Asymmetric

R
Aminohydroxylation of Alkenes

XNClNa (X=Ts, Ms, CBz, Boc, Teoc) NHX OH

R2 OR XNBrLi (X=Ac) R2 R2
R1 R1 + R1
4 mol% K 2 OsO 2 (OH)4
5 mol% (DHQ)2 PHAL OH NHX
1:1 ROH:H 2 O

• originally developed with chloramine T (Na+ClNTs -), as for a racemic protocol developed by Sharpless in the 1980s
1980s

• found that the reaction works better with smaller N-substituents, (eg MeSO2-), and even better still with salts of
N-halocarbamates (NC(O)OR; ease of deprotection!) or N-haloamides

• regiocontrol is a problem, particularly with electronically unbiased alkene substituents

• in most respects the reaction is similar to the AD, including the model (DHQD)2 PHAL

for asymmetric induction β-face

(note that, for a given olefin, the HO/NHR are delivered slightly "HO/ NHR" "HO/ NHR"

to the same face in both regioisomeric products) hindered

chloramine-T: Angew. ., 1996, 35, 451 RS RM

chloramine-M: Angew. Chem., Int. Ed. Engl., 1996, 35, 2810 RL H
halocarbamates: Angew. Chem., Int. Ed. Engl., 1996, 35, 2813
haloamides: Org. Lett., 2000, 2, 2221
attractive area - very!!!!!
good for aromatic hindered
"HO/ NHR" "HO/ NHR"
and alkyl substituents
α-face
(DHQ)2PHAL
 Scope of the asymmetric aminohydroxylation
(all reactions shown carried out with (DHQ) 2 -PHAL; figure shown is ee)
Symmetrical trans-alkenes: Symmetrical cis-alkenes:
OH R = Ts 62
Ph R = Ms 75
Ph R = Cbz 91 RHN OH R = Ts 45
NHR R = Ac 94 R = Ms 66
R = Cbz 63
OH R = Ts 77 R = Ac --
CO 2 Et R = Ms 95
EtO 2 C R = Cbz 84
NHR R = Ac --

Styrenes: Cinnamates (electronically distinguished):

RNH O OH O
NHR OH
OH NHR OMe OMe
Ph Ph OH NHR

regiochemistry
R = Ts 50 2:1
R = Ms -- R = Ts 81 5 : 1
--
R = Cbz 93 R = Ms 95 9 : 1
1:1
R = Ac 88 R = Cbz 94 10 : 1
1:6
R = Ac* 99 20 : 1
* - iPr ester
•
 Regiochemical control by adjustment of aromatic linking group

O CBzNH O OH O

(DHQ)2 PHAL
OMe OMe + OMe
or (DHQ) 2 AQN OH NHCBz

(DHQ) 2 PHAL (94% ee) >10 : 1

(DHQ )2 AQN 21 : 79 (95% ee)

(DHQ) 2 PHAL NHCbz OH

Ph OH + NHCbz
or (DHQ)2 AQN Ph Ph

(DHQ) 2PHAL (93% ee) ca. 1 : 1

(DHQ )2 AQN 1 : 13 (88% ee)
Et Et
N N
H H
O O
H H
Me O O O OM e
Tetrahedron Lett., 1998, 39, 2507;
Angew. Chem., Int. Ed. Engl., 1997, 36, 1483
N N
(DHQ) 2AQN
 Asymmetric Hydrogenation of Alkenes

• H2 is cheap and reduction is atom efficient! Can generate two asymmetric

centres simultaneously

• Homogeneous catalysts based on Rh (I) or Ru (II) with chiral phosphine

ligands
electron
withdrawing
X E group
P
For Rh catalysts, general substrate structure: Rh
O
P
Ph
e.g. Aminoacrylates (X=NH, E=CO2R)
basic carbonyl group

Also (usually Ru catalysts):

• Enamides
• Acrylic acids
• Allylic alcohols
 Asymmetric Homogeneous Hydrogenation with
Chiral Diphosphines: Monsanto synthesis of L-DOPA
CO2Me CO2Me

NHAc NHAc
0.1% [(R,R)-(dipamp)Rh(COD)]+BF4

3 atm H2, 50°C, H2O / iPrOH 94% ee

MeO OMe MeO OMe

HBr

OMe
CO2-
Ph
P P NH3+
Ph

MeO
HO OH
= (R,R)-dipamp
L-DOPA
(anti-Parkinson's)

• W.S. Knowles – share of 2001 Nobel Prize.

Review of Monsanto work on L-DOPA synthesis: J. Chem. Ed., 1986, 63, 222
• First large-scale application of asymmetric hydrogenation, but the ligand lacks generality.
 Mechanism of hydrogenation with Rh(I)dipamp

+ + +
H H H
N E N E N E
H2 H S
P H H
Rh Rh Rh
P O slow P O P O
Ph P Ph P Ph
fast
more stable NHCOMe
(major isomer) H
+ CO2Me
P S minor
Rh Ph
P S
NHCOMe
major H
CO2Me
less stable
fast (minor isomer) Ph
+ + +
H H H
N N H E N S
E E
P H H
H2 Rh
Rh Rh
O O P O P
P
fast P P
Ph Ph Ph

But…recent work suggests that this does not operate in all cases (e.g. electron-rich phosphines)…
See commentary in Angew. Chem. Int. Ed. 2001, 40, 4611.
 Rh(I)-BINAP Complexes
• Axially chiral binaphthyl diphosphine ligands offer improved ee's and wider substrate tolerance
in aminoacrylate reduction.

Ph
Ph
P
axial
L
P P
P Rh
Ph equatorial L
Ph

(S)-BINAP

axial equatorially disposed phenyl

Simplified by removing backbone: P P
Rh groups block coordination
equatorial
L L in that 'quadrant'

Chiral enviromnment has 4 quadrants, blocked

two "blocked" and two "open": open

For alternative pictures, see Figure 8 in: Noyori, J. Am. Chem. Soc. 2002, 124, 6649
 Rh(I)-BINAP-catalysed hydrogenation of aminoacrylates
Noyori, J. Am. Chem. Soc. 1980, 102, 7932.

Note that for a given ligand enantiomer, the sense of asymmetric induction is determined by acrylate geometry
(hence need geometrically pure starting materials):

CO2R [(S)-(BINAP)Rh(nbd)]+ClO4- CO2R

R=Me 98%, 93% ee
H2, MeOH R=H 97%, 100% ee
Ph NHAc Ph NHAc

Ph CO2H [(S)-(BINAP)Rh(nbd)]+ClO4- CO2H

93%, 87% ee
H2, MeOH
NHAc Ph NHAc

One drawback is that chirality transfer from chiral backbone to coordinating PPh2 groups PPh2
is not always efficient.
PPh2
Also, no bis(diarylphosphine) ligand gives >99% ee for a range of acylaminoacrylates

(S)-BINAP
 Rhodium (I)-diphosphole complexes:
electron rich, sterically demanding ligand systems
Review: Burk, Acc. Chem. Res. 2000, 33, 363

R
R R
P
P P R = Me, Et, Pr R R
(R,R)-DuPHOS
(R,R)-BPE
P
R R

electron rich alkylphosphines allow increased back-bonding to alkene substrates - more tightly held
flexible backbone in BPE leads to two ligand environments, one less selective than the other:

R R R R

R groups held away P Rh P Rh P

R groups held towards
P
from coordination sites coordination sites
R R R R

...so rigid DuPHOS generally better (although BPE can still be useful with VERY hindered substrates)
M. J. Burk, J. Am. Chem. Soc., 1993, 115, 10125
 DuPHOS and BPE are outstanding ligands
for Rh catalysed hydrogenation of aminoacrylates
unlike BINAP, the sense of enantioselectivity is independent of acrylamide geometry - mixtures can be used!
CO2Me
0.05% [Rh(R,R-nPr-DuPHOS)(COD)]+ TfO- CO2Me R1 = R2 = H 99.8% ee
R1 R1 = H, R2 = Me 99.6% ee
NHAc MeOH, 2 atm. H2
NHAc R1 = Me, R2 = H 99.4% ee
R2

also works for N-Cbz aminoacrylates - direct access to usefully protected amino acids

very substrate tolerant - the following all give >99% ee with Et-DuPHOS

CO2Me
R = H, Me, Et, i-Pr, Ph, 1-naph, 2-naph, 2-thiophenyl, ferrocenyl,
4-(X)-Ph, 3-(X)-Ph, 3,5-di(X)-Ph (X = F, Br, OMe, CF3)
R NHAc

even works for tetrasubstituted aminoacrylates - other ligands give <70% ee and are slow
Et Et
CO2Me 0.2% [Rh((S,S)-Me-DuPHOS)(COD)]+ TfO- CO2Me
Ph Ph
MeOH, 90 psi H2 88% ee
NHAc NHAc

M. J. Burk, J. Am. Chem. Soc., 1993, 115, 10125; J. Am. Chem. Soc., 1995, 117, 9375
 Asymmetric reduction of enamides
ruthenium BINAP mediated reduction of cyclic enamides

MeO MeO

NAc [Ru(R-BINAP)(COD)]+ TfO - NAc 100%,

MeO MeO 99.5% ee
4 atm. H2, EtOH/DCM
OMe OMe
(rhodium BINAP gives 70% ee)
OMe OMe
N-acetyl-tetrahydropapaverine
Noyori, Takaya, J. Am. Chem. Soc., 1986, 108, 7117

rhodium DuPHOS mediated reduction of acyclic enamides

enamide
geometry +
0.2% [Rh((S,S)-Me-DuPHOS)(COD)] TfO
-

unimportant 96%ee
60 psi H2, MeOH
Ph NHAc Ph NHAc

Burk, J. Am. Chem. Soc., 1996, 118, 5142

 Ru-diphosphine catalysed reduction of acrylic acids

R3 CO2H R3 CO2H
(BINAP)Ru(OAc)2
* 83-97% ee
H2 *
R2 R1 R2 R1

e.g.

1% (S-BINAP)Ru(OAc)2
CO2H CO2H
100 atm H2, MeOH
MeO MeO
92%, 97% ee
(S)-naproxen
(anti-inflammatory)

Noyori, Takaya, Inorg. Chem., 1988, 27, 566; J. Org. Chem. 1987, 52, 3174.

• Corresponding methyl esters are inert to this catalyst

For use of Rh-DuPHOS catalysts in acrylate reduction, see: Burk. J. Org. Chem., 1999, 64, 3290.
 Mechanism of hydrogenation with Ru BINAP complexes
is different from Rh
Like the rhodium counterpart, the hydrogenation is stereospecifically syn; but unlike the rhodium reaction,
the α-hydrogen is incorporated from the gas source, the β-hydrogen from protonolysis by solvent

D2, CH3OH CO2H H2, CD3OD CO2H

CO2H (R-BINAP)Ru(OAc) H CO2H
2
D D
D2, CD3OD
Me Me
H 0.95 D 0.34 D 1.06 H 0.71

Ruthenium (II) prefers to form monohydrides, whereas rhodium (I) prefers to form dihydrides
(G. Wilkinson, Nature, 1965, 208, 1203)

HO2C protonolysis
H2 O
HO2C P O
Ru O
P O
O
O
O P
O O
P O H2 O Ru
P O P O
Ru P S
Ru Ru
P O (-AcOH) S
P O P H
O O S O
rearrangement P insertion
Ru
P H
S
H. Takaya, R. Noyori, Tetrahedron Lett., 1990, 31, 7189, J. Am. Chem. Soc. 2002, 124, 6649
 Ru-BINAP catalysed reduction of allylic alcohols

•Sense of induction depends on alkene geometry:

0.2% (S-BINAP)Ru(OAc)2
96% ee
OH 30 atm H2, MeOH OH

0.2% (S-BINAP)Ru(OAc)2
30 atm H2, MeOH 98% ee
OH

OH

Noyori, Takaya, J. Am. Chem. Soc.., 1987, 109, 1596; J. Org. Chem. 1988, 53, 708.