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Synlett 2014; 25(11): 1487-1493
DOI: 10.1055/s-0033-1341082
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© Georg Thieme Verlag Stuttgart · New York

Synthetic Strategies toward the Indoxamycin Family

Chi He
Department of Chemistry, Zhejiang University, 148 Tianmushan Road, Hangzhou 310028, P. R. of China   Fax: +86(571)88273332   Email: hfding@zju.edu.cn
,
Chenlong Zhu
Department of Chemistry, Zhejiang University, 148 Tianmushan Road, Hangzhou 310028, P. R. of China   Fax: +86(571)88273332   Email: hfding@zju.edu.cn
,
Hanfeng Ding*
Department of Chemistry, Zhejiang University, 148 Tianmushan Road, Hangzhou 310028, P. R. of China   Fax: +86(571)88273332   Email: hfding@zju.edu.cn
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Further Information

Publication History

Received: 14 January 2014

Accepted after revision: 10 March 2014

Publication Date:
03 April 2014 (online)

 
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Abstract

Indoxamycins A–F represent a novel class of polyketides isolated from saline cultures of actinomycetes. Owing to their stereochemically congested tricyclic structure and potent biological activities, indoxamycins are attractive targets for synthetic chemists. This report discusses recent progress toward the total synthesis of indoxamycins both by Carreira’s group and ours.


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Key words

polycycles - enynes - rearrangement - tandem reaction - total synthesis

As Gram-positive bacteria, the actinomycetes have provided a rich source of bioactive secondary metabolites for more than 50 years. Although started several decades ago, research on the metabolites of marine plants and animals has only recently received significant attention from scientists. To date, a large number of structurally diverse natural products that possess potent biological activities have been isolated from microorganisms derived from aquatic environments.[1] In 2009, Sato et al. discovered that the ethyl acetate extract of the acetinomycete strain, NPS-643, which was obtained from a sediment sample collected at a depth of 30 meters near Kochi Harbor, Japan, displayed in vitro cytotoxicity against the HT-29 human colon adenocarcinoma cell line. Activity-guided fractionation using various chromatographic methods led to the isolation of a novel class of polyketides, the constituents of which were subsequently named indoxamycins A–F (1–6) (Figure [1]).[2]

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Chi He(left) received his BS degree in chemistry in 2012 from Zhejiang University. He is currently a PhD candidate in organic synthesis under the guidance of Professor Ding at Zhejiang University. Chenlong Zhu (middle) received his BS degree in chemistry in 2012 from Anhui University of Science & Technology. Currently, he is pursuing his PhD with Professor Ding at Zhejiang University. Hanfeng Ding (right) received his BS degree from Zhejiang University in 2003. In 2008, he obtained his PhD from Zhejiang University under the supervision of Professor Cheng Ma and Professor Yanguang Wang. From 2009 to 2011, he was a postdoctoral fellow working with Professor David Yu-Kai Chen in Professor K. C. Nicolaou’s group at CSL@Biopolis, Singapore. He began his independent career as a professor in the Department of Chemistry at Zhejiang University in September 2011. His current research interests focus on the development of novel strategies and methodologies for the total synthesis of structurally complex and biologically active natural products.
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Figure 1 The structures of indoxamycins A–F as originally reported by Sato et al.

Among the indoxamycin family, indoxamycins A (1) and F (6) caused significant growth inhibition against HT-29 tumor cell lines, with IC50 values of 0.59 μM and 0.31 μM, respectively, which are similar to that of the chemotherapeutic agent, mitomycin. The structures of the indoxamycins were initially assigned based on extensive NMR studies, which revealed the presence of an unprecedented [5,5,6] tricyclic cage-like carbon framework, an α,β-unsaturated carboxylic acid side chain, and a trisubstituted alkene appendage. The highly congested core structure consists of six contiguous stereogenic centers, of which three are quaternary, including two vicinal carbon atoms embedded in the synthetically challenging tetrahydrofuran ring. The significant biological activities combined with the intriguing structural features make the indoxamycins attractive targets for total synthesis. In early 2012, Carreira and co-workers reported an exquisite approach for the total synthesis of rac-indoxamycin B.[3] Our group has also made progress toward the total synthesis of indoxamycins A, C and F.[4] In this article, we discuss these two approaches in order to highlight the recent developments toward the total synthesis of this natural product family.

Total Synthesis of rac-Indoxamycins A and B

The synthetic strategy adopted by Carreira and co-workers relies on the implementation of a series of modern metal-catalyzed reactions to construct the tricyclic core framework. Their retrosynthetic analysis is outlined in Scheme [1]. It was envisaged that indoxamycin B could be synthesized from the tetracyclic intermediate 7 by installation of the side chains. Construction of 7 was achieved by using a Saucy–Marbet rearrangement and a cationic gold-catalyzed allene hydroxylation as key steps. The required bicyclic intermediate 8 could be obtained through an anionic oxy-Cope rearrangement followed by a palladium-catalyzed oxidative cyclization from 9, which was then traced to 10 based on a titanium-mediated ketone crotylation.

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Scheme 1 Retrosynthetic analysis of the revised structure of rac-indoxamycin B [(1′′E)-2-epi-2] according to Carreira and co-workers

The synthesis commenced with the C 2v-symmetric cyclohexa-2,5-dienone precursor 10 (Scheme [2, a]), which was prepared in 59% overall yield from commercially available methyl 3,5-dimethylbenzoate through a four-step sequence including a dissolving metal reduction followed by alkylation of the resulting ester enolate, a lithium aluminum hydride (LAH)-mediated reduction and an acetonide protection. Treatment of 10 with an in situ generated 1,3-dimethylallyltitanocene reagent[5] gave the crotylation product 9 in 62% yield as a 3.8:1 mixture of alkene isomers. Subsequent anionic Cope rearrangement of 9 took place smoothly to afford the resulting ketone enolate, which was trapped with chlorotriethylsilane (TESCl) to yield compound 12 in 70% yield (dr = 3.6:1), setting the stage for the oxidative cyclization. By employing catalytic palladium(II) acetate [Pd(OAc)2] in dimethyl sulfoxide in the presence of an oxygen atmosphere,[6] the expected dihydroindenone 8 was obtained in 74% yield, with the desired stereochemistry at the newly formed quaternary center (C7b).

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Scheme 2 Total synthesis of indoxamycins A [(1′′E)-2-epi-1] and B [(1′′E)-2-epi-2] by Carreira and co-workers

With ketone 8 in hand, the elaboration of the polycyclic core structure was explored. The two alcohol side chains were released under acidic conditions, which were then differentiated by group-selective intramolecular epoxide ring-opening, leading to the formation of tricycle 14 in 75% yield over the two steps. The next task was to install the quaternary center at C2, which was initially expected to be realized by Saucy–Marbet rearrangement of the corresponding propargyl vinyl ether. However, normal thermodynamic conditions failed to give any of the desired product. After extensive experiments, the gold(I)–oxo complex, [(PPh3PAu)3O]BF4, was found to be an effective catalyst for this reaction,[7] giving the desired allene 16 in 84% yield as the only isomer. Diastereoselective reduction of the enone followed by intramolecular cationic gold(I)-catalyzed allene hydroalkoxylation[8] afforded tetracyclic intermediate 7 possessing the indoxamycin framework, in 58% combined yield as a 3.2:1 mixture of diastereomers at C2.

Exposure of 7 to hydration–oxidation conditions gave 17 as a single isomer in 53% yield over the two steps. Subsequent Wittig olefination provided tetracycle 18 in 80% yield as a 2.5:1 to 15:1 mixture of alkene diastereomers in favor of the E-configuration. Finally, a six-step functionalization sequence gave rise to indoxamycin B [(1′′E)-2-epi-2] uneventfully (51% overall yield).

Later, encouraged by these achievements, Carreira and co-workers accomplished the total synthesis of indoxamycin A (Scheme [2, b]).[9] Removal of the tert-butyldimethylsilyl group in (1′′E)-18 followed by phosphoramidite transfer furnished phosphate 19 as an inconsequential 1:1 mixture of epimers. Radical deoxygenation afforded the C10 deoxygenated product 20 in 63% yield over the two steps. By employing similar protocols to those used previously, the advancement of 20 led to indoxamycin A [(1′′E)-2-epi-1] in six steps and 49% overall yield.

Carreira’s total synthesis of indoxamycin B was the first reported synthesis of a member of the indoxamycin family. More importantly, they have revised the structures of indoxamycins A and B [1 into (1′′E)-2-epi-1, and 2 into (1′′E)-2-epi-2], with respect to the relative configuration at C2 and the geometry of the trisubstituted alkene side chain. Based on these outcomes, Carreira further proposed that the structural revision was also valid for the other members in this family. However, validation of this hypothesis requires additional experimentation.

Total Synthesis of Indoxamycins A, C and F

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Scheme 3 Retrosynthetic analysis of indoxamycins A, C and F
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Scheme 4 Synthesis of the common intermediate (1′′E)-21; CCDC 953500 (39), CCDC 953501 (1′′Z)-39

With a divergent concept in mind, and inspired by Carreira’s elegant total synthesis of indoxamycin B, we decided to develop a concise and flexible route toward the indoxamycin family. Our retrosynthetic analysis is outlined in Scheme [3]. By looking into the structures carefully, we envisioned that indoxamycins A, C and F might be accessed divergently from the common late-stage intermediate 21. Construction of 21 could be achieved based on a substrate-controlled tandem reaction[10] involving a 1,2-addition/oxa-Michael/methylenation sequence, which would forge the [5,5,6] tricyclic ring system of the molecule. The required enone-aldehyde precursor 22 was expected to arise from 1,6-dienyne 23 through a palladium-catalyzed reductive cyclization.[11] 1,6-Dienyne 23 could be furnished via the introduction of the two vicinal quaternary centers at C2a and C7b through an Ireland–Claisen rearrangement from allyl ester 24, which could be easily prepared from the readily available intermediates 25 and 26.

According to the retrosynthetic blueprint, our synthetic endeavor started with the construction of the required [5,6] bicyclic enone-aldehyde precursor 22 (Scheme [4]). Allyl ester 24 was obtained in 90% yield through esterification of acid 25 with alcohol 26, and was then subjected to Ireland–Claisen rearrangement studies. After significant investigation, to our delight, alkyne 27 was formed in 85% yield as a 1.5:1 mixture of diastereomers. Although the yield was satisfying, attempts to improve the diastereoselectivity met with failure. In order to make full use of the material, an allylic oxidation followed by 2,3-dichloro-5,6-dicyano-1,4-benzoquinone (DDQ) mediated dehydrogenation were carried out to yield dienone 28. After deprotection of the trimethylsilyl group, dienyne 23 was obtained in 61% yield over the three steps, which was ready for the next enyne cyclization step.

In our preliminary attempts on the enyne cyclization, radical conditions were employed but proved fruitless, affording the desired product in poor yields. We then moved on to study transition-metal-catalyzed reductive cyclizations. Although there were no literature precedents for the reductive cyclizations of cyclohexadienone-containing terminal alkynes, we were pleased to obtain the bicyclic product 30 in 87% yield by simple modification of Trost’s standard conditions.[12] The stereochemical outcome, with the two methyl groups at C2a and C7b in a syn-relationship in bicyclic 30, was presumably the result of synergistic effects from both the six-membered transition state 29 and the formation of the more thermodynamically stable cis-5,6-fused ring system.

Following the successful construction of 30, a two-step installation of the quaternary center at C5 delivered compound 32 in 78% yield, together with the formation of the enol ether 31 (ca. a 5:1 mixture), which could be recycled through hydrolysis using p-toluenesulfonic acid monohydrate (p-TsOH·H2O). Subsequent regioselective reduction of 32 was well-controlled in the presence of diisobutylaluminum hydride (DIBAL-H) at low temperature, presumably via the chelated alkoxyaluminum intermediate 33. Treatment of the resulting diol 34 with Dess–Martin periodinane (DMP) gave 22 in 76% yield over the two steps.

Having secured enone-aldehyde precursor 22, we next turned our attention to synthesize the common intermediate 21. After extensive optimization, the expected tandem 1,2-addition/oxa-Michael/methylenation sequence promoted by a Grignard reagent proceeded smoothly to afford the tricyclic enone 38 with no detectable diastereomers. It is worth noting that oxa-Michael reactions have rarely been considered in the design of domino reactions due to the inherent instability of the in situ generated enolate toward elimination or a retro-Michael process. The only recent example was from Menche and co-workers,[13] who developed a tandem oxa-Michael/Tsuji–Trost reaction to facilitate the concise synthesis of functionalized tetrahydropyrans. Therefore, our procedure described herein has expanded the scope of its application.

We proposed that the instability of the intermediate 37 might be the driving force to facilitate the spontaneous elimination, thus giving an excellent yield of the product without prior oxidation or adding any base. Quenching the reaction with aqueous ammonium chloride prior to the methylenation yielded compound 39 in 84% yield, the stereochemistry of which was assigned unambiguously by X-ray crystallographic analysis (see the crystal structure in Scheme [4]). This proved our initial prediction for the relative configuration of C2, which was based on the Si-face attack of the Grignard reagent on the aldehyde moiety of 22. Similarly, when the corresponding Z-Grignard reagent was employed, (1′′Z)-39 was obtained. Furthermore, an approximate 1:1 mixture of the C2 epimers of 39 was isolated on using the respective organolithium reagent. Therefore, at this stage, we have prepared all the four isomers of compound 39 for evaluation of the relative configuration at the C2 position and the geometry of the trisubstituted alkene appendage, which was critical to the final structural determination of the natural products. Subsequently, acid-catalyzed exo-double bond isomerization of 38 afforded the desired product, (1′′E)-21, in 82% yield.

The late stages of the syntheses are outlined in Scheme [5], which entails a divergent route to the revised structures of indoxamycins A, C and F. 1,4-Reduction of (1′′E)-21 with L-Selectride followed by capture of the resulting enolate with N-phenyl-bis(trifluoromethanesulfonimide) (PhNTf2) gave enol-triflate 40 in 79% yield. Subsequent palladium-catalyzed reductive detriflation provided alkene 41 in 85% yield. Reduction of 41 gave aldehyde 42 and Horner–Wadsworth–Emmons olefination afforded smoothly (1′′E)-2-epi-1 in 77% yield over the two steps.

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Scheme 5 Divergent total syntheses of indoxamycins A, C and F

On the other hand, a sequential reduction of enone ester (1′′E)-21 gave allylic alcohol 45 in 84% yield as a single diastereomer. Nucleophilic chlorination of 45 on treatment with thionyl chloride (SOCl2) afforded allylic chloride 46 in 97% yield. Olefination gave enoic acid 47, which on hydrolysis with silver nitrate (AgNO3) in acetone–water provided (1′′E)-2-epi-3 in 78% yield over the two steps.

To synthesize indoxamycin F, compound 48 was constructed initially from intermediate 45 through olefination and saponification. Unfortunately, the NMR spectra of 48 deviated from those reported for natural indoxamycin F. Careful examination of the NMR data revealed the misassignment of the configuration at C6. However, attempts to invert the configuration by carrying out a Mitsunobu reaction or sequential oxidation and reduction were not successful in this case. Finally, we switched to the sulfoxide–sulfenate rearrangement.[14] Allylic alcohol 45 was first treated with benzenesulfenyl chloride to give sulfoxide 49 in 92% yield. To our surprise, the Mislow–Evans rearrangement[15] took place unexpectedly during Horner–Wadsworth–Emmons olefination, presumably induced by the in situ generated phosphate, which might act as a thiophile. More detailed mechanistic studies on this transformation are currently underway in our laboratory. Therefore, the desired allylic alcohol 50 was obtained in 95% yield after only one step. Finally, saponification of 50 afforded (1′′E)-2,6-di-epi-6 in 92% yield.

The spectroscopic and mass spectrometric data of synthetic (1′′E)-2-epi-1, (1′′E)-2-epi-3, and (1′′E)-2,6-di-epi-6 were consistent with those reported for natural indoxamycins A, C and F, respectively, which thus confirmed unambiguously their relative configurations.

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Equation 1 Enantioselective 1,6-enyne reductive cyclization

The asymmetric approach to (–)-indoxamycins A, C and F was based on an enantioselective version of the palladium-catalyzed reductive 1,6-enyne cyclization of dienyne 23 (Equation 1).[16] Various palladium catalysts, chiral bidentate phosphorus ligands and additives were screened in order to obtain optimized conditions. Gratifyingly, we found that by using [Pd(MeCN)4](BF4)2/Segphos as the catalyst combination and formic acid as the additive, (+)-30 could be obtained with excellent enantioselectivity (93% ee) and yield (46%), along with the stereodivergent formation of 2a-epi-30 in 43% yield and enantioselectivity (80% ee). By utilizing the racemic route, further elaboration of (+)-30 rendered the asymmetric total synthesis of (–)-indoxamycins A [(1′′E)-2-epi-1], C [(1′′E)-2-epi-3], and F [(1′′E)-2,6-di-epi-6].

In conclusion, the salient features of Carreira’s strategy include a carboannulation sequence involving a titanium-mediated crotylation, an anionic oxy-Cope rearrangement and a palladium-catalyzed oxidative cyclization, as well as a gold(I)-catalyzed Saucy–Marbet rearrangement and allene hydroalkoxylation. Our total syntheses of (–)-indoxamycins A, C and F were based on an Ireland–Claisen rearrangement, an enantioselective 1,6-enyne reductive cyclization, and a tandem 1,2-addition/oxa-Michael/methylenation sequence. Moreover, our synthesis unambiguously determined the stereochemistry of these natural products, which also validated Carreira’s hypothesis. We believe that the work described herein should pave the way for the synthesis of other members of the indoxamycin family (D and E), and a diverse array of rationally designed analogues for further chemical and biological investigations. These studies are currently under way in our laboratory.


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Acknowledgment

We thank the NSFC (21202144), Zhejiang Provincial NSFC (LQ12B02003), and the New Teacher’s Fund for Doctor Stations, Ministry of Education (20120101120087) for financial support.



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Zoom Image
Chi He(left) received his BS degree in chemistry in 2012 from Zhejiang University. He is currently a PhD candidate in organic synthesis under the guidance of Professor Ding at Zhejiang University. Chenlong Zhu (middle) received his BS degree in chemistry in 2012 from Anhui University of Science & Technology. Currently, he is pursuing his PhD with Professor Ding at Zhejiang University. Hanfeng Ding (right) received his BS degree from Zhejiang University in 2003. In 2008, he obtained his PhD from Zhejiang University under the supervision of Professor Cheng Ma and Professor Yanguang Wang. From 2009 to 2011, he was a postdoctoral fellow working with Professor David Yu-Kai Chen in Professor K. C. Nicolaou’s group at CSL@Biopolis, Singapore. He began his independent career as a professor in the Department of Chemistry at Zhejiang University in September 2011. His current research interests focus on the development of novel strategies and methodologies for the total synthesis of structurally complex and biologically active natural products.
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Figure 1 The structures of indoxamycins A–F as originally reported by Sato et al.
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Scheme 1 Retrosynthetic analysis of the revised structure of rac-indoxamycin B [(1′′E)-2-epi-2] according to Carreira and co-workers
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Scheme 2 Total synthesis of indoxamycins A [(1′′E)-2-epi-1] and B [(1′′E)-2-epi-2] by Carreira and co-workers
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Scheme 3 Retrosynthetic analysis of indoxamycins A, C and F
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Scheme 4 Synthesis of the common intermediate (1′′E)-21; CCDC 953500 (39), CCDC 953501 (1′′Z)-39
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Scheme 5 Divergent total syntheses of indoxamycins A, C and F
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Equation 1 Enantioselective 1,6-enyne reductive cyclization