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Synthesis 2024; 56(01): 87-106
DOI: 10.1055/s-0042-1751446
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Advances in Skeletal Editing and Rearrangement Reactions

Recent Applications of Ammonium Ylide Based [2,3]-Sigmatropic and [1,2]-Stevens Rearrangements To Transform Amines into Natural Products

Zachary Schwartz‡
,
Chelsea Valiton‡
,
Myles Lovasz‡
,
Andrew G. Roberts  ∗

We are grateful for financial support from the University of Utah Department of Chemistry and the Donors of the American Chemical Society Petroleum Research Fund (ACS PRF 62220-DNI1).
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Abstract

Ammonium ylide based [2,3]-sigmatropic and [1,2]-Stevens rearrangements enable the transformation of tertiary amines into rearranged and functionalized intermediates en route to many polycyclic natural product targets. Herein, we summarize recent applications of these rearrangement reactions in formal and total synthesis endeavors while highlighting innovative improvements to these transforms.

1 Introduction

2 Ammonium Ylide Based [2,3]-Sigmatropic Rearrangements in Natural Product Synthesis

2.1 (–)-Cephalotaxine

2.2 (±)-Amathaspiramide F

2.3 (–)-Cephalezomine G and Its C3 Epimer

2.4 (±)-Strictamine

2.5 (–)-Doxycycline

3 [1,2]-Stevens Rearrangements Toward Natural Products

3.1 Ring-Expanding [1,2]-Stevens Rearrangements en route to (±)-Tylophorine, (±)-7-Methoxycryptopleurine, and (±)-Xylopinine

3.2 Enantioselective Synthesis of Iboga Alkaloids and (+)-Vinblastine

4 Selected Methodology

4.1 Ammonium Ylide Based [2,3]-Sigmatropic Rearrangements To Form Natural Product Cores

4.2 Cascade Reactions Involving [1,2]-Stevens Rearrangement/ Hofmann-Type Elimination Events

5 Conclusions


#

Key words

ammonium ylides - [1,2]-Stevens rearrangement - [2,3]-sigmatropic rearrangement - [2,3]-Stevens rearrangement - natural products - alkaloids
1

Introduction

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Pictured from left to rightZachary Schwartz, Myles Lovasz, Chelsea Valiton, and Andrew G. Roberts Andrew G. Roberts was born and raised in Long Beach, California. He earned his B.S. Chemistry degree in 2008 from UC San Diego where he first learned organic synthesis with Dr. Haim Weizman in the Tor laboratory. Andrew then conducted his Ph.D. thesis research concerning the total chemical synthesis of dimeric pyrrole–imidazole alkaloid natural products with Prof. Patrick G. Harran at UC Los Angeles (Ph.D. Chemistry, 2013). These bioactive and synthetically challenging molecules enabled the development of chemical methods for guanidine synthesis and manipulation. He went on to address questions at the interface of synthetic protein chemistry and cancer biology as an NIH postdoctoral fellow with Prof. Samuel J. Danishefsky at Memorial Sloan Kettering Cancer Center. At MSKCC Andrew collaborated with two teams to complete the chemical protein synthesis and evaluation of granulocyte colony-stimulating factor (G-CSF) and oncogenic KRas(G12V) proteins. Research in the Roberts laboratory at the University of Utah, Department of Chemistry, is focused on the synthesis of structure-stabilized peptide therapeutics and the development of novel amine-derived rearrangement and deaminative reactions to enable the total synthesis of bioactive natural products.

The Stevens rearrangement, also referred to as a Stevens [1,2]-shift, involves the rearrangement of an ammonium ylide into a tertiary amine with the cleavage of a carbon–nitrogen σ-bond and the formation of a carbon–carbon σ-bond (Scheme [1a]).[1] [2] [3] [4] [5] [6] [7] In their first report, Stevens and co-workers demonstrated that ammonium salt 1 is deprotonated under basic conditions, and the resultant ammonium ylide 2 rearranges via a [1,2]-shift to yield the tertiary amine 3 in 90% yield (Scheme [1b]).[1] Since this discovery, the Stevens rearrangement has been extensively studied and applied,[2] [3] [4] [5] [6] [7] with early mechanistic proposals suggesting processes that involve ion pairing,[8] a concerted [1,2]-shift,[9] and radical pairing.[10] In 2020, Baidilov expertly summarized the evolution of controversial mechanistic discussions pertaining to the Stevens rearrangement, and readers are directed to this review for the appropriate description of most Stevens rearrangements as a sequence that involves homolytic carbon–nitrogen σ-bond cleavage/single electron transfer/recombination events.[11] The [2,3]-sigmatropic rearrangement of ammonium ylides bearing allyl groups is related to the Stevens rearrangement in that a carbon–nitrogen σ-bond is exchanged with the formation of a carbon–carbon σ-bond (Scheme [1c]).[2] [3] [4] , [7] [11] However, this [2,3]-sigmatropic rearrangement is mechanistically distinct from the [1,2]-Stevens rearrangement as it proceeds via a concerted five-membered transition state and does not involve radical intermediates.[11] In 1971, Kaiser, Ashbrook, and Baldwin showed how an ammonium ylide based [2,3]-sigmatropic rearrangement can be used to allylate a penicillin derivative at C6 in a highly stereoselective fashion, highlighting the utility of ammonium ylide based rearrangement chemistry in the precise modification of complex amines (Scheme [1d]).[12]

This review covers selected applications of ammonium ylide based [2,3]-sigmatropic[13] [14] [15] [16] and [1,2]-Stevens rearrangements used in recent natural product syntheses.[4] Recent methodologies to regioselectively generate ammonium ylides by reacting tertiary amines with metal carbenoids have been reviewed[13] [14] and will not be discussed herein as the selected case studies generate ammonium ylides by alkylation/deprotonation sequences. Throughout this review we apply red and blue carbon labels in the schemes to help track the application of ammonium-derived [2,3]-sigmatropic and [1,2]-Stevens rearrangements in a complex setting, and emphasize retrosynthetic analyses in hopes of stimulating pattern recognition[17] for the development of novel applications.


# 2

Ammonium Ylide Based [2,3]-Sigmatropic Rearrangements in Natural Product Synthesis

2.1

(–)-Cephalotaxine

(–)-Cephalotaxine [(–)-8], a major constituent in plants of the genus Cephalotaxus, is an intriguing target for total synthesis due to its cytotoxic properties and a complex polycyclic framework that bears a benzazepine core fused to an azaspiro[4.4]nonane system (Scheme [2a]). Many Cephalotaxus alkaloids share the common bioactive pentacyclic scaffold, exemplified by the FDA approved antileukemia drug, homoharringtonine (9, HHT).[18] Synthetic efforts toward cephalotaxine and its structurally related congeners have enabled structure-activity relationship studies to decipher their selective cytotoxic properties and discover anticancer therapeutic leads. Accordingly, many creative strategies have been developed to access the bioactive polycyclic scaffold, including Beall and Padwa’s ammonium ylide based [1,2]-Stevens rearrangement to prepare the 5,7-fused benzazepine skeleton of the cephalotaxine ring system.[19] Their model study is showcased in Scheme [2b], which was previously discussed in detail by West and co-workers.[4] This rearrangement approach toward the cephalotaxine skeleton had a profound influence on the development of [1,2]-Stevens rearrangement[20] and ammonium ylide [2,3]-sigmatropic rearrangement approaches to achieve an efficient synthetic access to cephalotaxine.

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Scheme 1 The [1,2]-Stevens rearrangement and [2,3]-sigmatropic rearrangement of ammonium ylides
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Scheme 2 Cephalotaxine alkaloids as motivating targets for the development of ammonium ylide based rearrangement approaches

Multiple formal syntheses of (±)-cephalotaxine have been accomplished that incorporated an ammonium ylide based [2,3]-sigmatropic rearrangement as a key step. A common feature of the recent strategies is the use of proline-derived starting materials: because of their straightforward derivatization to form ammonium intermediates with predictable deprotonation at the α-position to generate a reactive ammonium ylide that can undergo stereoselective [2,3]-sigmatropic and [1,2]-Stevens rearrangements due to the rigidity enforced by the five-membered ring.[21] In the following applications, undesired ring contractions are minimized, including [1,2]-Stevens rearrangement pathways, demonstrating the selective nature of the rearrangement in appropriate systems.

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Scheme 3 Yang and Liu’s approach to (±)-cephalotaxine

Based on strategies previously developed by Hanaoka[22] and Li[23] (Scheme [3a]), Yang, Liu, and co-workers developed [2,3]-sigmatropic rearrangement based approaches to advance proline derivatives to (±)-cephalotaxine (Scheme [3b], routes A and B).[24] They proposed that either 13a or 13b could be derived from 3-methyl-butanolides 15a and 15b, respectively. These synthons would result from the [2,3]-sigmatropic rearrangement of a proline-derived ammonium ylide 18. They first developed a sequence that involved N-alkylation of methyl prolinate (21) to yield 22 in 87% (Scheme [4a]). Quaternization with allyl bromide to form ylide 18a was followed by in situ [2,3]-sigmatropic rearrangement furnishing 17a in 85% yield. While the [2,3]-rearrangement event proceeded efficiently, subsequent transformations to convert 17a into spirocyclopentenone 13a proved to be low yielding, prompting them to develop an alternative approach (Scheme [4b]). Guided by the alternative disconnection pattern (Scheme [3b]), proline derivative 24 was treated with benzyl bromide in basic acetonitrile, which triggered N-alkylation, ylide formation, and subsequent rearrangement returning 17b in 92% yield. This intermediate was advanced to the tertiary amide 13b, completing a formal synthesis of (±)-cephalotaxine [(±)-8].

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Scheme 4 Yang and Liu’s formal total synthesis of (±)-cephalotaxine
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Scheme 5 Zhang’s approach to (±)-cephalotaxine
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Scheme 6 The Somfai team’s synthesis of ent-cephalotaxine

In a fashion similar to Yang and Liu’s 2009 strategy, Zhang and co-workers developed a more recent (2022) formal synthesis of (±)-cephalotaxine that also leverages a [2,3]-sigmatropic rearrangement as a key step.[25] They targeted the allylic alcohol intermediate 27, a precursor for the key Friedel–Crafts cyclization step in Mori’s synthesis of (±)-cephalotaxine [(±)-8] (Scheme [5a]).[26] Allylic alcohol 27 would derive from spirocyclopentenone 28, which is a product of the [2,3]-sigmatropic rearrangement of proline-derived ammonium ylide 30 (Scheme [5b]). Here, N-Boc-proline 31 was derivatized to prepare tertiary amine 35, which underwent allylation, deprotonation, and a subsequent [2,3]-rearrangement under mild conditions to provide 29 in 97% yield (Scheme [5c]). The Weinreb derivative 29 was readily converted into spirocyclopentene 28 via allylation, alkene isomerization, and ring-closing metathesis. While not directly comparable to Yang and Liu’s developments from 2009, the novel demonstration of a proline-derived Weinreb amide 29 in a [2,3]-rearrangement derivatization sequence demonstrates a concise approach to a spirocyclic system of equal complexity.

In 2018, a team led by Somfai[27] achieved a formal synthesis of ent-cephalotaxine by targeting the Ishibashi intermediate 36,[28] employed in the synthesis of the natural enantiomer (Scheme [6a]). The team proposed that enone 36 could derive from the aldol condensation of enolate intermediate 37, which, in turn, would derive from the Parham cyclization of exo-butenolide 38 (Scheme [6a]).[27] Finally, the tertiary amine 38 would arise from iodolactonization and Lewis acid templated [2,3]-rearrangement, reducing the complexity of 38 down to N-allyl proline derivative 40. Having the optimized protocol for a Lewis acid templated [1,2]-Stevens rearrangement in hand (Scheme [6b]),[29] 44 was allylated and treated with BBr3 to form the iminium 45 (Scheme [6c]). The iminium underwent DBU-promoted conversion into enamine 46 and a subsequent [2,3]-rearrangement to transfer the allyl group in a diastereoselective fashion. The chirality was efficiently transferred from 44 to the secondary amine 39 (e.r. 96:4).

Notably, this strategy does not form a discrete anion at the α-position, but instead leverages the electron-rich dimethyl amide to promote the desired [2,3]-sigmatropic rearrangement. This creative approach avoids the use of a chiral auxiliary or amine protection, enabling concise access to chiral α-substituted proline derivatives. They used 39 to complete a succinct total synthesis of ent-cephalotaxine (ent-8b). This involved alkylation of 39 with nosylate 48 to access the tertiary amine 49 in 83% yield, which underwent iodolactonization/elimination to furnish exo-butenolide 38, the key Parham cyclization precursor, in 37% yield. Here, the team optimized conditions to achieve a one-pot Parham cyclization/aldol condensation sequence (Scheme [7]). They found that lithium–iodide exchange of 38 formed aryllithium intermediate 50 that underwent cyclization to a proposed stabilized intermediate 51. An early quench produced methyl ketone 52, however, subsequent addition of sodium methoxide collapsed 51 into sodium enolate 37. Upon heating, 37 underwent efficient aldol condensation to yield enone 36, that was converted into ent-cephalotaxine (ent-8) in several steps. Overall, the Lewis acid templated [2,3]-rearrangement reaction to form chiral proline derivative 39, and its subsequent elaboration to pentacycle 36, enabled by a carefully orchestrated one-pot Parham cyclization/aldol condensation sequence, define the highlights of this synthesis.

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Scheme 7 Somfai’s tandem Parham cyclization/aldol condensation strategy to access ent-cephalotaxine

# 2.2

(±)-Amathaspiramide F

The diverse biological properties exhibited by the amathaspiramide alkaloids, including antiviral, cytotoxic, and antimicrobial activities, have motivated the development of strategies for their synthetic assembly.[30] As exemplified by the structure of amathaspiramide F (53) (Scheme [8a]), their spirocyclic, and stereochemically dense ring systems pose synthetic challenges that have led to the development of stereocontrolled synthetic methodologies. The structural diversity of the amathaspiramide alkaloids and approaches relevant to their construction through total and formal synthesis endeavors, were recently reviewed.[31]

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Scheme 8 Soheili and Tambar’s retrosynthesis of (±)-amathaspiramide F

In 2011, Soheili and Tambar reported the development of a catalytic allylic amination/[2,3]-sigmatropic rearrangement sequence as a concise method for the stereocontrolled synthesis of homoallylic tertiary amines, setting up two contiguous stereocenters in the process.[32] In light of this utility, they proposed a formal synthesis of (±)-amathaspiramide F (53) that would quickly assemble a key homobenzylic tertiary amine, setting contiguous benzylic (C1) and spirocyclic (C2) stereocenters through a diastereoselective [2,3]-sigmatropic rearrangement (Scheme [8a]).[33]

Soheili and Tambar’s retrosynthetic analysis disconnected the aminal ring system of (±)-amathaspiramide F (53) to derive from aldehyde 54 (Scheme [8a]). This aldehyde would come from the oxidation of γ,δ-unsaturated amino ester 55. Here, they recognized that 55 contained the retron that could be obtained using a previously developed tandem Pd-catalyzed allylic amination/[2,3]-sigmatropic rearrangement sequence.[32] [34] [35]

Accordingly, amino ester 55 would be accessible from the coupling of benzylic carbonate 57 with proline derivative 58. Based on related transforms, and their prior study,[32] the [2,3]-sigmatropic rearrangement of ammonium ylide 56 was anticipated to adopt a favorable exo-transition state to produce the desired exo diastereomer 55. Their study led to a succinct formal synthesis of (±)-amathaspiramide F (53) and uncovered ortho-substitution as an unusual and adjustable feature for stereocontrol (Scheme [8b]).[33]

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Scheme 9 Soheili and Tambar uncover the impact of ortho-substitution on ammonium ylide based [2,3]-sigmatropic rearrangements

First, Soheili and Tambar evaluated the impact of amino ester substituents 58a–c on the Pd-catalyzed allylic amination–[2,3]-sigmatropic rearrangement sequence with benzylic carbonate 57 (Scheme [9a]). Unfortunately, the observed major product from each evaluated case was the endo transition state derived diastereomer 59a–c (exo/endo, 1:3, as determined by 1H NMR spectroscopy). Because all products derived from this subset favored the endo diastereomer 59, and their previous studies showed a preference for exo transition state derived products, they postulated that the substitution pattern about the benzene ring in 57 might be important.[32] [34] They evaluated a subsequent series, where a simpler, acyclic tert-butylamino ester was reacted with benzylic carbonates having various substitution patterns. This systematic study revealed that ortho-substitution led to a preference for endo transition state derived products, independent of the cyclic, proline-derived substrates. Benzylic carbonate substrates lacking ortho-substitution favored exo products. This unanticipated diastereoselectivity is thought to derive from the torsional strain associated with the nonplanar confirmation adopted by the ortho-substituted cinnamyl system. Fortunately, this trend was general for the Pd-catalyzed allylic amination/[2,3]-sigmatropic rearrangement sequence using proline-derived amino esters 62a,b with meta-substituted benzylic carbonate 63 as depicted in Scheme [9b]. The coupling of amino methyl ester 62a with benzylic carbonate 63 produced homobenzylic amino esters (64a/65a, 1:1), with no preference for either diastereomer. The use of the amino tert-butyl ester 62b restored the trend, forming the exo product 64b with a 3.5:1 exo/endo preference. Fortunately, Sakaguchi had previously demonstrated that a meta-OMOM substituted aromatic intermediate could be advanced to complete a synthesis of (–)-amathaspiramide F.[35]

Accordingly, Soheili and Tambar[33] went on to develop a revised synthesis of (±)-amathaspiramide F (53), where bromination would occur at a later stage according to Sakaguchi­’s strategy (Scheme [10]).[35] Their synthesis began with the preparation of amino tert-butyl ester 62b, prepared from l-proline tert-butyl ester, and benzylic carbonate 63, prepared in a few steps from the corresponding benzaldehyde. The Pd-catalyzed allylic amination of 62b with 63 produced ammonium ylide 68, which underwent an exo-preferred [2,3]-sigmatropic rearrangement to yield homoallylic amino ester 64b in 57% yield (exo/endo, 3.5:1). This key intermediate 64b was deprenylated to furnish the secondary amine 69, which was subjected to a series of functionalizations to access Sakaguchi’s phenol 70 in 46% yield, formalizing their synthetic endeavor.


# 2.3

(–)-Cephalezomine G and Its C3 Epimer

The cephalotaxus alkaloids have motivated the development of synthetic methods and total synthesis strategies for decades.[4] [36] Their pentacyclic structures contain various degrees and patterns of oxidation with over 70 alkaloids in this family sharing the common azaspiranic tetracyclic core, itself comprised of a benzazepine ring fused with a 1-azaspiro[4.4]nonane ring system. Despite this common structural feature, the varied oxidation pattern about the D-ring confounded the first structural elucidation of (–)-cephalezomine G (71) (Scheme [11]). A reevaluation of the spectroscopic data for (–)-cephalezomine G (proposed structure) led to its structural revision, where the C3 hydroxyl is inverted relative to the original assignment.[37] This makes 78 a 2α,3β-anti-diol instead of the originally proposed, 2α,3α-syn-diol 71.

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Scheme 10 Soheili and Tambar’s synthesis of (±)-amathaspiramide F
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Scheme 11 The Kim team’s retrosynthetic analysis of (–)-cephalezomine G accounts for a structural revision

Kim developed a route to prepare 71 that leveraged a stereocontrolled [2,3]-sigmatropic rearrangement to set the benzylic stereocenter.[38] Their retrosynthetic analysis viewed 71 deriving from the Friedel–Crafts cyclization of an intact 1-azaspiro[4,4]nonane ring system to build the benz­azepine ring (Scheme [11]). This strategy could be used to cyclize either C3 diastereomer, with the variable hydroxylation patterns deriving from the oxidation of spirocyclic alkene 72. The spirocyclopentene ring system would come from the ring-closing metathesis of diene 73. This diene could be prepared from homoallylic amino ester 74, itself proposed to come from a diastereoselective [2,3]-rearrangement of chiral allylic ammonium salt 75. Through the exo-selective [2,3]-sigmatropic rearrangement, the chirality at the ammonium nitrogen center would transfer to the α-carbon, affording the absolute stereochemistry required for the azaspiranic tetracyclic backbone of 72 en route to (–)-cephalezomine (71). The ammonium salt 75 would derive from d-proline tert-butyl ester. The success of this proposed strategy required the development of conditions to achieve a diastereoselective N-allylation.[39] Previous studies by the Kim group found 2,3-dimethylbenzyl groups to be particularly effective in achieving diastereoselective N-allylation upon reacting with (E)-cinnamyl bromides.[40] Interested in confirming the structure of (–)-cephalezomine G, the Kim team set out to complete a total synthesis. Inversion of stereochemistry at C3 of 80 would give back the epimer 79, which can be converted into 78 using a Friedel–Crafts cyclization as a key step (Scheme [11b]).

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Scheme 12 Kim’s [2,3]-sigmatropic rearrangement strategy en route to (–)-cephalezomine G

To start, N-allylation was achieved with 2,3-dimethylbenzyl d-proline tert-butyl ester (77) and (E)-cinnamyl bromide 76 in the presence of excess sodium iodide (Scheme [12]). The good yield and high diastereoselectivity of such quaternization processes have been attributed to the 2,3-dimethyl substitution pattern of 77 and electron-withdrawing nature of the acetate groups of 76.[40] To their delight, ammonium salt 81 was produced in excellent diastereomeric ratio of 93:7. Upon treatment with t-BuOK, the presumed ammonium ylide 75 undergoes a [2,3]-sigmatropic rearrangement leading to the desired exo-product 74 as the major diastereomer in 84% yield with diastereomeric ratio (>97:3).

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Scheme 13 Kim’s total synthesis of (–)-cephalezomine G

Kim advanced key intermediate 74 into the original 71 and revised 78 structures of (–)-cephalezomine G.[38] Thus, catechol 74 was converted into aziridine 82 via dioxolane formation, LiAlH4 reduction, and intramolecular N-alkylation in 46% yield over 3 steps (Scheme [13]). Vinylmagnesium bromide was then used to open the aziridinium ring at the less hindered position to produce diene 73. Ring-closing metathesis using Grubbs I catalyst 83, followed by dihydroxylation of the resultant endocyclic alkene, provided cis-diol 80 in 52% over three steps. Several anti-selective dihydroxylation reactions were evaluated but proved to be unsuccessful. Furthermore, attempts to invert the C3 stereocenter via sequences involving hydroxyl group activation and SN2-type displacement were met with disappointment. Both limitations were attributed to the system sterics, where the β-face approach is blocked by the aryl moiety. To overcome this challenge, the nitrogen center was used to direct the C3 inversion via intramolecular delivery of the oxygen. Accordingly, the benzyl group was removed by hydrogenolysis in the presence of di-tert-butyl dicarbonate (Boc2O), followed by protection of the less-hindered hydroxyl group to afford 84 in 60% yield. Next, the C3 hydroxyl was activated by treatment with diethylaminosulfur trifluoride (DAST), triggering the formation of the cyclic carbamate 85 in 81% yield. Cleavage of the cyclic carbamate 85 with phenyllithium gave the desired C3 hydroxyl 86 in 81% yield. Kim proposed to advance 86 into (–)-cephalezomine G (78) following a series of transformations inspired by Ishibashi’s route to cephalotaxine (8).[27] [37] They appended the last two carbons of the tetracyclic backbone by a reductive amination and protection sequence to yield 87 in 87% yield over two steps. Intermediate 87 underwent an intramolecular Friedel–Crafts reaction, followed by reduction to afford 88 in one-pot fashion in 80% yield. Finally, lithium aluminum hydride was employed to reductively cleave the pivaloyl group, furnishing (–)-cephalezomine G (78) in 96% yield, and overall showcasing the utility of nitrogen to α-carbon chirality transfer in an ammonium ylide based [2,3]-sigmatropic rearrangement.


# 2.4

(±)-Strictamine

Strictamine (89) is a member of the akuammiline family of alkaloids (Scheme [14a]). These monoterpenoid indole alkaloids, isolated from the African rainforest tree Picralima klaineana, possess antimalarial and anti-inflammatory properties. Extracts from this tree and related species have played an important role in traditional African medicine.[41] Many of the bioactive alkaloids contained in these extracts are characterized and have been studied for nearly a century.[42] Strictamine (89) was first isolated from Rhazya stricta, a plant in the same family as Picralima klaineana, in 1966.[43] It has since been shown to have an inhibitory effect on nuclear factor kappa B (NF-κB), an inducible transcription factor associated with gene regulation via immune and inflammatory responses.[44] Many creative approaches have been developed to prepare synthetic strictamine (89) and structurally related alkaloids.[45]

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Scheme 14 The Gaich group’s retrosynthetic analysis of (±)-strictamine

In 2016 and 2017, the Gaich group published a unique total synthesis of strictamine (89) incorporating two distinct [2,3]-sigmatropic rearrangements to form the C3–C12 and C15–C16 bonds of the D-ring.[46] [47] The complexity of these rearrangements is best appreciated by looking at several representations of strictamine (89) and the retrosynthetic analysis used by the Gaich group to uncover them (Scheme [14]). Their strategy is summarized in Scheme [14b]. They proposed that (±)-strictamine (89) would be derived from reductive indolene synthesis, and the E-ring would be formed by an established Ni-promoted 1,4-addition of the pendent vinyl iodide 90. They viewed bicycle 90 as a product of the [2,3]-sigmatropic rearrangement of an in situ formed ammonium ylide, which is attained by N-alkylation of 91 with 92. This event would define the 2nd [2,3]-shift used to forge the C15–C16 bond and would complete the D-ring assembly. Bridged bicycle 91 would come from an intramolecular N–H insertion reaction of functionalized pyrrolidine 93 bearing an α-diazo carbonyl group. This substituted pyrrolidine 93 scaffolds vicinal stereocenters, including a quaternary carbon center. The team proposed that the C3 α-stereocenter could be installed by the [2,3]-sigmatropic rearrangement of in situ formed quaternary salt 94. This event would define the 1st strategic [2,3]-shift used to forge the C3–C12 bond. Pyrrolidinium 94 would arise from known nitrobenzene 95, through a series of cyclization, alkylation (forming the quaternary carbon center highlighted in orange), and functionalization steps on nitrobenzene 96.

The Gaich group enacted the total synthesis of (±)-strictamine (89) following their creative retrosynthetic analysis. In this review we begin with a key intermediate, N-allyl pyrrolidine 97, (8 steps from 96, Scheme [15]). The allylation of 97 required the combination of allyl iodide with silver(I) triflate, and in situ formed ammonium 94 underwent deprotonation upon reaction with potassium tert-butoxide to provide presumed ammonium ylide intermediate 98. The [2,3]-shift of ylide 98 produced 99 in 53% isolated yield as a single diastereomer (d.r. 99:1). The excellent stereoselectivity in this event is attributed to the steric bulk of the nitrophenyl group in 97, which rigidifies the pyrrolidine ring and imparts a facially selective rearrangement from either allyl group. This key intermediate 99 was advanced in several steps to pyrrolidine 100, which underwent an intramolecular N–H insertion reaction to access the bridged bicycle 91 in 54% yield. Attainment of 100 set the stage for the 2nd [2,3]-sigmatropic rearrangement event. Again, N-allylation was carried out using allyl iodide 92 and silver(I) triflate. Proton-sponge® was employed as a base to facilitate the formation of ylide 101; subsequent [2,3]-shift yielded bridged bicycle 90. This remarkable transformation builds the D-ring of (±)-strictamine 89 by forming the C15–C16 bond. Due to the constrained nature of the bicyclic system 91, stereoselectivity was not a concern, and the desired product 90 was obtained in 42% yield. A two-step indolene synthesis was followed by Zhu’s intramolecular cyclization protocol, thereby completing the total synthesis of (±)-strictamine (89).[48] In summary, the Gaich group cleverly demonstrated the use of sequential [2,3]-sigmatropic rearrangements to construct the 2-azabicyclo[3.3.1]nonane system of (±)-strictamine (89). This synthesis will likely inspire others to further value the utility of ammonium ylide based rearrangements, especially when used to form challenging stereocenters in a complex setting.

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Scheme 15 The Gaich group’s total synthesis of (±)-strictamine

# 2.5

(–)-Doxycycline

The complexity of the bicycle 101 to bicycle 90 transformation involving a [2,3]-sigmatropic rearrangement (Scheme [15]) is comparable to the ammonium ylide based [2,3]-rearrangement demonstrated earlier by Myers and co-workers en route to structurally diverse 6-deoxytetracycline antibiotics (Scheme [16]).[49] Here, the Myers team showed that the AB-ring system of the 6-deoxytetracyclines could be accessed using a unique [2,3]-rearrangement as a key event.

Their synthesis began with a whole-cell microbial dihydroxylation of benzoic acid (103), followed by a hydroxyl-directed epoxidation to furnish 104. The carboxylic acid 104 was methylated with trimethylsilyldiazomethane, and the product was subjected to isomerization and silylation via a vinylogous Payne-type rearrangement to form allylic epoxide 105.[50] They then reacted the B-ring fragment 105 with a lithiated 5-(benzyloxy)isoxazole 106 to form ketone 107. Notably, this 5-(benzyloxy)isoxazole moiety masked the vinylogous carbamic acid functionality present in the target 6-deoxytetracyclines.[51] By design, the pendent tertiary amine enabled a notable C–C bond-forming [2,3]-rearrangement. Here, they propose that 107 is converted into ammonium ylide 108 via SN′-opening of the allylic epoxide, proton transfer, and finally, an ammonium ylide based [2,3]-rearrangement to forge the requisite AB-ring system. The rearranged product was selectively desilylated upon treatment with trifluoroacetic acid to produce 109, which could be advanced to (–)-doxycycline 110 in 11 steps.

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Scheme 16 Myers’ [2,3]-rearrangement approach to (–)-doxycycline

#
# 3

[1,2]-Stevens Rearrangements Toward Natural Products

3.1

Ring-Expanding [1,2]-Stevens Rearrangements en route to (±)-Tylophorine, (±)-7-Methoxycryptopleurine, and (±)-Xylopinine

Tylophorine (111), a secondary metabolite isolated in 1935 from Tylophora indica, exhibits several biological activities of interest, including reports of antiproliferative, anti-inflammatory, antibacterial, antiallergic, antifungal, and antiviral properties (Scheme [17]).[52] [53] [54] [55] The antiviral efficacy of 111, and its potential for structure-activity optimization, have renewed interest in 111 for the treatment of severe acute respiratory syndrome coronavirus.[56] A synthetic challenge of building fused phenanthrene-indolizidine cores has motivated the chemical community to devise efficient routes toward the natural product.[57] [58] [59] [60] [61] [62] [63] [64] [65] [66] Asymmetric syntheses of (R)-(–)-111, and the unnatural enantiomer, (S)-(+)-111, have used chiral auxiliaries, chiral pool, and asymmetric catalysis strategies. More recently, independent teams led by Ho[67] and Opatz,[55] [68] [69] recognized that the challenge of preparing the pseudosymmetric phenanthraindolizidine alkaloid 111 could be reduced to the synthesis of a symmetric phenanthrene derivative 112 (Scheme [17]). In their related analyses, a ring-expanding [1,2]-Stevens rearrangement of a spirocyclic ammonium ylides 113 would enable rapid access to (±)-tylophorine (111). The Opatz team proposed access to nitrile-stabilized ammonium ylide 113a.[55] The Ho team envisioned that a lithium–tin exchange of α-stannyl ammonium 114b could provide access to ammonium ylide 113b.[67] Later, the Opatz group recognized that the same strategy could be used to prepare (±)-7-methoxycryptopleurine 115, as it would derive from α-aminonitrile 119 (n = 2).[69]

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Scheme 17 Retrosynthetic analyses of (±)-tylophorine and (±)-7-methoxycryptopleurine unveil ring-expanding [1,2]-Stevens rearrangements

In 2012, the Opatz group prepared symmetric phenanthrene derivative 112 from the acid-mediated condensation of veratrole 121 and butane-2,3-dione 120 (Scheme [18a]).[55] Subsequently, 112 was converted into bis-benzyl bromide 122 using radical halogenation conditions. The double alkylation of pyrrolidine-2-carbonitrile 118 with 122 provided spirocyclic ammonium bromide 114a. The regioselective deprotonation of 114a formed nitrile-stabilized ammonium ylide 113a in situ, which underwent a ring-expanding [1,2]-Stevens rearrangement to form crude 123, which was directly reduced with sodium cyanoborohydride to yield (±)-tylophorine 111 in 85% yield over two steps.

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Scheme 18 The Opatz and Ho syntheses of (±)-tylophorine

In 2013, the Ho team developed a lithium–tin exchange strategy to regioselectively form ammonium ylide 113b (Scheme [18b]).[67] This required the preparation of an α-stannyl pyrrolidine derivative 120. First, 126 was deprotonated and reacted with tributyltin chloride to form stannyl derivative 127. Due to the sensitivity of α-stannyl pyrrolidine 127, 2-bromo-1,3,2-benzodioxaborole-promoted conditions were used to affect Boc-deprotection. Crude 120 was directly alkylated with bis-benzyl bromide 122 to provide spirocyclic ammonium bromide 114b. Upon treatment with n-butyllithium, spirocyclic ammonium ylide 113b was presumably formed in situ via lithium–tin exchange and underwent a ring-expanding [1,2]-Stevens rearrangement to form (±)-tylophorine (111) in 37% isolated yield. Similar ring-expanding [1,2]-Stevens rearrangement strategies were used by the Opatz and Ho teams to independently access (±)-tylophorine in five and six overall steps, respectively. While the use of an α-aminonitrile enabled regioselective access to ammonium ylide 113a, the Opatz group[55] noted a concern for iminium-based degradation pathways that could liberate HCN and generate undesired byproducts, such as the conjugated enamine 125. To circumvent such issues, they reduced crude 123 directly, via iminium 124. A method to affect the asymmetric reduction of conjugated enamine 125 could provide means to access either antipode of (±)-tylophorine (111). The Ho group[67] used a lithium–tin exchange approach to achieve regioselective formation of reactive ammonium ylide 113b, that formed (±)-tylophorine (111) directly. However, this strategy required the development of more specialized handling conditions to prepare and react α-stannyl pyrrolidine 120.

Like in their synthesis of (±)-tylophorine (111), the Opatz group has leveraged the use of α-aminonitriles for the rapid construction of spirocyclic ammonium intermediates en route to many other alkaloids.[55] [68] [69] In 2013, they reported several total syntheses using [1,2]-Stevens rearrangement events as key steps, where the nitrile group serves to direct the site of deprotonation and stabilize the resultant ammonium ylide.[69] As selected examples, their total syntheses of (±)-7-methoxycryptopleurine (115) and (±)-xylopinine (134b) are shown in Scheme [19a] and Scheme [19b], respectively. Toward (±)-7-methoxycryptopleurine (115) they reacted α-aminonitrile 119 with bis-benzyl bromide 122 to access spirocyclic ammonium 117 in quantitative yield. This crystalline intermediate 117 underwent regioselective deprotonation, [1,2]-Stevens rearrangement via ammonium ylide 116, and the crude product 128 (Z = CN) was treated directly with sodium borohydride to access (±)-7-methoxycryptopleurine (115; Z = H) in 82% isolated yield over two steps. In a similar fashion, (±)-xylopinine (134b) was accessible in five steps from 3,4-dimethoxyphenethylamine (129). First, they converted 129 into α-aminonitrile 130 in two steps. Then, α-aminonitrile 130 was doubly alkylated with bis-benzyl bromide 131 to prepare spirocyclic ammonium 132. The deprotonation of 132 formed ammonium ylide 133 that underwent a [1,2]-Stevens­ rearrangement to form 134a (Z = CN), that was directly reduced to efficiently furnish (±)-xylopinine (134b) in 98% isolated yield.

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Scheme 19 The Opatz team’s syntheses of (±)-7-methoxycryptopleurine and (±)-xylopinine

Overall, the Opatz group has demonstrated several natural product syntheses, and their recent review highlights[68] the utility of α-aminonitriles as simple-to-prepare precursors with predictable reactivity in approaches involving the [1,2]-Stevens rearrangement.


# 3.2

Enantioselective Synthesis of Iboga Alkaloids and (+)-Vinblastine

The development of rearrangement reactions that derive from the synthetic manipulation of monoterpene indoles can enable complex structural changes and unveil novel routes to iboga alkaloids. Sharing a common pentacyclic backbone, natural products in this class have shown neurological activities such as the capability to diminish addiction to a wide array of drugs.[70] In 2016, Luo and co-workers reported the enantioselective synthesis of (+)-epiibogamine (135), (+)-ibogamine (136), and (+)-catharanthine (137), through the [1,2]-Stevens rearrangement of the common intermediate 138 (Scheme [20]).[71]

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Scheme 20 Luo’s retrosynthetic analysis of iboga alkaloids

Inspired by previous efforts from the laboratories of Trost,[72] White,[73] and Oguri,[74] Luo and co-workers proposed that two intermediates, 138a (R1 = H) and 138b (R1 = CO2Me), could provide access to several iboga alkaloids.[71] To construct the C16–C21 bond, they proposed a regioselective [1,2]-Stevens rearrangement that would derive from treating ammonium 139 with base to deprotonate at C21. The ammonium 139 could be derived from the intramolecular alkylation of intermediate 140, which, in turn, could arise from recently developed Au-catalyzed oxidation of 141. Through reduction and propargylation, the terminal alkyne could be traced back to known amide 142, accessible in three steps from tryptamine (143).

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Scheme 21 A platform for the enantioselective syntheses of iboga alkaloids and a proposal for an organocatalyzed [1,2]-Stevens rearrangement

The organocatalytic Pictet–Spengler reaction reported by the Jacobsen group was employed to transform tryptamine (143) into the chiral amide 142 (95% ee) over three steps (Scheme [21a]).[75] The propargyl group was introduced over a four-step sequence, converting 142 into 141a. Then, a one-pot procedure involving a Au-catalyzed oxidation with 2-bromopyridine N-oxide (145) was optimized to yield intermediate 140a that underwent cyclization to obtain ammonium salt 139a in 73% yield. Next, conditions were evaluated to affect a [1,2]-Stevens rearrangement of 139a. Unfortunately, initial conditions that varied base, solvent, and temperature led to recovered 139a and decomposition. Inspired by the development of organocatalytic sigmatropic reactions, Luo and co-workers[71] shifted their focus to the formation of an enamine intermediate, and demonstrated that secondary amines, like piperidine (146), promoted the desired rearrangement.[76] To further support their claim of an organocatalytic [1,2]-Stevens rearrangement, they showed that a tertiary amine, N-methylmorpholine, was inactive. The recovery of 139a in this case supported that the [1,2]-Stevens rearrangement in this case was likely proceeding via an enamine intermediate (secondary amine catalysis) and was not simply base-promoted.

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Scheme 22 Iboga alkaloids accessible from a key intermediate and a one-pot Au-catalyzed oxidation/cyclization/[1,2]-shift used en route to (+)-dihydrocatharanthine and (+)-vinblastine

Two proposed reaction pathways were discussed to explain this phenomenon (Scheme [21b]).[71] The radical ionic pathway, where homolytic cleavage forms a radical benzylic cation, or an ionic pathway where heterolytic cleavage forms a benzylic carbocation. Similar pathways have been proposed in systems of related complexity.[77] Either pathway would proceed to 138a through the intermediacy of a nine-membered enamine-containing ring. With rearranged 138a in hand, Luo and co-workers[71] demonstrated that (+)-epiibogamine (135) and (+)-ibogamine (136) could be accessed via a Wittig reaction followed by a radical-based hydrogenation (Scheme [22a]). (+)-Catharanthine (137) was accessed from rearranged 138a following Büchi’s three step sequence.[78] Further demonstrating the streamlined utility of a [1,2]-Stevens rearrangement in polycyclic alkaloid total synthesis, Luo and co-workers[71] discovered that a one-pot Au-catalyzed oxidation/cyclization/[1,2]-Stevens rearrangement sequence was operative during the remarkable conversion of 141b into 138b. From 138b, the team demonstrated two-step access to (+)-dihydrocatharanthine (150) and (+)-vinblastine (151).[79]

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Scheme 23 Ammonium ylide based [2,3]-sigmatropic rearrangement approach to allyl and allenyl-bearing chiral indolizidines

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# 4

Selected Methodology

4.1

Ammonium Ylide Based [2,3]-Sigmatropic Rearrangements To Form Natural Product Cores

A common occurrence of chiral indolizidines possessing stereogenic centers at the bridgehead positions in alkaloids has made their synthesis an alluring challenge.[80] Considerable effort has led to the development of novel strategies for their construction, yet some of these advances are limited by longer routes to prepare requisite precursors. These issues led the Zhang group to develop a ring expansion/[2,3]-sigmatropic rearrangement cascade for the concise preparation of chiral indolizidines bearing allyl and allenyl substituents (Scheme [23]).[81] [82] The key N-allylated and N-propargylated substrates are readily prepared from chiral proline precursors. They developed a short route to access the substrates as depicted in Scheme [23a]. Here, N-allylated proline derivatives 152 were advanced to Weinreb amides 153 and converted into cyclopropyl ketones 155 in good yields, over two steps. These cyclopropyl ketones were then subject to ring expansion to form the key bicyclic ammonium ylide intermediates 156. These efficiently generated intermediates 156 underwent [2,3]-sigmatropic rearrangements, transferring chirality from the quaternary nitrogen center to the α-center, with excellent enantioselectivities as observed by the obtained chiral indolizidine products 157a–d bearing allyl substituents. They went on to show the utility of these product types by converting 157a into a derivative 158 of the indole alkaloid (+)-harmicine (159), and the 5,5,6-tricyclic enone skeleton 161 common to some securinega alkaloids like fluvirosaone B (162)[83] (Scheme [23b]).[81] The team also extended this reaction to access chiral indolizidines bearing allenyl groups (Scheme [23c]).[81] [82] Here, the proposed overall transformation is depicted beginning with N-propargyl derivatives 163. Treatment with magnesium iodide generated alkyl iodide intermediates 164 that cyclized to bicyclic ammoniums 165. Subsequent deprotonation provided ammonium ylides 166 that underwent a [2,3]-sigmatropic rearrangement to furnish a variety of allene-bearing products 167a–f in moderate to good yields and high enantioselectivities. It is likely that the methods outlined in Scheme [23b] will be used to access novel chiral indolizidines and may find future applications in the total synthesis of polycyclic alkaloids.

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Scheme 24 The Roberts team’s deaminative contraction strategy to access phenanthrene- and dihydrophenanthrene-containing natural products

# 4.2

Cascade Reactions Involving [1,2]-Stevens Rearrangement/Hofmann-Type Elimination Events

The challenge of preparing axially chiral natural products, such as mastigophorene A (168a) and B (168b), as well as bibenzyl congener, mastigophorene D (169),[84] [85] [86] [87] motivated our laboratory to develop catalytic methods for deamination and deaminative contraction reactions, respectively (Scheme [24a]). Similar to the Bringmann lactone method used for the stereoselective total synthesis of axially chiral natural products,[88] we proposed that axially chiral biaryls 170 could be derived from reductive cyclization/deamination of appropriately functionalized tertiary amines 172 (Scheme [24b]).[90] The deaminative contraction of biaryl-linked azepines 175 could also enable access to substituted phenanthrenes 173 and dihydrophenanthrenes 174. We wondered if polycyclic aromatics, like 173, could be accessed by a cascade process involving amine methylation/[1,2]-Stevens rearrangement (see 176)/and Hofmann-type elimination events.[90] Joshua, Gans, and Mislow demonstrated a related transformation to convert azepinium bromide 177 into 178 and 179 (Scheme [24c]).[89] They proposed the process involved [1,2]-Stevens rearrangement and Hofmann-type elimination events. Dihydrophenanthrene 178 was thought to derive from the reduction of 177. While dihydrophenanthrenes 178 could derive from the reduction of phenanthrenes 179, we proposed to develop reductive, Ni-catalyzed deaminative conditions that would be more direct.[89] [90] Recently, oxidative methods to deaminatively contract cyclic secondary amines were reported­ independently by the Levin,[91] [92] Lu,[93] and Antonchick­ groups.[94] These methods share our appreciation of amines as handles for carbon–carbon bond formation in a complex setting.[95] [96]

Our proposal to convert 175 into 174 (Scheme [24b]) led us to discover trimethyl phosphate as a unique reagent for iterative amine methylation/Ni-catalyzed C–N bond cleavage chemistry (Scheme [25a]).[90] The Ni-catalyzed conversion of N,N-dibenzylmethylamine (180) into 1,2-diphenylethane (181) highlights the utility of these conditions for iterative benzylic C–N bond cleavage of acyclic tertiary amines. However, asymmetric substrates, like 182, yield statistical product mixtures (Scheme [25a]), and attempts to convert cyclic tertiary amine substrates 184, led primarily to deamination without contraction (Scheme [25b]). Surprisingly, we discovered that trimethyl phosphate can operate as a unique reagent for iterative amine methylation/carbon–nitrogen bond cleavage chemistry in the absence of catalytic Ni, where 184 is efficiently converted into phenanthrene 189 and 2,2′-dimethylbiaryl 187 (Scheme [25c]).[90] [97] We suspected that the overall process involved a [1,2]-Stevens rearrangement as a key event and diverted our attention to develop this transformation.

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Scheme 25 The Roberts team discovers a methylation-induced/[1,2]-Stevens rearrangement/Hofmann-type elimination cascade reaction

In order to gain a better understanding of the [1,2]-Stevens­ rearrangement event, we highlight cases where base-promoted [1,2]-shifts of related azepenium salts have been studied. Mislow and co-workers found that an optically active bridged biphenyl azepinium bromide, (S)-(+)-190, will undergo a [1,2]-Stevens rearrangement to yield diastereomeric products, (S,9S)-(+)-191 and (R,9S)-(+)-191 (Scheme [26a]).[89] Asymmetry transfer is proposed, and lower temperature conditions are thought to produce a single diastereomer. However, at room temperature (S,9S)-(+)-191 and (R,9S)-(+)-191 can interconvert. A similar case was reported by Stara and co-workers, where optically pure dihydroazepinium iodide (S)-(+)-192 underwent a [1,2]-Stevens rearrangement to yield (R,3R)-(+)-193.[98] This study supported the assumption that axial chirality would be preserved during the [1,2]-shift. Building on these observations, Lacour and co-workers developed an enantioselective [1,2]-Stevens rearrangement using a supramolecular asymmetric ion pairing strategy, achieving up to 55% enantiomeric excess of 196 from chiral ion pair 194.[99] This proof-of-concept mechanistic study supported that enantioselectivity can be achieved, despite the proposed radical nature of the [1,2]-Stevens rearrangement (Scheme [26c]). In 2022, Maruoka and co-workers observed that the simplified Maruoka catalyst 200, useful as a phase transfer catalyst for the asymmetric alkylation of amino acid derivatives, will undergo a base-promoted degradation via a [1,2]-Stevens rearrangement of ammonium ylide 201 (Scheme [26c]).[100] [101] Interestingly, they showed that deuterium incorporation at the benzylic positions serves to impede the [1,2]-Stevens rearrangement, as demonstrated by a decreasing stability trend where, 200 < D2-200 < D4-200, under the basic conditions of asymmetric alkylation reactions (Scheme [26d]). While this stability difference has clear implications for the utility of a more robust phase transfer catalysts, we highlight this [1,2]-Stevens rearrangement instance as deuterium incorporation may be useful in directing regioselective ammonium ylide formation in more complex settings. Intriguingly, several of these studies observed that excess base can affect sequential [1,2]-Stevens rearrangement/Hofmann-type elimination events to form respective phenanthrene derivatives.

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Scheme 26 [1,2]-Stevens rearrangements of bridged biaryl azepiniums

In the first report in 1960, Stevens and co-workers found that biphenyl dihydroazepine 201 reacted with neat sodium amide to form phenanthrene (189) that was sublimed from the reaction in 40% isolated yield (Scheme [27a]).[102] This curious result did not require the preformation of a quaternary ammonium intermediate. The authors suggest the conditions induce a base-promoted [1,2]-Stevens-type rearrangement, forming the first C–C bond, followed by a Hofmann-type elimination to forge the phenanthrene system with the liberation of aniline. Similarly in 1968, Mislow and co-workers found that biaryl dihydroazepinium bromide 177 reacted with excess potassium amide to form the corresponding 1,10-dimethylphenanthrene (179) in 64% isolated yield (Scheme [27a]).[89] While the first [1,2]-Stevens­ rearrangement from 177 was understood, the Hofmann-type elimination of dimethyl amide was atypical and attributed to the favorable formation of the tricyclic aromatic system 179. In 1994, it followed that Stara and co-workers observed a similar cascading, [1,2]-Stevens rearrangement/Hofmann-type elimination, to convert optically pure (S)-(+)-192 into chiral pentahelicene [(P)-(+)-202] (Scheme [27a]).[98] The Stara team’s study was the first to show that a [1,2]-Stevens rearrangement/Hofmann-type elimination cascade reaction could be intentionally useful for the synthesis of polycyclic aromatics systems. However, the process was not shown to be general. They noted that, with regard to the [1,2]-Stevens rearrangement event, the binaphthyl derivatives 192 were several orders of magnitude more reactive than the biphenyl derivative 177. This emphasized the need for the development of general conditions to convert biaryl-linked azepines and azepiniums into polycyclic aromatics.

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Scheme 27 Cascade reactions involving [1,2]-Stevens rearrangement/Hofmann-type elimination sequences to prepare polycyclic aromatics

Based on the observation that biaryl-linked azepine 184 can be converted into phenanthrene 189 (Scheme [25c]), we posited that polarized, pyridyl-containing substrates might be better suited to undergo the cascade process involving amine methylation/[1,2]-Stevens rearrangement/and Hofmann-type elimination events as promoted by trimethyl phosphate.[97] We proposed that substituted benzo[h]quinoline-containing natural products, such as toddaquinoline (203), could be prepared in a concise manner using this strategy (Scheme [27b]). Accordingly, we optimized the deaminative contraction reaction using excess trimethyl phosphate to show that benzo[h]quinoline (206) can be formed in up to 40% isolated yield. In this study, we demonstrated that the transformation likely involves amine methylation/[1,2]-Stevens rearrangement/and Hofmann-type elimination events (Scheme [27c]).[99] However, the benzo[h]quinoline substrate scope was limited, low yielding in some cases, and the analogous transformation toward 1,10-phenanthroline produced 4-methyl-1,10-phenanthroline (209), exclusively. We proposed 4-methyl-1,10-phenanthroline (209) derives from intermediate ammonium ylide 208 that undergoes a 2nd [1,2]-Stevens rearrangement prior to a Hofmann-type elimination. Overall, understanding the conditions and mechanisms of this amine methylation/[1,2]-Stevens rearrangement/and Hofmann-type elimination process enabled the development of unique conditions to transform cyclic tertiary amines into polycyclic aromatics. This suggests that other ‘hidden’ [1,2]-Stevens rearrangement/Hofmann-type elimination pathways may be useful in settings where deaminative contractions are desired.


#
# 5

Conclusions

In recent years, ammonium ylide based [2,3]-sigmatropic rearrangements and [1,2]-Stevens rearrangements have seen significant use for the targeted synthesis of natural products. Perhaps due to the predictable reactivity, ammonium ylide based [2,3]-sigmatropic rearrangements found more frequent and rudimentary application for the synthesis of α-allyl proline derivatives used to complete formal syntheses of (±)-cephalotaxine and ent-cephalotaxine. The latter development by the Somfai team is notable in that ammonium ylide formation derives from a bicyclic oxazaborolidine intermediate, enabling exceptional nitrogen to α-carbon chirality transfer, and generates a rearranged secondary amine as opposed to the conventional tertiary amine product. In more advanced settings, ammonium ylide based [2,3]-sigmatropic rearrangements were used to complete total syntheses of (±)-amathaspiramide F, (–)-cephalezomine G, (±)-strictamine, and (–)-doxycycline. Soheili and Tambar uncovered ortho-substitution as a handle for stereocontrol in ammonium ylide based [2,3]-sigmatropic rearrangements toward the synthesis of (±)-amathaspiramide F. Building on advances by Soheili and Tambar, Kim and co-workers developed conditions to achieve diastereoselective N-allylation and show how chirality can be efficiently transferred from nitrogen to carbon via a [2,3]-sigmatropic rearrangement en route to (–)-cephalezomine G. Most notably, Myers’ synthesis of (–)-doxycycline, and Gaich’s synthesis of (±)-strictamine, demonstrate the utility of ammonium ylide based [2,3]-rearrangements as key structure-transforming events in bridged bicyclic ammonium ylide settings. Strategic application of [1,2]-Stevens­ rearrangements used to convert spirocyclic ammonium ylides by ring contraction en route into polycyclic natural products, (±)-tylophorine, (±)-7-methoxycryptopleurine, (±)-xylopinine, and other structurally related alkaloids have been demonstrated. A ring contracting [1,2]-Stevens rearrangement was instrumental in enabling the enantio­selective syntheses of several iboga alkaloids and (+)-vinblastine. This development is notable as the first demonstration of a secondary amine catalyzed [1,2]-Stevens rearrangement, which likely proceeds via the intermediacy of an enamine. We also highlighted more recent ammonium ylide based [2,3]-sigmatropic rearrangement and [1,2]-Stevens rearrangement reactions in development that may enable new strategies to prepare polycyclic alkaloids. These include developments led by He, Qiu, Zhang, and co-workers to access tricyclic tertiary amine containing scaffolds via a tandem cyclopropyl ring expansion/[2,3]-sigmatropic rearrangement, and our own efforts toward polycyclic aromatic natural products via deaminative contraction chemistry that involves sequential amine methylation/[1,2]-Stevens rearrangement/and Hofmann-type elimination events. Overall, it is clear that ammonium ylide based [2,3]-sigmatropic and [1,2]-Stevens rearrangements[103] have proven significant utility over the years as reliable and effective transformations that embrace the reactivity of amines and ammoniums to enable creative natural product syntheses.


#
#

Conflict of Interest

The authors declare no conflict of interest.

Acknowledgment

We thank Dr. Daler Baidilov for directing our attention to several key references during the preparation of this review. We thank Dr. Joel M. Smith (Florida State University) for helpful discussions.


Corresponding Author

Andrew G. Roberts
Department of Chemistry, University of Utah
315 South 1400 East, Salt Lake City, Utah 84112
USA   

Publication History

Received: 05 February 2023

Accepted after revision: 23 March 2023

Article published online:
04 May 2023

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Pictured from left to rightZachary Schwartz, Myles Lovasz, Chelsea Valiton, and Andrew G. Roberts Andrew G. Roberts was born and raised in Long Beach, California. He earned his B.S. Chemistry degree in 2008 from UC San Diego where he first learned organic synthesis with Dr. Haim Weizman in the Tor laboratory. Andrew then conducted his Ph.D. thesis research concerning the total chemical synthesis of dimeric pyrrole–imidazole alkaloid natural products with Prof. Patrick G. Harran at UC Los Angeles (Ph.D. Chemistry, 2013). These bioactive and synthetically challenging molecules enabled the development of chemical methods for guanidine synthesis and manipulation. He went on to address questions at the interface of synthetic protein chemistry and cancer biology as an NIH postdoctoral fellow with Prof. Samuel J. Danishefsky at Memorial Sloan Kettering Cancer Center. At MSKCC Andrew collaborated with two teams to complete the chemical protein synthesis and evaluation of granulocyte colony-stimulating factor (G-CSF) and oncogenic KRas(G12V) proteins. Research in the Roberts laboratory at the University of Utah, Department of Chemistry, is focused on the synthesis of structure-stabilized peptide therapeutics and the development of novel amine-derived rearrangement and deaminative reactions to enable the total synthesis of bioactive natural products.
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Scheme 1 The [1,2]-Stevens rearrangement and [2,3]-sigmatropic rearrangement of ammonium ylides
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Scheme 2 Cephalotaxine alkaloids as motivating targets for the development of ammonium ylide based rearrangement approaches
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Scheme 3 Yang and Liu’s approach to (±)-cephalotaxine
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Scheme 4 Yang and Liu’s formal total synthesis of (±)-cephalotaxine
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Scheme 5 Zhang’s approach to (±)-cephalotaxine
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Scheme 6 The Somfai team’s synthesis of ent-cephalotaxine
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Scheme 7 Somfai’s tandem Parham cyclization/aldol condensation strategy to access ent-cephalotaxine
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Scheme 8 Soheili and Tambar’s retrosynthesis of (±)-amathaspiramide F
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Scheme 9 Soheili and Tambar uncover the impact of ortho-substitution on ammonium ylide based [2,3]-sigmatropic rearrangements
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Scheme 10 Soheili and Tambar’s synthesis of (±)-amathaspiramide F
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Scheme 11 The Kim team’s retrosynthetic analysis of (–)-cephalezomine G accounts for a structural revision
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Scheme 12 Kim’s [2,3]-sigmatropic rearrangement strategy en route to (–)-cephalezomine G
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Scheme 13 Kim’s total synthesis of (–)-cephalezomine G
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Scheme 14 The Gaich group’s retrosynthetic analysis of (±)-strictamine
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Scheme 15 The Gaich group’s total synthesis of (±)-strictamine
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Scheme 16 Myers’ [2,3]-rearrangement approach to (–)-doxycycline
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Scheme 17 Retrosynthetic analyses of (±)-tylophorine and (±)-7-methoxycryptopleurine unveil ring-expanding [1,2]-Stevens rearrangements
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Scheme 18 The Opatz and Ho syntheses of (±)-tylophorine
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Scheme 19 The Opatz team’s syntheses of (±)-7-methoxycryptopleurine and (±)-xylopinine
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Scheme 20 Luo’s retrosynthetic analysis of iboga alkaloids
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Scheme 21 A platform for the enantioselective syntheses of iboga alkaloids and a proposal for an organocatalyzed [1,2]-Stevens rearrangement
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Scheme 22 Iboga alkaloids accessible from a key intermediate and a one-pot Au-catalyzed oxidation/cyclization/[1,2]-shift used en route to (+)-dihydrocatharanthine and (+)-vinblastine
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Scheme 23 Ammonium ylide based [2,3]-sigmatropic rearrangement approach to allyl and allenyl-bearing chiral indolizidines
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Scheme 24 The Roberts team’s deaminative contraction strategy to access phenanthrene- and dihydrophenanthrene-containing natural products
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Scheme 25 The Roberts team discovers a methylation-induced/[1,2]-Stevens rearrangement/Hofmann-type elimination cascade reaction
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Scheme 26 [1,2]-Stevens rearrangements of bridged biaryl azepiniums
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Scheme 27 Cascade reactions involving [1,2]-Stevens rearrangement/Hofmann-type elimination sequences to prepare polycyclic aromatics