-Promoted Reactivity in Organic Synthesis

Steph McCabe Frontiers of Chemistry 08/19/2017 Wipf Group

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Steph McCabe @Wipf Group Page 1 of 30 09/02/2017 2/10/2011

4.4 Conformations of

Cyclopropane • Most strained of all the rings • Angle strain – caused by 60º C-C-C bond angles • Torsional strain – caused by the eclipsed C-H bonds on neighboring atoms a) Structure of showing the eclipsing of neighboring C- H bonds giving rise to torsional strain b) Newman projection along a C-C bond of cyclopropane

Conformations of Cycloalkanes

• Bent C-C bonds • Orbitals can’t point directly toward each other • Orbitals overlap at a slight angle • Bonds are weaker and more reactive than typical bonds 2/10/20112/10/2011

• C-C bond: 4.4 Conformations255 kJ/mol (61 kcal/mol) of Cycloalkanes for cyclopropane What 4.4is ConformationsRing355 kJ/mol Strain? (85 ofkcal/mol) Cycloalkanes for open-chain propane Cyclopropane Cyclopropane• Most strained of all the rings Theory: Adolf von Baeyer• • (NobelMostAngle strained strain Prize of – allcaused in the Chemistry rings by 60º C-C- C1905) bond angles 1. Angle Strain: Expansion/compression• • AngleTorsional of strain ideal strain– caused(tetrahedral) – caused by 60 ºby C -the Cbond-C eclipsed bond angle angles C-H bonds on neighboring • Torsionalcarbon strainatoms – caused by the eclipsed C-H bonds on neighboring 2. Torsional Strain: Rotational strain e.g.carbon a)eclipsingStructure atoms bonds of cyclopropane on neighboring showing the eclipsing atoms of vs neighboring staggered C- 3. Steric Strain: Repulsive interaction whena) Structure atomsH bonds of giving approachcyclopropane rise to torsionaleach showing other strain the eclipsing too closely of neighboring C- b)H bondsNewman giving projection rise to alongtorsional a C strain-C bond of cyclopropane b) Newman projection along a C-C bond of cyclopropane Conformations of Cycloalkanes

Cyclobutane • Total strain is nearly same as cyclopropane

• Angle strain – less than cyclopropane

• Torsional strain – more than cyclopropane because of larger number of ringRing hydrogens strain: 27.5 kcal/mol ΔH"(strain)" • Not planar (not flat) ∠ (kcal/mol)" C–C–C 60° • One carbon atomC- liesC 25bond:º above 61 the kcal/mol plane of the(vs other85 kcal/mol three in • Newman projection along C1-C2 bond shows that neighboring C-H bonds are not quitepropane) eclipsed

Conformations of Cycloalkanes mainly"angle" mainly"transannular"strain" strain" Conformations• Bent C-C bonds of Cycloalkanes • Orbitals can’t point directly toward each other • Bent C-C bonds 1" • Orbitals overlap at a slight angle • Orbitals can’t point directly toward each other • Bonds are weaker and more reactive than typical alkane bonds C–C–C ∠109.5° • Orbitals overlap at a Ringslight Strain:angle 26.4 kcal/mol • Bonds are weaker andC–C– moreC reactive∠~88 °than typical alkane bonds C-C bond: 63 kcal/mol (vs 85 kcal/mol in butane)

2 Steph McCabe @Wipf Group Page 2 of 30 09/02/2017 2 • C-C bond: 255 kJ/mol (61 kcal/mol) for cyclopropane • C-C bond: 355 kJ/mol (85 kcal/mol) for open-chain propane 255 kJ/mol (61 kcal/mol) for cyclopropane 355 kJ/mol (85 kcal/mol) for open-chain propane

Conformations of Cycloalkanes ConformationsCyclobutane of Cycloalkanes • Total strain is nearly same as cyclopropane • Angle strain – less than cyclopropane • Total strain• Torsional is nearly strain same – asmore cyclopropane than cyclopropane because of larger number of ring hydrogens • Angle strain – less than cyclopropane • Not planar (not flat) • Torsional strain – more than cyclopropane because of larger • One carbon atom lies 25º above the plane of the other three number of ring hydrogens • Newman projection along C1-C2 bond shows that neighboring C-H • Not planarbonds (not are flat) not quite eclipsed • One carbon atom lies 25º above the plane of the other three • Newman projection along C1-C2 bond shows that neighboring C-H bonds are not quite eclipsed

2

2 Small Strained Aza- and Carbocycles

X

cyclopropane cyclopropene methylenecyclopropane vinylcyclopropane bicyclo[1.1.0]butane bicyclo[1.1.1] pentane [1.1.1]

N N N N N N H H NH aziridine 2H-azirine methylene aziridine N-vinylaziridine 1-azabicyclo[1.1.0]butane 1-azabicyclo[1.1.1]pentane 2-aza[1.1.1]propellane H *unknown NH HN N N H 1H-azirine 2-vinylaziridine 2-azabicyclo[1.1.0]butane 2-azabicyclo[1.1.1]pentane *unknown *unknown

cyclobutane cyclobutene methylenecyclobutane bicyclo[2.2.0]hexane bicyclo[2.1.0]pentane ‘housane’

NH N N NH N azetidine 1-azetine 2-methyleneazetidine 1-azabicyclo[2.2.0]hexane 1-azabicyclo[2.1.0]pentane *unknown NH HN NH N NH H 2-azetine 3-methyleneazetidine 2-azabicyclo[2.2.0]hexane 2-azabicyclo[2.1.0]pentane 5-azabicyclo[2.1.0]pentane

§ Cyclopropane (~27 000 hits in scifinder) vs (831), methyleneaziridine (89), azabicyclobutane (56) 3

Steph McCabe @Wipf Group Page 3 of 30 09/02/2017 Scope/Brief History

Scope of Presentation: 1. Reactivity/applications of underrepresented carbo- and azacycles containing a 3-membered ring 2. Proposal Section – Gaps in the synthesis and reactivity profile of strained ring systems and applications in total synthesis

N H N

methylene aziridine bicyclo[1.1.0]butane 1-azabicyclo[1.1.0]butane (MA) (BCB) (ABB)

1950s – 1990s 2001-2017 2008-2017 Theoretical/Synthetic Research General reactivity Applications § Useful models § Methods to form § Total synthesis to study ring strain small-medium § Chiral Ligands for in organic compounds sized rings and asymmetric catalysis § Synthesis: novel scaffolds § Medicinal chemistry MA (1951, Pollard) unnatural amino acids, peptide BCB (1959, Wiberg) labeling ABB (1969 Funke)

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Steph McCabe @Wipf Group Page 4 of 30 09/02/2017 Ring Strain Energies of [ 31 Radialenes The Journal of Physical Chemistry, Vol. 97, No. 19, 1993 4997

7038 J. INCE et aL 1.3116 c 3.0 1.5270 13079 1.4212 160.7 H 1.4622 c Our initial investigations focused on the preparation of N-benzyl substituted rncthyleneaziridines. This decisionH was made on the basis of the known stability of the N-benzyl group to a wide range of reaction conditions and the ease withH which the bcnzylic C-N bond can be cleaved by hydrogenation.8 Thus, three 3 04 related methylcneazin'dine precursors 5-7 were made differing only in the nature of the substituents attached to the benzylic carbon atom. Amine precursors 5 and 6 were prepared by alkylation of benzylamine and (S)- 1- phenylethylamine respectively with commercially available 2,3-dibromopropene. While the N-trityl derivative 7 could not be prepared in this way using the more sterically encumbered triphenylmethylamine, an alternative approach involving coupling of N-(2-bromoallyl)-amine4 9 and trityl chloride readily furnished this precursor in good yield (Scheme 2).

PtT/~NH2 i 1.3120

x"~ R~,~Ph 5 (R,, R2 = H); M~.,N~AO,, ii =, NH 6 (R"1 = H, FI2 = Me); 5 P H2 l 7 (R1, R2 = Ph) Br A;H 2 iii f d 5pl 6 Methyleneaziridines:4 Properties Scheme 2. Reagents & Co~li#ons: (i) 2,3-dibrompmpene,K2CO3, THF, reflux, 68% (5); (ii) 2,3-dibmmol~pene, K2CO3, Et20, reflux, 76% (6); (iii) Ph3CCI, Et3N, 121-121212,88% (7). § Ring strain ~43 kcal/molWith the requisite precursors in hand, we were ready to examine the conversion of these materials into the Ring Strain Energy (HF/6-31G*) corresponding methyleneaziridines employing the procedure described by Pollard and Parcell.1 Treatment of the N-benzyl1.4073 derivative 5 with differing amounts of amide (1.1-15 equiv) for varying reaction times (5- 120 rain) lead to the formation of complex mixtures of products from which no appreciable quantifies of the desired methyleneaziridine could be isolated. Since closely related compounds such as N-ethyl N methyleneaziridine canN be made using this chemistry, we reasoned that the increased acidity of the hydrogens on H the benzylic carbon atomH may be causing the deu'imental side reactions. To test this hypothesis, we next chose to examine the cyclisation of N-trityl derivative 7 which has no such acidic hydrogens. In this instance, we 29.71 kcal/molwere delighted to 42.55discover thatkcal/mol treatment of this 28.75substrate withkcal/mol 15 equivalents of sodium40.03 amide kcal/mol in liquid ammonia for 6 hours smoothly lead to the formation of desired methyleneaziridine 8 in 72% yield (Scheme 3). The structure of this compound was unambiguously established using x-ray crystallography. While Quast et al § Very little enamine havecharacter published an x-ray(Nitrogen crystallographic lone study of pair 1-(1-adamantyl)-2-isopropylidineazin'dine, is pyramidal) l0 we believe this represents the first crystallographic study of a simple methyleneaziridine.11

Ph~Ph 3 NaNH2, NHa =.. Ph~Ph 9 72% N

? Ph 8 Ph Scheme 3 Ph X-Ray CrystalStructure of N-(a'ipbcnylm¢~yl)-2- methyleneaziridine8 § Thermal decomposition to olefin and isonitrile (slow T>120 °C, fast T>190 °C)

N + CNR R

Calculated ring strain energy (HF/6-31G*)2.0 Bachrach J. Phys. Chem. 1993, 97, 4996; Shipman Tetrahedron, 1996, 52, 7037 3.9 A"....." A"....." 1.4652 1.4682 5 Steph McCabe @Wipf Group d Page 5 of 30 09/02/2017 Figure 1. Optimized geometries of the radialenes and lower homologs. The HF/6-31GS geometries are listed above the MP2/6-31G* results. All distances are in A and all angles are in deg. initio calculations of aza[ 31 radialene (5) and phospha [3]radialene structures are drawn in Figure 1 and the energies are listed in (6). In order to address the trends in ring strain energy due to Table I. The zero-point energies listed in Table I are unscaled; substitution with methylene groups, we have also examined all derived quantities (ring strain energies and inversion barriers) methyleneaziridine (9) and methylenephosphirane (lo), to com- were calculated with ZPE scaled by 0.89. pare with the series of eq 2. The inversion barriers The group equivalentz6reactions (eqs 4-6), a modification of of the nitrogen and phosphorus compounds were determined and homodesmic reaction schemes, were used to estimate the ring estimatesof the vibrational frequencies of these novel compounds strain energies. The group equivalent method conserves chemical are provided to aid in their future characterization. groups as defined by Benson.I2 All compounds needed to evaluate the reaction energies of eqs 4-6 were fully optimized at HF/6- Computational Methods 31G* and their analytical frequencies were used to obtain their The geometries of 1,3-6,9, and 10 were completely optimized zero-point energies. These auxiliary energies are listed in Table at the HF/6-31G* level using the standard techniques of 11. The resultant calculated RSEs are collected in Table 111. GAUSSIAN-90.24 We have previously shown that this com- In order to determine the inversion barriers of 5,6,9,and 10, putational level is suitable for obtaining geometries that agree we optimized their planar structures at HF/6-3 lG* (designated with experimental structures.25 Analytical frequency analysis of by "pl" following the number). Analytical frequency analysis these structures confirmed them to be local minimum. The confirmed that each planar structure is a transition structure, Methyleneaziridine Synthesis

4 *most general route 2 Br H NaNH , NH 2 3 N 1 N N R 77% R Ph R Ph n-BuLi, THF Olsen J. Org. Chem. 1963, 28, 3241 yield not reported N 4 4 N Br H 3 2 2 H 2 Mison Tetrahedron Lett. 1985, 26, 2637 N NaNH , NH 2 3 N 1 N N 1 N 1 75% R R R

OSiPh2t-Bu OH Shipman Org. Lett. 2005, 22, 4987 3 2 N 1 R

O OEt NEt3, CH2Cl2 6% N • O NH + O OEt Ar S O O Gilbert J. Org. Chem. 1975, 40, 224

O OO 2 2 O PhIO, Rh2(OAc)4 R S R S NO • O NH2 R1 R H Schomaker Org. Lett. 2017, 19, 3239

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Steph McCabe @Wipf Group Page 6 of 30 09/02/2017 Heterocycle Synthesis: Radical cyclization

5-exo trig N N N

Ph SePh Bu3SnH, AIBN Ph PhH, reflux; 67% N HN

Bu3SnH, AIBN PhH, reflux; H SePh then (Boc)2O, Et3N, 65% H N BocN

SePh Bu3SnH, AIBN PhH, reflux; 39% N N

Shipman Org. Lett. 2001, 3, 2383

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Steph McCabe @Wipf Group Page 7 of 30 09/02/2017 Transition Metal Catalyzed Ring-Expansion to b- lactams

Pd(PPh3)4 or Pd(OAc)2/ PPh3 (10 mol%) CO (balloon) CH Cl , RT 2 2 OMe N NR N N N R O Bu O O O OMe OMe 79% 75% 75%

1. R1MgCl, CuI 2 2. R X then AcOH O R 3. R3OCH=C=O N N O O PMB O PMB R ‘one pot’ R3O N N N R1 R2 BnO MeO BnO O • Ph Ph Ph

OR3 60% 55% 49% R MgCl 2 R ~1:1 cis:trans N R X N R1 R1 R2

Alper Tetrahedron Lett., 1987, 28, 3237; Shipman J. Org. Chem., 2008, 73, 9762 8

Steph McCabe @Wipf Group Page 8 of 30 09/02/2017 Heterocycle Synthesis: 3-Me-Pyrroles

N R Pd(PPh ) (30 mol%) 3 4 Ar O O O neat, 120 °C H Py or R R N R

N Ar O Ar R Ar Ar O H O H Pd H N R PdH O NR NR H

N N N N N O N O O Bn N Bn OMe N CH(CH3)Ph N CH(CH3)Ph N N Bn N Bn MeO 75% 78% 72% 96% 89% 49% 63%

Yamamoto J. Am. Chem. Soc., 2004, 126, 13898; Yamamoto Tetrahedron Lett. 2007, 48, 2267; Wan Chem. Commun., 2013, 49, 5073

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Steph McCabe @Wipf Group Page 9 of 30 09/02/2017 Lewis Acid Catalyzed [3+2]Cycloaddition

NC NC cat. Bu2SnI2 2 CN 2 CN 2 R R + R CN N R1 CN NR1 O

NC NC O CN Ph CN NC NC 2 CN R2 CN R H+ I Bu Sn I O O N 1 Bu 1 66% 80% O NR R Cl

LnSn I N NC NC NC • I CN Ph CN R1 N Ph R2 NR1 SnLn R2 CN O * O 84% 63% CN 81:19 dr + R1 N I OMe SnLn Ph NC O

O 75% Shibata Org. Lett., 2014, 16, 1192 10

Steph McCabe @Wipf Group Page 10 of 30 09/02/2017 Lewis Acid Catalyzed [4+3] Cycloaddition of 2-Amino- Allyl Cations

R1 1 O R H N N s-BuLi BF3•OEt2

X H 53% (56:44 ratio)

R1 1 LA 1 R N R LA N H N

H

Bn Bn N O Bn N H H BF3•OEt2 N BF •OEt O 3 2 O O O then H SO 67% 2 4(aq) 70%

Bn Bn N N BF3•OEt2 H O O

65%

Shipman Angew. Chem. Int. Ed. 2004, 43, 6517 11

Steph McCabe @Wipf Group Page 11 of 30 09/02/2017 C−F/C−N/C−O Stereotriads

O O OO S H cat. Rh2(OAc)4 O 2 S HN R H2O 2 PhIO N O 1 Selectfluor R • OSO2NH2 R R1 R1 H TBSOTf R2 OTBS NEt3

O O O S O O S O N R3M HN 3 R1 R1 R R2 R2 F OTBS F OTBS

O O O O O O O S O O S O S O HN HN HN S O H NC HN i-Pr H

F OTBS F OTBS F OTBS F OTBS 58% (dr 8:1) 52% (dr >19:1) 89% (dr >19:1) 19% (dr 3:1)

Schomaker Org. Lett. 2017, 19, 3239−3242 12

Steph McCabe @Wipf Group Page 12 of 30 09/02/2017 C−F/C−N/C−O Stereotriads

O O S O Boc HN F HO2C N >19: 1 dr C5H11 C5H11 72% F OTBS HO O 1. Et3N, Boc2O O 1. O3, then Et3N DMAP S O HN 2. NaClO2/ NaH2PO4 2. NaI, then NaH R /H O C5H11 2 2 R = CH=CH F OTBS 2 1. Boc O 2 1) BH3 then NaOH 2. PhSH, K CO 2 3 H2O2 1) O , NEt 3. Phenol, H O 3 3 2 2 2) 10% RuCl•H2O 2) NaClO , NaH PO 2 2 4 NaIO4, 45% over 30% aq H2O2 NHBoc 2 steps C5H11 3) TMSCHN 2 F OTBS

NHBoc NHBoc C5H11 C5H11 CO2Me CO2H F OTBS F OTBS β-amino acid γ-amino acid

Schomaker Org. Lett. 2017, 19, 3239−3242 13

Steph McCabe @Wipf Group Page 13 of 30 09/02/2017 Synthesis of the Aminocyclopentitol Core of Jogyamycin using an Allene Aziridination Strategy

O NMe2 § Antimalarial/ African sleeping sickness treatment HN HO O § IC = 1.5 nM Plasmodium falciparum K1 strain (drug resistant) NH2 50 HO § IC50 = 12.3 nM Trypanosoma brucei brucei strain GUTat 3 HN HO jogyamycin

1. H2O/MeCN OO 2. TBSOTf, lutidine H 1. Rh2(OAc)4 (1 mol%) S 50% (3 steps) PhIO, CH2Cl2, rt, 1 h N O H • OSO2NH2 Me Me H O aminolysis NMe O 2 O Mitsunobu HN Et S 9 steps O BocHN Et allylic oxidation HO HN NH2 Me OH HO Me OTBS Me HO

epoxidation/ epoxide opening jogyamycin

Schomaker, Org. Lett. 2016, 18, 284–287 14

Steph McCabe @Wipf Group Page 14 of 30 09/02/2017 Summary Methyleneaziridines

O RN O O S O H HN HO2C C5H11 NC H 2 F CN R OTBS α-amino acid Lewis acid promoted cycloaddition O R O radical N NHBoc NMe2 H HN Et cyclization Nu, E, 2+2 C5H11 R3O CO2H HO HN N E N NH2 Nu F OTBS R Nu, E, Nu R γ-amino acid O HO O jogyamycin core S O [M] HN NHBoc 1 Nu H Ar R C5H11 CO2Me 2 R F OTBS NR N R E Nu O β-amino acid

REACTIONS § Lewis Acid promoted cycloadditions § Radical/TM-catalyzed heterocycle synthesis § Sequential functionalization's to stereotriads/ b-lactams APPLICATIONS § a, b and g amino acids synthesis § total synthesis applications 15

Steph McCabe @Wipf Group Page 15 of 30 09/02/2017 Bicyclobutane Synthesis

Intramolecular displacement of a leaving group by a cyclopropyl anion Intermolecular (2x) of an alkyne

C2H5 C2H5 OMs i-Pr Zn(CH I) C H C H BuLi; 91% 2 2 2 5 2 5 SO2Ph C H i-Pr 2 5 SO2Ph 51% NP(O)Ph2 Ph NP(O)Ph Ph2(O)PHN 2 Gaoni Tetrahedron Lett., 1981, 4339 Wipf J. Am. Chem. Soc. 2003, 125, 14694−14695.

2 4 4

1 1 3 Intramolecular displacement of a Photochemical activation of leaving group across a cyclobutane

hv NC 2 4 CN + CN CN 1 KOBu-t; 82% CN 1 3 2 4 1:2 3 Cl 1 3 Sheppard J. Am. Chem. Soc., 1971, 93, 110

4 4

1 1 3 3

Intermolecular cyclopropanation Intramolecular cyclopropanation

N2 CO2Et Rh2OAc4 MeO C CO Me MeO2C CO2Me 2 2 + hv N CO2Et 2 CO2Et 51% 39% Maier, G.; Wolf, B. Synthesis 1985, 1985, 871 Ganem Tetrahedron Lett., 1981, 22, 4163

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Steph McCabe @Wipf Group Page 16 of 30 09/02/2017 Thermal Reactions Formal Alder-Ene

Br Ar Ph2(O)P NH Ph

Bu4NHSO4, NaOH (50% aq) Ph N Ph2(O)P H Ar PhMe, rt, 63 h; 63% + single diastereomer Br

H H Ar N N Ar Ph2OP Ph2OP Ph H Ph

CO2Me CO2Me CO2Me

Ph C6H11 Ph Ph

Ph (O) N N N 2 Ts N Ph (O)P Ph (O)P P H H 2 H 2 H

66% 62% TIPS 82% 51%

Wipf et al. Acc. Chem. Res., 2015, 48, 1149; Wipf and Walczak Angew. Chem. Int. Ed., 2006, 45, 4172 18

Steph McCabe @Wipf Group Page 17 of 30 09/02/2017 Thermal Reactions Formal Alder-Ene

TPAP, NMO

CH2Cl2, PhH CHO Ph (O)PN Ph2(O)PN rt to reflux Ph2(O)PN 2 OH O TrO TrO TrO 67% 6:1 dr

HO OH R OH 10 steps N X OBn N N

daphniglaucin A: R = H daphniglaucin B: R = OMe BnO

Wipf et al. Tetrahedron Lett. 2008, 49, 5989 19

Steph McCabe @Wipf Group Page 18 of 30 09/02/2017 Thermal Reactions [2+2] Cycloaddition

Ph Br

Bu NHSO Ar 4 4 Ph Ph2(O)P NH NaOH (50% aq) Ph Ph PhMe, rt, 36 h; 93% N Ar P(O)Ph2 Ph Br

Ph Ph Ar Ar H H Ph Ph NP(O)Ph2 NP(O)Ph2

CO2Me F3C Ph Ph N Ph Ph Ph Ph Ph

Ph Ph Ph t-Bu N N N N N P(O)Ph2 59% P(O)Ph2 93% Ts 68% P(O)Ph2 32% P(O)Ph2 54%

Wipf et al. Acc. Chem. Res., 2015, 48, 1149; Wipf and Walczak Angew. Chem. Int. Ed., 2006, 45, 4172

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Steph McCabe @Wipf Group Page 19 of 30 09/02/2017 Metal-Catalyzed Reactions Rh(I) Cycloisomerizations

[Rh(CO) Cl] [Rh(=) Cl] 2 2 Ts N 2 2 HN dppe PPh 3 Ts N R R R [RhI] Ts N Ts N Ts N Ts R Ts N R N [Rh] [Rh] [Rh] [Rh] R R R [Rh]

Ts N Ts N Ts N HN HN HN MeO

O O Cl MeO 67% 75% 53% MeO 87% 57% 80% OMe Cl

Wipf et al. Acc. Chem. Res., 2015, 48, 1149; Wipf and Walczak J. Am. Chem. Soc. 2008, 130, 6924 [Rh] [Rh] [Rh] 21

Steph McCabe @Wipf Group Page 20 of 30 09/02/2017 PtII Cycloisomerizations

PtCl2 (10 mol%) X R X PtCl2 (5 mol%) PhMe (0.05 M) X PhMe (0.05 M), 50 °C X µW, heating Ph O O Ph X = NTs X = NTs; 71% X = NPh, R = H X = NPh, R = H; 59%

X = O X = O; 52% X = CH2, R = Ph X = CH2, R = Ph; 61%

X PtCl (5 mol%) 2 X PhMe (0.05M, 50 °C Y Y X = NTs; 71% X = O; 52%

PtCl 2 PtCl PtCl2 Pt X X X X Y Y Y Y

Wipf et al. Acc. Chem. Res., 2015, 48, 1149 22

Steph McCabe @Wipf Group Page 21 of 30 09/02/2017 Applications: C–C Bond Functionalization

E 1. Nu EWG

EWG + 2. E or H Nu Nu

23

Steph McCabe @Wipf Group Page 22 of 30 09/02/2017 Strain-Release Hydrophosphination

R3 R3 P H BH3 R1 R1 1 NaH R R2 R1 R3 R2 P NC DMAc R3 NC 0 °C to rt BH3 syn diastereomer favoured

p-Tol p-Tol P H BH3 NaH, DMAc 1. DIBAL-H; 64% 0 °C to rt p-Tol 2. NaBH ; 82% p-Tol P 4 P p-Tol 76%; NC HO p-Tol NC BH3 BH3 1.7: 1 syn:anti

1. DABCO PhMe, 78%

2. S-BINOL, PCl3 O 37% P O p-Tol O P p-Tol

H2 (14 bar) bindentate phosphine

Rh(NBD)BF4 (1 mol%) MeOH, rt, 3 h CO2Me CO2Me Ph Ph (R) NHAc 73%, 96: 4 er NHAc

Wipf, Milligan et al Org. Lett. 2016, 18, 4300 24

Steph McCabe @Wipf Group Page 23 of 30 09/02/2017 Chiral via Homoconjugate Addition

1. Rh2(S-NTTL)4 (0.5 mol%), PhMe, -78 °C 1 O 2. R MgX, CuBr•Me2S (30 mol%), PBu3 (1.2 equiv.), THF Ar E CO2t-Bu + + Ar 3. H or E OtBu N2 R poor dr (~1:1 to 1:3)

O CO2t-Bu CO2t-Bu Ar Ot-Bu

Ar Ar R1 R1 >95% ee t-Bu group [M] blocks Nu attack at C=O

epimerization to thermodynamic product kinetic protonation t-Bu

O HO R KOt-Bu R t-Bu R Me Ot-Bu Me Ot-Bu R Me H Me Ot-Bu H H O K H O Ot-Bu O

R = Ph, 82%, 19:1 dr H-B R = Ph, 83%, 6:1 dr R = 1-naphthyl, 60%, 4: 1 dr R = 1-naphthyl, 53%, 17: 1 dr

§ One pot procedure (no b-H elimination to diene) § High ee (> 95%) in bicyclobutanation § d.r. upgraded by epimerization/ reversal od dr by kinetic protonation

Fox J. Am. Chem.Soc, 2013, 135, 9283 25

Steph McCabe @Wipf Group Page 24 of 30 09/02/2017 Chiral Cyclobutanes via Homoconjugate Addition

1) R1MgX Rh (S-NTTL) 2 4 CuBr•Me2S (30 mol%) O (0.5 mol%) H CO t-Bu E 2 PBu3 (1.2 equiv.) Ar CO2t-Bu Ar PhMe, -78 °C THF OtBu N2 Ar R 2. H+ or E+

H H CO2t-Bu CO2t-Bu CO2t-Bu Ph CO2t-Bu Ph CO2t-Bu Ph Ph Ph Et Ph

Ph Me Me Me Me

80%; E = HCl(aq) 82%; E = HCl(aq) 81%; E = AllylI 62%; E = EtI 72%; E = BnBr 1.1: 1 dr (21:1 dr epim.) 1.3: 1 dr (19:1 dr epim.) 8: 1 dr 7: 1 dr

CO2t-Bu CO2t-Bu H H H Ph Ph Ph CO2t-Bu Ph CO2t-Bu Ph CO2t-Bu O SPh Me Me Et Ph 77% E = (SPh) 76%; E = HCl 73%; E = HCl 68%; E = HCl 2 (aq) (aq) F (aq) Br 1:1.4 dr (21:1 dr epim.) 1:1.2 dr (17:1 dr epim.) 1:1 dr (21:1 dr epim.) 63%; E = p-Br(C6H4)COCl 14:1 dr, X-ray F § All other methods to form 1,3 H H Ph CO2t-Bu H CO t-Bu CO2t-Bu 2 functionalized cyclobutanes require prior functionalization of Me Me cyclobutane 72%; E = HCl 72%; E = HCl MeO (aq) 74%; E = HCl(aq) (aq) 1:1 dr (30:1 dr epim.) 1.4:1 dr (19:1 dr epim.) 1:3 dr (4:1 dr epim.) Fox J. Am. Chem. Soc. 2013, 135, 9283 26

Steph McCabe @Wipf Group Page 25 of 30 09/02/2017 Enantioselective Total Synthesis of Piperarborenine B

MeO OMe OMe MeO O § Homodimerization O O O § Pseudo- [2+2]? N § Orientation (head- N symmetric head vs head-tail) MeO OMe N § Anti-cancer § E/Z isomerization OMe O O O properties O OMe OMe N MeO

OMe t-Bu 4i. Rh (S-NTTL) •(dCPA) MeO 2 3 Ar iii. BHT, -78 to H O (0.1 mol%) t-Bu PhMe, -78 °C -10 °C Ar O Ot-Bu t-Bu ii. CuBr•SMe (0.5 equiv.) O 2 MgBr O N2 PPh3, THF, rt 3 conversions,Experimental one-pot, procedures gram scale MgBr CO2t-Bu Rh (S-NTTL) (dCPA) (3 steps) 2 3

OMe MeO

CO2tBu 6 steps piperarborenine B H

Rh2(S-NTTL)3•(dCPA) 10-steps/ 8% overall yield 3 69%; 4:1 dr 2,2-Dicyclohexyl-2-phenylacetic acid was prepared according to literature procedure. >400 mg prepared 92% ee To an oven-dried round bottomed flask fitted with a reflux condenser was added dirhodium tetrakis[N-naphthaloyl-(S)-tert-leucinate] (250 mg, 0.17 mmol, 1.0 equiv), and 2,2-dicyclohexyl- Fox Angew. Chem. Int. Ed., 2016, 55, 4983 2-phenylacetic acid (160 mg, 0.52 mmol, 3.0 equiv). The flask was evacuated27 and refilled with N2 and chlorobenzene (25 mL, 0.007 M) was added. The reaction mixture was heated to 160 °C Steph McCabe @Wipf Group Page 26 of 30for 12 hours. A second batch of 2,2-dicyclohexyl-2-phenylacetic acid09/02/2017 (52 mg, 0.17 mmol, 1.0 equiv) was added and heated at 160 °C for an additional 6 hours. The chlorobenzene was

removed by distillation under N2. The residue was dissolved in EtOAc and washed with

saturated aqueous NaHCO3, dried over MgSO4, filtered, and concentrated via rotary evaporation. The green solid was purified by column chromatography (4% EtOAc:toluene) to provide the title compound as a green solid (154 mg, 62% yield). Crystals suitable for X-ray crystallography were grown from methanol by slow evaporation.

1 H NMR (400 MHz, 3:1 CD2Cl2:CD3OD, referenced to CD3OD) δ: 9.07 (d, J = 7.2 Hz, 1H), 8.62 (d, J = 7.2 Hz, 1H), 8.59 (br s, 2H), 8.48 (d, J = 7.2 Hz, 2H), 8.22 (dd, J = 7.9, 5.2 Hz, 2H), 8.15 (t, J = 7.6 Hz, 4H), 7.92 (t, J = 7.8 Hz, 1H), 7.73 (t, J = 7.8 Hz, 1H), 7.67 (t, J = 7.8 Hz, 4H), 7.35 (br s, 2H), 7.15 (m, 3H), 6.03 (s, 1H), 5.71 (s, 2H), 2.26 – 2.06 (m, 2H), 1.86 – 1.77 (m, 1H), 1.74 – 1.62 (m, 3H), 1.58 – 1.40 (m, 5H), 1.40 – 1.10 (m, 28H), 1.10 – 0.97 (m, 3H), 0.92 – 0.62 (m, 4H), 0.55 – 0.22 (m, 3H). Peaks attributable to EtOAc were observed by 1H 13 NMR at 4.06, 1.99, and 1.20 ppm. C NMR (101 MHz, 3:1 CD2Cl2:CD3OD, referenced to CD3OD) δ: 193.3 (C), 187.7 (C), 187.5 (C), 165.7 (C), 165.4 (C), 163.8 (C), 163.4 (C), 140.0 (C), 134.4 (CH), 134.3 (CH), 134.03 (CH), 133.96 (CH), 133.5 (CH), 132.4 (CH), 132.0 (C), 131.6 (CH), 131.4 (CH), 128.6 (C), 128.5 (C), 127.8 (CH), 127.4 (CH), 127.2 (CH), 127.1 (CH), 127.0 (CH), 126.0 (CH), 123.4 (C), 123.27 (C), 123.25 (C), 123.1 (C), 65.5 (C), 62.1 (CH), 61.7

(CH), 41.2 (CH), 41.0 (CH), 36.8 (C), 36.7 (C), 29.5 (CH3), 29.3 (CH3), 27.9 (CH2), 27.8 (CH2), 27.7 (CH2), 27.6 (CH2), 27.3 (CH2), 27.1 (CH2). Peaks attributable to EtOAc were observed by 13C NMR at 172.4, 61.1, 21.1, and 14.2 ppm. A small peak at 30.2 ppm was attributed to an impurity.; FT-IR (NaCl, thin film): 2931, 1709, 1592, 1435, 1398, 1380, 1343, 1306, 1239, 1183,

S"#"4" Strain-Release Amination

1. oxone, acetone, H O 2 R1R2NH SO2Ar 2. BuLi; MsCl SO2Ar then LICl, DMSO BuLi SO2Ar Mg, MeOH 1 2 SO2Ar NHR R 1 2 R RN 1R2RN 37% overall Ar = 3,5-diF gram scale bench stable solid

Bn Ph Bn Ph Bn N N N N N N N Bn N Bn H H Me Me Boc N Me

97% 61% 40% 73% 93% 95% 68% O 60%

F F N N N F 76% 75% N 71% NBn OTBS O N

F

O Cl O Cl § 15 structurally diverse cyclic, acylic , 1° and 2° amines O or anilines N N § four late stage pharmaceuticals.

Baran JACS, 2017, 139, 3209 28

Steph McCabe @Wipf Group Page 27 of 30 09/02/2017 Journal of the American Chemical Society Article Peptide Labeling

SO2Ar

SH S K2CO3, H2O/DMF + N SO2Ar N H O H O

SO2Ar NH2 SO2Ar SO2Ph HO

S OH S S OO H O H WTPY GHNK N N OMe H O HO N OH H2N H O H N NH2 O O HN 76-91% 81-89% 88% N

Baran JACS, 2017, 139, 3209 29

Steph McCabe @Wipf Group Page 28 of 30 09/02/2017

Figure 9. (A) Chemoselectivity of bicyclobutylsulfones for Cys side chains over other proteinogenic amino acids. (B) Superior selectivity of reagent 8g over N-ethylmaleimide 147. (C) Optimized conditions and substrate scope of Cys “cyclobutylation.” (D) Temporal control of Cys labeling using electronically distinct bicyclobutylsulfones.

3217 DOI: 10.1021/jacs.6b13229 J. Am. Chem. Soc. 2017, 139, 3209−3226 Summary BCB

1 R 2 OMe O 1 R H MeO E R 3 O Ar R O H P OtBu R3 NC 1 2 N BH3 R RN R central C-C bond N OMe Ar functionalization Ts N O Ph 4 O 2 OMe O Ph R MeO OH 1 metal-catalyzed cycloadditions NH2 2 4 N 2 MeO cyclizations N OBn P(O)Ph2 X 1 Ph Ar HN S 2 daphniglaucin core Y N R Ph2(O)P H SO2Ph O P O p-Tol O P REACTIONS p-Tol § Thermal cycloadditions § TM-catalyzed heterocycle synthesis § C-C bond Difunctionalization

APPLICATIONS § Total synthesis § Peptide labeling § Chiral ligand synthesis 30

Steph McCabe @Wipf Group Page 29 of 30 09/02/2017 Thank you!

§ Dr Peter Wipf § Wipf group members past and present

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Steph McCabe @Wipf Group Page 30 of 30 09/02/2017