III. Brønsted Acid/Base-Catalyzed Halocyclizations and Carbon Dioxide-Fixation
3.1 History of Organocatalyzed, Asymmetric Halocyclizations
Chapter III
III. Brønsted Acid/Base-Catalyzed Halocyclizations and Carbon
(BAM) acid salt, to arrive at structurally unique iodo-γ-lactones in good yield and up to 98%
ee.124 A more significant aspect of this work was the finding that an achiral acid and a chiral Brønsted basic ligand dramatically affected the enantioselectivity of the halocyclization reaction (Scheme 57). The chiral Brønsted base ligand used in this study originated from the PBAM (2a) scaffold (Scheme 57) and achiral counterions were tested using this ligand system. Not only was the counterion effect crucial for this specific transformation, the catalyst backbone was also tuned, and the trans-stilbene diamine showed the highest efficacy in terms of both enantioselection and yield. This catalyst was dubbed StilbPBAM (stilbene pyrrolidine bis(amidine), 133) and was the first example of this catalyst being successfully employed in an asymmetric reaction in the Johnston group (Scheme 57).
trans-Stilbene diamine is reported to have a smaller N-C-C-N dihedral angle as compared to trans-cyclohexane diamine (52° compared to 69°, respectively),125 and may present the polar- ionic hydrogen bonding network in a more constrained and rigid manner (Figure 33). Soon after this reaction was developed, Dobish extended this methodology to substrates derived from
124 Dobish, M. C.; Johnston, J. N. J. Am. Chem. Soc. 2012, 134, 6068.
125 These dihedral angles were derived computationally: Kim, H.; Yen, C.; Preston, P.; Chin, J. Org. Lett. 2006, 8, 5239.
Figure 33. NCCN Dihedral angles of the two common chiral diamine backbones determined by density functional theory (DFT) calculations.125
N N N
R N R
R R
69° 52°
trans-stilbene diamine trans-cyclohexane diamine
H
H
H H
unactivated 1,2-disubstituted (internal) E-alkenes instead of 1,1-disubstituted alkenes. In this study, 6-membered lactones resulted from high catalyst-controlled regioselectivity favoring the 6-endo cyclization over the competing 5-exo cyclization.126
The first organocatalyzed, enantioselective iodolactonization was reported by Grossman in 1998 and presented the first reagent-controlled enantioselective halolactonization, although enantioselection was very low (15% ee, Scheme 58). Looking to expand the work of Grossman, Gao in 2004 investigated the use of cinchona-based alkaloid (199) as stoichiometric, chiral halogen equivalents in reagent-controlled asymmetric iodolactonizations – providing additional proof that this class of reactions can be stereochemically controlled using an organocatalyst
(Scheme 58).127 The highest enantioselectivity (19% ee) for the γ-lactone (5-exo, 198) was obtained from the ortho-tolyl analog 196 (though it only formed with 2:1 regioselectivity). Since then, similar halocyclization reactions employing organocatalysts have traditionally suffered from suboptimal stereoselectivity, regioselectivity (if applicable), and higher than ideal levels of catalyst loading.
126 Dobish, M. C., Johnston, J. N. unpublished results
127 Lu, X.-B.; Liang, B.; Zhang, Y.-J.; Tian, Y.-Z.; Wang, Y.-M.; Bai, C.-X.; Wang, H.; Zhang, R. J. Am. Chem.
Soc. 2004, 126, 3732.
Scheme 58. Seminal publications detailing the asymmetric halolactonizations of unsaturated acids mediated by organocatalysts.
Et
OH O
O Et O
I
-78 °C, 60 h 1952I+ BF4- (100 mol %)
DCM (0.03 M)
N
OBz
N Et
H OMe
HO O
Me O
O Me
I
Me
O I
* O
* *
* 0 °C, 10 h
XX (100 mol %) DCM, NaHCO3 (aq)
I2 150 mol % N OBz
N H OMe 26% ee (35:65) 19% ee
15% ee
(92%) 195
199 Grossman, 1998
Gao, 2004
194 193
196 197 198
More broadly, the field of alkene halo alkene-difunctionalization chemistry using organocatalysts has progressed at a relatively slow pace since pioneering efforts in the early 2000’s.128 In 2010, the Jacobsen group first reported the highly enantioselective iodolactonization reaction employing a tertiary aminourea derived organocatalyst.129 Other notable developments in this field over the past 5-7 years have examined chloro- and bromolactonizations,130 haloaminations,131 and even fluoroetherifications.132
The field has received increased attention as of late as catalysts advance, for widening synthetic utility of the products, and challenges associated with such a transformation from a growing number of groups including Borhan, Denmark, Jacobsen, Toste, Johnston, and Yeung (vida infra). New approaches to this class of reactions have been the result, many exploring novel and creative methods for activating the (pro)nucleophile, alkene nucleophile, and/or the terminal electrophile. Mechanistically, following olefin activation with a suitable electrophile in the presence of a chiral organocatalyst, various nucleophiles can be employed (primarily in intramolecular fashion) to set at least one stereocenter. Specific examples are illustrated in Figure 34. In 2012, Toste and coworkers optimized a highly unique set of conditions to afford bromocyclization products (201) with good enantioselection.133 The authors invented an interesting and unique electrophilic brominating reagent 202 that can be employed under phase transfer conditions in the presence of the chiral (and bulky) phosphoric acid catalyst 203 to afford highly selective cyclized product in high ee.
128 Fang, C.; Paull, D. H.; Hethcox, J. C.; Shugrue, C. R.; Martin, S. F. Org. Lett. 2012, 14, 6290. Tungen, J. E.;
Nolsoe, J. M. J.; Hansen, T. V. Org. Lett. 2012, 14, 5884.
129 Veitch, G. E.; Jacobsen, E. N. Angew. Chem. Int. Ed. 2010, 49, 7332.
130 Whitehead, D. C.; Yousefi, R.; Jaganathan, A.; Borhan, B. J. Am. Chem. Soc. 2010, 132, 3298. Yousefi, R.;
Whitehead, D. C.; Jaganathan, A.; Jamalifard, F.; Borhan, B. Abstr. Pap. Am. Chem. Soc. 2010, 239. Yousefi, R.;
Whitehead, D. C.; Mueller, J. M.; Staples, R. J.; Borhan, B. Org. Lett. 2011, 13, 608.
131 Zhou, L.; Chen, J.; Tan, C. K.; Yeung, Y. Y. J. Am. Chem. Soc. 2011, 133, 9164.
132 Lozano, O.; Blessley, G.; del Campo, T. M.; Thompson, A. L.; Giuffredi, G. T.; Bettati, M.; Walker, M.;
Borman, R.; Gouverneur, V. Angew. Chem. Int. Ed. 2011, 50, 8105.
133 Wang, Y.-M.; Wu, J.; Hoong, C.; Rauniyar, V.; Toste, F. D. J. Am. Chem. Soc. 2012, 134, 12928.
Another innovative approach involves expanding the use of various terminal electrophiles as can be seen in the heavily mechanism-driven field of “Lewis base activation of a Brønsted acid” pioneered by Scott Denmark134 (Figure 34). ‘Unactivated’ alkenes (206) are granted this namesake for the simple reason that the π-electrons of the alkene are weakly nucleophilic, and an activated electrophile is often needed to overcome this barrier of addition. Common pre-
134 Denmark, S. E.; Kalyani, D.; Collins, W. R. J. Am. Chem. Soc. 2010, 132, 15752. Denmark, S. E.; Burk, M. T.
Proc. Natl. Acad. Sci. U.S.A. 2010, 107, 20655. Collins, W. R.; Swager, T. M.; Denmark, S. E. Abstr. Pap. Am.
Chem. Soc. 2010, 240.
Figure 34. Reports from Toste, Zhang, and Denmark detailing each group’s respective reactions and modes of asymmetric catalysis.
NH Ph O
N N
Ar Br N N
Me Me
Me Me Me
+ + +
O TRIP
O P O
OH
TRIP TIPS
TIPS N
O Ph Br
PT Br+ 202 (10 mol%) PA cat 203 (1.3 equiv.)
Na3PO4 hexanes/xylenes
rt, 16 h
71% yield 98% ee
202
203
NHTf
205 (20 mol%) PhCO2H (1.1 equiv.)
NBS (1.1 equiv.) CHCl3, rt, 12 h
NHTf OBz
R R Br
R = OMe R = CH3 R = Ph
R = OMe, 21% ee, 55% yield R = CH3, 80% ee, 87% yield R = Ph, 90% ee, 82% yield
N N R1 R1
N O
N OMe
R1 = (DHQD)2PHAL Toste, 2012
Zhang, 2013
OH
N-phenylthiophthalamide MsOH (1 equiv.)
(R,R)-LB* 209 (10 mol%) CH2Cl2, -20 °C
O
R3
Denmark, 2014 R3
R1 R2 SPh
R2
R1 O
R3
R2 R1 PhS +
N N P
Se Me
Me N
(R,R)-LB* 209 Et
200 201
204 204
206 207 208
205
activated halogenated electrophiles are traditionally used, such as bromine135 (Br2), NBS (N- bromo succinimide), and N-iodo-4-fluorophthalimide (Jacobsen129) – the latter of which is additively activated due to the presence of an electron-withdrawing fluorine atom on the phthalimide’s aromatic ring. Denmark has mechanistically examined various Lewis base additives and catalysts to activate relatively sluggish main group electrophiles such as sulfur and selenium, in hopes of extending the breadth of electrophiles used in such a reaction. Another strong trend in the field is double activation of both the nucleophile and electrophile components with Brønsted acids or bases.
Figure 34 shows an example of a Lewis basic catalyst developed by Denmark appended to a chiral BINAM diamine backbone (R,R)-LB* 209. In the presence of a suitable Brønsted acid, a seleniranium136 or thiiranium137 activated ion pair is generated with the catalyst and the alkene can entrain the electrophile in this enantiodetermining step. Olefin to olefin transfer of these activated electrophiles is cited as a common process promoting non-selective additions not only Denmark’s chemistry, but in the halo alkene-difunctionalization field as a whole. Demark has successfully navigated around the issue by incorporating stronger Brønsted acids, but a full equivalent of an acid additive is often needed to observe desirable effects.138 Despite the pivotal advances in catalyst design and mechanistic understanding of these reactions, enantioselection in Denmark’s chemistry is modest to good at best, and extending this approach to other useful electrophiles is still in its infancy.
3.1.2 Efforts Towards a Multicomponent, Asymmetric Halocyclization Reaction
135 Denmark, S. E.; Burk, M. T.; Hoover, A. J. J. Am. Chem. Soc. 2010, 132, 1232.
136 Denmark, S. E.; Collins, W. R.; Cullen, M. D. J. Am. Chem. Soc. 2009, 131, 3490.
137 Denmark, S. E.; Kornfilt, D. J. P.; Vogler, T. J. Am. Chem. Soc. 2011, 133, 15308.
138 Denmark, S. E.; Kalyani, D.; Collins, W. R. J. Am. Chem. Soc. 2010, 132, 15752.
While halocyclization reactions have experienced much success and attention in recent years as previously discussed, an area mysteriously absent or perhaps unexplored is a multicomponent (3 or more), alkene activation-trap-halocyclization reaction. In such a reaction, greater increase in complexity could be achieved in a single pot using readily available reagents.
Scheme 59 depicts possible components an asymmetric 3-component reaction may entail.
Conceptually, the catalyst should be able to control the order of addition between all reaction components as well. A major driving force for a productive sequence may be the assembly of a thermodynamically-favored halocyclized product – non-productive reaction intermediates are in equilibrium and could revert to starting material.
Although we cannot say definitively where or when the enantiodetermining step is occurring using chiral BAM catalysts in Johnston group chemistry (Scheme 59), such as in the iodolactonization chemistry, we have evidence selectivity is dependent on both the carboxylate group and the hydrogen-bond accepting carbonyl of NIS (dual activation) in the iodolactonization chemistry that is responsible for stereocontrol. This has been shown in a number of experiments initially conducted by Dobish and others illustrating the fact that those two components are essential for stereocontrol. To date, other iodine sources and carboxylate
Scheme 59. Proposed 3-component, one-pot enantioselective iodocyclization. Although the enantiodetermining step is unclear, a 3-component process should mechanistically be feasible.
C Z Nuc : OH, SH, or NR Z : O, S, CR, NR, etc
Z
chiral bifunctional BAM catalyst
I+ R1
n
Nuc Z
Nuc Z
R1 I
n nucleophile electrophile
R R
N N
N N
H
N N
H HH organocatalyst
design
Bis(AMidine) R1
I Nuc R1
Nuc Z C Z I
non- reversible
n n
enantiodetermining?
N O O
ester moieties (i.e. tert-butyl ester or Boc group) result in lower ee or racemic product with almost no exception.
These data set the stage to explore carboxylate surrogates in the enantioselective halocyclization reaction, cognizant of the ultimate goal to uncover an asymmetric, three- component reaction. As outlined in Scheme 60, carbon dioxide via the carbonic acid (211) initially seemed like a reasonable substitute for a carboxylic acid, however optimizing CO2 as an electrophile in an organocatalyzed reaction could be challenging. If this hypothesis were to be supported, we would expect to see enantioselection under similar reaction conditions.
3.2 Initial Studies Towards a Bifunctional Brønsted Acid/Base Catalyzed,