The quest for highly enan2oselec2ve chiral hypervalent arylλ 3 iodane reagents Salinda Wijeratne CEM 958 12/7/11 Chiral arylλ 3 iodanes I OR O Me O OR O I(OAc) 2 O O OMe I(OAc) 2 O O MeO 1 O O OMe I(OAc) 2 O O MeO I OR O Me O OR O I(OAc) 2 O OR O I(OAc) 2 O O OMe I(OAc) 2 O O MeO
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Thequestforhighly$ enanoselecve $$ chiral$hypervalentarylλ ...€¦ · type 3 as electrophilic reagents, we observe a facial selectivity upon reaction with alkenes and ketones and
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The quest for highly enan2oselec2ve chiral hypervalent aryl-‐λ3-‐iodane reagents
Salinda Wijeratne
CEM 958
12/7/11
Chiral aryl-‐λ3-‐iodanes
IOR
OMeO OR
OI(OAc)2
OO
OMe
I(OAc)2O
O
MeO
1
OO
OMe
I(OAc)2O
O
MeO
IOR
OMeO OR
OI(OAc)2
O OR
OI(OAc)2
OO
OMe
I(OAc)2O
O
MeO
The versa2lity & demand for aryl-‐λ3-‐iodanes
• Chemical proper.es and reac.vity: similar to the heavy metal reagents such as Hg(III), Ti(III), Pb(IV)
• No toxicity and environmental issues
• Mild reac.on condi.ons and easy handling
• Commercial availability of key precursors
– e.g PhI(OAc)2 2
hJp://onlinelibrary.wiley.com/doi/10.1002/anie.v49:12/issuetoc Zhdankin, V. V.; Stang, P. J. Chem. Rev. 2002, 102, 2523-‐2584
• “Hypervalent”: exceeding octet rule
• Aryl-‐λ3-‐iodanes
− 10 valence electrons
− Important hypervalent aryl-‐λ3-‐iodanes
Hypervalent aryl-‐λ3-‐iodanes
Zhdankin, V. V.; Stang, P. J. Chem. Rev. 2002, 102, 2523-‐2584 3
I
L
Ar
L!"
!+
!"
#3-Iodanes (10-I-3)
IOTs
OTs
Koser'sReagent
I OF3C
CH3
CH3
Togni'sReagent
ICl
Cl
(Dichloroiodo)benzeneWillgerodt, Germany, 1886
Bonding orbital
nonbonding orbital
Antibonding orbital
I LL
Three centered four electron bonding
IOTs
OTs
Koser'sReagent
I OF3C
CH3
CH3
Togni'sReagent
ICl
Cl
(Dichloroiodo)benzeneWillgerodt, Germany, 1886
IOTs
OTs
Koser'sReagent
I OF3C
CH3
CH3
Togni'sReagent
ICl
Cl
(Dichloroiodo)benzeneWillgerodt, Germany, 1886
Classifica2on & reac2vity of aryl-‐λ3-‐iodanes
4 Wirth, T. Topics in Current Chemistry: Hypervalent Iodine Chemistry. Vol. 224. Springer. 2003, p 8-‐9
I
Ar
Ar
Cl
Two carbon-one heteroatom ligands systems (Ar2IL)
Pseudotrigonalbipyramid
R
O
R
O
Ar
1) base
2)Ar* I
Ar
X * Ar* I
reoxidize
I
OAc
Ar
OAc
Pseudotrigonalbipyramid
One carbon-two heteroatom ligands systems (ArIL2)
PhI
PhIOAc
OAc
R
O
I
R'
OAcPh
mCPBA
mCBA
R
OHR' R
OR'
R
OR'
OAc
Ligand exchange
Reductive elemination
OAc
(AcOH)
Asymmetric induc2ons using aryl-‐λ3-‐iodanes
5
O
O
O
OI
R!
R!
S!
H O
O
I
RO
O X XX
X = I, I(OAc)2
II
O
OAc
OAc
Type 1 Type 2 Type 4 Type 5
O !
O
ORR'
I(OAc)2I
OR'
R"'
R"
Type 3
R''
One carbon-two heteroatom ligands systems
IL*
Ar*IL
Type 2Type 1
Two carbon-one heteroatom ligandsystems
A -‐ Iodoaryl moiety B -‐ Chiral linker
One carbon-‐two heteroatom ligands systems
Two carbon-‐one heteroatom ligands systems
Outline
• Introduc.on
• Asymmetric induc.on using chiral aryl-‐λ3-‐iodane reagents
– Chiral aryl-‐λ3-‐iodanes with one carbon and two heteroatom ligands & their applica.ons in oxida2ve addi2on reac2ons
– Chiral aryl-‐λ3-‐iodanes with two carbon and one heteroatom ligands & their applica.ons in aryla.on reac.ons
6
One carbon and two heteroatom ligands chiral aryl-‐λ3-‐iodanes
7
O !
O
XRR'
I(OAc)2
I
OR'
R"'
R"Type 3
R''
O
O
O
OI
R!
R!
Type 1
S!
H O
O
I
RO
O
Type 2
X XX
X = I, I(OAc)2
Type 4
II
O
OAc
OAc
Type 5
R S R' R S R'
O
Oxidation of sulfide
R R'O
R R'O
OR"
! -
Oxy
gena
tion
of k
eton
es
R
R'
R
R'OR"
OR"
OH
R'
OH
R'
Nu
Dearomatization
O
O
O
OI
R"
R"
Type 1
S"
HO
O
I
RO
O
Type 2
Catalyst
Diox
ygen
atio
n &
diam
inat
ion
of a
lken
es
Flexible
Rigid
Type 1 chiral aryl-‐λ3-‐iodanes in oxida2on of sulfide
8
Type 2 chiral aryl-‐λ3-‐iodanes in α-‐oxygena2on of ketone
Imamoto, T.; Koto, H. Chem. LeD. 1886, 967-‐968 Hatzigrigoriou, E.; Varvoglis, A.; Chris.anopoulou, M. Org. Chem. 1990, 55, 315-‐318
O S OO
OIPh
OH
Ph
O OPh
O O
RHPh
O O
HR
O S OO
OR =
10-(+)-camphoryl
PhI
H2OMeCN, 45 min, 80 °C
(1 equiv) 5
90%, (S)-6 : (R)-6 = 1:1
4
o-CH3C6H4S CH3
O
Acetone, 3 h, r.t
O
O
t-BuCOOH
Ht-BuCOO
OO
I
o-CH3C6H4S CH3
(2 mmol) 2
75%, 53% ee,(S)-3
(1 mmol) 1
R S R' R S R'
O
Oxidation of sulfide
R R'O
R R'O
OR"
! -
Oxy
gena
tion
of k
eton
es
R
R'
R
R'XR"
XR"
Diox
ygen
atio
n &
diam
inat
ion
of a
lken
es
OH
R'
OH
R'
Nu
Dearomatization
Catalyst
I
OR'
R"'
R"
O "
O
XRR'
I(OAc)2R''
Type 3
9
O !
O
XRR'
I(OAc)2
I
OR'
R"'
R"Type 3
R''
O
O
O
OI
R!
R!
Type 1
S!
H O
O
I
RO
O
Type 2
X XX
X = I, I(OAc)2
Type 4
II
O
OAc
OAc
Type 5
One carbon and two heteroatom ligands chiral aryl-‐λ3-‐iodanes
Flexible
Rigid
Type 3 aryl-‐λ3-‐iodanes with ether moiety
10
O
O
O
O
I
R!
R!
S!
H O
O
I
RO
O
Chiral center faraway from reaction center
Liberation ofthe chiral ligand
Liberation ofthe chiral ligand
Type 1
Type 2
Results and Discussion
Hypervalent iodine compounds are electrophilic speciesand can attack double bonds as shown in Scheme 1. Weconfirmed this mechanism by converting either (E)- or(Z)-2-pentene with the hypervalent iodine compounds 3into syn- or anti-2,3-bis(tosyloxy)pentane selectively. Aclean SN2 type mechanism is the prerequisite for thedevelopment of asymmetric reactions with chiral hyper-valent iodine compounds. For these investigations wechose the dioxytosylation of styrene and the R-oxytosy-lation of propiophenone as test reactions (Scheme 2). Inthese reactions new stereocenters are created and theproducts of these reactions, 1,2-bis(tosyloxy)phenylethane(4) and R-(tosyloxy)propiophenone (5), are compoundscontaining asymmetric carbon atoms.
Employing chiral hypervalent iodine compounds oftype 3 as electrophilic reagents, we observe a facialselectivity upon reaction with alkenes and ketones andenantiomerically enriched products 4 and 5 are gener-ated. With compound 3a (R ) Et, R! ) Me, R!! ) H) wereported asymmetric reactions yielding 4 and 5 with 21%ee and 15% ee, respectively.10 Because of the lowstereoselectivities we tried to optimize the chiral hyper-valent iodine compounds of type 3. First we focused ourinterest on the substituents R and R! in the chiral moietyof 3. In a second step we then varied the substituent R!!to understand its influence on the electronic propertiesof the reagent. A further target was the optimization ofthe reaction conditions to obtain better yields and ste-reoselectivities.
We chose to synthesize the most simple compound 3bwith R ) R! ) Me and R!! ) H. The synthesis of thiscompound starts with an ortho-deprotonation of (S)-1-phenylethanol (6) with n-BuLi followed by introductionof iodine yielding compound 7a. The hydroxy group wasmethylated, and the precursor 7b was oxidized withsodium perborate in glacial acetic acid.12 Subsequenttreatment with p-toluenesulfonic acid monohydrate leadsto the hypervalent iodine compound 3b. An alternativeway to obtain 3b is chiral reduction13 of 2-bromoac-etophenone (8) followed by methylation. After the bro-mine-iodine exchange compound 7b can be oxidized asdescribed above. Because of the inefficent ortho-depro-
tonation of 6, the second route leads to a higher overallyield of 3b (43%) (Scheme 3).
The hypervalent iodine compound 3b can be purifiedonly by recrystallization. The X-ray structural analysisshows a strong interaction between the oxygen of themethoxy group and the iodine (Figure 1). The distancebetween these two atoms (2.47 Å) is much less than thedistance from the iodine to the oxygen of the tosyloxygroup (2.82 Å). Because the hydroxy group is tightlybound to the iodine (1.94 Å), we prefer writing thestructures of these hypervalent iodine compounds as saltsof p-toluenesulfonic acid.
Compound 3b shows a similar T-shaped structure likethe Koser reagent.14 Interestingly, the oxygen of themethoxy group is now replacing the tosylate leading toan oxygen-iodine-oxygen angle of 166° (Koser reagent:179°).14 Compared with the X-ray structural analysis of3a, the hypervalent iodine compound 3b shows a verysimilar geometry at the iodine atom. With 3b theproducts 4 and 5 were obtained with 33% ee and 15%ee, respectively.
Compared to 3a, the smaller substituent R ) Me in3b shows a higher enantiomeric excess in the product 4.If R! is changed into a larger substituent in 3c (R ) Me,R! ) Et), the product 4 is obtained with only 21% ee.
With the optimized chiral moiety in 3b (R ) R! ) Me),we started to synthesize derivatives with methoxy groups(R!! ) OMe) in the ortho-, meta-, and para-positions withrespect to iodine.
Two synthetic routes to the chiral hypervalent iodinecompound 3d with an ortho-methoxy substituent have
(12) McKillop, A.; Kemp, D. Tetrahedron 1989, 45, 3299-3306.(13) Resnick, S. M.; Torok, D. S.; Gibson, D. T. J. Org. Chem. 1995,
60, 3546-3549.(14) Koser, G. F.; Wettach, R. H.; Troup, J. M.; Frenz, B. A. J. Org.
Wirth, T.; Hirt, U. H. Tetrahedron Asymm. 1997, 8, 23
I+
OR'
-OTs
OH
R
Type 3 with ether moiety
Crystal structure of compound (S)-‐2
2.47 Å
I
EtOMe
OH
-OTs I
MeOMe
OH
-OTs
(S)-1 (S)-2
11
Type 3 chiral aryl-‐λ3-‐iodanes in α-‐oxygena2on of ketones
Ph
O
CH2Cl2, 0 °C Ph
O
OTsI
EtOMe
OH
(0.5 mmol) (S)-2 or 4(0.6 mmol) p-TsOH
(1.2 mmol) 1
-OTs
3(S)-2 =>10% ee(S)-4 =>15% ee
I
MeOMe
OH
-OTs
(S)-2 (S)-4
Hirt, U. H.; Spingler, B.; Wirth, T. J. Org. Chem. 1998, 63, 7674.
I
MeOMe
OH
-OTs
(S)-3
MeO
I
MeOMe
OH
-OTs
(S)-4
Et
Ph Ph OTsOTs
CH2Cl2, -30 °C
0.6 mmol 1
(0.5 mmol) 2,3 or 4, (0.6 mmol) p-TsOH
(R)-5(S)-2 =>33% ee(S)-3 =>53% ee(S)-4 =>55% ee
I
MeOMe
OH
-OTs
(S)-2
12
Op2miza2on of condi2ons for high enan2oselec2vity
1. Steric influence of chiral moiety
Results and Discussion
Hypervalent iodine compounds are electrophilic speciesand can attack double bonds as shown in Scheme 1. Weconfirmed this mechanism by converting either (E)- or(Z)-2-pentene with the hypervalent iodine compounds 3into syn- or anti-2,3-bis(tosyloxy)pentane selectively. Aclean SN2 type mechanism is the prerequisite for thedevelopment of asymmetric reactions with chiral hyper-valent iodine compounds. For these investigations wechose the dioxytosylation of styrene and the R-oxytosy-lation of propiophenone as test reactions (Scheme 2). Inthese reactions new stereocenters are created and theproducts of these reactions, 1,2-bis(tosyloxy)phenylethane(4) and R-(tosyloxy)propiophenone (5), are compoundscontaining asymmetric carbon atoms.
Employing chiral hypervalent iodine compounds oftype 3 as electrophilic reagents, we observe a facialselectivity upon reaction with alkenes and ketones andenantiomerically enriched products 4 and 5 are gener-ated. With compound 3a (R ) Et, R! ) Me, R!! ) H) wereported asymmetric reactions yielding 4 and 5 with 21%ee and 15% ee, respectively.10 Because of the lowstereoselectivities we tried to optimize the chiral hyper-valent iodine compounds of type 3. First we focused ourinterest on the substituents R and R! in the chiral moietyof 3. In a second step we then varied the substituent R!!to understand its influence on the electronic propertiesof the reagent. A further target was the optimization ofthe reaction conditions to obtain better yields and ste-reoselectivities.
We chose to synthesize the most simple compound 3bwith R ) R! ) Me and R!! ) H. The synthesis of thiscompound starts with an ortho-deprotonation of (S)-1-phenylethanol (6) with n-BuLi followed by introductionof iodine yielding compound 7a. The hydroxy group wasmethylated, and the precursor 7b was oxidized withsodium perborate in glacial acetic acid.12 Subsequenttreatment with p-toluenesulfonic acid monohydrate leadsto the hypervalent iodine compound 3b. An alternativeway to obtain 3b is chiral reduction13 of 2-bromoac-etophenone (8) followed by methylation. After the bro-mine-iodine exchange compound 7b can be oxidized asdescribed above. Because of the inefficent ortho-depro-
tonation of 6, the second route leads to a higher overallyield of 3b (43%) (Scheme 3).
The hypervalent iodine compound 3b can be purifiedonly by recrystallization. The X-ray structural analysisshows a strong interaction between the oxygen of themethoxy group and the iodine (Figure 1). The distancebetween these two atoms (2.47 Å) is much less than thedistance from the iodine to the oxygen of the tosyloxygroup (2.82 Å). Because the hydroxy group is tightlybound to the iodine (1.94 Å), we prefer writing thestructures of these hypervalent iodine compounds as saltsof p-toluenesulfonic acid.
Compound 3b shows a similar T-shaped structure likethe Koser reagent.14 Interestingly, the oxygen of themethoxy group is now replacing the tosylate leading toan oxygen-iodine-oxygen angle of 166° (Koser reagent:179°).14 Compared with the X-ray structural analysis of3a, the hypervalent iodine compound 3b shows a verysimilar geometry at the iodine atom. With 3b theproducts 4 and 5 were obtained with 33% ee and 15%ee, respectively.
Compared to 3a, the smaller substituent R ) Me in3b shows a higher enantiomeric excess in the product 4.If R! is changed into a larger substituent in 3c (R ) Me,R! ) Et), the product 4 is obtained with only 21% ee.
With the optimized chiral moiety in 3b (R ) R! ) Me),we started to synthesize derivatives with methoxy groups(R!! ) OMe) in the ortho-, meta-, and para-positions withrespect to iodine.
Two synthetic routes to the chiral hypervalent iodinecompound 3d with an ortho-methoxy substituent have
(12) McKillop, A.; Kemp, D. Tetrahedron 1989, 45, 3299-3306.(13) Resnick, S. M.; Torok, D. S.; Gibson, D. T. J. Org. Chem. 1995,
60, 3546-3549.(14) Koser, G. F.; Wettach, R. H.; Troup, J. M.; Frenz, B. A. J. Org.
Hirt, U. H.; Spingler, B.; Wirth, T. J. Org. Chem. 1998, 63, 7674.
Crystal structure of compound (S)-‐4
I
MeOMe
OH
-OTs
(S)-3
MeO
I
MeOMe
OH
-OTs
(S)-4
Et
Ph Ph OTsOTs
CH2Cl2, -30 °C
0.6 mmol 1
(0.5 mmol) 2,3 or 4, (0.6 mmol) p-TsOH
(R)-5(S)-2 =>33% ee(S)-3 =>53% ee(S)-4 =>55% ee
I
MeOMe
OH
-OTs
(S)-2
I
MeOMe
OH
-OTs
(S)-3
MeO
I
MeOMe
OH
-OTs
(S)-4
Et
Ph Ph OTsOTs
CH2Cl2, -30 °C
0.6 mmol 1
(0.5 mmol) 2,3 or 4, (0.6 mmol) p-TsOH
(R)-5(S)-2 =>33% ee(S)-3 =>53% ee(S)-4 =>55% ee
I
MeOMe
OH
-OTs
(S)-2
13
Op2miza2on of condi2ons for high enan2oselec2vity
1. Steric influence of chiral moiety
Hirt, U. H.; Spingler, B.; Wirth, T. J. Org. Chem. 1998, 63, 7674.
2. Steric influence at ortho posi2on
Ph
O
CH2Cl2, 0 °C Ph
O
OTsI
MeOMe
OH
(0.5 mmol) (S)-5,6 or 7(0.6 mmol) p-TsOH
(1.2 mmol) 1
-OTs
3(S)-5 =>10% ee(S)-6 =>40% ee(S)-7 =>0% ee
I
MeOMe
OH
-OTs
(S)-5 (S)-6
I
MeOMe
OH
-OTs
(S)-7
Me Et i-Pr
Ph
O
CH2Cl2, 0 °C Ph
O
OTsI
EtOMe
OH
(0.5 mmol) (S)-2 or 4(0.6 mmol) p-TsOH
(1.2 mmol) 1
-OTs
3(S)-2 =>10% ee(S)-4 =>15% ee
I
MeOMe
OH
-OTs
(S)-2 (S)-4
I
MeOMe
OH
-OTs
(S)-3
MeO
I
MeOMe
OH
-OTs
(S)-4
Et
Ph Ph OTsOTs
CH2Cl2, -30 °C
0.6 mmol 1
(0.5 mmol) 2,3 or 4, (0.6 mmol) p-TsOH
(R)-5(S)-2 =>33% ee(S)-3 =>53% ee(S)-4 =>55% ee
I
MeOMe
OH
-OTs
(S)-2
I
MeOMe
OH
-OTs
(S)-3
MeO
I
MeOMe
OH
-OTs
(S)-4
Et
Ph Ph OTsOTs
CH2Cl2, -30 °C
0.6 mmol 1
(0.5 mmol) 2,3 or 4, (0.6 mmol) p-TsOH
(R)-5(S)-2 =>33% ee(S)-3 =>53% ee(S)-4 =>55% ee
I
MeOMe
OH
-OTs
(S)-2
I
MeOMe
OH
-OTs
(S)-3
MeO
I
MeOMe
OH
-OTs
(S)-4
Et
Ph Ph OTsOTs
CH2Cl2, -30 °C
0.6 mmol 1
(0.5 mmol) 2,3 or 4, (0.6 mmol) p-TsOH
(R)-5(S)-2 =>33% ee(S)-3 =>53% ee(S)-4 =>55% ee
I
MeOMe
OH
-OTs
(S)-2
I
MeOMe
OH
-OTs
(S)-3
MeO
I
MeOMe
OH
-OTs
(S)-4
Et
Ph Ph OTsOTs
CH2Cl2, -30 °C
0.6 mmol 1
(0.5 mmol) 2,3 or 4, (0.6 mmol) p-TsOH
(R)-5(S)-2 =>33% ee(S)-3 =>53% ee(S)-4 =>55% ee
I
MeOMe
OH
-OTs
(S)-2
I
MeOMe
OH
-OTs
(S)-3
MeO
I
MeOMe
OH
-OTs
(S)-4
Et
Ph Ph OTsOTs
CH2Cl2, -30 °C
0.6 mmol 1
(0.5 mmol) 2,3 or 4, (0.6 mmol) p-TsOH
(R)-5(S)-2 =>33% ee(S)-3 =>53% ee(S)-4 =>55% ee
I
MeOMe
OH
-OTs
(S)-2
Type 3 chiral aryl-‐λ3-‐iodanes in dioxygena2on of alkenes
14
Proposed mechanism for dioxygena2on of styrene
H
Ph H
H H
Ph H
H
IAr!
HO
OTsH
Ph H
HOTs
IHO Ar
!
H
Ph H
HTsOOTs OTs
Ar*I(OH)OTs =
I
OR'
OTs
OH
RAr*I(OH)OTs2 OTs -IAr
-OH
R''1
3 4 (R)-3
I
MeOMe
OH
-OTs
(S)-3
MeO
I
MeOMe
OH
-OTs
(S)-4
Et
Ph Ph OTsOTs
CH2Cl2, -30 °C
0.6 mmol 1
(0.5 mmol) 2,3 or 4, (0.6 mmol) p-TsOH
(R)-5(S)-2 =>33% ee(S)-3 =>53% ee(S)-4 =>55% ee
I
MeOMe
OH
-OTs
(S)-2
Hirt, U. H.; Schuster, M. F. H.; French, A. N.; Wiest, O. G.; Wirth, T. Eur. J. Org. Chem. 2001, 1569
I
MeOMe
OH
-OTs
(S)-3
MeO
I
MeOMe
OH
-OTs
(S)-4
Et
Ph Ph OTsOTs
CH2Cl2, -30 °C
0.6 mmol 1
(0.5 mmol) 2,3 or 4, (0.6 mmol) p-TsOH
(R)-5(S)-2 =>33% ee(S)-3 =>53% ee(S)-4 =>55% ee
I
MeOMe
OH
-OTs
(S)-2
I
MeOMe
OH
-OTs
(S)-3
MeO
I
MeOMe
OH
-OTs
(S)-4
Et
Ph Ph OTsOTs
CH2Cl2, -30 °C
0.6 mmol 1
(0.5 mmol) 2,3 or 4, (0.6 mmol) p-TsOH
(R)-5(S)-2 =>33% ee(S)-3 =>53% ee(S)-4 =>55% ee
I
MeOMe
OH
-OTs
(S)-2
I
MeOMe
OH
-OTs
(S)-3
MeO
I
MeOMe
OH
-OTs
(S)-4
Et
Ph Ph OTsOTs
CH2Cl2, -30 °C
0.6 mmol 1
(0.5 mmol) 2,3 or 4, (0.6 mmol) p-TsOH
(R)-5(S)-2 =>33% ee(S)-3 =>53% ee(S)-4 =>55% ee
I
MeOMe
OH
-OTs
(S)-2
15
Why R-‐configura2on ?
PhA
B
A face addition
of Ar*I(OH)OTs
B face addition
of Ar*I(OH)OTs
OMe
MeI
HHH Ph
OMe
MeI
HHPh H
TsOH
TsOH
H
Ph
TsO(R)-3
H
H
OTs
3a+
3b+
H
H
TsO(S)-3
H
Ph
OTs
1
Hirt, U. H.; Schuster, M. F. H.; French, A. N.; Wiest, O. G.; Wirth, T. Eur. J. Org. Chem. 2001, 1569
Ra2onale for Stereoselec2vity
16
H
Ph
HO
SeAr!
(R)-2
CF3SO3H
MeOH
OH
EtSe
HHPh H H
Ph
OMe
SeAr!
(R)-3
H
Ph
HO
ArSe!
(S)-2
CF3SO3H
MeOH
OH
EtSe
HHH Ph H
Ph
MeO
ArSe!
(S)-3
H
Ph
OMe
SeAr!
(R)-3
Ph
A face addition
B face addition
3a+
3b+
1
Se)2
OH
Et
Br2
Se
OH
Et
TfO
Ph
MeOHAgOTfH
Ph
OMe
SeAr!
(R)-3
Wirth, T.; Fragale, G.; Spichty, M. J. Am. Chem. Soc. 1998, 120, 3376
Ra2onale for Stereoselec2vity
17
Se)2
OH
Et
Br2
Se
OH
Et
TfO
Ph
MeOHAgOTfH
Ph
OMe
SeAr!
(R)-3
H
Ph
HO
SeAr!
(R)-2
CF3SO3H
MeOH
OH
EtSe
HHPh H H
Ph
OMe
SeAr!
(R)-3
H
Ph
HO
ArSe!
(S)-2
CF3SO3H
MeOH
OH
EtSe
HHH Ph H
Ph
MeO
ArSe!
(S)-3
3a+
3b+
Ph+ ArSe
!
Wirth, T.; Fragale, G.; Spichty, M. J. Am. Chem. Soc. 1998, 120, 3376
Ra2onale for Stereoselec2vity: Stability of transi2on states
18
OH
MeSe
HHPh H
OH
MeSe
PhHH H
OH
MeSe
HPhH H
OH
MeSe
HHH Ph
3a+0.0 kcal/mol
3b+2.8 kcal/mol
3c+5.4 kcal/mol
3d+7.4 kcal/mol
bipyramidal structure resulting from an selenium-oxygenin-teraction can alternatively also be obtained by the conformationshown in 21+. Due to the strong steric interaction between themethyl group and the alkene, we focused our investigations onthe conformations of the diastereoisomers 20a+-20d+.The optimized geometries of the seleniranium ions 20a+-
20d+ are shown in Scheme 9. In all structures the alkene isbonded slightly asymmetrically to the selenium atom reflectingthe asymmetry of the highest occupied molecular orbital(HOMO) of styrene which is involved in the selenium-alkenebonding. The bond lengths vary from 2.03 to 2.10 Å for theshorter Se-C2 bond and from 2.13 to 2.17 Å for the Se-C1bond (Table 1). These bonds are longer than the selenium-aryl bond (Se-Caryl), which varies between 1.93 and 1.97 Å.There is a remarkable correlation between the Se-O distance
and the O-Se-alkene angle (see Table 1). In the structures20c+ and 20d+ the alkene and the oxygen are arranged in analmost T-shaped manner with an O-Se-alkene angle close to180°. This facilitates the interaction of the oxygen lone pairwith the antibonding molecular orbital of the selenium-alkene
bonding. Therefore stronger selenium-oxygen interactions andweaker selenium-alkene bondings are found for 20c+ and 20d+than for 20a+ and 20b+. That is expressed in the respectivebond lengths shown in Scheme 9 and Table 1.The natural population analysis (NPA) predicts a higher
charge of about 0.25 for atom C1 than for atom C2 in alldiastereomers (Table 1). This confirms the preference of carbonatom C1 over carbon atom C2 for a nucleophilic attack. Thisfact was also observed in all our methoxyselenenylationexperiments. For the structures 20c+ and 20d+, the charge ofthe selenium is less positive than for 20a+ and 20b+. This isin agreement with the stronger selenium-oxygen interactionin the diastereoisomers 20c+ and 20d+.Due to the reversibility of the seleniranium formation from
the selenium electrophile and the alkene, the stereoselectivityshould be influenced by the relative stabilities of the selenira-nium ions 20a+-20d+. The lowest energy is found for thediastereoisomer 20a+, which corresponds to the re attack ofthe selenium electrophile to styrene leading to the methoxyse-lenenylated product with the (R)-configuration at the newstereocenter. Diastereoisomer 20b+ is yielding the methoxy-selenenylated product with opposite configuration and is foundto be more than 2.5 kcal/mol (see Scheme 9) higher in energy.For the diastereoisomers 20c+ and 20d+ which cannot gain from!-stacking, energy differences of 5.4 and 7.4 kcal/mol arecalculated.
Conclusions
The asymmetric methoxyselenenylation reaction has beeninvestigated in detail. It was shown that the formation of theseleniranium ion intermediates is reversible. For the first timethe diastereomeric seleniranium ions, which are the intermediatesin the addition of chiral selenium electrophiles to alkenes, havebeen prepared independently. Therefore it was possible to detailby experiment the different stabilities of the seleniranium ionsinvolved in the asymmetric methoxyselenenylation. Further-
Scheme 9
Table 1. Geometry Parameters for the MP2/3-21G*-OptimizedSeleniranium Ions 20a+-20d+a
20a+ 20b+ 20c+ 20d+
Se-C1 2.13 2.13 2.15 2.17Se-C2 2.06 2.03 2.08 2.10Se-O 2.66 2.71 2.54 2.46Se-Caryl 1.94 1.93 1.96 1.97!O-Se-alkeneb 130.6 120.0 156.8 175.2!Caryl-Se-alkeneb 96.5 98.8 98.7 98.5atomic chargesSe +0.883 +0.904 +0.839 +0.813C1 -0.269 -0.306 -0.248 -0.255C2 -0.550 -0.523 -0.533 -0.505a Distances are in angstroms; angles are in degrees. The atomic
charges were determined by NPA using the MP2/6-31G*//MP2/3-21G*density. b Se-alkene stands for the bisector of the angle C1-Se-C2.
bipyramidal structure resulting from an selenium-oxygenin-teraction can alternatively also be obtained by the conformationshown in 21+. Due to the strong steric interaction between themethyl group and the alkene, we focused our investigations onthe conformations of the diastereoisomers 20a+-20d+.The optimized geometries of the seleniranium ions 20a+-
20d+ are shown in Scheme 9. In all structures the alkene isbonded slightly asymmetrically to the selenium atom reflectingthe asymmetry of the highest occupied molecular orbital(HOMO) of styrene which is involved in the selenium-alkenebonding. The bond lengths vary from 2.03 to 2.10 Å for theshorter Se-C2 bond and from 2.13 to 2.17 Å for the Se-C1bond (Table 1). These bonds are longer than the selenium-aryl bond (Se-Caryl), which varies between 1.93 and 1.97 Å.There is a remarkable correlation between the Se-O distance
and the O-Se-alkene angle (see Table 1). In the structures20c+ and 20d+ the alkene and the oxygen are arranged in analmost T-shaped manner with an O-Se-alkene angle close to180°. This facilitates the interaction of the oxygen lone pairwith the antibonding molecular orbital of the selenium-alkene
bonding. Therefore stronger selenium-oxygen interactions andweaker selenium-alkene bondings are found for 20c+ and 20d+than for 20a+ and 20b+. That is expressed in the respectivebond lengths shown in Scheme 9 and Table 1.The natural population analysis (NPA) predicts a higher
charge of about 0.25 for atom C1 than for atom C2 in alldiastereomers (Table 1). This confirms the preference of carbonatom C1 over carbon atom C2 for a nucleophilic attack. Thisfact was also observed in all our methoxyselenenylationexperiments. For the structures 20c+ and 20d+, the charge ofthe selenium is less positive than for 20a+ and 20b+. This isin agreement with the stronger selenium-oxygen interactionin the diastereoisomers 20c+ and 20d+.Due to the reversibility of the seleniranium formation from
the selenium electrophile and the alkene, the stereoselectivityshould be influenced by the relative stabilities of the selenira-nium ions 20a+-20d+. The lowest energy is found for thediastereoisomer 20a+, which corresponds to the re attack ofthe selenium electrophile to styrene leading to the methoxyse-lenenylated product with the (R)-configuration at the newstereocenter. Diastereoisomer 20b+ is yielding the methoxy-selenenylated product with opposite configuration and is foundto be more than 2.5 kcal/mol (see Scheme 9) higher in energy.For the diastereoisomers 20c+ and 20d+ which cannot gain from!-stacking, energy differences of 5.4 and 7.4 kcal/mol arecalculated.
Conclusions
The asymmetric methoxyselenenylation reaction has beeninvestigated in detail. It was shown that the formation of theseleniranium ion intermediates is reversible. For the first timethe diastereomeric seleniranium ions, which are the intermediatesin the addition of chiral selenium electrophiles to alkenes, havebeen prepared independently. Therefore it was possible to detailby experiment the different stabilities of the seleniranium ionsinvolved in the asymmetric methoxyselenenylation. Further-
Scheme 9
Table 1. Geometry Parameters for the MP2/3-21G*-OptimizedSeleniranium Ions 20a+-20d+a
20a+ 20b+ 20c+ 20d+
Se-C1 2.13 2.13 2.15 2.17Se-C2 2.06 2.03 2.08 2.10Se-O 2.66 2.71 2.54 2.46Se-Caryl 1.94 1.93 1.96 1.97!O-Se-alkeneb 130.6 120.0 156.8 175.2!Caryl-Se-alkeneb 96.5 98.8 98.7 98.5atomic chargesSe +0.883 +0.904 +0.839 +0.813C1 -0.269 -0.306 -0.248 -0.255C2 -0.550 -0.523 -0.533 -0.505a Distances are in angstroms; angles are in degrees. The atomic
charges were determined by NPA using the MP2/6-31G*//MP2/3-21G*density. b Se-alkene stands for the bisector of the angle C1-Se-C2.
bipyramidal structure resulting from an selenium-oxygenin-teraction can alternatively also be obtained by the conformationshown in 21+. Due to the strong steric interaction between themethyl group and the alkene, we focused our investigations onthe conformations of the diastereoisomers 20a+-20d+.The optimized geometries of the seleniranium ions 20a+-
20d+ are shown in Scheme 9. In all structures the alkene isbonded slightly asymmetrically to the selenium atom reflectingthe asymmetry of the highest occupied molecular orbital(HOMO) of styrene which is involved in the selenium-alkenebonding. The bond lengths vary from 2.03 to 2.10 Å for theshorter Se-C2 bond and from 2.13 to 2.17 Å for the Se-C1bond (Table 1). These bonds are longer than the selenium-aryl bond (Se-Caryl), which varies between 1.93 and 1.97 Å.There is a remarkable correlation between the Se-O distance
and the O-Se-alkene angle (see Table 1). In the structures20c+ and 20d+ the alkene and the oxygen are arranged in analmost T-shaped manner with an O-Se-alkene angle close to180°. This facilitates the interaction of the oxygen lone pairwith the antibonding molecular orbital of the selenium-alkene
bonding. Therefore stronger selenium-oxygen interactions andweaker selenium-alkene bondings are found for 20c+ and 20d+than for 20a+ and 20b+. That is expressed in the respectivebond lengths shown in Scheme 9 and Table 1.The natural population analysis (NPA) predicts a higher
charge of about 0.25 for atom C1 than for atom C2 in alldiastereomers (Table 1). This confirms the preference of carbonatom C1 over carbon atom C2 for a nucleophilic attack. Thisfact was also observed in all our methoxyselenenylationexperiments. For the structures 20c+ and 20d+, the charge ofthe selenium is less positive than for 20a+ and 20b+. This isin agreement with the stronger selenium-oxygen interactionin the diastereoisomers 20c+ and 20d+.Due to the reversibility of the seleniranium formation from
the selenium electrophile and the alkene, the stereoselectivityshould be influenced by the relative stabilities of the selenira-nium ions 20a+-20d+. The lowest energy is found for thediastereoisomer 20a+, which corresponds to the re attack ofthe selenium electrophile to styrene leading to the methoxyse-lenenylated product with the (R)-configuration at the newstereocenter. Diastereoisomer 20b+ is yielding the methoxy-selenenylated product with opposite configuration and is foundto be more than 2.5 kcal/mol (see Scheme 9) higher in energy.For the diastereoisomers 20c+ and 20d+ which cannot gain from!-stacking, energy differences of 5.4 and 7.4 kcal/mol arecalculated.
Conclusions
The asymmetric methoxyselenenylation reaction has beeninvestigated in detail. It was shown that the formation of theseleniranium ion intermediates is reversible. For the first timethe diastereomeric seleniranium ions, which are the intermediatesin the addition of chiral selenium electrophiles to alkenes, havebeen prepared independently. Therefore it was possible to detailby experiment the different stabilities of the seleniranium ionsinvolved in the asymmetric methoxyselenenylation. Further-
Scheme 9
Table 1. Geometry Parameters for the MP2/3-21G*-OptimizedSeleniranium Ions 20a+-20d+a
20a+ 20b+ 20c+ 20d+
Se-C1 2.13 2.13 2.15 2.17Se-C2 2.06 2.03 2.08 2.10Se-O 2.66 2.71 2.54 2.46Se-Caryl 1.94 1.93 1.96 1.97!O-Se-alkeneb 130.6 120.0 156.8 175.2!Caryl-Se-alkeneb 96.5 98.8 98.7 98.5atomic chargesSe +0.883 +0.904 +0.839 +0.813C1 -0.269 -0.306 -0.248 -0.255C2 -0.550 -0.523 -0.533 -0.505a Distances are in angstroms; angles are in degrees. The atomic
charges were determined by NPA using the MP2/6-31G*//MP2/3-21G*density. b Se-alkene stands for the bisector of the angle C1-Se-C2.
bipyramidal structure resulting from an selenium-oxygenin-teraction can alternatively also be obtained by the conformationshown in 21+. Due to the strong steric interaction between themethyl group and the alkene, we focused our investigations onthe conformations of the diastereoisomers 20a+-20d+.The optimized geometries of the seleniranium ions 20a+-
20d+ are shown in Scheme 9. In all structures the alkene isbonded slightly asymmetrically to the selenium atom reflectingthe asymmetry of the highest occupied molecular orbital(HOMO) of styrene which is involved in the selenium-alkenebonding. The bond lengths vary from 2.03 to 2.10 Å for theshorter Se-C2 bond and from 2.13 to 2.17 Å for the Se-C1bond (Table 1). These bonds are longer than the selenium-aryl bond (Se-Caryl), which varies between 1.93 and 1.97 Å.There is a remarkable correlation between the Se-O distance
and the O-Se-alkene angle (see Table 1). In the structures20c+ and 20d+ the alkene and the oxygen are arranged in analmost T-shaped manner with an O-Se-alkene angle close to180°. This facilitates the interaction of the oxygen lone pairwith the antibonding molecular orbital of the selenium-alkene
bonding. Therefore stronger selenium-oxygen interactions andweaker selenium-alkene bondings are found for 20c+ and 20d+than for 20a+ and 20b+. That is expressed in the respectivebond lengths shown in Scheme 9 and Table 1.The natural population analysis (NPA) predicts a higher
charge of about 0.25 for atom C1 than for atom C2 in alldiastereomers (Table 1). This confirms the preference of carbonatom C1 over carbon atom C2 for a nucleophilic attack. Thisfact was also observed in all our methoxyselenenylationexperiments. For the structures 20c+ and 20d+, the charge ofthe selenium is less positive than for 20a+ and 20b+. This isin agreement with the stronger selenium-oxygen interactionin the diastereoisomers 20c+ and 20d+.Due to the reversibility of the seleniranium formation from
the selenium electrophile and the alkene, the stereoselectivityshould be influenced by the relative stabilities of the selenira-nium ions 20a+-20d+. The lowest energy is found for thediastereoisomer 20a+, which corresponds to the re attack ofthe selenium electrophile to styrene leading to the methoxyse-lenenylated product with the (R)-configuration at the newstereocenter. Diastereoisomer 20b+ is yielding the methoxy-selenenylated product with opposite configuration and is foundto be more than 2.5 kcal/mol (see Scheme 9) higher in energy.For the diastereoisomers 20c+ and 20d+ which cannot gain from!-stacking, energy differences of 5.4 and 7.4 kcal/mol arecalculated.
Conclusions
The asymmetric methoxyselenenylation reaction has beeninvestigated in detail. It was shown that the formation of theseleniranium ion intermediates is reversible. For the first timethe diastereomeric seleniranium ions, which are the intermediatesin the addition of chiral selenium electrophiles to alkenes, havebeen prepared independently. Therefore it was possible to detailby experiment the different stabilities of the seleniranium ionsinvolved in the asymmetric methoxyselenenylation. Further-
Scheme 9
Table 1. Geometry Parameters for the MP2/3-21G*-OptimizedSeleniranium Ions 20a+-20d+a
20a+ 20b+ 20c+ 20d+
Se-C1 2.13 2.13 2.15 2.17Se-C2 2.06 2.03 2.08 2.10Se-O 2.66 2.71 2.54 2.46Se-Caryl 1.94 1.93 1.96 1.97!O-Se-alkeneb 130.6 120.0 156.8 175.2!Caryl-Se-alkeneb 96.5 98.8 98.7 98.5atomic chargesSe +0.883 +0.904 +0.839 +0.813C1 -0.269 -0.306 -0.248 -0.255C2 -0.550 -0.523 -0.533 -0.505a Distances are in angstroms; angles are in degrees. The atomic
charges were determined by NPA using the MP2/6-31G*//MP2/3-21G*density. b Se-alkene stands for the bisector of the angle C1-Se-C2.
• Asymmetric induc.on using chiral aryl-‐λ3-‐iodane reagents
– Chiral aryl-‐λ3-‐iodanes with one carbon and two heteroatom ligands & their applica.ons in oxida.ve addi.on reac.ons
– Chiral aryl-‐λ3-‐iodanes with two carbon and one heteroatom ligands & their applica.ons in aryla2on reac2ons
39
Two carbons and one heteroatom ligands chiral aryl-‐λ3-‐iodanes
40
R
OR
O
Ar*
Asymmetric !"arylation
Catalyst
IL
Ar*
Type 1
IL
Ar*
IL*
Ar
Type 1
Type 2
Asymmetric α-‐aryla2on with unsymmetric aryl-‐λ3-‐iodanes
41 Ochiai, M.; Kitagawa, Y.; Takayama, N.; Takaoka, Y.; Shiro, M. J. Am. Chem. Soc. 1999, 121, 9233
IBn
Ar
BF4CO2Me
O (0.20 mmol) (S)-3 (0.20 mmol) tBuOK
(0.20 mmol) 1
CO2MeO
Ar(R)-2
(4 ml) tBuOHr.t, 1 h
37% yield, 53% ee(S)-3
Possible pathways for α-‐aryla2on
42 Chen, K. C.; Koser, G. F. J. Org. Chem. 1991, 56, 5764 Ochiai, M.; Kitagawa, Y.; Toyonari, M. ARKIVOC 2003, 6, 43
IO
CO2MeIO
CO2Me
O-
CO2Me
K+
IO
CO2Me
IX
and/or
I O
MeO2C
!-
!+
and/orI!-
O
MeO2C !+
OCO2MeAryl radicals pathway
Ligand exchange-ligand coupling pathway
Evidence for ligand exchange-‐ligand coupling pathway
43
O O
No evidence forformation of 3-substituted
dihydrobenzofuran
Ochiai, M.; Kitagawa, Y.; Toyonari, M. ARKIVOC 2003, 6, 43
O-
CO2Me
K+ O
I+ BF4-
(2 ml) t-BuOH, 25 °C
OCO2Me
OCO2Me
O
IO
OCO2Me
OH
(0.09 mmol) 1
(0.09 mmol) 2
(61%) 3 (7%) 4
5 6
Ligand exchange-‐ligand coupling pathway
44 Ochiai, M.; Kitagawa, Y.; Toyonari, M. ARKIVOC 2003, 6, 43
O-
CO2Me
K+
O
I+Ph
BF4-
IO
O
MeO2C
I O
MeO2C
O
Ligand exchange Pseudo rotation
IO
O
MeO2C
!-
!+
I O
MeO2C
O
!-
!+
Ligand coupling
OCO2Me
OCO2Me
O
IO
!-
O
MeO2C!+
1
23 4
5 6
O-
CO2Me
K+ O
I+ BF4-
(2 ml) t-BuOH, 25 °C
OCO2Me
OCO2Me
O
IO
OCO2Me
OH
(0.09 mmol) 1
(0.09 mmol) 2
(61%) 3 (7%) 4
5 6
O-
CO2Me
K+ O
I+ BF4-
(2 ml) t-BuOH, 25 °C
OCO2Me
OCO2Me
O
IO
OCO2Me
OH
(0.09 mmol) 1
(0.09 mmol) 2
(61%) 3 (7%) 4
5 6
45
R
OR
O
Ar*
Asymmetric !"arylation
Catalyst
IL*
Ar
Type 2
IL
Ar*
IL*
Ar
Type 1
Type 2
Two carbons and one heteroatom ligands chiral aryl-‐λ3-‐iodanes
46
C
D
I
O
A
I
OOSO
O
OSOO
B
OCO2Et
2, 3
1, 2
O-I bondforms
C-I bondforms
O
CO2Et
I
O
OEt
O
I
O
OEt
O
4
Norrby, P. O.; Petersen, T. B.; Bielawski, M.; Olofsson, B. Chem-‐Eur. J. 2010, 16, 8251
O
OEt
O
(0.19 mmol) 2(0.17 mmol) CsOH,
(2 mL) toluene,
I
2
OO3S
O
OEt
O
racemic(0.15 mmol) 3
42
α-‐aryla2on using aryl-‐λ3-‐iodanes with chiral heteroatom ligand
Energy level diagram of aryla2on of acetaldehyde
good agreement with the lack of selectivity observed in theexperimental work (Scheme 2 and Supporting Information).
Thus, asymmetric induction in the arylation of enolates bydiaryliodonium salts could either be obtained by influencingthe neutral, prochiral complex C,[6] by differentiation of theenantiotopic faces irreversibly during the enolate forma-tion,[7] or by increasing the barrier to interconversion of theO!I and C!I intermediates. Ionic species are not expectedto have any beneficial interactions with neutral C. ChiralLewis bases could coordinate to the iodine in a similarmanner to chiral anions and give complexes like E and F,but rearrangements of those species have too high barriersto be competitive. Potentially fruitful approaches couldeither be based on covalently linked auxiliaries, or on chiral
Lewis acids that could associate with and favor reactions viaC-linked intermediate D. We are currently investigatingsuch systems[27] and will report the results in due time.
Experimental Section
Experimental procedures, analytical data, and computational details areavailable in the Supporting Information.
Acknowledgements
This work was financially supported by the Swedish Research Council,Carl Trygger Foundation, and K&AWallenberg Foundation.
[1] a) R. E. Gawley, J. Aub!, Principles of Asymmetric Synthesis, Perga-mon, Oxford, 1996 ; b) T. Ooi, K. Maruoka, Angew. Chem. 2007,119, 4300–4345; Angew. Chem. Int. Ed. 2007, 46, 4222–4266.
[2] A. C. B. Burtoloso, Synlett 2009, 0320–0327.[3] E. A. Merritt, B. Olofsson, Angew. Chem. 2009, 121, 9214–9234;
Angew. Chem. Int. Ed. 2009, 48, 9052–9070.[4] a) M. Bielawski, M. Zhu, B. Olofsson, Adv. Synth. Catal. 2007, 349,
2610–2618; b) M. Bielawski, D. Aili, B. Olofsson, J. Org. Chem.2008, 73, 4602–4607; c) E. A. Merritt, J. Malmgren, F. J. Klinke, B.
Figure 2. Energy levels (in kJmol!1) of possible intermediates and TS structures in the reaction of acetaldehyde enolate with Ph2ICl in THF. Dotted linesindicate rapid association/dissociation equilibria.
Figure 3. Favored [2,3] rearrangement TS in the arylation of enolate 1with Ph2ICl (hydrogen atoms are hidden).