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. 2026 Jan 7;11(2):3412–3422. doi: 10.1021/acsomega.5c10431

Stereoselective Synthesis of C‑Glycosylated Pyrrolizidines through Nitrone Cycloadditions

Francisco Franco-Montalban 1, Mónica Díaz-Gavilán 1, Daniele Lo Re 1,*, Juan A Tamayo 1,*
PMCID: PMC12824959  PMID: 41585647

Abstract

Polyhydroxylated alkaloids, among which iminosugars represent a prominent subclass, are a structurally diverse family of carbohydrate mimics with significant biological activity. Herein, we report a concise and stereoselective synthesis of five novel C-glycosylated pyrrolizidines (15–19) related to casuarine and hyacinthacines, achieved through 1,3-dipolar cycloadditions of nitrones with E-alkenes. The reactions of nitrone 21 with fructose-derived α,β-unsaturated ester 20a and ketone 20b proceeded with predictable anti-selectivity, affording isoxazolidine intermediates that were transformed into pyrrolizidines via reductive N–O cleavage and subsequent ring closure. Careful stereochemical assignments were established by NOE analyses.

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Introduction

Polyhydroxylated alkaloids represent a widely distributed group of natural compounds, typically isolated from the water-soluble fractions of medicinal plants as well as other organisms. − Within this family, iminosugars (also known as azasugars) constitute the best-studied subgroup and are commonly categorized into five structural classes: pyrrolidines, piperidines, pyrrolizidines (Figure ), indolizidines, and nortropanes. Members within each class differ primarily in their polyhydroxylation patterns.

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Examples of natural polyhydroxylated pyrrolizidine alkaloids.

As carbohydrate mimics, many polyhydroxylated alkaloids exhibit biological activity, and some glycoside-processing enzymes can recognize and interact with them. − Since the etiology of various diseases, including cancer, HIV, and diabetes, is mediated by these enzymes, polyhydroxylated alkaloids have attracted considerable attention as antiviral, antitumoral, antidiabetic, immunostimulatory, and anti-inflammatory agents, as well as for the treatment of lysosomal storage diseases, among others. ,,

Natural alkyl-substituted polyhydroxylated pyrrolizidines are structurally limited alkaloids. Apart from hydroxymethyl groups at C-3 and/or C-5, other naturally occurring alkyl substituents are mostly limited to a methyl group at C-5. ,− Natural and synthetic pyrrolizidine O-glycosides are well documented − Their disaccharide-like structures account for interesting inhibitory activities with higher enzyme selectivity. , In contrast, only a few alkylpolyhydroxylated pyrrolizidines with alternative substitution patterns have been reported, , and no examples are known where the iminosugar is directly attached to the anomeric carbon of a saccharide moiety via a C-glycosidic bond. This gap is relevant because the stability of C-glycosidic linkages makes iminosugars attractive targets for synthetic modification, particularly C-glycosylation, to probe new biological activities and bond stability.

Among the various approaches reported for pyrrolizidine synthesis, 1,3-dipolar cycloadditions (1,3DC) of suitable alkenes and nitrones − have proven particularly effective, enabling access to pyrrolizidines , via isoxazolidine intermediates. This well-studied strategy − allows the formation of multiple stereocenters with high regio- and stereoselectivity in a step-efficient, noncatalyzed process. For substituted five-membered cyclic nitrones, stereocontrol is guided by the nitrone configuration, with diastereoselectivity influenced by steric demands of both partners. , This predictable stereocontrol makes 1,3DC an ideal platform for the preparation of novel C-glycosylated pyrrolizidines, where precise stereochemistry is key to achieving biologically relevant enzyme inhibition and controlling the structural stability of the resulting glycosidic linkages.

Given the promising biological activity of pyrrolizidine O-glycosides, we pursued the preparation of C-glycosylated casuarine (15–17) and hyacinthacine (18–19) derivatives (Figure ) using a 1,3-dipolar cycloaddition strategy between fructose-derived E-alkenes 20a and 20b and the well-known nitrone 21 (Figure ).

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C-glycosylated derivatives 15–19.

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Retrosynthetic analysis for C-glycosylated casuarine (15–17) and hyacinthacine (18–19) derivatives.

Results and Discussion

A retrosynthetic analysis of pyrrolizidines 15–19 suggested that these compounds could be accessed through isoxazolidine intermediate A (Figure ). This key intermediate, in turn, was envisioned to arise from a 1,3-dipolar cycloaddition between an α,β-unsaturated ester or ketone (20a and 20b, respectively) and a suitably protected nitrone 21 with a d-arabinose configuration. Within this synthetic approach, α,β-unsaturated ester and ketone 20a and 20b serve to introduce the saccharide moiety, which remains directly attached to the bicyclic core via a C–C bond in the final pyrrolizidine rings. Compounds 20a, 20b, and nitrone 21 , were synthesized according to procedures reported in the literature.

Nitrone 21 , has been extensively reported by several authors ,,,,,− to undergo 1,3-dipolar cycloadditions with various types of alkenes, with the observed regio- and stereoselectivity depending on the alkene employed and being largely governed by both steric and electronic effects.

Regarding stereoselectivity, nitrone 21 follows the general trend of five-membered cyclic nitrones, where the nitrone configuration governs the outcome of the cycloaddition. ,,, The benzyl protecting groups at positions 3 and 5 of the nitrone strongly enforce an anti approach of the dipolarophile to nitrone 21, while the benzyl group at position 4 favors an exo approach over an endo approach in reactions with monosubstituted alkenes and Z-disubstituted alkenes. As a result, the observed diastereoselectivity reflects the combined effect of these steric constraints and the nature of the dipolarophile.

The cycloaddition between the α,β-unsaturated ester 20a and nitrone 21 was first explored under various conditions. When carried out in dichloromethane at 70 °C for 2.5 h under microwave irradiation, the reaction afforded anti-exo 22a and anti-endo 22b products in a 1:1.2 ratio with an overall yield of 54%. Importantly, anti refers to the relative orientation of the nitrone C-3 and C-5 substituents with respect to the approaching alkene, while endo and exo denote the approach of the carbonyl substituent. Extending the reaction time to 30 h in a sealed tube under otherwise identical conditions improved the yield to 83% while maintaining the same isomer ratio. Similarly, the reaction of α,β-unsaturated methylketone 20b with nitrone 21 was investigated under microwave irradiation in dichloromethane at 70 °C. In contrast to the reaction with 20a, which gave a mixture of stereoisomers, the cycloaddition with 20b proceeded stereoselectively, affording a single stereomer under the same conditions. After 2.5 h, anti-endo cycloadduct 23 was obtained in 49% yield. Performing the same transformation in a sealed tube under identical solvent and temperature conditions but extending the reaction time to 18 h significantly increased the yield to 71%. These results highlight the strong influence of the substituent in E-alkenes. In the case of ester 20a, the ester group in the E-alkene with the incoming sugar moiety leads to the formation of nearly equal amounts of the exo and endo products. In contrast, with ketone 20b, only the endo isomer was obtained, with the sugar moiety adopting an exo orientation. This outcome underscores the key role of the substituents in controlling the stereoisomeric outcome of the cycloaddition with disubstituted E-alkenes (Scheme ). It is noteworthy that the cycloaddition exhibited the opposite regioselectivity to that reported for a closely related system. This difference highlights the sensitivity of these reactions to structural and electronic variations and merits consideration in the interpretation of the reaction outcome (Figure ).

1. 1,3-Dipolar Cycloaddition of Nitrone 21 with Alkenes 20a and 20b .

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Transition state leading to (a) 22a, (b) 22b, and (c) 23.

Extensive NOE experiments were performed on isoxazolidines 22a, 22b, and 23 to establish their stereochemical relationships. These analyses confirmed that the cycloaddition consistently occurs with an anti relationship between C-3 and C-5 of the nitrone and the incoming alkene, in line with the expected behavior of nitrone 21, ,,, as the benzyl protecting groups at positions 3 and 5 strongly enforce an anti approach of the dipolarophile, minimizing steric interactions during the cycloaddition and leading to the observed anti C-3/C-5 relationship. Remarkably, this anti stereochemistry was observed across all of the examined products. For the reaction with ester 20a, NOE correlations confirmed that compound 22a adopts an exoanti orientation of the carboxylate group, as shown by interactions between H-2/H-4 and H-2/H-6, whereas compound 22b displays an endoanti approach, as evidenced by the NOE values between H-3 and H-6. In the case of the cycloaddition with ketone 20b, the NOE analysis confirmed that isoxazolidine 23 adopts an endoanti orientation of the acetyl group, as indicated by the correlation between H-3 and H-4. Figure depicts the structures of 22a, 22b, and 23, showing the NOE correlations used to assign their stereochemistry. NOE data for all other synthesized compounds are provided in the Supporting Information.

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NOE interactions in compounds 22a, 22b, and 23.

With these results in hand, we proceeded toward the synthesis of C-glycosylated pyrrolizidine by testing the reductive N–O cleavage of 22a. Molybdenum-mediated conditions (Mo­(CO)6 in MeCN–H2O , ) promoted N–O bond opening but, contrary to expectations, no spontaneous lactamization was observed, even after prolonged reflux. Instead, ester 24 was isolated in a moderate yield (Scheme ).

2. Synthetic Route toward Pyrrolizidine 15 from 22a .

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Conversion of 24 into lactam 25 required the presence of sodium methoxide (Table ). In all cases, long reaction times (>24 h) and high temperatures (>65 °C) were necessary to obtain lactam 25 in moderate yields (entries 2–4). Attempts to promote the transformation under microwave irradiation were completely ineffective (entries 5–7), leading to material loss and partial racemization at the α-position of the carbonyl group of 24. Other reported reductive protocols, like catalytic hydrogenation over Raney-Ni or Pd or reduction by Zn in acetic acid, , were unsuitable due to the presence of sensitive benzyl ethers and acetonide protecting groups in 24. Finally, reduction of lactam 25 with borane-dimethyl sulfide complex afforded the target pyrrolizidine 15 (overall yield 3% from 21), highlighting the reliability of this methodology for the synthesis of C-glycosylated pyrrolizidines (Scheme ).

1. Reaction Conditions Tested for the Lactamization of 24 .

Entry Reagent (equiv) Solvent Conditions Yield (% of 24)
1 NaOCH3 (1.6) CH3OH Reflux, 2 h NR
2 NaOCH3 (1.6) CH3OH Sealed tube, 100 °C, 30 h 41
3 NaOCH3 (2.5) CH3OH Sealed tube, 100 °C, 48 h 46
4 NaOCH3 (3.0) CH3OH Sealed tube, 100 °C, 30 h 30
5 NaOCH3 (1.6) CH3OH Microwave, 65 °C, 30 min NR
6 NEt3 (5.0) Toluene Microwave, 150 °C, 1 h NR
7 AcONa (5.0) CH3CN Microwave, 130 °C, 1 h NR
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a

All reactions were carried out using anhydrous solvents; NR: no reaction observed.

Similarly, cycloadduct 22b was subjected to the same sequence of transformations as that applied to 22a. In this case, the treatment of 22b with Mo­(CO)6 at reflux for 18 h led to spontaneous cyclization, affording lactam 26. Subsequent reduction with BH3·SMe2 furnished pyrrolizidine 16 in good yield (overall yield of 21% from 21). On the other hand, when compound 26 was treated with NaOMe at 100 °C, epimerization occurred, leading to the formation of compound 27. Subsequent reduction of 27 with BH3·SMe2 afforded pyrrolizidine 17 (overall yield of 17% from 21) (Scheme ).

3. Synthetic Route toward Pyrrolizidines 16 and 17 from 22b .

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The observed difference in lactamization rates between 22a and 22b can be attributed to their stereochemistry at C2 and C3. In 22a, the endo orientation of the sugar group increases the steric hindrance around the reactive center, making cyclization more difficult. In contrast, in 22b, the sugar adopts an exo orientation, which reduces steric hindrance and facilitates the reaction.

For the synthesis of C-glycosylated hyacinthacine, molybdenum-mediated reductive N–O cleavage of 23 was followed by amination and diastereoselective tautomerization in a tandem process, affording ketone 28 as a single stereoisomer. The newly formed stereocenter at C-5 oriented the methyl group toward the upper face of the bicyclic framework, stabilizing a low-energy conformation of 28, in which most substituents are directed toward the less hindered convex face (Scheme ). Ketone 28 was subsequently reduced to secondary alcohol 18 (overall yield 35% from 21) using sodium borohydride in methanol at room temperature. Higher temperatures led to decreased diastereoselectivity, yielding mixtures of 18 and 19 (overall yield of 14% from 21), whereas cooling the reaction to 0 °C resulted in no observable conversion (Scheme ).

4. Transformation of Isoxazolidine 27 to C-Glycosylated Hyacinthacines 18 and 19 .

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The stereochemistry of ketone 28 and its reduction products, 18 and 19, was determined by NOE experiments, as summarized in Figure . The orientation of the newly formed methyl group in 28 was established from its spatial interaction with the saccharide moiety on the upper face of the bicyclic system, as well as from the NOE correlation observed between H-3 and H-5 in derivative 18. Furthermore, the stereochemistry at C-2 of the two alcohols obtained from the reduction of 28 was determined by diagnostic NOE interactions: between H-2 and the methyl group in 18, and between H-2 and H-5 in 19. These correlations collectively confirm the relative configurations of the reduction products.

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NOE correlations supporting the stereochemical assignments of ketone 28 and reduction products 18 and 19.

As a proof of concept, the benzyl protecting groups of compound 18 were selectively removed while preserving the acetal moieties. This approach enabled the isolation of a well-defined intermediate, compound 29 (Scheme ), without generating hemiacetal mixtures. Initial attempts under various conditions were unsuccessful; however, prolonged catalytic hydrogenation with Pd–C at 60 psi for 4 days afforded compound 29 in good yield (overall yield 29% from 21). The fully characterized product confirmed the feasibility of selective benzyl deprotection in this system and provided a stable intermediate for further transformations.

5. Selective Benzyl Deprotection of Pyrrolizidine 18 to Afford 29 .

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In summary, five protected C-glycosylated pyrrolizidines (15–19) have been successfully synthesized through a short and efficient sequence based on 1,3-dipolar cycloaddition of nitrone 21 with suitably functionalized alkenes. The methodology proved versatile and reliable, allowing access to both casuarine- and hyacinthacine-type derivatives. These results highlight the utility of this approach for the preparation of novel C-glycosylated iminosugars, providing a solid framework for the further exploration of their biological and structural properties.

Conclusions

We have developed a concise and efficient synthetic route to five new C-glycosylated pyrrolizidines (15–19) using 1,3-dipolar cycloadditions of nitrone 21 with E-alkenes 20a and 20b. This strategy consistently delivered the desired isoxazolidine intermediates with high regio- and stereocontrol, highlighting the reliability of this methodology for complex iminosugar construction. Reductive transformations enabled access to both casuarine- and hyacinthacine-type frameworks, while stereochemical outcomes were established through NOE experiments.

The stereochemical outcome revealed a distinctive influence of the substituent on the dipolarophile: ester 20a gave nearly equal amounts of exo and endo adducts, whereas ketone 20b afforded exclusively the endo isomer of the carbonyl substituent, with the bulky sugar group adopting an exo orientation. This expands the understanding of stereocontrol in nitrone–alkene cycloadditions and emphasizes the critical role of the alkene geometry in directing product formation.

Overall, this work establishes an efficient platform for the preparation of novel iminosugar derivatives through 1,3-dipolar cycloadditions with E-alkenes, providing a solid foundation for further exploration of their structural stability and biological activity.

Experimental Section

Preparation of (2R,3R,3aR,4R,5R,6R)-Methyl 4,5-bis­(benzyloxy)-6-benzyloxymethyl-3-[(1S,2S,3R,4R)-(1,2:3,4-di-O-isopropylidene-β-D-arabinopyranos-1-yl)­hexahydropyrrolo­[1,2-b]­isoxazole-2-carboxylate, (22a)

A mixture of nitrone 21 (485 mg, 1.16 mmol) and alkene 20a (584 mg, 1.86 mmol) in anhydrous CH2Cl2 (5 mL) was prepared in a screw cap tube. The reaction mixture was heated at 70 °C for 30 h and monitored by TLC, showing the disappearance of the nitrone and the appearance of two new products. The solvent was then evaporated under reduced pressure, and the residue was purified by flash chromatography (hexane-Et2O 5:1→2:1). Two products were isolated and identified as diastereoisomer 22a (eluted first in hexane-Et2O 2:1, yellow oil, 319 mg, 38%) and 22b (eluted second in hexane-Et2O 2:1, yellow oil, 383 mg, 45%). 22a: R f = 0.53 (hexane-Et2O 1:2); [α]D – 60.8 (c 0.3, CHCl3); 1H NMR (500 MHz, CDCl3) δ 7.38–7.26 (m, 15H, H Ar ), 4.71 (bd, J = 6.1 Hz, 1H, H-2), 4.63–4.51 (m, 7H, H-3′, 3CH2Ph), 4.47 (brd, J = 2.7 Hz, 1H, H-2′), 4.34 (t, J = 5.5 Hz, 1H, H-4), 4.21 (dd, J 1 = 8.0 Hz, J 2 = 1.1 Hz, 1H, H-4′), 4.18 (t, J = 5.3 Hz, 1H, H-5), 3.93 (m, 2H, H-3, 3a), 3.85 (dd, J 1 = 12.9 Hz, J 2 = 1.8 Hz, 1H, H-5′A), 3.69 (d, J = 12.9 Hz, 1H, H-5′B), 3.64–3.56 (m, 3H, H-6,8A,8B), 3.59 (s, 3H, −OCH3), 1.55, 1.52, 1.48, and 1.35 (4s, 12H, 2CMe2); 13C NMR (125 MHz, CDCl3) δ 171.2 (C-7), 138.3, 138.2, 138.1 (C quatern Ar ), 128.40, 128.36, 128.11, 127.79, 127.75, 127.73, 127.67, 127.64 (CH-Ar), 109.3 and 109.1 (2CMe2), 103.1 (C-1′), 86.2 (CH-5), 85.4 (CH-4), 79.5 (CH-2), 73.4, 72.38, 72.36 (3CH2Ph), 71.1 (CH-4′), 70.8, 70.5, 70.4 (CH-3a, 3′, 2′), 69.6 (CH2-8), 69.4 (CH-6), 61.5 (CH2-5′), 52.1 (−OCH3), 51.5 (CH-3), 26.6, 25.9, 25.1, and 24.5 (2CMe2); HRMS (TOF ESI+, m/z) 732.3358 [M + H]+, calcd for C41H50NO11 732.3384.

Preparation of (2S,3S,3aR,4R,5R,6R)-Methyl 4,5-bis­(benzyloxy)-6-benzyloxymethyl-3-[(1S,2S,3R,4R)-(1,2:3,4-di-O-isopropylidene-β-D-arabinopyranos-1-yl)­hexahydropyrrolo­[1,2-b]­isoxazole-2-carboxylate, (22b)

R f = 0.37 (hexane-Et2O 1:2); 1H NMR (500 MHz, CDCl3) δ 7.37–7.28 (m, 15H, H Ar ), 4.73 (d, J = 9.0 Hz, 1H, H-2), 4.67 and 4.54 (2d, J = 12.5 Hz, 2H, CH2Ph), 4.60 (m, 3H, H-3′, CH2Ph), 4.54 (m, 1H, CH2Ph), 4.44–4.42 (m, 2H, H-2′, CH2Ph), 4.32 (br s, 1H, H-4), 4.24 (dd, J 1 = 9.7 Hz, J 2 = 1.3 Hz, 1H, H-4′), 4.20 (br d, J = 10.5 Hz, 1H, H-3a), 4.01–3.95 (m, 2H, H-5, 5′A), 3.86 (m, 1H, H-6), 3.82–3.78 (m, 2H, CH2OBn(A), 5′B), 3.73 (s, 3H, −OCH3), 3.60 (dd, J 1 = 12.3 Hz, J 2 = 9.3 Hz, 1H, CH2OBn(B)), 3.55 (dd, J 1 = 10.5 Hz, J 2 = 9.5 Hz, 1H, H-3), 1.56, 1.42, 1.38, and 1.33 (4s, 12H, 2CMe2); 13C NMR (125 MHz, CDCl3) δ 172.9 (COOMe), 138.6, 138.5, 138.2 (C quatern Ar ), 128.3, 128.2, 127.9, 127.7, 127.6, 127.5 (CH-Ar), 109.2 and 108.5 (2CMe2), 103.3 (C-1′), 85.7 (CH-4), 84.9 (CH-5), 79.8 (CH-2), 73.3 (CH2Ph), 72.4 (CH-2′), 71.6 and 71.5 (2CH2Ph), 71.6 (CH-3a), 70.6, 70.3, 70.2 (CH-6, 4′, 3′), 70.4 (CH2OBn), 61.8 (CH2-5′), 58.1 (CH-3), 52.5 (−OCH3), 26.8, 25.8, 25.7, and 23.9 (2CMe2); HRMS (TOF ESI+, m/z) 732.3370 [M + H]+, calcd for C41H50NO11 732.3384.

Preparation of (2R,3R)-Methyl 3-[(2R,3R,4R,5R)-3,4-bis­(benzyloxy)-5-benzyloxymethyl-2-pyrrolidinyl]-2-hydroxy-3-[(1S,2S,3R,4R)-(1,2:3,4-di-O-isopropylidene-β-D-arabinopyranos-1-yl)­propanoate, (24)

Mo­(CO)6 (197 mg, 0.75 mmol) was added to a solution of 22a (498 mg, 0.68 mmol) in MeCN–H2O (15:1, 20 mL). The mixture was refluxed under argon for 18 h, after which a new product with lower R f was observed on TLC. The mixture was cooled and filtered through Celite washing with CH2Cl2. Evaporation of the reaction solvent afforded a residue that was purified by flash chromatography (hexane-Et2O 1:1→1:2) to yield the open product 24 as a yellow oil (217 mg, 44%): R f = 0.27 (hexane-Et2O 1:2); [a]D + 1.6 (c 0.7, CHCl3); 1H NMR (500 MHz, CDCl3) δ 7.34–7.26 (m, 15H, H Ar ), 4.62–4.60 (m, 3H, H-3′, CH2Ph), 4.53 (s, 2H, CH2Ph), 4.49 (brd, J = 2.7 Hz, 1H, H-2″), 4.47 (2d, J = 10.0 Hz, 2H, CH2Ph), 4.23–4.22 (m, 2H, H-2, 4′), 4.14 (dd, J 1 = 7.8 Hz, J 2 = 5.4 Hz, 1H, H-3″), 4.00 (t, J = 5.3 Hz, 1H, H-4″), 3.85 (dd, J 1 = 12.8 Hz, J 2 = 1.5 Hz, 1H, H-5′A), 3.78 (m, 1H, H-2″), 3.71 (d, J = 12.8 Hz, 1H, H-5′B), 3.63 (s, 3H, −OCH3), 3.54–3.46 (m, 3H, H-5″, CH2OBn), 3.31 (t, J = 6.3 Hz, 1H, H-3), 1.49, 1.42, 1.36, and 1.34 (4s, 12H, 2CMe2); 13C NMR (125 MHz, CDCl3) δ 173.3 (C-1), 138.7, 138.4, 138.2 (C quatern Ar ), 128.50, 128.46, 128.39, 128.09, 128.02, 127.78, 127.77, 127.76, 127.66 (CH-Ar), 109.2 and 109.1 (2CMe2), 104.0 (C-1′), 88.0 (CH-3″), 85.2 (CH-4″), 74.0 (CH-2), 73.4, 72.5, and 72.0 (3CH2Ph), 71.1 (CH-4′), 70.8 (CH-2′), 70.6 (CH-3′), 69.0 (CH2OBn), 61.5 (CH2-5′), 60.7 (CH-5″), 59.5 (CH-2″), 51.7 (−OCH3), 44.6 (CH-3), 26.9, 25.8, 25.6, and 24.4 (2CMe2); HRMS (TOF ESI+, m/z) 734.3516 [M + H]+, calcd for C41H52NO11 734.3535.

Preparation of (1R,2R,5R,6R,7R,7aR)-6,7-Bis­(benzyloxy)-5-benzyloxymethyl-2-hydroxy-1-[(1S,2S,3R,4R)-(1,2:3,4-di-O-isopropylidene-β-D-arabinopyranos-1-yl)]­hexahydropyrrolizin-3-one, (25)

A solution of 24 (217 mg, 0.30 mmol) in anhydrous CH3OH (20 mL) was prepared in a screw cap tube. A 2 M methanolic solution of NaOCH3 (2.0 equiv, 0.30 mL) was then added, the tube was sealed, and the reaction mixture was stirred at 100 °C for 48 h. After this time, the solvent was evaporated under reduced pressure, and the residue was purified by flash chromatography (hexane-AcOEt 1:1 → EtOAc–MeCN–CH3OH–H2O 70:5:2.5:2.5) to give 25 (98 mg, 46%) as a colorless oil: R f = 0.38 (EtOAc–CH3CN–CH3OH–H2O 70:5:2.5:2.5); [a]D – 20.4 (c 0.7, CHCl3); 1H NMR (600 MHz, CDCl3) δ 7.32–7.24 (m, 13H, H Ar ), 7.21–7.19 (m, 2H, H Ar ), 4.70 (d, J = 11.5 Hz, 1H, CH2Ph), 4.62–4.58 (m, 3H, H-2′, 3′, CH2Ph), 4.55–4.53 (m, 2H, H-7, CH2Ph), 4.51 (d, J = 11.8 Hz, 1H, CH2Ph), 4.46 (d, J = 12.0 Hz, 1H, CH2Ph), 4.40 (d, J = 11.8 Hz, 1H, CH2Ph), 4.36 (brs, 1H, H-2), 4.17 (brd, J = 7.9 Hz, 1H, H-4′), 4.08 (brd, J = 8.9 Hz, 1H, H-7a), 3.91 (t, J = 5.5 Hz, 1H, H-6), 3.86 (brs, 1H, H-5), 3.81 (d, J = 12.6 Hz, 1H, H-5′A), 3.63 (d, J = 12.8 Hz, 1H, H-5′B), 3.56 (dd, J 1 = 10.3 Hz, J 2 = 3.6 Hz, 1H, CH2OBn(A)), 3.45 (dd, J 1 = 10.3 Hz, J 2 = 5.7 Hz, 1H, CH2OBn(B)), 3.34 (brs, 1H, H-1), 1.49 (s, 3H, CMe2), 1.35 (s, 6H, CMe2), 1.31 (s, 3H, CMe2); 13C NMR (150 MHz, CDCl3) δ 176.5 (C-3), 137.9, 137.7, 137.1 (C quatern Ar ), 128.69, 128.60, 128.59, 128.24, 128.12, 128.10, 128.03 (CH-Ar), 109.5 and 109.4 (2CMe2), 104.4 (C-1′), 85.6 (CH-7), 82.0 (CH-6), 73.5, 73.4, and 72.5 (3CH2Ph), 72.4 (CH-2), 71.1 (CH-4′), 70.7, 70.6 (CH-3′, CH-2′), 66.7 (CH2OBn), 61.6 (CH2-5′), 60.1 (CH-7a), 59.4 (CH-5), 44.9 (CH-1), 26.8, 26.2, 25.6, and 24.5 (2CMe2); HRMS (TOF ESI+, m/z) 702.3263 [M + H]+, calcd for C40H48NO10 702.3278.

Preparation of (1R,2R,5R,6R,7R,7aR)-6,7-Bis­(benzyloxy)-5-benzyloxymethyl-1-[(1S,2S,3R,4R)-(1,2:3,4-di-O-isopropylidene-β-D-arabinopyranos-1-yl)]­hexahydro-1H-pyrrolizin-2-ol, (15)

To a solution of 25 (98 mg, 0.14 mmol) in anhydrous THF (8 mL), BH3·S­(CH3)2 (106 mg, 1.40 mmol) was added dropwise. The mixture was stirred under argon at rt for 1.5 h. After this time, a new product with higher R f could be observed on TLC. The reaction was then quenched by careful addition of CH3OH (1 mL) at rt and subsequent evaporation of the organic solvent under vacuum. The remaining residue was resuspended in CH3OH (5 mL) and stirred at reflux for 4 h. TLC showed the disappearance of the high R f N–B complexes, and the mixture was cooled down to rt and evaporated under reduced pressure. The residue was purified by flash chromatography (CH2Cl2–CH3OH 10:0.5) to yield 15 (43 mg, 43%) as a colorless oil: R f = 0.30 (CH2Cl2–CH3OH 10:0.5); [a]D – 41.6 (c 0.9, CHCl3); 1H NMR (600 MHz, CDCl3) δ 7.35–7.26 (m, 15H, H Ar ), 4.61 (dd, J 1 = 7.8 Hz, J 2 = 2.4 Hz, 1H, H-3′), 4.60–4.55 (m, 5H, H-2′, 2CH2Ph), 4.50 and 4.48 (2d, J = 12.0 Hz, 2H, CH2Ph), 4.22 (brd, J = 7.9 Hz, 1H, H-4′), 4.20 (dd, J 1 = 7.1 Hz, J 2 = 4.5 Hz, 1H, H-7a), 4.06 (d, J = 2.9 Hz, 1H, H-6), 4.03 (dd, J 1 = 7.5 Hz, J 2 = 5.3 Hz, 1H, H-7), 4.00 (dd, J 1 = 12.0 Hz, J 2 = 4.5 Hz, 1H, CH2OBn(A)), 3.90–3.87 (m, 2H, H-1, 5′A), 3.82 (dd, J 1 = 11.7 Hz, J 2 = 3.6 Hz, 1H, CH2OBn(B)), 3.70 (d, J = 12.9 Hz, 1H, H-5′B), 3.49 (dd, J 1 = 9.6 Hz, J 2 = 6.2 Hz, 1H, H-3A), 3.45 (dd, J 1 = 9.7 Hz, J 2 = 5.1 Hz, 1H, H-3B), 3.33 (q, J = 3.6 Hz, 1H, H-2), 2.32 (m, 1H, H-5), 1.45, 1.45, 1.39, and 1.33 (4s, 12H, 2CMe2); 13C NMR δ (150 MHz, CDCl3) 138.3, 138.2, 138.0 (C quatern Ar ), 128.61, 128.58, 128.56, 128.10, 128.08, 127.97, 127.91, 127.86 (CH-Ar), 109.1 and 109.0 (2CMe2), 104.5 (C-1′), 86.2 (CH-7a), 85.1 (CH-1), 75.5 (CH-6), 73.4 (CH2Ph), 72.2 (2CH2Ph), 71.2 (CH-4′), 70.64, 70.61 (CH-3′, CH-2′), 69.1 (CH2-3), 64.7 (CH2-8), 61.5 (CH-7), 61.4 (CH2-5′), 61.1 (CH-5), 39.0 (CH-2), 27.0, 26.1, 25.9, and 24.3 (2CMe2); HRMS (TOF ESI+, m/z) 706.3601 [M + H + H2O]+, calcd for C40H52NO10 706.3586.

Preparation of (1S,2S,5R,6R,7R,7aR)-6,7-Bis­(benzyloxy)-5-benzyloxymethyl-2-hydroxy-1-[(1S,2S,3R,4R)-(1,2:3,4-di-O-isopropylidene-β-D-arabinopyranos-1-yl)]­hexahydropyrrolizin-3-one, (26)

Mo­(CO)6 (159 mg, 0.60 mmol) was added to a solution of 22b (400 mg, 0.55 mmol) in MeCN–H2O (15:1, 16 mL). The mixture was refluxed under argon for 18 h, after which a new product with lower R f was observed on TLC. The mixture was cooled and filtered through Celite washing with CH2Cl2. Evaporation of the reaction solvent afforded a residue that was purified by flash chromatography (hexane-Et2O 1:1→1:2) to yield the product 26 as a yellow oil (230 mg, 57%): R f = 0.4 (AcOEt-hexane 2:1); [a]D – 38 (c 1.0, CHCl3); 1H NMR (500 MHz, CDCl3) δ 7.28–7.19 (m, 15H, H Ar ), 4.59–4.45 (m, 8H, H-2′, H-3′, H-5, 5xCH2Ph), 4.33–4.30 (m, 3H, H-2, H-7a, CH2Ph), 4.20 (bd, J = 8.0 Hz, 1H, H-4′), 4.12 (s, 1H, H-6), 4.06 (bs, 1H, H-7), 3.97 (bd, J = 13.02 Hz, 1H, H-5′a), 3.72 (d, 1H, H-5′b), 3.59–3.56 (m, 2H, CH2OBn), 2.62 (dd, J = 8.9, 5.2 Hz, H-1), 1.52, 1.39, 1.30, and 1.28 (4s, 12H, 2CMe2); 13C NMR (125 MHz, CDCl3) δ 175.1 (C-3), 138.06, 137.99, 137.4 (C quatern Ar ), 128.3, 128.0, 127.66, 127.60, 127.54, 127.51 (CH-Ar), 109.2 and 109.1 (2CMe2), 103.0 (C-1′), 87.2 (CH-7), 84.2 (C-6), 74.0 and 66.5 (CH-2, 7a), 73.0, 72.0, and 71.1 (3CH2Ph), 71.7 and 58.8 (CH-5,2′), 70.3 (CH-4′), 69.9 (C-3′), 68.1 (CH2–OBn), 61.5 (CH2-5′), 51.9 (CH-1), 26.8, 25.9, 25.5, and 23.5 (2CMe2); HRMS (TOF ESI+, m/z) 702.3248 [M + H]+, calcd for C40H48NO10 702.3278.

Preparation of (1S,2S,5R,6R,7R,7aR)-6,7-Bis­(benzyloxy)-5-benzyloxymethyl-1-[(1S,2S,3R,4R)-(1,2:3,4-di-O-isopropylidene-β-D-arabinopyranos-1-yl)]­hexahydro-1H-pyrrolizin-2-ol, (16)

To a solution of 26 (40 mg, 0.057 mmol) in anhydrous THF (6 mL), BH3·S­(CH3)2 (2 M, 0.28 mL, 0.57 mmol) was added dropwise. The mixture was stirred under argon at rt for 1.5 h. After this time, a new product with higher R f could be observed on TLC. The reaction was then quenched by careful addition of CH3OH (1 mL) at rt and subsequent evaporation of the organic solvent under vacuum. The remaining residue was resuspended in CH3OH (5 mL) and stirred at reflux for 4 h. TLC showed the disappearance of the high R f N–B complexes, and the mixture was cooled down to rt and evaporated under reduced pressure. The residue was purified by flash chromatography (AcOEt → AcOEt-CH3OH 10:0.5) to yield 16 (31 mg, 79%) as a colorless oil: R f = 0.40 (AcOEt); [a]D – 34.8 (c 1.0, CHCl3); 1H NMR (500 MHz, CDCl3) δ 7.32–7.25 (m, 15H, H Ar ), 4.62–4.47 (m, 8H, H-2,2′,3′,5xCH2Ph), 4.43 (d, J = 11.93 Hz, 1H, CH2Ph), 4.27 (s, 1H, H-7), 4.23 (d, J 3′,4′ = 7.9 Hz, J 4′,5′ = 1.9 Hz, 1H, H-4′), 4.15 (s, 1H, H-6), 4.05 (bs, 1H, H-7a), 4.00 (dd, J 5′a,5′b = 13.0 Hz, J 4′,5′a = 2.0 Hz, 1H, H-5′a), 3.75 (d, 1H, H-1, 5′b), 3.55–3.62 (m, 1H, CH2OBn), 3.32 (m, 2H, H-3a,5), 3.09 (dd, J 3a,3b = 10.1 Hz, J 2,3b = 3.1 Hz, 1H, H-3b), 2.63 (dd, J 1 = 10.5 Hz, J 2 = 3.8 Hz, 1H, H-1), 1.45, 1.38, 1.37, and 1.31 (4s, 12H, 2CMe2); 13C NMR δ (125 MHz, CDCl3) 138.7, 138.6, 138.2 (C quatern Ar ), 128.27, 128.21, 128.1, 127.64, 127.58, 127.48, 127.36, 127.34, 127.22 (CH-Ar), 109.3 and 108.5 (2CMe2), 104.4 (C-1′), 87.9 (CH-7), 86.0 (CH-6), 73.4 (CH-2), 73.1 (CH2Ph), 72.1 (CH-2′), 71.9 (CH2–OBn), 71.4 and 71.2 (2CH2Ph), 70.5 (CH-4′), 70.3 (CH-3′), 70.0 (CH-5), 69.3 (CH-7a), 63.8 (CH-3), 61.4 (CH2-5′), 53.9 (CH-1), 26.7, 25.8, 25.7, and 23.8 (2CMe2); HRMS (TOF ESI+, m/z) 688.3445 [M + H]+, calcd for C40H50NO9 688.3486.

Preparation of (1S,2R,5R,6R,7R,7aR)-6,7-Bis­(benzyloxy)-5-benzyloxymethyl-2-hydroxy-1-[(1S,2S,3R,4R)-(1,2:3,4-di-O-isopropylidene-β-D-arabinopyranos-1-yl)]­hexahydropyrrolizin-3-one, (27)

A solution of 26 (75 mg, 0.32 mmol) in anhydrous CH3OH (10 mL) was prepared in a screw cap tube. A 2 M methanolic solution of NaOCH3 (2.0 equiv, 0.32 mL) was then added, the tube was sealed, and the reaction mixture was stirred at 60 °C for 24 h. After this time, the solvent was evaporated under reduced pressure, and the residue was purified by flash chromatography (hexane-Et2O 1:1→1:2) to give 27 (63 mg, 84%) as a colorless oil: R f = 0.5 (AcOEt-hexane 2:1); [a]D – 21.8 (c 0.1, CHCl3); 1H NMR (400 MHz, CDCl3) δ 7.32–7.14 (m, 15H, H Ar ), 4.65–4.62 (m, 2H, H-2′, CH2Ph), 4.60 (dd, 1H, J = 7.9 Hz, J = 2.8 Hz, 1H, H-3′), 4.56 (d, 1H, J = 10.1 Hz, H-2), 4.51 (m, 1H, H-5), 4.50 (s, 2H, CH2Ph), 4.45–4.42 (m, 2H, CH2Ph), 4.28 (d, J = 11.9 Hz, 1H, CH2Ph), 4.20 (brd, 1H, J = 7.9 Hz, H-4′), 4.09 (brs, 1H, H-7), 4.00–3.93 (m, 3H, H-6, 7a, 5′a), 3.68 (d, J = 12.8 Hz, 1H, H-5′b), 3.54–3.51 (m, 2H, CH2OBn), 2.72 (t, 1H, J = 9.9 Hz, H-1), 1.56 (s, 3H, CMe2), 1.45 (s, 3H, CMe2), 1.28 (s, 6H, CMe2); 13C NMR (100 MHz, CDCl3) δ 176.5 (C-3), 138.2, 138.0, 137.5 (C quatern Ar ), 128.30, 128.27, 128.24, 127.67, 127.62, 127.61, 127.55, 127.55 (CH-Ar), 109.0 and 108.8 (2CMe2), 102.9 (C-1′), 87.4 (CH-7), 83.8 (CH-6), 73.0, 72.3, and 70.9 (3CH2Ph), 71.3 and 71.2 (CH-2,2′), 70.7 (CH-4′), 70.0 (CH-3′), 67.8 (CH2OBn), 63.4 (CH-7a), 61.4 (CH2-5′), 59.5 (CH-5), 56.8 (CH-1), 26.8, 25.8, 25.4, and 23.7 (2CMe2); HRMS (TOF ESI+, m/z) 702.3278 [M + H]+, calcd for C40H48NO10 702.3251.

Preparation of (1S,2R,5R,6R,7R,7aR)-6,7-Bis­(benzyloxy)-5-benzyloxymethyl-1-[(1S,2S,3R,4R)-(1,2:3,4-di-O-isopropylidene-β-D-arabinopyranos-1-yl)]­hexahydro-1H-pyrrolizin-2-ol, (17)

To a solution of 27 (43 mg, 0.061 mmol) in anhydrous THF (6 mL), BH3·S­(CH3)2 (2 M, 0.3 mL, 0.6 mmol) was added dropwise. The mixture was stirred under argon at rt for 1.5 h. After this time, a new product with higher R f could be observed on TLC. The reaction was then quenched by careful addition of CH3OH (1 mL) at rt and subsequent evaporation of the organic solvent under vacuum. The remaining residue was resuspended in CH3OH (5 mL) and stirred at reflux for 4 h. TLC showed the disappearance of the high R f N–B complexes, and the mixture was cooled down to rt and evaporated under reduced pressure. The residue was purified by flash chromatography (AcOEt → AcOEt-CH3OH 10:0.5) to yield 17 (32 mg, 76%) as a colorless oil: R f = 0.40 (AcOEt); [a]D – 22.2 (c 1.0, CHCl3); 1H NMR (600 MHz, CD3CN) δ 7.37–7.28 (m, 15H, H Ar ), 4.65–4.47 (m, 8H, H-2′,3′,6xCH2Ph), 4.36 (m, 1H, H-2), 4.26 (s, 1H, H-7a), 4.22 (dd, J 3′,4′ = 8.0 Hz, J 4′,5′ = 1.8 Hz, 1H, H-4′), 4.02 (s, 1H, H-7), 3.93 (dd, J 5′a,5′b = 13.9 Hz, J 4′,5′a = 1.9 Hz, 1H, H-5′a), 3.80 (bs, 1H, H-6), 3.65 (d, 1H, H-5′b), 3.58–3.51 (m, 3H, H-5, CH2OBn), 3.36 (m, 1H, H-3a), 3.05 (m, 1H, H-3b), 2.60 (m, 1H, H-1), 1.53, 1.42, 1.35, and 1.30 (4s, 12H, 2CMe2); 13C NMR δ (150 MHz, CD3CN) 138.7, 138.21, 138.19 (C quatern Ar ), 128.28, 128.27, 127.80, 127.71, 127.65, 127.56, 127.44 (CH-Ar), 110.0 and 108.5 (2CMe2), 104.3 (C-1′), 88.4 (CH-7a), 86.1 (CH-7), 72.6 (CH2Ph), 72.05 (CH-2), 71.5 (CH2Ph), 71.4 (CH-2′), 71.3 (CH2Ph), 70.8 (CH-6), 70.7 (CH2–OBn), 70.4 (CH-4′), 70.1 (CH-3′), 69.7 (CH-5), 61.6 (CH-3), 61.20 (CH2-5′), 56.6 (CH-1), 26.0, 25.5, 25.1, and 23.1 (2CMe2); HRMS (TOF ESI+, m/z) 688.3519 [M + H]+, calcd for C40H50NO9 688.3486

Preparation of (2S,3S,3aR,4R,5R,6R)-2-Acetyl-4,5-bis­(benzyloxy)-6-benzyloxymethyl-3-[(1S,2S,3R,4R)-(1,2:3,4-di-O-isopropylidene-β-D-arabinopyranos-1-yl)]­hexahydropyrrolo­[1,2-b]­isoxazole, (23)

A mixture containing nitrone 21 (680 mg, 1.62 mmol) and alkene 20b (775 mg, 2.60 mmol) in anhydrous CH2Cl2 (5 mL) was prepared in a screw cap tube. The reaction mixture was heated at 70 °C for 18 h and monitored by TLC, showing the formation of a new product. The solvent was removed under reduced pressure to yield a viscous residue, which was purified by flash chromatography (hexane-Et2O 2:1→hexane-Et2O 1:1) to give 23 (565 mg, 71% yield) as a pure yellow oil: R f = 0.29 (hexane-AcOEt 2:1); [α]D – 41.5 (c 1.3, CHCl3); 1H NMR (500 MHz, CDCl3) δ 7.34–7.23 (m, 15H, H Ar ), 4.62 and 4.52 (2d, J = 11.9 Hz, 2H, CH2Ph), 4.59 (d, J = 7.3 Hz, 1H, H-2), 4.57 (dd, J 1 = 5.2 Hz, J 2 = 2.6 Hz, 1H, H-3′), 4.55 (brs, 2H, CH2Ph), 4.47 and 4.38 (2d, J = 11.8 Hz, 2H, CH2Ph), 4.33 (brd, J = 2.6 Hz, 1H, H-2′), 4.21 (m, 1H, H-4), 4.20 (dd, J 1 = 5.2 Hz, J 2 = 1.4 Hz, 1H, H-4′), 4.16 (dd, J 1 = 7.6 Hz, J 2 = 1.8 Hz, 1H, H-3a), 3.95–3.91 (m, 2H, H-5, 5′A), 3.76 (d, J = 13.0 Hz, H-5′B), 3.70 (dd, J 1 = 8.8 Hz, J 2 = 4.6 Hz, 1H, CH2OBn(A)), 3.53–3.46 (m, 2H, H-6, CH2OBn(B)), 3.39 (t, J = 7.5 Hz, 1H, H-3), 2.25 (s, 3H, CH3), 1.50, 1.39, 1.32, and 1.31 (4s, 12H, 2CMe2); 13C NMR (125 MHz, CDCl3) δ 208.2 (CO), 138.5, 138.4, 138.1 (C quatern Ar ), 128.47, 128.46, 128.41, 128.10, 127.92, 127.90, 127.76, 127.70, 127.68 (CH-Ar), 109.3 and 108.6 (2CMe2), 103.6 (C-1′), 86.9 (CH-4), 85.5 (CH-5), 85.2 (CH-2), 73.5 (CH2Ph), 72.29, 72.25 (CH-2′, 3a), 71.84 and 71.79 (2CH2Ph), 71.1 (CH-6), 70.7 (CH-4′), 70.7 (CH2OBn), 70.5 (CH-3′), 61.8 (CH2-5′), 56.4 (CH-3), 27.3 (CH3), 26.8, 26.0, 25.7, 24.0 (2CMe2); HRMS (LSIMS+, m/z) 738.3247 [M + Na]+, calcd for C41H49NO10Na 738.3254; LRMS (ESI+, m/z) 202, 242, 440, 738.

Preparation of (1S,3S,5R,6R,7R,7aR)-6,7-Bis­(benzyloxy)-5-benzyloxymethyl-1-[(1S,2S,3R,4R)-(1,2:3,4-di-O-isopropylidene-β-D-arabinopyranos-1-yl)]-3-methylhexahydropyrrolizin-2-one, (28)

To a solution of 23 (309 mg, 0.43 mmol) in CH3CN–H2O (15:1,35 mL), Mo­(CO)6 (126 mg, 0.47 mmol) was added. The solution was refluxed under argon for 2.5 h, after which a new product with higher R f could be observed on TLC. The mixture was cooled and filtered through Celite washing with CH2Cl2. Evaporation of the reaction solvent afforded a residue that was purified by flash chromatography (hexane-AcOEt 4:1) to give 28 (239 mg, 77%) as a colorless oil: R f = 0.40 (hexane-AcOEt 3:1); [α]D – 7.3 (c 0.9, CHCl3); 1H NMR (500 MHz, CDCl3) δ 7.37–7.13 (m, 15H, H Ar ), 5.13 (d, J = 2.8 Hz, 1H, H-2′), 4.69 and 4.54 (2 d, J = 12.1 Hz, 2H, CH2Ph), 4.63 (dd, J 1 = 7.9 Hz, J 2 = 2.9 Hz, 1H, H-3′), 4.52–4.47 (m, 2H, CH2Ph), 4.38–4.32 (m, 3H, H-7a, CH2Ph), 4.30 (brs, 1H, H-7), 4.20 (brd, J = 7.9 Hz, 1H, H-4′), 3.96 (d, J = 12.9 Hz, 1H, H-5′A), 3.86 (brd, J = 4.5 Hz, 1H, H-6), 3.68 (d, J = 12.9 Hz, 1H, H-5′B), 3.54 (m, 2H, CH2OBn), 3.48 (q, J = 7.3 Hz, 1H, H-3), 2.98 (m, 1H, H-5), 2.90 (brd, J = 10.6 Hz, 1H, H-1), 1.51, 1.29, 1.27, and 1.23 (4s, 12H, 2CMe2), 1.21 (d, J = 7.1 Hz, 3H, CH3); 13C NMR (125 MHz, CDCl3) δ 217.7 (CO), 138.8, 138.5, 138.1 (C quatern Ar ), 128.50, 128.41, 128.37, 128.16, 127.81, 127.80, 127.69, 127.64, 127.61 (CH-Ar), 109.22 and 109.16 (2CMe2), 102.8 (C-1′), 87.6 (CH-7), 87.1 (CH-6), 73.4 (CH2Ph), 73.2 (CH2OBn), 71.6 and 71.4 (2CH2Ph), 70.8 (CH-4′), 70.4 (CH-5), 70.2 (CH-3′), 70.0 (CH-2′), 68.1 (CH-3), 67.4 (CH-7a), 61.8 (CH2-5′), 53.1 (CH-1), 27.3, 24.0, 26.0, 25.6 (2CMe2), 16.8 (CH3); HRMS (LSIMS+, m/z) 700.3469 [M + H]+, calcd for C41H50NO9 700.3486. LRMS (ESI+, m/z): 244, 271, 382, 700, 722.

Preparation of (1R,2R,3S,5R,6R,7R,7aR)-6,7-Bis­(benzyloxy)-5-benzyloxymethyl-1-[(1S,2S,3R,4R)-(1,2:3,4-di-O-isopropylidene-β-D-arabinopyranos-1-yl)]-3-methylhexahydro-1H-pyrrolizin-2-ol, (18)

A solution of ketone 28 (239 mg, 0.34 mmol, 1.0 equiv) in CH3OH (5 mL) was cooled to 0 °C, and NaBH4 (25 mg, 0.68 mmol, 2.0 equiv) was added portionwise. The mixture was then gradually warmed to rt and stirred for 24 h (small portions of NaBH4 were added in 4 h intervals until the starting material was consumed, according to TLC analysis). The reaction was quenched by cooling to 0 °C and addition of sat. NH4Cl solution. The organic solvent was then removed by evaporation under reduced pressure, and the crude was extracted from the remaining aqueous layer with 50 mL of CH2Cl2 (×3). The combined organic extracts were dried on Na2SO4, filtered, and evaporated under reduced pressure. The final residue was purified by flash chromatography (hexane-AcOEt 3:1) to afford 18 (154 mg, 64%) as a colorless oil: R f = 0.50 (hexane-AcOEt 1:3); [α]D – 18.1 (c 1.7, CHCl3); 1H NMR (500 MHz, CDCl3) δ 7.34–7.20 (m, 15H, H Ar ), 4.60 (dd, J 1 = 7.9 Hz, J 2 = 2.5 Hz, 1H, H-3′), 4.57–4.53 (m, 2H, H-2′, CH2Ph), 4.52–4.45 (m, 4H, 2CH2Ph), 4.40 (d, J = 11.9 Hz, 1H, CH2Ph), 4.29 (brs, 1H, H-7), 4.22 (brd, J = 7.8 Hz, 1H, H-4′), 4.19 (brs, 1H, H-6), 4.14 (brs, 1H, CH-2), 4.07 (brd, J = 10.6 Hz, 1H, H-7a), 4.01 (brd, J = 12.5 Hz, 1H, H-5′A), 3.90 (brs, 1H, OH), 3.72 (d, J = 13.0 Hz, 1H, H-5′B), 3.57 (m, 1H, CH2OBn(A)) 3.51 (m, 1H, CH2OBn(B)), 3.38 (brdd, J 1 = 10.0 Hz, J 2 = 6.0 Hz, 1H, H-5), 3.24 (m, 1H, H-3), 2.73 (dd, J 1 = 10.6 Hz, J 2 = 2.7 Hz, 1H, H-1), 1.53, 1.40, 1.33, and 1.26 (4s, 12H, 2CMe2), 1.16 (d, J = 6.2 Hz, 3H, CH3); 13C NMR (125 MHz, CDCl3) δ 139.0, 138.9, 138.4 (C quatern Ar ), 128.44, 128.38, 128.30, 127.81, 127.71, 127.60, 127.47, 127.32 (CH-Ar), 109.4 and 108.8 (2CMe2), 104.2 (C-1′), 88.9 (CH-7), 86.4 (CH-6), 75.2 (CH-2), 73.3 (CH2Ph), 72.4 (CH2OBn), 72.1 (CH-2′), 71.5, 71.2 (2CH2Ph), 70.8 (CH-4′), 70.4, 70.3 (CH-3′, 7a), 68.0 (CH-5), 66.8 (CH-3), 61.6 (CH2-5′), 54.1 (CH-1), 27.3, 26.3, 25.8, and 23.8 (2CMe2), 15.4 (CH3); HRMS (LSIMS+, m/z) 702.3638 [M + H]+, calcd for C41H52NO9 702.3642.

Preparation of (1R,2S,3S,5R,6R,7R,7aR)-6,7-Bis­(benzyloxy)-5-benzyloxymethyl-1-[(1S,2S,3R,4R)-(1,2:3,4-di-O-isopropylidene-β-D-arabinopyranos-1-yl)]-3-methylhexahydro-1H-pyrrolizin-2-ol, (19)

A solution of ketone 28 (86 mg, 0.12 mmol) in CH3OH (4 mL) was cooled to 0 °C, and NaBH4 (9 mg, 0.24 mmol) was added portionwise. The mixture was then refluxed under argon for 18 h. After this time, two new products were seen on TLC. The mixture was then cooled to rt, and the solvent was removed under vacuum. The reaction crude was purified by flash chromatography (hexane-AcOEt 5:1→1:1) to yield 18 (16 mg, 19%) and 19 (21 mg, 25%, colorless liquid). 19: R f = 0.40 (hexane-AcOEt 1:3); 1H NMR (600 MHz, CDCl3) δ 7.40–7.19 (m, 15H, H Ar ), 4.60–4.52 (m, 4H, H-3′, CH2Ph, CH2Ph), 4.50 (brd, J = 11.9 Hz, 1H, CH2Ph), 4.44 (d, J = 12.5 Hz, 1H, CH2Ph), 4.41 (brd, J = 11.9 Hz, 1H, CH2Ph), 4.34 (brs, 1H, H-2′), 4.18 (brd, J = 7.7 Hz, 1H, H-4′), 4.04 (brs, 2H, H-2, 7a), 3.99 (brs, 2H, H-6, 7), 3.89 (brd, J = 12.9 Hz, 1H, H-5′A), 3.76 (brd, J = 13.0 Hz, 1H, H-5′B), 3.52 (brs, 1H, OH), 3.49 (brs, 1H, CH2OBn(A)), 3.40 (brs, 1H, CH2OBn(B)), 3.31 (brs, 1H, H-5), 3.21 (brs, 1H, H-3), 2.70 (t, J = 8.1 Hz, 1H, H-1), 1.50, 1.40, 1.30, and 1.28 (4s, 12H, 2CMe2), 1.23 (d, J = 6.9 Hz, 3H, CH3); 13C NMR (125 MHz, CDCl3) δ 128.52, 128.40, 127.90, 127.80, 127.71, 127.55 (CH-Ar), 109.4 (2CMe2), 105.9 (C-1′), 87.6, 86.5 (CH-6, CH-7), 78.8 (CH-2), 73.7, 73.4 (CH-2′, CH2OBn, CH2Ph), 71.7 (CH2Ph), 71.4 (CH2Ph), 70.7, 70.4 (CH-3′, CH-4′), 69.8 (CH-7a), 64.7 (CH-3), 62.8 (CH-5), 61.6 (CH2-5′), 51.7 (CH-1), 26.7, 26.2, 25.5, and 24.1 (2CMe2), 15.6 (CH3).

Preparation of (1R,2R,3R,5S,6R,7R,7aR)-3-Hydroxymethyl-7-[(1S,2S,3R,4R)-(1,2:3,4-di-O-isopropylidene-β-D-arabinopyranos-1-yl)]-5-methylhexahydro-1H-pyrrolizin-1,2,6-triol, (29)

A solution of 18 (30 mg, 0.04 mmol) in CH3OH (2 mL) was hydrogenated at room temperature (60 psi of H2) in the presence of 10% Pd–C (25 mg) for 4 days. The reaction was monitored by LCMS. The catalyst was filtered off, washed with CH3OH, and the filtrate and washings were evaporated to a residue that was purified using RP C-18 chromatography (H2O-MeCN) to afford pure 29 (15 mg, 81%) as a colorless syrup. 1H NMR (500 MHz, CD3OD) δ 4.70 (dd, 1H, J = 2.7, J = 7.9 Hz, H-3′), 4.60 (d, 1H, J = 2.7, H-2′), 4.47–4.44 (m, 2H, H-1, 7a), 4.40 (t, 1H, J = 2.7 Hz, H-6), 4.30 (dd, 1H, J = 2.0, J = 7.9 Hz, H-4′), 4.16 (brs, 1H, H-2), 4.07 (dd, 1H, J 1 = 2.0, J 2 = 13.0 Hz, H-5′A), 3.87 (dd, 1H, J 1 = 11.8, J 2 = 9.4 Hz, CH2OBn(A)), 3.75 (d, 1H, J = 13.0 Hz, H-5′B), 3.74 (dd, 1H, J 1 = 4.3, J 2 = 11.8 Hz, CH2OBn(B)), 3.69 (m, 1H, H-5), 3.57 (m, 1H, H-3), 3.08 (dd, 1H, J 1 = 2.7, J 2 = 11.5 Hz, H-7), 1.56, 1.50, 1.47, and 1.37 (4s, 12H, 2CMe2), 1.41 (d, 3H, J = 6.7 Hz, CH3); 13C NMR (125 MHz, CD3OD) δ 109.07 and 109.05 (2CMe2), 102.7 (C-1′), 79.6 (CH-2), 78.9 (CH-1), 74.4 (CH-7a), 73.5 (CH-6), 72.1 (CH-2′), 71.0 (CH-5), 70.4 (CH-4′), 70.0 (CH-3′), 61.3 (CH2-5′), 59.3 (CH2OBn), 54.0 (CH-7), 25.5, 24.82, 24.75, and 22.4 (2CMe2), 9.9 (CH3); HRMS (TOF ESI+, m/z) 432.2237 [M + H]+, calcd for C20H34NO9 432.2234.

Supplementary Material

ao5c10431_si_001.pdf (7.3MB, pdf)

Acknowledgments

Major support for this project was provided by the Ministerio de Educación y Ciencia of Spain (Project Ref. No. CTQ2006-14043). Additional support was provided by Junta de Andalucía (Group BIO-250).

The Supporting Information is available free of charge at https://pubs.acs.org/doi/10.1021/acsomega.5c10431.

  • Complementary experimental details, discussion on NOESY experiments, and copies of NMR spectra (PDF)

#.

D.L. and J.T. contributed equally and share last authorship.

The authors declare no competing financial interest.

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