Enantioselective Organocatalytic Desymmetric Acylation as an Access to Orthogonally Protected myo-Inositols

Abstract

Chiral cyclitols represent an important class of naturally occurring compounds. In particular, myo-inositol and its derivatives are essential for phosphorus storage and cell-signaling pathways in living organisms. Not surprisingly, these compounds constitute an emerging class of molecules with significant potential in both medicinal and synthetic chemistry. However, efficient catalytic methodologies for accessing chiral myo-inositol derivatives remain scarce. Herein, we report a metal-free, organocatalytic protocol for the desymmetric acylation of a readily available meso-myo-inositol diol. The reaction proceeds with high enantioselectivity, moderate to high yields, and broad tolerance to various functional groups. The developed methodology enables the efficient synthesis of chiral myo-inositol derivatives. Furthermore, its scalability and subsequent transformations into orthogonally protected building blocks for synthesizing myo-inositol phosphates underscore the practical utility of this approach.

Introduction

Cyclitols are cycloalkanes with hydroxyl groups attached to at least three carbon atoms. Among them, cyclohexane-derived polyols constitute a class of particular importance for the function and survival of living cells. The most important members are cyclohexanehexols, known as inositols. Of the nine stereoisomeric forms, myo-inositol with five equatorial and one axial hydroxy group is the most abundant isomer. Myo-inositol serves as a key structural unit in naturally occurring molecules (Figure A), widely distributed in plants and mammalian cells, and plays multiple roles in cell function and survival across both eukaryotic and prokaryotic systems. For instance, phosphatidylinositols (PIs) and their phosphorylated derivatives, such as inositol hexakisphosphate (phytic acid, IP₆) and inositol lipids, are involved in diverse physiological functions, including regulation of ion-channel permeability, phosphate homeostasis, metabolic flux, gene expression, insulin signaling, embryonic development, and stress response. Additionally, myo-inositol and its chiral derivatives have been successfully utilized as a versatile starting material for the synthesis of natural products , or biologically relevant inositol derivatives (Figure A).

1.

A) Selected examples of biologically relevant inositol and total synthesis products starting from inositols. B) Selected desymmetric approaches toward chiral inositol derivatives. C) Our proposed approach.

Myo-inositol is a meso compound that possesses a plane of symmetry. In contrast, unsymmetrical substitution breaks this symmetry, affording derivatives of high importance. Thus, developing efficient methodologies to access such myo-inositol units remains a central goal in modern synthetic chemistry. Several well-established approaches have been reported, including the separation of diastereomeric mixtures (via chiral auxiliaries), synthesis from enantiopure synthons such as the Ferrier carbocyclization of methylglucoside, or benzoin condensation. However, these methods are often hampered by low yields or demanding reaction conditions. These limitations can be overcome by adopting the concept of catalytic enantioselective desymmetrization. This strategy has been extensively studied by Scott J. Miller, who developed direct desymmetric sulfonylation and phosphorylations of inositols using peptide catalysis (Figure B). Another efficient approach was reported by J. Paradies in 2013, employing phosphinite catalysis with benzoyl chloride as the acylating agent (Figure B). Alternatively, enzymatic desymmetric transformations were reported. Despite these advances, the development of efficient methodologies to access highly substituted and orthogonally protected inositol derivatives remains highly desirable.

To address this challenge, N-heterocyclic carbene (NHC) catalysis could represent a promising strategy. Nowadays, NHC-catalyzed desymmetrizations of prochiral or meso compounds provide access to a variety of enantioenriched products, including selective functionalization of sugars. , However, efficient carbene-catalyzed desymmetrizations of diols remain rare. Motivated by the broad utility of precisely substituted chiral myo-inositol derivatives, we developed a novel enantioselective strategy: a desymmetric, nonoxidative acylation reaction catalyzed by chiral NHCs (Figure C).

Results and Discussion

At the outset of the study, we proposed myo-inositol 1c as an easily accessible prochiral starting material, considering the accessibility and versatility of both protecting groups. To our delight, simple mixing of this diol (1c) with α-bromocinnamic aldehyde 2a, a chiral NHC precursor (pre-C1, Bode catalyst), and an excess of base (cesium carbonate) resulted in the formation of the expected chiral product (3a). Compound 3a was obtained in 65% yield as an inseparable mixture of E/Z-isomers (6:1, based on NMR and HPLC) with moderate enantioselectivity (60:40 er, Table , entry 1). Building on this proof-of-concept experiment, we aimed to improve the yield and stereoselectivity of the model reaction by varying chiral precursors, bases, additives, and other reaction parameters (for a full optimization survey, please refer to the Supporting Information).

1. Optimization Studies.

Entry	pre-C	Base	Sol.	Time (h)	Yield (%)	E/Z	er
1	pre-C1	Cs2CO3	DCM	18	65	6:1	60:40
2	pre-C2	Cs2CO3	DCM	2	61	11:1	68:32
3	pre-C3	Cs2CO3	DCM	18	90	13:1	79:21
4	pre-C4	Cs2CO3	DCM	18	59	5:1	69:31
5	pre-C5	Cs2CO3	DCM	18	96	3:1	70:30
6	pre-C3	Na2CO3	DCM	18	98	20:1	79:21
7	pre-C3	DABCO	DCM	18	53	20:1	83:17
8	pre-C3	DABCO	CHCl3	18	47	20:1	88:12
9	pre-C3	DABCO	CCl4	18	57	20:1	91:9
10	pre-C3	Na2CO3	CCl4	18	45	20:1	87:13
11	pre-C3	DABCO	PhCl	1	61	20:1	85:15
12	pre-C3	DABCO	PhCl	2	54	20:1	84:16
13	pre-C3	DABCO	PhCl	18	65	20:1	85:15
14	pre-C3	DABCO	PhCl	42	53	20:1	86:14

^aReactions were conducted with 1c (0.10 mmol), 2a (0.12 mmol), selected base (0.12 mmol) and selected pre-Catalyst (20 mol %) in selected solvent (1.0 mL) at room temperature (∼21 °C).

^bIsolated yield after column chromatography.

^cDetermined by ¹H NMR and HPLC analysis.

^dDetermined by chiral HPLC analysis, only for major E-isomer; for er of minor isomer, please refer to the SI file.

^e CPA-1 (20 mol %) was used as an additive

^f1 mol % of pre-C3 was used.

^gReaction was conducted at 0 °C.

A slightly increased enantiopurity (68:32 er) was observed for the product 3a isolated from the model reaction catalyzed by a nitro-substituted Bode catalyst (pre-C2, entry 2). Further improvement in enantiocontrol was achieved by changing the precursor counteranion to tetrafluoroborate (pre-C3, entry 3), which led to the formation of the expected product in excellent isolated yield (90%) with a good level of stereocontrol (79:21 er, 13:1 E/Z). In contrast, no improvement in stereoselectivity was observed using other morpholine-based precursors (such as pre-C4) or bifunctional catalyst combining carbene and hydrogen-bond donor functionality (pre-C5, entry 5). Following the optimization of the model reaction catalyzed by pre-C3, it was revealed that the reaction is tolerant to changes in base or solvent. For example, substituting cesium carbonate with sodium carbonate resulted in a nearly quantitative yield of product 3a with retained enantioselectivity, obtained as a single E-isomer (entry 6). A decreased yield but improved enantiocontrol (83:17 er) was observed when the model reaction was conducted in the presence of DABCO (entry 7). Building on this result, we continued optimization using DABCO as the base. Upon the next optimization, we identified chlorinated solvents as particularly suitable for this transformation (entries 8, 9). For instance, the reaction conducted in tetrachloromethane (entry 9) provided product 3a in moderate yield (57%) with the highest enantiopurity observed (91:9 er). Encouragingly, the enantiopurity could be further increased to 99.7:0.3 er by crystallization from isopropanol. Other solvents, such as chlorobenzene, did not improve enantioselectivity (entry 11). However, the model reaction conducted in chlorobenzene reached full conversion of the starting material within 1 h, which we considered a promising outcome for the following optimization. Based on a previous report, we tested chiral phosphoric acid (CPA-1) as an additive for the desymmetric acylation. Notably, no improvement in yield or stereochemical outcome was observed (entry 12). Interestingly, lowering pre-C3 loading to 1 mol % (entry 13) did not result in a decrease in performance. Finally, performing the model reaction at 0 °C (entry 14) furnished the desired product in reduced yield (53%) with minimal change in enantiocontrol.

Considering the above-mentioned optimization results, we propose using 1 mol % of pre-C3 with DABCO in chlorobenzene as the optimal condition for the desymmetric acylation reaction (entry 13).

After optimizing the reaction conditions, we investigated various carbonyl derivatives as alternatives to α-bromocinnamic aldehydes (Scheme ). First, we tested carbonyl compounds, including activated ester and trans-cinnamaldehyde, as potential acylation partners leading to product 3a (Scheme A). Notably, in the reaction with trans-cinnamaldehyde, oxidation of the Breslow intermediate was required to generate the corresponding acylation partner. Drawing inspiration from previous studies, we employed an excess of DQ (Kharasch reagent, 3,3′,5,5′-tetra-tert-butyldiphenoquinone) as the oxidant. However, this approach did not improve either the yield or the stereochemical outcome. For example, oxidative esterification under the optimized conditions afforded the expected product in a lower isolated yield (44%) while maintaining enantioselectivity (83:17 er, single E-isomer). Next, we examined saturated analogues as possible alternatives. However, no acylation product was detected under the reaction conditions (Scheme B). As a final example, we explored dialdehyde-based ethers, which have been widely studied in desymmetric esterifications and are known to give rise to highly enantioenriched axially chiral derivatives. This concept, termed as “double desymmetrization” (Scheme C), was based on the hypothesis that the introduction of an additional stereogenic element (stereogenic axis) could enhance asymmetric induction in both desymmetrization processes and potentially allow diastereomer separation. Unfortunately, neither our optimized nor previously reported conditions resulted in full conversion of the starting material, and no improvement in stereochemical outcome was observed. For example, under our optimized conditions, the expected product 5b was isolated in moderate yield (49%) as an inseparable mixture of diastereomers (1:1.4 dr) with moderate enantiopurity (74:26/83:13 er).

1. Screening of Various Acylation Reagents.

Next, we investigated the effect of various substrates on reaction efficiency in terms of yield and stereochemical outcome (Scheme ). Interestingly, the model reaction performed with the opposite enantiomer of the chiral precatalyst (ent-pre-C3) provided the enantiomeric product ent-3a in high yield (92%) with virtually retained enantiopurity (88:12 er). Then, we examined the influence of protecting groups on the myo-inositol derivative 1 (Scheme A). Changing the orthobenzoate to an orthoformate resulted in both lower yield and reduced enantioselectivity of 3b. Variations of the silyl-protecting group did not improve the outcome; for example, replacement with a benzoyl group resulted in a nearly racemic mixture (53:47 er). Notably, the monoprotected derivative 1a (lacking protection at the equatorial hydroxyl group) afforded the diacylated product in low yield (23%) and moderate enantioselectivity (72:28 er).

2. Substrate Scope.

^a Ent-pre-C3 was used.

^b Full consumption of 1 was not observed, aldehyde 2 was consumed.

^c Separated after acetylation, yield refer to compound 4 (over two steps).

Later, we explored the influence of various α-bromocinnamic aldehydes 2 in the acylation reaction with 1c (Scheme B). Gratifyingly, no significant changes in yield or enantioselectivity were observed with a naphthalene-derived cinnamic aldehyde. However, significantly decreased yields were obtained with α-bromocinnamic aldehydes bearing electron-donating groups (EDGs) in the para-position of the aromatic ring. A similar trend was observed with strong electron-withdrawing groups (EWGs) at the same position. For example, the trifluoromethyl-substituted product 3j was obtained in 59% yield with 82:18 er. In contrast, aldehydes containing weak EWGs furnished the corresponding products in comparable yields to the model reaction but with reduced enantioselectivity. Overall, the expected products 3l-n were isolated in yields ranging from 55 to 67% yield with enantioselectivities above 83:17 er. We also investigated the effect of substituent position on the aromatic ring using chloro- and bromo-substituted cinnamic aldehydes. Notably, no significant effect was observed. For example, the desymmetric acylation of meta-bromo-α-bromocinnamic aldehyde with 1c furnished product 3q in 78% yield with 87:13 er. Gratifyingly, the substrate scope could be further extended to heterocyclic α-bromocinnamic aldehydes as well as to ester-derived aldehyde. In contrast, no conversion of the starting material was observed with an aliphatic α-bromounsaturated aldehydes.

Finally, to evaluate the practicality and synthetic utility of our methodology (Scheme ). We performed a gram-scale reaction of 1c under the optimized conditions (Scheme A). The desired product 3a was isolated in a 50% yield with enantioselectivity comparable to the small-scale reaction.

3. Gram-Scale Reaction and Synthetic Utility Demonstration.

Further transformation of the free hydroxyl group (Scheme B) was achieved by acylation with Boc or acetyl groups under DMAP-catalyzed conditions, affording fully protected derivatives in nearly quantitative yields while retaining enantiopurity. Inspired by the biological relevance of myo-inositols, we next introduced phosphorylated analogues. Using the chiral (+)-PSI reagent developed by Phil S. Baran and co-workers, phosphorylation of 3a furnished the expected, hardly separable diastereomeric products in excellent yield, with a diastereomeric ratio consistent with the enantiopurity of the starting material.

We further examined the synthetic utility of the cinnamyl group as a protecting group (Scheme C). To preserve molecular chirality, the free hydroxyl group was first protected with a tetrahydropyranyl (THP) group, affording the expected diastereomeric product 8 in excellent yield. Importantly, selective removal of the cinnamyl group under Zemplén-like conditions proceeded smoothly, giving the desired product 9 in excellent yield. To verify that enantiopurity was retained throughout, we carried out allylation of the free hydroxyl group under standard conditions, followed by selective THP deprotection. Notably, for the deprotection of THP magnesium bromide was used, under these conditions all protecting groups remained intact, and the final product was obtained in excellent yield with preserved optical purity from 3a.

Conclusion

In summary, we have developed an efficient and versatile methodology for the enantioselective desymmetric acylation of prochiral myo-inositol-derived diols, providing straightforward access to valuable chiral derivatives. This operationally simple approach demonstrates the potential of organocatalytic desymmetrization in the synthesis of biologically relevant molecules. The method features broad functional group tolerance, scalability, and synthetic applicability, as demonstrated by follow-up transformations. Ongoing studies in our laboratory are directed toward applying this methodology to the synthesis of biologically relevant myo-inositol derivatives.

Experimental Section

Chemicals and solvents were purchased from commercial suppliers and purified using standard techniques. Thin-layer chromatography (TLC) was performed using silica gel plates Merck 60 F₂₅₄. The compounds were visualized by irradiation with UV light and/or by treatment with a solution of phosphomolybdic acid (AMC) followed by heating. Column chromatography was performed using silica gel SiliCycle-SiliaFlash P60 (particle size: 40–63 μm, pore diameter: 60 Å. ¹H, ¹³C NMR, ¹⁹F and ³¹P spectra were recorded with Bruker AVANCE III 400. Chemical shifts for protons are given in δ relative to tetramethylsilane (TMS) and referenced to residual protium in the NMR solvent (CDCl₃: δ_H = 7.26 ppm, DMSO-d ₆: δ_H = 2.50 ppm, D₂O: δ_H = 4.79 ppm). Chemical shifts for carbon are referenced to the carbon of the NMR solvent (CDCl₃: δ_C = 77.16 ppm, DMSO-d ₆: δ_C = 39.52 ppm). The coupling constants J are given in hertz. IR DRIFT spectra were recorded on a Nicolet AVATAR 370 FT-IR in cm^–1. Chiral HPLC was performed on a LC20AD Shimadzu liquid chromatograph with an SPD-M20A diode array detector with Daicel Chiralpak IA, Daicel Chiralpak IB, Daicel Chiralpak IC, Daicel Chiralpak IG, Daicel Chiralpak IH and Daicel Chiralpak ODH columns. For chiral HPLC, the samples were prepared by dissolving them in i-PrOH. Optical rotations were measured on AU-Tomatica polarimeter, Autopol III, and specific optical rotations are given in concentrations c [g/100 mL], the samples were prepared by dissolving them in specified solvent for each compound. All melting points were measured on a Büchi melting point B-545 apparatus, in an open glass capillary, and all values are uncorrected. High-resolution mass spectra were recorded on an LCQ Fleet spectrometer using a Bruker Compact QTOF-MS controlled by the Compass 1.9 Control software to measure the ESI high-resolution mass spectra. The monoisotopic mass values were calculated using Data analysis software v 4.4. The analysis was conducted in the positive or negative ion mode at a scan range from m/z 50 to 1000, and nitrogen was used as nebulizer gas at a pressure of 4 psi and flow of 3 L/min for the dry gas. The capillary voltage and temperature were set at 4500 V and 220 °C, respectively. For HRMS, the samples were prepared by dissolving them in methanol.

General Procedure A: Preparation of Bridged myo-Inositols

Synthesis of protected myo-inositols (1a,b) was conducted under modified conditions previously reported in the literature.

Round bottom flask equipped with a magnetic stirring bar was charged with myo-inositol (1.0 equiv), trialkylorthoacylate (1.8–2.2 equiv), p-toluenesulfonic acid monohydrate (15–30 mol %) and DMF (1–1.5 mL/mmol). This mixture was then heated at 100–145 °C (oil bath) for 3–4 h. After cooling to the room temperature was the acid quenched by adding triethylamine (15–30 mol %). The solvent was evaporated under reduced pressure. Product was purified either by filtration or by column chromatography.

D-myo-Inositol-1,3,5-orthobenzoate (1a)

The title compound was synthesized according to the general procedure A, using myo-inositol (9.01 g, 50 mmol), trimethylorthobenzoate (18.9 mL, 110 mmol), p-toluenesulfonic acid monohydrate (2.76 g, 14.5 mmol) and DMF (80 mL) and heating to 145 °C overnight. The reaction was quenched by adding Et₃N (2.1 mL,15 mmol). The crude product was purified by column chromatography (hexane/EtOAc – 1:10), affording 1a (6.2 g, 47%) as a white amorphous solid.

¹H NMR (400 MHz, DMSO-d ₆ ) δ 7.60–7.53 (m, 2H), 7.41–7.29 (m, 3H), 5.51 (s, 2H), 5.33 (d, J = 6.3 Hz, 1H), 4.44–4.38 (m, 2H), 4.24–4.19 (m, 1H), 4.18–4.13 (m, 2H), 4.09 (d, J = 5.0 Hz, 1H) ppm. ¹³C­{¹H} NMR (101 MHz, DMSO-d ₆ ) δ 137.9, 129.0, 127.6 (2C), 125.5 (2C), 106.5, 75.8 (2C), 70.1, 67.2 (2C), 57.8. HRMS (ESI+) m/z: calcd. for C₁₃H₁₄NaO₆ [M + Na]⁺: 289.0683, found: 289.0679. Our physical and spectroscopic data matched previously reported data.

D-myo-Inositol-1,3,5-orthoformate (1b)

The title compound was synthesized according to the general procedure A, using myo-inositol (6.00 g, 33.3 mmol), triethylorthoformate (10.0 mL, 60.6 mmol), p-toluenesulfonic acid monohydrate (1.01 g, 5.3 mmol) and DMF (38 mL) and heating to 100 °C (oil bath) overnight. The product was purified by filtration from EtOAc/MeOH, affording 1b (1.89 g, 30%) as a white/beige amorphous solid.

¹H NMR (400 MHz, D₂O) δ 5.62 (s, 1H), 4.62–4.57 (m, 2H), 4.38–4.33 (m, 1H), 4.31–4.23 (m, 3H) ppm. ¹³C­{¹H} NMR (101 MHz, D₂O) δ 102.1, 73.8 (2C), 69.3, 66.7 (2C), 59.6 ppm. HRMS (ESI−) m/z: calcd. for C₇H₉O₆ [M - H]⁻: 189.0405, found: 189.0399. Our physical and spectroscopic data matched previously reported data.

General Procedure B: Preparation of 2-Protected Bridged myo-Inositols

To a stirred solution of a bridged myo-inositol (1.0 equiv) with 2,6-lutidine (2.5 equiv) or imidazole (2.2 equiv) in DMF (2.5 mL/mmol) was added the protecting agent (1.05 equiv) portionwise. The reaction was stirred at room temperature until full conversion (TLC monitored). The solvent was then evaporated under reduced pressure. The crude product was purified by column chromatography.

2-O-tert-Butyldimethylsilyl-d-myo-inositol-1,3,5-orthobenzoate (1c)

The title compound was synthesized according to the general procedure B, using bridged myo-inositol 1a (2.06 g, 7.74 mmol), TBDMSCl (1.22 g, 8.12 mmol), 2,6-lutidine (2.24 mL, 19.34 mmol) and DMF (20 mL). The crude product was purified by column chromatography (hexane/EtOAc – 10:1 to 1:1), affording 1c (1.59 g, 54%) as a white/beige amorphous solid.

¹H NMR (400 MHz, CDCl₃) δ 7.68–7.60 (m, 2H), 7.40–7.33 (m, 3H), 4.61–4.54 (m, 2H), 4.30–4.23 (m, 4H), 3.48 (s, 2H), 0.97 (s, 9H), 0.16 (s, 6H) ppm. ¹³C­{¹H} NMR (101 MHz, CDCl₃) δ 137.2, 129.7, 128.2 (2C), 125.5 (2C), 107.2, 76.1 (2C), 69.6, 68.5 (2C), 59.8, 26.0 (3C), 18.4, −4.4 (2C) ppm. HRMS (ESI+) m/z: calcd. for C₁₉H₂₉O₆Si [M + H]⁺: 381.1728, found: 381.1729. Our physical and spectroscopic data matched previously reported data.

2-O-tert-Butyldimethylsilyl-d-myo-inositol-1,3,5-orthoformate (1d)

The title compound was synthesized according to the general procedure B, using bridged myo-inositol 1b (800 mg, 4.21 mmol), TBDMSCl (666 mg, 4.42 mmol), 2,6-lutidine (1.22 mL, 10.52 mmol) and DMF (11 mL). The product was purified by column chromatography (hexane/EtOAc – 3:1 to 1:1), affording 1d (481 mg, 38%) as a white/beige amorphous solid.

¹H NMR (400 MHz, CDCl₃) δ 5.50 (s, 1H), 4.63–4.55 (m, 2H), 4.31–4.23 (m, 2H), 4.19–4.12 (m, 2H), 3.30–3.24 (m, 2H), 0.95 (s, 9H), 0.16 (s, 6H) ppm. ¹³C­{¹H} NMR (101 MHz, CDCl₃) δ 102.6, 74.8 (2C), 68.9, 68.8 (2C), 60.7, 26.1 (3C), 18.6, −4.5 (2C) ppm. HRMS (ESI+) m/z: calcd. for C₁₃H₂₄NaO₆Si [M + Na]⁺: 327.1234, found: 327.1235. Our physical and spectroscopic data matched previously reported data.

2-O-Trimethylsilyl-d-myo-inositol-1,3,5-orthobenzoate (1e)

The title compound was synthesized according to the general procedure B, using bridged myo-inositol 1a (500 mg, 1.88 mmol), TMSCl (260 μL, 2.07 mmol), imidazole (281 mg, 4.13 mmol) and DMF (5 mL). The product was purified by column chromatography (hexane/EtOAc – 10:1 to 1:1), affording 1e (75 mg, 12%) as a white/beige amorphous solid.

¹H NMR (400 MHz, CDCl₃) δ 7.70–7.61 (m, 2H), 7.41–7.31 (m, 3H), 4.72–4.63 (m, 2H), 4.38–4.34 (m, 1H), 4.34–4.27 (m, 3H), 3.34–3.25 (m, 2H), 0.22 (s, 9H) ppm. ¹³C­{¹H} NMR (101 MHz, CDCl₃) δ 137.1, 129.6, 128.2 (2C), 125.6 (2C), 107.2, 76.1 (2C), 69.8, 68.6 (2C), 59.6, 0.4 (3C) ppm. HRMS (ESI+) m/z: calcd. for C₁₆H₂₂NaO₆Si [M + Na]⁺: 361.1078, found: 361.1076.

2-O-tert-Butyldiphenylsilyl-d-myo-inositol-1,3,5-orthobenzoate (1f)

The title compound was synthesized according to the general procedure using bridged myo-inositol 1a (500 mg, 1.88 mmol), TBDPSCl (537 μL, 2.07 mmol), imidazole (281 mg, 4.13 mmol) and DMF (5 mL). The product was purified by column chromatography (hexane/EtOAc – 10:1 to 3:1), affording 1f (545 mg, 58%) as a white/beige amorphous solid.

¹H NMR (400 MHz, CDCl₃) δ 7.75–7.66 (m, 4H), 7.61–7.41 (m, 8H), 7.40–7.26 (m, 3H), 4.75–4.70 (m, 1H), 4.67–4.60 (m, 1H), 4.47–4.43 (m, 1H), 4.34–4.28 (m, 2H), 4.08 (d, J = 10.2 Hz, 1H), 4.05–4.00 (m, 1H), 3.20–3.12 (m, 1H), 1.12 (s, 9H) ppm. ¹³C­{¹H} NMR (101 MHz, CDCl₃) δ 136.6, 135.8 (2C), 135.7 (2C), 131.30, 131.26, 131.0, 130.8, 129.8, 128.5 (2C), 128.4 (2C), 128.2 (2C), 125.3 (2C), 107.2, 76.2, 75.1, 69.7, 69.3, 68.2, 60.0, 27.0 (3C), 19.1 ppm. IR (ATR): ν = 3494, 1338 (OH), 1099, 1055 (C–O) cm^–1. HRMS (ESI+) m/z: calcd. for C₂₉H₃₃O₆Si [M + H]⁺: 505.2041, found: 505.2062.

2-O-Benzoyl-d-myo-inositol-1,3,5-orthobenzoate (1g)

The title compound was prepared by alternative strategy. Bridged myo-inositol 1a (500 mg, 1.88 mmol) and imidazole (281 mg, 4.13 mmol, 2.2 equiv) were stirred at 0 °C in DMF (5 mL). Benzoyl chloride (240 μL, 2.07 mmol, 1.1 equiv) was added portionwise and the reaction mixture was stirred at room temperature for 2 days. The solvent was evaporated and the product was purified by column chromatography (hexane/EtOAc – 10:1 to 1:3), affording 1g (197 mg, 28%) as a white/beige amorphous solid.

¹H NMR (400 MHz, DMSO-d ₆ ) δ 8.09–7.99 (m, 2H), 7.74–7.65 (m, 1H), 7.62–7.53 (m, 4H), 7.45–7.33 (m, 3H), 5.83–5.74 (m, 2H), 5.60 (s, 1H), 4.55–4.50 (m, 2H), 4.50–4.46 (m, 2H), 4.38–4.31 (m, 1H) ppm. ¹³C­{¹H} NMR (101 MHz, DMSO-d ₆ ) δ 165.2, 137.5, 133.6, 129.5, 129.33 (2C), 129.28, 129.2, 128.9 (2C), 127.8 (2C), 125.3 (2C), 106.6, 73.3 (2C), 70.5, 66.9, 63.0 ppm. HRMS (ESI+) m/z: calcd. for C₂₀H₁₈NaO₇ [M + Na]⁺: 393.0945, found: 393.0944. Our physical and spectroscopic data matched previously reported data.

General Procedure C: Organocatalytic Desymmetrization

Vial (4 mL) was loaded with 1 (0.1 mmol), pre-C3 (0.5 mg, 0.001 mmol), DABCO (16.8 mg, 0.15 mmol) and chlorobenzene (1.0 mL) at room temperature. Then, the corresponding carbonyl reagent 2 (0.15 mmol) was added. The reaction was stirred for an indicated time at room temperature. After completion of the reaction (monitored by TLC) the crude mixture was purified by column chromatography (mixtures of hexane/EtOAc).

Note: Racemic products were prepared by reactions with pre-C6.

General Procedure D: Organocatalytic Desymmetrization Followed by Protection

Vial (4 mL) was loaded with 1 (0.1 mmol), pre-C3 (0.5 mg, 0.001 mmol), DABCO (16.8 mg, 0.15 mmol) and chlorobenzene (1.0 mL) at room temperature. Then, the corresponding carbonyl reagent 2 (0.15 mmol) was added. The reaction was stirred for an indicated time at room temperature. After completion of the reaction (monitored by TLC) the major impurities were separated by column chromatography (eluted by hexane/EtOAc 3:1). The obtained product with minor impurity was then mixed with Ac₂O (1.2 equiv), Et₃N (1.2 equiv), DMAP (10 mol %) in dry THF (10 mL/mmol) in a small vial (4 mL) at 0 °C. The reaction was stirred at room temperature until full conversion (monitored by TLC). Purifying by column chromatography (mixtures of hexane/EtOAc) afforded the product.

Note: Racemic products were prepared by reactions with pre-C6.

(1R,3R,5S,6R,7S,8R,9S)-8-((tert-Butyldimethylsilyl)­oxy)-9-hydroxy-3-phenyl-2,4,10-trioxaadamantan-6-yl cinnamate (3a)

The title compound was synthesized according to the general procedure C (reaction time: 18 h), using 1c (38.1 mg, 0.1 mmol) and (2Z)-2-bromo-3-phenyl-2-propenal (31.7 mg, 0.15 mmol). The crude product was purified by column chromatography (hexane/EtOAc – 10:1 to 5:1), affording 3a (33.0 mg, 65%) as a white amorphous solid.

Note: Crystals suitable for X-ray analysis (er = 99.7:0.3) were obtained by slow evaporation of i-PrOH at room temperature.

Er = 85.3:14.7 (ee = 70%), the enantiomeric excess of product 3a was determined by high-performance liquid chromatography (HPLC) using a Chiralpak IA column (n-heptane/i-PrOH – 95:5, flow rate = 1.0 mL/min, λ = 275 nm, t = 25 °C): t _R = 13.4 min (minor), t _R = 17.5 min (major). [α]_D = −18.3 (c = 0.4, CHCl₃). ¹H NMR (400 MHz, CDCl₃) δ 7.75 (d, J = 16.0 Hz, 1H), 7.72–7.66 (m, 2H), 7.58–7.51 (m, 2H), 7.48–7.32 (m, 6H), 6.42 (d, J = 16.0 Hz, 1H), 5.79–5.74 (m, 1H), 4.72–4.67 (m, 1H), 4.60–4.55 (m, 1H), 4.46–4.41 (m, 1H), 4.37–4.30 (m, 2H), 2.42 (bs, 1H), 0.97 (s, 9H), 0.17 (s, 3H), 0.17 (s, 3H) ppm. ¹³C­{¹H} NMR (101 MHz, CDCl₃) δ 165.3, 147.2, 137.2, 133.9, 131.1, 129.6, 129.2 (2C), 128.5 (2C), 128.1 (2C), 125.6 (2C), 116.4, 107.7, 76.0, 73.7, 69.4, 69.2, 68.1, 60.3, 26.0 (2C), 18.5, −4.4, −4.5. IR (ATR): ν = 3489 (OH), 1712 (CO, ester), 1633 (CC), 1101 (C–O, alcohol) cm^–1. HRMS (ESI+) m/z: calcd. for C₂₈H₃₅O₇Si [M + H]⁺: 511.2147, found: 511.2138.

(1S,3S,5R,6S,7R,8S,9R)-8-((tert-Butyldimethylsilyl)­oxy)-9-hydroxy-3-phenyl-2,4,10-trioxaadamantan-6-yl cinnamate (ent-3a)

The title compound was synthesized according to the general procedure C (reaction time: 18 h), using 1c (38.1 mg, 0.1 mmol) and (2Z)-2-bromo-3-phenyl-2-propenal (31.7 mg, 0.15 mmol) and ent-pre-C4 (0.5 mg, 0.001 mmol) instead pre- C4. The crude product was purified by column chromatography (hexane/EtOAc – 10:1 to 5:1), affording ent-3a (47.0 mg, 92%) as a white amorphous solid.

Er = 87.9:12.1 (ee = 76%), the enantiomeric excess of product ent-3a was determined by HPLC using a Chiralpak IA column (n-heptane/i-PrOH – 95:5, flow rate = 1.0 mL/min, λ = 275 nm, t = 25 °C): t _R = 13.4 min (major), t _R = 17.5 min (minor). [α]_D = +16.7 (c = 0.5, CHCl₃). Other analytical data agree with the data of the opposite enantiomer (3a).

(1R,3R,5S,6R,7S,8R,9S)-8-((tert-Butyldimethylsilyl)­oxy)-9-hydroxy-2,4,10-trioxaadamantan-6-yl cinnamate (3b)

The title compound was synthesized according to the general procedure C (reaction time: 18 h), using 1d (30.4 mg, 0.1 mmol) and (2Z)-2-bromo-3-phenyl-2-propenal (31.7 mg, 0.15 mmol). The crude product was purified by column chromatography (hexane/EtOAc – 10:1 to 3:1), affording 3b (21.0 mg, 48%) as a white amorphous solid.

Er = 73.2:26.8 (ee = 46%), the enantiomeric excess of product 3b was determined by HPLC using a Chiralpak IA column (n-heptane/i-PrOH – 95:5, flow rate = 1.0 mL/min, λ = 277 nm, t = 25 °C): t _R = 15.8 min (minor), t _R = 19.7 min (major). [α]_D = −16.9 (c = 0.7, CHCl₃). ¹H NMR (400 MHz, CDCl₃) δ 7.72 (d, J = 15.9 Hz, 1H), 7.56–7.51 (m, 2H), 7.47–7.36 (m, 3H), 6.38 (d, J = 15.9 Hz, 1H), 5.68–5.63 (m, 1H), 5.57 (d, J = 1.3 Hz, 1H), 4.64–4.58 (m, 1H), 4.48–4.43 (m, 1H), 4.31–4.24 (m, 2H), 4.19–4.15 (m, 1H), 2.38 (d, J = 7.2 Hz, 1H), 0.95 (s, 9H), 0.164 (s, 3H), 0.160 (s, 3H) ppm. ¹³C­{¹H} NMR (101 MHz, CDCl₃) δ 165.1, 147.2, 133.9, 131.1, 129.2 (2C), 128.5 (2C), 116.3, 103.0, 74.7, 72.3, 69.4, 68.4, 68.2, 61.2, 26.1 (3C), 18.6, −4.52, −4.49 ppm. IR (ATR): ν = 3492 (OH), 1714 (CO, ester), 1635, 984 (CC) cm^–1. HRMS (ESI+) m/z: calcd. for C₂₂H₃₁O₇Si [M + H]⁺: 435.1834, found: 435.1844.

(1R,3R,5S,6R,7S,8S,9R)-8-Hydroxy-3-phenyl-9-((trimethylsilyl)­oxy)-2,4,10-trioxaadamantan-6-yl cinnamate (3c)

The title compound was synthesized according to the general procedure C (reaction time: 22 h), using 1e (33.8 mg, 0.1 mmol) and (2Z)-2-bromo-3-phenyl-2-propenal (31.7 mg, 0.15 mmol). The crude product was purified by column chromatography (hexane/EtOAc – 10:1 to 3:1), affording 3c (10.0 mg, 21%) as a white amorphous solid.

Er = 85.1:14.9 (ee = 70%), the enantiomeric excess of product 3c was determined by HPLC using a Chiralpak IA column (n-heptane/i-PrOH – 95:5, flow rate = 1.0 mL/min, λ = 277 nm, t = 25 °C): t _R = 15.8 min (minor), t _R = 23.3 min (major). [α]_D = −15.5 (c = 0.3, CHCl₃). ¹H NMR (400 MHz, CDCl₃) δ 7.76 (d, J = 16.0 Hz, 1H), 7.71–7.67 (m, 2H), 7.58–7.53 (m, 2H), 7.45–7.34 (m, 6H), 6.43 (d, J = 15.9 Hz, 1H), 5.81–5.77 (m, 1H), 4.76–4.70 (m, 1H), 4.60–4.56 (m, 1H), 4.47–4.42 (m, 1H), 4.38–4.34 (m, 1H), 4.32–4.29 (m, 1H), 2.40 (d, J = 7.3 Hz, 1H), 0.22 (s, 9H) ppm. ¹³C­{¹H} NMR (101 MHz, CDCl₃) δ 165.2, 147.3, 137.0, 134.0, 131.2, 129.7, 129.2 (2C), 128.5 (2C), 128.1 (2C), 125.6 (2C), 116.3, 107.7, 76.0, 73.6, 69.4, 69.3, 68.1, 60.1, 0.4 (3C) ppm. IR (ATR): ν = 3379 (OH), 1712 (CO, ester), 1633, 976 (CC), 1101 (C–O, alcohol) cm^–1. HRMS (ESI+) m/z: calcd. for C₂₅H₂₉O₇Si [M + H]⁺: 469.1677, found: 469.1689.

(1R,3R,5S,6R,7S,8R,9S)-8-((tert-Butyldiphenylsilyl)­oxy)-9-hydroxy-3-phenyl-2,4,10-trioxaadamantan-6-yl cinnamate (3d)

The title compound was synthesized according to the general procedure C (reaction time: 42 h), using 1f (50.5 mg, 0.1 mmol) and (2Z)-2-bromo-3-phenyl-2-propenal (31.7 mg, 0.15 mmol). The crude product was purified by column chromatography (hexane/EtOAc – 10:1 to 5:1), affording 3d (28.0 mg, 44%) as a white amorphous solid.

Er = 71.6:28.4 (ee = 43%), the enantiomeric excess of product 3d was determined by HPLC using a Chiralpak IA column (n-heptane/i-PrOH – 97:3, flow rate = 1.0 mL/min, λ = 190 nm, t = 25 °C): t _R = 13.4 min (minor), t _R = 16.1 min (major). [α]_D = +33.0 (c = 1.0, CHCl₃). ¹H NMR (400 MHz, CDCl₃) δ 7.83 (d, J = 16.0 Hz, 1H), 7.80–7.76 (m, 2H), 7.74–7.69 (m, 2H), 7.61–7.38 (m, 14H), 7.35–7.30 (m, 2H), 6.61 (d, J = 16.0 Hz, 1H), 5.77–5.73 (m, 1H), 4.77–4.68 (m, 2H), 4.65–4.60 (m, 1H), 4.46–4.41 (m, 1H), 4.27–4.18 (m, 2H), 1.17 (s, 9H) ppm. ¹³C­{¹H} NMR (101 MHz, CDCl₃) δ 166.5, 146.0, 136.8, 136.1 (2C), 135.7 (2C), 134.5, 131.4, 131.15, 131.0, 130.8, 130.6, 129.7, 129.1 (2C), 128.41 (2C), 128.38 (4C), 128.2 (2C), 125.4 (2C), 117.8, 107.2, 74.1, 72.7, 69.8 (2C), 68.5, 62.1, 27.1 (3C), 19.1 ppm. IR (ATR): ν = 3490 (OH), 1712 (CO, ester), 1635, 978 (CC), 1101 (C–O, alcohol) cm^–1. HRMS (ESI+) m/z: calcd. for C₃₈H₃₉O₇Si [M + H]⁺: 635.2460, found: 635.2470.

(1S,3R,5R,6R,7S,8R,9S)-8-(Cinnamoyloxy)-9-hydroxy-3-phenyl-2,4,10-trioxaadamantan-6-yl benzoate (3e)

The title compound was synthesized according to the general procedure C (reaction time: 18 h), using 1g (37.0 mg, 0.1 mmol) and (2Z)-2-bromo-3-phenyl-2-propenal (31.7 mg, 0.15 mmol). The crude product was purified by column chromatography (hexane/EtOAc – 10.1 to 3:1), affording 3e (30.0 mg, 60%) as a white amorphous solid.

Er = 53.3:46.7 (ee = 7%), the enantiomeric excess of product 3e was determined by HPLC using a Chiralpak IA column (n-heptane/i-PrOH – 90:10, flow rate = 1.0 mL/min, λ = 276 nm, t = 25 °C): t _R = 16.9 min (major), t _R = 21.5 min (minor). [α]_D = −6.3 (c = 0.7, CHCl₃). ¹H NMR (400 MHz, CDCl₃) δ 8.19–8.13 (m, 2H), 7.79 (d, J = 16.0 Hz, 1H), 7.72 (dd, J = 6.7, 3.0 Hz, 2H), 7.62–7.51 (m, 3H), 7.52–7.37 (m, 8H), 6.52 (d, J = 16.0 Hz, 1H), 5.93–5.86 (m, 1H), 5.73–5.68 (m, 1H), 4.88–4.81 (m, 1H), 4.80–4.76 (m, 1H), 4.76–4.72 (m, 1H), 4.72–4.66 (m, 1H), 2.84 (d, J = 6.6 Hz, 1H) ppm. ¹³C­{¹H} NMR (101 MHz, CDCl₃) δ 166.4, 165.5, 147.4, 136.8, 134.0, 133.6, 131.0, 130.1 (2C), 129.9, 129.7, 129.1 (2C), 128.62 (2C), 128.55 (2C), 128.3, 125.5, 116.4, 107.8, 73.3, 71.1, 69.4, 68.6, 67.7, 63.0 ppm. IR (ATR): ν = 3485 (OH), 1712, 1693 (CO, ester), 1635, 968 (CC), 1103 (C–O, alcohol) cm^–1. HRMS (ESI+) m/z: calcd. for C₂₉H₂₅O₈ [M + H]⁺: 501.1544, found: 501.1554.

(1R,3R,5S,6R,7S,8R,9S)-9-Hydroxy-3-phenyl-2,4,10-trioxaadamantane-6,8-diyl (2E,2’E)-bis­(3-phenyl acrylate) (3f)

The title compound was synthesized according to the general procedure C (reaction time: 20 h), using 1a (26.6 mg, 0.1 mmol) and (2Z)-2-bromo-3-phenyl-2-propenal (52.8 mg, 0.25 mmol). The crude product was purified by column chromatography (hexane/EtOAc – 10:1 to 1:1), affording 3f (12.0 mg, 23%) as a beige amorphous solid.

Er = 72.4:27.6 (ee = 45%), the enantiomeric excess of product 3f was determined by HPLC using a Chiralpak IA column (n-heptane/i-PrOH – 90:10, flow rate = 1.0 mL/min, λ = 276 nm, t = 25 °C): t _R = 23.3 min (major), t _R = 43.4 min (minor). [α]_D = – 45.8 (c = 0.5, CHCl₃) ¹H NMR (400 MHz, CDCl₃) δ 7.80 (d, J = 16.0 Hz, 1H), 7.80 (d, J = 15.9 Hz, 1H), 7.75–7.68 (m, 2H), 7.55 (dq, J = 7.7, 2.8 Hz, 4H), 7.41 (dh, J = 6.3, 3.0 Hz, 9H), 6.61 (d, J = 16.0 Hz, 1H), 6.49 (d, J = 15.9 Hz, 1H), 5.90–5.84 (m, 1H), 5.59–5.54 (m, 1H), 4.84–4.77 (m, 1H), 4.73–4.66 (m, 2H), 4.66–4.61 (m, 1H), 2.56 (bs, 1H) ppm. ¹³C­{¹H} NMR (101 MHz, CDCl₃) δ 166.7, 165.3, 147.5, 146.3, 136.7, 134.3, 134.0, 131.1, 130.7, 129.9, 129.15 (2C), 129.08 (2C), 128.6 (2C), 128.4 (2C), 128.3 (2C), 125.5 (2C), 117.6, 116.3, 107.8, 73.4, 71.1, 69.4, 68.6, 67.8, 62.4 ppm. IR (ATR): ν = 3473 (OH), 1709 (CO, ester), 1633, 976 (CC), 1101 (C–O, alcohol) cm^–1. HRMS (ESI+) m/z: calcd. for C₃₁H₂₇O₈ [M + H]⁺: 527.1700, found: 527.1714.

(1R,3R,5S,6R,7S,8R,9S)-8-((tert-Butyldimethylsilyl)­oxy)-9-hydroxy-3-phenyl-2,4,10-trioxaadamantan-6-yl (E)-3-(naphthalen-2-yl)­acrylate (3g)

The title compound was synthesized according to the general procedure C (reaction time: 18 h), using 1c (38.1 mg, 0.1 mmol) and (2Z)-2-bromo-3-(naphtalen-2-yl)-2-propenal (39.2 mg, 0.15 mmol). The crude product was purified by column chromatography (hexane/EtOAc – 10:1 to 3:1), affording 3g (35.0 mg, 62%) as a white amorphous solid.

Er = 81.8:18.2 (ee = 64%), the enantiomeric excess of product 3g was determined by HPLC using a Chiralpak IA column (n-heptane/i-PrOH – 95:5, flow rate = 1.0 mL/min, λ = 271 nm, t = 25 °C): t _R = 17.2 min (minor), t _R = 24.5 min (major). [α]_D = −18.7 (c = 0.6, CHCl₃) ¹H NMR (400 MHz, CDCl₃) δ 7.97–7.79 (m, 5H), 7.75–7.63 (m, 3H), 7.60–7.49 (m, 2H), 7.40–7.36 (m, 3H), 6.53 (d, J = 15.9 Hz, 1H), 5.84–5.78 (m, 1H), 4.76–4.69 (m, 1H), 4.64–4.58 (m, 1H), 4.49–4.43 (m, 1H), 4.39–4.33 (m, 2H), 2.48 (s, 1H), 0.98 (s, 9H), 0.185 (s, 3H), 0.182 (s, 3H) ppm. ¹³C­{¹H} NMR (101 MHz, CDCl₃) δ 165.3, 147.3, 137.2, 134.6, 133.3, 131.4, 130.8, 129.6, 129.0, 128.8, 128.2 (2C), 128.0, 127.8, 127.1, 125.6 (2C), 123.5, 116.4, 107.7, 76.0, 73.7, 69.5, 69.3, 68.2, 60.3, 26.0 (3C), 18.5, −4.45, −4.35 ppm. IR (ATR): ν = 3452 (OH), 1709 (CO, ester), 1630, 958 (CC), 1099 (C–O, alcohol) cm^–1. HRMS (ESI+) m/z: calcd. for C₃₂H₃₆NaO₇Si [M + Na]⁺: 583.2123, found: 583.2114.

(1R,3R,5S,6R,7S,8R,9S)-8-((tert-Butyldimethylsilyl)­oxy)-9-hydroxy-3-phenyl-2,4,10-trioxaadamantan-6-yl (E)-3-(p-tolyl)­acrylate (3h)

The title compound was synthesized according to the general procedure C (reaction time: 18 h), using 1c (38.1 mg, 0.1 mmol) and (2Z)-2-bromo-3-(4-methylphenyl)-2-propenal (33.8 mg, 0.15 mmol). The crude product was purified by column chromatography (hexane/EtOAc – 7:1 to 3:1), affording 3h (17.0 mg, 32%) as a white amorphous solid.

Er = 82.3:17.7 (ee = 65%), the enantiomeric excess of product 3h was determined by HPLC using a Chiralpak IA column (n-heptane/i-PrOH – 95:5, flow rate = 1.0 mL/min, λ = 284 nm, t = 25 °C): t _R = 17.1 min (minor), t _R = 20.6 min (major). [α]_D = −15.8 (c = 0.7, CHCl₃) ¹H NMR (400 MHz, CDCl₃) δ 7.72 (d, J = 15.9 Hz, 1H), 7.71–7.65 (m, 2H), 7.44 (d, J = 8.0 Hz, 2H), 7.39–7.35 (m, 3H), 7.22 (d, J = 7.9 Hz, 2H), 6.37 (d, J = 15.9 Hz, 1H), 5.80–5.75 (m, 1H), 4.73–4.66 (m, 1H), 4.60–4.54 (m, 1H), 4.46–4.40 (m, 1H), 4.37–4.32 (m, 1H), 4.32–4.29 (m, 1H), 2.39 (s, 3H), 1.61 (bs, 1H), 0.96 (s, 9H), 0.164 (s, 3H), 0.160 (s, 3H) ppm. ¹³C­{¹H} NMR (101 MHz, CDCl₃) δ 165.4, 147.3, 141.8, 137.2, 131.2, 129.9 (2C), 129.6, 128.5 (2C), 128.2 (2C), 125.6 (2C), 115.1, 107.7, 76.0, 73.6, 69.4, 69.2, 68.2, 60.3, 26.0 (3C), 21.7, 18.5, −4.4, −4.5 ppm. IR (ATR): ν = 3500 (OH), 1712 (CO, ester), 1633, 960 (CC), 1101 (C–O, alcohol) cm^–1. HRMS (ESI+) m/z: calcd. for C₂₉H₃₇O₇Si [M + H]⁺: 525.2303, found: 525.2322.

(1R,3R,5S,6R,7S,8R,9S)-8-((tert-Butyldimethylsilyl)­oxy)-9-hydroxy-3-phenyl-2,4,10-trioxaadamantan-6-yl (E)-3-(4-methoxyphenyl)­acrylate (3j)

The title compound was synthesized according to the general procedure C (reaction time: 18 h), using 1c (38.1 mg, 0.1 mmol) and (2Z)-2-bromo-3-(4-trifluoromethylphenyl)-2-propenal (41.9 mg, 0.15 mmol). The crude product was purified by column chromatography (hexane/EtOAc – 5:1), affording 3j (34.0 mg, 59%) as a white amorphous solid.

Er = 81.9:18.1 (ee = 64%), the enantiomeric excess of product 3j was determined by HPLC using a Chiralpak IA column (n-heptane/i-PrOH – 95:5, flow rate = 1.0 mL/min, λ = 271 nm, t = 25 °C): t _R = 10.6 min (minor), t _R = 15.1 min (major). [α]_D = −13.3 (c = 0.4, CHCl₃. ¹H NMR (400 MHz, CDCl₃) δ 7.75 (d, J = 16.0 Hz, 1H), 7.70–7.62 (m, 6H), 7.41–7.33 (m, 3H), 6.49 (d, J = 16.0 Hz, 1H), 5.79–5.74 (m, 1H), 4.75–4.69 (m, 1H), 4.63–4.57 (m, 1H), 4.46–4.40 (m, 1H), 4.36–4.30 (m, 2H), 2.34 (d, J = 6.9 Hz, 1H), 0.97 (s, 9H), 0.17 (s, 3H), 0.16 (s, 3H) ppm. ¹³C­{¹H} NMR (101 MHz, CDCl₃) δ 164.9, 145.1, 137.3, 137.1, 132.5 (q, J = 32.8 Hz), 129.7, 128.6 (2C), 128.2 (2C), 126.1 (q, J = 3.7 Hz, 2C), 125.6 (2C), 123.8 (q, J = 272.3 Hz), 119.1, 107.7, 76.0, 73.6, 69.7, 69.2, 68.0, 60.3, 26.0 (3C), 18.5, −4.4, −4.5 ppm. ¹⁹F NMR (376 MHz, CDCl₃) δ – 62.94 (s, 3F). IR (ATR): ν = 3502 (OH), 1712 (CO, ester), 1635, 958 (CC), 1315 (C–F), 1101 (C–O, alcohol) cm^–1. HRMS (ESI+) m/z: calcd. for C₂₉H₃₃F₃NaO₇Si [M + Na]⁺: 601.1840, found: 601.1821.

(1R,3R,5S,6R,7S,8R,9S)-8-((tert-butyldimethylsilyl)­oxy)-9-hydroxy-3-phenyl-2,4,10-trioxaadamantan-6-yl (E)-3-(4-fluorophenyl)­acrylate (3l)

The title compound was synthesized according to the general procedure C (reaction time: 18 h), using 1c (38.1 mg, 0.1 mmol) and (2Z)-2-bromo-3-(4-fluorophenyl)-2-propenal (34.4 mg, 0.15 mmol). The crude product was purified by column chromatography (hexane/EtOAc – 8:1 to 3:1), affording 3l (29.0 mg, 55%) as a white amorphous solid.

Er = 85.8:14.2 (ee = 72%), the enantiomeric excess of product 3l was determined by HPLC using a Chiralpak IA column (n-heptane/i-PrOH – 95:5, flow rate = 1.0 mL/min, λ = 190 nm, t = 25 °C): t _R = 12.5 min (minor), t _R = 16.3 min (major). [α]_D = −18.8 (c = 0.4, CHCl₃). ¹H NMR (400 MHz, CDCl₃) δ 7.75–7.63 (m, 3H), 7.57–7.48 (m, 2H), 7.41–7.33 (m, 3H), 7.10 (t, J = 8.5 Hz, 2H), 6.34 (d, J = 15.9 Hz, 1H), 5.79–5.74 (m, 1H), 4.74–4.67 (m, 1H), 4.60–4.55 (m, 1H), 4.45–4.40 (m, 1H), 4.36–4.32 (m, 1H), 4.32–4.29 (m, 1H), 2.35 (s, 1H), 0.97 (s, 9H), 0.17 (s, 3H), 0.16 (s, 3H) ppm. ¹³C­{¹H} NMR (101 MHz, CDCl₃) δ 165.2, 164.4 (d, J = 252.7 Hz), 145.8, 137.1, 130.4 (d, J = 8.6 Hz, 2C), 130.2 (d, J = 3.4 Hz), 129.6, 128.2 (2C), 125.6 (2C), 116.4 (d, J = 22.0 Hz, 2C), 116.1 (d, J = 2.5 Hz), 107.7, 76.0, 73.6, 69.5, 69.2, 68.1, 60.3, 26.0 (3C), 18.5, −4.4, −4.5 ppm. ¹⁹F NMR (376 MHz, CDCl₃) δ – 108.23 (tt, J = 8.2, 5.2 Hz, 1F). IR (ATR): ν = 3500 (OH), 1716 (CO, ester), 1635, 962 (CC), 1325 (C–F), 1101 (C–O, alcohol) cm^–1. HRMS (ESI+) m/z: calcd. for C₂₈H₃₃FNaO₇Si [M + Na]⁺: 551.1872, found: 551.1862.

(1R,3R,5S,6R,7S,8R,9S)-8-((tert-Butyldimethylsilyl)­oxy)-9-hydroxy-3-phenyl-2,4,10-trioxaadamantan-6-yl (E)-3-(4-chlorophenyl)­acrylate (3m)

The title compound was synthesized according to the general procedure C (reaction time: 28 h), using 1c (38.1 mg, 0.1 mmol) and (2Z)-2-bromo-3-(4-chlorophenyl)-2-propenal (36.8 mg, 0.15 mmol). The crude product was purified by column chromatography (hexane/EtOAc – 7:1 to 3:1), affording 3m (34.0 mg, 62%) as a white amorphous solid.

Er = 82.7:17.3 (ee = 65%), the enantiomeric excess of product 3m was determined by HPLC using a Chiralpak IA column (n-heptane/i-PrOH – 95:5, flow rate = 1.0 mL/min, λ = 283 nm, t = 25 °C): t _R = 12.7 min (minor), t _R = 17.1 min (major). [α]_D = −16.5 (c = 0.7, CHCl₃) ¹H NMR (400 MHz, CDCl₃) δ 7.73–7.64 (m, 3H), 7.49–7.45 (m, 2H), 7.42–7.33 (m, 5H), 6.39 (dd, J = 16.0, 1.2 Hz, 1H), 5.78–5.73 (m, 1H), 4.74–4.68 (m, 1H), 4.61–4.55 (m, 1H), 4.45–4.39 (m, 1H), 4.36–4.29 (m, 2H), 2.29 (bs, 1H), 0.96 (s, 9H), 0.164 (s, 3H), 0.161 (s, 3H) ppm. ¹³C­{¹H} NMR (101 MHz, CDCl₃) δ 165.1, 145.7, 137.1, 137.1, 132.4, 129.63 (2C), 129.62, 129.5 (2C), 128.2 (2C), 125.6 (2C), 117.0, 107.7, 76.0, 73.6, 69.5, 69.2, 68.1, 60.3, 26.0 (3C), 18.5, −4.4, −4.5 ppm. IR (ATR): ν = 3508 (OH), 1712 (CO, ester), 1633, 960 (CC), 1101 (C–O, alcohol) cm^–1. HRMS (ESI+) m/z: calcd. for C₂₈H₃₃ClNaO₇Si [M + Na]⁺: 567.1576, found: 567.1564.

(1R,3R,5S,6R,7S,8R,9S)-8-((tert-Butyldimethylsilyl)­oxy)-9-hydroxy-3-phenyl-2,4,10-trioxaadamantan-6-yl (E)-3-(4-bromophenyl)­acrylate (3n)

The title compound was synthesized according to the general procedure C (reaction time: 18 h), using 1c (38.1 mg, 0.1 mmol) and (2Z)-2-bromo-3-(4-bromophenyl)-2-propenal (43.5 mg, 0.15 mmol). The crude product was purified by column chromatography (hexane/EtOAc – 10:1 to 6:1), affording 3n (39.0 mg, 66%) as a white amorphous solid.

Er = 84.6:15.4 (ee = 69%), the enantiomeric excess of product 3n was determined by HPLC using a Chiralpak IA column (n-heptane/i-PrOH – 95:5, flow rate = 1.0 mL/min, λ = 286 nm, t = 25 °C): t _R = 13.0 min (minor), t _R = 18.1 min (major). [α]_D = −23.6 (c = 0.5, CHCl₃) ¹H NMR (400 MHz, CDCl₃) δ 7.70–7.64 (m, 3H), 7.57–7.52 (m, 2H), 7.42–7.35 (m, 5H), 6.40 (d, J = 16.0 Hz, 1H), 5.79–5.73 (m, 1H), 4.73–4.67 (m, 1H), 4.60–4.55 (m, 1H), 4.44–4.39 (m, 1H), 4.36–4.29 (m, 2H), 2.39 (bs, 1H), 0.96 (s, 9H), 0.164 (s, 3H), 0.160 (s, 3H) ppm. ¹³C­{¹H} NMR (101 MHz, CDCl₃) δ 165.1, 145.7, 137.1, 132.8, 132.4 (2C), 129.8 (2C), 129.6, 128.2 (2C), 125.6 (2C), 125.5, 117.1, 107.7, 76.0, 73.6, 69.6, 69.2, 68.1, 60.3, 26.0 (3C), 18.5, −4.4, −4.5 ppm. IR (ATR): ν = 3475 (OH), 1712 (CO, ester), 1633, 982 (CC), 1101 (C–O, alcohol) cm^–1. HRMS (ESI+) m/z: calcd. for C₂₈H₃₃BrNaO₇Si [M + Na]⁺: 611.1071, found: 611.1057.

(1R,3R,5S,6R,7S,8R,9S)-8-((tert-Butyldimethylsilyl)­oxy)-9-hydroxy-3-phenyl-2,4,10-trioxaadamantan-6-yl (E)-3-(3-chlorophenyl)­acrylate (3o)

The title compound was synthesized according to the general procedure C (reaction time: 18 h), using 1c (38.1 mg, 0.1 mmol) and (2Z)-2-bromo-3-(3-chlorophenyl)-2-propenal (36.8 mg, 0.15 mmol). The crude product was purified by column chromatography (hexane/EtOAc – 7:1 to 3:1), affording 3o (31.0 mg, 57%) as a white amorphous solid.

Er = 87.3:12.7 (ee = 75%), the enantiomeric excess of product 3o was determined by HPLC using a Chiralpak IA column (n-heptane/i-PrOH – 95:5, flow rate = 1.0 mL/min, λ = 209 nm, t = 25 °C): t _R = 10.1 min (minor), t _R = 13.7 min (major). [α]_D = −19.8 (c = 1.4, CHCl₃) ¹H NMR (400 MHz, CDCl₃) δ 7.71–7.64 (m, 3H), 7.53 (t, J = 1.8 Hz, 1H), 7.44–7.31 (m, 6H), 6.42 (d, J = 15.9 Hz, 1H), 5.79–5.74 (m, 1H), 4.76–4.68 (m, 1H), 4.61–4.56 (m, 1H), 4.44–4.40 (m, 1H), 4.36–4.29 (m, 2H), 2.31 (bs, 1H), 0.97 (s, 9H), 0.17 (s, 3H), 0.16 (s, 3H) ppm. ¹³C­{¹H} NMR (101 MHz, CDCl₃) δ 164.9, 145.5, 137.1, 135.8, 135.2, 130.9, 130.4, 129.6, 128.2 (2C), 128.1, 126.7, 125.6 (2C), 117.9, 107.7, 76.0, 73.6, 69.6, 69.2, 68.1, 60.3, 26.0 (3C), 18.5, −4.4, −4.5 ppm. IR (ATR): ν = 3508 (OH), 1714 (CO, ester), 1633, 989 (CC), 1101 (C–O, alcohol) cm^–1. HRMS (ESI+) m/z: calcd. for C₂₈H₃₃ClNaO₇Si [M + Na]⁺: 567.1576, found: 567.1562.

(1R,3R,5S,6R,7S,8R,9S)-8-((tert-Butyldimethylsilyl)­oxy)-9-hydroxy-3-phenyl-2,4,10-trioxaadamantan-6-yl (E)-3-(2-chlorophenyl)­acrylate (3p)

The title compound was synthesized according to the general procedure C (reaction time: 18 h), using 1c (38.1 mg, 0.1 mmol) and (2Z)-2-bromo-3-(2-chlorophenyl)-2-propenal (36.8 mg, 0.15 mmol). The crude product was purified by column chromatography (hexane/EtOAc – 7:1 to 3:1), affording 3p (41.0 mg, 75%) as a white amorphous solid.

Er = 87.3:12.7 (ee = 75%), the enantiomeric excess of product 3p was determined by HPLC using a Chiralpak IA column (n-heptane/i-PrOH – 95:5, flow rate = 1.0 mL/min, λ = 276 nm, t = 25 °C): t _R = 13.4 min (minor), t _R = 15.9 min (major). [α]_D = −18.3 (c = 0.4, CHCl₃). ¹H NMR (400 MHz, CDCl₃) δ 8.17 (d, J = 16.0 Hz, 1H), 7.71–7.67 (m, 2H), 7.64 (dd, J = 7.7, 1.8 Hz, 1H), 7.44 (dd, J = 7.9, 1.5 Hz, 1H), 7.41–7.34 (m, 4H), 7.34–7.28 (m, 1H), 6.41 (d, J = 16.0 Hz, 1H), 5.81–5.74 (m, 1H), 4.75–4.68 (m, 1H), 4.63–4.57 (m, 1H), 4.46–4.40 (m, 1H), 4.37–4.32 (m, 2H), 2.32 (bs, 1H), 0.96 (s, 9H), 0.17 (s, 3H), 0.16 (s, 3H) ppm. ¹³C­{¹H} NMR (101 MHz, CDCl₃) δ 164.8, 142.6, 137.2, 135.4, 132.2, 131.8, 130.4, 129.6, 128.2 (2C), 127.8, 127.4, 125.6 (2C), 119.1, 107.7, 76.0, 73.7, 69.5, 69.2, 68.1, 60.3, 26.0 (3C), 18.4, −4.4, −4.5. IR (ATR): ν = 3471 (OH), 1697 (CO, ester), 1633, 989 (CC), 1101 (C–O, alcohol) cm^–1. HRMS (ESI+) m/z: calcd. for C₂₈H₃₃ClNaO₇Si [M + Na]⁺: 567.1576, found: 567.1561.

(1R,3R,5S,6R,7S,8R,9S)-8-((tert-Butyldimethylsilyl)­oxy)-9-hydroxy-3-phenyl-2,4,10-trioxaadamantan-6-yl (E)-3-(2-chlorophenyl)­acrylate (3q)

The title compound was synthesized according to the general procedure C (reaction time: 18 h), using 1c (38.1 mg, 0.1 mmol) and (2Z)-2-bromo-3-(3-bromophenyl)-2-propenal (43.5 mg, 0.15 mmol). The crude product was purified by column chromatography (hexane/EtOAc – 10:1 to 6:1), affording 3q (46.0 mg, 78%) as a white amorphous solid.

Er = 86.7:13.3 (ee = 73%), the enantiomeric excess of product 3q was determined by HPLC using a Chiralpak IA column (n-heptane/i-PrOH – 95:5, flow rate = 1.0 mL/min, λ = 275 nm, t = 25 °C): t _R = 13.2 min (minor), t _R = 15.9 min (major). [α]_D = −10.0 (c = 0.6, CHCl₃) ¹H NMR (400 MHz, CDCl₃) δ 8.12 (d, J = 15.9 Hz, 1H), 7.72–7.66 (m, 2H), 7.66–7.59 (m, 2H), 7.43–7.30 (m, 4H), 7.30–7.24 (m, 1H), 6.37 (d, J = 15.9 Hz, 1H), 5.81–5.75 (m, 1H), 4.75–4.69 (m, 1H), 4.62–4.56 (m, 1H), 4.45–4.40 (m, 1H), 4.37–4.32 (m, 2H), 2.34 (bs, 1H), 0.96 (s, 9H), 0.17 (s, 6H) ppm. ¹³C­{¹H} NMR (101 MHz, CDCl₃) δ 164.7, 145.1, 137.2, 134.0, 133.7, 131.9, 129.6, 128.2 (2C), 127.99, 127.97, 125.8, 125.6 (2C), 119.4, 107.7, 76.0, 73.7, 69.5, 69.2, 68.0, 60.3, 26.0 (3C), 18.4, −4.4, −4.4 ppm. IR (ATR): ν = 3479 (OH), 1716 (CO, ester), 1631, 976 (CC), 1099 (C–O, alcohol) cm^–1. HRMS (ESI+) m/z: calcd. for C₂₈H₃₃BrNaO₇Si [M + Na]⁺: 611.1071, found: 611.1057.

(1R,3R,5S,6R,7S,8R,9S)-8-((tert-Butyldimethylsilyl)­oxy)-9-hydroxy-3-phenyl-2,4,10-trioxaadamantan-6-yl (E)-3-(2-bromophenyl)­acrylate (3r)

The title compound was synthesized according to the general procedure C (reaction time: 18 h), using 1c (38.1 mg, 0.1 mmol) and (2Z)-2-bromo-3-(2-bromophenyl)-2-propenal (43.5 mg, 0.15 mmol). The crude product was purified by column chromatography (hexane/EtOAc – 10:1 to 6:1), affording 3r (28.0 mg, 47%) as a white amorphous solid.

Er = 87.0:13.0 (ee = 74%), the enantiomeric excess of product 3r was determined by HPLC using a Chiralpak IA column (n-heptane/i-PrOH – 95:5, flow rate = 1.0 mL/min, λ = 271 nm, t = 25 °C): t _R = 10.6 min (minor), t _R = 14.3 min (major). [α]_D = −23.0 (c = 0.4, CHCl₃) ¹H NMR (400 MHz, CDCl₃) δ 7.71–7.62 (m, 4H), 7.55 (ddd, J = 8.0, 1.9, 1.0 Hz, 1H), 7.45 (dd, J = 7.9, 1.4 Hz, 1H), 7.40–7.34 (m, 3H), 7.32–7.26 (m, 1H), 6.41 (d, J = 15.9 Hz, 1H), 5.78–5.73 (m, 1H), 4.73–4.68 (m, 1H), 4.60–4.56 (m, 1H), 4.44–4.40 (m, 1H), 4.35–4.29 (m, 2H), 2.23 (s, 1H), 0.97 (s, 9H), 0.17 (d, J = 1.6 Hz, 6H) ppm. ¹³C­{¹H} NMR (101 MHz, CDCl₃) δ 164.9, 145.3, 137.1, 136.0, 133.8, 131.0, 130.7, 129.6, 128.2 (2C), 127.2, 125.6 (2C), 123.3, 117.9, 107.7, 76.0, 73.6, 69.6, 69.2, 68.0, 60.3, 26.0 (3C), 18.5, −4.4, −4.5 ppm. IR (ATR): ν = 3514 (OH), 1714 (CO, ester), 1633, 962 (CC), 1101 (C–O, alcohol) cm^–1. HRMS (ESI+) m/z: calcd. for C₂₈H₃₃BrNaO₇Si [M + Na]⁺: 611.1071, found: 611.1063.

(1R,3R,5S,6R,7S,8R,9S)-8-((tert-Butyldimethylsilyl)­oxy)-9-hydroxy-3-phenyl-2,4,10-trioxaadamantan-6-yl (E)-3-(furan-2-yl)­acrylate (3s)

The title compound was synthesized according to the general procedure C (reaction time: 18 h), using 1c (38.1 mg, 0.1 mmol) and (2Z)-2-bromo-3-(furan-2-yl)-2-propenal (30.1 mg, 0.15 mmol). The crude product was purified by column chromatography (hexane/EtOAc – 8:1 to 4:1), affording 3s (31.0 mg, 62%) as a beige amorphous solid.

Er = 82.5:17.5 (ee = 65%), the enantiomeric excess of product 3s was determined by HPLC using a Chiralpak IA column (n-heptane/i-PrOH – 95:5, flow rate = 1.0 mL/min, λ = 303 nm, t = 25 °C): t _R = 13.2 min (minor), t _R = 20.5 min (major). [α]_D = −20.3 (c = 0.3, CHCl₃) ¹H NMR (400 MHz, CDCl₃) δ 7.71–7.65 (m, 2H), 7.52 (d, J = 1.8 Hz, 1H), 7.48 (d, J = 15.6 Hz, 1H), 7.42–7.33 (m, 3H), 6.68 (d, J = 3.4 Hz, 1H), 6.51 (dd, J = 3.4, 1.8 Hz, 1H), 6.29 (d, J = 15.6 Hz, 1H), 5.79–5.72 (m, 1H), 4.72–4.65 (m, 1H), 4.58–4.52 (m, 1H), 4.44–4.39 (m, 1H), 4.36–4.31 (m, 1H), 4.30–4.27 (m, 1H), 2.17 (bs, 1H), 0.96 (s, 9H), 0.16 (s, 3H), 0.15 (s, 3H) ppm. ¹³C­{¹H} NMR (101 MHz, CDCl₃) δ 165.3, 150.6, 145.6, 137.2, 133.1, 129.6, 128.2 (2C), 125.6 (2C), 116.4, 113.7, 112.8, 107.7, 76.0, 73.6, 69.4, 69.2, 68.2, 60.2, 26.0 (3C), 18.5, −4.4, −4.5 ppm. IR (ATR): ν = 3467 (OH), 1709 (CO, ester), 1630, 970 (CC), 1097 (C–O, alcohol) cm^–1. HRMS (ESI+) m/z: calcd. for C₂₆H₃₂NaO₈Si [M + Na]⁺: 523.1759, found: 523.1747.

(1R,3R,5S,6R,7S,8R,9S)-8-((tert-Butyldimethylsilyl)­oxy)-9-hydroxy-3-phenyl-2,4,10-trioxaadamantan-6-yl (E)-3-(thiophen-2-yl)­acrylate (3t)

The title compound was synthesized according to the general procedure C (reaction time: 18 h), using 1c (38.1 mg, 0.1 mmol) and (2Z)-2-bromo-3-(thiophen-2-yl)-2-propenal (32.6 mg, 0.15 mmol). The crude product was purified by column chromatography (hexane/EtOAc – 5:1), affording 3t (30.0 mg, 58%) as a beige amorphous solid.

Er = 80.0:20.0 (ee = 60%), the enantiomeric excess of product 3t was determined by HPLC using a Chiralpak IA column (n-heptane/i-PrOH – 95:5, flow rate = 1.0 mL/min, λ = 309 nm, t = 25 °C): t _R = 20.0 min (minor), t _R = 24.2 min (major). [α]_D = −18.4 (c = 0.4, CHCl₃). ¹H NMR (400 MHz, CDCl₃) δ 7.85 (d, J = 15.6 Hz, 1H), 7.73–7.64 (m, 2H), 7.46–7.43 (m, 1H), 7.40–7.35 (m, 3H), 7.30 (d, J = 3.6 Hz, 1H), 7.08 (dd, J = 5.1, 3.6 Hz, 1H), 6.20 (d, J = 15.6 Hz, 1H), 5.78–5.72 (m, 1H), 4.72–4.65 (m, 1H), 4.58–4.52 (m, 1H), 4.44–4.39 (m, 1H), 4.36–4.31 (m, 1H), 4.31–4.29 (m, 1H), 2.46 (s, 1H), 0.97 (s, 9H), 0.17 (s, 3H), 0.16 (s, 3H) ppm. ¹³C­{¹H} NMR (101 MHz, CDCl₃) δ 165.1, 139.5, 139.1, 137.2, 132.1, 129.64, 129.60, 128.5, 128.1 (2C), 125.6 (2C), 114.8, 107.7, 76.0, 73.6, 69.4, 69.2, 68.1, 60.3, 26.0 (3C), 18.5, −4.4, −4.5 ppm. IR (ATR): ν = 3489 (OH), 1712 (CO, ester), 1620, 970 (CC), 1101 (C–O, alcohol) cm^–1. HRMS (ESI+) m/z: calcd. for C₂₆H₃₂NaO₇SSi [M + Na]⁺: 539.1530, found: 539.1524.

(1R,3R,5S,6R,7S,8R,9S)-8-((tert-Butyldimethylsilyl)­oxy)-9-hydroxy-3-phenyl-2,4,10-trioxaadamantan-6-yl ethyl fumarate (3u)

The title compound was synthesized according to the general procedure C (reaction time: 18 h), using 1c (38.1 mg, 0.1 mmol) and ethyl (Z)-3-bromo-4-oxobut-2-enoate (31.1 mg, 0.15 mmol). The crude product was purified by column chromatography (hexane/EtOAc – 5:1), affording 3u (9.0 mg, 18%) as a beige amorphous solid.

Er = 74.1:25.9 (ee = 48%), the enantiomeric excess of product 3u was determined by HPLC using a Chiralpak IB column (n-heptane/i-PrOH – 80:20, flow rate = 1.0 mL/min, λ = 208 nm, t = 25 °C): t _R = 5.2 min (minor), t _R = 6.3 min (major). [α]_D = −11.1 (c = 0.5, CHCl₃). ¹H NMR (400 MHz, CDCl₃) δ 7.69–7.62 (m, 2H), 7.40–7.33 (m, 3H), 6.89 (d, J = 15.8 Hz, 1H), 6.84 (d, J = 15.7 Hz, 1H), 5.71–5.66 (m, 1H), 4.71–4.64 (m, 1H), 4.58–4.53 (m, 1H), 4.39–4.34 (m, 1H), 4.33–4.23 (m, 4H), 2.31 (d, J = 6.2 Hz, 1H), 1.34 (t, J = 7.1 Hz, 3H), 0.96 (s, 9H), 0.153 (s, 3H), 0.148 (s, 3H) ppm. ¹³C­{¹H} NMR (101 MHz, CDCl₃) δ 164.8, 163.7, 137.1, 135.4, 132.3, 129.7, 128.2 (2C), 125.5 (2C), 107.7, 75.9, 73.5, 70.0, 69.1, 67.7, 61.8, 60.2, 26.0 (3C), 18.4, 14.2, −4.4, −4.5 ppm. IR (ATR): ν = 3473 (OH), 1722 (CO, ester), 1101 (C–O, alcohol), 962 (CC) cm^–1. HRMS (ESI+) m/z: calcd. for C₂₅H₃₅O₉Si [M + H]⁺: 507.2045, found: 507.2055.

(1R,3R,5S,6R,7S,8S,9R)-8-Acetoxy-9-((tert-butyldimethylsilyl)­oxy)-3-phenyl-2,4,10-trioxaadamantan-6-yl (E)-3-(4-methoxyphenyl)­acrylate (4i)

The title compound was synthesized according to the general procedure D (reaction time of first step: 18 h), using 1c (38.1 mg, 0.1 mmol) and (2Z)-2-bromo-3-(4-methoxyphenyl)-2-propenal (36.2 mg, 0.15 mmol). The crude product was purified after the second step was purified by column chromatography (hexane/EtOAc – 10:1 to 7:1), affording 4i (18.0 mg, 31%) as a white amorphous solid.

Er = 73.5:26.5 (ee = 47%), the enantiomeric excess of product 4i was determined by HPLC using a Chiralpak IG column (n-heptane/i-PrOH – 80:20, flow rate = 1.0 mL/min, λ = 310 nm, t = 25 °C): t _R = 14.3 min (minor), t _R = 16.5 min (major). [α]_D = +6.3 (c = 0.4, CHCl₃). ¹H NMR (400 MHz, CDCl₃) δ 7.72–7.65 (m, 3H), 7.50–7.45 (m, 2H), 7.40–7.35 (m, 3H), 6.97–6.91 (m, 2H), 6.26 (d, J = 15.9 Hz, 1H), 5.71–5.66 (m, 1H), 5.66–5.62 (m, 1H), 4.81–4.77 (m, 1H), 4.44–4.39 (m, 1H), 4.39–4.35 (m, 1H), 4.31–4.27 (m, 1H), 3.86 (s, 3H), 2.03 (s, 3H), 0.98 (s, 9H), 0.17 (s, 6H) ppm. ¹³C­{¹H} NMR (101 MHz, CDCl₃) δ 169.4, 165.6, 162.1, 146.2, 137.0, 130.0 (2C), 129.7, 128.2 (2C), 126.6, 125.6 (2C), 114.7 (2C), 114.1, 108.0, 73.6, 73.4, 68.6, 68.5, 67.2, 60.9, 55.6, 26.0 (3C), 20.9, 18.5, −4.5 (2C). IR (ATR): ν = 1751, 1705 (CO, ester), 978 (CC) cm^–1. HRMS (ESI+) m/z: calcd. for C₃₁H₃₉O₉Si [M + H]⁺: 583.2358, found: 583.2362.

(1R,3R,5S,6R,7S,8S,9R)-8-Acetoxy-9-((tert-butyldimethylsilyl)­oxy)-3-phenyl-2,4,10-trioxaadamantan-6-yl (E)-3-(4-nitrophenyl)­acrylate (4k)

The title compound was synthesized according to the general procedure D (reaction time of first step: 42 h), using 1c (38.1 mg, 0.1 mmol) and (2Z)-2-bromo-3-(4-nitrophenyl)-2-propenal (38.4 mg, 0.15 mmol). The crude product was purified after the second step by column chromatography (hexane/EtOAc – 10:1 to 5:1), affording 4k (24.0 mg, 40%) as a white amorphous solid.

Er = 83.4:16.6 (ee = 67%), the enantiomeric excess of product 4k was determined by HPLC using a Chiralpak IB column (n-heptane/i-PrOH – 80:20, flow rate = 1.0 mL/min, λ = 294 nm, t = 25 °C): t _R = 18.9 min (minor), t _R = 20.9 min (major). [α]_D = +6.0 (c = 0.5, CHCl₃). ¹H NMR (400 MHz, CDCl₃) δ 8.30–8.25 (m, 2H), 7.78 (d, J = 16.0 Hz, 1H), 7.73–7.62 (m, 4H), 7.43–7.32 (m, 3H), 6.52 (d, J = 16.0 Hz, 1H), 5.75–5.69 (m, 1H), 5.67–5.62 (m, 1H), 4.82–4.77 (m, 1H), 4.46–4.41 (m, 1H), 4.41–4.36 (m, 1H), 4.28–4.24 (m, 1H), 2.04 (s, 3H), 0.97 (s, 9H), 0.17 (s, 6H) ppm. ¹³C­{¹H} NMR (101 MHz, CDCl₃) δ 169.1, 164.5, 149.0, 143.7, 139.8, 136.8, 129.8, 128.9 (2C), 128.2 (2C), 125.5 (2C), 124.5 (2C), 120.8, 108.0, 73.34, 73.27, 69.2, 68.6, 67.1, 60.7, 26.0 (3C), 20.9, 18.5, −4.44, −4.45 ppm. IR (ATR): ν = 1747, 1726 (CO, ester), 1520 (N–O), 993, 982 (CC) cm^–1. HRMS (ESI+) m/z: calcd. for C₃₀H₃₆NO₁₀Si [M + H]⁺: 598.2103, found: 598.2091.

(1R,3R,5S,6R,7S,8R,9S)-8-((tert-Butyldimethylsilyl)­oxy)-9-hydroxy-3-phenyl-2,4,10-trioxaadamantan-6-yl 2-(2-(tert-butyl)-6-methylphenoxy)-3-formylbenzoate (5b)

The title compound was synthesized according to the general procedure A. A small vial was loaded with 1c (38.1 mg, 0.1 mmol), 2-(2-(tert-butyl)-6-methylphenoxy)­isophthalaldehyde (44.5 mg, 0.15 mmol) and 3,3′,5,5′-tetra-tert-butyldiphenoquinone (61.3 mg, 0.15 mmol), DABCO (16.8 mg, 0.15 mmol), pre-C3 (0.5 mg, 1 mol %) and chlorobenzene (1 mL). The reaction mixture was stirred for 3 days at room temperature. The crude product was purified by column chromatography (hexane/EtOAc – 10:1 to 5:1), affording 5b (33.0 mg, 49%) as a white amorphous solid.

Note: Diastereomeric ratio was determined by ¹H NMR of crude reaction mixture.

Dr = 1:1.4, er = 74:26/83:17 (ee = 48/66%), the enantiomeric excess of product 5b was determined by HPLC using a Chiralpak IB column (n-heptane/i-PrOH – 97:3, flow rate = 1.0 mL/min, λ = 206 nm, t = 25 °C): t _R = 16.1 min (major), t _R = 17.6 min (minor), t _R = 20.2 min (minor’), t _R = 24.9 min (major’).

The title compound was also prepared according to the procedure reported in the literature. A small vial was loaded with 1c (190 mg, 0.5 mmol), 2-(2-(tert-butyl)-6-methylphenoxy)­isophthalaldehyde (30.0 mg, 0.1 mmol) and 3,3′,5,5′-tetra-tert-butyldiphenoquinone (49.0 mg, 0.12 mmol), DBU (22.0 μL, 0.15 mmol), pre-C4 (0.5 mg, 1 mol %) and 1,4-dioxane (1 mL). The reaction mixture was stirred for 3 days at room temperature. The crude product was purified by column chromatography (hexane/EtOAc – 10:1 to 5:1), affording 5b (43.0 mg, 64%).

Note: Diastereomeric ratio was determined by ¹H NMR of crude reaction mixture.

Dr = 1.4:1, er = 20:80/87:13 (ee = 60/74%), the enantiomeric excess of product 5b was determined by HPLC using a Chiralpak IB column (n-heptane/i-PrOH – 97:3, flow rate = 1.0 mL/min, λ = 208 nm, t = 25 °C): t _R = 16.1 min (minor), t _R = 17.6 min (major), t _R = 20.2 min (minor’), t _R = 24.9 min (major’).

¹H NMR (400 MHz, CDCl₃) δ 9.83 (s, 1H), 9.53 (s, 1H), 8.00–7.88 (m, ND), 7.69–7.62 (m, ND), 7.40–7.29 (m, ND), 7.23–7.07 (m, ND), 7.06–6.97 (m, ND), 5.74–5.68 (m, 1H), 5.44–5.39 (m, 1H’), 4.73–4.59 (m, 1H+2H’), 4.58–4.53 (m, 1H), 4.47–4.42 (m, 1H), 4.35–4.24 (m, 2H+3H’), 2.34 (bs, 1H+1H’), 1.93 (s, 3H), 1.91 (s, 3H’), 1.46 (s, 9H’), 1.44 (s, 9H), 0.94 (s, 9H), 0.93 (s, 9H’), 0.12 (s, 6H), 0.08 (s, 3H’), 0.04 (s, 3H’) ppm. ¹³C NMR (101 MHz, CDCl₃) δ 188.2 (C’), 187.8 (C), 163.92 (C), 163.86 (C’), 157.9 (C), 157.7 (C’), 155.1 (C), 154.7 (C’), 141.5 (C’), 141.1 (C), 137.12 (C’), 137.07 (C), 136.9 (C), 136.8 (C’), 133.8 (C), 133.1 (C’), 131.2 (C), 130.7 (C’), 129.7 (C), 129.6 (C’), 128.2 (2C+2C’), 127.7 (C), 127.5 (C’), 127.3 (C), 127.0 (C’), 126.4 (C+C’), 125.9 (C), 125.8 (C’), 125.5 (2C+2C’), 122.32 (C), 122.30 (C’), 122.1 (C+C’?), 107.7 (C+C’), 76.1, 75.90 (C’), 75.89 (C), 73.6 (C’), 73.5 (C), 70.3 (C), 70.1 (C’), 69.1 (C), 68.9 (C’), 67.82 (C’), 67.81 (C), 60.3 (C+C’), 35.5 (C’), 35.4 (C), 30.6 (3C’), 30.5 (3C), 25.98 (3C), 25.95 (3C’), 18.44 (C), 18.37 (C’), 17.74 (C’), 17.66 (C), −4.37 (C), −4.48 (C), −4.50 (C’), −4.6 (C’) ppm. IR (ATR): ν = 3479 (OH), 1739 (CO, ester), 1684 (CO, aldehyde), 1099 (C–O, alcohol) cm^–1. HRMS (ESI+) m/z: calcd. for C₃₈H₄₇O₉Si [M + H]⁺: 675.2984, found: 675.3002.

(1R,3R,5S,6R,7S,8R,9S)-8-((tert-Butyldimethylsilyl)­oxy)-9-hydroxy-3-phenyl-2,4,10-trioxaadamantan-6-yl cinnamate (3a)

The round-bottom flask (100 mL) was charged with inositol 1c (1.00 g, 2.63 mmol, 1.0 equiv), (2Z)-2-bromo-3-phenyl-2-propenal 2a (832 mg, 3.94 mmol, 1.5 equiv), pre-C4 (12 mg, 26.3 μmol, 1 mol %), DABCO (442 mg, 3.94 mmol, 1.5 equiv) and DCM (26 mL). The reaction was stirred at room temperature (∼23 °C) for 18 h. After full conversion of inositol the solvent was evaporated under reduced pressure. The crude product was purified by column chromatography (hexane/EtOAc – 10:1 to 3:1), affording 3a (669 mg, 50%) as a white amorphous solid. Er = 83.9:16.1 (68% ee).

All analytical data are consistent with those obtained for the compound prepared on a 0.1 mmol scale.

(1R,3S,5S,6R,7R,8S,9S)-8-((tert-Butoxycarbonyl)­oxy)-9-((tert-butyldimethylsilyl)­oxy)-3-phenyl-2,4,10-trioxaadamantan-6-yl cinnamate (6)

The product of desymmetrization 3a (51 mg, 0.1 mmol) was added to the vial (4 mL). Boc₂O (26 mg, 0.12 mmol), DMAP (0.6 mg, 5 mol %) and anhydrous THF (1 mL) were added. The reaction was heated to 50 °C and stirred until full conversion (monitored by TLC, ∼3 h). The crude product was purified by column chromatography (hexane/EtOAc – 5:1) affording 6 (52 mg, 85%) as a colorless oil.

Er = 84.3:15.7 (ee = 69%), the enantiomeric excess of product 6 was determined by HPLC using a Chiralpak ODH column (n-heptane/i-PrOH – 99:1, flow rate = 1.0 mL/min, λ = 275 nm, t = 25 °C): t _R = 17.4 min (major), t _R = 31.3 min (minor). [α]_D = +7.9 (c = 0.4, CHCl₃). ¹H NMR (400 MHz, CDCl₃) δ 7.75 (d, J = 16.1 Hz, 1H), 7.72–7.67 (m, 2H), 7.59–7.52 (m, 2H), 7.47–7.33 (m, 6H), 6.44 (d, J = 16.0 Hz, 1H), 5.77–5.71 (m, 1H), 5.45–5.39 (m, 1H), 4.87–4.81 (m, 1H), 4.47–4.38 (m, 2H), 4.35–4.30 (m, 1H), 1.37 (s, 9H), 0.98 (s, 9H), 0.18 (s, 6H) ppm. ¹³C­{¹H} NMR (101 MHz, CDCl₃) δ 165.3, 152.1, 146.4, 137.0, 134.2, 130.9, 129.7, 129.1 (2C), 128.3 (2C), 128.1 (2C), 125.6 (2C), 117.1, 107.9, 83.3, 73.4 (2C), 70.6, 68.1, 67.1, 60.8, 27.7 (3C), 26.0 (3C), 18.5, −4.4, −4.5 ppm. IR (ATR): ν = 1745, 1716 (CO, ester), 1635, 976 (CC) cm^–1. HRMS (ESI+) m/z: calcd. for C₃₃H₄₃O₉Si [M + H]⁺: 611.2671, found: 611.2674.

(1R,3R,5S,6R,7S,8S,9R)-8-acetoxy-9-((tert-Butyldimethylsilyl)­oxy)-3-phenyl-2,4,10-trioxaadamantan-6-yl cinnamate (4a)

The product of desymmetrization 3a (51 mg, 0.1 mmol) was added to the vial (4 mL). Ac₂O (11 μL, 0.12 mmol), DMAP (1.2 mg, 10 mol %), Et₃N (17 μL, 0.12 mmol) and dry THF (1 mL) were added. The reaction was stirred at room temperature until full conversion (monitored by TLC, ∼30 min). The crude product was purified by column chromatography (hexane/EtOAc – 5:1) affording 4a (50 mg, 90%) as a colorless oil.

Er = 84.0:16.0 (ee = 68%), the enantiomeric excess of product 4a was determined by HPLC using a Chiralpak IG column (n-heptane/i-PrOH – 95:5, flow rate = 1.0 mL/min, λ = 276 nm, t = 25 °C): t _R = 19.8 min (major), t _R = 22.1 min (minor). [α]_D = +9.8 (c = 0.4, CHCl₃). ¹H NMR (400 MHz, CDCl₃) δ 7.75 (d, J = 16.0 Hz, 1H), 7.72–7.67 (m, 2H), 7.53 (dt, J = 6.7, 2.3 Hz, 2H), 7.44 (dd, J = 5.1, 1.9 Hz, 3H), 7.41–7.36 (m, 3H), 6.41 (d, J = 16.0 Hz, 1H), 5.73–5.68 (m, 1H), 5.68–5.63 (m, 1H), 4.84–4.78 (m, 1H), 4.47–4.41 (m, 1H), 4.41–4.36 (m, 1H), 4.32–4.28 (m, 1H)­f, 2.04 (s, 3H), 0.98 (s, 9H), 0.18 (s, 6H) ppm. ¹³C­{¹H} NMR (101 MHz, CDCl₃) δ 169.3, 165.3, 146.5, 136.9, 133.9, 131.1, 129.7, 129.3 (2C), 128.2 (2C), 128.1 (2C), 125.6 (2C), 116.7, 108.0, 73.5, 73.4, 68.62, 68.57, 67.2, 60.8, 26.0 (3C), 20.9, 18.5, −4.5 (2C) ppm. IR (ATR): ν = 1749, 1712 (CO, ester), 978 (CC) cm^–1. HRMS (ESI+) m/z: calcd. for C₃₀H₃₇O₈Si [M + H]⁺: 553.2252, found: 553.2261.

(1S,3R,5R,6S,7S,8S,9S)-8-((tert-Butyldimethylsilyl)­oxy)-9-(((2S,3aS,6R,7aS)-3a-methyl-6-(prop-1-en-2-yl)-2-sulfidohexahydrobenzo­[d]­[1,3,2]­oxathiaphosphol-2-yl)­oxy)-3-phenyl-2,4,10-trioxaadamantan-6-yl cinnamate (7)

The vial (4 mL) was charged with the desymmetrization product 3a (51 mg, 0.1 mmol), PSI-reagent (67 mg, 0.15 mmol) and DCM (1 mL) under inert atmosphere. Then DBU (23 μL, 0.15 mmol) was slowly added. The reaction mixture was stirred at room temperature until full conversion (monitored by TLC, ∼30 min). The crude product was purified by column chromatography (hexane/EtOAc – 20:1 to 10:1) affording 7 (69 mg, 91%) as a colorless oil.

Dr = 5.6:1.0, the diastereomeric ratio product 7 was determined by NMR spectroscopy.

¹H NMR (400 MHz, CDCl₃, only major diastereomer) δ 7.75–7.66 (m, 3H), 7.55–7.50 (m, 2H), 7.44–7.35 (m, 6H), 6.40 (d, J = 16.1 Hz, 1H), 5.76–5.71 (m, 1H), 5.54–5.47 (m, 1H), 4.97–4.94 (m, 1H), 4.70–4.65 (m, 2H), 4.65–4.61 (m, 1H), 4.42–4.39 (m, 1H), 4.35–4.31 (m, 1H), 2.51–2.44 (m, 1H), 2.27–2.17 (m, 1H), 1.75–1.53 (m, 12H), 0.97 (s, 9H), 0.18 (s, 6H) ppm. ¹³C­{¹H} NMR (101 MHz, CDCl₃, only major diastereomer) δ 165.2, 146.2, 144.6, 136.8, 134.1, 130.9, 129.7, 129.1 (2C), 128.5 (2C), 128.1 (2C), 125.6 (2C), 117.3, 112.0, 86.3, 73.8 (d, J = 2.7 Hz), 73.6, 71.9 (d, J = 7.8 Hz), 68.5 (d, J = 5.5 Hz), 68.2, 66.3, 60.1, 38.7, 33.1 (d, J = 9.1 Hz), 27.8 (d, J = 15.4 Hz), 26.1 (3C), 23.2, 22.6, 21.9, 18.6, −4.4, −4.5 ppm, one qC was not assigned due to possible overlap with other signals. ³¹P NMR (162 MHz, CDCl₃, only major diastereomer) δ 100.9 ppm. IR (ATR): ν = 1716 (CO, ester), 1635, 980 (CC) cm^–1. HRMS (ESI+) m/z: calcd. for C₃₈H₅₀O₈PS₂Si [M + H]⁺: 757.2448, found: 757.2457.

(1S,3R,5S,6S,7R,8R,9R)-8-((tert-Butyldimethylsilyl)­oxy)-3-phenyl-9-(((E)-prop-1-en-1-yl)­oxy)-2,4,10-trioxaadamantan-6-ol (11)

To a solution of the product of desymmetrization 3a (102 mg, 200 μmol) and pyridinium p-toluenesulfonate (22 mg, 88 μmol, 44 mol %) in DCM (2 mL) was added 3,4-dihydropyran (80 mg, 880 μmol, 4.4 equiv). The reaction was stirred at room temperature for 16 h. The solvent was evaporated, crude product was dissolved in EtOAc and washed with water (1 × 30 mL), HCl (1m, 1 × 30 mL), sat. solution of NaHCO₃ (1 × 30 mL) and brine (1 × 30 mL). The organic phase was dried over MgSO₄ and the product was purified by a short column chromatography (hexane/EtOAc – 10:1 to 8:1) affording the first intermediate 8 (90 mg, 76%). This intermediate 8 (90 mg, 151 μmol) was then dissolved in MeOH (1.5 mL) and solution of NaOMe (10.2 mg, 189 μmol, 1.25 equiv) in MeOH (0.5 mL) was slowly added. The reaction mixture was stirred at room temperature for 1 h (full conversion monitored by TLC). Simple column chromatography (hexane/EtOAc – 10:1 to 8:1) yielded the intermediate 9 (55 mg, 78%). After that the intermediate 9 (55 mg, 118 μmol) was mixed with imidazole (0.4 mg, 6 μmol, 5 mol %) in dry DMF (1.1 mL) in a small vial (4 mL). NaH (9.5 mg, 237 μmol, 2.0 equiv) was added at 0 °C (water/ice cooling bath) and the mixture was stirred for 30 min at room temperature. Then allyl bromide (15 μL, 178 μmol, 1.5 equiv) was added dropwise at 0 °C (water/ice cooling bath). The reaction mixture was stirred at room temperature until full conversion (monitored by TLC, 1 h). The reaction was then quenched with MeOH (2 mL) and diluted with EtOAc (30 mL) and brine (30 mL). The water phase was extracted with EtOAc (3 × 30 mL). The combined organic phases were washed with brine (2 × 30 mL). After drying over MgSO₄ the crude product was purified by short column chromatography (hexane/EtOAc – 10:1 to 8:1) affording the intermediate 10 (39 mg, 65%). The intermediate 10 (39 mg, 77 μmol) was added to a small vial and mixed under argon atmosphere with MgBr₂·OEt₂ (94 mg, 363 μmol, 4.7 equiv) and Et₂O (1.5 mL). The reaction mixture was stirred at room temperature for 2 h. The reaction was then quenched by saturated NH₄Cl solution at 0 °C. The water phase was extracted with EtOAc and the combined organic phases were washed with water and brine. After drying over MgSO₄ the crude product was purified by a column chromatography (hexane/EtOAc – 10:1 to 7:1) affording the final product 11 (24 mg, 72%) as a colorless oil.

Er = 83.7:16.3 (ee = 67%), the enantiomeric excess of product 11 was determined by HPLC using a Chiralpak IH column (n-heptane/i-PrOH – 98:2, flow rate = 1.0 mL/min, λ = 207 nm, t = 25 °C): t _R = 6.4 min (major), t _R = 7.2 min (minor). [α]_D = +6.1 (c = 1.2, CHCl₃). ¹H NMR (400 MHz, CDCl₃) δ 7.69–7.60 (m, 2H), 7.39–7.31 (m, 3H), 5.97–5.85 (m, 1H), 5.39–5.27 (m, 2H), 4.59–4.52 (m, 1H), 4.48–4.41 (m, 2H), 4.39–4.35 (m, 1H), 4.33–4.29 (m, 1H), 4.24–4.21 (m, 1H), 4.20–4.16 (m, 2H), 3.67 (d, J = 10.2 Hz, 1H), 0.97 (s, 9H), 0.16 (s, 6H) ppm. ¹³C­{¹H} NMR (101 MHz, CDCl₃) δ 137.4, 133.0, 129.5, 128.1 (2C), 125.5 (2C), 119.5, 107.4, 76.5, 75.0, 74.1, 72.1, 68.5, 68.4, 60.1, 26.0 (3C), 18.4, −4.4, −4.5 ppm. IR (ATR): ν = 3479 (OH), 1716 (CO, ester), 978 (CC), 1101 (C–O, alcohol) cm^–1. HRMS (ESI+) m/z: calcd. for C₂₂H₃₃O₆Si [M + H]⁺: 421.2041, found: 421.2037.

The data underlying this study are available in the published article and its .

The Supporting Information is available free of charge at https://pubs.acs.org/doi/10.1021/acs.joc.5c02735.

• Reaction conditions optimization, copies of ¹H NMR, ¹³C NMR, ¹⁹F NMR, ³¹P NMR and copies of chiral HPLC (PDF)

• FAIR data, including the primary NMR FID files, for compounds 1a-1g, 3a-u, 4a, 4i, 4k, 5b, 6, 7, 11. (ZIP)

O.H. performed the synthesis. V.D. designed project and conceived the concept. I.C. performed X-ray analysis. J.V. directed the project. V.D. and J.V. wrote the manuscript. All authors have given approval to the final version of the manuscript.

The authors declare no competing financial interest.