A Dynamic Thermodynamic Resolution Strategy for the Stereocontrolled Synthesis of Streptonigrin

Abstract We report that axially chiral biaryl boronic esters can be generated with control of atroposelectivity by a Binol‐mediated dynamic thermodynamic resolution process. These intermediates can be progressed to enantioenriched products through stereoretentive functionalization of the carbon–boron bond. Finally, we have exploited this method in the first highly stereoselective total synthesis of P‐streptonigrin.

The discovery and synthesis of natural products that contain axial chirality has attracted the attention of the synthetic organic chemistry community, not only because of their promising properties, but also because of the intellectual and practical challenges that their syntheses represent. [1] In this context, streptonigrin 1 is a natural product first isolated by Rao and Cullen from Streptomyces flocculus that has been the focus of significant synthetic and biological studies. [2,3] Indeed, streptonigrin has recently been identified as a potential epigenetic cancer therapy treatment due to its ability to enhance heterochromatin formation at nanomolar concentrations. [4] Streptonigrin ( Figure 1) is composed of a densely functionalized quinoline moiety (A, B rings) connected to an atropisomeric heterobiaryl (C, B rings) system which is a deviation from more common chiral natural products that are composed of stereogenic centers. [5] This latter feature poses particular challenges as the synthetic route must avoid undesired atropisomerizaton that may erode the atropostereointegrity of any intermediates or the final product. The M-stereochemistry of 1 has been assigned on the basis of experimental and theoretical circular dichroism studies. [6] Several synthetic studies towards streptonigrin have been reported. In 1980, Weinreb devised a 31 step route where the key pyridine C ring was constructed by an imino Diels-Alder reaction. [7] A year later, Kende's group reported a 19 step route whereby the C ring was assembled by a regioselective condensation of α-ketoenamine with methyl acetoacetate, [8] while Boger presented a more concise strategy employing an inverse-electron-demand Diels-Alder reaction of a heterocyclic azadiene, obtaining an advanced intermediate in Kende's route. [9] More recently, Donohoe and co-workers applied their de novo pyridine synthesis through ring closing metathesis along with cross-coupling strategies in two different routes affording streptonigrin in 14 linear steps and 11 % overall yield. [10] Their investigations highlighted an enantioselective Suzuki-Miyaura cross-coupling that offered the first asymmetric approach to the synthesis of streptonigrin (up to 42 % ee). Herein we report a new synthetic approach for the enantioselective total synthesis of streptonigrin that takes advantage of a borondirected cycloaddition strategy developed in our group. [11] As shown in Scheme 1, central to our route design was the synthesis of a difluoroboranyl pyridine intermediate 2 that we planned to access using a boron-directed cycloaddition reaction of triazine 3 and potassium trifluoroborate salt 4. This process would offer a convergent means for assembling the A-D ring array while installing functionality that would enable interconversion towards the natural product. We envisaged that employment of the directed cycloaddition strategy would also overcome the low reac- Scheme 1. Directed cycloaddition strategy to the streptonigrin tetracyclic ring system. tivity and poor regiocontrol observed in Boger's classical inverse-electron-demand Diels-Alder method. [9] Our synthesis commenced with the preparation of fragments 3 and 4. 2-Cyanoquinoline 5 was converted into triazinone 6, whereupon successive deoxychlorination and displacement with cyanide provided a triazine intermediate that underwent nitration to provide 3 in 30 % overall yield. Synthesis of potassium trifluoroborate 4 consisted of a regioselective iodination of 2,3-dimethoxyphenol 7 followed by protection of the free phenol with benzyl bromide to give 8. Subsequent, Sonogashira cross-coupling and alkyne borylation provided the key alkyne substrate 4 in 46 % yield over 5 steps. Finally, we were delighted to find that the directed cycloaddition reaction proceeded smoothly in the presence of BF 3 · OEt 2 within 1 hr at 30°C to provide 2 with complete regiocontrol in 65 % yield (Scheme 2).
Evidence for atropisomerism in 2 was apparent from the 19 F NMR spectrum that exhibited two AB doublets indicating the presence of diastereotopic F-atoms (see the Supporting Information). With a view to separating the racemic mixture, we postulated that we could further exploit the presence of the boron moiety by generating a chiral boronate ester that could resolve the enantiomers by kinetic or classical resolution procedures. To test this hypothesis, we prepared model compounds 9 a,b (synthesis details are in the Supporting Information) and converted these to the corresponding (R)-1,1'-bi-2-naphthol (Binol) esters. Running the esterification of 9 a produced 10 a in 69 % yield as an equal mixture of diastereomers. Surprisingly however, the corresponding reaction of 9 b produced a 4 : 1 mixture of diastereomers 10 b in an overall yield of 57 % (Scheme 3). Notably, the intermediate boronic acid was completely consumed in this reaction, ruling out the possibility that selective diastereomer formation was the result of a kinetic resolution process. In addition, the reaction could be conducted on 0.8 mmol scale allowing the product to be isolated as a single diastereomer in 66 % yield after slow precipitation from MeCN (see the Supporting Information).

Scheme 3.
Model studies on resolution of atropisomeric boronates. [a] Compounds 9 e, 9 f, 9 g were hydrolyzed with Cs 2 CO 3 instead of NaOH. and amines (entry 4) provided marginally better diasteromeric ratios. Interestingly, the corresponding thioether 10 g was formed as a single diastereomer (entry 5). Overall, a consistent picture emerged with ortho-heteroatom groups providing approximately 80 : 20 diastereomeric ratios and ortho-Et producing the corresponding Binol esters in equal amounts. This study confirmed that the incorporation of a Lewis basic substituent provided an opportunity to convert racemic biaryl difluoroboranes into diastereomeric boronic esters with stereocontrolled resolution at the biaryl bond.
We next undertook a study of the dynamic behavior of these systems upon heating. Towards this end, we were able to generate a diastereoenriched sample of 10 a by chiral preparative HPLC (dr > 98 : 2), and an enriched sample of 10 b by precipitation (66 % yield, dr = 95 : 5). Heating these samples in toluene at 120°C overnight led to no change in diastereomeric ratio in the case of 10 a. In contrast, however, 10 b was returned as a 80 : 20 mixture of diastereomers (Scheme 4a). The observation that only those products bearing an ortho-Lewis base form diastereomerically enriched boronic esters, together with the stereochemical lability of these compounds under thermolysis (in contrast to ortho-ethyl analog 10 a) highlights that the presence of an ortho-heteroatom adjacent to the biaryl bond leads to a greater tendency for rotation around the biaryl bond, as compared to their simple hydrocarbon analogs. This in turn provides a pathway for a dynamic thermodynamic resolution process. [12,13] A mechanism that is consistent with these observations is shown in Scheme 4b. Diastereomers A and B are able to interconvert via a planar intermediate that is formed when the Lewis basic atom 'X' coordinates to the boron center. This type of isomerization is reminiscent of the Pd-promoted epimerization reported by Lassaletta and Stoltz which demonstrated that Lewis acid-base complexation can promote planarization of atropisomers. [14] Finally, X-ray crystal structures of compounds 10 b,g were obtained which highlight the potential for π-stacking between Binol and one of the biaryl rings (Scheme 4c). We speculate that the minor diastereomer in these cases engenders an unfavourable steric interaction of the ortho-substituent and the Binol ester oxygen atom. Furthermore, this analysis suggested that the incorporation of substituents at the 3,3'positions of Binol could influence diastereomer ratios, assuming that they did not impede atropisomerization. Indeed, preliminary results have highlighted that cyanomethyl-substituted Binols 10 m-10 o can offer improved diastereomeric ratios, and further studies relating to the generality of this effect are underway in our labs (Scheme 4d).
The stereochemical lability of the Binol esters raised an obvious concern regarding their suitability for stereoretentive functionalization reactions. Therefore, before continuing with our asymmetric synthesis of streptonigrin, we decided to explore the oxidation of boronates 10 b,e,g to establish whether it was possible to generate new products with useful levels of enantiocontrol. As shown in Scheme 5, boron oxidation provided the corresponding phenols with high levels of stereoretention and the configuration of 11 was unambiguously confirmed by single crystal X-ray diffraction analysis. Conversion of 10 g to 13 showed more pronounced racemization and concomitant oxidation at sulfur.
Having developed a protocol for the resolution of atropisomeric arylboranes, we continued with our synthesis towards streptonigrin (Scheme 6). To this end, difluoroboranyl pyridine 2 was subjected to hydrolysis, followed by esterification with (R)-Binol to give boronic ester 14 in 56 % as a 86 : 14 mixture of diastereomers (major diastereomer assignment made by analogy to structures 10 b,g). After column chromatography, the ratio could be improved up to 95 : 5, and the minor diastereomer recycled to an 86 : 14 ratio by simply refluxing the sample in toluene, thereby highlighting a practical advantage of the dynamic resolution approach. Finally, amination [15] of diastereoenriched 14 afforded picolinitrile 15 in 50 % yield with a 92 : 8 e.r. confirming that this transformation could proceed with minimal erosion of stereochemical integrity around the biaryl bond.
Our closing steps involved reduction of the cyano group of picolinitrile 15 to the corresponding picolinaldehyde with DIBAL-H, followed by Pinnick oxidation and methylation with TMSCHN 2 to obtain the corresponding methyl picolinate 16. Then, the nitro group of 16 was reduced with Na 2 S 2 O 4 and the resulting diamine was subjected to a twostep oxidation protocol (Fremy's salt followed by aq. CAN) to yield quinolone intermediate 17 in 47 % overall yield over 6 steps with a minimal loss of the stereochemical information (17; 90 : 10 e.r.). Notably, these steps could be done sequentially and only the last step required chromatographic purification. The A-ring amino group was introduced by a procedure successfully employed by Donohoe. [10] Accordingly, intermediate 17 was treated with bromine and pyridine, followed by sodium azide, and finally subjected to hydrogenolysis to obtain streptonigrin methyl ester 18 in 55 % yield over 3 steps with a 89 : 11 e.r. Concomitantly, we acquired a commercial sample of streptonigrin and converted this to the corresponding methyl ester, [16] thereby allowing us to confirm that 18 was the expected unnatural Patropisomer. Finally, hydrolysis of 18 with K 2 CO 3 afforded streptonigrin with a 3.7 % overall yield over 18 linear steps (Scheme 7). [17] In conclusion, we have demonstrated the versatility of organoboron chemistry for the stereocontrolled synthesis of atropisomeric biaryl compounds. Specifically, alkynylboranes allow the mild and regiocontrolled construction of highly functionalized aromatic products, and these can be resolved to deliver diastereoenriched boronate esters through a novel dynamic resolution process. Additionally, the versatility of the CÀ B bond allows new functionality to be introduced with stereoretention, providing a new way to access useful products in enantiomerically pure form. Finally, we have exploited this strategy for the first highly stereocontrolled synthesis of streptonigrin, thereby addressing a long-standing synthetic challenge associated with this natural product.