Guanidine and guanidinium salt catalyzed enantioselective phosphorus carbon bond formation reactions 1

Chapter 1


1


















Chapter 1

Asymmetric Phosphorus-Carbon Bond Formation Reactions





Chapter 1

2
Phosphorus is an essential element for synthetic chemistry and life science. After
the Wittig reaction was discovered in 1954, the organic chemistry of phosphorus
became a highly active field.
1
Phosphorus is not only critical for many reagents, but
also probably the most prominent ligands, in terms of structural and electronic
diversity in metal-catalyzed reactions
2
and nucleophilic phosphine organocatalysis.
3

Molecules containing a phosphonic [P(O)(OH)
2
], a phosphinic [P(O)(OH)R] or a
phosphonate [P(O)(OR)
2
] group and an amino group can be regarded as analogues of
amino acids. α-Amino phosphonic acids and their phosphonate esters are excellent
inhibitors of protease and antibodies.
4

The synthetic and biological abilities of phosphorus compounds depend on their
enantiopurities. Therefore, synthesis of enantiomerically pure organophosphorus
compounds has received considerable attention. Such compounds are typically
prepared by resolution of the racemic phosphorus compounds
5
, which limits the scope

of the enantiopure organophosphorus compounds. The direct approach to build
phosphorus-carbon (P-C) bonds, which was a convenient method to generate
structurally diversified organophosphorus compounds, provided many model
reactions to develop the asymmetric P-C bonds formation reactions.
There are several general methods to generate P-C bonds: (a) addition to
unactivated olefins promoted by radical initiators
6
or transition metals.
7
(b) the
phospha-Michael reaction of electron-deficient alkenes, most commonly promoted in
the presence of a basic catalyst (e.g. K
2
CO
3
,
8
alkaline alkoxides in alcoholic solution
9
)
or by using a strong base
10
(e.g. NaH, nBuLi, Et
2
Zn) in stoichiometric amount, the use
of tetramethylguanidine (TMG),
11
Lewis acid
12
or under microwave conditions;

13

Among various methods to generate P-C bonds, the direct addition of P(O)-H bonds
(dialkyl phosphonate [(RO)
2
P(O)H] or dialkyl phosphine oxides [R
2
R(O)H]) across
Chapter 1


3
alkenes is one of the most convenient and atom economical routes.
14

1.1 Asymmetric phospha-Michael reactions
1.1.1 Asymmetric phospha-Michael reactions through chiral starting materials
and chiral auxiliaries
Asymmetric versions of phospha-Michael reactions mainly deal with substrate-
controlled diastereoselective additions. Yamamoto and co-workers
15
developed the
first substrate-controlled diastereoselective addition of phosphorus nucleophiles to
unsaturated nitroalkenes derived from sugar. Albeit only with moderate
stereoselectivities under the reaction conditions (heated to 70
o
C for 12 h), this work
demonstrated a possible way for the preparation of sugar analogues with a phosphorus
atom in place of oxygen in the hemiacetal ring (Scheme 1.1).
MeO

O
O
2
N
O
O
Me
Me
Me
P
H
O
OMe
benzene, 70
o
C
MeO
O
O
2
N
O
O
Me
Me
P
O
Me
OMe
P

O
Me
HO
OR
HO
HO
OH
P
O
Me
HO
OR
HO
HO
OH
+
1
2
34

Scheme 1.1. Yamamoto’s substrate-controlled diastereoselective addition of P
nucleophiles to unsaturated nitrosaccharides.

Yamashita and co-workers
16
described the diastereoselective addition of various
phosphorus nucleophiles to Z-configured nitroalkene acceptors 5 bearing the sugar
residue in the presence of Et
3
N at 90

o
C (Scheme 1.2). The major product was L-Idose
derivatives due to the steric hindrance caused by 3-O-alkyl group of the sugar, as well
as R
2

and R
3
group of the phosphorous compounds. The ratio of L-Idose and D-gluco
Chapter 1


4
derivatives increased from 2:1 to 11:1 with different steric size of R
1
-R
3
(11:1 was
obtained when R
1
= Me, R
2

= R
3
= Ph, X = O). However, when primary phosphine
(R
1
= Bn, R
2

= mesityl, R
3

= H, X = lone pair) was employed, no reaction was
observed.
O
NO
2
R
1
O
OO
MeMe
+
R
2
P
H
X
R
3
Et
3
N, 90
o
C
O
NO
2

R
1
O
OO
MeMe
P
X
R
3
R
2
O
NO
2
R
1
O
OO
M
e
M
e
D-gluco
L-ido
R
1
=Me,Ac,Bn;
R
2
= OMe, OEt, Ph, O Bn, Mes;

R
3
=H,OMe,OEt,Ph,OBn;
X:Oorlonepairelectrons
56
(2:1 - 11:1 dr)

Scheme 1.2. Yamashita’s diastereoselective addition of various phosphorus
nucleophiles to Z-configured nitroalkene acceptors 5.

R
NO
2
Condition A:
Et
3
N (0.3 eq.), r.t.
C
ondition B:
100
o
C
P
NO
2
R
O
MeO
MeO
+

P
NO
2
R
O
MeO
MeO
O
AcO
OO
MeMe
O
OO
MeMe
O
AcO
OO
MeMe
O
BnO
OO
MeMe
O
OMe
O
O
Me
Me
R:
ab c

de f
7a-f
(R)-
8a-f
(S)
-8a-f
C
ondition A Condition B
8a
: 8 1% (89:11 R/S) 83% ( 35:65 R/S)
8b
: 94% ( 66:34 R/S ) 91% (48:52 R/S)
8c
: 5 7% (67:33 R/S) 55% ( 38:62 R/S)
8d
: 81% ( 87:13 R/S ) 65% (22:78 R/S)
8e
: 8% (66:34 R /S) 0%
8f:0% 0%
O
BnO
OO
MeMe
+
(MeO)
2
P( O)H
Scheme 1.3. Yamamoto’s stereoselective addition of dimethyl phosphonate to the E-
configured nitro olefins.

Chapter 1


5
Yamamoto and co-workers
17
carried out a systematic study on the stereoselective
addition of dimethyl phosphonate to the E-configured nitroalkenes 7a–f (Scheme 1.3).
Two different conditions were employed and it was found that the stereochemical
outcome were opposite. Condition A (0.3 eq of Et
3
N) gave predominantly the R
stereoisomer, whereas the S stereoisomer was obtained as a major component in the
case of condition B (heated to 100
o
C in the absence of base). In most cases (except e,
f), the yields obtained were moderate to good (55 to 94%).
O
O
Me
Me
O
P
O
O
H
Ph
Ph
Ph
Ph

a,b
98%
O
O
Me
Me
OH
OH
Ph
Ph
Ph
Ph
10
9
NO
2
R
NO
2
P
R
O
HO
HO
86-91 %
c
O
O
Me
Me

O
P
O
O
Ph
Ph
Ph
Ph
R
NO
2
d, e
65-94 %
R=Ph,pBip h, 3,4,5- (MeO)
3
Ph, pMePh, 2-Naphthyl
12, de = 84-96%
11 ee =81-95%

Scheme 1.4. Enders’s asymmetric phospha-Michael reaction to nitroalkenes.
Reagents and conditions: (a) 1.3 eq. PCl
3
/Et
3
N, THF, 0
o
C; (b) H
2
O/Et
3

N, THF, 0
o
C)
(R,R)-9, TMEDA, Et
2
Zn, -78
o
C; (d) TMSCl, NaI, CH
3
CN, reflux; (e) DCM/H
2
O, r.t.

Enders and co-workers
18
reported an asymmetric phospha-Michael reaction to
nitroalkenes in the presence of Et
2
Zn and N,N,N’,N’-tetramethylenediamine
(TMEDA). The phosphorus nucleophile 10 was easily synthesized from TADDOL (9)
and PCl
3
in excellent yield (Scheme 1.4). The C
2
-symmetry of the ligand avoided the
formation of a new stereogenic center at phosphorus. TMEDA played an essential
Chapter 1


6

role to greatly improve the solubility of the organozinc-phosphorus compounds,
which was reactive but insoluble. The addition of TMEDA made the reaction possible
even at -78
o
C with higher de values. This reaction was proven to be high yielding
(86–91 %) and a high stereoselectivity (84–96 % de) was also achieved. Moreover,
diastereomerically pure products could be obtained easily by recystallization or
preparative HPLC. The adducts could finally be converted into the phosphonic acid
without racemization.

The same group
19
used the phosphonate 10 to carry out the asymmetric addition of
acceptor 13 under heterogeneous conditions, Fe
2
O
3
mediated KOH (Scheme 1.5). No
reaction was observed when only KOH was used in the absence of metal oxide, which
indicated that the presence of the solid support was essential for the activation of the
P-H bond towards deprotonation. The phosphonates 16 were obtained in moderate to
good yields and with very good diastereoselectivities. The auxiliary was easily
cleaved without detectable epimerization or racemization to give compound 15, by
refluxing the addition products in MeCN in the presence of TMSCl/NaI and
subsequently hydrolyzing the resulting silyl ester. Due to their high polarity, 15 were
first converted into their respective methyl esters in order to facilitate their
purification. Although alkyl-substituted malonates showed even higher reactivity
leading to improved yields (85–87%), unsatisfactory ee values were obtained (15–30
%).
Haynes, Yeung and co-workers

20
reported the conjugate addition reaction of
configurationally stable lithiated P-chiral tert-butyl(phenyl)phosphine oxide 17 with
α,β-unsaturated carbonyl compounds (Scheme 1.6). Whereas aldehydes exclusively
underwent 1,2-addition, the cyclic enones 18 and 19 and the unsaturated esters 22a–c
yielded the 1,4-addition products 20, 21 and 23a–c, respectively, with moderate to
Chapter 1


7
excellent diastereoselectivities. It should be noted that this reaction proceeded with
retention of configuration at the phosphorus center.
O
O
Me
Me
O
P
O
O
H
Ph
Ph
Ph
Ph
10 16
,(84-94%ee)
CO
2
Me

P
R
O
MeO
MeO
O
O
Me
Me
O
P
O
O
Ph
Ph
Ph
Ph
R
CO
2
Me
CO
2
Me
a
64-75 %
R
CO
2
Me

CO
2
Me
13
CO
2
Me
b,c
CO
2
H
P
R
O
HO
HO
CO
2
H
d
72- 86 %
(2 steps)
14
,(82-94%de)
15
R=
Me
MeO
MeO
OMe

O
O

Scheme 1.5. Enders’s asymmetric phospha-Michael reaction under heterogeneous
conditions. Reagents and conditions: (a) Fe
2
O
3
/KOH, DCM, rt; (b) TMSCl, NaI,
MeCN, reflux; (c) DCM/H
2
O; (d) CH
2
N
2
, MeOH/H
2
O.

Helmchen and co-worker
21
utilized Ph
2
PLi for the addition to (–)-(1R)-tert-butyl
myrtenate (24) (Scheme 1.7). The reaction proceeded smoothly and
diastereoselectively to give 25, which was further transformed to the phosphine ligand
27 in 4 steps. This ligand was then employed in palladium-catalyzed asymmetric
allylic alkylation reactions with the cyclic substrates 28. Good yields of the
substitution products along with good to excellent enantioselectivities were easily
achieved in the case of six- and seven-membered rings.

Chapter 1


8
P
O
H
t
Bu
Ph
1. LDA or nBuLi
2.
O
n
18
: n =1
19: n =2
17
P
O
t
Bu
Ph
O
n
P
O
H
t

Bu
Ph
1. LDA or nBuLi
2.
17
P
O
t
Bu
Ph
23
R
O
OMe
22a
:R=H
22b:R=Ph
22c
:R=Me
R
OMe
O
20 or 21
P
O
t
Bu
Ph
O
20 78%, 96% de 21 81%, 96% de

P
O
t
Bu
Ph
O
P
O
t
Bu
Ph
23a
:63%
H
OMe
O
P
O
t
Bu
Ph
23b
:78%,82%de
Ph
OMe
O
P
O
t
Bu

Ph
23c
:67%,54%de
Me
OMe
O

Scheme 1.6. Haynes’s conjugate addition reaction of P-chiral tert-
butyl(phenyl)phosphine oxides.

CO
2
t
Bu
CO
2
H
PPh
2
CO
2
t
Bu
PPh
2
CO
2
H
PPh
2

BH
3
24
X
n
MCH(CO
2
R)
2
PdL
*
L=
27
n
CO
2
R
CO
2
R
28 29
n =1-3;X=Cl,OAc;R=Me,
t
Bu; M = Li, N a
yield: 73-93%; 70 - >99% ee
27
25
26, overall 54% yield
a
b

c

Scheme 1.7. Helmchen’s stereoselective addition of lithiated phosphines. Reagents
and conditions: (a) Ph
2
PH/BuLi (1.8 euqiv.), THF, -78
o
C, 3h, then Na
2
SO
4
.
10H
2
O;
(b) i BH
3
.
THF, -50
o
C; ii CF
3
CO
2
H, then NaOH, 90%; iii NaH, THF, 25
o
C,
BH
3
.

THF, -78
o
C, 1N HCl; (c) DABCO, 1.1 eq., 100
o
C, 1h.

Feringa and co-workers
22
presented the Michael reaction of lithio-
Chapter 1


9
diphenylphosphine to γ-butenolides (Scheme 1.8). The reaction with methoxy-2(5H)-
furanone (30a) furnished the lactone (31) in high yield and with high
diastereoselectivity in favor of trans-isomer. Moreover, using the enantiomerically
pure butenolide synthon (5R)-menthyloxy-2(5H)-furanone 30b, the asymmetric
Michael addition of lithio-diphenylphosphide followed by trapping the intermediate
with chlorodiphenylphosphine to afford lactone 32 as a single diastereoisomer. The
enantiomerically pure (S,S)-CHIRAPHOS 33 was obtained from 32 in an overall yield
of 35%.
O
O
OMe
Ph
2
PLi; H
3
O
+

74 %
O
O
OMe
Ph
2
P
O
O
OR
30b
:R=
iPr
Me
30a
31
1. LiPPh
2
2. Ph
2
PCl
O
O
OR
Ph
2
P
Ph
2
P

1. LiAlH
4
;2.TsCl/Py;3.LiAlH
4
PPh
2
Ph
2
P
32 33
35% overall yield

Scheme 1.8. Feringa’s Michael reaction of lithio-diphenylphosphine to γ-butenolides.

Phosphine-boranes can react as nucleophiles like their analogs of the
corresponding secondary phosphines which are unstable in air. Such phosphorus
nucleophiles are usually uncommon, since their synthetic method (prepared by
complexation of phosphines and boranes) involved handling of highly corrosive and
air-sensitive phosphines.
Corre and co-workers
23
used an in-situ protocol for the synthesis of phosphine-
boranes 34 from diphenylphosphine oxides (Scheme 1.9). The borane moiety can be
regarded as a protecting group, because it prevents oxidation of the phosphorus atom
and its cleavage can be easily achieved in the presence of an excess of a highly
Chapter 1


10
nucleophilic amine. 34 was shown to be applicable in NaH-catalyzed Michael

reactions to the biselectrophile 35. Although 35 was reacted as a mixture of E/Z
isomers, a single diastereomer 36c was obtained from the reaction of Ph
2
P(BH
3
)Na
and 35 in THF. On the other hand, the utilization of a stoichiometric amount of KOH
yielded both diastereoisomers 36a and 36b, which could be separated by
crystallization.
P
O
H
Ph
Ph
LiAlH
4
,NaBH
4
,CeCl
3
65 %
P
H
Ph
Ph
BH
3
34
O
O

Me O
2
C
Me O
2
C
Me
Me
34,NaH,THF
-30 to 0
o
C
50 %
O
O
Me O
2
C
Me O
2
C
Me
Me
PPh
2
PPh
2
BH
3
BH

3
E/Z-35
36c
O
O
Me O
2
C
Me O
2
C
Me
Me
PPh
2
PPh
2
BH
3
BH
3
O
O
Me O
2
C
Me O
2
C
Me

Me
PPh
2
PPh
2
BH
3
BH
3
+
34,KOH
MeOH, 0
o
C
36a (46%) 36b (14%)

Scheme 1.9. Corre’s stereoselective addition of Phosphine-borane complex to
biselectrophile 37.

Quirion and co-workers
24
described a diastereoselective synthetic route to obtain
chiral amidophosphonates. The nucleophilic attack of lithiated 34 occured from the Si
face to give the tertiary phosphine-boranes 38 in moderate yields and diastereomeric
excesses (Scheme 1.10).

Chapter 1


11

P
H
Ph
Ph
BH
3
1. nBuLi
R
H
N
O Ph
OH34
37a:R=Me
37b
:R=Et
37c
:R=
i
Pr
37d:R=Ph
P
Ph
Ph
BH
3
R
H
N
O
OH

Ph
P
Ph
Ph
BH
3
Me
H
N
O
OH
Ph
38a: 61%, 68% de
P
Ph
Ph
BH
3
Et
H
N
O
OH
Ph
38b:62%,74%de
P
Ph
Ph
BH
3

iPr
H
N
O
OH
Ph
38c: 75%, 64% de
P
Ph
Ph
BH
3
Ph
H
N
O
OH
Ph
38d: 76%, 45% de
2.

Scheme 1.10. Quirion’s diastereoselective synthetic route to chiral
amidophosphonates.

R
1
P
OH
O
H

TMSCl, Et
2
i
PrN
CH
2
Cl
2
,0
o
C to r.t., 3h
PR
1
OTMS
OTMS
39a
:R
1
= BnCH(NHAc)
39b:R
1
= naphthyl
39c:R
1
=Ph(CH
2
)
2
Bn
O

N
O
O
R
2
41a
:R
2
=Bn
41b:R
2
=Ph
2
CH
Bn
O
N
O
O
R
2
P
HO
O
R
1
42a-f
Product yield (%)
R
/

S
42a:R
1
= BnCH(NHAc), R
2
=Bn 94 3:1
42b:R
1
= Bn CH(NHAc), R
2
=Ph
2
CH 90 86:1
42c
:R
1
= naphthyl, R
2
=Bn 78 5:1
42d
:R
1
= naphthyl, R
2
=Ph
2
CH 73 55:1
42e
:R
1

=Ph(CH
2
)
2
,R
2
=Bn 91 12:1
42f:R
1
=Ph(CH
2
)
2
,R
2
=Ph
2
CH 90 54:1
O
N
O
O
R
2
P
TMS
O
R
1
TMSO

H
+
Transition State model:
43a-f
40
0
o
Ctor.t.,24h
EtOH, -10
o
C, 30min
Scheme 1.11. Ebetino’s asymmetric Michael addition of phosphinic and
aminophosphinic acid.

An asymmetric Michael addition of phosphinic and aminophosphinic acid have
been developed by Ebetino and co-workers
25
. The phosphinic acids 39a-c were first
Chapter 1


12
treated with TMSCl and transformed into the corresponding bis(trimethylsilyl)
phosphinites 40a–c. These compounds were then reacted with the enantiopure
acrylimides 41a, b yielding the addition products 42a–f. These enol ethers were
assumed to adopt the Z configuration as depicted 43. A diastereoselective protonation
process employing EtOH finally yielded the desired products phosphinic acids 42a–f
in very good yields. The diphenylmethyl-substituted oxazolidinone 41b gave much
better diastereoselectivities than its benzyl analogue 41a. The auxiliary could be
cleaved successfully using LiOH (Scheme 1.11).

1.1.2 Metal-catalyzed asymmetric phospha-Michael reactions.
The phospha-Michael addition of secondary phosphines was conducted via
organonickel complex catalyst.
26
A range of phosphines 44 were tested. Higher steric
hindrance led to a better result (46e, 95% yield, 94% ee), albeit longer reaction time
was required (Scheme 1.12).
R
2
PH +
CN
[(Pigip hos)Ni(THF)]( X)
2
CN
R
2
P
(R)-(S)-Pigiphos = P
Fe
Fe
PPh
2
Ph
2
P
44a-e
CN
P
Cy
Cy

CN
P
Ph
Ph
CN
P
i
Pr
i
Pr
CN
P
t
Bu
t
Bu
CN
P
Ad
Ad
46a
:8h71%yield70%ee
46b
: 24h 10%yield 3 2% ee
46c
:24h70%ee
46d
: 8h 87%yield 89% ee
46e
: 96h, 95%yield 94% ee

46a-e
45

Scheme 1.12. Organonickel complex catalyzed enantioselective phospha-Michael
addition of secondary phosphines.

1.1.3 Organocatalyst catalyzed asymmetric phospha-Michael reactions.
Recently, Melchiorre and co-workers
27
reported an organocatalytic asymmetric
Chapter 1


13
hydrophosphination of nitroalkenes. A bifunctional Cinchona alkaloid catalyst 47
provided a new organocatalytic strategy for the enantioselective addition of
diphenylphosphine to a wide range of nitroalkenes, yielding optically active β-
nitrophosphines. Considering the instability of phosphine adducts, a sequential one-
pot formation of the air-stable phosphine-borane complex derivative 49a-e facilitated
the purification process (Scheme 1.13). Due to the background reactions, only
moderate enantioselectivities (highest 67% ee) were observed. The synthetic potential
of this method was evaluated, affording the enantiopure aminophosphine 50 (ee of
49a was improved to 99% through a single crystallization), which could be a
potentially useful class of P, N-ligands.
(Ph)
2
PH +
Ph
NO
2

Cinchona alkaloid cataly st
=
Et
2
O-IPA 9:1, -40
o
C
Ph
NO
2
PPh
2
48a 86% yield , 67 % ee
HCOOH
NaBH
4
THF/-40
o
C
30 mi n
Ph
NO
2
P
BH
3
Ph
Ph
Catalyst 47
1. NiCl

2
.
6H
2
O
NaBH
4
,MeOH
-10
o
Ctor.t.
2. Boc
2
O, r.t.
Ph
NHBoc
P
BH
3
Ph
Ph
50 95% yield, 99 % ee
N
HN
N
MeO
SHN
F
3
C CF

3
47
NO
2
P
BH
3
Ph
Ph
Me
NO
2
P
BH
3
Ph
Ph
F
NO
2
P
BH
3
Ph
Ph
S
NO
2
P
BH

3
Ph
Ph
OBn
49e 90% yield, 60% ee
37 % yield, 99% ee
af ter crystallization
49b 67% yield, 52% ee
49c 83 % yield, 45% ee
24 % yield, 99% ee
after crystallization
49d 71% yield, 36% ee
49a
36 % yield, 99% ee (crystallization)

Scheme 1.13. Melchiorre’s organocatalytic asymmetric hydrophosphination of
nitroalkenes.

Melchiorre
28
and Cordova
29
published an asymmetric hydrophosphination of α,β-
Chapter 1


14
unsaturated aldehydes by the protected diarylprolinol on the same issue of Angew.
Chem. Int. Ed. independently. The former group employed the chiral pyrrolinol
derivative salts 50 as catalyst, affording the 1,4-addition products exclusively along

with up to 94% ee. Furthermore, an enantioenriched aminophosphine 54 was
synthesized to demonstrate the synthetic utility (Scheme 1.14A). Comparable results
were achieved by the latter group. In this case, the same catalyst 50 with different
anion was utilized. A β-phosphine oxide acid 55 was obtained from 52 through
oxidation by NaClO
2
(Scheme 1.14B).
O
R
+Ph
2
H
N
H
Ar
OTMS
Ar
Ar = 3,5
-
(CF
3
)
2
C
6
H
3
50
R
O

PPh
2
CH
3
CO
2
H
NaBH
4
THF, -40
o
C
30 min
R
OH
P
Ph BH
3
Ph
51a:R=Ph
51b
:R=Me
51c
:R=2-furyl
51d:R=oCl-C
6
H
4
50
.

p-NO
2
C
6
H
4
CO
2
H
Et
2
O
53a: 72% yield, 94% ee
53b: 60% yield, 84% ee
53c: 64% yield, 90% ee
53d
: 62% yield, 81% ee
52a-d
52a
1. BnNH
2
/NaBH
4
toluene
2. CH
3
CO
2
H, NaBH
4

Ph N
H
P
Ph BH
3
Ph
Ph
O
R
+Ph
2
H
R
O
PPh
2
CH
3
CO
2
H
NaBH
4
MeOH, 0
o
C
5min
R
OH
P

Ph BH
3
Ph
51a:R=Ph
51e
:R=4-ClC
6
H
4
50
.
2-f luorobenzoic acid
CHCl
3
,4
o
C
53a: 85% yield, 83% ee
53e: 79% yield,92% ee
52a, e
52e
NaClO
2
R
P
COOH
Ph
OPh
54 71% yield, 87% ee
55 65% yield, 92% ee

A
B
Scheme 1.14. Proline derivatives catalyzed hydrophosphination of α,β-unsaturated
aldehydes.

Wang and co-workers
30
developed the enantioselective conjugate addition of
diphenyl phosphonate to various nitroolefins catalyzed by quinine (56). The substrates
Chapter 1


15
included acceptors derived from aromatic, hetero-aromatic and aliphatic aldehydes.
To increase the level of ee, the reaction temperature was decreased to -50
o
C, and
moderate to good results were observed (45 – 88% ee). However, fairly long reaction
time (6 days) was required (Scheme 1.15).
+
R
NO
2
P
OPh
OPh O
H
10 mol% catalyst
56
xylene, -55

o
C
P
OPh
OPh O
R
NO
2
56
=
N
HO
H
N
MeO
H
Quinine
P
NO
2
OPh
OPhO
57a: 82% yield, 70% ee
P
NO
2
OPh
OPhO
57b: 85% yield, 77% ee
F

P
NO
2
OPh
OPhO
57c: 78% yield, 75% ee
MeO
P
NO
2
OPh
OPhO
57d: 79% yield, 88% ee
S
P
NO
2
OPh
OPhO
57e: 77% yield, 45% ee
P
NO
2
OPh
OPhO
57f: 62% yield, 60% ee
57

Scheme 1.15. Quinine catalyzed enantioselective conjugate addition of diphenyl
phosphonate to nitroolefins.

Terada and co-workers
31
demonstrated the highly enantioselective 1,4-addition
reaction of nitroalkenes with diphenyl phosphonate catalyzed by an axially chiral
guanidine 58. In order to obtain good results (85 – 97% ee), the reactions were
conducted under low reaction temperature (-40
o
C). More importantly, the low
catalyst loading (1 to 5 mmol %) did not affect the reaction rate (0.5 to 7h) and
chemical yields (84 to 98%). A broad range of nitroalkenes, bearing not only aromatic
but also aliphatic substituents, was applied to obtain enantioenriched products. β-
Chapter 1


16
amino phosphonate derivative 59 of biological and pharmaceutical importance was
synthesized without loss of the enantiopurity (Scheme 1.16).
+
R
NO
2
R
P
NO
2
OPh
OPhO
P
OPh

OPhO
H
(R)-58 (1mol%)
tert-butyl met hyl ether
-40
o
C, 0.5 to 7 h
Ph
P
NHBoc
OPh
OPhO
57a
NiCl
2
,NaBH
4
,Boc
2
O
MeOH/CF
3
CH
2
OH = 10/1
r.t. , 3.5 h 77% yield
59
N
N
Ar

Ar
N
G
H
H
58:G=Ph
2
CH-, Ar = 3,5-
t
Bu
2
C
6
H
3
-
P
NO
2
OPh
OPhO
57a: 94% yield, 92% ee
P
NO
2
OPh
OPhO
MeO
57c: 91% yield, 91% ee
P

NO
2
OPh
OPhO
Br
57g: 97% yield, 91% ee
P
NO
2
OPh
OPhO
NO
2
57h: 96% yield, 97% ee
P
NO
2
OPh
OPhO
O
57i: 79% yield, 89% ee
P
NO
2
OPh
OPhO
57f: 87% yield, 85% ee
57

Scheme 1.16. Terada’s guanidinine catalyzed 1,4-addition reaction of nitroalkenes

with diphenyl phosphonate.

1.2 Asymmetric hydrophosphonylation of imines
The hydrophosphonylation of imines afforded a method for construction of P-C
bonds,
32
which is usually promoted by metal complex
33
or base
34
.
1.2.1. Chiral starting materials and chiral auxiliaries assisted asymmetric
hydrophosphonylation of imines.
Smith and co-workers
35
reported the synthesis of a series of α-amino
phosphonates with high optical purities. Lithium diethyl phosphonate (LiPO
3
Et
2
) was
Chapter 1


17
found to afford a fast reaction with chiral imines derived from corresponding
enantiopure amine and aldehydes (Scheme 1.17). Moderate to good yields (36 – 81%)
and high diastereoselectivites (95 – 98% de) were observed when imine 60 derived
from aliphatic aldehydes were employed. However, the phenyl aldimine 61e only
yielded 76% de adducts. The chiral directing groups were removed and α-amino

phosphonates 62a-e were obtained without great loss of enantiomeric purity. A
transition state was proposed that the chelation of the lithium cation by the ether
oxygen and imine nitrogen created a rigid, five-membered ring. The phosphite anion
attacked from the Re face to generate R,R diastereomers.
R
N
CH
2
OMe
Ph
LiPO
3
Et
2
THF
R
P( OEt)
2
HN
O
Ph
CH
2
OMe
H
2
Pd(OH)
2
R P( OEt)
2

NH
2
O
61a
R = Cy 68 % yield 95% de
61b R = CyCH
2
70%yield98%de
61c R=
i
B u 81 % yield 98% de
61d
R=BnOCH
2
36% yield 96% de
61e
R=Phyield90%76%de
60 62a
96% ee
62b >9 9% ee
62c
> 99% ee
62d >9 8% ee
62e 71% ee
Li
O
N
H
R
H

Me
PO
3
Et
2
reface
63
selected ex amples:

Scheme 1.17. Smith’s synthesis of a series of α-amino phosphonates with high optical
purities.

Evans and co-workers
36
designed a synthetic approach to α-amino phosphonic
acids involving the addition of metallo phosphites to enantiomerical enriched
sulfinimines derived from sulfinate (Scheme 1.18). Two sulfinimines were tested (64a
Ar = Ph, 64b Ar = p-MeOPh) and up to 93% and 97% ee were obtained, respectively.
The major diastereisomer was purified after the desulfinylaion reaction was carried
out by using CF
3
CO
2
H and no epimerization of carbon chiral center was observed.
Chapter 1


18

p-Tol

S
N
O
Ar
H
(RO)
2
POM
THF, -78
o
C
H
N
S
(RO)
2
P
O
Ar
p-Tol
O
CF
3
CO
2
H
NH
2
(RO)
2

P
O
Ar
65a R=Et,Ar=Ph
65b
R=iPr, Ar = p-MeO Ph
64
66
NH
2
(RO)
2
P
O NH
2
(RO)
2
P
O
OMe
66a 93% ee 66b 97% ee

Scheme 1.18. Evans’s synthetic approach to chiral α-amino phosphonic acids.


1.2.2 Metal-catalyzed hydrophosphonylation reaction of imines
R
1
H
N

R
2
+
MeO
P
O
OMe
H
(R)-LPB
67
THF, - 15
o
C, 24h
R
1
P
HN
R
2
O
OMe
OMe
68
yield 27 - 87%
ee 49 - 96%
R
1
=alkyl
O
O

O
O
O
O
La
K
K
K
(R)-LPB67 =
68a
10 mol% (R)-LPB
67
70% yield, 96% ee
R
1
P
NH
O
OMe
OMe
OMe
Me O
R
1
P
NH
O
OMe
OMe
Ph

Ph
68b
5mol%(R)-LPB
67
82% yield, 92% ee

Scheme 1.19. Lanthanum-potassium-BINOL complex catalyzed hydrophosphination
of imines.

The first catalytic enantioselective example of hydrophosphonylation reaction of
imines was achieved by Shibasaki and co-workers.
37
Catalyst lanthanum-potassium-
Chapter 1


19
BINOL complex (R)-LPB 67 was found to be more effective than lanthanum-lithium-
BINOL complex. The best result 96% ee was given in 70% yield. A lower electron
density for product nitrogen could improve the catalyst turnover. 68b was obtained
with lower catalyst loading (5 mol%) and 92% ee was observed albeit 143 h was
required (scheme 1.19).
R
N
H
Ar
+
MeO
P
O

OMe
H
N N
t
Bu
t
Bu
t
Bu
t
Bu
O O
Al
Cl
69
(10 mol%)
70
THF, -15
o
C, 24 h
R
P
HN
OMe
O
OMe
Ar
Ar =
O
70

P
HN
OMe
O
OMe
O
anodic oxidation
MeOH /H
2
O, 0
o
C, 5 h
P
NH
2
OMe
O
OMe
70a 87% ee 71 72% yield
R
1
H
O
A and B
THF, r.t. 3 - 4 h
HP
O
OMe
OMe
69 (10 mol%)

THF, - 15
o
C, 24 h
R
1
P
HN
R
2
O
OMe
OMe
72
P
HN
OMe
O
OMe
Ar
70a
90% yield 87% ee
P
HN
OMe
O
OMe
Ar
Br
70b
>99% yield 95% ee

70c
>94% yield 69% ee
P
HN
OMe
O
OMe
Ar
O
A
H
2
N OMe
B
Ph
Ph
NH
2
P
HN
O
OMe
OMe
72a
28% yield 88% ee
OMe
P
HN
O
OMe

OMe
OMe
72b
84 % yield 94% ee
P
NH
O
OMe
OMe
Ph
Ph
Ph
72c
51% yi eld 15% ee

Chapter 1


20
Scheme 1.20. Enantioselective hydrophosphonylation of various aldimines with
Aluminum complex 69.
Katsuki and co-workers
38
demonstrated that Aluminum complex 69 was an
efficient catalyst for enantioselective hydrophosphonylation of various aldimines with
dimethyl phosphonate (Scheme 1.20). High yields and high enantioselectivities were
observed with the aromatic derived aldimines with N-protecting group 4-methoxy-3-
methylphenyl, which could be successfully deprotected to give the corresponding
amine in a good yield without loss of enantiopurity. The reaction of aliphatic
aldimines were conducted under condensation of aliphatic aldehydes and amines (A

or B) followed by the subsequent hydrophosphonylation in one pot.
Shibasaki and co-workers
39
reported the first enantioselective catalytic approach
to cyclic α-amino phosphonates by the hydrophosphonylation of cyclic imines in the
presence of heterobimetallic lanthanoid complex 73 (Scheme 1.21). The
pharmaceutically interesting (S)-4-thiazolidinylphosphonate 75 was obtained in
excellent optical purities of up to 95% ee.
O
O
O
O
O
O
Yb
K
K
K
N
S
H
3
C
H
3
C
CH
3
CH
3

HP
OMe
O
OMe
+
(R)-YbPB 73 (5 mol%)
THF/Toluene (1:7), 50
o
C, 4 8 h
NH
S
H
3
C
H
3
C
CH
3
CH
3
(MeO)
2
P
O
75 88% yield, 95% ee74
P=potassium;B=(R)-(+)-binaphthol
Scheme 1.21. Heterobimetallic lanthanoid complex 73 catalyzed
hydrophosphonylation of cyclic imines.

Chapter 1


21
1.2.2 Organocatalytic hydrophosphonylation of imines
Jacobsen and co-workers
40
described a general and convenient access to a wide
range of highly enantiomerically enriched α-amino phosphonates from N-
benzylimines 77 and di-(2-nitrobenzyl) phosphonate using chiral thiourea 76 (Scheme
1.22). The depronation of these products under mild conditions yielded the
corresponding α-amino phosphonic acids 79 without any loss of enantiopurity.
P
O
H
O
O
Ar
Ar
+
R
H
N Ph
76
(10 mol%)
Et
2
O
N
N

H
N
H
St-Bu
N
O
Me
Me
HO
Ot-Bu t-Bu
O
P
O
O
O
Ar
Ar
R
HN Ph
H
2
,Pd/C P
O
HO
HO
R
NH
2
78
18 examples

52 - 93% yield
81 - 99%
ee
77
Ar =
o-NO
2
C
6
H
4
P
O
O
O
Ar
Ar
Ph
HN Ph
78a 87% yield 98% ee
P
O
O
O
Ar
Ar
HN Ph
78b 90% yield 9 6% ee
79a 87% yield 97% ee
79b

89% yi eld 96%
ee
selected e xa mples
Scheme 1.22. Jacobsen’s chiral thiourea catalyzed hydrophosphination of imines.

Akiyama and co-workers
41
reported a chiral Brønsted acid, derived from (R)-
BINOL, which catalyzed reaction of the hydrophophonylation of imines with
diisopropyl phosphonates leading to α-amino phosphonates in good to high
enantioselectivity. Aldimines 81f derived from cinnamaldehyde derivatives exhibited
high enantioselectivity (Scheme 1.23).
The authors proposed a reaction mechanism with a nine-membered transition state
(Figure 1.1), wherein phosphate plays two roles: (1) the phosphoric acid hydrogen, as
a Brønsted acid, activates the imine and (2) phosphoryl oxygen, as a Brønsted base,
activates the nucleophile by coordinating with the hydrogen of phosphite, thereby
Chapter 1


22
promoting Re facial attack to the imine was promoted and the enantioselectivity was
increased by proximity effect. As can be seen, the phosphoric acid 80 worked as a
bifunctional chiral Brønsted acid bearing both Brønsted acid and Brønsted basic sites.
P
O
H
i-PrO
i-PrO
+
R

H
N
OMe
10 mol% 80
m-Xylene
P
O
i-PrO
i-PrO
R
HN
OMe
82 72 - 97% y ield 52 - 90% ee
CF
3
CF
3
CF
3
CF
3
O
O
P
O
OH
81
se lected exmples:
P
O

i-PrO
i-PrO
HN
OMe
82a 8 4% yield 52% ee
P
O
i-PrO
i-PrO
HN
OMe
82b 76%yield 69% ee
Me
P
O
i-PrO
i-PrO
HN
OMe
82c 7 2%y ield 77% ee
NO
2
P
O
i-PrO
i-PrO
HN
OMe
82d 92% yield 84% ee
P

O
i-PrO
i-PrO
HN
OMe
82e 9 7%y ield 84% ee
Cl
P
O
i-PrO
i-PrO
HN
OMe
82f 86%yield 9 0% ee
CF
3

Scheme 1.23. Akiyama’s chiral Brønsted acid catalyzed hydrophophonylation of
imines.
O
O
P
O
O
H
H
O
N
Ar
H

P
OR
OR
CF
3
CF
3
F
3
C
CF
3
Ar

Chapter 1


23
Figure 1.1. Plausible reaction mechanism of chiral phosphoric acid catalyzed
hydrophophonylation of imines.
Pettersen and co-workers
42
provided a straightforward and novel organocatalytic
approach for hydrophosphonylations of imines using commercially available quinine
as the catalyst and diethyl phosphonate as the nucleophile. This simple protocol which
led to the synthesis of α-amino phosphonates in good yield and with up to 94% ee,
made this asymmetric transformation practically important and extended the
generality of catalytic enantioselective hydrophosphonylations (Scheme 1.24).

N

HO
H
N
MeO
H
P
O
H
EtO
EtO
+
R
H
NBoc
10 mol% Quinine
-20
o
C, Xylene
P
O
EtO
EtO
R
NHBoc
83
56
P
O
EtO
EtO

NHBoc
83a
52 % yield 88% ee
P
O
EtO
EtO
NHBoc
83b
69% yield 92% ee
P
O
EtO
EtO
NHBoc
83c
61% yield 94% ee
Me
P
O
EtO
EtO
NHBoc
83d
62% yield 93% ee
Me
P
O
EtO
EtO

NHBoc
83e
57% yield 94% ee
OMe
P
O
EtO
EtO
NHBoc
83a
62 % yield 89% ee
Cl

Scheme 1.24. Pettersen’s hydrophosphonylations of imines using quinine.
Chapter 1


24
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