III. Brønsted Acid/Base-Catalyzed Halocyclizations and Carbon Dioxide-Fixation
3.2 Initial Studies Towards a Bifunctional Brønsted Acid/Base Catalyzed, Enantioselective
3.2.4 Exploring Useful Chemical Transformations of the Enantioenriched Iodocarbonates
From this simple and robust protocol for generating enantioenriched cyclic iodocarbonates, we next set out to establish useful transformations of these chemicals. The ability to use an inexpensive and readily accessible organocatalyst in conjunction with such a cheap, plentiful oxygen source like carbon dioxide could have wide synthetic implications and impact on the community. One can envision transforming these products into other chemical building blocks, pharmaceuticals, or agrochemicals. While these carbonates may be valuable in their own right, we envisioned their derivatization into unique (and oxygenated), chiral building blocks based on both known and less precedented methods in order to broaden their immediate
Table 18. Substitution attempts for the neopentyl iodide employing a range of nucleophiles.
O O
O
I nucleophile (5 equiv.) solvent (0.1 M)
temp.
O O
O X
Ph OH
retro-iodocarbonation alkene product
223 230
222
entry Nucleophile(s) solvent temp (ºC) time result
1 NaN3 DMSO 80 8 h 223
2 AgCN DMSO 80 24 h 223
3 MeNO2 neat 80 24 h 223
4 AgOAc DMSO 80 24 h 223
5 NaN3 DMSO 110 18 h 1:1 222:230
6 AgNO2/MeNO2 neat 110 18 h 1:1 byproduct:223
7 AgOAc H2O 110 18 h unfamiliar byproduct
8 NaN3 DMF 110 18 h ~1:1 222:230
9 NaN3 MeCN 110 5 d 223
10 NaN3 (15 equiv.) DMSO 110 18 h 222
11 NaN3 (2 equiv.) DMSO 110 18 h 223, trace 230
12 NaN3 (2 equiv.) DMF 110 18 h ~1:1 222:230
13 NaN3 /Ag2CO3 DMF 110 3 h 1:1:1 222:223:230
utility.
Derivatization attempts were initially focused on substituting a number of nucleophiles for the pendant iodide – conceivably feasible using small, strong nucleophiles such as –CN, –N3,
etc. An array of nucleophiles tested is listed in Table 18. Substitution attempts at this carbon largely failed and primarily resulted in retro-iodocarbonation product (222). Due to the steric congestion and sheer size of the iodine atom (via assumptions made from the resolved crystal structure of 223, Figure 38), even small nucleophiles presumably have trouble accessing the C–I anti-bonding orbital, and instead attack the more accessible (electrophilic) iodine. Silver(I) salts (halophiles) were also explored in hopes of polarizing the carbon-iodine bond to promote substitution and/or departure of iodide, but this approach also failed (entries 2,4/6-7, Table 18).
The best overall result obtained in these experiments was employing NaN3 in DMF at 110 °C (entry 8, Table 18), which resulted in 40% conversion to the desired azide adduct – although yield was incurably low and never exceed 25%. It was soon evident that substitution on the neopentyl iodide would be a significant challenge.
Figure 38. Single X-ray crystal structure of iodocarbonate 223 (courtesy of Maren Pink, Indiana U.).
Also evident was the possibility of assembling chiral tertiary alcohols beginning from these enantioenriched carbonates. Well known is a class of antifungal drugs known simply as the
‘triazole and imidazole antifungals’ (231, Scheme 71) – largely important to the global health community for treating a variety of parasitic and fungal infections.
Posaconazole (233) may be one of the more unique and structurally complex antifungals in this class and is also prescribed to treat Chagas disease (Scheme 71). It is marketed by Schering-Plough and the key synthetic step introducing the triazole ring is via displacement of a
Scheme 71. The common pharmacophore belonging to the triazole antifungals: tertiary alcohol, substituted arene, and pendant triazole are all necessary for activity. Literature precedence to posaconazole and our failed attempts to install the triazole.
O O
O
O O
O I N
223
N N base
variety of solvents N
N
NH 236
X OH
DMF, DMPU 100° C,
24 h N
N N
common pharmacophore for broad spectrum anti-fungals
Fluconazole consistently a Top 200 drug
F
F
O N
N N
O N N N
N N OMe
OH Me (–)-posaconazole
F
F
O I
N
N N
OBn Na+
F
F
O N
N N
OBn
81% yield en route to posaconazole
OH N N
N N
N N
F F
OH primarily
231 232
233
234 235
222
neopentyl iodide171 to give 235 as outlined in Scheme 71. Based on this scaffold and synthetic precedence, 1,2,4-triazole was employed in the substitution chemistry employing a range of bases, additives, and solvents. Similar to other small nucleophilic species previously attempted, these triazole nucleophiles were also not tolerated with this system, and primarily resulted in retro-iodocarbonation alkene product. Conceivably, any amine-based nucleophile that cooperates with these substrates could arrive at a similar, nitrogenated heterocycle needed to furnish the active triazole pharmacophore.
It has been reported that oxidants, specifically peracids like m-chloroperoxybenzoic acid (MCPBA), can react with alkyl (often primary) iodides and generate iodoso compounds in situ.172 In the reported work, the generated iodoso compounds undergo syn elimination to form alkenes from the loss of hypoiodous acid (IOH). In the absence of a suitable electron-withdrawing group, primary alcohols can be isolated from primary iodides in good yield as well (Scheme 72). It’s reasonable to postulate that upon iodoso formation, various nucleophiles may be introduced at this time promoting a substitution reaction. In our system, we saw a variety of interesting results.
Firstly, it was apparent the desired iodoso intermediate was forming in the reaction by TLC, what occurred following this event varied significantly.
171 Saksena, A. K.; Girijavallabhan, V. M.; Wang, H.; Liu, Y. T.; Pike, R. E.; Ganguly, A. K. Tet. Lett. 1996, 37, 6821.
172 Reich, H. J.; Peake, S. L. J. Am. Chem. Soc. 1978, 100, 4888.
Scheme 72. Literature precedent of alkyl iodine activation using peracids (MCPBA).
1.5 equiv. MCPBA DCM or CCl4
rt Ph S I
O O
Me Me
Ph S O O
Me
if EWG and β−
hydrogen present
1.5 equiv. MCPBA DCM or CCl4
rt
R I
R OH
Under the standard literature conditions using CCl4 or DCM, we witnessed low conversion to the desired primary alcohol, but dominant conversion to an achiral, rearranged compound 238 (Scheme 73). Mechanistically, we understand this to occur by the formation of the iodoso intermediate A, followed by the π-donation of the aromatic ring resulting in the phenonium ion cyclopropane intermediate B. At this stage, the phenonium ion is quenched to relieve ring strain through cyclopropane fragmentation and the resulting α-oxycarbocation (in C) is neutralized upon carbonate hydrolysis generating the achiral ketone. A recent report using a fluoro hypervalent iodine reagent proposes an analogous mechanism for a similarly rearranged product isolated.173
With these results in hand, it was apparent the intramolecular arene addition to the iodoso
carbon was fast and outcompeting the desired pathway of water/nucleophile addition to afford the alcohol product. We explored a variety of other solvents and conditions to no avail.
Additionally, other nucleophiles such as anisole (employed as a solvent) and fluoride (KF) were
173Intramolecular Fluorocyclization of Unsaturated Carboxylic Acids with a Stable Hypervalent Fluoroiodane Reagent. Angew. Chem. Int. Ed. 2015, Ahead of Print, DOI: 10.1002/anie.201507790
Scheme 73. Attempts to access iodoso intermediate A, and its possible role in formation of achiral ketone 238.
O O
O
O O
O OH MCPBA
DCM
up 60% yield MCPBA
tBuOH/H2O
O
OH MCPBA
CCl4
O O
O O I
O O
O
O O H2O O I
potential mechanism 223
- CO2
desired observed
O O
O
I MCPBA
A B C
237
223
238
examined resulting in unreacted starting material or undesired alkene. In summary, the nucleophiles and conditions employed were insufficient at displacing the generated iodoso intermediate. From these data, it is clear the combination of a neopentyl iodide and a vicinal carbonate narrowed the possible product transformations. Our focus then turned to the fragmentation of the carbonates taking advantage of these destabilizing features.
The primary iodide of iodocarbonate 223 can be reduced with HSnBu3 to generate 239 in good yield – notably little if any decarboxylation is observed (Scheme 74). Despite the success of this radical approach, other single electron donors (generated through light, thermally, or chemically) were not explored. The styrene-derived enantioenriched epoxide 240 was also formed under mild hydrolysis conditions using Amberlyst A26-OH in methanol.174 This is
significant from the viewpoint that carbon dioxide is effectively used as an equivalent to epoxidation, which normally requires an electrophilic source of oxygen (such as a peracid or dioxirane). As a further comparison and testament to the power of this derivatization approach,
174 Together with Thomas Struble
Scheme 74. Successful derivatizations of iodocarbonate 223 constructing enantioenriched, oxygenated compounds. Ee is maintained throughout.
O O
O I
91% ee benzene, 80 °C
AIBN Bu3SnH O
O O
Me
(95%) 90% ee
MeOH, 0 °C
Amberlyst A26–OH O
OH
(90%) 91% ee
OH OH Me
LiAlH4 THF, rt (91%)
91% ee
239 240
241
H O
H
OH CH3
-or- +
223
enantioselective epoxidations of 1,1-disubstituted alkenes are notoriously challenging and have only been reported on a few occasions by Shi, but in suboptimal enantioselection.175 Similarly, under reducing conditions with lithium aluminum hydride (LiAlH4) in THF, the enantioenriched tertiary diol 241 was formed (Scheme 74). Enantioenriched tertiary alcohols are also challenging to prepare by other more direct asymmetric methods such as Gringard/cuprate additions to ketones and aldol reactions. This CO2-fixation method therefore offers a two-step alternative to metal-free oxidations of homoallylic alcohols, for which CO2 is reduced and converted to either dialkyl carbonate (using Amberlyst) or methanol. The high levels of enantioselection are conserved in all of the transformations in Scheme 74.
3.3 An Enantioselective Approach to Chroman Natural Products via CO2-