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Synlett 2024; 35(15): 1813-1816
DOI: 10.1055/a-2251-4145
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Synthesis and α-Functionalisation of Cyclic Imines

Ze Kuang
a   School of Chemical Sciences, The University of Auckland, 23 Symonds Street, Auckland, 1010, New Zealand
,
Xiao-Bo Ding
a   School of Chemical Sciences, The University of Auckland, 23 Symonds Street, Auckland, 1010, New Zealand
b   The Maurice Wilkins Centre for Molecular Biodiscovery, The University of Auckland, 3 Symonds Street, Auckland, 1010, New Zealand
,
Daniel P. Furkert 
a   School of Chemical Sciences, The University of Auckland, 23 Symonds Street, Auckland, 1010, New Zealand
b   The Maurice Wilkins Centre for Molecular Biodiscovery, The University of Auckland, 3 Symonds Street, Auckland, 1010, New Zealand
,
Margaret A. Brimble  ∗
a   School of Chemical Sciences, The University of Auckland, 23 Symonds Street, Auckland, 1010, New Zealand
b   The Maurice Wilkins Centre for Molecular Biodiscovery, The University of Auckland, 3 Symonds Street, Auckland, 1010, New Zealand
› Author Affiliations

Financial support from the Maurice Wilkins Centre for Molecular Biodiscovery and the Royal Society Te Aparangi Marsdon Fund is gratefully acknowledged.
› Further Information
 
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Abstract

α-Functionalisation of cyclic imines is explored. The cyclic imine substrates are synthesised from their respective halonitrile precursors using a nucleophilic addition/cyclisation sequence. Selective monohalogenation of the cyclic imines yields α-haloimines, which serve as a platform to obtain various α-hydroxyimine derivatives. In addition, an unusual tautomerisation and oxidation sequence is observed in the attempted preparation of α-hydroxyimines.


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Key words

cyclic imine - spiroimine - α-functionalisation - α-hydroxyimine - α-bromoimine

Spirocyclic imines are a key structural feature of an important family of marine toxins.[1] Early members of this natural product family include spirolides,[2] [3] [4] pinnatoxins,[5,6] gymnodimines,[7–9] pteriatoxins,[10] spiro-prorocentrimines[11] and kabirimine[12] (Figure [1]). The cyclic imine moieties present in these compounds consist of a six- or seven-membered ring with a spiro-link to a cyclohexene ring.

The recently reported portimines A (1) and B (2) (Figure [1]), isolated from the benthic dinoflagellate Vulcanodinium rugosum in New Zealand waters, are distinct from previous examples, both biologically and structurally.[13] [14] In contrast to other cyclic imine toxins, which display strong acute neurotoxicity, portimine A (1) exhibits very low in vivo toxicity (mouse LD50 1570 mg/kg) but exhibits potent in vitro anticancer activity (P388, EC50 2.7 nM).[13] In addition, portimine A (1) exhibited strong antifouling activity in a panel of four macrofouling bioassays (EC50 0.06–62.5 ng/mL).[15] This activity is also distinct from that of the related spiroimine natural products. Portimines A (1) and B (2) not only possess the smallest five-membered imine ring, they are also the first examples of cyclic imine natural products that possess an α-functionalised cyclic imine motif; portimine A (1) possesses an α-hydroxyimine scaffold and portimine B (2) contains an α-ketoimine. Preliminary structure–activity relationship studies indicated that the cyclic imine moiety is critical to their activity.[15]

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Figure 1 Examples of cyclic imine natural products

To our knowledge, simple α-substituted cyclic imines have not been well studied in both synthetic and medicinal chemistry, and studies of the α-functionalisation of cyclic imines are limited. A few simple α-ketoimines such as 3 and 4 (Scheme [1], A) have been reported as Maillard products which display a characteristic strong cracker-like flavour.[16] [17] [18] Their synthesis has been reported via a few approaches, including a SeO2-induced direct α-oxidation of cyclic imines.[18] [19] Furthermore, oxidation of benzyl imines to α-ketoimines using oxygen has also been reported.[20] [21] [22] [23] The α-hydroxylation of cyclic imines had not been documented at outset of this project. The only example to date was reported recently in Baran’s synthesis of portimines, involving a Boekelheide-type rearrangement to install the hydroxy group adjacent to the imine (Scheme [1], B).[24] Additionally, De Kimpe et al. reported the multichlorination of simple cyclic imines in their synthesis of chloropyrroles (Scheme [1], C).[25] However, there are no documented examples of selective monohalogenation of cyclic imines.

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Scheme 1 α-Functionalisation of cyclic imines

As part of our ongoing studies into the synthesis of cyclic imine natural products,[26] [27] [28] [29] [30] we were interested in investigating the α-functionalisation of cyclic imines in order to gain insight into the chemistry of this unique scaffold and also lay the foundation for the synthesis of related cyclic imine natural products, particularly portimines A (1) and B (2). We envisaged installing a halogen group at the alpha carbon through direct halogenation, then using the resulting α-haloimine as a platform for further elaboration (Scheme [1], D).

To enable quick access to the cyclic imine substrates, we envisaged assembling the spiroimine system via reaction of a halonitrile (e.g., 6) (Scheme [2], A) with organometallic reagents.[31] [32] This strategy was practical since the required halonitrile intermediate could be prepared from commercially available carbonitriles.

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Scheme 2 Synthesis of cyclic imine 7 and investigation of the α-functionalisation

Our study commenced with alkylation of cyclohexane carbonitrile (5) using 1-bromo-2-chloroethane to provide the desired γ-chloronitrile 6 (Scheme [2], A). Despite the moderate 27% yield, the reaction was scalable, providing a sufficient quantity of material for further study. With γ-chloronitrile 6 in hand, the key tandem organometallic addition–cyclisation reaction was next investigated. Various Grignard reagents were initially investigated to effect the desired transformation,[31] however, no reaction was observed. Pleasingly, treatment of 6 using more reactive n-butyllithium afforded the desired cyclic imine 7 in 77% yield.

With the preparation of cyclic imine 7 established, we next shifted our attention to investigate the α-halogenation of 7. After screening several reaction conditions, three novel α-haloimine derivatives 8–10 were successfully prepared using NCS, NBS and NIS respectively, with the highest yield of 80% being obtained using NBS as the halogen source (Scheme [2], B). Therefore, α-bromoimine 9 was chosen as a key intermediate for further elaboration.

Substitution of the bromide in 9 using oxygen nucleophiles was next investigated. Treatment of 9 with KOAc in the presence of 18-crown-6 successfully afforded the corresponding product 11 in 70% yield. Substitution of the bromide 9 with PhOK also provided the corresponding phenyl ether 12 in 70% yield.

We next applied the established method to other cyclic imine substrates. Spirocyclic imine 14a and gem-dimethyl cyclic imines 14b,c were successfully synthesised (Scheme [3]). Halogenation of 14a–c resulted in a series of α-halogenated cyclic imine analogues 15a,b and 16a–c. Substitution of the bromides 16a–c with KOAc afforded the corresponding acetates 17a–c. Phenolic substitution of bromides 16a–c delivered phenoxy derivatives 18a and 18b, while 18c was not isolated due to the labile nature of this compound.

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Scheme 3 Preparation of cyclic imines and analogues

To obtain α-hydroxyimine 19 (Scheme [4], A), hydrolysis of the bromide 9 and iodide 10 was initially attempted. However, only recovery of the starting material or decomposition was observed under various conditions (see the Supporting Information). Alternatively, we attempted the cleavage of the acetyl group in 11. Interestingly, upon treatment of 11 with NaOMe in MeOH, a polar intermediate was detected, which turned into a less polar compound during work-up. Isolation of the final product afforded α-ketoimine 20 instead of the desired α-hydroxyimine 19.

It appeared that the desired α-hydroxyimine 19 was not stable. An unusual tautomerisation and oxidation sequence occurred during the reaction and work-up. To isolate the detected unstable polar intermediate, TFA was added to the reaction upon complete consumption of the starting material. After removal of the solvent and purification by flash chromatography, the TFA salt 21 was isolated in 90% yield (Scheme [4], B). It has been reported that α-ketoamines (e.g., 22) are not stable under neutral or basic conditions and are oxidised to α-ketoimines (e.g., 20) when exposed to air.[33] Therefore, it was postulated that deprotection of the acetate likely yielded the desired α-hydroxyimine 19 as an intermediate, which then tautomerised in situ to form α-ketoamine 22. Spontaneous oxidation of α-ketoamine 22 by atmospheric oxygen then afforded α-ketoimine 20.

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Scheme 4 Attempted preparation of α-hydroxyimine 19 and the proposed mechanism for the transformation of α-acetoxyimine 11 into α-ketoimine 20

In portimine A (1), the α-hydroxy cyclic imine functionality is stabilised by the rigidity of the unique multiple ring system, which may prevent tautomerisation of the α-hydroxy imine motif to some extent. This discovery suggests that portimine B (2) could be derived from portimine A (1) through a similar tautomerisation–oxidation process, either taking place in nature or during the isolation.

In conclusion, a facile synthesis and direct α-functionalisation of cyclic imines has been developed. The strategy involved a key nucleophilic addition/cyclisation sequence to assemble the cyclic imine functionality. Subsequent α-halogenation and substitution provided a series of α-substituted analogues. In addition, an unusual tautomerisation and oxidation sequence was observed in the attempted preparation of α-hydroxyimine 19, indicating that portimine B (2) could be derived from portimine A (1) through a similar tautomerisation–oxidation process. This study sheds light on the total synthesis of related natural products and also provides a foundation for further exploration of this unique class of compounds in both synthetic and medicinal chemistry.


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Conflict of Interest

The authors declare no conflict of interest.

Supporting Information

    Supporting information for this article is available online at https://doi-org.accesdistant.sorbonne-universite.fr/10.1055/a-2251-4145.
  • Supporting Information

Corresponding Author

Margaret A. Brimble
School of Chemical Sciences, The University of Auckland
23 Symonds Street, Auckland, 1010
New Zealand   

Publication History

Received: 16 November 2023

Accepted after revision: 22 January 2024

Accepted Manuscript online:
22 January 2024

Article published online:
13 February 2024

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Zoom Image
Figure 1 Examples of cyclic imine natural products
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Scheme 1 α-Functionalisation of cyclic imines
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Scheme 2 Synthesis of cyclic imine 7 and investigation of the α-functionalisation
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Scheme 3 Preparation of cyclic imines and analogues
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Scheme 4 Attempted preparation of α-hydroxyimine 19 and the proposed mechanism for the transformation of α-acetoxyimine 11 into α-ketoimine 20