Intramolecular Asymmetric Cyclopropanation Using Air-Stable Alkylboronic Esters

Abstract

The preparation of polysubstituted bicyclo[3.1.0]hexanes starting from air-stable substituted pent-4-en-1-ylboronic acid esters has been investigated. The method involves a Matteson homologation with LiCHCl₂, leading to 1-chlorohex-5-en-1-ylboronic acid ester intermediates. The subsequent intramolecular cyclopropanation step was performed in a one-pot process. With pinacol boronic esters, the cyclopropanation step was either performed thermally at 140 °C or at 70 °C after in situ transesterification to form a catechol boronic ester. This last approach is suitable for the preparation of enantioenriched bicyclo[3.1.0]hexanes using either chiral-auxiliary control or by taking advantage of the sparteine-controlled enantioselective boroalkylation of alcohols.

Bicyclo[3.1.0]hexanes are found in a variety of natural and nonnatural products, some of which possess interesting biological activities.[1] [2] [3] [4] They are also valuable synthetic intermediates, and are often involved in ring-opening processes as a result of the ring-strain present in such bicyclic structures.[5–8] For decades, their synthesis has attracted a lot of attention.[9–11] Methods based on highly reactive species such as carbenes and metallocarbenes have been applied for their preparation.[12] [13] [14] Approaches based on metalation of unsaturated terminal epoxides[15] [16] or aziridines,[17] intramolecular Simmons–Smith cyclopropanation,[18] or sulfur ylide chemistry[19] [20] have also been reported. The groups of Takai and Charette used pinacol (dichloromethyl)- or (diiodomethyl)boronic esters in intermolecular cyclopropanations of alkenes to give borylated cyclopropanes.[21] [22] [23] [24] Interestingly, (1-haloalkyl)boronates are potential precursors of carbenes and carbenoids, but their use in cyclopropanation is limited to a palladium-catalyzed intermolecular reaction (Scheme [1]A)[25] and to a radical-mediated process involving (iodomethyl)boronic esters[26] (Scheme [1]B). Some years ago, we reported a noncatalytic spontaneous intramolecular cyclopropanation process involving B-(1-chloro-5-alken-1-yl)catecholborane intermediates that were prepared through selective hydroboration of dienes and their subsequent Matteson homologation (Scheme [1]C).[27] Despite its efficacy, the utility of this process is hampered by the instability of the B-alkylcatecholborane (alkyl–Bcat) derivatives, which are notoriously air and moisture sensitive. Therefore, extending this reaction to air-stable pinacol boronic esters (R–Bpin) and related esters is highly desirable for practical reasons and for the development of an asymmetric version of this reaction. Herein, we report an intramolecular cyclopropanation involving pinacol boronic esters (Scheme [1]D), as well as a study on the stereochemical outcome of the process leading to enantioenriched substituted bicyclo[3.1.0]hexanes.

In our initial work,[27] the B-(4-alken-1-yl)catecholboranes used for the Matteson homologation-cyclopropanation process were obtained by selective rhodium-catalyzed hydroboration of 1,4-dienes, but this proved to be challenging. An improved synthesis was developed and is presented in Scheme [2]. Dialkylation of γ-butyrolactone afforded the debenzylated lactone 1 in 93% yield. Reduction of debenzylated lactone 1 with DIBAL-H followed by Wittig olefination provided the alcohol 2 in 85% yield. After esterification of 2 with 2,4,6-triisopropylbenzoyl chloride (TIB-Cl, 85% yield), the TIB-ester 3 was converted into the pinacol boronic ester in 71% yield by Aggarwal’s procedure, through metalation of the ester and treatment with H-Bpin.[28] Homologation of the boronic ester 4 to the (1-chloro-5-alken-1-yl)boronic ester 5 was performed with lithiated dichloromethane according to the original work of Matteson.[29] [30] The crude (1-chloroalkenyl)boronic ester 5 was formed in high yield and used without further purification for the cyclopropanation step. Product 5 is air stable, but decomposes during flash chromatography due to its instability on silica gel. It was characterized by means of ¹H and ¹³C NMR spectroscopy.

Next, the intramolecular cyclopropanation was investigated starting from boronic ester 4 through in situ formation of the 1-chlorinated boronic ester 5. The various reaction conditions tested for the cyclopropanation are summarized in Table [1]. The reaction was first attempted in toluene at 100 °C, but no reaction was observed (Table [1], entry 1). At 140 °C, the desired reaction took place and the bicyclo[3.1.0]hexane 6 was formed in 57% yield (determined by gas-chromatography analysis of the reaction mixture) (entry 2). However, isolation of analytically pure 6 was not possible due to contamination by several olefinic side products. The effects of AgBF₄ and silica gel as additives were tested, but they were either ineffective or detrimental to the reaction (entries 3 and 4). Interestingly, potassium benzoate at 140 °C was found to have a positive effect on the yield of the reaction, and the product 6 was formed in 75% yield (entry 5). The reaction time could not be shortened and the temperature could not be decreased, indicating that the additive might simply slow down the competing decomposition of the bicyclic cyclopropane 6.

Table 1 Optimization of the Cyclopropanation Step in the Presence of Additives

Entry	Additive (equiv)	Temp (°C)	Yielda (%)
1	–	100	–
2	–	140	57
3	AgBF4 (1)	140	51
4	silica gel	140	15
5	PhCO2K (1)	140	75

^a Yields determined by GC analysis.

When the thermal reaction in the presence of potassium benzoate was repeated on a preparative scale,[31] it afforded bicycle 6 in 70% isolated yield, together with a second product, the borylated bicycle 7, whose structure was unambiguously assigned by single-crystal X-ray crystallography,[32] but whose origin remains to be elucidated (Scheme [3]).

Despite its efficiency, this approach suffers from the high reaction temperature required and the necessity to work in a closed reaction vessel. Moreover, it was later found that significantly lower yields (≤30%) were obtained when α-chloroboronic esters derived from chiral diols were used.

The higher temperature required for reaction with pinacol and related boronic esters relative to that required for catechol boronic esters was attributed to their lower Lewis acidity. We therefore decided to investigate the activation of the pinacol boronic esters in situ through transesterification with more-acidic diols, such as catechol. Such an approach involving the in situ transesterification of R-Bpin derivatives to R–Bcat derivatives was recently reported to perform radical reactions.[33] Various transesterification procedures were tested, and the results are summarized in Table [2]. The reactions were run at 70 °C in toluene for 24 hours. The use of catechol as a transesterification agent was tested first. No reaction was observed upon the addition of catechol (2 equiv) to the reaction mixture (Table [2], entry 1). Attempts to catalyze the transesterification with a Lewis acid led to decomposition of the starting chloride 5 without any formation of 6 (entry 2). Interestingly, upon addition of naphthalene-1,2-diol (1.2 equiv) the desired cyclopropanation product 6 was obtained in 26% yield, together with the 2-propylidenecyclopentane 8 (entry 3). In a separate experiment, it was shown that 8 was formed by the reaction of 6 with HCl. Therefore, the addition of a base to the reaction mixture was examined. No change was observed when solid K₂CO₃ was added (entry 4). The addition of sym-collidine suppressed the formation of 8, but the yield of 6 remained low (entry 5); propylene oxide, a good HCl trap, gave a similar result (entry 6). To avoid the formation of HCl, transesterification with naphthalene-1,2-diol boronic (MeBnap) or boric (MeOBnap or HOBnap) esters were examined, but none of these reagents provided the desired product 6 (entries 7–9). Interestingly, the formation of 6 was observed with the catechol esters MeBcat, MeOBcat, and F₃CCH₂OBcat (Table [2], entries 10–12). The best result (a 53% yield) was obtained when catechol boric anhydride [O(Bcat)₂] was used (entry 13). Adding an acid to accelerate the transesterification led to complete decomposition of the starting material (entry 14), and decreasing the amount of O(Bcat)₂ gave a reduced yield (entry 15). A rapid solvent screening showed that 1,1,1-trifluorotoluene (TFT) works equally as well as toluene (entry 16). More-polar solvents such as THF, ethyl acetate, or DMF gave either a reduced yield (entries 17 and 18) or decomposition of the starting material (entry 19). The byproducts ClBcat and ClBpin did not promote the decomposition of product 6.

The reaction conditions described in Table [2], entry 16 (i.e., two equivalents of O(Bcat)₂) were adopted as standard reaction conditions for the cyclopropanation process. The conversion of the stable boronic ester 4 into 6 by a one-pot two-step process was examined next (Scheme [4]). To facilitate the purification of product 6, the crude mixture of products was treated with ozone/NaBH₄ to convert all unsaturated byproducts into more-polar compounds. The bicyclic product 6 was isolated in an overall yield of 54%, together with the hydroxy ketone 9, presumably formed by ozonolysis of the cyclopentene byproduct 8.

Table 2 Intramolecular Cyclopropanation Promoted by Transesterification

Entry	Transesterification reagent (equiv)	Yield (%)
1	catechol (2)	–
2	catechol (1.1), BF3·OEt2 (2)	–a
3	naphthalene-1,8-diol (1.2)	26b
4	naphthalene-1,8-diol (1.2), K2CO3 (2)	–a,b
5	naphthalene-1,8-diol (1.2), sym-collidine (2)	7
6	naphthalene-1,8-diol (1.2), propylene oxide (2)	18
7	MeBnap (2)	–
8	MeOBnap (2)	–
9	HOBnap (2)	–
10	MeBcat (2)	9
11	MeOBcat (2)	27
12	CF3CH2OBcat (2)	28
13	O(Bcat)2 (2)	53
14	O(Bcat)2 (2), TfOH (0.01)	–a
15	O(Bcat)2 (1.1)	39
16	O(Bcat)2 (2)	52c
17	O(Bcat)2 (2)	42d
18	O(Bcat)2 (2)	32e
19	O(Bcat)2 (2)	–a,f

^a Decomposed starting material.

^b Formation of alkene 8 was observed.

^c In TFT.

^d In THF.

^e In EtOAc.

^f In DMF.

The use of a chiral auxiliary to control the enantioselectivity of the intramolecular cyclopropanation process was investigated next. For this purpose, the chiral boronic ester 10 was prepared by treatment of 4 with (R,R)-1,2-dicyclohexylethane-1,2-diol [(R,R)-DICHED] in the presence of NaHCO₃.[34] [35] [36] A subsequent homologation was performed in THF in the presence of ZnCl₂, according to the original procedure of Matteson.[37,38] After replacing the solvent with TFT, the intramolecular cyclopropanation was run according to our standard procedure,[39] and afforded 6 as a 77:23 mixture of enantiomers (Scheme [5]). The complete diastereoselectivity of the Matteson homologation process was confirmed by NMR analysis of chloride 11 (see Supporting Information): the erosion of enantioselectivity observed during the formation of product 6 results either from epimerization of the chloride 11 during the cyclopropanation process or from a nonstereospecific cyclopropanation process. Next, a 1:1 diastereomeric mixture of 11 was prepared by transesterification of 5 with (R,R)-DICHED. As expected, this afforded racemic 6 (Scheme [5]), indicating that the stereochemical outcome of the process is controlled by the stereochemistry of the chlorinated α-center. In agreement with an early observation by Matteson,[40] epimerization of 11 could be discarded, as the product enantiomeric ratio did not significantly decrease during the reaction (see Supporting Information). Consequently, the stereochemical outcome of the process pointed toward a moderately stereoselective cyclization mechanism (see above). A single-crystal X-ray analysis of optically pure (+)-6 was performed, confirming its structure; however, its absolute configuration could not be established due to low anomalous scattering.[31]

To determine the absolute configuration of the final bicyclic product, the whole reaction sequence was repeated with the brominated compound 12, prepared by using an approach closely related to that used to obtain 4 (see Supporting Information). The (R,R)-DICHED boronic ester 12 was treated as previously described for 10, affording the bicycle 14 in 60% yield as a 80:20 mixture of enantiomers (Scheme [6]). Recrystallization of a sample of 14 afforded optically pure material suitable for single-crystal X-ray crystallography.[31] The absolute configuration of the major isomer of 14 was established to be (1S,5S).

Based on these results, the stereochemical outcome of the process can be explained by the following mechanism (Figure [1]). Transesterification of (R,R)-5/13 with O(Bcat)₂ affords the α-chlorinated catechol boronic ester 5′/13′. Nucleophilic substitution of the chloride by the alkene, probably assisted by the neighboring acidic boron atom, takes place stereospecifically with inversion of the configuration at C(1). The process affords a trans/cis mixture of the zwitterionic intermediate B. The major isomer, trans-B, results from the transition state A3 and/or A4, which minimizes steric interactions between the alkene and the Bcat residue, whereas the minor isomer cis-B results from transition state A1 and/or A2, destabilized by steric interactions between the alkene and the Bcat residue. The second cyclization converting B into the bicyclic product 6/14 takes place with retention of the stereochemistry at the α-boron center for cis-B and with inversion for trans-B. Both retention[41] and inversion[42] of the configuration at the carbon bearing the boron atom have been observed in reaction of boron ate complexes with electrophiles, including in cyclopropane formation.[27] ^, [43] [44] [45] [46] [47] Remarkably, the diastereoselectivity of the cyclization step of 5′/13′ leading to B is the major factor determining the enantiomeric purity of the final products 6/14.

Besides the chiral-auxiliary approach described above, the boronic ester approach offers another easy way to prepare substituted enantioenriched bicyclo[3.1.0]hexanes by using substrate control. Based on the work of Aggarwal and co-workers,[48] TIB esters such as 3 were expected to be suitable substrates for the preparation of enantioenriched α-alkylated boronic esters that could be used in our homologation–intramolecular cyclopropanation reaction. Treatment of 3 with s-BuLi/(–)-sparteine, followed by treatment with MeBpin, afforded the chiral boronic ester 15 in 40% yield (Scheme [7]). An enantiomeric ratio of 77:23 was measured after conversion into the corresponding secondary alcohol 16. The level of enantioselectivity was deceivingly low when compared with the closely related examples reported by Aggarwal and co-workers,[48] but was thought to be sufficient to provide proof of concept for our approach. The enantioenriched 15 underwent a homologation–intramolecular cyclopropanation to provide the bicycle 18 in 40% yield as a satisfactory 87:13 endo/exo mixture of diastereomers (Scheme [7]). As expected, the enantiomeric purity of the major endo-18 (er 76:24) matched that of the starting boronic ester 15 (er 77:23).

A crude NMR analysis of the intermediate α-chloro boronic ester 17 indicated that the Matteson homologation process afforded an 83:17 mixture of diastereomers. This value was higher than expected, and their relative configuration could not be attributed.[30] Both the syn- and anti-diastereomers of 17 can afford endo- and exo-18. The four most likely transition states C1–C4 are depicted in Figure [2]. The syn-isomer of 17 presumably affords mainly endo-18 via transition state C1 in preference to C2, due to minimization of the A^1,3-strain.[49] The anti-isomer of 17 is expected to afford exo-18 preferentially via transition state C4. The high endo diastereoselectivity observed suggests that the major diastereomer of 17 possesses a syn-configuration; however, this assumption was not experimentally confirmed.

In conclusion, a method for the preparation of polysubstituted bicyclo[3.1.0]hexanes starting from air-stable boronic esters has been developed. The method involves a Matteson homologation reaction affording an α-chloroboronic ester that undergoes an intramolecular cyclopropanation. With pinacol boronic esters, the cyclopropanation step can be run at 140 °C directly, or can be run at 70 °C after in situ transesterification to a catechol boronic ester. This latter approach was found to be suitable for the preparation of enantioenriched bicyclo[3.1.0]hexanes by either using chiral-auxiliary control or by taking advantage of the sparteine-controlled enantioselective boroalkylation of alcohols. The reaction presented here represents a proof of principle, and is expected to open a broad range of applications for the synthesis of fused bicyclic cyclopropanes.

Conflict of Interest

The authors declare no conflict of interest.

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Corresponding Authors

Publication History

Received: 27 July 2023

Accepted after revision: 22 August 2023

Accepted Manuscript online:
22 August 2023

Article published online:
28 September 2023

© 2023. Thieme. All rights reserved

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• References and Notes

• 1 Rynbrandt RH, Dutton FE, Schmidt FL. J. Med. Chem. 1972; 15: 424
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• 31 CCDC 2264981, 2264984, and 2264985 contain the supplementary crystallographic data for compounds 7, (+)-6, and (+)-14, respectively. The data can be obtained free of charge from The Cambridge Crystallographic Data Centre via www.ccdc.cam.ac.uk/structures
• 32 (±)-(1SR,5SR)-2,2-Dibenzyl-6,6-dimethylbicyclo[3.1.0]hexane [(±)-6]: Thermal Procedure A 2.5 M solution of BuLi in hexane (0.87 mL, 2.2 mmol) was slowly added to a solution of anhyd CH₂Cl₂ (0.35 mL, 5.4 mmol) in THF (10 mL) at such a rate that the internal temperature did not exceed –100 °C. The resulting mixture was stirred at below –100 °C for 30 min, then a solution of dioxaborolane 4 (730 mg, 1.81 mmol) in anhyd THF (4 mL) was added. The resulting mixture was allowed to reach rt and stirred for 5 h. The solvents were removed under reduced pressure and toluene (20 mL) was then added, resulting in the precipitation of LiCl. The supernatant was transferred through a cannula to a flask containing BzOK (265 mg, 1.8 mmol), and the resulting mixture was heated at 140 °C overnight in a closed vessel and then cooled. The solid residue was filtered off and the remaining solution was concentrated under reduced pressure. The residue was purified by flash chromatography [silica gel, heptane–EtOAc (100:1 to 30:1)] to give a clear liquid that solidified on refrigeration; yield: 368 mg( 1.27 mmol, 70%); mp 46.8–47.7 °C. IR (neat): 3021, 2999, 2943, 2913, 2859, 1602, 1494, 1452, 1373, 1186, 1126, 1076, 1031, 778, 754, 738, 702, 639 cm^–1. ¹H NMR (300 MHz, CDCl₃): δ = 7.35–7.13 (m, 10 H), 2.85 (d, J = 13.1 Hz, 1 H), 2.71 (d, J = 13.1 Hz, 1 H), 2.62 (d, J = 12.9 Hz, 1 H), 2.45 (d, J = 12.9 Hz, 1 H), 1.80–1.69 (m, 1 H), 1.44–1.24 (m, 2 H), 1.21 (s, 3 H), 1.01 (s, 3 H), 0.91–0.73 (m, 3 H). ¹³C NMR (75 MHz, CDCl₃): δ = 140.7 (Cq_Ar), 140.0 (Cq_Ar), 130.8 (2 × CH_Ar), 130.5 (2 × CH_Ar), 128.0 (2 × CH_Ar), 127.7 (2 × CH_Ar), 126.0 (CH_Ar), 125.8 (CH_Ar), 49.7, 48.0, 45.7, 39.7, 36.9, 31.5, 29.5, 25.1, 20.5, 17.3. HRMS (ESI): m/z [M + H]⁺ calcd for C₂₂H₂₇: 291.2107; found: 291.2108.
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• 39 (+)-(1S,5S)-2,2-Dibenzyl-6,6-dimethylbicyclo[3.1.0]hexane [(+)-6]: Transesterification Procedure A 2.5 M solution of BuLi in hexane (0.79 mL, 2.00 mmol) was slowly added to a solution of CH₂Cl₂ (0.17 mL, 2.70 mmol) in dry THF (15 mL) at –100 °C at such a rate that the internal temperature never exceeded –100 °C. The resulting mixture was then stirred at below –100 °C for 30 min, and then a solution of 10 (940 mg, 1.80 mmol) in dry THF (5 mL) was added. The mixture was stirred at below –100 °C for 15 min before anhyd ZnCl₂ (417 mg, 3.00 mmol, 1.70 equiv) was added in one portion, and the resulting mixture was stirred for 14 h at rt. Pentane (5 mL) was added, and the mixture was carefully treated with sat. aq NH₄Cl (5 mL) and H₂O (5 mL). The phases were separated, and the aqueous phase was extracted with pentane (2 × 10 mL). The combined organic phases were dried (Na₂SO₄) and filtered. Toluene (5 mL) was added to remove residual THF, and the mixture was concentrated under reduced pressure. The resulting residue was dissolved in pentane (10 mL), which resulted in a slightly turbid solution. This solution was filtered through a syringe filter and concentrated to give the α-chloroboronic ester intermediate (S)-11. The resulting residue was dissolved in dry TFT (20 mL), and O(Bcat)₂ (914 mg, 3.60 mmol) was added. The mixture was stirred at 70 °C for 24 h, then cooled to rt and concentrated under reduced pressure. The crude product was purified by flash chromatography (silica gel, pentane) to give (+)-6 as a clear oil, contaminated with olefinic impurities. Product (+)-6 contaminated with olefinic impurities was dissolved 1:5 MeOH–CH₂Cl₂ (6 mL) and the solution was cooled to –78 °C. Ozone was bubbled through the solution until its color turned light blue. N₂ was then bubbled through for 15 min to remove excess ozone. NaBH₄ (76 mg, 2.0 mmol) was carefully added at –78 °C, and the mixture was allowed to reach rt and stirred at rt for 3 h. The mixture was then treated with H₂O (2 mL) and sat. aq NaHCO₃ (2 mL). The phases were separated and the aqueous phase was extracted with CH₂Cl₂ (2 × 5 mL). The combined organic phases were washed with sat. aq NH₄Cl (5 mL), dried (Na₂SO₄), and concentrated under reduced pressure. The residue was purified by flash chromatography [silica gel, pentane] to give a clear oil that crystallized on refrigeration; yield: 209 mg (40%, 77:23 er); mp 41.0–42.1 °C. [α]_D ²⁰ +36.76 (c = 1, CH₂Cl₂). Other physical data were in accordance with those of the racemic compound (±)-6.
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• Supplementary Material