Comprehensive Chirality || 2.23 Selected Diastereoselective Reactions: Gold Catalyzed Cyclizations

2.23 Selected Diastereoselective Reactions: Gold Catalyzed CyclizationsASK Hashmi, Ruprecht-Karls-Universitat Heidelberg, Heidelberg, Germany

r 2012 Elsevier Ltd. All rights reserved.

2.23.1 Introduction 685
2.23.2 Asymmetric Aldol Reaction 685 2.23.3 Intrinsic Diastereoselectivity Based on Geometrical Restraints 686 2.23.4 Diastereoselective Formation of E/Z Isomers 688 2.23.5 sp3-Stereocenters from Enyne Substrates 690 2.23.6 sp3-Stereocenters from Enallene Substrates 706 2.23.7 sp3-Stereocenters from Alkyne Substrates 708 2.23.8 sp3-Stereocenters from Allenes 719 2.23.9 sp3-Stereocenters from Nucleophilic Additions to Alkenes 723 2.23.10 sp3-Stereocenters from Reactions with 1,3-Dipoles 728 2.23.11 sp3-Stereocenters from Nazarov-Like Cyclizations 730 2.23.12 sp3-Stereocenters from Wagner–Meerwein Shifts 730 2.23.13 sp3-Stereocenters from Indoles 733 2.23.14 Conclusion 735 References 735
2.23.1 Introduction

In the past 10 years homogeneous gold catalysis has become a very important tool for organic synthesis.1 Most of the conversions

are intramolecular reactions, and apart from enantioselective catalysis, these cyclizations often include diastereoselectivity aspects.

For most of the reactions in the field there exist reasonable assumptions about the reaction mechanism, which include the

diastereoselectivity-determining step. Still, for only a few reactions the mechanisms have been proven experimentally.2

2.23.2 Asymmetric Aldol Reaction

The historic milestone in the field of stereoselective gold catalysis is the Ito–Sawamura–Hayashi asymmetric aldol reaction, which

was the first catalytic and enantioselective aldol reaction ever. In addition to the excellent enantioselectivity, in this reaction of an

aldehyde 1 with an isocycanoacetate, the diastereoselectivity was also very good. The trans-isomer of the oxazoline 3 was formed as

the dominating product.3 Planar chiral ferrocen ligands of type 2 were applied as catalysts, and it is assumed that an orientation of

the two substrates at the metal center is assisted by the amino group in the side chain of the catalyst. As shown for intermediate A,

a hydrogen bridge could help to deprotonate and orient the isocyanoacetate, the nucleophilic attack at the aldehyde coordinated

to the metal template should prefer the trans-product.

RCHO O N O N

COOMeR R COOMe

+

1 mol% [Au(c-HexNC)2] BF4/2

CNCH2COOMe

CH2Cl2, r.t., 20 h

R: Ph Yield: 98%; trans/cis: 89/11

R: Ph, (E)-n-PrCH=CHCHO, (E)-MeCH=CMeCHO, MeCHO, iPrCHO, cHexCHO, tBuCHO

AuC N

O

OMe

O

H

R

N NHR2

P

P

*

via:

31

A

Comprehensive Chirality, Volume 2 http://dx.doi.org/10.1016/B978-0-08-095167-6.00222-6 685

686 Selected Diastereoselective Reactions: Gold Catalyzed Cyclizations

2:

Fe

PPh2

PPh2

C−NMeCH2CH2NR2H

Me

2a: NR2 = NEt22b: NR2 = NMe2

This reaction is of broad scope and has been investigated in a series of more than 30 publications,4 which includes diverse

applications in total synthesis (see Chapters 4.20 and 2.13).5

2.23.3 Intrinsic Diastereoselectivity Based on Geometrical Restraints

In a number of reactions, even though several new stereogenic centers are formed from previously sp2 or sp-hydridized carbon

atoms, only one diastereomer of the product can be formed. A very good example is the reaction of substrate 4, which delivers

the products 5 and 6.6 The ratio of these two products strongly depends on the catalyst used, but 5 is always the major product. The

six new stereogenic centers in 5 do not allow the theoretical number of 26¼ 32 stereoisomers. Since the three-membered rings can

only be anellated with the other rings in a cis-manner, only the diastereomer shown is obtained. The structure was unambiguously

confirmed by an X-ray crystal structure analysis. Similar principles apply to the second reaction product 5. With additional

substituents on the substrate, which create additional stereocenters, only moderate de values of up to 2:1 could be observed.

NTs

2 mol% IPrAuCl2 mol% AgBF4

toluene10−15 °C, 10 min

NTs

6 (16%)5 (82%)

+NTs

4

X 6-endo-dig5-exo-dig X

[Au]

X

[Au]

X

[Au]

−[Au]5 6

B

C

D

The reaction pathway to 4 probably involves the intermediates B and C after the stereoselectivity-determining steps, the side-

product 6 is formed via the carbenoid D. A related reaction is described for 7, the species E and F should be involved in the

formation of 8.7

TsN2 mol% [Au(PPh3)Cl] /AgSbF6

CH2Cl2, 0 °C, 15 min89% TsN

H

TsNH

HAu

H

Ph3P

TsNH

Ph3HPAu

H H

7 8

E

F

Selected Diastereoselective Reactions: Gold Catalyzed Cyclizations 687

The enyne can be prepared in situ by the reaction with allylsilanes, for example, the 1,5-enynes from 9. This first part of the

reaction is Bronsted acid-catalyzed. Then a subsequent gold catalyzed cycloisomerization gives the expected cis-anellation of the

bicyclo[3.1.0]hexane system 10.8 This sequence can be conducted as a one-pot synthesis.

R1

OH

R2

(i) CH2=CHCH2SiMe3,5 mol% p-TsOH, MeCN

(ii) 5 mol% Ph3PAuCl,5 mol% AgSbF6,MeCN, 20−50 °C

R1

H

R2

5 examples (50−82%)

9 10

An insertion into an sp3-CH bond can lead to a second three-membered ring. In the product 12 or the product 15, the latter

being accessible from both the alkyne 13 or the tautomeric allene 14 (identical intermediates have been proven by kinetic isotope

effects in labeled compounds), the five-membered ring has to be cis-anellated to the cyclopropyl rings, whereas the seven- and the

three-membered ring is anti-anellated.9 The two three-membered rings are positioned on opposite sides of the central five-

membered ring, as unambiguously shown in the X-ray crystal structure analysis of 12.

2 mol% t-Bu3PAuCl/AgSbF60.2 M CH2Cl2, r.t., 30 min

Ph

H

Ph

HH

11 12

Phn

n

•Ph

n

H

Ph

HH

2 mol% t-Bu3PAuCl/AgSbF60.2 M CH2Cl2, r.t., 1 h

n = 1 (80%) n = 2 (82%)

2 mol% t-Bu3PAuCl/AgBF40.2 M CH2Cl2, 60 °C, 2 h

n = 1 (88%)n = 2 (85%)

13

15

14

The substrate 16 shows a rearrangement to 17 as one reaction pathway, but as the major product the tricyclic heterocycle 18 is

obtained.10 The allylic stereocenter of the starting material induces the configuration of the newly formed stereocenters, and again

both six-membered rings are cis-anellated to the three-membered ring, which places them on opposite sides of the central ring.

OPh

O

AuCl3 (5 mol%)

toluene, 80 °C, 4 h O

OPh

H

O

Ph

O·

17 (34%) 18 (40%) 16

Another example, which includes both the need for a cis-anellation of two five-membered rings but at the same time also the

setting of an independent stereocenter, is the formation of the product 21 from the Munchnone 19 and N-phenylmaleinimid 20

as an electron-deficient alkene.11 The ester group is exclusively placed on the exo-face of the bicyclic system. The chiral ligand on

gold leads to highly enantioselective reactions, which are proposed to proceed via a N-aurated 1,3-dipole, leading to intermediate

22, the ring-opening of the lactone ring in 22 will then place the carboxylate on the exo-face of the diaza-bicylo[3.3.0]octane core.


O

N

N

Ar

O

Me OO

Ph

+N

N

ArCO2Me

Me

Ph

O

O

(S)-Cy-SEGPHOS(AuOBz)2 (2 mol%)PhF (0.5 M), r.t., 1.5−18 h

then TMSCHN2or CH2N2

1.5 equivalent

Ar = p-MeOC6H4, p-BrC6H4, p-ClC6H4, p-NO2C6H4, o-MeC6H4

(72−98%)

19 2021

O

NN

O

O

Ph

Ar

Me

AuL

O22

2.23.4 Diastereoselective Formation of E/Z Isomers

Whenever an exo-mode cyclization of an alkyne forms an exocyclic double bond in the product, a stereogenenic olefin is formed

in the case of internal alkynes. The examples of the conversion of 23 and 26 show only a moderate diastereoselectivity of 1.6:1 for

24:25 and 5.1:1 for 27:28.12 The preference for the (Z)-isomer in both cases results from the mechanism,2,13 which in both cases

should include the typical anti-oxyauration as the first and selectivity-determining step. This method for the synthesis of ben-

zoxazines is superior to previously reported mercury- or palladium/copper-catalyzed reactions.14

N

OH

Bz

AuCl (5 mol%)

K2CO3 (10 mol%)

DMF, 95 °C, 2 h O

N

Bz

O

N

Bz

24 (51%) 25 (32%)23

N

OH

Ts

AuCl (5 mol%)

K2CO3 (10 mol%)DMF, 95 °C, 2 h O

N

Ts

PhO

N

27 (36%) 28 (7%) Ph26

Ph

An example combining this with the formation of a stereocenter is the mixed inter- and intramolecular addition to 15.15 Again

the (Z)-isomer of 16 is the major product (de¼ 4:1), many more examples have been reported in that paper. The configuration of

the double bond was determined by a nuclear Overhauser effect (NOE) experiment for one of these examples.

O Ph3PAuCl/AgOTf (2 mol%)

MeOH, r.t.75% yield

O

OMe

O

OMe

(Z)-3029 (E)-314:1

Further examples of this type of diastereoselectivity resulting from an anti-addition of the nucleophile and the gold catalyst

have been reported.16 This includes the intramolecular addition of alcohols to 1,3-enynes 32, the (Z)-isomer 33 was obtained

exclusively.17 Once again the double bond geometry was assigned by NOE spectra, which as in the previous example is prob-

lematic, as these systems also show direct through-bond allylic coupling. In one of the other examples, 16b the assignment is

based on fully coupled 13C NMR spectra, which is more reliable and confirmed the anti-oxyauration step.


R4 R3

R5

R2

HO

R1

1 mol% PPh3AuCl,1 mol% AgOTfTHF, r.t.

or1 mol% AuCl3,DCM, r.t.30 min to 3 h

OR5

R4 R3

R2

R1

83−97%Pure diastereomer

32

33

The intramolecular addition of carboxylic acids to the alkyne in the substrates 34 and 36 delivers vinylesters 35 and 37.18 These

lactones with exocyclic double bond again show a (Z)-arrangement of the group R and the oxygen atom, as one would expect

from the anti-oxyauration mechanism. The effect has been investigated for both the formation of five- and six-membered rings.

Only in the case of the substrate with the n-butyl substituent on the alkyne the diastereoselectivity was lost even under these very

mild reaction conditions, it is unknown whether a subsequent double bond-isomerization or a change in reaction mechanism is

responsible for this lack of stereoselectivey in the case of butyl-35.

OH

O

RAuCl (10 mol%), K2CO3 (10 mol%)

acetonitrile, 20 °C, 2 h

O O

RR:

Yield:

dr:

Br

96%

100%

P

96%

100%

nBu

88%

1:134

35

R AuCl (10 mol%), K2CO3 (10 mol%)

acetonitrile, 20 °C, 2 h

O

OH

O

R

O

R:

Yield:

dr:

Br

98%

100%

Ph

97%

100%36 37

Similar principles were observed for the intramolecular addition of secondary nitrogen nucleophiles to alkynes, the o-alky-

nylphenethylamine 38 delivers only one diastereomer of the enamin substructure of the alkylidenetetrahydroisoquinolines 39.19

Again, NOE experiments were used to assign the double bond-geometry.

MeO

MeONH

R1

R2

3 mol% PPh3AuCl3 mol% AgNTf2EtOH (5 equivalents)DCE, r.t., 5−48 h

MeO

MeON

R1

R2

58−86%Pure diastereomer

38 39

The reaction pathway to the enyne-cyclization products is more complex, but still with the simple malonate 40 and the

tosylamide 43 gave diastereomerically pure products.20 In these reactions nitrogen acyclic carbene21 complexes of gold had

catalytic activities even superior to N-heterocyclic carbene (NHC) complexes. Compounds like 42 and 44 were known from the

previous work on enyne-cycloisomerizations, thus it was not necessary to proof the stereochemistry in these cases.

Z

45 (2 mol%)AgSbF6

DCM, r.t.2 min

Z

Z

41 (79%) 42 (5%)40 Z = C(CO2Me)2

45 Cl AuNH

HN

Z Ph

43 Z = NTs

45 (2 mol%)AgSbF6

DCM, r.t.2 min

Z Ph

44 (77%)


In reactions involving an external nucleophile like methanol, enyne substrates also delivered a specific double bond isomer, as

exemplified by the conversion of substrate 46.22 In addition to the diastereoselectivity, a very good enantioselectivity of 94% ee

was reported for the product 47 with an exocyclic double bond and an allylic stereocenter.

PhO2S

PhO2S

Ph

P

P

Au

Au

Cl

Cl

Tol Tol

Tol Tol 1.6 mol%

AgSF6 (2 mol%), MeOH, r.t., 168 h

PhO2S

PhO2S

Ph

OMe

47 (52%, 94% ee)46

2.23.5 sp3-Stereocenters from Enyne Substrates

The previous example represents the reaction type in homogeneous gold catalysis, which attracted the largest number of research

groups, the enyne cycloisomerization. Although the previous examples with the substrates 40, 43, and 46 only deliver diaster-

eomers in form of specific geometrical isomers of double bonds, a large number of enyne-cycloisomerizations provide products

with several sp3-configurated stereocenters. Their relative configuration defines the diastereoselectivity, even if the reactions are not

conducted in an enantioselective manner.

This, for example, always occurs when the enyne cycloisomerization is conducted in the presence of external nucleophiles, for

example, methanol in the conversion of 48 or 50.7 Depending on the olefin geometry in the substrate, either the diastereomer 49

or the opposite relative configuration in 51 is formed. For this conversion it is assumed that the stereoselectivity-determining step

is the formation of the intermediate D, which defines the relative configuration by the need of a cis-anellation of the three- and the

five-membered ring and at the same time conserves the trans- or cis-arrangement of the substrate’s double bond configuration in

the three-membered ring.

3 mol% [Au(PPh3)Me]6 mol% HBF4, MeOH

23 °C, 4 h82%

HOMe

MeO2C

MeO2C

MeO2C

MeO2C

48 49

3 mol% [Au(PPh3)Me]6 mol% HBF4, MeOH

23 °C, 4 h65%

HMeO

MeO2C

MeO2C

MeO2C

MeO2C

50 51

Z

H

R

H

Ph3PAu

Z

H

R

H

Ph3HPAu

Key intermediate

G

When starting from 52, for the indole ring (53) as the nucleophile, an identical relative configuration in 54 has been

reported.23 In addition, the stereochemical arrangement in side-product 55 nicely confirmed the assumptions made for inter-

mediate G.


NTs

Ph

5 mol% 56

1 h, r.t.CH2Cl2

74%4:1

tBu2P Au N CH3 SbF6

NT

H Ph

HN

+

NTs

H

Ph

NH

HN

+

52

53

54

55

56

This has been extended to enantioselective reactions with various other nucleophiles, a generalized scheme for the formation

of 58 is shown. In this case the authors explain the relative configuration by an anti-addition of the activated alkyne and the

nuclephile to the alkene, as shown in the intermediate H of the catalytic cycle.24

ZR1

R2

Z

HNu

R1R2

3 mol% 596 mol% AgSbF6NuH

Et2O, r.t. 15−20 h

P

P

AuCl

AuClAr Ar

Ar Ar

59

Ar = 4-MeO-3,5-(t-Bu)2C6H2(R)-4-MeO-3,5-(t-Bu)2MeOBIPHEP(AuCl)2

37−99%, 72−98% ee

Z = CH2(CO2Me)2, CH2(CO2i-Pr)2,CH2(CO2Bn)2, CH2(SO2Ph)2

R1 = Me, PhR2 = H, Me

5758

Z

HNu

R1R2

ZR1

R2

[AuL*]+

H+

Z

HNu

R1R2

[AuL*]

ZR1

R2

[AuL*]

Z

[AuL*]+

R1

R2

Nu

H

Interestingly, aldehydes can be used as nucleophiles, too. The 1,6-enyne 59 as well as the 1,5-enyne 62 can be used, the

products 60 and 63 are formed in good yield.25 The side-product 61 also shows good (E)-stereoselectivity. For 60 the diaster-

eoselectivity is explained by a bis-equatorial arrangement of the substituents in the six-membered intermediate of the


transformation, for 63 by an exo-position of the subsituent of the formyl group in the transition step of the cyclization to the five-

membered ring. Both pathways differ only in the regio-selectivty of the attack of the oxonium intermediate at an intermediate

vinylgold species.

MeO2C

MeO2C

O

H

(2 equivalent)

2 mol% [IPrAuNCPh]+SbF6−

CH2Cl2, −40 °C, 12 h

OH

MeO2C

MeO2C

MeO2C

MeO2C+

60 (85%) 61 (9%)59

O

H

(2 equivalent)

5 mol% [IPrAuNCPh]+SbF6−

CH2Cl2, 23 °C, 4 h 63 (95%)

PhO2S O

H

HPhO2S62

The intermediacy of gold(I) vinyl carbenoids26 in these reactions is documented by trapping reactions with diphenylsulfoxide,

with different enynes 64 the corresponding aldehydes 65 could be isolated in good diastereoselectivity from these oxidative

rearrangements.27 The trans-arrangement of the group R and the anellated five-membered ring on the cyclopropyl ring reflects the

(E)-geometry of the alkene in the starting materials.

X

R

X R

H

O

IPrAuCl/AgSbF6 (2.5−5 mol%)

Ph2SO (2 equivalent), CH2Cl2r.t., 2 h

X = (MeO2C2)2C, R = PhX = (MeO2C2)2C, R = vinylX = O, R = PhX = NTs, R = Ph

90%75%94%91%

64 65

For the cyclization of the enyne 66 the cation I was suggested as the intermediate.28 In addition to the inversion of one

stereocenter, which positions the two groups on the bridgehead positions on the same face of the bicycle 67, a stereogenic

exocyclic double bond is formed. The relative configuration was confirmed by a combination of 1H–1H COSY, HMBC, and

NOESY NMR spectra.

TMSO

R

10 mol% Ph3PAuCl,5 mol% AgSbF6,1.1 equivalent iPrOH

DCM, 40 °C

OR

Me

H

5 examples (63−95%)OTMS

[Au]R

+

66 67

I

A combination with a carboxylate group as an intramolecular nucleophile is possible, here the olefin geometry controls the

overall diastereoselectivity of the reaction.29 The (E)-geometry of the substrate 68 directly transfers to a trans-anellation of the two

six-membered rings in the product 69. Consequently, the (Z)-substrate 70 yields cis-71. The mechanistic explanation involves


intermediate J. Placing a methyl group on the olefin (72), changes the regioselectivtiy of the first ring closure and ultimately directs

the carboxylate group to the alkene, the product 73 is obtained. These results were part of an investigation addressing the

electronic nature of the intermediates of gold catalyzed organic reactions.

OH

OCOOMeMeOOC 5 mol% Ph3PAuCl5 mol% AgSbF6

CH2Cl2, r.t.80%

O OMeOOC

MeOOC

H68 69

COOMeMeOOC

OHO

5 mol% Ph3PAuCl5 mol% AgSbF6

CH2Cl2, r.t.62%

O OMeOOC

MeOOC

H70 71

OH

OEE R

O

E

E

ROH

[Au]

O

E

E

RO

E

E RO

[Au]

OH

[Au]

J

OH

OCOOMeMeOOC 3 mol% Ph3PAuCl3 mol% AgSbF6

CH2Cl2, r.t.82% O

MeOOCCOOMe

H

O

72 73

In the enol ether substrate 74 the olefin and the alkyne are in closer proximity, the six-membered lactal 75 is obtained, and the

diastereoselectivity in this dihydropyrane synthesis is better than 20:1 in favor of the trans-product 75.30 Consequently, with an

additional hydroxyl group in 76 the spiroacetal 77 is isolated, showing a very good diastereoselectivity also for the spiro-

stereocenter. In both cases the stereochemical assignments are based on NOE studies.

Ph

O

n-Bu

OR O

OH

n-BuPh

OR

1 mol% [(Ph3PAu)3O]BF4

H2O (1 equivalent), dioxane, r.t.

R = TBS, 85% yield (>20:1 dr)R = Ac, 88% yield (>20:1 dr)

74 75


Me

O

Me

OR O

Me

OAc

1 mol% [(Ph3PAu)3O]BF4

dioxane, r.t.

n = 1, 51% yield (>20:1 dr)

n = 2, 71% yield (>20:1 dr)

Me

HOn

O n

76 77

The use of a carbonyl group as the intramolecular nucleophile has been reported for a synthesis of Englerin A.31 Starting

from the precursor 78, with R¼H in a cascade reaction with high diastereoselectivity the tricyclic product 80 is obtained in very

good diastereoselectivity. For R¼Me, TMS, or TBS the major product is 79, it originates from an entirely different reaction

pathway.

Me

Me

OR O

Me

Me

10 mol% AuClDCM, r.t. 20−30 min.

Me Me

Me

O

OR

Me

H

[AuL]

Me Me

Me

O

OR

Me

H

[AuL]

for R = TBS,TMS,Me

for R = H

Me Me

Me

O

OR

Me

H

[AuL]

More stable,favored intermediate

Me Me

RO

O

Me

Me

Me Me

Me

O

OH

Me

H

[AuL]

[LAu]

Me H

O

Me

Me

O

Me

H

Me

Me Me

OOH

Me

or

R = TBS 80%TES 90%Mea 10%

48%

H

Me

Me Me

OO

Me

HO O

OH

OPh

Englerin A 8.1% over 15 steps

a10 mol%Ph3PAuCl/AgSbF6

78

79

80

Before this application, the basic reaction type (with the generation of fewer stereocenters) had been explored before

with substrate 81, which gave a 50:1 mixture of the diastereomers 82 and 83 and the 1,3-diene 84 as additional product. In

this context the authors also investigated the cyclopropylethers 85, which only gave a 1:1 mixture of diastereoisomers 86 and

87.32 The stereochemical assignments base on NMR spectroscopic analysis and one X-ray structure analysis in the case of 82,

the cis-configuration in 84 was assigned by vicinal olefinic coupling constant of 11.6 Hz in the case of R¼H and by NOESY

spectra in the other cases. 86/87 were known from previous Rh-catalyzed reactions, thus no specific stereochemical analysis was

necessary.


3 mol% Au(I) catalyst23 °C, 5–30 min

H

MeO2C

MeO2C

MeO2C

MeO2C

R

O

R

O

H

MeO2C

MeO2C

R

O+

MeO2C

MeO2C

RO

81 82 83

84 (9−52%)+

up to 84% (>50:1)

Z

R OEt

3 mol% Au(I) catalystCH2Cl2, 23 °C, 5 min Z

OEt

HR

ZOEt

HR

+

39–91%dr 1:1–30:1

85 86 87Z = C(CO2Me)2, C(CH2O)2CMe2

In substrates 88 the two reactive groups are more remote, in this case a cyclobutene derivative 89 is formed.33 The diaster-

eoselective outcome of the reaction is explained by the following mechanism, the authors assume the formation of intermediate

K. From there the reaction is believed to proceed via L and M, the geometry of the olefin in the starting material is carried through

to the final product.

R2

R3

R1

X

R4

R5

4 mol% 90

DCM, r.t.

XR1 R2

R3

R4

R5

i-Pr

i-Pr

i-Pr

PCy

AuNTf2Cy

90

R1 = H, MeR2 = H, Me, PhR3 = H, MeR4 = HR5 = H, Me, C5H11R4−R5 = (CH2)3, (CH2)4, (CH)4X = C (CH2OAc), C(CO2Me)2

88 89 (41−90%)

Rtrans

Rcis

R

X

LAu+

Rtrans

Rcis

R

X

X

R Rtrans

RcisH

AuL

XR Rtrans

Rcis

AuL

AuL+

XR Rtrans

Rcis

AuL

XR Rtrans

Rcis

88

88

K

L

M


Related four-membered rings could be obtained in a sequence involving a Nicolas-like substitution of a propargylic ether in 91

by allylsilane, the 1,2-shift in intermediate N then places the group R on the endo-side of the bicyclic product 92. A second allyl

group is transferred to the bridgehead, which then defines the overall diastereoselectivity (values between 12:1 and 30:1 were

reached), that is, cis-anellation of the four- and the five-membered ring and endo-position of the group R.34 In the manuscript it is

not clearly described how the stereochemical assignments were done.

Ar

OMe

R

OH

4 equivalent allylTMS5 mol% Ph3PAuCl5 mol% AgNTf2

0.10 M in DCM, r.t.6−10 h

R

Ar 53−94%dr 12:1 to 30:1

Ar

R

OHLAu+

OH

RLAu+

H

Ar

OH

R

Ar

R

Ar

R

Ar

TMS

LAuOH

LAu+

allylTMS

TMSOMe

LAu+

Ar = Ph, 4-MeOC6H4, 4-FC6H4,4-ClC6H4, 4-BrC6H4, 2-thienyl

R = H, Me, i-Pr, i-Bu, n-Bu, Bn

LAuOH

91

92

N

Another enyne-type substrate is compound 93. With a gold catalyst a Rautenstrauch rearrangement was observed, in this case

there was no diastereoselectivity, a 1:1 mixture of both diasteromers of 94 was observed.35

OPiv

Ph3PAuNTf2 (1 mol%)

acetonitrile, 5 °C, 75 min

O

H

94 (81%; dr = 1:1)93

In a related publication the diastereoselective isomerization of the substrate 95 is described. Starting from a 5:1 syn:anti mixture

of 95 yielded a 9:1 mixture with the all-exo arrangement of the substituents in the compound 96 shown as the main product. The

closely related substrate 97 gave the monocyclic product 98 with a trans-arrangement of the two substituents and an (E)-

configuration of the exocyclic double bond.35

Ph

OAc OAc

H

Ph

Ph3P-Au-NTf2 (0.1 mol%)

CH2Cl2, r.t., 15 min

89%; dr > 9:1syn:anti = 5:1

95

96


Ph

OBn

Ph

OBnPh3P-Au-NTf2 (0.1 mol%)

CH2Cl2, −20 °C, 15 min

78%syn:anti = 6:197 98

The related alcohol 99 has a mixture of 100 and 101 with a diastereomeric ratio of 1:4.1.36 A large number of examples for this

type of substrate were compiled.

C5H11

OH

Ph

H

C5H11

H

C5H11

Ph

O O

Ph

+2 mol% (PPh3)AuBF4

CH2Cl2, r.t. 5 min

100 (17%) 101 (70%, dr = 1:4.1)99

Another type of enyne is the dienyne 102, which gave the bicyclic 103.37 The related aryl-substituted substrate 106 provided the

benzo-anellated bicycle 107, again in good diastereoselectivtiy. The stereochemical assignment is based on NOESY spectra.

H3COOC

H3COOC

Ph

H3COOC

H3COOCPh

H

2 mol% 104

DCM, r.t., 2 h, 77%

(tBu)2P−Au−NCHMe

SbF6−

+

102 103

104

H3COOC

H3COOC

Ph

Ph

H3COOC

H3COOC

PhH

2 mol% 104

DCM, 80 °C (µW),20 min, 85%

105 106

The enantiomerically pure dienyne substrate 107 with acetoxy group delivers the polycyclic product 108 as a single diaster-

eoisomer (as proven by the X-ray crystal structure analysis of the corresponding para-nitrobenzoate instead of the acetate).

Interestingly, the structurally related allenes 109 gave similar products with the same relative configuration of the stereocenters

(stereochemical analysis is based on NOE experiments).38 This was applied in the synthesis of Capnellene from 111. During the

synthesis a 1:1 mixture of the diastereomers 112a and 112b was isolated, which was not a problem as the ill-defined stereocenter is

converted to a planar sp2-center in the further course of the synthesis of the natural product.

OAc

Ph3PAuCl (2 mol%)AgSbF6 (2 mol%)

DCM, −30 °C, 4 h

OAc

HH

107 108 (100%, 89% ee)


•R

109R = H, Me, t-Bu

Ph3PAuCl (2 mol%)AgSbF6 (2 mol%)

DCM, 0 °C, 30 min

R

HH

110 (62−80%)

112a:112b (90%, 2 steps)dr 1:1

OAcTBSO DCM, 0 °C, 2 h

Pt-Bu

t-BuAuMeCN

SbF6

(2 mol%)

OAc

TBSOHH

K2CO3 (20 mol%)

MeOH

OAc

TBSOHH

OAc

TBSOHH

Capnellene

6 steps HH

111

Another type of enyne is the furan-yne substrate 113. Here one of the two diastereotopic alkynyl groups reacts preferentially.

The other conceivable diastereomer could not be detected, the relative configuration of the product 115 could be proven by the

X-ray crystal structure ananlysis of the dicobalthexacarbonyl complex of the product.39

OR1 OH

R2OH

R1

R2

OH

OH

R1

R2

OH*+

5 mol% AuCl3 * *

114 (not observed)

R1 = Me, PhR2 = H, alkyl 115 (46−87%)

113

The furan-yne 116 with an alkynylether moiety delivers the polycyclic product 117. The anellation of the dihydrofuran

and the pyran ring is cis, the relative configuration of these two sterocenters and the stereocenter bearing the group R could

be identified by the X-ray crystal structure of the substrate with R¼ tBu. Depending on the group R, the diastereomeric ratio (dr)

varied from 71:29 to 90:10.40


O NTsO

MeO

R O

O

NTsMeO

R

R = Me, Et, tBudr from 71:29 to 90:10diastereoisomersidentified by X-raycrystal structureanalyses for R = tBu

117 (75−83%)

Mes3PAuNTf2

CHCl3

116

A further application in total synthesis is the sequence from 118 to Sesquicarene. The key step, the gold(III)-catalyzed

cyclization of 119–120, is highly diastereoselective.41

H

H

O OO H

HOAc

2 steps 5 mol% AuCl3

1,2-dichloroethane, r.t.,12 h

2 steps

98%, <94% pure byGC

(−)-Sesquicarene

118 119

120

1,5-Enyne with acetoxy group in allylic position is another type of enyne which was investigated intensively. For example,

acetate 121 diastereoselectively delivers the product 122, the acetoxy and the allylic substituents on the ring are trans, but the

configuration of the third stereocenter is not defined. The mechanistic suggestion again involves a cyclopropyl carbenoid O, which

then stereoselectively is attacked by the nucleophile from the backside.42

AcO

R1

R2

R1

AcOR2

OMe1 mol% 123

CH2Cl2/MeOH (10:1) orCH2Cl2/acetone/H2O (8:2:1)

20 min−24 h, r.t.64−93%

iPr

iPr

iPr

Cy2P Au NTf2

121122

123


AcOPh

Rcis

Rtrans

[Au]AcO Rcis

Rtrans

Ph

[Au]

AcO

Rcis Rtrans

Ph

[Au]

RHO

AcO

Rcis Rtrans

[Au]

Ph

OR

−H

+H−[Au]

AcO

RcisRtrans

H

Ph

OR

O

A more complex example is the cyclization of 124 with two allylic acetates in the molecule.43 The formation of the three

additional stereocenters in 125 is highly diastereoselective, which is explained by the preferred formation of intermediate P with

an equatorial acetoxy group. Finally, external water is incorporated as the nucleophile, avoiding the 1,3-diaxial interaction of R3

with R1 after the addition of water to intermediate Q.

AcO

ROAc

iPr

iPr

iPr

Cy2P−Au−NTf2

[Au]

4 mol% [Au]1.5 equivalent H2O

CH2Cl2, r.t.

AcOH R

HO

OAc

R = CH3 79%

80%

124 125

R3

OAc

R2

R1[Au]

H

AcOR1 R2

R3

[Au]

AcO

HR1 R2

R3

ax

eq

[Au]

[Au]

R3R1

R2AcO

H

[Au]

R3R1

R2H

AcO

P Q

Changing to the Boc protecting group gave the bicyclic carbonate 126 as the reaction product. The cis-anellation of the rings is

a result of the ring-closure in intermediate R, which automatically directs the carbonyl nucleophile to the same face of the six-

membered ring, the tBu group is eliminated in the process.44 If the internal nucleophile is placed in a different position as in 128,

two six-membered rings form, a trans-anellation now is preferred in 129. The relative configurations were proven by NOE

spectroscopy.


R2

R3

R1

OBoc

2 mol% [Au]

DCE, r.t. R1

R2

O

OBut

O

R3

[Au]

R1

R2

O

OBut

O

R3

[Au]R3

R1

O

R2

O

O

127 (73−88%)

R1 = R2 = Me, (CH2)5

R3 = PhPt-Bu

AuSbF6t-Bu

[Au]

126 R

Ph

BocO

O

O

OMe

HPh

129 (58%)128

This reaction has also been investigated with one additional stereocenter, dr of up to 20:1 could be achieved in substrates like

130. Again a species similar to R, the cyclopropyl carbenoid S, was proposed as intermediate.45 An X-ray crystal structure analysis

of one of the major diastereomers confirmed the stereochemical assignement.

R1

R4

R2

OBoc

R3 2 mol% [Au(t-Bu2P(o-biphenyl)]Cl,2 mol% AgSbF6,

DCE, r.t., 30−60 min

OO

O

R4

R3

R1

R2

14 examples46−87%up to dr >20:1

R3

OR1

R2

[Au]+

O

OtBu

R4

130131

S

In the case of a directly conjugated 1,3-enyne, an ester group can serve as the reaction partner, from the gold(III)-catalyzed

conversion of 132 the diastereomer of tricyclic ketone 133 could be isolated. With a tBu substituent on the remote position of the

six-membered ring as in 134, in addition to the cis-anellation, a good induction of 6:1 in favor of the relative configuration shown

in 135.46 The relative configuration is based on NMR spectroscopic evidence including NOE spectra, in an other example the

assignment was confirmed by a X-ray crystal structure analysis.

EtOO

OH

Et

2 mol% AuCl3,6 mol% AgSbF6,

toluene, 50 °C,1 h, 80%

132 133


EtOO

OH

Et

2 mol% AuCl3,6 mol% AgSbF6,

toluene, 50 °C,2 h, 85%, dr 6:1134

135

In a large number of reactions alcohol groups or derivatives participate. One mode of reaction is the use of silylenolethers as

ene-component of the enyne. This provides the products 137 and 138 as single diastereoisomers.47 The second example represents

a key step in the total synthesis of (þ )-lycopladine A.

H

O

CO2MeCO2Me

TIPSO

HCO2Me

CO2Me

10 mol% [Au(PPh3)Cl]/AgBF4

CH2Cl2/H2O 10:1, 40 °C94%

136 137

OBn

OTBS

I

H

10 mol% [Au(PPh3)Cl]/AgBF4

CH2Cl2/H2O 10:1, 40 °C95%

O I

H

BnO

138 139

Closely related is the use of an alkynylamide instead of the alkyne. In the conversion of the amino acid-derived 140 and 142

the cyclobutanones 141 and 143 could be isolated, for the induction and the selectivity-determining step the intermediates T and

U have been proposed. Substrate 144 includes a hydroxy group, now the bicyclic aldehyde 145 is obtained with 95:5 diastereo-

selectivity.48

O

MeO2C

NHTs

MeO2CN

Ts5 mol% AuCl

CH2Cl2, r.t., 24 h65%

141 (dr 95:5)

NTs

H

H

H

ClAu

MeO2C

Key intermediate

N

BnO

TsTMS

O

NH

5 mol% AuCl

CH2Cl2, r.t., 24 h65%

143 (dr 90:10)

Ts

OBn

140

142

T


PhN

Ts

5 mol% AuCl

CH2Cl2, r.t., 24 h61%

OH

NPh

Ts O

145 (dr 95:5)

NTs

H

H

H

ClAu

Key intermediate

BnO

144

U

The allylic alcohol in substrate 146 yields a keto group in the product 147. The transposition of the oxygen atom and the

diastereoselectivity is explained by the intermediate V.49 For several of the product molecules the relative configuration was

initially assigned by coupling constants in the 1H NMR and then confirmed by X-ray structure analyses.

Ar

NTs

OH

R

PPh3AuCl/AgOTf (10 mol%)

DCM, r.t., 2 hNTs

O

Ar

R

146R = H, Ar = PhR = H, Ar = naphthylR = H, Ar = 4-nitrophenylR = Me, Ar = Ph

147R = H, Ar = Ph (87%)R = H, Ar = naphthyl (77%)R = H, Ar = 4-nitrophenyl (55%)R = Me, Ar = Ph (71%)

ONTs

Ar

H

AuLClaisen

NTs

OH

Ar

LAu H

V

Having a propargylic hydroxy group in 148 leads to either the dihydropyrane ring 149 by a gold catalyzed addition of the

hydroxy group to the allene or, with AuCl3 in toluene, the strained bicyclic ketone 150 with exocyclic double bond and cis-

anellation of the two rings.50

•

CH2OMeHO

Me

Me

O

MeMe

H CH2OMeO

MeMe

CH2OMe

toluene, reflux, 6 h

58%

AuCl3 (2 mol%)(i) AuCl3 (2 mol%), CH2Cl2, r.t., 6 hor

(ii) [AuCl(PPh3)] (2 mol%),AgSbF6 (2 mol%), CH2Cl2, reflux, 1 h

(i) 55%(ii) 73%

148149 150

The conversion of the substrate 151 and the subsequent intermolecular trapping of the key intermediate W with an alkene also

leads to highly strained bis(cyclopropyl) product 152.51 Here the relative configuration of the stereocenters was proven by an X-ray

crystal structure analysis.


Z

Ph

ZH

HPh

R2

R1

H

H

R3Z = C(CO2Me)2Z = C(SO2Ph)2Z = NTs

5 mol% [Au(IMes)Cl]/AgSbF6CH2Cl2, −50 to 23 °C

Z HPh

H

AuR1

R3R2

L

152 (up to 77%)

Key intermediate

151

W

R1 R2

R3

The enyne ethers 155 are formed in situ by the gold catalyzed substitution of the allylic acetate 153 with 6 equivalents of

propargyl alcohol 154. The cis-arrangement of the two phenyl groups on the cyclopropyl ring of 156 is, as discussed above for

intermediate S in the conversion of 130, the direct result of the (E)-configuration of the olefin in the starting material of this

tandem reaction. The allylic stereocenter in the substrate induced the configuration of the three newly formed stereocenters in the

product by the transition state X.52 An X-ray crystal structure analysis confirmed the assignment for 156.

Ph Ph

OAc

Ph

OH5 mol% Ph3PAuNTf2

DCM, 30 °C, 1 h86%

PhPh

OPh

Ph

PhPh

155 (traces) 156 (86%)

O

R1

R1

Au

R4

R2

Favored transition state X

route 1

R4 = H

O

H

R4

R2

AuO

R1

H

R4

R2

153 1541:6

A very different mode of reaction is observed with many enynes containing 1,3-diene substructures. Although the substrate 157

with the silylenolether substructure yields the bicyclic ketone 158, other 1,3-enynes can react differently. In 157 the stereocenter

defines the face of the 1,3-diene which is attacked by the alkynyl group, the product is formed diastereoselectively.53

TIPSO

OSEM2 mol% Ph3PAuCl

2 mol% AgBF4

toluene/MeOH (10:1)25 °C, 30 min

94%

O

OSEM

157 158

However, in substrates 158 overall a Diels–Alder reaction is observed, the relative configuration of the two new stereocenters

in 159 is identical to the one expected in the case of a concerted Diels–Alder reaction. The conversion of 160 with an

additional OH group as the nucleophile in addition to 161 delivers 15% of 162, which indicates a participation of the cyclopropyl

carbenoid Y.54 For one of the related products described, the relative configuration could be confirmed by an X-ray crystal structure

analysis.


TMS

EtOOC COOEt5 mol% Ph3PAuCl5 mol% AgSbF6

CH2Cl2, r.t.81%

EtOOC COOEt

H

158 159

TMS

N N

H[Au]

TMS


CH2Cl2, r.t.

OH

OH

N

H

OH

161 (68%)

+

N

Ts Ts

Ts

Ts

O

162 (15%)

160Y

But thermal Diels–Alder reactions and gold catalyzed conversions can also give different stereochemical results. From 163

under thermal conditions 164 was obtained, whereas with the gold catalyst 165 is the product. The authors explain this by a

mechanism involving the intermediates Z and AA.55 NOE data was used for the assignment of the diastereomers.

R1

TIPSO

X

R3

R2

X

TIPSO

R1

R2H R3

X

TIPSO

R1

R2H R3

98% from (Z )-163R1 = Ph; R2 = H; R3 = Ph; X = C(CO2Me)2

163

toluene,reflux, 1.5 h

10 mol% Ph3PAuCl10 mol% AgSbF64 Å M.S.

DCE, r.t., 1 h

Diels−Alder

45−88%R1 = Ph, MeR2 = H, MeR3 = Ph, Me, H

164

165

X = C(CO2Me)2, CH2, N-Ms, N-Ts, O


H

Ph

TIPSO

Ph

H

E

E

[Au]

Ph

H

E

E

[Au]

H

OTIPSPh

favored

unfavored

H

E E

OTIPS

PhH

Ph

[Au]

H

E EPhH

H

OTIPSH

Ph

[Au]

E

EPh

H

Ph H

TIPSO

[Au]H

E

EPh

H

H Ph

TIPSO

[Au]H

164

165

Z AA

In intermolecular alkyne–diene reactions, which do not represent an enyne substrate but still are closely related to the

chemistry discussed here, the propargylic carboxylate 166 delivers a mixture of pure diastereoisomers 167 and 168.56 At 110 1C the

mixture can be converted to 168 completely.

O

O

+ HH

O

OO

O

110 °C

1 mol% IPrAuNTf21 mol% AgSbF6

92%,ratio 167/168: 1:1.6 167

Pure diastereomer

168Pure diastereomer

166

2.23.6 sp3-Stereocenters from Enallene Substrates

The allenes are isomers of alkynes, thus a similar reactivity can be observed. With the ene-allene 169 the cyclobutane 170 is

formed. The geometry of the exocyclic double bond in the product results from an electrophilic attack of the benzylic cation at the

vinylgold intermediate AB.57 The two rings have to be cis-anellated, the exo-position of the Ar group also results from a preference

of this attack in intermediate AB.

X •Ar

RL

RS X •Ar

RL

RS

[Au] XAr

HH [Au]

RLRS

−[Au] XAr

HH

H

RS

RL

Ph3PAuCl (5 mol%),AgBF4 (5 mol%)

CH2Cl2, r.t.

X = NTs, C(CO2allyl)2, C(CO2Bn)2 C(SO2Ph)2, CH2, C(CO2Me)2, C(CH2OMe)2RL, RS = CH3, −(CH2)4−

170 (92–80%)169 AB

In the case of the allenic substrate 171 with a 1,3-diene unit, gold also induces a Diels–Alder reaction to the trans-anellated

product 172. Indirect evidence for a concerted mechanism comes from the conversion of 173, which delivers the seven-membered

ring in 174 by a [4þ 3]cycloaddition.58 Depending on the catalyst, with the deuterated substrates 175 or 176 both products (177/

179 or 178/180) can be observed and the diastereoselectivity of the overall process is determined by the olefin geometry of the

distal double bond of the 1,3-diene unit.


X

• R

R

(ArO)3PAuCl (5 mol%)AgSbF6 (5 mol%)

DCM, r.t.X

H

H

RR

171

X = C(CO2Me), NTsR = Me, −(CH2)5−

172 (7 examples, 43–92%)

X• R

R

(o-biphenyl)(t-Bu)2PAuCl (5 mol%)AgSbF6 (5 mol%)

DCM, r.t.

173

X = C(CO2Me)2, NTsR = Me, −(CH2)5−

X

H

RR

174 (5 examples, 75–85%)

X•

175 (R1 = D, R2 = H)176 (R1 = H, R2 = D)

R2

R1

X = C(CO2Me)2

(o-biphenyl)(t-Bu)2PAuCl (5 mol%)AgSbF6 (5 mol%)

DCM, r.t.

(ArO)3PAuCl (5 mol%)AgSbF6 (5 mol%)

DCM, r.t.

X

H

R1

R2

X

H

H R1

R2

177 (R1 = D, R2 = H)178 (R1 = H, R2 = D)

179 (R1 = D, R2 = H)180 (R1 = H, R2 = D)

A mixture of the two diastereomers 181 and 182 with an N,O-complex of gold(III)59 gave a mixture of the two diastereo-

isomers 183 and 184.60 NOESY experiments confirmed the relative configuration for 183.

•

Et

Et

OTMS

OMOM

+•

Et

OTMS

OMOM

Et

N

Au OCl

Cl

O

2 mol%

wet CH2Cl2, r.t.

85%

OMOM

HEt

Et

O HOMOM

EtH

Et

O H

+

2.79:1181 182 2.81:1183 184

Intramolecular and diastereoselective [4þ 3] cycloadditions have been reported for other 1,3-dienes like 185 and the furan

derivative 188. In both cases with 1:2 or 1:3 the dr values for the products 186/187 and 189/190 were low.61


10 mol% IPrAuCl/AgSbF6CH2Cl2, 25 °C, 3 h

+

186 187

85%

1:2

•

Ph

MeO2C

MeO2C

MeO2C

MeO2C

MeO2C

MeO2CPh Ph

H H

H

185

10 mol% IPrAuCl/AgSbF6CH2Cl2, 25 °C, 1 h

+

189 190

82%

1:3

•

Me

EtO2C

EtO2C

EtO2C

EtO2C Me

O EtO2C

EtO2C Me

O

H

O

188

Even furanophanes like 191 react, with the gold(III) catalyst initially the anellated, seven-membered 192 with the oxa-bridge is

formed. Then a subsequent gold(I)-catalyzed step isomerizes this product to the tricyclic ketone 193.62 The solid-state structure of

a derivative of 192 confirmed the stereochemical assignment.

OAc

OO

HAcO

O

AcOH

H

N

Au O

O

Cl

Cl

III5 mol%

1 equivalent NaHCO3CH2Cl2, r.t., 2.5 h

192 (86%)

5 mol%

CH2Cl2, r.t.

P Au CltButBu

I

5 mol% AgSbF6

191 193

Still, this reaction is not always chemoselective, the two isomers 195 and 196 form from the allene 194.63 Both products form

in good diasteroselectivity. The stereochemical assignment of 195 is based on a NOESY spectrum.

•

O

H

O OH

10 mol%

PtBu

tBu

AuCl

10 mol% AgSbF6DCM, r.t.

+

195 (38%) 196 (34%)194

2.23.7 sp3-Stereocenters from Alkyne Substrates

Different types of nucleophiles can react with alkynes, in most cases following the principles discussed in Section 2.23.6. The

intramolecular addition of tert-butyl carbonate in the alkynes 197 delivers the cyclic vinylcarbonates 198 with high (E)-select-

ivity.64 However, with a stereocenter in the substrate 199 the observed diastereselectivities are moderate, values of 1:1.6 and 1:3.9

were observed for 200.


R

O

R′R″

O

O(Ph3P)AuNTf2 (1 mol%)

DCM, r.t., 30 min–2 h

O

O

O

R

R′ R″

R = Br; R′ = R″ = H 87%R = CO2Et; R′ = R″ = Me 87%R = CH2OBoc, R′ = R″ = H 62%R = CH2OBoc, R′ = H, R″ = Me 77%

(E )-selective

197

198

O

O

O

R

[(pCF3Ph)3P]AuNTf2 (1 mol%)

DCM, r.t., 20 h

O

O

O

R

R = VinylR = Ph

dr = 1:1.6dr = 1:3.9

68%66%

199

200

The diyne 201 shows a cyclization to the nonconjugated ketone 202, the (Z)-diastereomer shown is the only product, as shown

by COSY, HMQC, and NOESY spectra.65

5 mol% IPrAuCl6 mol% AgSbF6

MeOH, r.t., 6 h tBuOOC

tBuOOC

tBuOOCtBuOOC

O

202 (72%)Pure diastereomer

201

Compound 203 contains an 1,4-enyne substructure, in this case the nucleophilic addition outruns any potential reaction

pathway involving the alkene. Overall, one diastereoisomer of the product 204 was reported, the authors suggest the syn-addition,

but taking the mechanistic knowledge on homogeneous gold catalysis into account, the same product could also be formed by the

normal anti-addition pathway.66

O

O OTBDPS

H

H

MeO

PMBOOH

8 mol% AuCl8 mol% PPTS

MeOH20 min75%

O

O OTBDPS

H

H

MeO

[Au]OH

O

O OTBDPS

H

H

MeO

O

O OTBDPS

H

H

OO

OPMB

O

OPMB

203

204


Another enyne substructure can be found in substrates 205. Again the nucleophilic addition first outruns any potential alkene

reactivity, the 1,3-diene formed that way then undergoes a Diels–Alder reaction to deliver, depending on the tether length, the

bicyclic olefins of type 206 or spirocycles of type 207.67 Specific examples are shown for the formation of 208 and 209. The

authors only reported the diastereomers shown, the assignments were based on X-ray crystal structure analyses.

XH

R1

R2

R

n +

3 mol% AuCl3CH2Cl2, r.t.

X = O, Nn = 1

3 mol% AuCl3ClCH2CH2Cl, reflux

X = On = 2, 3

X

R1

R2

n E

RE

O

R

n−1

E

R2

R1

E = N Ph

O

O

NC CN

CNNC

or

205 206

207

OH

+

3 mol% AuCl3CH2Cl2, r.t.

O

N Ph

O

O NH

H

H

O

O

Ph

208 (70%)

3 mol% AuCl3ClCH2CH2Cl, reflux

O

N

O

OPh

HH

+ N Ph

O

O

209 (70%)

OH

The Michael-acceptor substructure in 210 directs the incoming nucleophile to the proximal position, then the second addition

of the external nucleophile methanol is perfectly diastereoselective, placing the methoxy substituent in 211 in the axial position

and the other three substituents in equatorial positions as determined by HMQC, HMBC, COSY, and NOESY spectra.68

OH

R2

R1

CO2R3

(i) AuCl3 (2 mol%)MeOH, r.t., 2.5 h

(ii) NaHCO3 (sat.)

O

R2

OMeCO2R3

R1

210 211(82–99%)

R1:H, Me, Et, i-Pr, Bn, Vinyl, Ph; R2:H, OPMB; R3:Et, Bn.

A carbon nucleophil is formed from the 1,3-dicarbonyl compound 212, after activation of the triple bond by the gold catalyst

the enol-tautomer adds into form the new C�C bond and a stereocenter at the same time. Only the cis-diastereomer of the bicyclic

products 213 was observed.69


OCO2Me

R

O RCO2Me

Hn n

1 mol% [Au(PPh3)Cl]/AgOTfCH2Cl2, r.t.

n = 1, R = H, 1 h, 83%n = 1, R = Ph, 10 min, 94% n = 2, R = H, 20 h, 80%a

a2 mol% catalyst212 213

An interesting example is the reaction of the two compounds 214 and 215. Although the intramolecular lactone in 215

formation should outrun any intermolecular reaction (especially in the presence of an amine like 214, when the carboxylate rather

than the carboxylic acid is the nucleophile), the product of an intermolecular reaction is formed. The polycyclic N,O-ketals 216 are

isolated with moderate diasteroselectivtiy. This is explained by the mechanism shown below. The first intermediate indeed is the

lactone AC, then the reaction of the amine with the enol-ester delivers the amide AD subsequent condensation/addition reactions

provide product, the alcohol addition to the iminium species AE being the stereoselectivity-determining step.70 The authors did

not assign the diastereomers.

OH

R2

NH2

R1

R3

OH

O

+O

R2

N

R1

O R3

2 mol%

THF, 120 °C, 24 h

R1 = H, F, Cl, Me, PhR2 = H, MeR3 = H, Hexyl 65–96%

dr 1:1.1−1:1.4dr 5:1 for R1 = R3 = H, R2 = MeP

t-BuAuNCCH3

t-Bu

SbF6

214 215 216

OH

R2

NH2

R1

R3

OH

O

O

O

R3

[Au]

OH

R2

NH

R1

O

R3

O

OH

R2

N

R1

OR3

[Au]

R1

N

O

O R3

R2

ACAD

AE

This also works for heterocycles as the nucleophile. Instead of 214 from the previous example, 217 can be used.71 Again for the

polyanellated heterocyclic product 218 the diastereoselectivities are not very good and the relative configuration has not been

assigned.


N

NH2

R3

R1

OH

O

+

2 mol% 5610 mol% TFA

THF, 120 °C, 24 h

R1 = HexylR2 = H, Et, annulated ArR3 = H, Me

85–98%dr 1:1.5–1.5:1

XR2

Pt-Bu

AuNCCH3t-Bu

56

SbF6

R3

N

N

O R1

R2

217 215

218

Moderate to good diastereoselectivity was observed in the cyclization of the acetals 219. Both the cis- (220) and the trans-

isomer (221) of the pyranone were isolated.72 Mechanistically, the transfer of the ethoxy group to the alkyne delivers the

carboxonium intermediate AF, which then forms the new C�C bond by attack at the vinylgold73 intermediate. In this inter-

mediate seemingly an equatorial arrangement of the groups R1 and R2 in the transition state of the ring-closure is preferred.

n-C10H21 O

OEt

CH3(i) 3 mol% [Au]

(ii) 10 mol% p-TsOH1 h, r.t.

On-C10H21 CH3

O

On-C10H21 CH3

O

+

[Au{P(C6F5)3}]SbF6

yield

55% : 31%

72% : 9%[Au{P(tBu)2(o-biphenyl)}(CH3CN)]SbF6

219 220 221

R1 O

OEt

R2

R1 O

OEt

CH3

OAuR1

EtO R2

OAuR1

EtO

R2

O R2R1

OEt

O R2R1

OEt

AF

For the dimerization of propargylic alcohols a very good diastereoselectivity was reported for 222 (R¼H), the diastereoisomer

223 of the product was reported.74

OHO

O

MeOOMe

R

R

R [Au]

MeOH R = H, Me

222 223

The homopropargylic alcohols 224 undergo a cyclization to tetrahydrofurans 225.75 With both a stereocenter next to the

alkyne (R3 not H) or the hydroxy group (R2 not H), a moderately diastereoselective reaction was observed with regard to the newly

formed stereocenter, the ketal carbon atom in 225. The authors did not assign the relative configuration.


R3

OH

R2

R1 O

R2

R3R1

R4O

Ph3PAuCl/AgBF4 (2 mol%)

R4OH, pTsOH (10 mol%), r.t.

R1

PhPhnBu

R2

PhHH

R3

HPhMe

R4 y

Et 69%Et 72%Et 44%

dr = 60:40

224 225

With a gold(III) catalyst the diyne 226 provides the bicyclic ketals 227.76 The latter with a preference for the relative con-

figuration shown, this could be assigned by an X-ray crystal structure analysis. With an additional hydroxyl group as an internal

nucleophile as in 228, the polycycle 229 is obtained, now in moderate diastereoselectivity (dr between 4:1 and 10:1). Once more,

a solid-state structure confirmed the relative configuration.

O O

NHR1

+ R2OH + H2OOO

R2O OR2

NHR1O

AuCl3 (3 mol%), 4 h

alkanol/H2O (8.0 ml; 25:1)

R1 = C6H5, 4-ClC6H4, 2-ClC6H4, 4-MeOC6H4,2-MeOC6H4, 4-MeC6H4, 4-EtOC6H4, H.;

R2 = propargyl, allyl

227 (82–93%)

226

O O

NHR1

+ R2OH + H2OOOO

OR2

NHR1O

AuCl3 (5 mol%), 10 h

alkanol/H2O (8.0 ml; 25:1)OHR

HR

R = C6H5, 2-ClC6H4, 4-FC6H4, 3,4-CH2O2C6H3;

R1 = C6H5, 4-EtOC6H4; R2 = propargyl

229 (40–52%)

228

Two gold catalyzed steps are involved in the isomerization/cyclization of 230 and 232.77 After a [3,3]sigmatropic rearrange-

ment to the allene, the axial chirality of the allene is converted to the double bond geometry of the vinylacetate 231. The product

233 with the additional substituent on the ring again forms mainly the (Z)-isomer, which is explained by a preference for

intermediate AG in the cyclization.

OAc OH

Ph

5 mol% AuCl,

THF, r.t., 30 min

OPh

OAc

231, 83% (Z:E 50:1)230


OAc OH

H3C(H2C)5

5 mol% AuCl,

THF, r.t., 30 min

OH3C(H2C)5

OAc

233, 93% (Z:E 2.4:1, 2.5% trans)232 (dr 1:1)

O

H

R

H

•H

AcO

R′

O

H

R

H

•H

R′

AcOClAu ClAu AG

Another way to such cis-substituted tetrahydropyranes is the isomerization of substrate 234, which delivers diastereomerically

pure 235.78 With a shorter tether in 236 the corresponding tetrahydrofuran 237 is formed in a nondiastereoselective manner. Bis-

ether 238, with the stereocenter in the tether between the reactive groups, delivers 239 with a dr of 2:1. Overall, the stereochemical

outcome of the reaction is explained by a gold catalyzed hydration of the triple bond followed by an elimination of the methoxy

group to deliver AH. The latter then coordinates gold again and closes the ring by intramolecular addition of the alcohol

nucleophile.

O

OH NaAuCl4 (5 mol%)

DCM, 35 °C

O

O

235 (79%)Single diastereomer

234

O

OH

NaAuCl4 (5 mol%)

DCM, 35 °CO

O

237 (92%)dr = 55:45

236

O

OH NaAuCl4 (5 mol%)

DCM, 35 °C OO

OMe

239 (71%)dr = 2:1

O

O

OH[Au]

238

AH

A much more complex mechanism is involved in the reaction of 240.79 The anellated, eight-memembered dimers 241 and 242

were obtained with a clear preference for the racemic chiral product 241. The authors suggested a dimerization of two of the gold-

containing intermediates AI. Thus, the stereoselectivity-determining step would be the formation of the C�C bond in the step

from AJ to 241/242. The diastereomer 241 could be assigned by an X-ray crystal structure analysis.


O O

N Au

O

OCl

Cl 5 mol%

Dichlorethan60 °C,1h

56%

ON

O

NO

O

H

H

+

ON

O

NO

O

H

H

4.2 : 1

racmeso

240241 242

ON

O

AuIII

NO

AuIII

O

NO

AuIII

O

NO

AuIIIO

NO

AuIII

N

OO

ON

O

NO

O

H

H

AI

AJ

241/242

A highly interesting product-type is observed in the AuCl3-catalyzed conversion of 243. The oxabicyclic products 244 can be

obtained. The first obvious intermediate is the enol ether 245, then a second cyclization has to occur on the side of the allyl group.

The alcohol R2OH is exclusively delivered to the exo-face of the bicylo[3.3.1]system.80 NOESY spectra in combination with other

NMR spectra allowed the stereochemical assignments.

OH

R1 R1

XO

OR2

2 mol% AuCl3, R2OH, r.t., 1 hup to 96%

R1, R2 = alkylX = CH2 or O

O

R1

R2OH O

R2O

AuCl3

243 244

245

The epoxides 246 and 248 gave cyclic acetals 247 and 249. The author explains the stereochemical outcome of the reaction by

a preference for intermediate AK.81 The structures were confirmed by X-ray crystal structure analyses for each of the two product

types.


TsN

O5 mol% Ph3PAuCl5 mol% AgSbF6

H2O, DCE, r.t., 68%TsN O

O

H

246 247

TsN

O

5 mol% Ph3PAuCl5 mol% AgSbF6,10 mol% p-TsOH

H2O, MeOH, r.t., 75%TsN O

HOMe

OMe

248 249

ONTs

CH2OMe

H

Au

ROH

ONTs

CH2OMe

HAu

ROH

Favored Disfavored

If Au

if TsOH O

TsN

ROH2C

ROH

ROH

+

HH

Me

AK

Closely related are the results observed with the substrates 250 and 253, both containing an oxygen atom in the tether. Trioxa-

bicyclic acetals can be isolated.82 For the pair 251/252 a moderate selectivity of less than 2:1 was detected, whereas 254 gave a

single stereoisomer. These assignments in part base on X-ray structure analyses of related products.

OPh

O

OOO

Ph

+O

OO

Ph

251 (42%) 252 (25%)

2 mol% PPh3AuCl/2 mol% AgSbF6

acetone, reflux250

O

O

BnO OOO

Ph

254 (73%)single diastereomer

same conditions

OR

OO

Diastereoselectivitydependent on cation stabilitySN1 vs. SN2

253

A new and very hot topic are hydride transfers. Ether 255 delivers two different products, the exocyclic olefin in 256 is formed

with (Z)-configuration, the endocyclic olefin 257 is the other product. Both products show a cis-anellation of the two rings. The

same reaction type can also deliver dihydropyranes, 259 is obtained from 258 with a cis/trans-ratio of better than 25:1.83


OR1

X

R2

[Au] (4 mol%)

CH3NO2, 100 °C

X = C(CO2Me)2R1 = H, i-Pr, n-PentylR2 = H, CO2Et, Br

O

XH

H

R2

R1+

O

X

R2

R1

H

H

(overall yield: 75–95%) (only observed forR1 = H, R2 = H or Br)

256 257255

O

H

H

R1

AuLH

CO2Et

CO2Et

H255

AuL

O Ph

CO2Et

R2

R1

[Au] (4 mol%)

CH3NO2, 100 °C O

CO2Et

Ph

R2

R1

258 259

R1 = i-Pr, R2 = HR1 = R2 = −(CH2)2−

(74%, cis:trans > 25:1)(88%, cis:trans > 25:1)

[Au] =t-Bu

t-Bu

O P Au NCPh, SbF6

3

Anellated bicyclic cages are accessible from the propargylic acetates 260. In the initial step these isomerize to the allenic acetate

AL, then the cyclization with the formyl group and the subsequent cycloaddition with the enol ether 261 furnishes 262 with four

stereocenters and one stereogenic double bond. 262 is formed as a single diastereomer. Base-induced hydolysis of the vinylacetate

forms the ketone 263 with one additional stereocenter, again as a single diastereomer.84 The stereochemical assignments in part

are based on X-ray crystal structure analyses, in part on NOE measurements.

R1

OAc

O

R2

+

R3

OR4

ClAuP(t-Bu)2(o-biphenyl) (3 mol%)AgNTf2 (3 mol%)

DCM1–5 h

O

R3R4O

R2

OAcR1

NaOMe

1 h O

R3R4O

R2

H

O

R1

260 261 262

263


(yield: 31–82%, dr = 6.5:1–20:1)

R1 = Me, n-Bu, i-Bu, PhR2 = Me, n-PrR3 = Me, R4 −(CH2)n−

R4 = Et, R3 −(CH2)n−

R2

O

•OAc

R1

Au

AL

An earlier and again highly diastereoselective example for such cyclizations involving o-unsaturated benzaldenydes is the

alkyne 265. Here, the polycyclic 266 is formed, the diastereoselectivity is explained by the selectivity-determining transition state

AM of the inverse electron-demand Diels–Alder reaction of the initially formed aurated pyrylium species.85

O

O

Ph

O

OH

PhO

O

O

Ph

Cl3AuKey intermediate

3 mol% AuCl3MeCN, 3 h, 80 °C

61%+

264 265

266

AM

The chromium complexes of the similar substrates can also undergo this cyclization mode, then the pyrylium species can be

attacked by alcohol R2OH as the nucleophile. The latter addition is perfectly diastereoselective, 268 is formed only by addition to

the p-face opposite to the Cr(CO)3 moiety.86 With other nucleophiles at low temperature the initial reaction occurs at the

carbonyl group, then at room temperature the cyclization of the alcohol places the group Nu and the Cr(CO)3 moiety on the same

face of the molecule.

R1

O

(OC)3Cr5 mol% PPh3AuNTf2

DCM, r.t., 30–60 min

R2-OH (5 equivalents)

O

R1

OR2

(OC)3CrR1 = alkyl, aryl, TMSR2 = alkyl, allyl, propargyl

268 (66–80%) Pure diastereomere

Me

(OC)3Cr

Nu

HOH

5 mol% PPh3AuNTf2, DCMNu, −20 °C

Nu:CH2=C(OSiMe3)OEt (58%)Nu:CH2=CCH2Sn(n-Bu)3 (73)

5 mol% PPh3AuNTf2,DCM, r.t. O

Nu

Me

(OC)3Cr

68–69%

Pure diastereomere

267

269270

A different setup is found in substrate 271. Now the nucleophilic nitrogen atom is directly on the aromatic ring, the cyclization

with the tert-butyl-vinyl ether provides 272 in a moderate diastereoselectivity of 73:27.87


N

R1

R2

OtBu N

R1

OtBu

R2

(4 equivalents), AuBr3 (1–10 mol%)

MS 4 A, toluene, r.t.

R1 = Ph, OiPrR2 = nPr, Me, Cy, Ph

272 (60–89%)syn:anti = 73:27 (for R1 = Ph; R2 = Cy)

271

Other pathways to polycyclic compounds include the reaction of diamine 273 and alkyne 274. The N,N-ketal 275 is formed

diastereoselectively with a trans-arrangement of the Ph and the Me substituent of the lactam ring.88 The homolog of 273, the

diamine 276, as expected with the same alkyne 274 leads to the six-membered ring in the center of the molecule, but at the same

time the two substituent on the lactame ring are now positioned in a cis-manner.

NH2

NH2

Ph

OHO

+PPh3AuOTf (1 mol%)

DCE, 100 °C, 24 hNH

N

OPh

Me

273 274 275 (78%)

NH2

NH2

Ph

OHO

+PPh3AuOTf (1 mol%)

DCE, 100 °C, 24 hNH

N

O

Ph

Me

276 274 277 (74%)

N

O

H

Ph

HN

HH

N

HN

HH

Me

H

O>>

2.23.8 sp3-Stereocenters from Allenes

The oxidative dimerization of allenes 278 by a gold catalyst and selectfluor as stoichiometric reagent delivers the bis-lactones 279.

Due to the large distance of the sterocenters, there is no stereoselectivity observed.89

•O

O

O

OO

O

71%

(i) Ph3PAu+

(ii) Select fluor

278 279

A perfect diastereoselectivity is observed in the cyclization of allenyl carbinols 280. Only one single stereoisomer of the product

281 is isolated, the configuration of the new stereocenter of the N,O-acetal is perfectly controlled.90 Here, the selectivity-

determining step is the intramolecular nucleophilic addition of the hydroxyl group to the acylimininum-species AN.


•

TMSOH

R

NH

OO

Ph

Ph5 mol% Au(PPh3)Cl/AgBF4

CH2Cl2, r.t., < 5 min O NR O

O

Ph Ph

5 examples, 78–87%

TMS

O N O

TMSO

Ph

Au(I)Ph

via:

Ph

100% diastereoselective

R = Ph, iPr, , ,OBn

OTBS

280

281

AN

A mixed situation we find in 283, the product of the gold(I)-catalyzed cycloisomerization of the alcohol 282. Although the

anellation of the two five-membered rings has to be cis, the relative configuration of these stereocenters and the stereocenter

bearing the phenyl substituent is not controlled, a 1:1 mixture of the two conceivable diastereomers was observed.91

Ph

OHO

H

Ph


CH3NO223 °C, 8 h

30%(dr = 1:1)

282283

A number of different intramolecular additions of nucleophiles to allenes proceeds with decent diastereoselecitivities.92

Hydroamination of the allene 284 provides the tetrahydropyrrole 285, in the case of a methyl substituent next to the new

stereocenter a 4:1 selectivity for the trans-isomer was detected, in the case of a phenyl group next to nitrogen, the dr was 16:1. Six-

membered ring formation was investigated with alcohol 286, tetrahydropyrans 287 can be isolated. In the case of the substrate

with a phenyl group next to oxygen, a 7.2:1 diastereoselectivity was observed, the diphenyl-substituted substrate with a methyl

group next to the allene again gave an inferior value of only 5.6:1. Using indole 288 as the nucleophile, delivered the carbocycle

289 with a cis-arrangement of the two substituents (dr 5:1).

NHCbz 5 mol% Au[P(t-Bu)2(o-biphenyl)]Cl/AgOTf

dioxane, 60 °C, 18 h

CbzN

R2R2

R1R1

a: R1:H; R2:CH3

b: R1:Ph; R2:H 80% (dr 16:1)

90% (dr 4:1)

284 285

5 mol% Au[P(t-Bu)2(o-biphenyl)]Cl/AgOTs

toluene, r.t., 5–75 min

R1 OOH

R3R2

R2R2

R2 R3

R1

286 287

a: R1:Ph; R2:H, R3:H

b: R1:H; R2:Ph, R3:CH3 96% (dr 5.6:1)

96% (dr 7.2:1)


5 mol% Au[P(t-Bu)2(o-biphenyl)]Cl/AgOTf

dioxane, r.t., 30 min

MeN

MeN

EE

289 (94%, dr 5:1)288

The combination of gold catalysis and halogen electrophiles has been used in the case of substrates 290 and 292. In both cases

diasteromerically pure starting materials were used and the axial-to-central chirality transfer worked well, for 291 a dr of 93:7 and

for 293 a dr of 95:5 was detected. The cyclic allenyl carbinol 294 also gave a decent result for the nonhalogenating reaction (dr

89:11), but a good result in the case of the halogenating reaction (dr 95:5).93

•

HO

OMe

Me

H

Ph

OH

Ph

OMe

Me

I

291 (68%, dr 93:7)

5 mol% AuCl1.1–1.5 equivalent NISCH2Cl2, r.t., 1 h

290

•

HO

OAc

Me

H

i-Pr

O

I Me

OAci-Pr

294 (traces)

+

293 (73%, dr > 95:5)

OH

i-Pr

OAc

Me

I

5 mol% Ph3PAuCl/AgBF41.1–1.5 equivalent NIStoluene, r.t., 1 min

292

OMe

Me

OH

•

1.5 equivalent NIStoluene, r.t., 25 min

Ph

i-Pr

OMe

Me

O

XH

i-PrPh

(A) 5 mol% Ph3PAuCl/AgBF4

(B) 5 mol% Ph3PAuCl/AgBF4

toluene, r.t., 2 h

A: X = H 76%, dr 89:11B: X = I 84%, dr > 95:5

295 (dr > 95:5)

296

A very useful case of diamination of an allene is found in the reaction of substrate 297. The reaction like a zipper closes the

bicyclic system via intermediates AO, AP, and AQ, the methyl substituent is positioned on the exo-face of the product 298, with an

outstanding dr of 50:1.94

C

PhPh N

H

O

NH

NO2IPrAuCl (5 mol%)AgPF6 (5 mol%)

DCM, r.t., 2 h93% Yield

NN

Ph

Ph O

NO2

H Me

298 (dr 50:1)

297


C

PhPh N

H

O

NHAr LAu

C

PhPh N

H

O

NHAr

LAu

HN

AuL

O

NHArPh

Ph

N

O

NHArPh

PhLAu

N

O

NHArPh

Ph

LAu

NN

Ph

Ph

O

H

AuL

HAr

NN

Ph

Ph

O

H

Ar

AO

APAQ

Another twofold reaction of an allenic substrate is found in the conversion of 299 with Gagosz’s catalyst. This time the

conversion is done under oxidative conditions, thus one double bond remains in the product 300. The lactone preferentially is

formed with a trans-arrangement of the methyl group and the oxygen substituent on the central five-membered ring (dr better

than 20:1).95

•O

O O

O

Select fluor (2.5 equivalent), Ph3PAuNTf2 (10 mol%)

MeCN (0.01 M), H2O (10 equivalent), r.t.

(2S,5S)-299 (dr > 20:1)(8R,8aS)-300 (80%, dr > 20:1)

If the allene is positioned in proper distance to an acetal group, a cyclization/cycloaddition with the silyl-protected allylsilane

can be observed. 301 provides aldehyde 302 in decent yields and with diastereomeric ratios between 8:1 and 11:1.96 The

unprotected homolog of the allylsilane, the alcohol 305, rather than an aldehyde provided the spiro-compound 306. Again in

good but unexplained diastereoselectivity.

CHO

H

R

CHO

H

R

R

OCH3

OCH3

OTMS

TMS

5 mol% Ph3PAuSbF6CH2Cl2, 25 °C, 30 min

10 mol% NEt3CH2Cl2, 25 °C, 16 h

(i)

(ii)

+

R = HR = MeR = nPr

302 303

(63%)(61%)(64%)

302/303 8.0:1302/303 8.9:1302/303 11.1:1

301


H

OCH3

OCH3

TMS

5 mol% Ph3PAuSbF6CH2Cl2, 25 °C, 4 h

306 (50%, dr > 20:1)

OH

O

304

305

Although substrate 307 seems to cover alkyne reactivity, in the initial gold catalyzed step an (achiral) allene AR is formed. Only

in the subsequent step, the cyclization of the allene, the new stereocenters are generated. Ultimately, the bicylohexanes 308 were

isolated, in very good diastereoselectivity.97

R1

OAc

R3

R2

R1:Ph, CH3, C5H11, , ,

R2:H, CH3

R3:H, CH3, CH2OAc,

R4

PhO

Cl

ClPh

R4:H, CH3

OAc

R3R1

R2

R4

1 mol% [Au]

CH2Cl2, r.t., 5 min–5 h

307 308

R1 OAc

Mechanism via:

[Au]

AcO AuLR1

H[Au] OAc

R1

Pt-Bu

t-Bu

Au NTf2

[Au]:

AR

2.23.9 sp3-Stereocenters from Nucleophilic Additions to Alkenes

For alkenes the intramolecular addition of nucleophiles has been investigated, too. The hydroamination of 309 for both an ethyl

and a phenyl substituent a similar dr of 3.6:1 or 3.9:1 was detected, the major diastereomer being the cis-product 310.98 With a

different position of the directing substituent in 311, the induction varied much stronger, values of 2.9:1 to 5.5:1 could be

observed for 312.


NH

Ph O

NHRN

NHR

O

Ph

IPrAuCl (5 mol%), AgOTf (5 mol%)

MeOH, r.t., 15–24 h

R = EtR = Ph

y = 99%y = 92%

dr = 3.9:1dr = 3.6:1

309310

NH

O

NHR2

N

NHR2

OIPrAuCl (5 mol%), AgOTf (5 mol%)

MeOH, r.t., 15–24 h

R1 R1

R1 = R2 = PhR1 = Ph; R2 = EtR1 = iPr; R2 = Ph

y = 99%y = 84%y = 98%

dr = 2.9:1dr = 3.3:1dr = 5.5:1

311312

In the case of 313 the spiro-product 314 could be isolated with a 3.6:1 ratio of stereoisomers.99

CbzN

OH

5 mol% Au[P(tBu)2(o-biphenyl)]Cl/AgOTf, dioxane, 60 °C, 22 h

91% (3.6:1)

NHCbz

OH313 314

Mechanistic control experiments with deuterated compounds can potentially also indicate a diastereoselective reaction

pathway, but for compound 315 only a mixture of both diastereomers 316 and 317 could be detected, the anellation of the rings

being cis in both isomers.100

D

PhPh

D

NH

Ts

N N+

DHHD

HHD

DTs Ts

PhPh Ph

Ph5 mol% Ph3PAuOTf2

toluene, 85 °C

Yield oleated yield of both diastereomers: 96%

185 316 317

The situation was different for the intramolecular hydroamination. The (E)-isomer 318 gave 319 with a 22:1 selectivity, after

the conversion of the (Z)-isomer 320 an excellent 43:1 selectivity toward 321 was detected. This directly resulted from the high

trans-selectivity of the aminoauration step, as shown below for intermediate AS.101


NHTs

D

NHTs

D

Ph3PAuCl (5 mol%)Select fluor (2.0 equivalent)

MeCN (anhyd.)60 °C, 2 h

+ PhB(OH)2

TsN

Ph

H D

TsN

Ph

D H

319 (83%, dr = 22:1)

321 (74%, dr = 43:1)

NH D

AuPh X

PPh3X = Cl or F

Ts

318

320

AS

The diyne substrate 322 in an initial step delivers the vinylfuran AT by a cyclization/hydroarylation, the final hydroalkoxylation

is not diastereoselective, a 1:1 ratio of the product-stereoisomers 323 was isolated.102

O

OH

1 mol% AuCl3

MeCN

O

OH

O

O

3241:1 mixture ofdiastereoisomers

322 AT

Even dithioketals are tolerated in gold(I)-catalyzed conversions, the gold catalyzed allylic substitution with allyl alcohols 325

and 327 gave the products 326 and 328. The piperidine 326 shows a cis-arrangement of the two substituents (dr 25:1). In the case

of the allylic alcohol 327 with a methyl substituent, the (E)-configurated double bond is formed in 327 (dr 50:1).103

S S

OHNH

Bn

S S

N

Bn

326(91%, dr 25:1)

5 mol% AuCl,5 mol% AgSbF6

dioxane, 100 °C,48 h325

OHNH

Bn

same conditions

14 h

N

Bn

327(99%, dr 50:1)326

Usually, malonate moieties are frequently used as tethering elements in substrates for methodology investigation. Although the

allylic substrates 328, 329, and 332 indeed give the products of an electrophilic cyclization/water addition with 1,3-trans


arrangement of the hydroxy and the vinyl group in 330, 331, and 333 (dr between 40:1 and 99:1), the tertiary or benzylic allylic

alcohols 334 and 335 incorporate one ester group of the malonate unit to deliver 336 and 337. For the latter, again a trans-

arrangement of the oxygen substituent and the vinyl group are observed (dr 66:1 to 99:1). This can be explained by the transition

state AS, minimizing unfavorable interactions in the approach of the hydroxyl nucleophile to the cationic intermediate.104

OAc

R

O

O

O

O

328, R = H329, R = Cl

AuCl3 (5 mol%)H2O (1 equivalent)

DCE, r.t., 1.5 h O

O

OO

OH

R

330, R = H (79%), dr = 50:1331, R = Cl (74%), dr = 40:1

OAc

O

O

O

O

AuCl3 (5 mol%)H2O (1 equivalent)

DCE, r.t., 1.5 h O

O

OO

OH

332 333 (86%), dr = 99:1

OAc

R

O

O

O

O

334, R = H335, R = Cl

AuCl3/AgPF6 (1 mol%)H2O (1 equivalent)

DCE, 50 °C, 1.5 hOO

R

336, R = H (84%, dr = 66:1)337, R = Cl (98%,dr = 99:1)

O

O

OAc

O

O

O

O

338 339 (79%, dr = 99:1)

AuCl3/AgPF6 (1 mol%)H2O (1 equivalent)

DCE, 50 °C, 1.5 hOO

O

O

RCO2Me

OOMe

H2O

HH

H

AS

If no second olefin is present, the allylic group directly reacts with the malonate. This is exemplified by the reaction of 340,

which in a diastereoselective cyclization (dr 1.5:1 to 99:1) delivers the five-membered carbocycles 341 with a 1,3-cis-orientation of

the ester group and the vinyl group on the lactone ring. This relative configuration is dictated by the bicyclic intermediates AT or

AU.105


OAcR1O2C

R1O2C R4

O

R2

O

R1O

O

R3R2

R3R4

O

BnO

BnO2C

Me

H H

OMeO2C

H H

MeO

R1 = MeR2 = HR3 = R4 = (CH2)2

R1 = BnR2 = MeR3 = R4 = (CH2)2

Possible intermediates

A: 2 mol% AuBr3DCE, 40 °C

B: 2 mol% Ph3PAuCl2 mol% AgSbF6DCE, 70 °C

Conditions A or B

341 45–99%,dr 1.5:1 to > 99:1

340

AT AU

Once more, the (E)- and the (Z)-isomer of the deuterated olefins 342 and 344 stereoselectively gave the cis- (343) or the trans-

diastereomer (345) of the 6-endo-trig cyclization. In these oxidative cyclizations once more selectfluor is used, the stereochemical

outcome confirms the initial anti-aminoauration and a subsequent C�O bond formation without change of configuration at the

C-atom bearing the gold. Without water as the nucleophile, the phenyl groups are attacked, the anellated bicycle 347 could be

isolated. The conversion only afforded the diastereomer depicted.106 Intermediate AV has been suggested for the stereoselectivity-

determining step.

NHTs

D

PhPh 5 mol% [(Ph3P)AuSbF6],

1.1 equivalent NaHCO3, 2 equivalent Selectfluor,

CH3CN/H2O (20:1), 80 °C, 2 h

NTsPhPh

OH

D

343(79%, Single diastereomer)

342

NHTsPh

PhD same conditions NTsPh

Ph

OH

D

345(78%, Single diastereomer)

344

NHR1

R2

PhPh 5 mol% [(Ph3P)AuSbF6],

1.1 equivalent NaHCO3,2 equivalent PhI(Phtal),

DCE, 90 °C, 12 hR1= Ts, MsR2= Me, Ph

NR1

R2

PhNR1

Ph

[Au]III

H

R2

SN2

via

347Diastereomerically pure

42–71%

346

AV

In the anellation of phenols like 348, 350 or 352 a clear preference for the syn-product was observed. With the simplest phenol

(348), a dr of only 3:1 was detected in 349, whereas 350 with three methyl substituents and an additional hydroxyl group gave a

selective reaction at the less hindered hydroxyl group with the free ortho-position, a dr of 12:1 was obtained for 351. The b-naphtol

352 yielded 353, a dr of 11:1 was reported.107


OH O

2 equivalent, AuCl3 (5 mol%), AgOTf (15 mol%)

DCM, 40 °C, 16 h

349 (71%, syn:anti = 3:1)348

OH O


DCM, 40 °C, 16 h

351 (72%, syn:anti = 12:1)

HO HO

350

OH O


DCM, 40 °C, 16 h

353 (80%, syn:anti = 11:1)352

Six- and seven-membered 1,3-dienes 354 could be converted to the anellated heterocycles 355. The stereocenter at the linkage

of the tether between the 1,3-diene and the incoming nucleophile is efficiently directing the nucleophile to the cis-face of the p-

system. A selective 1,4-addition is observed.108

n = 1,2Ph Ph

NHSO2ArSO2ArN

PhPhn

5 mol% PPh3AuCl5 mol% AgOTf

toluene, 85 °C, 18 h355(78−88%,Single diastereomer)

n

354

2.23.10 sp3-Stereocenters from Reactions with 1,3-Dipoles

Interesting effects were observed in 1,3-dipolar cycloadditions of the nitrone 356. With methyl acrylate in the absence of a catalyst

the conversion needed 96 h and gave an endo/exo-ratio of 73:27. With gold(III) chloride the reaction time was reduced to 72%, at

the same time the dr changed to 55:45. Sodium tetrachloroaurate as catalyst further reduced the reaction time (54 h), and again

shifted the product ratio toward the exo-product 359 (44:56). With a gold(I) catalyst the reaction was even faster (48 h), but the

diastereoselectivity switched back to 66:34.109


N

N

O

Ph +OMe

O

N N

N O N O

COOMe COOMe

Ph Ph

+

5−10 mol% Au(I)/Au(III)

acetone, reflux, 46−120 h

Catalyst:

None

PPN[Au(I)(mes)Cl]

[Au(III)Cl3(tht)]

73/27, 100% conversion in 96 h

endo exo


Na[Au(III)Cl4] 44/56, 100% conversion in 54 h


356 357358 359

endo/exo

In the case of substrate 360, again containing not only a nitrone but also an alkyne and a tertiary alcohol, an intramolecular

transfer of the oxygen atom from nitrogen to the benzylic carbon of the triple bond was observed. In the course of that transfer, a

ring-expansion of the cyclopentanol to the cyclohexanon-enol is assumed, then the diastereoselectivity-determining step is the

addition of that enol to the benzylimin in the presumed intermediate AW. Here, the authors suggest a template effect of the

gold(III) catalyst as depicted below in structure AW. Thus, the only diastereomer of the product which is observed is the spiro-

compound shown (361). The reaction can be extended to allylic-propargylic alcohols 362, which then again provide a single

diastereomer of the indanone derivative 363.110

NBn

O−

OH

+

2 mol% AuCl3

MeNO2, r.t., 1 h, 78%

NHBn

O O

BnN

O

OAu−

NPh

O

OH

+

−2 mol% AuCl3

DCM, r.t., 75%, dr 14:1

NHPh

O

MeO

Me

360 361

362 363

AW

In addition to the example of 356 above, another [3þ 2] cycloaddition which can be conducted in both a diastereoselective

and an enantioselective way, is the reaction of N-methylmaleinimid 364 and the imine 365. The reaction exclusively provides the

endo-product 366.111

N OO

NPh COOMe

+

10 mol% (Sa)-BinapAuCl10 mol% AgTFA

toluene, r.t., 16 hNH

N OO

COOMePh

endo-366

90% conversion by NMR99% ee

364

365


2.23.11 sp3-Stereocenters from Nazarov-Like Cyclizations

The intermediacy of pentadienyl cation-like structures and their cyclization to five-membered rings is an important principle in

gold catalyzed reactions, as found in several examples.112 With regard to diastereoselectivity, the conversion of the 1,3-enyne 367,

bearing a propargylic acetoxy group, could be a good example. In the course of the conversion two new stereocenters are formed,

but only for R2 and R3 representing an anellated ring a good cis-selectivity (minimum 94:6) was described for 368, noncyclic cases

with both R1 and R2 a H have not been discussed.113

R

OAc

R1

R2

1 mol% AuCl[PPh3)/AgSbF6

wet CH2Cl2, r.t., 0.5−2 h

O

R

R3

R2

8 examplesyields: 74−95%

R = c-Hexyl, t-Bu, n-pentyl

R1 = H, CH3, Ph, CH2CH2OTIPS

R1/R2 = c-Pentene, c-Hexene, c-Heptene

R2 = H

367368

2.23.12 sp3-Stereocenters from Wagner–Meerwein Shifts

1,2-Transposition of groups by Wagner–Meerwein shifts are an interesting and useful principle for organic synthesis. Although in

many of these reactions ultimately aromatic products are formed, there are some examples which involve the aspect of diaster-

eoselectivity. One example being the transformation of the silyl-protected allylic-homopropargylic alcohols 369. These deliver the

bicyclic formyl compounds 370 with a cis-anellation of the two rings. The mechanistic interpretation involves a number of different

intermediates like AX and AY, and a Wagner–Meerwein shift in AX would set the new stereocenter bearing the formyl group.114

Et3SiO R CHO

H R


1.1 equivalent iPrOH

CH2Cl2r.t., 20 min

54−83%

Et3SiO H

R4

R1

[Au]

R2

R3

R2

Et3SiO

R1R4

H

[Au]R3

−SiEt3

[Au]

R1

R4R3O

R2

H R4

R1

[Au]

R3

R2

Et3SiO

H2C

R4

R1

R3

R2

OSiEt3

[Au]

369 370

A AY


More examples of this diastereoselecitve mode of reaction have been reported, for example, the rearrangement of the silyl-

protected allylalcohol 370, which delivers a single diastereomer of 371.115

OSiEt3

OMe 10 mol% PPh3AuCl5 mol% AgSbF6

i-PrOH (1.2 equivalent)DCM, r.t., 10 min

OMe

CHO

H

371(83%,Pure diastereomer)

370

Another ring-expansion is involved in the formation of 373 from 372. The product shows a specific trans-arrangement of the

methyl and the phenyl group. With a different counter ion a different product is obtained, 374 is isolated with (E)-configuration

of the exocyclic olefin.116 Even more complex is the connectivity change in the transformation of 375 to 376.

(E)

PhE

EMe

O PhE

O

E

E

E

Ph

Ph

Me

E

Ph

E E

OMe Ph

DCE, 80 °C, 3 h(A) 5 mol% IPrAuCl/AgOMs

DCE, 80 °C, 22 h(B) 5 mol% IPrAuCl/AgPF6E = CO2Me

373 (94%)

374 (84%)

372

E E

O E

H

O

H

Ph

E

EE

5 mol% IPrAuCl/AgPF6

DCE, 80 °C, 4 h

376 (98%)E = CO2Me

375

Ph

The isomerization of the epoxide 377 with a strained cyclopropyl ring and an alkynyl group shows a ring-expansion to an

eight-membered ring in 380 in the presence of NCS. With NBS or NIS the six-membered vinyl halides 379 were formed. The

diastereoselectivity was reported to be very good.117


O

Ar

H R2

R1

O

Ar

O

R2

R1Cl

O

HO

H

R1Ar

X

R2

O

HO

H

R1ArR2

5 mol% [Au]

DCM, r.t.O

H

R1ArR2

2 equivalent H2O

O

HO

H

R1ArR2

[Au][Au]NCl

O

O

5 mol% Ph3PO1 equivalent NCS

Ph3PO

5 mol% Ph3PO1 equivalent NBS/NIS

2 equivalent H2O

[Au] = AuCl3 380 (53−83%)[Au] = PicAuCl2R1 = Me, n-pentylR2 = H, Me

379 (56−75%)[Au] = AuCl3R1 = Me, n-pentylR2 = H, Me

377

378

AZ

H+− −

The reaction mechanism shown above is well-proven, in the absence of halogenating agents the product of the proto-

deauration of the intermediate AZ, the bicyclic enol ether 378 could be isolated.

The same is true for the substrate 381. There is a pronounced preference for the group R being in an endo-position in 382/383.

Depending on the group, R dr values between 10:1 and 17:1 were observed. With an a,b-unsaturated carbonyl compound 386 as

reaction partner the tetracyclic bis-acetal 387 is isolated, again as a single diastereomer. The reaction can also be conducted in the

presence of an 1,3-diene 388 as the nucleophile, this yielded the tricyclic product 389 with R1 on an endo- and R4 on an exo-

position. In the latter two reaction types the reaction was conducted in dry dichloromethane with 2 equivalents of water.

Presumably, the authors did limit the amount of the potentially competing water to exactly 2 equivalents.118

5 mol% AuCl3, 2 equivalent H2O

CH2Cl2, 25 °C, 40 min+

R = MeR = n-C5H11

382 383

(83%)(79%)

382/383 10:1382/383 17:1

OH H

R

O

HO

H

R O

HO

H

R

381

CH2Cl2, 25 °C, 1 hO

R2

H H

R1

O

10 mol% Ph3PAuCl/AgSbF6CH2Cl2, 25 °C, 6−10 h

(i) 5 mol% AuCl3, 2 equivalent H2O)

(ii) SiO2 filtration

(2 equivalent)

R3

O

O

HH R1

H

OR2

R3

386 (71−91%)

R1 = n-C5H11, MeR2 = ArylR3 = Me, Et, n-C5H11

384

385


CH2Cl2, 25 °C, 1 hO

Ph

H H

R1

10 mol% Ph3PAuCl/AgSbF6CH2Cl2, 25 °C, 6−10 h

(i) 5 mol% AuCl3, 2 equivalent H2O

(ii) SiO2 filtration

(2 equivalent)

O

HH R1

R2

388 (45−78%)

R1 = n-C5H11, MeR2 = H, MeR3 = H, MeR4 = H, Me, Et

R3

R4

Ph

R2 R3

R4

384

387

2.23.13 sp3-Stereocenters from Indoles

Indoles represent a class of substrates which in gold catalysis shows an interesting and useful reactivity. A beautiful example is the

reaction of substrate 389 which delivers a [3.3.3]propellane product (390, confirmed by an X-ray crystal structure analysis), by

definition all the five-membered rings have to be cis-anellated. An example of an intermolecular reaction is the tetramerization of

two indole molecules (391) and two molecules of 392. The two stereoisomers 393 and 394 form with a moderate diastereo-

selectivity of aprroximately 2:1.119

NH

N Ts

Me

NH

MeNTs

[Au] 5 mol%

toluene, 90 °C, 48 h

390 (58%)389

NH

+

CF3

CF3

[Au] 5 mol%

toluene, r.t., 12 h

HN

Me CF3

CF3

CF3

F3C

NH

HN

Me CF3

CF3

CF3

F3C

NH

+

393 (45%) 394 (28%)

P Au NCMe

SbF6

[Au]=

392

391

With the propargylic esters 395 the products of a formal [2þ 2]cycloaddition can be obtained. The proposed mechanism for

the formation of 396 involves the intermediates BA and BB. The diastereoselectivity-determining step is the formation of the

species BD from BC, in this spirocycle the attack of the vinylgold-moiety with the electrophilic center has to occur in the shown

way for geometrical reasons.120


N

O

O

R1

R2

RN

OO

R1

R2

R

1−10 mol% AuCl[PPh3]/AgSbF6

CH2Cl2, r.t., 2−12 h

3966 examples(69−98%)

R = H, CH3

R1 = n-pentyl, Ph, i-Pr

R2 = CH3, Bu, CH2CH2CH2Br, Ph, c-hexyl

H

395

Mechanism via:

N

O

O

R

R2

R1

Au(PPh3)

N

O

O

R

R2

(Ph3P)AuR1

N

O

O

R

R2

Au(PPh3)

R1

N

OO

R1

R2

R

Au(PPh3)

BA BB BC

BD

The regio-selectivity of the electrophilic attack on the vinylgold intermediate strongly depends on the catalyst, the example of

397 shows that with gold(I) 398 is formed preferentially, whereras gold(III) delivered 399.121 Again both compounds are formed

in perfect diastereoselectivity.

NO

O

Me

nBu

Me

N

Me

O

Me

O

H

nBu

+N

Me

O

O

MeH

nBu

ClAu(PPh3)/AgSbF6 (5mol%), CH2Cl2, r.t., 0.5 h

Dichloro(pyridine-2-carboxylato)gold(III) (5 mol%), THF, reflux, 2 h

<2%52%

83%14%

397398 399

With the propargylic alcohol in 400 an enyne cycloisomerization and an intramolecular and regio-selective alcohol addition

provide 401. The protected amine 402 delivers the [4.3.3]propellane 403, again the other diastereomer is not accessible for

geometrical reasons.122


N

COOMe

OHPh3PAuCl/AgSbF6

r.t., 1 h,83%

N

COOMe

O

401400

NH

NHBoc

5 mol% Ph3AuSbF6

Toluene, 60 °C,87%

NH

NBoc

402 403

2.23.14 Conclusion

After 10 years of exponential growth in homogeneous gold catalysis there exist numerous examples of diastereoselective

homogeneous gold catalyzed reactions. Most of the publications either provide clear evidence for the relative configuration of the

stereocenters in the products or deliver products with known relative configuration. But there is also a number of publications,

where the assignment of the relative configuration is not discussed in detail.

Due to the many different reaction pathways and the many different intermediates involved in the diastereoselectivity-

determining step, it is impossible to use only a few generalized concepts to prognosticate the outcome of such reactions.

In combination with the numerous enantioselective gold catalyzed reactions, the intrinsically high diastereoselectivity found

in many reactions will be highly useful in organic synthesis.

References

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