiCH₃), 0.16 (s, 3H, SiCH₃), 1.00 (s, 9H, SiC(CH₃)₃), 1.39–1.53 (m, 4H, OCH(CH₂CH₂)₂), 1.56–1.71 (m, 4H, OCH(CH₂CH₂)₂), 2.84 (dd, J = 14.7, 4.8 Hz, 1H) and 3.00 (dd, J = 14.7, 9.3 Hz, 1H) (AB part of ABX syst., PhCH₂CH), 3.35 (ddd, J = 9.3, 4.8, 2.4 Hz, 1H, CHN), 3.55 (d, J = 14.0 Hz, 2H) and 3.93 (d, J = 14.0 Hz, 2H) (AB syst., N(CH₂Ph)₂), 4.68 (d, J = 2.4 Hz, 1H, CHOTBS), 4.96–5.03 (m, 1H, OCH(CH₂CH₂)₂), 6.95–7.03 (m, 2H, Ph), 7.07–7.13 (m, 4H, Ph), 7.15–7.25 (m, 9H, Ph). ¹³C NMR (90.6 MHz, CDCl₃), δ −4.6 (SiCH₃), −4.4 (SiCH₃), 18.2 (SiC(CH₃)₃), 23.5 (OCHCH₂CH₂), 23.6 (OCHCH₂CH₂), 25.9 (SiC(CH₃)₃), 32.3 (PhCH₂CH), 32.5 (OCH(CH₂CH₂)₂), 54.4 (N(CH₂Ph)₂), 62.4 (CHN), 70.6 (CHOTBS), 77.6 (OCH(CH₂CH₂)₂), 125.7 (CH_Ph), 126.7 (CH_Ph), 127.9 (CH_Ph), 128.0 (CH_Ph), 128.6 (CH_Ph), 129.7 (CH_Ph), 139.7 (C_Ph), 140.0 (C_Ph), 173.1 (COOCH).

Methyl (2S,3S)-3-amino-2-hydroxy-4-phenylbutanoate (16). Palladium hydroxide (20 wt%) on activated carbon (7.2 mg) was added to a solution of methyl (2S,3S)-3-(dibenzylamino)-2-hydroxy-4-phenylbutanoate 5 (55 mg, 0.14 mmol) in MeOH (10 mL). The resulting mixture was stirred under H₂ (1 atm) for 1 h at room temperature and then filtered through a pad of Celite which was washed through with MeOH. The combined filtrate and washings were concentrated under reduced pressure. The residual pale yellow oil was taken up in Et₂O, filtered through a PVDF membrane (0.22 μm pore size) and the filtrate was evaporated under reduced pressure to furnish (2S,3S)-allophenylnorstatin methyl ester 16 (26 mg, 88%), as a colorless oil. R_f 0.50 (MeOH). [α]²²_D = +24.1 (c 1.0, CH₃OH). IR (ATR): ν 3474, 3357, 3297, 3028, 2953, 2922, 2853, 1732, 1601, 1583, 1496, 1452, 1438, 1207 cm⁻¹. HRMS (ES⁺): calcd for C₁₁H₁₆NO₃ [M + H]⁺ 210.1125; found 210.1119. ¹H NMR (360 MHz, CD₃OD), δ 2.63 (dd, J = 13.7, 8.6 Hz, 1H) and 2.86 (dd, J = 13.7, 6.0 Hz, 1H) (AB part of ABX syst., PhCH₂CH), 3.27–3.36 (m, 1H, CHN), 3.67 (s, 3H, OCH₃), 4.14 (d, J = 4.0 Hz, 1H, CHOH), 7.18–7.25 (m, 3H, Ph), 7.26–7.33 (m, 2H, Ph). ¹³C NMR (90.6 MHz, CD₃OD), δ 39.5 (PhCH₂CH), 52.4 (OCH₃), 57.0 (CHN), 74.8 (CHOH), 127.5 (CH_Ph), 129.5 (CH_Ph), 130.5 (CH_Ph), 139.8 (C_Ph), 174.6 (COOMe).

Ethyl (2S,3S)-3-(dibenzylamino)-2-hydroxy-4-phenylbutanoate (17). Tetrabutylammonium fluoride (1 M in THF, 930 μL, 0.93 mmol) was added dropwise to a stirred solution of ethyl (2SR,3S)-2-(tert-butyldimethylsilyloxy)-3-(dibenzylamino)-4-phenyl-butanoate 6a/6a′ (dr 92 : 8; 322 mg, 0.62 mmol) in dry THF (15 mL) at 0 °C. After stirring for 2 h at 0 °C, the reaction mixture was quenched by addition of a saturated aqueous NH₄Cl solution (5 mL) and extracted with EtOAc (3 × 10 mL). The combined organic phases were washed with brine (20 mL), dried over Na₂SO₄ and concentrated under reduced pressure. The crude product was purified by flash chromatography (pentane/CH₂Cl₂/Et₂O, 10 : 1 : 1 then pentane/EtOAc, 5 : 1) to furnish the anti alcohol 17 (229 mg, 91%), as a colorless oil. R_f 0.34 (pentane/EtOAc, 5 : 1). [α]¹⁹_D = +70.4 (c 1.0, CHCl₃). IR (ATR): ν 3499, 3062, 3025, 2974, 2804, 1724, 1603, 1495, 1452, 1368, 1249, 1215, 1105 cm⁻¹. HRMS (ES⁺): calcd for C₂₆H₃₀NO₃ [M + H]⁺ 404.2220; found 404.2204. ¹H NMR (360 MHz, CDCl₃), δ 1.11 (t, J = 7.2 Hz, 3H, OCH₂CH₃), 2.78 (dd, J = 14.0, 7.2 Hz, 1H) and 3.00 (dd, J = 14.0, 7.2 Hz, 1H) (AB part of ABX syst., PhCH₂CH), 3.12 (d, J = 6.1 Hz, 1H, CHOH), 3.44 (ddd, J = 7.2, 7.2, 2.1 Hz, 1H, CHN), 3.64 (d, J = 14.0 Hz, 2H) and 3.86 (d, J = 14.0 Hz, 2H) (AB syst., N(CH₂Ph)₂), 3.89–4.05 (m, 2H, OCH₂CH₃), 4.52 (dd, J = 6.1, 2.1 Hz, 1H, CHOH), 7.00–7.05 (m, 2H, Ph), 7.19–7.28 (m, 13H, Ph). ¹³C NMR (90.6 MHz, CDCl₃), δ 13.8 (OCH₂CH₃), 31.9 (PhCH₂CH), 54.5 (N(CH₂Ph)₂), 61.6 (OCH₂CH₃), 61.9 (CHN), 69.4 (CHOH), 126.0 (CH_Ph), 126.8 (CH_Ph), 128.0 (CH_Ph), 128.1 (CH_Ph), 128.8 (CH_Ph), 129.5 (CH_Ph), 139.0 (C_Ph), 139.6 (C_Ph), 174.6 (COOEt).

Ethyl (2S,3S)-3-amino-2-hydroxy-4-phenylbutanoate (18). Palladium hydroxide (20 wt%) on activated carbon (4 mg) was added to a solution of ethyl (2S,3S)-3-(dibenzylamino)-2-hydroxy-4-phenylbutanoate 17 (37 mg, 0.09 mmol) in EtOH (10 mL). The resulting mixture was stirred under H₂ (1 atm) for 2 h at room temperature and then filtered through a pad of Celite which was washed with EtOH. The combined filtrate and washings were concentrated under reduced pressure. The residual pale yellow oil was taken up in Et₂O, filtered through a PVDF membrane (0.22 μm pore size) and the filtrate was evaporated under reduced pressure to furnish (2S,3S)-allophenylnorstatin ethyl ester 18 (15 mg, 73%), as a colorless oil. R_f 0.57 (MeOH). [α]²⁴_D = +20.0 (c 1.0, CH₃OH). IR (ATR): ν 3478, 3362, 3287, 3064, 2924, 2859, 1731, 1602, 1496, 1454, 1368, 1202 cm⁻¹. HRMS (ES⁺): calcd for C₁₂H₁₈NO₃ [M + H]⁺ 224.1281; found 224.1274. ¹H NMR (400 MHz, DMSO-d₆), δ 1.21 (t, J = 7.2 Hz, 3H, OCH₂CH₃), 1.36 (br s, 2H, NH₂), 2.46 (dd, J = 13.2, 8.8 Hz, 1H) and 2.76 (dd, J = 13.2, 4.2 Hz, 1H) (AB part of ABX syst., PhCH₂CH), 3.01–3.10 (m, 1H, CHN), 3.85 (br d, J = 4.8 Hz, 1H, CHOH), 4.02–4.12 (m, 2H, OCH₂CH₃), 5.52 (br s, 1H, CHOH), 7.15–7.23 (m, 3H, Ph), 7.24–7.31 (m, 2H, Ph). ¹³C NMR (100 MHz, DMSO-d₆), δ 14.1 (OCH₂CH₃), 38.8 (PhCH₂CH), 56.0 (CHN), 59.8 (OCH₂CH₃), 74.5 (CHOH), 125.8 (CH_Ph), 128.0 (CH_Ph), 129.3 (CH_Ph), 139.5 (C_Ph), 172.7 (COOEt).

Benzyl (2S,3S)-3-(dibenzylamino)-2-hydroxy-4-phenylbutanoate (19). To a stirred solution of benzyl (2SR,3S)-2-(tert-butyldimethylsilyloxy)-3-(dibenzylamino)-4-phenylbutanoate 7/7′ (dr 92 : 8; 173 mg, 0.30 mmol) in dry THF (4 mL) at 0 °C under argon, was added dropwise tetrabutylammonium fluoride (1 M in THF, 450 μL, 0.45 mmol). After stirring for 50 minutes at 0 °C, the reaction mixture was quenched by addition of a saturated aqueous NH₄Cl solution (10 mL) and extracted with EtOAc (3 × 10 mL). The combined organic phases were washed with brine (20 mL), dried over Na₂SO₄ and concentrated under reduced pressure. The crude product was purified by flash chromatography (pentane/EtOAc, 10 : 1) to furnish the anti alcohol 19 (117 mg, 84%), as a colorless oil. R_f 0.32 (pentane/EtOAc, 5 : 1). [α]²²_D = +28.7 (c 1.0, CHCl₃). IR (ATR): ν 3514, 3066, 3028, 2926, 2804, 1730, 1599, 1496, 1452, 1258, 1211, 1104 cm⁻¹. HRMS (ES⁺): calcd for C₃₁H₃₂NO₃ [M + H]⁺ 466.2376; found 466.2365. ¹H NMR (300 MHz, CDCl₃), δ 2.68 (dd, J = 14.1, 6.9 Hz, 1H) and 2.96 (dd, J = 14.1, 7.8 Hz, 1H) (AB part of ABX syst., PhCH₂CH), 3.09 (d, J = 6.0 Hz, 1H, CHOH), 3.44 (ddd, J = 7.8, 6.9, 1.8 Hz, 1H, CHN), 3.61 (d, J = 14.0 Hz, 2H) and 3.86 (d, J = 14.0 Hz, 2H) (AB syst., N(CH₂Ph)₂), 4.60 (dd, J = 6.0, 1.8 Hz, 1H, CHOH), 4.88 (d, J = 12.3 Hz, 1H) and 4.92 (d, J = 12.3 Hz, 1H) (AB syst., OCH₂Ph), 6.85–6.90 (m, 2H, Ph), 7.04–7.09 (m, 2H, Ph), 7.11–7.16 (m, 3H, Ph), 7.18–7.24 (m, 10H, Ph), 7.26–7.32 (m, 3H, Ph). ¹³C NMR (75.5 MHz, CDCl₃), δ 31.9 (PhCH₂CH), 54.5 (N(CH₂Ph)₂), 61.9 (CHN), 67.2 (OCH₂Ph), 69.4 (CHOH), 126.0 (CH_Ph), 126.8 (CH_Ph), 127.9 (CH_Ph), 128.0 (CH_Ph), 128.1 (CH_Ph), 128.3 (CH_Ph), 128.5 (CH_Ph), 128.7 (CH_Ph), 129.6 (CH_Ph), 134.8 (C_Ph), 138.9 (C_Ph), 139.6 (C_Ph), 174.5 (COOBn).

(2S,3S)-3-Amino-2-hydroxy-4-phenylbutanoic acid, (−)-allophenylnorstatin (20). Palladium (10 wt%) on activated carbon (6 mg) was added to a solution of benzyl (2S,3S)-3-(dibenzylamino)-2-hydroxy-4-phenylbutanoate 19 (50 mg, 0.10 mmol) in EtOAc (8 mL). The resulting mixture was stirred under H₂ (1 atm pressure) for 24 h at room temperature and then filtered through a short pad of Celite which was washed through with further EtOAc. Water (3 × 5 mL) was then allowed to percolate through the solid material that remained on the Celite pad. The combined aqueous extracts were concentrated under reduced pressure and dried under high vacuum to furnish (2S,3S)-allophenylnorstatin 20 (20 mg, 95%), as a white powder. Mp 196 °C (dec.) [lit.^15p 195 °C (dec.)]. R_f 0.53 (MeOH). [α]²³_D = −5.6 (c 0.1, 1 M HCl) [lit.^15m [α]²⁰_D = −5.5 (c 0.1, 1 M HCl)]. IR (ATR): ν 3369, 3024, 1599, 1549, 1417, 1342, 1301, 1062 cm⁻¹. HRMS (ES⁻): calcd for C₁₀H₁₂NO₃ [M − H]⁻ 194.0822; found 194.0819. ¹H NMR (300 MHz, D₂O), δ 2.91 (dd, J = 14.4, 10.5 Hz, 1H) and 3.02 (dd, J = 14.4, 3.9 Hz, 1H) (AB part of ABX syst., PhCH₂CH), 3.89 (ddd, J = 10.5, 3.9, 3.3 Hz, 1H, CHNH₂), 4.33 (d, J = 3.3 Hz, 1H, CHOH), 7.33–7.52 (m, 5H, Ph). ¹³C NMR (75.5 MHz, D₂O), δ 33.1 (PhCH₂CH), 55.7 (CHNH₂), 71.4 (CHOH), 127.6 (CH_Ph), 129.2 (CH_Ph), 129.4 (CH_Ph), 135.4 (C_Ph), 176.4 (COOH). ¹H and ¹³C NMR data were in agreement with those described in literature.^15m,p

Conflicts of interest

There are no conflicts to declare.

Acknowledgements

The award of a Guangzhou Elite Project Doctoral Research Scholarship (to X. H.) is acknowledged.

Notes and references

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Footnote

† Electronic supplementary information (ESI) available: Copies of NMR spectra and X-ray diffraction data. CCDC 2088378. For ESI and crystallographic data in CIF or other electronic format see DOI: 10.1039/d1ob02411f

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