Asymmetric carbamoyl anion additions to chiral N-phosphonyl imines via the GAP chemistry process and stereoselectivity enrichments

Article abstract of DOI:10.1021/jo5024443

Carbamoyl anions were found to smoothly react with chiral N-phosphonyl imines in toluene at -78 °C to r.t. using LiHMDS as the base. Group-assisted purification (GAP) has been utilized to give the pure amides without using column chromatography or recryst

Full text of DOI:10.1021/jo5024443

Article
pubs.acs.org/joc
Asymmetric Carbamoyl Anion Additions to Chiral N‑Phosphonyl
Imines via the GAP Chemistry Process and Stereoselectivity
Enrichments
Cole W. Seifert,† Suresh Pindi,† and Guigen Li*,†,‡
†Department of Chemistry and Biochemistry, Texas Tech University, Lubbock, Texas 79409-1061, United States
‡Institute of Chemistry & BioMedical Sciences (ICBMS), Nanjing University, Nanjing 210093, P. R. China
S
* Supporting Information
ABSTRACT: Carbamoyl anions were found to smoothly react
with chiral N-phosphonyl imines in toluene at −78 °C to r.t.
using LiHMDS as the base. Group-assisted purification (GAP)
has been utilized to give the pure amides without using column
chromatography or recrystallization. The asymmetric reaction
resulted in chiral N-phosphonyl amino amides with good to
excellent yields (71−99%) and good crude diastereoselectivities
(dr 84:16−95:5). In this GAP procedure, the crude solids are
washed with diethyl ether to afford the pure products, as revealed
1
by H NMR analysis; GAP washing consistently increases the
diastereopurity of the products, resulting in excellent diaster-
eoselectivities, often with final dr > 99:1. Interestingly, the diastereoenriched products can be obtained either in the ether solution
or as the suspended solid, depending on the substrate.
from the chiral auxiliary-protected imines.18−21 This new class
of chiral auxiliaries has been applied to various asymmetric
INTRODUCTION
■
Chiral amines are ubiquitous throughout natural products and
reactions, such as borylation, the Umpolung reaction, the aza-
pharmaceuticals, and their efficient and economical synthesis is
Henry reaction, and several others.22−25 In addition to their
still a highly active research area.1−6 The most important
ability to effectively induce asymmetry in a variety of ways,
subclass of chiral amines are chiral α-amino amides, which form
the basic chemical unit of amino acids and peptides.7 The
these new auxiliaries also have the added bonus of simplifying
the purification process by eliminating the need for silica
synthesis of unnatural α-amino amides is often carried out via a
Strecker-type process.8−11 This process frequently employs the
column chromatography. While silica column chromatography
is a standard purification method used in organic synthesis, it is
cyanide ion, which requires two additional steps using harsh
conditions to achieve the desired amides. Strong acids and heat
often unsuitable for large-scale purification due to the high cost
of silica. Also, the large amount of solvent waste generated can
are usually needed to convert the cyanide group into the
carboxylic acid, followed by amide formation.12−14 Phenyl-
prove harmful to the environment. In contrast, compounds
glycine has been shown to racemize under these conditions,15
containing our phosphonyl auxiliaries can be purified by
washing the crude solid products with simple solvents or
and therefore, the synthesis of phenylglycine amides would be
solvent mixtures.22−25 This cuts costs by reducing labor and by
better accomplished through other routes. One alternative for
eliminating the expensive silica gel associated with column
the synthesis of phenylglycine amides is through the direct
chromatography; it also greatly reduces solvent waste, creating
addition of a carbamoyl anion to the corresponding imine.
a more environmentally friendly procedure. In some cases, this
Carbamoyl anions can be easily generated from the appropriate
washing procedure can even increase the diastereomeric and/or
formamide through simple deprotonation with amide bases,
enantiomeric purity of the final product.24−26 This simplified
and more economical purification method has been termed
GAP chemistry: A chemistry for organic synthesis that avoids
traditional purification methods such as chromatography and/or
recrystallization. GAP chemistry requires considerations in
regard to (1) adequate stability and chemical reactivity of
functional group-attached substrates; (2) solid products that are
such as lithium diisopropyl amide.16 Senanayake and co-
workers recently reported the asymmetric carbamoyl anion
addition to imines as a direct synthetic route to chiral α-amino
amides, through the use of chiral N-sulfinyl auxiliary
chemistry.17 In their report, the carbamoyl anion can directly
add to the imine of choice, affording the α-amino amide in one
step under mild conditions.
Over the past few years, our research group has focused on
the synthesis of various chiral N-phosphonyl and N-phosphinyl
auxiliaries, for use in asymmetric syntheses of chiral amines
Received: October 25, 2014
© XXXX American Chemical Society
A
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soluble in some solvents (e.g., THF and DCM), but not well
soluble in some other solvents (e.g., petroleum ethers, hexane,
and their cosolvents with EtOAc, etc.); (3) stereoselectivity
control in asymmetric reactions (for chiral GAP reagents); (4)
substrate scope; (5) cleavage and recyclability for reuse, etc. In
this paper, we report the asymmetric addition of carbamoyl
anions to chiral N-phosphonyl imines for the synthesis of
various derivatized phenylglycine amides, followed by GAP
(Scheme 1).
tions.16,17,27 Our starting substrate was 1-protected benzylidine
imine; to our surprise, no desired product was observed. 31P
and 1H NMR analysis of the reaction mixture revealed that the
imine was suffering from decomposition, affording benzalde-
hyde and 1-NH2 as the reaction products. In an attempt to
stabilize the imine, various solvents were tested, including THF,
DCM, acetonitrile, and DMF, but none were successful as all
gave the same, undesired decomposition product (entries 2−5).
In an effort to stabilize the imine by weakening the electron-
withdrawing nature of the auxiliary, we changed from N-
phosphinyl 1 to N-phosphonyl 2. The change proved effective,
and we obtained the desired product in 70% conversion with dr
= 75:25 (entry 6). Changing the base to LiHMDS further
improved the reaction, increasing the conversion to 87% (entry
7). Changing the solvent to THF reduced the conversion to
61%, affording a greater portion of the decomposition
byproducts (entry 8). In an effort to increase the dr, we
changed the auxiliary to 3. Using toluene as the solvent, with
LiHMDS as the base, we obtained our best result with 91%
conversion to product and dr = 85:15 (entry 9).
Scheme 1
We next examined the GAP capabilities of this product using
compound 5a. Washing the crude (after extraction) with
diethyl ether showed promise by providing a white solid after
washing. To our delight, NMR analysis of the solid after
washing showed slight diastereoenrichment. We later found
that suspension of the crude solid in diethyl ether for 24 h,
followed by filtration, could afford a highly diastereoenriched
product as the suspended solid. During our examination of the
substrate scope, we also discovered that some substrates were
diastereoenriched in the ether solution, and not in the
suspended solid. This is in direct contrast to our previous
observations of GAP chemistry, where washing has consistently
enriched the solid products by removing the minor isomer in
the wash solution. We have termed this observation as a
reverse-GAP stereoselectivity enrichment, due to its reverse
nature from the previously observed GAP phenomenon. As can
be seen in Table 2, both GAP and reverse-GAP enhancements
are highly effective at diastereoenrichment, with seven examples
showing dr > 99:1. As an added bonus, the phase not
containing the enriched product generally has a diastereomeric
ratio near 50:50. This phenomenon is equally true for both the
GAP and the reverse-GAP enhancements, and results in high
yields for the isolated, enriched products. This can be easily
seen through 31P NMR analysis of two substrates: 5c for the
GAP process, and 5d for the reverse-GAP stereoselectivity
enhancement (Figure 1). For the reverse-GAP enhancement,
pure enriched products can be precipitated from the diethyl
ether solution via addition of petroleum ether, to remove any
nondiastereomeric impurities, which tend to stay in the ether
solution during GAP ether washing. In order to isolate the α-
amino amides, the auxiliary can be cleaved from the products
under mild conditions, using a 5:1 mixture of methanol:1.0 N
HCl (aq) at room temperature over 1 h, followed by Boc
protection, affording 6c, which is a known compound28
(Scheme 2).
RESULTS AND DISCUSSION
■
Our studies began by optimizing the reaction conditions (Table
1). We started by testing the reaction in toluene at −78 °C
using LDA, one of the most common amide bases and a
relatively standard condition for carbamoyl anion addi-
Table 1. Optimization of Reaction Conditions and Auxiliary
a
b
entry
aux*
solvent
base
LDA
yield (%)
dr
c
1
2
3
4
5
6
7
8
9
1
1
1
1
1
2
2
2
3
PhCH3
THF
0
N/A
N/A
N/A
N/A
N/A
75:25
75:25
75:25
85:15
c
LDA
0
c
DCM
LDA
0
d
c
MeCN
LDA
0
d
c
DMF
LDA
0
PhCH3
PhCH3
THF
LDA
70
87
61
91
Absolute configuration was determined from X-ray analysis
of 5c, revealing the newly formed stereocenter to be (S). The
crystal structure is shown in Figure 2. From this information,
we can propose a possible transition state for this trans-
formation. As seen in Figure 3, we propose a six-membered
transition state, with the lithium coordinating both to the
phosphonyl and the carbamoyl oxygens, as well as the
carbamoyl carbon. Studies by Senanayake and co-workers
LiHMDS
LiHMDS
LiHMDS
PhCH3
a
b
% conversion based on 31P NMR of reaction mixture. Based on
c
analysis of 1H and 31P NMR data of reaction mixture. Imine
d
decomposed into phosphinamide and benzaldehyde. Reaction
mixture solidified at −78 °C, then liquefied with slow warming to r.t.
B
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Table 2. Substrate Scope with GAP and Reverse-GAP Purification
a
b
c
d
imine
product
R
NR′2
NMe2
yield (%)
dr
GAP yield (%)
GAP dr (g/rg)
4a
4b
4c
4d
4e
4f
5a
5b
5c
5d
5e
5f
Ph
Ph
Ph
74
99
97
90
73
86
81
84
71
99
75
85:15
84:16
87:13
85:15
86:14
86:14
86:14
86:14
84:16
85:15
95:5
45
55
63
54
60
50
52
41
36
62
59
93:7 (g)
pyrrolidine
morpholine
morpholine
morpholine
morpholine
morpholine
morpholine
morpholine
morpholine
morpholine
93:7 (g)
>99:1 (g)
>99:1 (rg)
92:8 (g)
1-Nap
p-FPh
p-ClPh
m-BrPh
p-MePh
o-MePh
p-BnOPh
tBu
>99:1 (rg)
95:5 (g)
4g
4h
4i
5g
5h
5i
>99:1 (rg)
>99:1 (g)
>99:1 (rg)
>99:1 (rg)
4j
5j
4k
5k
a
b
c
Isolated crude yields after workup and extraction. Crude dr as determined by 1H and 31P NMR analysis of the crude solids. Isolated total yields of
d
purified compounds after GAP ether washing. Products purified by either the GAP (g) or reverse-GAP (rg) enrichment; dr values after GAP ether
washing as determined by H and 31P NMR analysis.
1
Figure 1. 31P NMR spectra of solid and solution phase after GAP ether washing for substrates 5c and 5d.
have shown through 13C NMR data that, after carbamoyl anion
formation, the lithium is coordinated to both the carbamoyl
carbon and oxygen, and so this has been included in our
transition state.17 The position of the isopropyl group partially
below the ring creates a strong 1,3-diaxial steric interaction,
causing the imine to orient itself such that the R group is in the
equatorial position. This facilitates Re face attack by the
carbamoyl carbon, selectively forming the (S) isomer.
C
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Scheme 2
EXPERIMENTAL SECTION
■
General Methods. ACS grade toluene was distilled over CaH2
under argon prior to use. LiHMDS in THF/ethylbenzene was
purchased and used within 1 month after arrival. HRMS analysis of
new compounds was performed using an Orbitrap mass analyzer.
Synthesis of Compounds 4a−j. These compounds were
synthesized according to the procedures found in the literature.19,21,22
1H and 31P NMR data for these compounds match the literature data.
Synthesis of Compound 4k. 3-NH2 (736 mg, 2.84 mmol),
pivalaldehyde (316 μL, 2.84 mmol), DCM (12.0 mL), and
triethylamine (1.20 mL, 8.52 mmol) were added, respectively, in a
20 mL scintillation vial and stirred at rt until dissolved. TiCl4 (2.41 mL
of 1.0 M solution in DCM) was added dropwise, the vial was capped,
and the solution was stirred at rt overnight. After completion of the
reaction, the reaction mixture was filtered through a short pad of silica.
The silica pad was washed with DCM to remove any unreacted
aldehyde, and then washed with ethyl acetate to recover the product.
Evacuation of the solvent afforded 4k (563 mg, 61%) as a yellow oil.
The compound was not pure enough for analysis and was carried on to
the next step as an intermediate without further purification. This
course of action was taken due to the instability of the compound on
silica, preventing further purification.
General Procedure for the Synthesis of Compounds 5a−k. A
10 mL Schlenk tube was equipped with a stir bar, flame-dried under
vacuum, and backfilled with argon under positive pressure. Imine (1.0
mmol), toluene (3.0 mL), and then formamide (3.0 mmol) were
added, respectively, with stirring. The reaction was cooled to −78 °C
with CO2/acetone, followed by the dropwise addition of LiHMDS
(3.0 mL of a 1.0 M solution in THF/ethylbenzene). After stirring
overnight with slow warming to room temperature, the reaction was
quenched with 0.3 M citric acid. The bilayer was separated, the organic
layer washed ×2 with citric acid, and the aqueous layer washed ×1
with toluene. The combined organic layers were washed ×2 with 30%
methanol/water to remove the formamide, and the aqueous layer was
washed again ×1 with toluene. Finally, the combined organic layers
were washed with brine, dried over MgSO4, filtered, and evacuated to
afford the crude product.
Figure 2. X-ray structure of 5c.
General Procedure for GAP Purification (Solid Enrichment).
At room temperature, the crude solid was suspended in an appropriate
amount of diethyl ether, such that there was 30 μL ether/mg solid.
The suspension was stirred overnight, after which the suspended solid
was removed via filtration. The filtered solid was washed once with
diethyl ether, then dried under vacuum to afford the diastereoenriched
and purified product.
General Procedure for Reverse-GAP Purification (Liquid
Enrichment). At room temperature, the crude solid was suspended in
an appropriate amount of diethyl ether, such that there was 10 μL
ether/mg solid. The suspension was stirred overnight, after which the
suspended solid was removed via filtration. The filtered solution was
evacuated, and the resulting solid was redissolved in a minimal amount
of diethyl ether. Addition of petroleum ether caused a white solid
precipitate, which solid was recovered via a second filtration as the
diastereoenriched and purified product.
Figure 3. Proposed six-membered transition state.
CONCLUSION
Data for Pure Compounds 5a−k. Compound 5a. White solid;
■
yield 454 mg, 74%; mp 162−164 °C; [α]1D0 = +14.82° (c 0.162,
In summary, we have been able to successfully apply the
carbamoyl anion addition to chiral N-phosphonyl imines for the
direct synthesis of phenylglycine amide derivatives, without
using column chromatography or recrystallization. The amides
can be synthesized in good yields and diastereoselectivities,
with excellent diastereoselectivities after purification. Both GAP
and reverse-GAP enrichments were developed for the
purification of these isomeric products. Simply washing the
crudes via suspension in ether can afford the diastereoenriched
products in either the suspended solid (GAP enrichment) or
the ether solution (reverse-GAP enrichment). Selection for
either process is determined by the chemical nature of the
substrate.
CHCl3); 1H NMR (400 MHz, CDCl3): δ = 7.42−7.39 (m, 2H), 7.32−
7.28 (m, 2H), 7.25−7.21 (m, 1H), 5.35−5.31 (t, J = 9.2 Hz, 1H),
3.75−3.70 (t, J = 10.4 Hz, 1H), 3.40−3.28 (m, 1H), 3.12−2.97 (m,
1H), 2.95 (s, 6H), 2.93−2.85 (m, 1H), 2.79−2.72 (m, 1H), 2.03−1.94
(m, 2H), 1.77−1.68 (m, 2H), 1.35−1.09 (m, 4H), 1.19−1.17 (d, J =
6.8 Hz, 3H), 1.12−1.10 (d, J = 6.8 Hz, 3H), 1.02−1.01 (d, J = 6.8 Hz,
3H), 0.88−0.87 (d, J = 6.8 Hz, 3H); 13C NMR (100 MHz, CDCl3): δ
= 171.86−171.79 (d, J = 6.6 Hz), 140.85, 128.80, 127.68, 127.62,
60.04−59.93 (d, J = 10.5 Hz), 59.01−58.90 (d, J = 10.5 Hz), 56.38−
56.35 (d, J = 2.9 Hz), 53.56, 44.18−44.14 (d, J = 3.8 Hz), 44.03−44.00
(d, J = 2.7 Hz), 37.24, 36.17, 31.73, 31.24−31.13 (d, J = 11.4 Hz),
30.36−30.26 (d, J = 9.6 Hz), 24.49, 23.05−22.99 (d, J = 5.7 Hz),
D
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22.79, 22.20−22.17 (d, J = 2.9 Hz), 20.09, 19.82, 14.26; 31P NMR
(162 MHz, CDCl3): δ = 21.91; HRMS (ESI): m/z calcd for
3.8 Hz), 44.04−44.01 (d, J = 2.9 Hz), 42.84, 31.09−30.97 (d, J = 11.5
Hz), 30.23−30.14 (d, J = 9.6 Hz), 24.43, 22.98−22.91 (d, J = 6.7 Hz),
[C22H37N4O2P + H]+: 421.2732, found: 421.2736.
22.08−22.04 (d, J = 3.8 Hz), 20.22, 19.88; 31P NMR (162 MHz,
CDCl3): δ = 21.72; HRMS (ESI): m/z calcd for [C24H38FN4O3P +
Compound 5b. White solid; yield 446 mg, 99%; mp 163−165 °C;
1
[α]1D0 = +3.22° (c 0.250, CHCl3); H NMR (400 MHz, CDCl3): δ =
H]+: 481.2744, found: 481.2760.
7.42−7.39 (m, 2H), 7.31−7.27 (m, 2H), 7.25−7.20 (m, 1H), 5.14−
5.10 (t, J = 9.0 Hz, 1H), 3.75−3.70 (t, J = 10.4 Hz, 1H), 3.65−3.59 (m,
1H), 3.55−3.47 (m, 1H), 3.43−3.27 (m, 2H), 3.20−3.00 (m, 2H),
2.92−2.84 (m, 1H), 2.79−2.71 (m, 1H), 2.04−1.94 (m, 2H), 1.94−
1.76 (m, 4H), 1.76−1.67 (m, 2H), 1.38−1.18 (m, 4H), 1.12−1.15 (d, J
= 6.8 Hz, 3H), 1.10−1.08 (d, J = 6.4 Hz, 3H), 1.04−1.02 (d, J = 6.8
Compound 5f. White solid; yield 427 mg, 86%; mp 207−209 °C;
1
[α]1D0 = +4.00° (c 0.200, CHCl3); H NMR (400 MHz, CDCl3): δ =
7.36−7.34 (d, J = 8.4 Hz, 2H), 7.31−7.28 (d, J = 8.4 Hz, 2H), 5.38−
5.34 (t, J = 9.0 Hz, 1H), 3.68−3.45 (m, 7H), 3.40−3.20 (m, 3H),
3.07−2.96 (m, 1H), 2.92−2.86 (m, 1H), 2.77−2.72 (m, 1H), 2.04−
1.96 (m, 2H), 1.79−1.71 (m, 2H), 1.37−1.10 (m, 4H), 1.23−1.22 (d, J
= 6.8 Hz, 3H), 1.15−1.13 (d, J = 6.4 Hz, 3H), 1.02−1.00 (d, J = 7.2
Hz, 3H), 0.90−0.89 (d, J = 6.8 Hz, 3H); 13C NMR (100 MHz,
CDCl3): δ = 170.21−170.14 (d, J = 6.7 Hz), 140.66, 128.70, 127.75,
127.66, 60.03−59.92 (d, J = 10.5 Hz), 59.01−58.91 (d, J = 9.5 Hz),
57.81, 46.43, 46.24, 44.12−44.08 (d, J = 3.8 Hz), 31.20−31.09 (d, J =
11.4 Hz), 30.37−30.28 (d, J = 9.6 Hz), 26.08, 24.47, 24.18, 22.99−
Hz, 3H), 0.90−0.89 (d, J = 7.2 Hz, 3H); 13C NMR (100 MHz,
CDCl3): δ = 170.14−170.06 (d, J = 7.6 Hz), 139.52−139.50 (d, J = 1.9
Hz), 133.75, 129.14, 128.88, 66.83, 66.42, 59.98−59.88 (d, J = 10.5
Hz), 59.02−58.91 (d, J = 10.5 Hz), 55.56−55.54 (d, J = 2.8 Hz),
46.14, 44.21−44.17 (d, J = 3.8 Hz), 44.10−44.08 (d, J = 2.9 Hz),
31.12−31.00 (d, J = 11.5 Hz), 30.26−30.16 (d, J = 9.5 Hz), 24.46,
23.01−22.96 (d, J = 5.7 Hz), 22.12−22.08 (d, J = 3.8 Hz), 20.27,
22.94 (d, J = 5.7 Hz), 22.25, 20.03, 19.83; 31P NMR (162 MHz,
CDCl3): δ = 21.98; HRMS (ESI): m/z calcd for [C24H39N4O2P +
H]+: 447.2889, found: 447.2893.
19.94; 31P NMR (162 MHz, CDCl3): δ = 21.72; HRMS (ESI): m/z
calcd for [C24H38ClN4O3P + H]+: 497.2448, found: 497.2460.
Compound 5c. White solid; yield 446 mg, 97%; mp 176−178 °C;
1
[α]1D0 = +5.91° (c 0.238, CHCl3); H NMR (400 MHz, CDCl3): δ =
7.39−7.37 (m, 2H), 7.32−7.28 (m, 2H), 7.26−7.22 (m, 1H), 5.36−
5.32 (t, J = 8.8 Hz, 1H), 3.68−3.46 (m, 7H), 3.40−3.30 (m, 2H),
3.17−3.07 (m, 1H), 3.07−2.95 (m, 1H), 2.91−2.85 (m, 1H), 2.76−
2.72 (m, 1H), 2.03−1.92 (m, 2H), 1.78−1.67 (m, 2H), 1.37−1.14 (m,
4H), 1.21−1.19 (d, J = 7.2 Hz, 3H), 1.13−1.11 (d, J = 7.2 Hz, 3H),
Compound 5g. White solid; yield 438 mg, 81%; mp 212−214 °C;
1
[α]1D0 = +1.86° (c 0.700, CHCl3); H NMR (400 MHz, CDCl3): δ =
7.56−7.55 (t, J = 1.8 Hz, 1H), 7.40−7.36 (m, 1H), 7.34−7.30 (m,
1H), 7.19−7.15 (t, J = 7.8 Hz, 1H), 5.37−5.32 (t, J = 8.8 Hz, 1H),
3.69−3.49 (m, 7H), 3.40−3.20 (m, 3H), 3.07−2.94 (m, 1H), 2.91−
2.84 (m, 1H), 2.77−2.68 (m, 1H), 2.03−1.93 (m, 2H), 1.78−1.67 (m,
2H), 1.37−1.10 (m, 4H), 1.21−1.19 (d, J = 7.2 Hz, 3H), 1.13−1.11
(d, J = 6.8 Hz, 3H), 1.02−1.00 (d, J = 6.8 Hz, 3H), 0.90−0.89 (d, J =
1.01−0.99 (d, J = 6.8 Hz, 3H), 0.86−0.84 (d, J = 6.8 Hz, 3H); 13C
NMR (100 MHz, CDCl3): δ = 170.46−170.38 (d, J = 7.6 Hz),
140.88−140.86 (d, J = 1.9 Hz), 128.96, 127.85, 127.42, 66.80, 66.34,
59.99−59.87 (d, J = 12.4), 58.96−58.86 (d, J = 9.5 Hz), 56.33−56.30
(d, J = 2.9 Hz), 46.12, 44.17−44.13 (d, J = 3.8 Hz), 43.99−43.96 (d, J
= 2.8 Hz), 42.86, 31.18−31.07 (d, J = 11.4 Hz), 30.29−30.19 (d, J =
9.5 Hz), 24.45, 23.04−22.97 (d, J = 6.7 Hz), 22.13−22.11 (d, J = 2.9
6.8 Hz, 3H); 13C NMR (100 MHz, CDCl3): δ = 169.87−169.80 (d, J
= 7.6 Hz), 143.15, 131.01, 130.48, 130.31, 126.14, 122.96, 66.82,
66.39, 59.94−59.85 (d, J = 10.5 Hz), 58.98−58.87 (d, J = 10.5 Hz),
55.64−55.60 (d, J = 3.8 Hz), 46.15, 44.17−44.13 (d, J = 3.8 Hz),
44.08−44.05 (d, J = 2.9 Hz), 42.88, 31.11−30.99 (d, J = 11.4 Hz),
30.20−30.11 (d, J = 9.5 Hz), 24.42, 23.04−22.98 (d, J = 6.7 Hz),
Hz), 20.17, 19.84; 31P NMR (162 MHz, CDCl3): δ = 21.79; HRMS
(ESI): m/z calcd for [C24H39N4O3P + H]+: 463.2838, found:
463.2839.
22.02−21.99 (d, J = 2.9 Hz), 20.23, 19.85; 31P NMR (162 MHz,
CDCl3): δ = 21.67; HRMS (ESI): m/z calcd for [C24H38BrN4O3P +
H]+: 541.1943, found: 541.1960.
Compound 5d. White solid; yield 461 mg, 90%; mp 105−107 °C;
[α]1D0 = +15.11° (c 0.225, CHCl3); 1H NMR (400 MHz, CDCl3): δ =
8.71−8.69 (d, J = 8.0 Hz, 1H), 7.85−7.83 (d, J = 8.0 Hz, 1H), 7.79−
7.77 (d, J = 8.1 Hz, 1H), 7.61−7.56 (m, 1H), 7.52−7.48 (m, 2H),
7.42−7.38 (t, J = 7.6 Hz, 1H), 6.11−6.06 (t, J = 9.6 Hz, 1H), 3.79−
3.29 (m, 8H), 3.07−2.75 (m, 5H), 2.01−1.89 (m, 2H), 1.74−1.65 (m,
2H), 1.35−1.07 (m, 4H), 1.24−1.23 (d, J = 6.8 Hz, 3H), 1.16−1.15
(d, J = 6.8 Hz, 3H), 0.86−0.84 (d, J = 6.8 Hz, 3H), 0.54−0.52 (d, J =
Compound 5h. White solid; yield 400 mg, 84%; mp 195−197 °C;
1
[α]1D0 = +4.32° (c 0.162, CHCl3); H NMR (400 MHz, CDCl3): δ =
7.27−7.24 (d, J = 8.4 Hz, 2H), 7.11−7.09 (d, J = 8.0 Hz, 2H), 5.33−
5.29 (t, J = 9.0 Hz, 1H), 3.67−3.46 (m, 7H), 3.40−3.28 (m, 2H),
3.18−3.13 (m, 1H), 3.11−3.00 (m, 1H), 2.91−2.85 (m, 1H), 2.77−
2.70 (m, 1H), 2.31 (s, 3H), 2.20−1.94 (m, 2H), 1.77−1.68 (m, 2H),
1.38−1.90 (m, 4H), 1.21−1.19 (d, J = 6.8 Hz, 3H), 1.13−1.11 (d, J =
6.8 Hz, 3H), 1.03−1.02 (d, J = 6.8 Hz, 3H), 0.88−0.86 (d, J = 6.8 Hz,
6.8 Hz, 3H); 13C NMR (100 MHz, CDCl3): δ = 171.25−171.19 (d, J
= 5.7 Hz), 137.01−136.98 (d, J = 3.0 Hz), 134.29, 130.61, 128.88−
128.79 (d, J = 9.5 Hz), 126.82, 126.12, 125.55, 124.32, 66.79, 66.12,
59.90−59.79 (d, J = 11.4 Hz), 59.06−58.96 (d, J = 10.5 Hz), 53.96,
45.99, 44.16−44.12 (d, J = 3.8 Hz), 43.78−43.74 (d, J = 3.8 Hz),
43.06, 31.26-31.15 (d, J = 11.5 Hz), 30.54−30.44 (d, J = 9.5 Hz),
24.48, 22.92−22.85 (d, J = 6.7 Hz), 22.56−22.53 (d, J = 3.8 Hz),
3H); 13C NMR (100 MHz, CDCl3): δ = 170.67−170.60 (d, J = 6.7
Hz), 137.81, 137.53, 129.59, 127.32, 66.82, 66.40, 60.02−59.90 (d, J =
11.5 Hz), 59.01−58.90 (d, J = 10.5 Hz), 55.94, 46.13, 44.15−44.01 (d,
J = 14.3 Hz), 42.84, 31.21−31.10 (d, J = 11.5 Hz), 30.34−30.24 (d, J =
9.6 Hz), 24.47, 23.08−23.02 (d, J = 5.7 Hz), 22.15, 21.25, 20.18,
20.08, 19.42; 31P NMR (162 MHz, CDCl3): δ = 21.67; HRMS (ESI):
19.89; 31P NMR (162 MHz, CDCl3): δ = 21.94; HRMS (ESI): m/z
calcd for [C25H41N4O3P + H]+: 477.2995, found: 477.2994.
Compound 5i. White solid; yield 340 mg, 71%; mp 162−164 °C;
m/z calcd for [C28H41N4O3P + H]+: 513.2995, found: 513.3005.
Compound 5e. White solid; yield 340 mg, 73%; mp 215−217 °C;
1
[α]1D0 = +7.76° (c 0.438, CHCl3); H NMR (400 MHz, CDCl3): δ =
[α]1D0 = +24.06° (c 0.188, CHCl3); 1H NMR (400 MHz, CDCl3): δ =
7.33−7.28 (m, 1H), 7.16−7.11 (m, 3H), 5.51−5.46 (t, J = 9.2 Hz,
1H), 3.76−3.31 (m, 8H), 3.15−3.30 (m, 1H), 3.04−2.93 (m, 2H),
2.92−2.83 (m, 1H), 2.82−2.73 (m, 1H), 2.05−1.92 (m, 2H), 1.77−
1.68 (m, 2H), 1.40−1.10 (m, 4H), 1.24−1.22 (d, J = 6.8 Hz, 3H),
1.16−1.15 (d, J = 6.4 Hz, 3H), 0.98−0.96 (d, J = 6.8 Hz, 3H), 0.84−
7.39−7.35 (m, 2H), 7.02−6.96 (t, J = 8.8 Hz, 2H), 5.37−5.33 (t, J =
8.8 Hz, 1H), 3.67−3.48 (m, 7H), 3.39−3.26 (m, 2H), 3.20−3.13 (m,
1H), 3.04−2.94 (m, 1H), 2.90−2.84 (m, 1H), 2.75−2.69 (m, 1H),
1.35−1.09 (m, 4H), 1.22−1.20 (t, J = 7.2 Hz, 3H), 1.13−1.12 (t, J =
6.8 Hz, 3H), 1.00−0.98 (t, J = 6.8 Hz, 3H), 0.88−0.86 (t, J = 7.2 Hz,
3H); 13C NMR (100 MHz, CDCl3): δ = 170.29−170.23 (d, J = 6.7
Hz), 163.54, 161.09, 136.92, 129.23−129.14 (d, J = 8.5 Hz), 115.91,
155.67, 66.81, 66.37, 59.95−59.84 (d, J = 10.5 Hz), 58.97−58.86 (d, J
= 10.5 Hz), 55.49−55.45 (d, J = 3.8 Hz), 46.11, 44.18−44.14 (d, J =
0.82 (d, J = 6.8 Hz, 3H); 13C NMR (100 MHz, CDCl3): δ = 171.06−
170.99 (d, J = 6.7 Hz), 139.15, 135.44, 131.25, 127.80, 126.70, 66.82,
66.25, 59.92−59.81 (d, J = 11.4 Hz), 59.09−58.99 (d, J = 10.5 Hz),
E
dx.doi.org/10.1021/jo5024443 | J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Article
54.10, 45.80, 44.10, 43.15, 31.05−30.95 (d, J = 10.5 Hz), 30.59−30.50
(d, J = 9.5 Hz), 24.49, 22.91−22.84 (d, J = 6.7 Hz), 22.60−22.56 (d, J
ACKNOWLEDGMENTS
■
We thank the NIH (R33DA031860), the Robert A. Welch
Foundation (D-1361), NSFC (No. 21332005, P. R. China),
and the Jiangsu Innovation Programs (P. R. China) for their
generous support of this research. We also thank the NSF
(CHE-1048553) and the CRIF program for support of our
NMR facility. We also wish to thank our current and former co-
workers, Siqi Lin, Padmanabha V. Kattamuri, Shuo Qiao, Wei
Zhou, Dr. Jianbo Xie, Dr. Jianbin Wu, and Dr. Guanghui An for
their valuable suggestions and assistance. Special thanks to Dr.
Daniel Unruh for the X-ray analysis and to Dr. Kazimirez
Surowiec and Dr. Yehia Mechref for the HR-MS analysis.
= 3.8 Hz), 20.05, 19.70; 31P NMR (162 MHz, CDCl3): δ = 21.84;
HRMS (ESI): m/z calcd for [C25H41N4O3P + H]+: 477.2995, found:
477.3003.
Compound 5j. White solid; yield 561 mg, 99%; mp 60−62 °C;
1
[α]1D0 = +3.73° (c 0.375, CHCl3); H NMR (400 MHz, CDCl3): δ =
7.42−7.28 (m, 7H), 6.92−6.88 (d, J = 8.8 Hz, 2H), 5.32−5.27 (t, J =
8.6 Hz, 1H), 5.04 (s, 2H), 3.70−3.46 (m, 7H), 3.40−3.27 (m, 2H),
3.19−3.10 (m, 1H), 3.08−2.98 (m, 1H), 2.91−2.85 (m, 1H), 2.70−
2.77 (m, 1H), 2.02−1.93 (m, 2H), 1.79−1.67 (m, 2H), 1.36−1.09 (m,
4H), 1.21−1.20 (t, J = 6.8 Hz, 3H), 1.13−1.12 (t, J = 6.4 Hz, 3H),
1.02−1.00 (t, J = 6.8 Hz, 3H), 0.87−0.86 (t, J = 6.4 Hz, 3H); 13C
NMR (100 MHz, CDCl3): δ = 170.62−170.55 (d, J = 6.7 Hz), 158.32,
136.94, 133.44, 128.67, 128.08, 127.55, 115.26, 70.08, 66.82, 66.39,
59.97−59.86 (d, J = 10.5 Hz), 58.95−58.85 (d, J = 9.5 Hz), 55.62−
55.59 (d, J = 2.8 Hz), 46.11, 44.17−44.13 (d, J = 3.8 Hz), 43.99−43.96
(d, J = 2.8 Hz), 42.83, 31.18−31.06 (d, J = 11.5 Hz), 30.28−30.18 (d, J
= 9.5 Hz), 24.44, 23.07−23.01 (d, J = 5.7 Hz), 22.13−22.09 (d, J = 3.8
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[α]1D0 = +3.05° (c 0.525, CHCl3); H NMR (400 MHz, CDCl3): δ =
4.23−4.18 (t, J = 10.4 Hz, 3H), 3.82−3.40 (m, 9H), 3.28−3.14 (m,
1H), 2.94−2.89 (m, 1H), 2.78−2.70 (m, 2H), 2.05−1.98 (m, 2H),
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26.66, 24.77−24.69 (d, J = 7.6 Hz), 24.42, 23.29−23.24 (d, J = 4.8
Hz), 19.68; 31P NMR (162 MHz, CDCl3): δ = 23.57; HRMS (ESI):
m/z calcd for [C22H43N4O3P + H]+: 443.3151, found: 443.3144.
Compound 6c. Compound 5c (100 mg, 0.216 mmol) was
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ASSOCIATED CONTENT
* Supporting Information
■
S
1H, 13C, and 31P NMR spectra of all compounds, as well as data
for the X-ray crystal structure of 5c (CCDC 1022082) and the
accompanying CIF file are included. This material is available
free of charge via the Internet at http://pubs.acs.org.
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AUTHOR INFORMATION
Corresponding Author
*E-mail: guigen.li@ttu.edu (G.L.).
■
Notes
The authors declare no competing financial interest.
F
dx.doi.org/10.1021/jo5024443 | J. Org. Chem. XXXX, XXX, XXX−XXX