I may have made my passion for sushi known and hoped I could pass it on to other Reisman Lab members. I started in the early days of the lab with Sean Feng, where we would travel around Pasadena testing different sushi places, then rate them on a chart of price vs. quality (the answer is always sushi gen). Next, the development of a convergent fragment joining tactic, based on the semi-pinacol rearrangement, is evaluated for its generality inspired by the total synthesis of several C19 diterpenoid alkaloids.
Finally, a convergent fragment coupling approach is applied to the total synthesis of falcatin A based on a Mukaiyama Michael tandem Mukaiyama aldol reaction.
INTRODUCTION
Bioinspired or biomimetic total synthesis can be used to validate biosynthetic hypotheses, providing evidence that specific transformations can occur in biological systems. A highlighted example of total synthesis used to validate a biosynthetic hypothesis is in the synthesis of the endiandriic acids by Nicolaou (Scheme 1.3B)13. As highlighted in the previous examples, the innovation that inspires total synthesis is a central theme in organic chemistry and for the work presented in this thesis.
We developed a 1,2-addition semi-pinacol rearrangement sequence to form quaternary stereocenters via a convergent fragment coupling approach motivated by our total synthesis of the C19 diterpenoid alkaloids.
THESIS OUTLINE
Our total synthesis inspired us to explore the generality of this transformation toward the formation of quaternary stereocenters in polycyclic systems.21 We found that the reaction can transfer a variety of functional groups, including enol ethers, allylic silyl ethers, alkenyl and aryl bromides, esters, and aryl triflate. The yields for the semi-pinacol rearrangement were uniformly high, and this strategy is currently being used for the total synthesis of additional diterpenoid alkaloids in our laboratory. The fourth chapter of this thesis focuses on work towards the total synthesis of falcatin A (43), a highly oxygenated myrzinane diterpene (Scheme 1.6B).22 The central seven-membered ring was a key strategic challenge and the main focus of our proposed synthesis.
Activating methods such as the NHK reaction and Mukaiyama aldol addition help create an efficient synthesis of falcatin A, which shows the importance of new methods in the synthesis.
CONCLUDING REMARKS
The theme of total synthesis driving innovation in organic chemistry underlies the topics presented in this thesis. The total synthesis of the C19 diterpenoid alkaloids motivated the development of a convergent fragment coupling methodology for the formation of quaternary centers. The development of more efficient synthetic methods has proved useful on the way towards the total synthesis of falcatin A.
In summary, total synthesis is a driver of innovation and a critical aspect of modern organic chemistry, where it inspires reaction development, reagent invention, and can prove to be a testing ground for biosynthetic hypotheses.
NOTES AND REFERENCES
The need for a concise route to the lupine alkaloids led to the development of a novel cyclization cascade between pyridine and glutaryl chloride to efficiently construct the carbon scaffold of these natural products in a single step. The NHK reaction and Mukaiyama-Michael addition are examples of where practical robust methods help to create more efficient syntheses. Discovery of new synthetic methodologies and reagents during natural product synthesis in the post-palytoxin era.
Endiandriic acid derivatives and other constituents of plants of the genera Beilschmiedia and Endiandra (Lauraceae).
INTRODUCTION
In this key transformation, two molecules of pyridine are joined with one molecule of glutaryl chloride to give the complete tetracyclic framework of the matrine alkaloids in a single step. The preference for the syn boat compared to the anti boat TS is likely due to favorable dispersive interactions between the heteroaryl ring and the oxygen-bearing carbon of the enolate, as well as minimization of the dipole moment in syn TS. When (S)-2-phthaloylglutaryl chloride was used, the product was formed in a 27% yield; however, significant erosion of the enantiomeric excess occurred.
Deprotonation of the BF3 complex (+)-24 with a mixture of t-BuLi and t-BuOK in N,N,N,N-tetramethylethylenediamine (TMEDA) proceeded with good selectivity for the less sterically encumbered C15 over C17 (10:1) as was found by trapping with deuterated methanol (103, Scheme 2.6).28 Unfortunately, trapping this anion with other electrophiles proved challenging.
CONCLUDING REMARKS
Based on a mechanistic study of the cyclization reaction, it was discovered that the dearomatic pyridine cyclization proceeds through two distinct steps with significantly different rates. The first product of the cyclization can be obtained selectively by stopping the reaction before the second cyclization takes place with methanol. Global reduction of the obtained quinolizidine has resulted in the production of lupine in a total of three steps and 35% overall yield.
The five-step transformation of the resulting quinolizidine 107 to sparteine has been accomplished on a gram scale, providing a supply of this challenging natural product.
EXPERIMENTAL SECTION
Upon completion, the reaction was concentrated under reduced pressure to afford a brown solid which was suspended in MeOH (800 mL). Upon completion, the reaction was concentrated under reduced pressure to afford a brown solid which was suspended in MeOH (200 mL). Upon completion, the reaction was concentrated under reduced pressure to afford a brown solid which was suspended in MeOH (40 mL).
After completion of the addition (ca. 10 minutes), the reaction was allowed to stir for 30 minutes while cooling to 0°C on an ice bath. After completion of quenching, 3 M NaOH (1 L) was added to the reaction mixture, which was then stirred at 21 °C until the aluminum salts had changed from a gray sediment to a white slurry (approx. amounts of the supernatant (250 mL) . μl), obtained by stopping stirring and allowing the solids to settle out of solution (ca. 10 minutes), were concentrated under vacuum (0.3 torr) on a Schlenk line and then dissolved in CDCl3.
The resulting white suspension was stirred for five minutes at 21 °C, followed by removal of the diethyl ether under vacuum (0.3 torr) on a Schlenk line; the solids were allowed to dry for an additional 30 minutes. A solution of potassium tert-butoxide (1.72 g, 15.4 mmol, 6.0 equiv) in tetramethylethylenediamine (TMEDA) (12.8 mL, 0.2 M), prepared by potassium tert-butoxide in TMEDA in an inert atmosphere, followed by clarification of the suspension by syringe filtration, was added via syringe, allowing the solution to flow down the side of the flask to pre-cool it before encountering the solids. Traces of solid tert-butyllithium tend to stick to the inside of the rubber septum, and this must be replaced before oxygen is introduced into the flask.
A solution of potassium tert-butoxide (8.96 g, 79.9 mmol, 6.0 equiv) in TMEDA (67 mL, 0.2 M), prepared by dissolving potassium tert-butoxide in TMEDA in a inert atmosphere, followed by clarification of the suspension via syringe filtration, was added via syringe, allowing the solution to flow down the side of the flask to precool it before encountering the solids. The resulting white suspension was stirred at 21°C for five minutes followed by removal of the diethyl ether under vacuum (0.3 torr) on a Schlenk line; the solids were allowed to dry for an additional 30 minutes. A solution of potassium tert-butoxide (446 mg, 3.97 mmol, 6.0 equiv) in TMEDA (3.3 mL, 0.2 M), prepared by dissolving potassium tert-butoxide in TMEDA in a inert atmosphere followed by clarification of the suspension via syringe filtration, was added via syringe by allowing the solution to flow down the side of the flask to precool it before it encountered the solids.
The flask was closed with a rubber septum and trifluoroacetic acid (1.0 mL, 13.2 mmol, 20.0 equiv) was added (caution! HCN fumes are produced!) The reaction was stirred until the starting material was completely consumed, as assessed by TLC (approx. 2 hours).
Once the flask was under an atmosphere of H2, it was placed in a preheated oil bath at 98°C and the mixture was stirred at 1500 rpm for 15 minutes. The catalyst was removed by filtration through a syringe filter, then the filter was washed with water (3 x 5 ml).
The X-ray structure of sophoridine has been previously published (CCDC
The X-ray structure of isosophoridine has been previously published (CCDC
P. decomposed at 180 °C
- X-RAY CRYSTALLOGRAPHY REPORTS
The reaction was stirred at 0 °C for 5 min, then at room temperature until complete by TLC (ca. 18 h). After completion, the reaction was diluted in water (200 mL), and the reaction mixture was extracted with DCM (3 x 50 mL). After the reaction was complete, K2CO3 was added and the reaction was stirred for 10 min.
The reaction mixture was extracted with DCM (3 x 20 mL), dried over anhydrous Na2SO4, filtered, and. After completion, the reaction was concentrated under reduced pressure, then under vacuum on a Schlenk line (0.3 torr, 30 minutes). The reaction was then monitored by 1H qNMR over the course of 24 hours (PhSiMe3 internal standard).
The reaction was stirred vigorously (1500 rpm) until complete consumption of the starting material was observed by TLC (ca. 3 hours). After completion, the reaction was filtered over Celite, concentrated under reduced pressure and purified via a SiO 2 column. After completion, the reaction was cooled to ambient temperature and quenched by dropwise addition of a saturated solution of Rochelles salt (10 ml).
The flask was purged with N2 followed by H2, then the reaction was stirred at 1500 rpm and 21°C until complete consumption of the starting material was observed by TLC (ca. 2 hours). The reaction mixture was then heated to 100°C until complete consumption of the starting material was observed by TLC (approximately 3 hours).
Crystallographic Analysis of (±)-105
Crystallographic Analysis of (+)-25
Crystallographic Analysis of (+)-76
The compound (±)-101 monochloroform adduct crystallizes in the monoclinic space group P21/n with one molecule in the asymmetric unit. Compound (±)-90 mono-chloroform adduct crystallizes in triclinic space group P-1 with one molecule in the asymmetric unit. Compound (–)-81 crystallizes in the monoclinic space group Cc with one molecule in the asymmetric unit.
Compound (±)-85 crystallizes in the orthorhombic space group Pbca with one molecule in the asymmetric unit. The dihydrate of compound (±)-96 crystallizes in the orthorhombic space group Pbcn with one molecule in the asymmetric unit.
