Diastereoselective Michael addition of 2H-2-oxo-1,4,2-oxaza phosphinanes to olefins

Article abstract of DOI:10.1016/j.tet.2010.10.078

Diastereoselective Michael additions of 2-hydrogeno-2-oxo-1,4,2- oxazaphosphinanes to olefins were described. Phosphinopeptide compounds were obtained in very good yield (up to 90%) and diasteromeric excesses ranging from 26 to 78%. Copyright

Full text of DOI:10.1016/j.tet.2010.10.078

Tetrahedron 67 (2011) 540e545
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Tetrahedron
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Diastereoselective Michael addition of 2H-2-oxo-1,4,2-oxaza phosphinanes
to olefins
ˇ
*
*
ꢀ
ꢀ ꢀ
€
Jerome Monbrun, Benedicte Dayde, Henri-Jean Cristau, Jean-Noel Volle, David Virieux , Jean-Luc Pirat
Institut Charles GerhardtdUMR5253dAM2NdENSCM, 8, Rue de l’Ecole Normale, F34296 Montpellier Cedex 5, France
a r t i c l e i n f o
a b s t r a c t
Article history:
Diastereoselective Michael additions of 2-hydrogeno-2-oxo-1,4,2-oxazaphosphinanes to olefins were
described. Phosphinopeptide compounds were obtained in very good yield (up to 90%) and diasteromeric
excesses ranging from 26 to 78%.
Received 17 September 2010
Received in revised form 22 October 2010
Accepted 26 October 2010
Crown Copyright Ó 2010 Published by Elsevier Ltd. All rights reserved.
Available online 12 November 2010
1. Introduction
the diastereoselective Michael addition for the preparation of
phosphinodipeptide analogs (Scheme 1).
As a part of our search for new biologically active compounds in
the field of human health or plant protection, we are interested in
introducing PeC-heteroatom framework into heterocyclic struc-
tures. According to literature, there are still a few general methods
for the formation or modification of phosphorus heterocycles.1a On
the other hand, aminophosphinic acids and their derivatives play
an important role as metal-complexing agents and have a range of
diagnostic and therapeutic applications (Fig. 1).1b
Ph
Ph
O
OH
N
R
R
P
CO2H
H2N
P
H2N
P
OH
Ph
N
OH
O
O
R'
O
Ph
Leucine aminopeptidase2a
Zinc peptidase2b
HIV-1 protease3 Atheroscleoris agent4
Scheme 1. Racemic 2H-2-oxo-1,4,2-oxazaphosphinane 1a for the preparation of
phosphinodipeptide analogs.
Fig. 1. Biologically active phosphinic derivatives.
Compound (ꢀ)-1a was chosen by the fact that this diastereomer
presents the three bulkiest groups on the same side of the reactive
PeH bond. Then, it could induce better diastereoselectivity on the
P-Michael addition process.
We described, in previous publications, the synthesis of a new
class of phosphorus heterocycles, the 2H-2-oxo-1,4,2-oxaza phos-
phinanes (ꢀ)-1a and (ꢀ)-1b bearing a reactive PeH bond and the
diastereoselective additions of 1a to aldehydes or imines, as well as
palladium catalysed P-arylations or P-vinylation.5aeh
2H-2-Oxo-1,4,2-oxaza phosphinanes 1a and 1b were syn-
thesised from the addition of methyl hypophosphite to a racemic
imino-alcohol followed by an intramolecular transesterification.
After the investigation of the reactivity of the major isomer (ꢀ)-1a,
which was isolated by preferential crystallization, in nucleophilic
additions on aldehydes and aldimides, we decided to investigate
2. Results and discussion
According to the previous publications,5c the reaction required
catalytic amounts of potassium tert-butoxide as base for the acti-
vation of the nucleophilic phosphorus site.
a-Substituted, b-
substituted, and cyclic olefins were used in order to investigate the
influence of steric hindrance on diastereoselectivity (Scheme 2,
Table 1). On this way, the proximity effect of the reactive pro-chiral
center conjugated to the bulky groups has been studied, as well as
the effect of the substituted olefin and rigid olefins on the Michael
diastereoselection addition.
* Corresponding authors. E-mail address: pirat@enscm.fr (J.-L. Pirat).
0040-4020/$ e see front matter Crown Copyright Ó 2010 Published by Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2010.10.078

J. Monbrun et al. / Tetrahedron 67 (2011) 540e545
541
The corresponding enantiopur imine was easily accessible
through the same reaction previously described for the racemic,5c
via condensation under drying agent (MgSO4) of benzaldehyde on
the commercial chiral (ꢁ)-(1R,2S) 2-amino-1,2-diphenylethanol
(yield¼80% after crystallization). Following, the heterocyclic phos-
phorus compounds, the 2H-2-oxo-1,4,2-oxaza phosphinanes
(þ)-(2R,3S,5S,6R)-1a was prepared by a similar way than its racemic
form and recovered pure by precipitationwith 30% yield (Scheme 4).
Scheme 2. Michael reaction of 1a to electron deficient olefins.
Table 1
Substitution effects of electron deficient olefins on diastereoselectivity of Michael reaction with 1a
Entry
R
R0
R00
Compounds (ꢀ)-(2R
*
,3S
*
,5S
*
,6R
*
)-2a
Yield
Isolated Yield
de
and -2b (
d
31P NMR, CDCl3)
1
2
3
4
5
6
7
8
9
Me
Bn
H
H
H
H
H
H
H
CO2Me
CO2Me
CO2Me
CO2Me
CO2Me
CO2Me
CN
2.1a (50.7), 2.1b (50.2)
2.2a (50.4), 2.2b (50.0)
2.3a (51.9), 2.3b (51.8)
2.4a (54.1), 2.4b (52.6)
2.5a (48.7), 2.5b (45.2)
2.6a (49.5), 2.6b (46.2)
2.7a (46.1), 2.7b (41.9)
2.8a (48.9), 2.8b (47.5)
2.9a (49.3), 2.9b (46.8)
98
82
90
91
91
98
99
97
94
75
60
68
60
70
70
84
76
68
26
32
54
50
70
64
70
78
70
Me
i-Pr
Ph
Tol
Ph
Cyclohexenone
5,6-Dihydro-2H-pyran-2-one
First of all, we noticed that reactions occurred in very good to
excellent yields (82e99%) and with complete retention of configu-
ration at the phosphorus atom.6 Indeed, only two diastereomers
were obtained which is consistent with the absence of epimeriza-
tion. New stereogenic centers, respectively, in a- and / or b-position
to phosphorus atom can be formed depending on the nature of R and
R0 substituents in diastereomeric excess ranging from 26 to 78%.
Diastereoselectivity was deeply influenced by the position of sub-
Scheme 4. Synthesis of the enantiopure oxazaphosphinane (þ)-(2R,3S,5S,6R)-1a.
The addition was made as described for the racemic compound
and led to a mixture of two diastereomers in 85/15 ratio (Scheme 5).
The major stereoisomer was isolated after column chromatography
on silica gel. The diastereoisomeric excess obtained during the Mi-
chael additions with (þ)-(2R,3S,5S,6R)-1a was identical to the ra-
cemic series (Table 2).
stituents on the olefins: whereas
2) gave poor diastereoselectivity with de about 30% even with the
larger benzyl group instead of methyl one, -substituted olefins
a-substituted olefins (entries 1 and
b
(entries 3e7) permitted to reach 50% de in aliphatic series (R¼Me,
i-Pr), and up to 70% from methyl (2E)-3-phenylacrylate (entry 5). In
the same time, cyclic substrates, such as cyclohexenone or lactone
(entries 8 and 9) gave, respectively, de equals to 78% and 70%, clearly
confirming that the restricted conformation has significant impact
on diastereoselectivity. Furthermore, we noticed that for acryloni-
trile (entry 7), diastereoselectivity was comparable to the ester.
Concomitantly with the formation of 2.1, two more compounds
Ph
O
P
O
P
methyl-cinnamate (2 eq.)
Ph
Ph
O
H
Ph
Ph
O
CO2Me
t-BuOK (0.2 eq.), -7°C-> r.t. (24h)
Yield = 92%, de = 70%
N
H
Ph
N
H
Ph
(+)-(2R,3S,5S,6R)-1a
(-)-2.5a, 2.5b
(
31PNMR:
d¼46.6and 46.2 ppm) were formedin20%yield when using
Scheme 5. Michael addition on the enantiopure methyl cinnamate (þ)-(2R,3S,5S,6R)-2.5.
0.13 equiv of potassium tert-butoxide instead of 0.08 equiv showing
a high sensitivity of the reaction to the quantity of base. Addition of
0.4 equiv increased the ratio of such compounds. In parallel, we
reproduced the reaction starting from the diastereomer (ꢀ)-1b and
methyl methacrylate (Scheme 3). Yield and diastereoselectivity (90%,
de¼30%) were similar to those observed with (ꢀ)-1a (97% yield,
de¼26%)and afforded diastereomeric adducts 3a and 3b. Then, mixing
the two reaction mixtures showed that side products formed from
(ꢀ)-1a corresponded to 3a and 3b clearly demonstrating a double
epimerisation both at carbon and phosphorus atom.
Table 2
Comparison of the additions for (þ)-(2R,3S,5S,6R)-1a and (ꢀ)-ulu-1a
2-H-[1,4,2]Oxazaphosphinane
NMR yield (%)
de (ratio)
(ꢀ)-(2R
*
,3S ,5S ,6R )-1a
*
*
*
99
92
70% (85/15)
70% (85/15)
(þ)-(2R,3S,5S,6R)-1a
3. Conclusion
In conclusion, we demonstrated the good reactivity of either
racemic or enantiopur 2H-[1,4,2]-oxazaphosphinane as a nucleo-
phile reagent in Michael addition to olefins activated by electron
withdrawing group (isolated yield >60%). Besides, we were able to
demonstrate its efficiency as asymmetric inductor for chiral center
newly created. This diastereoselectivity showed the interest of the
cyclic oxazaphosphinane structure during diastereoselective Mi-
chael additions on racemic or enantiopur oxazaphosphinane.
2.1. Synthesis of enantiopur oxazaphosphinanes
The study was done to quantify the diastereoselectivity with the
enantiopur oxazaphosphinane (þ)-(2R,3S,5S,6R)-1a instead of the
racemic.
4. Experimental
4.1. General
All reactions were carried out under nitrogen atmosphere
using Schlenk techniques. The solvents were dried using standard
Scheme 3. Michael addition of 1b to a-methyl methacrylate.

542
J. Monbrun et al. / Tetrahedron 67 (2011) 540e545
methods, distilled, and stored under nitrogen. Reactions were
monitored by 31P NMR using DMSO-d6 as internal references. Col-
umn chromatographies were performed on silica gel (Merck 60 AC.
990, 950, 810, 760, 700 cmꢁ1; HRMS m/z (MHþ) 450.1834 (calcd for
C26H28NO4P: 450.1830).
35e70 mm).
31P, 1H, and 13C NMR spectra were recorded on BRUKER AVANCE
250 and BRUKER AC-200 spectrometers. MS and HRMS were
recorded on a JEOL JMS DX-300 using NBA as matrix in FABþ ion-
ization mode. IR spectra were measured on a PerkineElmer 377
spectrometer.
4.2.2. (2S
-[1,4,2]oxazaphosphinan-2-yl)-methyl propionate. de¼26%.
Starting from 530 mg of (ꢀ)-1b (1.52 mmol, 1 equiv) and 243
of methyl methacrylate (2.28 mmol, 1.5 equiv) followed by 506
*
,3R
*
,5R
*
,6S
*
)-(ꢀ)-2-Methyl-3-(2-oxo-3,5,6-triphenyl-
2l 5
* *
4.2. General procedure
mL
L
m
At ꢁ5 ꢂC, under N2 and in a 20 mL flask containing 600 mg of
(ꢀ)-1a (1.72 mmol, 1 equiv), are added successively 14 mL of
of a solution of t-BuOK (0.6 M) in THF (0.3 mmol, 0.2 equiv). The
crude material recovered was purified by column chromatography
(hexane/ethyl acetate gradient: 30/70 to 0/100) to give a white solid
containing two diastereoisomers (512 mg, yield 75%).
dichloromethane, 200
1.1 equiv), and 230
mL of methyl methacrylate (1.89 mmol,
m
L of a solution of t-BuOK in THF (0.6 M,
0.14 mmol, 0.08 equiv). Under stirring, the solution returned
slowly to ambient temperature. A yellow tint appeared some
minutes after addition of the base. At the end of the process two
O
4
21
3
5
20
O
18
widely major compounds were obtained (d
31P: 2.1a 50.33 and 2.1b
19
O
2
O
12 P
1
23
22
15
50.77 ppm) with a ratio of 37/63 and 26% de. After addition of
water until reaching pH¼7, extraction with dichloromethane,
drying over Na2SO4, and evaporation of solvents under vacuum,
a white solid was recovered. Further, purification by column
chromatography on silica (hexane/ethyl acetate gradient: 70/30 to
0/100) gave a final white solid containing two diastereoisomers
(580 mg, 75% yield).
8
26
16
24
6
13
H11
9
N
7
14
25
4.2.3. (2R
*
,3S
*
,5S10
*
,6R
*
)-(ꢀ)-2-Benzyl-137-(2-oxo-3,5,6-triphenyl-
2l
*
5
*
-[1,4,2]oxazaphosphinan-2-yl)-methyl propionate. de¼32%.
Starting from 556 mg of (ꢀ)-1a (1.59 mmol, 1 equiv) and 350
mL
of
a
-benzyl methacrylate followed by 265 L of a solution of t-BuOK
m
(0.6 M) in THF (0.16 mmol, 0.1 equiv).1.20 g was purified by column
chromatography (hexane/ethyl acetate gradient: 50/50 to 40/60).
White solid (501 mg); Rf¼0.14 (Hex/AcOEt: 50/50); two di-
astereoisomers. Yield 60%.
4
O
3
5
21
O
12 P
18
19
15
20
O
O
2
1
Compound 2.2a: 31P NMR (101.25 MHz, CDCl3):
d
50.4; 1H NMR
22
8
16
6
13
H11
9
N
(250.13 MHz, CDCl3):
d
1.02e2.85 (m, 6H, 11NH, CH18CHP,
7
14
CH19CH2CO2CH3, Ph22CH2CH), 3.48 (s, 3H, CO221CH3), 4.76 (d, 1H,
3JHH¼5.3 Hz, N6CHPh), 4.88 (d, 1H, 2JPH¼14.1 Hz, P13CHPh), 5.85 (dd,
17
10
3
3
1H, JHH¼5.5 Hz, JPH¼7.8 Hz, O1CHPh), 6.97e7.60 (m, 20H, CHar);
4.2.1. (2R
*
,3S
*
,5S
*
,6R
*
)-(ꢀ)-2-Methyl-3-(2-oxo-3,5,6-triphenyl-
13C NMR (62.90 MHz, CDCl3):
d
26.23 (d, 1JPC¼96.4 Hz, P18CH2CH),
2l
*
5
*
-[1,4,2]oxazaphosphinan-2-yl)-methyl propionate. de¼26%.
39.45 (d, JPC¼8.2 Hz, CH219CHCO2CH3), 40.92 (d, JPC¼3.4 Hz,
2
2
Compound 2.1a: 31P NMR (81.02 MHz, CDCl3):
d
50.65; 1H NMR
Ph22CH2CH), 52.16 (s, CO221CH3), 62.74 (d, JPC¼93.1 Hz, P13CHPh),
3
(200.13 MHz, CDCl3):
d
1.20 (d, 3H, 3JHH¼7.1 Hz, 22CH3CHCH2), 1.83
63.91 (d, JPC¼1.4 Hz, N6CHPh), 79.40 (d, JPC¼6.7 Hz, O1CHPh),
3
2
(m, 1H,
P
18aCH2CH), 2.19 (m, 1H, P18bCH2CH), 2.44 (m, 1H,
127.09e129.72 (m, CHar), 135.54 (d, 2JPC¼5.3 Hz, 14CarCH[(P)(NH)]),
CH319CHCH2), 2.28 (d, 1H, JPH¼29.4 Hz, 11NH), 3.60 (s, 3H,
3
136.61 (d, JPC¼6.2 Hz, 2CarCHO), 138.45 (s, 23CarCH2), 139.01 (s,
3
CO221CH3), 4.88 (m, 1H, N6CHPh), 4.92 (d, 1H, JPH¼14.1 Hz,
2
7CarCHN), 174.82 (d, 3JPC¼10.1 Hz, 20CO2CH3).
3
3
P
13CHN), 5.90 (dd, 1H, JHH¼5.4 Hz, JPH¼8.4 Hz, O1CHPh), 7.1e7.7
Compound 2.2b: 31P NMR (101.25 MHz, CDCl3):
d
50.0; 1H NMR
(m, 15H, CHar); 13C NMR (50.32 MHz, CDCl3):
d 19.15 (d,
(250.13 MHz, CDCl3):
d
1.02e2.85 (m, 6H, 11NH, CH18CHP,
3JPC¼4.8 Hz, 22CH3CHCH2), 27.95 (d, 1JPC¼96.5 Hz, P18CH2CH), 33.61
CH19CH2CO2CH3, Ph22CH2CH), 3.43 (s, 3H, CO221CH3), 4.73 (d, 1H,
3JHH¼7.4 Hz, N6CHPh), 4.88 (d, 1H, 2JPH¼14.1 Hz, P13CHPh), 5.85 (dd,
(d, JPC¼2.9 Hz, CH319CHCH2), 52.37 (s, CO221CH3), 62.36 (d,
2
1JPC¼92.9 Hz, P13CHN), 63.94 (d, JPC¼1.4 Hz, N6CHPh), 79.24
3
3
3
1H, JHH¼5.5 Hz, JPH¼7.8 Hz, O1CHPh), 6.97e7.60 (m, 20H, CHar);
2
(d, JPC¼7.0 Hz, O1CHPh), 127.14e129.59 (m, CHar), 135.46 (d,
13C NMR (62.90 MHz, CDCl3):
d
26.84 (d, 1JPC¼96.0 Hz, P18CH2CH),
2JPC¼5.5 Hz, 14CarCHP), 136.57 (d, 3JPC¼6.5 Hz, CarCHO), 139.07 (s,
2
40.38 (d, JPC¼11.5 Hz, CH219CHCO2CH3), 41.19 (d, JPC¼3.4 Hz,
2
2
7CarCHN), 176.23 (d, 3JPC¼14.4 Hz, 20CO2CH3).
Ph22CH2CH), 52.08 (s, CO221CH3), 61.91 (d, JPC¼92.1 Hz, P13CHPh),
3
Compound 2.1b: 31P NMR (81.0 MHz, CDCl3): 50.19; 1H NMR
63.98 (s, N6CHPh), 79.08 (d, JPC¼7.2 Hz, O1CHPh), 127.09e129.72
2
(200.13 MHz, CDCl3):
d
1.08 (d, 3H, 3JHH¼7.1 Hz, 22CH3CHCH2), 1.53
(m, CHar), 135.33 (d, JPC¼5.3 Hz, 14CarCH[(P).(NH)]), 136.56 (d,
2
(m, 1H,
P
18aCH2CH), 2.44 (m, 1H, P18bCH2CH), 2.66 (m, 1H,
3JPC¼6.2 Hz, 2CarCHO), 138.24 (s, 23CarCH2), 139.12 (s, 7CarCHN),
CH319CHCH2), 2.28 (d, 1H, JPH¼29.4 Hz, 11NH), 3.63 (s, 3H,
3
175.04 (d, 3JPC¼6.2 Hz, 20CO2CH3).
CO221CH3), 4.77 (m, 1H, N6CHPh), 4.92 (d, 1H, JPH¼14.1 Hz,
2
IR (KBr): 3440, 3430, 3280, 3080, 3050, 3020, 2940, 2850, 1730,
1600, 1490, 1450, 1430, 1230, 1175, 1080, 950, 700 cmꢁ1; HRMS m/z
(MHþ) 526.2147 (calcd for C26H28NO4P: 523.2180).
3
3
P
13CHN), 5.90 (dd, 1H, JHH¼5.4 Hz, JPH¼8.4 Hz , O1CHPh), 7.1e7.7
(m, 15H, CHar); 13C NMR (50.32 MHz, CDCl3):
d 19.38 (d,
3JPC¼8.64 Hz, 22CH3CHCH2), 28.13 (d, JPC¼96.0 Hz, P18CH2CH),
1
33.62 (d, JPC¼3.8 Hz, CH319CHCH2), 52.40 (s, CO221CH3), 62.00 (d,
2
4
1JPC¼92.9 Hz, P13CHN), 64.07 (d, JPC¼1.0 Hz, N6CHPh), 79.05
3
22
3
O
5
21
2
(d, JPC¼7.0 Hz, O1CHPh), 127.14e129.59 (m, CHar), 135.34 (d,
O
12 P
20
O
O
2JPC¼5.3 Hz, 14CarCHP), 136.55 (d, JPC¼6.5 Hz, 2CarCHO), 139.11 (s,
3
2
18
19
15
1
8
7CarCHN), 176.28 (d, 3JPC¼10.1 Hz, 20CO2CH3).
16
6
13
H11
9
N
7
14
IR (KBr): 3440, 3270, 3080, 3050, 3020, 2950, 2870, 1730, 1600,
1490,1450,1430,1230.1210,1190, 1160,1180,1120, 1080,1060,1030,
17
10

J. Monbrun et al. / Tetrahedron 67 (2011) 540e545
543
3
2
4.2.4. (2R
oxazaphosphinan-2-yl)-methyl butyrate. de¼54%.
Starting from 469 mg of (ꢀ)-1a (1.34 mmol, 1 equiv) and 185
of methyl crotonate (1.75 mmol, 1.3 equiv) followed by 560 L of
*
,3S
*
,5S
*
,6R
*
)-(ꢀ)-3-(2-Oxo-3,5,6-triphenyl-2
l
*
5
*
-[1,4,2]
23CH3CH), 21.50 (d, JPC¼13.4 Hz, 24CH3CH), 27.90 (d, JPC¼4.8 Hz,
CH22CHCH3), 28.97 (s, CH19CH2CO2CH3), 35.64 (d, JPC¼92.6 Hz,
1
P18CHCH2), 52.06 (s, CO221CH3), 62.26 (d, JPC¼89.3 Hz, P13CHPh),
1
mL
2
m
63.94 (s, N6CHPh), 78.53 (d, JPC¼6.7 Hz, O1CHPh), 127.17e128.66
a solution of t-BuOK (0.6 M) in THF (0.33 mmol, 0.25 equiv). 543 mg
was purified by column chromatography (hexane/ethyl acetate
gradient: 45/55 to 0/100). White solid (410 mg); two di-
astereoisomers. Yield 68%.
(m, CHar), 135.24 (d, 2JPC¼4.8 Hz, 14CarCHP), 136.84 (d, 3JPC¼7.2 Hz,
2CarCHO), 139.27 (s, 7CarCHN), 172.93 (d, JPC¼17.3 Hz, 20CO2CH3);
3
Rf¼0.34 (hexane/ethyl acetate: 50/50).
Compound 2.4b: 31P NMR (101.25 MHz, CDCl3):
d
52.60; 1H NMR
3
3
Compound 2.3a: 31P NMR (101.25 MHz, CDCl3):
d
51.77; 1H NMR
1.22 (dd, 3H, JHH¼7.1 Hz, JPH¼15.6 Hz,
(250.13 MHz, CDCl3):
d
0.55 (dd, 3H, JHH¼6.9 Hz, JPH¼1.0 Hz,
3
3
3
(250.13 MHz, CDCl3):
d
23CH3CH), 0.92 (d, 3H, JHH¼6.6 Hz, 24CH3CH), 1.39 (m, 1H,
CH22CHCH3), 2.41 (ddd, 1H, 3JHH¼5.9 Hz, 3JPH¼14.3 Hz,
2JHH¼16.6 Hz, CH19CH2CO2CH3), 2.86(ddd, 1H, 3JHH¼6.3 Hz,
3
3
2
22CH3CH), 1.64 (ddd, 1H, JHH¼9.9 Hz, JPH¼1.4 Hz, JHH¼16.5 Hz,
3
3
CH19CH2CO2CH3), 2.11 (ddd, 1H, JHH¼4.3 Hz, JPH¼11.3 Hz,
2JHH¼16.8 Hz, CH19CH2CO2CH3), 2.72 (m, 1H, P18CHCH3), 3.60 (s, 3H,
3JPH¼15.2 Hz, JHH¼16.4 Hz, CH19CH2CO2CH3), 2.58 (tdd, 1H,
2
CO221CH3), 4.67 (d, 1H, JHH¼5.2 Hz, N6CHPh), 5.01 (d, 1H,
3JHH¼2.0 Hz, JHH¼5.9 Hz, JPH¼12.9 Hz, CH18CHP), 3.57 (s, 3H,
3
3
3
2JHH¼13.6 Hz, P13CHPh), 5.95 (dd, 1H, JHH¼5.5 Hz, JPH¼7.6 Hz,
CO221CH3), 4.78 (d, 1H, JHH¼5.7 Hz, N6CHPh), 4.89 (d, 1H,
3
3
3
O1CHPh), 7.05e7.75 (m, 15H, CHar); 13C NMR (62.90 MHz, CDCl3):
2JPH¼13.1 Hz, P13CHPh), 5.89 (dd, 1H, JHH¼6.2 Hz, JPH¼12.3 Hz,
3
3
2
1
d
13.40 (d, JPC¼6.2 Hz, 22CH3CH), 26.44 (d, JPC¼96.9 Hz,
O1CHPh), 6.96e7.68 (m, 15H, CHar); 13C NMR (62.90 MHz, CDCl3):
P18CHCH3), 34.85 (s, CH19CH2CO2CH3), 52.05 (s, CO221CH3),61.95 (d,
d
18.39 (s, 23CH3CH), 21.88 (d, JPC¼16.3 Hz, 24CH3CH), 28.19 (d,
3
2JPC¼90.2 Hz, P13CHPh), 63.99 (s, N6CHPh), 78.60 (d, JPC¼6.7 Hz,
2JPC¼3.4 Hz, CH22CHCH3), 27.16 (s, CH19CH2CO2CH3), 36.26 (d,
1JPC¼90.2 Hz, P18CHCH2), 52.19 (s, CO221CH3), 63.57 (d, 1JPC¼87.8 Hz,
2
2
O1CHPh), 125.61e130.06 (m, CHar), 135.18 (d, JPC¼6.2 Hz,
14CarCHP), 136.74 (d, JPC¼6.2 Hz, 2CarCHO), 139.18 (s, 7CarCHN),
P13CHPh), 63.74 (s, N6CHPh), 77.73 (d, JPC¼4.8 Hz, O1CHPh),
3
2
172.40 (d, 3JPC¼20.2 Hz, 20CO2CH3).
127.01e129.52 (m, CHar), 135.98 (d, JPC¼4.8 Hz, 14CarCHP), 136.99
2
Compound 2.3b: 31P NMR (101.25 MHz, CDCl3):
d
51.86; 1H NMR
0.61 (dd, 3H, JHH¼7 Hz, JPH¼17.4 Hz,
(d, JPC¼7.2 Hz, 2CarCHO), 139.24 (s, 7CarCHN), 172.55 (d,
3
3
3
(250.13 MHz, CDCl3):
d
3JPC¼9.6 Hz, 20CO2CH3); Rf¼0.18 (hexane/ethyl acetate: 50/50).
3
3
2
22CH3CH), 2.28 (ddd, 1H, JHH¼9.9 Hz, JPH¼7.2 Hz, JHH¼16.8 Hz,
IR (KBr): 3300, 3060, 3040, 3020, 2960, 2940, 2850, 1735, 1595,
CH19CH2CO2CH3), 2.72 (m, 1H, P18CHCH3), 2.92 (ddd, 1H,
1480, 1450, 1430, 1470, 1380, 1360, 1220, 1185, 1060, 960, 710 cmꢁ1
;
3JHH¼10.0 Hz, JPH¼3.2 Hz, JHH¼16.0 Hz, CH19CH2CO2CH3), 3.66 (s,
HRMS m/z (MHþ) 478.2147 (calcd for C28H32NO4P: 478.2144); MS
FAB(þ) 478 (15%), 284 (100%),180 (25%),106 (15%).
3
2
3H, CO221CH3), 4.80 (d, 1H, JHH¼4.1 Hz, N6CHPh), 4.98 (d, 1H,
3
3
3
2JPH¼13.8 Hz, P13CHPh), 5.93 (dd, 1H, JHH¼5.3 Hz, JPH¼5.3 Hz,
25
24
O1CHPh), 7.05e7.75 (m, 5H, CHar); 13C NMR (62.90 MHz, CDCl3):
d
14.16 (d, 2JPC¼3.4 Hz, 22CH3CH), 26.96 (d, 1JPC¼94.5 Hz, P18CHCH3),
4
23
34.62(d, 2JPC¼2.9 Hz, CH19CH2CO2CH3), 52.19 (s, CO221CH3), 62.44 (d,
3
7
O
5
22
18
21
O
12 P
2
2JPC¼89.7 Hz, P13CHPh), 64.05 (s, N6CHPh), 78.95 (d, JPC¼6.7 Hz,
20
O
O
2
19
15
1
2
O1CHPh), 125.61e130.06 (m, CHar), 135.27 (d, JPC¼6.7 Hz,
8
14CarCHP), 136.69 (d, JPC¼6.7 Hz, 2CarCHO), 139.07 (s, 7CarCHN),
3
16
6
13
H11
9
N
14
172.62 (d, 3JPC¼15.8 Hz, 20CO2CH3).
17
10
IR (KBr): 3450, 3290, 3080, 3060, 3030, 2950, 2870, 1735, 1490,
1450, 1430, 1230, 1185, 955, 700 cmꢁ1; HRMS m/z (MHþ) 450.1834
(calcd for C26H28NO4P: 450.1833); MS FAB(þ) 284 (98%),180
(70%),106 (10%).
4.2.6. (2R
*
,3S
*
,5S
*
,6R
*
)-(ꢀ)-3-Phenyl-3-(2-oxo-3,5,6-triphenyl-
2l
*
5
*
-[1,4,2]oxazaphosphinan-2-yl)-methyl propionate. de¼70%.
Starting from 500 mg of (ꢀ)-1a (1.43 mmol,1 equiv) and 463 mg
of methyl cinnamate (2.86 mmol, 2.7 equiv) followed by 239 L of
4
23
3
24 O
5
m
22
18
21
O
12 P
a solution of t-BuOK (0.6 N) in THF (0.14 mmol, 0.1 equiv). The
crude material, 1.2 g, was purified by column chromatography
(hexane/ethyl acetate gradient: 50/50 to 30/70). White solid
(550 mg); two diastereoisomers. Yield 70%.
20
O
O
2
19
15
1
8
16
17
6
13
H11
9
N
7
14
10
Compound 2.5a: 31P NMR (101.25 MHz, CDCl3):
d
48.67; 1H NMR
3
3
(250.13 MHz, CDCl3):
d
1.86 (ddd, 1H, JHH¼2.9 Hz, JPH¼8.3 Hz,
2JHH¼16.8 Hz, CH19aCH2CO2CH3), 2.16 (d, 1H, JHH¼5.5 Hz, 11NH),
2.71 (ddd, 1H, 3JHH¼11.7 Hz, 3JPH¼5.3 Hz, 2JHH¼17.0 Hz,
CH19bCH2CO2CH3), 3.41 (s, 3H, CO221CH3), 3.91(ddd, 1H,
3
4.2.5. (2R
*
,3S
*
,5S
*
,6R
*
)-(ꢀ)-3-(2-Oxo-3,5,6-triphenyl-2
l 5 -[1,4,2]
* *
oxazaphosphinan-2-yl)-4-methyl-methyl pentanoate. de¼50%.
Starting from 491 mg of (ꢀ)-1a (1.41 mmol, 1 equiv) and 263
of 4-methylpent-2-enoate(1.82 mmol,1.3 equiv)followed by583
m
m
L
L
3JHH¼2.9 Hz, JHH¼11.7 Hz, JPH¼12.9 Hz, CH18CHP), 4.63 (s, 1H,
3
3
N6CHPh), 5.01 (d, 1H, JPH¼12.5 Hz, P13CHPh), 5.89 (dd, 1H,
2
of a solution of t-BuOK (0.6 M) in THF (0.35 mmol, 0.25 equiv).
550 mg was purified by column chromatography (hexane/ethyl ac-
etate gradient: 40/60 to 20/80). White solid (404 mg); two di-
astereoisomers. Yield 60%.
3JHH¼5.7 Hz, JPH¼8.0 Hz, O1CHPh), 6.65e7.72 (m, 20H, CHar); 13C
3
NMR (62.90 MHz, CDCl3):
d
35.16 (s, CH19CH2CO2CH3), 38.18 (d,
1JPC¼91.9 Hz, P18CHCH2), 51.57 (s, CO221CH3), 60.37 (d, 1JPC¼89.3 Hz,
Compound 2.4a: 31P NMR (101.25 MHz, CDCl3):
d
54.13; 1H NMR
2
P
13CHPh), 63.37 (s, N6CHPh), 76.89 (d, JPC¼6.3 Hz, O1CHPh),
3
(250.13 MHz, CDCl3):
d
0.84 (d, 3H, JHH¼6.8 Hz, 23CH3CH), 1.07 (d,
126.13e129.58 (m, CHar),134.53 (d, 2JPC¼4.1 Hz, 14CarCH[(P),(NH)]),
3H, 3JHH¼6.9 Hz, 24CH3CH), 1.74 (ddd, 1H, 3JHH¼2.9 Hz,
135.41 (d, JPC¼8.2 Hz, 22CarCH[(P),(CH)]), 136.22 (d, JPC¼6.7 Hz,
2
3
2
3JPH¼15.0 Hz, JHH¼18.0 Hz, CH19CH2CO2CH3), 2.21 (ddd, 1H
,
2CarCHO), 138.76 (s, 7CarCHN), 171.14 (d, JPC¼20.1 Hz, 20CO2CH3);
3
3
2
3JHH¼9.0 Hz, JPH¼6.5 Hz, JHH¼18.0 Hz, CH19CH2CO2CH3), 2.37(m,
Rf¼0.32 (hexane/ethyl acetate: 50/50). [
a
]
20 ꢁ146 (c 0.2, CHCl3).
D
3
3
1H, CH22CHCH3), 2.82 (dddd, 1H, JHH¼2.7 Hz, JHH¼2.7 Hz,
Compound 2.5b: 31P NMR (101.25 MHz, CDCl3):
d
45.18; 1H NMR
3JPH¼15.9 Hz, JHH¼8.8 Hz, CH18CHP), 3.52 (s, 3H, CO221CH3), 4.75
3
3
3
(250.13 MHz, CDCl3):
d
2.15 (ddd, 1H, JHH¼10.6 Hz, JPH¼7.6 Hz,
3
2
(d, 1H, JHH¼5.5 Hz, N6CHPh), 4.92 (d, 1H, JPH¼13.3 Hz, P13CHPh),
2JHH¼16.4 Hz, CH19aCH2CO2CH3), 3.23 (ddd, 1H, JHH¼4.1 Hz,
3
5.96 (dd, 1H, 3JHH¼5.5 Hz, 3JPH¼8.0 Hz, O1CHPh), 7.05e7.75 (m, 15H,
3JPH¼9.0 Hz, 2JHH¼16.2 Hz, CH19bCH2CO2CH3), 3.42 (s, 3H,
3
CHar); 13C NMR (62.90 MHz, CDCl3):
d
19.77 (d, JPC¼1.4 Hz,
CO221CH3), 3.73 (ddd, 1H, JHH¼3.9, 10.6 Hz, JPH¼14.3 Hz,
3
3

544
J. Monbrun et al. / Tetrahedron 67 (2011) 540e545
CH218CHP), 4.86 (d, 1H, JHH¼6.0 Hz, N6CHPh), 4.88 (d, 1H,
C
32H32NO4P: 525.2135); MS FAB(þ) 526 (29%), 348 (57%), 284
3
2JPH¼12.9 Hz, P13CHPh), 5.86 (dd, 1H, JHH¼5.5 Hz, JPH¼5.5 Hz,
(95%), 194 (62%), 180 (72%),106 (30%), 91 (50%).
3
3
O1CHPh), 6.92e7.42 (m, 20H, CHar); 13C NMR (62.90 MHz, CDCl3):
2
1
d
36.12 (d, JPC¼2.4 Hz, CH19CH2CO2CH3), 40.34 (d, JPC¼91.2 Hz,
25
24
P18CHCH2), 52.12 (s, CO221CH3), 64.38 (d, JPC¼86.4 Hz, P13CHPh),
3
4
3
2
64.36 (d, JPC¼2.4 Hz, N6CHPh), 79.87 (d, JPC¼7.2 Hz, O1CHPh),
23
3
7
5
22
18
N
O
12 P
2
127.09e129.72 (m, CHar), 135.05 (d, JPC¼4.1 Hz, 14CarCH
O
1
20
2
19
15
2
[(P),(NH)]), 135.36 (d, JPC¼3.4 Hz, 22CarCH[(P),(CH)]), 136.75 (d,
8
3JPC¼6.2 Hz, 2CarCHO), 138.83 (s, 7CarCHN), 171.76 (d, 3JPC¼15.8 Hz,
16
17
6
13
H11
9
N
14
20CO2CH3); Rf¼0.20 (hexane/ethyl acetate: 50/50).
10
IR (KBr): 3440, 3200, 3090, 3070, 3030, 2950, 2840, 1735, 1600,
1490, 1450, 1430, 1215, 1175, 950, 700 cmꢁ1; HRMS m/z (MHþ)
512.1991 (calcd for C31H30NO4P: 512.1978); MS FAB(þ) 512 (7%),
284 (43%),180 (12%),106 (24%).
4.2.8. (2R
*
,3S
*
,5S
*
,6R
*
)-(ꢀ)-3-Phenyl-3-(2-oxo-3,5,6-triphenyl-
2
l
*
5
*
-[1,4,2]oxazaphosphinan-2-yl) propionitrile. de¼70%.
Starting from 528 mg of (ꢀ)-1a (1.51 mmol, 1 equiv) and 285
of cinnamonitrile (2.27 mmol, 1.5 equiv) followed by 250 L of
mL
26
m
a solution of t-BuOK (0.6 M) in THF (0.15 mmol, 0.1 equiv). The
crude material was purified by column chromatography (hexane/
ethyl acetate gradient: 50/50 to 0/100). White solid (530 mg); two
diastereoisomers. Yield 84%.
24
23
25
4
8
3
7
O
5
22
18
21
O
12 P
20
O
O
2
Compound 2.7a: 31P NMR (101.25 MHz, CDCl3):
d
46.07; 1H NMR
19
15
1
3
3
(250.13 MHz, CDCl3):
d
1.55 (ddd, 1H, JHH¼3.2 Hz, JPH¼5.5 Hz,
16
6
13
H11
9
N
14
2JHH¼17.1 Hz, CH19CH2CN), 2.35 (d, 1H, JHH¼30.7 Hz, 11NH), 2.68
3
17
10
(ddd, 1H, 3JHH¼12.5 Hz, 3JPH¼6.1 Hz, 2JHH¼17.1 Hz, CH19CH2CO2CH3),
3.66 (td, 1H, JHH¼3.2 Hz, JHH¼12.5 Hz, JPH¼12.5 Hz, CH218CHP),
3
3
3
4.68 (d, 1H, JHH¼4.7 Hz, N6CHPh), 5.08 (d, 1H, JPH¼12.1 Hz,
3
2
4.2.7. (2R
*
,3S
*
,5S
*
,6R
*
)-(ꢀ)-3-Tolyl-3-(2-oxo-3,5,6-triphenyl-2
l 5 -
* *
P
13CHPh), 5.92 (dd,1H, 3JHH¼5.6 Hz, 3JPH¼8.6 Hz, O1CHPh), 6.68e7.76
[1,4,2]oxazaphosphinan-2-yl)-methyl propionate. de¼64%.
Starting from 502 mg of (ꢀ)-1a (1.44 mmol,1 equiv) and 506 mg
of methyl cinnamate (2.88 mmol, 2 equiv) followed by 480 L of
(m, 20H, CHar); 13C NMR (62.90 MHz, CDCl3):
d
20.18 (d, 2JPC¼3.3 Hz,
CH19CH2CO2CH3), 38.50 (d, JPC¼91.9 Hz, P18CHCH2), 59.97 (d,
1
m
1JPC¼92.3 Hz, P13CHPh), 63.21 (s, N6CHPh), 77.68 (d, JPC¼6.3 Hz,
2
a solution of t-BuOK (0.6 M) in THF (0.29 mmol, 0.2 equiv). The
crude material, 1.2 g, was purified by column chromatography
(hexane/ethyl acetate gradient: 30/70 to 0/100). White solid
(530 mg); two diastereoisomers. Yield 70%.
O1CHPh),117.37 (d, 3JPC¼22.3 Hz, CH220CN),125.06e129.85 (m, CHar),
133.39 (d, JPC¼7.8 Hz, 14CarCH[(P),(NH)]), 133.99 (d, JPC¼5.6 Hz,
21CarCH[(P),(CH2)]),135.68 (d, 2JPC¼7.4 Hz, 22CarCH[(P),(CH)]),138.42
(s, 7CarCHN); Rf¼0.35 (hexane/ethyl acetate: 50/50).
2
2
Compound 2.6a: 31P NMR (101.25 MHz, CDCl3):
d
49.45; 1H NMR
Compound 2.7b: 31P NMR (101.25 MHz, CDCl3):
d
42.06; 1H NMR
3
3
(250.13 MHz, CDCl3):
d
1.94 (ddd, 1H, JHH¼2.9 Hz, JPH¼8.4 Hz,
3
3
(250.13 MHz, CDCl3):
d
2.83 (ddd, 1H, JHH¼11.9 Hz, JPH¼6.7 Hz,
2JHH¼16.9 Hz,
19aCH2),
2.16
(ddd,
1H,
3JHH¼6.2,
2JHH¼16.9 Hz, CH19CH2CN), 2.26 (d, 1H, JHH¼30.0 Hz, 11NH), 3.16
3
3.2 Hz, JPH¼26.2 Hz, 11NH), 2.68 (s, 3H, 26CH3), 2.74 (ddd, 1H,
3
(ddd, 1H, JHH¼3.7 Hz, JPH¼6.6 Hz, JHH¼17.0 Hz, CH19CH2CO2CH3),
3
3
2
3JHH¼11.5 Hz, JPH¼5.4 Hz, JHH¼16.9 Hz, 19bCH2), 3.45 (s, 3H,
3
2
3.37 (td,1H, 3JHH¼3.7 Hz, 3JHH¼11.9 Hz, 3JPH¼13.3 Hz, CH218CHP), 4.95
CO221CH3), 3.91 (ddd, 1H, JHH¼2.9 Hz, JPH¼13.0 Hz, CH218CHP),
3
3
(d, 1H, JHH¼4.5 Hz, N6CHPh), 4.92 (d, 1H, JPH¼10.9 Hz, P13CHPh),
3
2
4.65 (dd, 1H, JHH¼4.4 Hz, N6CHPh), 5.04 (d, 1H, JPH¼12.8 Hz,
3
2
5.88 (dd, 1H, 3JHH¼5.7 Hz, 3JPH¼5.7 Hz, O1CHPh), 6.97e7.41 (m, 20H,
3
3
P
13CHPh), 5.92 (dd, 1H, JHH¼5.9 Hz, JPH¼7.9 Hz, O1CHPh),
2
CHar); 13C NMR (62.90 MHz, CDCl3):
d
20.67 (d, JPC¼0.7 Hz,
6.74e7.75 (m, 19H, CHar); 13C NMR (62.90 MHz, CDCl3):
d 21.56 (s,
CH19CH2CO2CH3), 40.29 (d, JPC¼90.4 Hz, P18CHCH2), 64.41 (d,
1
26CH3), 35.43 (s, 19CH2), 38.15 (d, 1JPC¼91.7 Hz, P18CHCH2), 52.05 (s,
1JPC¼91.9 Hz, P13CHPh), 63.29 (s, N6CHPh), 80.66 (d, JPC¼7.1 Hz,
2
CO221CH3), 60.64 (d, JPC¼88.8 Hz, P13CHPh), 63.82 (s, N6CHPh),
1
O1CHPh),117.34 (d, 3JPC¼19.4 Hz, CH220CN),125.06e129.85 (m, CHar),
77.20 (d, 2JPC¼6.2 Hz, O1CHPh), 126.56e129.81 (m, CHar), 132.62 (d,
JPC¼8.2 Hz, Car), 135.01 (d, JPC¼4.3 Hz, Car), 136.72 (d, JPC¼6.7 Hz,
Car), 137.32 (d, JPC¼2.4 Hz, Car), 139.23 (s, Car), 171.67 (d,
3JPC¼20.6 Hz, 20CO2); Rf¼0.32 (hexane/ethyl acetate: 50/50).
132.95 (d, JPC¼3.0 Hz, 14CarCH[(P),(NH)]), 133.99 (d, JPC¼5.6 Hz,
21CarCH[(P),(CH2)]), 135.83 (d, 2JPC¼7.1 Hz, 22CarCH[(P),(CH)]), 137.90
(s, 7CarCHN); Rf¼0.23 (hexane/ethyl acetate: 50/50).
2
2
IR (KBr): 3400, 3280, 3070, 3040, 3010, 2940, 2830, 2790, 2230,
Compound 2.6b: 31P NMR (101.25 MHz, CDCl3):
d
45.18; 1H NMR
1590, 1480, 1440, 1410, 1230, 1170, 1060, 1080, 950, 700 cmꢁ1
;
3
3
(250.13 MHz, CDCl3):
d
2.16 (ddd, 1H, JHH¼3.2 Hz, JPH¼6.2 Hz,
HRMS m/z (MHþ) 479.1888 (calcd for C32H32NO4P: 479.1895).
2JHH¼26.2 Hz, 11NH), 2.34 (s, 3H, 26CH3), 2.74 (m, 1H, 18aCH2), 3.46 (s,
3H, CO221CH3), 3.25 (ddd, 1H, 3JHH¼3.8 Hz, 3JPH¼9.0 Hz,
22
2JHH¼16.1 Hz, 18bCH2), 3.74 (ddd, 1H, JHH¼4.1 Hz, JHH¼10.8 Hz,
3
3
4
8
21
3
7
5
23
O
12 P
2JPH¼13.8 Hz, CH219CHP), 4.88 (dd, 1H, JHH¼3.3 Hz, N6CHPh), 4.92
3
20
O
(dd, 1H, JPH¼15.0 Hz, JHH¼4.0 Hz, P13CHPh), 5.90 (dd, 1H,
2
3
O
2
18
19
15
1
3JHH¼5.5 Hz, JPH¼5.7 Hz, O1CHPh), 6.74e7.75 (m, 19H, CHar); 13C
3
16
6
13
9
N
14
H11
NMR (62.90 MHz, CDCl3):
d
21.46 (s, 26CH3), 35.97 (s, 19CH2), 39.36
(d, JPC¼91.2 Hz, P18CHCH2), 52.13 (s, CO221CH3), 63.99 (d,
1
17
10
1JPC¼87.8 Hz, P13CHPh), 63.68 (s, N6CHPh), 79.50 (d, JPC¼7.2 Hz,
2
O1CHPh), 126.56e129.81 (m, CHar), 132.13 (d, JPC¼3.8 Hz, Car),
135.13 (d, JPC¼4.3 Hz, Car), 136.79 (d, JPC¼8.6 Hz, Car), 137.32 (d,
4.2.9. (2R
oxazaphosphinan-2-yl)-cyclohexanone. de¼78%.
Starting from 528 mg of (ꢀ)-1a (1.51 mmol, 1 equiv) and 220
of 2-cyclohexen-1-one (2.27 mmol, 1.5 equiv) followed by 250 L of
*
,3S
*
,5S
*
,6R
*
)-(ꢀ)-3-(2-Oxo-3,5,6-triphenyl-2
l
*
5
*
-[1,4,2]
JPC¼2.4 Hz, Car), 138.91 (s, Car), 171.82 (d, JPC¼16.8 Hz, 20CO2);
3
Rf¼0.20 (hexane/ethyl acetate: 50/50).
mL
IR (KBr): 3280, 3080, 3050, 3020, 2940, 2890, 2800, 1730, 1590,
1480, 1450, 1430, 1230,1210, 1180, 1160, 1110, 1080, 1060, 1030, 1010,
1000, 950, 770, 700 cmꢁ1; HRMS m/z (MHþ) 525.2147 (calcd for
m
a solution of t-BuOK (0.6 M) in THF (0.15 mmol, 0.1 equiv). The
crude material was purified by column chromatography (hexane/

J. Monbrun et al. / Tetrahedron 67 (2011) 540e545
545
3
2
ethyl acetate gradient: 30/70 to 0/100). White solid (511 mg); two
diastereoisomers. Yield 76%.
(dd, 1H, JPH¼2.7 Hz, JHH¼10.9 Hz, P18aCH2CH), 2.23 (d, 1H,
2JHH¼11.2 Hz, P18bCH2CH), 2.56 (m, 1H, CH319CHCH2), 2.43 (s large,
1H, 11NH), 3.57 (s, 3H, CO221CH3), 4.67 (d, 3JHH¼2.7 Hz, 1H, N6CHPh),
de¼78%.
Compound 2.8a: 31P NMR (101.25 MHz, CDCl3):
d
48.90; 1H NMR
4.43 (d, 1H, JPH¼17.4 Hz, P13CHN), 6.01 (s large, 1H, O1CHPh),
2
(250.13 MHz, CDCl3):
d
0.77e2.61 (m, 10H, P18CHCH2, 19,21,22,23CH2,
7.1e7.6 (m, 15H, CHar); 13C NMR (62.90 MHz, CDCl3):
d 18.64 (d,
and 11NH), 4.72 (d, 1H, JHH¼4.9 Hz, N6CHPh), 4.96 (d, 1H,
3JPC¼3.8 Hz, 22CH3CHCH2), 23.25 (d, 1JPC¼86.9 Hz, P18CH2CH), 33.38
3
2JPH¼13.3 Hz, P13CHPh), 5.91 (dd, 1H, JHH¼5.7 Hz, JPH¼7.6 Hz,
(d, JPC¼3.4 Hz, CH319CHCH2), 52.38 (s, CO221CH3), 56.56 (d,
3
3
2
O1CHPh), 7.01e7.66 (m, 15H, CHar); 13C NMR (62.90 MHz, CDCl3):
1JPC¼95.0 Hz, P13CHN), 62.36 (s, N6CHPh), 83.33 (d, JPC¼7.7 Hz,
2
3
2
d
24.52 (d, JPC¼2.7 Hz, CH222CH2CH2), 25.79 (d, JPC¼17.2 Hz,
O1CHPh), 125.61e130.06 (m, CHar), 134.99 (d, JPC¼6.2 Hz, Car),
CH23CH2CH2), 33.98 (d, JPC¼94.3 Hz, P18CHCH2), 39.33 (d,
137.56 (d, JPC¼6.7 Hz, Car), 136.63 (s, Car), 176.18 (d, JPC¼14.4 Hz,
1
3
2JPC¼5.9 Hz, PCH19CH2), 41.27 (s, CH221CH2C]O), 60.96 (d,
20CO2CH3).
1JPC¼91.6 Hz, P13CHPh), 63.35 (s, N6CHPh), 77.93 (d, JPC¼6.6 Hz,
Compound 3.b: 31P NMR (101.25 MHz, CDCl3): 46.15; 1H NMR
d
2
O1CHPh), 126.60e129.33 (m, CHar), 134.73 (d, JPC¼5.5 Hz, Car),
(250.13 MHz, CDCl3):
d
1.14 (d, 3H, 3JHH¼6.5 Hz, 22CH3CHCH2), 1.40
3
136.09 (d, JPC¼7.0 Hz, Car), 138.68 (s, Car), 209.15 (d, JPC¼13.3 Hz,
(m, 2H, P18CH2CH), 2.85(m,1H, CH319CHCH2), 2.83(s large,1H,11NH),
3.77 (s, 3H, CO221CH3), 4.77 (d,1H, 3JHH¼2.7 Hz, N6CHPh), 4.62 (d,1H,
CH220COCH2).
Compound 2.8b: 31P NMR (101.25 MHz, CDCl3)
d
47.52.
2JPH¼17.4 Hz, P13CHN), 6.01 (s large, 1H, O1CHPh), 7.1e7.7 (m, 15H,
3
IR (KBr): 3380, 3260, 3080, 3050, 3020, 2940, 2860, 1710, 1600,
CHar); 13C NMR (62.90 MHz, CDCl3):
d
20.19 (d, JPC¼10.6 Hz,
1490, 1455, 1420, 1210, 1235, 1190, 1080, 1060, 960, 700 cmꢁ1
;
22CH3CHCH2), 24.11 (d, JPC¼86.9 Hz, P18CH2CH), 32.72 (d,
1
HRMS m/z (MHþ) 446.1885 (calcd for C27H28NO3P: 446.1897).
2JPC¼4.8 Hz, CH319CHCH2), 52.32 (s, CO221CH3), 56.36 (d,
1JPC¼94.5 Hz, P13CHN), 62.39 (s, N6CHPh), 83.44 (d, JPC¼7.7 Hz,
2
O1CHPh),127.14e129.59 (m, CHar),134.99 (d, JPC¼6.2 Hz, Car),137.77
(d, JPC¼6.7 Hz, Car),136.75 (s, Car),176.53 (d, 3JPC¼6.2 Hz, 20CO2CH3).
HRMS m/z (MHþ) 450.1834 (calcd for C26H28NO4P: 450.1836);
MS FAB(þ) 284 (98%), 180 (70%), 106 (10%).
Supplementary data
Supplementary data associated with this article can be found in
the online version at doi:10.1016/j.tet.2010.10.078.
4.2.10. (2R
oxazaphosphinan-2-yl)-tetrahydro-pyran-2-one. de¼70%.
Starting from 511 mg of (ꢀ)-1a (1.46 mmol, 1 equiv) and 189
of 5,6-dihydro-2H-pyran-2-one (2.20 mmol, 1.5 equiv) followed by
243 L of a solution of t-BuOK (0.6 M) in THF (0.15 mmol, 0.1 equiv).
*
,3S
*
,5S
*
,6R
*
)-(ꢀ)-4-(2-Oxo-3,5,6-triphenyl-2
l 5 -[1,4,2]
* *
mL
References and notes
1. (a) Mathey, F. PhosphoruseCarbon Heterocyclic Chemistry. The Rise of a New Do-
main; Elsevier: Oxford, 2001; (b) Kukhar, V. P.; Hudson, H. R. Aminophosphonic
and Aminophosphinic Acids: Chemistry and Biological Activity; John Wiley: Chi-
chester, 2000.
2. (a) Grembecka, J.; Mucha, A.; Cierpicki, T.; Kafarski, P. J. Med. Chem. 2003, 46,
2641; (b) Maskos, K.; Jozic, D.; Kaiser, J. T.; Huber, R.; Bode, W. J. Mol. Biol. 2003,
332, 243.
3. (a) Stowasser, B.; Budt, K.-H.; Jian-Qi, L.; Peyman, A.; Ruppert, D. Tetrahedron Lett.
1992, 33, 6625; (b) Stowasser, B.; Li, J.Q.; Peyman, A.; Budt, K.H. US Patent
5663139, 1997; Chem. Abstr. 121, 280877; (c) Dreyer, G. B.; Abdel-Meguid, S. S.;
Zhao, B.; Murthy, K.; Winborne, E.; Choi, J. W.; DesJarlais, R. L.; Minnich, M. D.;
Culp, J. S.; Debouck, C.; Tomaszek, T. A., Jr.; Meek, T. D. Biochemistry 1993, 32,
7972; (d) Dreyer, G.B. World Patent 9200954, 1992; Chem. Abstr. 116, 236170; (e)
Peyman, A.; Stahl, W.; Budt, K.-H.; Ruppert, D.; Schuessler, H.; Wagner, K. US
patent 5707979, 1998; Chem. Abstr. 124, 261356.
m
The crude material was purified by column chromatography
(hexane/ethyl acetate gradient: 20/80 to 0/100). White (444 mg);
two diastereoisomers. Yield 68%.
Compound 2.9a: 31P NMR (101.25 MHz, CDCl3): 48.32; 1H NMR
d
(250.13 MHz, CDCl3):
d
0.86e2.90 (m, 6H, 11NH, 18CH, and 22,19CH2),
3.98 (m, 1H, 21aCH2), 4.18 (m, 1H, 21bCH2), 4.80 (d, 1H, 3JHH¼5.2 Hz,
2
N6CHPh), 5.02 (d, 1H, JPH¼13.6 Hz, P13CHPh), 5.93 (dd, 1H,
3
3JHH¼5.5 Hz, JPH¼7.9 Hz, O1CHPh), 7.09e7.71 (m, 15H, CHar); 13C
NMR (62.90 MHz, CDCl3):
d
22.05 (s, CH22CH2CH2), 24.63 (d,
2
1JPC¼131.8 Hz, P18CHCH2), 27.49 (d, JPC¼7.8 Hz, PCH19CH2), 66.65
3
1
(d, JPC¼91.6 Hz, CH221CH2OeC]O), 58.14 (d, JPC¼127.2 Hz,
P13CHPh), 62.17 (s, N6CHPh), 76.35 (s, O1CHPh), 126.26e128.45 (m,
CHar), 134.69 (d, JPC¼7.2 Hz, Car), 136.93 (d, JPC¼8.8 Hz, Car), 139.75
(s, Car), 169.72 (d, 3JPC¼15.5 Hz, 20CO2). Rf¼0.39 (Hex/AcOEt: 10/90).
4. Bolton, G.L.; Padia, J.K.; Trivedi, B.K. US Patent 5208224, 1993; Chem. Abstr. 119,
95833.
5. (a) Cristau, H.-J.; Coulombeau, A.; Genevois-Borella, A.; Pirat, J.-L. Tetrahedron
Lett. 2001, 42, 4491; (b) Cristau, H.-J.; Coulombeau, A.; Genevois-Borella, A.;
Sanchez, F.; Pirat, J.-L. J. Organomet. Chem. 2002, 643, 381; (c) Cristau, H.-J.;
Monbrun, J.; Tillard, M.; Pirat, J.-L. Tetrahedron Lett. 2003, 44, 3183; (d) Pirat,
J.-L.; Monbrun, J.; Virieux, D.; Cristau, H.-J. Tetrahedron 2005, 61, 7029; (e)
Cristau, H.-J.; Pirat, J.-L.; Virieux, D.; Monbrun, J.; Ciptadi, C.; Bekro, Y.-A.
J. Organomet. Chem. 2005, 690, 2472; (f) Pirat, J.-L.; Monbrun, J.; Virieux, D.;
Volle, J.-N.; Tillard, M.; Cristau, H.-J. J. Org. Chem. 2005, 70, 7035; (g) Volle, J.-N.;
Virieux, D.; Starck, M.; Monbrun, J.; Clarion, L.; Pirat, J.-L. Tetrahedron: Asymmetry
2006,17,1402; (h) Volle, J.-N.; Filippini, D.; Krawczy, B.; Kaloyanov, N.; Van der Lee,
A.; Maurice, T.; Pirat, J.-L.; Virieux, D. Org. Biomol. Chem. 2010, 8, 1438.
6. Yamagishi, T.; Ichikawa, H.; Haruki, T.; Yokomatsu, T. Org. Lett. 2008, 10, 4347.
Compound 2.9b: 31P NMR (101.25 MHz, CDCl3):
d 46.84.
IR (KBr): 3420, 3260, 3080, 3050, 3020, 2970, 2850, 1740, 1595,
1490,1450,1400,1240,1225,1210,1185,1080, 950, 700 cmꢁ1; HRMS
m/z (MHþ) 448.1678 (calcd for C26H26NO4P: 448.1663); MS FAB(þ)
448 [MþH]þ (15%); 284 (100%); 180 (45%); 106 (24%); 91 (22%).
Compound 3.a: 31P NMR (101.25 MHz, CDCl3):
d
46.64; 1H NMR
(250.13 MHz, CDCl3):
d
1.27 (d, 3H, 3JHH¼7.1 Hz, 22CH3CHCH2), 2.20