Skip to main content
NCBI home page
NIHPA Author Manuscripts logoLink to NIHPA Author Manuscripts
. Author manuscript; available in PMC: 2026 Feb 15.
Published in final edited form as: J Am Chem Soc. 2025 Feb 17;147(8):6318–6325. doi: 10.1021/jacs.4c13298

Facile Synthesis of Housanes by an Unexpected Strategy

Yanyao Liu 1,#, Somanea Tranin 2,#, Yu-Che Chang 3, Evan B Piper 4, Thomas Fessard 5, Ryan Van Hoveln 6,*, Christophe Salome 7,*, M Kevin Brown 8,*
PMCID: PMC12905797  NIHMSID: NIHMS2135105  PMID: 39962893

Abstract

Rigid bicyclic hydrocarbons have emerged as important building blocks in the drug discovery industry. Despite progress in this general area, bicyclo[2.1.0]pentanes (housanes) are an understudied class of molecules. Herein we report an unconventional synthesis of borylated housanes. Our method features a broad scope and high diastereoselectivities in the synthesis of versatile intermediates. The route involves a strain-release diboration of bicyclo[1.1.0]butane and intramolecular deborylative alkylation. The versatility of the bridgehead boronic ester was demonstrated in several functionalizations. Lastly, the mechanism of the reaction was investigated, and an unusual stereospecific and diastereoselective ring expansion was uncovered.

Graphical Abstract

graphic file with name nihms-2135105-f0001.jpg

In recent years, there has been significant effort directed toward the design and development of new classes of saturated bicyclic hydrocarbons for applications in medicinal chemistry. This is due to several factors such as (1) isosteric replacement, generally for aromatic rings, (2) rigidification of flexible hydrocarbons, and (3) increasing Csp3 content to “escape from flatland.”1 In this regard, various bicyclic hydrocarbon scaffolds have been developed, including, but not limited to, bicyclo[1.1.1]pentane,2 bicyclo[2.1.1]hexane,3 bicyclo[3.1.1]heptane,4 cubane,5 etc.6 (Scheme 1a).

Scheme 1.

Scheme 1.

Open in a new tab

Rigid Hydrocarbons as Building Blocks for Medicinal Chemistry

Given our ongoing interest in cyclobutylboronates7 and novel building blocks for medicinal chemistry,8 we were interested in developing a synthesis of borylated bicyclo[1.1.1]pentanes (BCPs) (Scheme 1b). The route to be investigated was an intramolecular substitution between a gem-diboron and a pendant electrophile.9 To our surprise, when substrate 1 was treated with KOH, bicyclo[2.1.0]pentane (housane) 3 was unexpectedly observed as the major product with excellent diastereoselectivity (BCP 2 was not detected). While the BCP product was not obtained, housanes represent interesting and underexplored saturated bicyclic building blocks. Moreover, to the best of our knowledge, there are no reports on the preparation of borylated housanes. This latter point is of practical significance, as C–B bonds can be elaborated to many other groups, often with control of stereochemistry.10 Thus, a wide variety of substituted housanes can be accessed from a common precursor.

There are three primary approaches toward the synthesis of housanes: (1) cyclopropanation, (2) diazine homolysis, and (3) enolate alkylation (Scheme 1c). With respect to cyclopropanations, early work by Gassman reported a Simmons–Smith reaction of cyclobutene, albeit in low yield.11 More recently, Rh- or Pd-catalyzed intra-12 or intermolecular13 cyclopropanations have been developed as an effective strategy. Another less explored approach involves the photolysis of bicylic diazines.14,15 While interesting, these methods require the multistep synthesis of substrates, which results in laborious sequences. Finally, intramolecular alkylations have been used to prepare housanes.16 The Lindsay group recently reported one-pot synthesis of sulfone-substituted housanes.17 More relevantly, a recent report from Grygorenko et al. disclosed a diastereoselective approach to 1,3-disubstituted housanes.18 While a series of substitution patterns can be synthesized in both cis and trans manners, manipulation of the carboxylic acid to other groups was challenging. In contrast, the strategy outlined herein leads to the synthesis of borylated housanes, which are useful intermediates due to the versatility of the C–B bond.10

The route to borylated housanes reported herein requires the preparation of gem-diboryl cyclobutanes. Despite various reported methods for preparation of gem-diboron compounds,19 they were not applicable to cyclobutanes.20 Inspired by work from Aggarwal on ring opening of bicyclo[1.1.0]butanes,21 we modified this strategy to function with diboron reagents and aldehydes (Scheme 2a). The synthesis commenced with the in situ synthesis of lithiobicyclo[1.1.0]butane from 4 as reported by Aggarwal. Subsequent treatment with (Bpin)2 and the addition of aldehyde resulted in the formation of 5 in good yield.

Scheme 2.

Scheme 2.

Open in a new tab

Reaction Optimization

Optimization of the reaction was approached from multiple fronts. First, the nature of the leaving group was explored. Evaluation of phosphate, methyl carbonate, and halides led to the finding that alkyl iodides were superior (Scheme 2b, entries 1 and 3–6). While the iodide led to a slightly higher yield than the bromide, it also had the advantage that it did not require purification of the alcohol intermediate prior to use. Other bases were examined; however, inferior results were obtained (Scheme 2b, entries 7–10). Finally, it was observed that setting the reaction up in a glovebox allowed for the reaction to function in 93% yield in only 4 h.

Under the optimized conditions, the scope of the reaction was evaluated (Scheme 3). The method tolerated a wide range of substituted aryl groups, such as bromide (10), nitrile (11), ester (14), amide (23), and sulfonamide (24). While arenes with electron-withdrawing groups worked smoothly (11–14), the preparation of electron-rich aromatic substrates was problematic due to spontaneous elimination during substitution with iodide (see the Supporting Information for details). Alkyne (15) and π-extended arene substrates (16) delivered the products in good yields. In the latter case, the bromide was used to mitigate substrate elimination. For this example, the structure was unequivocally determined by an X-ray crystallographic analysis. More substituents, such as valuable heterocycles, were also tolerated. For example, various pyridines (17–19), thiazole (20), imidazole (21), and pyrazole (25) all worked well. These examples are particularly notable due to their prevalence in pharmaceutical agents.22 Finally, it must be emphasized that in all cases a single diastereomer was observed, and a variety of medicinal-chemistry-relevant scaffolds were tolerated. All substrates were fully consumed despite minor elimination byproduct and some loss on chromatography.

Scheme 3. Substrate Scopea.

Scheme 3.

Open in a new tab

aReactions were run on a 0.05–0.2 mmol scale. Diastereomeric ratios (dr) of the unpurified reaction mixtures were determined by 1H NMR analysis. Yields of isolated products are reported. The default leaving group (LG) was iodide unless noted otherwise.

This method was also applicable to the synthesis of simple borylated housane (26). For alkyl-substituted substrates, the use of the corresponding mesylate was found to be optimal for high diastereoselectivity (27, LG = I vs OMs). With the mesylates, both linear (30, 34, 35, and 37) and α-branched (28, 29, and 31–33) alkyl substrates are competent in housane synthesis. Sterically demanding groups can also be installed efficiently (product 29). The diastereoselectivity was dependent on the size of the alkyl group, with moderate to good selectivity for the linear examples and high to excellent selectivity for bulkier groups. Additionally, various heteroatoms and heterocycles, including azetidine (31), piperidine (32), and thiopyran (33), were compatible under the reaction conditions. It is noteworthy that a tert-butyl ester (which can be viewed as a protected acid) can also be incorporated in the housane (product 36), as this allows for downstream functionalization. Lastly, highly functionalized and rigid scaffolds such as spirocyclic housanes (products 38 and 39) can also be achieved in high yields using this method.

The robustness of this reaction was also highlighted by the preparation of housane 3 on a gram scale (10 mmol) in comparable yield to the smaller-scale reaction (Scheme 4a). Product derivatizations were then explored. One early direction explored the use of the borylated housanes as strain-release agents akin to their homologues, borylated bicyclo[1.1.0]butanes.23 However, no signs of success were observed, with >80% of the starting material generally being recovered despite our attempts under various conditions. The reluctance of strain-release ring opening highlights the underestimated stability of the housane, which indicates its potential to serve as a useful saturated building block in medicinal chemistry. Our efforts were next switched to functionalizing the boronic ester while maintaining the housane core. While attempted use of radical-based methods24 for cross-coupling resulted in housane decomposition, we were delighted to see that Suzuki coupling worked smoothly under mild conditions (Scheme 4b, 40 and 41). This was surprising, as alkylboronic esters are known to be sluggish in cross-coupling reactions compared to aryl or alkenyl counterparts.25 It was reasoned that the strained housane backbone renders the C–B bond to have more sp2 character, causing it to undergo transmetalation more readily. To further take advantage of the special properties of housane boronic ester, we applied Morken’s conditions for copper-catalyzed coupling.26 The ate complex formed from housane Bpin and tert-butyllithium undergoes coupling reactions with different electrophiles to achieve allyl (43), alkynyl (44), and allenyl (45)-substituted housanes. It should be noted that in all these cases, the transmetalations were highly regioselective, as no tert-butyl coupling products were detected. These results again highlighted the differences between a housane Bpin and a typical tertiary alkyl Bpin. In addition, an alkene group can be easily installed by using Zweifel–Evans olefinations (product 42). Lastly, the tert-butyl ester on the housane was also functionalized, as shown by reduction to aldehyde (46) and conversion to free carboxylic acid (47) (Scheme 4c). The latter one was further transformed into a protected amine (48) via a Curtius rearrangement. In the last two cases, while the starting material was fully consumed, the yield suffered, likely due to product stabilities and harsh conditions.

Scheme 4.

Scheme 4.

Open in a new tab

Synthetic Utility of Housane Products

During optimization, we found that when the reaction was promoted with a weaker base, such as LiOH, or at lower temperatures, a cyclopentane (e.g., 49) was isolated in varying quantities. For example, when 6 was treated with LiOH and quenched after 4 h, cyclopentane 49 was observed in 20% yield alongside housane 3 in 15% yield (Scheme 5a). Moreover, when cyclopentane 49 was treated with KOH, it was converted to housane 3. These data strongly suggest that 49 is an intermediate on the pathway to formation of 3. To investigate the mechanism further, the enantiospecificity of the process was probed. This was most readily accomplished by examining enantiomerically enriched phosphate 127,28 (this was already demonstrated to be a competent leaving group; see Scheme 2b, entry 1). When (S)-1 was treated with KOH at 0 °C, the cyclopentyl product 50 and (1R,3R,4S)-housane product 3 were formed with high enantiospecificity. Additionally, intermediate 50 can also be converted to housane in a discrete reaction with KOH while maintaining the enantiomeric purity.

Scheme 5.

Scheme 5.

Open in a new tab

Mechanism Studies and Control Experiments

To probe the nature of the ring enlargement, simple cyclobutane substrate 51 was first treated with KOH at 0 °C, and <2% yield of the cyclopentane 52 was observed (Scheme 5b). Cyclobutanes bearing substitutions, including a single methyl group (53) and gem-dimethyl groups (54), were also subjected to the reaction conditions, yet no rearranged products were observed. These results suggest that the ring expansion was not triggered by simple steric repulsion or the Thorpe–Ingold effect. Additionally, the fact that substrate 55 was successfully prepared and remained intact under the conditions implies that simple Lewis basic groups are not strong enough to promote the ring expansion. Lastly and most importantly, replacing one of the geminal diboron groups with a phenyl group also does not lead to rearrangement (substrate 56). Shibata has demonstrated that geminal diborons readily bind hydroxide while simple monoboranes do not.29 It is therefore hypothesized that the ring expansion process is triggered by a hydroxide-bound borate complex.

It was envisioned that the ring enlargement could proceed via a dyotropic rearrangement (via III) or by a 1,2-shift (via IV) to generate intermediate II (Scheme 5c). Since monitoring the reaction by 11B NMR did not provide much useful information (see the Supporting Information), computational tools were applied to shed light on the details of the mechanism. After significant effort, a minimum for the carbocationic intermediate that results from transition state IV in Scheme 5c could not be found. Instead, attempts to optimize this intermediate resulted in elimination products or ring opening of the dioxaborolane. However, the typical synchronous dyotropic rearrangement transition state leading to the cyclopentane intermediate could not be found either.30 The optimization instead converged to an asynchronous concerted dyotropic transition state (Figure 1).31 In this transition state, the C–O bond breaks rapidly, followed by ring expansion (Figure 1d). After C–C bond cleavage/formation has progressed significantly, the C–O bond forms. The ring-opening mechanism was also calculated for cyclobutane SM-2 to help elucidate why the borate was necessary for rearrangement (Figure 1b). After natural bond orbital (NBO) analysis of TS-1a and TS-1d, there is significant electronic communication between the C–borate bond and the C1–C2–C3 three-center, two-electron bond in TS-1a that is mainly absent in TS-1d. This electronic communication likely accounts for the significant energy difference between the two pathways and the importance of borate formation in this transformation. Finally, a concerted stereoinvertive alkylation32 seems energetically feasible to form the housane from the cyclopentane.33

Figure 1.

Figure 1.

Open in a new tab

Computational studies. (a) Complete reaction with asynchronous concerted transition state leading to a cyclopentane intermediate. (b) Alternate pathway where the borons have been replaced with methyl groups. (c) Free energy profile calculated at the ωB97XD/def2-TZVP,SMD(THF) level of theory. All energies are in kcal mol−1. (d) Evidence of an asynchronous concerted transition state for TS-1a.

Lastly, the high diastereoselectivity of housane formation is believed to be a result of the preferred reactive conformation (Scheme 5d). For ring expansion to occur, one C–C bond would be antiperiplanar to the leaving group for better orbital alignment. Therefore, the cyclobutane adopts a conformation that places the H atoms antiperiplanar (VI-b) rather than synclinal (VI-a). This differentiation between the two conformations is reduced when the R group is smaller (e.g., linear alkane); therefore, a lower dr was observed in those substrates.

In conclusion, an unexpected housane synthesis method has been discovered. The method allows for rapid access to various substituted housanes with high diastereoselectivity. The boron unit serves as a useful handle for derivatizations. Mechanistic insight was provided that suggested a possible cyclopentane intermediate. We suspect that this method will be useful for the incorporation of housanes in drug discovery efforts.

Supplementary Material

Supporting Info

ASSOCIATED CONTENT

Supporting Information

The Supporting Information is available free of charge at https://pubs.acs.org/doi/10.1021/jacs.4c13298.

Experimental procedures and analytical data for all new compounds (PDF)

ACKNOWLEDGMENTS

We thank Indiana University, NIH (R35GM131755), and SpiroChem AG for financial support. This project was partially funded by the Vice Provost for Research through the Research Equipment Fund and the NSF MRI Program (CHE-1726633 and CHE-1920026). We thank Dr. Maren Pink of the IU Molecular Structure Center for acquisition of X-ray crystal structure data. Support for the acquisition of the Bruker Venture D8 diffractometer through the Major Scientific Research Equipment Fund from the President of Indiana University and the Office of the Vice President for Research is gratefully acknowledged.

Footnotes

The authors declare no competing financial interest.

Accession Codes

Deposition number 2386119 contains the supplementary crystallographic data for this paper. These data can be obtained free of charge via the joint Cambridge Crystallographic Data Centre (CCDC) and Fachinformationszentrum Karlsruhe Access Structures service.

Contributor Information

Yanyao Liu, Department of Chemistry, Indiana University, Bloomington, Indiana 47405, United States.

Somanea Tranin, Department of Chemistry, Indiana University, Bloomington, Indiana 47405, United States.

Yu-Che Chang, Department of Chemistry, Indiana University, Bloomington, Indiana 47405, United States.

Evan B. Piper, Department of Chemistry, Indiana University, Bloomington, Indiana 47405, United States

Thomas Fessard, SpiroChem AG, 4058 Basel, Switzerland.

Ryan Van Hoveln, Department of Chemistry and Physics, Indiana State University, Terre Haute, Indiana 47809, United States.

Christophe Salome, SpiroChem AG, 4058 Basel, Switzerland.

M. Kevin Brown, Department of Chemistry, Indiana University, Bloomington, Indiana 47405, United States.

REFERENCES

  • (1).Lovering F; Bikker J; Humblet C Escape from flatland: increasing saturation as an approach to improving clinical success. J. Med. Chem. 2009, 52, 6752–6756. [DOI] [PubMed] [Google Scholar]
  • (2).For selected examples, see: Zhao J-X; Chang Y-X; He C; Burke BJ; Collins MR; Del Bel M; Elleraas J; Gallego GM; Montgomery TP; Mousseau JJ; Nair SK; Perry MA; Spangler JE; Vantourout JC; Baran PS 1,2-Difunctionalized Bicyclo[1.1.1]Pentanes: Long-Sought-After Mimetics for ortho/meta-Substituted Arenes. Proc. Natl. Acad. Sci. U. S. A. 2021, 118, No. e2108881118. Yang Y; Tsien J; Hughes JME; Peters BK; Merchant RR; Qin T An Intramolecular Coupling Approach to AlkylBioisosteres for the Synthesis of Multisubstituted BicycloalkylBoronates. Nat. Chem. 2021, 13, 950–955. Ma X; Han Y; Bennett DJ Selective Synthesis of 1-Dialkylamino-2-Alkylbicyclo-[1.1.1]Pentanes. Org. Lett. 2020, 22, 9133–9138. Garry OL; Heilmann M; Chen J; Liang Y; Zhang X; Ma X; Yeung CS; Bennett DJ; MacMillan DWC Rapid Access to2-Substituted Bicyclo[1.1.1]Pentanes. J. Am. Chem. Soc. 2023, 145, 3092–3100.
  • (3).For selected examples, see: Denisenko A; Garbuz P; Shishkina SV; Voloshchuk NM; Mykhailiuk PK Saturated bioisosteres of ortho-substituted benzenes. Angew. Chem. 2020, 132, 20696–20702.Rigotti T; Bach T Bicyclo[2.1.1]hexanes by Visible Light-Driven Intra-molecular Crossed [2 + 2] Photocycloadditions. Org. Lett. 2022, 24, 8821–8825. Herter L; Koutsopetras I; Turelli TL; Fessard TF; Salome C Preparation of new bicyclo[2.1.1]hexanecompact modules: an opening towards novel sp3-rich chemical space. Org. Biomol. Chem. 2022, 20, 9108–9111. Reinhold M; Steinebach J; Golz C; Walker JCL Synthesis of polysubstituted bicyclo[2.1.1]hexanes enabling access to new chemical space. Chem.Sci. 2023, 14, 9885–9891. Denisenko A; Garbuz P; Makovetska Y; Shablykin O; Lesyk D; Al-Maali G; Korzh R; Sadkova IV; Mykhailiuk PK 1,2-Disubstituted bicyclo[2.1.1]hexanes as saturated bioisosteres of ortho-substituted benzene. Chem. Sci. 2023, 14, 14092–14099.
  • (4).For selected examples, see: Harmata AS; Spiller TE; Sowden MJ; Stephenson CR Photochemical Formal (4 + 2)-Cycloaddition of Imine-Substituted Bicyclo[1.1.1]pentanes and Alkenes. J. Am. Chem. Soc. 2021, 143, 21223–21228. Frank N; Nugent J; Shire BR; Pickford HD; Rabe P; Sterling AJ; Zarganes-Tzitzikas T; Grimes T; Thompson AL; Smith RC; Schofield CJ; Brennan PE; Duarte F; Anderson EA Synthesis of meta-substituted arene bioisosteres from [3.1.1]propellane. Nature 2022, 611, 721–726. Iida T; Kanazawa J; Matsunaga T; Miyamoto K; Hirano K; Uchiyama M Practical and Facile Access to Bicyclo[3.1.1]heptanes: Potent Bioisosteres of meta-Substituted Benzenes. J. Am. Chem. Soc. 2022, 144, 21848–21852. Zheng Y; Huang W; Dhungana RK; Granados A; Keess S; Makvandi M; Molander GA Photochemical Intermolecular [3σ + 2σ]-Cycloaddition for theConstruction of Aminobicyclo[3.1.1]heptanes. J. Am. Chem. Soc. 2022, 144, 23685–23690. Yu T; Yang J; Wang Z; Ding Z; Xu M; Wen J; Xu L; Li P Selective [2σ + 2σ] Cycloaddition Enabled by Boronyl Radical Catalysis: Synthesis of Highly Substituted Bicyclo[3.1.1]heptanes. J. Am. Chem. Soc. 2023, 145, 4304–4310.Nguyen TV; Bossonnet A; Wodrich MD; Waser J Photocatalyzed [2σ + 2σ] and [2σ + 2π] Cycloadditions for the Synthesis of Bicyclo[3.1.1]heptanes and 5- or 6-Membered Carbocycles. J. Am. Chem. Soc. 2023, 145, 25411–25421.
  • (5).Wiesenfeldt MP; Rossi-Ashton JA; Perry IB; Diesel J; Garry OL; Bartels F; Coote SC; Ma X; Yeung CS; Bennett DJ; MacMillan DW General access to cubanes as benzene bioisosteres. Nature 2023, 618, 513–518. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • (6).For selected examples, see: Son JY; Aikonen S; Morgan N; Harmata AS; Sabatini JJ; Sausa RC; Byrd EF; Ess DH; Paton RS; Stephenson CR Exploring Cuneanes as Potential Benzene Isosteres and Energetic Materials: Scope and Mechanistic Investigations into Regioselective Rearrangements from Cubanes. J. Am. Chem. Soc. 2023, 145, 16355–16364. Denisenko A; Garbuz P; Voloshchuk NM; Holota Y; Al-Maali G; Borysko P; Mykhailiuk PK 2-Oxabicyclo[2.1.1]hexanes as saturated bioisosteres of the ortho-substituted phenyl ring. Nat. Chem. 2023, 15, 1155–1163.
  • (7).(a) Liu Y; Ni D; Stevenson BG; Tripathy V; Braley SE; Raghavachari K; Swierk JR; Brown MK Photosensitized [2 + 2]-Cycloadditions of Alkenylboronates and Alkenes. Angew. Chem., Int. Ed. 2022, 61, No. e202200725. [DOI] [PMC free article] [PubMed] [Google Scholar]; (b) Liu Y; Ni D; Brown MK Boronic Ester Enabled [2 + 2]-Cycloadditions by Temporary Coordination: Synthesis of Artochamin J and Piperarborenine B. J. Am. Chem. Soc. 2022, 144, 18790–18796. [DOI] [PMC free article] [PubMed] [Google Scholar]; (c) Posz JM; Sharma N; Royalty PA; Liu Y; Salome C; Fessard TC; Brown MK Synthesis of Borylated Carbocycles by [2+ 2]-Cycloadditions and Photo-Ene Reactions. J. Am. Chem. Soc. 2024, 146, 10142–10149. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • (8).(a) Epplin RC; Paul S; Herter L; Salome C; Hancock EN; Larrow JF; Baum EW; Dunstan DR; Ginsburg-Moraff C; Fessard TC; Brown MK [2]-Ladderanes as isosteres for meta-substituted aromatic rings and rigidified cyclohexanes. Nat. Commun. 2022, 13, 6056. [DOI] [PMC free article] [PubMed] [Google Scholar]; (b) Paul S; Adelfinsky D; Salome C; Fessard T; Brown MK 2,5-disubstituted bicyclo[2.1.1]hexanes as rigidified cyclopentane variants. Chem. Sci. 2023, 14, 8070–8075. [DOI] [PMC free article] [PubMed] [Google Scholar]; (c) Guo R; Chang YC; Herter L; Salome C; Braley SE; Fessard TC; Brown MK Strain-release [2π + 2σ] cycloadditions for the synthesis of bicyclo [2.1. 1] hexanes initiated by energy transfer. J. Am. Chem. Soc. 2022, 144, 7988–7994. [DOI] [PMC free article] [PubMed] [Google Scholar]; (d) Chang YC; Salome C; Fessard T; Brown MK Synthesis of 2-Azanorbornanes via Strain-Release Formal Cycloadditions Initiated by Energy Transfer. Angew. Chem., Int. Ed. 2023, 62, No. e202314700. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • (9).(a) Hong K; Liu X; Morken JP Simple Access to Elusive α-Boryl Carbanions and Their Alkylation: An Umpolung Construction for Organic Synthesis. J. Am. Chem. Soc. 2014, 136, 10581–10584. [DOI] [PMC free article] [PubMed] [Google Scholar]; (b) Murray SA; Liang MZ; Meek SJ Stereoselective Tandem Bis-Electrophile Couplings of Diborylmethane. J. Am. Chem. Soc. 2017, 139, 14061–14064. [DOI] [PMC free article] [PubMed] [Google Scholar]; (c) Chen XY; Gao FC; Ning PF; Wei Y; Hong K Facile Access to Cyclopropylboronates via Stereospecific Deborylative Cyclization: A Leaving Group-Assisted Activation of Geminal Diborons. Angew. Chem., Int. Ed. 2023, 62, No. e202302638. [DOI] [PubMed] [Google Scholar]; (d) Kim G; Kim M; Ryu C; Choi J; Cho SH Anion-mediated, stereospecific synthesis of secondary and tertiary cyclopropylboronates from chiral epoxides and gem-diborylalkanes. Org. Lett. 2023, 25, 4130–4134. [DOI] [PubMed] [Google Scholar]; (e) McDonald TR; Rousseaux SA Synthesis of 3-borylated cyclobutanols from epihalohydrins or epoxy alcohol derivatives. Chem. Sci. 2023, 14, 963–969. For a review, see: [DOI] [PMC free article] [PubMed] [Google Scholar]; (f) Fernández E α-Boryl Carbanions: The Influence of Geminal Heteroatoms in C-C Bond Formation. Chem. Rec. 2024, 24, No. e202300349. [DOI] [PubMed] [Google Scholar]
  • (10).Sandford C; Aggarwal VK Stereospecific functionalizations and transformations of secondary and tertiary boronic esters. Chem. Commun. 2017, 53, 5481–5494. [DOI] [PubMed] [Google Scholar]
  • (11).Gassman PG; Mansfield KT Bridgehead Substituted Bicyclo[2.1.0]Pentanes. J. Org. Chem. 1967, 32, 915–920. [Google Scholar]
  • (12).(a) Shi G; Cai W Rhodium-catalysed decomposition of δ,ε-unsaturated β,β-difluoro-α-diazo esters, the direct formation of bicyclo [2.1.0]pentane ring systems via intramolecular cyclopropanation. J. Chem. Soc., Perkin Trans. 1 1996, No. 47, 2337–2338. [Google Scholar]; (b) Sharland JC; Davies HM One-Pot Synthesis of Difluorobicyclo[1.1.1]pentanes from α-Allyldiazoacetates. Org. Lett. 2023, 25, 5214–5219. [DOI] [PMC free article] [PubMed] [Google Scholar]; (c) Eckart-Frank IK; Wilkerson-Hill SM Palladium-catalyzed trans-selective synthesis of spirocyclic cyclobutanes using α, α-dialkylcrotyl-and allylhydrazones. J. Am. Chem. Soc. 2023, 145, 18591–18597. [DOI] [PubMed] [Google Scholar]; (d) Coto D; Suárez-García D; Mata S; López LA; Fernández I; Vicente R From Cyclopropene to Housane Derivatives Via Intramolecular Cyclopropanation. Angew. Chem., Int. Ed. 2024, 63, No. e202409226. [DOI] [PubMed] [Google Scholar]
  • (13).(a) McNamee RE; Haugland MM; Nugent J; Chan R; Christensen KE; Anderson EA Synthesis of 1,3-disubstituted bicyclo[1.1.0]butanes via directed bridgehead functionalization. Chem. Sci. 2021, 12, 7480–7485. [DOI] [PMC free article] [PubMed] [Google Scholar]; (b) Lin SL; Chen YH; Liu HH; Xiang SH; Tan B Enantioselective Synthesis of Chiral Cyclobutenes Enabled by Brønsted Acid-Catalyzed Isomerization of BCBs. J. Am. Chem. Soc. 2023, 145, 21152–21158. [DOI] [PubMed] [Google Scholar]
  • (14).For examples, see: Dauben WG; Wiseman JR Solvolysis of Bicyclo[2.1.0]-Pentanyl-1-Methyl p-Nitro-Benzoate. J. Am. Chem. Soc. 1967, 89, 3545–3549.Kinstle TH; Welch RL; Exley RW Substituted Bicyclo[2.1.0]Pentanes. J. Am. Chem. Soc. 1967, 89, 3660–3661.Mcdonald RN; Reitz RR Strained Ring Systems. XII. Synthesis of Several Dimethyl Δ1-Cycloalkene-1,2-Dicarboxylates and Certain 4-Substituted Bicyclo[2.1.0]Pentane-1-Carboxylic Acids. J. Org. Chem. 1972, 37, 2418–2423.Franck-Neumann M; Miesch M; Gross L Synthesis of the Angular Triquinane (±)-Pentalenene via Small Ring Intermediates. Tetrahedron Lett. 1992, 33, 3879–3882.
  • (15).Criegee R; Rimmelin A Darstellung und Eigenschaften von Bicyclo-[0.1.2]-Pentan. Chem. Ber. 1957, 90, 414–417. [Google Scholar]
  • (16).Hall HK Synthesis and Polymerization Studies of Bicyclo [2.1.0] pentane-1-carbonitrile and Bicyclo [3.1.0] hexane-1-carbonitrile. Macromolecules 1971, 4, 139–142. [Google Scholar]
  • (17).Jung M; Lindsay VNG One-Pot Synthesis of Strain-Release Reagents from Methyl Sulfones. J. Am. Chem. Soc. 2022, 144, 4764–4769. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • (18).Semeno VV; Vasylchenko VO; Vashchenko BV; Lutsenko DO; Iminov RT; Volovenko OB; Grygorenko OO Building the Housane: Diastereoselective Synthesis and Characterization of Bicyclo[2.1.0]pentane Carboxylic Acids. J. Org. Chem. 2020, 85, 2321–2337. [DOI] [PubMed] [Google Scholar]
  • (19).(a) Li H; Shangguan X; Zhang Z; Huang S; Zhang Y; Wang J Formal Carbon Insertion of N-Tosylhydrazone into B–B and B–Si Bonds: gem-Diborylation and gem-Silylborylation of sp3 Carbon. Org. Lett. 2014, 16, 448–451. [DOI] [PubMed] [Google Scholar]; (b) Wang L; Zhang T; Sun W; He Z; Xia C; Lan Y; Liu C C–O Functionalization of α-Oxyboronates: A Deoxygenative gem-Diborylation and gem-Silylborylation of Aldehydes and Ketones. J. Am. Chem. Soc. 2017, 139, 5257–5264. For a review, see: [DOI] [PubMed] [Google Scholar]; (c) Nallagonda R; Padala K; Masarwa A gem-Diborylalkanes: recent advances in their preparation, transformation and application. Org. Biomol. Chem. 2018, 16, 1050–1064. [DOI] [PubMed] [Google Scholar]
  • (20).During the investigation of this project, a [2 + 2]-cycloaddition was reported to make gem-diboryl cyclobutanes. See: Hanania, N.; Eghbarieh, N.; Masarwa, A. PolyBorylated Alkenes as Energy-Transfer Reactive Groups: Access to Multi-Borylated Cyclobutanes Combined with Hydrogen Atom Transfer Event. Angew. Chem., Int. Ed. 2024, 63, No. e202405898. [DOI] [PubMed] [Google Scholar]
  • (21).(a) Fawcett A; Biberger T; Aggarwal VK Carbopalladation of C–C σ-bonds enabled by strained boronate complexes. Nat. Chem. 2019, 11, 117–122. [DOI] [PubMed] [Google Scholar]; (b) Silvi M; Aggarwal VK Radical Addition to Strained σ-Bonds Enables the Stereocontrolled Synthesis of Cyclobutyl Boronic Esters. J. Am. Chem. Soc. 2019, 141, 9511–9515. [DOI] [PubMed] [Google Scholar]; (c) Bennett SH; Fawcett A; Denton EH; Biberger T; Fasano V; Winter N; Aggarwal VK Difunctionalization of C–C σ-Bonds Enabled by the Reaction of Bicyclo[1.1.0]butyl Boronate Complexes with Electrophiles: Reaction Development, Scope, and Stereochemical Origins. J. Am. Chem. Soc. 2020, 142, 16766–16775. [DOI] [PubMed] [Google Scholar]; (d) Shen HC; Popescu MV; Wang ZS; de Lescure L; Noble A; Paton RS; Aggarwal VK Iridium-Catalyzed Asymmetric Difunctionalization of C–C σ-Bonds Enabled by Ring-Strained Boronate Complexes. J. Am. Chem. Soc. 2023, 145, 16508–16516. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • (22).Vitaku E; Smith DT; Njardarson JT Analysis of the Structural Diversity, Substitution Patterns, andFrequency of Nitrogen Heterocycles among U.S. FDA Approved Pharmaceuticals. J. Med. Chem. 2014, 57, 10257–10274. [DOI] [PubMed] [Google Scholar]
  • (23).See ref 20 and: Guo L; Noble A; Aggarwal VK α-Selective Ring-Opening Reactions of Bicyclo[1.1.0]butyl Boronic Ester with Nucleophiles. Angew. Chem. 2021, 133, 214–218.
  • (24).For examples, see: Tellis JC; Primer DN; Molander GA Single-electron transmetalation in organoboron cross-coupling by photoredox/nickel dual catalysis. Science 2014, 345, 433–436. Speckmeier E; Maier TC ART—An Amino Radical Transfer Strategy for C(sp2)–C(sp3) Coupling Reactions, Enabled by Dual Photo/Nickel Catalysis. J. Am. Chem. Soc. 2022, 144, 9997–10005.
  • (25).For selected reviews on Suzuki coupling of alkylboronates, see: Jana R; Pathak TP; Sigman MS Advances in Transition Metal (Pd,Ni,Fe)-Catalyzed Cross-Coupling Reactions Using Alkyl-organometallics as Reaction Partners. Chem. Rev. 2011, 111, 1417–1492. Leonori D; Aggarwal VK Stereospecific Couplings of Secondary and Tertiary Boronic Esters. Angew. Chem., Int. Ed. 2015, 54, 1082–1096.Cherney AH; Kadunce NT; Reisman SE Enantioselective and Enantiospecific Transition-Metal-Catalyzed Cross-Coupling Reactions of Organometallic Reagents To Construct C–C Bonds. Chem. Rev. 2015, 115, 9587–9652.
  • (26).(a) Xu N; Liang H; Morken JP Copper-Catalyzed Stereospecific Transformations of Alkylboronic Esters. J. Am. Chem. Soc. 2022, 144, 11546–11552. [DOI] [PMC free article] [PubMed] [Google Scholar]; (b) Liang H; Morken JP Substrate Plasticity Enables Group-Selective Transmetalation: Catalytic Stereospecific Cross-Couplings of Tertiary Boronic Esters. J. Am. Chem. Soc. 2023, 145, 20755–20760. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • (27).Li X; Jiang H; Uffman EW; Guo L; Zhang Y; Yang X; Birman VB Kinetic Resolution of Secondary Alcohols Using Amidine-Based Catalysts. J. Org. Chem. 2012, 77, 1722–1737. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • (28).This is primarily due to ease of synthesis of 1 from enantiomerically enriched alcohol 5 and straightforward purification/enantiomeric ratio determination of 50.
  • (29).Endo K; Ohkubo T; Hirokami M; Shibata T Chemoselective and regiospecific Suzuki coupling on a multisubstituted sp3-carbon in 1, 1-diborylalkanes at room temperature. J. Am. Chem. Soc. 2010, 132, 11033–11035. [DOI] [PubMed] [Google Scholar]
  • (30).For a review on dyotropic reactions, see: Fernandez I; Cossio FP; Sierra MA Dyotropic Reactions: Mechanisms and Synthetic Applications Chem. Rev. 2009, 109, 6687.
  • (31).For examples of asynchronous concerted transition states see: Hong YJ; Ponec R; Tantillo DJ Changes in Charge Distribution, Molecular Volume, Accessible Surface Area and Electronic Structure along the Reaction Coordinate for a Carbocationic Triple Shift Rearrangement of Relevance to Diterpene Biosynthesis. J. Phys. Chem. A 2012, 116, 8902–8909. Hong YJ; Tantillo DJ A Maze of Dyotropic Rearrangements and Triple Shifts: Carbocation Rearrangements Connecting Stemarene, Stemodene, Betaerdene, Aphidicolene, and Scopadulanol. J. Org. Chem. 2018, 83, 3780–3793. Hashimoto Y; Kong W-Y; Tantillo DJ Discovery of a Formal Dyotropic Rearrangement during Acid-Mediated Dioxabicyclo[4.2.1]-nonanone Formation. Org. Lett. 2024, 26, 5441–5446. Li Y-Y; Zhang S-Q; Hong X An Asynchronous Concerted Mechanism and Its Origin in Lewis Acid-Mediated Carbonyl-Olefin [2 + 2] Cycloaddition. Chem.—Asian J. 2023, 18, No. e202300375.
  • (32).See ref 9c and: Goering HL; Trenbeath SL Stereochemistry of conversion of allylic halides to cyclopropanes via γ-haloalkylboranes. J. Am. Chem. Soc. 1976, 98, 5016–5017.Larouche-Gauthier R; Elford TG; Aggarwal VK Ate Complexes of Secondary Boronic Esters as Chiral Organometallic-Type Nucleophiles for Asymmetric Synthesis. J. Am. Chem. Soc. 2011, 133, 16794–16797.
  • (33).While the calculations were conducted with the phosphate, it is reasonable to assume that the iodide also proceeds via a concerted synchronous ring enlargement, as this type of process has been well-documented in the literature (see ref 30).

Associated Data

This section collects any data citations, data availability statements, or supplementary materials included in this article.

Supplementary Materials

Supporting Info
NIHMS2135105-supplement-Supporting_Info.pdf (18.7MB, pdf)

RESOURCES