Provided herein are cell-free systems for generating carbapenems, e.g., a compound of the Formula (I): or salts thereof; wherein , R1, R2, R3, R4, R5, and R6 are defined herein. Also provided are pharmaceutical compositions comprising a compound generated by the inventive cell-free system, and use
Provided herein are cell-free systems for generating carbapenems, e.g., a compound of the Formula (I): or salts thereof; wherein , R1, R2, R3, R4, R5, and R6 are defined herein. Also provided are pharmaceutical compositions comprising a compound generated by the inventive cell-free system, and use of these compounds and compositions for the treatment of bacterial infections.
대표청구항▼
1. A method of generating a compound of Formula (I-a): or a salt or tautomer thereof, or a combination thereof; the method comprising:(1) providing one or more cell lysates comprising: a. ProA and ProB, or γ-glutamyl kinase-GP-reductase multienzyme complex;b. Glk;c. Pgi;d. PfkA;e. Fba;f. TpiA;g. Ga
1. A method of generating a compound of Formula (I-a): or a salt or tautomer thereof, or a combination thereof; the method comprising:(1) providing one or more cell lysates comprising: a. ProA and ProB, or γ-glutamyl kinase-GP-reductase multienzyme complex;b. Glk;c. Pgi;d. PfkA;e. Fba;f. TpiA;g. GapA;h. Pgk;i. GpmA;j. Eno;k. PykA;l. PykF;m. AceE;n. AceF;o. acetyl-CoA acetyltransferase;p. acetyl-CoA carboxylase and malonyl-CoA reductase, or beta-alanine transaminase;q. S-hydratase and 3-hydroxyacyl-CoA dehydrogenese, or beta-oxidation multienzyme;r. crotonyl-CoA reductase;s. threonine aldolase;t. carboxymethyl-Pro synthase;u. carbapenam synthetase or beta-lactam synthetase; andv. carbapenem synthase; or isozymes thereof; wherein the one or more cell lysates are contacted with glucose and glycine, or salts thereof, to provide a compound of Formula (I-a) or a salt or tautomer thereof or a combination thereof, wherein R1 is hydrogen, R2 is —CH2CH3, R3 is hydrogen, R4 is hydrogen, and R5 is —OH; or(2) providing one or more cell lysates comprising: a. ProA and ProB, or γ-glutamyl kinase-GP-reductase multienzyme complex;b. Glk;c. Pgi;d. PfkA;e. Fba;f. TpiA;g. GapA;h. Pgk;i. GpmA;j. Eno;k. PykA;l. PykF;m. AceE;n. AceF;o. acetyl-CoA carboxylase and malonyl-CoA reductase, or beta-alanine transaminase;p. threonine aldolase;q. carboxymethyl-Pro synthase;r. carbapenam synthetase or beta-lactam synthetase; ands. carbapenem synthase; or isozymes thereof; wherein the one or more cell lysates are contacted with glucose and glycine, or salts thereof, to provide a compound of Formula (I-a) or a salt or tautomer thereof or a combination thereof, wherein R1 is hydrogen, R2 is hydrogen, R3 is hydrogen, R4 is hydrogen, and R5 is —OH; or(3) providing one or more cell lysates comprising: a. ProA and ProB, or γ-glutamyl kinase-GP-reductase multienzyme complex;b. Glk;c. Pgi;d. PfkA;e. Fba;f. TpiA;g. GapA;h. Pgk;i. GpmA;j. Eno;k. PykA;l. PykF;m. AceE;n. AceF;o. acetyl-CoA acetyltransferase;p. S-hydratase and 3-hydroxyacyl-CoA dehydrogenese, or beta-oxidation multienzyme;q. crotonyl-CoA reductase;r. carboxymethyl-Pro synthase;s. carbapenam synthetase or beta-lactam synthetase; andt. carbapenem synthase; or isozymes thereof; wherein the one or more cell lysates are contacted with glucose and an optionally substituted glutamate of the formula (i): or salts thereof, to provide a compound of Formula (I-a) or a salt or tautomer thereof or a combination thereof, wherein R1 is hydrogen and R2 is —CH2CH3; or (4) providing one or more cell lysates comprising: a. ProA and ProB, or γ-glutamyl kinase-GP-reductase multienzyme complex;b. Glk;c. Pgi;d. PfkA;e. Fba;f. TpiA;g. GapA;h. Pgk;i. GpmA;j. Eno;k. PykA;l. PykF;m. AceE;n. AceF;o. acetyl-CoA carboxylase;p. carboxymethyl-Pro synthase;q. carbapenam synthetase or beta-lactam synthetase; andr. carbapenem synthase; or isozymes thereof; wherein the one or more cell lysates are contacted with glucose and an optionally substituted glutamate of the formula (i): or salts thereof, to provide a compound of Formula (I-a) or a salt or tautomer thereof or a combination thereof, wherein R1 is hydrogen and R2 is hydrogen; or (5) providing one or more cell lysates comprising: a. Glk;b. Pgi;c. PfkA;d. Fba;e. TpiA;f. GapA;g. Pgk;h. GpmA;i. Eno;j. PykA;k. PykF;l. AceE;m. AceF;n. acetyl-CoA acetyltransferase;o. S-hydratase and 3-hydroxyacyl-CoA dehyrogenase, beta-oxidation multienzyme;p. crotonyl-CoA reductase,q. proline 3-hydroxylase;r. proline oxidase;s. carboxymethyl-Pro synthase;t. carbapenam synthetase or beta-lactam synthetase; andu. carbapenem synthase; or isozymes thereof; wherein the one or more cell lysates are contacted with glucose and a proline compound of formula (iv): or salts thereof, wherein R5 is hydrogen, to provide a compound of Formula (I-a) or a salt or tautomer thereof or a combination thereof, wherein R1 is hydrogen, R2 is —CH2CH3, and R5 is —OH; or (6) providing one or more cell lysates comprising: a. Glk;b. Pgi;c. PfkA;d. Fba;e. TpiA;f. GapA;g. Pgk;h. GpmA;i. Eno;j. PykA;k. PykF;l. AceE;m. AceF;n. acetyl-CoA carboxylase;o. proline 3-hydroxylase;p. proline oxidase;q. carboxymethyl-Pro synthase;r. carbapenam synthetase or beta-lactam synthetase; ands. carbapenem synthase; or isozymes thereof; wherein the one or more cell lysates are contacted with glucose and a proline compound of formula (iv): or salts thereof, wherein R5 is hydrogen, to provide a compound of Formula (I-a) or a salt or tautomer thereof or a combination thereof, wherein R1 is hydrogen, R2 is hydrogen, and R5 is —OH; or (7) providing one or more cell lysates comprising: a. Glk;b. Pgi;c. PfkA;d. Fba;e. TpiA;f. GapA;g. Pgk;h. GpmA;i. Eno;j. PykA;k. PykF;l. AceE;m. AceF;n. acetyl-CoA acetyltransferase;o. S-hydratase and 3-hydroxyacyl-CoA dehydrogenase, or beta-oxidation multienzyme;p. crotonyl-CoA reductase,q. proline oxidase;r. carboxymethyl-Pro synthase;s. carbapenam synthetase or beta-lactam synthetase; andt. carbapenem synthase; or isozymes thereof; wherein the one or more cell lysates are contacted with glucose and a proline compound of formula (iv): or salts thereof, to provide a compound of Formula (I-a) or a salt or tautomer thereof or a combination thereof, wherein R1 is hydrogen and R2 is —CH2CH3; or (8) providing one or more cell lysates comprising: a. Glk;b. Pgi;c. PfkA;d. Fba;e. TpiA;f. GapA;g. Pgk;h. GpmA;i. Eno;j. PykA;k. PykF;l. AceE;m. AceF;n. acetyl-CoA carboxylase;o. proline oxidase;p. carboxymethyl-Pro synthase;q. carbapenam synthetase or beta-lactam synthetase; andr. carbapenem synthase; or isozymes thereof; wherein the one or more cell lysates are contacted with glucose and a proline compound of formula (iv): or salts thereof, to provide a compound of Formula (I-a) or a salt or tautomer thereof or a combination thereof, wherein R1 is hydrogen and R2 is hydrogen; wherein: the dashed line represents a double bond;each instance of R3 and R4 is independently selected from the group consisting of hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted heteroalkyl, optionally substituted heteroalkenyl, optionally substituted heteroalkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, and optionally substituted heteroaryl;R5 is hydrogen or —OR8;each instance of R8 is independently selected from the group consisting of hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted heteroalkyl, optionally substituted heteroalkenyl, optionally substituted heteroalkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, —C(═O)R8a, —C(═O)OR8a, —C(═O)SR8a, —C(═O)N(R8b)2, —C(═NR8b)R8a, —C(═NR8b)OR8a, —C(═NR8b)SR8a, —C(═NR8b)N(R8b)2, —C(═S)R8a, —C(═S)OR8a, —C(═S)SR8a, —C(═S)N(R8b)2, —C(═O)NR8bSO2R8a, —S(═O)R8a, —SO2R8a, —SO2N(R8a)2, —Si(R8a)3, —P(═O)(R8a)2, —P(═O)(OR8a)2, —P(═O)(R8a)(OR8a), —P(═O)(R8a)(N(R8b)2), —P(═O)(N(R8b)2)2, —P(═O)2R8a, —P(═O)2OR8a, —P(═O)2N(R8b)2, —B(R8a)2, —B(OR8a)2, and —BR8a(OR8a), wherein R8a is selected from the group consisting of optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted heteroalkyl, optionally substituted heteroalkenyl, optionally substituted heteroalkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, if attached to an oxygen atom an oxygen protecting group, and if attached to a sulfur atom a sulfur protecting group, or two R8a groups or an R8a and R8b group are joined to form an optionally substituted heterocyclic ring; and each instance of R8b is independently selected from the group consisting of hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted heteroalkyl, optionally substituted heteroalkenyl, optionally substituted heteroalkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, and a nitrogen protecting group, or two R8b are joined to form an optionally substituted heterocyclic ring; andR7a is hydrogen;wherein one or more enzymes selected from the group consisting of carboxymethyl-Pro synthase, carbapenam synthetase, beta-lactam synthetase, carbapenem synthase, and isozymes thereof, is sequestered in the periplasmic space of the cell prior to lysing; andwherein the one or more cell lysates are bacterial cell lysates. 2. The method of claim 1, wherein R3 is hydrogen or —CH3. 3. The method of claim 1, wherein R4 is hydrogen. 4. The method of claim 1, wherein one or more enzymes selected from the group consisting of ProA, ProB, γ-glutamyl kinase-GP-reductase multienzyme complex, Glk, Pgi, PfkA, Fba, TpiA, GapA, Pgk, GpmA, Eno, PykA, PykF, AceE, Ace, acetyl-CoA acetyltransferase, beta-oxidation multienzyme, S-hydratase, 3-hydroxyacyl-CoA dehydrogenase, crotonyl CoA reductase, acetyl-CoA carboxylase, malonyl-CoA reductase, threonine aldolase, beta-alanine transaminase, proline 3-hydroxylase, proline oxidase, and isozymes thereof, were present in the cell cytoplasm prior to lysing. 5. The method of claim 1, wherein the cell lysate is a lysate of an E. coli organism engineered to overexpress the group of enzymes. 6. The method of claim 1, wherein R5 is hydrogen or —OH, and the proline compound of formula (iv): or salt thereof, is enzymatically converted to a compound of formula: or salt thereof; upon contact with proline oxidase; and wherein glucose or salt thereof is enzymatically converted to an optionally substituted CoA compound of formula (iii): or salt thereof; wherein —SCoA is Coenzyme A monoradical. 7. The method of claim 1, wherein the proline compound of formula (iv): or salt thereof, wherein R5 is hydrogen, is enzymatically converted to a 3-hydroxylated proline compound of formula: or salt thereof; upon contact with proline-3-hydroxylase, and the 3-hydroxylated proline compound of formula (iv-a) or salt thereof, is enzymatically converted to a 3-hydroxylated compound of formula: upon contact with proline oxidase. 8. The method of claim 1, wherein R5 is —OH, and the glucose and glycine or salts thereof are enzymatically converted to an optionally substituted glutamate semialdehyde of formula (ii): or salt thereof, upon contact with ProA and ProB, or γ-glutamyl kinase-GP-reductase multienzyme complex; acetyl-CoA carboxylase and malonyl-CoA reductase, or a beta-alanine transaminase; Glk; Pgi; PfkA; Fba; TpiA; GapA; Pgk; GpmA; Eno; PykA; PykF; AceE; AceF; and threonine aldolase; or isozymes thereof; andwherein glucose or salt thereof is enzymatically converted to an optionally substituted CoA compound of formula (iii): or salt thereof; wherein —SCoA is Coenzyme A monoradical. 9. The method of claim 1, wherein R5 is hydrogen or —OH, and the optionally substituted glutamate of formula (i) or salt thereof is enzymatically converted to an optionally substituted glutamate semialdehyde compound of formula (ii): or salt thereof; upon contact with ProA and ProB, or γ-glutamyl kinase-GP-reductase multienzyme complex; andwherein glucose or salt thereof is enzymatically converted to an optionally substituted CoA compound of formula (iii): or salt thereof; wherein —SCoA is Coenzyme A monoradical. 10. The method of claim 1, wherein the optionally substituted glutamate of formula (i): or salt thereof, is enzymatically converted to a compound of formula (v): or salt thereof; upon contact with ProA and ProB, or γ-glutamyl kinase-GP-reductase multienzyme complex. 11. A method of generating a compound of Formula (I-a): or a salt or tautomer thereof, or a combination thereof, the method comprising:(1) providing one or more cell lysates comprising: a. ProA and ProB, or γ-glutamyl kinase-GP-reductase multienzyme complex;b. Glk;c. Pgi;d. PfkA;e. Fba;f. TpiA;g. GapA;h. Pgk;i. GpmA;j. Eno;k. PykA;l. PykF;m. AceE;n. AceF;o. acetyl-CoA acetyltransferase;p. acetyl-CoA carboxylase and malonyl-CoA reductase, or beta-alanine transaminase;q. S-hydratase and 3-hydroxyacyl-CoA dehydrogenase, or beta-oxidation multienzyme;r. crotonyl-CoA reductase;s. threonine aldolase;t. carboxymethyl-Pro synthase;u. carbapenam synthetase or beta-lactam synthetase; andv. carbapenem synthase; or isozymes thereof; wherein the one or more cell lysates are contacted with glucose and glycine, or salts thereof, to provide a compound of Formula (I-a) or a salt or tautomer thereof or a combination thereof, wherein R1 is hydrogen, R2 is —CH2CH3, R3 is hydrogen, R4 is hydrogen, and R5 is —OH; or(2) providing one or more cell lysates comprising: a. ProA and ProB, or γ-glutamyl kinase-GP-reductase multienzyme complex;b. Glk;c. Pgi;d. PfkA;e. Fba;f. TpiA;g. GapA;h. Pgk;i. GpmA;j. Eno;k. PykA;l. PykF;m. AceE;n. AceF;o. acetyl-CoA carboxylase and malonyl-CoA reductase, or beta-alanine transaminase;p. threonine aldolase;q. carboxymethyl-Pro synthase;r. carbapenam synthetase or beta-lactam synthetase; ands. carbapenem synthase; or isozymes thereof; wherein the one or more cell lysates are contacted with glucose and glycine, or salts thereof, to provide a compound of Formula (I-a) or a salt or tautomer thereof or a combination thereof, wherein R1 is hydrogen, R2 is hydrogen, R3 is hydrogen, R4 is hydrogen, and R5 is —OH; or(3) providing one or more cell lysates comprising: a. ProA and ProB, or γ-glutamyl kinase-GP-reductase multienzyme complex;b. Glk;c. Pgi;d. PfkA;e. Fba;f. TpiA;g. GapA;h. Pgk;i. GpmA;j. Eno;k. PykA;l. PykF;m. AceE;n. AceF;o. acetyl-CoA acetyltransferase;p. S-hydratase and 3-hydroxyacyl-CoA dehydrogenese, or beta-oxidation multienzyme;q. crotonyl-CoA reductase,r. carboxymethyl-Pro synthase;s. carbapenam synthetase or beta-lactam synthetase; andt. carbapenem synthase; or isozymes thereof; wherein the one or more cell lysates are contacted with glucose and an optionally substituted glutamate of the formula (i): or salts thereof, wherein R5 is —OH, to provide a compound of Formula (I-a) or a salt or tautomer thereof or a combination thereof, wherein R1 is hydrogen, R2 is —CH2CH3, and R5 is —OH; or (4) providing one or more cell lysates comprising: a. ProA and ProB, or γ-glutamyl kinase-GP-reductase multienzyme complex;b. Glk;c. Pgi;d. PfkA;e. Fba;f. TpiA;g. GapA;h. Pgk;i. GpmA;j. Eno;k. PykA;l. PykF;m. AceE;n. AceF;o. acetyl-CoA carboxylase;p. carboxymethyl-Pro synthase;q. carbapenam synthetase or beta-lactam synthetase; andr. carbapenem synthase; or isozymes thereof; wherein the one or more cell lysates are contacted with glucose and an optionally substituted glutamate of the formula (i): or salts thereof, wherein R5 is —OH, to provide a compound of Formula (I-a) or a salt or tautomer thereof or a combination thereof, wherein R1 is hydrogen, R2 is hydrogen, and R5 is —OH; or (5) providing one or more cell lysates comprising: a. Glk;b. Pgi;c. PfkA;d. Fba;e. TpiA;f. GapA;g. Pgk;h. GpmA;i. Eno;j. PykA;k. PykF;l. AceE;m. AceF;n. acetyl-CoA acetyltransferase;o. S-hydratase and 3-hydroxyacyl-CoA dehydrogenese, or beta-oxidation multienzyme;p. crotonyl-CoA reductase,q. proline 3-hydroxylase;r. proline oxidase;s. carboxymethyl-Pro synthase;t. carbapenam synthetase or beta-lactam synthetase; andu. carbapenem synthase; or isozymes thereof; wherein the one or more cell lysates are contacted with glucose and a proline compound of formula (iv): or salts thereof, wherein R5 is hydrogen, to provide a compound of Formula (I-a) or a salt or tautomer thereof or a combination thereof, wherein R1 is hydrogen, R2 is —CH2CH3, and R5 is —OH; or (6) providing one or more cell lysates comprising: a. Glk;b. Pgi;c. PfkA;d. Fba;e. TpiA;f. GapA;g. Pgk;h. GpmA;i. Eno;j. PykA;k. PykF;l. AceE;m. AceF;n. acetyl-CoA carboxylase;o. proline 3-hydroxylase;p. proline oxidase;q. carboxymethyl-Pro synthase;r. carbapenam synthetase or beta-lactam synthetase; ands. carbapenem synthase; or isozymes thereof; wherein the one or more cell lysates are contacted with glucose and a proline compound of formula (iv): or salts thereof, wherein R5 is hydrogen, to provide a compound of Formula (I-a) or a salt or tautomer thereof or a combination thereof, wherein R1 is hydrogen, R2 is hydrogen, and R5 is —OH; or (7) providing one or more cell lysates comprising: a. Glk;b. Pgi;c. PfkA;d. Fba;e. TpiA;f. GapA;g. Pgk;h. GpmA;i. Eno;j. PykA;k. PykF;l. AceE;m. AceF;n. acetyl-CoA acetyltransferase;o. S-hydratase and 3-hydroxyacyl-CoA dehydrogenese, or beta-oxidation multienzyme;p. crotonyl-CoA reductase,q. proline oxidase;r. carboxymethyl-Pro synthase;s. carbapenam synthetase or beta-lactam synthetase; andt. carbapenem synthase; or isozymes thereof; wherein the one or more cell lysates are contacted with glucose and a proline compound of formula (iv): or salts thereof, wherein R5 is —OH, to provide a compound of Formula (I-a) or a salt or tautomer thereof or a combination thereof, wherein R1 is hydrogen, R2 is —CH2CH3, and R5 is —OH; or (8) providing one or more cell lysates comprising: a. Glk;b. Pgi;c. PfkA;d. Fba;e. TpiA;f. GapA;g. Pgk;h. GpmA;i. Eno;j. PykA;k. PykF;l. AceE;m. AceF;n. acetyl-CoA carboxylase;o. proline oxidase;p. carboxymethyl-Pro synthase;q. carbapenam synthetase or beta-lactam synthetase; andr. carbapenem synthase; or isozymes thereof; wherein the one or more cell lysates are contacted with glucose and a proline compound of formula (iv): or salts thereof, wherein R5 is —OH, to provide a compound of Formula (I-a) or a salt or tautomer thereof or a combination thereof, wherein R1 is hydrogen, R2 is hydrogen, and R5 is —OH; wherein: the dashed line represents a double bond;each instance of R3 and R4 is independently selected from the group consisting of hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted heteroalkyl, optionally substituted heteroalkenyl, optionally substituted heteroalkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, and optionally substituted heteroaryl;R7a is hydrogen; andwherein the one or more cell lysates are bacterial cell lysates;wherein the combination of glucose and glycine, or salts thereof, or the combination of glucose and an optionally substituted glutamate of the formula (i), or salts thereof, is enzymatically converted to an optionally substituted CoA compound of formula (iii), or salt thereof, and an optionally substituted glutamate semialdehyde of formula (ii), or salt thereof: wherein —SCoA is Coenzyme A monoradical; and wherein the optionally substituted glutamate semialdehyde of formula (ii) or salt thereof and the optionally substituted CoA compound of formula (iii) or salt thereof are enzymatically converted to a pyrrolidinyl compound of Formula (II-a): or salt thereof, upon contact with carboxymethylPro synthase or an isozyme thereof; further wherein the pyrrolidinyl compound (II-a) or salt thereof is enzymatically converted to a β-lactam compound of Formula (III-a): or salt thereof, upon contact with carbapenam synthetase or beta-lactam synthetase, or an isozyme thereof; and further wherein the β-lactam compound of Formula (III-a) or salt thereof generates a compound of Formula (I-a): or salt thereof, wherein represents a double bond, upon contact with carbapenem synthase or isozyme thereof. 12. The method of claim 1, wherein R5 is hydrogen or —OH, and the combination of glucose or salt thereof and the proline compound of formula (iv) or salt thereof is enzymatically converted to an optionally substituted CoA compound of formula (iii), or salt thereof, and a compound of formula (v), or salt thereof: wherein —SCoA is Coenzyme A monoradical; and wherein the optionally substituted CoA compound of formula (iii), or salt thereof, and the compound of formula (v), or salt thereof are enzymatically converted to a pyrrolidinyl compound of Formula (II-a): or salt thereof, upon contact with carboxymethylPro synthase or an isozyme thereof. 13. The method of claim 11, wherein the compound of Formula (I-a): or a salt or tautomer thereof, or a combination thereof, wherein represents a double bond; is contacted with a compound of the formula: R8′—X wherein: X is a leaving group; andR8′ is selected from the group consisting of —C(═O)R8a, —C(═O)OR8a, —C(═O)SR8a, —C(═O)N(R8b)2, —C(═NR8b)R8a, —C(═NR8b)OR8a, —C(═NR8b)SR8a, —C(═NR8b)N(R8b)2, —C(═S)R8a, —C(═S)OR8a, —C(═S)SR8a, —C(═S)N(R8b)2, —C(═O)NR8bSO2R8a, —S(═O)R8a, —SO2R8a, —SO2N(R8a)2, —Si(R8a)3, —P(═O)(R8a)2, —P(═O)(OR8a)2, —P(═O)(R8a)(OR8a), —P(═O)(R8a)(N(R8b)2), —P(═O)(N(R8b)2)2, —P(═O)2R8a, —P(═O)2OR8a, —P(═O)2N(R8b)2, —B(R8a)2, —B(OR8a)2, and —BR8a(OR8a), wherein R8a is selected from the group consisting of optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted heteroalkyl, optionally substituted heteroalkenyl, optionally substituted heteroalkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, if attached to an oxygen atom an oxygen protecting group, and if attached to a sulfur atom a sulfur protecting group, or two R8a groups or an R8a and R8b group are joined to form an optionally substituted heterocyclic ring; and each instance of R8b is independently selected from the group consisting of hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted heteroalkyl, optionally substituted heteroalkenyl, optionally substituted heteroalkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, and a nitrogen protecting group, or two R8b are joined to form an optionally substituted heterocyclic ring;to provide a compound of Formula (I-e): or salt thereof. 14. The method of claim 13, wherein the compound of Formula (I-e) is contacted with a compound of the formula HS—R8, wherein R8 is selected from the group consisting of optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted heteroalkyl, optionally substituted heteroalkenyl, optionally substituted heteroalkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, and optionally substituted heteroaryl;to provide a thiol-containing compound of Formula (I-c): or salt thereof. 15. The method of claim 11, wherein R2 is —CH2CH3. 16. The method of claim 15, further comprising contacting the compound with an oxygenase enzyme to provide a hydroxylated compound wherein R2 is —CH(OH)CH3. 17. The method of claim 11, wherein R1 and R2 are both hydrogen. 18. The method of claim 17, further comprising contacting the compound with a methyltransferase enzyme to provide a compound wherein R1 is hydrogen and R2 is —CH3 or —CH2CH3. 19. The method of claim 18, further comprising contacting the compound wherein R2 is —CH2CH3 with an oxygenase enzyme to provide a hydroxylated compound wherein R2 is —CH(OH)CH3. 20. The method of claim 14, wherein R8 is an optionally substituted alkyl, optionally substituted heteroalkyl, or optionally substituted heterocyclyl. 21. The method of claim 20, wherein R8 is selected from the group consisting of: wherein X− is a counterion.
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