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. Author manuscript; available in PMC: 2022 Mar 30.
Published in final edited form as: Org Lett. 2022 Jan 18;24(3):939–943. doi: 10.1021/acs.orglett.1c04310

Ring-Opening of Epoxides by Pendant Silanols

Someshwar Nagamalla a, Joel T Mague b, Shyam Sathyamoorthi a,*
PMCID: PMC8965746  NIHMSID: NIHMS1790898  PMID: 35041437

Abstract

We present a new ring-opening reaction of epoxides by pendant silanols, catalyzed by either Ph3C+BF4− or BINOL-phosphoric acid. Silanol epoxides derived from trans-allylic alcohols, cis-allylic alcohols, trans-homoallylic alcohols, and cis-homoallylic alcohols were all compatible and gave products from either endo- or exo-ring opening. With silanol epoxides derived from 4-alkenyl silanols, an unusual rearrangement to tetrahydrofuran products was observed. The utility of this methodology was demonstrated in a short preparation of protected D-arabitol.

Graphical Abstract

graphic file with name nihms-1790898-f0001.jpg

Epoxides are one of the most versatile functional groups in synthetic chemistry, and their cleavage has been investigated in a variety of contexts (Scheme 1).1-4 Nucleophilic opening of epoxides can be broadly characterized as either intermolecular or intramolecular. Intramolecular opening of epoxides by pendant alcohols is a known route to a variety of oxygen heterocycles, including furans, pyrans, and medium-sized rings,5, 6 and this strategy has been applied on numerous occasions in natural products synthesis.7-10 Several laboratories have established that “temporary tethering” is an effective strategy for regiocontrol in intermolecular ring-opening reactions of epoxides.11-16 In such reactions, a Lewis acid or organocatalyst non-covalently binds to both the substrate and the nucleophile and templates attack at a single site of the epoxide. In contrast to these two areas, the use of covalent tethers for epoxide opening is much less established, and most explorations have focused on carbonates,17-20 carbamates,21-23 and trichloroacetamidates.24 Of these tethers, only carbonates cleave epoxides with a masked hydroxy group.

Scheme 1.

Scheme 1.

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Previous efforts with ring cleavage of epoxides inspire our silanoxy-tethered ring-opening approach.

Our laboratory is deeply invested in exploring di-tert-butylsilanols as covalent tethers for the intramolecular installation of hydroxy groups.25-28 The triol motif is prevalent in a variety of carbohydrate and polyketide natural products with attractive biological activity (Figure 1). We envisioned a ring opening reaction of epoxides by pendant di-tert-butylsilanols, which would form a variety of protected triols in a single transformation. While triols can be synthesized by other methods, such as dihydroxylation of allylic alcohols, differential protection of the resulting hydroxyl groups can be a major challenge.29-32 Due to geometric constraints on the transition states of these intramolecular reactions, we reasoned that such openings were likely to be highly regioselective and diastereoselective. Here, we describe our efforts to reduce this concept to practice.

Figure 1.

Figure 1.

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The triol motif is prevalent in natural products with potent biological activity.

The substrate silanol epoxides could be conveniently prepared using one of two methods (Scheme 2). m-CPBA oxidation of the alkenyl silanol26 delivered the silanol epoxide in good yields, and, in our hands, this proved to be a very general procedure (Scheme 2A). As there is much technology33-35 for the stereocontrolled synthesis of epoxides from alkenyl alcohols, we reasoned that developing a method to attach the silanol auxiliary directly to epoxy-alcohols would be particularly impactful. Our standard silylating conditions26 failed to deliver product in reasonable yields with these particularly delicate substrates (Scheme 2B). We found that replacing DMAP with two equivalents of NaHCO3 and dropping the initial reaction temperature to −40 °C allowed for silanol epoxide formation reproducibly and in much better yields (Scheme 2B).

Scheme 2.

Scheme 2.

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Two methods to synthesize silanol epoxides.

With two protocols allowing reliable access to silanol epoxides, we began optimizing our envisioned ring-opening reaction. Treatment of di-tert-butyl(3-propyloxiran-2-yl)(methoxy) silanol with 5 mol% of Sc(OTf)3 and 1 equivalent of NaHCO3 in CH2Cl2 for 3 hours gave 20% of the desired product (Table 1, Entry 1). Increasing the reaction time to 14 hours led to complete consumption of starting material with 65% of product formation (Table 1, Entry 2). In both cases, a major side product was di-tert-butylsilanediol, suggesting that starting material was fragmenting unproductively in the presence of Sc(OTf)3. Switching solvents to benzene, dichloroethane, chloroform, or ethyl acetate (Table 1, Entries 3-6) was markedly deleterious. We thus decided to try different Lewis acids with the goal of reducing di-tert-butylsilanediol formation. While triflate salts of zinc, indium, and ytterbium (Table 1, Entries 7-9) did not help reaction performance, with 10 mol% of the unusual Lewis acid triphenylcarbenium tetrafluoroborate36 (Table 1, Entry 10), product formation was excellent with no discernible starting material fragmentation.

Table 1.

Optimization of epoxide opening by pendant silanols.

graphic file with name nihms-1790898-t0009.jpg
Lewis Acid (equiv.) Solvent Time P/SMa
1 Sc(OTf)3 (5%) CH2Cl2 3h 20/65
2 Sc(OTf)3 (5%) CH2Cl2 14h 65/0
3 Sc(OTf)3 (5%) C6H6 14h 0/100
4 Sc(OTf)3 (5%) C2H4Cl2 14h 27/49
5 Sc(OTf)3 (5%) CHCl3 14h 10/84
6 Sc(OTf)3 (5%) EtOAc 14h 0/100
7 Zn(OTf)3 (5%) CH2Cl2 14h 0/100
8 In(OTf)3 (5%) CH2Cl2 14h 45/25
9 Yb(OTf)3 (5%) CH2Cl2 14h 0/100
10 Ph3C+ BF4− (10%) CH2Cl2 2h 80/0
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a

yield estimated from 1H NMR integration with 4-nitrotoluene as an internal standard.

Encouraged by this very positive result, we next began the substrate scope exploration (Scheme 3). Our optimized conditions proved general for a variety of silanol epoxides, including those with branched alkyl chains (Scheme 3, Entries 1-2), substituted aryl rings (Scheme 3, Entries 3-4), and heteroaryl rings (Scheme 3, Entry 5). Importantly, we were not limited to di-substituted trans-epoxides derived from allylic silanols. Epoxides prepared from tri-substituted allylic silanols (Scheme 3, Entry 6), trans-homoallylic silanols (Scheme 3, Entry 7), and cis-homoallylic silanols (Scheme 3, Entry 8) were all compatible with our optimized conditions. Epoxides derived from cis-allylic silanols were particularly problematic, likely due to unfavorable 1,3-allylic strain37 during the cyclization event. However, we were pleased to find that maintaining the reaction temperature at −10 °C delivered desired cyclized product in a respectable 40% yield (Scheme 3, Entry 9). When treated with Ph3C+BF4–, epoxides derived from aryl alkenes failed to cyclize cleanly and, in all cases examined, gave intractable mixtures of products (Table 2, Entry 1). Use of Bi(OTf)3 as a Lewis acid (Table 2, Entry 2) or HFIP as the solvent (Table 2, Entry 3) did little to improve reaction performance, but a more positive result came with treatment of 10-CSA5, 6 (Table 2, Entries 4-5). We hypothesized that a milder Bronsted acid would lead to a cleaner reaction and were pleased to see that with BINOL-phosphoric acid, cyclization proceeded smoothly and with no discernible side products (Table 2, Entry 6).

Scheme 3. Substrate scope with alkyl epoxides.

Scheme 3.

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Note: Starting material is often fully consumed with few side products. At present, we are unable to account for the decreased mass balance in some cases.

Table 2.

Aryl epoxide opening by pendant silanols

graphic file with name nihms-1790898-t0010.jpg
Additive Solvent Time P/SMa
1 Ph3C+ BF4− (10%) NaHCO3 (1 equiv.) CH2Cl2 2h 40/0b
2 Bi(OTf)3 (5%) NaHCO3 (1 equiv.) CH2Cl2 2h 30/0b
3 None HFIP 6h 0/40b
4 10-CSA (1 equiv.) CH2Cl2 1h 50/0b
5 10-CSA (0.25 equiv.) CH2Cl2 1h 50/0b
6 BINOL-Phosphoric Acid (30%) c CH2Cl2 14h 80/0
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a

Yield estimated from 1H NMR integration with 4-nitrotoluene as an internal standard.

b

mixture of side products.

c

(R)-(−)-1,1′-Binaphthyl-2,2′-diyl hydrogenphosphate, arbitrarily chosen

These conditions proved to be excellent for cyclization of aryl epoxide substrates and a variety of substitution patterns on the aromatic ring were well tolerated (Scheme 4, Entry 1). Furthermore, several substrates which failed to cyclize with Ph3C+BF4−/NaHCO3 reacted cleanly under these alternate conditions (Scheme 4, Entries 2-3). In all cases (Schemes 3-4), the cyclization reactions were perfectly regioselective and diastereoselective, attesting to the utility of our protocols. A crystal structure of 41 (CCDC: 2126173) enabled us to unambiguously establish its relative stereochemistry, and we have assigned the stereochemistry of other products by analogy.

Scheme 4. Substrate scope with BINOL-phosphoric acid conditions.

Scheme 4.

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aYield estimated by 1H NMR integration against an internal standard; 30% recovered starting material also noted.

Our success with both allylic and homoallylic silanols prompted us to test our reaction with more remote silanol epoxides (Scheme 5). We simply expected the product of either 7-exo or 8-endo cyclization. What we found, however, was very unexpected and much more interesting. When trans-epoxide 49 was treated with our optimized protocol of Ph3C+BF4−(15 mol%) and NaHCO3 (1 equiv.) in CH2Cl2, tetrahydrofuran 50 formed in a 60% yield (Scheme 5A)! We hypothesize that two tandem cyclizations took place. The first was the expected 8-endo cyclization, which was followed by an unexpected 5-exo ring opening. We were pleased to find that with cis-epoxide 51, diastereomeric tetrahydrofuran 52 formed in similar yields (Scheme 5B). These reactions were scaled 5 to 7-fold, with no degradation in yield or selectivity.

Scheme 5.

Scheme 5.

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An unexpected rearrangement with silanol epoxides derived from 4-alkenyl silanols.

We envisioned a short preparation of protected D-arabitol utilizing our ring-opening reaction as a key step (Scheme 6). With our laboratory’s standard silylating conditions,26 enantiopure silanol (+)-54 was prepared from known chiron (+)-53.38 m-CPBA epoxidation of (+)-53 proceeded in excellent yield to give a separable mixture of (+)-55 and (−)-57 (Scheme 6A). When major diastereomer (+)-55 was treated with Ph3C+BF4− (10 mol%) and NaHCO3 (1 equiv.), cyclized product (−)-56 (protected D-arabitol) formed in a 65% yield (Scheme 6B). Minor diastereomer (−)-57 was de-silylated using TBAF (1.5 equivalents) in THF to yield known alcohol (−)-58,38, 39 allowing us to assign the absolute stereochemistry of diastereomers (+)-55 and (−)-57 (Scheme 6C).

Scheme 6.

Scheme 6.

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A short preparation of protected D-arabitol.

In summary, we present a new ring-opening reaction of epoxides by pendant silanols.40 In all cases examined, the reaction is perfectly regioselective and diastereoselective. Silanol epoxides derived from trans-allylic alcohols, cis-allylic alcohols, trans-homoallylic alcohols, and cis-homoallylic alcohols were all compatible and gave products from either endo- or exo-ring opening. With silanol epoxides derived from 4-alkenyl silanols, an unusual rearrangement to tetrahydrofuran products was observed, which is likely the result of tandem nucleophilic attacks. The utility of this reaction was demonstrated in a short preparation of protected D-arabitol. We are optimistic that this methodology will enjoy much use in the pursuit of complex, polyhydroxylated molecules.

Supplementary Material

SI

ACKNOWLEDGMENT

This work was supported by a National Institutes of Health grant R35GM142499 awarded to Shyam Sathyamoorthi. Justin Douglas and Sarah Neuenswander (KU NMR Lab) are acknowledged for help with structural elucidation. Lawrence Seib and Anita Saraf (KU Mass Spectrometry Facility) are acknowledged for help acquiring HRMS data. Joel T. Mague thanks Tulane University for support of the Tulane Crystallography Laboratory.

Footnotes

Supporting Information

Experimental Procedures, Reasoning for Structural Assignments, NMR Spectra, and Crystallographic Information.

The Supporting Information is available free of charge on the ACS Publications website.

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Supplementary Materials

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