Iron-Catalyzed Asymmetric α-Alkylation of 2-Acylimidazoles via Dehydrogenative Radical Cross-Coupling with Alkanes.

The direct α-alkylation of acyclic carbonyls with nonactivated hydrocarbons through C(sp3 )-H functionalization is both extremely promising and notably challenging, especially when attempting to achieve enantioselectivity using iron-based catalysts. We have identified a robust chiral iron complex for the oxidative cross-coupling of 2-acylimidazoles with benzylic and allylic hydrocarbons, as well as nonactivated alkanes. The readily available and tunable N,N'-dioxide catalysts of iron in connection with oxidants exhibit precise asymmetric induction (up to 99 % ee) with good compatibility in moderate to good yields (up to 88 % yield). This protocol provides an elegant and straightforward access to optically active acyclic carbonyl derivatives starting from simple alkanes without prefunctionalization. Density functional theory (DFT) calculations and control experiments were made to gain insight into the nature of C-C bond formation and the origin of enantioselectivity. We propose a radical-radical cross-coupling process enabled by the immediate interconversion between chiral ferric species and ferrous species.

Monetary payoffs modulate reciprocity expectations in outcome evaluations: An event-related potential study.

Choosing cooperation or aggression relies on reciprocity preferences which refer to the tendency of an individual to return cooperative or aggressive action for cooperative or aggressive action (i.e., positive or negative reciprocity preference). The reciprocity preference is positively correlated with reciprocity expectation, wherein individuals with stronger reciprocity preferences may have higher expectations than future cooperative or aggressive behavior should be delivered by beneficiaries (positive reciprocity expectation) or victims (negative reciprocity expectation). Although previous studies have demonstrated that the presence of monetary payoffs enhances reciprocity preferences, the modulation of monetary payoffs in reciprocity expectations remains unclear. Using event-related potentials (ERPs), we examined how monetary payoffs modulated reciprocity expectations by adopting the Chicken game. Participants were asked to choose between cooperation and aggression with a putative opponent in the Chicken game involving the monetary (vs. non-monetary) payoffs. Participants' electroencephalogram (EEG) was recorded when they saw the opponent's cooperative or aggressive decision. Results showed that compared to the non-monetary payoff trials, the feedback-related negativity (FRN) effect in response to the opponent's decisions was stronger following the participant's aggressive decision in the monetary payoff trials, whereas P3 was insensitive to monetary payoffs. These findings suggest that monetary payoffs heighten expectations of negative reciprocity at the earlier and automatic outcome processing stage.

Asymmetric Catalytic Synthesis of Hexahydropyrrolo-isoquinolines via Three-Component 1,3-Dipolar-Cycloaddition.

An asymmetric three-component 1,3-dipolar cycloaddition of 3,4-dihydroisoquinolines, bromoacetates and α,ß-unsaturated pyrazole amide is realized by using a chiral N,N'-dioxide-Y(OTf)3 complex as the catalyst. The process includes a base-promoted formation of dihydroisoquinolium ylides in situ, and a chiral Lewis acid-catalyzed asymmetric [3+2] cycloaddition with α,ß-unsaturated pyrazole amides. A series of hexahydropyrrolo-isoquinolines are obtained in moderate to good yields with excellent diastereo- and enantioselectivities.

Monitoring seasonal distribution of an endangered anadromous sturgeon in a large river using environmental DNA.

Monitoring dynamic distribution is crucial to conservation management of anadromous sturgeons, but traditional survey methods are less efficient for low-density populations in a large river. Natural propagation of Chinese sturgeon has been monitored annually mainly at the spawning ground using netting for eggs and hydroacoustics for broodstock. However, absence of spawning was observed sporadically in recent years, indicating further crises for the declining population. We analyzed eDNA of water samples collected from 24 sites across 1360 km of the migratory route of anadromous Chinese sturgeon in the middle and lower reaches of the Yangtze River. Chinese sturgeon was detected at 9 sites during the spawning season and 14 sites after the spawning season. We found that positive eDNA detection rates remained constant in the middle reaches but dramatically changed in the lower reaches, reflecting seasonal migration pattern of Chinese sturgeon. Invasive sturgeons were detected in the river, indicating their possible escape from aquaculture facilities. This study established a protocol for the use of eDNA to monitor distribution of Chinese sturgeon and could be valuable in making better policies for the conservation of this endangered species.

Discovery of novel PDE9A inhibitors with antioxidant activities for treatment of Alzheimer's disease.

Phosphodiesterase-9 (PDE9) is a promising target for treatment of Alzheimer's disease (AD). To discover multifunctional anti-AD agents with capability of PDE9 inhibition and antioxidant activity, a series of novel pyrazolopyrimidinone derivatives, coupling with the pharmacophore of antioxidants such as ferulic and lipolic acids have been designed with the assistance of molecular docking and dynamics simulations. Twelve out of 14 synthesised compounds inhibited PDE9A with IC50 below 200 nM, and showed good antioxidant capacities in the ORAC assay. Compound 1h, the most promising multifunctional anti-AD agent, had IC50 of 56 nM against PDE9A and good antioxidant ability (ORAC (trolox) = 3.3). The selectivity of 1h over other PDEs was acceptable. In addition, 1h showed no cytotoxicity to human neuroblastoma SH-SY5Y cells. The analysis on structure-activity relationship (SAR) and binding modes of the compounds may provide insight into further modification.

1,8- and 1,4-cineole enhance spontaneous excitatory transmission by activating different types of transient receptor potential channels in the rat spinal substantia gelatinosa.

Although transient receptor potential (TRP) channels expressed in the spinal substantia gelatinosa play a role in modulating nociceptive transmission, their properties have not been fully examined yet. In order to address this issue, the effects of 1,8-cineole and its stereoisomer 1,4-cineole on excitatory transmission were examined by applying the whole-cell patch-clamp technique to substantia gelatinosa neurons in adult rat spinal cord slices. Miniature excitatory postsynaptic current frequency was increased by 1,8- and 1,4-cineole. The cineole activities were repeated and resistant to voltage-gated Na+ -channel blocker tetrodotoxin. The 1,8-cineole activity was inhibited by TRP ankyrin-1 (TRPA1) antagonists (HC-030031 and mecamylamine) but not TRP vanilloid-1 (TRPV1) antagonists (capsazepine and SB-366791), whereas the 1,4-cineole activity was depressed by the TRPV1 but not TRPA1 antagonists. Although 1,8- and 1,4-cineole reportedly activate TRP melastatin-8 (TRPM8) channels, their activities were unaffected by TRPM8 antagonist 4-(3-chloro-2-pyridinyl)-N-[4-(1,1-dimethylethyl)phenyl]-1-piperazinecarboxamide. Monosynaptically evoked C-fiber, but not Aδ-fiber excitatory postsynaptic current amplitude, was reduced by 1,8- and 1,4-cineole. These results indicate that 1,8- and 1,4-cineole increase spontaneous l-glutamate release from nerve terminals by activating TRPA1 and TRPV1 channels, respectively, while inhibiting C-fiber but not Aδ-fiber evoked l-glutamate release. This difference between 1,8- and 1,4-cineole may serve to know the properties of TRP channels located in the central terminals of primary-afferent neurons. The spinal dorsal horn lamina II (substantia gelatinosa; SG) plays a pivotal role in regulating nociceptive transmission from the periphery. We found out in the SG that 1,4- and 1,8-cineole activate TRPV1 and TRPA1 channels, respectively, located in primary-afferent, possibly C-fiber, central terminals. This difference may serve to know the properties of TRP channels expressed in the central terminals.

Ameliorative effects of physcion 8-O-ß-glucopyranoside isolated from Polygonum cuspidatum on learning and memory in dementia rats induced by Aß1-40.

CONTEXT: Polygonum cuspidatum Sieb. Et Zucc. (Polygonaceae) has been traditionally used in folk medicine to treat various diseases. OBJECTIVE: This study investigates the ameliorative effects of physcion 8-O-ß-glucopyranoside (PSG) isolated from P. cuspidatum on learning and memory in dementia rats induced by Aß1-40. MATERIALS AND METHODS: Dementia rats were prepared by intracerebroventricular injection of Aß1-40. PSG (5, 10, 20, and 40 mg/kg/d, for 5 d) was administered orally. Ameliorative activity of PSG in dementia rats was evaluated by the Morris water maze (MWM) test, and its mechanisms were explored by evaluating AchE activity, levels of DA, NE, and 5-HT in hippocampus, and drebrin protein expressions in hippocampus. RESULTS: Our results indicated that PSG (5, 10, 20, and 40 mg/kg/d) significantly inhibited the prolonged latency in dementia rats (p < 0.05), and inhibitory rates were 16.5, 22.7, 33.0, and 44.8% after 5 d of learning, indicating that PSG improves learning and memory of dementia rats. Furthermore, PSG significantly decreased AchE activity (10, 20, and 40 mg/kg/d; p < 0.05), increased 5-HT (20 and 40 mg/kg/d, p < 0.05), NE (10, 20, and 40 mg/kg/d; p < 0.05), and DA levels (5, 10, 20, and 40 mg/kg; p < 0.05) in the hippocampus. Additionally, PSG obviously decreased the Aß contents in hippocampus (10, 20, and 40 mg/kg/d; p < 0.05), and up-regulated drebrin protein expressions (5, 10, 20, and 40 mg/kg/d; p < 0.05). CONCLUSIONS: PSG can significantly enhance learning and memory in Aß1-40-induced dementia rats, and the mechanisms may be related to increase levels of Ach, 5-HT, NE, and DA, decrease Aß contents, and up-regulation of drebrin proteins in hippocampus.

Phorbol 12-myristate 13-acetate inhibits P-glycoprotein-mediated efflux of digoxin in MDCKII-MDR1 and Caco-2 cell monolayer models.

AIM: To investigate the effects of phorbol 12-myristate 13-acetate (PMA), a PKC activator, on P-glycoprotein-mediated efflux of digoxin in two cell transport models. METHODS: Caco-2 cells, wild MDCKII cells (MDCKII-WT) and MDCKII cells transfected stably with human MDR1-gene encoding P-gp (MDCKII-MDR1) were examined. Cell viability was evaluated with MTT assay. Bidirectional transport of digoxin was evaluated in these cells. Intracellular ATP level was measured using ATP assay. P-gp ATPase activity was analyzed using a Pgp-Glo(TM) assay. RESULTS: PMA (10 µmol/L) did not reduce the viability of the 3 types of cells. In Caco-2 and MDCKII-MDR1 cell monolayers, PMA (1, 10 and 100 nmol/L) dose-dependently inhibited the basolateral to apical transport of digoxin, but did not change the apical to basolateral transport. In addition, PMA did not affect both the basolateral to apical and apical to basolateral transport of digoxin in MDCKII-WT cell monolayer. In agreement with the above results, PMA dose-dependently reduced intracellular ATP level and stimulated P-gp ATPase activity in both Caco-2 and MDCKII-MDR1 cells. Verapamil (a positive control, 100 µmol/L) caused similar inhibition on digoxin efflux as PMA did, whereas 4α-PMA (a negative control, 100 nmol/L) had no effect. CONCLUSION: PMA significantly inhibited P-gp-mediated efflux of digoxin in both Caco-2 and MDCKII-MDR1 cell monolayers via PKC activation.

Multiple paradoxical embolisms caused by central venous catheter thrombus passing through a patent foramen ovale: A case report.

BACKGROUND: To date, this is the first case of a paradoxical embolism (PDE) that concurrently manifested in the coronary and lower limb arteries and was secondary to a central venous catheter (CVC) thrombus via a patent foramen ovale (PFO). CASE SUMMARY: Here, we report a case of simultaneous coronary and lower limb artery embolism in a PFO patient carrier of a CVC. The patient presented to the hospital with acute chest pain and lower limb fatigue. Doppler ultrasound showed a large thrombus in the right internal jugular vein, precisely at the tip of the CVC. Transthoracic and transesophageal echocardiography confirmed the existence of a PFO, with inducible right-to-left shunting by the Valsalva maneuver. The patient was administered an extended course of anticoagulation therapy, and then the CVC was successfully removed. Percutaneous PFO closure was not undertaken. There was no recurrence during follow-up. CONCLUSION: Thus, CVC-associated thrombosis is a potential source for multiple PDE in PFO patients.

Fabrication of a Coculture Organoid Model in the Biomimetic Matrix of Alginate to Investigate Breast Cancer Progression in a TAMs-Leading Immune Microenvironment.

The current research models of breast cancer are usually limited in their capacity to recapitulate the tumor microenvironment in vitro. The lack of an extracellular matrix (ECM) oversimplifies cell-cell or cell-ECM cross-talks. Moreover, the lack of tumor-associated macrophages (TAMs), that can comprise up to 50% of some solid neoplasms, poses a major problem for recognizing various hallmarks of cancer. To address these concerns, a type of direct breast cancer cells (BCCs)-TAMs coculture organoid model was well developed by a sequential culture method in this study. Alginate cryogels were fabricated with appropriate physical and mechanical properties to serve as an alternative ECM. Then, our previous experience was leveraged to polarize TAMs inside of the cryogels for creating an in vitro immune microenvironment. The direct coculture significantly enhanced BCCs organoid growth and cancer aggressive phenotypes, including the stemness, migration, ECM remodeling, and cytokine secretion. Furthermore, transcriptomic analysis and protein-protein interaction networks implied certain pathways (PI3K-Akt pathway, MAPK signaling pathway, etc.) and targets (TNF, PPARG, TLR2, etc.) during breast cancer progression in a TAM-leading immune microenvironment. Future studies to advance treatment strategies for BCC patients may benefit from using this facile model to reveal and target the interactions between cancer signaling and the immune microenvironment.

Higher adiposity predicts greater intra-individual inconsistencies in postprandial glycemic measurements-an analysis of three randomized controlled trials in Asian populations.

BACKGROUND/OBJECTIVES: Acute glycemic responses offer important insights into glucose homeostasis although the repeatability of these measurements particularly in Asian populations remains unclear. This research aimed to critically investigate the inconsistencies of the postprandial glycemic profile within individuals, and identify potential variables predicting greater inconsistencies. SUBJECTS/METHODS: This was a secondary analysis of three randomized controlled trials which fed subjects with glucose (and other carbohydrate-rich foods), and measured postprandial blood glucose at regular intervals. Intra-individual rank-order consistency in the glycemic profile between acute glucose treatments was evaluated and compared against demographic, anthropometric and cardio-metabolic health related indicators to delineate potential confounding variables. Correlations between the incremental area under curve at 120 min (iAUC120 min) for glucose and the carbohydrate-rich foods were further explored. RESULTS: Rank-order consistency was identified to be moderate, with intra-individual inconsistencies marginally lower than inter-individual inconsistencies. Notably, greater inconsistencies within individuals were directly correlated with BMI and fat-mass index (P < 0.01) albeit non-significant for age, ethnicity, and other cardio-metabolic health-related risk indicators. Across the trials, there were positive monotonic correlations between the iAUC120 min for glucose and simple sugars (sucrose, isomaltulose), as well as different varieties of rice (jasmine white, Bapatla brown, Bapatla white; p < 0.05). However, there were a lack of associations between iAUC120 min for glucose with pastas (semolina and wholegrain penne, spaghetti) and mee pok noodles. CONCLUSION: There are inherent inconsistencies in postprandial glycemic measurements within individuals, particularly among those with higher adiposity. These confounders need to be kept in mind for appropriate and meaningful interpretations of glycemia.

[Induction of UGT1A1 expression by praeruptorin A and praeruptorin C through hCAR pathway].

This study is purposed to investigate the effects of praeruptorin A (PA) and praeruptorin C (PC) on UGT1A1 in HepG2 cells through hCAR pathway. PA and PC were incubated with HepG2 cells for 24 h and 48 h, mRNA and protein expressions of UGT1A1 were determined by real-time PCR and Western blotting assays. Additionally, effects of PA and PC on UGT1A1 mRNA and protein expressions were also measured after transient transfection of a specific CAR siRNA for 72 h in HepG2 cells. UGT1A1 mRNA and protein expression levels were significantly increased by PA and PC after incubation for 48 h. Moreover, the mRNA and protein up-regulations of UGT1A1 were attenuated by transient transfection of a specific CAR siRNA, suggesting the induction was mediated by CAR. The results suggest that PA and PC can significantly up-regulate UGT1A1 expression partially via the CAR-mediated pathway.

[DNA extraction from bones and teeth using AutoMate Express forensic DNA extraction system].

OBJECTIVE: To explore a new method in order to extract DNA from bones and teeth automatically. METHODS: Samples of 33 bones and 15 teeth were acquired by freeze-mill method and manual method, respectively. DNA materials were extracted and quantified from the triturated samples by AutoMate Express forensic DNA extraction system. RESULTS: DNA extraction from bones and teeth were completed in 3 hours using the AutoMate Express forensic DNA extraction system. There was no statistical difference between the two methods in the DNA concentration of bones. Both bones and teeth got the good STR typing by freeze-mill method, and the DNA concentration of teeth was higher than those by manual method. CONCLUSION: AutoMate Express forensic DNA extraction system is a new method to extract DNA from bones and teeth, which can be applied in forensic practice.

A 3D-printed scaffold-based osteosarcoma model allows to investigate tumor phenotypes and pathogenesis in an in vitro bone-mimicking niche.

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Physical confinement in alginate cryogels determines macrophage polarization to a M2 phenotype by regulating a STAT-related mRNA transcription pathway.

The immunologic response is considered to play a pivotal role in the application of biomaterial implants, and intrinsic properties of biomaterials can significantly modulate the anti-inflammatory effects. However, how physical confinement influences M2 polarization of macrophages and the relevant mechanisms have not been clearly elucidated. In this study, pore size and porosity in cryogels can be mediated by utilizing alginates with different viscosities. Cryogels of small pore size and low porosity can restrict M2 polarization of macrophages in vitro, judging from cell morphology, secretion of cytokines and expression of key M2-related genes. In comparison, cryogels of large pore size or high porosity can induce M2 polarization in vivo, resulting in the anti-inflammation effects. High-throughput RNA-seq analysis demonstrates that the mRNA surveillance pathway is key in the polarization process, and four primary transcription factors (PPAR-γ, STAT6, NF-κB, and STAT1) participate probably by competition in DNA binding to regulate M2-related gene expression. This study confirms that enough physical space inside is necessary to promote M2 polarization for the anti-inflammatory performance, which can be applied widely in the fields of tissue engineering and regenerative medicine.

Targeted Deletion of the First Intron of the Wxb Allele via CRISPR/Cas9 Significantly Increases Grain Amylose Content in Rice.

BACKGROUND: The rice Waxy (Wx) gene plays a major role in seed amylose synthesis and consequently controls grain amylose content. Wx gene expression is highly regulated at the post-transcriptional level. In particular, the GT/TT polymorphism at the 5'splicing site of its 1st intron greatly affects this intron's splicing efficiency and defines two predominant Wx alleles, Wxa and Wxb. Wxa rice often harbours intermediate to high amylose contents, whereas Wxb rice exhibits low to intermediate amylose contents. By deleting the Wx 1st intron using CRISPR/Cas9 technology, we generate a completely novel Wx allele and further investigate how intron removal affects Wx gene expression and rice grain amylose content. RESULTS: CRISPR/Cas9-mediated targeted deletion of the Wx 1st intron was performed on 4 rice inbred lines: KY131 (Wxb), X32 (Wxb), X35 (Wxa) and X55 (Wxlv). Deletion of the 1st intron occurred in 8.6-11.8% of the primary transformants of these 4 inbred lines. Compared to wild-type plants, amylose content was significantly increased from 13.0% to approximately 24.0% in KY131 and X32 mutant lines, which both carried the Wxb allele. However, no significant difference in amylose content was observed between wild-type plants and X35 and X55 mutant lines, which carried the Wxa and Wxlv alleles, respectively. Wx gene expression analysis of wild-type plants and mutants yielded results that were highly consistent with amylose content results. KY131 and X32 mutants accumulated increased levels of steady mRNA transcripts compared with wild-type plants, whereas steady mRNA levels were not altered in X35 and X55 mutants compared with wild-type plants. Grain quality, including appearance quality and eating and cooking quality, which are tightly associated with amylose content, was also assessed in wild-type and mutant plants, and data were presented and analysed. CONCLUSIONS: This study presents a novel and rapid strategy to increase amylose content in inbred rice carrying a Wxb allele. Our data strongly suggest that the 1st intron of the Wx gene regulates Wx gene expression mainly at the post-transcriptional level in rice. This finding is in contrast to a previous hypothesis suggesting that it influences Wx gene transcription. In addition, removal of the first intron generates a completely novel Wx allele. Further studies on this new Wx allele will provide invaluable insights into the regulation of Wx gene expression, which will help researchers engineer new Wx alleles to facilitate the breeding of rice cultivars with better eating and cooking quality.

Structure-based discovery of orally efficient inhibitors via unique interactions with H-pocket of PDE8 for the treatment of vascular dementia.

Our previous study demonstrated that phosphodiesterase 8 (PDE8) could work as a potential target for vascular dementia (VaD) using a chemical probe 3a. However, compound 3a is a chiral compound which was obtained by chiral resolution on HPLC, restricting its usage in clinic. Herein, a series of non-chiral 9-benzyl-2-chloro-adenine derivatives were discovered as novel PDE8 inhibitors. Lead 15 exhibited potent inhibitory activity against PDE8A (IC50 = 11 nmol/L), high selectivity over other PDEs, and remarkable drug-like properties (worthy to mention is that its bioavailability was up to 100%). Oral administration of 15 significantly improved the cAMP level of the right brain and exhibited dose-dependent effects on cognitive improvement in a VaD mouse model. Notably, the X-ray crystal structure of the PDE8A-15 complex showed that the potent affinity and high selectivity of 15 might come from the distinctive interactions with H-pocket including T-shaped π-π interactions with Phe785 as well as a unique H-bond network, which have never been observed in other PDE-inhibitor complex before, providing new strategies for the further rational design of novel selective inhibitors against PDE8.

Free energy perturbation (FEP)-guided scaffold hopping.

Scaffold hopping refers to computer-aided screening for active compounds with different structures against the same receptor to enrich privileged scaffolds, which is a topic of high interest in organic and medicinal chemistry. However, most approaches cannot efficiently predict the potency level of candidates after scaffold hopping. Herein, we identified potent PDE5 inhibitors with a novel scaffold via a free energy perturbation (FEP)-guided scaffold-hopping strategy, and FEP shows great advantages to precisely predict the theoretical binding potencies ΔG FEP between ligands and their target, which were more consistent with the experimental binding potencies ΔG EXP (the mean absolute deviations | Δ G FEP - Δ G EXP |  < 2 kcal/mol) than those ΔG MM-PBSA or ΔG MM-GBSA predicted by the MM-PBSA or MM-GBSA method. Lead L12 had an IC50 of 8.7 nmol/L and exhibited a different binding pattern in its crystal structure with PDE5 from the famous starting drug tadalafil. Our work provides the first report via the FEP-guided scaffold hopping strategy for potent inhibitor discovery with a novel scaffold, implying that it will have a variety of future applications in rational molecular design and drug discovery.

A novel inhibitor of N 6-methyladenosine demethylase FTO induces mRNA methylation and shows anti-cancer activities.

N 6-methyladenosine (m6A) modification is critical for mRNA splicing, nuclear export, stability and translation. Fat mass and obesity-associated protein (FTO), the first identified m6A demethylase, is critical for cancer progression. Herein, we developed small-molecule inhibitors of FTO by virtual screening, structural optimization, and bioassay. As a result, two FTO inhibitors namely 18077 and 18097 were identified, which can selectively inhibit demethylase activity of FTO. Specifically, 18097 bound to the active site of FTO and then inhibited cell cycle process and migration of cancer cells. In addition, 18097 reprogrammed the epi-transcriptome of breast cancer cells, particularly for genes related to P53 pathway. 18097 increased the abundance of m6A modification of suppressor of cytokine signaling 1 (SOCS1) mRNA, which recruited IGF2BP1 to increase mRNA stability of SOCS1 and subsequently activated the P53 signaling pathway. Further, 18097 suppressed cellular lipogenesis via downregulation of peroxisome proliferator-activated receptor gamma (PPARγ), CCAAT/enhancer-binding protein alpha (C/EBPα), and C/EBPß. Animal studies confirmed that 18097 can significantly suppress in vivo growth and lung colonization of breast cancer cells. Collectively, we identified that FTO can work as a potential drug target and the small-molecule inhibitor 18097 can serve as a potential agent against breast cancer.

Enantioselective [4 + 2] Cycloaddition/Cyclization Cascade Reaction and Total Synthesis of cis-Bis(cyclotryptamine) Alkaloids.

The asymmetric catalytic synthesis of 3-cyclotryptamine substituted oxindoles through formal [4 + 2] cycloaddition/cyclization cascade is described. A wide range of cyclotryptamine derivatives were obtained in enantioenriched form under mild reaction conditions and were found to have potential anticancer activity. The strategy enables ready assembly of cyclotryptamine subunits at the C3a-C3a' positions with two quaternary stereogenic centers in cis-selectivity, leading to the concise synthesis of optically active cis-bis(hexahydropyrroloindole) and others of the cyclotryptamine alkaloid family.