catalytic prins cyclization using in(otf) 3 and silyl ...cbc/cv/teckpeng/prof loh research...

2 0 0 5 © T H I E M E S T U T T G A R T • N E W Y O R K 319

Category

Metal-Catalyzed Asymmetric Synthesis and Stereoselective Reactions

Key words

Prins cyclization

diastereoselectivity

tetrahydropyrans

trimethylsilyl halides

K . - P . C H A N , T . - P . L O H * ( N A N Y A N G T E C H N O L O G I C A L U N I V E R S I T Y , S I N G A P O R E )

Prins Cyclizations in Silyl Additives with Suppression of Epimerization: Versatile Tool in the Synthesis of the

Tetrahydropyran Backbone of Natural Products

Org. Lett. 2005, 7, 4491-4494.

Catalytic Prins Cyclization using In(OTf)3 and Silyl Additives

Significance: Use of a catalytic amount of In(OTf)3 (5 mol%) and trimethylsilyl halides gave a highly diastereoselective Prins cyclization. Re-duced epimerization was achieved by using a weaker Lewis acid, In(OTf)3 and also TMSBr as additive which also acts as the halide source. Ex-cellent diastereoselectivity for the 2,4,6-trisubsti-tuted tetrahydropyran products were observed.

Comment: Although the Prins cyclization is the most common method to synthesize a THP ring, there are limitations such as substrate scope, the need to use a stoichiometric amount of Lewis acid and epimerization of the starting homoallylic alco-hols due to transfer between the homoallylic alco-hol and aldehyde. By using a catalytic amount of a weak Lewis acid and silyl additives to suppress epimerization, the latter two problems are avoid-ed. Sterically hindered substituents such as cyclo-hexyl were tolerated as well as a,b-unsaturated al-dehydes. The key reaction was successfully applied towards the total synthesis of (–)-centro-lobine.

OHO

H R

TMSX (1.2 equiv)In(OTf)3 (5 mol%)

CH2Cl2, 0 °C O R

X

X = Cl, Br, IR = Alk, Ar, Vinyl 25 examples

61–94% yield ee = 76–84%

SYNFACTS Contributors: Mark Lautens, Josephine YuenSynfacts 2005, 3, 0319-0319 Published online:01.12.2005 Published online: 21.11.2005

DOI: 10.1055/s-2005-916140; Reg-No.: L07005SF © Georg Thieme Verlag Stuttgart · New York

Dow

nloa

ded

by: N

anya

ng T

echn

olog

ical

Uni

vers

ity. C

opyr

ight

ed m

ater

ial.

2 0 0 5 © T H I E M E S T U T T G A R T • N E W Y O R K54

Category


Key Words

asymmetric catalysis

allylation

trialkylallyl-stannanes

indium

aldehydes

homoallylic alcohols

Y. -C T E O , K . - T. TA N , T. - P. L O H * ( NAT I O NA L U N I V E R S I T Y O F S IN G A P O R E , S IN G A P O RE )

Catalytic Asymmetric Allylation of Aldehydes via a Chiral Indium(III) Complex

Chem. Commun. 2005, 1318-1320.

Asymmetric Allylation of Aldehydes Catalyzed by a Chiral Indium(III)-BINOL Complex

Significance: The first chiral indium(III)-catalyzed allylation reaction of aldehydes is disclosed. By using catalytic InCl3/(S)-BINOL, highly enantiose-lective formation of homoallylic alcohols was achieved using allyltributylstannane.

Comments: This allylation protocol developed is relatively simple, mild and affords excellent enan-tioselectivity with both aromatic and aliphatic al-dehydes. The most likely drawback is the high toxicity of organotin reagents. Further studies to determine the scope of the reaction with a variety of aromatic aldehydes is required. Preliminary mechanistic studies revealed that the active chiral Lewis acid catalyst is a BINOL-In(III)-allyl complex. There are many asymmetric allylation reagents or allylation catalysts present in the literature (for a review see: S. E. Denmark, J. Fu Chem. Rev. 2003, 103, 2763-2794).

RCHO SnBu3+R

*

OH

(S)-BINOL/InCl3 (20 mol%)

4Å MS/CH2Cl2

53–76%7 examples

ee = 90–96%

SYNFACTS Contributors: Mark Lautens, Y. Eric FangSynfacts 2005, 0, 0054-0054 Published online: xx.xx.2005 DOI: 10.1055/s-2005-869936; Reg-No.: L00405SF © Georg Thieme Verlag Stuttgart · New York

Dow

nloa

ded

by: N

anya

ng T

echn

olog

ical

Uni

vers

ity. C

opyr

ight

ed m

ater

ial.


Category

Synthesis of Natural Products and Potential Drugs

Key words

Barbier allylation

ring-closing metathesis

T . - P . L O H , * C . - L . K . L E E ( N A N Y A N G T E CH N I C A L U N I V E R S I T Y , S IN G A P O R E )

Gram-Scale Synthesis of (–)-Epibatidine

Org. Lett. 2005, 7, 2965-2967.

Synthesis of (–)-Epibatidine

Significance: (–)-Epibatidine, an alkaloid isolated from the Ecuadorian dendrobatid poison frog Epipedobates tricolor, is a nonopiate analgesic 200 times more potent than morphine. The scarci-ty of (–)-Epibatidine (1 mg from 750 frogs) has hampered its biological evaluation. There are many syntheses of Epibatidine but few of them are practical. The present synthesis is short (12 steps, 12% overall yield) and scalable.

Review: Recent syntheses of Epibatidine: H. F. Olivo, M. S. Hemenway Org. Prep. Proced. Int. 2002, 34, 1-26.

Comment: The key steps are (a) a diastereoselec-tive Barbier allylation of the imine A derived from (S)-phenylglycine and (b) a ring-closing metathesis to generate cyclohexene C. A regrettable step was the bromination of alkene C, which was effi-cient (92%) but the diastereoselectivity was poor (2:1), the desired isomer (corresponding to D) be-ing the minor isomer. The undesired major isomer could be recycled by reductive debromination to return to C.

HN

H

N

Cl

HN

H

NCl

AB C

D (dr = 2:1)

(−)-Epibatidine

endo-Epibatidine

Br N

Cl

Zn

THF, 0 °C93%

RuClCl

PCy3Ph

NMesMesN

(10 mol%)

CH2Cl2, r.t.94%

Barbier allylation

ring-closing metathesis

4 steps

1. MeCN, 82 °C

2. Bu3SnH, ACCN PhH, 80 °C 84% (2 steps)

t-BuOK

t-BuOH, 83 °C58%

intramolecular substitution

N

CO2Me

Ph HN

CO2Me

Ph

N

ClHN

CO2Me

Ph

N

Cl

NH2

N

Cl

Br

Br

SYNFACTS Contributors: Philip Kocienski, John CookseySynfacts 2006, 1, 0006-0006 Published online: 05.01.2005 Published online: 16.12.2005

DOI: 10.1055/s-2005-621659; Reg-No.: K06605SF © Georg Thieme Verlag Stuttgart · New York

Dow

nloa

ded

by: N

anya

ng T

echn

olog

ical

Uni

vers

ity. C

opyr

ight

ed m

ater

ial.


Category

Metal-Mediated Synthesis

Key words

copper(I)

Tol-BINAP

asymmetric addition

Michael addition

Grignard reagents

a,b-unsaturated esters

S . -Y . W A N G , S . - J . J I , * T . -P . L O H * ( N A N Y A N G T E CH N O L O G IC A L U N IV E R S IT Y , S IN G A P O R E

A N D S U Z H O U ( S O O C H O W ) U N I V E RS IT Y , J I A N G S U , P . R . O F C H I N A )

Cu(I) Tol-BINAP-Catalyzed Enantioselective Michael Reactions of Grignard Reagents and Unsaturated Esters

J. Am. Chem. Soc. 2007, 129, 276-277.

Cu(I)-Catalyzed Asymmetric Michael Addition of Grignard Reagents to a,b-Unsaturated Esters

Significance: In this article, an extension to the Cu(I)-catalyzed asymmetric Michael addition of various Grignard reagents to a,b-unsaturated esters is presented. CuI along with the chiral Tol-BINAP ligand is used as catalyst system in this re-action. A major advantage to previously described methods is the unproblematic addition of bulky alkyl and homoallylic Grignard reagents which still gives high enantioselectivities and good to excel-lent yields. The authors also report that the abso-lute stereochemistry of the products resulting from the asymmetric Michael addition can be reversed with equally good enantioselectivities by using ei-ther the enantiomer of the chiral ligand or by using the geometrical isomer of the respective unsatur-ated ester.

Comment: The method allows the performance of a highly regio- and enantioselective Cu(I)-cata-lyzed Michael addition reaction even with sterically hindered and homoallylic Grignard reagents. It is thereby applicable to a variety of a,b-unsaturated esters and gives good to excellent yields and enantioselectivities.

OMe

O

R' OMe

O

OMe

O

OMeO

EtMgBr

R OMe

OEt

OMe

OR

OMe

OEt

OMe

Et O

PTol2PTol2

(R)-Tol-BINAP

RMgBr,CuI (1.0 mol%),

(R)-Tol-BINAP (1.5 mol%)

t-BuOMe, –40 °C

R = Et, n-Pr, n-Bu, n-Pent, Hept, i-Pr, i-Bu, homoallyl

86–90% yield90–93% ee

Et-MgBr,CuI (1.0 mol%),


t-BuOMe, –40 °C *

R' = Me, Pr, i-Pr, Ph, 2-furyl, BnOCH2, Bn, Ph(CH2)2

E or Z

80–90% yield70–95% ee


93% ee


94% ee

(S)-Tol-BINAP (1.5 mol%)94% ee

93% ee

SYNFACTS Contributors: Paul Knochel, Tobias ThalerSynfacts 2007, 4, 0425-0425 Published online:03.04.2007 Published online: 23.03.2007

DOI: 10.1055/s-2007-968325; Reg-No.: P02407SF © Georg Thieme Verlag Stuttgart · New York

Dow

nloa

ded

by: N

anya

ng T

echn

olog

ical

Uni

vers

ity. C

opyr

ight

ed m

ater

ial.


Category


Key words

polyene cyclization

tin

cationic

Y . - J . Z H A O , S . - S . C H N G , T . -P . L O H * (N A N Y A N G T E CH N O L O G IC A L U N IV E R S I T Y ,

S I N G A P O R E )

Lewis Acid-Promoted Intermolecular Acetal-Initiated Cationic Polyene Cyclizations

J. Am. Chem. Soc. 2007, 129, 492-493.

Intermolecular Acetal-Initiated Cationic Polyene Cyclizations

Significance: This report describes the intermo-lecular acetal-initiated polyene cyclization induced by SnCl4. The authors do a nice job in optimizing the reaction and find a chiral templated acetal that allows for considerably high dr values. The abso-lute and relative stereochemistry were determined for the products through derivatization and X-ray crystallography. Some of the cyclization products were also functionalized to various terpenes. Im-portantly, this report does not require the some-times difficult and tedious incorporation of the ac-etal into the cyclization precursor.

Comment: While intramolecular polyene cycliza-tions have received attention over the years, the intermolecular acetal-initiated counterpart has not. Many of the previous reports by W. S. Johnson deal with intramolecular cyclizations using a chiral acetal at the terminal position (see review below). This intermolecular version is much more difficult. It provides a very interesting foundation for future exploration of this operationally simple cyclization to complex architecture.

Review: W. S. Johnson Tetrahedron, 1991, 47, xi-l.

R

O

O

Ph+

SnCl4 (2.0 equiv)

CH2Cl2 (0.05 M)–78 °C, 0.5 h

R*O

Ph

R

R = H, i-Pr, OMe, Me

HH

R*O

Ph

R

HH

R*O

Ph

R

HH1

1''

1'

65–89% yield (1 + 1' + 1'')dr = 82:18–86:14 [(1 + 1''):1']

OO

H

PhMe

H

MeH

OO

H

PhMe

H

MeH

SnCl4

OO

H

PhMe

H

MeH

SnCl3

Ph

OHO Ph

MeH

MeH

H

major product

Major pathway

SYNFACTS Contributors: Hisashi Yamamoto, Matthew B. BoxerSynfacts 2007, 4, 0407-0407 Published online:03.04.2007 Published online: 23.03.2007

DOI: 10.1055/s-2007-968360; Reg-No.: H01507SF © Georg Thieme Verlag Stuttgart · New York

Dow

nloa

ded

by: N

anya

ng T

echn

olog

ical

Uni

vers

ity. C

opyr

ight

ed m

ater

ial.


Category


Key words

imines

indium

secondary amines

Z . - L . S H E N , T . - P . L O H * ( N A N Y A N G T E C H N O L O G I CA L U N I V E R S IT Y , S I N G A P O R E )

Indium-Copper-Mediated Barbier-Grignard-Type Alkylation Reaction of Imines in Aqueous Media

Org. Lett. 2007, 9, 5413-5416.

In(0)/Cu(I)-Mediated Alkylation of Imines in Aqueous Media

Significance: The direct addition of alkyl organo-metallic to imines is known to be a challenging re-action. A Barbier–Grignard-type alkylation of imi-nes with secondary alkyl iodides in water, as reported here, is a good alternative. The imines are obtained in situ from aldehydes and amines. Both aliphatic and aromatic aldehydes can be successfully used. A diastereoselective variant of this reaction, using an enantiopure amine, is also described. The mild condition and simplicity makes this method attractive for scale-up pro-cesses.

Comment: This reaction can be considered as a three-component condensation and may find use in combinatorial chemistry. In the absence of CuI, the yields are low, and CuBr and CuCl are less ef-ficient. Admittedly, the In-Cu pair causes the for-mation of a radical from the alkyl iodide, which fur-ther reacts with an imine. L-Val-OMe demonstrated the best diastereoselectivity in the addition reac-tion among the tested chiral auxiliaries. It can also be readily cleaved after the reaction (see scheme).

R1

O

H

R2 NH2

R3

R4

I

NH

Br

NH Cl

HN

Br

CO2Me HN CO2Me

Me

Me

HN CO2Me

CH2Cl2

HNOH

NH

Me

Me

CH2Cl2–MeOH

R4

R3

R1

NHR2

Pb(OAc)4

NH2

Me(CH2)7

NH CO2Me

NH

Me

Me

+ +In (6 equiv), CuI (4 equiv)

InCl3 (0.1 equiv)H2O, r.t., 1 d

R1 = Ar, n-Alk

R2 = Ar, Bn, n-Alk

R3, R4 = n-Alk, (CH2)n

84% 68% 88% 61%, dr = 3:2

63%, dr = 88:12 63%, dr = 82:18 69%, dr = 89:11

DIBAL-H

75% 60%

SYNFACTS Contributors: Paul Knochel, Andrei Gavryushin Synfacts 2008, 3, 0296-0296 Published online: 03.03.2008 Published online: 21.02.2008


Dow

nloa

ded

by: N

anya

ng T

echn

olog

ical

Uni

vers

ity. C

opyr

ight

ed m

ater

ial.


Category


Key words

carbonyl-ene reaction

indium(III)–PyBox

glyoxylates

J . F. Z H A O , H . - Y. T S U I , P. J . WU , J . L U , T. - P. L O H * ( N A N Y A N G TE CH N O L O G IC A L

U N IVE R S I T Y, S I N G A P O R E )

Highly Enantioselective Carbonyl-ene Reactions Catalyzed by In(III)–PyBox Complex

J. Am. Chem. Soc. 2008, 130, 16492-16493.

Indium(III)–PyBox-Catalyzed Carbonyl-ene Reaction of Glyoxylates

Significance: The indium(III)–PyBox catalyst sys-tem is shown to mediate the enantioselective carbonyl-ene reaction of glyoxylates with good yield and ee values. The catalyst loading can be lowered to 5 mol%, and only two equivalents of a-methylstyrene substrate is used. Unfortunately, the rate of the reaction is relatively slow and takes a few days to complete.

Comment: The metal source and chiral ligand used in this study are both commercially available now, making this reaction very attractive for the preparation of chiral homoallylic alcohol building blocks. Although this reaction needs days to com-plete, it still can serve well if it is applied on a large scale.

RO CHO

O+

R'

In(OTf)3 (5 mol%),

N

N

OO

N

H

H H

H

R'O

OR

OH

4 Å MS, DCE, r.t., 4–6 d

13 examples, 18–96% yield, 76–96% ee

Additional products:

O

OR

OH

75% yield, 95% ee

O

OR

OH

96% yield, 95% ee

O

OR

OH

O

OR

OH

single isomer, 60% yield, 99% ee97% yield, 90% ee

Ph

(6 mol%)

SYNFACTS Contributors: Hisashi Yamamoto, Pingfan LiSynfacts 2009, 3, 0283-0283 Published online:02.03.2009 Published online: 19.02.2009



Category


Key words


indium

PyBox ligand

J . - F. Z H A O , H . - Y. T S U I , P. - J . WU , J . L U , T. - P. L O H * ( N A N Y A N G TE CH N O L O G IC A L


Highly Enantioselective Carbonyl-ene Reactions Catalyzed by In(III)-PyBox Complex

J. Am. Chem. Soc. 2008, 130, 16492-16493.

In(III)-PyBox Complex Catalyzed Enantioselective Carbonyl-ene Reaction

Significance: In this paper, the authors have de-veloped highly enantioselective and efficient car-bonyl-ene reactions of ethyl glyoxylate catalyzed by the In(III)-PyBox complex. This methodology has several advantages, such as operational sim-plicity, mild reaction conditions, low catalyst load-ing (<5 mol%), and high enantioselectivities and yields.

Comment: The Loh group has developed the In(III)-PyBox complex and successfully applied it to various reactions (Chem. Commun. 2006, 2739, and references therein). In this paper, they extended its application to carbonyl-ene reac-tions. Both aromatic and aliphatic alkenes afford-ed the expected homoallylic alcohols in good to excellent yields and excellent enantioselectivities. Moreover, it is notable that the reaction of a trisub-stituted alkene gave the single regioisomer with high diastereoselectivity (>99:1) and enantio-selectivity albeit in moderate yield. However, hopefully the substrate scope and reaction condi-tions will be improved in the future.

Selected examples:

O

EtOH

O

+ R2

R1

R3In(OTf)3 (5 mol%)

Ligand (6 mol%)

4 A MS, 0 °CDCE, 4–6 d

EtO

O

OH

R1

R2

R3

N

N

OO

N

H

H

H

H

Ligand

EtO

O

OH

96% yield, 95% ee

EtO

O

OH

96% yield, 94% ee

Me

EtO

O

OH

95% yield, 90% ee

Cl

EtO

O

OH

96% yield, 96% ee

OMe EtO

O

OH

75% yield, 95% ee

EtO

O

OH

60% yieldsingle regioisomerdr > 99:1, 96% ee

Ph

SYNFACTS Contributors: Hisashi Yamamoto, Cheol Hong CheonSynfacts 2009, 2, 0187-0187 Published online:02.02.2009 Published online: 22.01.2009



Category


Key words

indium

addition to aldehydes

reactions in water

Z . - L . S H E N , Y. - L . YE O , T. - P. L O H * ( N A N Y A N G TE C H N O L O G I C A L U N IV E R S I T Y, S I N G A P O R E )

Indium-Copper and Indium-Silver Mediated Barbier–Grignard-Type Alkylation Reaction of Aldehydes Using

Unactivated Alkyl Halides in Water

J. Org. Chem. 2008, 73, 3922-3924.

Indium-Mediated Addition of Unactivated Alkyl Halides to Aldehydes in Water

Significance: The authors report here an interest-ing variation of the Barbier–Grignard-type alkyl-ation of aldehydes, including both aromatic and aliphatic ones, using non-activated alkyl iodides in water. This method offers an interesting method-ological approach toward new green synthetic chemistry. Besides, it may be quite useful for the functionalization of molecules bearing acidic pro-tons, which are not compatible with the conven-tional Grignard chemistry. The reaction is very sim-ple to perform and offers moderate to good product yields.

Comment: The reaction mechanism was studied using 4-pentenal, which gives a tetrahydrofuran derivative as the main product, thus proving the radical character of the reaction intermediates. Noticeably, the reaction proceeds less efficiently in any solvent other than water, or even in their mix-tures with water. Mostly, but not always, the addi-tion of CuI gives better results than AgI.

Review: For a review on organic reactions in wa-ter, see: C. I. Herrerías, X. Yao, Z. Li, C.-J. Li Chem. Rev. 2007, 107, 2546-2562.

R1

O

H

+ CuI (3 equiv) or AgI (5 equiv)

(5 equiv) In (6 equiv), I2 (0.2 equiv), H2O, r.t., 2 d R1 R2

OH up to 86% yield

R1 = Ar, Alk

R2 = primary or secondary Alk

OH

Br

n-Hex

OH

Br

56% (with CuI) 52% (with CuI)

OHMe

67% (with AgI)

OH

78% (with AgI)

Ph

Proposed reaction mechanism:

R2-IIn(Cu) InI

H2OR2•

R1 R2

O In In+

R1 R2

O–

R1 R2

OHH2O

R2I

R1CHO

SYNFACTS Contributors: Paul Knochel, Andrei GavryushinSynfacts 2008, 8, 0861-0861 Published online:01.08.2008 Published online: 23.07.2008



Category


Key words

palladium

cross-coupling

dienoates

Y. -H . X U , J . L U , T. - P. L O H * (N A NY A N G TE C H N O L O G I C A L U N IV E R S IT Y, S I N G A P O R E )

Direct Cross-Coupling Reaction of Simple Alkenes with Acrylates Catalyzed by Palladium Catalyst

J. Am. Chem. Soc. 2009, 131, 1372-1373.

Palladium-Catalyzed Direct Cross-Coupling of Alkenes and Acrylates

Significance: A palladium-catalyzed direct cross-coupling between alkenes and acrylates is report-ed. The scope is broad and the E/Z selectivities are good, although the yields are moderate to low. Overall, this is an efficient method for synthesizing dienoates using simple olefins and mild reaction conditions.

Comment: Reports of alkenyl C–H bond activa-tion are limited, and this reaction may or may not proceed through this mechanism. A sequential 1,2-addition pathway explains the formation of the product and the authors could not discriminate between this mechanism and that of direct C–H activation. Only 2,2-disubstituted olefins were suitable substrates for the reaction.

R1

R2

R3

H

+ OR4

H

R5

R6

OPd(OAc)2 (20 mol%)Cu(OAc)2 (1 equiv)

O2 (1 atm)

DMSO–AcOH (1:1), 60 °C, 24 h15 examples

33–87%

R4

R2

R1

R3

O

O

R6

R5

E/Z up to >99:1

Selected examples:

Ot-Bu

O

52%E/Z = 62:38

Ot-Bu

O

87%E/Z > 99:1

Ot-Bu

O

41%E/Z = 68:32

OMe

O

34%E/Z = 83:17

MeMeO

CO2Et

Proposed mechanism:

R1

R2

R3

H

Pd(OAc)2

R2Pd(OAc)

R1

AcO

R3

1,2-addition intermediate

OR

R2Pd(OAc)

R1

R3

C–H activation intermediate

OR4

H

R5

R6

OR2

R1

AcO

R3 [Pd] R5O

H R4 O

R6

OR

R2

R1

R3

O

H R4

[Pd] R5

O

R6

β-hydride elimination(+ AcOH elimination)

R4

R2

R1

R3

O

O

R6

R5

+Pd OAcH

Cu(OAc)2O2 product

Cu(OAc)H2O

SYNFACTS Contributors: Mark Lautens, Praew ThansandoteSynfacts 2009, 4, 0417-0417 Published online:01.04.2009 Published online: 23.03.2009



Category


Key words

nitrones

amines

indium

zinc

copper

Y. - S . YA N G , Z . - L . S H E N , T. - P. L O H * ( N A N Y A N G TE CH N O L O G IC A L U N IVE R S I T Y,

S I N G A P O R E )

Indium (Zinc)–Copper-Mediated Barbier-Type Alkylation Reaction of Nitrones in Water: Synthesis of Amines and

Hydroxylamines

Org. Lett. 2009, 11, 1209-1212.

Alkylation of Nitrones in Water: Synthesis of Amines and Hydroxylamines

Significance: This indium (zinc)–copper-mediat-ed Barbier-type alkylation of nitrones is reported to give secondary amines or hydroxylamines, de-pending on the use of indium or zinc metal, re-spectively. The products are obtained in good yields enabling a straightforward synthesis of a large library of amines or hydroxylamines. The reaction setup is simple and attractive for an even-tual scale-up.

Comment: Chiral nitrones are also converted into the corresponding amines or hydroxylamines in a good diastereomeric ratio. For the synthesis of amines, the authors propose a radical mechanism initiated by a single-electron transfer from indium/copper to the alkyl iodide generating an alkyl radi-cal which then attacks the nitrone. Subsequent re-duction of the nitrone radical anion and quenching by water affords the hydroxylamine which in turn is further reduced by indium metal to yield the desired amine.

R1N R3

O–

+ R2 IIn/CuI

H2O, 24 h

Zn/CuI

H2O, 24 hR1N R3

R2

OH

R1

HN R3

R2

up to 90% up to 88%R1, R3 = Alk, Ar R2 = Alk

Examples of amines:

Ph NH

88%

Br

Ph NH

81%

ClPh

NH

Ph

46%

NH

Ph

MeO2C

72%dr = 98:2

Examples of hydroxylamines:

Ph N Ph

90%

OH

Ph N Ph

83%

OH

80%

Ph N

ClOH

N Ph

MeO2C

72%dr = 88:12

OH

+

SYNFACTS Contributors: Paul Knochel, Andreas J. WagnerSynfacts 2009, 6, 0657-0657 Published online:xx.xx.2009 Published online: 25.05.2009



Category


Key words

ketone–ene reaction

indium

J . - F. Z H A O , T. - B . W. T J A N , B . - H . TA N , T. - P. L O H * ( N A N Y A N G TE CH N O L O G IC A L

U N IVE R S I T Y, S IN G A P O R E )

Highly Enantioselective Ketone–Ene Reactions of Trifluoropyruvate: Significant Counterion Effect of the

In(III)–PyBox Complex

Org. Lett. 2009, 11, 5714-5716.

Enantioselective In(III)-Catalyzed Ketone–Ene Reaction

Significance: Building upon their previous work (J. Am. Chem. Soc. 2008, 130, 16492) the au-thors report on an indium(III)–pybox-based cata-lyst system of enhanced reactivity for the ketone–ene reactions of trifluoropyruvate, providing ho-moallylic alcohols with a quaternary stereocenter in high yield and enantioselectivity.

Comment: The authors hypothesized that the Lewis acidity of the catalyst could be increased by replacing the counterion of the parent complex by a more non-coordinating anion. The authors sys-tematically investigated several silver salts as ad-ditives and found a significant counterion effect verifying their hypothesis. The efficiency of the catalyst increased with decreasing basicity of the counterion. Furthermore, it was found that the enantioselectivity was dependent upon the amount of additive present. In general the yields and enantioselectivity are excellent. The transfor-mation is sensitive to both the sterics and elec-tronics of the substrate. Electron-withdrawing groups dramatically increase the reaction time and steric bulk at the ortho-position decreases the selectivity.

MeO

O

O

CF3 +R2

InCl3 (10 mol%)AgSbF6 (20 mol%)

L (12 mol%)4 Å MSDCE, r.t.

R2

R1

O

OMe

HO CF3

R1

56–99% yield64–98% eeSelected examples:

R1 = H, AlkR2 = Ar, Alk

Ph

O

OMe

HO CF3

99% yield95% ee

2-FC6H4

O

OMe

HO CF3

56% yield87% ee

2-MeOC6H4

O

OMe

HO CF3

86% yield85% ee

O

OMe

HO CF3

79% yield96% ee

O

OMe

HO CF3

95% yield98% ee

N

ON

N

O H

HH

H

L =

SYNFACTS Contributors: Mark Lautens, David A. CanditoSynfacts 2010, 2, 0206-0206 Published online: xx.xx.2010 Published online: 21.01.2010



Category


Key words

terpenoids

polyene cyclization

indium

Y. - J . Z H A O , L . - J . S . TA N , B . L I , S . -M . L I , T. -P. L O H * ( N A NY A N G TE C H N O L O G IC A L

U N IVE R S I T Y, S IN G A P O R E )

Bio-Inspired Polyene Cyclization: Aziridinyl Polyene Cyclization Catalyzed by InBr3

Chem. Commun. 2009, 3738-3740.

Indium Bromide Catalyzed Aziridinyl Polyene Cyclization

Significance: Aziridine-initiated polyene cycliza-tion similar to the process mediated by 2,3-oxi-dosqualene cyclase can be a useful approach towards a number of biologically interesting aza-terpenes. This paper shows the first example of such a transformation mediated by a catalytic amount of Lewis acid. The developed protocol provides easy access to chiral terpenoid com-pounds containing a 3-amino group in the A ring.

Comment: Various tri- and tetracyclic products were prepared with good yields and high diaste-reoselectivities. Using an enantiomerically en-riched substrate furnished the corresponding product with full retention of enantiomeric purity. The procedure involves the use of 20 mol% of indium bromide under generally mild conditions. It is noteworthy that other indium salts demon-strated lower yields. Other Lewis acids tested also showed inferior results. The relative stereochemis-try was determined by X-ray crystal structure anal-ysis.

NTs

TsHNH

R R

InBr3

CH2Cl2, r.t., 2 h69–75% yield

NTs

RR

InBr3

CH2Cl2, r.t., 2 h51–65% yield TsHN

H

H

tetracyclic/bicyclic up to 88:12

NCbz

CbzHNH

InBr3

CH2Cl2, r.t., 2 h67% yield

97% ee 97% ee

H2, 10% Pd/C

EtOH, 95% yield

H2NH

SYNFACTS Contributors: Hisashi Yamamoto, Dmitry L. UsanovSynfacts 2009, 10, 1108-1108 Published online:xx.xx.2009 Published online: 22.09.2009



Category


Key words

dioxygenation

oximes

palladium

M . - K . Z H U , J . - F. Z H A O , T. - P. L O H * ( N A N Y A N G TE C H N O L O G I C A L U N IV E R S I T Y,

S I N G A P O R E )

Palladium-Catalyzed Oxime Assisted Intramolecular Dioxygenation of Alkenes with 1 atm of Air as the Sole Oxidant

J. Am. Chem. Soc. 2010, 132, 6284-6285.

Palladium-Catalyzed Dioxygenation of Alkenes

Significance: This work examines a palladium-catalyzed dioxygenation of alkenes under an air atmosphere. Several examples of analogous dioxygenations have recently emerged from the groups of Sigman (J. Am. Chem. Soc. 2009, 131, 17074), Dong and Song (J. Am. Chem. Soc. 2008, 130, 2962), and Jiang (J. Am. Chem. Soc. 2009, 131, 3846). This work is significant since atmospheric oxygen is the sole oxidant utilized throughout the reaction. The scope is general in substitution at the oxime (R1).

Comment: The reaction yields a mixture of the free alcohol and the acetylated alcohol, which is hydrolyzed with potassium carbonate in methanol before workup. Substitution at the oxime is well tolerated with both aliphatic and aromatic groups giving good results. Instead of air, hydrogen per-oxide can be used as an oxidant to yield similar results. The mechanism seems to involve the in-tramolecular addition of the oxime OH group to the alkene to yield an alkylpalladium intermediate which is oxidized to furnish the products. Substit-uents at the alkene bearing b-hydrogens exclu-sively give the products of b-hydride elimination. A labeling experiment using 18O2 shows incorpo-ration in the hydroxyl-containing products.

R1

NOH

R2

R3 N O N OOH

R3R3

R2OH

R2R1 R1

or

1) Pd(OAc)2 (10 mol%) L (12 mol%) AcOH (10 equiv) H2O (15 equiv) air, 40 °C

R1 = Ph, Ar, Hetar, AlkR2 = H, Me, PhR3 = H, Me, Ph

14 examples36–76% yielddr up to >99:1

2 examplesdr > 99:1

N

N

L1,10-phenanthroline

R1

NOH

R2

R3N O 18OH

R3

R2R1

Pd(OAc)2 (10 mol%)L (12 mol%)

AcOH (10 equiv)H2O (15 equiv)

N O OAc

R3

R2R1

+

18O experiment:

2) K2CO3 (2 equiv) MeOH, r.t.

90% yield deuteriumincorporation

DCE, 25 °C18O2

SYNFACTS Contributors: Mark Lautens, Jane Panteleev Synfacts 2010, 7, 0789-0789 Published online:xx.xx.2010 Published online: 22.06.2010



Category


Key words

homoenolates

palladium coupling

indium

Z . -L . S H E N , K . K . K . G O H , H . - L . CH E O N G , C . H . A . WO N G , Y. -C . L A I , Y. - S . YA N G ,

T. - P. L O H * ( N A NY A N G TE C H N O L O G I CA L U N IVE R S IT Y, S I N G A P O RE )

Synthesis of Water-Tolerant Indium Homoenolate in Aqueous Media and Its Application in the Synthesis of

1,4-Dicarbonyl Compounds via Palladium-Catalyzed Coupling with Acid Chloride

J. Am. Chem. Soc. 2010, 132, 15852-15855.

Coupling of Indium Homoenolates with Acid Chlorides

Significance: In this work the preparation of water-tolerant indium homoenolates is reported. The reaction proceeds exclusively in aqueous solution by the oxidative addition of In/InCl3. The synthetic value of these homoenolates is shown in a palladium-catalyzed coupling with various acid chlorides, providing 1,4-dicarbonyl compounds in excellent yield.

Comment: The structure of the indium homoeno-late was confirmed by single crystal X-ray diffrac-tion. Both indium(0) and indium(III) chloride are necessary for an effective transformation of the enone; water is needed for the protonation of the a-position to generate the final indium homoenolate. Various acid chlorides with electron-withdrawing or -donating groups react well under these conditions.

Et

O

Et

O In

Et

OCl

O2N

COCl

In/InCl3

MeCN–H2Or.t., 24 h

PdCl2(PPh3)2THF, reflux, 24 h

Et

O

O

NO2

82% yield84% yield

Et

O

O

Cl

84% yield

Et

O

O

OMe

74% yield

Et

O

O

98% yield

O

O

98% yield

O

O

O

78% yield

O

O

85% yieldCl

S

SYNFACTS Contributors: Paul Knochel, Thomas KunzSynfacts 2011, 2, 0200-0200 Published online: xx.xx.2011 Published online: 19.01.2011



Category


Key words

bisolefination

naphthalenes

palladium

C . F E N G , T. - P. L O H * ( N A N Y A N G TE CH N O L O G IC A L U N IVE R S I T Y, S IN G A P O R E )

Palladium-Catalyzed Bisolefination of C–C Triple Bonds: A Facile Method for the Synthesis of Naphthalene

Derivatives

J. Am. Chem. Soc. 2010, 132, 17710-17712.

Palladium-Catalyzed Bisolefination of C–C Triple Bonds to Yield Naphthalene Derivatives

Significance: A palladium-catalyzed bisolefina-tion of C–C triple bonds via sequential intra- and intermolecular coupling reaction is described. The method yields naphthalene derivatives with high regioselectivity.

Comment: Interestingly, the described palladium-catalyzed coupling reaction is achieved with mo-lecular oxygen as the exclusive oxidizing agent.

R2

R4

R1

R3PdCl2 (5 mol%), O2

DMSO, 110 °CR5

Selected examples:

t-Bu

Ph

CO2Et

Ph

Cl

Ph

MeO

CO2Et CO2Et

OMe

Ph

CO2Et

up to 92% yield

61% yield 92% yield 68% yield 55% yield 69% yield

Proposed catalytic cycle:R2

R4

R1

R3

PdCl2

R2

R4

R1

R3

Cl2Pd

R1

R2

R3

R4

PdClR5

R1

R2

R3

R4

R5

R1

R2

R3

R4

R5

R1

R2

R3

R4

R5

XPdCl

Pd(0)

H2O

X = OAc, TMS

HCl + O2

R1

R2

R3

R4

PdCl

+

+

SYNFACTS Contributors: Paul Knochel, Andreas K. SteibSynfacts 2011, 3, 0311-0311 Published online:xx.xx.2011 Published online: 16.02.2011



Category


Key words

asymmetric catalysis


ionic liquids

indium

J . - F. Z H A O , B . - H . TA N , M . - K . Z H U , T. - B . W. T J A N , T. - P. L O H * ( N A N Y A N G TE C H N O L O G I C A L


Enantioselective Carbonyl-Ene Reactions of Trifluoropyruvate in Ionic Liquid via a Recyclable Indium(III)–Pybox

Complex

Adv. Synth. Catal. 2010, 352, 2085-2088.

Indium-Catalyzed Enantioselective Carbonyl-Ene Reaction of Trifluoropyruvate

Significance: Asymmetric ketone-ene reaction involving trifluoropyruvate allows the preparation of enantiomerically enriched tertiary homoallylic alcohols containing a CF3 group, which are impor-tant building blocks for agrochemicals and phar-maceuticals. This methodology received rather limited attention despite the extensive studies of asymmetric aldehyde-ene reactions. In this paper, a highly enantioselective protocol involving the use of indium(III)–pybox catalyst in an ionic liquid is reported; a range of products were obtained in 74–98% yields and with up to 98% ee.

Comment: The developed procedure is notable for a number of important advantages, such as easy accessibility of the catalyst, moisture toler-ance, and operational simplicity. The use of ionic liquid allows easy separation of the products and recyclability of the catalyst: the system could be reused for up to seven times with excellent cata-lytic outcome. The ionic liquid [hmim]PF6 proved to be the optimum reaction media. Most of the reactions proceeded faster in the ionic liquid than in the organic solvents with comparable or better yields and enantioselectivities. The expansion of the method to substrates containing substituents other than CF3 (Ar, Alk) would be highly desirable.

NO

N N

O H

HH

H

R1 +

O

F3C

O

OMe

InCl3 (10 mol%) AgSbF6 (20 mol%)

R21 (12 mol%), 4 Å MS[hmim]PF6–DCE, r.t.

1O

OMe

F3C OHR1

R2

74–98% yieldsup to 98% ee

14 examples

Selected examples:

O

OMe

F3C OH

O

OMe

F3C OH

O

OMe

F3C

F

O

OMe

F3C OH

95% yield, 96% ee 90% yield, 97% ee

78% yield, 98% ee 98% yield, 98% ee

O

OMe

F3C OH

92% yield, 95% ee

O

OMe

F3C OH

74% yield, 80% ee

O

OMe

F3C OH

80% yield, 96% ee

O

OMe

F3C OH

98% yield, 92% ee

OMe

SYNFACTS Contributors: Hisashi Yamamoto, Dmitry L. UsanovSynfacts 2011, 1, 0071-0071 Published online:xx.xx.2010 Published online: 21.12.2010


Potatoes and other crops may getprotection against a devastatingplant disease that caused the Irishpotato famine.Credit: iStock

FOR IMMEDIATE RELEASE

“Total Synthesis of Phytophthora Mating Hormone alpha-1”Organic Letters

Scientists are reporting a key advance toward development of a way to combat theterrible plant diseases that caused the Irish potato famine and still inflict billions ofdollars of damage to crops each year around the world. Their study appears in ACS’bi-weekly journal Organic Letters.

Teck-Peng Loh and colleagues point out that the Phytophthora fungi cause extensivedamage to food crops such as potatoes and soybeans as well as to ornamental plantslike azaleas and rhododendrons. One species of the fungus caused the Irish potato famine in the mid 1840s. Thatdisaster resulted in nearly one million deaths from starvation and forced millions more people to flee Ireland forthe United States and other countries. Still difficult to control despite the use of modern pesticides, the funguscontinues to cause $6 billion in damage to global potato crops annually. Scientists, however, have isolated a keyhormone, alpha-1, that allows Phytophthora to reproduce. The hormone exists in several different forms, and asynthetic version of the most biologically active form could provide the basis for developing a way to control thefungus and reduce its threat, the scientists suggest.

They describe an advance toward this goal, the synthesis of a particularly active form of the mating hormonecalled (3R,7R,11R,15R)-hormone alpha-1. The scientists also showed that they could make relatively largequantities of the hormone. The advance could open the door to an effective method to fight this ancient scourge,they suggest.

The authors acknowledged funding from the Nanyang Technological University, Ministry of Education andBiomedical Research Council (A*STAR grant M47110006).

Science Inquiries: Michael Woods, Editor, 202-872-6293General Inquiries: Michael Bernstein, 202-872-6042


Category

Organo- and Biocatalysis

Key words

Michael addition

vinyl sulfones

tricyclic catalysts

J . X I A O , Y. - P. L U , Y. - L . L IU , P. - S . WO N G , T. -P. L O H * ( N A NY A N G TE C H N O L O G IC A L

U N IVE R S I T Y, S I N G A P O R E A N D D A L I A N I N S T I T U T E O F CH E M I C A L P H Y S I CS ,

P. R . OF CH IN A)

A New Class of Structurally Rigid Tricyclic Chiral Secondary Amine Organocatalyst: Highly Enantioselective

Organocatalytic Michael Addition of Aldehydes to Vinyl Sulfones

Org. Lett. 2011, 13, 876-879.

Michael Addition of Aldehydes to Vinyl Sulfones

Significance: Loh and co-workers report a cata-lytic asymmetric Michael addition of aldehydes to vinyl sulfones using newly designed catalyst 2, synthesized on the basis of natural product struc-tures. The authors demonstrated that catalyst 2 is efficient in the Michael reaction of aldehydes to vinyl sulfones. This class of the Michael reaction typically requires high catalyst loading and low reaction temperature. The new catalyst system provides milder reaction conditions.

Comment: Synthesis of new catalysts is very im-portant in that it provides a route to solve chal-lenging reactions and overcome the limitations of existing methods. Recently, the authors reported a catalytic asymmetric Michael addition of unmod-ified aldehydes to nitroalkenes using the new tri-cyclic catalyst 1 (Org. Lett. 2010, 12, 1220). Through a simple modification of catalyst 1, the authors found that catalyst 2 is able to mediate the Michael addition of aldehydes to vinyl sulfones successfully. The reaction was carried out under mild reaction conditions in the presence of a rela-tively low catalyst loading (5–10 mol%).

N N

MeMe H

MeHNO2C

Physostigmine

N

N

NH

HN

O

OH

H H

Amauromine

N

NH

N

O

OH

HHO

NH

Okaramine C

NH

NH

N NH

H

HEtO2C

O

O

natural product based skeleton

chiral pocket

enamine reaction site

face-shielding group

New catalyst design:

N NH

H

HEtO2C

CO2H

12

Asymmetric Michael addition of aldehydes to vinyl sulfone:

HR

O

+SO2Ph

SO2Ph

2 (5–10 mol%)

CH2Cl2, r.t., 4–8 h

NaBH4

MeOHHO

SO2Ph

SO2PhRR = Alk, Ar 9 examples

55–99% yielder from 95:5 to 99.5:0.5

SYNFACTS Contributors: Benjamin List, Anna LeeSynfacts 2011, 5, 0561-0561 Published online:xx.xx.2011 Published online: 15.04.2011

DOI: 10.1055/s-0030-1259856; Reg-No.: B03111SF © Georg Thieme Verlag Stuttgart · New York


Category


Key words

Mukaiyama aldol reaction

PyBox ligands

indium

J . - F. Z H A O , B . - H . TA N , T. - P. L O H * ( N A N Y A N G TE C H N O L O G I C A L U N IVE R S I T Y, S I N G A P O R E )

In(III)–Pybox Complex Catalyzed Enantioselective Mukaiyama Aldol Reactions between Polymeric or Hydrated

Glyoxylates and Enolsilanes Derived from Aryl Ketones

Chem. Sci. 2011, 2, 349-352.

Enantioselective Mukaiyama Aldol Reactions with Glyoxylates

Significance: The enantioselective aldol reaction is among the most useful and well-developed transformations for the synthesis of chiral materi-als. Despite this, gaps in asymmetric aldol meth-odology still exist. The authors present the first example of a general, highly enantioselective Mukaiyama aldol reaction between aryl ketones and glyoxylates. An indium–PyBox complex is used as a chiral Lewis acid to induce asymmetry.

Comment: Both polymeric and hydrated glyoxy-late esters can be used directly without purifica-tion, providing practical advantages over similar enantioselective Mukaiyama aldol reactions. Sub-stituents in the ortho position of the enolsilane required extended reaction times of up to three days. Notably, the alcohol is obtained directly from the reaction, with no TIPS-protected product ob-served.

InBr (5 mol%)AgSbF6 (5 mol%)ligand (6 mol%)

Selected examples:

17 examples60–94% yield90–98% ee

OSii-Pr3

R

+

O

Oi-Pr

O(2 equiv)

4 Å MS, MeCN–20 or 0 °C

R

O

Oi-Pr

O

OH

O

Oi-Pr

O

OH O

Oi-Pr

O

OH O

Oi-Pr

O

OH

O

Oi-Pr

O

OH O

Oi-Pr

O

OH O

Oi-Pr

O

OH

91% yield96% ee

80% yield95% ee

92% yield96% ee

S

Br

85% yield97% ee

89% yield98% ee

83% yield92% ee

OMe

NO

N N

O H

HH

H

ligand

Diastereoselective variant:

O

Oi-Pr

O

OSii-Pr3

+as above

O

O

Oi-Pr

OH

93% yield98% ee94% dr

SYNFACTS Contributors: Mark Lautens, Stephen G. NewmanSynfacts 2011, 4, 0413-0413 Published online:xx.xx.2011 Published online: 18.03.2011


catalytic prins cyclization using in(otf) 3 and silyl ...cbc/cv/teckpeng/prof loh research...

Documents