6,6-Dimethyl-3-azabicyclo [3.1.0]hexane (6,6-DMABH) is a fundamental building block in numerous antiviral drugs, including boceprevir and pf-07321332. To enable more efficient synthesis of 6,6-DMABH, we developed an innovative approach that utilizes the intramolecular cyclopropanation of alpha-diazoacetates via Ru (II) catalysis and Gabriel synthesis. Our method enabled the synthesis of 6,6-DMABH from 3-methyl-2-butenol in seven distinct steps, yielding a total of 28%.
Research Article
Synthesis of 6,6-Dimethyl-3-azabicyclo [3.1.0]hexane via Ru (II)-Catalyzed Intramolecular Cyclopropanation
https://doi.org/10.21203/rs.3.rs-3113159/v1
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Journal Publication
published 14 Oct, 2023
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6
6-DMABH
intramolecular cyclopropanation
Ru (II) catalysis
Gabriel synthesis
6,6-Dimethyl-3-azabicyclo [3.1.0]hexane (6,6-DMABH) is a crucial pharmaceutical intermediate and key raw material utilized in the synthesis of numerous drugs. For instance, it plays a key role in the production of boceprevir [1–3], which is a well-known protease inhibitor for hepatitis C virus. Additionally, it is instrumental in the synthesis of pf-07321332 [4–7], an oral drug used to treat COVID-19.
Currently, there are two main methods for the synthesis of 3-azabicyclo [3.1.0]hexane scaffolds: cyclization reaction [8–11] and catalytic hydrogenation reaction[12, 13]. While these methods differ in terms of their reaction conditions, yields, and operational difficulties, they both have notable drawbacks. Although the conditions for cyclization reactions are relatively mild, their yields are low. In contrast, catalytic hydrogenation reactions require more stringent conditions and expensive maleic anhydride, and exhibit poor atom economy.
In this study, we present a more efficient synthetic method for producing 6,6-DMABH through the intramolecular cyclopropanation of alpha-diazoacetates using Ru(II) catalysis (Scheme 1).
We initiated our synthesis by reacting bromoacetyl bromide 1 with 3-methyl-2-butenol 2 in the presence of sodium bicarbonate, yielding bromoacetate 3 with a 97% yield. We then utilized an alkaline reaction in anhydrous THF, combining intermediate 3 with N,N'-Bis(p-toluenesulfonyl) hydrazine to produce alpha-diazoacetate 4. Due to its instability, we immediately employed compound 4 for the subsequent reaction (Scheme 1).
We then proceeded to investigate the intramolecular cyclopropanation of alpha-diazoacetates 4 and evaluated various transition metal-catalyzed methods (Table 1). Of the screened options, RuII-(S)-(Ph-pheox) exhibited the most promising performance. [14, 15, 8–11] Using DCM as a solvent and RuII-(S)-(Ph-pheox) as catalyst at 0℃, we obtained the desired product 5 in 86% yield (entry 10).
To convert lactone 5 to lactam, we attempted a range of aminolysis conditions, including trimethylaluminum/ammonia [16], [Cp*IrCl2]2/ benzylamine [17], and methanol solution of ammonia [18], but these efforts proved unsuccessful. (Scheme 1).
To prepare lactam 8, we employed Gabriel synthesis as an alternative approach. Specifically, we refluxed compound 5 in a potassium phthalate imide solution in DMF, which yielded product 6. We then hydrolyzed 6 using hydrochloric acid to generate amine 7 as hydrochloride, with a combined yield of 81% for these two steps. The intramolecular cyclization of 7 with dichlorosulfoxide resulted in lactam 8, with a yield of 70%. Finally, we reduced 8 using lithium aluminum hydride to obtain the target product 9 (6,6-DMABH), with a yield of 80%.
In summary, we have developed a highly efficient method for synthesizing 6,6-dimethyl-3-azabicyclo[3.1.0]hexane in just seven steps, with a total yield of 28%. Our approach utilizes Ru(II)-catalyzed intramolecular cyclopropanation and Gabriel synthesis. Notably, this protocol offers several advantages, including the use of inexpensive starting materials, straightforward work-up procedures, and high catalytic activity in the cyclopropanation reaction.
Acknowledgements
The authors are grateful for financial support provided by the ABA Chemicals Corporation.
Conflict of Interest
The authors declare no conflict of interest.
Data Availability Statement
The data that support the findings of this study are available in the supplementary material of this article.
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