III. Brønsted Acid/Base-Catalyzed Halocyclizations and Carbon Dioxide-Fixation
3.3 An Enantioselective Approach to Chroman Natural Products via CO 2 -Fixation
3.3.3 Optimization Attempts Employing Aliphatic Homoallylic Alcohols in the
method) via chiral HPLC confirming enantioselection was maintained at 50% ee. Additional data acquired (NMR, IR) matched that of the previously reported compound.191
From commercially available starting materials, the enantioenriched chromane 254 can be reached in four synthetic steps using 1 atm of CO2, a chiral non-racemic organocatalyst, and a final transition metal catalyzed etherification in overall good yield. In summary, the synthetic route (unoptimized) outlined in Scheme 79 illustrates the potential of this enantioselective approach to installing the critical tertiary ether moiety of BTHP natural products, in moderate to good yields and offers a complementary approach to literature precedent.
3.3.3 Optimization Attempts Employing Aliphatic Homoallylic Alcohols in the
While we were able to successfully achieve the synthesis of the basic enantioenriched chroman scaffold from the chiral iodocarbonate precursor in 50% ee, significant reaction optimization for these aliphatic homoallylic alcohols was necessary to provide the needed iodocarbonate intermediates in higher levels of enantioselection in order to be synthetically applicable. Considering the extensive optimization events carried out at the beginning of this project using 3-methyl-3-buten-1-ol, approaching these aliphatic substrates as a general class
Table 19. The study of catalyst ligand, acid, and temperature combinations in order to increase ee for carbonate 263.a
OH
toluene (0.4 M)
10 mol% catalyst O O
O
Br
I
261 temp, time Br 263
NIS (1.2 equiv.), CO2
entry ligand+counterion temp
(ºC) yield (%)a ee (%) rxn time (d)
1 StilbPBAMHNTf2 -50 23 (iso.) 70 6
2 StilbPBAMHNTf2 -20 67 (iso.) 50 3
3 PBAMHNTf2 -20 56 35 2
4 5MeStilbPBAMHNTf2 -20 70 25 2
5 7(MeO)StilbPBAMHNTf2 -20 60 20 2
6 StilbPBAM -20 60 21 2
7 StilbPBAMFLAC -20 44 21 2
8 StilbPBAMC3F6NTf2 -20 60 41 2
9 StilbPBAMBTPF -20 65 40 4
10 StilbPBAMBr3CCO2H -20 95 42 4
aNMR yield was determined by the use of the internal standard, CH2Br2. 1 atm CO2 employed. (iso.)
= isolated yield
FLAC:
N S CF3 O
O H F
F F F F
SO2CF3
SO2CF3 F
F
F F
F H BTPF:
Br OH Br Br
O Br3CCO2H:
needs novel and innovative strategies to dramatically increase enantioselection. A simple screen of counterions for example would not suffice. The bromine atom in the ortho position obviously had an effect on ee as well and was another enigmatic factor to be cognizant of and overcome.
Predictably, cooling the reaction further to -50 °C resulted in an increase in ee up to 70%
(as dictated by the Arrhenius equation) – this was the first and easiest modification to make in order to probe what temperatures would be tolerated (entry 1, Table 19). Notably, the solubility of NIS at this temperature was very low and the reaction proceeded at a prohibitively slow pace (6 days, 23% yield).
From here PBAMHNTf2 was examined and performed poorer at -20 °C than StilbPBAMHNTf2 (entry 3). Backbone modifications were then examined to investigate the sterics of the binding pocket(s). 5MeStilbPBAMHNTf2 and 7(MeO)StilbPBAMHNTf2 also performed poorly, yielding 263 in 25% and 20% ee, respectively. A newly developed achiral Brønsted acid FLAC (entry 7, Table 19) was examined, and StilbPBAMFLAC acid salt was prepared, yet provided no benefit to the system. The strong carbon acid bis((trifluoromethyl)sulfonyl)methyl pentafluorobenzene (BTPF) developed by Yamamoto192 was purchased and tested in the iodocarbonation reaction and also afforded the carbonate in low ee (40% ee, entry 9, Table 19).
192 Hasegawa, A.; Ishikawa, T.; Ishihara, K.; Yamamoto, H., Bull. Chem. Soc. Jpn. 2005, 78, 1401.
These nominal studies suggest the bromine adversely affects this system, and perhaps interferes with the formation and/or stabilization of the iodonium intermediate. Conceptually, it possible that 1) the bromine disrupts the favorable energetic dynamics of the iodonium delivery or transition state, 2) polarizes the iodonium to more carbocation-like character at the benzylic position or 3) some combination of these factors through halogen-halogen-type interactions (Figure 40). Thus, facial selectivity of the incoming carbonic acid is more variable leading to the lower enantioselection observed. To disrupt this potential deleterious interaction, StilbPBAMBr3CCO2H (entry 10, Table 19) was prepared and tested as a source of bromine that may disrupt Br–I intramolecular interactions or may assist in substrate catalyst/counterion Br–Br
interactions. This catalyst system did not provide the carbonate in overall better ee (42% ee), but was in line with many of the best catalysts systems examined (i.e. entry 8, 40% ee, StilbPBAMC3F6NTf2; Table 19).
To further probe this notion of halogen-halogen interactions, a smaller, less electron-rich functional handle was installed in the ortho-position – the fluorine analogue 265 was prepared in
Figure 40. Proposed deleterious interactions of the ortho-bromoarene on the formation/stabilization of the iodonium.
O O O I
O O I O Br
polarized iodonium normal
high ee
O O O
steric conjestion at the alkene
Br()
I I
cat* cat* cat*
O O O
bromonium-assisted polarized iodonium
cat*
BrI
Scheme 80. Comparisons of the various halogenated arene derivatives and resulting ee.
R
OH
StilbPBAM•HNTf2 NIS (1.2 equiv.)
toluene, -20 °C
R
O I O CO2 (1 atm) O
223l, R = H, 68% ee 263, R = Br, 50% ee 266, R = F, 57% ee 262, R = H
261, R = Br 265, R = F
analogous fashion. In line with our hypothesis, 265 proved mildly better in the enantioselective iodocarbonation reaction than compared to the bromine alcohol 261, yet still poorer than the saturated phenyl derivative 262 (Scheme 80). Fluorine could still be a competent functional handle through coupling reactions or SNAr chemistry.
A reaction temperature of -50 °C could increase enantioselection to more synthetically
useful levels, yet yield decreased. Employing alcohol 265 at -50 °C under the optimized iodocarbonation conditions afforded carbonate 266 in 84% ee – a significant improvement compared to all past aliphatic substrates, yet the yield was unfortunately low (12% yield) after 4 days (Table 20). Attempts to improve reaction yield was next pursued. It was evident that NIS was sparingly soluble in toluene at these temperatures and a number of tactics, such as
Table 20. Optimization attempts employing the fluorinated analogue 266.a
OH
toluene (0.4 M) 10 mol%
O O
O
F
I
265 F 266
temp 2 d NIS (1.2 equiv.), CO2
StilbPBAM•HNTf2
entry temp (ºC) yield (%) ee (%) notes
1 -20 53 57 n/a
2 -50 12 84 4 d
3 -50 17 82 pulverized NIS
4 -50 12 85 3 equiv. NIS
5 -50 8 83 3 equiv. NIS+IPA (5 equiv.)
6 -50 14 85 1.3 equiv. NIS+IPA (5 equiv.)
7 -50 17 84 0.5 M
8 -50 21 80 0.7 M
9 -50 24 80 20 mol % cat.
10 -50 28 68 1.5 M
11 -50 35 62 2.0 M
aReaction conditions are outlined above and below the arrows unless stated otherwise. Isolated yields reported. ee determined by HPLC using a chiral stationary phase. 1 atm CO2 employed.
pulverizing the NIS, adding NIS in portions, and polar solvent additives, were employed to address this issue. These unfortunately resulted in only marginal improvements to chemical yield although enantioselection remained constant.
The concentration of the iodocarbonation reaction was next examined to explore 1) NIS solubility and 2) changes in enantioselection. Concentrating the reaction further to 0.5 M from 0.4 M in toluene at -50 °C resulted in slight improvement in yield (Table 20). This was pushed further and soon recognized an interesting inverse relationship between concentrations and enantioselection – as concentration was increased, yield improved (trendline R2 = 0.997) yet
enantioselection decreased significantly (trendline R2 = 0.976; Chart 4). This is analogous to what was observed in the iodocarbonation of styrene-derived homoallylic alcohols where higher concentrations generally improved the chemical yield. If we extrapolate these trendlines in order to reach desirable yields (100% yield) we arrive at very high concentrations (~7 M toluene) at
Chart 4. Relationship of concentration vs. enantioselection and yield in the iodocarbonation with fluorinated analogue 265. Trendlines and R2 values added for clarity.
which point the ee would be near 0% or racemic. After this realization, this approach was no longer pursued.
As a final push to examine this carbon capture approach to enantioselective chroman formation, the steric effects of the brominated alcohol substrate was next explored. Perhaps if the pendant aryl halide (bromine) was more shielded from the forming iodonium during the halocyclization reaction, together with a favorable catalyst combination, enantioselection could improve. The decorated arylbromo alcohol 271 was prepared from a modified literature protocol on preparative scale (> 1g) – this iodocarbonate intermediate would be a direct oxygenated
precursor to the vitamin E (α-tocopherol) chroman core (Scheme 81). After screening a host of catalysts and reaction modifications based on previous data (not all reaction data provided), only disappointing results were observed. Enantioselection for carbonate 272 topped out at 61% ee in
Scheme 81. Decorated alcohol 271 was prepared and set the stage for the enantioselective iodocarbonation reaction.
Me O
Me HO
Me
Me Me
Me
Me Me α-tocopherol
Vitamin E
HO
Me Me
Me HO
Me Me
Me
Br Br2
AcOH, 1 h
O
Me Me
Me
Br MeI, K2CO3
acetone, o/n Me
(87%) (quant) 6.3 g
MeO
Me Me
Me
Br CH2O, HCl
AcOH 130 °C, 30 min
MW
Cl
Me OH
i. 2 equiv. nBuLi TMEDA ii. (Bn chloride)
Et2O,
0 °C to rt Me
Br Me
MeO Me
OH
(72%)
(57%)
271
267 268 269
270
trace yield after 4 days (entry 3, Table 21). The insolubility of both NIS and alcohol 271 in this case was largely responsible for low yield.
At this stage it was apparent that simple catalyst, concentration, temperature, and additive adjustments to the enantioselective iodocarbonation reaction with aliphatic homoallylic alcohols were not effective in enhancing enantioselection. At present, the outlook is brightest if a new Brønsted basic ligand and/or achiral Brønsted acid combination is developed as an effective system for more challenging aliphatic homoallylic alcohols.
3.4 AnthPBAM: Synthesis and Potential Applications of a New Chiral, C2-