Skip to main content
NCBI home page
ACS AuthorChoice logoLink to ACS AuthorChoice
. 2023 Jun 16;145(25):14124–14132. doi: 10.1021/jacs.3c04582

De Novo Synthesis of Dihydrobenzofurans and Indolines and Its Application to a Modular, Asymmetric Synthesis of Beraprost

Ze-Shu Wang 1, Steven H Bennett 1, Bilal Kicin 1, Changcheng Jing 1, Johan A Pradeilles 1, Karen Thai 1, James R Smith 1, P David Bacoş 1, Valerio Fasano 1, Carla M Saunders 1, Varinder K Aggarwal 1,*
PMCID: PMC10311537  PMID: 37326516

Abstract

graphic file with name ja3c04582_0010.jpg

Dihydrobenzofurans and indolines are important constituents of pharmaceuticals. Herein, we describe a novel strategy for their construction in which the aromatic ring is created de novo through an inverse-electron demand Diels–Alder reaction and cheletropic extrusion sequence of a 2-halothiophene-1,1-dioxide with an enol ether/enamide, followed by aromatization. Unusually, the aromatization process proved to be highly challenging, but it was discovered that treatment of the halocyclohexadienes with a base effected an α-elimination–aromatization reaction. Mechanistic investigation of this step using deuterium-labeling studies indicated the intermediacy of a carbene which undergoes a 1,2-hydrogen shift and subsequent aromatization. The methodology was applied to a modular and stereoselective total synthesis of the antiplatelet drug beraprost in only 8 steps from a key enal-lactone. This lactone provided the core of beraprost to which both its sidechains could be appended through a 1,4-conjugate addition process (lower ω-sidechain), followed by de novo construction of beraprost’s dihydrobenzofuran (upper α-sidechain) using our newly developed methodology. Additionally, we have demonstrated the breadth of our newly established protocol in the synthesis of functionalized indolines, which occurred with high levels of regiocontrol. According to density-functional theory (DFT) calculations, the high selectivity originates from attractive London dispersion interactions in the TS of the Diels–Alder reaction.

Introduction

Pulmonary arterial hypertension (PAH) is a rare and incurable cardiovascular disease (CVD) that is characterized by high blood pressure in the arteries of the lungs, which ultimately leads to right ventricular heart failure and premature death.1 Typical treatment for this life-threatening illness involves the administration of the potent anti-hypertensive, prostacyclin (PGI2, epoprostenol, 2).2 Unfortunately, due to the short metabolic half-life of PGI2 in blood (t1/2 = 3–6 min)3 continuous intravenous (IV) infusion is required.2 To address the practical issues associated with such treatment, a number of more stable PGI2 analogues have been developed, e.g., cicaprost,4 iloprost5 and more recently, beraprost (1)6 (Figure 1).

Figure 1.

Figure 1

Open in a new tab

Structural comparison of beraprost (1) vs prostacyclin (PGI2, 2).

Beraprost (beraprost sodium, 1)7 is a more stable (t1/2 = 60 min) and less cytotoxic prostacyclin analogue and can be administered orally. It has been used successfully in the treatment of peripheral arterial disease (Buerger’s disease and arteriosclerosis obliterans) and shows promise as a potential therapeutic for the treatment of PAH due to its ability to drastically reduce pulmonary arterial pressure and resistance.7

Most strategies for the enantioselective synthesis of beraprost have focused on using either resolution strategies,8 or the enantiopure (−)-Corey lactone.9 Recently, Hayashi,10 reported an asymmetric organocatalytic synthesis of beraprost through a formal [3+2] cycloaddition reaction catalyzed by diphenylprolinol silyl ether as the key step to construct the cyclopentane core.11 We have previously reported enantioselective syntheses of several prostanoids from enal-lactone 7 (or the related hemi-acetal), which is prepared by a stereocontrolled organocatalytic dimerization of succinaldehyde in 3 steps with >99% e.e.12 We were keen to broaden the reach of this chemistry further and now report its use in a 14 step [longest linear sequence (LLS)] synthesis of beraprost. Furthermore, during the course of the synthesis, we discovered a conceptually novel route to access dihydrobenzofurans, which we demonstrate is more general and can also be applied to the de novo synthesis of indolines.

Retrosynthetic Analysis

In terms of retrosynthesis, we envisaged a modular approach involving three key building blocks: enal-lactone 7, upper α-sidechain 4, and lower ω-sidechain 6. The upper α-sidechain was proposed to be installed through an inverse-electron demand Diels–Alder reaction (IEDDA) between enol ether 5 and thiophene-1,1-dioxide 4, followed by cheletropic extrusion of SO2. Subsequent dehalogenation and aromatization would furnish beraprost’s dihydrobenzofuran core. The lower ω-sidechain could be introduced through a 1,4-conjugate addition of vinyl iodide 6 and key enal-lactone 7 (Scheme 1). A critical issue that we were uncertain about initially was the regiochemistry of the IEDDA process, as most Diels–Alder reactions of thiophene 1,1-dioxides use symmetrical substrates.13a−13d Additionally, monosubstituted thiophene 1,1-dioxides are known to be unstable and prone to rapid cyclodimerization.13e,13f We therefore decided to introduce a halogen substituent in the 2-position to stabilize the thiophene 1,1-dioxide, which, in addition, would also lower the LUMO of the diene for the IEDDA.14 Such a substituent would also be easily removable at a later stage.

Scheme 1. Proposed Modular Retrosynthetic Analysis of Beraprost.

Scheme 1

Open in a new tab

Results and Discussion

Asymmetric Synthesis of Beraprost

Starting from commercially available thiophene 8, we prepared thiophene 1,1-dioxide 4 in two steps following a regioselective chlorination using N-chlorosuccinimide (NCS) and subsequent oxidation with meta-chloroperoxybenzoic acid (m-CPBA) (Scheme 2a). This afforded the desired upper α-sidechain in 51% yield on a gram scale. The lower ω-sidechain (Scheme 2b) required for 1,4-conjugate addition was prepared from ynal 10,15 which itself could be synthesized on a decagram scale from (triethylsilyl)acetylene. Ynal 10 readily underwent a prolinol-catalyzed aldol reaction with propionaldehyde,16 followed by in situ reduction with NaBH4 to give diol 12 with near-perfect enantioselectivity (98.5:1.5 e.r.) and high diastereoselectivity (9.1:1 d.r.) that was improved to >95:5 d.r. following flash column chromatography. The primary alcohol of diol 12 was then selectively transformed into a triflate and the remaining secondary alcohol was protected as its corresponding tert-butylsilyl (TBS) ether. This allowed for the selective substitution of the triflate with propynyllithium to afford di-alkyne 13 in 51% over two steps. Subsequent alkyne deprotection under basic conditions followed by hydrozirconation/iodination of the resultant terminal alkyne produced vinyl iodide 6 in 37% over two steps.

Scheme 2. Modular Asymmetric Synthesis of Beraprost.

Scheme 2

Open in a new tab

Following gram-scale synthesis of enal-lactone 7,12b and with vinyl iodide 6 in hand, the 1,4-conjugate addition of in situ-generated higher-order cyanocuprate 14 was performed (Scheme 2c). Following 1,4-addition onto the enal of 7 and trapping with trimethylsilyl chloride (TMSCl), a TMS enol ether was produced, which was perfectly set up to undergo selective ozonolysis of the more electron-rich alkene. Subsequent reductive work-up with NaBH4 and TBSCl protection delivered protected secondary alcohol 15 in 41% yield over 3 steps as a single diastereomer. The high stereocontrol observed in this sequence is a consequence of the convex shape of enal-lactone 7, which favors attack from the more exposed exo face (see the X-ray structure). The lactone moiety of 15 was reduced with DIBAL-H to give a hemiacetal, which, following mesylation and subsequent heating under reflux, underwent elimination to produce enol ether 5 in 60% yield over 2 steps. Heating enol ether 5 in the presence of thiophene 1,1-dioxide 4 and 2,6-lutidine effected the desired IEDDA/cheletropic extrusion process giving chlorocyclohexadiene 3 in 49% yield and 4.4:1 regioisomeric ratio (r.r.). We believe the selectivity is controlled by steric repulsion between the two long linear sidechains rather than by any possible electronic effects (vide infra). Indeed, the more hindered t-Bu ester of thiophene 1,1-dioxide 4 gave the corresponding chlorocyclohexadiene with an improved 5.2:1 r.r. The success of the IEDDA reaction provided vindication of our strategy since we were only a few steps from beraprost. However, the seemingly facile oxidation of the diene to the aromatic ring, which can often occur spontaneously in air,17 was unexpectedly found to be the most challenging step in the synthesis.

Dehalogenation–Aromatization of the Model System

To further explore and optimize our dehalogenation–aromatization step, we used the simple model compounds 20a–c, prepared from cycloaddition of (−)-Corey lactone derived enol ether 18 with various thiophene-1,1-dioxides in moderate regioselectivity (20a, 3.5:1 r.r.; 20b, 4.6:1 r.r.; 20c, 4.0:1 r.r.) (Scheme 2d). We initially tested the bromo-diene and tert-butyl protected ester form (20a), which we believed would be easier to guide our initial efforts toward aromatization. At first, we focused on the use of palladium or platinum catalysis to effect simultaneous aromatization and dehalogenation (a redox neutral process), but unfortunately, we observed decomposition under the majority of conditions.9,18 No aromatization was observed under a number of other conditions: DBU/air,19 DDQ,20 KMnO4·Al2O3,21 MnO2,22 and PdCl2/HSi(OEt)3.23 In fact, in many cases, aromatization by elimination of the alcohol occurred rather than oxidation.24 Indeed, a survey of the literature revealed that similar cis-fused 5,6-cyclohexadiene ring systems often show remarkable resistance toward aromatization, requiring either novel strategies25a or harsh conditions25b,25c to effect the transformation. Furthermore, our system incorporated an additional steric challenge with the ring-junction hydrogens presenting into the concave face of the molecule, making their removal more difficult. At this point, we wanted to determine if the halogen (bromide) was somehow inhibiting aromatization and as such sought the bromide-free cyclohexadiene. Thus, bromocyclohexadiene 20a was subjected to a lithium–halogen exchange reaction using 2.0 equiv of tert-butyllithium (t-BuLi) in THF at −78 °C, followed by quenching with MeOH. However, surprisingly, the expected lithium–halogen exchange product was not observed. Instead, the highly sought-after aromatic product 21a was found in 7% yield alongside the tert-butyl ketone derivative 22, formed by over-reaction of the excess t-BuLi (Table 1, entry 1).

Table 1. Optimization of the Dehalogenation–Aromatization Model Reactiona.

graphic file with name ja3c04582_0008.jpg

      yield (%)b
entry substrate t-BuLi (equiv) 20 21 22
1 20a (R = R’ = t-Bu, X = Br) 2.0 29 7 2
2c 20a (R = R′ = t-Bu, X = Br) 2.0 21 21 8
3c,d 20a (R = R′ = t-Bu, X = Br) 3.0 23 33 13
4c,d 20b (R = R′ = t-Bu, X = Cl) 3.0 0 56 32
5c,d 20c (R = H, R′ = t-Bu, X = Cl) 4.0 20 38 N/A
6c 20c (R = H, R′ = t-Bu, X = Cl) 4.0 trace 66e N/A
7c 20c (R = H, R′ = t-Bu, X = Cl) 3.0 trace 49e N/A
8c 20c (R = H, R′ = t-Bu, X = Cl) n-BuLi (4.0) 59e 0 N/A
9c 20c (R = H, R′ = t-Bu, X = CI) s-BuLi (4.0) trace 60e N/A
Open in a new tab
a

Reaction conditions: 20 (0.05 mmol), THF (0.5 mL).

b

Measured by 1H NMR spectroscopy using 1,3,5-trimethoxybenzene as an internal standard.

c

n-hexane:THF (95:5) was used instead of THF.

d

Inverse addition of lithium reagent was operated.

e

Isolated yields.

Optimization of Dehalogenation–Aromatization and Completion of the Synthesis

This discovery provided a potential solution to our problem and so we set about optimizing the process. Through optimization, we found that our desired aromatic product could be obtained in increasing yield by (i) switching from THF to a cosolvent system of n-hexane:THF (95:5) (entry 2), (ii) increasing the equivalents of t-BuLi (entry 3), and (iii) replacing the bromide with a chloride (entry 4). This afforded a 56% yield of the desired product but together with an increased 32% yield of the undesired tert-butyl ketone product. Using the carboxylic acid instead of the ester, the undesired tert-butyl ketone product could be avoided, giving the desired aromatic product in 66% yield (entry 6). Finally, n-BuLi and s-BuLi were both tested under the optimized conditions (entries 8 and 9) with only s-BuLi providing the desired compound in a slightly reduced yield compared to t-BuLi (60 vs 66%). Applying these optimized conditions to our total synthesis worked effectively, and the desired aromatic product 16 was obtained in 77% yield (Scheme 2c). Finally, treatment with TBAF effected deprotection of the TBS groups and afforded beraprost 1 in only 8 steps from enal-lactone 7 (14 steps LLS).

Mechanistic Studies of Aromatization

Having completed the total synthesis, we wanted to understand the mechanism of the intriguing dehalogenation–aromatization process and in particular the fate of the two hydrogen atoms at the pre-aromatized ring junction (Scheme 3a). Thus, mono-deuterated chlorocyclohexadienes 23a and 23b were prepared (see the Supporting Information for details), and each was treated with t-BuLi under the optimized reaction conditions. Chlorocyclohexadiene 23a gave aromatized product 24 with complete incorporation of deuterium into the aromatic ring. In contrast, no deuteration was observed when isomer 23b was used nor when the reaction was quenched with methanol-d4. The 1,2-hydrogen atom shift that clearly occurred is likely to have resulted from the intermediacy of a carbene species.

Scheme 3. Mechanistic Studies of Aromatization.

Scheme 3

Open in a new tab

Such a species could arise from an ether-directed deprotonation [complex-induced proximity effect (CIPE)] to give 27/28 followed by α-elimination to form carbene intermediate 29 (Scheme 3b).26 The energy barrier for the resultant 1,2-hydrogen shift of this carbene was calculated to be almost barrierless (1 kcal mol–1), which would make deprotonation the slowest step along this pathway. The fact that the chloride gave higher yields than the bromide suggests that lithium–halogen exchange, which would be more efficient with the bromide, is unlikely to be involved. Improved results using non-coordinating solvents also point to the importance of a complex-induced proximity effect to both break up any organolithium aggregates and direct deprotonation adjacent to the ether. The observation that s-BuLi was less effective and n-BuLi was ineffective to producing the desired aromatic product provides further evidence for our proposed mechanism since the reactivity of the various alkyllithiums to effect α-ether deprotonation decreases in the order of t-BuLi > s-BuLi ≫ n-BuLi.27

Modular Synthesis of Functionalized Indolines

We wanted to explore the generality of the novel IEDDA/cheletropic extrusion and dehalogenation–aromatization process, in particular to determine whether it could be applied to the synthesis of the all-important indoline skeletons as well. In fact, this methodology could prove valuable in the synthesis of C-4/C-7 functionalized indoline scaffolds, which are commonly found in natural products and medicinal chemistry programs.28 Most strategies for the synthesis of indolines focus either on the reduction of indoles or the synthesis of the 5-membered nitrogen heterocycle.29 Very few of these approaches target the aromatic ring, which would allow for a greater degree of modularity to be accessed in the synthesis of these important scaffolds.

The reaction of symmetrical 2,5-dihalogenated thiophene 1,1-dioxides 32a/b with N-Boc-2,3-dihydropyrrole 31 gave di-halodienes 33a/b in almost quantitative yield (Scheme 4).

Scheme 4. Synthesis of Mono- and Di-Halodienes and Their Selective Dehalogenation– or Detosylation–Aromatization Reactions.

Scheme 4

Open in a new tab

However, while subsequent treatment with t-BuLi led to a complex mixture, we found that reaction with potassium tert-butoxide (KOt-Bu) was able to effect dehalogenation–aromatization. In contrast to the dihydrofuran cycloadducts where deprotonation occurred adjacent to the oxygen, in this case, the proton distal to the nitrogen was removed giving 4-bromoindoline 34a in good yield and as a single regioisomer (Scheme 4). The chlorodiene 33b also worked equally well, giving 34b as a single regioisomer. Using N-Ts-2,3-dihydropyrrole 35, a different pathway for elimination–aromatization was available, enabling us to retain both halogens. Thus, following another high yielding IEDDA/cheletropic extrusion, cycloadducts 36a/b, were obtained in 92% yield. Treatment with KOt-Bu now resulted in elimination of the tosyl group and led to dibromo- and dichloroindoline 37a and 37b in 61 and 59% yield, respectively. It is noteworthy that in the two substrate classes a different proton is removed: with 33a/b the proton distal to the N-Boc group (blue proton) is removed, whereas in the case of the 36a/b, it is the proton proximal to the N-Ts group (red proton) that is removed.

Finally, we explored the IEDDA/cheletropic extrusion of unsymmetrical thiophene 1,1-dioxides 19a/b with N-Boc-2,3-dihydropyrrole 31 and N-Ts-2,3-dihydropyrrole 35. Surprisingly, in each case, this gave the adduct with high regioselectivity in which the alkyl chain was syn to the N-Boc/N-Ts group (the more hindered adduct). Subsequent treatment of cycloadducts 38a/b with KOt-Bu unfortunately resulted in substantial quantities of elimination of the N-Boc group, likely due to the fact that the proton distal to the N-Boc group (blue proton) would be preferentially removed, by analogy with substrate 33a/b. A brief optimization revealed that increased preference for the desired dehalogenation–aromatization process was observed in non-polar solvents and that the bromide behaved better than the chloride giving indoline 39 in 42% yield. A Similar treatment of cycloadduct 40 with KOt-Bu also resulted in competing elimination, but nevertheless, elimination of the tosyl group followed by tautomerization and intramolecular amidation delivered aza-tricycle 41 in 44% yield. It is notable that such aza-tricyclic skeletons are prevalent in many natural products and bioactive molecules.30

Computational Studies of Regioselective IEDDA

The high regioselectivity observed in the IEDDA/cheletropic extrusion in favor of the more hindered adduct was unexpected and so we performed computational analysis to try to understand the origin of the selectivity. One possibility was that the cycloaddition was governed by electronic factors in which the polarity of the HOMO of the enamide matched the polarity of the LUMO of the diene. However, frontier molecular orbital calculations31 on a model dienophile, N-CO2Me-2,3-dihydro-1H-pyrrole (truncated 31), and model dienes, 2-methyl-5-halothiophene 1,1-dioxide, 42a/b (truncated 19a/b), showed that the LUMO lobes of the unsymmetrical diene, despite having very different electron donating and withdrawing groups attached, had similar coefficients at the two ends, indicating that there would be no preferred orientation, which can be seen when visualizing the relevant orbitals (Scheme 5a). Modeling the cycloaddition reaction between 31 and the same diene 42b gave rise to two endo TSs (we established that the endo TSs were lower than the exo TSs in the reaction of diene 42b with dihydrofuran – see ESI) in which the one where the Boc group was syn to the alkyl chain, leading to the observed and more hindered product, was 0.9 kcal mol–1 lower in energy than the alternative where the Boc group was anti to the alkyl chain (Scheme 5b). This was not enough to account for the experimental selectivity seen, and so the endo TSs for the full system, 19a/b as the diene and 31 as the dienophile, were modeled. They now showed a substantial difference in energy of ∼3.5 kcal mol–1 when London dispersion interactions were included. The London dispersion interactions were found to have contributed between 0.6 and 3.9 kcal mol–1, depending on the level of theory with which they were studied. This suggests that a significant portion of the selectivity can be accounted for by London dispersion interactions, stabilizing the former TS (Scheme 5d), which is not present in the transition state with truncated diene 2-methyl-5-chlorothiophene 1,1-dioxide 42b. This was verified experimentally: using smaller substituents on the diene (Me, Et) in place of the longer propanyl ester led to progressively lower regioselectivity (Scheme 5e). It may seem unusual that LD interactions could lead to such high selectivity, but there are numerous cases where it is surprisingly large and can dominate selectivity.33,34 Our observations add to the growing recognition of the importance of London dispersion interactions contributing to selectivity in chemical reactions.33

Scheme 5. Computational Studies of Regioselective IEDDA.

Scheme 5

Open in a new tab

(a) Frontier molecular orbital energies and coefficients (HF/6-31G). The lobes of reacting orbital coefficients are expected to match in magnitude to have a good overlap for reactivity. (b) Reaction energies for the cycloaddition reaction with dihydropyrrole. (c) Reaction energies for the cycloaddition reaction with 19a/19b. (d) Plot of noncovalent interactions (NCI)32 showing the weakly attractive van der Waals interaction consistent with LD forces in the TS of major isomer formation, which is absent in the TS of minor isomer formation (B3LYP/6-31G* with D3 dispersion correction and PCM solvation for dichloroethane). Dashed green lines have been included to indicate the location of the surfaces between the bulky alkyl groups. (e) Experiments of regioselective IEDDA.

Conclusions

In conclusion, we have developed a highly stereoselective and modular synthesis of the potent anti-platelet agent, beraprost, in only 14 steps (LLS) in >99% e.e. The two sidechains of beraprost were readily introduced through a 1,4-conjugate addition of a higher-order cyanocuprate and a powerful IEDDA/cheletropic extrusion process, which produced a chloro-diene system that set the stage for a unique dehalogenation–aromatization reaction using t-BuLi. The chloride present in the thiophene 1,1-dioxide served a dual role: it inhibited cyclodimerization of the thiophene 1,1-dioxide and enabled a unique dehalogenation–aromatization. Mechanistic analysis of this step through deuterium-labeling studies showed the intermediacy of a carbene which underwent an aromatizing 1,2-hydrogen shift. Finally, we showed the applicability of our IEDDA/cheletropic extrusion and dehalogenation–aromatization process to the synthesis of indolines. Reaction of symmetrical 2,5-dihalogenated thiophene 1,1-dioxides and 2,3-dihydropyrroles gave cycloadducts which underwent selective elimination–aromatization to afford either C-4 halogenated indolines or C-4/C-7 dihaloindolines depending on the nature of the nitrogen protecting group. Using nonsymmetric 2-halo,5-alkyl thiophene 1,1-dioxides with 2,3-dihydropyrroles gave cycloadducts with high regioselectivity. Subsequent dehalogenation–aromatization then gave the C-7 indoline, providing a unique and modular approach to these medicinally relevant scaffolds.

Acknowledgments

We thank EPSRC (EP/M012530/1) for financial support. V.F. thanks the University of Bristol for awarding the EPSRC Doctoral Prize Fellowship (EP/R513179/1). Z.-S.W. thanks the Foundation of Wenzhou Science and Technology Bureau (No. ZY2020027) for financial support. We thank Dr. Hazel A. Sparkes and Dr. Natalie E. Pridmore for X-ray analysis and Dr. Natalie Fey for helpful discussions of the computational results. This work was carried out using the computational facilities of the Advanced Computing Research Centre, University of Bristol - http://www.bristol.ac.uk/acrc/.

Supporting Information Available

The Supporting Information is available free of charge at https://pubs.acs.org/doi/10.1021/jacs.3c04582.

  • Experimental procedures, spectroscopic data (1H NMR, 13C NMR, IR, HRMS) (PDF)

  • Geometry coordinates for calculated structures (XYZ)

Author Contributions

§ Z.-S.W., S.H.B., and B.K. contributed equally to this work.

The authors declare no competing financial interest.

Supplementary Material

ja3c04582_si_001.pdf (9.7MB, pdf)
ja3c04582_si_002.xyz (35.5KB, xyz)

References

  1. a Galiè N.; Torbicki A.; Barst R.; Dartevelle P.; Haworth S.; Higenbottam T.; Olschewski H.; Peacock A.; Pietra G.; Rubin L. J.; Simonneau G. Guidelines on diagnosis and treatment of pulmonary arterial hypertension: The Task Force on Diagnosis and Treatment of Pulmonary Arterial Hypertension of the European Society of Cardiology. Eur. Heart J. 2004, 25, 2243–2278. 10.1016/j.ehj.2004.09.014. [DOI] [PubMed] [Google Scholar]; b Ruan C.-H.; Dixon R. A. F.; Willerson J. T.; Ruan K.-H. Prostacyclin Therapy for Pulmonary Arterial Hypertension. Tex. Heart Inst. J. 2010, 37, 391–399. [PMC free article] [PubMed] [Google Scholar]
  2. Sitbon O.; Noordegraaf A. V. Epoprostenol and Pulmonary Arterial Hypertension: 20 Years of Clinical Experience. Eur. Respir. Rev. 2017, 26, 160055–160069. 10.1183/16000617.0055-2016. [DOI] [PMC free article] [PubMed] [Google Scholar]
  3. a Lucas F. V.; Skrinska V. A.; Chisolm G. M.; Hesse B. L. Stability of Prostacyclin in Human and Rabbit Whole Blood and Plasma. Thromb. Res. 1986, 43, 379–387. 10.1016/0049-3848(86)90082-4. [DOI] [PubMed] [Google Scholar]; b Wong P. Y.; Lee W. H.; Chao P. H.; Reiss R. F.; McGiff J. C. Metabolism of Prostacyclin by 9-Hydroxyprostaglandin Dehydrogenase in Human Platelets. Formation of a Potent Inhibitor of Platelet Aggregation and Enzyme Purification. J. Biol. Chem. 1980, 255, 9021–9024. 10.1016/S0021-9258(19)70518-3. [DOI] [PubMed] [Google Scholar]
  4. Belch J. J. F.; McLaren M.; Lau C. S.; Mackay I. R.; Bancroft A.; McEwen J.; Thompson J. M. Cicaprost, an Orally Active Prostacyclin Analogue: Its Effects on Platelet Aggregation and Skin Blood Flow in Normal Volunteers. Br. J. Clin. Pharmacol. 1993, 35, 643–647. 10.1111/j.1365-2125.1993.tb04195.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  5. a Schrör K.; Darius H.; Matzky R.; Ohlendorf R. The Antiplatelet and Cardiovascular Actions of a New Carbacyclin Derivative (ZK 36 374) — Equipotent to PGI2 in Vitro. Naunyn-Schmiedeberg’s Arch. Pharmacol. 1981, 316, 252–255. 10.1007/BF00505658. [DOI] [PubMed] [Google Scholar]; b Casals-Stenzel J.; Buse M.; Losert W. Comparison of the Vasodepressor Action of ZK 36 374, a Stable Prostacyclin Derivative, PGI2 And PGE1 with Their Effect on Platelet Aggregation and Bleeding Time in Rats. Prostaglandins, Leukotrienes Med. 1983, 10, 197–212. 10.1016/S0262-1746(83)80010-9. [DOI] [PubMed] [Google Scholar]
  6. a Bannai K.; Toru T.; O̅ba T.; Tanaka T.; Okamura N.; Watanabe K.; Hazato A.; Kurozumi S. Synthesis of Chemically Stable Prostacyclin Analogs. Tetrahedron 1983, 39, 3807–3819. 10.1016/S0040-4020(01)88623-3. [DOI] [Google Scholar]; b Bannai K.; Toru T.; O̅ba T.; Tanaka T.; Okamura N.; Watanabe K.; Hazato A.; Kurozumi S. Synthesis of Chemically Stable PGI2 Analogs II - Synthesis of Halogen Substituted PGI2 Analogs. Tetrahedron 1986, 42, 6735–6746. 10.1016/S0040-4020(01)82114-1. [DOI] [Google Scholar]; c Skuballa W.; Schillinger E.; Stürzbecher C. S.; Vorbrüggen H. Prostaglandin Analogs. Part 9. Synthesis of a New Chemically and Metabolically Stable Prostacyclin Analog with High and Long-Lasting Oral Activity. J. Med. Chem. 1986, 29, 313–315. 10.1021/jm00153a001. [DOI] [PubMed] [Google Scholar]; d Nakano T.; Makino M.; Morizawa Y.; Matsumura Y. Synthesis of Novel Difluoroprostacyclin Derivatives: Unprecedented Stabilizing Effect of Fluorine Substituents. Angew. Chem., Int. Ed. 1996, 35, 1019–1021. 10.1002/anie.199610191. [DOI] [Google Scholar]
  7. Melian E. B.; Goa K. L. Beraprost. Drugs 2002, 62, 107–133. 10.2165/00003495-200262010-00005. [DOI] [PubMed] [Google Scholar]
  8. a Wakita H.; Yoshiwara H.; Tajima A.; Kitano Y.; Nagase H. Preparative Resolution of a Key Intermediate for the Synthesis of Optically Active m-Phenylene PGI2 Derivatives. Tetrahedron: Asymmetry 1999, 10, 4099–4105. 10.1016/S0957-4166(99)00442-5. [DOI] [Google Scholar]; b Wakita H.; Yoshiwara H.; Nishiyama H.; Nagase H. Total Synthesis of Optically Active m-Phenylene PGl2 Derivative: Beraprost. Heterocycles 2000, 53, 1085–1110. 10.3987/COM-00-8868. [DOI] [Google Scholar]; c Wakita H.; Yoshiwara H.; Kitano Y.; Nishiyama H.; Nagase H. Preparative Resolution of 2-Methyl-4-Hexynic Acid for the Synthesis of Optically Active m-Phenylene PGI2 Derivatives and Determination of Their Absolute Configuration. Tetrahedron: Asymmetry 2000, 11, 2981–2989. 10.1016/S0957-4166(00)00251-2. [DOI] [Google Scholar]; d Reddy K. N.; Vijaykumar B. V. D.; Chandrasekhar S. Formal Synthesis of Antiplatelet Drug, Beraprost. Org. Lett. 2012, 14, 299–301. 10.1021/ol203060v. [DOI] [PubMed] [Google Scholar]
  9. a Liu X.; Tian C.; Jiao X.; Li X.; Yang H.; Yao Y.; Xie P. A Practical Synthesis of Chiral Tricyclic Cyclopenta[b]benzofuran, a Key Intermediate of Beraprost. Org. Biomol. Chem. 2016, 14, 7715. 10.1039/C6OB01346E. [DOI] [PubMed] [Google Scholar]; b Sharma V.; Batra H.; Tuladhar S.. Method of Producing Beraprost. Inter. Pat. Appl. WO2017027706, 20 Dec, 2012.
  10. Umemiya S.; Sakamoto D.; Kawauchi G.; Hayashi Y. Enantioselective Total Synthesis of Beraprost Using Organocatalyst. Org. Lett. 2017, 19, 1112–1115. 10.1021/acs.orglett.7b00134. [DOI] [PubMed] [Google Scholar]
  11. For a recent, transition-metal catalyzed, asymmetric route to construct the cyclopentane core and its applications to prostaglandins, see:; Zhang F.; Zeng J.; Gao M.; Wang L.; Chen G.-Q.; Lu Y.; Zhang X. Concise, Scalable and Enantioselective Total Synthesis of Prostaglandins. Nat. Chem. 2021, 13, 692–697. 10.1038/s41557-021-00706-1. [DOI] [PubMed] [Google Scholar]
  12. a Coulthard G.; Erb W.; Aggarwal V. K. Stereocontrolled Organocatalytic Synthesis of Prostaglandin PGF2α in Seven Steps. Nature 2012, 489, 278–281. 10.1038/nature11411. [DOI] [PubMed] [Google Scholar]; b Prévost S.; Thai K.; Schützenmeister N.; Coulthard G.; Erb W.; Aggarwal V. K. Synthesis of Prostaglandin Analogues, Latanoprost and Bimatoprost, Using Organocatalysis via a Key Bicyclic Enal Intermediate. Org. Lett. 2015, 17, 504–507. 10.1021/ol503520f. [DOI] [PubMed] [Google Scholar]; c Baars H.; Classen M. J.; Aggarwal V. K. Synthesis of Alfaprostol and PGF2α through 1,4-Addition of an Alkyne to an Enal Intermediate as the Key Step. Org. Lett. 2017, 19, 6008–6011. 10.1021/acs.orglett.7b03057. [DOI] [PubMed] [Google Scholar]; d Pelšs A.; Gandhamsetty N.; Smith J. R.; Mailhol D.; Silvi M.; Watson A.; Perez-Powell I.; Prévost S.; Schützenmeister N.; Moore P. R.; Aggarwal V. K. Reoptimization of the Organocatalyzed Double Aldol Domino Process to a Key Enal Intermediate and its Application to the Total Synthesis of Δ12-Prostaglandin J3. Chem. - Eur. J. 2018, 24, 9542–9545. 10.1002/chem.201802498. [DOI] [PMC free article] [PubMed] [Google Scholar]; e Jing C.; Mallah S.; Kriemen E.; Bennett S. H.; Fasano V.; Lennox A. J. J.; Hers I.; Aggarwal V. K. Synthesis, Stability, and Biological Studies of Fluorinated Analogues of Thromboxane A2. ACS Cent. Sci. 2020, 6, 995–1000. 10.1021/acscentsci.0c00310. [DOI] [PMC free article] [PubMed] [Google Scholar]; f Bennett S. H.; Coulthard G.; Aggarwal V. K. Prostaglandin Total Synthesis Enabled by the Organocatalytic Dimerization of Succinaldehyde. Chem. Rec. 2020, 20, 936–947. 10.1002/tcr.202000054. [DOI] [PubMed] [Google Scholar]; g Jing C.; Aggarwal V. K. Total Synthesis of Thromboxane B2 via a Key Bicyclic Enal Intermediate. Org. Lett. 2020, 22, 6505–6509. 10.1021/acs.orglett.0c02299. [DOI] [PubMed] [Google Scholar]; h Bennett S. H.; Aggarwal V. K. Organocatalytic Dimerization of Succinaldehyde. Org. Synth. 2022, 99, 139. 10.15227/orgsyn.099.0139. [DOI] [PubMed] [Google Scholar]
  13. a Bailey W. J.; Cummins E. W. Cyclic Dienes. IV. The Dimierization of Thiophene 1-Dioxide. J. Am. Chem. Soc. 1954, 7, 1936–1939. 10.1021/ja01636a059. [DOI] [Google Scholar]; b Bailey W. J.; Cummins E. W. Cyclic Dienes. V. Diels-Alder Reactions of Thiophene 1-Dioxide. J. Am. Chem. Soc. 1954, 7, 1940–1942. 10.1021/ja01636a060. [DOI] [Google Scholar]; c Nakayama J.; Sugihara Y.. Chemistry of Thiophene 1,1-Dioxides in Organosulfur Chemistry II in Topics in Current Chemistry; Page P. C. B., Ed.; Springer: Berlin, Heidelberg, 1999; Vol. 205, pp 131–195. [Google Scholar]; d Lu Y.; Dong Z.; Wang P.; Zhou H.-B.. Thiophene Oxidation and Reduction Chemistry in Thiophenes in Topics in Heterocyclic Chemistry; Joule J. A., Ed.; Springer: Berlin, Heidelberg, 2015; Vol. 39, pp 227–293. [Google Scholar]; e Miyahara Y.; Inazu T. An Extremely Efficient Synthesis of Thiophene 1,1-Dioxides. Oxidation of Thiophene Derivatives with Dimethyldioxirane. Tetrahedron Lett. 1990, 31, 5955–5958. 10.1016/S0040-4039(00)98003-1. [DOI] [Google Scholar]; f Nakayama J.; Nagasawa H.; Sugihara Y.; Ishii A. Synthesis, Isolation, and Full Characterization of the Parent Thiophene 1,1-Dioxide. J. Am. Chem. Soc. 1997, 119, 9077–9078. 10.1021/ja971934z. [DOI] [Google Scholar]
  14. For impressive recent publications on the use of non-symmetrical thiophene 1,1-dioxides in total synthesis, see:; a Park K. H. K.; Frank N.; Duarte F.; Anderson E. A. Collective Synthesis of Illudalane Sesquiterpenes via Cascade Inverse Electron Demand (4 + 2) Cycloadditions of Thiophene S,S-Dioxides. J. Am. Chem. Soc. 2022, 144, 10017–10024. 10.1021/jacs.2c03304. [DOI] [PMC free article] [PubMed] [Google Scholar]; b Kabuki A.; Yamaguchi J. Formal Syntheses of Dictyodendrins B, C, and E by a Multi-Substituted Indole Synthesis. Synthesis 2022, 54, 4963–4970. 10.1055/a-1786-9881. [DOI] [Google Scholar]
  15. Mukherjee S.; Lee D. Application of Tandem Ring-Closing Enyne Metathesis: Formal Total Synthesis of (−)-Cochleamycin A. Org. Lett. 2009, 11, 2916–2919. 10.1021/ol900923c. [DOI] [PMC free article] [PubMed] [Google Scholar]
  16. Hayashi Y.; Kojima M.; Yasui Y.; Kanda Y.; Mukaiyama T.; Shomura H.; Nakamura D.; Ritmaleni; Sato I. Diarylprolinol in an Asymmetric, Direct Cross-Aldol Reaction with Alkynyl Aldehydes. ChemCatChem 2013, 5, 2887–2892. 10.1002/cctc.201300390. [DOI] [Google Scholar]
  17. Illa O.; Arshad M.; Ros A.; McGarrigle E. M.; Aggarwal V. K. Practical and Highly Selective Sulfur Ylide-Mediated Asymmetric Epoxidations and Aziridinations Using a Cheap and Readily Available Chiral Sulfide. Application to the Total Synthesis of Quinine and Quinidine. J. Am. Chem. Soc. 2010, 132, 1828–1830. 10.1021/ja9100276. [DOI] [PubMed] [Google Scholar]
  18. a Iosub A. V.; Stahl S. S. Palladium-Catalyzed Aerobic Oxidative Dehydrogenation of Cyclohexenes to Substituted Arene Derivatives. J. Am. Chem. Soc. 2015, 137, 3454–3457. 10.1021/ja512770u. [DOI] [PMC free article] [PubMed] [Google Scholar]; b Horrillo-Martínez P.; Virolleaud M.-A.; Jaekel C. Selective Palladium-Catalyzed Dehydrogenation of Limonene to Dimethylstyrene. ChemCatChem 2010, 2, 175–181. 10.1002/cctc.200900200. [DOI] [Google Scholar]
  19. a Ikeda S.-i.; Mori N.; Sato Y. Regioselective Cyclic Cotrimerization of α,β-Enones and Alkynes by a Nickel—Aluminum Catalyst System. J. Am. Chem. Soc. 1997, 119, 4779–4780. 10.1021/ja9704491. [DOI] [Google Scholar]; b Lu Z.; Li Y.; Deng J.; Li A. Total Synthesis of the Daphniphyllum Alkaloid Daphenylline. Nat. Chem. 2013, 5, 679–684. 10.1038/nchem.1694. [DOI] [PubMed] [Google Scholar]
  20. a London G.; von Wantoch Rekowski M.; Dumele O.; Schweizer W. B.; Gisselbrecht J.-P.; Boudon C.; Diederich F. Pentalenes with Novel Topologies: Exploiting the Cascade Carbopalladation Reaction between Alkynes and Gem-Dibromoolefins. Chem. Sci. 2014, 5, 965–972. 10.1039/C3SC52623B. [DOI] [Google Scholar]; b Geist E.; Berneaud-Kötz H.; Baikstis T.; Dräger G.; Kirschning A. Toward Chromanes by de Novo Construction of the Benzene Ring. Org. Lett. 2019, 21, 8930–8933. 10.1021/acs.orglett.9b03209. [DOI] [PubMed] [Google Scholar]
  21. Revés M.; Ferrer C.; León T.; Doran S.; Etayo P.; Vidal-Ferran A.; Riera A.; Verdaguer X. Primary and Secondary Aminophosphines as Novel P-Stereogenic Building Blocks for Ligand Synthesis. Angew. Chem., Int. Ed. 2010, 49, 9452–9455. 10.1002/anie.201004041. [DOI] [PubMed] [Google Scholar]
  22. Mashraqui S.; Keehn P. Active MnO2. Oxidative Dehydrogenations. Synth. Commun. 1982, 12, 637–645. 10.1080/00397918208061895. [DOI] [Google Scholar]
  23. Chen W.; Chen Y.; Gu X.; Chen Z.; Ho C.-Y. (NHC)Pd(II) Hydride-Catalyzed Dehydroaromatization by Olefin Chain-Walking Isomerization and Transfer-Dehydrogenation. Nat. Commun. 2022, 13, 5507. 10.1038/s41467-022-33163-6. [DOI] [PMC free article] [PubMed] [Google Scholar]
  24. a Raasch M. S. Addition–Rearrangement Reactions of Halogenated Thiophene Dioxides with Furans. J. Org. Chem. 1980, 45, 867–870. 10.1021/jo01293a020. [DOI] [Google Scholar]; b Nakayama J.; Yamaoka S.; Nakanishi T.; Hoshino M. 3,4-Di-tert-butylthiophene 1,1-dioxide, a Convenient Precursor of o-Di-tert-butylbenzene and its Derivatives. J. Am. Chem. Soc. 1988, 110, 6598–6599. 10.1021/ja00227a069. [DOI] [Google Scholar]; c Moiseev A. M.; Balenkova E. S.; Nenajdenko V. G. Reactions of Electron-Withdrawing Thiophene 1,1-dioxides with Furans. A Novel Reaction Pathway. Russ. Chem. Bull. 2006, 55, 712–717. 10.1007/s11172-006-0318-8. [DOI] [Google Scholar]
  25. a Clayden J.; Menet C. J. 2,3-Dihydroisoindolones by Cyclisation and Rearomatisation of Lithiated Benzamides. Tetrahedron Lett. 2003, 44, 3059–3062. 10.1016/S0040-4039(03)00545-8. [DOI] [Google Scholar]; b Knölker H.-J.; Filali S. Transition Metal Complexes in Organic Synthesis, Part 69. [1] Total Synthesis of the Amaryllidaceae Alkaloids Anhydrolycorinone and Hippadine Using Iron- and Palladium-Mediated Coupling Reactions. Synlett 2003, 11, 1752–1754. 10.1055/s-2003-41438. [DOI] [Google Scholar]; c Kondratov I. S.; Tolmachova N. A.; Dolovanyuk V. G.; Gerus I. I.; Daniliuc C.-G.; Haufe G. Synthesis of Trifluoromethyl-Containing Polysubstituted Aromatic Compounds by Diels–Alder Reaction of Ethyl 3-Benzamido-2-oxo-6-(trifluoromethyl)-2H-pyran-5-carboxylate. Eur. J. Org. Chem. 2015, 2015, 2482–2491. 10.1002/ejoc.201500032. [DOI] [Google Scholar]
  26. Whisler M. C.; MacNeil S.; Snieckus V.; Beak P. Beyond Thermodynamic Acidity: A Perspective on the Complex-Induced Proximity Effect (CIPE) in Deprotonation Reactions. Angew. Chem., Int. Ed. 2004, 43, 2206–2225. 10.1002/anie.200300590. [DOI] [PubMed] [Google Scholar]
  27. Fitt J. J.; Gschwend H. W. Reaction of n-, sec-, and tert-Butyllithium with Dimethoxyethane (DME): A Correction. J. Org. Chem. 1984, 49, 209–210. 10.1021/jo00175a056. [DOI] [Google Scholar]
  28. a Axten J. M.; Romeril S. P.; Shu A.; Ralph J.; Medina J. R.; Feng Y.; Li W. H. H.; Grant S. W.; Heerding D. A.; Minthorn E.; Mencken T.; Gaul N.; Goetz A.; Stanley T.; Hassell A. M.; Gampe R. T.; Atkins C.; Kumar R. Discovery of GSK2656157: An Optimized PERK Inhibitor Selected for Preclinical Development. ACS Med. Chem. Lett. 2013, 4, 964–968. 10.1021/ml400228e. [DOI] [PMC free article] [PubMed] [Google Scholar]; b Zeeli S.; Weill T.; Finkin-Groner E.; Bejar C.; Melamed M.; Furman S.; Zhenin M.; Nudelman A.; Weinstock M. Synthesis and Biological Evaluation of Derivatives of Indoline as Highly Potent Antioxidant and Anti-inflammatory Agents. J. Med. Chem. 2018, 61, 4004–4019. 10.1021/acs.jmedchem.8b00001. [DOI] [PubMed] [Google Scholar]; c Yang Y.; Wang K.; Chen H.; Feng Z. Design, Synthesis, Evaluation, and SAR of 4-Phenylindoline Derivatives, a Novel Class of Small-Molecule Inhibitors of the Programmed Cell Death-1/ Programmed Cell Death-Ligand 1 (PD-1/PD-L1) Interaction. Eur. J. Med. Chem. 2021, 211, 113001–113021. 10.1016/j.ejmech.2020.113001. [DOI] [PubMed] [Google Scholar]
  29. a Liu D.; Zhao G.; Xiang L. Diverse Strategies for the Synthesis of the Indoline Scaffold. Eur. J. Org. Chem. 2010, 2010, 3975–3984. 10.1002/ejoc.201000323. [DOI] [Google Scholar]; b Silva T. S.; Rodrigues M. T. Jr.; Santos H.; Zeoly L. A.; Almeida W. P.; Barcelos R. C.; Gomes R. C.; Fernandes F. S.; Coelho F. Recent Advances in Indoline Synthesis. Tetrahedron 2019, 75, 2063–2097. 10.1016/j.tet.2019.02.006. [DOI] [Google Scholar]
  30. For selected examples on natural products and bioactive molecules containing aza-tricyclic skeletons, see:; a Mandal P. K.; Gao F.; Lu Z.; Ren Z.; Ramesh R.; Birtwistle J. S.; Kaluarachchi K. K.; Chen X.; Bast R. C.; Liao W. S.; McMurray J. S. Potent and Selective Phosphopeptide Mimetic Prodrugs Targeted to the Src Homology 2 (SH2) Domain of Signal Transducer and Activator of Transcription 3. J. Med. Chem. 2011, 54, 3549–3563. 10.1021/jm2000882. [DOI] [PMC free article] [PubMed] [Google Scholar]; b Willoughby C. A.; Bull H. G.; Garcia-Calvo M.; Jiang J.; Chapmana K. T.; Thornberry N. A. Discovery of Potent, Selective Human Granzyme B Inhibitors That Inhibit CTL Mediated Apoptosis. Bioorg. Med. Chem. Lett. 2002, 12, 2197–2200. 10.1016/S0960-894X(02)00363-3. [DOI] [PubMed] [Google Scholar]
  31. Ess D.; Jones G.; Houk K. Conceptual, Qualitative, and Quantitative Theories of 1,3-Dipolar and Diels–Alder Cycloadditions Used in Synthesis. Adv. Synth. Catal. 2006, 348, 2337–2361. 10.1002/adsc.200600431. [DOI] [Google Scholar]
  32. Johnson E. R.; Keinan S.; Mori-Sánchez P.; Contreras-García J.; Cohen A. J.; Yang W. Revealing Noncovalent Interactions. J. Am. Chem. Soc. 2010, 132, 6498–6506. 10.1021/ja100936w. [DOI] [PMC free article] [PubMed] [Google Scholar]
  33. a Wagner J. P.; Schreiner P. R. London Dispersion in Molecular Chemistry—Reconsidering Steric Effects. Angew. Chem., Int. Ed. 2015, 54, 12274–12296. 10.1002/anie.201503476. [DOI] [PubMed] [Google Scholar]; b McFord A. W.; Butts C. P.; Fey N.; Alder R. W. 3× Axial vs 3× Equatorial: The ΔGGA Value Is a Robust Computational Measure of Substituent Steric Effects. J. Am. Chem. Soc. 2021, 143, 13573–13578. 10.1021/jacs.1c04247. [DOI] [PubMed] [Google Scholar]
  34. For example, in the cycloaddition shown below, the apparently sterically more hindered product was obtained, favored by London dispersion attraction between the two large alkyl groups in the transition structure; a Aikawa H.; Takahira Y.; Yamaguchi M. Synthesis of 1,8-Di(1-adamantyl)naphthalenes as Single Enantiomers Stable at Ambient Temperatures. Chem. Commun. 2011, 47, 1479–1481. 10.1039/C0CC03025B. [DOI] [PubMed] [Google Scholar]; An alternative explanation for this aryne selectivity could also be a “stepwise,” nucleophilic addition connecting the two less hindered carbons followed by ring closure; b Garr A. N.; Luo D.; Brown N.; Cramer C. J.; Buszek K. R.; VanderVelde D. Experimental and Theoretical Investigations into the Unusual Regioselectivity of 4,5-, 5,6-, and 6,7-Indole Aryne Cycloadditions. Org. Lett. 2010, 12, 96–99. 10.1021/ol902415s. [DOI] [PMC free article] [PubMed] [Google Scholar]

Associated Data

This section collects any data citations, data availability statements, or supplementary materials included in this article.

Supplementary Materials

ja3c04582_si_001.pdf (9.7MB, pdf)
ja3c04582_si_002.xyz (35.5KB, xyz)

Articles from Journal of the American Chemical Society are provided here courtesy of American Chemical Society

RESOURCES