Each of the remaining members of the dissertation committee greatly influenced the development of my scientific interests. Personally, the most important member of staff during my time here was Dr.
Abstract
Ray Crystallography Reports Relevant to Chapter 3
A Revised Scheme for the Synthesis of Ineleganolide: An Alternative Advance to the Asymmetric Total Synthesis of Ineleganolide by Manipulation of the Late-Stage Oxidation State.
Ray Crystallography Reports Relevant to Chapter 4
Ray Crystallography Reports Relevant to Chapter 5
Ray Crystallography Reports Relevant to Chapter 6
LIST OF SCHEMES
LIST OF TABLES
LIST OF ABBREVIATIONS
Selectfluor 1-chloromethyl-4-fluoro-1,4-
- Introduction
- Statement of Purpose
- Polycyclic Furanobutenolide Cembranoids and Norcembranoids
- Brief Summary of Biosynthetic Connections
- Biosynthesis of Polycyclic Furanobutenolide Cembranoids
- Biosynthesis of Polycyclic Furanobutenolide Norcembranoids
Although the comprehensive overview of the biosynthesis of the natural products cembranoid and norcembranoid can be found elsewhere,1a,13,14,15. The biosynthetic formation of the remaining two members of the polycyclic cembranoid natural product family remains unclear.
- Synthetic Studies Toward Polycyclic Cembranoids and Norcembranoids Norcembranoids
- Synthetic Efforts Toward Bielschowskysin (BSK, 6)
- Synthetic Efforts Toward Verrillin (13)
- Synthetic Efforts Toward Havellockate (14)
- Synthetic Efforts Toward Intricarene (7)
Construction of the central macrocycle would be accomplished by an intramolecular Heck reaction of vinyl bromide 61. Subsequently, construction of the central macrocycle would be necessary to progress toward BSK. Enantioselective synthesis of the macrocyclic cycloaddition precursor 69 began with the coupling of furan 70 and β-ketoester 71 (Scheme B).
In light of the challenges encountered in their pursuit of BSK (6), Mulzer and co-workers devised a 3rd-generation synthetic strategy for BSK based on the production of core framework 91 from a cyclobutane-containing starting material (93, Scheme Enantioselective Access to tricycle 91). was conceived from cyclobutanol (+)-92.
Synthetic Efforts Toward Rameswaralide (8)
Several approaches to the core structure of rameswaralide (8) have been described, although the synthesis of rameswaralide itself has not yet been achieved. Access to enone 145 will be accomplished by functionalization of bicyclic lactone 146, a derivative of the Corey lactone. The pursuit of (±)-rameswaralide was accomplished from bicyclic ketone 148, which was available from acetate 147 in 49% yield over six steps (Scheme 1.5.5.2).
Synthetic Efforts Toward Rameswaralide (8), Mandapamates (17–
Pattenden and co-workers also developed synthetic access to the core of rameswarellides during their pursuit of a unified biomimetic approach to the mandapamats and plumarellids.45 The mandapamats (17–19) and plumarellids (15 and 16) share a common carbocyclic scaffold (Figure 1.5). 6.1). Although they differ to varying degrees in the overall oxidation state and relative configuration at the spirocyclic furan ring point, Pattenden and co-workers sought to test their biosynthetic hypotheses for the construction of each of these 5 natural products through related mechanisms. Hypotheses that each of the mandapamates and plumarellides arise in vivo from the corresponding macrocyclic precursor by an intramolecular [4 + 2] cycloaddition (e.g.
- Synthetic Efforts Toward Mandapamates (17–19), Plumarellides (15–16), and Dissectolide (22) (15–16), and Dissectolide (22)
This empirical evidence suggests that the influence of C(8) stereochemistry is critical for the productive intramolecular formal cycloaddition of non-macrocyclic substrates 179 and 180. Although these results did not contradict the originally proposed biosynthesis of mandapamates and plumarellides, the exploration and work of plumarellids began. alternative biosynthetic pathways for the formation of these two families of natural products. Oxidation of the olefin between C(7) and C(8) followed by olefin transposition and intramolecular Michael addition would provide ketal intermediate 194 .
Although the exact biosynthesis of the mandapamates and plumarellides remains unknown, the work done by Pattenden and coworkers has provided a wealth of information on the chemistry of the furanobutenolide cembranoid natural products.
Synthetic Efforts Toward Yonarolide (25)
The synthesis of ionarolide (25) was only studied by Ito and colleagues in their development of a strategy for the construction of the tricyclic portion if its core scaffold (203, Scheme Cyclopentene 206 would be formed after intramolecular aldol condensation of methyl ketone 207). Synthesis of bicyclic cyclohexenone 207 would be constructed by the Diels–Alder cycloaddition of bisenolide 208 and butenolide 209. In the forward sense, Ito and co-workers pursued the racemic synthesis of the core structure of ionarolide starting with butenolide 209, which was available from β - ketoester 210 in 65% yield over four steps.
With this synthetic route, Ito and co-workers demonstrated the viability of their retrosynthetic strategy to access the core of yonarolide (206), however, the use of this method in further advancement to yonarolide has not yet been discovered.
Synthetic Efforts Toward Ineleganolide (9) and Sinulochmodin C (10)
Although methyl ketone 212 contained the incorrect relative stereochemistry at the lactone carbinol, exposure of the substrate to TFA in toluene at elevated temperature resulted in isomerization of configuration at this stereocenter (probably via a retroconjugate addition and cyclization pathway) and the desired aldol condensation to provide the ionarolide nucleus (206) in 55% yield (Scheme 1.5.8.3). Synthesis of the Yonarolide Core by Tandem Isomerization-Aldol Cyclization (Ito). Scheme Previously, Pattenden and colleagues postulated that the biosynthesis of both ineleganolide (9) and sinulochmodin C (10) occurred sequentially.
- Conclusion
- Notes and References
- The initial studies to determine the absolute stereochemistry of the cembranoid diterpenes were performed on rubifolide (11, R = CH 3 ) and confirmed by
- For isolation of rameswaralide (8) and initial biosynthetic speculation, see
- Introduction
- Retrosynthetic Analysis
- Intramolecular Aldol Cyclization
- Intramolecular Wittig Cyclization
- Completion of Hydroxymethyl-cis-1,3-cyclopentenediol 262
- Conclusion
- Experimental Methods and Analytical Data
As such, in concert with our research program dedicated to the development and application of the palladium-catalyzed asymmetric allylic alkylation,10 we developed an efficient and general route for the enantioselective synthesis of cis-1,3-cyclopentanediol building block 238. Despite these unsuccessful attempts, we remained inspired by the successful isolation of the desired enone 250. Upon closer inspection of the oxidative α-bromination procedure, we identified two possible sources of inconsistency.
Efforts are currently underway to use this building block in the synthesis of members of the norcembranoid diterpene family of natural products.
Quenching led to the vigorous evolution of gas and the spread of the orange color, resulting in two colorless phases. The solution was diluted with heptane (10 mL), and the reaction was concentrated under reduced pressure until about 0.6 mL of solution remained. The reaction was rapidly purified through a SiO2 plug (10% Et2O in hexanes eluent) and partially concentrated under reduced pressure to give the desired α-bromoketone 256 as a yellow solution, which was immediately triturated with anhydrous toluene (1 mL) diluted and used immediately. .32.
The suspension was stirred for 48 h and then filtered and the solids washed with EtOAc (4 x 120 mL).
Chloroallylmesylate 253: A flask was charged with 2-chloroallyl alcohol (274, 4.78 mL,
Chloroallyl ketal 258: A 500 mL Schlenk flask was immersed in a 20:1 i-PrOH:toluene bath saturated with KOH for 12 h, rinsed with deionized H2O, acetone, and allowed to dry. The resulting yellow-brown reaction was then allowed to cool to room temperature, filtered through a pad of SiO2 using hexanes as eluent to remove toluene, at which time separate fractions were collected, eluting.
The reaction was allowed to stir for 5 min after white precipitate on the first drops. The reaction was allowed to stir for 5 minutes, after which the vessel was sealed with a Teflon® stopcock and introduced into a preheated 110°C. The reaction solution was allowed to stir vigorously for 16 hours, after which the dark brown reaction mixture was removed from the bath and allowed to cool to ambient temperature with stirring.
The vessel was then opened to the atmosphere in a well-ventilated fume hood and allowed to stir for an additional hour.
The combined organic layers were washed with saturated NH 4 Cl (5 x 500 mL), dried over Na 2 SO 4 , filtered and concentrated in vacuo to afford benzoylated alcohol g, >99%. yield) as a light gold oil that was typically used without further purification.
- Ligand Synthesis
- Ligand Screen in Palladium-Catalyzed Intermolecular Enantioselective Allylic Alkylation Enantioselective Allylic Alkylation
- Notes and References
- The procedure for the conversion of silyl enol ether 248 to chloroallylketone 254 with the associated characterization data has been reported by our group, see
- For full details and optimized procedure, see section 2.7.2
The yellow reaction mixture was then diluted with CH 2 Cl 2 (100 mL) and poured onto saturated aqueous NaHCO 3 (100 mL). The reaction vessel, which contained a homogeneous yellow solution, was then closed and introduced into a preheated bath at 140 °C. The resulting blue-green reaction mixture was allowed to stir for 20 h when consumption of the starting material was complete as determined by TLC (eluent 1:19 Et2O:hexanes).
The resulting tan reaction was then allowed to cool to ambient temperature (about 23 °C), filtered through a pad of SiO2 using hexanes as the eluent to remove toluene, at which time separate fractions were collected, eluted with Et2O, to isolate the volatile reaction products.
- For details concerning the synthesis of silyl enol ether 257, see Section 2.7.2
- For the experimental procedure and full details, see Section 2.7.2
- Only one diastereomer is observed as a product. The stereochemistry of the reduction has been confirmed by NOE studies of alcohol 261 after benzoylation
- Repetition of this procedure provided cyclopentenone 250 in yields ranging from 0 to 82%
- It was observed that slow addition via addition funnel of the bright yellow, transparent NaOBr solution into the reaction mixture resulted in clouding and
Epoxidation conditions tested include: Oxone®, magnesium monoperoxyphthalate hydrate (MMPP•6H2O), t-BuOOH/SiO2, t-monoperoxyphthalate hydrate (MMPP•6H2O), t-BuOOH/SiO2, t-BuOOH/VO(acac)2, m -CPBA, m-CPBA/Jacobsen's catalyst. A number of conditions were found to be ineffective in forming the desired brominated product, including: NaOH/Br2/CeCl3, Ca(OH)2/Br2, the desired brominated product, including: NaOH/Br2/CeCl3, Ca(OH)2 / Br2, Selectfluor/KBr, LiBr/NaIO4/AcOH. It was found that the slow addition of a light yellow, clear NaOBr solution to the reaction mixture via the addition funnel caused turbidity, and the addition of a clear NaOBr solution to the reaction mixture caused turbidity and discoloration of the solution remaining in the funnel.
We believed that the vapors in the headspace of the reaction vessel facilitated this apparent decomposition and lowered the yield in the process.
35. Although storage of this intermediate in a benzene matrix is possible for extended
Procedure adapted from reference 26
Access to allyldioxanone 243 will be accomplished in an asymmetric manner by the enantioselective palladium-catalyzed allylic alkylation of enol ether 244. Synthesis of diethyl ketal 285 was accomplished by modifying the procedure used for the synthesis of cyclohexyl1,1 starting with cyclohexyl . transketalization of 3,3-dimethoxypentane (286)3 with the hydrogen chloride salt of aminoalcohol 270 (Scheme A3.2.2). Ketone 288 was then alkylated by a two-step procedure starting with cyclohexyl imine formation followed by deprotonation using LDA to provide methylated dioxanone 289 in 44% yield.
Finally, the palladium-catalyzed allylic alkylation of TES enol ether was smoothly accomplished using mesylate 253 as the external electrophile to give chloroallyl ketone 291 in 73% yield.4.
Exposure of the intermediate ammonium salt to excess Et3N afforded the amino alcohol 287 in 19% yield over two steps. Unfortunately, even using the more robust cyclohexyl ketal 295 , we were never able to achieve removal of the more robust cyclohexyl ketal 295 , we were never able to remove the TES group. Most of the reaction conditions examined resulted in cleavage of the ketal group or complete decomposition of the reactant.
Fortunately, switching from allylketone 249 to chloroallylketone 254 furnished synvinyl alcohol 298 as the major product in a 2.8:1.0 ratio with anti-vinyl alcohol 299. Switching the identity of the ketal to the diethyl ketal slightly improved the ratio of the cyclohex product, while the ketal variant provided an interim product report. Ultimately, we decided to explore the advancement of chloroallyl alcohol 302 , due to the improved stability of the cyclohexyl ketal, along with allyl alcohol 296 .
Having installed an oxidized allyl fragment earlier in the synthetic route with a chloroallyl electrophile to provide vinyl chloride 311, we only had to effect a 1,3-allylic transposition under redox neutral conditions to directly provide bicyclic cyclopentenone 242 (Table A3.6.1) . Under rhenium catalysis, the substrate protected with an acetonide ketal decomposed (Entries 1 and 2) and the cyclohexyl ketal variant failed to react (Entry 3).11 Comparatively, using PCC (Entry 4)9 and SO3•pyridine (Entry 5) ) 7 did not cause any reactivity at all, leading to the quantitative recovery of starting material. Fortunately, we found that exposure of vinyl chloride 311 (R,R = (CH2)5, Entry 6) to SO3•pyridine followed by a phosphate buffer produced traces of cyclopentenone.12 Although we were encouraged by this result, we quickly discovered that Scaling up the transformation failed to produce any isolable amounts of cyclopentenone 242 .
We established the substitution in the 2-position of the allyl fragment of allylic alkylation product 243 has a profound effect on the diastereoselective addition of a vinyl group in a 1,2-way to the carbonyl moiety.
