Aggarwal Group Research

Practical Guides

Lithiation-Borylation: What this chemistry can do Practical Lithiation-Borylation: How to achieve best results Sparteine Sources

Research Overview

Aggarwal Research Table of Contents Lithiation-Borylation Transition-Metal Free Cross-Couplings Zweifel Olefinations and Enantiospecific Alkynylations Total Synthesis of Prostanoids Total Synthesis

Lithiation-Borylation

Lithiation–borylation is an invaluable carbon-carbon bond forming technique, which has been both pioneered and used extensively within our group to homologate organoboron species in high yields with excellent stereocontrol. This technique has allowed us to access to a wide-range of complex 3D structures that were previously inaccessible by traditional synthetic means [1-4].

The versatility of organoboron chemistry allows for the homologated organoboron species to be utilised in a number of ways, a prominent example of this is in Assembly-Line Synthesis. This is where up to 4 consecutive lithiation–borylation reactions can be carried out iteratively with exquisite 3D control to produce multiple contiguous stereogenic centres before a single aqueous work-up is required [5, 6].

Lithiation-Borylation and Assembly-Line Synthesis

Assembly-Line Synthesis mimics the way that complex natural products are biosynthesised in nature by essentially “growing” molecules with total control over their 3D shape [5, 6]. This has been demonstrated well within the context of total synthesis, where our group has quickly produced a number of synthetically challenging 3D structures [6, 7].

Lithiation-Borylation in Synthesis Sch725674 Stemaphylline Atorvastatin (Lipitor) Derivative Giganin Mycolactone Core Erogorgiaene Solandelactone E Clavosolide A Kalkitoxin Hydroxyphthioceranic Acid Faranal All-Syn Helical Structure Tatanan A

References

[1] Leonori, D., Aggarwal, V. K., Acc. Chem. Res., 2014, 47, 3174–3183 doi

[2] Essafi, S., Tomasi, S., Aggarwal, V. K., Harvey, J. N., J. Org. Chem., 2014, 79, 12148 − 12158 doi

[3] Fawcett, A., Nitsch, D., Ali, M., Bateman, J. M., Myers, E. L., Aggarwal, V. K., Angew. Chem. Int. Ed., 2016, 55, 14663–14667 doi

[4] Varela, A., Garve, L. K. B., Leonori, D., Aggarwal, V. K., Angew. Chem. Int. Ed., 2017, 56, 2127–2131 doi

[5] Burns, M., Essafi, S., Bame, J. R., Bull, S. P., Webster, M. P., Balieu, S., Dale, J. W., Butts, C. P., Harvey, J. N., Aggarwal, V. K., Nature, 2014, 513, 183–188 doi

[6] Balieu, S., Hallett, G. E., Burns, M., Bootwicha, T., Studley, J., Aggarwal, V. K., J. Am. Chem. Soc., 2015, 137, 4398–4403 doi

[7] Noble, A., Roesner, S., Aggarwal, V. K., Angew. Chem. Int. Ed., 2016, 55, 15920–15924 doi

Transition-Metal Free Cross-Couplings

Cross-coupling reactions account for the formation of over 60% of C-C bonds in the pharmaceutical industry. However, traditional cross-coupling reactions often rely heavily on the use of expensive or toxic transition-metal catalysts. As such, there is significant interest in developing more efficient transition-metal free methods.

Recently, our group has successfully developed new methodology towards transition-metal free cross-coupling reactions based upon our lithiation-borylation chemistry. The methodology allows for the reliable enantiospecific sp2-sp3 coupling of both secondary and tertiary boronic esters with electron-rich aryl lithium reagents [1-3].

Note: The transition-metal free cross-couplings of electron-deficient pyridines take place via a different mechanism than that shown below, for further information see reference 3.

Transition-Metal Free Cross-Couplings

References

[1] Bonet, A., Odachowski, M., Leonori, D., Essafi, S., Aggarwal, V. K., Nat. Chem., 2014, 6, 584–589 doi

[2] Odachowski, M., Bonet, A., Essafi, S., Conti-Ramsden, P., Harvey, J. N., Leonori, D., Aggarwal, V. K., J. Am. Chem. Soc., 2016, 138, 9521–9532 doi

[3] Llaveria J., Leonori D., Aggarwal, V. K., J. Am. Chem. Soc., 2015, 137, 10958–10961 doi

Boronates as Nucleophiles

Expanding upon our transition-metal free cross-coupling chemistry, we have developed an efficient method for the enantiospecific conversion of boronic esters into an array of synthetically useful functional groups [1, 2].

By trapping chiral boronic esters with readily-available electron-deficient organolithium reagents, we can form chiral boronates. These boronates act as organometallic-type nucleophiles, reacting with a wide-range of electrophiles and delivering synthetically useful products through the reliable net inversion of stereochemistry [1, 2].

Boronates as Nucleophiles

References:

[1] Larouche-Gauthier, R., Elford, T. G., Aggarwal, V. K., J. Am. Chem. Soc., 2011, 133, 16794–16797 doi

[2] Sandford, C., Rasappan, R., Aggarwal, V. K., J. Am. Chem. Soc., 2015, 137, 10100–10103 doi

Zweifel Olefinations and Enantiospecific Alkynylations

Our group has also successfully developed the transition-metal free stereodivergent coupling of vinyl halides with boronic esters, based upon the Zweifel olefination [1].

The process can be used to couple sp2 and chiral sp3 boronic esters with complete enantiospecificity, and most importantly, it allows for the highly stereoselective synthesis of either the E- or Z-alkene from a single isomer of vinyl coupling partner [1].

Stereodivergent Zweifel Olefinations

Expanding upon our Zweifel olefination methodology, we have also successfully developed a novel approach towards the enantiospecific deborylative alkynylation of enantioenriched secondary and tertiary boronic esters [2].

The process allows for the conversion of chiral boronic esters into terminal alkynes with high yields and excellent levels of enantiospecificity. Furthermore, internal and silyl-protected alkynes can also be produced with this process [2].

Enantiospecific Alkynylations

References

[1] Armstrong, R. J., García-Ruiz, C., Myers, E. L., Aggarwal, V. K., Angew. Chem. Int. Ed., 2017, 56, 786–790 doi

[2] Wang, Y., Noble, A., Myers, E. L., Aggarwal, V. K., Angew. Chem. Int. Ed., 2016, 55, 4270–4274 doi

Total Synthesis of Prostanoids

Prostanoids are a family of biologically significant natural products derived from arachidonic acid, which are known to play crucial roles in inflammation, blood pressure control and platelet formation. Prostanoid total synthesis has been an active area of research since the 1970s and has led to the development of a number of impressive, yet lengthy, routes.

Our uniform strategy towards the total synthesis of various prostanoids and their derivatives exploits a key enal intermediate, which is prepared via a stereocontrolled organocatalytic dimerisation of succinaldehyde [1, 2].

This crystalline intermediate can be readily produced on gram-scale and serves as an advanced intermediate for the quick and efficient synthesis of a number of complex prostanoids, including PGF, a medicinally important natural product that was synthesised by our group on gram-scale in only 7 steps [1, 2].

Total Synthesis of Prostanoids

References

[1] Coulthard, G., Erb, W., Aggarwal, V. K., Nature, 2012, 489, 278–281 doi

[2] Prévost, S., Thai, K., Schützenmeister, N., Coulthard, G., Erb, W., Aggarwal, V. K., Org. Lett., 2015, 17, 504–507 doi

Total Synthesis

Our group has a keen interest in using total synthesis to showcase the utility of our methodology in enabling facile access to a range of complex natural products.

These currently include α-Cyclopiazonic Acid, 6-Deoxyerythronolide B and the Bahamaolides A and B.

Current Total Synthesis Targets

(Original text and schemes prepared by Steven Bennett. HTML coding and corrections by Oleksandr Zhurakovskyi.)