Increasing the versatility of the biphenyl-fused-dioxacyclodecyne class of strained alkynes.

Biphenyl-fused-dioxacyclodecynes are a promising class of strained alkyne for use in Cu-free 'click' reactions. In this paper, a series of functionalised derivatives of this class of reagent, containing fluorescent groups, are described. Studies aimed at understanding and increasing the reactivity of the alkynes are also presented, together with an investigation of the bioconjugation of the reagents with an azide-labelled protein.

A Retrospective, Single-Agency Analysis of Ambulance Crashes during a 3-Year Period: Association with EMS Driver Characteristics and a Telematics-Measured Safe Driving Score.

BACKGROUND: Driver demographics and aggressive driving behavior are established risk factors for traffic accidents, yet their role in ambulance crashes remains poorly studied. We reviewed all ambulance crashes that occurred in our emergency medical services (EMS) agency during a 3-year period, and examined incidence rates (IR) by driver characteristics and telematics-measured driver behavior. METHODS: This retrospective study was conducted in a U.S. EMS agency that operates 75 Type III ambulances and requires personnel to document all ambulance collisions, regardless of severity. Crashes reported between September 2017 and August 2020 were reviewed, and established criteria were used to classify injury and vehicle damage severity. Serious crashes were defined as events with any injury and/or functional or disabling damage. A vehicle telematics system installed fleet-wide in 2017 continuously captures driver-specific data, including miles driven and indicators related to speeding, harsh cornering and braking, and seatbelt use. A composite score characterizes compliance with safe driving behaviors (1 = low compliance to 5 = high compliance). Crash IR per 100,000 miles, IR ratios (IRR), and Poisson regression were used in analysis. Driver sex, age, agency tenure, miles driven, and safe driving score were examined. RESULTS: Clinicians reported 214 crashes and the IR of any crash and serious crash were 2.1 and 0.63 per 100,000 miles, respectively. Injuries occurred in 8% of crashes and were all of low acuity. About one third of crashes produced functional (21%) or disabling (8%) vehicle damage, and the ambulance required towing in 10%. In a multivariate model, female sex (IRR = 1.50, 95%CI = 1.13-1.97), age 18-24 (IRR = 1.67, 95%CI = 1.06-2.66), and being in the lowest quartile of safe driving score (IRR = 1.51, 95%CI = 1.14-2.02) were EMS driver factors independently associated with an increased risk of any collision. CONCLUSION: Most ambulance crashes are minor events, but the proportion that result in injury and/or functional or disabling vehicle damage may be as high as one-third. Poor driver compliance with objectively measured safe driving behaviors may increase risk for collisions independent of driver sex and age. The EMS industry would benefit from additional studies that examine the full spectrum of ambulance crashes and expand understanding of EMS driver-related risk factors.

Evaluation of an EMS-Based Community Paramedic Pilot Program to Reduce Frequency of 9-1-1 Calls among High Utilizers.

BACKGROUND: Many community paramedic interventions aim to reduce unnecessary emergency department visits among high utilizers of acute care, but fewer focus specifically on reducing summons for emergency medical services (EMS). We implemented an EMS-based pilot program that identified high utilizers of 9-1-1 and facilitated community paramedic outreach encounters to understand and address potentially unnecessary 9-1-1 calls. This study compares the pre- and post-intervention incidence rate of 9-1-1 calls among program participants. METHODS: This retrospective evaluation was conducted using pilot data from a single U.S. EMS agency that responds to approximately 100,000 9-1-1 calls annually. High utilizers, defined as individuals with ≥3 9-1-1 calls in 90 days, were identified for recruitment between February 1, 2019 and December 31, 2019. Community paramedics recruited participants via phone and then conducted home visits to assist them with navigation away from unnecessary 9-1-1 use. Dispatch data from September 1, 2018 to December 31, 2019 were used to compute the incidence rate of 9-1-1 calls per 30 person-days of observation before and after the initial home visits. RESULTS: Data from 108 program participants were analyzed. The majority were over the age of 50 (79%), and 33% completed more than one visit. Median person-days of observation before and after the initial home visit were 354 days and 132 days, respectively. Participants called 9-1-1 an average of 0.68 times per 30 person-days prior to the community paramedic intervention, and 0.51 times per 30 person-days after the intervention, which represents an overall mean decrease in 9-1-1 utilization of 25% (p < 0.001). Although a decrease in 9-1-1 utilization was observed in the majority of participants, the 9-1-1 call rate increased in 29% of participants. No statistically significant changes in 9-1-1 use were observed in participants who received more than one home visit or who were in the highest quartile of 9-1-1 use prior to the intervention. CONCLUSION: This pilot work demonstrates the feasibility of an EMS-based, community paramedic-only intervention to reduce unnecessary 9-1-1 calls and suggests that some modest reductions in EMS use may be achievable by dispatching community paramedics to conduct home visits with frequent users of 9-1-1.

Trends in fall-related encounters and predictors of non-transport at a US Emergency Medical Services Agency.

Non-transport to a hospital after emergency medical services (EMS) encounters for falls is common. However, incident factors associated with non-transport have not been well studied, especially beyond older adults. The objectives of this study are to (1) describe trends in fall-related EMS utilisation among adult patients from 2010 to 2018; (2) describe incident characteristics by age; and (3) identify incident factors associated with non-transport following a fall. This retrospective observational study includes prehospital clinical records data on falls from a large ambulance service in Minnesota, USA. Multivariable logistic regression was used to assess the independent association between non-transport and the following factors: sex, age, race, previous fall-related EMS encounter, incident location and primary impression. Of 62,835 fall-related encounters studied, 14.7% (9,245) did not result in transport by EMS. Fall calls were less common among younger people and the location and medical conditions primarily treated by an EMS provider during a 9-1-1 call differed greatly from those occurring among patients 65 and older. Factors most strongly associated with an increased risk of non-transport in the multivariable model were a primary impression of 'No apparent illness/injury' (OR = 34.5, 95% CI = 30.7-38.7), falling in a public location (OR = 2.09, CI = 1.96-2.22) and having had a fall-related EMS encounter during the prior year (OR = 1.15, CI = 1.1-1.2). Falls that occur in public locations, in patients with a previous fall, or result in no clinical detection of apparent illness or injury have a significantly increased odds of non-transport. Non-transport fall incidents in the United States require significant agency resources. Knowledge about the incident factors associated with non-transport calls is informative for development of alternative models for prehospital care delivery and initiatives to better serve patients.

Development of a Large-Scale Cyanation Process Using Continuous Flow Chemistry En Route to the Synthesis of Remdesivir.

The implementation of cyanation chemistry at manufacturing scales using batch equipment can be challenging because of the hazardous nature of the reagents employed and the tight control of reaction parameters, including cryogenic temperatures, that help to afford acceptable selectivity and conversion for the desired reaction. Application of continuous flow chemistry offers a means to mitigate the risk associated with handling large amounts of hazardous reagents and to better control the reaction parameters. A case study describing the cyanation of a glycoside using continuous flow chemistry toward the synthesis of the drug candidate remdesivir is presented.

Social Support Outside the Workplace, Coping Styles, and Burnout in a Cohort of EMS Providers From Minnesota.

Occupational burnout has been linked to the delivery of lower quality of care in some health care professions, including with turnover intentions and absenteeism in emergency medical services (EMS) workers. Thus, studies that identify factors associated with burnout may be integral to optimizing quality and workforce engagement among EMS professionals. A survey was conducted to assess social support outside the workplace, coping styles, and occupational burnout in a cohort of EMS providers from Minnesota. Surveys were returned by 217 providers (54% response), of which 167 had provided data on burnout, social support, and coping styles and were included in the analysis. The mean age was 41 years, 62% were male, and the prevalence of burnout was 17%. After adjustment for age and EMS tenure, the odds of burnout was higher among those characterized as socially isolated as compared with providers who were integrated socially or moderately integrated (odds ratio = 3.52; 95% confidence interval = [1.13, 10.98]). Common coping responses included planning, positive reframing, and active coping, while behavioral disengagement and denial were rarely used. Lack of social networks outside the workplace and frequent use of self-blame, food, or substance use as coping strategies were associated with burnout. Conversely, social integration and use of religion and instrumental support to cope with stressors were associated with reduced burnout.

Emergency Medical Services Provider Perspectives on Pediatric Calls: A Qualitative Study.

Objective: Previous research indicates that 9-1-1 response to incidents involving children is particularly distressing for emergency medical services (EMS) clinicians. This qualitative study was conducted to increase understanding about the difficulties of responding to pediatric calls and to obtain information about how organizations can better support EMS providers in managing potentially difficult calls. Methods: Paramedics and emergency medical technicians from a single U.S. ambulance service were invited to participate in focus groups about responding to 9-1-1 calls involving pediatric patients. A total of 17 providers from both rural and metro service regions participated in six focus groups held in community meeting spaces. A semi-structured focus group guide was used to explore (1) elements that make pediatric calls difficult, (2) pre-arrival preparation practices, (3) experiences with coping after difficult pediatric calls, and (4) perspectives about offered and desired resources or support. Focus groups were audio recorded and transcripts were analyzed using standard coding, memoing, and content analysis methods in qualitative analysis software (NVivo). Results: Responses about elements that make pediatric calls difficult were organized into the following themes: (1) special social value of children, (2) clinical difficulties with pediatric patients, (3) added acuity to already challenging calls, (4) caregivers as secondary patient, and (5) identifying with patient or patient's family. Pre-arrival preparation methods included mental or verbal review of hypothetical scenarios and refocusing nerves or emotions back to the technical aspect of the job. Participants described using available resources that largely took the form of social support. Suggestions for additional resources included: increased opportunities for external feedback; more frequent pediatric clinical training; institutionalization of recovery time after difficult calls; and improved storage and labeling of pediatric equipment. Conclusions: This study provides qualitative data about the difficulties of responding to pediatric calls and resources needed to support clinicians. Findings from this study can be used to guide EMS leaders in designing and implementing institutional initiatives to enhance training and support for prehospital clinicians providing care to children.

Burnout and Exposure to Critical Incidents in a Cohort of Emergency Medical Services Workers from Minnesota.

INTRODUCTION: Very little quantitative data on occupational burnout and exposure to critical incidents are available from contemporary United States emergency medical services (EMS) cohorts. Given that burnout has been associated positively with turnover intentions and absenteeism in EMS workers, studies that uncover correlates of burnout may be integral to combating growing concerns around retention in the profession. METHODS: We administered a 167-item electronic survey that included the Maslach Burnout Inventory (MBI) and a modified version of the Critical Incident History Questionnaire (n=29 incident types) to paramedics, emergency medical technicians (EMTs), and dispatchers of a single ambulance service. We defined the presence of burnout as a high score on either the emotional exhaustion or depersonalization subscales of the MBI. RESULTS: Survey respondents who provided regular 911 response at the time of the survey and completed the MBI portion of the survey were included in our analysis (190 paramedics/EMTs, 19 dispatchers; 54% response). The overall prevalence of burnout was 18%, with prevalence reaching 32% among dispatchers. The seven pediatric critical incident types presented in the survey accounted for seven of the top eight rated most difficult to cope with, and severity ratings for pediatric critical incidents did not differ by parental status (all p>0.30). A significant number of respondents reported that they had been threatened with a gun/weapon (43%) or assaulted by a patient (68%) at least once while on duty. Being over the age of 50, a parent, or in a committed relationship was associated with reduced odds of burnout in unadjusted models; however, these associations did not remain statistically significant in multivariate analysis. Increasing tertile of career exposure to critical incidents was not associated with burnout. CONCLUSION: Medical dispatchers may be an EMS subgroup particularly susceptible to burnout. These data also demonstrate quantitatively that in this EMS agency, responders find pediatric critical incidents especially distressing and that violence against responders is commonplace. In this study, a simple measure of career exposure to potentially critical incidents was not associated with burnout; however, individual reactions to incidents are heterogeneous, and assessment tools that more accurately enumerate encounters that result in distress are needed.

Plasmacytoid Urothelial Carcinoma of Ureter with Retroperitoneal Metastasis: A Case Report.

BACKGROUND Plasmacytoid is a rare histological variant of urothelial carcinoma (UC). Since the first reported case of plasmacytoid urothelial carcinoma (PUC), in 1991, only about 100 cases have since been reported, with most cases involving the bladder. Urothelial carcinomas of the upper urinary tract represent only 5% of urothelial cancers. To the best of our knowledge, there has only been 1 reported case of PUC of the ureter. PUC is a highly aggressive disease, with a poor prognosis. We present a rare biopsy-proven case of PUC of the ureter with retroperitoneal metastasis. CASE REPORT A 60-year-old man came into the hospital with complaints of a 5-day history of generalized abdominal pain, nausea, and vomiting, with no associated urinary symptoms prior to admission. CT demonstrated small bowel obstruction (SBO) and obstructive uropathy due to a right ureteric mass. Exploratory laparotomy, small bowel resection, gastrostomy tube placement, and umbilical hernia repair were all done. Histology and immunohistochemistry were compatible with plasmacytoid variant of urothelial cancer. He underwent a cystouretoscopy and a right ureteral stent placement with a right ureteroscopy. Final CT abdomen/pelvis revealed recurrent SBO before the ileocecal valve, possibly due to carcinomatosis. Ileocecal resection with end ileostomy placement was done. Systemic treatment will begin as an outpatient. CONCLUSIONS PUC arising from the ureter is rare, and retroperitoneal metastatic disease has not been reported previously. Here, we compare the clinical manifestations of the more common PUC of the bladder with our case. From this we are able to learn more about the disease and its presentation.

Minnesota Heart Safe Communities: Are community-based initiatives increasing pre-ambulance CPR and AED use?

AIM: Implementation research that describes how successfully resuscitation guidelines are translated into practice are lacking. We examined whether recent community-based initiatives being conducted as part of the Minnesota Heart Safe (HS) Communities program increase the delivery of CPR and use of automated external defibrillators (AED) by bystanders and first responders prior to ambulance arrival. METHODS: Non-EMS witnessed out-of-hospital cardiac arrests (OHCA) with presumed cardiac etiology treated by a single ambulance service in 2013-2015 were studied. Data were obtained from the Minnesota HS program and the Cardiac Arrest Registry to Enhance Survival (CARES) Surveillance Registry. Pre-ambulance CPR and AED use within HS communities before and after completion of the program were compared. RESULTS: As of July 2016, 17 Minnesota communities within the ambulance service area had achieved HS designation and 294 OHCAs that occurred in these communities met inclusion criteria for analysis (120 before HS designation, 174 after). CPR was initiated by bystanders or first responders prior to ambulance arrival in 83% of OHCA events that occurred before HS designation and in 95% of events that occurred after designation (OR=4.23 [1.80-9.98]). Pre-ambulance AED use increased from 63% to 77% after the community intervention (OR=1.94 [1.16-3.24]). Overall unadjusted survival to hospital discharge increased slightly after HS designation, but this difference was not statistically significant (17% vs 20%, p=0.32). CONCLUSION: Implementation of the Heart Safe program in communities within our ambulance service area in Minnesota has increased use of CPR and AEDs by bystanders and first responders prior to ambulance arrival.

Feasibility of upright patient positioning and intubation success rates At two academic EDs.

OBJECTIVES: Endotracheal intubation is most commonly taught and performed in the supine position. Recent literature suggests that elevating the patient's head to a more upright position may decrease peri-intubation complications. However, there is little data on the feasibility of upright intubation in the emergency department. The goal of this study was to measure the success rate of emergency medicine residents performing intubation in supine and non-supine, including upright positions. METHODS: This was a prospective observational study. Residents performing intubation recorded the angle of the head of the bed. The number of attempts required for successful intubation was recorded by faculty and espiratory therapists. The primary outcome of first past success was calculated with respect to three groups: 0-10° (supine), 11-44° (inclined), and ≥45° (upright); first past success was also analyzed in 5 degree angle increments. RESULTS: A total of 231 intubations performed by 58 residents were analyzed. First pass success was 65.8% for the supine group, 77.9% for the inclined group, and 85.6% for the upright group (p=0.024). For every 5 degree increase in angle, there was increased likelihood of first pass success (AOR=1.11; 95% CI=1.01-1.22, p=0.043). CONCLUSIONS: In our study emergency medicine residents had a high rate of success intubating in the upright position. While this does not demonstrate causation, it correlates with recent literature challenging the traditional supine approach to intubation and indicates that further investigation into optimal positioning during emergency department intubations is warranted.

Diabetic Myonecrosis: A Rare Complication of Diabetes Mellitus Mimicking Deep Vein Thrombosis.

BACKGROUND Diabetic myonecrosis is an uncommon complication of long-standing poorly controlled diabetes mellitus. It presents as acute non-traumatic swelling and pain of the lower extremity, which can mimic deep vein thrombosis (DVT). The clinical course is usually self-limiting and patients respond well to supportive medical therapy. CASE REPORT A 54-year-old male with past medical history of poorly controlled diabetes mellitus type II, hyperlipidemia, gastroesophageal reflux disease (GERD), and remote history of DVT presented to our emergency department with 2-week history of progressively worsening left calf pain and swelling. On physical examination, the patient had increased warmth, edema, erythema, and tenderness in the left calf, with positive Homan's sign. A lower-extremity venous Doppler was negative for DVT. His creatinine phosphokinase (CPK) level was normal, but hemoglobin A1C was 11.0%, reflective of poor glycemic control. Magnetic resonance imaging (MRI) of the left calf revealed a focus of non-enhancement in the gastrocnemius muscle along with increased enhancement of the rest of the muscle, suggestive of diabetic myonecrosis. CONCLUSIONS Diabetic myonecrosis is a rare complication of long-standing diabetes mellitus that can often mimic DVT. Diagnosis can be made on an MRI, and treatment involves strict glycemic control along with antiplatelet therapy and non-steroidal anti-inflammatories (NSAIDs).

Pharmacist Involvement in a Community Paramedicine Team.

BACKGROUND: Hospital readmissions have recently gained scrutiny by health systems as a result of their high costs of care and potential for financial penalty in hospital reimbursement. Mobile-integrated health and community paramedicine (MIH-CP) programs have expanded to serve patients at high risk of hospital readmission. Pharmacists have also improved clinical outcomes for patients during in-home visits. However, pharmacists working with a MIH-CP program have not been previously described. This project utilized a novel multidisciplinary Community Paramedicine Team (CPT) consisting of a pharmacist, paramedic, and social worker to target patients with heart failure at high risk of readmission to assist with coordination of care and education. OBJECTIVES: This article describes the development of the CPT, delineation of CPT member responsibilities, and outcomes from pilot visits. METHODS: The CPT visited eligible patients in their homes to provide services. Patients with heart failure who were readmitted within 30 days were eligible for a home visit. RESULTS: A total of 6 patients were seen during the pilot, and 2 additional patients were seen after the pilot. CONCLUSION: Imbedding a pharmacist into a CPT provides a unique expansion of pharmacy services and a novel approach to address hospital readmissions.

Cross-over study of novice intubators performing endotracheal intubation in an upright versus supine position.

There are a number of potential physical advantages to performing orotracheal intubation in an upright position. The objective of this study was to measure the success of intubation of a simulated patient in an upright versus supine position by novice intubators after brief training. This was a cross-over design study in which learners (medical students, physician assistant students, and paramedic students) intubated mannequins in both a supine (head of the bed at 0°) and upright (head of bed elevated at 45°) position. The primary outcome of interest was successful intubation of the trachea. Secondary outcomes included log time to intubation, Cormack-Lehane view obtained, Percent of Glottic Opening score, provider assessment of difficulty, and overall provider satisfaction with the position. There were a total of 126 participants: 34 medical students, 84 physician assistant students, and 8 paramedic students. Successful tracheal intubation was achieved in 114 supine attempts (90.5 %) and 123 upright attempts (97.6 %; P = 0.283). Upright positioning was associated with significantly faster log time to intubation, higher likelihood of achieving Grade I Cormack-Lehane view, higher Percent of Glottic Opening score, lower perceived difficulty, and higher provider satisfaction. A subset of 74 participants had no previous intubation training or experience. For these providers, there was a non-significant trend toward improved intubation success with upright positioning vs supine positioning (98.6 % vs. 87.8 %, P = 0.283). For all secondary outcomes in this group, upright positioning significantly outperformed supine positioning.

Radiation exposure as a consequence of spinal immobilization and extrication.

BACKGROUND: Extrication and spinal immobilization in the trauma patient with unknown injuries is a common practice of emergency medical services. High-speed crashes occurring in open-wheel racing seldom result in extrication or spinal immobilization. OBJECTIVES: To evaluate the safety of self-extrication in IndyCar® (Indianapolis, IN) by comparing drivers self extricated with full spinal immobilization and subsequent radiation exposure. METHODS: A retrospective review of prospectively collected de-identified IndyCar® crash and drivers' medical records was performed at treating Level I trauma centers. One hundred thirty-five crash incidents involving drivers evaluated by a medical team were included. Any driver with severe multiple trauma was excluded due to distracting injuries. Drivers underwent standard protocol for postcrash injury. Diagnostic and treatment outcomes including spinal and neurologic injury, need for surgery, and radiation exposure were collected for review. RESULTS: Self-extrication occurred in 121 (90%) crashes, and overall cumulative radiation exposure ranged from 100 to 250 mSv, or 0.82-2.06 mSv per driver. Extrication with full spinal immobilization occurred in 14 (10%) drivers, with overall cumulative radiation exposure ranging from 140 to 350 mSv, or 10-25 mSv per driver. A total of 29 injuries were identified, nine of which (31%) were spinal. In these, six were emergency medical services extricated and three self extricated. None were unstable spinal fractures resulting in surgical care, surgical disease, or neurologic deficit. CONCLUSION: In our IndyCar® racing experience, a protocol-led self-extrication system resulted in neither a mismanagement of an unstable spinal fracture nor neurological deficit, and reduced radiation exposure.

The [4+2] cycloaddition of donor-acceptor cyclobutanes and nitrosoarenes.

The Yb(OTf)3 catalyzed [4+2] cycloaddition between donor-acceptor cyclobutanes and nitrosoarenes is disclosed. This method facilitates the synthesis of tetrahydro-1,2-oxazines in good to excellent yields as single diastereomers. Except for a few electron-deficient nitrosoarenes, excellent regioselectivity was observed throughout these studies.

Effect of introducing the mucosal atomization device for fentanyl use in out-of-hospital pediatric trauma patients.

BACKGROUND: Pain associated with pediatric trauma is often under-assessed and under-treated in the out-of-hospital setting. Administering an opioid such as fentanyl via the intranasal route is a safe and efficacious alternative to traditional routes of analgesic delivery and could potentially improve pain management in pediatric trauma patients. OBJECTIVE: The study sought to examine the effect of introducing the mucosal atomization device (MAD) on analgesia administration as an alternative to intravenous fentanyl delivery in pediatric trauma patients. The hypothesis for the study is that the introduction of the MAD would increase the administration of fentanyl in pediatric trauma patients. METHODS: The research utilized a 2-group design (pre-MAD and post-MAD) to study 946 pediatric trauma patients (age <16) transported by a large, urban EMS agency to one of eight hospitals in Marion County, which is located in Indianapolis Indiana. Two emergency medicine physicians independently determined whether the patient met criteria for pain medication receipt and a third reviewer resolved any disagreements. A comparison of the rates of fentanyl administration in both groups was then conducted. RESULTS: There was no statistically significant difference in the rate of fentanyl administration between the pre-MAD (30.4%) and post-MAD groups (37.8%) (P = .238). A subgroup analysis showed that age and mechanism of injury were stronger predictors of fentanyl administration. CONCLUSION: Contrary to the hypothesis, the addition of the MAD device did not increase fentanyl administration rates in pediatric trauma patients. Future research is needed to address the barriers to analgesia administration in pediatric trauma patients.

The formal [4+3] cycloaddition between donor-acceptor cyclobutanes and nitrones.

The formal [4+3] cycloaddition of 2-alkoxy-1,1-dicarboxylate activated donor-acceptor cyclobutanes with nitrones is disclosed. The reaction forms structurally unique oxazepines in moderate to high yield with a wide scope of nitrones. In most cases either a diastereomeric mixture or a single diastereomer may be formed, depending on the reaction conditions.

Formal [4 + 2] cycloaddition of alkoxy-substituted donor-acceptor cyclobutanes and aldehydes catalyzed by Yb(OTf)3.

The cycloaddition between 2-alkoxy-1,1-cyclobutane diesters and aromatic, heteroaromatic, or aliphatic aldehydes under Yb(OTf)(3) catalysis generates tetrahydropyrans in high yields with exclusive cis-stereochemistry.

Diels-Alder chemistry of siloles and their transformation into cyclohex-2-ene-1,4-cis-diols.

The synthesis of siloles with substitution patterns that are continuative toward natural product synthesis are described. Their reactivity in Diels-Alder chemistry was explored through thermal, Lewis acid, and high-pressure reactions. Furthermore, bicyclic adducts were oxidatively cleaved to reveal a highly functionalized cyclohexene core.