III. Brønsted Acid/Base-Catalyzed Halocyclizations and Carbon Dioxide-Fixation
3.3 An Enantioselective Approach to Chroman Natural Products via CO 2 -Fixation
3.3.2 A Novel Route to Access Enantioenriched Chiral Chromans via Carbon-Capture
By examining the various iodocarbonates and derivatized products prepared from our enantioselective, CO2-fixation reaction,188 it was soon apparent the aliphatic variants in this chemistry could in principle, be transformed into chromans while maintaining ee throughout.
From the outset, unfortunately, the aliphatic homoallylic alcohols needed for this conversion only afforded iodocarbonates in lower ee, topping out at 68% ee under optimized conditions.
Thus a more selective and reliable catalytic system would need to be developed in order to increase enantioselectivity to more synthetically useful levels.
187 Uyanik, M.; Okamoto, H.; Yasui, T.; Ishihara, K. Science 2010, 328, 1376.
188 Vara, B. A.; Struble, T. J.; Wang, W. W.; Dobish, M. C.; Johnston, J. N. J. Am. Chem. Soc. 2015, 137, 7302.
Retrosynthetically, our devised approach to obtain the chiral chroman scaffold is outlined in Scheme 76. First, we previously showed the iodocarbonates can be reduced (LiAlH4) to afford the enantioenriched tertiary alcohols – 255 would stand as the key oxygenated intermediate en route to the desired chroman. From here, cyclization of 255 (6-membered cyclization favored over the 8-membered) onto the pendant aryl group (though C-H activation or by some other means) furnishes the BTHP (254), while presumably maintaining the stereochemical integrity of the chiral center. Also worth noting using this approach, is the conceptual notion of the oxygen
atom (highlighted in blue) from carbon dioxide contained in the carbonate would be incorporated into the final chroman core, effectively utilizing CO2 as an oxygen source or formal oxidative reagent to access a natural product – an appealing notion from a “green chemistry” perspective.
Furthermore, the resulting chroman ethanol 254 (Scheme 76) presents a useful handle for additional synthetic manipulations.
Scheme 76. Retrosynthetic analysis to prepare chroman 254 from chiral iodocarbonate 256.
X
O I O
O
X
OH Me OH
O Me OH chiral (BTHP) chroman core
256 255
254
Known etherification methods are reported in the literature to access chroman/chroman- type heterocycles forging new aryl C-O bonds. One approach uses electrophilic 1,3-diiodo-5,5- dimethylhydantoin (DIH) to promote the electrophilic aromatic substitution followed by the pendant oxygen displacement of the aryl iodide. Alternate approaches use aryl bromides to complete the aryl C-O etherification cross-coupling reaction using transition metal catalysis. One report uses copper189while another report developed by Hartwig uses palladium and a ferrocenyl phosphine ligand known as Q-Phos (259, Scheme 77).190
Although ee for the desired substrates was low at this juncture, we first needed to test this proposed synthesis for feasibility, efficiency, and practicality. We elected to attempt one of the transition metal coupling conditions using an aryl bromide tether. While substrate 223l (Scheme 78) had been previously prepared in 68% ee, ortho-bromo alcohol 261 was analogously prepared in moderate yields from 2-bromobenzyl bromide (260). This double-deprotonation method employing an excess of n-BuLi is effective, although rigorous exclusion of water is needed to achieve moderate yields.
189 Niu, J.; Guo, P.; Kang, J.; Li, Z.; Xu, J.; Hu, S. J. Org. Chem. 2009, 74, 5075.
190 Kataoka, N.; Shelby, Q.; Stambuli, J. P.; Hartwig, J. F. J. Org. Chem. 2002, 67, 5553.
Scheme 77. Pertinent aryl etherification reaction. Successful synthesis of bromo alcohol 261 and previous enantioselection iodocarbonation results.
Br OH
Me Me
O Me
Me 5 mol % Pd(dba)2
5 mol % Q-phos toluene, rt, 15 min
(93%)
P
tBu
tBu
Q-phos 259 Ph Ph Ph
Ph Ph
Fe
257 258
68% ee 71% yield
recall:
O I O
O
Br
OH Br
Br nBuLi (2 equiv.), TMEDA dry Et2O
Me OH
(47%) 261
OH
260 262
113
223l
When 261 was initially subjected to the enantioselective iodocarbonation conditions with StilbPBAMHNTf2, an unexpected drop in ee of roughly 15%, relative to the debromo substrate 262 was observed with the installment of the bromine atom in the 2-position of the arene (from 67% ee when R = H, to 50% ee when R = Br) – although the yield was in line (64%) with similar
aliphatic substrates at -20 ºC (Scheme 78).
Optimization of the enantioselective iodocarbonation reaction remains needed, yet carbonate 263 (50% ee) was prepared to carry through to the final chroman. Reduction of this material with LiAlH4 in dry THF went smoothly at room temperature, affording the desired diol in 94% yield (Scheme 79).
From this enantioenriched tertiary alcohol intermediate 264, we first attempted the Hartwig conditions using palladium at room temperature. We were confident in this method since the authors explored a very similar substrate (Scheme 77), containing a tertiary alcohol and aryl bromide forming the tetrahydropyran in good yield. The developed protocol called for 5 mol
% Pd(dba)2 and 5 mol % Q-Phos (259), however, this failed to yield any product after several attempts (Scheme 79). After careful scrutiny, catalyst loading for palladium and Q-Phos was increased (20 and 30 mol%, respectively), NaOtBu was increased (3 equiv.) and the reaction was heated at 80 °C for 90 minutes – full conversion was observed under the modified protocol.
Chroman ethanol 254 (Scheme 79) was compared to its racemate (also synthesized using this
Scheme 78. Similar alkyl homoallylic alcohol substrates 261 and 262 in the enantioselective iodocarbonation reaction.
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 262, R = H
261, R = Br
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