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Strategies for Stereocontrolled Synthesis

Chemistry 5.511 Synthetic Organic Chemistry II

Lecture 4 October 12, 2007

Rick L. Danheiser Massachusetts Institute of Technology

Strategies for Stereocontrolled Synthesis

! Thermodynamic control strategies " What determines the relative E of stereoisomers " Tactics for establishing thermodynamic control

O S HO N O

O OH O

epothilone A Strategies for Stereocontrolled Synthesis

! Thermodynamic control strategies " What determines the relative E of stereoisomers " Tactics for establishing thermodynamic control ! Kinetic control strategies " control strategies " control strategies " Dynamic kinetic resolution

Strategies for Stereocontrolled Synthesis

! Thermodynamic control strategies ! Kinetic control strategies " Substrate control strategies # Steric approach control # Stereoelectronic control # Internal stereodirection and transfer " Reagent control strategies # Achiral substrate: enantiotopic face selectivity # Achiral substrate: enantiotopic group selectivity # Chiral substrate: double asymmetric synthesis " Dynamic kinetic resolution Strategies for Stereocontrolled Synthesis

Substrate Kinetic Control Strategies

Steric Approach Control

m-CPBA CH2Cl2 O

Strategies for Stereocontrolled Synthesis

Substrate Kinetic Control Strategies

CH3 1.74 Cyclohexane Et 1.70 F 0.25-0.42 i-Pr 2.21 A Values Cl 0.53-0.64 t-Bu 4.7-4.9 (kcal/mol) Br 0.48-0.67 Vinyl 1.5-1.7 I 0.47-0.61 Ethynyl 0.41-0.52 Ph 2.8 OMe 0.55-0.75 OAc 0.68-0.87 CN 0.2 CHO 0.56-0.8 OSiMe3 0.74 CH2OH 1.76 COMe 1.0-1.5 NH2 1.23-1.7 CO Me 1.2-1.3 NMe2 1.5-2.1 2

SiMe3 2.5 Strategies for Stereocontrolled Synthesis

! Thermodynamic control strategies ! Kinetic control strategies " Substrate control strategies # Steric approach control # Stereoelectronic control # Internal stereodirection and chirality transfer " Reagent control strategies # Achiral substrate: enantiotopic face selectivity # Achiral substrate: enantiotopic group selectivity # Chiral substrate: double asymmetric synthesis " Dynamic kinetic resolution

Strategies for Stereocontrolled Synthesis

Substrate Kinetic Control Strategies Non-covalent internal stereodirection

Z Z R' m-CPBA R' benzene O

R' Z Rel. Rate Major H H 1.0 - H. B. Henbest and R. A. Wilson H OH 0.55 syn (10:1) H OMe 0.067 anti J. Chem. Soc. 1959, 1958 H OAc 0.046 anti (20:80) OH H 0.42 ca. 1 : 1 Review on “Substrate Directable Reactions” Hoveyda, A. H.; Evans, D. A.; Fu, G. C. Chem. Rev. 1993, 93, 1307 Strategies for Stereocontrolled Synthesis

Substrate Kinetic Control Strategies

Chirality Transfer

CH3C(OEt)3 cat. EtCO2H 140 °C OEt

HO O

CO2Et (vi(via Lai s-BuLAHBH red3 urectdiounct)ion)

Johnson Orthoester Claisen Rearrangement

See Langlois, Y. In The Claisen Rearrangement, Hiersemann, M.; Nubbemeyer, U., Eds.; Wiley-VCH, 2007, pp 301-366

Strategies for Stereocontrolled Synthesis

! Thermodynamic control strategies ! Kinetic control strategies " Substrate control strategies # Steric approach control # Stereoelectronic control # Internal stereodirection and chirality transfer " Reagent control strategies # Achiral substrate: enantiotopic face selectivity # Achiral substrate: enantiotopic group selectivity # Chiral substrate: double asymmetric synthesis " Dynamic kinetic resolution Strategies for Stereocontrolled Synthesis

Reagent Kinetic Control Strategies Achiral Substrate: Enantiotopic Face Selectivity

Katsuki-Sharpless Asymmetric Epoxidation

Strategies for Stereocontrolled Synthesis Reagent Kinetic Control Strategies

Katsuki-Sharpless Asymmetric Epoxidation Strategies for Stereocontrolled Synthesis

Reagent Kinetic Control Strategies Achiral Substrate: Enantiotopic Face Selectivity

Katsuki-Sharpless Asymmetric Epoxidation

OH OH t-BuOOH, Ti(Oi-Pr)4 (-)-DET, CH2Cl2 92% ee O (96 : 4)

Reviews on Asymmetric Epoxidation "Catalytic Asymmetric Epoxidation of Allylic Alcohols" Johnson, R. A.; Sharpless, K. B. In Catalytic Asymmetric Synthesis; Ojima, I., Ed.; W iley-VCH, 2000, pp 231-285 "Asymmetric Epoxidation of Unfunctionalized Olefins and Related Reactions" Katsuki, T. In Catalytic Asymmetric Synthesis; Ojima, I., Ed.; W iley-VCH, 2000, pp 287-326. "Asymmetric Epoxidation of Allylic Alcohols: The Katsuki-Sharpless Epoxidation Reaction", Katsuki, T.; Martin, V. S. Org. Reactions 1996, 48, 1.

Strategies for Stereocontrolled Synthesis Reagent Kinetic Control Strategies Katsuki-Sharpless Asymmetric Epoxidation

OH OH t-BuOOH, Ti(Oi-Pr)4 (-)-DET, CH2Cl2 O

! Reaction can be run as a stoichiometric (100 mol%) or catalytic (5-10 mol%) process ! For high enantioselectivities use excess of tartrate (5% Ti and 6% tartrate) ! Catalytic reactions can be run up to 1.0 M in concentration; stoichiometric at 0.1 M ! TBHP should be as concentrated as possible (commercial 5.5 M preferred to 3.0 M) ! Use of activated molecular sieves greatly expanded the catalytic version Strategies for Stereocontrolled Synthesis Reagent Kinetic Control Strategies Katsuki-Sharpless Asymmetric Epoxidation

OH OH t-BuOOH, Ti(Oi-Pr)4 (-)-DET, CH2Cl2 O

Compatible Functional Groups Incompatible Groups Acetals, ketals Nitriles Amines (most) Acetylenes Nitro Carboxylic acids Alcohols (remote) Olefins Mercaptans Aldehydes Pyridines Phenols (most) Amides Silyl ethers Phosphines Azides Sulfones Carboxylic Sulfoxides Epoxides Tetrazoles Ethers Ureas Hydrazides Urethanes Ketones

Strategies for Stereocontrolled Synthesis Reagent Kinetic Control Strategies Achiral Substrate: Enantiotopic Face Selectivity Katsuki-Sharpless Asymmetric Epoxidation Chiral Substrates

OH OH OH t-BuOOH, Ti(Oi-Pr)4 OH t-BuOOH,, Tii((Oii--Prr))44 (-)-DET, CH2Cl2 (-))--DET,, CH22Cll22 AAmm O AAmm O

92% ee (96 : 4) OH OH OH tt-BuOOH, Ti(Oi-Pr)4 (-)-DET, CH2Cl2 Am + Am Am O O

67 : 33 Strategies for Stereocontrolled Synthesis Reagent Kinetic Control Strategies Achiral Substrate: Enantiotopic Group Selectivity

Review on enzymatic enantioselective group Lipase-Based Desymmetrization Reactions desymmetrization: V. Gotor Chem. Rev. 2005, 105, 313

OAc OAc

PPL PLE MeO2C CO2Me HO2C CO2Me 93% 60% NHCO2Bn NHCO2Bn 100%ee 96%ee OAc OH M. Ohno J. Am. Chem. Soc. 1981, 103, 2405 J. Nokami Tetrahedron Lett. 32, 2409, 1991

Baker's yeast O sucrose O CO2Me CO2H H2O PLE 47-52% 98% 96-98.8% ee CO2Me 96%ee CO2Me O OH K. Mori and H. Mori M. Ohno Org. Synth. Coll. Vol. 8, 312, 1993 Tetrahedron Lett. 1984, 25, 2557 Another example of biotransformations in asymmetric synthesis

Strategies for Stereocontrolled Synthesis Reagent Kinetic Control Strategies Achiral Substrate: Enantiotopic Group Selectivity Coupled to Kinetic Resolution

1) HCO2Me BnO 2) RedAl Li OH OH AE (-)-DIPT O OBn OBn OBn OBn 70-80% 1 h 93% ee 44 h >97% ee >97% de S. L. Schreiber ( [A + ent-A]/[B + ent-B] ) J. Am. Chem. Soc. 1987, 109, 1525

OH OH OH OH

O O O O OBn OBn OBn OBn OBn OBn OBn OBn A B ent-B ent-A Strategies for Stereocontrolled Synthesis

! Thermodynamic control strategies ! Kinetic control strategies " Substrate control strategies # Steric approach control # Stereoelectronic control # Internal stereodirection and chirality transfer " Reagent control strategies # Achiral substrate: enantiotopic face selectivity # Achiral substrate: enantiotopic group selectivity # Chiral substrate: double asymmetric synthesis " Dynamic kinetic resolution

Strategies for Stereocontrolled Synthesis Reagent Kinetic Control Strategies Chiral Substrate: Double Asymmetric Synthesis

O Ti(OiPr) O O O OH 4 O OH + O OH TBHP O O 2.3 : 1

Ti(OiPr)4 TBHP OH OH OH Ph O Ph O + Ph O (+)-DET O O 99 : 1 Strategies for Stereocontrolled Synthesis Reagent Kinetic Control Strategies Chiral Substrate: Double Asymmetric Synthesis

O O Ti(OiPr)4 O TBHP O OH + O O OH OH (+)-DET O O 1 : 22 calcd “mismatched” (1 : 43)

O O Ti(OiPr)4 O TBHP O OH + O O OH OH (-)-DET O O 90 : 1 (227 : 1) “matched”

Selectivity Benchmarks Useful selectivity 91:9 (10:1) Double asymmetric synthesis 98:2 (50:1)

Strategies for Stereocontrolled Synthesis Reagent Kinetic Control Strategies Chiral Substrate: Double Asymmetric Synthesis

"What changes may undergo? . . . . With appropriate chiral and catalysts at hand, the synthetic design of many natural (and unnatural) products will become straightforward, and as a result some of the aesthetic elements of traditional organic synthesis, as exemplified by the synthesis of erythronolide A in Section 7, may well be lost. . . . . However, the power of the new strategy has already made possible what appeared to be almost impossible even a few years ago. In this sense a new era which is characterized by the evolution from substrate-controlled to reagent-controlled organic synthesis is definitely emerging."

S. Masamune et al., "Double Asymmetric Synthesis and a New Strategy for Stereochemical Control in Organic Synthesis", Angew. Chem. Int. Ed. 1985, 24, 1. Strategies for Stereocontrolled Synthesis

Reagent Kinetic Control Strategies Chiral Substrate: Double Asymmetric Synthesis

Comparison of Substrate and Reagent Control Strategies

“ . . . . Less commendable is the use of this insightful new chemistry as a platform for offering futuristic and murky pontifications about “reagent control” vs. “substrate control” as strategic frameworks in stereospecific synthesis. In the opinion of this reader, the substantive importance of this distinction has been vastly overstated. Clearly in many instances so-called substrate control works very well. In other cases, where the stereochemical connectivity between the “in place” stereogenicity, and the stereogenicity to be created is tenuous, recourse to so-called “reagent control” may be the only solution. To debate, as an abstract matter, the general superiority of one method over the other is not unlike debating whether steamship transportation or rail transportation is the more effective. Obviously, this is a type of circumstance- dependent question which does not permit a general resolution. It must be Samuel Danishefsky handled on a case-to-case basis by sensible people.” C&EN August 26, 1985

Strategies for Stereocontrolled Synthesis

Reagent Kinetic Control Strategies Chiral Substrate: Double Asymmetric Synthesis

Comparison of Substrate and Reagent Control Strategies

Advantages Disadvantages

Substrate ! Exploits resident chirality ! Requires strong bias in substrate Control ! Different strategy needed for each epimer

Reagent ! Same strategy sometimes applicable ! Not applicable if substrate has strong Control to synthesis of both epimers bias ! Applicable to substrates with low bias ! Requires reagents with very strong bias Strategies for Stereocontrolled Synthesis

Reagent Kinetic Control Strategies Chiral Substrate: Double Asymmetric Synthesis

Comparison of Substrate and Reagent Control Strategies

OH O CH CH3MgBr 3

Strategies for Stereocontrolled Synthesis

Reagent Kinetic Control Strategies Chiral Substrate: Double Asymmetric Synthesis

Comparison of Substrate and Reagent Control Strategies

CH O 1) Ph3P=CH2 3 2) m-CPBA OH 3) LiAlH4 Strategies for Stereocontrolled Synthesis

! Thermodynamic control strategies ! Kinetic control strategies " Substrate control strategies # Steric approach control # Stereoelectronic control # Internal stereodirection and chirality transfer " Reagent control strategies # Achiral substrate: enantiotopic face selectivity # Achiral substrate: enantiotopic group selectivity # Chiral substrate: double asymmetric synthesis " Dynamic kinetic resolution

Strategies for Stereocontrolled Synthesis

Kinetic Control Strategies Classical Kinetic Resolution

B*chiral A k1 FAST A-B*

+ B*chiral k SLOW ent-A 2 ent-A-B* Strategies for Stereocontrolled Synthesis

Kinetic Control Strategies Classical Kinetic Resolution

B*chiral

k1 FAST A A-B* + B*chiral

k2 SLOW ent-A ent-A-B*

Strategies for Stereocontrolled Synthesis

Kinetic Control Strategies Classical Kinetic Resolution

Selectivity B*chiral Factor k1 FAST A-B* s = k1/k2

B*chiral 10

k2 SLOW ent-A ent-A-B* 50 Strategies for Stereocontrolled Synthesis

Kinetic Control Strategies Dynamic Kinetic Resolution

B*chiral A FAST A-B*

FAST B*chiral SLOW ent-A ent-A-B*

Review: H. Pellissier Tetrahedron 2003, 59, 8291

Strategies for Stereocontrolled Synthesis

General Strategies for the Stereocontrolled Synthesis of Acyclic Target

" Chiron Approach " Ring Template Approach " Chirality Transfer " Acyclic Asymmetric Synthesis Strategies for Stereocontrolled Synthesis

! Thermodynamic Control Strategies ! Kinetic Control Strategies ! Strategies for the Synthesis of Acyclic Target Molecules: Case Studies " Prostaglandins from Sugars (Stork)

Strategies for Stereocontrolled Synthesis

General Strategies for the Stereocontrolled Synthesis of Acyclic Target Molecules

" Chiron Approach " Ring Template Approach " Chirality Transfer " Acyclic Asymmetric Synthesis Strategies for Stereocontrolled Synthesis Case Studies (2) Prostaglandins from Sugars (Stork)

O OH

CO2H CO2H 9 8 6 5 11 12 14 HO 13 15 OH OH

Prostaglandin A2 Prostaglandin F2!

G. Stork and S. Raucher J. Am. Chem. Soc. 1976, 98, 1583 G. Stork, T. Takahashi, I. Kawamoto, and T. Suzuki J. Am. Chem. Soc. 1978, 100, 8272

For discussions of the use of chiral natural products as starting materials for the synthesis of complex molecules, see (1) S. Hanessian " of Natural Products: The 'Chiron Approach' ", Pergamon Press: Oxford, 1983. (2) T.-L. Ho "Enantioselective Synthesis: Natural Products from Chiral Terpenes", W iley Interscience: New York, 1992.

Strategies for Stereocontrolled Synthesis Case Studies (2) Prostaglandins from Sugars (Stork)

G. Stork and S. Raucher J. Am. Chem. Soc. 1976, 98, 1583 G. Stork, T. Takahashi, I. Kawamoto, and T. Suzuki J. Am. Chem. Soc. 1978, 100, 8272 Strategies for Stereocontrolled Synthesis Case Studies (2) Prostaglandins from Sugars (Stork)

OH

CO2H 9 8 6 5 11 12 14 HO 13 15 OH Prostaglandin F2!

Strategies for Stereocontrolled Synthesis

Case Studies O (2) Prostaglandins from Sugars CO2H (Gilbert Stork)

OH Prostaglandin A2

! Install C-8 side chain by enolate alkylation ! Thermodynamic control of at C-8

O CO2R X

R1 Strategies for Stereocontrolled Synthesis Case Studies OH CO2H (2) Prostaglandins from Sugars 9 8 (Gilbert Stork) 6 5 11 12 14 HO 13 15 OH Prostaglandin F2!

! Install C-8 side chain by enolate alkylation ! Thermodynamic control of stereochemistry at C-8

! [For PGF2!] C-9 stereochemistry by steric approach substrate control

H O CO2R X RO R2 O 1 R R1

Strategies for Stereocontrolled Synthesis Case Studies OH CO2H (2) Prostaglandins from Sugars 9 8 6 5 (Gilbert Stork) 11 12 14 HO 13 15 OH Prostaglandin F2! ! Form cyclopentanone from acyclic precursor by nucleophilic cyclization

O O X

EWG R2 or X R2 12 12 umpolung R1 RO R1

(R2) CO2R (R2) CO2R New Am Am Subtargets RO2C 12 X 12 OR OR OR Strategies for Stereocontrolled Synthesis Case Studies OH CO2H (2) Prostaglandins from Sugars 9 8 6 5 (Gilbert Stork) 11 12 14 HO 13 15 OH Prostaglandin F2! ! The “sugar connection”: requires translation of C-OH stereogenic centers into C-C centers

(R2) CO2R (R2) CO2R New Am Am Subtargets RO2C 12 X 12 OR OR OR

HO OH OH C Sugars as H starting materials n

Strategies for Stereocontrolled Synthesis Case Studies OH CO2H (2) Prostaglandins from Sugars 9 8 6 5 (Gilbert Stork) 11 12 14 HO 13 15 OH Prostaglandin F2! ! Set C-12 stereochemistry by chirality transfer via [3,3] sigmatropic rearrangement

(R2) CO2R (R2) CO2R

Subtargets Am Am RO2C 12 X 12 OR OR OR

Z Z

(R) ! (R) O O OH

" $ " $ # #

Retron for [3,3] sigmatropic shift: #,$-unsaturated carbonyl compound Strategies for Stereocontrolled Synthesis Case Studies OH CO2H (2) Prostaglandins from Sugars 9 8 6 5 (Gilbert Stork) 11 12 14 HO 13 15 OH Prostaglandin F2! ! Set C-12 stereochemistry by chirality transfer via [3,3] sigmatropic rearrangement

(R2) CO2R (R2) CO2R Previous Am Am subtargets RO2C 12 X 12 OR OR OR

OH OH 12 12 New Am Am Subtargets RO2C X OR OR OR

Strategies for Stereocontrolled Synthesis Case Studies (2) Prostaglandins from Sugars (Gilbert Stork)

! Set C-12 stereochemistry by chirality transfer via [3,3] sigmatropic rearrangement

COZ top face H H H H attack Z Z 1 1 R R2 R R2 O O R1 R2 OH

R1 R2 2 Z Z R R2 COZ bottom face H H attack H R2 O O 1 H R R1 R1 Strategies for Stereocontrolled Synthesis Case Studies OH CO2H (2) Prostaglandins from Sugars 9 8 6 5 (Gilbert Stork) 11 12 14 HO 13 15 OH Prostaglandin F2! ! Set C-12 stereochemistry by chirality transfer via [3,3] sigmatropic rearrangement

(R2) CO2R (R2) CO2R Previous Am Am subtargets RO2C 12 X 12 OR OR OR

OH OH 12 12 New Am Am Subtargets RO2C X OR OR OR

Strategies for Stereocontrolled Synthesis

Case Studies O CO2H (2) Prostaglandins from Sugars (Stork)

OH Prostaglandin A For PGA2 2

OH 2 2 [3,3] OR OR 12 12 Am Am Am " RO2C OHC # OR OH OR1 OR1

Bu CuLi OH OR2 2 +

OHC OH OHC OTs L-erythrose OH OR1 Strategies for Stereocontrolled Synthesis Case Studies OH CO2H (2) Prostaglandins from Sugars 9 8 6 5 (Gilbert Stork) 11 12 14 HO 13 15 OH Prostaglandin F2! For PGF2!

OH OH OR Am Am X RO OR OR OR OH OR OH OR1 (both ! or ") 1,2-deoxygenation R1O OR2 OR1 OH OR1

OH OH OH D-Glycero-D-guloheptono-1,4-lactone HO One step from D-glucose OH O O

Strategies for Stereocontrolled Synthesis

Case Studies O CO2H (2) Prostaglandins from Sugars (Stork)

Total Synthesis of PGA2 OH Prostaglandin A2

O H C=CHMgCl HO 2 O O ClCO2Me THF-CH2Cl2 0° 4 h pyr, -30!0° OH OCO2Me O O 96% OH O OH O

10 eq CH3C(OMe)3 cat EtCO2H 140° 72 h

OH 25% aq AcOH O 120° 1 h

MeO2C OCO2Me MeO2C OCO2Me

OH 83% O Strategies for Stereocontrolled Synthesis

Case Studies O CO2H (2) Prostaglandins from Sugars (Stork)

Total Synthesis of PGA2 OH Prostaglandin A2

OH 1 eq Et3N CH2Cl2 rt 1 h MeO2C OCO2Me

OH

OH

MeO2C O O O

0.1 eq K CO 2 3 MeO2C 1:1 MeOH CO2Me xyl 160° 1 h rt 30 min H 2 eq 59% overall MeO2C OH H (MeO)3C OH CO2Me

Strategies for Stereocontrolled Synthesis

Case Studies O CO2H (2) Prostaglandins from Sugars (Stork)

Total Synthesis of PGA2 OH Prostaglandin A2

1) H2, Pd-BaSO4 MeOH 2) TsCl, pyr MeO2C 1:1 CO2Me -20° 7 d MeO2C H 3) EVE CO2Me H MeO2C OH H MeO2C OTs OH OCH(Me)OEt 79%

5 eq Bu2CuLi Et2O -40° 2 h

O 10 eq KOt-Bu MeO2C 0.5 N NaOH CO2Me CO H THF 2 ! 10 min rt 45 min H Am Am MeO2C 77% 67% OCH(Me)OEt OCH(Me)OEt Strategies for Stereocontrolled Synthesis

Case Studies O CO2H (2) Prostaglandins from Sugars (Stork)

Total Synthesis of PGA2 OH Prostaglandin A2

O O 2.2 eq LDA 4 eq NaIO4 CO2H THF MeOH CO2H + 3 eq PhSeCl rt H3O Am Am

OCH(Me)OEt OH

Prostaglandin A2

16 steps in the longest linear sequence

Strategies for Stereocontrolled Synthesis Case Studies OH CO2H 9 8 6 5 (2) Prostaglandins from Sugars (Stork) 11 12 14 HO 13 15 OH Total Synthesis of PGF2! Prostaglandin F2!

OH OH OH O 10 NaBH4 HO O + OH O OH HCN 11 13 15 aq 10% H2SO4 H HO HO 12 14 HO OH OH O OH 90% 75% O O D-glucose O O

commercially available NaBH4 D-Glycero-D-guloheptono-1,4-lactone MeOH 10 °C 1.5 h

Ac2O, pyr CH2Cl2 -7 °C 18 h

1) K CO , MeOH OH 2 3 O OH O 2) ClCO2Me, pyr 1) Me2NCH(OMe)2 3) CuSO , aq MeOH 2) Ac O, ! HO 4 2 O O OAc O OAc OH O 4) PhH, ! O O 40% overall O OH O O Strategies for Stereocontrolled Synthesis Case Studies OH CO2H 9 8 6 5 (2) Prostaglandins from Sugars (Stork) 11 12 14 HO 13 15 OH Total Synthesis of PGF2! Prostaglandin F2!

OH

HO O OH O

acetone O cat H2SO4

CO2Me CO2Me 1) K CO , MeOH OH CH3(OMe)3 2 3 2) TsCl, pyr cat EtCO2H 3) EVE ! OTs O O O O O O O O OR 80% O O O 54% overall O

1) 10 eq Bu2CuLi O Et O, -40 °C 2 h O 2 LiHMDS 2) aq H2SO4 OSit-BuPh2 O RBr THF, rt 15 h THF-HMPA EVE O RO Am HO Am 35% overall OR OR = OC(H)MeOEt 71% OH

Strategies for Stereocontrolled Synthesis Case Studies OH CO2H 9 8 6 5 (2) Prostaglandins from Sugars (Stork) 11 12 14 HO 13 15 OH Total Synthesis of PGF2! Prostaglandin F2!

O HCN OH OSit-BuPh NC 2 EtOH 50% aq AcOH O OSiR3 DIBAL -10 °C THF, 35 °C HO RO Am HO Am OR OR = OC(H)MeOEt OH

1.5 eq TsCl pyr, -15 °C

OR OH NC 6 eq KHMDS NC OSit-BuPh2 benzene OSiR3 ! 5 h EVE HO Am TsO Am RO 72% OR OH 37% overall Strategies for Stereocontrolled Synthesis Case Studies OH CO2H 9 8 6 5 (2) Prostaglandins from Sugars (Stork) 11 12 14 HO 13 15 OH Total Synthesis of PGF2! Prostaglandin F2!

NC OR

OSit-BuPh2

Am RO OR OR = OC(H)MeOEt 1) TBAF, THF 31 steps in the longest 2) Collins Ox linear sequence 3) AgNO3, KOH aq EtOH

OH NC OR AcOH H2O-THF Lis-Bu3BH CO2H 40 °C 5 h THF, -78 °C 1.5 h CO2H Am RO 73% HO OR OH

Prostaglandin F2!

Strategies for Stereocontrolled Synthesis

[1,3] O$C Chirality Transfer

OH CO2R 3 1 * R2 * R2 R1 1 R1 3 2 2 X Y X Y

[1,3] O$N Chirality Transfer

OH NR2 3 1 * R2 * R2 R1 1 R1 3 2 2 X Y X Y

Review of chirality transfer via sigmatropic rearrangements Hill, R. K. In Asymmetric Synthesis; Morrison, J. D., Ed.; Academic Press: Orlando, 1984; Vol. 3, pp 503-572 Strategies for Stereocontrolled Synthesis

OH NR2 [1,3] O$N 3 1 * R2 * R2 R1 1 R1 3 Chirality Transfer 2 2 X Y X Y

Overman Rearrangement of Allylic Trihaloacetimidates

KH, CCl CN 140 °C 3 BnO BnO Et2O xylene BnO HN O HN CCl3 OH 45% overall CCl3 O

1) DBU, CCl3CN Bu CH2Cl2 Bu OSiR3 OSiR3 2) 1% PdCl (PhCN) OH 2 2 NHCOCCl benzene, rt 72% 3

Review: Overman, L. E.; Carpenter, N. E. Org. React. 2005, 66, 1