16 Cycloaddition Rxns 1

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Problem of the Day:

The Diels-Alder Cycloaddition Reactions

"Diels-Alder Reactions". Evans, D. A.; Johnson J. S. In

Comprehensive Asymmetric Catalysis, Jacobsen, E. N.; Pfaltz, A.; and

Yamamoto, H. Editors; Springer Verlag: Heidelberg, 1999; Vol III,

1178-1235

(electronic handout)

X CHO R X CHO R

+

5% catalyst MeOH-H₂O N H N O Me PhCH₂ Me Me catalyst

Rationalize the sense of asymmetric induction for this Diels-Alder

Reaction reported by MacMillan, JACS, 2000, 122, 4243.

(pdf)

The Diels-Alder Reaction in Total Synthesis, K. C. Nicolaou,

Angew Chem. Int. Ed. 2002, 41, 1668-1698

(electronic handout)

Catalytic Enantioselective Diels–Alder Reactions: Methods,

Mechanistic Fundamentals, Pathways, and Applications, E. J.

Corey, Angew Chem. Int. Ed. 2002, 41, 1650-1667

(electronic

handout)

Chemistry and Biology of Biosynthetic Diels–Alder Reactions

Emily M. Stocking and Robert M. Williams, Angew Chem. Int. Ed.

2003,

42, 3078-3115

(electronic handout)

Pavel Nagorny

Wednesday,

October 25, 2006

Reading Assignment for week:

Carey & Sundberg: Part A; Chapter 11

Concerted Pericyclic Reactions

Chemistry 206

Advanced Organic Chemistry

Lecture Number 16

Cycloaddition Reactions-1

! Cycloadditions: Introduction

! Ketene Cycloadditions

! The Diels-Alder Reaction

Carey & Sundberg: Part B; Chapter 6

Cycloadditions, Unimolecular Rearrangements

Thermal Eliminations

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Problem 210. Question and Answer. The carbonyl ene reaction is illustrated below. Using FMO analysis, evaluate the

transition state of this reaction. Your answer should include: a transition state drawing; clear orbital depictions and

HOMO-LUMO assignments; an indication of the number of electrons from each segment; and indication of whether the reaction is

thermally allowed.

O

H

R

_a

O

_CH

2

R

_a

_R

b

H

R

_b

+

The Carbonyl Ene Reaction

The carbonyl ene reaction is a very powerful transformation that I want to introduce to you. Accordingly, I have prepared a

series of problems taken from the Problems Database to familiarize you with this reaction. Problem 210 is provided as an

introduction to the FMO analysis for the process. Subsequent problems have the ene reaction imbedded in reaction

cascades.

Chem 206

D.A. Evans

H

O

R

_a

H

R

b

H

H Rb Ra H

The ene transition state

H Rb

Ra

H

View the ene TS as a 3-component

cycloaddition

allyl HOMO carbonyl LUMO Rb H Ra H

bonding

[2!s + 2!s +2"s]

One possible analysis:

allyl anion: 4 e

-Proton

carbonyl: 2 e

-6!e

-

_{"cycloaddition"}

suprafacial

thermally allowed

Answer O C O C O C O Ra H CH2 Rb H

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Why does maleic anhydride react easily with 1,3-butadiene, but not with

ethylene? So what are the "rules"?

O O O O O O O O O

X

[4+2] [2+2] heat

! The related reaction of 2 ethylenes is nonconcerted: [2 + 2] cycloaddition

X Y X Y Y X • •

! We also know that the photochemical variant is concerted

The frontier orbitals of the reacting species must have the proper symmetries

! Nomenclature C C

!2s

C C

!2a

Using this nomenclature, the Diels-Alder reaction is a

!4s + !2s

cycloaddition

antarafacial

suprafacial

bonding

! Consider [2 + 2] cycloaddition: Thermal activation [

!2s + !2s

]

C C

!2s

C C

!2s

antibonding [

!2s + !2s

] "forbidden" C C

!2a

C C

!2s

[

!2s + !2a

] "allowed" bonding bonding

!

!*

! Consider [2 + 2] cycloaddition: Photochemical activation [

!2s + !2s

]

C C

!*

!

light ! new HOMO light C C concerted _{+ energy} ! + C C C C C C C C C C ! bonding bonding HOMO LUMO C C C C [2+2] Cycloaddition - Examples Me h! ["2 s + "2s] Me Me Me Me Me Me h! ["2 s + "2s] Me Me Me Me Me Quadricyclane Prismane-Der. Dauben, Tet. 1961, 15, 197. Schäfer, AC 1967, 79, 54. Dewar benzene-Derivative [!2 s + !2a] H TL 1967, 4357, 4723. must be antarafical for indicated stereochem

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Cycloaddition Reactions-2

Chem 30

D. A. Evans

C O R R' O R R' O R R' R' R O O O R R' R' R Alkene

Summary of Ketene Cycloadditions

N O R R' O O R R' Imine Carbonyl X Y Y X O R' R O R' R = -CH=CH2

Ketene Preparation

H Cl O R3N R C O H R H Cl O R B: B–H Cl E2 Elimination H OR O R H OR O R LiNR₂ C O H R E1cb Elimination –ZnCl₂ Cl Cl O R C O H R Cl Cl O R B: Zn O R R R C O R R R h! or " Electrocyclic Ring Opening R H O N₂ C O H R or ! h" R H O R H O O [!2 s!2a] ! C O R R C R R R R Antarafacial Suprafacial

Cycloaddition: FMO Analysis

R

HOMO

R

LUMO

C

R

O

bonding

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[2+2]: Stepwise Versus Concerted

H R H R C C O R' H R H H R C R' H O O R' R R least hindered bond rotation

• Very large polar effects

• E olefins yield a mixture of cis and trans products

• Solvent effects observed, but it could merely be a ground state effect • KIE seen for many reactions support stepwise mechanism

• Calculations show a highly asynchronus transition state.

• Stereochemical consequence can be rationalized by stepwise mechanism

Stepwise

Concerted

• Ketenes add stereoselectively to Z alkenes. • Z olefins are much more reactive than E olefins

O C Me Me O C Me Me Me Me O Me Me Me Me O Me Me Me Me O Me Me Me Me + Fast 1 : 2 ! ! Me Me + + Ketene-Alkene [2+2] O C Me Me Me + C Me Me C H Me Me H O C Me Me C Me H Me H O Me O CMe₃ CO₂H 1. (COCl)2, PhH, ! 2. NBu3, toluene, ! O CMe₃ H O H CH₂COCl H NEt3 O C O H MeO C O Cl Cl O Cl Cl C O Cl Cl Cl Cl Zn + O H H O C H H O O H H H H O O H H H H O O + 38 kcal/mol 32 kcal/mol

Ketenes + Aldehydes Afford !-Lactones

path A

path B ab initio Calulations

Pons, J. -M.; et. al. JACS 1997, 119, 3333.

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Cycloaddition Reactions-4

Chem 30

D. A. Evans

Transformations of !-Lactones

O R2 R1 O _R2 R1 O O S O O _ + " or BF3 -CO2 Me₂S O R2N O R2N CO2H R' CuCN R'Li (2eq) Vederas et al JACS 1987, 107, 4649.

Most soft Nu

attack C

sp3

The Staudinger Reaction

In this process, the illustrated ketene, generated

in situ from an acid

chloride, undergoes reaction with the indicated substrates to form

!-lactams in a stereoselective process.

When the azo-methine (RN=CHR)

geometry in the reactant is (Z) the product stereochemistry is trans (eq 1).

In a complementary fashion, the

(E) imine affords the cis-substituted

product (eq 2).

While this transformatlion could be viewed as a [2s+2a]

cycloaddition, it is felt that this reaction is stepwise.

N S O H H R N S C O H R Et3N O R Cl N R R O H H R N R R (1) (2) H H (Z) (E)

The stepwise mechanism,,,,

C O H R N R R H N R H R R O H N R R O H H R

(E) Imine ! Cis Product

conrotatory closure N R H R R O H N R R O H H R N S H R O H C O H R N S H N S O H H R conrotatory closure N S H R O H N S O H H R

There are two contortaory modes. If you control the conrotatory mode, you control the absolute stereochemistry of the reaction:

(Z) Imine ! Trans Product

See also Evans, Williams, Tet. Lett. 1988, 29, 5065. Evans, SjogrenTet. Lett. 1985, 26, 3783, 3787.

N Bn Ar O H H N O Ph O O Cl N Bn Ar H N O Ph O Et3N N Bn Ar O H H N O Ph O diastereoselection > 95:5 80-90% yields +

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Me O Br H R O _O O R O C CH₂ N N N F₃CO₂S SO2CF3 Bn Al R i-Pr i-Pr 5a: R = Me 5b: R = Cl + catalyst (10 mol%) i-Pr₂NEt [RCHO • cat.] R₃N cat. =

Enantioselective Ketene-Aldehyde Cycloaddiitons

R₃NH•Br

Nelson, S. G.; Peelen, T. J.; Wan, Z. JACS, 1999, 121, 9742-9743 Me3C BnOCH2 a b c d 92 (R) Aldehyde 2 (R) entry % yield CH2CH(CH2)8— % ee 3 (configuration) 91 89 (R) 74 92 (S) 93 91 (S) 91 91 (S) 90 54 (R) 56 e 93 (S) 80 f catalyst [time (h), temp (°C)] 5b (8, -40) 5a (16, -50) 95 (S) 89 5a (72, -78) 5b (16, -50) 5b (16, -40) 5a (24, -50) 5b (16, -40) 5b (24, -40) 93 (R) 86 g _{5a (16, -50)} 85 (R) 91 h _{5a (16, -50)} i BnOCH2— C6H11— PhCH2CH2— BnOCH2CH2— TBDPSOCH2— Me2CHCH2— PhCH2CH2— O Me3Si H O O OEt + 1 mol%, THF, 3Å MS -78 °C, 24 h C 77% yield, 93% ee N Cu N O O Me3C H2O OH2CMe3 OTf Me Me + OTf_ H 3: >99% yield, 92% ee O O EtO2C KF, CH3CN O O PhMe₂Si EtO2C 1) O O PhMe₂Si EtO2C N CuN O O O OR2 Me R R H H O Me₃Si H O C C R1 Me observed product O O O R2O R1 Me3Si 2+ Cu OH₂ Me N N CMe3 Me₃C Me O O H₂O + 2 CF₃SO₃– 2+

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The Diels-Alder Reaction

Chem 206

D. A. Evans

! Representative natural products displaying the Diels-Alder retron:

+

‡

! The Reaction:

Articles and monographs of Significance

"Diels-Alder Reactions". Evans, D. A.; Johnson J. S. In Comprehensive Asymmetric Catalysis, Jacobsen, E. N.; Pfaltz, A.; and Yamamoto, H. Editors; Springer Verlag: Heidelberg, 1999; Vol III, 1178-1235 (pdf)

The Diels-Alder Reaction in Total Synthesis, K. C. Nicolaou, Angew Chem. Int. Ed. 2002, 41, 1668-1698 (pdf)

Catalytic Enantioselective Diels–Alder Reactions: Methods, Mechanistic Fundamentals, Pathways, and Applications, E. J. Corey, Angew Chem. Int. Ed. 2002, 41, 1650-1667 (pdf)

Chemistry and Biology of Biosynthetic Diels–Alder Reactions

Emily M. Stocking and Robert M. Williams, Angew Chem. Int. Ed. 2003, 42, 3078-3115 (pdf)

Recent Advances in Natural Product Synthesis by Using Intramolecular Diels-Alder Reactions, Tadano et al. Chem Rev. 2005, 105, ASAP (pdf)

These natural products could well have incorporated the DA rxn into the

biosynthesis

Endiandric Acid B

(Syntheses) Nicolaou, JACS 1982, 104, 5555-5562

Endiandric Acid C

HO2C H H _Ph H H H H Ph CO2H H H _H H

X-14547A

Hirama, JACS 1982, 104, 4251 Girotra, Tet. Let. 1983, 24, 3687 Heathcock, JACS 1985, 107, 3731

Grieco, JACS 1986, 108, 5908 Keck, JOC 1986, 51, 2487 Kozikowski, JOC 1987, 52, 3541 Clive, JACS 1988, 110, 6914

Ley Chem. Commun. 1983, 630 Nicolaou JOC 1985, 50, 1440 Roush JOC 1984, 49, 3429 (Biosynthesis) JACS 1985, 107, 3694

Mevinolin: R = Me

Compactin: R = H

(Synthesis) JACS, 1993, 115, 4497

Lepicidin

O H O Me OMe MeO OMe NMe₂ O O O O Me Et H O H H H H H H Me H H H H R Me O O HO H O Et H O Me O Me Me Et Et HN O COOH H H H H ent-FR182877 (WS9885B) H OH HO Me Me O O O Me Me H H J. Antibiotics 2000, 53, 204 CO2Et Me TBSO Me TBSO OTBS Me O Br Sorensen, JACS 2003, 125, 5393 Evans, JACS 2003, 125, 13531 DA Het DA O Br TBSO TBSO OTBS Me Me Me H H H CO2Et H

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E n e rg y disfavored _favored

The Alder Endo Rule The following observation illustrates an example of the _{Alder Rule which will be defined below.}

+

"Endo product" "Exo product"

Observation: The endo Diels-Alder adduct is formed faster even though the exo

product is more stable. There is thus some special stabilization in the transition state leading to the endo product which is lacking the exo transition state.

2 Exo TS ‡ Endo TS ‡ H H H H H H HH

If the symmetries of the frontier MO's of reacting partners are "properly matched" the reaction is referred to as "symmetry-allowed". The Diels-Alder reaction is such a case. As illustrated, the HOMO and LUMO of both the diene and dienophile, which in this case are the same, will constructively overlap as indicated in formation of both sigma bonds.

Orbital Symmetry Considerations for Diels Alder Reaction

LUMO-!₃ HOMO-!₂

C

_C

C

LUMO-!₃ HOMO-!₂

C

_C

C

! Secondary (transient) orbital overlap can also occcur in the stabilization of certain transition state geometries. Such a transient stabilizing interaction can occur in the endo, but not exo, transition state:

LUMO-!3

HOMO-!2 Frontier MO Explanation for the Endo Rule

C C C C C C C _C

! Note that the termini only match at one end for the HOMO-LUMO pairing. Hence we say that the symmetry requirements for the reaction in question are not met. This does not mean that the reaction will not occur, only that the reaction will not be concerted. Such reactions

are called "symmetry-forbidden". LUMO-!3

HOMO-!2

Does the possibility for the following concerted dimerization exist?

The Other Dimerization Possibility for Butadiene

C _C C C C C _C C "

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Chem 206

D. A. Evans

Diels-Alder Reaction: The Transition Structure

Houk, Jorgensen, JACS 1989, 111, 9172 Jorgensen, JACS 1993, 115, 2936-2942 leading references:

! The lengths of the forming C–C bonds are Ca. 1.5 times the normal bond distance. This factor comes out of the

ab initio

work of Jorgensen & Houk

Transition State Modelling is Coming of Age

Transition Structures of Hydrocarbon Pericyclic Reactions Houk Angew. chem. Int. Ed. 1992, 31, 682-708

‡ +

! Diene Reactivity as measured against Maleic anhydride

Sauer, Angew. Chem. Int. Ed., 1980, 19, 779-807

log k = 4.96 log k = 2.36 log k = 2.19 log k = 2.12 log k = 1.83 Me Me Dienophile E(LUMO1) - E(HOMO2) or E(LUMO2) - E(HOMO1)

! The closer the two orbitals are in energy, the better they interact

! As !E decreases for the relevant ground state FMOs, rxn rates increase

LUMO1 LUMO2

HOMO2

HOMO1

Diene

The Critical Energy

Difference

: e n e rg y

! Lewis Acid Catalysis of the reaction is possible: Yates & Eaton, JACS 1960, 82, 4436

Lewis acid catalysis not only dramatically increases rates by ca 10

+6

it also improves reaction regiochemistry & endo diastereoselectivity

Ethylene & Butadiene Vs Butadiene & Acrolein

Rate Acceleration

!E (LUMO3-HOMO1) < !E (LUMO2-HOMO1) + LUMO1 HOMO1 + E HOMO3 LUMO3 HOMO2 LUMO2 H O O H

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Orientation of Reacting Partners

favored

disfavored

4.5 : 01 @ 100 °C CO₂H CO2H CO2H CO2H CO₂H CO₂H disfavored favored toluene, 120 °C 59 : 41 96 : 04 C6H6, SnCl4, 25 °C

Lewis acid catalysis improves orientation

In general, 1-substituted dienes are more regioselective than their

2-substituted counterparts: Sauer, Angew. Chem. Int. Ed., 1967, 6, 16-33

COX Me Me COX Me COX favored disfavored C6H6, SnCl4, 25 °C 95 : 05 80 : 20 CH₂Cl₂, 0 °C

Lewis acid catalysis improves endo diastereoselection

DA Reactions Part II: The Reaction Mechanism, Sauer, Angew. Chem. Int. Ed., 1967, 6, 16-33 CO2Me

CO₂Me

H CO2Me

H

Here is an interesting problem in reaction design

favored disfavored

However, what if you need the disfavored product?

COX RO COX RO RO COX disfavored favored Ni(Raney) Trost, JACS 1980, 102, 3554 PhS _PhS AcO AcO COMe AcO COMe PhS COMe MgBr2

By employing a removable substituent, it is possible to access the normally disfavored product diastereomer

Danishefsky, JACS 1978, 100, 2918: The NO2 FG completely dominates directivity

CO2Me RO NO2 RO O2N CO2Me –NO2– base It then can be removed by elimination or by reduction Ono, Tet. 1985, 4013 83% 86% mixture of ring-fusion isomers

Ono, Chem. Commun. 1982, 33-34

CO2Me RO CO2Me NO2 RO CO2Me RO NO2 RO CO2Me NO2 O O O2N Me H Me _Me H H O R3SnH R3SnH

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Chem 206

D. A. Evans

Diels-Alder Reaction: Regiochemistry

Instructive Issues of Regiocontrol with Quinone Dienophiles

Orientation of Reacting Partners controlled by Lewis acid structure

Conditions Ratio thermal (100 °) SnCl₄ (-20 °) 50 : 50 <5 : 95 80 : 20 BF₃•OEt₂ (-20 °) Reusch JOC 1980, 45, 5013 O O MeO Me Me Me MeO O O H Me Me H O O MeO Me !+

_{selection 80 : 20}

selection >95 :5

!+

Similar results provided by Stoodley Chem. Comm. 1982, 929 Me O O O Me Me _Me H O O MeO Me Me H O O MeO Me Me O Sn Cl4 O Me O Me F₃B 0.5 equiv 0.4 equiv

selection >95 :5

Kelly Tet. Let. 1978, 4311

O O OH RO OMe Me OMe Me RO OH O O OMe Me Me OMe O O OH RO MgI2 BF3•OEt2

Corey, JACS 1969, 91, 5675 Ratio: 90 : 10

0 °C CN CN Cl Cl CN CH₂OMe Cl MeOCH2 H H CH2OMe Cu(BF4)2 25-50 °C

4.1 Intermolecular Diels-Alder Reactions, W. Oppolzer, See page 347

Comprehensive Organic Synthesis, Vol. 5, Trost, Ed. 1991

83 : 17 >97 : 3 36 : 64 Ratio –OH –OMe –Me X = Overman, JACS 1988, 110, 4625 X Ph–N X H O O H O O X Ph–N H H O O N–Ph

Diels-Alder Reactions with Chiral Dienes

25-50 °C

Franck, Tet. Lett. 1985, 26, 3187 Franck, JACS 1988,110, 3257 R = Me: Ratio; 83 : 17 R = Me3Si: Ratio; 88 : 12 N–Ph O O Me OR Me OR Me Me Me OR O O N–Ph Me O O N–Ph better than Comments on the Transition State

! Avoid Eclipsing allylic substituents ! better donor (Me) anti to forming bond

! avoid gauche OR interaction PhN

O O Me Me OR H PhN O O RO H Me Me

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Problem 76, Bodwell has disclosed an interesting thermally initiated reaction cascade that was designed to cuminate in a formal synthesis of strychnine(Angew. Chem. Int. Ed 2002, 41, 3261). One of his reported transformations is illustrated below.

Provide a detailed mechanism for this reaction cascade. Your answer should include three-dimensional structures that accurately depict ground and transition state representations.

N N N NCO2Me N NCO2Me heat, 48 h –N2

Problem 86. In 1983 Masamune introduced a new family of chiral controllers for the Diels-Alder reaction (J. Org. Chem. 1983, 48, 4441).

O OH CMe3 exo:endo = 94:6 endo diastereoselection >99:1 (1) O OH CMe₃ ZnCl₂

Please provide a mechanism for the reaction shown in equation 1. Be sure to include clear transition state drawings in your answer, and predict the stereochemistry of the major product diastereomer.

–45 °C

Problem 112. In a recent article, Roush reported the highly endo-selective, Lewis acid catalyzed Diels-alder reaction illustrated below (Org. Lett 2001, 3, 957). Using your knowledge of Diels-Alder transition states, draw the transition state of this reaction, and from this drawing, predict the relative stereochemical relationships that are to be anticipated in the product. Me Me R Me O MeAlCl2 CH2Cl2 Me R Me Me O diastereoselection >99:1

Problem 157. A short reaction sequence that results in the rapid assemblage of the taxane skeleton has been reported by Winkler (Tetrahedron Lett.1995, 36, 687). This

transformation is illustrated below wherein intermediate A is subsequently induced to react with divinyl ketone.

Provide a concise mechanism for this reaction. For full credit, the relative stereochemical relationships at the indicated stereocenters must be provided.

Me S Me Me O O heat A O + Lewis acid O Me Me Me ❊ ❊ ❊ OEt O OH EtO C7H15 O O HO H H C7H15 O 160 o_C 1 3 MgBr2•Et3N

Problem 739. The rapid assembly of the bicyclo[5.3.1]undecane core of penostatin F was recently reported by Barriault and coworkers (Org. Lett. 2004, 6, 1317). In this remarkable transformation dihydropyran 1 is converted to the highly complex tricycle 3 in only two operations. Please provide a detailed mechanism for this reaction sequence. Be sure to indicate all pericyclic reactions.

O H OEt C7H15 O OH 2

Problem 778. Boger and co-workers recently reported the synthesis of the indole alkaloid minovine (1). This pivotal transformations leads to the construction of the minovine skeleton. Provide plausible mechanisms for this transformation.

heat

Problem 794. Doering and Rosenthal reported the interesting conversion of Nenitzescu's hydrocarbon (1) to dihydro-naphthalene (2). Provide a mechanistic rationalization for this transformation. (Reference: Doering, W.v.E.; Rosenthal, J.W., JACS 1966, 88, 2078)

300 °C