Asymmetric catalytic n -phosphonyl imine chemistry: The use of primary free amino acids and Et2AlCN for asymmetric catalytic strecker reaction

Article abstract of DOI:10.1021/jo100865q

(Figure presented) The new asymmetric catalytic Strecker reaction of achiral N-phosphonyl imines has been established. Excellent enantioselectivity (95.2-99.7% ee) and yields (89-97%) have been achieved by using primary free natural amino acids as catalysts and Et₂AlCN as nucleophile. This work also presents the novel use of nonvolatile and inexpensive Et ₂AlCN in asymmetric catalysis. The N-phosphonyl protecting group enabled simple product purification to be achieved simply by washing the crude products with hexane, which is defined as the GAP chemistry (GAP: Group-Assistant-Purification).(17)It can also be readily cleaved and recycled under mild condition to give a quantitative recovery of N,N′- bis(naphthalen-1-ylmethyl)ethane-1,2-diamine. A new mechanism was proposed for this reaction and was supported by experimental observations.

Full text of DOI:10.1021/jo100865q

pubs.acs.org/joc
Asymmetric Catalytic N-Phosphonyl Imine Chemistry: The Use of
Primary Free Amino Acids and Et2AlCN for Asymmetric Catalytic
Strecker Reaction
Parminder Kaur, Suresh Pindi, Walter Wever, Trideep Rajale, and Guigen Li*
Department of Chemistry & Biochemistry, Texas Tech University, Lubbock, Texas 79409-1061
guigen.li@ttu.edu
Received May 3, 2010
The new asymmetric catalytic Strecker reaction of achiral N-phosphonyl imines has been established.
Excellent enantioselectivity (95.2-99.7% ee) and yields (89-97%) have been achieved by using
primary free natural amino acids as catalysts and Et2AlCN as nucleophile. This work also presents
the novel use of nonvolatile and inexpensive Et2AlCN in asymmetric catalysis. The N-phosphonyl
protecting group enabled simple product purification to be achieved simply by washing the crude
products with hexane, which is defined as the GAP chemistry (GAP: Group-Assistant-
Purification).15 It can also be readily cleaved and recycled under mild condition to give a quantitative
recovery of N,N0-bis(naphthalen-1-ylmethyl)ethane-1,2-diamine. A new mechanism was proposed
for this reaction and was supported by experimental observations.
Introduction
serve as both electrophiles and dienophiles for many asym-
metric reactions;2,3 they are represented by Ar2CH-/Bn-,4
Imine chemistry has been one of the most important and
active topics in asymmetric catalysis and synthesis due to its
importance in drug discovery and development, which heavily
depend on the amine functionality.1-3 N-protected imines
8
alkoxycarbonyl,5 Ar2PO-,6 aryl-,7 and ArSO2 imines in
which the protecting groups are often crucial for controlling
regio-, enantio-, and chemoselectivity for asymmetric
reactions.9 The search for novel imines of general use for
both racemic and asymmetric reactions, particularly for
asymmetric catalysis, has been challenging.1-3 In the past
several years, we have established chiral N-phosphonyl imine
chemistry and successfully utilized it for a variety of asym-
metric reactions to produce chiral amino products in good
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Published on Web 07/02/2010
DOI: 10.1021/jo100865q
r
2010 American Chemical Society

Kaur et al.
JOCArticle
SCHEME 1
yields and excellent diastereoselectivities.10 During our con-
tinuous study of this project, we envisioned that if achiral
N-phosphonyl imines are designed and synthesized, they would
serve as a new family of CdN electrophiles and dienophiles for
general use in advanced synthesis and asymmetric catalysis.
N,N-dialkyl diamineauxiliary canbe recoveredquantitatively
for reuse; (6) free primary natural amino acid catalysts are
common commercial chemicals; and (7) the modifiable flexi-
bility of C2-symmetric structure by changing its ring sizes and
N,N-protection groups can result in various CdN electro-
philes with changed reactivity for different catalytic reactions.
Results and Discussion
SCHEME 2
N-Phosphonyl imines and N-phosphoramides have stron-
ger Lewis basicity as compared with their counterparts.11
During the reaction process, the resulting N-phosphoramide
species can strongly bind to catalytic centers and thus retard
catalytic cycles, which consequently makes it extremely
difficult to achieve asymmetric catalysis with N-phosphonyl
imines as electrophiles. In this report, we would like to
describe the new asymmetric catalytic Strecker reaction of
N-phosphonyl imines under a concise catalytic system
(Scheme 1); in fact, this reaction has recently become an
active topic due to its practical use for the synthesis of
unnatural R-amino acids and their derivatives and its versa-
tility as a superior model reaction for organocatalysis.2-4,6
The present N-phosphonyl imine-based Strecker reaction
was conducted by using free primary amino acids as catalysts
and Et2AlCN12 as nucleophile. Excellent chemical yields
(89-97%) and enantioselectivities (95.2-99.7% ee) have
been achieved by performing the reaction at -78 °C in dry
˚
toluene in the presence of 4 A mol sieves (Scheme 1).
Our new work described here shows several attractive
characteristics as compared with previous known systems:
(1) the first asymmetric catalytic reaction of achiral N-phos-
phonyl imines; (2) the first use of nonvolatile and inexpensive
Et2AlCN as the cyanide source for catalytic Strecker reac-
tion; (3) N-phosphonyl group can be readily cleaved under
mild conditions without racemization; (4) the new N-phos-
phonyl protection group enabled the pure Strecker pro-
ducts to be obtained simply by washing the crude products
with hexane without further purification; (5) the cleavaged
The reaction is believed to proceed through the mecha-
nism as shown in Scheme 2. The first step is the reaction of
amino acid A with Et2AlCN to form the catalytic species B.
The evolution of ethane gas and the solubility change of
amino acid (which is insoluble in toluene but was dissolved
after species B was formed) are evidence of this step occur-
ring. The Lewis acidic center can activate the oxygen of the
N-phosphonyl group of the substrate before species B deli-
vers cyanide onto the CdN bond from its Si-face to afford
intermediate C. During the reaction process, Et2AlCN reacts
with additive i-PrOH to give species Et(i-PrO)AlCN, and its
activation of imine nitrogen is also anticipated prior to CdN
addition. At the third step, the catalyst B is regenerated via
the homotransmetalation between species C and Et(i-PrO)-
AlCN, which is derived from the reaction of Et2AlCN
and i-PrOH; simultaneously, the actual catalytic complex D
was generated, which was followed by deprotonation and
quenching to afford the final product.
(10) (a) Kaur, P.; Shakya, G.; Sun, H.; Pan, Y.; Li, G. Org. Biomol. Chem.
2010, 8, 1091. (b) Kaur, P.; Nguyen, T.; Li, G. Eur. J. Org. Chem. 2009, 912–
916. (c) Ai, T.; Li, G. Bioorg. Med. Chem. Lett. 2009, 19, 3967–3969. (d) Ai,
T.; Han, J.; Chen, Z. X.; Li, G. Chem. Biol. Drug Des. 2009, 73, 203–208.
(e) Kattuboina, A.; Li, G. Tetrahedron Lett. 2008, 49, 1573–1577.
(11) Denmark, S. E.; Beutner, G. L. Angew. Chem., Int. Ed. 2008, 47,
1560–1638.
(12) (a) Nagata, W.; Yoshioka, M.; Hirai, S. J. Am. Chem. Soc. 1972, 94,
4635–4643. (b) Benedetti, F.; Berti, F.; Norbedo, S. Tetrahedron Lett. 1999,
40, 1041–1044. (c) Nakamura, S.; Sato, N.; Sugimoto, M.; Toru, T. Tetra-
hedron: Asymmetry 2004, 15, 1513–1516. (d) Davis, F. A.; Zhang, H.; Lee,
S. H. Org. Lett. 2001, 3, 759–762.
J. Org. Chem. Vol. 75, No. 15, 2010 5145

Kaur et al.
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i-PrOH has been proven to be a crucial additive for this
reaction, which is similar to other asymmetric Strecker
processes.6a,12d A tiny amount of product was formed with-
out the addition of i-PrOH in the reaction mixture. Usually,
in aromatic solvents, Et2AlCN exists as tetramers or
pentamers6a that show lower reactivity. However, its coor-
dination with phosphonyl imine followed by conversion to
intermediate B and Et(i-PrO)AlCN, which was evidenced by
the release of ethane bubbles during the reaction process, led
to the present success.
SCHEME 3. Results of Screening Catalysts
Starting materials, achiral N-phosphonyl imines (1a-k),
were readily prepared by following the procedure which is
similar to that developed by our group for asymmetric chiral
N-phosphonyl imine chemistry.10 The four-step preparation
of N-phosphoramides showed quantitative yields for all
steps. Products were obtained as white solids without the
need of special purification. The final step of imine formation
showed higher yields (76-87%) than the formation of
N-phosphonyl imine counterparts. It is somewhat surprising
that the design and synthesis of achiral N-phosphonyl imines
have not been well documented in the literature so far.
Our initial effort on this reaction was made with the use
N,N-dibenzyl N-phosphonyl imine as the substrate and free
primary amino acid,13 L-valine, as the catalyst in dry toluene
TABLE 1. Results of the Synthesis of N-Phosphonyl-Substituted Chiral
R-Aminonitriles 4a-ka
entry
substrate
R1
product
yield (%)b
eec
˚
in the presence of 4 A MS. The reaction was conducted by
1
2
3
4
5
6
7
8
9
1a
1b
1c
1d
1e
1f
1g
1h
1i
H
4a
4b
4c
4d
4e
4f
4g
4h
4i
95
96
97
95
94
93
94
92
90
92
89
99.7
94
96
p-fluoro
p-bromo
p-chloro
p-methyl
p-methoxy
o-fluoro
o-bromo
o-chloro
o-methyl
o-furyl
using Et2AlCN (1.5 equiv, 1.0 M in toluene) together with
i-PrOH (1.0 equiv) as an additive at -78 °C for 5 h, followed
by quenching with dilute aq HCl to produce product in 75%
yield and poor enantioselectivity (22.6% ee). Next, we
attempted to improve the reaction by replacing benzyl with
isopropyl in N-phosphonyl imine substrates, which has been
proven to be successful for several chiral N-phosphonyl
imine-based reactions. However, the resulting N-diisopropyl
phosphonyl imine was found to be insoluble in toluene at
-78 °C and even at rt. We then utilized N,N-naphthalen-1-
ylmethyl to replace benzyl, i.e., to use N,N-naphthalen-1-
ylmethyl N-phosphonyl imine (1a) as the electrophile. We
were pleased to find that not only the solubility problem was
solved, but also enantioselectivity and chemical yield were
substantially increased to 70% ee and 98%, respectively.
Several catalysts were then screened under the above
conditions. As revealed in Scheme 3, N-tosyl L-valine re-
sulted in a much lower enantioselectivity of 38% ee, albeit
the yield remained high. This was somewhat surprising
because nearly all successful asymmetric catalytic reactions
utilize amino acids that are based on the use of N-protected
ones.14 N-Tosyl phenylalanine and N-tosyl phenylglycine
also showed poor enantioselectivities of 28% ee and 36%
ee, respectively. We then turned our attention back to free
amino acids and found that free L-phenylalanine afforded
63% ee and 65% yield. Amazingly, the use of free L-phenyl-
glycine (10 mol %) as the catalyst resulted in 99% ee and
95% yield under this new catalytic system.
95.2
98.8
97.6
96.1
97
95.2
98.9
99
10
11
1j
1k
4j
4k
aAll reactions were carried out at -78 °C in 0.06 M solution of imine
in toluene. bCombined yields of both isomers. cEnantiomeric ratio has
been determined by using chiral HPLC OD-H column (3:7 IPA:hexane),
flow rate = 0.60 mL/min.
THF, and CHCl3, proved to be unsuitable for this reaction as
they afforded poor yields and percent ee values. During the
preparation of catalytic species, it is important to allow chiral
amino acids to react with Et2AlCN for at least 15 min at rt
before the reaction mixture is cooled to -78 °C. Keeping the
reaction at -78 °C was necessary for achieving high enantio-
selectivity, albeit yield was not affected by temperature.
TMSCN was also employed as the nucleophile, but poor
yields (<10%) were obtained.
Having identified the optimal catalyst and catalytic con-
dition, we turned our attention to the substrate scope.
As shown in Table 1, the reaction proceeded very well for
all eleven substrates that were examined with excellent
enantioselectivities (95.2-99.7% ee) and chemical yields
(89-97%) (Scheme 4). Electron-rich substrates (entries 5
and 6) showed nearly the same reaction rates as other
substrates and led to similar results. Strong electron-defi-
cient substrates (entries 2 and 7) that sometimes showed less
efficiency in chiral N-phosphonyl imine-based asymmetric
reactions10 resulted in excellent yields (96% and 94%,
respectively) and enantioselectivity (94% and 96.1% ee,
respectively) under the present system. Interestingly, the
present N-phosphonyl protection group enabled the pure
products to be obtained simply by washing with hexane
˚
It should be noted that well-activated 4 A MS are also very
important for this reaction. Much lower yields were observed
˚
in the absence of 4 A MS. Other solvents, such as DCM,
(13) (a) Paradowska, J.; Stodulski, M.; Mlynarski, J. Angew. Chem., Int.
ꢀ
Ed. 2009, 48, 4288–4297. (b) Cordova, A.; Zou, W.; Ibrahem, I.; Reyes, E.;
Engqvist, M.; Liao, W.-W. Chem. Commun. 2005, 3586–3588.
(14) (a) Corey, E. J.; Loh, T. P.; Roper, T. D.; Azimioara, M. D.; Noe,
M. C. J. Am. Chem. Soc. 1992, 114, 8290–8292. (b) Li, G.; Wei, H. X.; Phelps,
B. S.; Purkiss, D. W.; Kim, S. H. Org. Lett. 2001, 3, 823–826.
5146 J. Org. Chem. Vol. 75, No. 15, 2010

Kaur et al.
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FIGURE 1. Working model of asymmetric induction in which the nucleophilic species of -CN attacks N-phosphonyl imine from its Si face.
SCHEME 4
SCHEME 5
without further purification; we tentatively define this phe-
nomenon as the GAP Chemistry (GAP: Goup-Assistant-
Purification).15 It is noteworthy that the resulting haloge-
nated Strecker adducts (entries 3, 4, 8, and 9) can be readily
converted to a variety of useful synthetic building blocks via
metal-catalyzed coupling reactions.16 2-Furyl substrate led
to complete enantioselectivity (99% ee) and 89% yield,
which is important because the furyl functionality can be
subjected to other transformations, such as Diels-Alder and
oxidative ring-opening.3 Our preliminary results also con-
firmed that this asymmetric catalytic system showed promis-
ing results for aliphatic N-dialkoxyphosphoryl imines.17
More substrates will be under investigation with this system.
The absolute configuration for this asymmetric induction
was determined by converting product (4a) to an authentic
sample.18 In this conversion, 4a was subjected to deprotec-
tion with 2.0 M aq HCl at rt in methanol followed by in situ
t-Boc protection by treating with (t-Boc)2O in the presence of
triethylamine (Scheme 5) to yield product 5. Optical rotation
of this product was confirmed to be consistent with that of
the known sample with S configuration. During this trans-
formation, the cleaved N1,N2-bis(naphthalen-1-ylmethyl)-
ethane-1,2-diamine was subjected to a one-time extraction
with n-butanol from the acidic mixture, prior to t-Boc
protection, to give a quantitative recovery yield.
(15) So far, the GAP chemistry has been realized by eight asymmetric
reactions that were developed in our labs. These reactions were associated
with achiral/chiral N-phosphonyl groups and chiral N-phosphinyl group,
and have resulted in similar simple purification and recovery of auxiliary
quantitatively for re-use. It is anticipated more reactions will be converted
into GAP chemistry when C2-groups of auxiliaries are re-designed in the near
future.
(16) (a) Fu, G. C. Acc. Chem. Res. 2008, 41, 1555–1564. (b) Guram, A. S.;
Buchwald, S. L. J. Am. Chem. Soc. 1994, 116, 7901–7902. (c) Paul, F.; Patt, J.;
Hartwig, J. F. J. Am. Chem. Soc. 1994, 116, 5969–5970.
(17) An aliphatic N-phosphonyl-substituted imine was prepared in situ
and subject to asymmetric strecker reaction with the optimized conditions.
Yellow oil, yield (0.090 g, 92%); [R]24D þ12.0 (c 0.8, CHCl3); 1H NMR (500
MHz, CDCl3) δ 4.16-4.08 (m, 4H), 3.96-3.84 (m, 3H), 3.35 (br s, 1H), 1.32
(t, J = 5.5 Hz, 1H), 1.25 (s, 3H), 1.07 (s, 3H), 0.93 (s, 3H), 0.85 (s, 3H); 13C
NMR (125 MHz, CDCl3) δ 128.7, 76.3 (2C), 68.0, 45.5, 38.5, 21.5, 21.49,
21.43, 20.8, 19.9; 31P NMR (202 MHz, CDCl3) δ 22.1. Ee 92% (retention
time = 5.43 (major) and 5.86 (minor); flow rate = 0.60 mL/min, OD-H
chiral column (7:3 hexane:IPA solvent system). HPLC conditions need to be
further optimized (overlapping of peaks still exists).
(18) Kuo, C.-W.; Zhu, J.-L.; Wu, J.-D.; Chu, C.-M.; Yao, C.-F.; Shia,
K.-S. Chem. Commun. 2007, 3, 301–303.
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Kaur et al.
JOCArticle
On the basis of the assignment of absolute configuration of
the resulting products, a working model has been proposed
and shown in Figure 1 to explain the possible source of
asymmetric induction. In this model, N-phosphonyl imine
approaches the catalytic nucleophilic source of -CN from its
less hindered side of hydrogen instead of the bulkier phenyl
group of the chiral center of the catalyst. Although several
conformational arrangements are possible, it is more likely
for the CdN bond to be arranged on the anti position of the
Al-CN bond as shown in Figure 1.
Compound 1c: pale yellow solid; yield 0.355 g (82%); mp
60-62 °C; 1H NMR (500 MHz, CDCl3) δ 8.83 (d, J = 33.0 Hz,
1H), 8.24 (d, J = 8 Hz, 2H), 7.83 (dd, J = 2.5, 7.5 Hz, 2H), 7.77
(d, J = 8.0 Hz, 2H), 7.62 (d, J = 11 Hz, 2H), 7.51-7.47 (m, 8H),
7.41-7.38 (m, 2H), 4.64 (dd, J = 7.5, 15.0 Hz, 2H), 4.52 (dd, J =
5.5, 15.0 Hz, 2H), 3.13 (d, J = 9.0 Hz, 4H); 13C NMR (125 MHz,
CDCl3) δ 172.3 (d, J = 6.9 Hz), 134.6, 134.4, 133.7 (2C), 132.5
(d, J = 6.9 Hz, 2C), 132.0 (2C), 131.7 (2C), 131.5, 131.1 (2C),
128.4 (d, J = 7.5 Hz, 2C), 127.9, 126.8 (2C), 126.3 (2C), 125.7
(2C), 125.1 (2C), 123.8 (2C), 47.4 (d, J = 4.5 Hz, 2C), 45.0 (d,
J = 10.9 Hz, 2C); 31P NMR (202 MHz, CDCl3) δ 26.0.
Compound 1e: white solid; yield 0.208 g (87%); mp 64-66 °C;
1H NMR (500 MHz, CDCl3) δ 9.33 (d, J = 33.3 Hz, 1H), 8.27
(d, J = 8.5 Hz, 2H), 8.02 (d, J = 8.0 Hz, 1H), 7.83 (d, J = 8.0 Hz,
2H), 7.78 (d, J = 8.5 Hz, 2H), 7.53-7.39 (m, 9H), 7.31 (t, J = 7.5
Hz, 1H), 7.23 (d, J = 8.0 Hz, 1H), 4.66 (d, J = 7.0 Hz, 2H), 4.55
(d, J = 5.0 Hz, 2H), 3.13 (d, J = 10.0 Hz, 4H), 2.49 (s, 3H); 13C
NMR (125 MHz, CDCl3) δ 172.5 (d, J = 12.5 Hz), 140.6 (2C),
133.7 (2C), 132.8 (d, J = 7.4 Hz), 132.6 (2C), 131.7, 131.2 (2C),
129.3 (2C), 128.4 (2C), 128.3 (2C), 126.5 (2C), 126.3 (2C), 126.1,
125.7 (2C), 125.1 (2C), 123.8 (2C), 47.5 (d, J = 4.7 Hz, 2C), 45.0
(d, J = 10.6 Hz, 2C), 19.4; 31P NMR (202 MHz, CDCl3) δ 26.4.
Compound 1f: white solid; yield 0.198 g (87%); mp 64-66 °C;
1H NMR (500 MHz, CDCl3) δ 8.98 (d, J = 33.3 Hz, 1H), 8.31
(d, J = 8.4 Hz, 2H), 7.88-7.79 (m, 6H), 7.57-7.41 (m, 8H), 7.02
(d, J = 8.7 Hz, 2H), 4.71-4.53 (m, 4H), 3.92 (s, 3H), 3.13 (d, J =
9.6 Hz, 4H); 13C NMR (125 MHz, CDCl3) δ 173.4 (d, J = 6.52
Hz), 164.1 (2C), 134.1 (2C), 133.16 (d, J = 7.4 Hz, 2C), 132.4
(2C), 132.1 (2C), 128.7 (2C), 128.6 (2C), 127.0 (2C), 126.6 (2C),
126.0 (2C), 125.4 (2C), 124.2 (2C), 114.4 (2C), 55.8, 47.8 (d, J =
4.7 Hz, 2C), 45.3 (d, J = 10.6 Hz, 2C); 31P NMR (202 MHz,
CDCl3) δ 26.8.
Conclusion
The new asymmetric catalytic Strecker reaction of achiral
N-phosphonyl imines has been established. Excellent enan-
tioselectivities and yields have been achieved by using pri-
mary free natural primary amino acids as catalysts and
Et2AlCN as the nucleophile. This work presents a new use
of nonvolatile Et2AlCN in asymmetric catalysis. N,N0-Pro-
tection groups on achiral N-phosphonyl imine were found to
play an important role for the present success. This new
protection group enabled simple product purification to be
achieved simply by washing the crude products with hexane;
it can also be readily cleaved and recycled under mild con-
dition to give a quantitative recovery of N,N0-bis(naphthalen-
1-ylmethyl)ethane-1,2-diamine. A new mechanism has been
proposed that is consistent with experimental observations.
Experimental Section
Typical Procedure for the Synthesis of Achiral N-Phosphonyl
Imine (1a-k). In a dry vial, under inert gas protection, N,N-
naphthalen-1-ylmethyl phosphoramide (1.0 equiv) was taken
and dissolved in dry dichloromethane. To the solution was
added corresponding aldehyde (1.5 equiv) followed by the
addition of triethylamine (3.0 equiv). The reaction was cooled
to 0 °C and titanium(IV) chloride (1.0 M solution in DCM,
0.5 equiv) was added to the reaction (Scheme 1). The reaction
was allowed to stir at room temperature for 36 h and after that
the mixture was loaded directly to silica gel. The reaction
mixture was purified through column chromatography (ethyl
acetate:hexane:1% Et3N). Pure product was obtained by eluting
the reaction mixture with ethyl acetate:hexane:triethylamine
(60:40:1 mL) as a white or pale yellow solid in all of the cases
reported.
Compound 1a: white solid; yield 0.172 g (76%); mp 84-86 °C;
1H NMR (500 MHz, CDCl3) δ 9.03 (d, J = 33.5 Hz, 1H), 8.28
(d, J = 9.0 Hz, 2H), 7.86-7.82 (m, 4H), 7.78 (d, J = 8.0 Hz, 2H),
7.53-7.46 (m, 9H), 7.42-7.39 (m, 2H), 4.67-4.64 (m, 2H),
4.55-4.52 (m, 2H), 3.13 (d, J = 9.5 Hz, 4H); 13C NMR (125
MHz, CDCl3) δ 173.5 (d, J = 7.0 Hz), 139.6, 135.8, 135.6 (2C),
133.7, 133.1, 132.7(2C), 132.6, 131.7 (2C), 129.9 (2C), 128.7
(2C), 128.4, 128.3, 126.7 (2C), 126.2, 125.7, 125.4, 125.0 (2C),
123.8, 120.5, 47.43, 47.40 (d, J = 7.3 Hz), 44.9, 42.3; 31P NMR
(202 MHz, CDCl3) δ 24.2.
Compound 1b: white foamy solid; yield 0.214 g (82%); mp
68-70 °C; 1H NMR (500 MHz, CDCl3) δ 8.87 (d, J = 32.9 Hz,
1H), 8.24 (dd, J = 8.9, 1.8 Hz, 2H), 7.83-7.76 (m, 6H),
7.52-7.46 (m, 6H), 7.41-7.38 (m, 2H), 7.15 (t, J = 8.5 Hz,
2H), 4.66-4.49 (m, 4H), 3.15-3.11 (m, 4H); 13C NMR (125
MHz, CDCl3) δ 172.3 (d, J = 6.45 Hz), 166.8, 164.8, 133.8 (2C),
132.65 (d, J = 6.94 Hz, 2C), 132.18 (d, J = 8.9 Hz, 2C), 131.7
(2C), 128.5 (2C), 128.4 (2C), 126.8 (2C), 126.3 (2C), 125.8 (2C),
125.1 (2C), 123.9 (2C), 116.1, 115.9, 47.5 (d, J = 4.9 Hz,
2C), 45.0 (d, J = 10.4 Hz, 2C); 31P NMR (202 MHz, CDCl3)
δ 26.1.
Compound 1g: white solid; yield 0.214 g (81%); mp 64-66 °C ;
1H NMR (500 MHz, CDCl3) δ 9.30 (d, J = 33.0 Hz, 1H),
8.32-8.25 (m, 2H), 8.12-8.07 (m, 1H), 7.88-7.56 (m, 5H),
7.59-7.38 (m, 10H), 4.72-4.49 (m, 4H), 3.13-2.92 (m, 4H); 31
P
NMR (202 MHz, CDCl3) δ 26.3;. HRMS (ESI) m/z calcd for
C31H28FN3OP 508.1954, found 508.1983.
Compound 1h: pale yellow solid; yield 0.362 g (79%); mp
54-56 °C; 1H NMR (500 MHz, CDCl3) δ 9.32 (d, J = 32.5 Hz,
1H), 8.27 (d, J = 8.5 Hz, 2H), 8.15-8.13 (m, 1H), 7.83 (d, J =
8.25 Hz, 2H), 7.77 (d, J = 8.0 Hz, 2H), 7.62-7.60 (m,1H),
7.54-7.44 (m, 6H), 7.42-7.36 (m, 4H), 4.71 (dd, J = 7.0, 15.0
Hz, 2H), 4.56 (dd, J = 5.0, 14.5 Hz, 2H), 3.12 (d, J = 10.0 Hz,
4H); 13C NMR (125 MHz, CDCl3) δ 171.4 (d, J = 5.4 Hz),
134.23, 133.9, 133.8, 133.4, 132.6 (d, J = 7.0 Hz, 2C), 131.7 (2C),
129.6 (2C), 128.4 (d, 11.2 Hz, 2C), 127.6 (2C), 127.5 (2C), 126.6
(2C), 126.4 (2C), 125.8 (2C), 125.1 (2C), 123.8 (2C), 47.5 (d, J =
4.5 Hz, 2C), 44.9 (d, J = 10.7 Hz, 2C); 31P NMR (202 MHz,
CDCl3) δ 26.0
Compound 1i: white foamy solid; yield 0.225 g (85%); mp
66-68 °C; 1H NMR (500 MHz, CDCl3) δ 9.39 (d, J = 32.7 Hz,
1H), 8.43-8.14 (m, 2H), 7.88-7.75 (m, 5H), 7.58-7.29 (m,
11H), 4.74-4.52 (m, 4H), 3.14-2.85 (m, 4H); 13C NMR (125
MHz, CDCl3) δ 167.0 (d, J = 5.7 Hz), 135.1 (d, J = 8.9 Hz),
134.0 (2C), 132.8 (d, J = 6.8 Hz), 131.9 (2C), 128.8, 128.7 (2C),
128.6 (2C), 128.5 (2C), 126.9 (2C), 126.5 (2C), 126.5, 126.0 (2C),
125.4, 125.3 (2C), 124.6, 124.0 (2C), 123.9, 116.4, 47.6 (d, J = 4.8
Hz, 2C), 45.1 (d, J = 10.9 Hz, 2C); 31P NMR (202 MHz, CDCl3)
δ 26.2; HRMS (ESI) m/z calcd for C31H28ClN3OP 524.1659,
found 524.0652.
Compound 1j: pale yellow solid; yield 0.284 g (82%); mp
1
62-64 °C; H NMR (500 MHz, CDCl3) δ 9.62 (d, J = 33.5
Hz, 1H), 8.29 (d, J = 8.0 Hz, 2H), 7.82-7.76 (m, 6H), 7.53-7.38
(m, 10H), 4.69 (dd, J = 7.0, 15.0 Hz, 2H), 4.54 (dd, J = 5.0, 14.5
Hz, 2H), 3.08 (d, J = 10.0 Hz, 4H), 2.04 (s, 3H); 13C NMR (125
MHz, CDCl3) δ 169.8 (d, J = 5.4 Hz), 134.7 (2C), 133.6 (2C),
132.8 (d, J = 7.3 Hz, 2C), 131.6 (2C), 128.3 (2C), 128.2 (2C),
5148 J. Org. Chem. Vol. 75, No. 15, 2010

Kaur et al.
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128.0 (2C), 126.4, (2C), 126.2 (2C), 125.8 (2C), 125.1 (2C), 123.8
(2C), 120.4, 111.1, 47.3 (d, J = 4.5 Hz, 2C), 44.8 (d, J = 10.7,
2C), 14.0; 31P NMR (202 MHz, CDCl3) δ 25.8.
δ 8.14 (dd, J = 7.5, 16.5 Hz, 2H), 7.86 (d, J = 7.5 Hz, 2H), 7.79
(d, J = 8.0 Hz, 2H), 7.51-7.45 (m, 6H), 7.43-7.36 (m, 4H), 7.20
(d, J = 8.0 Hz, 2H), 5.32 (t, J = 9.0 Hz, 1H), 4.66-4.49 (m, 4H),
3.90 (q, J = 6.5 Hz, 1H), 3.11-3.05 (m, 4H); 13C NMR (125
MHz, CDCl3) δ 134.4 (d, J = 5.9 Hz), 133.8 (d, J = 7.9 Hz),
132.3 (2C), 132.2, 131.6 (d, J = 8.4 Hz), 128.7 (d, J = 3.5 Hz,
2C), 128.5 (2C), 128.4 (2C), 128.3 (2C), 126.6 (2C), 126.4 (d, J =
7.9 Hz, 2C), 126.2 (2C), 125.9 (d, J = 7.5 Hz, 2C), 125.2 (d, J =
2.9 Hz, 2C), 123.4, 123.3 (d, J = 12.8 Hz), 119.5 (d, J = 3.5 Hz),
46.9, 46.8 (d, J = 4.4 Hz), 46.1 (d, J = 4.9 Hz), 44.8 (d, J = 12.2
Hz), 44.1 (d, J = 13.4 Hz); 31P NMR (202 MHz, CDCl3) δ 23.0;
HRMS (ESI) m/z calcd for C32H29BrN4OP 595.1257, found
595.1262; 96% ee, retention time = 6.41 (minor) and 6.84
(major), flow rate = 0.60 mL/min, OD-H chiral column (7:3
hexane:IPA solvent system).
Compound 1k: yellow color solid; yield 0.216 g (90%); mp
68-70 °C; 1H NMR (500 MHz, CDCl3) δ 8.85 (d, J = 34.2 Hz,
1H), 8.29 (d, J = 7.8 Hz, 2H), 7.86-7.78 (m, 4H), 7.71 (s, 1H),
7.57-7.41 (m, 8H), 7.07(d, J = 3.6 Hz, 1H), 6.62-6.61 (m, 1H),
4.71-4.64 (m, 2H), 4.56-4.49 (m, 2H), 3.22-3.09 (m, 4H); 13
C
NMR (125 MHz, CDCl3) δ 161.2 (d, J = 5.9 Hz), 152.1, 151.8,
147.4, 133.7 (2C), 132.6 (d, J = 7.3 Hz), 131.7 (2C), 128.4 (d, J =
13.7 Hz, 2C), 126.7 (2C), 126.3 (2C), 125.7 (2C), 125.1 (2C),
123.8 (2C), 121.2 (2C), 112.7 (2C), 47.2 (d, J = 5.0 Hz, 2C), 44.8
(d, J = 10.3 Hz, 2C); 31P NMR (202 MHz; CDCl3) δ 26.4;
HRMS (ESI) m/z calcd for C29H27N3O2P 480.1841, found
480.1839.
Typical Procedure for the Synthesis of N,N-Naphthalen-1-
ylmethyl N-Phosphonyl Imine-Substituted r-Aminonitriles. In a
dry vial, under inert gas protection, 4 A MS and the chiral amino
Compound 4d: pale yellow color solid; yield 0.128 g (95%); mp
134-136 °C, [R]24D þ8.60 (c 0.6, CHCl3); 1H NMR (500 MHz,
CDCl3) δ 8.15 (dd, J = 8.3, 23.4 Hz, 2H), 7.86 (d, J = 7.8 Hz,
2H), 7.78 (d, J = 8.1 Hz, 2H), 7.51-7.45 (m, 6H), 7.40 (q, J =
7.8 Hz, 2H), 7.28-7.22 (m, 4H), 5.35 (t, J = 9.0 Hz, 1H),
4.66-4.51 (m, 4H), 3.77 (br s, 1H, NH), 3.12-3.03 (m, 4H); 13C
NMR (125 MHz, CDCl3) δ 135.2, 133.85, 133.81, 133.7, 132.27,
132.25, 132.21, 131.5 (d, J = 9.9 Hz), 129.3 (2C), 128.7 (d, J =
4.9 Hz, 2C), 128.5 (d, J = 17.9 Hz, 2C), 127.9 (2C), 126.7, 126.4
(d, J = 9.9 Hz, 2C), 126.3, 125.9 (d, J = 8.4 Hz, 2C), 125.3 (d,
J = 2.9 Hz, 2C), 123.2 (d, J = 14.4 Hz, 2C), 119.5 (d, J = 3.5
Hz), 46.9, 46.8 (d, J = 4.5 Hz), 46.1 (d, J = 5.4 Hz), 44.8 (d, J =
11.9 Hz), 44.1 (d, J = 13.4 Hz); 31P NMR (202 MHz, CDCl3) δ
22.6; HRMS (ESI) m/z calcd for C32H29ClN4OP 551.1761,
found 551.1768; 95.2% ee, retention time = 6.27 (minor) and
6.72 (major), flow rate = 0.60 mL/min, OD-H chiral column
(7:3 hexane:IPA solvent system).
˚
acid (3) were added followed by loading dry toluene. A turbid
solution was obtained in which diethylaluminium cyanide (2, 1.0
M solution in toluene, 1.50 mmol) was added followed by the
addition of i-PrOH (1.0 mmol). The reaction was stirred for
15 min at room temperature, and then cooled to -78 °C. The
resulting mixture was stirred at -78 °C for 30 min followed by
the addition of achiral N-phosphonyl imine, which was dis-
solved in 3 mL of toluene. The reaction mixture was stirred for
5 h at this temperature before it was quenched by aq 0.05 M HCl,
followed by addition of ethyl acetate (10 mL) and water (10 mL).
The reaction mixture was filter off through Celite. The organic
layer was separated (3 ꢀ 10 mL of ethyl acetate) and dried over
anhydrous sodium sulfate. Sodium sulfate was filtered off, and
organic phase was evaporated to obtain crude product, which
upon washing with hexane afforded the pure product as a white
solid without further purification.
Compound 4e: white solid; yield 0.110 g (94%); mp 176-
D
178 °C; [R]24 þ7.45 (c 0.7, CHCl3); 1H NMR (500 MHz,
Compound 4a: yield 0.246 g (92%); mp 112-114 °C; [R]24
CDCl3) δ 8.20 (d, J = 7.0 Hz, 1H), 8.15 (d, J = 7.5 Hz, 1H),
7.87-7.85 (m, 2H), 7.79 (d, J = 5.0 Hz, 1H), 7.31 (d, J = 7.0 Hz,
7H), 7.12 (d, J = 7.0 Hz, 6H), 5.37 (t, J = 8.5 Hz, 1H),
4.66-4.48 (m, 4H), 3.67 (t, J = 10.0 Hz, 1H, NH), 3.07-2.99
(m, 4H), 2.30 (s, 3H); 13C NMR (125 MHz, CDCl3) δ 139.2,
133.7 (d, J = 8.4 Hz), 132.5 (d, J = 6.5 Hz), 132.4 (d, J = 5.5
Hz), 132.3 (d, J = 6.0 Hz), 131.6 (d, J = 8.4 Hz), 129.8 (2C),
128.6 (2C), 128.5 (2C), 128.4 (2C), 128.3, 126.5 (2C), 126.4 (d,
J = 6.4 Hz), 126.3, 125.8 (2C), 125.7 (2C), 125.2 (d, J = 4.0 Hz),
123.3 (d, J = 7.5 Hz), 120.0 (d, J = 4.0 Hz), 47.2, 46.6 (d, J = 4.5
Hz), 46.1 (d, J = 5.4 Hz), 44.6 (d, J = 11.9 Hz), 44.0 (d, J = 12.9
Hz), 21.0; 31P NMR (202 MHz, CDCl3) δ 22.5. HRMS (ESI) m/
z calcd for C33H31N4O2PNa 569.2077, found 569.2070; 98.8%
ee, retention time = 6.82 (major), flow rate = 0.60 mL/min,
OD-H chiral column (7:3 hexane:IPA solvent system).
D
þ2.52 (c 1.0, CHCl3); 1H NMR (500 MHz, CDCl3) δ 8.22
(d, J = 9.5 Hz, 2H), 8.15 (d, J = 7.5 Hz, 2H), 7.86 (t, J = 7.0
Hz, 2H), 7.80 (d, J = 8.0 Hz, 2H), 7.51-7.45 (m, 5H), 7.44-7.39
(m, 4H), 7.35-7.34 (m, 2H), 5.42 (t, J = 9.0 Hz, 1H), 4.65-4.55
(m, 4H), 3.44 (t, J = 9.5 Hz, 1H), 3.05-3.01 (m, 4H); 13C NMR
(125 MHz, CDCl3) δ 135.36, 135.31, 133.8, 133.7, 132.37,
132.31, 131.6 (d, J = 8.0 Hz, 2C), 128.6 (d, J = 7.3 Hz, 2C),
128.5, 128.4, 128.3, 126.7, 126.6, 126.5, 126.4, 126.3, 125.9,
125.8, 125.24, 125.20, 123.4, 123.3 (2C), 119.98, 119.92, 47.5,
46.8 (d, J = 7.3 Hz), 44.6 (d, J = 7.8 Hz), 44.0, 43.9; 31P NMR
(202 MHz, CDCl3) δ 22.9; HRMS (ESI) m/z calcd for
C32H30N4OP 517.2152, found 517.2156; 99.7% ee, retention
time = 6.77 (major), flow rate = 0.60 mL/min, OD-H chiral
column (hexane:i-PrOH (v/v) = 3:7).
Compound 4b: off-white solid; yield 0.172 g (96%); mp
126-128 °C; [R]24D þ7.0 (c 0.8, CHCl3); 1H NMR (500 MHz,
CDCl3) δ 8.16 (dd, J = 9.2, 27.2 Hz, 2H), 7.82 (dd, J = 8.0, 36.0
Hz, 4H), 7.51-7.44 (m, 6H), 7.40 (q, J = 8.2 Hz, 2H), 7.33 (q,
J = 5.1 Hz, 2H), 6.95 (t, J = 8.5 Hz, 2H), 5.36 (t, J = 9.0Hz, 1H),
4.67-4.52 (m, 4H), 3.82 (q, J = 9.8 Hz, 1H, NH), 3.12-3.02 (m,
4H); 13C NMR (125 MHz, CDCl3) δ 163.9, 161.9, 133.8 (d, J =
8.9 Hz, 2C), 132.3 (d, J = 2.5 Hz), 132.2, 131.5 (d, J = 9.9 Hz),
131.2, 128.7 (d, J = 6.9 Hz, 2C), 128.6 (2C), 128.5, 128.4, 126.7,
126.4 (d, J = 12.4 Hz, 2C), 126.3, 125.9 (d, J = 9.9 Hz, 2C), 125.2
(d, J = 3.9 Hz, 2C), 123.3 (d, J = 12.9 Hz, 2C), 119.7 (d, J = 3.5
Hz), 116.14 (d, J = 21.8 Hz, 2C), 46.84 (d, J = 3.9 Hz), 46.82,
46.1 (d, J = 4.9 Hz), 44.8 (d, J = 12.4 Hz), 44.0 (d, J = 13.4 Hz);
31P NMR (202 MHz, CDCl3) δ 22.1; HRMS (ESI) m/z calcd for
C32H28FN4OPNa 557.1877, found 557.1884; 94% ee, retention
time = 6.49 (minor) and 7.17 (major), flow rate = 0.60 mL/min,
OD-H chiral column (7:3 hexane:IPA solvent system).
Compound 4f: white solid; yield 0.132 g (93%); mp 182-
D
184 °C; [R]24 þ1.45 (c 1.1, CHCl3); 1H NMR (500 MHz,
CDCl3) δ 8.23-8.19 (m, 1H), 8.16-8.14 (m, 1H), 7.89-7.84
(m, 2H), 7.80-7.78 (m, 2H), 7.52-7.47 (m, 6H), 7.43-7.39 (m,
2H), 7.32-7.28 (m, 2H), 6.83-6.79 (m, 2H), 5.34 (t, J = 8.7 Hz,
1H), 4.66-4.52 (m, 4H), 3.75 (s, 3H), 3.50 (t, J = 9.6 Hz, 1H,
NH), 3.09-3.00 (m, 4H); 13C NMR (125 MHz, CDCl3) δ 160.2,
133.8 (d, J = 8.4 Hz), 132.4 (d, J = 6.5 Hz), 131.6 (d, J = 8.4 Hz,
2C), 128.7 (2C), 128.6 (2C), 128.5 (2C), 128.3 (2C), 128.0 (2C),
127.5 (d, J = 6.4 Hz), 126.6, 126.4, 126.3, 125.9 (2C), 125.8 (2C),
125.2 (d, J = 4.0 Hz), 123.4 (d, J = 7.5 Hz), 120.1 (d, J = 4.0
Hz), 114.5 (2C), 55.3, 46.9, 46.7 (d, J = 4.5 Hz), 46.1 (d, J = 5.4
Hz), 44.7 (d, J = 11.9 Hz), 44.0 (d, J = 12.9 Hz); 31P NMR (202
MHz, CDCl3) δ 22.5; HRMS (ESI) m/z calcd for C33H31N4O2P-
Na 569.2077, found 569.2070; 97.6% ee, retention time = 6.06
(minor) and 6.88 (major), flow rate = 0.60 mL/min, OD-H
chiral column (7:3 hexane:IPA solvent system).
Compound 4c: white solid; yield 0.13 5 g (97%); mp 138-
Compound 4g: off-white solid; yield 0.101 g (94%); mp
140 °C; [R]25D þ8.0 (c 0.6, CHCl3); 1H NMR (500 MHz, CDCl3)
180-182 °C; [R]24 þ3.30 (c 1.1, CHCl3); 1H NMR (500
D
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MHz, CDCl3) δ 8.21 (d, J = 8.2 Hz, 1H), 8.11 (d, J = 8.1 Hz,
1H), 7.86-7.83 (m, 2H), 7.79-7.76 (m, 2H), 7.54-7.29 (m,
10H), 7.13-7.05 (m, 2H), 5.64 (t, J = 9.8 Hz, 1H), 4.66-4.39
(m, 4H), 3.95 (t, J = 10.0 Hz, 1H, NH), 2.99 (d, J = 10.7 Hz,
4H); 13C NMR (125 MHz, CDCl3) δ 160.9, 158.9, 133.72 (d,
J = 4.9 Hz, 2C), 132.29 (d, J = 6.9 Hz), 132.23 (d, J = 8.4 Hz),
131.6 (d, J = 8.9 Hz), 131.3 (d, J = 8.4 Hz), 128.7 (d, J = 2.5
Hz), 128.6 (d, J = 3.5 Hz, 2C), 128.4 (d, J = 12.4 Hz, 2C), 126.6,
126.4 (2C), 126.3, 126.2 (2C), 125.8 (d, J = 6.9 Hz, 2C), 125.1 (d,
J = 4.9 Hz, 2C), 125.0 (d, J = 3.5 Hz), 123.3 (d, J = 10.9 Hz,
2C), 116.2 (d, J = 20.3 Hz), 46.3 (d, J = 4.9 Hz), 46.1 (d, J = 4.9
Hz), 44.1 (dd, J = 20.3, 12.9 Hz, 2C), 42.6; 31P NMR (202 MHz,
CDCl3) δ 22.0; HRMS (ESI) m/z calcd for C32H28FN4OPNa
557.1877, found 557.1886; 96.1% ee, retention time = 6.52
(minor) and 7.04 (major), flow rate = 0.60 mL/min, OD-H
chiral column (7:3 hexane:IPA solvent system).
CDCl3) δ 8.31 (d, J = 7.2 Hz, 1H), 8.18 (d, J = 8.0 Hz,
1H), 7.88-7.78 (d, J = 7.8 Hz, 7H), 7.50-7.26 (m, 10H), 5.56
(t, J = 9.8 Hz, 1H), 4.46-4.14 (m, 4H), 3.52 (t, J = 10.0 Hz, 1H,
NH), 3.04-2.96 (m, 4H), 2.41 (s, 3H); 13C NMR (125 MHz,
CDCl3) δ 135.6, 133.7 (d, J = 4.9 Hz), 132.3, 131.7 (d, J = 6.9
Hz), 131.4 (2C), 129.4 (2C), 128.6 (2C), 128.4 (d, J = 5.4 Hz,
2C), 128.2, 126.9 (d, J = 7.5 Hz, 2C), 126.6 (2C), 126.4 (d, J =
20.8 Hz, 2C), 126.3 (d, J = 4.9 Hz, 2C), 125.8, 125.1 (d, J = 9.0
Hz, 2C), 123.6, 123.4, 123.3, 46.9 (d, J = 4.9 Hz), 46.6 (d, J = 4.9
Hz), 46.3 (d, J = 2.5 Hz), 44.3 (t, J = 2.9 Hz), 43.9 (d, J = 3.0
Hz), 19.0; 31P NMR (202 MHz, CDCl3) δ 22.3; 98.9% ee,
retention time = 6.13 (minor) and 6.68 (major), flow rate =
0.60 mL/min, OD-H chiral column (7:3 hexane:IPA solvent
system).
Compound 4k: white solid; yield 0.156 g (89%); mp 148-
D
150 °C; [R]25 þ1.74 (c 1.1, CHCl3); 1H NMR (500 MHz,
Compound 4h: white solid; yield 0.135 g (94%); mp 128-
130 °C; [R]25D þ7.7 (c 1.1, CHCl3); 1H NMR (500 MHz, CDCl3)
δ 8.19 (d, J = 8.5 Hz, 1H), 8.11 (d, J = 8.0 Hz, 1H), 7.85 (d, J =
7.5 Hz, 2 H), 7.77 (d, J = 8.0 Hz, 2H), 7.60-7.57 (m, 2H),
7.54-7.37 (m, 8 H), 7.33-7.30 (m, 1H), 7.21-7.18 (m, 1H), 5.77
(t, J = 9.5 Hz, 1H), 4.64 (dd, J = 6.5, 14.5 Hz, 1H), 4.57 (t, J =
6 Hz, 2H), 4.36 (dd, J = 6.5, 15 Hz, 1H), 3.88 (t, J = 10 Hz, 1H),
3.03-2.94 (m, 4H); 13C NMR (125 MHz, CDCl3) δ 135.0 (d, J =
5.0 Hz), 133.8 (d, J = 8.9 Hz, 2C), 132.4, 132.3 (d, J = 3.4 Hz),
132.2, 131.6 (d, J = 6.4 Hz), 130.9 (s, 2C), 129.3 (s, 2C), 128.6 (d,
J = 1.4 Hz, 2C), 128.4 (t, J = 3.0 Hz, 2C), 126.5 (d, J = 4.9 Hz,
2C), 126.3 (s, 2C), 125.8 (d, J = 5.4 Hz, 2C), 125.2 (d, J = 9.9 Hz,
2C), 123.4 (d, J = 5.5 Hz, 2C), 122.6, 118.8 (d, J = 5.4 Hz), 47.8
(d, J = 2 Hz), 46.4 (t, J = 5.9 Hz, 2C), 44.2 (dd, J = 6.0, 12.9 Hz,
2C); 31P NMR (202 MHz, CDCl3) δ 22.1; HRMS (ESI) m/z calcd
for C32H29BrN4OP 595.1257, found 595.1253; 97% ee, retention
time = 6.49 (minor) and 6.95 (major), flow rate = 0.60 mL/min,
OD-H chiral column (7:3 hexane:IPA solvent system).
CDCl3) δ 8.25(d, J = 8.5 Hz, 1H), 8.19-8.17 (m, 1H),
7.88-7.84 (m, 2H), 7.79 (t, J = 7.0 Hz, 2H), 7.55-7.47 (m,
6H), 7.43-7.39 (m, 2H), 7.37-7.36 (m, 1H), 6.46-6.45 (m, 1H),
6.35-6.34 (m, 1H), 5.60 (t, J = 9.5 Hz, 1H), 4.65-4.53 (m, 4H),
3.62 (t, J = 10.0 Hz, 1H), 3.03-2.93 (m, 4H); 13C NMR (125
MHz, CDCl3) δ 147.5 (d, J = 6.4 Hz), 143.8, 133.8 (d, J = 7.8
Hz), 132.3, 131.7 (d, J = 7.3 Hz), 128.7, 128.4, 126.9, 126.5 (d,
J = 13.4 Hz), 125.9 (d, J = 7.8 Hz), 125.2 (d, J = 5.9 Hz), 123.4
(d, J = 9.3 Hz), 117.9 (d, J = 4.4 Hz), 46.6 (d, J = 5.0 Hz), 46.1
(d, J = 5.3 Hz), 44.4 (d, J = 12.8 Hz), 43.9 (d, J = 13.3 Hz), 41.9
(d, J = 1.0 Hz); 31P NMR (202 MHz; CDCl3) δ 21.6; HRMS
(ESI) m/z calcd for C30H27N4O2PNa 529.1764, found 529.1761;
99% ee, retention time = 6.55 (minor) and 6.83 (major), flow
rate = 0.60 mL/min, OD-H chiral column (7:3 hexane:IPA
solvent system).
Absolute Configuration Determination. The absolute config-
uration for this asymmetric induction was determined by con-
verting a product (4a) to an authentic sample.18 In this
conversion, 4a was subjected to deprotection with 2.0 M aq
HCl at rt in methanol followed by in situ t-Boc protection by
treating with (t-Boc)2O in the presence of Et3N to give product 5.
The optical rotation of this product was confirmed to be
consistent with that of the known sample with S configuration.
During this transformation, the cleaved N1,N2-bis(naphthalen-
1-ylmethyl)ethane-1,2-diamine (6) was extracted with n-butanol
from the acidic mixture prior to t-Boc protection to give a
quantitative yield. [R]24 -1.71 (c 1.2, CHCl3) {lit. [R]24
Compound 4i: white solid; yield 0.146 g (90%); mp 220-
D
222 °C; [R]24 þ4.50 (c 1.1, CHCl3); 1H NMR (500 MHz,
CDCl3) δ 8.19 (d, J = 8.2 Hz, 1H), 8.10 (d, J = 8.3 Hz, 1H),
7.84 (d, J = 7.8 Hz, 2H), 7.77 (d, J = 8.1 Hz, 2H), 7.60 (dd, J =
2.0, 7.2 Hz, 1H), 7.53-7.37 (m, 9H), 7.28-7.22 (m, 2H), 5.76 (t,
J = 9.8 Hz, 1H), 4.63 (dd, J = 6.5, 14.8 Hz, 1H), 4.55 (d, J = 6.3
Hz, 2H), 4.36 (dd, J = 6.2, 14.8 Hz, 1H), 4.13 (t, J = 10.0 Hz,
1H, NH), 3.04-2.96 (m, 4H); 13C NMR (125 MHz, CDCl3) δ
133.72 (d, J = 1.5 Hz), 133.44 (d, J = 4.9 Hz), 132.7, 132.3 (d,
J = 6.9 Hz), 132.2 (d, J = 7.4 Hz), 131.6 (d, J = 6.9 Hz), 130.6
(d, J = 32.3 Hz, 2C), 129.1 (2C), 128.6 (2C), 128.4 (d, J = 5.4
Hz, 2C), 127.8 (2C), 126.4 (2C), 126.3 (d, J = 20.8 Hz, 2C), 125.8
(d, J = 4.9 Hz, 2C), 125.2 (d, J = 9.4 Hz, 2C), 123.3 (d, J = 7.9
Hz, 2C), 118.8 (d, J = 5.5 Hz), 46.4 (d, J = 4.9 Hz), 46.2 (d, J =
4.9 Hz), 45.6 (d, J = 2.5 Hz), 44.2 (d, J = 2.9 Hz), 44.1 (d, J =
2.9 Hz); 31P NMR (202 MHz, CDCl3) δ 22.3; HRMS (ESI) m/z
calcd for C32H29ClN4OP 551.1761, found 551.1757; 95.2% ee,
retention time = 6.28 (minor) and 6.82 (major), flow rate =
0.60 mL/min, OD-H chiral column (7:3 hexane:IPA solvent
system).
D
D
-1.82 (c 1.1, CHCl3)}.
Acknowledgment. We would like to thank the Robert A.
Welch Foundation (D-1361) for providing us with financial
assistance. Partial support from NIH (R03DA026960) and
NSFC (20928001) is also acknowledged. We thank our co-
workers, Teng Ai, Venkatesh Kattamuri, Hao Sun, Austin
Ballew, and Raizada Milles, for their assistance.
Supporting Information Available: 1H and 13C NMR spec-
tra of all pure products 1a-k and 4a-k. This material is
available free of charge via the Internet at http://pubs.acs.org.
Compound 4j: white solid; yield 0.152 g (92%); mp 204-
D
206 °C; [R]24 þ3.50 (c 1.1, CHCl3); 1H NMR (500 MHz,
5150 J. Org. Chem. Vol. 75, No. 15, 2010