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Thomas R. Hoye Jacob T. Edwards 7/1/17 Research Interests Total - - PowerPoint PPT Presentation

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Baran Group Meeting Thomas R. Hoye Jacob T. Edwards 7/1/17 Research Interests Total synthesis of complex natural products, organometallic chemistry, olefin metathesis (RRCM), stereochemistry determination via NMR, No-D NMR spectroscopy,

slide-1
SLIDE 1

Thomas R. Hoye

Jacob T. Edwards Baran Group Meeting 7/1/17 Thomas R. Hoye

Education B.S. Bucknell University, 1972 M.S. Bucknell University, 1972 (Harold W. Heine) Ph.D. Harvard University, 1976 (Robert B. Woodward) Professional Career Assistant Professor, University of Minnesota, 1976 Professor, University of Minnesota, 1988 Awards and Honors Alfred P. Sloan Foundation Research Fellowship, 1985 Award for Outstanding Contributions to Post-baccalaureate, Graduate, and Professional Education, 1999 Academy of Distinguished Teachers, University of Minnesota, 1999 Merck Professor of Chemistry, University of Minnesota, 2002–2007, 2009–2014 Morse-Alumni Award for Excellence in Undergraduate Teaching, University of Minnesota, 2007 Minnesota Award for Outstanding Contributions to the Chemical Sciences, ACS Minnesota Section, 2014 Ernest Guenther Award in the Chemistry of Natural Products, American Chemical Society, 2015 Royal Society of Chemistry Robert Robinson Award, 2016 Arthur C. Cope Scholar Award, American Chemical Society, 2017 College of Science and Engineering Distinguished Professor, University of Minnesota

Career Snapshot

  • > 200 publications
  • 14 patents
  • > 150 undergraduates, 14 masters students, 81 Ph.D. students, and > 40 postdocs
  • Trimethyl Phosphonoacetate (EROS Article)
  • Academic offspring include Bongjin Moon (Sogang University, Seoul, South Korea), Paul R.

Hanson (University of Kansas), Mark J. Kurth (UC-Davis), Christopher S. Jeffrey (University of Nevada, Reno), Dawen Niu (Sichuan University)

  • Collaborators include P. Sorensen (UMN Department of Fisheries), M. Hillmyer (UMN

Department of Chemistry), C. Macoscko (UMN Department of Chemical Engineering and Materials Science), K. Mayo (UMN College of Biological Sciences) Top Six Most Cited Works: Determination of absolute configuration of stereogenic carbinol centers in annonaceous cetogenins by proton and fluorine 19-NMR analysis of Mosher ester derivatives, J. Am. Chem

  • Soc. 1992, 114, 10203 (263 citations)

Mosher ester analysis for the determination of absolute configuration of stereogenic (chiral) carbinol carbons, Nature Protocols 2007, 2, 2451 (242 citations) Some allylic substituent effects in ring-closing metathesis reactions: Allylic alcohol activation,

  • Org. Lett. 1999, 1, 1123 (167 citations)

Mixture of new sulfated steroids functions as a migratory pheromone in the sea lamprey,

  • Nat. Chem. Biol. 2005, 1, 324 (153 citations)

The hexadehydro-Diels-Alder reaction, Nature, 2012, 490, 208 (149 citations) Relay ring-closing meathesis (RRCM): A strategy for directing metal movement throughout

  • lefin metathesis sequences, J. Am. Chem. Soc. 2004, 126, 10210 (141 citations)

Research Interests

Total synthesis of complex natural products, organometallic chemistry, olefin metathesis (RRCM), stereochemistry determination via NMR, No-D NMR spectroscopy, polymer synthesis, natural product structure determination, hexadehydro-Diels- Alder reaction, and more

slide-2
SLIDE 2

Thomas R. Hoye

Jacob T. Edwards Baran Group Meeting 7/1/17

O OMe OH Me (±)-megaphone (formal)

  • Tet. Lett. 1983, 24, 4769

O Me Br O H O Me H Me (±)-aplysistatin

  • J. Am. Chem. Soc.

1979, 101, 5065

  • J. Am. Chem. Soc. 1982, 104, 6704

O CO2Me O H H Me (±)-sarracenin

  • J. Org. Chem. 1989, 54, 688

O O O O Me HO AcO Me (+)-(15,16,19,20,23,24)-hexepi-uvaricin

  • J. Am. Chem. Soc. 1991, 113, 9369

O O O O Me HO HO Me OH (–)-bullatacin

  • Tet. Lett. 1993, 34, 5043

(+)-bullatacin (shown above)

  • Tet. Lett. 1995, 36, 1981

N O H N O H (+)-xestospongin A

  • J. Am. Chem. Soc. 1994, 116, 2617

(–)-xestospongin C (C9 epimer)

  • J. Am. Chem. Soc. 1996, 118, 12074

michellamines A–C

  • Tet. Lett. 1994, 35, 8747

O O Me H O Me H (±)-carabrone (formal)

  • J. Org. Chem. 1995, 60, 4184

korupensamine C

  • Tet. Lett. 1996, 37, 3097

HN OMe OH OMe Me Me Me OMe ancistrobrevine B

  • Tet. Lett. 1996, 37, 3097

(ent)-korupensamine D

  • Tet. Lett. 1996, 37, 3099

korupensamine D

  • J. Org. Chem. 1999, 64, 7184

9

O O O O (±)-differolide

  • Org. Lett. 1999, 1, 277

OH HO Me Me Me Me (–)-cylindocyclophane A

  • J. Am. Chem. Soc. 2000, 122, 4982

O Br Me Me Me Me (±)-3β-bromo-8-epicaparrapi oxide

  • J. Org. Chem. 1979, 44, 3461

OH HO OH HO (±)-ancistrofuran

  • J. Org. Chem. 1981, 46, 1198

O O Me H Me Me NH HN OH HO Me OMe OH OH OH Me Me Me Me OH Me OMe Targets Completed by the Hoye Group NH OH HO Me OMe OH Me Me korupensamine B

  • J. Org. Chem. 1999, 64, 7184

N OH HO Me OMe OH Me Me Me NH OH HO Me OMe OMe Me Me NH OH HO Me OMe OR Me Me korupensamine A

  • J. Org. Chem. 1999, 64, 7184

O O O O Me HO HO Me OH (+)-asamicin

  • Tet. Lett. 1995, 36, 1981
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SLIDE 3

Thomas R. Hoye

Jacob T. Edwards Baran Group Meeting 7/1/17

O Me O O H O O Me (–)-dactylolide

  • J. Am. Chem. Soc.

2003, 125, 9576 zampanolide

  • J. Am. Chem. Soc.

2003, 125, 9576 O Me O O OH O Me N H O Me Me OAc Cl O O H Me CO2H O (–)-haterumalide NA/(–)-oocydin A

  • J. Am. Chem. Soc.

2005, 127, 6950 O N H H O O OH O H H Me H (±)-UCS1025A

  • J. Am. Chem. Soc.

2006, 128, 2551 O C12H25 OH OH O HO O O Me (+)-gigantecin

  • Org. Lett. 2006, 8, 3383

O O O Cl O NH O O Me Me Me H OH MeO Me O (–)-callipeltoside A

  • J. Org. Chem. 2010, 75, 7052

Me Me Me Me Me NH O O OH HO O (+)-scyphostatin (core)

  • Org. Lett. 2010, 12, 52

O O O HO OMe Me Me OH MeO Me Me HO OMe OH OH (+)-peloruside A

  • Angew. Chem. Int. Ed.

2010, 49, 6151 Me Me Me O OH Me O O Me (–)-okilactomycin D

  • Org. Lett. 2012, 14, 828

NH O N O HO Et (±)-leuconolam

  • Chem. Sci. 2013, 9, 589

N H O Me Me Me N H O Me Me (±)-mahanimbine

  • J. Am. Chem. Soc.

2016, 138, 13870 koenidine

  • J. Am. Chem. Soc.

2016, 138, 13870 Useful Resources A practical guide to first-order multiplet analysis in 1H NMR spectroscopy.

  • J. Org. Chem. 1994, 59, 4096.

A method for easily determining coupling constant (J) values

  • J. Org. Chem. 2002, 67, 4014

MTPA (Mosher) amides of cyclic secondary amines: Conformational aspects and a useful method for assignment of amine configuration.

  • J. Org. Chem. 1996, 61, 2056.

A convenient synthesis of dimethyl(diazomethyl)phosphonate (Seyferth/Gilbert reagent).

  • J. Org. Chem. 1996, 61, 2540.

No-D NMR (no deuterium proton NMR) spectroscopy: A simple yet powerful method for analyzing reaction and reagent solutions. Org. Lett. 2004, 6, 953 No-D NMR spectroscopy as a convenient method for titering organolithium (RLi), RMgX, and LDA solutions. Org. Lett. 2004, 6, 2567. Reaction titration: A convenient method for titering reactive hydride agents (Red-Al, LiAlH4, DIBALH, L-Selectride, NaH, and KH) by No-D NMR Spectroscopy. Org. Lett. 2005, 7, 2205. Mosher ester analysis for the determination of absolute configuration of stereogenic (chiral) carbinol carbons. Nature Protocols 2007, 2, 2451 A guide to small-molecule structure assignment through computation of (1H and 13C) NMR chemical shifts. Nature Protocols 2014, 9, 643

  • R. B. Woodward lectures: http://www1.chem.umn.edu/groups/hoye/links/index.php

O O O O O Me Me C12H25 C12H25 (±)-paracaseolide A Nature Chemistry 2015, 7, 641 OH OH H Targets Completed by the Hoye Group

slide-4
SLIDE 4

Thomas R. Hoye

Jacob T. Edwards Baran Group Meeting 7/1/17

Graduate studies (R. B. Woodward, Harvard University) Total synthesis of illudinine, illudalic acid, and illudacetallic acid.

  • J. Am. Chem. Soc. 1977, 99, 8007

N Me Me OMe CO2H Me Me OH OHC O HO O Me Me OMe O HO O MeO OMe illudinine (for recent synthesis, see Org. Lett. 2017, 19, 858) illudalic acid illudacetalic acid (proposed structure) Cl O Cl AlCl3 1.

  • 2. H2SO4, 100 ℃

71% (2 steps) O O +

  • 2. Zn/Hg, HCl,

66.5% (2 steps, BRSM) Me Me Br2, MeNO2 95% Me Me Br Br n-BuLi; B(OMe)3; AcOH; H2O2 (aq.) 55.5% Me Me OH Br

  • 1. Me2SO4
  • 2. Mg, then

ClCO2Me Me Me OMe CO2Me 94% (2 steps) OHC Me Me OMe CO2Me OHC

  • 1. HC(OMe)3, H+
  • 2. NaOH, MeOH

90% (2 steps) Me Me OMe CO2H O OMe MeO illudacetalic acid (revised structure) HCl (10%, aq.) THF quant. Me Me OMe OHC O HO O NH4OH AcOH N Me Me OMe CO2H illudinine 75% BBr3 27% Me Me OH OHC O HO O Independent Career: Brominative Cyclizations Mercuric Trifluoroacetate Mediated Brominative Cyclizations of Dienes. Total Synthesis of dl,-3βibromo-8-epicaparrapi oxide

  • J. Org. Chem. 1979, 44, 3461

O Br Me Me Me Me 1.Hg(TFA)2; KBr (sat. aq.)

  • 2. Br2, LiBr,

pyr., O2 44% (ca. 1:1 dr, 2 steps) (+ C8-epimer)

  • 1. DIBAL
  • 2. TsCl, pyr.

MeO2C

  • 3. PhSeNa
  • 4. NaIO4

43% (4 steps) O Br Me Me Me Me (±)-3β-bromo-8-epicaparrapi oxide O Me Br O H O Me H Me (±)-aplysistatin Methodology was applied to (±)-aplysistatin: see JACS 1979 (Edwards, 2015) Me Me Me CO2Me HO Me For early work on brominative cyclizations (Ag+/Br2): Hoye and Kurth, J. Org. Chem. 1978, 43, 3693 OH Me Br OR O Me H Me X Me CO2R OR HO Me Me Br+

  • J. Am. Chem. Soc.

1979, 101, 5065

  • J. Am. Chem. Soc.

1982, 104, 6704 O O Me Br H Me Me

  • 1. DIBAL
  • 2. LDA,

then OLi OtBu

  • 3. p-NO2BzCl

78% (3 steps) OH Me Br OtBu O Me H Me OPNB

  • 1. Hg(TFA)2; KBr
  • 2. PyrHBr3
  • 3. TFA
  • 4. Et3N

O Me Br O H O Me H Me OPNB Et3N (excess) O Me Br O H O Me H Me (±)-aplysistatin Modern approach to brominative cyclization: Et S Br Et SbCl5Br BDSB Snyder and Treitler,

  • Angew. Chem.
  • Int. Ed.

2009, 48, 7899 homogeranic acid 1.Hg(TFA)2; KBr (sat. aq.)

  • 2. Br2, LiBr,

pyr., O2 33% (2 steps)

  • 1. MeI, KOtBu

tBuOH, reflux MeCN 56% (5 steps)

  • 1. CrO3,

AcOH

  • 2. NaBH4
  • 3. TsOH,

PhMe, Δ

  • 4. OsO4
  • 5. NaIO4

35% (5 steps) exists as bishemiacetal in solid state illudalic acid

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SLIDE 5

Thomas R. Hoye

Jacob T. Edwards Baran Group Meeting 7/1/17

Bistetrahydrofuranyl Natural Products C10H21 EtO2C

  • 1. AD-Mix-β
  • 2. dimethoxypropane

TsOH,acetone 72% (2 steps) OH O O C10H21 O O Me Me

  • 1. TsCl
  • 2. K2CO3, MeOH

91% (2 steps) CO2Me O C10H21 O O Me Me BF3•OEt2 (20 mol %) CH2Cl2 63% O O O HO C10H21

  • 1. TBSCl
  • 2. DIBAL
  • 3. Wittig
  • 4. DIBAL

OH O TBSO C10H21 OH

  • 1. (+)-DET

Ti(OiPr)4, TBHP

  • 3. TsCl
  • 4. TBAF (excess)

65% ( 4 steps) O O HO C10H21 O Li TMS BF3•OEt2 1.

  • 2. K2CO3,

MeOH, 70% (2 steps) 66%

  • 2. TBDPSCl

O O HO C10H21 HO MeO OMe O

5

Li BF3•OEt2 1. OTBS Me

  • 2. PPTS, MeOH
  • 3. TBDPSCl
  • 4. PPTS, MeOH

R1 OR2 Me OH

24

C24 hydroxyl group was inverted via Mitsunobu sequence to access (+)-bullatacin

  • 1. Red-Al; I2

O O R1 OR2 Me R1 = R2 = TBDPS K2CO3, THF 83% (2 steps)

  • 1. TFA, H2O,

CHCl3

  • 2. CrCl2, CHI3

O O OR2 Me I

5

  • 2. cat. PdII

CO (45 psi), NH2NH2 72% (2 steps)

  • 1. PdII (cat.)

CuI, Et3N

  • 2. Rh(PPh3)3Cl (cat.)

H2 (1 atm)

  • 3. AcCl, MeOH,

Et2O, 44% (3 steps) O O HO HO (+)-asamicin Me OH O For the synthesis of other bis-THF-containing natural products/analogues: (–)-bullatacin, Tet. Lett. 1993, 34, 5043 (+)-(15,16,19,20,23,24)-hexepi-uvaricin, J. Am. Chem. Soc. 1991, 113, 9369 Highly Efficient Synthesis of the Potent Antitumor Annonaceous Acetogenin (+)-parviflorin

  • J. Am. Chem. Soc. 1996, 118, 1801
  • 1. OsO4, NMO
  • 2. KIO4;

3. Ph3P CO2Et

  • 4. DIBAL, –78 ℃

51% (4 steps) OH HO

  • 1. (+)-DET

Ti(OiPr)4, TBHP

  • 2. TBDPSCl

O O O O Li TMS BF3•OEt2 O O HO HO C7H15 I O O Me OR

3

  • cat. PdII, CuI, Et3N
  • 2. (PPh3)3RhCl, H2
  • 3. AcCl, MeOH, Et2O

48% ( 3 steps) O O HO HO C9H19 (+)-parviflorin Li C7H15 BF3•OEt2

  • 3. K2CO3, MeOH

54% (3 steps, BRSM) 1. 2. 1.

  • 1. AD-Mix-β
  • 2. TFA
  • 3. TsCl
  • 4. TBAF

OR RO O O OH

7

O O Me Total Synthesis of the Potent Antitumor, bis-Tetrahydrofuranyl Annonaceous Acetogenins

  • Tet. Lett. 1995, 36, 1981

For a discussion on the synthesis of 2,5-linked bistetrahydrofurans via cascade reactions, see: J. Am. Chem. Soc. 1985, 107, 5312 for (+)-asamicin O O HO C10H21 HO O O OR2 Me I

5

+ R = TBDPS > 99% ee 64% (6 steps) R = TBDPS (0.5 equiv.) OMe MeO

5

Me from undecanal (iterative Johnson- Claisens)

slide-6
SLIDE 6

Thomas R. Hoye

Jacob T. Edwards Baran Group Meeting 7/1/17

Organometallic Chemistry: Synthesis and Reactions of Fischer Carbenes Cr(CO)5 X Me MeO2C MeO2C Me MeO2C MeO2C Me Me O X = OMe, 22% X = N , 58% MeO2C MeO2C Me O O Me major byproduct for X = OMe (30%) Stronger donor group reduces propensity for CO insertion: why? Reactions of Manganese Fischer Carbene Complexes Organometallics 1990, 9, 3014 MeO2C MeO2C Me Me O MeO2C MeO2C Me MeLi X = OMe, 71% X = Li, 83% MCMT (gasoline additive) in situ X = Li For X = OMe, product can be isolated as methyl vinyl ether In situ generation of acyl metallates and reactions with alkynes and enynes

  • J. Am. Chem. Soc. 1990, 112, 2841

Mn(CO)2Cp’ X Me R1 CO2Me R2 R1 = H, Me R2 = H, Me 61–79% Me O R1 R2 CO2Me (OC)5Cr OMe Me Me Me C6H6, 80 ℃ 60% (single diastereomer) Me H Me O Me NaOMe, MeOH Me H Me O Me 32% (4 steps)

  • 1. K-Selectride
  • 2. Ac2O
  • 3. O3

83% (3 steps) Me H Me O CHO

  • 1. AgNO3,

NaOH

  • 2. H3O+

69% (2 steps) Me H Me O O O OAc formal synthesis O O Me H O Me H (±)-carabrone Fischer carbenes in synthesis: formal synthesis of (±)-carabrone J. Org. Chem. 1995, 60, 4184 For total synthesis, see:

  • Chem. Commun.

1967, 358 Cr(CO)6 RM Cr(CO)5 OM R MeO2C MeO2C Me R= Me, Et, allyl, benzyl M = Li, MgX, NMe4 Bu O O Bu R MeO2C MeO2C Me Me O For R = Me, 74% 41–58% Reaction of enynes with Fischer carbene metal complexes

  • J. Am. Chem. Soc. 1988, 110, 2676

Organometallics 1989, 8, 2070 Fischer carbene complex preparation by alkylation

  • f acyl metallates with

alkyl iodides, Organometallics 1993, 12, 2806 Pauson-Khand Type Reactions O N2 Me Rh2(OAc)4 (cat.) rt, 40% Me Me Me Me O Me Me Me Me Me Rh2(OAc)4 (cat.) 80 ℃, 51% Me Me Me O Me Me

  • Tet. Lett. 1991, 32, 3755

E E W(CO)5•THF THF, 65 to 110 ℃ X E E X O 17–71% 10 examples W(CO)6 can be recovered after reaction via CO bubbling (ca. 95%)

  • J. Am. Chem. Soc. 1993, 115, 1154

Product initially observed as byproduct during studies with tungsten Fischer carbene complexes: see Organometallics, 1992, 11, 2044 (1.1 equiv.)

  • J. Org. Chem. 1993, 58, 1659

O Me Bu + Co2(CO)8 MeCN, 75 ℃ 32–82% 10 examples (1.1 equiv.) O HH Bu Et O 60% (1.4:1 dr) Limited reports

  • f alkynones

reacting under PK conditions Double alkyne insertion of α-diazoketones with Rh O O Bu Me Bu THF, 65 ℃, 67%

slide-7
SLIDE 7

Thomas R. Hoye

Jacob T. Edwards Baran Group Meeting 7/1/17

Total Synthesis of Michellamines A–C, Korupensamines A–D, and Ancistrobrevine B

  • J. Org. Chem. 1999, 64, 7184

NH HN OH HO Me OMe OH OH OH Me Me Me Me

5 8’

michellamine A SS (5/8’’) michellamine B RS (5/8’’) (shown above) michellamine C RR (5/8’’)

8’’ 5’’’

Me OMe

  • 1. NBS
  • 2. PhSO2Na
  • 3. LDA; methyl crotonate
  • 4. KOH
  • 5. TFAA
  • 6. NaOH or KOtBu

40% (6 steps) Me OH OR Br Br Br MOMO LICA; Me NEt2 OLi 20% OH Me OMe NH OH HO Me OMe OR Me Me

5 8’

korupensamine A (R = H) korupensamine C (R = Me) NH OH HO Me OMe OH Me Me korupensamine B NH OH HO Me OMe OR Me Me B(OH)2 I

  • 1. Me2SO4, NaOH,

Bu4NBr

  • 2. n-BuLi,

B(OMe)3; H2O Me OMe OR B(OH)2 MeO CO2Me OMe

  • 1. LAH
  • 2. Swern
  • 3. EtNO2, NH4OAc
  • 4. Fe, AcOH
  • 5. (R)-PhCH(Me)NH2
  • 6. H2, Ra-Ni

MeO OMe HN Ph Me H Me 1.HCO2NH4, Pd

  • 2. Ac2O, Et3N
  • 3. POCl3
  • 4. LAH/AlMe3

MeO OMe NH Me Me

  • 1. BBr3, CH2Cl2
  • 2. BnBr, Cs2CO3 DMF
  • 3. I2, AgSO4, EtOH

BnO OBn NBn Me Me I [Pd] [ox] + BnO OBn NBn Me Me I Me OMe OMOM B(OH)2 + Pd(PPh3)4 (cat.) PhMe, EtOH NaHCO3 (sat. aq.) 100–110 ℃, 81% (5:4) BnO OBn NBn Me Me Me OMe OMOM BnO OBn NBn Me Me Me OMe OMOM + HCl (conc.) MeOH/CH2Cl2 Ag2O CH2Cl2 NBn BnN OBn BnO Me OMe O OBn OBn Me Me Me Me O Me OMe BnO OBn NBn Me Me Me OMe OH BnO OBn NBn Me Me Me OMe OH + H2 Pd/C CH2Cl2/MeOH

  • quant. (2 steps)

NH HN OH HO Me OMe OH OH OH Me Me Me Me OH Me OMe michellamine A–C (1:2:1) H2 Pd/C CH2Cl2/MeOH 87% NH OH HO Me OMe OH Me Me NH OH HO Me OMe OH Me Me korupensamine B korupensamine A Synthesis of boronic acid: Synthesis of aryl halide: Asymmetric Suzuki strategy (chiral monophosphorus ligand): Tang, J. Am. Chem. Soc. 2014, 136, 570 Studies on Pd-catalyzed hindered biaryl formation:

  • J. Org. Chem. 1996, 61, 7940

Synthesis of anti-HIV agents via Pd-catalyzed cross-coupling

slide-8
SLIDE 8

Thomas R. Hoye

Jacob T. Edwards Baran Group Meeting 7/1/17

Some Allylic Substituent Effects in Ring-Closing Metathesis Reactions: Allylic Alcohol

  • Activation. Org. Lett. 1999, 1, 1123

X R Me Me X R Grubbs I (4–100 mol%) R X relative reactivity H OH 60 Me OH 12 Me H 8 H OMe 1 Me OMe ~0 An Enyne Metathesis/(4 + 2) Dimerization Route to (±)-differolide

  • Org. Lett. 1999, 1, 277

O O Grubbs I (10 mol%) (0.1 M) CH2Cl2, rt 37h, 40% O O methylene blue C6D6, 12h, 75 ℃ spontaneously dimerizes neat at RT O O O O 89% (±)-differolide + O O O O H 11% Me Me OH OH H + Me Me Me O R [Ru] OH R [Ru] OH H Grubbs I (1.5 equiv.) 1 : 1.5 R O [Ru] H R O H Possible Mechanism of Ketone Formation: For such an observation in an RCM-based route to callipeltoside A, see: Org. Lett. 1999, 1, 169 Disclosure of Grubbs 2nd Generation Catalyst: Org. Lett. 1999, 1, 953 Entry into Olefin Metathesis Studies Relay Ring-Closing Metathesis (RRCM): A Strategy for Directing Movement Throughout Olefin Metathesis Sequences, J. Am. Chem. Soc. 2004, 126, 10210 Olefin Metathesis: Relay-Ring Closing Metathesis and More Problem: Sterically hindered or electronically deactivated olefins fail to undergo RCM Solution: Design a substrate that allows for initiation at a less troublesome position Me Me E E [Ru] Me Me E E Grubbs I Me Me E E Me Grubbs I Me Me E E Me [Ru] RCM Me Me Et Et Can also be accessed via RCM with Grubbs II Proof of concept: Synthesis of tetrasubstituted olefins (Example 1) O R2 Me Me R1 O – Me O Me [Ru] R2 left-to-right vs. Me O Me [Ru] R1 right-to-left O Me Me O Me Me A: R1 = H, R2 = H B: R1 = X, R2 = H C: R1 = H, R2 = X C6D6, RT Grubbs II X = O A: 1:2 B: 4.7:1 C: 1:7 C6D6, 50 ℃ Grubbs I A: – B: 26:1 C: 1:45 Cat./ Cond. Ratio (ltr:rtl) Control of “endedness” (Example 2) Use of Less Accessible Olefins as Initations Sites for Ring Closure (Example 3) B A Cl O Me O O Grubbs II PhMe, 100 ℃ N2 sparge 50–70% B A Cl O O O Me Me Me B A = B A = OH B A = O (Z only) (E only) (E only) O O MeO2C CO2Me OH OMe OMOM OMOM OMe OH OMe O MeO2C OMe MOMO OMOM OMe MeO2C CO2Me HO MOMO MeO MeO2C OMe OMOM OMe O TMG O O MOMO MeO OMe OMOM CO2Me then TFA

  • 1. L-selectride
  • 2. prenyl bromide/In0
  • 3. AlCl3/NaI
  • 4. ArCH(OMe)2, CSA

69% (4 steps) O O O OMOM O Me Me PMP OMe OMe 98% (12:1 dr) H O CO2Me Me Me OTBS O OMe OMOM OMe O PMB BPS For a comparison on diastereoselective kinetic control of lactonization by acid/base catalysis vs ozonolysis,see: Hoye and Ryba, J. Am. Chem.

  • Soc. 2005, 127, 8256

Application in total synthesis: peloruside A Total Synthesis of peloruside A through Kinetic Lactonization and Relay Ring-Closing Metathesis Cyclization Reactions, Angew. Chem. Int. Ed. 2010, 49, 6151 TFA, TMG ltr rtl

slide-9
SLIDE 9

Thomas R. Hoye

Jacob T. Edwards Baran Group Meeting 7/1/17

Et OH + Me NC OH Me Ph2SiCl2, pyr. 41% (2 steps) Non-obvious Advantages of RRCM (Example 4) O SiPh2 O Me CN Et O SiPh2 O CN Et Me Me Grubbs II enzymatic kinetic resolution afforded enantiopure material (substrate without relay could not be resolved) PhMe, 65 ℃ 92%

  • 1. TBAF
  • 2. TBSCl, Et3N
  • 3. Cl3CC(=NH)OPMB, CSA

OPMB Me CN Et OTBS 59% (3 steps) AllylO O Br Zn, Cp2TiCl2 (cat.) THF, 60 ℃

  • 2. pH 3 buffer,

iPrOH/H2O/THF 1. OPMB Me Et OTBS O OAllyl O Pd(PPh3)4 (cat.) HCO2H, Et3N THF, rt 61% OPMB Me Et OTBS Me O CO2Me Me Me OTBS O OMe OMOM OMe O PMB BPS OPMB Me Et OTBS Me O + Cy2BCl, Et3N, Et2O Me Et OTBS O OH O PMB

15

CO2Me Me Me OTBS O OMe OMOM OMe O PMB BPS O O O O HO OMe Me Me OH MeO Me Me HO OMe OH OH –78 ℃ to –40 ℃; then aldehyde, –78 ℃ to –20 ℃ 64% (+)-peloruside A

15

Reduction/ Yamaguchi Macrocyclization/ Deprotection Allylmalonate and RRCM: a (+)-gigantecin inspired study O O SiR2 O O TIPSO C12H25 R2 R1 HG-II, CH2Cl2, O O SiR2 O O TIPSO C12H25 Si O Me Me A Si O B O C E E E = CO2Me D R1 R2 Yield (%) A H B B C D H A H B C H – – – – – 88% benzoquinone, 45 ℃ Total Synthesis of (+)-gigantecin

  • Org. Lett. 2006, 8, 3383

O O SiPh2 O O TIPSO C12H25 5 steps (LLS)

  • 1. HG-II, PhMe,

80 ℃ O O SiPh2 O O TIPSO C12H25

  • 1. Grubbs-II, CH2Cl2

45 ℃

  • 2. HF (5%)/MeCN,

CH2Cl2, rt 69% (2 steps) O Me TIPSO O C12H25 HO OH O HO O O Me R1 R2 R1 = OH, R2 = H, (+)-gigantecin (CM then RCM) R1 = H, R2 = OH, (+)-14-deoxy-9-oxygigantecin (RCM then CM) (A) A, Grubbs II (20 mol%), CH2Cl2 45 ℃ O O SiPh2 O O TIPSO C12H25 R 63%

  • 1. TsNHNH2, NaOAc

H2O, DME, reflux

  • 3. HF (5%)/MeCN,

CH2Cl2, rt 48% (3 steps)

  • 2. TsNHNH2, NaOAc

H2O, DME, reflux

  • Angew. Chem. Int. Ed.

2011, 50, 2141 Employment of relay metathesis by others : O OH O OH H N N OMe O

  • ximidine III

Porco, Angew. Chem. Int. Ed. 2004, 43, 3601 O HO O O Me HO H H OH O HO H H C10H21

7

(–)-mucocin Crimmins, Org. Lett. 2006, 8, 2369 Relay cross-metathesis: Hansen and Lee, Org. Lett. 2004, 6, 2035 O

slide-10
SLIDE 10

Thomas R. Hoye

Jacob T. Edwards Baran Group Meeting 7/1/17

Natural Product Structure Determination Structural Determination and Synthesis of a migratory pheromone in the sea lamprey With Peter W. Sorensen (Department of Fisheries, University of Minnesota)

  • Nat. Chem. Biol. 2005, 1, 324
  • J. Org. Chem. 2007, 72, 7544

Steroids 2011, 76, 291 Sea Lamprey Background: – Found in Atlantic Ocean along Europe and North American shores, western Mediterranean Sea, the Black Sea, and the Great Lakes – Compounds secreted from the mouth of the lamprey inhibit blood clotting – Considered to be pest/invasive species in the Great Lakes (caused significant decrease in indigenous fish population, especially trout) – 3–20 year larval phase – Yearlong parasitic phase – Move from lakes/ocean to freshwater streams prior to spawning OH CF3 NO2 TMF: common lampricide – uncouples electron transport chain from ATP synthesis – does not harm other fish but can affect amphibians Me H Me N H Me Me Me OSO3Na N O H H H Me Me Me Me Me OH H H H O OSO3Na OMOM from chenodeoxycholic acid (7 steps, known) N O NH2

  • 1. MeOH, 3Å MS
  • 2. NaBH4, –78 °C
  • 3. HCl, MeOH
  • 4. SO3•py, 50 °C

Goal of the study: Identify compounds released by lamprey larvae and examine biological properties to determine the main constituents of the pheromone in the hopes to potentially control lamprey migration Sea Lamprey Pheromones – Correlation between streams chosen by migrating adult lampreys and number of larvae living in the chosen stream – petromyzonol sulfate and allocholic acid were secreted by lamprey larvae – lampreys are attracted to streams at very dilute pheromone concentration; one larva “activates” 400L of water per hour Unknown Compound 1: petromyzonamine disulfate (PADS) – C34H60N2O9S2 – most potent compound (10-13 M) isolated (500 grams for Niagara Falls for 1 month petromyzonamine disulfate (PADS) Synthesis of an authentic sample of PADS Me H Me N H Me Me Me OSO3Na N H H H H OH NH2 squalamine Me H Me HN N O H H H OH Me H H H H detected by COSY and 1H NMR Methods: – 3 compounds identified as having significant olfactory activity (two-choice maze test) – 8000L of water (35000 larvae) afforded 0.2–1.0 mg (with purity ca. 80%) of each compound Me H Me NaO3SO Me Me Me OSO3Na H H OH Me H Me Me OSO3Na H H H OH HO OH Unknown Compound 2: petromyzosterol disulfate (PSDS) –C28H46O9S2 A/B ring were compared to cholesterol/ cholesterol sulfate Compound 3: petromyzosterol disulfate (PS) Synthesis of unnatural bile acids: Steroids, 2011, 76, 291 (24-epi-PADS was also synthesized) 4.45 ppm (ddd, J = 2.3 Hz) 3.78 ppm ΣJ = 8 Hz

slide-11
SLIDE 11

Thomas R. Hoye

Jacob T. Edwards Baran Group Meeting 7/1/17

Total Synthesis A Total Synthesis of (+)-xestospongin A/(+)-araguspongine D, J. Am. Chem. Soc. 1994, 116, 2617 Macrolactonization via Ti(IV)-Mediated Epoxy-Acid Coupling: A Total Synthesis of (–)- dactyolide (and zampanolide)

  • J. Am. Chem. Soc. 2003, 125, 9576

N O H N O H (–)-xestospongin C (C9 epimer)

  • J. Am. Chem. Soc. 1996, 118, 12074

Cl OH

  • 1. NBS, PPh3
  • 2. DIBAL, CH2Cl2, –78 ℃
  • 3. HC(OMe)3, CSA, MeOH

49% (3 steps) CN Cl Br OMe OMe S Li THF, 0 ℃ to rt 1.

  • 2. n-BuLi,

DMF, –78 ℃

  • 3. LiCH2CN, –78 ℃

35% (3 steps) Cl OMe OMe S OH NC Cl OMe OMe S OH NC AMANO P-30 38% Cl O S OH NC Cl S HO NH2 DMSO 65 ℃ quant. LAH, Et2O, 0 ℃ to rt, 92%

  • 1. CH2Cl2
  • 2. NaOH

(5% aq.) 42% (trans) N O S CN OH S OMe MeO Cl ~2.3:1 trans:cis

  • 1. LAH, Et2O,

0 ℃ to rt

  • 2. TFA, H2O,

DMSO 65 ℃ N+ O S OH S O Cl NH3+ H 2CF3CO2- (+)-xestospongin A

  • 1. CH2Cl2,

H2O, pH > 12

  • 2. RaNi, H2

48% (2 steps) Cl OMe MeO OH NH3+ N O N O pH 7, 9:1 MeOH:buffer 50% (2.5:1 A:C) O Me O O H O O Me RCM Sakurai epoxide

  • pening

OTBDPS Me CHO + PivO TMS TMSO

  • 1. CSA (cat.), Et2O
  • 2. DIBAL
  • 3. DMP

4.

  • 5. TBAF
  • 6. SAE.,–25 ℃

Ph3P 39% (5 steps) O Me OH O O HO Me OTBS Ti(Ot-Bu)4, CH2Cl2 75 ℃, 67% O Me O O Me HO HO OTBS

  • 1. BSA, PhH;

then Grubbs II, 60 ℃

  • 2. TBAF

68% (2 steps) O Me O O Me HO HO Pb(OAc)4 O Me O O H O O Me 90% (–)-dactyolide Me NH OAli-Bu2 O Me O O OH O Me N H O Me

20

OH O Me O O Me HO HO O Bobbitt’s Salt SiO2, CH2Cl2 80%

  • ca. 1:1 C20 epimers

zampanolide TFA, H2O +

  • rganometallic

addition Ac2O OMe MeO

slide-12
SLIDE 12

Thomas R. Hoye

Jacob T. Edwards Baran Group Meeting 7/1/17

Alkyne Haloallylation [with Pd(II)] as a Core Strategy for Macrocycle Synthesis: A Total Synthesis of (–)-haterumalide NA/(–)-oocydine A, J. Am. Chem. Soc. 2005, 127, 6950 Me OAc Cl O O H Me CO2H O Snider, Yamaguchi Macrolactonization, competitive dimer/trimer formation Kigoshi, Reformatsky, low yielding (9%) Kaneda Haloallylation (J. Org. Chem. 1979, 44, 55) RRCM Me OAc O O H Me CO2H O Cl OH Cl O O H R O Me H R1 Me OH Cl O O H R O Me R1

  • nly truncation

products observed (RCM did not proceed) Grubbs II Me O O H R O Cl PdCl2(PhCN)2 (20–30 mol%) THF, rt 91% (1:1.4 Z/E) R = CH2OPMB Me Cl O O H OPMB O H O O H

  • 1. NaBH4,

CeCl3•7H2O

  • 2. Ac2O
  • 3. DDQ
  • 4. DMP

Me Cl O O H O O H OAc I CO2PMB Me CrCl2/ NiCl2, DMSO 42% (5 steps, 10:1 dr) Me OAc Cl O O H Me CO2PMB O H TFA, Et3SiH CH2Cl2, 0 ℃, 1h (–)-haterumalide N/ (–)-oocydine A via: R1 H PdX2L2 R2 R3 H X R1 X [Pd] R2 R3 H X R1 X R2 [Pd] R3 H X –PdX2L2 R1 X R2 R3 H O N H H O O OH O H H Me H Comparative Diels-Alder Reactivities within a Family of Valence Bond Isomers: A Biomimetic Total Synthesis of (±)-UCS1025A, J. Am. Chem. Soc. 2006, 128, 2550 For an alternative Reformatsky strategy to forge C7–C8, see: Lambert and Danishefsky, J. Am.

  • Chem. Soc. 2006, 128, 426

O N H H O O OH O H [4 + 2] Me N O OTIPS CO2TIPS O Me CDCl3 t1/2= 6d (rt) 65 ℃, 3h 69% N O OTIPS CO2TIPS O H H Me

10 9 18 15

(4:3 desired: C9,10,15,18 epimer) HF•py O N H H O O OH O Me pH 7.2, D2O accessed in 5 steps (25% overall yield) KF, MeOH KF, MeOH O N H H O O OTIPS Me O H O N H H O O OTIPS O H H Me H (±)-UCS1025A ZnCl2•Et2O CH2Cl2, rt 18h, 56% (or CDCl3, 65 ℃) N O OH CO2- O H H Me N O OH CO2- O Me pH 3 t1/2 = 10 min t1/2 = 26h, rt, CDCl3 t1/2 = 4d, rt, CD3OD N O OTIPS CO2TIPS O Me

7 8

OH OH H H H quant. 74% (1:1 desired: C9,10,15,18 epimer) 56% (1:2 desired: C9,10,15,18 epimer) HF•py 56%

slide-13
SLIDE 13

Thomas R. Hoye

Jacob T. Edwards Baran Group Meeting 7/1/17

Initial report: The hexadehydro-Diels-Alder reaction, Nature 2012, 490, 208 Diels-Alder Didehydro-Diels-Alder (DDDA) The hexadehydro-Diels-Alder reaction and subsequent work [4+2] [4+2] [4+2] [1,5] Tetradehydro-Diels-Alder (TDDA) + + Hexadehydro-Diels-Alder (HDDA) [4+2] + Nu El trap Nu El Reaction Discovery HO OTBS O SiMe2tBu MnO2 O OTBS O SiMe2tBu O O TBS not isolated O O TBS retro- Brook O O TBS CH2Cl2, rt 53% (isolated) Examples from scope: Intramolecular Trapping Starting Material Product Conditions Yield (%) X CO2Et TBSO O X TBS CO2Et X = O, 110 ℃, d8-PhMe X = NTs, 65 ℃, CDCl3 86 95 X CO2Et TBSO O X TBS CO2Et X = O, 110 ℃, PhMe X = NPh, 120 ℃, PhMe 86 92 Examples from scope: Intermolecular Trapping O O TMS O Me Me O O Me Me 85 ℃, CHCl3 85 O TMS O O O Me H Me H 97 ℃, heptane 83 O TMS R PhH (solvent): 70% O TMS R H H norbornene: 63% (single diastereomer) O TMS R phenol: 85% (single isomer) For more examples, see:

  • Org. Lett. 2016, 18, 3396

HO O TMS R acetic acid: 89% H OAc O TMS R PhNHAc: 82% (19:1 rr) H N Ac Ph O TMS R BrCH2CH2NH3Br: 72% (6:1 rr) H Br For a study of benzyne trapping by tethered arenes, see:

  • Org. Lett. 2015, 17, 856

For early reports of HDDA, see:

  • J. Am. Chem. Soc.

1997, 119, 9917

  • Tet. Lett. 1997, 38, 3943

Starting Material Product Conditions Yield (%) O Alkane desaturation by concerted double hydrogen atom transfer to benzyne, Nature 2013, 501, 534 R O TMS THF 85 ℃ 75% O TMS R O TMS R H/D H/D Solvent Product ratio (h2:d2) THF-h8 THF-d8 THF-h8:THF-d8 (1:1) THF-h8:THF-d8 (1:6) 100:0 0:100 6:1 1:1 monodeuterated products were not observed R= (CH2)3OAc Solvent Yield Cyclooctane 97 Cycloheptane 94 Cyclopentane 84 Norbornane 66 Cyclohexane 20 THF 60 1,4-dioxane

slide-14
SLIDE 14

Thomas R. Hoye

Jacob T. Edwards Baran Group Meeting 7/1/17

The hexadehydro-Diels-Alder reaction: Mechanism and Applications The aromatic ene reaction, Nature Chemistry, 2013, 6, 34 X Me HDDA X H aromatic ene X H X > 15 examples 55–90% B A Alder ene X A B D D D2O D 10 examples 63–85% R2 R2 R1 R1 HDDA R2 R1 X Hetereocycles, 2014, 88, 1191 X = O, NR3 49–61% O Ph Ph Ph Ph MeO2C MeO2C Ph Ph Ph Ph Ar Ar

  • J. Am. Chem. Soc.

2016, 138, 12739 O R3 R4 N H Me O Me Me MeO MeO X X X

  • J. Am. Chem. Soc.

2016, 138, 13870 Competent enophiles: X O O X = O, NPh EtO2C O EtO2C O CF3 NTs Cl N Me O O Mechanistic Studies

  • J. Am. Chem. Soc. 2016, 138, 7832

TsN R TBSO N Ts O R TBS p-NO2PhMe 110 ℃, PhMe-d8 R t1/2 krel RSE (kcal mol-1) Me CHO COMe CO2Me CONEt2 H CF3 0.26 0.82 5.1 9.2 84 >400 >600 320 100 16 9.1 1 – – –12.1 –7.7 –6.7 –4.9 –4.9 +1.9 TsN R1 R2 rds TsN R2 R1 δ δ N Ts R2 R1 N Ts R2 R1 δ δ N Ts O R TBS N Ts R1 R2 For a related computation study, see: J. Org. Chem. 2015, 80, 11744 For a recent report on the photochemical hexadehydro-Diels-Alder reaction:

  • J. Am. Chem. Soc. 2017, 139, 4318

Applications of the HDDA S

n

HNu R2 R1 X S Nu

n

  • J. Am. Chem. Soc.

2016, 138, 4318 Li2CuCl4 R2 R1 X Cl Cl

  • Org. Lett.

2014, 16, 254 [dichlorination] [carbazolynes] koenidine [blue luminescence] R X Ar [polycyclic aromatics]

  • Org. Lett.

2016, 18, 5636 S NR2 Ar R2 R1 X N R S R Ar

  • Org. Lett.

2016, 18, 6312 Pentadehydro-Diels-Alder reaction Nature 2016, 532, 484 RN n-Pr n-Pr NuH (solvent) DBU (1–5 equiv.) rt, 17h R = Ts, Ms, Bz RN N Me Me Me RN Nu n-Pr

  • r

N RN Nu Me Me Me Nu = piperidine, pyrollidine, etc X –CO [benzyne] 48–94% 43–100% 37–94% 93% D incorporation RN R D D 0.03 0.42 0.34 0.34 0.26 0.54 σp –H2 via: