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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
3 Diastereoselective reactions
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
3 Diastereoselective reactions
3.3 Chiral substratesAlkenes
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
3 Diastereoselective reactions
3.3 Chiral substratesAlkenes
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
3 Diastereoselective reactions
3.3 Chiral substratesAlkenes
Heterogeneous hydrogenation of C=C bonds
JOC 1975, 3073 (Sehgal)
JOC 1985, 4270 (Thompson)5
3 Diastereoselective reactions
3.3 Chiral substratesAlkenes
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
3 Diastereoselective reactions
3.3 Chiral substratesAlkenes
Homogeneous hydrogenation of C=C bonds – cyclic systems
JACS 1974, 6232 (Thompson)
closer the coordination site, higher the selectivity
TL 1984, 4637 (Evans) 7
3 Diastereoselective reactions
3.3 Chiral substratesAlkenes
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
3 Diastereoselective reactions
3.3 Chiral substratesAlkenes
Hydrogenation – C=C bonds – acyclic stereocontrol – allylic alcohols
steric constraint
diastereoselectivity rationale
disfavoredfavored
syn (minor)anti (major)
9
3 Diastereoselective reactions
3.3 Chiral substratesAlkenes
Hydrogenation – C=C bonds – acyclic stereocontrol – allylic alcohols
steric constraint
diastereoselectivity rationale
disfavoredfavored
anti (minor)syn (major)
10
3 Diastereoselective reactions
3.3 Chiral substratesAlkenes
Hydrogenation – C=C bonds – acyclic stereocontrol – allylic alcohols
JACS 1984, 3866 (Evans)
anti (major)
syn (major)
11
3 Diastereoselective reactions
3.3 Chiral substratesAlkenes
Hydrogenation – C=C bonds – acyclic stereocontrol – homoallylic alcohols
steric constraint
diastereoselectivity rationale
anti (minor) syn (major)
disfavored favored
12
3 Diastereoselective reactions
3.3 Chiral substratesAlkenes
Hydrogenation – C=C bonds – acyclic stereocontrol – allylic alcohols
JACS 1990, 5290 (Evans)
anti (major)
syn (major)
13
3 Diastereoselective reactions
3.3 Chiral substratesAlkenes
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
3 Diastereoselective reactions
3.3 Chiral substratesAlkenes
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
3 Diastereoselective reactions
3.3 Chiral substratesAlkenes
Hydroboration of chiral olefins – acyclic series – reaction with BH3
most destabilizinginteraction
„steric shield“
rationale onstereoselectivity
Tet. 1984, 2257 (Houk)
16
3 Diastereoselective reactions
3.3 Chiral substratesAlkenes
Hydroboration of chiral olefins – acyclic series – reaction with BH3
JACS 1979, 259 (Kishi)
TL 1984, 243 (Heathcock)
RL
R
17
3 Diastereoselective reactions
3.3 Chiral substratesAlkenes
diastereotopic faces
Hydroboration of chiral olefins – acyclic series
with BH3 with R2BH
18
3 Diastereoselective reactions
3.3 Chiral substratesAlkenes
Hydroboration of chiral olefins – acyclic series
with BH3
RL
RM
19
3 Diastereoselective reactions
3.3 Chiral substratesAlkenes
Hydroboration of chiral olefins – acyclic series
with R2BH
9-BBN
20
3 Diastereoselective reactions
3.3 Chiral substratesAlkenes
Hydroboration of chiral olefins – acyclic series
with thexylBH2
thexylBH2
21
3 Diastereoselective reactions
3.3 Chiral substratesAlkenes
Fürst-Plattner rule – cyclic olefins
pseudo-axial
pseudo-equatorial
controls the conformation
of the half-chair
disfavored(twisted boat)
favored(chair)
majordiastereoisomer 22
3 Diastereoselective reactions
3.3 Chiral substratesAlkenes
Bromination – cyclic series (adaptation of the Fürst-Plattner rule)
Explain the outcome of the following reactions
case 1
case 2
23
3 Diastereoselective reactions
3.3 Chiral substratesAlkenes
Bromination – cyclic series (adaptation of the Fürst-Plattner rule)
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
3 Diastereoselective reactions
3.3 Chiral substratesAlkenes
Bromination – cyclic series (adaptation of the Fürst-Plattner rule)
case 2
electronically disfavored
follows the Fürst-Plattner rule (adaptation)
electronically favored
stabilized notstabilized
exclusiveproduct 25
3 Diastereoselective reactions
3.3 Chiral substratesAlkenes
Bromination – cyclic series (adaptation of the Fürst-Plattner rule)
exclusiveproduct
least hindereddiastereotopic face
26
3 Diastereoselective reactions
3.3 Chiral substratesAlkenes
Bromination – cyclic series (adaptation of the Fürst-Plattner rule)
least hindereddiastereotopic face
exclusive product
27
3 Diastereoselective reactions
3.3 Chiral substratesAlkenes
Oxy-mercuration – cyclic series (adaptation of the Fürst-Plattner rule)
least stabilized carbocation
electrophilic position leadingto a chair conformation
28
3 Diastereoselective reactions
3.3 Chiral substratesAlkenes
„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
favored
3 Diastereoselective reactions
3.3 Chiral substratesAlkenes
Iodonium formation - acyclic series
30
favored
3 Diastereoselective reactions
3.3 Chiral substratesAlkenes
Iodine-promoted lactonization – R is a nucleophile
less stable(more reactive)
more stable(less reactive)
faster complexation
slower complexation31
diastereoselective TS
3 Diastereoselective reactions
3.3 Chiral substratesAlkenes
Epoxidation – endocyclic allylic alcohols and peracids
diastereoselective TS
32
diastereoselective TS
3 Diastereoselective reactions
3.3 Chiral substratesAlkenes
Epoxidation – endocyclic allylic ethers and peracids
diastereoselective TS„H“ is much more acidic
33
3 Diastereoselective reactions
3.3 Chiral substratesAlkenes
Epoxidation – endo/exocyclic homoallylic alcohols and peracids
diastereoselective TSACIE 2015, 15884 (Didier)
JCS 1965, 2054 (Meakins)
34
3 Diastereoselective reactions
3.3 Chiral substratesAlkenes
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
3 Diastereoselective reactions
3.3 Chiral substratesAlkenes
Epoxidation – acyclic allylic acohols with mCPBA
stereochemical considerations
favoreddisfavored
36
favored
3 Diastereoselective reactions
3.3 Chiral substratesAlkenes
Epoxidation – acyclic allylic acohols VO(acac)2/TBHP
stereochemical considerations
disfavored
37
3 Diastereoselective reactions
3.3 Chiral substratesAlkenes
Epoxidation – acyclic allylic acohols VO(acac)2/TBHP
stereochemical considerations
destabilizing 1,2-interactions
38
favored
3 Diastereoselective reactions
3.3 Chiral substratesAlkenes
Epoxidation – acyclic homoallylic acohols VO(acac)2/TBHP
stereochemical considerations
JACS 1981, 7690 (Mihelich)
control element: 1,3-strain
39
favored
3 Diastereoselective reactions
3.3 Chiral substratesAlkenes
Epoxidation – acyclic homoallylic acohols VO(acac)2/TBHP
stereochemical considerations
JACS 1981, 7690 (Mihelich) 40
3 Diastereoselective reactions
3.3 Chiral substratesAlkenes
Epoxidation – acyclic homoallylic acohols VO(acac)2/TBHP
anti-diastereoisomer syn-diastereoisomer
What diastereoisomer supposedly gives the highest diastereoselectionunder oxidative conditions with VO(acac)2/TBHP?
41
3 Diastereoselective reactions
3.3 Chiral substratesAlkenes
Epoxidation – acyclic homoallylic acohols VO(acac)2/TBHP
anti-diastereoisomer
ax-ax
eq-eq
42
3 Diastereoselective reactions
3.3 Chiral substratesAlkenes
Epoxidation – acyclic homoallylic acohols VO(acac)2/TBHP
syn-diastereoisomer
ax-eq
eq-ax
most destabilizing1,3-interactions
least destabilizing1,3-interactions
43
3 Diastereoselective reactions
3.3 Chiral substratesAlkenes
Epoxidation – acyclic homoallylic acohols VO(acac)2/TBHP
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
3 Diastereoselective reactions
3.3 Chiral substratesAlkenes
Epoxidation – acyclic bishomoallylic acohols VO(acac)2/TBHP
stereochemical considerations
TL 1978, 2741 (Kishi) 45
3 Diastereoselective reactions
3.3 Chiral substratesAlkenes
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
3 Diastereoselective reactions
3.3 Chiral substratesAlkenes
Cyclopropanation – cyclic olefins – reaction rates
which of the two following substrates reacts faster?
47
3 Diastereoselective reactions
3.3 Chiral substratesAlkenes
Cyclopropanation – cyclic olefins – reaction rates
krel > 3 krel = 1
48
3 Diastereoselective reactions
3.3 Chiral substratesAlkenes
Cyclopropanation – acyclic olefins
stereochemical considerations
conformation of lowest energyfavored TS
49
3 Diastereoselective reactions
3.3 Chiral substratesAlkenes
[3,3]-sigmatropic rearrangement – Claisen / Ireland-Claisen – cyclic substrates
reactiveconformation
unreactiveconformation
50
3 Diastereoselective reactions
3.3 Chiral substratesAlkenes
[3,3]-sigmatropic rearrangement – Claisen / Ireland-Claisen – cyclic substrates
reactiveconformation
reactiveconformation
reaction should be slower for the trans isomer
51
3 Diastereoselective reactions
3.3 Chiral substratesAlkenes
[3,3]-sigmatropic rearrangement – Ireland-Claisen – acyclic substrates
(Z)minor
(E)major
JOC 1991, 650 (Ireland)52
favored
3 Diastereoselective reactions
3.3 Chiral substratesDiels-Alder
[4+2]-cycloaddition – chiral cyclic diene
stereochemical considerations
OL 2017, 2114 (Didier)
53
3 Diastereoselective reactions
3.3 Chiral substratesDiels-Alder
[4+2]-cycloaddition – chiral cyclic dienophile
stereochemical considerations
OL 2000, 2711 (Rawal)
favored54
3 Diastereoselective reactions
3.3 Chiral substratesDiels-Alder
[4+2]-cycloaddition – chiral acyclic diene
stereochemical considerations
JOC 2018, 783 (Didier)
favored TS steric clash 55
3 Diastereoselective reactions
3.3 Chiral substratesDiels-Alder
[4+2]-cycloaddition – example of chiral acyclic diene/dienophile (intramolecular)
stereochemical considerations
JOC 1987, 1236 (Marshall)
56
3 Diastereoselective reactions
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
3 Diastereoselective reactions
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
3 Diastereoselective reactions
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
59
3 Diastereoselective reactions
3.3 Chiral substratesElectrophilic allenylation
SN2‘ reaction – with organocopper reagents and propargylic substrates
stereochemical considerations
Chem. Sci. 2020, xxx (Knochel)
syn-carbometalation
anti-elimination
60
3 Diastereoselective reactions
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)
61
3 Diastereoselective reactions
3.3 Chiral substratesCarbometalation
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]
62
3 Diastereoselective reactions
3.3 Chiral substratesCarbometalation
Carbometalation – chiral cyclopropenes
JACS 2002, 14322 (Fox)
CEJ 2014, 1038 (Marek)
63
3 Diastereoselective reactions
3.3 Chiral substratesCarbonyls
1,2-addition – cyclic substrates
ACIE 2019, 1188 (Didier)
64
3 Diastereoselective reactions
3.3 Chiral substratesCarbonyls
1,2-addition – cyclic oxocarbenium ions
65
stereochemical considerations
JACS 2000, 168 (Woerpel)
favored
3 Diastereoselective reactions
3.3 Chiral substratesCarbonyls
1,2-addition – cyclic oxocarbenium ions
66
stereochemical considerations
JACS 2000, 168 (Woerpel)
favored
stabilizedconformation
reactiveoxocarbenium ion
3 Diastereoselective reactions
3.3 Chiral substratesCarbonyls
1,2-addition – acyclic substrates
Chem. Rev. 1999, 1191 (Reiser)
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 67
Fischer Cram Conforth FelkinAhn-
EisensteinCieplak Tomoda
3 Diastereoselective reactions
3.3 Chiral substratesCarbonyls
1,2-addition – Cram‘s model
68
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
3 Diastereoselective reactions
3.3 Chiral substratesCarbonyls
1,2-addition – Cram‘s model
69
stereochemical considerations
TL 1992, 1817 (Grieco)
3 Diastereoselective reactions
3.3 Chiral substratesCarbonyls
1,2-addition – Cram‘s model
70
stereochemical considerations
TL 1980, 1031 (Still)
3 Diastereoselective reactions
3.3 Chiral substratesCarbonyls
1,2-addition – Cram‘s model
71
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
3 Diastereoselective reactions
3.3 Chiral substratesCarbonyls
1,2-addition – Cram‘s model
72
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”
Chem. Rev. 1999, 1191 (Reiser)
“[…] The steric bulk of the carbonyl group was overestimated, resulting in an unfavorable alignment of RL and R, especially in ketones (R ≠ H)”
3 Diastereoselective reactions
3.3 Chiral substratesCarbonyls
1,2-addition – Cram‘s model
73
Cram modelIn summary: good model for additions onto aldehydes with no polar groups at the a-position
JOC 1990, 4990 (Molander)
favored
unfavored
3 Diastereoselective reactions
3.3 Chiral substratesCarbonyls
1,2-addition – Felkin-Ahn‘s model
74
Felkin-Ahn modelIn summary: complements and generalizes the initial model proposed by Cram
JCS Perkin Trans. 2 1983, 1645 (Pérez-Ossorio)
unfavored
favored
3 Diastereoselective reactions
3.3 Chiral substratesCarbonyls
1,2-addition – Felkin-Ahn‘s model – Influence of reagents and substrate nature
75
unfavored
favored
Size of the nucleophile
Size of the conter ion
Size of R in substrate
MeMgBr
3 Diastereoselective reactions
3.3 Chiral substratesCarbonyls
1,2-addition – Felkin-Ahn model
76
Previous models rely on steric analysis and therefore, cannot fully explain the differences in following selectivities
3 Diastereoselective reactions
3.3 Chiral substratesCarbonyls
1,2-addition – Ahn-Eisenstein considerations
77
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
3 Diastereoselective reactions
3.3 Chiral substratesCarbonyls
1,2-addition – Felkin-Ahn-Eisenstein model
78
stereochemical considerations
TL 1984, 265 (Keck)
major
3 Diastereoselective reactions
3.3 Chiral substratesCarbonyls
79
stereochemical considerations
TL 1983, 2653 (Oishi)
major
1,2-addition – Felkin-Ahn-Eisenstein model
favored
3 Diastereoselective reactions
3.3 Chiral substratesCarbonyls
1,2-addition – Felkin-Ahn-Eisenstein and Conforth models
80
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
3 Diastereoselective reactions
3.3 Chiral substratesCarbonyls
Allylboration – Combination of Felkin-Ahn and Zimmermann-Traxler models
81
stereochemical considerations
for steric reasons, RL points
preferentially outward
(Z)-allylboronspecies
destabilizing interactions:1: 1,3-diaxial
2: gauche
favored
(2,3-syn-3,4-anti)
3 Diastereoselective reactions
3.3 Chiral substratesCarbonyls
Allylboration – Combination of Felkin-Ahn and Zimmermann-Traxler models
82
stereochemical considerations
for steric reasons, RL points
preferentially outward
(E)-allylboronspecies
destabilizing interactions:1: 1,3-diaxial
2: gauche
favored
(2,3-anti-3,4-syn)