Abstract

Graphical Abstract

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Introduction

(–)-Strempeliopine (1) was first isolated from the roots of Strempeliopsis strempelioides K. Schum by Laguna et al.,¹ and is the parent base² of the antimicrobial^3,4 schizozygane alkaloids (2a–2e, Figure 1A). Its structural complexity, being composed of a highly fused hexacyclic core with an embedded transannular ethane bridge, has attracted the attention of several groups that have culminated in total syntheses by Hajicek (asymmetric and racemic syntheses of 1),^5,6 Padwa (racemic synthesis of 1),⁷ Qin (asymmetric synthesis of 1),⁸ and Anderson (synthesis of 14,15-dehydro-(+)-1).⁹ The schizozygane alkaloids are thought to be biogenetically related to the Aspidosperma alkaloids,^2,6 arising through a [1,5]-sigmatropic rearrangement of a dehydroaspidospermane 3 to an azabenzfulvene^10,11 followed by reduction and subsequent lactamization (Figure 1B).

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Figure 1.

A) Structure of 1 and related schizozygane alkaloids. B) Proposed biosynthesis of schizozyganes.

This skeletal rearrangement was realized by Hajicek in his total syntheses of 1 with the employment of Zn and CuSO₄•5H₂O in AcOH,^5,6 conditions first reported by Le Men and coworkers.^12,13 However, Hajicek noted the ratio and yields of reaction products from this reductive rearrangement varied with the nature of zinc used,⁵ differed from those of Le Men, and demonstrated that two zinc sources, which appeared to differ only in the range of particle size, greatly affected the reaction outcome⁶ (Figure 2A). The use of “zinc A” (particle size up to 5–7 µm) gave predominantly indoline 7 by direct reduction of indolenine 5, whereas the use of “zinc B” (particle size up to 17 µm) afforded predominantly the desired rearranged product 6, albeit in modest yield. Later Saxton and coworkers attempted to use an analogous reductive rearrangement on the closely related indolenine 8 but were unable to affect its rearrangement. Instead, they observed byproducts 9a–9c derived from direct imine reduction of 8¹⁴ using their available zinc sources (Figure 2B).

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Figure 2.

A) Reductive rearrangement by Hajicek. B) Attempted rearrangement by Saxton.

The Hajicek reports on the reductive rearrangement of dehydroaspidospermanes to schizozyganes^5,6,12–15 attracted our attention in targeting 1, where we envisioned its use in our divergent syntheses of a series of indole alkaloids.¹⁶ In that work, we successfully completed the total syntheses of six different classes of indole alkaloids from the common intermediate 10,^17–20 utilizing the late-stage formation of the strategic bonds²¹ that define their individual skeletons (Figure 3). The implementation of the dehydro-aspidospermane rearrangement (C19–C2 bond formation) would allow access to an additional class of indole alkaloids, culminating in divergent syntheses of seven classes of natural products from the same common intermediate. As detailed herein, the Hajicek rearrangement proved unsuccessful in our hands but led to the discovery and development of an effective alternative that made use of the C21 functionality uniquely found in 10 to stably trap the intermediate iminium ion. In turn, this permitted its in situ regeneration, single electron reduction, and subsequent diastereoselective transannular free radical cyclization with dearomative C2 indole addition, congested quaternary center formation, and key C19–C2 bond formation.

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Figure 3.

Divergent total syntheses of seven natural product classes from common intermediate 10, assemblage of which employed the [4+2]/[3+2] cycloaddition cascade of 11, and the underlying umpolung strategy used to target 1 from 10.

Results and Discussion

Central to the assemblage of 10 was the [4+2]/[3+2] cycloaddition cascade of 1,3,4-oxadiazole 11, which has been easily prepared in 4 steps from N-benzyltryptamine and 4-(2-tert-butyldimethylsilyloxy)pent-4-enoic acid, requiring only two purifications.¹⁷ As detailed previously,¹⁷ warming a solution of 11 in o-dichlorobenzene (o-DCB) initiates an intramolecular [4+2] cycloaddition between the tethered alkene and 1,3,4-oxadiazole, which is followed by a loss of N₂ to generate a stabilized 1,3-dipole. This intermediate undergoes a [3+2] cycloaddition with the tethered indole with complete endo selectivity directed to the face opposite the newly formed lactam to give 10 as a single diastereomer (71%, gram-scale), a stereochemical outcome dictated by the linking tether.²²

Unfortunately, Hajicek’s previously reported reductive rearrangement of indolenine 5⁶ was not observed in our hands and, like Saxton,¹⁴ only 1,2-imine reduction was observed. This included not only our examination of a range of C21 protected alcohols derived from 10 (eq 1), but also with the substrates reported by Hajicek (both C5 Et (5) and C5 vinyl). Extensive screens that spanned years were not successful (see Supporting Information for brief summary) and intermittently examined various sources and activation of zinc, its particle size, its age and quality, the metal co-reductant (Cu(II)) and even other reducing metals.

(1)

As a result, a new and more reliable approach was developed to implement the desired rearrangement. In the Hajicek reductive rearrangement²³ (Figure 3), an acid-catalyzed Grob-type fragmentation first forms an equilibrium between 12 and 13 that is then proposed to be followed by indole C2 addition to the electrophilic iminium ion 13 to provide azabenzfulvene 14, which in turn is reduced to 15. As an alternative, a reversed or umpolung strategy was conceived where single electron reduction of the intermediate electrophilic iminium ion 13 would convert it to a nucleophilic radical 16 potentially capable of subsequent transannular cyclization onto the indole at C2 to generate a more stable benzylic radical 17,²⁴ affording 15 after quench. This approach was especially attractive since embedded in our precursors derived from 10 was the ability of a C21 alcohol to serve not only as functionality for penultimate lactam formation but also as an effective, reversible trap of the intermediate iminium ion. Intramolecular cyclizations of α-aminoalkyl radicals with alkenes have been systematically explored²⁵ most notably by Hart,²⁶ including those generated by single electron reduction of iminium ions as first described by Martin²⁷ or more recently through photoredox catalysis.^28,29 However, it remained unclear whether iminium ions such as 13 would be capable of single electron reduction (vs reversion to 12) and there was no precedent for a subsequent α-aminoalkyl radical transannular cyclization, much less one that involves a dearomative C2 indole addition with congested quaternary center formation. Even the regio- and diastereoselectivty of such a cyclization was difficult to anticipate.

In targeting 1 with this and the umpolung strategy in mind, 10 was converted to (+)-18 in five steps as previously detailed²⁰ and with the previously disclosed simple and scalable chromatographic resolution of an intermediate (α = 1.8, Chiralcel OD) to provide enantiomerically pure material for which the absolute configuration was unambiguously assigned by X-ray.^18b Intermediate (+)-18 was subjected to conditions (KOH, THF/MeOH/H₂O, 70 °C) that not only hydrolyzed the methyl ester, but also led to concurrent cleavage of the carbamate and silyl ether to afford carboxylic acid 19 (Scheme 1). Compound 19, which is unstable and undergoes slow decarboxylation, was subjected directly to thermal decarboxylation conditions, resulting in formation of (–)-22 (toluene, 108 °C, 95% from (+)-18). This series of transformations is initiated by thermal decarboxylation of 19 to generate 20 in situ. Subsequent Grob-type fragmentation affords the transient intermediate 21, the N-acyl iminium of which is trapped by the proximal C21 primary alcohol to yield (–)-22. This provided the key intermediate (–)-22 in only two operations with a single purification in superb overall yield (95% from (+)-18).

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Scheme 1.

Synthesis of (–)-23.

The protection of indole (–)-22 proved nontrivial, as most methods failed to provide the desired protected products, largely resulting only in recovered starting materials (see Supporting Information). However, the use of the CbzIm/DBU system developed by Sarpong³⁰ provided the carbamate (–)-23 in high yield (CbzIm, DBU, 73% (92% BRSM)), setting stage for the investigations on the proposed transannular dearomative radical cyclization with formation of a challenging quaternary center.

Based on the precedent of Huang,^31–33 detailing combined Lewis acid/SmI₂-mediated reductive couplings of N-acyl hemiaminals, we examined its use in the first example this speculative transannular dearomative cyclization. This followed efforts with SmI2 alone that led simply to recovered starting materials. Gratifyingly, subjection of (–)-23 to optimized conditions for in situ iminium ion formation, and its single electron reduction and subsequent radical cyclization (SmI₂, BF₃•OEt₂, CH₃CN, 25 ^oC, 63%) regioselectively (8:1) and diastereoselectively (>30:1) afforded (+)-24 when conducted in acetonitrile at room temperature (Figure 4, entry 1). The unusual solvent choice proved important to the success of the reaction, as both the reported use THF as well as benzene (Figure 4, entries 3–5) only gave trace amounts of (+)-24 even in the presence of an added proton source as reported.^31–33 Presumably, competitive THF coordination but not that of CH₃CN precludes effective complexation of BF₃•OEt₂ with the N-acyl hemiaminal and diminishes its capabilities to promote the intermediate iminium ion formation. The absence of BF₃•OEt₂ (Figure 4, entries 6–7), employment of lower reaction temperatures (Figure 4, entry 2; no/low iminium ion formation), or the use of Brønsted acids (Figure 4, entries 8–10) resulted in either no reaction or nonproductive consumption of (–)-23. In addition, limited efforts to enlist the free indole (–)-22 directly were not successful in promoting this reaction, necessitating the indole Cbz protection. Similarly, but also not examined in detail, the iminium ion corresponding to the C9 amine versus lactam 21 proved to be a stable, isolable intermediate (see Supporting Information) but failed to undergo the transannular radical cyclization upon treatment with SmI₂.

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Figure 4.

Radical transannular cyclization of (–)-23.

The reaction outcome can be rationalized as shown in Scheme 2. Upon activation by complexation with BF₃•OEt₂, N,O-ketal (–)-23 cleaves to generate the N-acyliminium ion 23a, which is reduced by Sm(II) to the N-acyl α-aminoalkyl radical 23b.^31–33 The radical undergoes a regioselective transannular addition to C2 versus C3 of the proximal indole with generation of a quaternary center, formation of the key strategic C19–C2 bond, and indole dearomatization to give the benzylic radical 23c. Subsequent solvent H-atom abstraction³⁴ or a more likely further reduction by Sm(II) to 23d and protonation provides (+)-24. The quench of the radical or 23d preferentially occurs from the convex face and anti to the methine proton, accounting for the formation of (+)-24 as a single diastereomer and bearing the preferred cis versus trans fused indoline.³⁵ Notably, the alternative transannular addition of the intermediate radical 23b to c3 (<8%) versus C2 (63%) is minor and is either kinetically less favored or preferentially rearranges to 23c prior to quench. Although we have not yet been able to experimentally establish whether 23c represents a kinetic or thermodynamic product of the transannular addition, it has been shown that intermolecular free radical addition to C2 versus C3 of indole is preferred.²⁴ Finally and since a Zn/Cu couple has been proposed to be capable of single electron reduction of imines,³⁶ it is tempting to speculate that the zinc dependence in the Hajicek reductive rearrangement of dehydroaspidospermanes (see Figure 2) is not due to particle size, but rather the activity of the Zn/Cu couple used in the reactions and that it and perhaps even the proposed biosynthetic transformation itself may involve such a one electron versus two electron reaction process.

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Scheme 2.

Rationale for selective formation of (+)-24.

Cbz deprotection of (+)-24 (Pd/C, H₂, 98%) afforded (+)-25, the amide of which was reduced to give amine (+)-26 (LiAlH₄, 85%) (Scheme 3). Single-step oxidative lactam formation of (+)-26⁹ (NMO, TPAP, 48%) afforded 1, displaying spectroscopic properties identical in all respects with that reported for natural and synthetic material.

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Scheme 3.

Completion of the total synthesis of 1.

Conclusion

In summary, our previously reported (+)-18¹⁹ was converted to (–)-strempeliopine (1) in seven steps, utilizing a powerful SmI₂-mediated and BF₃•OEt₂-initiated dearomative transannular radical cyclization onto an indole by an N-acyl α-aminoalkyl radical derived by single electron reduction of an in situ generated iminium ion for formation of the strategic C19–C2 bond embedded in its core structure. Central to synthesis of (+)-18 was 10, the cycloadduct of a [4+2]/[3+2] cycloaddition cascade of 11, making use of its C21 functionality to stably and reversibly trap the requisite intermediate N-acyliminium ion. Finally, this work complements our previous work,^17–20 culminating in the divergent total syntheses³⁷ of now seven distinct naturally occurring alkaloid classes from the same common intermediate 10, each enlisting a different late-stage key strategic bond formation that defines their core structures.

Supplementary Material

ACKNOWLEDGMENT

Footnotes

Contributor Information

Xianhuang Zeng, Department of Chemistry and the Skaggs Institute for Chemical Biology, the Scripps Research Institute, 10550 North Torrey Pines Road, La Jolla, California 92037, United States.

Dale L. Boger, Department of Chemistry and the Skaggs Institute for Chemical Biology, the Scripps Research Institute, 10550 North Torrey Pines Road, La Jolla, California 92037, United States.

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