advanced organic chemistry iii

1

Advanced Organic Chemistry III Contents

1. Stereochemistry of Organic Compounds 2. Stereocontrol in Organic Reactions 3. Stereocontrol in Catalytic Reactions

References General Eliel, E. L.; Wilen, S. H. Stereochemistry of Organic Compounds, Wiley, 1993. Robinson, M. J. T. Organic Stereochemistry, Oxford University Press, 2000.

( , , 2002.) Kagan, H. B. La Stereochimie Organique, Press Universitaires de France, 1975.

( , , 1981.) , , NMR , , 2012. Abbreviations of substituents http://pubs.acs.org/paragonplus/submission/joceah/joceah_abbreviations.pdf

1. Stereochemistry of Organic Compounds (1) Structure and size of organic compounds

(a) Bond length bond length () bond length () bond length () bond length () CH 1.09 CF 1.38 CC 1.53 C=C 1.34 CC 1.53 CCl 1.77 CC= 1.50 C=C= 1.31 CN 1.47 CBr 1.94 CC 1.46 =C=C= 1.28 CO 1.43 CI 2.14 =CC= 1.48 CF 1.38 =CC 1.4 CC 1.20 C=O 1.22 CC 1.38 CC (in C6H6) 1.39

Bond length is defined as the distance between two nuclei. Distortion hardly affects bond length.

(b) Bond angle Bond angle is defined with the positions of three nuclei. Typically, the bond angles involved with sp-, sp2-, and sp3-hybridized carbons are 180, 120, and

109.5, respectively. Distortion hardly restricts the bond angles. Therefore, the CCC bond angle in cyclopropane is

allowed to be 60. However, the strain does not highly distort the angle of two sp3 orbitals. The CC bond in cyclopropane is constituted with a banana shaped orbital.

(c) Dihedral angle

Bond angle is defined with the positions of four nuclei. Shape of molecule can be defined with bond lengths, bond angles, and dihedral angles. In stable conformation, each dihedral angle should be 60, 180, or 120 (if the molecule have

sp2-hybridized atom). (see Conformation of organic molecules)

(d) Van der Waals radius Bondi, A. J. Phys. Chem. 1964, 68, 441. atom H C N O F P S Cl Br I radii () 1.20 1.70 1.55 1.52 1.47 1.80 1.80 1.75 1.85 1.98

CH3 2.0 C6H6 (thickness) 1.7 Generally, van der Waals radius is useful for considering the

bulkiness of substituent. However, van der Waals volume, which is calculated from the radii,

does not contains the effect of bond rotation. Solvent accessible surface area is sometimes used for evaluating

the accessibility of a reagent to a substrate.

e

Cf dC

b a

c

e

f d

b a

c

dihedral angle

2

(e) A-value

R A-value R A-value R A-value R A-value R A-value H 0.00 CCH 0.41 F 0.25 OMe 0.55 CHO 0.56 Me 1.74 CH=CH2 1.49 Cl 0.53 O(t-Bu) 0.75 COMe 1.02 Et 1.79 Ph 2.8 Br 0.48 OSiMe3 0.74 CO2H 1.4 i-Pr 2.21 SiH3 1.45 I 0.47 NHMe 1.29 CO2Me 1.2 Cy 2.2 SiMe3 2.5 OH 0.60 NMe2 1.53 CN 0.2 t-Bu 4.7 SnMe3 1.0 NH2 1.23 PMe2 1.5 CF3 2.4 Sn(i-Pr)3 1.10 NH3+ 1.7 PPh2 1.8

A-value is widely used for discussing the steric effect of substituent. In general, A-value correlates with the size of substituent. Furthermore, the value includes the

effect of bond rotation. Therefore, the value reflects the steric environment around the atom bearing the substituent.

A-value is affected by bond length (CR) as well as by van der Waals radius.

(f) Tips to consider steric effect of a substituent i) Where is the most important for the related steric repulsion (near or far)?

If you will consider the steric effect around the atom , t-Bu or 2,6-xylyl must be larger than

-CC(t-Bu) group. If you would like to create a steric hindrance far from , -CC(t-Bu) should be larger than t-Bu

and 2,6-xylyl. ii) Snapshot or motion blur? (in the case of aryl group)

(top view) (side view) (snapshot) (motion blur) Snapshot may be preferable when you consider the steric hindrance in dynamic phenomena. Motion blur may be suitable for thermodynamic phenomena. In snapshot steric effect, phenyl group can be regarded as a smaller substituent than methyl one. In motion blur steric effect, phenyl group can be regarded as a larger substituent than secondary

alkyl ones.

(2) Chiral Compounds and Enantiomers Chiral molecule can not overlap with its mirror image. Therefore, chiral compounds have no

symmetry plane () or rotation-reflection axis (Sn). Achiral compounds are the compounds that are not chiral. "Chiral molecule" means the molecule possessing any chirality. "Chiral compound" means the mass of chiral molecules. "Racemic compound (racemate)" means the 1:1 mixture of both enantiomers (R and S). Each

molecule constituting a racemic compound should be "chiral molecule". "Optically active compound" means the chiral compound other than racemate. A mixture of

enantiomers is often categorized as optically active compounds, even if R:S is 51:49. However, the term often indicates pure enantiomer (enantiopure compound or optically pure compound).

"Enantiomer" originally means the mirror image of a chiral molecule (e.g. (S)-2-octanol is the enantiomer of (R)-2-octanol.). The term often indicates the enantiopure compound, whose absolute configuration has been known.

"Diastereomer" means any stereoisomers other than enantiomer. "Epimer" means stereoisomers bearing only one chiral center with the opposite absolute

configuration. The configuration of other chiral centers in the epimer must be identical to the original compound.

(a) Central chirality

The chirality caused by asymmetric atom is called "central chirality". Asymmetric atom is not limited to carbon (e.g. N, S, P, etc.). Lone pair can function as a

substituent and is regarded as atomic number 0 in CIP rule (see 35).

Spiro compound 6 is chiral, although they seem to have no asymmetric atom. However,

compound 7 is achiral because its tetrahydrofuran ring is symmetry plane.

The molecules possessing symmetry plane (see 8, 9) or rotation-reflection axis (see 10) must be

achiral, even if they have asymmetric atoms (e.g. meso compound).

Metal complexes are possible to be chiral when they are tetrahedral, trigonal bipyramidal, or

octahedral.

RR

Geq GaxA value = G0 = Gax Geq (in kcal/mol)

MeMe

Me

Me

Me

Me

MeMevs vs

Me

Me

Cl

d

Ca

bc

d

Ca

bc =

d

Ca

cb

180

NH2Me CO2HH

+N

Ph MePh

N

N

1 2 3

Me PPh

OMe:

Ph SMe

O

:

4 5

O O OO=180

OO

6O7

Me MeOH

OHMe Me

OHOH =Me Me

HO OH

8 9O

OO

Me O

Me

10

3

(b) Axial chirality Axial chirality takes two forms: atropisomerism and isomerism in allenes. Atropisomerism Atropisomerism is caused by inhibition of free rotation of a single bond. The inhibition of free

rotation is often observed in the biaryl compounds bearing four ortho-substituents or some sterically hindered carboxamides.

A racemate of axially chiral compound can be resolved into each enantiomer when the rotation

barrier is over 20 kcal/mol. Axial chirality will be stable at room temperature when the rotation barrier is over 30 kcal/mol. Herical chirality is originated from the accumulation of axial chirality.

Isomerism in allenes Each terminal carbon in C=C=C is plane because it is sp2-hybridized. One of the planes is

perpendicular to another because the internal carbon in C=C=C is linear and hybridized in sp manner to form two CC double bonds. Therefore, substituted allenes are possible to be chiral as with biaryls.

The chirality is seen in some spiro bicyclic compounds and alkylidene cycloalkanes.

(c) Planar chirality

Planar chirality appears when a planar molecule loses its symmetry plane by bridging with short tether or forming -complex.

The chirality is seen in some cyclophanes, metallocenes, and trans-cycloalkenes.

(d) Notations of absolute configuration 1) R/S notation

According to CIP rule, determine the priority of each substituent involved with the chirality. Central chirality

(in the case of spiro compounds)

Axial chirality

i) Determine the priority of the two substituents on each atom involved with the chiral axis. ii) The sequence of substituents becomes a > b > c > d or c > d > a > b. Both sequences result

in the same configuration. iii) Put the substituent with the lowest priority (d or b) on the location far from you. Confirm the

direction of a b c (or c d a).

iv) To distinguish the axial chirality from others, prefix 'a' (or sufix 'a') is sometimes attached to the

chiral descriptor R or S (e.g. (aS)-2,3-pentadiene or (Sa)-2,3-pentadiene) Planar chirality (cyclophanes, trans-cycloalkenes etc.)

i) Determine 'pilot atom' from the bridging tether. The pilot atom is out of the plane and closest to the plane. There are two candidates in general. The pilot atom is the candidate binding to the in-plane atom with higher priority in CIP rule.

ii) Among the atoms in the chiral plane, the atom binding the pilot atom is assigned to 'a'. The next atom is 'b', and the third atom is 'c'. If there are two candidates, the atom with higher priority is assigned to 'c' (or 'b').

iii) View the molecule from the pilot atom.

iv) To distinguish the planar chirality from others, prefix 'p' (or sufix 'p') is sometimes attached to

the chiral descriptor R or S (e.g. (pS)-(E)-cyclooctene or (Sp)-(E)-cyclooctene) Planar chirality (metallocenes) Three rules have been proposed to assign the stereochemical descriptor, R or S, for the planar

chiral metallocenes. One is based on central chirality and proposed by Prelog, Cahn, and Schloegl (Rule 3). Others are based on planar chirality and proposed by Ugi and Schloegl,

b

aa

bb

aa

b

=180

a

ba

b a b

OHOH

N

O

Pht-Bu

NO

Me

Me

a

b

ab

a b

CO2H

HH

HO2CHMe

HO2C

H

FeCO2Me

BrCO2H

=

aCbcd

a > b > c > d

a

b c

d

a C a'b b'

a > b

1 2

3 4

a

b a'

b'

d

ca

b a > b, c > d

=a

b dc

b

acd

Br cb a

Br: pilot atom

a b c clockwise R anticlockwise S

a a' b clockwise R anticlockwise S



4

independently (Rule 1 and 2). Unfortunately, the rules 1 and 2 resulted in configuration different from each other. However,

rules 2 and 3 reach the same result in most cases. Rule 1 (i) View the substituted Cp ligand from the side opposite to the metal atom. (ii) Confirm the direction of a b.

I. Ugi et al., J. Am. Chem. Soc. 92, 5389 (1970).

Rule 2 (i) Assign the metal atom to the pilot atom. (ii) Regard the centroid of the substituted Cp ligand as atom 'a'. (iii) The cyclopentadienyl atom bearing the substituent with the highest priority is 'b'. (iv) The ortho-atom with higher priority is assigned to 'c'. (v) View the Cp ring from the pilot atom, and then confirm the direction of a b c.

K. Schloegl, J. Organomet. Chem. 300, 219 (1986).

Rule 3 (i) Treat chirality of metallocene as central chirality of the cyclopentadienyl carbon with the

highest priority. (ii) Consider the metal atom to bond to the carbons in Cp ring. (iii) The absolute configuration can be similarly assigned to R or S with the rule for central

chirality.

K. Schloegl, Forschr. Chem. Forsch. 6, 479 (1966).

2) P/M notation P/M notation is based on the chirality of helix (helicity). The descriptor P is used for right-handed helicity, and M is used for left-handed helicity (from

before backward).

The notation can be applied to axial and planar chiralities. In the case of planar chirality, pR and pS configurations correspond to P and M, respectively.

3) D/L notation

D/L notation is sometimes used for the stereochemistries of carbohydrates and -amino acids. Descriptors D and L strongly relate to the stereochemistries of (R)-(+)- and (S)-()-glyceraldehyde,

respectively. D and L, must be smaller in size than other characters.

4) Notations based on the direction of optical rotation

Descriptor (+) or () corresponds to the direction of optical rotation. (+) and () are used for dextrorotatory and levorotatory compounds, respectively.

Descriptors d and l are equivalent to (+) and (), respectively. dl notation is not related to D/L notation.

(e) Characteristic properties of chiral compounds Most properties of an enantiopure compounds are identical to those of its enantiomer.

Exceptionally, the direction of optical rotation is different. However, an enantiopure compound is different in most properties from its racemate. 1) Crystals of racemate

Three types of crystalline racemate are known, as follows: racemic conglomerate, racemic compound, and psudoracemate. Most racemates preferentially to form racemic compounds.

Racemic conglomerate Racemic conglomerate is a mechanical 1:1 mixture of R crystals and S crystals. Each crystal in

the mixture is homochiral (constits of a sole enantiomer). Preferential formation of racemic conglomerate requires that the interaction between R and R (or

S and S) is stronger than that between R and S. Racemic conglomate is much rarer than racemic compound.

Feb

a Fe b

a

90

a > b

FeBr

Mec b BrMe

a

FeBr

MeC Br

Me

Fe2

1

3

4FeC

BrCC4

3Me

1

2

(P)-[6]helicene (M)-[6]helicene

c dd

ca

ba > b, c > d

a

b

90a

bd cor

For axial chirality

For planar chirality

ab

dc

Br

The abcd unit can be regarded as a helix. View the helix from a. Confirm the direction of the helix.

HOOH

CHO

D-glyceraldehyde

HOOH

CHO

L-glyceraldehyde

CHOOHH

CH2OH

CHOHHO

CH2OH

CHOHH2N

CH2OHL-serine

OOH

HOHOHO

OH

CHOOHH

HO HH OH

HO HOH

=

D-glucose

a b clockwise R anticlockwise S


1 2 3 clockwise R anticlockwise S

from before backward clockwise P anticlockwise M

5

Chiral compounds, which preferentially form racemic conglomerate, can be resolved into each enantiomer through preferential crystallization without any other chiral source.

Racemic compound In racemic compound (true racemate), each crystal contains R and S molecules in 1:1 ratio.

The both enantiomers form a racemic pair in a unit cell. Most chiral compounds prefer the formation of racemic compound to that of racemic

conglomerate. In many cases, a chiral molecule has stronger affinity for its enantiomer than for itself.

Nevertheless, homochiral crystals are preferentially obtained from the compound with relatively high enantiomeric excess

Psudoracemate In crystals of psudoracemate, both enantiomers coexist in an unordered manner. This type of chiral compound is very rare.

2) Melting point

Melting point of chiral compound is affected by its enantiomeric excess. Each type of crystalline racemate exhibits characteristic behavior in solid-liquid phase transition.

In racemic compound, racemate is generally higher in melting point than its enantiopure form.

Binary phase diagrams describing the melting behavior of a) 3-fluoromandelic acid (racemic compound); b) 2,3-diacetoxybutane (psudoracemate); c) 1.2-diphenylethane-1,2-diol (racemic conglomerate).

(f) Resolution of chiral compounds 1) Use of resolving agent

Although an enantiomer is impossible to be separated from its racemate, an epimer is physically separable from the mixture of diastereomers.

Therefore, formation of diastereomers with an optically active resolving agent is very useful for the optical resolution of racemates.

Crystallization of diastereomeric salts This method is useful for resolution of chiral carboxylic (phosphonic or sulfonic) acids, amines,

and phosphine oxides. Acidic functional group (e.g. -CO2H, -SO3H) can readily form salts with basic functional groups

(e.g. -NH2). The acidbase pair is easier to crystallize from organic solvent than each compound, because the salt is generally less soluble.

Treating racemic carboxylic acid 1 with stoichiometric enantiopure amine 2 gives the mixture of

ammonium salt 3RR and 3SR. If 3RR is less soluble than 3SR, 3RR can selectively be obtained through crystallization. Purity of the crystals can be enhanced by recrystallization. Enantiopure (R)-1 will be obtained by decomposing the pure 3RR in hand with acid.

Equimolar resolving agent (to racemate) is requires for the resolution controlled by type 1

thermodynamics. Halfmolar resolving agent may be enough for an efficient resolution, if it is controlled by type 2 or 3 thermodynamics.

Representative resolving agents

Crystallization or chromatographic separation after derivatization This method is useful for the resolution of chiral alcohols and ketones. It is applicable for the

resolution of chiral (secondary or primary) amines and acids. In the resolution of a racemic alcohol 4 (e.q. R and S), the racemate is esterified with an

enantiopure acid anhydride 5 (e.g. R), which is the resolving agent. The esterification will give a mixture of diastereomeric esters 6RR and 6SR (RR and SR). Both diastereomers can be separated by column chromatography or crystallization. Each pure diastereomer in hand can be transformed to (R)- or (S)-alcohol through hydrolysis.

RRRRRR

SSSSSS

RSRSRS

SRSRSR

racemic conglomerate racemic compound

RRSRSS

SRRSSR

psudoracemate(true racemate)

CO2HMeO

PhH

CO2HMeO

HPh

+ H2NH

MePh

R

R

S

CO2MeO

PhHR H2N

H

MePh

R+

CO2MeO

HPhS H2N

H

MePh

R+

3RR

3SR

(R)-1

(S)-12

(crystallize)

(in solution)

H3O+ CO2HMeO

PhHR

(R)-1

R + S

S + S

RS (less soluble)

(more soluble)

Type 1R + S

S + S

RS (less soluble)

(soluble)

Type 2

SS SS

R + S

S + S

RSType 3

SS

N

O

O

N

H

H

HH

R

R

for acids

brucine (R = OMe)strychnine (R = H)

N

NOH

OMe

quinine

NOH

N

OMequinidine Me

NH2

Me

NH2

for bases

HO2C CO2HOH

OH

tartaric acid

HO2C CO2HOBz

OBz

HO2C CO2H

OH

malic acid

CO2H

OH

mandelic acid

O

Me Me

HO3Scamphorsulfonic acid

OP

O OOH

6

A racemic chiral ketone or aldehyde can be resolved through the reaction with an enantiopure

primary amine, which gives a mixture of diasteromeric imines. Representative resolving agents

2) Chiral HPLC

A racemate is resolved to each enantiomer through the column chromatography with a chiral stationary phase, which is typically composed of a chiral compound and silica gel.

Information of each chiral column can be obtained from the following web sites.

Daicel: http://www.daicelchiral.com Sumichiral: http://www.scas.co.jp/service/apparatus/

hplc/sumichiral_introduction.html Astec: http://www.sigmaaldrich.com/japan/

analytical-chromatography/hplc/chiral-astec.html 3) Preferential crystallization

Racemic conglomerate can be resolved through recrystallization without resolving agent, if you have its homochiral single crystal.

To a saturated hot solution of the racemate, its homochiral crystal (e.g. R) is installed. The same enantiomer (R) will be crystallized in preference to the antipode (S). The resulting mother liquor

will be S-enriched. The recrystallization of the mother liquor will preferentially form the crystals of S-compound.

4) Kinetic resolution In general, chiral reagents and catalysts exhibit different reaction rate for each enantiomer of

substrates. If the reaction of the R-enantiomer is faster than that of S-isomer, the recovered substrate should be S-enriched. Therefore, the reaction of a racemate with a chiral reagent (or through asymmetric catalysis) is usable for the resolution.

The efficiency of kinetic resolution (s) is expressed by the ratio of the reaction rate of each

enantiomer (kR/kS). s = kR/kS = ln[(1C)(1-ee)]/ln[(1C)(1+ee)] = ln[1C(1+ee')]/ ln[1C(1ee')]

C: conversion ee = enatiomeric excess of unreacted substrate ee' = enatiomeric excess of product

Examples

Marshall, J. A. Org. Synth. 2005, 82, 43.

Sharpless, K. B. J. Am. Chem. Soc. 1981, 103, 6237.

(g) How to determine absolute configuration 1) Chemical transformation

a) The target molecule is reacted with a known optically active compound. If the product, which must have two chiral centers, is crystalline solid, it is subjected to X-ray crystal structure analysis. The absolute configuration of the target is found through the resulting structure, because the absolute configuration of one of its chiral centers is known.

b) The target molecule is transformed to a known optically active compound. Possibility for

racemization must be considered during the transformation. The specific rotation of the resulting product is compared with the reported []D. Comparison of the retention times in the chiral HPLC analyses is also useful for the assignment of absolute configuration.

MeOH

PhHO

H

H

O

OMe

OHHPh

R

S

RR+

(R)-4

(S)-4HO2C

O

O

PhMeH

5HO2C

O

O

PhHMe

R S

6RR 6SR

(separable with chromatography or crystallization)

hydrolysis(R)-4 (S)-4

for alcohols

O

O

O

H

H

O

O

OH

H

H

Me

Me Me

NCO

(for urea derivatization)

(for lactor derivatization)(for ester derivatization)

O

O

CO2HMe Me

Me OH

O

OMe

MeMe Me Me Me

H

for ketones and aldehydes

Noe reagent

EtO2C CO2EtOH

OH

diethyl tartarate

NNH2 OMe

SAMPMeHN NHMe

Ph Ph

kR R&S

(50:50)

+ aR + a R a

kSS + a S a(fast)

(slow)

if kR >> kS R a&S (almost enantiopure)

Me

OH

TMS

Amano Lipase AKOAc , pentane Me

OH

TMS49%

Me

OAc

TMS47%

C6H13

OH Ti(O-i-Pr)4 & (+)-DIPTt-BuOOH C6H13

OH

C6H13

OH

Os = 83

R1 R2

OH

(target)

Ph COCl

OMe

S

Ph O

O

R1R1MeO

SX-ray crystal structure

a

b Compare the stereochemistry of chiral center a with that of chiral center b.

7

c) The authentic sample of the target molecule is synthesized from a known optically active

compound. The specific rotation or the chiral HPLC retention time of the authentic sample allow us to assign the absolute configuration.

2) Crystallography (Bijvoet method)

Commonly, X-ray single crystal analysis gives no information about the absolute configuration of the chiral compound. However, the configuration can be determined with the crystallography, when the compound has one heavy-weight atom.

The heavy-weight atom induces anomalous X-ray scattering, which caused that intensity F(h k l) is not equal to that of F(h k l) in a chiral crystal.

Flack parameter (x) is widely used for estimating the absolute configuration of crystal structure. I(h k l) = (1x)|F(h k l)|2 + x|F(h k l)|2

x: Flack parameter I: the square of the scaled observed structure factor F: the calculated structure factor

If x is near 0, the crystal structure has the correct absolute configuration. If the crystal structure has the inverted configuration, x is near 1.

Bijvoet method is applicable for chiral compounds bearing no heavy-weight atom. In this case, a protective group containing a heavy-weight atom (e.g. p-bromobenzoyl) is installed to the target molecule.

3) Advanced Mosher method and its related methods see: Riguera, R. Chem. Rev. 2004, 104, 17. Advanced Mosher method Advanced Mosher method is empirical, but very useful for determining the absolute configuration

of an unknown chiral secondary alcohol. This method is applicable for the chiral secondary alkyl primary amines.

(original) Mosher, H. S. J. Am. Chem. Soc. 1973, 95, 512.

(alcohol) Kusumi, T.; Kakisawa, H. J. Am. Chem. Soc. 1991, 113, 4092. (amine) Kusumi, T.; Kakisawa, H. Tetrahedron Lett. 1991, 32, 2939.

Prepare two samples of the secondary alcohol. Each Sample is esterified with (R)- or (S)-MTPA to prepare (R)- and (S)-MTPA esters (MTPA is 3,3,3-trifluoro-2-methoxy-2-phenylpropionic acid). For each proton in the secondary alcohol moiety, calculate the difference between the 1H NMR chemical shifts of (S)- and (R)-MTPA esters ( = S R) as shown in above figure.

In MTPA esters, their CF3 groups are located at the pseudo eclipse of the proton attaching to the chiral carbon of the secondary alcohol. The aromatic ring in MTPA induces upfield shift of the resonances of the protons in the secondary alcohol moiety. Therefore, if is negative, the proton should be located over the aromatic ring of (S)-MTPA.

Trost method Trost method uses O-methylmandelic acid instead of MTPA. The procedure is very similar to

advanced Mosher method. O-Methylmandelic acid is easier to react with secondary alcohols than MTPA, but may be

racemized during the esterification. In the O-methylmandelates, their OMe groups are located at the pseudo eclipse of the proton

attaching to the chiral carbon of the secondary alcohol.

Trost, B. M. J. Org. Chem. 1986, 51, 2370.

PGME method PGME (phenylglycine methyl ester) method is useful for determining the absolute configuration of

the chiral -carbon of carboxylic acid. In the PGME amides, their CO2Me groups are located at the pseudo eclipse of the -proton of the

chiral carboxylic acid.

Kusumi, T. Tetrahedron Lett. 1995, 36, 1853; J. Org. Chem. 2000, 65, 397.

4) Circular dichroism (CD) spectrum Circular dichroism is active for only optically active compounds. Positive Cotton effect means that an enantiomer gives a positive peak in its CD spectrum. Octant rule This method is empirical and useful for determining the absolute configuration of cyclic ketones. First, consider the most stable conformation for the target molecule. Geometry optimization with

MO or MM may be useful for the consideration.

target other compound(Its []D has been reported.)

Measure its optical rotation and caluculate []D.

Compare it with the []D reported in the literature.

other compound(Its []D has been reported.)

authenticsample optical rotation.retention time in chiral HPLC.Measure its

Compare the value with that of the target.

R1H

O

O

OMeCF3

R2S

(S)-MTPA ester

upfield shift

R1H

O

O

MeOCF3

R2R

(R)-MTPA ester

upfield shift

= S RIf > 0, the proton belongs to R2.If < 0, the proton belongs to R1.

R1H

O

O

HOMe

R2R

(R)-O-methylmandelate

upfield shift

R1H

O

O

HOMe

R2S

upfield shift


(S)-O-methylmandelate

R1H

R2

(S)-PGME amide

upfield shift

R1H

NH

HCO2Me

R2R

upfield shift

NH

HCO2Me

O O

S

(R)-PGME amide


8

Space around the carbonyl group is divided into eight sectors as shown in figure (a).

In octant rule, the atoms in the + sectors induces a positive Cotton effect. The atoms in the sectors induces a negative Cotton effect.

The Cotton effect can be predicted as above. Compare the prediction with the observed CD spectrum (n* (C=O), ca. 300 nm).

Exciton chirality method This method is theoretical and useful for determining the absolute configuration of

cycloalkanediol or diamine. Two equivalent chromophores (e.g. p-Me2NC6H4CO2-) in a molecule are required for the assignment.

The two chromophores cause the split of their CD peak. One is negative and the other is positive.

When the longer wavelength band of the split peak describes a positive Cotton effect and the shorter one describes a negative Cotton effect, the two chromophores arranged in a right-handed helix.

(h) How to analyze enantiomeric excess

Percentage of enantiomeric excess (% ee) is commonly used for representing the ratio of enantiomers. (% ee (R-enriched) = ([R] [S])/([R] + [S]) 100)

1) Specific rotation Specific rotation is usable for measuring enantiomeric excess, if specific rotation of enantiopure

compound has been reported. % ee = [a]D (sample)/[a]D (100% ee) 100

However, the specific rotation is significantly affected by inpurity, solvent, and temperature. Sometimes, concentration of the sample affects the specific rotation.

2) Chiral HPLC and GC Chiral HPLC or GC analysis is commonly used for measuring enantiomeric excess. Chiral HPLC is effective for relatively polar compounds (alcohol, ketone, ester, amide etc.) with a

UV active moiety (-bond). Chiral GC is usable for less polar compounds (hydrocarbon, ether etc.) as well as above

compounds. UV active moiety is not required, but the sample must be volatile. 3) Chiral shift reagent

Prepare NMR sample of the target compound in CDCl3 or C6D6 and measure 1H NMR. Add a small amount of a shift reagent to the NMR sample, and then measure 1H NMR again. Repeat the process several times until a proton signal completely splits. The enantiomeric excess of the sample is calculated from the ratio of the integrals of each split peak.

Representative chiral shift reagents

OH

NMe2

OO

Ar

O

O

ArOHOH

Ar

O

Cl==

HO

HO

NMe2

O

OM

Rf

Me

Me

Me 3

Rf = CF3 (tfc) or C3F7 (hfc)M = Yb or Eu

NO2

HNO

OHN

N

N

O

O

HN

HN

O

OM(tfc)3 or M(hfc)3

Octant rule for standard ketones. (a) Signs of the sectors in a left-handed Cartesian coordinate system; (b) projection of the rear sectors (z < 0).

9

(3) Diastereomers (a) Notations of diastereomeric stereochemistry

1) E/Z notation for alkenes As with R/S notation, E/Z notation unambiguously defines the geometrical configuration of

alkenes. The notation is based on CIP rule. i) Determine the priority of the two substituents on each atom involved with the CC double bond. ii) Confirm the positional relationship of each substituent with higher priority.

2) cis/trans notation

Cis/Trans notation is ambiguous, but often used for indicating the geometrical configuration of alkenes or the relative configuration of cyclic skeletons including two chiral centers.

Priority of each substituent is determined with common sense, which causes the ambiguity (CIP priority or main chain in IUPAC nomenclature?).

In the case of alkene geometry, cis and trans configurations correspond to Z and E, respectively.

3) erythro/threo notation for relative configuration

Erythro/threo notation is ambiguous, but often used for indicating the relative configuration of acyclic vicinal chiral centers. Erythro and threo forms are strongly related to the stereochemistry of erythrose and threose.

If the substituents on each chiral carbon are arranged in a similar manner, the configuration is threo. Otherwise, the configuration is erythro.

4) syn/anti notation for relative configuration

Syn/anti notation is less ambiguous than erythro/threo notation and applicable to various acyclic compounds.

Draw the structure of the target compound with zig-zag projection. If two substituents are arranged on the same face, the configuration is syn. Otherwise, the configuration is anti.

5) R*/S* (or RS/SR) notation for relative configuration R/S notation is applicable in relative configuration. This notation is unambiguous. Assign the absolute configurations of all chiral center in an enantiomer. Attach an asterisk to

each R or S descriptor. (2R*, 3S*) is equivalent to (2S*, 3R*).

6) l/u notation for relative configuration

Determine the absolute configurations (R/S or P/M) of all chiral centers, and then arrange them according to the numbering rule in IUPAC nomenculture.

If the absolute configurations of two neighboring chiral centers are identical or similar each other, the relative configuration is l (like). Otherwise, u (unlike) must be used as the stereochemical descriptor. For example, uu-1,2,3,5-hexanetetraol is equivalent to (2R*,3S*,5R*)-1,2,3,5-hexanetetraol.

(b) Treatment of stereochemistry in CIP rule

In CIP rule Atomic number larger higher priority Isotope atomic mass: larger higher priority Alkene stereochemistry priority: Z > E (cis > trans)

In most cases, the priority of two geometrically isomeric groups can be determined by Z/E system. However, the system is useless to 4-substituted alkylidenecyclohexanes, although they can be regarded as axially chiral molecules. In this case, the alkene configuration is determined from the substituent bearing the chiral center.

Diastereomeric groups priority: l > u ( Enantiomeric groups R > S or M > P?)

(c) How to determine stereochemistry of diastereomer 1) Crystallography

If the sample is crystalline solid, its X-ray crystal structure analysis is the most reliable. 2) NMR

i) 1,2-Disubstituted alkene nOe (nuclear Overhauser effect) difference spectrum Positive nOe will be observed between two substituents, which are located in the cis position

a

b

c

da > b, c > d

a

b

c

d

a

b

c

da > b, c > d

a

b

c

d

a

d

bc

a

d

bc

CHOOH

OHD-erythrose HO

CHOOH

OHD-threose HO

==

==

CH2OH

H OH

OHC

H OH

CH2OH

H OH

OHC

HO H

b'

c' a'

b

c a

b'

c' a'

b

a c

2

13

3

1

2

2

13

3

1

2

Me

OH OH

OH2 4

5 Me 2,4-syn, 2.5-anti

Me OHOH

OHOH(2R*,3S*,5R*)-1,2,3,5-hexanetetraol

= (2S*,3R*,5S*)-1,2,3,5-hexanetetraol

O OHOH

HOHOHO

CHO

OH

OH

OH

OHHO RRR S

D-glucose uul-2,3,4,5,6-pentahydroxyhexanal

CO2H

H MeH Me

HO2C

CO2Hcistrans

12

34S

positional relationship between a and c the same side Z opposite side E

positional relationship between a and c the same side cis opposite side trans

a b c vs a' b' c' the same direction erythro opposite direction threo

10

each other. NOESY should be avoid to use for the purpose.

Vicinal HH coupling (3JHH) In general, the coupling constant between the two alkenyl the alkenyl protons is 1013 Hz when

the protons are arranged with cis configuration. In the trans isomer, the coupling constant is 1517 Hz.

The above rule is useful only when a carbon atom attaches to each alkenyl carbon. Heteroatom substituents causes decrease in the coupling constant.

ii) Saturated four- and five-membered ring

NOESY or nOe difference spectrum Use only transannular nOe. Sometimes, nOe is observed between vicinal hydrogens with

trans configurations, because these protons couple with each other.

iii) Saturated six-membered ring

Chemical shift In general, an axial proton appears in higher field (ca. 0.5 ppm) than its corresponding

equatorial proton. Vicinal HH coupling Karplus equation: 3JHH = A cos2 + B cos + C (: dihedral angle)

(e.g. A = 9.4, B = 1.4, C = 0.4 (for hydrocarbons)) 3JHaxHax is 814 Hz, because dihedral angle for HaxCCHax is 180. 3JHaxHeq and 3JHeqHeq

is 24 Hz, because the related dihedral angles are 60. Higher magnetic field NMR spectrometer should be used for assigning the relative configuration

of cyclohexane derivative. Assign as many paeks as possible by using not only 1D-NMR but also HH cosy, HMBC. HSQC etc.

Assign the stereochemistry by using each coupling constant in a similar way to solving a puzzle.

iv) Acyclic compound see: Bifulco, G.; Riccio, R. Chem. Rev. 2007, 107, 3744. General methods JBCA (J-based configuration analysis) see, Murata, M. J. Org. Chem. 1999, 64, 866. UDB (Universal NMR Database) see, Kishi, Y. Org. Lett. 1999, 1, 2177 and 2188. Use of quantum mechanical calculation 1,2- or 1,3-diols (diamine) Protect the diol with acetone (or 2,2-dimethoxy propane, phosgene etc.) to give the

corresponding acetonide. Analyze the resulting cyclic acetal with NOESY, nOe difference spectrum, HH coupling constrants etc.

1,3-diols Acetonides of syn-1,3-diols have chair conformation, while those of anti-1,3-diols prefer twist

boat conformation. Therefor, the relative configuration of 1,3-diols can be elucidated with the 13C NMR resonances of the methyl groups of their acetonides.

H H H CHR2 R2HC CHR2 H OCH3

HOCH3

O?

CH3OCH3

O?

H H

C C3JHH = 1013 Hz

H C

C H3JHH = 1517 Hz

abd

c

The nOe between a and d (red) is reliable for determing the relative configulation. The nOe between a and b (blue) should be avoid to use for the purpose, because an nOe is sometimes observed between a and c.

R1 R2OH OH

R1 R2O O

Me Me

R1 R2OH OH

R1 R2O O

Me Me

==

==

OO

R1

R2 Me

Me

OO

R1

R2Me

MeOOR2R1

H

H

MeMe 24.6 0.76

19.4 0.21

30.0 0.15

98.1 0.83

100.6 0.25syn-1,3-diol

anti-1,3-diol

11

(4) Conformation of organic compounds (a) Acyclic saturated compounds

1) Ethane The staggered conformer ( = 60 or

180) is more stable than the eclipsed one ( = 0 or 120) (E = 2.9 kcal /mol).

The ecripsed conformer is a transition state and not energy minimum.

The CH*CH interaction stabilizes the staggered conformer.

The steric repulsion between the vicinal protons scarcely contributes to rotational barrier.

2) Butane Butane has two energy minima: one is anti, and the

other is gauche. Anti conformer is more stable than gauche one (E =

0.9 kcal /mol). Each conformer, including unstable conformers, can be

named with the dihedral angle as shown below.

3) Pentane

In the conformational analysis of pentane, the free rotations of C2C3 and C3C4 should be considered.

Conformer aa is the most stable conformer of pentane. Conformers g+g and gg+ are the least stable. The energies of these

conformers has been estimated to lie over 3.3 kcal/mol above that of conformer aa.

The steric repulsion is called 'syn-pentane interaction'.

4) Effect of * or n* interaction Conformation involved with C(sp3)C(sp3) bond is affected by the hyperconjugation between

vicinal CX bonds. In the hyperconjugation, one of the orbital of CX bond donates electrons to *-orbital of another CX.

Electron donating ability: nN > nO > CC, CH > CX (X: N > O > S > Hal) Electron accepting ability: C=O > *CHal > *CO > *CN > *CC, *CH Gauche effect: In some compounds, gauche conformer is preferable to anti conformer.

Anomeric effect: The ratio of - and -glucose is 38:62 in water. The unusual ratio (A value of

OH is 0.60) is caused by anomeric effect, the interaction between nO and *CO orbital.

(b) Acyclic unsaturated compounds

1) XCH2CH=Y (Y = CH2, O) Energy minima appear when the C(sp3)X (or H) bond overlaps to the C=Y bond in the Newman

projection. Another conformer, in which the CX bond overlaps to the C(sp2)H bond, is a torsional barrier.

Steric repulsion between X and Y is often considerable in the eclipsed conformer (1,3-allylic strain). Therefore, the gauche conformer is generally preferable to the eclipsed one.

The gauche or ecripsed conformation is stable in substituted benzenes. Allylic strain:

2) X=CHCH=Y

In general, s-trans conformer is more stable than s-cis, when there is no steric repulsion in the conjugated molecule.

However, gauche conformer is preferable to s-cis one, if X and/or Y have a substituent and both double bonds have Z-configuration.

Ra

bb

ccd

RC A

B

a: synperiplanar (ecripsed, 30 < < 30)b: synclinal (gauche, 30 < < 90 ())c: anticlinal (90 < < 150 ())d: antiperiplanar (anti, 150 < < 180 ())

CH2FCH2F:

F

FHH H

H F

HHH H

FE = 2.02.6 kcal/mol

OHOHO

HOOH

HO OHOHO

HOOH

HO

-glucose -glucoseOH

OnO

*CO

X

HH

Y

H

H

XH

Y

HH

XH

Y

Hbisecting

(rotational barrier)gauche

(a stable confomer)eclipsed

(less stable than gauche)

XH

H Y

HFelkinAnh-type

(not stable)

RR

HHHRH

HHR

1,3-allylic strain (A(1,3)-strain)

R

HH

H

RH

RR1,2-allylic strain (A(1,2)-strain)

The * interation between the vicinal CH bonds.

syn-pentane interaction

12

3) Carboxamides

CN bond of carboxamide possesses double bond character, because structure 2 remarkably contributes to the resonance hybrid. Therefore, the rotation of CN bond is relatively slow.

In NMR analysis, a set of signals are often observed because the ZE isomerization of amide is slow in NMR time scale.

(c) 4-Membered rings

In 4-membered rings, planar structure is unfavorable because torsional strain is maximum. Puckered structure is preferable to planar one in order to escape the strain. The 4-membered

ring is released from the ecripsed conformation. The angle of pucker is 28 and the barrier of ring inversion is 1.45 kcal/mol in cyclobutane.

(d) 5-Membered rings

Conformation analysis of 5-mambered rings is significantly complicated as compared to those of 4- and 6-membered rings, because their conformation is very flexible.

Stable conformations of cyclopentane are envelope and half-chair conformations. The former is more stable than latter, but the energy difference of both conformers is very small (0.5 kcal/mol).

The envelope conformer is Cs-symmetry, and the half-chair conformer is C2-symmetry. Equilibrium between envelope and half-chair conformers is remarkably affected by substituents.

(e) 6-Membered rings

1) Saturated rings Stable conformations of saturated 6-membered rings are chair and twist boat. Boat

configuration is the transition state of the interconversion between two twist boat conformers. In most cases, chair conformer is more stable than twist boat conformer. Rarely, twist boat is

preferable to chair in order to avoid large 1,3-diaxial interaction.

Stability of conformer of substituted 6-membered rings is affected by A-value, 1,3-diaxial interaction, and the presence of gauche conformation etc.

Fused ring systems Bicyclic system of cis-fused cyclohexane, such as cis-decaline, is possible to invert. In contrast,

ring inversion of the trans-isomer is impossible.

2) Cyclohexene

The most stable conformation of cyclohexene is half-chair.

In 1,6-disubstituted cyclohexenes, substituent R' at the 6-position induces considerable

A(1,2)-strain if it occupies the pseudo-equatorial position. To avoid the strain, R' tends to occupy the psudo-axial position.

3) Cyclohexanone

Cyclohexanones prefer chair conformation. Their conformations are affected by the dipole and planar structure of carbonyl group.

Y

H

X

H

X YH

Y

X

H

XY

s-ciss-trans

Y

H

X

H

X Y

gauche

O

R1N

R2

R3 O

R1N+

R2

R3

1 2

ON

H

Me

HE = 20.6 kcal/mol

ON

Me

Me

HE = 21.3 kcal/mol

5

67

84

3

1

2

2

14

37

8

6

5

E = 1.45 kcal/mol

envelope

C2

half-chair

chair half-chair twist boat boatR

R

axialequatorial

cis-decaline trans-decaline

==

half-chair

pseudo-axialpseudo-equatorial

R'R'

H HR RA(1,2)-strain

more stable

R R 1,3-diaxial interaction

advanced organic chemistry iii

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