Group-assisted purification (gap) for protection of amino acids using n-phosphonyl functional groups

Article abstract of DOI:10.3987/COM-14-S(K)25

Various phosphonyl halides have been synthesized and utilized as protection groups for amino acids. The protection synthesis was performed via GAP (Group-Assisted Purification) procedure under convenient conditions without the use of column chromatography

Full text of DOI:10.3987/COM-14-S(K)25

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HETEROCYCLES, Vol. 90, No. 1, 2015
HETEROCYCLES, Vol. 90, No. 1, 2015, pp. 344 - 356. © 2015 The Japan Institute of Heterocyclic Chemistry
Received, 4th May, 2014, Accepted, 17th June, 2014, Published online, 19th June, 2014
DOI: 10.3987/COM-14-S(K)25
GROUP-ASSISTED PURIFICATION (GAP) FOR PROTECTION OF
AMINO ACIDS USING N-PHOSPHONYL FUNCTIONAL GROUPS
a
a
b
b
a,b*
Guanghui An, Cole Seifert, Hao Sun, Yi Pan, and Guigen Li
a
Department of Chemistry and Biochemistry, Texas Tech University, Lubbock,
b
Texas 79409-106, USA; Institute of Chemistry & BioMedical Sciences, Nanjing
University, Nanjing 210093, P. R. China; guigen.li@ttu.edu (G.-G. Li)
Abstract – Various phosphonyl halides have been synthesized and utilized as
protection groups for amino acids. The protection synthesis was performed via
GAP (Group-Assisted Purification) procedure under convenient conditions
without the use of column chromatography and recrystallization. The synthesis
can be carried out on applicational scales with excellent yields (82% - 98%). The
phosphonyl protection of amino acids would provide a new greener tool for GAP
peptide synthesis.
INTRODUCTION
Chemical synthesis of peptides and proteins heavily depends on individual N- or O-protected amino acid
1
building blocks. In both solution phase and solid phase peptide synthesis, the most common protection
groups have been represented by Cbz, t-Boc and Fmoc functionalities, that can be deprotected under
1
,2
different acidic or basic conditions.
However, the synthesis of the protected amino acids by using
these classical functional groups often resulted in glassy oils or poor quality of solids that required
purification via either column chromatography or recrystallization. The traditional tedious purifications
need large amounts of silica gels, petroleum solvents, much energy and manpower with time-consuming.
More seriously, the waste generation of substantial amounts of silica gels, solvents as well as side
products derived from low efficient synthesis results in environmental problem for the global
environment, particularly, on industrial scale of production of amino acid and peptide drugs as well as
numerous chemicals and their precursors.
In the past several years, our group has been attempting to solve this global problem and to improve the
contamination/pollution image of chemical and material sciences by establishing new concepts and
technologies for organic synthesis and chemical production. The GAP (Group-Assisted Purification)
3
-10
chemistry has thus been developed for this purpose.
GAP chemistry is to introduce well engineered

HETEROCYCLES, Vol. 90, No. 1, 2015
345
functional groups onto reaction substrates for synthetic reactions to result in solid products that can be
purified simply by washing with common solvents or co-solvents without using column chromatography
and recrystallization. In addition, the GAP functional groups or auxiliaries can be readily cleaved and
recycled for re-use.
The GAP chemistry takes the advantage of solid phase peptide synthesis (for simple purification) and
solution phase peptide synthesis (for large scale production). In the meanwhile, GAP chemistry can avoid
their disadvantages, such as tedious purification (for the latter) and difficulties of large scale synthesis, the
use of large amounts of coupling reagents, expensive resins, etc (for the former). The GAP chemistry has
been proven to be efficient for a series of carbonyl addition reactions of N-phosphonyl and N-phosphinyl
3
-9
imines with nucleophiles. Both chiral auxiliary-controlled diastereroselective synthesis and asymmetric
catalytic reactions using achiral N-phosphonyl imines have shown the great success of using GAP
4
chemistry.
Very recently, the GAP chemistry has been successfully utilized for the asymmetric synthesis of
anti-cancer drug, Velcade, by performing asymmetric borylation of chiral N-phosphinyl imine. In this
synthesis, the optically pure isomer (dr > 99:1) can be readily obtained by washing the crude mixture of
the asymmetric borylation products with hexane; the chiral N-phosphinyl auxiliary has be easily
9
recovered after deprotection was performed. Meanwhile, we have utilized the GAP chemistry for the
solution phase synthesis of peptides, biphalin derivatives, as well as several N-protected amino acid
1
0
building blocks. Herein, we would like to report our systematic study of N-phosphonyl protection of
amino acids (Scheme 1) for complementing the traditional protecting groups of Cbz, Boc and Fmoc
2
counterparts that have been widely employed in academic and industry for several decades. Our effort on
this topic would result in economic, greener and environmentally friendly synthesis of protected amino
acids and peptides in future.
Scheme 1. Phosphonyl protecting group for amino acid esters
RESULTS AND DISCUSSION
Our protection strategy was started from the synthesis of N-phosphonyl chlorides as shown in Scheme 2.
3
,5d
These chlorides were synthesized according to the former published procedure with modifications. The

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HETEROCYCLES, Vol. 90, No. 1, 2015
commercial free diamines were first subjected to condensation reactions with aldehydes or ketones
followed by reduction with by sodium borohydride (NaBH ) in ethanol at ambient temperature to give
N,N'-protected diamine precusors. The N,N'-protected diamine were then reacted with POCl in presence
4
3
of triethyl amine at rt to afford N-phosphonyl chlorides. The synthesis of 1-naphthyl
branched-phosphonyl chlorides has to be conducted by refluxing the reaction mixture in toluene to get
completion conversion. The N-phosphonyl chloride products were simply purified by filtering through
3
,5d
silica gel packed short column.
For the two N-phosphonyl chlorides, 2a and 2b (in Scheme 2), the
Cl /hexanes (1/1, v/v)
purification can also be performed by washing the crude solid products with CH
2
2
cosolvent. In fact, the entire process for the synthesis of the above chlorides was conducted without the
use of column or recrystallization, which meets the criteria of the GAP chemistry.
H
H
N
O
N
N
O
N
P
P
Cl
Cl
2a
2b
H
H
N
O
N
P
N
O
N
Cl
P
Cl
2c
2d
POCl3
Et3N
R1
R2
R1
R2
R1
R2
R1
R2
NH HN
N
O
N
P
Cl
1a-d
2a-d
Scheme 2. Synthesis of N-phosphonyl chlorides
With these chlorides in hand, we systematically investigated the protection of various amino acids.
2
N,N’-CH -dinaphthylcyclohexyldiaminophosphonyl chloride (2a) was first employed for the protection of
glycine methyl ester hydrochloride. The HPLC grade of commercial solvents, such as THF,
dichloromethane, toluene, DMSO and DMF, were directly utilized for this reaction. Among these
solvents, dichloromethane was found to perform most efficiently while others resulted in lower chemical
yields (due to solubility or partial decomposing problems). We found the reaction proceeded efficiently at
o
9
0 C to afford 92% yield (Scheme 3). The 4 Ǻ MS was found to be important for the high yield. The
entire purification process can be achieved through GAP chemistry. Deprotection of the protected esters
10
can be readily achieved under known systems, which is GAP process as well.

HETEROCYCLES, Vol. 90, No. 1, 2015
347
H
H
o
Et N, DCM, 90 C
O
3
N
O
N
H
H
+
P
NH2 HCl
NH
O
N
O
N
4 Å
M
S
P
O
Cl
O
2a
3a
12 h, 92%
Scheme 3. Protection of glycine methyl ester hydrochloride with chloride (2a)
1
0
Different amino acids were sujected to the protection reaction under the standard condition.
D-Ala-OMe·HCl, L-Pro-OBn·HCl and L-Phe-OMe·HCl were protected smoothly, but the protection
turned out ineffective for L-Val-OBn·HCl. Different chlorides as shown in Scheme 2 were thus employed
for the protection of L-Val-OBn·HCl. We found achiral N,N’-dinaphthyl-diamino phosphonyl chloride
o
(
2b) underwent the protection smoothly to give 90% yield after the reaction was conducted 90 C for 12
hours (Scheme 4). Other counterparts, N,N’-diisopropylphosphonyl chloride (2c) and achiral chloride
(
2d) resulted in incomplete conversion after their protections were performed for 12 h.
Scheme 4. Protection of valine benzyl ester hydrochloride with 2b
Table 1. Protection of amino acid ester salts with achiral phosphonyl chloride
Entry chloride
amino acid ester Product
Yield [%]
1
2
3
4
5
6
7
8
9
1
L-Val-OBn·HCl 3b
90
98
95
92
98
96
90
88
86
82
2
2
2b
b
b
Gly-OMe·HCl
3c
Gly-OBn·HCl
3d
L-Phe-OMe·HCl 3e
L-Pro-OBn·HCl 3f
D-Ala-OBn·HCl 3g
L-Tyr-OBn·HCl 3h
L-Leu-OBn·HCl 3i
2b
2b
2b
2b
2b
2d
2d
Gly-OMe·HCl
3j
0
L-Phe-OMe·HCl 3k
Since achiral N,N’-dinaphthyl-diaminophosphonyl chloride (2b) showed a greater scope than (2a), it was
o
used for the protection of other amino acid esters (Table 1). For the 2b-based reaction, 2 amino acid
o
proline also underwent protection as smoothly as 1 amino acid esters (Table 1, entry 5). Both Val and

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HETEROCYCLES, Vol. 90, No. 1, 2015
D-Ala substrates gave excellent yield, 90% and 96%, respectively (entries 1 & 6, Table 1). It should be
noted that there is no need to pre-protect hydroxyl group of tyrosine benzyl ester hydrochloride prior to
the protection of its amino group to achieve 90% yield (entry 7, Table 1), which is different from the
1
0-11
previous protection by using N-diphenylphosphinyl group and N,N'-di-phenyl-N-phosphonyl group.
For the use of achiral chlorides, N,N’-diisopropylphosphonyl chloride (2d) also showed similar reactivity
and efficiency to give yields of 86% and 82%, respectively (entries 9 & 10, Table 1). We also employed
11
N-diphenylphosphinyl group (Dpp) for the protection of L-Phe-OMe·HCl by addition of diphenyl-
2 2
phosphinyl chloride into the CH Cl solution consisting of N-methylmorpholine and L-Phe-OMe·HCl at 0
o
C followed by stirring at rt overnight to give 4a in 90% yield. All of above protection processes met the
GAP chemistry criteria without requiring recrystallization and column chromatography. However, when
the hydrolyzed product 4b was utilized for peptide synthesis, racemization was observed.
NH2 HCl
O
4
Å MS, NMM
o
Ph
O
+
Ph
P
Ph
DPP-Phe-OMe
DCM, 0 C to rt
Cl
O
4a
90%, GAP
LiOH, MeOH, H2O
0 o
DPP-Phe-OH
C
4b
95%
Scheme 5. GAP synthesis and hydrolysis of Dpp-Phe-OMe
Scheme 6. Direct synthesis routine of phosphonyl amide via bromide (sequence and one-pot procedure)
After we took the advantage of N-phosphonyl chlorides, we also synthesized N-phosphonyl bromides
attempting to further improve the above protection, and more importantly, to synthesize N-phosphonyl

HETEROCYCLES, Vol. 90, No. 1, 2015
349
amides directly by treating N-phosphonyl bromides with amonia, which failed for this synthesis using
3
N-phosphonyl chlorides. During this synthesis, N,N’-dinaphthylcyclohexyldiamine was first treated with
3
POBr and dried triethyl amine in dichloromethane at rt to give the bromide 2e in 80% yield (Scheme 6).
Since N,N'-diisopropyl-N-phosphonyl bromide is not very stable under air and moisture, we conducted
the in situ generation of N-phosphonyl bromide followed by the direct reaction with ammonia. The
o
reaction was performed by stirring pre-formed N-phosphonyl bromide at – 40 C for 2 h and then at rt
overnight to afford amide 2g in an overall yield of 90% via GAP work-up (Scheme 6). Further
investigation of N-phosphonyl bromide for large-scale production of N-phosphonyl amides will be
conducted in due course.
In conclusion, the synthesis of various N-phosphonyl chlorides and bromides and the protection of amino
acid esters has been developed. The in situ generation of of N-phosphonyl amides can avoid the use of
sodium azide making their large-scale production of more convenient. The above synthesis can be
conducted through GAP work-up without the use of chromatography and recrystallization. The new
protected amino acids will be applied on peptide and peptidomimetic research in future.
EXPERIMENTAL
All commercially available solvents, unless otherwise mentioned, were used without purification. 4 Ǻ MS
was heated for over 72 h before utility. All melting points are uncorrected. The NMR spectra were
1
13
31
recorded at 400, 125, 202 MHz for H, C and P respectively. Shifts are reported in ppm based on an
1
13
31
internal TMS standard (for H/CDCl
were referenced to external H PO (0.00 ppm). Flash chromatographic columns were carried out on silica
gel 60 (230-400 mesh). Spectra of compound 2a, 2c were compared to the literature data. Synthesis of
3 3
) or on residual solvent peaks (for C/CDCl ). P NMR spectra
3
4
3
-5
compound 2d are similar to the compound 2c.
General procedure for synthesis of N, N’-dinaphthyldiaminophosphonyl chloride (2a and 2b):
o
To diamine’s toluene solution (12 g diamine in 120 mL toluene) in 500 mL single-necked flask at 0 C, 4
mL POCl followed by 10.1 mL Et N were slowly added with stirring vigorously. The reaction solution is
3
3
stirring at refluxing until the reaction finished. The reaction mixture was filter through the Celite in
Büchner’s funnel and the filtrate cake was washed by toluene for 3 times. Collect all filtrates and
evaporated on rotavapor. Add CH Cl to dissolve the residue and wash it with 1 M HCl solution and brine.
2
2
Dry over Na
hexane/CH Cl
Compound 2b: white solid; mp 114-116 C; H NMR (CDCl , 400 MHz): δ = 8.30 (d, J = 8.5 Hz, 2H),
2
4
SO and evaporate it. The solid obtained can be purified by simple washing with
2
2
solution to give the chlorides as white solid.
o
1
3
7
4
.84 (dd, J = 18.3, 8.0 Hz, 4H), 7.65 – 7.35 (m, 8H), 4.91 (dd, J = 14.4, 7.8 Hz, 2H), 4.36 (dd, J = 14.0,
1
3
3
.6 Hz, 2H), 2.90 (d, J = 11.3 Hz, 4H). C NMR (CDCl , 101 MHz): δ = 133.95, 131.75, 131.11 (d, J =

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HETEROCYCLES, Vol. 90, No. 1, 2015
9.6 Hz), 129.12, 128.74, 127.22, 126.81, 126.21, 125.22, 123.82, 47.22 (d, J = 4.9 Hz), 43.02 (d, J = 13.4
3
1
Hz). P NMR (CDCl
found 443.1051.
3
2
, 162 MHz) δ = 27.83. HRMS (ESI) m/z calcd for C24H22ClN OPNa 443.1056,
1
Compound 2d: colorless liquid; H NMR (CDCl
3
, 400 MHz): δ = 3.63 – 3.49 (m, 2H), 3.30 – 3.15 (m,
1
3
2
3
H), 3.09 – 2.97 (m, 2H), 1.18 (ddd, J = 12.6, 6.6, 2.0 Hz, 12H). C NMR (CDCl , 101 MHz): δ = 45.31
3
1
(
d, J = 4.8 Hz), 38.25 (d, J = 15.1 Hz), 20.97 (d, J = 4.7 Hz), 19.84 (d, J = 3.8 Hz). P NMR (CDCl
MHz) δ = 23.68. HRMS (ESI) m/z calcd for C OPNa 247.0743, found 247.0749.
General procedure for synthesis of phosphonyl bromide:
To diamine’s toluene solution (12 g diamine in 120 mL toluene) in 500 mL single-necked flask at 0 C, 6
3
, 162
8 2
H18ClN
o
g POBr
3
3
followed by 10.1 mL Et N were slowly added with stirring vigorously. The reaction solution is
o
stirring at 0 C until the reaction finished. The reaction mixture was filter through the Celite in Büchner’s
funnel and the filtrate cake was washed by toluene for 3 times. Collect all filtrates and evaporated on
rotavapor. Add CH
2
Cl
2
to dissolve the residue and wash it with 1 M HCl solution and brine. Dry over
Cl
2
Na SO and evaporate it. The solid you obtain can be purified by simple washing with hexane/CH
2
4
2
solution. 9 g of bromide 2e was obtained as brownish solid.
o
1
2
D
5
Compound 2e: brownish solid; mp 216-218 C; [] - 42.6 (c 1.0, CH
2
Cl
2
); H NMR (CDCl
3
, 400
MHz): δ = 8.28 (d, J = 8.5 Hz, 1H), 8.07 (d, J = 8.4 Hz, 1H), 7.88 (dd, J = 8.0, 1.3 Hz, 2H), 7.76 (ddd, J =
2
4
1
3.1, 11.9, 5.0 Hz, 4H), 7.64 – 7.40 (m, 6H), 5.10 (dd, J = 16.5, 12.1 Hz, 1H), 4.93 (t, J = 15.1 Hz, 1H),
.63 (dd, J = 16.7, 11.7 Hz, 1H), 4.24 (dd, J = 15.7, 8.8 Hz, 1H), 3.26 (t, J = 10.5 Hz, 1H), 3.04 (t, J =
0.6 Hz, 1H), 1.72 (d, J = 11.8 Hz, 1H), 1.59 (dd, J = 22.6, 12.5 Hz, 3H), 1.32 – 1.12 (m, 2H), 1.11 – 0.93
1
3
(
m, 2H). C NMR (CDCl
3
, 101 MHz): δ = 133.75 (d, J = 11.8 Hz), 132.73, 132.71, 132.68, 131.38,
30.96, 128.88 (d, J = 10.7 Hz), 128.51, 128.07 , 126.57, 126.45, 126.37, 125.88 (d, J = 8.3 Hz), 125.47,
25.25, 123.57, 122.78, 64.91 (d, J = 9.2 Hz), 63.39 (d, J = 10.1 Hz), 46.65 (d, J = 3.1 Hz), 44.75 (d, J =
1
1
5
2
31
.0 Hz), 29.34 (d, J = 7.1 Hz), 28.85 (d, J = 13.3 Hz), 24.26 , 23.90. P NMR (CDCl
5.03. HRMS (ESI) m/z calcd for C28 OPNa 541.1020, found 541.1013.
3
, 162 MHz) δ =
H28BrN
2
Synthesis of phosphonyl amide from bromide:
To a flame dried flask, bromide 2e (5.19 g, 10.0 mmol), ammonium chloride (20.0 mmol), triethylamine
(
2 2
4.2 mL, 3.0 mmol), 4A MS (5g) and CH Cl (20 mL) was added in sequence. The reaction flask was
o
sealed and stirred at 90 C until the bromide was consumed up. After it’s cooled to room temperature, the
reaction mixture was filter through the Celite and the filtrate cake was washed by CH
2 2
Cl for 3 times.
Collect all filtrates and wash it with 1 M HCl solution and brine. Dry over Na SO and evaporate it. The
2
4
2 2
solid can be purified by simple washing with hexane/CH Cl solution.
1
Amide 2f: white solid; H NMR (CDCl , 400 MHz): δ = 8.16 (dd, J = 15.1, 8.2 Hz, 2H), 7.85 (t, J = 7.8
3
Hz, 2H), 7.75 (dd, J = 12.6, 6.4 Hz, 4H), 7.60 – 7.36 (m, 6H), 4.86 (ddd, J = 17.2, 11.1, 6.1 Hz, 2H), 4.55

HETEROCYCLES, Vol. 90, No. 1, 2015
351
–
2
2
4.41 (m, 1H), 4.35 (dd, J = 16.5, 8.0 Hz, 1H), 3.08 (dd, J = 12.9, 6.4 Hz, 1H), 2.95 (t, J = 9.9 Hz, 1H),
3
1
.31 (d, J = 3.9 Hz, 2H), 1.68 – 1.50 (m, 3H), 1.32 – 0.85 (m, 5H). P NMR (CDCl
3
, 162 MHz) δ =
8.33.
One-pot procedure for synthesis of phosphonyl amide:
To the diamine (7.5 mmol) solution of CH
2
Cl
2
(15 mL) in the three-necked flask, POBr
3
(1.2 equiv.) was
o
added under N
2
. Triethylamine (3 equiv.) was added at 0 C. The resulting mixture was warmed to room
o
temperature slowly and stirred overnight. The reaction system was cooled to -40 C and plugged with a
balloon. The ammonia gas was injected into the solution via pipe carefully till the balloon grew up. The
reaction was stirred for 2 h and warmed to room temperature slowly. After stirring overnight at room
2 2
temperature, the mixture was filtered and washed with CH Cl . The filtrate was extracted with water. The
organic layer was dried and evaporated to give the amide product as a white solid in 90% yield.
1
Amide 2g: white solid; H NMR (CDCl
3
, 400 MHz): δ = 3.57 – 3.37 (m, 2H), 2.94 – 2.85 (m, 1H), 2.76 –
3
1
2
.62 (m, 1H), 2.43 (s, 2H), 2.02 (d, J = 9.6 Hz, 2H), 1.80 – 1.61 (m, 3H), 1.38 – 1.12 (m, 15H). P NMR
CDCl , 162 MHz) δ = 24.22.
General procedure for the protection of amino acid esters:
To a flame dried flask, chloride (10.0 mmol), amino acid ester (12.0 -15.0 mmol), triethylamine (4.2 mL,
(
3
3
2 2
0.0 mmol), 4A MS (5 g) and CH Cl (20 mL) was added in sequence. The reaction flask was sealed and
o
stirred at 90 C until the chloride was consumed up. After it’s cooled to room temperature, the reaction
mixture was filter through the Celite and the filtrate cake was washed by CH
2
Cl
2
for 3 times. Collect all
filtrates and wash it with water, 1 M HCl solution and brine. Dry over Na SO
2
4
and evaporate it. The solid
2 2
can be purified by simple washing with hexane/CH Cl solution.
o
1
2
D
5
Compound 3a: white solid; mp 98-99 C; [] - 82.8 (c 1.0, CH
2
Cl
2
); H NMR (CDCl
3
, 400 MHz): δ =
8
4
.14 (dd, J = 8.3, 2.3 Hz, 2H), 7.86 – 7.70 (m, 6H), 7.55 – 7.41 (m, 6H), 4.80 (dd, J = 16.6, 11.2 Hz, 1H),
.68 (dd, J = 14.5, 9.4 Hz, 1H), 4.59 – 4.47 (m, 1H), 4.33 (dd, J = 16.6, 8.6 Hz, 1H), 3.45 (s, 3H), 3.24
(
ddd, J = 17.8, 9.3, 6.3 Hz, 1H), 3.16 – 3.04 (m, 2H), 3.03 – 2.93 (m, 1H), 2.62 (dt, J = 9.9, 5.9 Hz, 1H),
1
3
2
.02 (d, J = 11.7 Hz, 1H), 1.71 (d, J = 11.4 Hz, 1H), 1.59 (t, J = 12.5 Hz, 2H), 1.39 – 1.04 (m, 4H). C
, 101 MHz): δ = 171.20 (d, J = 8.7 Hz), 135.22 (d, J = 4.7 Hz), 133.76, 133.67, 133.63,
31.62, 131.05, 128.78, 128.07, 127.56, 127.26, 126.08 (d, J = 1.8 Hz), 125.64, 125.59, 125.56, 125.53,
NMR (CDCl
3
1
1
4
25.42, 123.48, 123.05, 65.26 (d, J = 10.1 Hz), 63.71 (d, J = 8.8 Hz), 53.61, 52.05, 45.39 (d, J = 2.0 Hz),
4.51 (d, J = 4.5 Hz), 42.61 (d, J = 1.7 Hz), 29.93 (d, J = 8.3 Hz), 29.37 (d, J = 10.6 Hz), 24.36 (d, J = 9.9
3
1
Hz). P NMR (CDCl
50.2230.
Compound 3b: white solid; mp 144-146 C; [] - 11.9 (c 1.0, CH
3 34 3 3
, 162 MHz) δ = 27.59. HRMS (ESI) m/z calcd for C31H N O PNa 550.2235, found
5
o
1
2
D
5
2
Cl
2 3
); H NMR (CDCl , 400 MHz): δ
=
8.28 (d, J = 8.4 Hz, 1H), 8.21 (d, J = 8.3 Hz, 1H), 7.86 (d, J = 7.8 Hz, 2H), 7.78 (dd, J = 8.0, 3.0 Hz,

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HETEROCYCLES, Vol. 90, No. 1, 2015
2
H), 7.59 – 7.40 (m, 8H), 7.25 – 7.19 (m, 5H), 4.99 (q, J = 12.2 Hz, 2H), 4.73 – 4.39 (m, 4H), 4.00 – 3.90
(
m, 1H), 3.24 – 3.13 (m, 1H), 3.10 – 2.84 (m, 4H), 2.06 (dd, J = 12.7, 6.3 Hz, 1H), 0.93 (dd, J = 26.8, 6.8
1
3
Hz, 6H). C NMR (CDCl
3
, 101 MHz): δ = 173.89 (d, J = 2.2 Hz), 135.38, 133.84 (d, J = 2.8 Hz), 133.00
(
dd, J = 7.6, 6.3 Hz), 131.79 (d, J = 10.2 Hz), 128.70 (d, J = 4.9 Hz), 128.63, 128.51, 128.48, 128.27,
1
1
28.14, 126.41 (d, J = 5.8 Hz), 126.13, 125.91 (d, J = 2.2 Hz), 125.58, 125.36 (d, J = 6.6 Hz), 123.71,
23.50, 67.00, 60.17, 46.72 (d, J = 5.1 Hz), 46.52 (d, J = 5.1 Hz), 44.55 (d, J = 8.5 Hz), 44.43 (d, J = 8.1
3
1
Hz), 32.69 (d, J = 6.5 Hz), 19.02, 17.97. P NMR (CDCl
3
, 162 MHz) δ = 25.02. HRMS (ESI) m/z calcd
38 3 3
for C36H N O
PNa 614.2548, found 614.2552.
o
1
Compound 3c: white solid; mp 120-121 C; H NMR (CDCl
3
, 400 MHz): δ = 8.23 (d, J = 8.3 Hz, 2H),
.88 – 7.81 (m, 2H), 7.77 (d, J = 8.1 Hz, 2H), 7.51 (ddd, J = 17.7, 10.4, 3.7 Hz, 6H), 7.45 – 7.37 (m, 2H),
.67 – 4.47 (m, 4H), 3.62 (s, 3H), 3.57 (dd, J = 10.0, 6.2 Hz, 2H), 3.39 – 3.29 (m, 1H), 3.09 – 2.88 (m,
7
4
4
1
1
3
H). C NMR (CDCl
3
, 101 MHz): δ = 171.79 (d, J = 7.6 Hz), 133.91, 133.02 (d, J = 7.1 Hz), 131.79,
28.73, 128.41, 126.51, 126.40, 125.92, 125.36, 123.62, 52.27, 46.82 (d, J = 5.1 Hz), 44.77 (d, J = 12.3
3
1
Hz), 43.17 (d, J = 1.3 Hz). P NMR (CDCl , 162 MHz) δ = 24.90. HRMS (ESI) m/z calcd for
3
C
27
H
28
N
3
O
3
PNa 496.1766, found 496.1762.
o
1
Compound 3d: white solid; mp 155-157 C; H NMR (CDCl
3
, 400 MHz): δ = 8.25 (d, J = 8.2 Hz, 2H),
7
6
.81 (dd, J = 26.7, 7.9 Hz, 4H), 7.56 – 7.37 (m, 8H), 7.31 (d, J = 3.9 Hz, 5H), 5.08 (s, 2H), 4.58 (d, J =
.1 Hz, 4H), 3.63 (dd, J = 9.8, 6.2 Hz, 2H), 3.51 (dd, J = 10.3, 5.9 Hz, 1H), 2.95 (dd, J = 9.2, 4.8 Hz, 4H).
1
3
C NMR (CDCl
3
, 101 MHz): δ = 171.19 (d, J = 8.0 Hz), 135.32, 133.94, 133.09 (d, J = 7.2 Hz), 131.83,
1
28.76, 128.74, 128.65, 128.59, 128.43, 126.58, 126.43, 125.95, 125.39, 123.68, 67.16, 46.85 (d, J = 5.1
3
1
Hz), 44.77 (d, J = 12.3 Hz), 43.38. P NMR (CDCl
3
, 162 MHz) δ = 24.83. HRMS (ESI) m/z calcd for
C
33
H
32
N
3
O
3
PNa 572.2079, found 572.2082.
o
1
2
D
5
Compound 3e: white solid; mp 115-117 C; [] 5.1 (c 1.0, CH Cl ); H NMR (CDCl , 400 MHz): δ =
2
2
3
8
–
3
1
1
1
4
.26 (d, J = 8.4 Hz, 1H), 8.13 (d, J = 8.3 Hz, 1H), 7.85 (d, J = 8.0 Hz, 2H), 7.78 (d, J = 8.4 Hz, 2H), 7.59
7.41 (m, 8H), 7.20 – 7.08 (m, 5H), 4.57 – 4.43 (m, 2H), 4.37 – 4.19 (m, 3H), 3.52 (d, J = 1.0 Hz, 3H),
1
3
3
.21 – 3.09 (m, 1H), 3.08 – 2.84 (m, 6H). C NMR (CDCl , 101 MHz): δ = 174.26 (d, J = 2.4 Hz),
36.49 (d, J = 2.4 Hz), 133.87, 133.82, 133.18, 133.11, 133.09 (d, J = 1.0 Hz), 133.01, 131.85, 131.68,
29.57, 128.74, 128.70, 128.66, 128.30, 128.04, 127.14, 126.40, 126.37, 126.24, 125.92 (d, J = 2.0 Hz),
25.41 (d, J = 1.8 Hz), 125.16, 123.82, 123.45, 56.25, 52.21, 46.36 (d, J = 5.0 Hz), 46.19 (d, J = 5.1 Hz),
3
1
3
4.60 (d, J = 3.6 Hz), 44.48 (d, J = 3.2 Hz), 41.02 (d, J = 6.7 Hz). P NMR (CDCl , 162 MHz) δ = 24.21.
HRMS (ESI) m/z calcd for C34
H
34
N O
3 3
PNa 586.2235, found 586.2239.
o
1
2
D
5
Compound 3f: white solid; mp 134-136 C; [] - 71.9 (c 1.0, CH
2
Cl
2
); H NMR (CDCl
3
, 400 MHz): δ
=
8.49 (d, J = 8.1 Hz, 1H), 8.21 (d, J = 8.0 Hz, 1H), 7.81 (dd, J = 25.7, 7.5 Hz, 4H), 7.48 (dd, J = 37.9,
2
1.8 Hz, 8H), 7.25 (dd, J = 27.9, 6.7 Hz, 5H), 5.13 (s, 2H), 4.90 (dd, J = 14.0, 5.4 Hz, 1H), 4.60 – 4.32 (m,

HETEROCYCLES, Vol. 90, No. 1, 2015
353
3
0
1
1
4
2
H), 4.12 (d, J = 6.8 Hz, 1H), 3.17 (s, 1H), 3.08 – 2.78 (m, 5H), 1.78 (s, 1H), 1.56 (s, 1H), 1.32 (s, 1H),
1
3
3
.99 – 0.82 (m, 1H). C NMR (CDCl , 101 MHz): δ = 175.02, 136.05, 134.03, 133.98, 133.87, 133.41,
32.12 (d, J = 12.9 Hz), 128.78, 128.58, 128.50, 128.26, 128.18, 127.34, 126.98, 126.28, 125.98, 125.92,
25.57, 125.36, 124.60, 124.00, 66.67, 64.57, 60.71 (d, J = 6.7 Hz), 47.77, 46.93, 45.81 (d, J = 12.7 Hz),
3
1
3
4.73 (d, J = 12.3 Hz), 31.04 (d, J = 8.4 Hz), 25.10 (d, J = 7.8 Hz). P NMR (CDCl , 162 MHz) δ =
2.96. HRMS (ESI) m/z calcd for C36
H
36
N
3
O
3
PNa 612.2392, found 612.2397.
o
1
2
D
5
Compound 3g: white solid; mp 155-156 C; [] - 30.1 (c 1.0, CH
2
Cl
2
); H NMR (CDCl
3
, 400 MHz): δ
=
8.26 (d, J = 8.4 Hz, 1H), 8.21 (d, J = 8.4 Hz, 1H), 7.85 (d, J = 8.1 Hz, 2H), 7.78 (dd, J = 8.0, 3.5 Hz,
2H), 7.61 – 7.26 (m, 13H), 5.05 (s, 2H), 4.65 – 4.52 (m, 3H), 4.41 (dd, J = 15.1, 6.3 Hz, 1H), 4.11 – 3.98
1
3
(
m, 1H), 3.32 (t, J = 10.1 Hz, 1H), 3.03 – 2.88 (m, 4H), 1.36 (d, J = 7.1 Hz, 3H). C NMR (CDCl
MHz): δ = 174.60 (d, J = 4.3 Hz), 135.45, 133.87 (d, J = 2.7 Hz), 133.05 (t, J = 7.2 Hz), 131.82 (d, J =
.6 Hz), 128.70 (d, J = 2.6 Hz), 128.50, 128.30 (d, J = 5.6 Hz), 128.29 (d, J = 0.8 Hz), 126.42 (d, J = 2.3
Hz), 126.31, 126.00, 125.93 (d, J = 3.9 Hz), 125.39, 123.66 (d, J = 12.8 Hz), 67.11, 50.45, 46.88 (d, J =
3
, 101
4
3
1
4
.8 Hz), 46.51 (d, J = 5.1 Hz), 44.76 (d, J = 12.3 Hz), 44.45 (d, J = 12.3 Hz), 21.69 (d, J = 5.7 Hz). P
NMR (CDCl
10.1927.
3
, 162 MHz) δ = 23.99. HRMS (ESI) m/z calcd for C28
H
30
N
3
O
3
PNa 510.1922, found
5
o
1
2
D
5
Compound 3h: white solid; mp 110 C start decompose; [] - 41.9 (c 1.0, CH
2
Cl
2
); H NMR (CDCl
3
,
4
1
5
1
1
4
00 MHz): δ = 8.93 (s, 1H), 8.21 – 8.13 (m, 1H), 8.11 – 8.03 (m, 1H), 7.90 – 7.69 (m, 4H), 7.45 (ddd, J =
1.1, 8.2, 5.2 Hz, 6H), 7.15 (dd, J = 4.8, 1.7 Hz, 2H), 6.75 (s, 4H), 5.02 – 4.78 (m, 2H), 4.55 – 4.07 (m,
1
3
3
H), 3.19 (t, J = 10.2 Hz, 1H), 3.08 – 2.73 (m, 6H). C NMR (CDCl , 101 MHz): δ = 173.72, 156.75,
35.19, 133.81, 132.78 (d, J = 7.4 Hz), 131.72 (d, J = 7.8 Hz), 130.53, 128.72, 128.66, 128.60, 128.54,
28.33, 128.13, 126.58, 126.45, 126.37, 126.13, 125.96, 125.41, 123.70, 123.48, 115.86, 67.24, 56.27,
3
1
6.29 (d, J = 4.2 Hz), 46.10 (d, J = 5.5 Hz), 44.67 (d, J = 13.5 Hz), 44.38 (d, J = 12.1 Hz), 40.06. P
, 162 MHz) δ = 24.47. HRMS (ESI) m/z calcd for C40 PNa 678.2498, found
NMR (CDCl
78.2501.
Compound 3i: white solid; mp 130-131 C; [] - 32.9 (c 1.0, CH
3
38 3 4
H N O
6
o
1
2
D
5
2
Cl
.28 (dd, J = 19.9, 8.4 Hz, 2H), 7.90 (d, J = 7.8 Hz, 2H), 7.82 (dd, J = 7.7, 3.3 Hz, 2H), 7.65 – 7.40 (m,
H), 7.28 – 7.24 (m, 4H), 5.12 – 5.00 (m, 2H), 4.72 – 4.42 (m, 4H), 4.17 – 4.00 (m, 1H), 3.15 – 2.91 (m,
2 3
); H NMR (CDCl , 400 MHz): δ =
8
9
5
1
1
3
H), 1.75 – 1.57 (m, 2H), 1.46 (dt, J = 13.4, 7.2 Hz, 1H), 0.89 (dd, J = 9.6, 6.4 Hz, 6H). C NMR (CDCl
3
,
01 MHz): δ = 174.78 (d, J = 2.5 Hz), 135.39, 133.85 (d, J = 4.1 Hz), 133.13, 133.05, 132.98, 131.81 (d,
J = 10.1 Hz), 128.69, 128.62, 128.44, 128.38 (d, J = 1.3 Hz), 128.29, 128.19, 126.45, 126.37, 126.24,
1
4
25.90 (d, J = 2.3 Hz), 125.82, 125.36 (d, J = 1.3 Hz), 123.73, 123.54, 66.99, 53.57, 46.68 (d, J = 5.0 Hz),
6.41 (d, J = 5.2 Hz), 44.67 (d, J = 12.3 Hz), 44.43 (d, J = 9.1 Hz), 44.33 (d, J = 3.3 Hz), 24.82, 22.57,

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HETEROCYCLES, Vol. 90, No. 1, 2015
3
1
2
2.46. P NMR (CDCl
found 628.2709.
Compound 3j: white solid; mp 90-91 C; H NMR (CDCl
3
40 3 3
, 162 MHz) δ = 24.49. HRMS (ESI) m/z calcd for C37H N O PNa 628.2705,
o
1
3
, 400 MHz): δ = 3.64 – 3.47 (m, 3H), 3.47 –
1
3
3
5
3
.24 (m, 4H), 3.09 – 2.73 (m, 5H), 1.16 – 0.71 (m, 12H). C NMR (CDCl , 101 MHz): δ = 172.03 (d, J =
3
1
3
.5 Hz), 51.91, 43.86 (d, J = 5.2 Hz), 43.30, 38.42 (d, J = 13.7 Hz), 20.98. P NMR (CDCl , 162 MHz) δ
=
21.55. HRMS (ESI) m/z calcd for C11
H
24
N
3
O
3
PNa 300.1453, found 300.1458.
o
1
2
D
5
Compound 3k: white solid; mp 99-100 C; [] - 4.3 (c 1.0, CH
2
Cl
2
); H NMR (CDCl
3
, 400 MHz): δ =
7
.45 – 7.02 (m, 5H), 4.04 – 3.85 (m, 1H), 3.60 (s, 3H), 3.35 (ddd, J = 19.5, 13.3, 6.6 Hz, 2H), 3.18 – 2.71
1
3
(
m, 7H), 1.34 – 0.68 (m, 12H). C NMR (CDCl
3
, 101 MHz): δ = 174.10 (d, J = 2.7 Hz), 136.32, 129.48,
1
28.56, 127.05, 56.02, 51.86, 43.83 (dd, J = 9.6, 5.3 Hz), 41.37 (d, J = 6.3 Hz), 38.09 (dd, J = 21.7, 13.8
3
1
Hz), 21.29 (dd, J = 12.6, 6.1 Hz), 21.01 (d, J = 27.8 Hz). P NMR (CDCl
ESI) m/z calcd for C18 PNa 390.1922, found 390.1920.
Procedure for the protection of amino acid esters with diphenylphosphinyl chloride:
3
, 162 MHz) δ = 21.30. HRMS
(
30 3 3
H N O
2 2
To a mixture of NMM (3 mmol), amino acid ester (2 mmol) and CH Cl (10 mL) was added Dpp-Cl (1
o
mmol) in CH
2
Cl
2
(5 mL) solution at 0 C. The resulting mixture was stirred at room temperature for 24
hours. The mixture was then filtered through Celite, washed with by 5% citric acid aqueous solution, sat.
aqueous NaHCO
3
2 2 4
solution, H O and then brine, dried over Na SO , filtered, and evaporated to give a
white solid.
1
Compound 4a: white solid; H NMR (CDCl
3
, 400 MHz): δ = 7.85 – 7.76 (m, 2H), 7.70 – 7.62 (m, 2H),
7
3
.52 – 7.38 (m, 4H), 7.37 – 7.31 (m, 2H), 7.30 – 7.20 (m, 3H), 7.16 – 7.10 (m, 2H), 4.10 – 4.00 (m, 1H),
1
3
3
.64 (s, 3H), 3.53 (dd, J = 10.8, 7.0 Hz, 1H), 3.08 (dd, J = 6.0, 2.2 Hz, 2H). C NMR (CDCl , 101 MHz):
δ = 173.35 (d, J = 5.8 Hz), 136.08, 132.70 (d, J = 10.9 Hz), 132.24 (d, J = 9.7 Hz), 132.14 (d, J = 2.8 Hz),
1
32.03 (d, J = 2.8 Hz), 132.03 (d, J = 9.5 Hz), 131.42 (d, J = 9.5 Hz), 129.79 (d, J = 1.3 Hz), 128.70 (d, J
3
1
=
10.2 Hz), 128.59, 128.57 (d, J = 10.1 Hz), 127.14, 54.88, 52.33, 41.35 (d, J = 4.9 Hz). P NMR (CDCl
3
,
1
62 MHz) δ = 23.76.
Procedure for hydrolysis of Dpp-Phe-OMe (4a):
To a flask, compound 4a (1.0 mmol) was suspended in a 10 mL MeOH/H
2
O (v:v, 9:1) solution. The
o
mixture was cooled to 0 C followed by addition of LiOH·H
2
O (5 mmol). The reaction was allowed to
warm to room temperature and stirred overnight. HCl (1.0 M aqueous solution) was added to neutralize
the reaction. The water phase was extracted by CH Cl for 3 times. Combine all organic phase. Dry over
Na SO and evaporate to get the corresponding acid.
Compound 4b: white solid; H NMR (CDCl
0.5, 3.9, 2.3 Hz, 2H), 7.50 – 7.13 (m, 13H), 3.94 – 3.76 (m, 1H), 3.69 (dd, J = 8.2, 4.4 Hz, 1H), 3.18 (d,
2
2
2
4
1
3
, 400 MHz): δ = 13.10 (d, J = 75.9 Hz, 1H), 7.79 (ddd, J =
1
1
3
J = 13.4 Hz, 1H), 2.95 – 2.76 (m, 1H). C NMR (CDCl , 101 MHz): δ = 174.33, 137.24, 132.78 (d, J =
3

HETEROCYCLES, Vol. 90, No. 1, 2015
355
1
5
0.0 Hz), 132.47, 132.14, 131.88 (d, J = 9.8 Hz), 130.83, 130.11, 129.77, 128.76, 128.61, 128.53, 126.97,
3
1
3
5.83, 40.79 (d, J = 9.9 Hz). P NMR (CDCl , 162 MHz) δ = 26.77.
ACKNOWLEDGEMENTS
We gratefully acknowledge the financial support from the NIH (R33DA031860), the Robert A. Welch
Foundation (D-1361), the National Natural Science Foundation of China (21332005) and Jiangsu
Educational Innovation Team Program (P.R. China) for their generous support of this research. We also
thank NSF Grant CHE-1048553 and the CRIF program for supporting our NMR facility.
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1
.
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3
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(a) P. G. M. Wuts and T. W. Greene, Protective Groups in Organic Synthesis, Wiley, 2006; (b) P. J.
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2
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7
(a) For chiral N–phosphinyl imine chemistry, see: S. Pindi, P. Kaur, G. Shakya, and G. Li, Chem.
Biol. Drug Des., 2010, 77, 20; (b) For chiral N–phosphonylyl imine chemistry, see: H. Sun, T.
Rajale, Y. Pan, and G. Li, Tetrahedron Lett., 2010, 51, 4403; (c) For chiral sulfinyl imine, see: S.
Pindi, J. B. Wu, and G. Li, J. Org. Chem., 2013, 78, 4006.

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HETEROCYCLES, Vol. 90, No. 1, 2015
8
.
For umpolung reaction, see: P. V. Kattamuri, T. Ai, S. Pindi, Y. Sun, P. Gu, M. Shi, and G. Li, J.
Org. Chem., 2011, 76, 2792. For GAP aminohalogenation, see: H. Sun, J. L. Han, P. V. Kattamuri,
Y. Pan, and G. Li, J. Org. Chem., 2013, 78, 1171.
9
1
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J. B. Xie, J. Luo, T. R. Winn, D. Cordes, and G. Li, Beilstein J. Org. Chem., 2014, 10, 746.
0. J. B. Wu, G. H. An, S. Q. Lin, J. B. Xie, W. Zhou, H. Sun, Y. Pan, and G. Li, Chem. Commun., 2014,
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1. G. W. Kenner, G. A. Moore, and R. Ramage, Tetrahedron Lett., 1976, 17, 3623.
5
1