123 3.6.14 Organometallic Complexes of Gold (Update 1, 2012)123 3.6.14 Organometallic Complexes of Gold (Update 1, 2012) M. J. Campbell and F. D. Toste 3.6.14.1 Asymmetric Gold-Catalyzed

123

3.6.14 Organometallic Complexes of Gold (Update 1, 2012)

M. J. Campbell and F. D. Toste

3.6.14.1 Asymmetric Gold-Catalyzed Transformations

Homogeneous gold catalysis has seen tremendous developmental growth over the past 10years. The seminal reports documenting its potential utility were just appearing at thesame time as catalysis using other main-block transition metals was maturing, researchfor which the Nobel Prize was awarded in 2001, 2005, and 2010. Gold salts were initiallythought to be largely devoid of catalytic activity and were initially overlooked becausethey do not readily cycle through oxidation states within a system; indeed, this prohibitsmost catalysis that requires oxidative addition and reductive elimination processes. How-ever, it also provides orthogonal reactivity relative to other metals and permits an array ofunique transformations. Secondly, an initial lack of asymmetric gold-catalyzed reactionsraised debate as to whether ligands could be identified that overcome the natural limita-tions of the linear geometry of gold(I). Further research has now affirmed that common li-gand scaffolds are often suitable, but the challenges have resulted in some unusual solu-tions. For example, the first highly enantioselective catalysis using chiral counterionshas been reported using gold(I).

Simple gold(I) and gold(III) halides were used in the earliest examples of homogene-ous gold catalysis, but properties such as poor solubility in organic solvents and catalystinstability led researchers to investigate the use of ligands, typically phosphines forgold(I) and polydentate ligands such as porphyrins for gold(III).[1–5] The use of cationic out-er-sphere complexes, generated by protonation of alkylgold species or anion metathesisof gold halides with a suitable silver salt, revolutionized the field by enhancing the Lewisacidity of the gold metal center, permitting the development of new transformations.Soft yet highly electrophilic 12-electron [Au(L)]+ species allow the selective activation ofalkenes, allenes, and especially alkynes over functional groups within the substrate orsolvent containing hard Lewis basic sites. Furthermore, gold catalysts are not easily oxi-dized by molecular oxygen. Thus, the use of rigorously dry and oxygen-free reaction con-ditions is rarely necessary. Recent research efforts in homogeneous gold catalysis havebeen able to identify reactions that display a diverse chemistry including Lewis acidic ac-tivation of heteroatoms, carbenoid chemistry, and even cross couplings. However, activa-tion of C-C p-bonds toward heteroatom and carbon nucleophiles is by far most preva-lent.

In the context of asymmetric reactions, there are three manifolds within alkyne p-ac-tivation chemistry that have been exploited to date: reaction with protic heteroatom nu-cleophiles, reaction with tethered p-systems, and the rearrangement of propargyl carbox-ylate esters (Schemes 1–3). The reaction with protic nucleophiles (Scheme 1) is straight-forward. After nucleophile addition to afford an intermediate vinylgold species, protontransfer occurs to release the catalyst. The analogous addition to alkenes and allenes cre-ates a center of chirality directly, but when alkynes are used the site of addition does notbecome a stereocenter. However, the desymmetrization of suitably engineered substratesenables reactions with alkynes to be rendered asymmetric. Reaction of an alkene (typical-ly intramolecularly) with a cationic gold(I)–alkyne complex initially generates a homoal-lylic cation, which can also be represented as a gold carbenoid stabilized cyclopropane(Scheme 2). Several pathways are available dependent on the structural features of thesubstrate and the reaction conditions. The carbocation can be trapped with an exogenous

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124 Science of Synthesis 3.6 Organometallic Complexes of Gold

nucleophile (path a) or converted into an alkene by the elimination of an adjacent proton(path b). Alternatively, the gold carbenoid can undergo a 1,2-hydride shift with concur-rent elimination of the gold cation to form a vinylcyclopropane (path c). Propargyl carbox-ylates are a convenient source of gold carbenoids, obtained through a 1,2-carboxylate mi-gration and p-bond reorganization (Scheme 3). The electrophilic gold carbenoids exhibitreactivity analogous to other late transition metal carbenoids. They can react with al-kenes to prepare cyclopropanes or be trapped by nucleophiles to afford cationic alkylgoldspecies that undergo further reaction. These prototypical reactivity patterns are influ-enced substantially by the nature of the ligand bound to the gold(I) center, especially forreactions of the type shown in Scheme 2.

Scheme 1 Typical Reactivity Patterns for Cationic Gold Catalysts: Activation of Alkynestoward the Addition of Protic Nucleophiles

R1 R1

Au(L)

NuH

(L)Au

R1 Nu

R1

H

H

R1 Nu

R1

Scheme 2 Typical Reactivity Patterns for Cationic Gold Catalysts: Activation of Alkynestoward the Addition of Alkenes

(L)Au R1R2

R3

R1R2

R3

R1R2

R3

H

R1R2

R3

R1

Au(L)

path a

path b

path c

(L)Au R1R2

H

R3

NuH

(L)Au R1R2

H

R3

(L)Au R1R2

H

R3

Nu

R3

R2+


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1253.6.14 Organometallic Complexes of Gold (Update 1)

Scheme 3 Typical Reactivity Patterns for Cationic Gold Catalysts: Rearrangement ofPropargyl Carboxylates

Au(L)

O

OOO

(L)Au

R2

R1 O

O

(L)Au

R2

R1 O

O

R2

R1 O

O

(L)Au

Nu

cyclopropanation

nucleophilic addition

R5

R4 R6

R3

R5

R6

R3

R4

R1

R2

R1

R2

The identification of suitable ligands for asymmetric gold catalysis was not a trivial ac-complishment for early researchers within the field.[6–9] Although the same statement isbroadly true for any metal, it was unknown if the established classes of chiral ligandswould effectively parlay stereochemical information within the two-coordinate linear ge-ometry of gold(I). Because of its inability to form chelates with typical bidentate ligands, itis fairly surprising that these ligands, especially bisphosphines 1–9 (Scheme 4), whichwere developed in the context of metals that do form chelates, have proven competentfor a number of gold(I)-catalyzed transformations. Although a number of biaryl scaffoldshave been used (BINAP, SEGPHOS, BIPHEP, etc.), some general trends have been estab-lished regarding ligand selection. The most often used ligand, applicable to both enantio-selective carbon-carbon and carbon-heteroatom bond-forming reactions, is DTBM-MeO-BIPHEP (3, R1 = 3,5-t-Bu2-4-MeOC6H2), though SEGPHOS and BIPHEP ligands containingsimilar bulky P-aryl groups often exhibit similar selectivities. Ligands bearing unsubsti-tuted phosphorus-bound phenyl rings are, with some exceptions, only useful for hydroal-koxylations and hydroaminations. There has been some effort to reconcile crystal struc-tures solved for the various digold complexes with the selectivities imparted; however,drawing an analogy between solid- and solution-state conformations is tenuous at best.In particular, three related digold biaryl bisphosphine complexes {[Au2Cl2(DM-BINAP)],[Au2Cl2(DTBM-MeO-BIPHEP)], and [Au2Cl2(C1-TunaPhos)]} that display similar reaction effi-ciencies and selectivities have drastically different conformations in the solid state.[10] Fur-thermore, the conformation of the catalytically active species likely changes dependingon the reaction parameters such as solvent, identity of the weakly coordinating counter-ion, equivalents of the silver salt (mono- vs dicationic digold complex), and even on thenature of the transformation sought.





Scheme 4 Chiral Ligands and Counterions Successfully Used with Gold(I)

PR12

PR12

PR12

PR12

O

O

O

O

MeO

MeO

PR12

PR12

(R)-1 BINAP (R1 = Ph) R1 = 4-Tol

R1 = 3,5-Me2C6H3 R1 = Cy

(R)-2 SEGPHOS (R1 = Ph) R1 = Cy

R1 = 3,5-t-Bu2-4-MeOC6H2

(R)-3 MeO-BIPHEP (R1 = Ph) R1 = 3,5-t-Bu2-4-MeOC6H2 R1 = 3,5-t-Bu2C6H3 R1 = 3,5-Me2C6H3

O

OPPh2

PPh2 PPh2

PPh2

O

O

O

O

F

F

F

F

(R)-4 C1-TunaPhos (R)-5 DIFLUORPHOS

P

P

(R,R)-6 (R,R)-Me-DuPhos

8

PP

Ph

PhOMe

MeO

(S,S)-7 9 R1 = Me, Et

PP 2

2

Fe PPh2

PPh2

NMe NR12

O

O

R1

R1

PO

O

P

MeO

MeO

(R,R,R,R)-12(R,R,R)-11 R1 = 9-anthryl, pyren-1-yl

PPh2

NH

SO

Pri

Pri

Pri

(S,S)-10

N

Ph

PhN

Ph

Ph

ButBut

But

But

O

O

O

O

O

(R)-14(R,R,R)-13

O

OP N

Ph

Ph

3

P




NN

Ph

(S,S)-15

NN

PhPh

HH

16

Ph OO

NN

NN

Mes Mes

(S,S)-17

O

OP

O

O

(R)-19

NH

N

NHN

HNHN

(R)-18

CF3

F3C

Pri Pri

Pri

Pri

PriPri

Because only a single coordination site is available for a chiral ligand, it is not surprisingthat monodentate ligands such as chiral phosphoramidites (e.g., 11–13), phosphites(e.g., 14), and N-stabilized carbenes (e.g., 15–18) have emerged as important ligands forasymmetric gold catalysis. Echavarren first used a simple BINOL-derived phosphorami-dite ligand in 2005, with little success,[11] but more complex BINOL- and TADDOL-derivedligands have been established of late as being capable of providing high selectivities.The variety of selective N-heterocyclic carbene ligands is lacking compared to phosphinesand phosphoramidites, but initial reports are promising. Specifically, the Toste group hasrecently reported a new class of biaryl bis(N-stabilized carbenes) (e.g., 18) that are able tocyclize propargyl phenolic esters into benzopyranyl pivalates with mostly >90% ee.[12]

Still, further research with N-stabilized heterocyclic carbenes is of paramount impor-tance in asymmetric gold catalysis. Their development is not merely an esoteric pursuit;the field will benefit when effective phosphines, phosphoramidites, and N-heterocycliccarbenes are all available because of their varying electronic properties (s-donating andp-accepting). Ligand electronics have been shown to affect reactivity and selectivity in sys-tems where several mechanistic pathways can operate;[13] therefore, ligands from the var-ious classes are needed to obtain both the desired reactivity as well as facial selectivity. Fi-nally, the first examples of highly enantioselective catalysis using the chiral biaryl phos-phate 19 to form C-O and C-N bonds has been reported using gold(I) via ion-pair interac-tions with organogold(I) intermediates.

The future for asymmetric gold catalysis is certainly very bright. Because of themounting number of examples available from which current researchers can draw analo-gy and gain inspiration, it is often feasible for enantioselective conditions to be identifiedwithin a short period of time. There remains significant room for innovative ligand andreaction design, as certain transformations have not been rendered highly facially selec-tive using the available pool of ligands. However, the rapidly maturing development ofphosphoramidites and the recent disclosure of a novel BINOL-derived bis(N-stabilized car-bene) scaffold discussed in the sections below are evidence that the community is andwill continue to be able to quickly provide solutions to these challenges. It remains to beseen if additional chiral anions will be developed in order to provide an alternative tophosphate 19 in circumstances where it is not suitable. Biaryl bissulfonates have been re-ported, but do not yet provide comparable selectivities.[14] It is of fundamental importance





that reliable models are developed to account for the often drastically variable efficaciesof seemingly similar ligands. Given that the known solid-state conformations are likelynot retained in solution, this is a clear opportunity to demonstrate the power of computa-tional methods. The development of an understanding of the subtle interplay betweenthe variables of ligand substituents, counterions, and solvents could establish a protocolfor proper ligand selection and design beyond the current system of trial and error.

3.6.14.1.1 Asymmetric Gold(I)-Catalyzed Transformations Proceeding via Initial Alkynep-Activation

3.6.14.1.1.1 Cycloisomerization Reactions

Cationic gold(I) salts are powerful carbophilic p-acids, capable of activating alkynes, al-lenes, and even alkenes toward intra- and intermolecular nucleophilic attack. This ismost common with heteroatomic nucleophiles, but attack by relatively weak nucleo-philes such as arenes and even simple alkenes can occur, especially intramolecularly, toprovide cycloisomerization and formal cycloaddition products. Although a multitude ofpathways are available, selectivity can be achieved through the use of specific substitu-tion patterns (often in order to stabilize a particular transient carbocation), conformation-al constraints, and proper ancillary ligand selection. The variety of cycloisomerizationproducts that are accessible has resulted in this chemistry emerging as a particularlyrich area of development within homogeneous asymmetric gold catalysis.

3.6.14.1.1.1.1 Method 1:Cycloisomerizations of 1,6-Enynes

The gold(I)-catalyzed cycloisomerization of 1,6-enynes can form five-membered carbo- orheterocycles and six-membered carbocycles in the presence of an external or internal nu-cleophile, and bicyclo[4.1.0]heptenes in the absence of a nucleophile. Specifically, alco-hols and indoles have been used to trap the putative carbocation obtained upon attackof the pendant alkene upon the gold–alkyne coordination complex. Complete diastereo-control has been observed when the site of nucleophilic attack is a center of chirality,which is evidence against an intermediate planar and freely rotating carbocation. Twomodels have been proposed to explain this stereochemical result (see Table 1): (1) C-Cbond formation between the alkyne and alkene occurs in a concerted fashion with C-Cor C-O bond formation between the exogenous nucleophile and the alkene; this modelis analogous to the Stork–Eschenmoser hypothesis used to rationalize the stereoselectivi-ty observed in steroid biosynthesis; or (2) an initial gold-catalyzed reaction occurs to forman intermediate gold carbenoid stabilized bicyclo[3.1.0]hexane, which undergoes ringopening of the cyclopropane by the nucleophile with inversion of configuration at theelectrophilic carbon.

3.6.14.1.1.1.1.1 Variation 1:5-exo-dig Cyclization

Initially, the Echavarren group examined a diverse range of ligands including ferrocene-containing ligands (Josiphos, Walphos, Taniaphos, etc.), binaphthol-derived bisphos-phines and monophosphines, as well as a simple phosphoramidite.[11] The use of the ferro-cene class was presumably an attempt to use precedent from the gold-catalyzed aldol re-actions developed in the late 1980s by Ito, Hayashi, and others using bisphosphineamines.[15] An attractive electrostatic interaction between an ammonium moiety in the li-gand and the enolate (and not the axial chirality of the bisphosphine) has been proposedto be responsible for the high enantioselectivities observed in the aldol reactions. The




lack of an analogous interaction in the cycloisomerization of 1,6-enynes and other gold-catalyzed reactions proceeding via p-activation mechanisms may explain the negligibleselectivities imparted by ferrocene-derived amino bisphosphines. The ligand (R)-Tol-BI-NAP [(R)-1, R1 = 4-Tol] was identified through the screening to provide a bissulfone in 94%ee (Table 1, entry 1), but is generally not suitable for other substrate classes. Similar cyclo-pentanes were prepared in only 36 and 2% ee (entries 2 and 3), respectively.

Developments within gold(I)-catalyzed cyclopropanation chemistry (vide infra) haveestablished that bisphosphine ligands bearing sterically bulky and electron-rich P-arylsubstituents can create the chiral environment surrounding the gold metal center thatis requisite for asymmetric catalysis. The use of a ligand representative of this class, (R)-DTBM-MeO-BIPHEP [(R)-3, R1 = 3,5-t-Bu2-4-MeOC6H2], allows cycloisomerization of 1,6-enynes using an arene as the terminating nucleophile to proceed with high enantioselec-tivity.[16] Again, complete diastereoselectivity is reported. Both isopropyl diesters (entry 6)and phenyl bissulfones within the tether are tolerated with similar efficacies. The use ofsmaller methyl and benzyl diesters causes a slight decrease of enantioselectivity thoughee values >80% are still achieved (compare entries 5 and 7 to entry 6). Removal of the fullysubstituted carbon atom within the tether, as in the use of an ether, results in only 53% eein the tetrahydrofuran product (entry 8). A pendant terminating arene nucleophile can beused as in the production of a tricyclic diester (entry 9).

In an application of the chiral N-heterocyclic carbene ligand (S,S)-15 to gold-catalyzedC-C bond formation, Tomioka has prepared a diester with a promising 54% ee (entry 4).[17]The use of 2,5-dimethylphenyl groups greatly impacts selectivity; the corresponding li-gand containing unsubstituted phenyl rings provides only 8% ee. Based upon these re-sults, a model has been proposed in which two of the four arenes are projected aroundthe gold center and partially surround the open coordination site. The 2,5-dimethyl sub-stituents are necessary to provide additional steric bulk for enhanced interaction withthe substrate.





Table 1 Asymmetric 5-exo-dig Cycloisomerizations of 1,6-Enynes[11,16,17]

X

R3R4

R2

X

R3

R4Nu

Au(L∗)

X

(L∗)Au R2

R2

R4

R3

NuH

AunCln(L)

NuH, AgX

AunCln(L)

NuH, AgX

XR2

R3

R4NuH

Entry Substrate Conditions Product Yield(%)

ee(%)

Ref

1

PhO2S

PhO2S Ph

Au2Cl2[(R)-1 (R1 =

4-Tol)] (1.6 mol%),AgSbF6 (2.0 mol%),MeOH, rt

PhO2S

PhO2S

OMe

Ph

H 52 94[11]

2PhO2S

PhO2S

Ph Au2Cl2[(R)-1 (R1 =

4-Tol)] (1.6 mol%),AgSbF6 (2.0 mol%),H2C=CHCH2OH, rt

MeO2S

MeO2S

O

Ph

H46 36 [11]

3

MeO2C

MeO2C

Au2Cl2[(R)-1 (R1 =

4-Tol)] (1.6 mol%),AgSbF6 (2.0 mol%),MeOH, rt

MeO2C

MeO2C

OMeH 91 ca.

2

[11]

4MeO2C

MeO2C

AuCl[(S,S)-15](6.0 mol%), AgSbF6(6.0 mol%), MeOH, rt

MeO2C

MeO2C

OMeH 95 54 [17]

5

MeO2C

MeO2C

PhAu2Cl2[(R)-3 (R

1 =3,5-t-Bu2-4-MeOC6H2)](3.0 mol%), AgOTf(6.0 mol%),1-methyl-1H-indole,Et2O, rt

MeO2C

MeO2C

Ph

MeN

H

99 83 [16]

6

PriO2C

PriO2C

PhAu2Cl2[(R)-3 (R


PriO2C

PriO2C

Ph

MeN

H

94 95 [17]




Table 1 (cont.)

Entry Substrate Conditions Product Yield(%)

ee(%)

Ref

7 BnO2C

BnO2C

PhAu2Cl2[(R)-3 (R


BnO2C

BnO2C

Ph

MeN

H 99 81 [16]

8

O

O

O Au2Cl2[(R)-3 (R1 =

3,5-t-Bu2-4-MeOC6H2)](3.0 mol%), AgOTf(6.0 mol%),1-methyl-1H-indole,Et2O, rt

OO

O

MeN

H

99 53 [17]

9MeO2C

MeO2C

Au2Cl2[(R)-3 (R1 =

3,5-t-Bu2-4-MeOC6H2)](3.0 mol%), AgOTf(6.0 mol%), CH2Cl2, rt

MeO2C

MeO2C

99 93a [16]

a Configuration of product not determined.

Cyclopentanes and Tetrahydrofurans (Table 1, Entries 5–9); General Procedure:[16]

AgOTf (6 mol%) was added to a 0.01 M soln of Au2Cl2[(R)-3 (R1 = 3,5-t-Bu2-4-MeOC6H2)](3 mol%) in anhyd Et2O or CH2Cl2, and the mixture was stirred for 30 min. The aromaticnucleophile (3 equiv), when appropriate, was added, followed by the correspondingenyne (1 equiv). The resulting mixture was stirred until the starting material was com-pletely consumed. The mixture was then filtered through a short pad of silica gel to re-move the catalyst (EtOAc), and the solvents were evaporated under reduced pressure.The crude product was purified by flash chromatography (silica gel, petroleum ether/EtOAc 90:10 to 70:30) if necessary.

3.6.14.1.1.1.1.2 Variation 2:6-endo-dig Cyclization

The examples of cycloisomerizations of 1,6-enynes discussed in Section 3.6.14.1.1.1.1.1proceed through a 5-exo-dig pathway, but systems have also been developed to provideproducts derived from initial 6-exo-dig and 6-endo-dig cyclizations. In an isolated example,the reaction of alkylidenecyclopropane 20 yields tetracycle 21 in good enantioselectivityusing the spiro ligand 8 (Scheme 5).[18] This ligand has not been applied subsequently ingold catalysis. The reaction proceeds via a 6-exo-dig cyclization to afford a gold(I)-stabi-lized cyclopropylcarbinyl cation, followed by ring expansion to a cyclobutyl cation thatis finally trapped through a Friedel–Crafts reaction with the pendant arene. The prefer-ence for 6-exo rather than 5-exo can be explained by formation of the more stable cyclo-propylcarbinyl cation, rather than the corresponding cyclopropyl cation.





Scheme 5 Cycloisomerization of an Alkylidenecyclopropane[18]

5 mol% Au2Cl2[(R)-8]

5 mol% AgSbF6CH2Cl2, rt

I

2120

82% ee

I

EtO2C

EtO2C

EtO2C

EtO2C

This strategy has been further applied to the synthesis of bi-, tri-, and tetracycles from 1,6-enynes and 1,6,11-dienynes through a polycyclization cascade reaction in which variableterminating nucleophiles, including acids, amides (Table 2, entry 1), aromatic rings (en-tries 2 and 4), and phenols (entry 3), are tolerated equally well.[19] These reactions all pro-ceed via 6-exo-dig cyclizations, which is again favored by the substrate substitution pat-tern; a tertiary carbocation is formed by 6-exo-dig, whereas a less stable secondary carbo-cation would be formed via 5-exo-dig. The relative stereochemistry found in the productscan be explained by invoking the Stork–Eschenmoser postulate,[20,21] in which extendedchair-like conformations are adopted by the acyclic substrate prior to cyclization. The bul-ky ligand (R)-DTB-MeO-BIPHEP [(R)-3, R1 = 3,5-t-Bu2C6H3] is optimal, in conjunction with ar-omatic solvents. With regards to aromatic solvents, higher selectivities are obtained withincreasing solvent polarity (m-xylene > toluene > benzene). Indicative of the often ex-treme differences observed in asymmetric gold catalysis using similar biaryl bisphos-phine backbones, (R)-DTBM-SEGPHOS (2, R1 = 3,5-t-Bu2-4-MeOC6H2) provided nearly race-mic products during optimization studies.




Table 2 Gold(I)-Catalyzed Polycyclization Cascade of 1,6-Enynes and 1,6,11-Dienynes[19]

XHn

EtO2C

EtO2C

3 mol% Au2Cl2(L)

3 mol% AgSbF6m-xylene, rt

X

H

H

X

H

L = (R)-DTB-MeO-BIPHEP [(R)-3, R1 = 3,5-t-Bu2C6H3]

EtO2C

EtO2C

EtO2C

EtO2C

n = 1

n = 2

Entry Substrate Product Yield(%)

ee(%)

Ref

1

NHTsEtO2C

EtO2C 3

TsN

H

EtO2C

EtO2C 75 92 [19]

2

EtO2C

EtO2COMe

OMe H

MeO OMe

EtO2C

EtO2C 98 94[19]

3

EtO2C

EtO2COH

H

EtO2C

EtO2CO

H

50 88 [19]

42

EtO2C

EtO2COMe

OMeH

EtO2C

EtO2C

OMe

OMeH

61 97 [19]

An enantioselective cycloisomerization of 1,6-enynes proceeding via 6-endo-dig cycliza-tion to form bicyclo[4.1.0]heptenes has been reported by Michelet (Scheme 6).[22] Withthe exception that a nucleophilic trapping agent is not present, the reaction conditionsare similar to those used to prepare substituted cyclopentenes in terms of the ligand,counterion, and substrate substitution pattern (see Section 3.6.14.1.1.1.1.1). These simi-larities, especially regarding the substrates used, raise the possibility that the presenceof a nucleophile can directly affect the cyclization mode. The high yields obtained duringnucleophile-assisted 5-exo-dig reaction of 1,6-enynes suggest this mode of cyclization isfaster than the corresponding 6-endo-dig. However, in the absence of an irreversible trap-ping agent (external nucleophile or a proton susceptible to elimination), the intermediate





obtained by 5-exo-dig cyclization can revert to the starting material, which is convertedinto a gold carbenoid containing bicycle (Scheme 6). Irreversible 1,2-hydride shift and pro-todeauration then furnishes the product 22. This analysis is complicated by the pooryields observed in this reaction (24–74%) and the lack of information regarding the identi-ty of the major byproducts. Regardless, high enantioselectivities are obtained using bothoxygen (X = O) and sulfonamide (X = NTs) tethers.

Scheme 6 Gold(I)-Catalyzed Cycloisomerization of 1,6-Enynes in the Absence of anExternal Nucleophile[22]

3.0 mol% Au2Cl2(L)

6.0 mol% AgOTf

tolueneX

R3

R2

X

R2H

R3

X

R2H

R3

[Au]

22

L = (R)-DTBM-MeO-BIPHEP [(R)-3, R1 = 3,5-t-Bu2-4-MeOC6H2]

R2 R3 X Temp ( 8C) Yield (%) ee (%) Ref

Ph 4-O2NC6H4 O 0 39 96 [22]

Ph 3-BrC6H4 O 0 59 95 [22]

Ph Ph O 0 34 98 [22]

Ph 4-MeOC6H4 O 23 47 96 [22]

O

O

Ph O 0 51 90 [22]

Ph Et O 0 24 91 [22]

H Ph NTs 60 74 98 [22]

Polycycles (Table 2, Entries 1–4); General Procedure:[19]

AgSbF6 (3.3 mg, 3 mol%) was added to a soln of Au2Cl2[(R)-3 (R1 = 3,5-t-Bu2C6H3)] (0.8 mg,3 mol%) in m-xylene (300 mL) and the mixture was stirred for 15 min. The resulting suspen-sion was filtered through a glass microfiber plug directly into a soln of substrate(0.044 mmol) in m-xylene (600 mL), thorough mixing was ensured, and the resulting homo-genous soln was allowed to stand until such time as the substrate was fully consumed (asevident by TLC or 1H NMR analysis). Determination of the yield was made based on cali-bration with an internal standard (9-bromophenanthrene) prior to addition of catalyst.Upon consumption of the starting material, an aliquot containing ca. 4 mg of crude prod-uct was concentrated under a stream of N2 until a thick oil was obtained. This was dis-solved in benzene-d6 (100 mL) (CAUTION: carcinogen) and the soln was concentrated underflowing N2 (two cycles) to provide a residual oil free from excessive m-xylene, which wassubsequently analyzed by 1H NMR. The product was isolated in analytically pure form byconcentration of the mixture to a volume of ca. 100 mL and then elution through a shortcolumn (silica gel).




[4.1.0] Bicycles 22; General Procedure:[22]

AgOTf (6 mol%) was added to a 0.5 M soln of Au2Cl2[(R)-3 (R1 = 3,5-t-Bu2-4-MeOC6H2)](3 mol%) in distilled toluene, and the mixture was stirred for 30 min at rt. The enyne(1 equiv) was added, and the resulting mixture was stirred until the starting materialwas completely consumed (as evident by TLC). The mixture was filtered through a shortpad of silica gel, and then the solvent was removed under reduced pressure. The cruderesidue was purified by flash chromatography (silica gel, petroleum ether/EtOAc 98:2 to80:20) if necessary.

3.6.14.1.1.1.2 Method 2:Cycloisomerizations of 1,5-Enynes

The cyclization of 1-alkynyl-2-(prop-1-enyl)benzenes is known to provide naphthaleneproducts via 6-endo-dig reaction using cationic gold(I) salts, with good selectivity over thecompeting 5-exo-dig pathway. By altering the substitution pattern to stabilize the homo-benzylic carbocation (instead of the benzylic carbocation), the 5-endo-dig pathway can befavored (Scheme 7). Using (S)-DM-MeO-BIPHEP [(S)-3, R1 = 3,5-Me2C6H3], enantioenriched1-vinylindenes 23 can be synthesized with variable selectivity.[23] The addition of wateror an alcohol provides alcohols or ethers 24 by nucleophilic trapping of the carbocation.Selectivity is nearly independent of the trapping agent used, but the reaction is sensitiveto the identity of the terminal acetylenic substituent; a butyl substituent results in only20–30% ee.

Scheme 7 Cycloisomerization of 1,5-Enynes To Form Indene Derivatives[23]

5 mol% Au2Cl2(L)

10 mol% AgX

CH2Cl2, −30 oC

R3

R2

R3

R2

R4

R4

L = (S)-DM-MeO-BIPHEP [(S)-3, R1 = 3,5-Me2C6H3]

23

R2 R3 R4 X Yield (%) ee (%) Ref

Ph Me H OTs 81 82 [23]

3-thienyl Me H OTs 81 68 [23]

Bu Me H OTs 80 20 [23]

5 mol% Au2Cl2(L)

10 mol% AgX

R5OH (30 equiv)

CH2Cl2, −30 oC

R3

R4

R2

L = (S)-DM-MeO-BIPHEP [(S)-3, R1 = 3,5-Me2C6H3]

24

R2H

R4

R3

OR5

R2 R3 R4 X R5 Yield (%) ee (%) Ref

Ph Me Me SbF6 H 93 86 [23]

Ph Me Me OTs Me 99 88 [23]

3-thienyl Me Me SbF6 H 91 78 [23]





R2 R3 R4 X R5 Yield (%) ee (%) Ref

3-thienyl Me Me OTs Me 90 75 [23]

Bu Me Me SbF6 H 90 28 [23]

Bu Me Me OTs Me 88 30 [23]

Ph (CH2)4 SbF6 H 87 80 [23]

Ph (CH2)4 OTs Me 77 84 [23]

Indenes 23 and 24; General Procedure:[23]

AgSbF6 (5.1 mg, 10 mol%) or AgOTs (8.4 mg, 10 mol%) was added to a soln of Au2Cl2[(S)-3(R1 = 3,5-Me2C6H3)] (17.4 mg, 5 mol%) in dry CH2Cl2, and the mixture was stirred for 5–10 min and then cooled to –30 8C. The nucleophile (H2O or MeOH; 9 mmol, 30 equiv),when appropriate, was added, followed by a soln of the corresponding 2-alkynylstyrenederivative (0.3 mmol) in dry CH2Cl2. The resulting mixture was stirred until the startingmaterial was completely consumed (as evident by TLC or GC/MS analysis). The mixturewas diluted with hexanes and filtered through a pad of silica gel. The solvent was re-moved, and the crude residue was purified by flash chromatography (silica gel, hexanes/EtOAc).

3.6.14.1.1.1.3 Method 3:Cyclizations of 1,3-Enynes

An enantioselective cyclization/cycloaddition of a-alkynyl enones with nitrones has beenreported using either DTBM-MeO-BIPHEP (3, R1 = 3,5-t-Bu2-4-MeOC6H2) or C1-TunaPhos (4),with both giving similarly high yields and selectivities (Scheme 8).[10] Upon scale-up to5 mmol of 25, the catalyst loading can be reduced to 0.2 mol%, affording a nearly quantita-tive yield of bicyclic furan 26 while retaining high enantio- and diastereoselectivity. Theefficacy of C1-TunaPhos (4), containing only simple diphenylphosphino residues, is un-usual within C-C bond-forming reactions and merits further study when it is consideredthat bulky electron-rich P-aryl groups are typically required for biaryl bisphosphines inasymmetric gold(I) catalysis. A new, privileged ligand scaffold would be of great utility tothe emerging field. The solid state structure of the gold complex of ligand 4 exhibits agold–gold interaction, which had not been observed previously in the crystal structuresof other biaryl phosphines.

Scheme 8 Gold(I)-Catalyzed Intermolecular Tandem Cyclization/Cycloaddition of ana-Alkynyl Enone with a Nitrone[10]

0.2 mol% Au2Cl2[(R)-4]

0.2 mol% AgOTf

1,2-dichloroethane, 0 oC

26

Ph

Ph

O

NPh

Ph

O

+

NO

O Ph

Ph

Ph Ph

25

99.5%; 93% ee; dr >20:1

This reaction is hypothesized to occur in a stepwise process (Scheme 9). Initial gold-cata-lyzed cyclization of the enone affords an intermediate benzylic carbocation. The cationis first trapped by the nitrone in the enantiodetermining step, and then nucleophilic dia-stereoselective ring closure yields the 3,4-dihydro-1H-furo[3,4-d][1,2]oxazine with con-




comitant regeneration of the cationic gold catalyst. This reaction is mechanistically dis-tinct from the previously mentioned gold(I)-catalyzed reactions that proceed via initialp-activation of alkynes, where nucleophilic attack onto the alkyne is instead the enantio-determining step.

Scheme 9 Proposed Mechanism of Gold(I)-Catalyzed Intermolecular Tandem Cyclization/Cycloaddition of a-Alkynyl Enones with Nitrones[10]

Au(L)X

Ph

Ph

O

N

Ph

PhO

Au(L)X

O Ph

Ph

Au(L)X

O Ph

Ph

O N

Ph

Ph− Au(L)X NO

O Ph

Ph

Ph Ph

26

(1S,4R)-7-Methyl-1,3,4,5-tetraphenyl-3,4-dihydro-1H-furo[3,4-d][1,2]oxazine (26);Typical Procedure:[10]

AuCl•DMS (6 mg, 0.02 mmol) was added to a soln of C1-TunaPhos [(R)-4; 6 mg, 0.01 mmol]in CH2Cl2 and the mixture was stirred at rt for 2 h, after which the solvent was removedunder reduced pressure. A soln of AgOTf (3 mg, 0.01 mmol) in 1,2-dichloroethane (10 mL)was then added to the residue, and the mixture was stirred at 0 8C for 15 min. A soln of ke-tone 25 (1.25 g, 5.0 mmol) and N-benzylideneaniline oxide (1.09 g, 5.5 mmol) in 1,2-di-chloroethane (40 mL) at 0 8C was transferred into the above catalyst soln. The resultingmixture was stirred until the starting material was completely consumed (as evident byTLC). The solvent was removed under reduced pressure, and the diastereomeric ratio(>20:1) was determined by 1H NMR analysis. The resulting crude mixture was purified byflash column chromatography (silica gel, hexanes/EtOAc 20:1) to afford the product as awhite solid; yield: 2.23 g (99.5%); 93% ee [determined by HPLC using a Chiralpak AD-H col-umn; hexanes/iPrOH 90:10; flow rate: 0.8 mL·min–1; 230 nm; tR 6.1 min (minor), 10.3 min(major)].

3.6.14.1.1.1.4 Method 4:Cyclopropanations

3.6.14.1.1.1.4.1 Variation 1:Intermolecular Cyclopropanation

A second class of reactions in which the gold catalyst is covalently bound to the substrateduring the enantiodetermining step is the reaction of propargyl alcohol carboxylateswith alkenes to provide cis-1,2-disubstituted cyclopropanes 27 stereoselectively (Scheme10).[24] The diastereoselectivity is derived from a repulsive steric interaction that controlsthe approach of the alkene to the gold(I) carbenoid; the alkene substituent is oriented tothe opposite direction from the ancillary ligand. The use of (R)-DTBM-SEGPHOS [(R)-2,R1 = 3,5-t-Bu2-4-MeOC6H2] provides high levels of facial selectivity during the cyclopropa-





nation of styrenes. A positive correlation between the size of the carboxylate and enantio-selectivity exists; pivalates (R3 = COt-Bu) were found to be optimal. The use of even largercarboxylates results in a dramatic decrease in yield. The use of substituted, particularly or-tho-substituted, styrenes increases the facial selectivity. However, extremely bulky sty-renes (R2 = 2,6-Me2-4-t-BuC6H2) are necessary for selectivities greater than 90% ee. Forma-tion of the reactive gold carbenoid enol carboxylate occurs by initial p-coordination ofthe gold(I) cation to the alkyne. 1,2-Migration of the propargyl ester then takes place viaintramolecular attack of the carboxylate onto the alkyne followed by p-bond reorganiza-tion to afford the gold carbenoid enol carboxylate. An isolated example has been reportedby F�rstner, using the bulky phosphoramidite 11 (R1 = pyren-1-yl), for the cyclopropana-tion of mesitylethene.[25]

Scheme 10 Gold(I)-Catalyzed Formation of cis-Cyclopropanes from Propargyl Carboxylatesand Styrenes[24]

OR3

+

R2OR3

R2

Au(L)

H

H

OR3R2

H

27 (cis/trans) >20:1

2.5 mol% Au2Cl2(L)

5 mol% AgSbF6MeNO2, rt

δ+

δ−

L = (R)-DTBM-SEGPHOS [(R)-2, R1 = 3,5-t-Bu2-4-MeOC6H2]

R2 R3 Yield (%) ee (%) Ref

Ph Ac 72 60 [24]

Ph Bz 73 68 [24]

Ph COt-Bu 70 81 [24]

2-Tol COt-Bu 83 68 [24]

2-BrC6H4 COt-Bu 60 76 [24]

4-FC6H4 COt-Bu 85 82 [24]

2,6-Me2-4-t-BuC6H2 COt-Bu 71 94 [24]

Vinylcyclopropanes 27; General Procedure:[24]

CAUTION: Nitromethane is flammable, a shock- and heat-sensitive explosive, and an eye, skin,and respiratory tract irritant.

In a 1-dram vial, AgSbF6 (5 mol%) was added to a soln of Au2Cl2[(R)-2 (R1 = 3,5-t-Bu2-4-MeOC6H2)] (2.5 mol%) in MeNO2 (0.1 M with respect to the propargyl ester), and the mix-ture was allowed to stand for 10 min. The alkene (4 equiv) was added, followed by a0.1 M soln of the propargyl ester (1 equiv) in MeNO2. The resulting mixture (0.05 M) wasmonitored until the starting material was completely consumed (as evident by TLC analy-sis, 20–40 min). The solvent was removed, and the crude residue was purified by flashchromatography (silica gel, hexanes/EtOAc) to afford the enantioenriched cyclopropane.




3.6.14.1.1.1.4.2 Variation 2:Intramolecular Cyclopropanation

Stereoselective intramolecular cyclopropanations have also been reported to form medi-um-sized rings 28 (Scheme 11).[26] Gold is uniquely suited for this reaction, because gold(I)carbenoids are not as prone to dimerization as other transition metal carbenoids, whichallows the cyclopropanation to occur to form strained rings. It is remarkable that high di-lution is not necessary; the reactions are run at 0.1 M of substrate. High enantioselectivi-ties are achieved for both seven- and eight-membered rings through careful selection ofthe reaction conditions. Particularly, the ligand and carboxylate identity have to be variedthrough the substrate scope, though some trends have been established. The ligand (R)-DM-BINAP [(R)-1, R1 = 3,5-Me2C6H3] is most general, especially for the formation of eight-membered rings, but (R)-DTBM-SEGPHOS [(R)-2, R1 = 3,5-t-Bu2-4-MeOC6H2] and (R)-DI-FLUORPHOS [(R)-5] can be used in specific cases. In contrast to the intermolecularreaction, propargyl acetates have been used with the sole exception occurring duringthe formation of a seven-membered ring, where a pivalate is clearly superior [15 vs 85%ee in the formation of 28 (R2 = H; R3 = H; n = 1)].

Scheme 11 Gold(I)-Catalyzed Cyclopropanation To Prepare Medium-Sized Rings[26]

2.5 mol% Au2Cl2(L)

5.0 mol% AgSbF6MeNO2

R2OR4

28

R3

OR4R2

n nR3

R2 R3 R4 n L Temp ( 8C) Yield (%) ee (%) Ref

Me H Ac 2 (R)-1 (R1 = 3,5-Me2C6H3) –25 94 92 [26]

Et H Ac 2 (R)-1 (R1 = 3,5-Me2C6H3) –25 91 92 [26]

CH2CH=CH2 H Ac 2 (R)-1 (R1 = 3,5-Me2C6H3) –25 98 90 [26]

Me Me Ac 2 (R)-5 –25 88 75 [26]

Me H Ac 1 (R)-1 (R1 = 3,5-Me2C6H3) rt 91 49 [26]

H H Ac 1 (R)-2 (R1 = 3,5-t-Bu2-4-MeOC6H2) rt 49 15 [26]

H H COt-Bu 1 (R)-2 (R1 = 3,5-t-Bu2-4-MeOC6H2) rt 44 85 [26]

1,1a,2,7,8,8a-Hexahydrobenzo[a]cyclopropa[d]cycloheptenes 28 (n = 1) and 1a,2,3,8,9,9a-Hexahydro-1H-benzo[a]cyclopropa[e]cyclooctenes 28 (n = 2); General Procedure:[26]


In a scintillation vial, AgSbF6 (5 mol%) was added to a soln of Au2Cl2[(R)-1 (R1 = 3,5-Me2C6H3)], Au2Cl2[(R)-5], or Au2Cl2[(R)-2 (R1 = 3,5-t-Bu2-4-MeOC6H2)] (2.5 mol%) in MeNO2(0.2 M with respect to the propargyl ester), and the mixture was allowed to stand for10 min at rt. The cloudy soln was filtered through a glass microfiber filter (Whatman GF/D), resulting in a clear, colorless soln. This soln was then cooled to –25 8C using a Cryocooland allowed to equilibrate for 30 min, or used at rt. To this soln was quickly added thepropargyl ester substrate in MeNO2 (0.2 M), also either cooled at –25 8C or at rt. The resul-tant soln (0.1 M overall) was allowed to sit at –25 8C or rt until the starting material was





completely consumed (as evident by TLC analysis, ca. 6 h). The reaction was quenchedwith a few drops of Et3N, and the mixture was warmed to rt and directly purified by flashchromatography (silica gel, hexanes/EtOAc) to afford the enantioenriched cyclopropane.

3.6.14.1.1.1.5 Method 5:Analogous Cycloisomerizations Proceeding through Gold(I) Carbenoids

Enantioenriched benzopyrans 30 bearing a quaternary all-carbon center can be preparedwith excellent enantiomeric excess values from o-(allyloxy)aryl propargylic pivalates 29, areaction which again proceeds via initial 1,2-acyloxy migration to form a reactive gold(I)carbenoid (Scheme 12).[27] Solvent selection is not critical for enantioselectivity, but aceto-nitrile provides the highest reaction efficiency. It is essential that the ligand contains bul-ky P-aryl groups; both (R)-DTBM-SEGPHOS [(R)-2, R1 = 3,5-t-Bu2-4-MeOC6H2] and (R)-DTBM-MeO-BIPHEP [(R)-3, R1 = 3,5-t-Bu2-4-MeOC6H2] are equally selective. In contrast to the intra-molecular cyclopropanation, nearly perfect selectivities are obtained across a wide rangeof substrates with a single set of conditions. Various substituents on the arene are tolerat-ed without deleterious effects. Although styrenyl-containing migratory groups were gen-erally used, other alkene-containing moieties are also successful.

Scheme 12 Gold(I)-Catalyzed Formation of Benzopyrans[27]

O O

O

5 mol% Au2Cl2(L)

10 mol% AgSbF6MeCN, rt

R2

R3

R4 R5

R6

OR4

R2

R3

R5

R6

29

But

O

30

L = (R)-DTBM-MeO-BIPHEP [(R)-3, R1 = 3,5-t-Bu2-4-MeOC6H2]

But

R2 R3 R4 R5 R6 Yield (%) ee (%) Ref

H H Me Ph H 74 97 [27]

Cl H Me Ph H 69 97 [27]

Ph H Me Ph H 64 97 [27]

t-Bu H Me Ph H 65 99 [27]

H t-Bu Me Ph H 64 98 [27]

H H Me Me Me 55 97 [27]

H H CH2CH=CH2 Ph H 44 99 [27]

Upon formation of the enol pivalate gold carbenoid, nucleophilic attack by the pendantallyl ether occurs to generate an allyl oxonium species with subsequent dissociation tothe allyl cation (Scheme 13). Recombination occurs at the benzylic carbon to generatethe quaternary stereocenter and release the cationic gold(I) catalyst. A sequential 2,3/3,3migration pathway of the allyl oxonium is not favored because (a) simple alkyl groupsare unable to migrate using this chemistry, unlike analogous transition-metal-catalyzed2,3-migrations, and (b) the migration of a 4-methoxybenzyl group is unlikely to proceedvia this pathway; the reaction is successful nonetheless. The selective formation of benzo-pyrans, e.g. 31, over possible cyclopropanes is noteworthy. The competing intramolecu-




lar cyclopropanation to form an eight-membered ring is disfavored by ring strain and un-favorable sterics from the 1,2-di- and 1,2,2-trisubstituted alkenes, as the successful forma-tion of medium-ring cyclopropanes occurs only with mono- and 1,1-disubstituted alkenes(Scheme 11). However, even when this class of alkenes is employed, the benzopyran isstill formed selectively over the corresponding bicyclo[6.1.0]nonene.

Scheme 13 Proposed Mechanism for Benzopyran Formation through an OxoniumIntermediate[27]

O

Ph

Au(L)

OEt

O

Ph

Au(L)

OEt

O

Ph

Au(L)

OEt

O

Ph

Au(L)

O

O

Et

− Au(L)

Ph

31 53%; 99% ee

OEtBut

O

O

But

But

O

But

O

But

O

4H-1-Benzopyrans 30; General Procedure:[27]

The complex Au2Cl2[(R)-3 (R1 = 3,5-t-Bu2-4-MeOC6H2)] (7.8 mg, 0.005 mmol) was added to asuspension of AgSbF6 (3.4 mg, 0.01 mmol) in MeCN (0.5 mL), and the mixture was sonicat-ed for 30 s. The suspension was filtered through a glass microfiber filter (Whatman GF/D),and the clear filtrate was added to a soln of the propargyl pivalate (0.10 mmol) in MeCN(0.5 mL, 0.1 M overall) at rt. The resulting mixture was monitored until the starting mate-rial was completely consumed (as evident by TLC analysis, ca. 1 h). The reaction wasquenched with a few drops of Et3N and the mixture was filtered through a glass microfib-er filter (Whatman GF/D). The filtrate was concentrated under reduced pressure and puri-fied by flash chromatography [silica gel (pretreated with 1% Et3N/hexanes), Et2O/hexanes1:50] to afford the enantioenriched benzopyran.

3.6.14.1.1.1.6 Method 6:Other Cycloisomerization Reactions of Propargyl Carboxylates

The Toste group has also reported a cyclization of 2-alkynylphenols and 2-alkynylphenolethers to prepare 2H-1-benzopyran-4-yl pivalates (Scheme 14).[12] It is proposed that inthese systems the gold(I) species first catalyzes an enantiospecific [3,3]-sigmatropic rear-rangement to form an intermediate allene. The electrophilic gold(I)-coordinated alleneenantiomers equilibrate, with the goal that one is preferentially trapped by the phenol(or phenol ether) to yield the enantioenriched 2H-1-benzopyran-4-yl pivalates after proto-demetalation (or carbodemetalation). The use of (R)-DTBM-MeO-BIPHEP [(R)-3, R1 = 3,5-t-





Bu2-4-MeOC6H2] as a chiral ligand provides benzopyrans 32 in a promising 60% ee (entry1), but this level of selectivity is not increased by switching to other bisphosphines orphosphoramidites. Postulating that slow equilibration of the allene enantiomers is toblame for the poor facial selectivity (particularly with phosphoramidites which providenearly racemic products), the authors believed a strong s-donor ligand such as an N-heterocyclic carbene would be beneficial insofar that the rate of racemization would bedecreased. The previously developed N-heterocyclic carbene (R,R)-15 gives a disappoint-ing 7% ee. Amazingly, the authors were able to overcome the inherent challenge of thissystem by developing the bis(N-stabilized carbene) ligand (R)-18. This ligand successfullycyclizes phenols and phenol ethers to afford the benzopyranyl pivalates 32 in good yieldsand with high enantiomeric excesses. This represents substantial progress toward thegoal of identifying selective gold(I) ligands with electronic properties complementary tophosphines and phosphoramidites.

Scheme 14 Gold(I)-Catalyzed Formation of Benzopyranyl Pivalates[12]

5 mol% AunCln(L)

5 or 10 mol% Na[BARF] or AgOTf

rtOR2R3

O

OR2

R3

O But

O

But

O

32

R2 R3 Conditions Yield(%)

ee(%)

Ref

H Ph Au2Cl2[(R)-3 (R1 = 3,5-t-Bu2-4-MeOC6H2)],

Na[BARF], CH2Cl2–a 60 [12]

H Ph AuCl[(R,R)-15], Na[BARF], CH2Cl2 –a 7 [12]

H Ph Au2Cl2[(R)-18], AgOTf, CDCl3 85 91 [12]

H 2-naphthyl Au2Cl2[(R)-18], AgOTf, CDCl3 68 84 [12]

O

OPh Au2Cl2[(R)-18], AgOTf, CDCl3 91 >99 [12]

NBoc

Ph Au2Cl2[(R)-18], AgOTf, CDCl3 94 95 [12]

a Yield not determined; BARF = tetrakis[3,5-bis(trifluoromethyl)phenyl]borate.

3.6.14.1.1.2 Desymmetrization Reactions

3.6.14.1.1.2.1 Method 1:Desymmetrization of Diynes

Hashmi has reported the desymmetrization of diynes to provide enantioenrichedphenols, e.g. 33 (Scheme 15).[28] Although extensive ligand screening has been conducted,essentially racemic product is formed in most cases using ferrocene-containing mono-and bisphosphines, MeO-BIPHEP ligands, and BINOL-derived phosphoramidites. Excep-




tions are found with the use of (S)-DTBM-MeO-BIPHEP [(S)-3, R1 = 3,5-t-Bu2-4-MeOC6H2] (55%ee) and two Mandyphos ligands (41% ee). The enantiodetermining step is not known de-finitively, but several limiting scenarios are possible. If p-coordination is slow relative tothe rate of irreversible addition of the furan with the activated alkyne, then the coordina-tion event would determine the selectivity. If the converse is true, enantioselection wouldoccur by selective furan addition to one of the two rapidly equilibrating diastereomericgold–alkyne complexes (Curtin–Hammett). Similarly, Curtin–Hammett conditions, withselection occurring on an intermediate further down the reaction pathway, are also possi-ble if the initial furan addition is reversible. The authors favor discrimination during p-co-ordination, but no experimental data is given to support this preference.

Scheme 15 Gold(I)-Catalyzed Desymmetrization of a Diyne via Phenol Synthesis[28]

1 mol% Au2Cl2(L)

2 mol% AgBF4CD2Cl2, rt

OHO

OH

99%; 55% ee OH

33

L = (S)-DTBM-MeO-BIPHEP [(S)-3, R1 = 3,5-t-Bu2-4-MeOC6H2]

A second desymmetrization of diynes was concurrently reported by Czekelius to prepare2,3,4,7-tetrahydro-1,4-oxazepine 35 using a pendant sulfonamide nucleophile in diyne34 (Scheme 16).[29] Proof of concept is provided with the use of MeO-BIPHEP (3, R1 = Ph)and the known chiral N-heterocyclic carbene 16, but neither ligand provides highly enan-tioenriched product.

Scheme 16 Gold(I)-Catalyzed Desymmetrization of a Diyne via Hydroamination[29]

10 mol% catalyst

10 mol% AgBF4toluene

Cy

ONHTs

Cy

ONTs

34 35

Catalyst Yield (%) ee (%) Ref

Au2Cl2[3 (R1 = Ph)] 23 60 [29]

AuCl(16) 66 17 [29]

2-Methyl-7-(prop-2-ynyl)-5,6,7,8-tetrahydronaphthalene-1,7-diol (33);Typical Procedure:[28]

The complex Au2Cl2[(S)-3 (R1 = 3,5-t-Bu2-4-MeOC6H2)] (1 mol%) was added to a suspension ofAgBF4 (2 mol%) in CD2Cl2 (0.12 M), and the mixture was stirred for 30 min at rt. 4-[2-(5-Methylfuran-2-yl)ethyl]hepta-1,6-diyn-4-ol (1 equiv) was added to the catalyst. The result-ing mixture was monitored until the starting material was completely consumed (as evi-dent by 1H NMR analysis, ca. 24 h). The solvent was removed under reduced pressure,and the residue was purified by flash chromatography (silica gel, pentane/EtOAc/CH2Cl23:1:2).





3.6.14.1.1.2.2 Method 2:Desymmetrization of Diols

Uemura and coworkers have reported the efficient desymmetrization of alkyne diols toafford chiral 1H-2-benzopyran chromium complexes (Table 3).[30] Compared to the synthe-sis of phenols and 2,3,4,7-tetrahydro-1,4-oxazepines (Section 3.6.14.1.1.2.1), these hydro-alkoxylation reactions occur to give synthetically useful yields and selectivities withgold(I) complexes containing the simple ligands (R)-BINAP [(R)-1, R1 = Ph] and (R)-DM-BI-NAP [(R)-1, R1 = 3,5-Me2C6H3]. The enantioselectivity is strongly affected by the counterionemployed; the weakly coordinating bis(trifluoromethylsulfonyl)amide and hexafluoroan-timonate anions are superior to tetrafluoroborate and trifluoromethanesulfonate. Bothprimary (Table 3, entry 1) and meso-secondary (entries 2 and 3) diols are transformedsmoothly into the corresponding 1H-2-benzopyran complexes. Additionally, it is benefi-cial to use chromium–arene complexes, but not essential; a 1H-2-benzopyran (entry 5)was prepared with 84% ee using the standard conditions. The products are amenable tofurther functionalization at both the residual alcohol and enol ether.

Table 3 Gold(I)-Catalyzed Desymmetrization of meso-Diols via Alkyne Hydroalkoxylation[30]

10 mol% Au2Cl2(L)

20 mol% AgX

CH2Cl2, rt, 5−20 min

OH

OH

BuR2

R2

OH

O

R2

R2

Bu

Z Z

Entry Substrate L X Product Yield(%)

ee(%)

Ref

1

OH

(OC)3Cr

OH

Bu

(R)-1(R1 = 3,5-Me2C6H3)

SbF6

O

Bu

OH

(OC)3Cr

87 99 [30]

2

OH

(OC)3Cr

OH

Bu

(R)-1(R1 = 3,5-Me2C6H3)

SbF6

O

Bu

OH

(OC)3Cr

27 56 [30]

3

OH

(OC)3Cr

OH

Bu

(R)-1 (R1 = Ph) NTf2O

Bu

OH

(OC)3Cr

69 95 [30]

4

OH

(OC)3Cr

OH

Bu

(R)-1(R1 = 3,5-Me2C6H3)

SbF6

O

Bu

OH

(OC)3Cr

43 98 [30]




Table 3 (cont.)

Entry Substrate L X Product Yield(%)

ee(%)

Ref

5

OH

OH

Bu

(R)-1(R1 = 3,5-Me2C6H3)

SbF6O

Bu

OH

71 84 [30]

(RP)-[h6-3-Butyl-5-(hydroxymethyl)-1H-2-benzopyran]tricarbonylchromium(0) (Table 3,Entry 1); Typical Procedure:[30]

AgSbF6 (3.3 mg, 0.0096 mmol) was added to a soln of Au2Cl2[(R)-1 (R1 = 3,5-Me2C6H3)](5.8 mg, 0.0048 mmol) in CH2Cl2 (1.0 mL), and the mixture was stirred for 10 min at rt un-der N2. A soln of [h

6-1,3-bis(hydroxymethyl)-2-(hex-1-ynyl)benzene]tricarbonylchromi-um(0) (0.048 mmol) in CH2Cl2 (2.0 mL) was added, and the resulting mixture was stirredfor 5 min. The mixture was filtered through a short pad of silica gel, and then the solventwas removed under reduced pressure. The crude residue was purified by flash chromatog-raphy (silica gel, Et2O/hexanes 5:95) to afford yellow crystals; yield: 87%; 99% ee.

3.6.14.1.2 Asymmetric Gold(I)-Catalyzed Transformations Proceeding via Initial Allenep-Activation

Alkyne p-activation has been a fertile area for asymmetric gold-catalyzed C-C bond for-mation. With the exception of desymmetrizations, asymmetric reactions to form C-Oor C-N bonds have not been reported because oxygen or nitrogen attack onto an alkynedoes not generate a stereocenter. In contrast, allenes provide a suitable platform forasymmetric C-C, C-O, and C-N bond formation. Allenes also present two enantiotopicfaces to chiral catalysts. Thus, substrate complexation can function as the enantioselectiv-ity-determining step during the cyclizations of allenes, but not alkynes.

3.6.14.1.2.1 Cycloisomerization Reactions

3.6.14.1.2.1.1 Method 1:Hydroindolization

Enantioselective intramolecular hydroindolization of allenes 36 occurs using a gold–DTBM-MeO-BIPHEP complex {Au2(BF4)2[(S)-3 (R1 = 3,5-t-Bu2-4-MeOC6H2)]} to provide 4-vinyl-tetrahydro-1H-carbazoles 37 and a seven-membered ring homologue (Scheme 17).[31] Dur-ing optimization studies, the parent (S)-MeO-BIPHEP ligand [(S)-3, R1 = Ph] was found to beless effective for the cyclization of 36 (R2 = CO2Me; R

3 = R4 = Me; n = 1; 76 vs 55% ee). Mono-and trisubstituted allenes both cyclize efficiently, but a 1,3-disubstituted allene affordspredominantly the E-product in 9% ee. A quaternary tether is essential for high enantiose-lectivities, with diesters typically used. Incorporation of a diol-containing tether providesa tetrahydro-1H-carbazole in only 50% yield and 72% ee. The cause of the low yield for thissubstrate is not specified, but potentially could be attributed to a competitive hydroalkox-ylation process.





Scheme 17 Gold(I)-Catalyzed Intramolecular Hydroindolization of Allenes[31]

2.5 mol% Au2Cl2(L)

5.0 mol% AgBF4

MeN

R2

R2

•

MeN

R2

R2

R4

R3R3

R4

36 37

R2 R3 R4 n L Conditions Yielda (%) ee (%) Ref

CO2Me H H 1 (S)-3(R1 = 3,5-t-Bu2-4-MeOC6H2)

toluene,–10 8C

88 92 [31]


toluene, rt n.r. 81 [31]


dioxane, rt n.r. 76 [31]

CO2Me H H 1 (S)-3 (R1 = Ph) dioxane, rt n.r. 55 [31]

CH2OH H H 1 (S)-3(R1 = 3,5-t-Bu2-4-MeOC6H2)

toluene,–10 8C

50 72 [31]

CO2Me Me Me 1 (S)-3(R1 = 3,5-t-Bu2-4-MeOC6H2)

toluene,–10 8C

82 91 [31]


toluene,–10 8C

80 91 [31]

CO2Me H (CH2)4Me 1 (S)-3(R1 = 3,5-t-Bu2-4-MeOC6H2)

toluene,–10 8C

77b 9b [31]

a n.r. = not reported.b A 3% yield (ca. 60% ee) of the Z-isomer was also obtained.

Dimethyl 9-Methyl-4-vinyl-3,4-dihydro-1H-carbazole-2,2(9H)-dicarboxylate (37,R2 = CO2Me; R3 = R4 = H; n = 1); Typical Procedure:[31]

AgBF4 (1.2 mg, 0.0063 mmol) was added to Au2Cl2[(S)-3 (R1 = 3,5-t-Bu2-4-MeOC6H2)] (5.1 mg,0.0031 mmol) in toluene (0.2 mL), and the mixture was stirred for 10 min at –20 8C. Asoln of the indole 36 (R2 = CO2Me; R

3 = R4 = H; n = 1; 41 mg, 0.13 mmol) in toluene (0.3 mL)was added, and the resulting mixture was stirred at –10 8C for 17 h. The mixture was di-rectly purified by flash chromatography (silica gel, EtOAc/hexanes 10:1 to 5:1 gradient)to afford a yellow oil; yield: 87%.

3.6.14.1.2.1.2 Method 2:Cycloisomerization of 1,6-Allenenes

The reaction using unactivated alkene nucleophiles analogous to that shown in Section3.6.14.1.2.1.1 has also been reported (Scheme 18).[32] Best results are obtained withAu2Cl2[(R)-1 (R1 = 3,5-Me2C6H3)]; Au2Cl2[(S)-3 (R1 = 3,5-t-Bu2-4-MeOC6H2)], used in the relatedhydroindolizations, is unreactive. 1,1-Disubstituted alkenes are necessary for reactivity,presumably to stabilize an intermediate carbocation. Further substitution is beneficial,providing complete regiocontrol of the elimination favoring the formation of tetrasubsti-tuted alkene 38. The identity of the tether has an effect on both the regio- and enantiose-lectivity. A single regioisomer is obtained using either a barbituric acid [R2,R3 = C(O)NH-




C(O)NHC(O)] or bissulfone (R2 = R3 = SO2Ph) tether, but in the latter case the product is iso-lated in nearly racemic form. The best counterion for facial selectivity (trifluoromethane-sulfonate) is, unfortunately, not the optimal counterion for regioselectivity (4-toluene-sulfonate). The isolation and subsequent reuse of Au2(OTf)2[(R)-1 (R1 = 3,5-Me2C6H3)] resultsin a slow, unselective cycloisomerization (21 vs 72% ee). The addition of silver(I) trifluoro-methanesulfonate re-establishes reactivity but not selectivity, whereas the addition of sil-ver(I) chloride increases the selectivity to an intermediate 34% ee. These observationshave not been satisfactorily explained; the assumption that the addition of excess AgXsalts to Au2Cl2(L) leads to distinct Au2X2(L) complexes may not be accurate under all condi-tions.

Scheme 18 Gold(I)-Catalyzed Cycloisomerization of 1,6-Allenenes To Prepare CyclohexeneDerivatives[32]

5 mol% AunCln[(R)-1 (R1 = 3,5-Me2C6H3)]

15 mol% AgOTf

MeNO2, rt

R4 •

R2 R3

R4

R2 R3

R4

R2 R3

R5 R5 R5

+

38 39

R2 R3 R4 R5 Ratio (38/39) Yield (%) ee (%) of 38 Ref

CO2Me CO2Me Me H 78:22 83 72 [32]

HN NH

O

O

O

Me H >99:1 82 57 [32]

CH2OMe CH2OMe Me H 50:50 77 64 [32]

SO2Ph SO2Ph Me H >99:1 82 6 [32]

CO2Me CO2Me Ph H 60:40 70 45 [32]

CO2Me CO2Me (CH2)4 >99:1 70 65 [32]

Cyclohexenes 38 and 39; General Procedure:[32]


In a glovebox charged with N2, an oven-dried 1-dram vial was charged with AgOTf (3.0 mg,0.013 mmol) and Au2Cl2[(R)-1 (R1 = 3,5-Me2C6H3)] (5.0 mg, 0.004 mmol) in MeNO2 (0.9 mL),and the mixture was stirred for 5 min at rt. The allenene (0.084 mmol) was added, andthe resulting mixture was stirred until the starting material was completely consumed(as evident by 1H NMR analysis). The mixture was directly purified by flash chromatogra-phy (silica gel, hexanes/EtOAc).

3.6.14.1.2.1.3 Method 3:Formal [2 + 2]-Cycloaddition Reactions

Toste has reported the formal [2 + 2] cycloaddition of 1,6-allenenes to form bicy-clo[3.2.0]heptanes 40 (Scheme 19).[33] The reaction is initiated by a 5-exo-dig cyclization ofthe alkene onto the gold-activated allene to form a secondary benzylic carbocation. Its for-mation provides selectivity over competing 6-exo-dig cyclization that would result in a





less stable secondary carbocation. The vinylgold species then reacts with the cation toyield the product. If methanol is present in the reaction mixture the carbocation is trap-ped to form trans-cyclopentanes, providing evidence that the initial cyclization formsthe trans-ring fusion. In the absence of an external nucleophile this vinylgold intermedi-ate reverts to the starting material, because the resulting trans-bicyclo[3.1.0]heptanewould be prohibitively strained. Eventually, the cis-disubstituted intermediate is formedand the benzylic cation is irreversibly trapped by the vinylgold(I) species to produce thecis-bicyclo[3.2.0]heptane.

This reaction can be performed with excellent enantioselectivity for substrates con-taining malonate diester tethers using (R)-DTBM-SEGPHOS [(R)-2, R1 = 3,5-t-Bu2-4-MeOC6H2]and silver(I) tetrafluoroborate (Scheme 16). However, with this catalyst, a substrate con-taining a 4-toluenesulfonamide linker provides the bicycle with only 54% ee. Subsequent-ly, TADDOL-based phosphoramidite ligand (R,R,R,R)-12 has been found to provide en-hanced levels of selectivity, with 95% ee for 40 (X = NTs; R2 = Ph; R3 = Me) obtained.[25] Ace-tonide-containing TADDOL catalysts were initially studied, but the analysis of crystalstructures and molecular modeling successfully predicts ligands containing acyclic TAD-DOL backbones would create a tighter, more regular chiral pocket. More recently, the spi-ro phosphoramidite 13 has been used to effectively prepare products containing N-(tert-butoxycarbonyl)amino and bissulfone linkers.[34]

Scheme 19 Gold(I)-Catalyzed Formal [2 + 2] Cycloaddition of 1,7-Allenenes[25,33,34]

X

R4

R3

R2X

H

H R2

R3

R4AunCln(L) catalyst (6.0 mol% [Au])5.0−6.0 mol% AgBF4CH2Cl2, rt

•

40

X R2 R3 R4 L n Yield (%) ee (%) Ref

C(CO2Me)2 Ph Me Me (R)-2 (R1 = 3,5-t-Bu2-4-MeOC6H2) 2 92 95 [33]

C(CO2Me)2 Ph Me Me (R,R,R,R)-12 1 91 99a [25]

C(CO2Me)2 2-naphthyl Me Me (R)-2 (R1 = 3,5-t-Bu2-4-MeOC6H2) 2 81 97 [33]

C(CO2Me)2 2-naphthyl Me Me (R,R,R,R)-12 1 87 98 [25]

C(CO2Me)2 Ph (CH2)5 (R)-2 (R1 = 3,5-t-Bu2-4-MeOC6H2) 2 86 95 [33]

C(CO2Me)2 Ph (CH2)5 (R,R,R,R)-12 1 93 99a [25]

NTs Ph Me Me (R)-2 (R1 = 3,5-t-Bu2-4-MeOC6H2) 2 70 54 [33]

NTs Ph Me Me (R,R,R,R)-12 1 52 95 [25]

NBoc Ph Me Me (R,R,R)-13 1 52 81 [34]

C(SO2Ph)2 Ph Me Me (R,R,R)-13 1 82 85 [34]

a The opposite enantiomer of 40 to that shown was formed.

[3.2.0] Bicycles 40; General Procedure:[33]

AgBF4 (6 mol%) was added to a soln of Au2Cl2[(R)-2 (R1 = 3,5-t-Bu2-4-MeOC6H2)] (3 mol%) inCH2Cl2, and the mixture was stirred for 5 min at rt. The mixture was added to a 1-dramvial containing the allenene (1 equiv) in CH2Cl2 (0.1 M overall). The resulting mixturewas stirred until the starting material was completely consumed (as evident by TLC). Themixture was filtered through a short pad of silica gel, and then the solvent was removed




under reduced pressure. The crude residue was purified by flash chromatography (silicagel) to afford the desired bicycle.

3.6.14.1.2.1.4 Method 4:Formal [4 + 2]-Cycloaddition Reactions

The gold-catalyzed cycloaddition of structurally similar allenedienes produces eitherfused cycloheptadienes or [4.3.0] bicycles 41 via formal [4 + 3] and [4 + 2] cycloadditions,respectively. Mechanistic and computational studies give support to the proposal thatboth types of products are formed through a common gold carbenoid intermediate thatcan undergo 1,2-hydride shift or ring-contractive 1,2-alkyl migration (Scheme 20).[35,36]

The electronic properties of the ancillary ligand have been shown to dramatically impactthe outcome of the reaction, with phosphite ligands selectively providing the [4 + 2]-cyclo-addition products. Electronically similar phosphoramidite ligands are therefore the obvi-ous choice for this transformation, rather than bisphosphines. Several groups have pub-lished highly enantioselective variants using phosphoramidites containing either BINOLor TADDOL backbones. MascareÇas[35] and, subsequently, Toste[37] have developed similarBINOL-derived ligands, bearing anthracenyl [(R,R,R)-11 (R1 = 9-anthryl)] or pyrenyl [(S,S,S)-11 (R1 = pyren-1-yl)] substituents at the 3 and 3¢ positions, respectively. Both are compe-tent for a range of substrates, though the latter provides nearly perfect facial selectivity.F�rstner has applied the TADDOL phosphoramidite ligand (R,R,R,R)-12, developed forthe [2 + 2] cycloaddition, also to the [4 + 2] cycloadditions; however, only a single exampleis reported.[25] The optimized reaction conditions are essentially identical for each of theseligands.





Scheme 20 Gold(I)-Catalyzed Formal [4 + 2] Cycloaddition of Allenedienes To Prepare [3.1.0] Bicycles withSulfonamide Tethers[25,35,37]

TsN

R3

R2

TsN

H

H

R2R3

TsN

H

R3

R2(L)Au

+

HAu2Cl2(L), Ag saltCH2Cl2

•

41

R2 R3 L mol% ofCatalyst

Conditions Yield(%)

ee(%)

Ref

Me Me (R,R,R)-11 (R1 = 9-anthryl) 2 AgSbF6 (2 mol%),–15 8C

92 92 [35]

Me Me (S,S,S)-11(R1 = pyren-1-yl)

5 AgSbF6 (5 mol%),–15 8C

83 99a [37]

Me Me (R,R,R,R)-12 5 AgBF4 (5 mol%), 0 8C 90 91 [25]

(CH2)5 (R,R,R)-11 (R1 = 9-anthryl) 2 AgSbF6 (2 mol%),

–15 8C87 92 [35]

(CH2)5 (S,S,S)-11(R1 = pyren-1-yl)

5 AgSbF6 (5 mol%),–15 8C

91 99a [37]

a The opposite enantiomer of 41 to that shown was formed.

Although phosphoramidite ligands provide highly enantioenriched [4 + 2]-cycloadditionproducts from substrates containing sulfonamide linkers, these scaffolds are not general-ly applicable to similar substrates where the identity of the linker is varied. In this light,Toste has developed a C3-symmetric phosphite ligand synthesized from BINOL to addressthis limitation.[37] The use of phosphite (S)-14 enables substrates containing geminal di-ester linkers to undergo selective cycloadditions (Scheme 21). Typical of the substrate spe-cificity often observed in gold-catalyzed transformations, this ligand is in turn ineffectivefor the toluenesulfonamide substrate class shown in Scheme 20 (24–34% ee). Followingthe cycloaddition, the addition of sodium chloride re-forms the precatalyst {AuCl[(S)-14]}, which can be purified by flash column chromatography. The recovered complex re-tains efficacy when used in subsequent reactions.




Scheme 21 Gold(I)-Catalyzed Formal [4 + 2] Cycloaddition of Allenedienes To Prepare[3.1.0] Bicycles with Diester Tethers[37]

H

R5

5.0 mol% AuCl[(S)-14]

5.0 mol% AgBF4

R4R3R3

R4

R5R2O2C

R2O2C

R2O2C

R2O2C

•

R2 R3 R4 R5 Conditions Yield (%) ee (%) Ref

Me Me Me H benzene, rt 87 92 [37]

Me Me Me Me benzene, rt 50 82 [37]

Me (CH2)4 H benzene, rt 93 86 [37]

Me (CH2)5 H benzene, rt 92 82 [37]

Bn Me Me H CH2Cl2, –30 8C 94 83 [37]

4-Alkylidene-2,3,3a,4,5,7a-hexahydro-1H-isoindoles 41; General Procedure:[37]

AgSbF6 (1.7 mg, 0.005 mmol) was added to a soln of Au2Cl2[(S,S,S)-11 (R1 = pyren-1-yl)](3.1 mg, 0.005 mmol) in CH2Cl2 or benzene (0.2 mL) (CAUTION: carcinogen). The mixturewas stirred for 5 min at rt, and then the suspension was passed through a glass microfiberfilter. The clear soln was added to a 1-dram vial containing the allenediene (0.1 mmol,1 equiv) in CH2Cl2 (0.8 mL) at the indicated temperature (–30 8C, –15 8C, or rt). The result-ing mixture was stirred for 12–24 h at this temperature. The mixture was filtered througha short pad of silica gel, and then the solvent was removed under reduced pressure. Thecrude residue was purified by flash chromatography (silica gel) to afford the desired bicy-cle.

3.6.14.1.2.1.5 Method 5:Ring Expansion of Allenylcyclopropanols

Kleinbeck and Toste have reported the asymmetric synthesis of cyclobutanones 42 pos-sessing a vinyl-substituted quaternary all-carbon stereocenter from the ring expansionof allenylcyclopropanols (Scheme 22).[38] Biaryl bisphosphines bearing 3,5-dimethylphen-yl groups provide the highest selectivity during optimization studies, with the BIPHEP li-gand superior to the corresponding BINAP derivative. Good to excellent enantiomeric ex-cesses are obtained in all cases, with the scope demonstrating that a variety of sensitivefunctionalities are tolerated, including acetals, esters, and aryl halides. Furthermore, thecatalyst loading can be reduced to 0.5 mol% when the reaction is conducted on a 1.5-mmol scale.





Scheme 22 Gold(I)-Catalyzed Ring Expansion of Allenylcyclopropanols To PrepareCyclobutanones[38]

2.5 mol% Au2Cl2(L)

5 mol% Na[BARF]

1,2-dichloroethane, −30 oC

•

R2O

42

L = (R)-DM-MeO-BIPHEP [(R)-3, R1 = 3,5-Me2C6H3]

BARF = tetrakis[3,5-bis(trifluoromethyl)phenyl]borate

R2

OH

R2 Yield (%) ee (%) Ref

Ph 76 91 [38]

4-BrC6H4 80 91 [38]

Cy 85 86 [38]

(CH2)2OBz 99 92 [38]

CH2CH=CHPh 99 84 [38]

(R)-2-Phenyl-2-vinylcyclobutanone (42, R2 = Ph); Typical Procedure:[38]

Na[BARF] (4.4 mg, 0.005 mmol) was added to a soln of Au2Cl2[(R)-3 (R1 = 3,5-Me2C6H3)](2.9 mg, 0.0025 mmol) in 1,2-dichloroethane (0.4 mL). The mixture was stirred for 15 minat rt, and then the suspension was passed through a glass microfiber filter and cooled to–30 8C for 1 h. The clear soln was added to a 1-dram vial containing 1-(1-phenylpropa-1,2-dienyl)cyclopropanol (17.2 mg, 0.10 mmol) in 1,2-dichloroethane (0.4 mL) at –30 8C. Theresulting mixture was stirred for 24 h at –30 8C. The mixture was quenched with Et3N(10 mL), diluted with pentane (0.4 mL), and directly purified by flash chromatography (sili-ca gel, Et2O/pentane 1:29) to afford the cyclobutanone as a clear, colorless oil; yield:13.0 mg (76%).

3.6.14.1.2.2 Addition Reactions

3.6.14.1.2.2.1 Method 1:Intramolecular Hydroalkoxylation and Hydroamination

In contrast to the paucity of enantioselective C-O and C-N bond-forming reactions fromalkynes, many examples of the corresponding reactions from allenes are known. Impor-tant developments, such as the first use of DTBM-MeO-BIPHEP (3, R1 = 3,5-t-Bu2-4-MeOC6H2) and chiral phosphate counterions in gold(I) catalysis, were made during re-search in this area. All reported transformations occur via intramolecular attack to affordeither five- or six-membered heterocycles. Unlike C-C bond-forming reactions, which re-quire weakly coordinating anions [e.g., tetrafluoroborate, hexafluoroantimonate, orbis(trifluoromethylsulfonyl)amide], gold(I) complexes containing relatively strongly coor-dinating counterions (4-nitrobenzoate, 4-toluenesulfonate, and phosphates) are generallycapable of effecting these cyclizations. Notably, coordinating counterions enhance facialselectivity for these reactions. An enantioselective C-S bond-forming reaction analogousto the following hydroalkoxylations and -aminations has not been developed, althoughcyclizations of optically enriched allenyl thiols that proceed with efficient chirality trans-fer are known.[39]




Reports in this area began to appear in 2007 from both the Widenhoefer and Toste re-search groups. The Widenhoefer group have shown that the ligand (S)-DTBM-MeO-BIPHEP[(S)-3, R1 = 3,5-t-Bu2-4-MeOC6H2] is effective for the synthesis of 2-vinyltetrahydrofuransand -tetrahydropyrans 44, and 2-vinylpyrrolidines 46 with excellent enantiopurities(Schemes 23 and 24).[40,41] The selectivity during the cyclization of alcohols 43 is stronglydependent on the counterion used, with 4-toluenesulfonate being optimal. No reactionis observed with the corresponding acetate. In contrast, the selectivity is only slightlycounterion dependent for the formation of pyrrolidines 46. Although perchlorate pro-vides the best enantiomeric excess value, it was also chosen because of the rate enhance-ment it offers. At room temperature, the perchlorate is nearly 1000 times more activethan the 4-toluenesulfonate. This permits the reaction to be performed at reduced tem-perature (–40 8C), with a corresponding increase from 66 to 81% ee for 46 (R2 = R3 = Ph;R4 = H). Benzyloxycarbonyl-protected amines 45 are generally employed, but other carba-mates, as well as acetamides, can be used. Sulfonamides react sluggishly to afford nearlyracemic products. Terminally unsubstituted and disubstituted allenes are tolerated, butdiverging from diphenyl-containing tethers as in 45 [R2,R3 = (CH2)5] or 45 (R

2 = R3 = H) is ac-companied by a significant drop in selectivity. The formation of piperidines was not re-ported.

Scheme 23 Chiral Ligand Controlled Gold(I)-Catalyzed Hydroalkoxylation of AllenylAlcohols[40]

OH

•

O

2.5 mol% Au2Cl2(L)

5.0 mol% AgOTs

toluene, −20 oC

44

n n

43


Ph

Ph

Ph

Ph

n Yield (%) ee (%) Ref

1 67 93 [40]

2 96 88 [40]





Scheme 24 Chiral Ligand Controlled Gold(I)-Catalyzed Hydroamination of AllenylCarbamates[41]

NHCbz

•

2.5 mol% Au2Cl2(L)

5.0 mol% AgClO4m-xylene

R4

R4

CbzN

R4

R4

4645


R2

R3R2

R3

R2 R3 R4 Conditions Yield (%) ee (%) Ref

Ph Ph Me –20 8C, 48 h 80 80 [41]

Ph Ph H –40 8C, 48 h 97 81 [41]

(CH2)5 H –40 8C, 24 h 98 50 [41]

H H H –20 8C, 24 h 99 34 [41]

An interesting dichotomy has been found during the cyclization of the racemic pentyl-substituted allenyl alcohol 47 and carbamate 49 (Scheme 25). Tetrahydrofurans (E)- and(Z)-48 are formed in a 1:1 ratio, but with excellent overall yield and enantiopurity. Theenantiopurity of the products has been confirmed by comparison after hydrogenation us-ing palladium on carbon. In this case, the gold(I) catalyst controls the hydroalkoxylationevent, overriding any inherent bias derived from the axial chirality present in the allene(catalyst control). Conversely, the hydroamination of rac-49 proceeds in high yield withnearly exclusive formation of vinylpyrrolidine (E)-50 but with only 6% ee. This representsthe reversed situation, with the facial selectivity determined entirely by the allene axialchirality instead of the chiral gold(I) complex (substrate control). These results can be ra-tionalized by the relative size of the incoming nucleophile; A large nucleophile (carba-mate) is predisposed to attack anti to the allenyl substituent R2, because of a steric interac-tion between the two groups (Scheme 25). Evidently, the penalty is much larger than en-ergy differences between the various substrate–catalyst complexes. This steric interac-tion is not present during the addition of a small nucleophile (alcohol).

Scheme 25 Divergent Behavior of an Analogous Hydroalkoxylation (Catalyst Control) andHydroamination (Substrate Control)[41]


OH

•

2.5 mol% Au2Cl2(L)

5.0 mol% AgOTs

toluene, −20 oC

48rac-47

O

4

494%; (E/Z) 1:1; both >95% ee

Ph

PhPh

Ph





NHCbz

•

2.5 mol% Au2Cl2(L)

5.0 mol% AgClO4m-xylene, −20 oC

50rac-49

CbzN

4

486%; (E/Z) 25:1; 6% ee

Ph

PhPh

Ph

attack anti to R2XHPh

Ph

• R2

AuL

anti

XR2

PhPh

XHPh

Ph

•

AuL

syn R2X

R2PhPh

attack syn to R2

A dynamic kinetic enantioselective hydroamination (DKEH) of racemic trisubstituted al-lenes has been successfully developed through the rational design of appropriate sub-strates (Scheme 26).[42] Although the racemization of chiral allenes can be catalyzed bygold(I), the hydroamination of trisubstituted allene 51 is fast relative to equilibration. Asmentioned, the axial chirality of this allene also completely dictates the facial selectivityduring the cyclization. Both of these problems have been solved through the use of trisub-stituted allenes containing distinct, but similarly sized terminal substituents. The rate ofC-N bond formation is retarded relative to racemization, and substrate control is dimin-ished because the energy penalty for attack syn to either of the two alkyl substituents iscomparable. Without modifying the reaction conditions from the prior study, efficientDKEH of racemic allenes could be realized. In the best case, a 94% yield of a 91:9 mixtureof (Z)- and (E)-52 is obtained in 91 and 9% ee, respectively. When the size difference ofthe terminal substituents is large (Me vs t-Bu), substrate control is again dominant.

Scheme

Documents

123 3.6.14 Organometallic Complexes of Gold (Update 1, 2012)123 3.6.14 Organometallic Complexes of Gold (Update 1, 2012) M. J. Campbell and F. D. Toste 3.6.14.1 Asymmetric Gold-Catalyzed