Vladimir Birman

Total synthesis. In 2004, we completed total syntheses of the unusual marine alkaloid sceptrin.[1]  In 2007, we disclosed a regioselective synthesis of the antibiotic prekinamycin,[2] utilizing a novel annulation reaction and an enantioselective synthesis of the alkaloid lobeline[3] via the desymmetrization of a meso-diol precursor using one of our catalysts, BTM (see below). In 2016, we achieved a concise enantioselective synthesis of the meroterpenoid lingzhiol[4] featuring a biogenetically-inspired semipinacol rearrangement (Figure 1).

 

Figure 1. Completed synthetic targets

Asymmetric catalysis. Our efforts in the area of asymmetric catalysis have concentrated on enantioselective acyl transfer.  Our group has developed a new class of enantioselective acyl transfer catalysts (ABCs, for Amidine-Based Catalysts, Figure 2).[5]  These compounds, easily obtained from commercially available starting materials, are highly effective in the kinetic resolution (KR) of several classes of chiral secondary alcohols (Figure 3a).[6]  In addition, we have demonstrated for the first time the KR of chiral lactams and thiolactams via catalytic, enantioselective N-acylation (Figure 3b).[7] The enantioselectivities observed in all these cases are consistent with a transition state model based on cation-p interactions between the acylated intermediate and the substrate. Our computational studies in collaboration with the Houk group (UCLA) support this hypothesis.[8] Most recently, we also achieved KR of cyclic hydroxamic acids via O-acylation (Figure 3c).[9]  ABCs have also proved effective in promoting enantioselective alcoholysis of several classes of racemic acyl donors (Figure 4).[10] Some of these reactions proceed in the dynamic kinetic resolution (DKR) mode converting both enantiomers of the starting material into a signle enantiomer of the product.

 

Figure 2. Evolution of amidine-based catalysts (ABCs)

Figure 3. Enantioselective catalytic acylation promoted by ABCs

Figure 4. Enantioselective catalytic alcoholysis promoted by ABCs

A different type of applications in which ABCs have demonstrated their unique efficacy is cascade reactions accompanied by generation of new stereocenters. For example, we have disclosed a highly enantioselective transformation of thioesters into chiral thiochromenes requiring no additional reagents and giving off carbon dioxide as the only byproduct (Figure 5a).[11]^a Interestingly, a closely related rearrangement of thioesters into tricyclic thiochromanes (Figure 5b) proceeded very slowly with HBTM-2. By contrast, the electron-rich catalyst H-PIP (shown) displayed excellent rates and enantioselectivities in this reaction.^10b

 

Figure 5. Enantioselective rearrangement of thioesters promoted by ABCs

 

Another useful application of ABCs that we have developed is the enantio- and diastereo-selective synthesis of α-fluoro-β-amino acid derivatives by way of fluorinated β-lactams (Figure 6).[12]

 

Figure 6. Synthesis of α-fluoro-β-amino acid esters

 

Redox-responsive molecular switches and oligomers. Several years ago, we became interested in the de novo design of “molecular muscles”. In this context, we envisioned phenazine-1,6-dicarboxamides functioning as double molecular switches unfolding upon reduction and folding back upon re-oxidation (Figure 7a). A chain composed of such molecular switches would extend and contract reversibly in response to reduction-oxidation thus mimicking the function of actin-myosin filaments in Nature (Figure 7b). In 2020, we published our first proof-of-principle study (Figure 8).[13] Recently, we demonstrated that phenazine-based oligomers such as those shown in Figure 9 undergo fully reversible extension-contraction in response to chemical or electrochemical stimulation.[14]

 

Figure 7. Phenazine-based molecular switch: the concept

 

Figure 8. Proof-of-principle study.

 

Figure 9. Redox-responsive phenazine-based oligomers

 

For more details and other projects pursued in our group, please see additional references provided in the CV.

 

 

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[10] (a) Yang, X.; Birman, V. B. Chem. Eur. J. 2011, 17, 11296. DOI: 10.1002/chem.201101028 and references cited therein. (b) Yang, X.; Lu, G.; Birman, V. B. Org. Lett. 2010, 12, 892. DOI: 10.1021/ol902969j (c) Bumbu, V. D.; Birman, V. B. J. Am. Chem. Soc. 2011, 133, 13902. DOI: 10.1021/ja2058633 (d) Bumbu, V. D.; Yang, X.; Birman, V. B. Org. Lett. 2013, 15, 2790. DOI: 10.1021/ol401122g

[11](a) Ahlemeyer, N. A.; Birman, V. B. Org. Lett. 2016, 18, 3454 DOI: 10.1021/acs.orglett.6b01639 (b) Ahlemeyer, N. A.; Streff, E. V.; Muthupandi, P.; Birman, V. B. Org. Lett. 2017, 19, 6486. DOI:10.1021/acs.orglett.7b03044

[13] Yin, J.; Khalilov, A. N.; Muthupandi, P.; Ladd, R.; Birman, V. B., J. Am. Chem. Soc. 2020, 142, 60-63. DOI: 10.1021/jacs.9b11160

[14] (a) Yin, J.; Birman, V. B. Org. Lett. 2022, 24, 8759-8763. DOI: 10.1021/acs.orglett.2c03450 (b) Yin, J.; Birman, V. B. J. Org. Chem. 2022, 87, 15744-15753. DOI: 10.1021/acs.joc.2c01445