PART I: TOTAL SYNTHESIS AND RACEMIZATION OF (–)-SINORACUTINE
1. INTRODUCTION
1.3. Project Aims
2.2.4. Formation of the Pyrrolidine Ring
Although the product derived from the reaction using NIS defied our isolation attempts, we decided to carry on with the formed intermediate and optimize its formation. From a screening of several electrophilic iodination reagents and their stoichiometry, NIS (2 eq.) emerged as the optimal reagent (Table 19).[160–162]
Table 19. Conditions for the iodocyclization of 108.
Entrya Reagent Eq. Solvent Yieldb (%)
1 NIS 2 CH2Cl2 64
2 122 2 CH2Cl2 58
3 123 2 CH2Cl2 43
4 124 2 CH2Cl2 12
5 125 1 CH2Cl2 49
6 126 2 CH2Cl2 12
7 NIS 0.5 CD2Cl2 7
8 NIS 1 CD2Cl2 33
9 NIS 1.5 CD2Cl2 42
11 NIS 2.5 CD2Cl2 38
12 NIS 2 MeCN 45
13c NIS 2 MeCN 52
a) Reactions performed at room temperature except entries 12 and 13 (–20 °C) b) determined by 1H NMR using diphenyl-methane as internal standard c) solution of NIS added slowly via syringe pump.
As can be seen in Table 20, treatment of 108 with NIS in different aprotic solvents led to the formation of the product in low to moderate yields. The reaction occurred in all the solvents examined, but CH2Cl2 and MeCN provided the cleanest reaction profile and were selected for further optimization (Entries 1 and 5).
Table 20. Solvents examined for the iodocyclization of 108 using NIS.
Entry Solvent Yielda (%) Comment
1 CH2Cl2 47 clean conversion
2 CHCl3 56 several side products
3 DCE 42 -
4 DME 40 -
5 MeCN 53 clean conversion
6 THF 42 -
7 DMF 44 several side products
8 benzene 42 -
9 DMSO 27 several side products
10 toluene 42 -
a) determined by 1H NMR using diphenylmethane as internal standard.
We observed that in all cases the consumption of starting material was very fast (< 10 minutes), but the product yield was moderate. Therefore, we attempted to lower the reaction temperature and decrease the concentration to slow down the reaction, diminish side product formation, and improve the yield of the major product (Table 21).
Table 21. Variation of reaction conditions for iodocyclization reaction of alkene 108.
Entrya Solvent Conc. (mM) Temp. (°C) Yieldb (%)
1 CH2Cl2 12 –20 55
2 CH2Cl2 20 –20 49
3 CH2Cl2 40 –20 56c
4 CH2Cl2 12 rt 53
5 CH2Cl2 25 rt 53
6 CH2Cl2 50 rt 53
7 CH2Cl2 62 rt 38
8 MeCN 10 –20 54
9 MeCN 20 –20 59
Although the reaction was complete within 30 minutes even at –20 °C, lowering the temperature only gave minimal improvements in yield. For example, a reaction in CH2Cl2 at 12 mM carried out at –20 °C gave the product in 55% yield, while the reaction at room temperature gave the product in 53% yield (cf. Entries 1 and 4). Furthermore, NMR analysis showed that increasing concentration led to several unidentified side products and lower overall yields. Optimum concentrations for the CH2Cl2 reaction was found to be 12 mM, while in MeCN the best yield was achieved at 20 mM and at ambient temperature.
To displace the iodine atom with an oxygen nucleophile, the reaction mixture containing 119 was diluted with DMSO in the presence of halophilic silver tetrafluoroborate.[163] Addition of an amine base (i.e. triethylamine) would then effect deprotonation of the sulfonium ion resulting from substitution of the secondary iodide, lead to the loss of dimethyl sulfide, and give ketone 120 (see Scheme in Table 22). Indeed, the desired ketone could be synthesized in moderate yield. Whereas in typical Kornblum conditions the base is added after several hours in order to complete the substitution reaction of DMSO with the halide, we found that the Et3N could be added to the reaction from the beginning to achieve the same result. Furthermore, these substitutions in Kornblum oxidations generally require elevated temperatures and are only successful for activated alkyl halides (i.e.
primary, or benzylic, allylic).[164] In our case, the reaction proceeds readily at room temperature, and is similarly efficient if carried out without silver salts (cf. Entries 1 and 2 or Entries 3 and 4). These results suggest the neighboring group participation of the adjacent amine to form aziridinium 127 that obviates the use of silver salts by internal displacement of the iodide and conformationally locks intermediate 127 to favor the attack by DMSO.
Table 22. Proposed neighboring-group participation Kornblum reaction of iodide 119.
Entrya Solvent Base Additive Yieldb
1 50% DMSO in CH2Cl2 Et3N AgBF4 54%
2 50% DMSO in CH2Cl2 Et3N none 53%
3 50% DMSO in CH2Cl2 Et3N AgBF4 53%
4 50% DMSO in MeCN Et3N none 50%
a) substitution reaction carried out at –15 °C to room temperature for 16 hours;
As can be seen in Table 23, the requirement for low concentrations during the oxidation is instrumental for high yield of ketone 120 in both CH2Cl2 and MeCN. Decreasing the temperature for the addition of Et3N from room temperature to –20 °C gave similar yields for both solvent mixtures when the reaction was performed in comparable concentrations (Entries 2 and 10).
Table 23. Reaction conditions for the synthesis of ketone 120 via Kornblum oxidation.
Entry Cyclizationa Oxidationb
Yieldc solvent Temp. (°C) Conc. (mM) solvent Temp. (°C) Conc. (mM)
1 MeCN –20 °C 20 50% MeCN in DMSO –15 10 63%
2 MeCN –20 °C 40 50% MeCN in DMSO –15 20 52%
3 MeCN –20 °C 72 50% MeCN in DMSO –15 38 53%
4 MeCN –20 °C 150 50% MeCN in DMSO –15 75 38%
5 MeCN 0 °C 20 50% MeCN in DMSO rt 10 65%
6 MeCN –20 °C 40 50% MeCN in DMSO rt 20 56%
7 MeCN –20 °C 75 50% MeCN in DMSO rt 38 48%
8 MeCN –20 °C 150 50% MeCN in DMSO rt 75 42%
9 MeCN –20 °C 20 50% MeCN in DMSO rt 10 62%
10 CH2Cl2 –20 °C 40 50% CH2Cl2 in DMSO –15 20 54%
11 CH2Cl2 –20 °C 20 50% CH2Cl2 in DMSO rt 10 58%
12 CH2Cl2 0 °C 20 50% CH2Cl2 in DMSO rt 10 61%
a) performed using 2 eq. of NIS; time: 15 min; b) performed using 3 eq. of Et3N, time: 24 h; c) isolated yield.
In a last series of experiments we examined the possibility of performing a solvent switch to DMSO after the iodocyclization reaction. As 119 was not stable towards aqueous workup and silica gel chromatography, we feared it would also be unstable during the required manipulations. In fact, we determined that solvent removal had to be performed in the dark while setting the water bath temperature below 25 °C (at 35 °C, 50% of the product decomposed upon redissolution). In doing so, solvent-free 119 could be handled in air for short time and used for the substitution reactions.
As can be seen by the comparison of Table 23 with Table 24, DMSO alone was slightly superior for the Kornblum oxidation to mixtures containing either MeCN of CH2Cl2. For example, oxidation in DMSO at room temperature in 5 mM solution yielded in 73% (Table 24, Entry 3), whereas the highest yields achieved with 1/1 mixtures of MeCN/DMSO or CH2Cl2/DMSO were 65% and 61%
respectively (Table 23, Entries 5 and 12).
Table 24 Variation of reaction conditions for the synthesis of ketone 120 in pure DMSO.
Entry Cyclizationa Oxidationb
Yieldc solvent Temp. (°C) Conc. (mM) solvent Temp. (°C) Conc. (mM)
1 CH2Cl2 –20 °C 12.5 DMSO rt 5 64
Additionally, we determined that ketone 120 was heavily retained on regular silica gel, which led to a yield loss of 20%. This issue could be resolved by pretreatment of silica gel with the eluent mixture containing 1% Et3N followed by loading and elution with amine-free eluent. Interestingly, purification using Et3N in the eluent mixture resulted in lower yields (10%). Using the optimized conditions described above, 120 could reliably be accessed on scales up to 1 mmol in 60 to 70%
isolated yield.