Lithiation-Borylation Methodology and Its Application in Synthesis. Literature Seminar 2018/06/23 Hongyu CHEN (M1)

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1 thiation-orylation thodology and Its Application in Synthesis terature Seminar 2018/06/23 ongyu CEN (M1)

2 Contents Introduction Part 1 : Factors responsible for the 1,2-migration Part 2 : Factors responsible for stereocontrol Part 3 : Application of lithiation-borylation reaction in synthesis Summary

3 Contents Introduction Part 1 : Factors responsible for the 1,2-migration Part 2 : Factors responsible for stereocontrol Part 3 : Application of lithiation-borylation reaction in synthesis Summary

4 Anatomy of The thiation-orylation eaction Stereoretentive 3 () 2 () 2 X 3 () 2 orylation 2 LG oronate complex 1,2-tallate earrangement 3 2 omologated product 2 LG thiation 2 LG LG = Cb or TI X = or Sn 3 thium carbenoid Stereoinvertive orylation 2 3 LG () 2 oronate complex 1,2-tallate earrangement () 2 omologated product, 2 and 3 = Alkyl, Alkenyl or Aryl eagent Control Complete Stereospecificity Contiguous Stereocenters Quaternary Stereocenters Natural Product Synthesis Assembly-ne Synthesis Arylation Alkynylation xidation Fluorination Assembly-ne Synthesis

5 The First Nonenzymatic Asymmetric Synthesis (. C. rown, 1961) + 3 DG 0 ) 2 [] ) 2 90% yield, 87% ee * cis, cis; cis, trans; trans, trans etc. *CCCC * ' * *C 2 General Asymmetric Synthesis via Chiral rganoboranes * * ' ' *D *C *C 2 *N 2 *C 2 CC 2 * * N *CC *CC *C * CN 2 *C 2 C * C *C 2 CN *C 2 C 2 Et *CCC rown,. C. et al. Pure & Appl. Chem., 1991, 63, 307. *C(CN) 2 * 2 C

6 Complementary outes to Chiral oronic Esters A) Matteson: Stepwise substrate-controlled approach C 2 2 -Mgr 2 ) oppe: Stepwise reagent-controlled approach (i-pr)3 (pin) 2 -Mgr 2 Cb then pinacol Cb (pin) C) thiation-orylation: Iterative reagent-controlled approach Cb 2 -(pin) 2 3 Cb (pin) 2 3 (pin) Aggarwal, V. K. et al. Acc. Chem. es., 2014, 47, 3174.

Prof. Varinder Kumar Aggarwal 1980-1983 A, University of Cambridge 1983-1986 D, University of Cambridge (Prof. Stuart Warren) 1986-1988 Postdoctoral Position, Columbia University (Prof.

7 Prof. Varinder Kumar Aggarwal A, University of Cambridge D, University of Cambridge (Prof. Stuart Warren) Postdoctoral Position, Columbia University (Prof. Gilbert Stork) Lecturer in Chemistry, University of ath Lecturer in Chemistry, University of Sheffield eader in Chemistry, University of Sheffield Professor in Chemistry, University of Sheffield 2000-present Professor in Synthetic Chemistry, University of ristol Current esearch Interests: Stereoselective synthesis / chanistic studies / Total synthesis of natural and non-natural products ur current focus is in the field of organoboron chemistry, since boron seems to possess a unique ability to orchestrate many processes cleanly and with high stereochemical fidelity.

8 Contents Introduction Part 1 : Factors responsible for the 1,2-migration Part 2 : Factors responsible for stereocontrol Part 3 : Application of lithiation-borylation reaction in synthesis Summary

9 What Affects the Migratory Aptitude of Alkyl Groups? (Steric & Electronic Factors) 1,2-earrangement of borate complexes Migrating terminus X X 2 Y Y Migrating origin 1. Steric hindrance around boron. 2. Steric hindrance around the migrating terminus. 3. Compression of the bond angles in the migrating group at the transition state for migration. 4. Nonbonded interactions of the substituents at the migrating terminus with the substituents attached to boron. 5. The stability of the migrating group which carries partial negative charge. Aggarwal, V. K. et al. Pure & Appl. Chem., 2006, 78, 215.

10 Example 1. Iodine-Induced earrangement of Ethynyltrialkylborates (1) I 2 3 I I I 2 3 I I S. W. Slayden. J. rg. Chem., 1981, 46, 2311.

11 Example 1. Iodine-Induced earrangement of Ethynyltrialkylborates (2) A partial relative migratory aptitude order: bicyclooctyl > n-butyl > cyclohexyl, isobutyl, sec-butyl > thexyl. Generally 1 > 2 > 3 (except for bicyclo group). Inexact ordering of the cyclohexyl, isobutyl, and sec-butyl groups. Can be explained by the stability of the migrating goup that carries partial negative charge (factor 5). S. W. Slayden. J. rg. Chem., 1981, 46, 2311.

12 Example 1. Iodine-Induced earrangement of Ethynyltrialkylborates (3) For 4-6, An approximate twofold increase in M in the series n-butyl < sec-butyl < isobutyl but no such regularity for 7-9. Can be explained by the steric acceleration due to strain (factor 1). S. W. Slayden. J. rg. Chem., 1981, 46, 2311.

13 Example 2. earrangement of 9-N Derivatives Migrating group n-c 8 17 I -9-N n-c 8 17 C I I Cn-C 8 17 n-c 8 17 C I n-c 8 17 C = c-c 5 9, c-c 6 11, n-c 6 13 Conformation of the ate complex dominates outcome (factor 4). M. chiai. et al. rg. Lett., 2004, 6, I 2 Nonmigrating group I 2 r -9-N r -9-N = n-utyl, sec-utyl, isobutyl = C 2, C 2 3, CN Torsional strain in expansion of 9-N.. C. rown. et al. J. Am. Chem. Soc., 1969, 91, C. rown. et al. J. Am. Chem. Soc., 1969, 91, C. rown. et al. J. Am. Chem. Soc., 1969, 91, 6855.

14 xample 3. xidation of Trialkylborane with TMAN t-x c-x n-x t-x TMAN c-x n-x N 3 c-x n-x n-x t-x t-x c-x N 3 3 N N 3 n-x relative yield The bulkier groups are preferentially oxidized (migratory aptitude decreases in the order 3 > 2 > 1 ). 78% 20% 2% Can be accounted for the preferred conformation of the ate complex (factor 4). [] The intermediate alkoxyboranes are easy to be hydrolyzed. 3 TMAN (1eq), 0 TMAN (2eq), 25 2 () 2 TMAN (3eq), reflux, 24h () 3 The oxidation process can be controlled depending on the stoichiometry and reaction conditions. J. A. Soderquist. et al. J. rg. Chem., 1986, 51, 1330.

15 Example 4. Carbonylation of rganoboranes 2 3 C 2 C [] 2 3 KCN TFAA 2 CN 3 2 C 3 N CF N CF N CF 3 [] 2 (1) C (2) [], p 8 60% yield, 99% ee, >99% trans (1) NaCN (2) TFAA (3) [], p 8 75% yield, 99% ee, 99% trans No ketones bearing the most hindered group were isolated. The order in the migration step is 1 > 2 > 3. Suggesting that the 1,2-migration is dominated by electronic factors relating to the ability of the migrating group to carry negative charge (factor 5).. C. rown. et al. J. Am. Chem. Soc., 1988, 110, 1529.

16 Short Summary Several factors should be considered when thinking about which group will migrate preferentially. There is no migrating / nonmigrating group absolutely. A consideration of the conformation required for migration of the ate complex is important.

17 Contents Introduction Part 1 : Factors responsible for the 1,2-migration Part 2 : Factors responsible for stereocontrol Part 3 : Application of lithiation-borylation reaction in synthesis Summary

18 Stereocontrol: Substrate Control VS eagent Control Complementary routes to homochiral organoboranes involving 1,2-metallate rearrangement Substrate control (Matteson) * * C 2 - * * * 2 M * * M * 2 -M eagent control (Aggarwal) M 2 * * * 2 * LG LG * M 2 -MLG V. K. Aggarwal. et al. Chemical ecord., 2009, 9, 24.

19 Substrate Control: Anatomy And Application Matteson homologation-alkylation sequence Zn 2 C 2 Zn Zn Zn 2 TF, -78 r.t Favoured Disfavoured 2 MgX 2 MgX 2 MgX M X X 2 2 Synthetic Applications C 8 17 Japonilure (2S,3,1 )-Stegobinone L-(+)-ribose Serricornin D. S. Matteson. et al. J. rg. Chem., 2013, 78,

20 mitations of the Matteson-type omologation-alkylation (1) eaction of diastereomeric boronic esters with grignard reagents lead to different outcome. X Mgr Mg X n X Mgr Mg X n Mgr X X Mg Mg X X n n D. S. Matteson. et al. Synthesis., 1990, 200.

21 mitations of the Matteson-type omologation-alkylation (2) Additional steps are required when changing the stereochemistry of boronic ester. Cy Cy Cy Cy Cy (1) Na Cy (1) C 2 (C 2 ) 3 C- (2) n Cy n (2) + Cy n (1) C 2 (2) Mgr Cy Cy n Cy Cy ent-19 + n n 23 D. S. Matteson. et al. J. rg. Chem., 1996, 61, 6047.

22 mitations of the Matteson-type omologation-alkylation (3) mited success for the synthesis of quaternary stereocenters. C 3 Zn 2 + S dr a Et /S = 8 b c d u Cy S/ = 24 /S = 1.04 S/ = 1.5 Variable levels of selectivity were obtained. e f 3 C i-pr n?/? = 40?/? = 10 The sense of asymmetric induction was unpredictable. g 3 C /S = 1.5 D. S. Matteson. J. rg. Chem., 2013, 78,

23 eagent Control: omologation-alkylation of oronic Esters and oranes using Chiral Carbanions Complementary routes to homochiral organoboranes involving 1,2-metallate rearrangement Substrate control (Matteson) * * C 2 - * * * 2 M * * M * 2 -M eagent control (Aggarwal) M 2 * * * 2 * LG LG * M 2 -MLG V. K. Aggarwal. et al. Chemical ecord., 2009, 9, 24.

24 Chiral Carbanions Derived from Sulfur Ylides F 4 S + 3 (1) 1.2 eq, MDS dioxane, TF, 5 (2) F 3 (3) 2 2, Na or N 2 S 3 /N % yield 95-97% ee Et3 S Et 3 S Et 2 Et major product ΔE = 4.37 kcal/mol Et3 S Et 3 S Et 2 Et minor product V. K. Aggarwal. et al. J. Am. Chem. Soc., 2005, 127, 1642.

25 utcome of the 1,2-tallate earrangement Ate Complexes esulting from the 9-N Derivatives S F 4 + (1) MDS, -78 (2) -100 to r.t. (3) 2 2, Na + Entry Yield Yield 1 exyl 56% 41% 2 Allyl 51% 39% 3 enzyl 51% 35% 4 i-pr Trace 77% 5 Cyclopropyl 89% Trace 6 Trace 94% 7 1-exenyl Trace 21% 8 1-exynyl 92% Trace S S S a b c V. K. Aggarwal. et al. J. Am. Chem. Soc., 2007, 129,

26 Chiral Carbanions of thiated Alkyl Chlorides p-tol S nu or EtMg M TF, -78 M = or Mg -78 n (neo) =, nu, (C 2 ) 2, c-hex n 1 (neo) Ar S 24 (1) C 2 n tu (2eq) n n n (pin) n a n 25 n (pin) 26 n n (2) a (3) 2 2 n 27 (,) 38% yield 99:1 er, 79:21 dr n (pin) (1) a or ent-a (2) C 2 (3) a or ent-a (4) 2 2 n n n n n n or or n n n (,S) (S,S) (S,) 97:3 er, 81:19 dr 99:1 er, 76:24 dr 99:1 er, 80:20 dr P.. lakemore. et al. J. Am. Chem. Soc., 2007, 129, 3068.

27 Chiral Carbanions of thiated Carbamates (1) Cb su Et 2, -78 (-)-sparteine N N (1) 2 ( 3 ) 2 (2) Lewis Acid 2 ( 3 ) 2 Cb 2 ( 3 ) 2 2 (1) warm (2) 2 2 N i Pr 2 V. K. Aggarwal. et al. Angew Chem Int Ed., 2007, 46, 7491.

28 Chiral Carbanions of thiated Carbamates (2) N N N N (-)-Sparteine (sp) (+)-Sparteine surrogate (sps) Cb Cb su (-)-sparteine su (+)-sparteine surrogate -sp -sps Cb -sp -sp Cb Et(pin) (pin) Cb 82% yield er > 98:2, dr = 96:4 64% yield er > 98:2, dr = 94:6 Cb Et(pin) (pin) (78% yield, er = 98:2) -sps Cb 63% yield er > 98:2, dr = 94:6 63% yield er > 98:2, dr = 90:10 -sps Cb (75% yield, er = 97:3)

29 Short Summary Substrate control and reagent control are two routes to homochiral organoboranes involving 1,2-metallate rearrangement. Although a powerful transformation, Matteson s homologation-alkylation sequence (substrate control) suffers from a number of drawbacks (limitation 1-3). The reactions between chiral carbanions bearing potential leaving groups with achiral boronic esters (reagent control) is complementary to the Matteson approach.

30 Contents Introduction Part 1 : Factors responsible for the 1,2-migration Part 2 : Factors responsible for stereocontrol Part 3 : Application of lithiation-borylation reaction in synthesis Summary

31 Wide Application of thiation-orylation eaction Secondary boronic esters and derivatives 2 Nn % yield, >95:5 er Tertiary benzylic boronic esters and derivatives Ar % yield, >95:5 er 2 Ar 69-95% yield, >95:5 er Et 1,2-diols Et 70% yield, 99:1 er, >95:5 dr i-pr -Amino alcohols Noc 90% yield, >99:1 er, >95:5 dr Nus 80-87% yield, >99:1 er Tertiary alkyl boronic esters and derivatives % yield, >97:3 er 3 Allylic boronic esters and homoallylic alcohols % yield, >95:5 er, >99:1 dr % yield, 99:1 er, >99:1 dr % yield, >95:5 er, >99:1 dr -ydroxy allylsilanes 2 Si % yield, >94:6 er, >25:1 dr 2 Si % yield, >93:7 er, >25:1 dr Acyclic γ-dimethylamino tertiary boronic esters pin N 44-75% yield -Silyl boronic esters pin Si % yield, >96:4 er 2 pin Si 52-84% yield, >97:3 er Tertiary allylic boronic esters and derivatives % yield, >98:2 er Tertiary propargylic boronic esters and derivatives 2 t u 42-58% yield, >95:5 er Contiguous quaternary stereocenters Ar Ar 32-85% yield, >95:5 dr, >99:1 er 1,3-is(boronic esters) and derivatives % yield, >95:5 dr, 99:1 er

32 thiation-orylation in Total Synthesis N N N TS NC N 2 Sch (-)-Stemaphylline F Atorvastatin (pitor) Derivative (+)-Erogorgiaene F Escitalopram C C 5 11 (+)-Giganin ( ) 5 Mycolactone Core (-)-Decarestrictine Solandelactone E r (-)-Filiformin (-)-avosolide A -1 ormone N (+)-Sertraline

33 Assembly-ne Synthesis Examples N S (+)-kalkitoxin N All-Syn elical Structure pin (+)-Faranal Tatanan A aulamycin A ( = C 2 C 3 ) aulamycin ( = C3) 2 C C (+)-ydroxyphthioceranic Acid

34 Iterative Assembly-ne Synthesis 99.3:0.7 er pin TI TI TI TI TI TI TI TI TI 58% yield (9 steps) 9-mer:10-mer:11-mer = 1:97:2 pin pin TI TI TI TI TI pin 99.3:0.7 er TI TI TI TI 44% yield (9 steps) 9-mer:10-mer:11-mer = 1:94:5 pin TI TI TI TI TI pin 98.7:1.3 er TI TI TI TI 45% yield (9 steps) 9-mer:10-mer:11-mer = 0:97:3 pin TI e-entry into iterative cycle TI pin Ten contiguous, stereochemically defined methyl groups. Total stereocontrol. No extra manipulation required. V. K. Aggarwal. et al. Nature., 2014, 513, 183.

Iterative Assembly ne Synthesis of Polypropionates n pin [SI] [Ir] [] LEDs n Si pin [SI] [Ir] [] LEDs [C] n Si Si pin m-cpa KF 2, DMF n 70% yield, >95:5 dr 58% yield, 94:6 dr 66% yield, >95:5 dr n n

35 Iterative Assembly ne Synthesis of Polypropionates n pin [SI] [Ir] [] LEDs n Si pin [SI] [Ir] [] LEDs [C] n Si Si pin m-cpa KF 2, DMF n 70% yield, >95:5 dr 58% yield, 94:6 dr 66% yield, >95:5 dr n n 75% yield, >95:5 dr 52% yield, >95:5 dr 71% yield, >95:5 dr [] = [] = [C] = TI TI N [Si] = [Si] = Si [Ir] LEDs = otoredox cleavage N Si Five contiguous stereocenters. Full stereocontrol in an effectively one-pot process. Purification of intermediates is not required. V. K. Aggarwal. et al. Nature Chem., 2017, 9, 896.

Stereocontrolled omologation of thiated α- chloromethyl silane with boronic esters N Si s-u, Et 2-78, 1h N Si -pin, Et 2-78 N Si -78 to rt 1h N Si pin 60%-92% yield, >85:15 dr = alkanes, aromatic

36 Stereocontrolled omologation of thiated α- chloromethyl silane with boronic esters N Si s-u, Et 2-78, 1h N Si -pin, Et 2-78 N Si -78 to rt 1h N Si pin 60%-92% yield, >85:15 dr = alkanes, aromatic substituted alkanes, alkenes, protected alcohols, tert-butyl esters, azides Since the boronate complex is prone to undergo β-elimination rather than the desired 1,2-migration, the oxygen functionality is masked as a silyl group. The silyl group renders an adjacent carbanion configurationally unstable even at low temperature, lithiated benzylsilane bearing a tethered chiral methoxymethyl pyrrolidinomethyl moiety is used. The pronounced tetrahedral nature of organoithium together with its potential to complex with the oxygen atoms of the boronic ester directs the reagent to the same face as the lithium atom, accounts for the origin of the retention of configuration observed. A good leaving group - is used to improve the reactivity of the 1,2-migration instead of utilizing additives such as Mg( 4 ) 2. V. K. Aggarwal. et al. Nature Chem., 2017, 9, 896.

37 Assembly ne Synthesis Protocol for the construction of polypropionates n [Si] 28 pin TI n 2 Si N pin N Si No reaction 61% yield, >95:5 dr [Ir] LEDs [Ir] LEDs 2 Si n pin 29 79% yield TI N TI 2 Si Si Si [Si] n pin pin 31 n 33 (1) Si Si I 2, Na n pin (2) Urea- 2 2, KF KC n 34 3, TF, 35 92% yield, >95:5 dr 59% yield, >95:5 dr V. K. Aggarwal. et al. Nature Chem., 2017, 9, 896.

38 Contents Introduction Part 1 : Factors responsible for the 1,2-migration Part 2 : Factors responsible for stereocontrol Part 3 : Application of lithiation-borylation reaction in synthesis Summary

39 Summary Several factors should be considered when thinking about 1,2-migraton and stereoselectivity of lithiation-borylation reaction. thiation-orylation is a powerful method in assembly-line synthesis.

40 Thank You!

41 Appendix Proposed catalytic cycle for photoredox cleavage of aminosilane V. K. Aggarwal. et al. Nature Chem., 2017, 9, 896.

1. WORK PROGRESS AND ACHIEVEMENTS DURING THE PERIOD. A summary of progress towards objectives and details for each task;

1. WORK PROGRESS AND ACHIEVEMENTS DURING THE PERIOD A summary of progress towards objectives and details for each task; In Nature, a vast array of complex biomolecules, including peptides, oligonucleotides,