3 diastereoselective reactions by d. didier (lmu)

3 Diastereoselective reactions

3.3 Chiral substrates

Important reviews

Chem. Rev. 1993, 1307 (Hoveyda, Evans)

Chem. Rev. 1999, 1191 (Reiser)

Science 1986, 231, 1108 (Houk)

Chem. Rev. 1999, 1265 (Cieplak)

Chem. Rev. 1999, 1437 (Mehta)

This chapter gives a general overview on selected stereoselective reactions.Exceptions to the models that are proposed here cannot be excluded.

1

by D. Didier (LMU)


3.3 Chiral substratesAlkenes

Cyclic systems

models relie on configurational analysis models relie on conformational analysis

Acyclic systems

steric hindrance coordination steric hindrance coordination

different models, different ways of interpreting the stereoselectivity

and can induce - steric constraints- electronic effects- stereoelectronic effects

2

by D. Didier (LMU)



seen in Chapter 1

Conformational analysis of acyclic olefins

most stable conformationsfor different acyclic olefins

in following acyclic models, Newman and Sägebock

projectionswill be employed Newman Sägebock

RL is the largest

substituent

3

by D. Didier (LMU)



Heterogeneous hydrogenation of C=C bonds

steric interactions disfavor the approach of H2 from the top face

H2 adds from the least hindered faces of the double bond (bottom)

ChemCatChem 2019, 1518 (Xie, Yu)

4

by D. Didier (LMU)



Heterogeneous hydrogenation of C=C bonds

JOC 1975, 3073 (Sehgal)

JOC 1985, 4270 (Thompson)5

by D. Didier (LMU)



Homogeneous hydrogenation of C=C bonds

J. Organomet. Chem. 1977, 141, 205 (Crabtree)

J. Organomet. Chem. 1981, 216, 263 (Sidebottom)

coordinationligand exchange

oxidativeaddition

migratoryinsertion

reductiveelimination

6

by D. Didier (LMU)



Homogeneous hydrogenation of C=C bonds – cyclic systems

JACS 1974, 6232 (Thompson)

closer the coordination site, higher the selectivity

TL 1984, 4637 (Evans) 7

by D. Didier (LMU)



Homogeneous hydrogenation of C=C bonds – cyclic systems

coordination can circumvent steric effects JACS 1984, 3866 (Evans)

JOC 1986, 2655 (Crabtree)J. Organomet. Chem. 1985, 285, 333 (Hall)8

by D. Didier (LMU)



Hydrogenation – C=C bonds – acyclic stereocontrol – allylic alcohols

steric constraint

diastereoselectivity rationale

disfavoredfavored

syn (minor)anti (major)

9

by D. Didier (LMU)




steric constraint


disfavoredfavored

anti (minor)syn (major)

10

by D. Didier (LMU)




JACS 1984, 3866 (Evans)

anti (major)

syn (major)

11

by D. Didier (LMU)



Hydrogenation – C=C bonds – acyclic stereocontrol – homoallylic alcohols

steric constraint


anti (minor) syn (major)

disfavored favored

12

by D. Didier (LMU)




JACS 1990, 5290 (Evans)

anti (major)

syn (major)

13

by D. Didier (LMU)



Hydroboration of chiral olefins – cyclic series

most hindereddiastereotopic face

least hindereddiastereotopic face

about stereoselectivity about regioselectivity

most hinderedolefin site

most d + due tohyperconjugation

least substitutedmost stable

C-B bondd - d +

14

by D. Didier (LMU)



Hydroboration of chiral olefins – acyclic series

Intermolecular hydroboration reactions proceed without coordination ofoxygen-containing groups to the boron atom

RL = large size substituent

RM = medium size substituent

most destabilizinginteraction

15

by D. Didier (LMU)



Hydroboration of chiral olefins – acyclic series – reaction with BH3

most destabilizinginteraction

„steric shield“

rationale onstereoselectivity

Tet. 1984, 2257 (Houk)

16

by D. Didier (LMU)



Hydroboration of chiral olefins – acyclic series – reaction with BH3

JACS 1979, 259 (Kishi)

TL 1984, 243 (Heathcock)

RL

R

17

by D. Didier (LMU)



diastereotopic faces


with BH3 with R2BH

18

by D. Didier (LMU)




with BH3

RL

RM

19

by D. Didier (LMU)




with R2BH

9-BBN

20

by D. Didier (LMU)




with thexylBH2

thexylBH2

21

by D. Didier (LMU)



Fürst-Plattner rule – cyclic olefins

pseudo-axial

pseudo-equatorial

controls the conformation

of the half-chair

disfavored(twisted boat)

favored(chair)

majordiastereoisomer 22

by D. Didier (LMU)



Bromination – cyclic series (adaptation of the Fürst-Plattner rule)

Explain the outcome of the following reactions

case 1

case 2

23

by D. Didier (LMU)




case 1

controls the conformation

of the half-chair-

not close enoughto direct the

addition of Br+

attacks at these positions lead to a twisted boat transition state (Fürst-Plattner)

„almost statisticaldistribution“

24

by D. Didier (LMU)




case 2

electronically disfavored

follows the Fürst-Plattner rule (adaptation)

electronically favored

stabilized notstabilized

exclusiveproduct 25

by D. Didier (LMU)




exclusiveproduct


26

by D. Didier (LMU)





exclusive product

27

by D. Didier (LMU)



Oxy-mercuration – cyclic series (adaptation of the Fürst-Plattner rule)

least stabilized carbocation

electrophilic position leadingto a chair conformation

28

by D. Didier (LMU)



„Onium“ formation in acyclic seriespC-C

s*C-O

less stable(more reactive)

more stable(less reactive)

faster complexation

more stable productdestabilizing

interaction

slower complexationreaction with „X+“

29

by D. Didier (LMU)

favored



Iodonium formation - acyclic series

30

by D. Didier (LMU)

favored



Iodine-promoted lactonization – R is a nucleophile

less stable(more reactive)

more stable(less reactive)

faster complexation

slower complexation31

by D. Didier (LMU)

diastereoselective TS



Epoxidation – endocyclic allylic alcohols and peracids


32

by D. Didier (LMU)




Epoxidation – endocyclic allylic ethers and peracids

diastereoselective TS„H“ is much more acidic

33

by D. Didier (LMU)



Epoxidation – endo/exocyclic homoallylic alcohols and peracids

diastereoselective TSACIE 2015, 15884 (Didier)

JCS 1965, 2054 (Meakins)

34

by D. Didier (LMU)



Epoxidation – acyclic allylic acohols – mCPBA vs. VO(acac)2/TBHP

the modelization and stereochemical outcome depend on the method employed

with mCPBA with „[V]-O“

ca. 120 °ca. 40 °

35

by D. Didier (LMU)



Epoxidation – acyclic allylic acohols with mCPBA

stereochemical considerations

favoreddisfavored

36

by D. Didier (LMU)

favored



Epoxidation – acyclic allylic acohols VO(acac)2/TBHP


disfavored

37

by D. Didier (LMU)



Epoxidation – acyclic allylic acohols VO(acac)2/TBHP


destabilizing 1,2-interactions

38

by D. Didier (LMU)

favored



Epoxidation – acyclic homoallylic acohols VO(acac)2/TBHP


JACS 1981, 7690 (Mihelich)

control element: 1,3-strain

39

by D. Didier (LMU)

favored





JACS 1981, 7690 (Mihelich) 40

by D. Didier (LMU)




anti-diastereoisomer syn-diastereoisomer

What diastereoisomer supposedly gives the highest diastereoselectionunder oxidative conditions with VO(acac)2/TBHP?

41

by D. Didier (LMU)




anti-diastereoisomer

eq-eq

ax-ax

42

by D. Didier (LMU)




syn-diastereoisomer

ax-eq

eq-ax

most destabilizing1,3-interactions

least destabilizing1,3-interactions

43

by D. Didier (LMU)




anti-diastereoisomer syn-diastereoisomer

What diastereoisomer supposedly gives the highest diastereoselectionunder oxidative conditions with VO(acac)2/TBHP?

full minimization of 1,3 strain=

better diastereoselectivity

one of the Me group has to be in a pseudo-axial position

gives > 400:1 dr gives a 85:1 dr

44

by D. Didier (LMU)



Epoxidation – acyclic bishomoallylic acohols VO(acac)2/TBHP


TL 1978, 2741 (Kishi) 45

by D. Didier (LMU)



Cyclopropanation – zinc and samarium carbenoids

pC=CHOMO

s*C-I

LUMO

p*C=C

LUMO

sC-ZnHOMO

s*C-O

pC=C stabilization through orbital overlap

=less reactive

46

by D. Didier (LMU)



Cyclopropanation – cyclic olefins – reaction rates

which of the two following substrates reacts faster?

47

by D. Didier (LMU)



Cyclopropanation – cyclic olefins – reaction rates

krel > 3 krel = 1

48

by D. Didier (LMU)



Cyclopropanation – acyclic olefins


conformation of lowest energyfavored TS

49

by D. Didier (LMU)



[3,3]-sigmatropic rearrangement – Claisen / Ireland-Claisen – cyclic substrates

reactiveconformation

unreactiveconformation

50

by D. Didier (LMU)



[3,3]-sigmatropic rearrangement – Claisen / Ireland-Claisen – cyclic substrates



reaction should be slower for the trans isomer

51

by D. Didier (LMU)



[3,3]-sigmatropic rearrangement – Ireland-Claisen – acyclic substrates

(Z)minor

(E)major

JOC 1991, 650 (Ireland)52

by D. Didier (LMU)

favored


3.3 Chiral substratesDiels-Alder

[4+2]-cycloaddition – chiral cyclic diene


OL 2017, 2114 (Didier)

53

by D. Didier (LMU)



[4+2]-cycloaddition – chiral cyclic dienophile


OL 2000, 2711 (Rawal)

favored54

by D. Didier (LMU)



[4+2]-cycloaddition – chiral acyclic diene


JOC 2018, 783 (Didier)

favored TS steric clash 55

by D. Didier (LMU)



[4+2]-cycloaddition – example of chiral acyclic diene/dienophile (intramolecular)


JOC 1987, 1236 (Marshall)

56

by D. Didier (LMU)


3.3 Chiral substratesSN2 vs. SN2‘

SN2 reactions

SN2‘ reactions

SN2 is stereospecific

SN2‘ is stereoselective

achiral achiral

achiral chiral

X = leaving group

a-substitution

g-substitution

57

by D. Didier (LMU)


3.3 Chiral substratesElectrophilic allylation

SN2‘ reaction – with organocopper reagents

substrate/reagent interactions stereochemical considerations

ACIE 2019, 1509 (Knochel)

dxz

HOMO

p*C=C

LUMO

anti-substitution

58

by D. Didier (LMU)



SN2‘ reaction – with organocopper reagents

JOC 1993, 5121 (Nakamura)

59


minor major

favoreddisfavored

by D. Didier (LMU)



SN2‘ reaction – with organocopper reagents – „inside alkoxy effect“

60


(re-re)-attack

(si-si)-attack

inside alkoxy(1st favored)

anti alkoxy(2st favored)

by D. Didier (LMU)



SN2‘ reaction – with organocopper reagents – „inside alkoxy effect“

61

“Why does the allylic ether prefer the inside conformation in these transition states?

In electrophilic attack upon an allylic ether, the p bond becomes electron deficient. Electron-donor substituents on the alkene stabilize the transition state, while electron-withdrawing substituents

destabilize the transition state.

When the allylic ether is anti, the CHROR' group is electron withdrawing, since the s*c-o orbital overlaps with, and withdraws electron density from, the alkene p orbital. When C-O is inside, it is near

the plane, and overlap of s*c-o with p is minimized.

Now, overlap of electron-donating sC-H and sC-R orbitals with the p orbital is maximized, and the transition state is stabilized.”

JACS 1984, 3880 (Houk)potential explanation(formulated for

1,3-cycloadditions)

by D. Didier (LMU)


3.3 Chiral substratesElectrophilic allenylation

SN2‘ reaction – with organocopper reagents and propargylic substrates

formation of the nucleophile stereochemical considerations

OL 2011, 4462 (Oestreich)

activenucleophile

species

syn-carbometalation

anti-elimination

62

by D. Didier (LMU)


3.3 Chiral substratesElectrophilic allenylation

SN2‘ reaction – with organocopper reagents and propargylic substrates


Chem. Sci. 2020, xxx (Knochel)

syn-carbometalation

anti-elimination

63

by D. Didier (LMU)


3.3 Chiral substratesCarbometalation

Beilstein JOC 2013, 278 (Yorimitsu)

Chem. Soc. Rev. 2016, 4552 (Marek)

Carbometalation reactions

or carbometallation:addition of a C-[M] bond across a C-C unsaturated system leading to a new organometallic species

carbometalation reactions are syn-stereospecific (most cases)

64

by D. Didier (LMU)



Carbometalation – generalities

Alkynes Cyclopropenes

X = C, Si, S, O, N, P...Y = NR2 or OR

= coordinating group= bulky group

[Cu] =organocuprate

reagent

[M] =[Cu], [Mg] or [Zn]

65

by D. Didier (LMU)



Carbometalation – chiral cyclopropenes

JACS 2002, 14322 (Fox)

CEJ 2014, 1038 (Marek)

66

by D. Didier (LMU)


3.3 Chiral substratesCarbonyls

1,2-addition – cyclic substrates

ACIE 2019, 1188 (Didier)

67

by D. Didier (LMU)



1,2-addition – cyclic oxocarbenium ions

68


JACS 2000, 168 (Woerpel)

favored

by D. Didier (LMU)



1,2-addition – cyclic oxocarbenium ions

69


JACS 2000, 168 (Woerpel)

favored

stabilizedconformation

reactiveoxocarbenium ion

by D. Didier (LMU)



1,2-addition – acyclic substrates


Important review on directed 1,2- carbonyl additions

Inspired by D. Evans and A. Myers lecture notes:https://www.pdfdrive.com/evans-and-myers-organic-chemistry-lecture-

notes-chem-206-and-215-e183957509.html 70

Fischer Cram Conforth FelkinAhn-

EisensteinCieplak Tomoda

by D. Didier (LMU)

https://www.pdfdrive.com/evans-and-myers-organic-chemistry-lecture-notes-chem-206-and-215-e183957509.html

https://www.pdfdrive.com/evans-and-myers-organic-chemistry-lecture-notes-chem-206-and-215-e183957509.html



1,2-addition – Cram‘s model

71

Cram chelate model

If chelation between the carbonyl group and one of the substituents of the a-stereocenter facilitated by a metal cation can occur, the substrate will be locked into a defined conformation

JACS 1952, 5828(Cram)

1987

by D. Didier (LMU)




72


TL 1992, 1817 (Grieco)

by D. Didier (LMU)




73


TL 1980, 1031 (Still)

by D. Didier (LMU)




74

Cram model

If chelation cannot occur, steric effects have to be considered. It was assumed (at the time) that the decisive interaction to be avoided is between RL and the carbonyl group.

Felkin-Ahn model RL is placed orthogonal to the carbonyl group.

favoredfavored

Crammodel

Felkin-Ahnmodel

by D. Didier (LMU)




75

Cram model

If chelation cannot occur, steric effects have to be considered. It was assumed (at the time) that the decisive interaction to be avoided is between RL and the carbonyl group.

favored

“The Cram rule proved to be a reliable tool to explain the preferred diastereoselection in carbonyl addition if no polar substituents were present on the a-stereocenter”


“[…] The steric bulk of the carbonyl group was overestimated, resulting in an unfavorable alignment of RL and R, especially in ketones (R ≠ H)”

by D. Didier (LMU)




76

Cram modelIn summary: good model for additions onto aldehydes with no polar groups at the a-position

JOC 1990, 4990 (Molander)

favored

unfavored

by D. Didier (LMU)



1,2-addition – Felkin-Ahn‘s model

77

Felkin-Ahn modelIn summary: complements and generalizes the initial model proposed by Cram

JCS Perkin Trans. 2 1983, 1645 (Pérez-Ossorio)

unfavored

favored

by D. Didier (LMU)



1,2-addition – Felkin-Ahn‘s model – Influence of reagents and substrate nature

78

unfavored

favored

Size of the nucleophile

Size of the conter ion

Size of R in substrate

MeMgBr

by D. Didier (LMU)



1,2-addition – Felkin-Ahn model

79

Previous models rely on steric analysis and therefore, cannot fully explain the differences in following selectivities

by D. Didier (LMU)



1,2-addition – Ahn-Eisenstein considerations

80

Ahn-Eisenstein considerationsBest acceptor s* orbital is oriented antiperiplanar to forming bond

sC-Ph

Csp3-Csp

3 Csp3-Csp

2

sC-c-hex

s*C-c-hex

s*C-Ph

by D. Didier (LMU)



1,2-addition – Felkin-Ahn-Eisenstein model

81


TL 1984, 265 (Keck)

major

by D. Didier (LMU)



82


TL 1983, 2653 (Oishi)

major

1,2-addition – Felkin-Ahn-Eisenstein model

by D. Didier (LMU)

favored



1,2-addition – Felkin-Ahn-Eisenstein and Conforth models

83

Felkin-Ahn-Eisenstein modelBest acceptor s* orbital is oriented antiperiplanar to forming bond

Conforth modelConformational analysis rely on minimization of the dipolemoment

Conforthmodel

Felkin-Ahn-Eisensteinmodel favored

by D. Didier (LMU)



Allylboration – Combination of Felkin-Ahn and Zimmermann-Traxler models

84


for steric reasons, RL points

preferentially outward

(Z)-allylboronspecies

destabilizing interactions:1: 1,3-diaxial

2: gauche

favored

(2,3-syn-3,4-anti)

by D. Didier (LMU)



Allylboration – Combination of Felkin-Ahn and Zimmermann-Traxler models

85




(E)-allylboronspecies

destabilizing interactions:1: 1,3-diaxial

2: gauche

favored

(2,3-anti-3,4-syn)

by D. Didier (LMU)



Conjugate additions – cyclic enones

86favored

substrate / reagent interactions stereochemical considerations

TL 1988, 439 (Smith III)

by D. Didier (LMU)

TL 1970, 1579 (Rivière)




87


face of the attack follows the Fürst-Plattner rule

by D. Didier (LMU)

JACS 1995, 6126 (Lipshutz)




88

JOC 1968, 949 (Fischer)

Heterocycles 2000, 1029 (Inoue)

by D. Didier (LMU)




89

Tet. 1990, 4091 (Smith)


locked conformation

by D. Didier (LMU)



Conjugate additions – acyclic systems

90

as seen in carbometallation and SN2‘ reactions, there is an important interaction of [Cu] and the C=C bond systems in the addition of organocopper reagents (including cuprates)

coordination of the C=C bond to the metal lowers the electron density of the former and therefore supports the inside alkoxy effects (slide 61)

by D. Didier (LMU)




91

Synth. 1991, 1083 (Hanessian)


favored disfavored

by D. Didier (LMU)




92

JACS 1989, 2984 (Roush)


favored disfavored

by D. Didier (LMU)



Conjugate additions – acyclic systems – (E)- vs. (Z)-enones

JCS CC 1987, 464 (Yamamoto)

favored


by D. Didier (LMU)

favored



Conjugate additions – acyclic systems – (E)- vs. (Z)-enones

94

JCS CC 1987, 464 (Yamamoto)


by D. Didier (LMU)



Conjugate additions – acyclic systems – more than 1,4-additions to carbonyls

95

TL 1996, 3055 (Cossio)

TL 1997, 3471 (Warren)

this paper also discusses the „inside O-substituent effect“

by D. Didier (LMU)



Conjugate additions – acyclic systems without „inside alkoxy effect“

96

by D. Didier (LMU)

if the „inside alkoxy effect“ is justified by pre-complexation of a metallic species to the p-bond system, „non-metallic nucleophiles“ should follow the polar Felkin-Ahn model

Stereosel. Synth. 1995, 4818 (Houben-Weyl Meth. of Org. Chem. Vol. E 21e, 4th Ed.) (Berkessel)



a-Alkylations – cyclic carbonyls

97

by D. Didier (LMU)

JACS 1997, 4565 (Padwa)


- 3 kcal.mol-1

E+

E+ favored

disfavored



a-Alkylations – cyclic carbonyls

98

by D. Didier (LMU)

JOC 1988, 4094 (Koga)




a-Alkylations – polycyclic fused systems

99

by D. Didier (LMU)

JACS 1978, 1627 (Marshall)

E+

favored

stereoselective step



a-Alkylations – polycyclic fused systems

100

by D. Didier (LMU)

JACS 1978, 1627 (Marshall)

E+

favored

stereoselective step



a-Alkylations – acyclic systems

101

by D. Didier (LMU)

ACIE 1981, 971 (Seebach)


E+

E+favored disfavored




102

by D. Didier (LMU)

HCA 1988, 1824 (Seebach)


E+

E+favored disfavored




103

by D. Didier (LMU)

ACIE 2000, 4612 (Williams)


E+

E+

favoreddisfavored



a-Alkylations – acyclic g-susbstituted systems

104

by D. Didier (LMU)

ACIE 2000, 4612 (Williams)


E+



1,4-addition / alkylation sequence – total synthesis of prostaglandin derivatives

105

by D. Didier (LMU)

JACS 1994, 11689 (Lipshutz)



Aldol – Combination of Felkin-Ahn and Zimmermann-Traxler models

106

by D. Didier (LMU)



(Z)-enolates



favored



Aldol – Combination of Felkin-Ahn and Zimmermann-Traxler models

107

by D. Didier (LMU)


(E)-enolates



favored

3 diastereoselective reactions by d. didier (lmu)

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