Tetrahedron Letters 56 (2015) 6523–6535

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Tetrahedron Letters journal homepage: www.elsevier.com/locate/tetlet

Digest Paper

Nonenzymatic enantioselective synthesis of all-carbon quaternary centers through desymmetrization Kimberly S. Petersen Department of Chemistry and Biochemistry, University of North Carolina at Greensboro, Greensboro, NC 27402, United States

a r t i c l e

i n f o

a b s t r a c t

Article history: Received 28 July 2015 Revised 24 September 2015 Accepted 24 September 2015 Available online 9 October 2015

The asymmetric desymmetrization of meso or prochiral compounds containing an all-carbon quaternary center is an attractive alternative to classical synthetic approaches aimed at the asymmetric formation of a new C–C bond. This review focuses on nonenzymatic desymmetrizations that utilize transition metal catalysts or organocatalysts to distinguish between enantiotopic groups to generate enantioenriched compounds containing all-carbon quaternary stereocenters. Ó 2015 Elsevier Ltd. All rights reserved.

Keywords: Desymmetrization All-carbon quaternary center Asymmetric Organocatalysis Transition-metal catalysis

Contents Organometallic . . . . . . . Cu . . . . . . . . . . . . . . . . . . Rh . . . . . . . . . . . . . . . . . . Pd . . . . . . . . . . . . . . . . . . Other . . . . . . . . . . . . . . . Organocatalytic . . . . . . . Conclusion and outlook Acknowledgments . . . . . References and notes . .

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The stereoselective formation of all-carbon quaternary centers remains a significant challenge in synthesis due to the steric repulsion between the carbon substituents.1 Most commonly, construction of stereocenters has focused on the asymmetric formation of a new C–C bond. Desymmetrization of prochiral or meso compounds offers an alternative approach, where the formation of a quaternary center is separate from the enantiodetermining step (Scheme 1). Here a chiral reagent or catalyst is used to distinguish between two enantiotopic groups. This approach is particularly attractive when the meso or achiral precursors are readily available and when low catalyst loadings can be utilized. While previous reviews have focused on enzymatic reactions,2 this review focuses on catalytic nonenzymatic desymmetrization approaches for the

E-mail address: [email protected] http://dx.doi.org/10.1016/j.tetlet.2015.09.134 0040-4039/Ó 2015 Elsevier Ltd. All rights reserved.

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6523 6524 6525 6526 6529 6530 6534 6535 6535

enantioselective synthesis of compounds containing all-carbon quaternary centers. The review is divided into transition-metal catalyzed and organocatalyzed reactions. Organometallic Since the first reports of a homogeneous transition-metal complex catalyzing an asymmetric reaction in 1968, the field has grown in importance and scope.3 Traditionally, these types of enantioselective reactions depend on in situ formation of a tightly bound metal complex of a chiral ligand and transition metal precursor. More recently, the formation of ion pairs have been invoked in asymmetric transition-metal catalysis.4 The reactions usually rely on the enantioselective formation of a new bond. Herein we will examine their use in desymmetrization strategies for the formation of enantioenriched quaternary carbon chiral stereocenters.

6524

K. S. Petersen / Tetrahedron Letters 56 (2015) 6523–6535 enantiotopic groups

X plane of symmetry

modified group chiral catalyst*

X

X * Y

R R'

R R'

achiral precursor with pre-existing all-carbon quaternary center

new compound with all-carbon quaternary stereocenter

Scheme 1. General desymmetrization strategy to set all-carbon quaternary stereocenters.

Cu Recently, the desymmetrization of 2,2-dicarbon substituted 1,3diols has successfully been achieved using a functionalized Cu-(II)pyridinebisoxazoline (Pybox) system.5 Monobenzylation of diols such as 2 to benzoate esters 3 proceeded in overall excellent yield and generally good enantioselectivities following the pre-formation of the catalytic system using copper(II) chloride and Pybox 1 possessing 4-phenyl and 5,5-di-n-butyl substituents (Scheme 2). Remarkably, differentiation of R1 = methyl and R2 = ethyl (2b to 3b) was accomplished in a greater than 10:1 enantiomeric ratio. The authors postulate an octahedral complex between the Pybox–Cu(II) catalyst, 1,3-diol and benzoyl chloride, which allows the two phenyl and oxazoline planes to cross vertically consequently allowing just enough space for the smaller R group to occupy (intermediate I). Mikami and co-workers designed an asymmetric synthesis of highly functionalized five-membered-ring compounds bearing quaternary stereocenters through a desymmetrization strategy.6 Their strategy involves the conjugate addition of a zinc alkylating agent to a symmetric cyclopentene-1,3-dione 4 to yield enantioenriched compounds such as 5 using a copper(II) salt and phosphoramidite ligand in as low as 0.5 mol % (Scheme 3). Initial optimization identified Cu(OTf)2 as the ideal copper salt and BINOL based phosphoramidite ligand 6 with a biaryl substituent at the 3

and 30 position. A broad range of substitution patterns were tolerated on precursor 4 including esters and protected alcohols and various alkyl zinc reagents were appropriate. The one pot reaction proceeded in excellent yield with generally good diastereo- and enantiocontrol. One notable exception was the silyl protected alcohol, 5l-Et, which was formed in only 36% ee and as the opposite diastereomer. The methodology was utilized in the synthesis of a precursor of madindolines A and B.7 A method for the desymmetrization of 1,6-heptadiynes via click chemistry,8 Cu(I)-catalyzed azide alkyne cycloaddition (CuAAC), was recently reported (Scheme 4).9 This novel approach is only the second report of an asymmetric CuAAC reaction.10 Treatment of dialkynes such as 7 in the presence of CuCl and Pybox ligand 11 in the unusual solvent 2,5-hexanedione led to enantiomerically enriched chiral quaternary oxindoles bearing a 1,2,3-triazole moiety 9. In this methodology, generation of triazole 10 was a major side product, although it could generally be limited (typically 95:5 dr, 97% ee 5a-Me: 96% yield, >95:5 dr, >99% ee 5a-Bu: 98% yield, >95:5 dr, 98% ee

O

Et

O OPMB 5b-Me: 93% yield, >95:5 dr, >99% ee

CH3 Et

O CO2Me 5c-Et: 99% yield, >95:5 dr, 95% ee

O CH2 CH3

Et

O OBn 5d-Et: >99% yield, >95:5 dr, 98% ee O

O Ph 5g-Et: 95% yield, >95:5 dr, 88% ee O

Et

O OBn 5e-Et: 97% yield, >95:5 dr, 97% ee O

O 5j-Et: 92% yield, 93:7 dr, 75% ee

Ph Et

O OBn 5f-Et: >99% yield, 90:10 dr, 91% ee O

CH3 Et

O 2-Nap 5h-Et: 96% yield, 80:20 dr, 70% ee O

CH3 Ph

O i-Pr

CH3 Et

OH

H O O (+)-Madindoline B

CH 3

O

Et

Me N

O CH 3

n-Bu n-Bu

O

n Bu

Me

R

RL

O

O

O Bu

O 5

3 I

n-Bu n-Bu

n

R1

R

R

O N

O

Cu(OTf) 2 (4 mol%) 6 (8 mol%)

Et O 5i-Et: 85% yield, 91:9 dr, 88% ee O

CH3 Et

2-Nap

O 5k-Et: 96% yield, 90:10 dr, 81% ee

CH3 Et

O OTBDPS 5l-Et: 41% yield, 5:95 dr, 36% ee

Scheme 3. Desymmetrization of cyclopenten-1,3-diones.

6525

K. S. Petersen / Tetrahedron Letters 56 (2015) 6523–6535 PPh2

O N R

Ph

1

O N R2

+

R3 N 3

R3

O

N

R3 N N N

N

11 (18 mol%) CuCl (15 mol%)

Ph 1

R

O

+

OH OH

R1

O

N Ar

10

9n: R 1 = H, R 2 = Bn, R3 =

O

O

Si(CH 3) 3

R1

O

N R2

9

8

9a: R 1 = H, R2 = Me, R 3 = Bn 7:1 (9:10 ), 77% yield, 90% ee 9b: R 1 = H, R 2 = Bn, R3 = Bn 7:1 (9:10 ), 70% yield, 94% ee 9c: R 1 = H, R2 = i-Pr, R 3 = Bn 6:1 (9:10 ), 70% yield, 95% ee 9d: R 1 = H, R 2 = Ac, R 3 = Bn 4:1 (9:10 ), 64% yield, 90% ee 9e: R 1 = H, R2 = Bn, R 3 = 2-FC 6 H4 CH2 10:1 (9:10 ), 70% yield, 92% ee 9f: R 1 = H, R2 = Bn, R 3 = 3-FC 6 H4 CH2 12:1 (9:10 ), 82% yield, 89% ee 9g: R 1 = H, R 2 = Bn, R3 = 4-ClC 6 H4 CH2 10:1 (9:10 ), 79% yield, 88% ee 9h: R 1 = H, R 2 = Bn, R3 = 2-MeC 6 H4 CH2 11:1 (9:10 ), 77% yield, 93% ee 9i: R 1 = H, R 2 = Bn, R 3 = 3-MeC 6H 4 CH2 12:1 (9:10 ), 78% yield, 93% ee 9j: R 1 = H, R 2 = Bn, R 3 = 4-MeC 6H 4 CH2 10:1 (9:10 ), 82% yield, 93% ee 9k: R 1 = H, R2 = Bn, R 3 = 2-OHC 6 H4 CH2 6:1 (9:10 ), 75% yield, 95% ee 9l: R 1 = H, R2 = Bn, R 3 = 4-OHC 6 H4 CH2 8:1 (9:10 ), 77% yield, 94% ee 9m: R1 = H, R 2 = Bn, R 3 = CH2 CO2Bn 3:1 (9:10), 49% yield, 89% ee

R

1

N R2

2,5-hexanedione 0 °C, 96 h

7

N N

R3 N N N

N

+ N3

COOR 2 17

19 (15 mol%) CuF 2 (15 mol%) CH3CN, 0 °C, 12 h

16

O N Ar O N N 18 N

COOR 2

N

18a: R1 = 2-Br, R 2 = Et, Ar = Ph 68% yield, 87% ee 18b: R 1 = 3-Br, R2 = Et, Ar = Ph 69% yield, 74% ee 18c: R1 = 4-Br, R 2 = Et, Ar = Ph 71% yield, 82% ee 18d: R 1 = 2-Br, R2 = Et, Ar = 3-ClPh 73% yield, 89% ee 18e: R1 = 2-Me, R 2 = Et, Ar = Ph 74% yield, 76% ee 18f: R1 = 3-Me, R 2 = Et, Ar = Ph 72% yield, 78% ee 18g: R 1 = 4-Me, R2 = Et, Ar = Ph 71% yield, 80% ee 18h: R 1 = 4-Br, R2 = Me, Ar = Ph 69% yield, 70% ee 18i : R1 = 2-Cl, R 2 = Et, Ar = Ph 72% yield, 83% ee 18j : R1 = 3-Cl, R 2 = Et, Ar = Ph 74% yield, 80% ee 18k: R1 = 4-Cl, R 2 = Et, Ar = Ph 70% yield, 77% ee 18l : R1 = 2-Br, R 2 = Et, Ar = 3-BrPh 67% yield, 86% ee 18m : R 1 = 2-OMe, R 2 = Et, Ar = Ph 69% yield, 73% ee

O

11:1 (9:10 ), 56% yield, 98% ee 9o: R 1 = H, R 2 = Bn, R3 = c-hexyl 13% yield, 86% ee 9p: R 1 = H, R 2 = Bnr, R 3 = Ph 2:1 (9:10 ), 35% yield, 84% ee 9q: R 1 = 5-F, R2 = Bn, R 3 = 2-OHC 6 H4 CH2 10:1 (9:10 ), 71% yield, 94% ee 9r: R 1 = 7-Me, R 2 = Bn, R3 = 2-OHC 6H 4CH 2 10:1 (9:10 ), 81% yield, 95% ee 9s: R 1 = 5-OMe, R 2 = Bn, R 3 = 2-OHC 6 H4 CH2 8:1 (9:10 ), 62% yield, 95% ee 9t: R 1 = 6-OMe, R 2 = Bn, R 3 = 2-OHC 6 H4 CH2 7:1 (9:10 ), 48% yield, 95% ee 9u: R 1 = 6-Cl-7-Me, R 2 = Bn, R 3 = 2-OHC 6 H 4CH2 9:1 (9:10 ), 81% yield, 95% ee 9v: R 1 = 7-Cl, R2 = Bn, R3 = 2-OHC 6H 4 CH2 7:1 (9:10 ), 78% yield, 93% ee 9w: R 1 = 7-Br, R 2 = Bn, R3 = 2-OHC 6H 4CH 2 11:1 (9:10 ), 76% yield, 95% ee

Scheme 4. Desymmetrization of dialkynes via CuAAC.

18n: R 1 = 3-OMe, R 2 = Et, Ar = Ph 72% yield, 74% ee 18o: R 1 = 4-OMe, R 2 = Et, Ar = Ph 71% yield, 76% ee 18p: R 1 = 2-Br, R 2 = Et, Ar = 4-OMePh 60% yield, 73% ee 18q: R 1 = H, R2 = Et, Ar = Ph 71% yield, 82% ee 18r: R 1 = Naphthyl, R2 = Et, Ar = Ph 75% yield, 77% ee 18s: R 1 = 4-Ph, R2 = Et, Ar = Ph 70% yield, 76% ee 18t: R1 = 2-Br, R2 = Et, Ar = 4-OEtPh 65% yield, >98% ee 18u: R 1 = 2-F, R 2 = Et, Ar = 4-OEtPh 71% yield, 80% ee 18v: R 1 = 2-Cl, R 2 = Et, Ar = 4-OEtPh 75% yield, 91% ee 18w: R1 = 3-Cl, R 2 = Et, Ar = 4-OEtPh 79% yield, 85% ee 18x: R 1 = 4-Cl, R 2 = Et, Ar = 4-OEtPh 80% yield, 88% ee 18y: R 1 = 2-Br, R2 = Me, Ar = Ph 72% yield, 86% ee 18z: R1 = 2-Br, R 2 = Me, Ar = 3-BrPh 67% yield, 80% ee

Scheme 6. Asymmetric copper catalyzed azide–alkyne click cycloaddition. Tol Bn N N N

N O

Ph

a)

b)

60% 94% ee

O N Bn 12

Bn N N N

Bn N N N

81% 94% ee

O N Bn 13

O Bn N N N O N Bn 14

N Bn

Bn N N N

9b c)

d)

79% 94% ee

82% 94% ee

involving coordination of an amine–copper(I) complex with the BINOL OH in the transition state (Fig. 1). As a follow-up to their copper-catalyzed asymmetric desymmetrization, which differentiates between two aryl halides, Cai and co-workers reported an analogous reaction that differentiates between two amide moieties (Scheme 8).13 This desymmetrization utilized diamide substrates 23 and a more nucleophilic 1,2diamine catalyst 25 to control enantioselectivity. Quinolinone products 24 were generally formed in high yields and modest enantiopurity for a variety of substitution patterns.

O N Bn 15

Scheme 5. Synthetic manipulation of alkyne product. Reagents and conditions: (a) N-Hydroxy-4-methylbenzimidoyl chloride (2.5 equiv), CH2Cl2, 10 h.; (b) PhI (1.5 equiv). Pd(PPh3)4 (5 mol %), CuI (5 mol %) Et3N (10.0 equiv), DMF, 4 h; (c) Raney Ni, MeOH, H2, 4 h; (d) Lindlar’s catalyst, quinine (10.0 equiv), MeOH, H2, 5 h.

Cai and co-workers reported that 1,2,3,4-tetrahydroquinolines and 2,3,4,5-tetrahydro-1H-benzo[b]azepines with quaternary stereocenters could be prepared asymmetrically via a desymmetrization process utilizing a copper-catalyzed N-arylation in combination with BINOL-derived ligand 22 (Scheme 7).12 Aryl iodides or bromides 20 yielded heterocyclic products 21 containing a cyano-bearing quaternary carbon in a remote position from the reaction center in good yields (47–91%) and enantioselectivities (76–94%). Although, no rational was provided, the cyano group was essential to the reaction, with other functional groups such as methyl or esters giving lower yields and/or enantiopurity of product. The reaction was tolerant to functionalization of the aromatic ring such as ester substituents (21k) and less reactive halogens (21g–21i). A one carbon homologation of the substrate led to formation of a seven-membered ring heterocycle (21n–21p, n = 2). The origin of enantioselectivity is explained through a model

Rh Krische and co-workers utilized a rhodium catalyzed tandem conjugate addition–aldol cyclization of keto–enones to desymmetrize cyclic diones with high stereocontrol (Table 1).14 In this methodology, enone–diones 26 were treated with a phenyl boronic acid in the presence of an oxidation resistant methoxy-bridged rhodium dimer [Rh(COD)(OCH3)]2, (S)-BINAP (28), and KOH to yield bicyclic compounds 27. The rhodium catalyzed conjugate addition was followed by a diastereoselective aldol addition invoking a Z-enolate and a Zimmerman–Traxler type transition state (IV). While the products formed have 4 continuous stereocenters, in all cases essentially a single relative stereoisomer (>99:1 dr) is produced with high levels of enantiopurity (P85% ee). The process efficiently forms diquinane, hydrindane, and cis-decalone ring systems, however the reaction is limited to a,b-unsaturated ketone substrates (esters underwent conjugate addition but failed to undergo subsequent aldolization). Products such as 27ea map nicely onto the ring system of the cardiotonic steroid digitoxin (Scheme 9).15 An enantioselective desymmetrization of boryl-substituted cyclobutanones 29 through cleavage of a carbon–carbon single bond to create 1-indanones 30 containing benzylic quaternary carbon centers was shown by Murakami and co-workers

6526

K. S. Petersen / Tetrahedron Letters 56 (2015) 6523–6535 Ar

Ph

OH OH

X

Ar 22: Ar = 9-anthracenyl (15 mol%) CuI (10 mol%) Cs 2CO3 , 1,4-dioxane

X n

R

R

CN NH2

I

R

X = I, 85 °C X = Br, 110 °C

20 I

CN

CN

CONH2

CN

N H

21c : 93% yield, 90% ee

I

N H

21d: 65% yield, 91% ee

N H

O 2N

21f: 73% yield, 83% ee

I

O

F3 C

CN F

N H

N H

N H

21h: 77% yield, 94% ee

I CN

O

N H

O

OCH 3

EtO2C

N H

CN

N H

N H

21l: 64% yield, 81% ee

O

N H

N H

R

Ar

O H Ar

I Cu N H

H O CN I

II

N H

O

24i : 68% yield, 73% ee CONH2

Cl

N H

O

CF3

24l : 75% yield, 52% ee

CONH2

N H

O

24o: 88% yield, 58% ee

CONH 2 Ph N H

O

24q: 78% yield, 44% ee

Scheme 8. Asymmetric desymmetrization of diamides.

N H 21q: 90% yield, 93% ee

Ar

H

O

24p: 81% yield, 58% ee

CN

CN N H 21n: R = H, 56% yield, 90% ee 21o: R = Cl, 87% yield, 89% ee 21p: R = Me, 47% yield, 83% ee

Scheme 7. Desymmetrization by copper-catalyzed N-arylation.

O

O

24n: 89% yield, 68% ee

CONH2

I

I

R

O

24k : 95% yield, 67% ee

NHBoc Br

21m : 74% yield, 91% ee

H3 CO

N H

21k: 85% yield, 87% ee

Br

O

CONH2

24m : 88% yield, 61% ee

CN

O

CONH2

CONH2

CONH2

Br

CN

N H

N H

24f: 72% yield, 57% ee

24h: 98% yield, 60% ee

24j : 88% yield, 72% ee

CO2Et

CN

Br

MeO 2 C

21i: 90% yield, 87% ee

I

N H

O

CONH2

CONH2

Cl N H

21j : 98% yield, 84% ee

N H

CONH2

24e : 87% yield, 77% ee

24g: 52% yield, 70% ee

I

CN

Br

NC

N O H 24c : 92% yield, 69% ee

F

N H 21g: 88% yield, 90% ee

N O H 24b: 72% yield, 73% ee

CONH2

N H

Cl

CN

CONH2

Cl

CN

21e: 60% yield, 85% ee

I Br

O

CONH2

24d: 97% yield, 80% ee

I

CN OMe MeO

F

CONH2

Cl

N H

21b: 65% yield, 76% ee

CN

N H 24

CONH2

N O H 24a: 77% yield, 78% ee

OMe

MeO

NH2 R1

R

23

I

CN

I

K3PO4 (2 equiv.), CH3 CN

O

O

21

N H

21a: 75% yield, 89% ee

H2 N

N H

I

N H

NH2

R n

NHMe 25 (15 mol%) CuI (10 mol%)

O

R

X X

R1

NHMe Ph

I Cu

O H

N H NC

Ar

I

III

Figure 1. Origin of enantioselectivity for 21q.

(Scheme 10).16 In this reaction, transmetalation of boron with rhodium(I) is followed by intramolecular addition of the arylrhodium species to the carbonyl. The resultant bicyclic structure undergoes an enantioselective b-elimination and protonolysis. Ideal conditions included the use of the chiral biaryl diphosphine ligand (S)SEGPHOS (31) with a Rh(I) dimer and was shown to accommodate four different groups at the 3-position including the bulky isopropyl group (29c?30c) with excellent yields (81–96%) and enantioselectivities (79–95%). Indanone 30d was then applied to the formal synthesis of a-herbertenol.17 A drawback of this methodology is the synthesis of the boryl-substituted cyclobutanones which is quite laborious. Recently, Dong and co-workers reported an enantioselective desymmetrization of cyclopropenes 33 bearing a quaternary carbon through an intermolecular Rh-catalyzed hydroacylation that is favored by the resulting release of strain energy to form

cyclopropanes 34 with a quaternary stereocenter (Scheme 11).18 This methodology utilizes a rhodium(I) dimer and a ferrocenebased phosphine ligand 35 for the in situ formation of a chiral catalyst. Salicylaldehyde derivatives 32 were used as hydroacylation agents due to the known coordination of the phenolic oxygen to rhodium. Various arylaldehydes with electron-donating or electron-withdrawing substituents in the ortho-, meta-, or para-positions were readily oxidized. The cyclopropene structure could be modified to accommodate a wide range of aryl groups. The reaction favors the formation of the trans-diastereomer of 34 (dr’s range from >20:1 to 6:1) and the enantiopurity of both diastereomers is generally excellent (P95%). Prochiral c,d-unsaturated amides 36 were shown to undergo an enantioselective desymmetrization via a rhodium catalyzed asymmetric hydroboration (Table 2).19 The amide directs a cis addition of boron 39 and BINOL-derived phenyl phosphite 38 controlled the enantioselectivity of the reaction. Organoboronate intermediates were then oxidized to yield the alcohol products 37. Alternatively, intermediates were converted into trifluoroborates 40 and underwent a palladium catalyzed cross-coupling reaction to yield arylated products 41. Modest variation of the substituent a to the amide (R1) and on the amide nitrogen was tolerated (R2). Pd Asymmetric palladium-catalyzed coupling reactions have been an area of growing interest.20 Other than nucleophilic substitutions pioneered by Trost and Stoltz, palladium-catalyzed methods to generate enantioenriched quaternary carbons have been limited

6527

K. S. Petersen / Tetrahedron Letters 56 (2015) 6523–6535 Table 1 Conjugate addition–aldol cyclization of prochiral diones

Table 1 (continued) Entry

Substrate

Product

O PPh 2 PPh 2

14

R1

O RhL n O

H

O (S)-BINAP-28 (7.5 mol%) [Rh(COD)(OCH 3 )]2 (2.5 mol%)

R2

O

Ar

n

HO

O IV

OH CH 3

CH3 26h

95% yield >99:1 dr, 87% ee

CH3 27hb

O

R2

O

R3

n

ArB(OH) 2 (200 mol%) KOH (10 mol%), H 2O (500 mol%) Dioxane (0.1 M), 95 °C

O 26

R

Ph

CH 3

O

Ar

n

R3

1

O

H 3C

Results O

m

O

O 27

O O

Entry

Substrate

Product

O

1

H 3CO O

27aa

87% yield >99:1 dr, 90% ee

O OH

Ph

5

97% yield >99:1 dr, 90% ee 27ca

O

Cy2 P

87% yield >99:1 dr, 91% ee

26c

OH

27cc O O

Ph

O OH

86% yield >99:1 dr, 85% ee

8 27db

O

26d H 3C

O

H 3CO

O

H 3C

O OH

O

80% yield >99:1 dr, 86% ee

9 26e

27ea

O H 3C

10

82% yield >99:1 dr, 85% ee

26e 27eb Br

11

O

H 3C

O OH

85% yield >99:1 dr, 86% ee

26e 27ec H 3C

O

H 3C O

26f

27fb

O H 3C

O

26g

O

O

O OH

H3C 27gb

K3 PO4 (10 mol%) toluene, 70 °C, 12 h

O H R2 Me 34trans

Ar +

O H R2 Me 34cis

34a : R 1 = H, R2 = Ph dr (trans:cis) = 13:1, yield (trans ) = 86%, ee (trans) = 98% 34b: R1 = 3-Cl, R 2 = Ph dr (trans:cis) = 13:1, yield (trans ) = 85%, ee (trans ) = >99% 34c: R 1 = 3-Me, R 2 = Ph dr (trans:cis) = 10:1, yield (trans ) = 85%, ee (trans) = 99% 34d: R1 = 3-OMe, R 2 = Ph dr (trans:cis) = 14:1, yield (trans ) = 92%, ee (trans ) = >99% 34e: R 1 = 4-Me, R2 = Ph dr (trans:cis) = 10:1, yield (trans ) = 89%, ee (trans) = 98% 34f : R 1 = 5-t-Bu, R 2 = Ph dr (trans:cis) = 12:1, yield (trans ) = 86%, ee (trans) = 99% 34g: R1 = 5-OMe, R 2 = Ph dr (trans:cis) = 11:1, yield (trans ) = 88%, ee (trans) = 99% 34h: R1 = 5-COOMe, R 2 = Ph dr (trans:cis) = 10:1, yield (trans ) = 86%, ee (trans) = 99% 34i: R1 = 5-Cl, R 2 = Ph dr (trans:cis) = 11:1, yield (trans ) = 84%, ee (trans) = 97% 34j: R1 = F, R2 = Ph dr (trans:cis) = 12:1, yield (trans ) = 79%, ee (trans) = 97% 34k: R 1 = 6-Me, R2 = Ph dr (trans:cis) = 12:1, yield (trans ) = 84%, ee (trans) = 99% CHO R 2 = Ph 34l: R1 = OH

dr (trans:cis) = 13:1, yield (trans ) = 82%, ee (trans) = 95%

65% yield >99:1 dr, 88% ee

O

33

Ar

O

O OH

12

13

O

O OH

35 (5 mol%) [Rh(COD)Cl] 2 (2.5 mol%)

+ 32

77% yield >99:1 dr, 92% ee

Ph

Me R 2

OH

O

Br

O

CHO R1

O H3 C

Fe H

OH

26c 27cb

7

P( tBu) 2 Me

O O

H3 C

6

Scheme 10. Desymmetrization of boryl-substituted cyclcobutanones.

OH

H 3CO 26c

O (S)-SEGPHOS (31)

O O

O

30a: R = Et 96% yield, 95% ee 30b: R = Ph 93% yield, 79% ee 30c: R = i-Pr 81% yield, 94% ee 30d: R = CH2 CH2CH 2OBn 84% yield, 94% ee

PPh2 PPh2

O

H3 C

O

H 3C

*

30

94% yield >99:1 dr, 87% ee

27bb

R Me

0.5 equiv K3PO4 dioxane/H 2 O (20:1), 100 °C

O

OH

O

[RhCl(CH2 =CH2) 2]2 (3.5 mol%) (S)-SEGPHOS- 31 (7 mol%)

O

O

4 O

OH O

27ea

29

88% yield >99:1 dr, 94% ee

O

Ph 26b

O B(pin)

27ac

O

R

O

Br

O

B H 3C

Scheme 9. Products as precursors to steroids.

OH

H3 C

26a

H 3CO

Digitoxin: R = (Digitoxose) 3 Digitoxigenin, R = H

O

26a 27ab

3

A

OH

H

D

O

H3 C

2

RO

83% yield > 99:1 dr, 90% ee

C

H H

OH

H 3C

26a

H 3C

O

H3 C

O

H

Results

93% yield >99:1 dr, 88% ee O

34m : R 1 = H, R 2 = 3-BrC 6H 4 dr (trans :cis) = 10:1, yield (trans) = 80%, ee (trans ) = 99% 34n: R 1 = H, R2 = 3-CF 3C 6H 4 dr (trans :cis) = 6:1, yield (trans ) = 78%, ee (trans) = 98% 34o: R 1 = H, R 2 = 2-furanyl dr (trans :cis) = >20:1, yield (trans) = 81%, ee (trans ) = 99% 34p: R 1 = H, R2 = 2-thiofuranyl dr (trans :cis) = >20:1, yield (trans) = 88%, ee (trans ) = 99% 34q: R 1 = H, R2 = CH2 OMe dr (trans :cis) = 6.5:1, yield (trans) = 76%, ee (trans ) = 98% 34r: R 1 = H, R 2 = 2-napthyl dr (trans :cis) = 10:1, yield (trans) = 91%, ee (trans ) = 99%

Scheme 11. Hydroacylation of prochiral cyclopropenes.

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K. S. Petersen / Tetrahedron Letters 56 (2015) 6523–6535

Table 2 Desymmetrization via catalytic asymmetric hydroboration

O

1. [Rh(ndb) 2 BF4/2 38] (1 mol%), 39 (2 equiv.), R1 NHR2 THF, 40 °C O

R1

36

NHR2

O

O BH O 39 (tmdBH)

38

R1

1. CAHB 2. KHF2 , KF3 B MeCN/H2 O (4:1), rt, 2 h

37

O Bn P N Ph O

52 or 53

R

HO

2. H 2O 2/NaOH, rt

Table 3 Desymmetrization of oxetanes with (salen)Co(III) complexes

OH 50

NHR2

R 51

OH

O O

40 t

O

t

t

Bu

N

1

Bu

N

N

N

OTf

O OTf

O

N Co

TfO

O

O

O

t

t

Bu

t

Bu

O Co

O Co

NHR2

O

Bu

t

R Ar

O

O

7.5% 42 3 equiv Cs3CO3 aryl halide (1 equiv) 10:1 tolune/H 2O 100 °C, 24 h

NH2 Pd OMs Ad Ad n Bu 42

O

23 °C

N

Bu

Bu

41 yields ≥ 63%

Entry

R1

R2

Product

Yield (%)

ee (%)

1 2 3 4 5 6 7 8

Me Ph CF3 Me Ph CF3 Ph Ph

Ph Ph Ph Bn Bn Bn (R)-CH(Me)Ph (S)-CH(Me)Ph

37a 37b 37c 37d 37e 37f 37g 37h

65 72 78 62 70 71 76 74

92 92 94 84 86 92 76 60

O t

Entry

Substrate

1 2

H3 C

H 3C

Ph

TfO

OTf

(HO) 2B–Ar (2 equiv) Pd(OAc) 2 (10 mol%) 45 (11 mol%)

CsF, dioxane, RT

43

45

Product

O

O

OH

HO

TfO

5 6

O

HO

O

ee (%)

52 (1) 53 (0.01)

6 6

87 88

99 96

52 (1) 53 (0.01)

24 24

96 98

98 99

52 (1) 53 (0.01)

2 12

93 97

99 99

52 (1) 53 (0.01)

5 5

88 98

97 99

52 (10) 53 (1)

8 8

77 95

96 98

i

Pr

OH

HO

50c

51c

O

O

OH 50e

9 10

Yield (%)

51b

i Pr

HO

Time (h)

Ph

O

7 8

Catalyst (mol %)

CH3

O

50b

Ar

n

51a

Ph

Ph

O O

53 (n = 1– 4)

OH

H 3C

44a: Ar = 4-C6 H 5C(O)Me 46% yield, 77% ee 44b: Ar = 3-C 6 H5 C(O)Me 51% yield, 86% ee 44c: Ar = 2-C6 H 5C(O)Me 99%, ee 92% 55b: R = 3-OMe-C 6 H4 yield 94%, ee 77% 55c: R = 4-Me-C 6 H4 yield >99%, ee 86% 55d: R = 4-OMe-C 6 H4 yield 93%, ee 82% 55e: R = 3-CF3 -C 6H 4 yield 87%, ee 81% 55f: R = cyclohex yield 67%, ee 82% 55g: R = CH2 Ph yield 80%, ee 74%

55

Scheme 14. Enantioselective cyclization of diynamides.

utilizing a desymmetrization strategy (Scheme 12).22 The achiral 5-membered ditriflate 43 was selectively monocoupled with a variety of aromatic boronic esters in the presence of palladium diacetate and the monodentate phosphine ligand 45 to produce mono arylated products, 44. Boronic acids with para, meta, and heterocyclic substitution patterns performed moderately well in

6529

K. S. Petersen / Tetrahedron Letters 56 (2015) 6523–6535 Table 4 Zirconium catalyzed enantioselective desymmetrization of dienes Ph B O O

N N

Zr NMe 2 NMe2 R2

R1 R

Entry

Substrate Ph

1

n

2

57

59 (10 mol%)

NH2 n

n

R

Product NH2

2

benzene, rt

HN

R1

R2

n

58

[Substrate] (mM)

Time

Yield (%)

cis/trans

ee (%)

5.45

6h

94

8.9:1

96

5.45

2d

84

4.2:1

93

5.45

3h

95

8:1

95

65.4

48 h

78

>20:1

97

10.9

8d

75

8:1

92

4d

76

6.6:1

32

6d

74

7:1

89

5.45

2h

95

n.a.

91

5.45

48 h

94

n.a.

77

5.45

72 h

89

n.a.

89

Ph HN

57a

58a NH2

2

HN

57b BrC 6H 4

3

58b NH2

C6 H4 Br HN

57c MeO

4

58c NH2

OMe HN

57d

58d

Ph

5

NH2

Ph HN

57e

Ph

6

NH2

2

57f

Ph

7

58e

5.45

Ph

HN

2

58f

2

NH2

3

57g

HN

3

16.4

Ph

58g

3

H2 N Ph

Ph

8

N

57h

58h

H2 N Ph

N

9 2

57i

2

H2 N Ph

10

3

57j

Ph 2

58i Ph

N

3

58j

Ph 3

N

O N

O

N BF4

O

O

62 (10 mol%) KHMDS (10 mol%) Me

Me Me O 60

O

Toluene, 0.008 M 23 °C, 95:5 dr

Scheme 15. Desymmetrization via an intramolecular Stetter reaction.

the procedure (46–66% yield and 72–85% ee). The exception of ortho-substituted boronic acids (20:1 dr). The process tolerates a variety of aryl thiols (entries 1–11) and some modest substitution on the oxindole ring (entries 12–14). Overall yields were excellent (P77%) and enantioselectivities good (P82%). The desymmetrization of meso diols such as 78 through a selective acylation was recently described by Chuzel and co-workers (Scheme 17).33 This process, which utilizes the ferrocenyl Fu based chiral dialkylaminopyridine derivative 8034 as a catalyst yields monoesters such as 79 bearing 5 contiguous asymmetric centers, including 2 all-carbon quaternary stereocenters with up to 94% enantioselectivity. The authors explored two different sets of conditions. The first condition (A) consisted of standard Fu protocols using t-AmOH as the solvent and led to high enantioselectivity. The second condition (B) utilized a C6F6/CHCl3 solvent mixture and generally gave higher yields. Mechanistically, the authors postulate that in C6F6 p–p complexation between solvent and the chiral DMAP catalyst led to a standard desymmetrization event. In tert-amyl alcohol however, a desymmetrization reaction followed by a kinetic resolution may have been responsible for the higher

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K. S. Petersen / Tetrahedron Letters 56 (2015) 6523–6535 O

1. NaH, RX 2. NaH, BrCH2(CH2) 2OAc

O

O

O

O

O

O O

87 O

O O

O

TRIP (85, 5 mol%)

O n OH

R

52% overall yield for R = Me

86

O

O

3. K2CO 3, MeOH

O O

88c 89% yield 90% ee

96% yield 97% ee

O

O O

O

O

O H3 C

O Bn

O

88e a

88f

88g

95% yield

67% yield 94% ee

84% yield 86% ee

94% ee

O 88d

88b

O

O

O

93% yield 95% ee

O

O n

O

O

O

O

88a

O

* R 88

95% yield 98% ee

O

O

O O

CH2Cl2

Scheme 20. Enantioselective desymmetrization of diesters. aUnpublished data.

H N

O

O

O b)

a)

HO

O OH

(+)-89

O

O

(–)-90 OH

O

O

O

O

92% 98% ee

65% 96% ee

O

O (–)-88a 98% ee O

O

H N

Ph

d)

c)

BnHN O

76% 98% ee

56% 98% ee

(+)-91

O OH

(–)-92

Scheme 21. Synthetic transformations. Reagents and conditions: (a) (1) NH4OH, (2) Ac2O, DMAP, (3) Pb(OAc)4, tBuOH, (4) K2CO3, MeOH; (b) LiAl(OtBu)3H, THF; (c) (1) TFA, (2) Cl3CCN, NaN3, Ph3P, MeCN, (3) THF/H2O, lW, (4) K2CO3, H2O, PhCOCl; (d) BnNH2, THF.

enantioselectivities seen. Manipulation of monoacetate products led to complex polyketide fragments 81 (Scheme 18). Desymmetrization of 2,2-disubstituted 1,3-diols via a chiral phosphoric acid catalyzed oxidative cleavage of benzylidene acetals was recently realized (Scheme 19).35 Dimethyldioxirane (DMDO) was used in combination with catalyst 85 (TRIP) to selectively oxidize benzylidene acetals 82 to esters such as 84 via the proposed intermediate 83 in excellent yields and good enantiopurity. DFT calculations showed that the rate determining step was oxidation by DMDO and that aryl–aryl interactions between the substrate and catalyst are responsible for the high enantioselectivities seen. We have recently reported the desymmetrization of prochiral diesters 87 through a Brønsted acid catalyzed intramolecular cyclization with phosphoric acid 85 to yield lactones 88 containing an all-carbon quaternary center (Scheme 20).36 Desymmetrization substrates were prepared in 3 steps and high yields from commercially available tert-butyl malonate (86). Lactonization yields were generally high and enantioselectivities of products excellent (P90% ee for c-lactones and 86% ee for d-lactone). Recently, we have found that catalyst loading could be reduced to 1 mol % and reaction times lowered through the use of toluene at 80 °C with only minimal loss in yield and no loss in enantioselectivity (88a was prepared in 95% yield and 98% ee).37 Lactone 88a readily underwent synthetic transformations to yield new useful building blocks with little to no loss in enantioselectivity (Scheme 21). Asymmetric synthesis of cycloalkanones with an a-quaternary stereocenter such as 95 was accomplished through a chlorination/ring expansion cascade (Table 8).38 Desymmetrization of cyclic substrates 93 was accomplished using 1,3-dichloro-3,3-dimethylhydantoin (94) as a chlorine source in combination with organocatalysts (DHQD)2PHAL and N-boc-L-phenylglycine. Choice of solvent had a

Table 8 Enantioselective desymmetrization through chlorination/ring expansion

OH +

R X

Cl N

O N Cl

93

(DHQD) 2PHAL (73, 10 mol%) N-Boc-L-phenylglycine (20 mol%) O 3 Å MS, Toluene

94

R O

X

Cl 95

Entry

X

R

Product

Time (h)

Temp (°C)

Yield (%)

1 2 3 4 5 6 7 8 9 10 11 12 13

CH2 CH2 CH2 CH2 CH2 CH2 CH2 O O O O O CH2CH2

H 3-Me 4-Me 4-tButyl 3-F 4-F 4-Cl H 3-Me 4-Me 4-F 4-Cl H

95a 95b 95c 95d 95e 95f 95g 95h 95i 95j 95k 95l 95m

96 96 96 96 96 96 96 72 72 72 120 120 96

40 40 40 40 40 40 40 40 40 40 20 20 40

76 82 70 75 55 80 72 73 67 72 73 63 58

ee (%) 96 97 93 91 92 96 95 93 93 90 91 87 77

95n

96

40

70

93

95o

96

40

70

94

95p

96

40

53 cis/trans = 4.5:1

95q

96

40

76 dr > 35:1

O Ph

14 Cl O Ph

15

Cl O Ph

16

94, 92

Cl Ph

17

O Cl

75

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K. S. Petersen / Tetrahedron Letters 56 (2015) 6523–6535 Table 9 Asymmetric bromoetherification and desymmetrization of diols

EtO

S N H

O N

N O

O

O 2

R

98 (5 mol%) NBS, MsOH (1 equiv)

OH

Ph

R1

OH

R1

OH

R1

CH2 Cl2 –78 °C, 3 d

Ph

102 (10 mol%) NBP (1.2 equiv)

OH

R2

O Br

96

R2 HO 100

Br

Br

O

O S

4 ÅM.S. CHCl3/n-hexane (4:7) –60 °C, 12 h

NBS (1.2 equiv) R 1 SPPh3 (10 mol%)

O

R1

R2

CH2 Cl2 , –50 °C

O

O

OH

R1

103 Br

101

97

Entry

Diol, R1, R2

Product

Yield (%)

dr

ee (%)

1 2 3 4 5 6 7 8 9 10 11 12

96a, Ph, H 96b, 4-Me-C6H4, H 96c, 2-naphthyl, H 96d, 4-F-C6H4, H 96e, 4-CF3O-C6H4, H 96f, 4-Cl-C6H4, H 96g, 4-Et-C6H4, Ph 96h, 3-MeO-C6H4, Ph 96i, 4-Ph-C6H4, Ph 96j, 4-F-C6H4, Ph 96k, 4-CF3O-C6H4, Ph 96l, Ph, Et

97a 97b 97c 97d 97e 97f 97g 97h 97i 97j 97k 97l

92 96 97 91 93 86 96 99 98 94 93 99

93:7 >99:1 92:8 95:5 85:15 89:11 92:8 71:29 91:9 >99:1 >99:1 >99:1

87 80 64 86 60 88 90 95 92 82 84 85

73

72:25

82

Br Ph

HO

Br 2-Me-C 6 H4

O

101a 93% yield 84:16 dr 92% ee

Br 4-Me-C 6 H4

HO

Br 4-Cl-C 6 H4

Ph

O

HO

Br 1-naphthyl

Br 3-Me-C 6 H4

O

2-Me-C 6 H4 101b 90% yield 95:5 dr 92% ee

O

HO

Br 4-F-C 6 H4

O

4-Me-C 6 H4 HO 1-naphthyl 101d 101e 92% yield 96% yield 82:18 dr 95:5 dr 90% ee 86% ee Br O O Ph

3-Me-C 6 H4 101c 89% yield 80:20 dr 64% ee O

4-F-C 6H 4 HO 101f 93% yield 79:21 dr 64% ee Br Ph

O

OH

13

Ph Br

OH

Ph 96m

OH O 97m

HO

Br Me

HO

MsOH

+

NBS succinimide

*R

S 98

R*

*R

S Br 99

OH

OH

Br

OH

R1 *R

97

R*

Bn 96

Br R2

OH Bn

R1

Ph 101j 90% yield 86:14 dr 40% ee

Br Ph

HO

HO

Br Ph

O

101i 91% yield 94:6 dr 80% ee O

Ph 101k 94% yield 79:21 dr 84% ee

HO

101l 91% yield 84:16 dr 98% ee

OMs

R2

O

O

HO 101h Bn 90% yield 88:12 dr 86% ee

Scheme 23. Desymmetrization diolefinic diols.

R*

Bn R1 R2

4-Cl-C 6 H4 101g 92% yield 76:24 dr 64% ee

HO VII

Scheme 22. Plausible mechanism for bromocyclization.

large impact on the enantioselectivity of the reaction, with toluene performing the best and the addition of molecular sieves led to decreased reaction times. Halogens and alkyl groups in the meta or para position were tolerated on the aromatic ring, and notably, this was the first time oxa-cyclobutanol substrates (93h–93l) were used as ring expansion substrates en route to dihydrofuran4-(2H)-ones. Olefinic 1,3-diols 96 were shown to undergo a desymmetrization event through bromoetherification catalyzed by C2-symmetric sulfide 98 to yield substituted tetrahedrofurans with 3 stereogenic centers, including a quaternary carbon such as 97 by Yeung and coworkers (Table 9).39 N-Bromosuccinimide (NBS) was used as the halogen source and key to the reaction was addition of 1 equiv of MsOH (other acids were less effective). In general the reaction proceeded with good diastereoselectivity, the exceptions being for meta-substituted aromatics (entry 8, 96h?97h) and when a methyl replaces the benzyl group at the diol stereocenter (entry 13, 96m?97m). Enantioselectivities for the reaction range from 64% to 92%. The nature of the substituent on the aromatic ring did not significantly affect the reaction. Notably, the reaction required 3 days at 78 °C for completion. The bromocyclization

is thought to go through active species 99 which could deliver Br to olefin 96 through a transition state such as VII (Scheme 22). Yeung and co-workers expanded upon their desymmetrization of diols through bromoetherification by utilizing diolefinic substrates 100 to yield tetrahydrofuran substrates with two quaternary stereogenic carbon atoms such as 101 (Scheme 23).40 This cyclization utilized chiral amino-thiocarbamate catalyst 102 and N-bromophthalimide (NBP) as the bromine source. Substrates with symmetric diolefins (i.e.; R1 = R2) were first examined and yielded heterocycles with reasonable dr and enantioselectivities. Diols with unsymmetric diolefins (R1 – R2), usually favored cyclization onto the phenyl olefin (100h, 100i, 100k, and 100l); however, when the mixed methyl olefin was used, cyclization occurred at the less hindered olefin (100j). Interestingly, several of the tetrahydrofuran substrates were able to undergo a second halocyclization of the intermediate olefin to yield spirocyclic compounds 103. Prochiral 2,2-disubstituted cyclopentene-1,3-diones 104 underwent an enantioselective desymmetrization via a formal C(sp2)–H alkylation to substituted products 106 which contain a quaternary carbon (Table 10).41 The reaction is catalyzed by tertiary aminourea-based catalyst 107 and utilizes readily available nitroalkanes 105 as the alkylating agents. The reaction presumably proceeds via an addition reaction followed by an in situ elimination and isomerization. Choice of the external base, Na2CO3, was carefully examined such that the base would not participate in the conjugate addition (only facilitate the elimination). The substrate scope for the reaction is quite general, accommodating a wide array of substitution on the dione 104 and the nitroalkane 105. Yields were generally good and enantioselectivities of up to 96% were seen for this process. Manipulation of products into more complicated structures was explored and reactions were generally diastereoselective (products 109–111, Scheme 24). A second alkylation of

6534

K. S. Petersen / Tetrahedron Letters 56 (2015) 6523–6535

Table 10 Enantioselective desymmetrization of cyclopentene-1,3-diones N

H N

H MeO

+

3 4

5

6 7 8 9

O

105

R1

R2

CH2Ph (104a) CH2-4-Me-C6H4 (104b) CH2-2-Me-C6H4 (104c) CH2-1naphthyl (104d) CH2-2naphthyl (104e) CH2-4-Cl-C6H4 (104f) CH2-3-Cl-C6H4 (104g) CH2-2-Cl-C6H4 (104h) CH2-4-Br-C6H4 (104i)

Product

O

11

(104j )

(93k)

Time (h)

Yield (%)

ee (%)

Me (105a) Me (105a)

106aa 106ba

48 48

88 83

94 93

Me (105a)

106ca

48

79

88

Me (105a)

106da

60

83

94

Me (105a)

106ea

48

90

94

Me (105a)

106fa

48

84

88

Me (105a)

106ga

48

88

90

Me (105a)

106ha

70

80

74

Me (105a)

106ia

48

82

87

Me (105a)

106ja

48

85

93

Me (105a)

106ka

72

84

84

(104l ) 4-Cl-C 6H 4

Me (105a)

106la

72

73

95

Me (105a) Me (105a)

106ma 106na

72 72

78 82

80 92

Me (105a) Me (105a) Me (105a)

106oa 106pa 106qa

48 70 48

90 86 83

67 96 96

n Bu (105b) CH2Ph (105c) CH2-4-Me-C6H4 (105d) CH2CH2Ph (105e) CH2CH2-2-furyl (105f) CH2CH2NHPh (105g) CH2CH2NBzPh (105h) CH2CH2OH (105i) CH2CH2OTBS (105j) Et (105k) Et (105k)

106ab 106ac 106ad

70 72 70

82 86 78

70 88 88

106ae

70

88

85

106af

56

51

86

106ag

72

72

80

106ah

72

90

82

106ai

60

82

55

106aj

72

92

88

106ak 106ek

60 60

74 79

90 85

21

CH2Ph (104a)

22

CH2Ph (104a)

23

CH2Ph (104a)

24

CH2Ph (104a)

25

CH2Ph (104a)

26

CH2Ph (104a)

27 28

CH2Ph (104a) CH2-2naphthyl (104e)

Me CH2 OTBS

Me O 106aj

O

106aj gave compound 112 which is the core of the antibiotic natural product (+)-madindoline B.42 The asymmetric synthesis of bicyclo[3.2.1]octanes and bicyclo [3.3.1]nonanes containing an all-carbon quaternary center such as 114 and 115 was achieved via the desymmetrization of 2,2disubstituted cyclic 1,3-diketones 113 (Table 11).43 The process involves a chiral phosphoric acid (TRIP, 85) promoted reversible enolization followed by an intramolecular Michael addition. The

2

Cs2 CO3 toluene (0.1 M) 120 °C, 12 h

O

nBu

Me CH2OTBS

Me O 112 80% yield

O

n

Bu Me

OH

N Me

H

O O (+)-Madindoline B

Scheme 24. Synthetic transformations of alkenes.

Table 11 Enantioselective desymmetrizing Michael cyclizations TRIP (85, 3 mol%) O

O R

R1 O

113

O

R1

2

n

i

18 19 20

nBuNO

O

O

13 14 15 16 17

Me Bn

O Me

111 78% yield (>20:1 dr)

12

Bu (104m) CH2OTBS (104n) Ph (104o) CHPh2 (104p) CH(4-Br-C6H4)2 (104q) CH2Ph (104a) CH2Ph (104a) CH2Ph (104a)

O H 2O 2 Na2CO3 acetone 0 °C, 4 h

O 106

O

10

O 106aa (R = Me) 106ak (R = Et)

109 22% yield

R1

R2

OH 110 55% yield (major, 5:1 dr)

Bn

R

Me Bn

Me

Me

MeOH (0.1 M) 25 °C, 3 h

O Me

R2 NO2 Na2 CO3 (1.5 equiv) PhCF3 (0.5 M) –10 °C

Bn

Et

CF3

O

Pd/C (5 mol%) H2 (1 atm)

Me

107 (10 mol%)

O 104

1 2

CF3

N

Me

Entry

O

H N O

O R1

O CeCl3•7H 2O NaBH4 MeOH (0.1 M) 0 °C, 10 min

cyclohexane 50 °C, 24 h O

O

O R2 R1 or

114

O

R2

115

Entry

n

R1

R2

Product

Yield (%)

ee (%)

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29

1 1 1 1 1 1 1 1 1 1 1 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2

Me Me Me Me Me Me Me Me Me Me Et Me Me Me Me Me Me Me Me Me Me Me Me Allyl Allyl Ph Ph PMP PMP

Ph 4-Me-C6H4 4-MeO-C6H4 4-Cl-C6H4 3-Cl-C6H4 2-Naphthyl t Bu 2-Pyridyl 2-Furyl 2-Thienyl Ph Ph 4-Me-C6H4 4-MeO-C6H4 4-F-C6H4 4-Cl-C6H4 4-NO2-C6H4 3-CF3-C6H4 2-MeO-C6H4 2-Cl-C6H4 2-Naphthyl 2-Pyridyl CH2CH2OBn Ph 4-Cl-C6H4 Ph 2-Thienyl Ph 2-Thienyl

114a 114b 114c 114d 114e 114f 114g 114h 114i 114j 114k 115a 115b 115c 115d 115e 115f 115g 115h 115i 115j 115k 115l 115m 115n 115o 115p 115q 115r

93 91 92 80 79 97 96 76 80 97 95 77 95 94 82 73 85 68 60 75 96 75 35 89 94 68 50 63 49

91 92 91 94 86 91 95 87 88 92 93 82 86 87 86 87 72 86 83 92 87 82 92 86 88 94 97 94 92

major product for the reaction is a bicyclic compound with the substituent in the equatorial position. Yields and enantioselectivities were good to excellent, although slightly lower for the bicyclo [3.3.1]nonanes 115 (n = 2). Conclusion and outlook The asymmetric formation of all-carbon quaternary centers continues to be of significant interest to the synthetic community as seen by the vast number of publications in recent years. Desymmetrization is an increasingly attractive method for the enantioselective preparation of these challenging stereocenters. Advantages

K. S. Petersen / Tetrahedron Letters 56 (2015) 6523–6535

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