Copper-Catalyzed Diastereoselective Arylation of Tryptophan Derivatives: Total Synthesis of (+)-Naseseazines A and B

Abstract

A copper-catalyzed arylation of tryptophan derivatives is reported. The reaction proceeds with high site- and diastereoselectivity to provide aryl pyrroloindoline products in one step from simple starting materials. The utility of this transformation is highlighted in the five step syntheses of the natural products (+)-naseseazine A and B.

The pyrroloindoline is a common structural motif that unites several biosynthetically distinct families of alkaloids.¹ The prevalence of this indole-derived heterocyclic framework continues to inspire the development of new reactions for its construction,² and these efforts have delivered increasingly efficient total syntheses of biologically active natural products.³ Specifically, the development of tandem C3-functionalization/cyclization reactions of tryptamine and tryptophan derivatives has proven to be a particularly fruitful line of research. Such methods include a variety of oxidative cyclization reactions,⁴ as well as recently discovered organocatalyzed⁵ and transition metal-catalyzed⁶ C-C bond forming processes.

Despite the advances described above, the direct preparation of aryl-substituted pyrroloindolines has, until recently, remained a challenge.⁷ In 2011, Movassaghi and coworkers reported a Friedel–Crafts-type arylation of 3-bromocyclotryptophans, which provides access to aryl pyrroloindolines in two steps from the corresponding tryptophan derivatives (Figure 2, a).⁸ In an effort to further streamline this overall transformation, we subsequently developed a one-step synthesis of aryl pyrroloindolines by the Cu-catalyzed arylation of N-tosyltryptamines (Figure 2, b).⁹ Concomitant to our studies, MacMillan and coworkers reported a catalytic asymmetric arylation of indole-3-carboxamides to generate arylated 2-oxo-pyrroloindolines in high yields and ee’s (Figure 2, c).¹⁰ Although the latter two methodologies both provide direct access to aryl pyrroloindolines from simple starting materials, in neither case do the products obtained contain an appropriate carboxylate functionality for direct elaboration to diketopiperazine-containing natural products such as 1–3 (Figure 1).^11,12

Figure 2.

Strategies for aryl pyrroloindoline formation.

Figure 1.

Pyrroloindoline alkaloids.

Given our interest in the synthesis of such compounds, we sought to develop a complementary, diastereoselective arylation of tryptophan derivatives (Figure 2, d). We hypothesized that reductive elimination from a Cu^III-aryl complex involving bidentate substrate coordination (e.g. 6) could permit transmission of the stereochemical information from the tryptophan α-carbon to the newly formed quaternary center. In this communication, we report the successful execution of this synthetic plan, which has enabled a concise, diastereoselective synthesis of the pyrroloindoline alkaloids (+)-naseseazines A and B.

We began our studies by investigating the Cu-catalyzed arylation of cyclo-(Trp-Phe) 4a, readily accessible by cyclocondensation of the corresponding amino acids.¹³ Exposure of 4a to 10 mol % (CuOTf)₂•PhMe and 1.1 equivalents of diphenyliodonium hexafluorophosphate in dichloromethane furnished pyrroloindoline 5a in low yield as a mixture of diastereomers (Table 1, entry 2). Under these conditions, pyrroloindoline 5a was formed in an equimolar ratio with the corresponding C2-arylated product (not shown). A control experiment confirmed that no reaction occurs in the absence of copper (entry 1).

Table 1.

Optimization studies.

Entry	Ligand	[Ph2I]X	C3:C2a	dra	yield (%)a
1	– b	[Ph2I]PF6	–	–	0
2	–	[Ph2I]PF6	1:1	3:1	22
3	L1	[Ph2I]PF6	1:1	3:1	15
4	L2	[Ph2I]PF6	1:2	2:1	<5
5	L3	[Ph2I]PF6	6:1	10:1	20
6	L4	[Ph2I]PF6	12:1	12:1	38
7	L5	[Ph2I]PF6	2:1	5:1	26
8	L6	[Ph2I]PF6	1:1	4:1	24
9	L7	[Ph2I]PF6	>20:1	>20:1	70
10	L8	[Ph2I]PF6	1:1	4:1	15
11	L9	[Ph2I]PF6	2:1	20:1	35
12	L7	[Ph2I]BF4	>20:1	>20:1	76
13	L7	[Ph2I]AsF6	>20:1	>20:1	81
14	L7	[Ph2I]OTf	>20:1	>20:1	83 (85)c

^aYield of major diastereomer as determined by ¹H NMR analysis of the crude reaction mixture.

^bNo (CuOTf)₂•PhMe was used.

^cIsolated yield.

In an effort to improve both the C3:C2 arylation ratio and diastereoselectivity, a survey of several achiral, bidentate ligands was conducted. We were pleased to find that use of readily available bis-mesityl-α-diimine ligand L7¹⁴ (^MesDAB_Me) delivers pyrroloindoline 5a in 70% yield, with high C3:C2 selectivity and excellent levels of diastereocontrol (Table 1, entry 9). Comparison of a series of α-diimine ligands revealed that the aryl substitution pattern exerts a significant effect on both the yield and the C3:C2 selectivity (entries 7–9). The yield of the reaction could be further improved by using diphenyliodonium triflate (entry 14). Under our optimal conditions, pyrroloindoline 5a is isolated in 85% yield as a single diastereomer. Interestingly, use of either enantiomer of the chiral bisoxazoline ligand (L8 or L9) previously employed by MacMillan for enantioselective pyrroloindoline formation¹⁰ gave poor yields and low C3:C2 arylation ratios (entries 10 and 11). As might be expected, a clear matching and mismatching between the diketopiperazine substrate and chiral ligand was observed, with L9 providing higher dr and C3 selectivity.

As demonstrated in Table 2, a variety of arylated pyrroloindolines can be prepared in one step from the corresponding diketopiperazines. The diketopiperazines derived from either L- or D-alanine react to deliver diastereomeric pyrroloindolines 5b and 5c, respectively, which possess the same configuration at the newly formed quaternary center. This observation indicates that the chirality at the tryptophan-derived stereogenic center is the dominant stereocontrolling factor. The relatively modest yields obtained for the formation of 5b and 5c reflect the poor solubility and slower reaction rates for these substrates; in both cases, high site- and diastereoselectivity is still observed. In contrast, the cyclo-(Pro-Trp) diketopiperazine (4f) proved to be a challenging substrate, providing 5f in low yield as a result of poor C3:C2 selectivity under our standard conditions. We hypothesized that the increased rigidity of the bicyclic diketopiperazine may result in destabilizing non-bonding interactions with the Cu^I(L7)OTf catalyst. A screen of α-diimine ligands possessing less steric encumberance at the ortho positions revealed that use of Cu^I(L6)OTf in conjunction with diphenyliodonium hexafluorophosphate restores the C3:C2 selectivity and delivers pyrroloindoline 5f in 71% yield.

Table 2.

Substrate scope of pyrroloindoline formation.^a

^aReactions conducted on 0.3 mmol scale using symmetric diaryliodonium triflate unless otherwise noted. Isolated yields are reported.

^b40 mol % Ligand L6 was used with diphenyliodonium hexafluorophosphate.

^cNon-symmetric aryl[p-xylyl]iodonium triflate was used.

The scope of the aryl coupling partner was also investigated. Whereas symmetric diaryliodonium salts reacted smoothly under the reaction conditions (Table 2, products 5g–j), the use of iodonium salts containing the more hindered mesityl substituent as a non-transferable group¹⁵ exhibited slower reaction rates and diminished C3:C2 selectivity under the standard conditions. Fortunately, mitigating the steric demand of these non-symmetric iodonium salts by using a p-xylyl substituent as a non-transferable group restores both reaction rates and site selectivity.¹⁶ Thus, using either the symmetric or p-xylyl-substituted non-symmetric iodonium salts, a variety of arenes bearing either electron-donating or electron-withdrawing substituents at the p- or m-positions could be coupled, providing the pyrroloindolines in moderate to excellent yields as single diastereomers. Unfortunately, o-substituted arenes are not transferred efficiently, and represent one limitation of the existing methodology.

Although our initial studies focused on the arylation of tryptophan-derived diketopiperazines, we wondered whether the simple tryptophan carboxamide 7 would be a suitable substrate. We were pleased to find that subjection of 7 to our optimized reaction conditions affords arylated pyrroloindoline 8 in 81% yield as a single diastereomer (Scheme 1). However, upon careful analysis by a variety of NMR spectroscopic methods, we determined that 8 possesses the opposite configuration at the newly-formed quaternary center relative to the diketopiperazine-containing products in Table 2. At this time, the origin of this stereodivergent reactivity remains unclear. Nonetheless, this finding presents the exciting opportunity to generate either enantiomeric series of pyrroloindoline products from naturally occurring L-tryptophan.

Scheme 1.

Arylation of tryptophan carboxamide 7.

In order to highlight the utility and efficiency of this direct arylation methodology for the synthesis of pyrroloindoline natural products, we sought to complete a total synthesis of the bisindole alkaloids naseseazines A (3a) and B (3b). To this end, diaryliodonium salt 9, containing a protected o-bromoaniline, was efficiently prepared on gram scale from 2-bromo-5-iodoaniline in 70% overall yield. Addition of diketopiperazine 4f and iodonium 9 to a pre-stirred solution of (CuOTf)₂•PhMe (10 mol %) and L6 (40 mol %) in dichloromethane – the conditions previously developed for the arylation of 4f – delivered the desired pyrroloindoline 11 in 62% yield. This direct and efficient procedure is easily performed on large scale, and provides the desired pyrroloindoline with excellent levels of diastereocontrol. Although reactions conducted with the corresponding p-xylyl iodonium salt provided higher conversions of 4f, the yields of 11 were lower due to competitive transfer of the p-xylyl group. The coupling of cyclo-(Ala-Trp) 4b and iodonium 9 under the same conditions provided the related pyrroloindoline 12 in 59% yield.

To complete the synthesis of 3a and 3b, diketopiperazine-containing alkyne 10 was prepared in four steps from commercially available N-Boc-β-iodoalanine methyl ester. Following cleavage of the trifluoroacetamide group in 11, coupling with alkyne 10 by a modified Larock indolization^17,18 procedure provided, upon acidic workup, naseseazine B in 51% yield. Elaboration of 12 by the same sequence delivered naseseazine A in 56% yield. Enabled by the Cu-catalyzed arylation chemistry developed herein, these complex polycyclic alkaloids are available in five steps (longest linear sequence) from commercially available starting materials.

In conclusion, a Cu-catalyzed site- and diastereoselective arylation of tryptophan derivatives has been developed. This reaction provides direct access to aryl pyrroloindolines under mild conditions and with good functional group tolerance. Using this transformation to assemble the pyrroloindoline core, concise, stereoselective syntheses of the bisindole alkaloids (+)-naseseazines A and B were completed in 25% and 19% overall yield, respectively. The further development and application of this transformation in natural product synthesis is the subject of ongoing research in our laboratory.

Scheme 2.

Concise total synthesis of (+)-naseseazines A (3a) and B (3b).