Olefin Addition Reactions-1Chlorination and Iodination

Evans Group Friday SeminarBichu Cheng

November 20th 2009

Outline

chiral "I+"

I

H

H

Me

Cl

Cl

O

Cl

Cl

Cl

Cl( )6

SO3H

chlorosulpholipid

• Basic mechanism

• Applications in synthetic organic chemistry

• Total syntheses of halogen-containing natural products

Olefin Halogenations - Thermodynamics

Ethylene halogenations

F2 + C2H4 C2H4F2

!Hr (kcal/mol)calculated lit. value

Cl2 + C2H4 C2H4Cl2

Br2 + C2H4 C2H4Br2

I2 + C2H4 C2H4I2

-131 NA

-44 -43.65 ± 0.15

-29 -28.90 ± 0.30

-2 -11.5 ± 0.2

calculation based on bond dissociation energy(BDE).!Hr = 2 " BDE(C-X) + BDE(C-C) - BDE(X-X) - BDE(C=C)

Lit. value obtained from NIST: http://webbook.nist.gov/chemistry/

Olefin Halogenation - Kinetics♦ Tools for following the kinetics of a reaction. (Mayr J Phys Org Chem 2008, 21, 584)

rate law: -d[I2]/dt = k4[Alkene][I2]3 + k3[Alkene][I2]2

The first term being chief operative in non-polar solvents such as PhCl, CCl4 and CS2; and the second term inpolar solvent iBu2O, HOAc, and PhNO2.

Alkenes: 1-hexene, 2-pentene, cyclopentene, 1-decene, undecenoic acid and oelic acid.

! Kinetics of iodine addition to alkenes (Robertson J. Chem. Soc. 1950, 2191.)

Alkene solvent t1/2 (s) I2 order

cyclohexne Cl(CH2)2Cl 315 1stcyclohexne HOAc 525 2nd1-pentene Cl(CH2)2Cl 2500 1st1-pentene HOAc 4400 2ndcis-2-pentene Cl(CH2)2Cl 270 3rdcis-2-pentene HOAc 900 2nd

[alkene] = 0.30 M, [I2] = 0.020 M, rt

! Kinetics of iodine addition to alkenes (Field J. Chem. Edu. 1987, 269.)

! Kinetics of Chlorine Addition to Styrenes in HOAc. (Yates J. Org. Chem. 1980, 1401.)

rate law: -d[Cl2]/dt = k[Alkene][Cl2]

styrene 72.1 stopped-flowp-chlorostyrene 18.6m-fluorostyrene 4.06 m-chlorostyrene 3.75p-fluorostyrene 65.6m-nitrostyrene 0.45 potentiometricp-nitrostyrene 0.21 3,5-dinitrostyrene 0.081(Z)-1-phenylpropene 145 stopped-flow(E)-1-phenylpropene >10001-hexene 76.73-hexene >1000

olefin 10-2k (L mol-1 s-1) method

Olefin Halogenations - General Mechanism

X2X

X2n+1X

! complex halonium ionnonbridged

cation

X2+(X2)n

X2n+1

Nuproduct

Olefin-Halogen π Complex

♦ Labile and reactive. π complex formation is followed rapidly by the formation of ionicintermediates and further chemical transformations. Mostly studied with Br2.

♦ olefin chlorine π complex was studied by low temperature spectroscopic methodsand computations.

1. An C2H4/Cl2 complex was prepared in a N2 matrix at 20 K. Its UV and IR spectra havebeen recorded. Both IR data and CNDO/2 calculations favor a C2v symmetric complex.The CNDO/2 calculations predict that the Cl-Cl bond is orthogonal to the ethylene plane.The IR data give no evidence for or against this prediction.

J. Mol. Struct. 1973, 205.

2. An ethane solution of C2H4/Cl2 was studied by IR as a function of temperature andconcentration. ΔGf (0.9 kJ.mol-1), ΔHf ( -8.6 kJ.mol-1) ), ΔSf (-70 J.mol-1K-1) were obtained.

J. Mol. Struct. 1983, 269.

3. The rotational spectrum of a complex of C2v symmetry has been detected in a mixture of C2H4/Cl2 . Force constant k = 7.05(5) N m-1

(Force constant k for a C-C bond is about 450 N m-1) Chem. Comm. 1994, 1321. Angew.. Chem. Ind. Ed. 1995, 51.

3.128 Å

Bridged Halonium

• First proposed by Irving Roberts in 1937 to explain the stereospecific formationof trans halogenation products. (J. Am. Chem. Soc., 1937, 947)

• NMR observation by George Olah.

H2C CH2

ISbF5CNICN-SbF5

XSbF5CNXCN-SbF5

X = Br, I

From alkene (J. Am. Chem. Soc., 1974, 3581.)

polymeric material with BrCN-SbF5

and no reaction with ClCN-SbF5

X XXSbF5!SO2

X F

Cl 2.72(s) Br 2.86(s) I 3.05(s)

or

X " (ppm)

!60 °C

no change in 1H NMR down to -95 °C;

in SO2ClF, no change down to -120 ~ -130°C

From 1,2-dihaloalkane (J. Am. Chem. Soc., 1967, 4744)

Bridged Halonium: Isolation

Ad=Ad

adamantylideneadamantane

Cl2/CCl4

-20 °C

ClCln

white precipitate

10 °C

Cl

disubstituted isomers

+Ad=AdAd=Ad

and

! Reaction with Cl2 (Wynberg H., Tetrahedron Lett. 1970, 4579. )

+

Ad=Ad

OsO4

Ad=Ad•OsO4

observed by UV-visible spectra

OOs

O

OO

LiAlH4OHHO

rt

! Reaction with meatl oxidants (Nugent W.A.. J. Org. Chem. 1980, 4533.)

2 MoOCl4 Ad=Ad

Cl

Ad AdMo2O2Cl7+

-78 °C

Cl

Ad AdSbCl6 SbCl32 SbCl5 Ad=Ad+ +

-78 °C

cis-chlorination reagents

gold, paramagnetic solidelemental analysis, IR,

white, diamagnetic solid

elemental analysis, IR

and 13C NMR

Unexpected halonium formation

Bridge Iodonium: x-Ray Structure and Reactivity

♦ Two ORTEP views of the iodonium momohydrate.

C-C10-C 110.6(5) 110.9C-C20-C 111.8(5) 110.9C10-I-C20 36.0(1) 36.2I-C10-C20 71.1(4) 71.9I-C20-C10 72.9(4) 71.9

C10-C20 1.454(6) 1.485I-C10 2.362(6) 2.389I-C20 2.338(6) 2.389I-O4 2.630(4)O4-O1 2.796(8)O4-O3' 2.752(8)

Interatomic Distances (Å)

Interatomic Angles (deg)

observed calculated

! Selected Interatomic Distances and Angles from X-ray Diffraction and from ab Initio SCF Calculation.

ITfO

AgOTf

I2, CH2Cl20 °C

1020

! Preparation of iodonium(J. Am. Chem. Soc. 1994, 2448)

second-order

rate constant

(7.6 ± 0.8) x 106 M–1 s-1

TfO

Ad=Ad

TfO+

Ad=Ad

+

-78 °C

I

Ad Ad

I

AdAd

! Reactivity: I+ site exchange

ROH

OH

COOH

R = H, n = 2, 3, 4

R = CH3, n = 3

( )n

COOH

!Halocyclization initiated by halonium(J. Org. Chem. 1996, 962)

Bridged Chloronium: x-Ray Structure and Reactivity

♦ ORTEP diagram of two chloroniums

-78 °C

ClSO2Cl2,

adventitious H2O

1.506

1.997 1.997

ClClH HCl

3.373

Cl

SbCl6

+ +

Cl

Cl

CH2Cl20 °C

SbCl5

1.485

2.075 1.924

3.492

an ineffective Cl+

transfer reagent;

a one-electron oxidant

! Preparation of chloronium by Cl+ transfer

(Kochi Chem. Comm. 1998, 927.)

(Kochi J. Org. Chem. 2002, 67, 5106)

Outline

chiral "I+"

I

H

H

Me

Cl

Cl

O

Cl

Cl

Cl

Cl( )6

SO3H

chlorosulpholipid

• Basic mechanisms

• Applications in synthetic organic chemistry

• Total syntheses of halogen-containing natural products

Dichlorination

O

O

O

OH

MOMO

O

O

O

OH

MOMO

BH3•THF (4 equiv.), (S)-9 (4 equiv.)Cl2, THF, -78°C

(93% yield, 87% ee;95% ee after

crystallization)

Cl

Cl

(!)-Napyradiomycin A1

" First reagent-controlled highly stereoselective olefin dichlorination

Snyder, S. A. J. Am. Chem. Soc. 2009, 131 (16), 5744-5745

Et4NCl3Et4NClCH2Cl2

Cl2

Et4NCl3

RCH=CHR'

RCOCClRCO2R'

RCHClCHClR'

R R'

Cl

R Cl

R'

RCOCHRCO2R'

RCOCH2R' RCOCHClR'

RCH2CHO RCCl2CHO

O

O

H

R

O

O

Cl

R

PhOR p-Cl-PhOR

Substrates Products

! Et4NCl3: A benchstable equivalent to Cl2

Mioskowski Angew. Chem. Int. Ed. 1997, 36 (21), 2342-2344.

The content of active chloride was 3.2 mmol g-1,

and no decrease in activity was observed upon

storage for several months at room temperature.

Iodination• Common I+ source: I2, ICl, IBr, IOAc, NIS, Py2IBF4.• Kinetic control: I2/NaHCO3, NIS in CHCl3, I2 in CHCl3 and I2 in pyridine/THF;

Thermodynamic control: I2 in MeCN.• Diiodination of olefin is reversible and product usually unstable.• More common and useful: electrophilic iodine induced alkene functionalization with other

external and internal nucleophiles.

nBu

OH

nBu

OH OAc

I

N

Cbz

N

Cbz

I

X

I2, HOAc

Regiochemistry is controlled by a combination of electronic (Markovnikov rule), stereoelectronic (trans diaxial addition to cyclohexenes)and sterics factors.

! External Nucleophile

some stereoselective examples

67% overall

n-Bu3SnH, toluene, 25 °CTsOH, (CH3)2C(OCH3)2, 25 °CI2, THF, 4 °C

0.25 M KH2PO4,

diastereoselection 96 : 4

Et

TIPSO

Me

OH

Et

TIPSO

Me

OH

I

OH O

Me

O

Me

TIPSO

Et

Me

Evans, J. Am. Chem. Soc. 1990, 112, 7001.

! Internal Nucleophile

Additional conformational and entropic factors. General preference for cyclization: 5-endo > 4-exo, 5-exo > 6-endo, 6-exo > 7-endo.

Reviews: Tetrahedron 1990, 3321. Tetrahedron 2004, 5273. Chemical Society Reviews 2004, 354. Tetrahedron 2008, 2683. Comprehensive Organic Synthesis B.M. Trost Vol. 4, Chapter 1.9. Advanced Organic Chemistry, F.A. Carey and R.J. Sundberg, 5th Ed. Part A, Chapter 5; Part B, Chapter 4.

1,2-Cis Induction in Iodolactonization and IntramolecularIodoetherification of Allylic Alcohol Derivatives

Chamberlin J. Am. Chem. Soc. 1983, 105, 5819.

OH

Ph

OH

R1

R3

R2

O

OH

R2R1

PhR3

I

O

OH

R2R1

PhR3

I

OPh

OH

I

R2

R3

R1

I2, NaHCO3+

+

H H H 81% 94 : 6 : 0Me H H 94% 39 : 61 : 0H Me H 82% 13 :1 : 86H H Me 81% 27 : 0 : 73

R1 R2 R3 yield ratio

Yoshida, Tetrahedron Lett.,1985, 2885; J. Org. Chem. 1987,52, 4062.

O

HO

IOH

O

HO

R3O

Me

R3R1 R2

R1

R2

H Me H 41% 87:13H Me Me 94% 90:10Me H H 74% 77:23Me H Me 81% 42:58Me Me Me 93% 72:28

R1 R2 R3 yield cis:trans

I2, NaHCO3

OH

Ph

OH

R1

R3

R2

O

OH

R2R1

PhR3

I

O

OH

R2R1

PhR3

I

H H H 98% 100:0Me H H 93% 98:2 H Me H 79% 93:7H H Me 87% 19:81

+I2, NaHCO3

R1 R2 R3 yield cis:trans

OH

HO

R

O

HO

I

R

H 87% 95:5 Me 94% 91:9 i-Pr 73% 100:0

O

HO

I

R

! 1,2-cis Selective Iodoetherification

I2, NaHCO3+

R yield cis:trans

O

HO

IOH

O

HO

R3O

R2

R3

R1

R2

H H H 66% 93:7H Me H 49% >95:5H H Me 74% 95:5H Me Me 82% 96:4Me Me H 8% <10:90

R1 R2 R3 yield cis:trans

R1

! 1,2-cis Selective Iodolactonization

I2, NaHCO3

Chem 206D. A. Evans Applications in Synthesis

For a review of elctrophilic induced olefin cyclization reactions see:G. Cardillo & M. Orena, Tetrahedron 1990, 46, 3321.

cis : trans 95 : 5

ratio 99 : 1

A complete turnover in olefin diastereofacial selectivity observed when adding internal and external nucleophiles

For electrophiles that react via onium intermediates (I2, Br2, Hg(OAc)2, PhSeCl), the major diastereomer from electrophile-induced cyclization is opposite to that observed in the analogous intermolecular electrophilic addition.

General Observation:

Bu

HHO

OH

Bu Me

Me

OH

HO

O

OO

Me

OH

H

H

O

O–

H

HO

Me

Me

IH

OH

MeBu

OH

I

! "Facial preferences in electrophilic addition reactions are not invariant with respect to the location of the transition state along the reaction coordinate."

Chamberlin & Hehre, J. Am. Chem. Soc. 1987, 109, 672-677.

Chamberlin & Hehre's Rationalization

! Analysis of the stereoselectivity of electrophilic addition to chiral olefins:

1. Relative abundances of conformational minima

2. Relative reactivities of the available forms

3. Stereoselectivies of the individual conformers

! Change in diastereoselectivity is a consequence of a change in the rate-limiting step

" Addition reactions: Formation of an onium ion intermediate

(subsequently trapped by a Nu from the medium)

" Cyclization reactions: Intramolecular attack on a !–complex (not an onium ion)

+

+

Nu

Nu

Disfavored !–complex

Favored !–complex Disfavored iodonium ion

Favored iodonium ion

Cyclization product

Addition product

Favored ground-state conformer

More reactiveground-state conformer

Hehre's Analysis

OO

HO

OH

MeBu

OH

I

Me

IH

I

OH

Bu Me

OH

HI

Me

HO

OO

I2

H

R

H

OH

Me Me

OH

H

R

H

I

Me

HR

HO

H

H H H

H

H

HO

R

H

MeMe

H

R

HO

H

H H

H

OH

RH

MeI

I2

! "The presence or absence of an internal nucleophile acts to determine the stereochemical outcome of the reaction by modifying the nature (timing) oftransition state.

! Onium ion formation is rate determing in the addition reactions

! !–complex cyclizes if R contains a Nu and its formation is rate determining

Houk: Argument for the "inside alkoxy effect" in !–complex formation

RDS

RDS

I2

I2

OH2

I2

I2

H2O

1,3-Trans Induction: Halolactonization of α- and α,β-substituted γ,δ-unsaturated amides

Yoshida J. Am. Chem. Soc. 1984, 106, 1079

Y

NMe2

R2

R1 Y

O

I

R2

H

R1

H

Y

O

I

H

R2

R1

HI2

DME/H2O+

! 1,3-Trans-Selective Lactonization of 2-substituted Amides and Thioamides

entry R1 R2 Y yield ratio 1 Me H O 85 90:10 2 Bn H O 84 >99:1 3 Bn Me O 82 >99:1 4 Me H S 42 91:9 5 Bn H S 67 >99:1

Y

NH3C

H3C

H

H R2

H

R1

I

! Stereoselectivity due to A(1,3) strain between R1 and N-methyl groups

O

NMe2

R3

O

O

I

R3

HH

O

O

I

HR3

HI2

DME/H2O+

! Stereoselective Iodolactonization of 2,3-Disubstituted N,N-Dimethyl-4-penteneamide

R1

R2

R1

R2R2

R1

entry R1 R2 R3 yield ratio 1 Me H H 63 97:3 2 H Me H 63 97:3 3 OH H H 88 20: 80 4 H OH H 84 >99:1 5 OAc H H 68 45:55 6 H OAc H 95 >99: 1 7 H OAc Me 75 >99: 1

allylic OH1,2-cis directing ability

Double Diastereoselection in the Iodolactonization of1,6-Heptadien-4-Carboxylic Acids

Kurth, M. J J. Am. Chem. Soc. 1987, 6844.

COOH

I2, NaHCO3O

OI

OO

I

O IO

142 4.7

1

O IO

0

3 51

olefin selectivity (147 : 1)face selectivity (30 : 1)

79%

COOHI2, NaHCO3

OO

I OO

I3 51

> 95%

14 : 1

COOH

I2, NaHCO33 51

> 95%

O IO

O IO

7.9 : 1

! Diastereoselectve Iodolactonization of 1,6-Heptadien-4-Carboxylic Acids

+

+

+

+

HOOC

H

CH3

HH

3H

COOHH

H

5

! Olefin selectivity: acyclic conformational control

COOH and C1 olefinin close proximity

Minimizing gauche interaction in the Newman projection

COOH and C6 olefinantiperiplanar

C3-C4 C5-C4

Stereoelectronic Effects in Iodoetherification of Allylic AlcoholDerivatives

OHO

H

CO2Et

Me

O

OH

H

CO2EtMe

I

I

H

C

I

CEtO2C

MeH

OH

CH2CH2

O

C

I

CEtO2CH2

MeH

H

OH

CH2

CH2

O

!Proposed two trans-predictive transition states

sterically favored

stereoelectronically favored

CO2Et

OH OH

CO2Et

OH OH

OHO

H

CO2Et

MeI

Me

OHO

H

CO2Et

MeI

O

OH

H

CO2EtMe

I

Me

O

OH

H

CO2EtMe

I

Me

OH

OH

I

CO2Et

OH

OH

I

CO2Et

! Diols 3 and 5 as probes to differentiate between two trans-predictive transition states

3 4

5 6

or

or

3 reacts faster if steric controlled

5 reacts faster if torsional strain minimization and stereoelectronic arguments are involved

! Trans Selectivity in Iodoetherification of 1

CO2Et

OH OH

OH

OH

I

CO2EtI2, NaHCO3

THF

91%

1 2

Guindon J. Org. Chem. 2001, 66, 8992-8996

Stereoelectronic Effects in Iodoetherification of AllylicAlcohol Derivatives

EtO2C CO2Et

OH OHOH

EtO2C

OHO

H H

OHCO2Et

I

path A path B

O

H

CO2Et

Me

I

R

HO

O

H

CO2Et

Me

IHO

R

O

R

OH HCHO2Et

I

O

OH HCHO2Et

IR

EtO2C

OHO

H H

OHCO2Et

I

A

A

B

B

7

89

8 9

! Two-directional synthesis: compound with pseudo C2 axis of symmetry as a probe.

sterically favored

stereoelectronically favored

EtO2C

OHO

H H

OHCO2Et

I

EtO2C

OHO

H H

OHCO2Et

I

Iodoetherifications Outcome and Conclusion

! Iodoetherifications of Diols 3 and 5 under Kinetic Conditions

CO2Et

OH OH

OH

OH

I

CO2Et

3 4

CO2Et

OH OH

OH

OH

I

CO2Et

5 6

I2, NaHCO3

rt, THF

6 h, 86%

I2, NaHCO3

rt, THF

24 h, 20%

CH3CN 36 h, 55%

OOH

H

CO2EtMe

I

Me

OOH

H

CO2EtMe

I

Me

O

R

OH HCHO2Et

I

O

OH HCHO2Et

IR

! Operative transition states

Both stereoelectronic effects and allylic 1,3-strain are important controlling factors in thecyclofunctionalization reaction when an electron withdrawing group is at the allylic position.

! Conclusion

EtO2C CO2Et

OH OHOHI2, NaHCO3

CH3CN

36 h, 46%

EtO2C

OHO

H H

OHCO2Et

I 8

9

+1 : 10

! Group-selective iodoetherification

EtO2C

OHO

H H

OHCO2Et

I

Reagent-Controlled Stereoselective Iodinations

Chiral catalysts

Chiral reagents

1. NCS, toluene, rt, 30 min.

2. I2, -78 °C

3. -78 °C, 20h

R

OH

OR

I

67-90% ee

N

N

Et

AcOMeO

BF4I

2

5-exo iodolactonisationup to 14% ee

R. J. Trupp, Can. J. Chem., 1998, 76, 1233.

NH2

ICl

5-exo iodolactonisation up to 50% ee

T. Wirth, Org. Lett., 2002, 4, 297.

N N

Co

O OtBu tBu

tBu tBu

S. H. Kang, J. Am. Chem. Soc., 2003, 125, 15748.

O

O

O

Ti

O

Ph

Ph

Ph

Ph 2

Ti(TADDOLate)2

Taguchi T., Synlett , 1999, 1191.

X CO2R

CO2R

X CO2R

CO2R

I

XO

RO2C

H

O

Ti(TADDOLate)2 (20-30 mol %),DMP (2 eq), I2 (4eq), DCM/THF (4:1)

60-87% yield, 96-99% ee

X = CH2, CMe2, O; R = Bn, Me;DMP = 2,6-dimethoxypyridine.

! Iodocarbocyclization "

CO2CH3

CO2CH3 CO2CH3

CO2CH3O

H3CO2C

H

O

O

H3CO2C

H

O

as above as above

67% yield95% ee

80% yield99% ee

! Enantiotopic group selective reaction

Enantioselective halocyclization of polyprenoidsinduced by nucleophilic phosphoramidites

PBu3 P[C6H4(p-OMe)]3

PPh3 P(OPh)3 DABCO DMAP

No catalyst

99876751003

Nucleophile Yield of 2

R = m-Men = 1

R = p-MeOn = 1

R = p-Men = 2

15 (100) toluene 64 91

15 (100) toluene 58 91

15 (100) toluene 52 99

N

O

O

X

LA*

Nu*

N

O

O

X

LA*

N

O

O

X Nu*

!"

!+

# Nucleophilic promoters versus Lewis acid promotersfor the activation of N-halosuccinimides.

IH

IHNIS (1 equiv)

nucleophile (30 mol%)

DCM, -78 °C, 20 hthen -40 °C, 6 h

+

ClSO3H

1

3

2

product ratio 2/3 ~ 7:3

iPrNO2 -78°C, 4 h

! Activities of achiral nucleophiles for halopolycyclization of 1.

SiPh3

O

OP N

SiPh3

H

RO

OP R

R = N

H

Ph

R = NMe2

R = Ph R = Ph

PhR =

13

14

15 16

17

! Structure of chiral promoters

n

R

I

R

NIS (1 equiv)Promoter*

solvent, -40 °C, 24 h;

ClSO3H, iPrNO2, -78°C, 4 h

! Enantioselective halocyclization induced by chiral nucleophilic promoters

13 (30) DCM 95 0 13 (100) toluene 11 0 14 (30) DCM 46 0 15 (100) DCM 95 0 15 (100) toluene 57 95 16 (100) toluene 0 - 17 (100) toluene 34 34

substrate promoter (mol%) solvent yield (%) ee (%)

1

Ishihara Nature, 2007, 445, 900.

Enantioselective halocyclization of polyprenoidsinduced by nucleophilic phosphoramidites

Outline

chiral "I+"

I

H

H

Me

Cl

Cl

O

Cl

Cl

Cl

Cl( )6

SO3H

chlorosulpholipid

• Basic mechanisms

• Applications in synthetic organic chemistry

• Total syntheses of halogen-containing natural products

Halogenated Natural Products

As of 2006, more than 4500 halogenated natural products have beendiscovered, though it is likely to be a substantially incompleteinventory. These include 30 organofluorines, 2300 organochlorines,2100 organobromines, and 120 organoiodines.

HOH H

N

HO

Cl

OH O HO O

OH

O

NH2

chlortetracycline

OO

O

•

Br

H

Br

H

laurallene

O

HO

I

I

I

I

COOH

NH2

thyroxine; T4

O

O

F

fluoroacetate

Walsh CT. Chem. Rev. 2006, 106, 3364-3378

chlorosulpholipid

Cl

Cl

O Cl

Cl

Cl

Cl

OH

Cl

OH

ClCl

OH

HO3S

Cl

OH

Cl

OH

O

O

C15H31

Chlorosulfolipids

Freshwater algae

Mussels

C6H13

Cl

Cl

O

Cl Cl

OSO3H( )8

SO3H

ClCl

J. Org. Chem. 2009, 74, 6016–6024

Me

Cl

Cl

O

Cl

Cl

Cl

Cl( )6

SO3H

J. Org. Chem. 2001, 66, 578-582

Cl

Cl

O Cl

Cl

Cl

Cl

OH

Cl

X

ClCl

OH

HO3S

Cl

OH

Cl

OH

O

O

C15H31

X = OH J. Am. Chem. Soc. 2002, 124, 13114-13120X = H Tetrahedron 2004, 60, 7093–7098

C6H13

Cl

Cl

O

Cl Cl

OSO3H( )8

SO3H

ClCl

Biochemistry 1970, 9, 3110-3126

C8H17

Cl

Cl

OH

Cl Cl

( )8

Cl

Cl

J. Nat. Prod. 1994, 57, 524-527

OSO3H

Structure

MS, NMR and degradation

planar structure

J-based configuration analysisMosher’s method

Murata J. Org. Chem. 1999, 64, 866-876

relative and absolute configuration

Stereoselective Dichlorination of Allylic Alcohol Derivatives

Vanderwal C.D. J. Am. Chem. Soc., 2008, 130, 12514–12518

Cl

O

H

Cl

TCAO n-Bu1. 2. H2, Pd/CaCO3/Pb3. (Cl3CO)2O

dr 30:1

Et4NCl3,DCM, !90 °C

76%10.5:1 dr

Cl

TCAO

Cl

Cl

n-Bu

Li n-Bu

" Synthesis of a stereotetrad relevant to chlorosulfolipid

major anomer

TCAO

Cl

Cl OMe

OMeO

Cl

OMeH

H

Cl

H

1. Me2NH2. cat. TFA

2.8:1 ratio of anomers

54

3

3JH3-H4 = 2.7 Hz: gauche3JH4-H5 = 1.2 Hz: gauche

! Stereochemical proof: transform to epoxide or Eq 1

Eq 1

Me

Cl

Cl

O

Cl

Cl

Cl

Cl( )6

SO3H

R

OX R'

R

OX

Cl

Cl

R'

R

OX

Cl

Cl

R'

R

OX

Cl

Cl

R'

R

OX

Cl

Cl

R'

antidichlorination

syndichlorination

! Dichlorination of (Z)-allylic alcohol derivatives

Me

Cl

Cl

O

Cl

Cl

Cl

Cl( )6

SO3H

C6H13

Cl

Cl

O

Cl Cl

OSO3H( )8

SO3H

ClCl

R

TCAO R'Et4NCl3,

DCM, !90 °CR

TCAO

Cl

Cl

R' R

TCAO

Cl

Cl

R'+

yield: 67%!82% dr: 4.6:1!>20:1

" Stereoselective dichlorination (TCA = trichloroacetyl)

R, R' = alkyl

Synthesis and Characterization of All Four Diastereomers of3,4-Dichloro-2-pentanol

Vanderwal C.D. J. Org. Chem. 2009, 74, 2175–2178

TsO

Cl

Cl

x-Ray structure

TsCl

J. Am. Chem. Soc., 2003, 125 (47), 14379.

! Kishi's Universal NMR Databases

HO

OH

OH

OH

OH OH

OH OH

OH

Cl

Cl OH

Cl

Cl OH

Cl

Cl OH

Cl

Cl

TBSO

1. Et4NCl3

2. HCl/MeOH

HO

Et4NCl3

44% 30%

++

20% 11%

! Synthesis and Characterization of All Four Diastereomers

H

Cl

H

ClH

H

ClCl

H

Cl

H

R

OSO3H

Me

Cl

Cl

O

Cl

Cl

Cl

Cl( )6

SO3H

9

12

14

912

14

Cl

Cl

OTs

TsO

Cl

Cl

3J13,14 = 1.5 Hz

3J12,13 = 9.9 Hz

3J11,12 = 0 Hz

3J10,11 = 9.9 Hz3J9,10 = 1.1 Hz

24

3J2,3 = 6.4 Hz

3J3,4 = 3.6 Hz

2 4

3J3,4 = 8.3 Hz

3J2,3 = 4.5 Hz

! Comparasion with natural chlorosulfolipid

“The high degree of conformational order thatcharacterizes the chlorosulfolipids might only bepossible when more than three contiguousstereogenic centers are present and workingin concert.”

! Conclusion

Conformational and Configurational Analysis of TrichlorinatedHexane-1,2- and -1,3-diols

Cl

H

tBu

Cl

ClCltBu

Cl

tBu

(BuN4)4Mo8O26

CH3COCl

Cl

H

1

2

34

1

4

2

3

! Coupling constants for model system

3J(H2,H3) +2.9 Hz small

3J(H2,C4) +0.8 Hz small

3J(H3,C1) +4.7 Hz large

2J(H2,C3) +3.6 Hz small

2J(H3,C2) -4.5 Hz large

♦ Fragments Prepared (Black) and Spectroscopically Examined

Carreira J. Am. Chem. Soc., 2009, 15866.

OH

Cl

Cl

OH

OH

Cl

Cl

OH

Cl

C8H17

Cl

Cl

OH

ClCl

( )8

Cl

Cl

C8H17

Cl

Cl

OH

ClCl

( )8

Cl

Cl

Cl

1,2-diol

1,3-diol

! Trichlorinated hexane-1,2- and -1,3-diols: stereotetrad of chlorosulfolipid

OSO3H

OSO3H

Me

Cl

Cl

O

OH

Me

Cl

Cl

O

OH

ZrCl4or

Ti(OiPr)3Cl

MeCO2Et

ethyl sorbate

trans

cis

or

J-Based-Configuration Analysis Methodfor Polychlorinated Systems

Cl

Hy R2Hx

ClR1R1

R2

Cl

ClHy

R2 ClHx

ClR1

R1R2

Cl

Cl R2

Hy ClHx

ClR1Cl

R2 HyHx

ClR1 Hy

Cl R2Hx

ClR1

H,H-gauche H,H-anti

threo I threo II

erythro I erythro II erythro III

H ClMe

Cl

H OH

HH

CH2OHCl 1

5

! NMR Spectroscopic Analysis: HSQC-HECADE, HMBC, NOESY

36

For most 1,2- and 1,3-diols, the data were interpreted as the existence of one predominating conformer in solution

R2

Cl HyHx

ClR1

threo II(not observed)

1H

1H1H

1H

13C

1H13C

1H

1H

13C

Cl

1H13C

Cl

3J(H,H)-coupling constants

2J(H,C)-coupling constants3J(H,C)-coupling constants

+7.5- +10.5 Hzlarge

+1.0- +3.5 Hzsmall

+4.5- +5.0 Hzlarge

0.0- +3.0 Hz)small

-0.5- +4.0 Hzsmall

-3.5- -6.5 Hzlarge

! Generalized homo- and heteronuclear coupling constants for vicinal dichlorides and chlorohydrins as a function of the dihedral angle.

Comparison of the X-ray Structures of Diols withthe Predominant Conformation in Solution

Conformational Analysis of Trichlorohexanediols.

H

Me Me

Cl Cl

ClH

Me

Me

ClMe

HMe

Cl

Cl

H

Preferred conformation of 2,4-dichloropentane

gg ttgg:tt >10:1

Both conformers avoid syn-pentane interactionsA value: Cl(0.6), Me(1.7)Bond length: C-Cl(1.8Å), C-C(1.5Å)

! The dominant determinant of the preferred conformation is the minimization of syn-pentane interactions.

H ClMe

Cl

H OH

HH

CH2OHCl 1

5

36

! Gauche-effect and dipole minimization

HCl

H

H

H

HOOH

Cl

Cl

H

HMe

CH2OHHH

HO

HCl

Me

HClCl

ClH

HCH2OH

OH

ClH

MeHCl

H OHCl

OH

HH

ClH

H

ClMe

H

32 Solid State (x-Ray) 32 Solution (NMR)

41 Solid State (x-Ray) 41 Solution (NMR)

gauche vic-dichloride antiperiplanarvic-dichloride

Total Synthesis of Chlorosulfolipids-1

Carreira E.M. Nature, 2009,457, 573-577.

Me

Cl

Cl

O

OTBS( )6 Me

Cl

Cl

OH

Cl

OTBS( )6 Me

Cl

Cl

OH

Cl

Cl

Cl

OTBS( )6

Cl

HCl

H R

H

ClCl

HOEt4NCl3

Cl

natural product

TMSCl

! Revised and completion of total synthesis of chlorosulpholipid

3 steps from A

Me

Cl

Cl

OH

Cl

OTBS( )6

TMSCl

Me

Cl

Cl

O

Cl

Cl

Cl

Cl( )6 Me

Cl

Cl

OH

Cl

Cl

Cl

OTBS( )6

SO3H

natural product

Me

Cl

Cl

O

OTBS( )6Me

Cl

Cl R

O

SiMe3

Cl

Et4NCl3

Cl

ClOTMS

H R Me

Cl

Cl

OH

Cl

OTBS( )6

39% major product4% minor product expected product

Me

Cl

Cl

O

Cl

Cl

Cl

Cl( )6

SO3H

ClMeCO2Et

Et4NCl3

MeCO2Et

Cl

Cl

! Initial synthetic studies of chlorosulpholipid

A

Total Synthesis of Chlorosulfolipids-2

Vanderwal C.D. J. Am. Chem. Soc. 2009, 131, 7570–7572.