Organocatalytic enantioselective hydrophosphonylation of sulfonylimines having a heteroarenesulfonyl group as a novel stereocontroller

Article abstract of DOI:10.1002/adsc.200800134

Organocatalytic enantioselective hydrophosphonylation of imines having the a heteroarenesulfonyl group afforded the respective products with high enantioselectivity. Both enantiomers of α-amino phosphonates were obtained by using different Cinchona alkalo

Full text of DOI:10.1002/adsc.200800134

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DOI: 10.1002/adsc.200800134
Organocatalytic Enantioselective Hydrophosphonylation of
Sulfonylimines having a Heteroarenesulfonyl Group as a Novel
Stereocontroller
Shuichi Nakamura,a,* Hiroki Nakashima,a Akiko Yamamura,a Norio Shibata,a
and Takeshi Torua,*
a
Department of Applied Chemistry, Graduate School of Engineering, Nagoya Institute of Technology, Gokiso, Showa-ku,
Nagoya 466-8555, Japan
Fax : (+81)-52-735-5442; e-mail: snakamur@nitech.ac.jp or toru@nitech.ac.jp
Received: March 4, 2008; Published online: May 16, 2008
Supportinginformation for this article is available on the WWW under http://asc.wiley-vch.de/home/.
Abstract: Organocatalytic enantioselective hydro-
phosphonylation of imines havingthe a heteroare-
nesulfonyl group afforded the respective products
with high enantioselectivity. Both enantiomers of a-
amino phosphonates were obtained by usingdiffer-
ent Cinchona alkaloids with up to 98% ee.
tional coordinative heteroarenesulfonyl groups to
control the conformations and reactivities by chela-
tion with chiral Lewis acids.[12] Herein, we report the
first organocatalytic enantiocomplementary hydro-
phosphonylation of sulfonyl
ACHTREUNG
mercially available pseudo
kaloids.
ACHTREUNG
Keywords: asymmetric synthesis; heteroarenesul-
fonyl group; hydrophosphonylation; organic cataly-
sis; stereocontroller
The enantioselective hydrophosphonylation reac-
tion of various sulfonylimines[13] with diethyl phos-
phite (1.5 equiv.) was carried out using10 mol% of a
variety of Cinchona alkaloids as organocatalysts
(Table 1). The reaction of N-p-methoxyphenyl- and
N-2-pyridylmethylimines (1a, b) with diethyl phos-
phite in the presence of quinine did not afford the
Optically active a-amino phosphonic acids and their products 2a, b (entries 1,2), whereas the reaction of
derivatives have proved to be useful buildingblocks
N-phenylsulfonyl-, N-p-tolylsulfonyl-, and N-(o-nitro-
for the preparation of pharmaceutical targets,[1] such phenylsulfonyl)imines (1c–e) gave the products (2c–e)
as the antibacterial agent alafosfalin,[2] anti-HIV in good yield but with low enantioselectivity (en-
agents,[3] inhibitors of enzymes[4] and peptidic materi- tries 3–5). On the other hand, the reaction of N-(2-
als havingunique structural properties. The diastereo-
pyridylsulfony)-, N-(6-methyl-2-pyridylsulfonyl)-, and
selective addition of phosphite derivatives to chiral N-(2-quinolylsulfonyl)imines 1f–h afforded the hydro-
imines[5] and chiral Lewis acid-catalyzed enantioselec- phosphonylated products 2f–h with good enantiose-
tive addition of phosphites to imines (aza-Pudovik re- lectivity (entries 6–8). The reaction of 1f with diethyl
action)[6,7] have been extensively investigated, whereas trimethylsilyl phosphite instead of diethyl phosphite
only a few studies exist on the organocatalytic enan- gave the racemic product 2f (entry 9). The reaction of
tioselective hydrophosphonylations of imines.[8] Jacob- 1f with diphenyl phosphite showed higher enantiose-
sen and his co-worker have reported highly enantiose- lectivity than with diethyl phosphite, although the re-
lective hydrophosphonylation usinga highly elaborat-
action of 1g with diphenyl phosphite showed slightly
ed thiourea catalyst prepared from a chiral diamine lower enantioselectivity (entries 10 and 11). Highly
and l-tert-leucine.[8a] Recently, Pettersen and co-work- reactive diphenyl phosphite can react with 1g at
ers have reported the organocatalytic enantioselective À408C for 1 h, and the reaction showed a marked in-
hydrophosphonylation of N-Boc-imines with diethyl crease in enantioselectivity (entry 12).[14] Performing
phosphite in the presence of quinine giving products optimization experiments with various organocata-
with good enantioselectivity after 2–7 days. However, lysts, the reactions with hydroquinine and hydroquini-
highly reactive N-tosylimines afforded products with dine were found to afford both enantiomers of 2j with
low enantioselectivity.[8c] Recently, we[10] and others[11] good enantioselectivity (entries 13-16, see also sup-
have reported enantioselective reactions usingbifunc-
portingInformation). The reaction usingacetylated
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Table 1. Enantioselective addition of phosphites to aldimines
1a–h usingvarious Cinchona alkaloids.
Table 2. Enantioselective hydrophosphonylation to aldi-
mines 1g, i–p usingvarious Cinchona alkaloids.
Entry 1
Ar
Cat. Product Yield
[%]
ee
[%][a]
Run
1
Catalyst
R2
2
Yield [%] ee[a] [%]
1[b]
2[b]
3[b]
4[b]
5
1g Ph
1i p-Tolyl
A
A
A
A
B
A
A
B
(S)-2j
(S)-3
(S)-4
(S)-5
(S)-6
(S)-7
(S)-8
(S)-9
(S)-10
98
97 (99)
92 (99)
94 (98)
85 (96)
81 (83)
87 (98)
82 (97)
92 (95)
85 (92)
1
2
3
4
5
6
7
8
1a Quinine
1b Quinine
1c Quinine
1d Quinine
1e Quinine
1f Quinine
1g Quinine
1h Quinine
1f Quinine
1f Quinine
1g Quinine
Et
Et
Et
Et
Et
Et
Et
Et
2a
2b
0
0
-
-
49
40
>99
>99
>99
>99
>99
>99
>99
>99
2c 68[b]
2d 65[b]
2e 62[b]
2f 98
1j p-MeOC6H4
1k o-MeOC6H4
1l m-MeOC6H4
1m p-ClC6H4
1n 1-Naphthyl
1o 2-Naphthyl
1p trans-Cin-
namyl
30
6[b]
7[b]
8
65 (S)
64 (S)
51
2g 98
2h 70
9
10
11
Et[c] 2f 90
0
9
B
Ph
Ph
Ph
Ph
2i 94
61 (S)
71 (S)
92 (S)
91 (S)
92 (R)
97 (S)
98 (R)
36 (S)
92 (S)
92 (S)
10[b] 1g Ph
C
C
C
C
C
C
C
C
C
(R)-2j 95
98 (99)
89 (97)
93 (92)
91 (98)
89 (93)
86 (99)
91 (99)
92 (96)
82 (92)
2j >99
2j >99
2j >99
2j >99
2j 98
2j 95
2j 50
12[d] 1g Quinine
11
1i p-Tolyl
(R)-3
(R)-4
(R)-5
(R)-6
(R)-7
(R)-8
(R)-9
>99
13[d] 1g Hydroquinine
12[b] 1j p-MeOC6H4
>99
>99
>99
>99
>99
>99
14[d] 1g Hydroquinidine Ph
13[b] 1k o-MeOC6H4
15[e] 1g Hydroquinine
Ph
14
1l m-MeOC6H4
16[e] 1g Hydroquinidine Ph
15[b] 1m p-ClC6H4
17[d] 1g Acetylquinine
18[d,f] 1g Quinine
19[d,g] 1g Quinine
Ph
Ph
Ph
16[b] 1n 1-Naphthyl
2j >99
2j >99
17
18
1o 2-Naphthyl
1p trans-Cin-
namyl
(R)-10 >99
[a]
The ee was determined by HPLC analysis.
Conversion yield.
[b]
[c]
[d]
[e]
[f]
[a]
[b]
The ee obtained after single recrystallization from
hexane/ethyl acetate is shown in parenthesis.
The reaction was carried out at À788C for 5–6 h.
TMSOP(OEt)2 was used as a phosphite.
A
The reaction was carried out at À408C for 1 h.
The reaction was carried out at À788C for 1 h.
Quinine (5 mol%) was used.
[g]
Under aerobic conditions.
tion. For example, recrystallization of 97% ee of (S)-
2j from hexane/ethyl acetate afforded enantiomeri-
cally pure (S)-2j in 76% yield (entry 1).
quinine had a decreased enantioselectivity (entry 17).
The catalyst loadingcould be reduced to 5 mol% in
Larger scale synthesis starting with 300 mg of 1g
also gave 97% ee and 99% yield of (S)-2j by simple
the case of quinine (entry 18). The reaction under filtration without purification (Scheme 1). Recrystalli-
aerobic conditions also afforded 2g in high yield with zation of the crude (S)-2j, followed by desulfonation
good enantioselectivity (entry 19).
afforded the optically pure a-amino phosphonate (S)-
A series of sulfonylimines 1g, i–p derived from aro- 11, which was converted to the highly optically pure
matic aldehydes all proved to be excellent substrates known a-amino phosphonic acid (S)-12. The optical
with respect to enantioselectivity and chemical yield purity of (S)-12 was confirmed after conversion to the
usingquinine or hydroquinine (Table 2, entries 1–8).
N-Cbz dimethylphosphonate derivative.[8a] The abso-
The reaction was completed within 1 h at À408C or lute configurations of other products 3–10 were tenta-
within 6 h at À788C. The sulfonylimine 1p havingan
unsaturated bond also afforded the product (S)-10
tively assigned by analogy.
The enantioselective hydrophosphonylation of N-
with high enantioselectivity (entry 9). Furthermore, (heteroarenesulfonyl)imines 1f–h gave products in
the reaction usinghydroquinidine afforded the oppo- good yield with good enantioselectivity, although the
site enantiomer of the products 2j, 3–10 with high reaction of N-(arenesulfonyl)imines 1c–e did not
enantioselectivity (entries 10–18). Since most of the afford good results. These results show that the
products were crystalline, enantiomerically pure sulfo- hetero
A
namides were easily obtainable by single recrystalliza- ingrgoup but also as an efficient stereocontroller.
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Organocatalytic Enantioselective Hydrophosphonylation of Sulfonylimines
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the active intermediate (RO)2POH over (RO)2P(=
O)OH in the presence of hydroquinine. Further stud-
ies are required to fully elucidate the mechanistic
detail of the hydrophosphonylation.
In conclusion, we found that the heteroarenesulfon-
yl group works as a good activating group of the
imino group in hydrophosphonylation. The first orga-
nocatalytic highly enantiocomplementary hydrophos-
phonylation of N-(heteroarenesulfonyl)imines was
achieved usinga catalytic amount of commercially
available organocatalysts. The 6-methyl-2-pyridinesul-
fonyl group was shown to be an easily removable, ef-
ficient protective group, having notable properties
such as high chiral inducibility and activation of the
imino group toward the addition of nucleophiles.
Scheme 1. Desulfonylation from (S)-2j.
Since protection of the hydroxy group in quinine de-
creases the enantioselectivity in comparison with the
reaction usingnon-protected quinine (Table 1, en-
tries 12 vs. 17), hydrogen bonding between the Cin-
chona alkaloid’s hydroxy group and (heteroarenesul-
fonyl)imines plays a key role in exertingenantioselec-
tivity. In addition, the reaction of 1g with diethyl
phosphite in toluene using10 mol% of isopropyl alco-
hol did not afford the product, whereas the reaction
with diethyl trimethylsilyl phosphite in the presence
of quinine afforded the racemic product (Table 1,
entry 8). These results imply that the nitrogen in Cin-
chona alkaloids, as a Brønsted base, activates phos-
phite by coordination with the acidic proton, and,
hence, Cinchona alkaloids act as dual activatingorga-
nocatalysts. From the above consideration, the as-
sumed transition state for the enantioselective hydro-
phosphonylation usinghydroquinine is shown in
Experimental Section
General Procedure for the Enantioselective
Hydro
A
(6-Methyl-2-pyridinesulfonylaminophenyl)methanephos-
phonate (2j)
To a solution of 1g (40 mg, 0.154 mol) and (À)-hydroquinine
(5.0 mg, 0.0154 mmol) in toluene (1.9 mL) was added di-
phenyl phosphite (39 mL, 0.200 mmol) at À788C. The reac-
tion mixture was stirred for 60 min. Water was then added
to the reaction mixture, and aqueous layer was extracted
with CHCl3. The combined organic extracts were dried over
Na2SO4, filtered, and concentrated under reduced pressure
to give the crude product which was purified by column
chromatography (silica gel, hexane/ethyl acetate=50/50) to
give 2j; yield: 73.9 mg(99%, 98% ee). A single recrystalliza-
Figure 1 on the basis that the equilibrium would favor tion of 2j (98% ee) afforded 99.4% ee for 2j.
Figure 1. Assumed transition state for the hydrophosphonylation of 1g.
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Shuichi Nakamura et al.
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This work was supported by the Yazaki Foundation, and the
Sankyo Award in Synthetic Organic Chemistry, Japan.
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