Chiral N-phosphonylimine chemistry: Asymmetric synthesis of N-phosphonyl β-amino Weinreb amides

Article abstract of DOI:10.1002/ejoc.200801061

Various chiral N-phosphonyl β-amino Weinreb amides were synthesized by treating chiral N-phosphonyl imines with the lithium enolate of N-methoxy-N-methylacetamide. The N,N-protection groups on chiral N-phosphonyl imines and the types of deprotonation base

Full text of DOI:10.1002/ejoc.200801061

FULL PAPER
DOI: 10.1002/ejoc.200801061
Chiral N-Phosphonylimine Chemistry: Asymmetric Synthesis of N-Phosphonyl
β-Amino Weinreb Amides
Parminder Kaur,[a] Thao Nguyen,[a] and Guigen Li*[a]
Keywords: Asymmetric synthesis / Phosphorus / Amides / Chiral auxiliaries
Various chiral N-phosphonyl β-amino Weinreb amides were
synthesized by treating chiral N-phosphonyl imines with the
lithium enolate of N-methoxy-N-methylacetamide. The N,N-
protection groups on chiral N-phosphonyl imines and the
types of deprotonation bases for enolate generation were
found to be crucial for the successful synthesis. Eleven Wein-
reb amides were obtained in excellent chemical yields (92 to
98%) and good to excellent diastereoselectivities (up to dr =
99:1). The absolute structures were unambiguously deter-
mined by converting the products into authentic samples and
by comparing their optical rotation values.
(© Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim,
Germany, 2009)
Introduction
α-Amino aldehydes and ketones have been widely used
in the synthesis of many natural products and related biolo-
gically important compounds, and they are also found to
exist in many natural products.[1–3] In addition, they can be
utilized as useful building blocks for general organic synthe-
sis.[4–9] The syntheses of these compounds are usually con-
ducted by using Mannich-type reactions, aminoalkylations,
oxidations of γ-amino alcohols,[4] and the selective re-
ductions of N-protected β-amino esters.[6] The asymmetric
synthesis of chiral β-amino carbonyl derivatives sometime
faces challenges because of the inherent instability and ten-
dency of these compounds to undergo self condensation in
the absence of suitable N-protection.[10–11] Among carbonyl
derivatives, Weinreb amides have been paid special attention
in organic synthesis, because they can be readily converted
into ketones.[12–15] For example, Weinreb amides have been
successfully utilized for the asymmetric synthesis of 1,3-
aminoketals[14a] and α-amino ketones.[14b] Recently, several
methods for the asymmetric synthesis of β-amino Weinreb
amides have been reported,[15–17] which include the use of
N-sulfinyl imine based carbonyl-type addition and lithium
(S)-N-benzyl-N-α-methylbenzylamide-based α,β-conjugate
addition reactions.
Scheme 1. Asymmetric reaction with the use of chiral N-phos-
phonyl imines.
Very recently, our group developed new chiral N-phos-
phonylimine chemistry. We successfully synthesized and uti-
lized a series of chiral N-phosphonyl imines as electrophiles
for several nucleophilic addition reactions, such as aza-
Darzens reaction, aza-Henry reaction, and allylmagnesium
bromide based addition (Scheme 1).[18]
The resulting chiral products were isolated in excellent
yields and good to excellent diastereoselectivities. Mean-
while, the C2-symmetric diamine chiral auxiliary was easily
recovered in quantitative yield.[18b] We now turn our atten-
tion to the use of Weinreb amide derived enolates for the
electrophilic addition to chiral N-phosphonyl imines.
Herein we report our preliminary results on this reaction
and its application to the asymmetric synthesis of N-phos-
phonyl β-amino Weinreb amides (Scheme 2).
[a] Department of Chemistry and Biochemistry, Texas Tech Uni-
versity,
Lubbock, TX 79409-1061, USA
E-mail: guigen.li@ttu.edu
912
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Asymmetric Synthesis of N-Phosphonyl β-Amino Weinreb Amides
Table 1. Optimization results by using different R groups on the
chiral N-phosphonyl imines.[a]
Scheme 2.
Results and Discussion
Entry Substrate RЈ
Product Time Yield[b,c]
dr[d]
Chiral N-phosphonyl imine 1 having a benzyl group in
its N,N-positions was employed as the electrophile for the
model reaction. The enolate was first generated by treating
N-methoxy-N-methylacetamide (0.02 mL, 0.30 mmol) with
KHMDS (20% solution in toluene, 1.5 mL, 0.30 mmol) at
–78 °C in dry THF (2 mL). The reaction was performed by
adding chiral N-phosphonyl imine 1 (0.087 g, 0.25 mmol,
2 mL of solution in THF) into the resulting mixture. The
reaction was stirred at –78 °C for 2 h and constantly moni-
tored by TLC (EtOAc/MeOH, 9:1). After the starting mate-
rials were consumed completely, the reaction was quenched
with the addition of saturated NH4Cl. Surprisingly, only
moderate yields (40%) and very poor diastereoselectivities
(Ͻ55:45) were observed. To improve the yields and selectivi-
ties, the reaction was optimized by using different bases at
different temperatures and reaction times. LiHMDS was
thus used as the base for enolate generation. This modifica-
tion resulted in an improved yield of 60% and a slightly
higher diastereoselectivity (60:40) when the reaction was
conducted at –78 °C. The use of other bases including LDA
did not give any further improvements in either the chemi-
cal yield or the diastereoselectivity.
[h]
[%]
1
2
1
2
benzyl
isobutyl
6
7
2
2
10
2
10
2
10
2
60
30
40
30
30
40
50
96
60:40
50:50
50:50
50:50
50:50
70:30
70:30
87:13
3
4
5
3
neopentyl
1-naphthyl
isopropyl
8
9
4
5a
10a
[a] All reactions were carried out at –78 °C in 0.06  solution of
THF. [b] Yield calculated by 1H NMR spectroscopic analysis of the
crude product. [c] Combined yields of both isomers. [d] Dia-
stereomeric ratio determined by 31P and 1H NMR spectroscopic
analysis of the crude products.
of chiral N-phosphonyl imines 5a–k derived from various
aromatic aldehydes were then synthesized[18b] and subjected
to reactions with the lithium enolate of N-methoxy-N-
methylacetamide. The results are summarized in Table 2.
Excellent chemical yields were achieved for all the cases that
we studied. The highest diastereoselectivities (dr = 96:4 to
99:1) were observed in those cases where ortho substituents
We then turned our attention to modification of N,N-
protection groups on the chiral auxiliary. Five different
N,N-protection substituents, such as benzyl, isobutyl, neo-
pentyl, naphthyl, and isopropyl were examined. The optimi-
zation results with the use of these N,N-protection groups
are summarized in Table 1.
Table 2. Results of the synthesis of N-phosphonyl-β-amino Weinreb
amides with the use of chiral N-phosphonyl imines 5a–k.
As revealed in Table 1, when the isobutyl group (in auxil-
iary 2) was used to replace the benzyl counterpart, no selec-
tivity was observed. The same situation was encountered
when the neopentyl group (in auxiliary 3) was employed.
For these two cases, a large amount of unreacted imine re-
mained, as revealed by TLC, even after a prolonged reac-
tion period. The third attempt was to use the naphthyl
group as the N,N-protection group (in auxiliary 4), where
an improved diastereoselectivity (70:30) was observed, but
the reaction conversion was only 50%. Pleasantly, when the
isopropyl group (in auxiliary 5a) was used the diastereo-
selectivity increased to 87:13 and the yield increased to
96%. The diastereoselectivity enhancement obtained with
the use of the isopropyl group should be attributed to the
larger steric effect from the secondary alkyl group. This ob-
servation is in accordance with our previous observations
in the aza-Henry and Grignard reactions.[18b–18c]
Entry Substrate
R
Product Yield[a,b] [%] dr[c]
1
2
3
4
5
6
7
8
5a
5b
5c
5d
5e
5f
5g
5h
5i
H
10a
10b
10c
10d
10e
10f
10g
10h
10i
96
96
94
95
98
93
95
96
93
95
92
87:13
86:14
85:15
88:12
96:4
99:1
99:1
98:2
98:2
98:2
4-fluoro
4-chloro
4-bromo
2-fluoro
2-methoxy
2-nitro
2-methyl
2-chloro
2-bromo
thienyl
9
10
11
5j
5k
10j
10k
78:22
[a] Yields after standard aqueous workup. [b] Combined yields of
both isomers. [c] Diastereomeric ratio determined by 31P and 1H
On the basis of the above-encouraging results with the
use of the isopropyl group in the chiral auxiliary, a series NMR spectroscopic analysis of the crude sample.
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© 2009 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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P. Kaur, T. Nguyen, G. Li
FULL PAPER
amide (0.70 mmol) and THF (4 mL). The reaction vial was cooled
to –78 °C and LiHMDS (1  in THF, 0.70 ml, 0.70 mmol) was
added dropwise. The reaction solution was stirred at –78 °C for 1 h.
At this time, phosphonyl imine (0.2 g, 0.60 mmol) in THF (4 mL)
was added to the reaction mixture. The reaction mixture stirred for
another 1 h. Further, the reaction was quenched by adding satu-
rated NH4Cl solution followed by water (10 mL). The reaction mix-
ture was then transferred to the separatory funnel and extracted
with diethyl ether (2ϫ20 mL). The combined organic layer was
washed with water (1ϫ20 mL) and dried with anhydrous sodium
are present on the aromatic rings (Table 2, Entries 5–10).
However, for those cases where para substituents are at-
tached to the aromatic rings (Table 2, Entries 2–4), the dia-
stereoselectivity decreased to dr = 88:12 to 86:14. In con-
trast, chiral N-phosphonyl imines derived from a heteroaro-
matic aldehyde gave relatively low diastereoselectivity (dr =
78:22; Table 2, Entry 11).
The absolute configuration of the product was deter-
mined by removing the chiral auxiliary from compound 10a
followed by treatment with aqueous HCl in methanol as sulfate. Sodium sulfate was filtered off, and the organic layer was
concentrated to obtain the desired products as oils. For the 4-fluoro
and 4-chloro derivatives, the product was purified by flash
chromatography (EtOAc/MeOH, 5:1).
shown in Scheme 3. The optical rotation value of the depro-
tected product was proven to be comparable to that of
known compound 11.[14a]
10a: Yellow oil. Yield: 0.26 g, 96%. [α]2D5 = –30.1 (c = 0.62, CHCl3).
1H NMR (500 MHz, CDCl3): δ = 7.36 (d, J = 7.5 Hz, 2 H), 7.28
(t, J = 7.0 Hz, 2 H), 7.18 (t, J = 7.5 Hz, 1 H), 4.83–4.77 (m, 1 H),
3.86 (t, J = 10.5 Hz, 1 H, NH), 3.43–3.38 (m, 1 H), 3.36 (s, 3 H),
3.13–3.07 (m, 1 H), 3.03 (s, 3 H), 2.97–2.78 (m, 4 H), 2.07–1.96 (m,
2 H), 1.75 (s, 3 H), 1.34–1.28 (m, 4 H), 1.20 (d, J = 7.0 Hz, 4 H),
1.15 (d, J = 7.0 Hz, 2 H), 1.09 (d, J = 6.5 Hz, 2 H), 1.05 (d, J =
10 Hz, 3 H) ppm. 13C NMR (125 MHz, CDCl3): δ = 171.8, 144.1,
128.1 (2 C), 126.7, 126.5 (2 C), 60.9, 59.8 (d, J = 11.3 Hz), 58.9 (d,
J = 9.8 Hz), 52.7, 45.7, 43.9 (d, J = 3.0 Hz), 43.8 (d, J = 3.8 Hz),
31.4 (d, J = 11.8 Hz), 30.8 (d, J = 10 Hz), 24.3 (d, J = 12.5 Hz),
23.6 (d, J = 7.8 Hz), 23.1, 23.0, 19.6, 19.5 (d, J = 2.0 Hz) ppm. 31P
NMR (202 MHz, CDCl3): δ = 22.6 ppm.
Scheme 3. Removal of the chiral N-phosphonyl auxiliary from
product 10a.
10b: Colorless oil. Yield: 0.269 g, 96%. [α]2D5 = –33.2 (c = 2.23,
CHCl3). 1H NMR (500 MHz, CDCl3): δ = 7.36–7.32 (m, 2 H),
7.00–6.95 (m, 2 H), 4.84–4.78 (m, 1 H), 3.96 (t, J = 10.0 Hz, 1 H,
NH), 3.41 (s, 3 H), 3.35–3.27 (m, 3 H), 3.04 (s, 3 H), 2.96–2.77 (m,
4 H), 2.07–2.00 (m, 2 H), 1.74 (s, 2 H), 1.40 (t, J = 7.5 Hz, 1 H),
1.34–1.25 (m, 3 H), 1.19 (d, J = 7.0 Hz, 3 H), 1.14 (d, J = 7.0 Hz,
3 H), 1.08 (dd, J = 6.5, 12.5 Hz, 5 H) ppm. 13C NMR (125 MHz,
CDCl3): δ = 171.7, 160.6, 140.0, 128.1, 128.0, 114.9, 114.7, 61.0,
59.8 (d, J = 10.8 Hz), 58.8 (d, J = 9.8 Hz), 52.0, 45.7, 43.9 (d, J =
4.0 Hz), 43.8 (d, J = 4.0 Hz), 31.3 (d, J = 11.8 Hz), 30.7 (d, J =
10 Hz), 24.3, 24.2, 23.6 (d, J = 7.8 Hz), 23.0 (d, J = 3.5 Hz), 19.6,
19.5 (d, J = 2.0 Hz) ppm. 31P NMR (202 MHz, CDCl3): δ =
22.6 ppm.
Conclusions
Chiral N-phosphonyl imines were found to react with
Weinreb amide derived enolates under convenient condi-
tions. The deprotonation base and the N,N-protection
groups were proven to be crucial for the success of this reac-
tion. The secondary protection group, isopropyl, resulted in
excellent chemical yields and good to excellent diastereo-
selectivities. The new method provides easy access to N-
phosphonyl β-amino Weinreb amides. Further modifica-
tions by using various other N-substituents in N-phos-
phonyl imines under different conditions will be studied in
the future.
10c: Colorless oil. Yield: 0.276 g, 94%. [α]2D5 = –35.3 (c = 1.72,
CHCl3). 1H NMR (500 MHz, CDCl3): δ = 7.33–7.30 (m, 2 H),
7.27–7.24 (m, 2 H), 4.84–4.71 (m, 1 H), 3.97 (t, J = 10.0 Hz, 1 H,
NH), 3.43 (s, 3 H), 3.39–3.26 (m, 2 H), 3.04 (s, 3 H), 2.96–2.90 (m,
2 H), 2.87–2.76 (m, 2 H), 2.07–1.97 (m, 3 H), 1.74 (s, 2 H), 1.31–
1.23 (m, 4 H), 1.18–1.08 (m, 10 H), 0.82 (d, J = 6.5 Hz, 1 H) ppm.
13C NMR (125 MHz, CDCl3): δ = 171.7, 142.8, 132.4, 128.2 (2 C),
128.0 (2 C), 61.0, 59.8 (d, J = 11.3 Hz), 58.9 (d, J = 9.8 Hz), 52.1,
44.0 (d, J = 3.3 Hz), 43.9 (d, J = 4.0 Hz), 39.9, 31.3 (d, J =
11.8 Hz), 30.7 (d, J = 9.3 Hz), 24.3, 24.2, 23.7 (d, J = 7.3 Hz), 23.0
(d, J = 3.5 Hz), 19.64, 19.61 (d, J = 2.0 Hz) ppm. 31P NMR
(202 MHz, CDCl3): δ = 22.4 ppm.
Experimental Section
General Methods: All solvents, unless otherwise mentioned, used
for the reactions were purified and dried by passing through an
alumina column prior to use. THF was distilled from sodium/
benzophenone ketyl. All the glassware used was dried overnight at
100 °C. NMR spectra were recorded at 500, 125, and 202 MHz for
1H, 13C, and 31P nuclei, respectively. Shifts are reported in ppm on
the basis of an internal TMS standard (for 1H/CDCl3) or on resid-
ual solvent peaks (for 13C/CDCl3). 31P NMR spectra were refer-
enced to external H3PO4 (δ =0.00 ppm). Lithium bis(trimethylsilyl-
amide) (1  in THF) was obtained from Aldrich and used as ob-
tained from commercial sources without further purification.
10d: Colorless oil. Yield: 0.288 g, 95%. [α]2D5 = –27.1 (c = 4.70,
1
CHCl3). H NMR (500 MHz, CDCl3): δ = 7.41 (d, J = 8.5 Hz, 2
H), 7.29 (d, J = 8.5 Hz, 2 H), 4.81–4.76 (m, 1 H), 4.09 (t, J =
8.0 Hz, 1 H, NH), 3.43 (s, 3 H), 3.40–3.26 (m, 3 H), 3.04 (s, 3 H),
2.96–2.85 (m, 3 H), 2.80–2.77 (m, 1 H), 2.07–1.97 (m, 2 H), 1.74
(s, 2 H), 1.31–1.27 (m, 3 H), 1.18 (d, J = 7.0 Hz, 4 H), 1.15 (d, J
= 7.0 Hz, 4 H), 1.08 (d, J = 6.5 Hz, 3 H), 0.78 (d, J = 7.0 Hz, 1 H)
ppm. 13C NMR (125 MHz, CDCl3): δ = 171.5, 143.2, 130.9 (2 C),
128.3 (2 C), 120.3, 60.9, 59.6 (d, J = 10.8 Hz), 58.7 (d, J = 9.8 Hz),
51.9, 43.8 (d, J = 3.5 Hz), 43.7 (d, J = 4.3 Hz), 39.8, 31.2 (d, J =
Typical Procedure for the Synthesis of N-Phosphonyl β-Amino Wein-
reb Amides by Using Chiral N-Phosphonyl Imines: In a dry vial,
under inert gas protection, was loaded N-methoxy-N-methylacet-
914
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Asymmetric Synthesis of N-Phosphonyl β-Amino Weinreb Amides
11.8 Hz), 30.5 (d, J = 9.3 Hz), 24.1, 24.0, 23.5 (d, J = 7.8 Hz), 22.8
(d, J = 3.3 Hz), 19.49, 19.46 (d, J = 2.0 Hz) ppm. 31P NMR
(202 MHz, CDCl3): δ = 22.6 ppm.
3.42 (s, 3 H), 3.40–3.31 (s, 2 H), 3.27–3.24 (m, 1 H), 3.00 (s, 3 H),
2.98–2.93 (m, 1 H), 2.86–2.79 (m, 2 H), 2.09–2.08 (m, 1 H), 2.00
(d, J = 7.0 Hz, 1 H), 2.01 (m, 2 H), 1.75 (m, 2 H), 1.37–1.28 (m, 2
H), 1.21 (dd, J = 7.0, 5.0 Hz, 6 H), 1.04 (d, J = 6.5 Hz, 3 H), 0.92
(d, J = 7.0 Hz, 3 H) ppm. 13C NMR (125 MHz, CDCl3): δ = 171.6,
140.7, 131.8, 129.4, 129.0, 128.0, 126.4, 60.9, 59.8 (d, J = 11.3 Hz),
58.8 (d, J = 9.8 Hz), 50.0, 43.8 (d, J = 3.0 Hz), 43.5 (d, J = 4.5 Hz),
36.5, 31.4 (d, J = 11.8 Hz), 30.9 (d, J = 8.8 Hz), 24.2, 24.1, 23.8 (d,
J = 7.8 Hz), 23.2 (d, J = 3.5 Hz), 19.5, 19.0 (d, J = 2.0 Hz) ppm.
31P NMR (202 MHz, CDCl3): δ = 23.2 ppm.
10j: Yellow oil. Yield: 0.285 g, 95%. [α]2D5 = –30.6 (c = 4.15, CHCl3).
1H NMR (500 MHz, CDCl3): δ = 7.64 (d, J = 9.0 Hz, 1 H), 7.47
(d, J = 9.0 Hz, 1 H), 7.28 (t, J = 8.0 Hz, 1 H), 7.08 (t, J = 9.0 Hz,
1 H), 5.07–4.92 (m, 1 H), 4.62 (t, J = 11.2 Hz, 1 H, NH), 3.48–
3.41 (m, 1 H), 3.40 (s, 3 H), 3.37–3.28 (m, 2 H), 3.00 (s, 3 H), 2.90–
2.94 (m, 1 H), 2.84–2.76 (m, 2 H), 2.10 (d, J = 7.0 Hz, 1 H), 2.00
(d, J = 7.0 Hz, 1 H), 1.75–1.74 (m, 2 H), 1.34–1.28 (m, 4 H), 1.23
(dd, J = 7.0, 4.5 Hz, 6 H), 1.01 (d, J = 6.5 Hz, 3 H), 0.84 (d, J =
6.5 Hz, 3 H) ppm. 13C NMR (125 MHz, CDCl3): δ = 171.6, 142.2,
132.2, 129.6, 128.3, 127.0, 122.2, 60.9, 59.7 (d, J = 11.3 Hz), 58.8
(d, J = 9.9 Hz), 51.9, 43.8 (d, J = 3.0 Hz), 43.5 (d, J = 4.8 Hz),
36.3, 31.4 (d, J = 11.8 Hz), 30.9 (d, J = 8.7 Hz), 24.2, 24.1, 23.9 (d,
J = 7.8 Hz), 23.3 (d, J = 3.0 Hz), 19.5, 18.8 (d, J = 2.0 Hz) ppm.
31P NMR (202 MHz, CDCl3): δ = 23.2 ppm.
10k: Yellow oil. Yield: 0.238 g, 92%. [α]2D5 = –29.7 (c = 1.68,
CHCl3). 1H NMR (500 MHz, CDCl3): δ = 7.13–7.11 (m, 1 H),
6.96–6.95 (m, 1 H), 6.90–6.88 (m, 1 H), 5.10–5.04 (m, 1 H), 3.84
(t, J = 11.0 Hz, 1 H, NH), 3.53 (s, 3 H), 3.48–3.41 (m, 2 H), 3.11
(s, 3 H), 2.98–2.93 (m, 2 H), 2.84–2.80 (m, 1 H), 2.07–2.03 (m, 2
H), 1.74 (m, 2 H), 1.33–1.29 (m, 4 H), 1.25–1.22 (m, 4 H), 1.15
(dd, J = 6.5, 12.5 Hz, 8 H), 0.96 (d, J = 7.0 Hz, 1 H) ppm. 13C
NMR (125 MHz, CDCl3): δ = 171.6, 148.8 (d, J = 2.5 Hz), 126.3,
123.9, 123.4, 61.0, 59.5 (d, J = 10.8 Hz), 58.8 (d, J = 9.8 Hz), 48.8,
43.9 (d, J = 2.8 Hz), 43.8 (d, J = 4.0 Hz), 40.3, 31.2 (d, J =
11.8 Hz), 30.7 (d, J = 9.3 Hz), 24.2, 24.1, 23.5 (d, J = 7.8 Hz), 23.1
(d, J = 4.0 Hz), 19.5, 19.4 (d, J = 2.0 Hz) ppm. 31P NMR
(202 MHz, CDCl3): δ = 22.6 ppm.
10e: Yellow oil. Yield: 0.265 g, 98%. [α]2D5 = –23.0 (c = 4.28,
1
CHCl3). H NMR (500 MHz, CDCl3): δ = 7.51 (t, J = 8.0 Hz, 1
H), 7.21–7.16 (m, 1 H), 7.09 (t, J = 8.5 Hz, 1 H), 6.97 (t, J =
8.0 Hz, 1 H), 5.01–4.95 (m, 1 H), 4.04 (t, J = 11.5 Hz, 1 H, NH),
3.49 (s, 3 H), 3.41–3.32 (m, 2 H), 3.14–3.11 (m, 1 H), 3.01 (s, 3 H),
2.97–2.91 (m, 2 H), 2.83–2.79 (m, 1 H), 2.08–2.01 (m, 2 H), 1.75
(s, 2 H), 1.33–1.27 (m, 4 H), 1.21 (d, J = 6.5 Hz, 3 H), 1.17 (d, J
= 6.5 Hz, 3 H), 1.07 (d, J = 6.5 Hz, 3 H), 1.04 (d, J = 7.0 Hz, 3 H)
ppm. 13C NMR (125 MHz, CDCl3): δ = 171.8, 160.9, 158.9, 129.3
(d, J = 4.5 Hz), 128.4 (d, J = 7.8 Hz), 123.7 (d, J = 3.0 Hz), 115.0
(d, J = 21 Hz), 61.0, 59.8 (d, J = 11.3 Hz), 58.8 (d, J = 9.8 Hz),
48.0, 43.9 (d, J = 3.0 Hz), 43.7 (d, J = 4.5 Hz), 38.3, 31.3 (d, J =
11.3 Hz), 30.7 (d, J = 9.3 Hz), 24.2, 24.1, 23.7 (d, J = 8.3 Hz), 22.9
(d, J = 4.0 Hz), 19.5, 19.4 (d, J = 2.0 Hz) ppm. 31P NMR
(202 MHz, CDCl3): δ = 23.2 ppm.
10f: Colorless oil. Yield: 0.27 g, 93%. [α]2D5 = –24.1 (c = 1.65,
1
CHCl3). H NMR (500 MHz, CDCl3): δ = 7.36 (d, J = 7.5 Hz, 1
H), 7.17 (t, J = 7.5 Hz, 1 H), 6.88 (t, J = 7.5 Hz, 1 H), 6.83 (d, J
= 7.5 Hz, 1 H), 4.91–4.85 (m, 1 H), 4.21 (t, J = 12.0 Hz, 1 H, NH),
3.85 (m, 3 H), 3.42 (s, 3 H), 3.40–3.29 (m, 2 H), 2.99 (s, 3 H), 2.97–
2.92 (m, 3 H), 2.86–2.82 (m, 1 H), 2.06–2.00 (m, 2 H), 1.75 (s, 2
H), 1.38–1.27 (m, 4 H), 1.25 (dd, J = 7.0, 10 Hz, 6 H), 1.17 (d, J
= 7.0 Hz, 3 H), 1.03 (d, J = 6.5 Hz, 3 H) ppm. 13C NMR
(125 MHz, CDCl3): δ = 172.1, 156.1, 130.9, 128.7, 127.7, 119.9,
109.9, 60.7, 59.7 (d, J = 11.3 Hz), 58.7 (d, J = 9.8 Hz), 54.8, 44.9,
43.7 (d, J = 2.8 Hz), 43.5 (d, J = 4.3 Hz), 37.8, 31.2 (d, J =
11.8 Hz), 30.6 (d, J = 8.8 Hz), 24.1, 24.0, 23.5 (d, J = 7.8 Hz), 22.8
(d, J = 3.3 Hz), 19.3, 8.8 ppm. 31P NMR (202 MHz, CDCl3): δ =
23.5 ppm.
10g: Colorless oil. Yield: 0.28 g, 95%. [α]2D5 = –28.9 (c = 0.39,
1
CHCl3). H NMR (500 MHz, CDCl3): δ = 7.89 (t, J = 8.0 Hz, 2
H), 7.60 (t, J = 7.5 Hz, 1 H), 7.38 (t, J = 7.5 Hz, 1 H), 5.43–5.36
(m, 1 H), 4.57 (t, J = 11.0 Hz, 1 H, NH), 3.46 (s, 3 H), 3.39–3.26
(m, 2 H), 3.21–3.17 (m, 1 H), 3.00 (m, 3 H), 2.95–2.91 (m, 2 H),
2.79–2.76 (m, 1 H), 2.08–1.97 (m, 3 H), 1.75–1.72 (m, 2 H), 1.38–
1.25 (m, 3 H), 1.20 (dd, J = 6.5, 11.0 Hz, 6 H), 1.01 (d, J = 7.0 Hz,
3 H), 0.88 (d, J = 7.0 Hz, 3 H) ppm. 13C NMR (125 MHz, CDCl3):
δ = 171.6, 147.9, 139.0, 132.8, 130.4, 127.8, 124.3, 61.1, 59.8 (d, J
= 11.3 Hz), 58.7 (d, J = 9.8 Hz), 48.6, 43.9 (d, J = 3.5 Hz), 43.7 (d,
J = 5.0 Hz), 38.0, 31.3 (d, J = 11.0 Hz), 30.9 (d, J = 8.8 Hz), 24.3,
24.1, 23.8 (d, J = 7.8 Hz), 23.2 (d, J = 3.0 Hz), 19.5, 19.2 (d, J =
2.0 Hz) ppm. 31P NMR (202 MHz, CDCl3): δ = 23.2 ppm.
Procedure for the Removal of the Chiral N-Phosphonyl Group from
10a: Into a 50-mL round-bottomed flask was added product 10a
(0.438 g) and methanol (6.0 mL). To this solution was added aque-
ous HCl (8.0 equiv.), and the reaction mixture was stirred at room
temperature for 5 h. The reaction was monitored by TLC, and
completion of the reaction was indicated by the disappearance of
the starting material on TLC. Volatiles were evaporated under vac-
uum, and the solid residue was extracted with ethyl acetate and
saturated NaHCO3. The organic layer was dried with sodium sul-
fate. Sodium sulfate was filtered off, and the organic layer was dried
under vacuum to get the crude reaction mixture, which was further
subjected to column chromatography to obtain pure product 11 as
a yellow oil. [α]2D5 = +22.8 (c = 0.90, CHCl3) {ref.[14a] [α] = –23.8 (c
10h: Yellow oil. Yield: 0.264 g, 96%. [α]2D5 = –23.5 (c = 0.42,
1
CHCl3). H NMR (500 MHz, CDCl3): δ = 7.43 (d, J = 8.0 Hz, 1
H), 7.17–7.14 (m, 1 H), 7.10–7.06 (m, 2 H), 5.06–5.00 (m, 1 H),
4.05 (t, J = 11.0 Hz, 1 H, NH), 3.37–3.24 (m, 5 H), 3.03 (s, 3 H),
3.00–2.90 (m, 1 H), 2.77–2.75 (m, 2 H), 2.42 (s, 3 H), 2.07–1.99 (m,
2 H), 1.74–1.73 (m, 2 H), 1.33–1.25 (m, 5 H), 1.16 (d, J = 7.0 Hz,
3 H), 1.12 (d, J = 7.0 Hz, 3 H), 1.08 (d, J = 7.0 Hz, 3 H), 1.01 (d,
J = 7.0 Hz, 3 H) ppm. 13C NMR (125 MHz, CDCl3): δ = 171.7,
142.4, 134.1, 130.1, 126.6, 126.4, 125.8, 64.2, 60.8, 59.8 (d, J =
11.0 Hz), 58.8 (d, J = 9.8 Hz), 49.2, 45.4, 43.8 (d, J = 3.0 Hz), 38.5,
31.5 (d, J = 11.8 Hz), 30.8 (d, J = 9.3 Hz), 29.6, 24.3 (d, J =
7.3 Hz), 23.7 (d, J = 7.8 Hz), 23.0 (d, J = 3.5 Hz), 19.5, 19.2 (d, J
= 2.5 Hz) ppm. 31P NMR (202 MHz, CDCl3): δ = 23.3 ppm.
1
= 1.00, CHCl3)}. H NMR (500 MHz, CDCl3): δ = 7.36–7.32 (m,
5 H, Ph), 4.50 (dd, J = 3.0, 9.0 Hz, 1 H), 3.62 (s, 3 H, OCH3), 3.17
(s, 3 H, NCH3), 2.91–2.76 (m, 2 H), 1.68 (s, 2 H, NH2) ppm. 13C
NMR (125 MHz, CDCl3): δ = 172.5, 144.0, 128.6 (2 C), 127.4,
126.7, 126.2, 61.1, 52.1, 41.0, 21.8 ppm.
Acknowledgments
10i: Colorless oil. Yield: 0.271 g, 93%. [α]2D5 = –26.7 (c = 1.65,
1
CHCl3). H NMR (500 MHz, CDCl3): δ = 7.63 (d, J = 8.0 Hz, 1 We would like to thank the Robert A. Welch Foundation (D-1361)
H), 7.29 (d, J = 10.0 Hz, 1 H), 7.24 (t, J = 8.0 Hz, 1 H), 7.15 (t, J
= 8.0 Hz, 1 H), 5.07–5.02 (m, 1 H), 4.49 (t, J = 11.5 Hz, 1 H, NH),
and the National Science Foundation-MRI (DMR-0619215) for
providing us with financial assistance. We thank our coworkers Dr.
Eur. J. Org. Chem. 2009, 912–916
© 2009 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
915

P. Kaur, T. Nguyen, G. Li
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Received: October 28, 2008
Published Online: January 12, 2009
2914.
916
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Eur. J. Org. Chem. 2009, 912–916