Discussion Addendum for: Preparation of (S)-tert-ButylPHOX ...orgsyn.org/Content/pdfs/procedures/v95p0439.pdf · 6/11/2018 · R N H O RO2C R • Pd/(S)-t-BuPHOX ... .30–35 This

Org. Synth. 2018, 95, 439-454 Published on the Web 11/6/2018 DOI: 10.15227/orgsyn.095.0439 Ó 2018 Organic Syntheses, Inc.

439

DiscussionAddendumfor:Preparationof(S)-tert-ButylPHOXand(S)-2-Allyl-2-Methylcyclohexanone Alexander W. Sun and Brian M. Stoltz*1 Warren and Katharine Schlinger Laboratory for Chemistry and Chemical Engineering, Division of Chemistry and Chemical Engineering, California Institute of Technology, Pasadena, California 91125, United States Original Articles: Krout, M. R.; Mohr, J. T.; Stoltz, B. M. Org. Synth. 2009, 86, 181–193; Krout, M. R.; Mohr, J. T.; Stoltz, B. M. Org. Synth. 2009, 86, 194–211.

Phosphinooxazoline (PHOX) ligands, originally developed by Pfaltz,

Helmchen, and Williams,2-4 comprise a privileged class of P,N type ligands with extensive applications in various transition-metal catalyzed processes, including allylic alkylations, Heck-type reactions, and catalytic hydrogenation.5,6 The PHOX ligand class is highly modular and has grown to encompass numerous structural variations, of which only a few major classes are shown in Figure 1. Every component of the ligand scaffold is modifiable as exemplified by R1 variations on the oxazoline ring (1, 2), substitution of the aryl rings with perfluoroalkyl groups (2) or ferrocenyl

O

O

O

O

OH

O

OH

O

O

O O

O O

1. allyl alcohol, p-TsOH toluene, reflux

2. NaH, THF, 40 °C then CH3I

Pd2(dba)3(S)-tert-ButylPHOX

THF, 30 °C

1. semicarbazide·HCl NaOAc, H2O

2. recrystallization3. 3 N HCl (aq), Et2O

A.

B.

C.

Org. Synth. 2018, 95, 439-454 DOI: 10.15227/orgsyn.095.0439 440

systems (3), and various alkyl and spirocyclic7 linkers joining the oxazoline ring to the phosphine backbone (4a-b).6

Figure 1. Phosphinooxazoline (PHOX) ligands are highly modular

The substituted tri-aryl PHOX ligands 1 are of particular interest to our

laboratory. Since our 2009 Organic Syntheses articles, which described an optimized route to the valuable PHOX ligand (S)-t-BuPHOX 1a and its use in a Pd-catalyzed decarboxylative allylic alkylation reaction toward the synthesis of (S)-2-allyl-2-methylcyclohexanone,8,9 electronic and steric modifications to the scaffold of 1a have found increasing traction in the literature.10-12 In particular, electron-deficient counterparts such as (S)-(CF3)3-t-BuPHOX (5), (S)-(CF3)4-t-BuPHOX (6), and (S)-(CF3)4(F)-t-BuPHOX (7), which contain trifluoromethyl groups at strategic positions on the aryl rings, have been uniquely effective and in many cases superior to 1a in various highly enantioselective metal-catalyzed reactions.13,14 These ligands may be synthesized through modified procedures based on our original Organic Syntheses article.8,10,13 This Discussion Addendum highlights recent

Figure 2. Electron-deficient variants of (S)-t-BuPHOX

PHOX Ligands in Reaction Development

PPh2 N

O

R1

1

P(F3C)2 N

O

R1

Fe N

O

R2PAr2

NO

R1

P(CF3)2

2 3 4aR2 = t-Bu, Bn

R1 = i-Pr, t-Bu, Ph, Bn

PAr2

4b

N

O

Bn

P

CF3

F3C

CF3

N

O

tBuP N

O

tBuP

R3

N

O

tBu

F3C

F3CF3C CF3

5: (S)-(CF3)3-t-BuPHOX 6: R3 = H; (S)-(CF3)4-t-BuPHOX7: R3 = F; (S)-(CF3)4(F)-t-BuPHOX

1a: (S)-t-BuPHOX


applications of 1a and its electron-deficient variants 5-7 in total synthesis and reaction development, with an emphasis on decarboxylative asymmetric allylic alkylation reactions.

Aside from their common use in various asymmetric allylic allylation-type reactions,15,16,17 PHOX ligands 1a and 5-7 have recently been utilized in diverse transformations including sigmatropic rearrangements,18 hydroarylation reactions,19 carboaminations,20 asymmetric alkylations and protonations,21,22 and cascade reactions.23 The chemical motifs produced by these PHOX-catalyzed reactions are often found in biologically active small molecules and can also serve as synthetically valuable intermediates. For instance in 2012, Kozlowski presented a rare example of a catalytic enantioselective Saucy-Marbet Claisen rearrangement using 1a to effect the transformation of propargyl ethers 8 into allenyl oxindoles 9 (Scheme 1).18 However, 1a was effective only for a subset of aryl-substituted alkyne substrates.

Scheme 1. Synthesis of quaternary allenyl indoles using an enantioselective Saucy-Marbet Claisen rearrangement

Later in 2015, 1a was also utilized by Wolfe in a Pd-catalyzed alkene

carboamination reaction involving allylphenyltriflates 10 and aliphatic amines to generate chiral aminoindanes 11, a motif that appears in a variety of pharmacologically active molecules (Scheme 2).20 Interestingly, the crucial aminopalladation step consists of an intermolecular reaction.

Scheme 2. Synthesis of aminoindanes via alkene carboamination

NH

CO2R

O

R

NH

O

RO2CR

•Pd/(S)-t-BuPHOX (1a)

CH2Cl2, 0 °C

8 9

OTfR R NR2+ amine

Pd/(S)-t-BuPHOX (1a)

LiO-t-Bu, PhMe, 95 °C10 11

up to 98% eeup to 98% yield


In 2017, Zhu used 1a and a stoichiometric amount of tetrahydroxy diboron-water as the hydride donor to effect an asymmetric intramolecular reductive Heck reaction of N-aryl acrylamides 12 to give 3,3-disubstituted oxindoles 13 (Scheme 3).19 Notably, the choice of ligand affected the reaction pathway: whereas PPh3 led to carboboration products, 1a gave the desired hydroarylation product 13.

Scheme 3. Synthesis of quaternary oxindoles via asymmetric

intramolecular reductive Heck reaction Recently, in an elegant extension of our work on asymmetric alkylation

of 3-halooxindoles,24 Bisai and co-workers disclosed the use of a Cu-1a catalyst to effect malonate addition onto 3-hydroxy 3-indolyl-2-oxindoles 14 (Scheme 4).21 It is thought that the copper catalyst facilitates a stereoablative elimination of water, followed by asymmetric addition of the malonate.

Scheme 4. Synthesis of quaternary dimeric oxindoles by malonate

addition onto 3-hydroxy-2-oxindoles

Lam discovered that a Nickel-PHOX catalyst comprised of 1a or (S)-PhPHOX effectively catalyzed the coupling of alkynyl malonate esters 16 with arylboronic esters in a desymmetrizing arylative cyclization (Scheme 5).23 The resulting cyclopentenone products 17 contain a synthetically challenging fully substituted olefin and a chiral quaternary center.

OTfNR

O

RR

NR

OPd/(S)-t-BuPHOX (1a)

B2(OH)4, H2O

DABCO, MeCN80 °C

RMe

R

13up to 90% yieldup to 94% ee

12

HN

O

HONH

XY + O

OR

O

OR

HN O

NHX

Y

O

OR

O

OR

Cu/(S)-t-BuPHOX (1a)

CH2Cl2, -5 °C

15Up to 92% yieldUp to 99% ee

14


Scheme 5. Synthesis of chiral cyclopentenones via nickel-catalyzed

desymmetrization of alkynyl malonate esters with arylboronic acids

With regard to allylic alkylation-type reactions, 1a and its electron deficient counterparts 5-7 have found extensive applications: After our initial reports on asymmetric decarboxylative protonation,25,26 the Guiry group has continued to expand the scope and understanding of this reaction. In one example in 2017, they utilized (S)-(CF3)3-t-BuPHOX (5) to enable the enantioselective synthesis of tertiary α -arylated indanones 19 (Scheme 6).27

Scheme 6. Synthesis of chiral tertiary α -aryl indanones using

decarboxylative protonation In 2017, Malcolmson introduced a method to synthesize chiral allylic

amines 21 through the intermolecular addition of aliphatic amines to acyclic 1,3-dienes 20 (Scheme 7).15 Here, the electron deficient PHOX ligand 6 was critical in achieving high regioselectivity for the desired 1,2-hydroamination product.

Scheme 7. Synthesis of allylic amines via diene hydroamination

Recently, You employed a Pd-7 catalyst in a dearomative formal [3+2]

cycloaddition of nitroindoles 22 and epoxybutenes 23 to synthesize chiral quaternary tetrahydrofuroindoles 24 (Scheme 8).14 Notably, the

O

O

O

O

CF3F3CR

Ar1

Ar2B(OH)2Ni/(S)-PhPHOX or(S)-t-BuPHOX (1a)

TFE, 80 °C Ar2

Ar1O

CO2CH2CF3

R

1716

OAr

O

OO

ArPd/(S)-(CF3)3-t-BuPHOX (5)

Meldrum’s acidTHF, 40 °C 19

up to 94% eeup to 95% yield

18

Ph + amine Ph Me

NR2Pd/(S)-(CF3)4-t-BuPHOX (6)

AgBF4, CH2Cl2, 22 °C20 21up to 91% yieldup to 92% ee


diastereoselectivity of this reaction was affected by the choice of solvent, with toluene and acetonitrile providing differing diastereomers.

Scheme 8. Synthesis of tetrahydrofuroindoles via dearomative formal

[3+2] cycloaddition of nitroindoles and epoxybutenes

Along with the Trost laboratory and others, our group has pioneered the development of transition metal-catalyzed decarboxylative asymmetric allylic alkylation reactions to generate quaternary stereocenter-containing compounds. Following our initial efforts on cycloalkanone systems using (S)-t-BuPHOX,28,29 we have extended the reaction to a wide range of cyclic substrates important in pharmaceuticals and natural product synthesis (Table 1).30–35 This versatile methodology now enables the synthesis of chiral disubstituted carbocycles of ring size four to eight, “Mannich” adducts, and heterocycles. Especially in the case of lactam systems 29-36, the electron deficient ligand 5 was hypothesized to generate a more reactive palladium catalyst and was required to achieve high levels of asymmetry.

NBoc

NO2O

RRNBoc

O2N

R O

R

Pd/(S)-(CF3)4(F)-t-BuPHOX (7)

Cs2CO3, PhMert 24

up to 98% yieldup to 98% eeup to 93/7 dr

+

22 23


Table 1. Chiral α -disubstituted carbocycles and lactams accessible by decarboxylative allylic alkylation

a(S)-t-BuPHOX (1a) instead of (S)-(CF3)3-t-BuPHOX (5)

Furthermore, in an effort to reduce catalyst loadings to facilitate

industrial scale applications, we developed a low-catalyst loading method employing Pd(OAc)2 instead of the usual zero-valent palladium source (Scheme 9).36 With this protocol, catalyst loadings as low as 0.075 mol %, corresponding with turnover numbers (TON) of up to 1320, could be used while still providing yields and ee’s up to 99%.

BzN

O

O

NBn

O NHBoc

BzNNBn

O Me

BzNO

O O

BzNO

Me

Ph

26reference 28

27reference 29

30reference 31

29reference 31

BzN

OF

31reference 31

N

OO

MeO

BzN

O

32reference 31

O

34reference 32

35reference 32

Cl

33reference 33

N

O

36reference 31

O

BnO

O Me

CN

28a

reference 30

O Et

BuOiCl

25a

reference 26, 27

X

O RO

OPd/(S)-(CF3)3-t-BuPHOX (5)

solvent, tempnX = CH2, Nn = 1, 2, 3, 4

X

O R

R RUp to 99% yieldUp to 99% ee

CO2Me


Scheme 9. Low-palladium loading protocol for decarboxylative allylic

alkylation

Most recently in 2018, we extended the scope of decarboxylative allylic alkylation toward challenging acyclic substrates by reporting the first asymmetric decarboxylative alkylation of fully substituted acyclic enol carbonates to provide linear α -quaternary ketones 38, again employing electronic deficient PHOX ligand 5 (Scheme 10).37,38 Of particular interest, the same enantiomer of product was obtained with comparably high ee regardless of the E/Z ratio of the starting material, suggesting a possible dynamic kinetic enolate equilibration during the reaction.

Scheme 10. Synthesis of acyclic α -quaternary ketones using

decarboxylative alkylation

PHOX ligands in Natural Product Synthesis As a testament to the versatility of allylic alkylation-type reactions,

recent total syntheses that utilize PHOX ligands do so heavily in the context of transition-metal catalyzed allylic alkylations and protonations. For instance, in Takemoto’s 2014 synthesis of the tricyclic alkaloid (–)-aurantioclavine (39), 1a was used in an intramolecular allylic amination of allyl carbonate 37 to generate an unusual seven-membered azepane 38 (Scheme 11).39

Pd(OAc)2 0.075 - 0.50 mol %PHOX ligand (0.75 - 5.0 mol %)

MTBE, 40 - 60 °CX = CH2, N

n = 1, 2

X

O

OMe

n

O

X

O Me

n

Ar

OR

Ar

O

O Pd/(S)-(CF3)3-t-BuPHOX (5)

3:1 hexane/toluene, 25 °C Ar

O

Ar

R

37 38up to 99% yieldup to 92% ee


Scheme 11. Total synthesis of (–)-aurantioclavine via allylic amination

Similarly, in 2012 and 2014, we used a series of powerful allylic

alkylations to intercept chiral gem-disubstituted cyclic intermediates 41, 44, and 47 en route to the formal syntheses of seven natural products including (–)-thujopsene (42), (–)-quinic acid (45), and (+)-rhazinilam (48) (Scheme 12).33,40

Scheme 12. Formal syntheses of diverse natural products via allylic

alkylation

Decarboxylative protonation has also found utility in natural product synthesis. In route to a 2014 catalytic enantioselective formal synthesis of

NO2

HN

39(–)-aurantioclavine

NO2

OCO2Me

CO2iPr

NHTsPd cat.

(S)-t-BuPHOX (1a)

Bu4NClCH2Cl2, rt

NH

HN

CO2iPr

3877% yield95% ee

37

O

4194% yield91% ee

42(–)-thujopsene

O O

O CO2HHO

OHOH

HO

45(–)-quinic acid

4483% yield92% ee

BzN

O

4797% yield99% ee

HNO

N

Et

48(+)-rhazinilam

O O

O Pd/(S)-t-BuPHOX (1a)

THF, 23 °C

40

O O

OTES

43

BzN

O

OEt O

46

Pd/1a

PhMe, 25 °C

diallyl carbonate

Pd/5

PhMe, 40 °C


the hexacyclic caged indole alkaloid (–)-aspidofractinine (51), Shao used 1a in an enantioselective decarboxylative protonation reaction to forge C3-monosubstitutions on medicinally important carbazolone heterocycles 50 (Scheme 13).41 Later in 2017, Robinson and co-workers also used 1a in a decarboxylative protonation protocol to make α -substituted ketone 53, which was then divergently advanced toward the spirocyclic marine alkaloids (–)-fasicularin (54) and (–)-lepadiformine (55).42

Scheme 13. Total syntheses of (–)-aspidofractinine, (–)-lepadiformine,

and (–)-fasicularin using decarboxylative protonation

Most of the remaining recent examples of PHOX ligands 1a and 5-7 in total synthesis have been found in the context of decarboxylative allylic alkylation toward the synthesis of indole alkaloid natural products (Scheme 14).43 For example, vinylogous ether 56, prepared from a (S)-t-BuPHOX (1a)-catalyzed allylic alkylation, can be advanced to (–)-aspidospermidine (57) in a formal total synthesis.40 Similarly, the familiar gem-disubstituted lactam 47 serves as an intermediate in the formal syntheses of (+)-quebrachamine (60) and (–)-vincadifformine (61).40 In 2014, Mukai synthesized the pentacyclic indole (+)-kopsihainanine A (59) utilizing (S)-(CF3)3-t-BuPHOX (5) in a decarboxylative alkylation to generate lactam intermediate 58.44 Notably, (+)-kopsihainanine A was previously independently synthesized by both Shao and Lupton in 2013, who also also utilized decarboxylative alkylation to synthesize a structurally distinct carbazolone intermediate.45,46 In 2016,

OO

O

C6H13OTBS

O

C6H13

OTBSPd/1aMeldrum’s Acid

1,4-Dioxane 13 °C

N

HO

C6H13

55(–)-lepadiformine A

NC6H13

NCS

54(–)-fasicularin

NBn

O

O

O

CONH2NBn

OCONH2

Pd/(S)-t-BuPHOX (1a)

PhMe, 80 °C

O

OMe

O

NBn

N

51(–)-aspidofractinine

5092% yield88% ee

49

5382% yield8:1 dr

52


Scheme 14. Decarboxylative allylic alkylation in the total synthesis of

indole alkaloid natural products Zhu accomplished the syntheses of indole alkaloids (–)-rhazinilam (63), (–)-leucomidine B (64), and (+)-leuconodine F (65) via a divergent route from quaternary cyclopentanone 62, which was synthesized via allylic alkylation using ligand 1a.47 Ligand 5 was again utilized to obtain the dihydropyrido[1,2-a]indolone (DHPI) scaffold 66, which was crucial in our 2016 and 2017 total and formal syntheses of five indole alkaloids, (+)-

BzN

O

BocN N

H

NO

HO

H

59(+)-kopsihainanine A

5882% yield98% ee

OEt

HNO

N

Et

63(–)-rhazinilam

HN N

O

Et

MeO2C

H

64(–)-leucomidine B

NN

OOH

O

Et

65(+)-leuconodine F

6287% yield86% ee

N

O R5NH

NO

HO

H

59(+)-kopsihainanine A

NH

N

HO

67(+)-limaspermidine

R4

NH

N

Et

NH

N

Et

69(+)-aspidospermidine

68(–)-quebrachamine

N

HNH

Et

OH

70(–)-goniomitine

NBoc

O

ON

Br

NH

NOH

O N

N

74(–)-isokopsine

N

NO

CO2MeMeO2C

73(+)-methyl chanofruticosinate

N

NO

OH

MeO2C

72(–)-fruticosine

7191% yield94% ee

75 (–)-kopsine: R6 = CO2Me, R7 = OH76 (–)-kopsanone: R6, R7 = H

R7

O

R6

66

BzN

O

4797% yield99% ee

NH

N

Et

60(+)-quebrachamine

61(–)-vincadifformine

NH

N

CO2Me

EtH

O

O57

(–)-aspidospermidine 5682% yield86% ee

NH

N

Et


limaspermidine (67), (+)-kopsihainanine (59), (–)-quebrachamine (68), (+)-aspidospermidine (69), and (-)-goniomitine (70).48,49 Most recently, Qin in 2017 leveraged ligand 1a to synthesize the quaternary indole 71, paving the way to a divergent synthesis of five Kopsia indole alkaloids: (–)-fruticosine (72), (+)-methyl chanofruticosinate (73), (–)-isokopsine (74), (–)-kopsine (75), and (–)-kopsanone (76).50

Finally, in 2018 Li and co-workers reported an asymmetric synthesis of the pentacyclic anti-tumor alkaloid (–)-cephalotaxine (79) using decarboxylative alkylation on allyl enol carbonate precursor 77.51 Here, they utilized ligand 5 to attain 78 with high enantioselectivity; in contrast, (S)-t-BuPHOX (1a) provided the desired product in only 80% ee.

Scheme 15. Total synthesis of (–)-cephalotaxine

These aforementioned natural product syntheses highlight the

impressive synthetic versatility of enantioselective allylic alkylation reactions facilitated by PHOX ligands. Especially in the cases of indole alkaloid syntheses, decarboxylative alkylation was used to synthesize a range of structurally diverse quaternary stereocenter-bearing intermediates, which were advanced toward the desired natural products. Additionally, electron-deficient variants of (S)-t-BuPHOX (1a) such as (S)-(CF3)3-t-BuPHOX (5) have demonstrated superior efficacy in many instances, and are likely to find even wider use in the future, especially toward the synthesis of novel all-carbon quaternary stereocenter-bearing scaffolds using decarboxylative asymmetric allylic alkylation methodologies. The PHOX ligand class has shown extensive versatility in various transition-metal catalyzed asymmetric transformations, thus enabling access to novel and biologically important chemical space. Their modular nature ensures the continual development of new electronically and sterically modified versions with even greater catalytic potential.

O O

N

O

O OO

O O

N

O

OPd/(S)-(CF3)3-t-BuPHOX (5)

MTBE, 40 °C

O O

N OMe

OHH

79(–)-cephalotaxine

7882% yield98% ee

77

Org. Synth. 2018, 95, 439-454 DOI: 10.15227/orgsyn.095.0439451

References

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Alexander W. Sun was born in Eugene, OR in 1990 and obtained his B.A. and M.Sc. in Chemistry in 2012 from the University of Pennsylvania, having worked in the laboratories of Amos B. Smith, III and David R. Tyler. He then matriculated into the UCLA-Caltech MD/PhD program, where he is currently a 5thyear Ph.D. candidate in the laboratory of Brian M. Stoltz. His research focuses on asymmetric catalysis and medicinal chemistry.


Brian M. Stoltz was born in Philadelphia, PA in 1970 and obtained his B.S. degree from the Indiana University of Pennsylvania in Indiana, PA. After graduate work at Yale University in the labs of John L. Wood and an NIH postdoctoral fellowship at Harvard with E. J. Corey, he took a position at the California Institute of Technology. A member of the Caltech faculty since 2000, he is currently Professor of Chemistry. His research interests lie in the development of new methodology for general applications in synthetic chemistry.

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Discussion Addendum for: Preparation of (S)-tert-ButylPHOX ...orgsyn.org/Content/pdfs/procedures/v95p0439.pdf · 6/11/2018 · R N H O RO2C R • Pd/(S)-t-BuPHOX ... .30–35 This