Synthetic and theoretical investigation on the one-pot halogenation of β-amino alcohols and nucleophilic ring opening of aziridinium ions

Article abstract of DOI:10.1039/c5ob01692d

Aziridinium ions are useful reactive intermediates for the synthesis of enantiomerically enriched building blocks. However, N,N-dialkyl aziridinium ions are relatively underutilized in the synthesis of optically active molecules as compared to other three

Full text of DOI:10.1039/c5ob01692d

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Synthetic and theoretical investigation on the
one-pot halogenation of β-amino alcohols and
nucleophilic ring opening of aziridinium ions†
Cite this: DOI: 10.1039/c5ob01692d
Yunwei Chen, Xiang Sun, Ningjie Wu, Jingbai Li, Shengnan Jin, Yongliang Zhong,
Zirui Liu, Andrey Rogachev and Hyun-Soon Chong*
Aziridinium ions are useful reactive intermediates for the synthesis of enantiomerically enriched building
blocks. However, N,N-dialkyl aziridinium ions are relatively underutilized in the synthesis of optically active
molecules as compared to other three-membered ring cogeners, aziridines and epoxides. The character-
ization of both optically active aziridinium ions and secondary β-halo amines as the precursor molecules
of aziridinium ions has been scarcely reported and is often unclear. In this paper, we report for the first
time the preparation and experimental and theoretical characterization of optically active aziridinium ions
and secondary β-halo amines. Optically active secondary N,N-substituted β-halo amines were efficiently
synthesized from N,N-substituted alaninol via formation and ring opening at the more hindered carbon of
aziridinium ions by halides. Optically active β-halo amines and aziridinium ions were characterized by
NMR and computational analyses. The structure of an optically active β-chloro amine was confirmed via
X-ray crystallographic analysis. The aziridinium ions derived from N,N-dibenzyl alaniol remained stable
only for several hours, which was long enough for analyses of NMR and optical activity. The stereospecific
ring opening of aziridinium ions by halides was computationally studied using DFT and highly-accurate
DLPNO-CCSD(T) methods. The highly regioselective and stereoselective ring opening of aziridinium ions
was applied for efficient one-pot conversion of β-alaninols to enantiomerically enriched β-amino alco-
hols, β-amino nitriles, and vicinal diamine derivatives.
Received 12th August 2015,
Accepted 17th November 2015
DOI: 10.1039/c5ob01692d
www.rsc.org/obc
activity of the mustards results from the reaction of the aziridi-
nium ions derived from the mustards with guanine residues in
Introduction
Aziridinium ions are strained three-membered ring systems DNA to form interstrand cross-links.3b Since the Leonard
containing two electrophilic carbons and positively charged group reported on various aziridinium ions as reactive inter-
nitrogen.1 Optically active small and complex molecules such mediates in the 1960s,4 the formation of aziridinium ions and
as vicinal diamines, 1,2-amino alcohols, 1,2-amino ethers, 3,4- their application in the synthesis of optically active synthons
diamino nitriles, and α,β-diamino esters have been prepared have been explored.5 In contrast to the relatively well known
via nucleophilic ring opening reactions of aziridinium ions.1,2 chemistry of other heterocyclic cogeners, aziridines and epox-
In addition, aziridinium ions are involved in anti-cancer ides, the ring opening chemistry of N,N-dialkyl aziridinium
activity of nitrogen mustards such as chlorambucil, mechlor- ions remains underutilized in the synthesis of enantiomeri-
ethamine, and phosphamide derivatives.3 The biological cally enriched small and complex molecules.6
We recently reported that aziridinium ions with various
structural functionalities were prepared in two steps starting
from primary β-amino alcohols via formation of secondary
Department of Chemistry, Illinois Institute of Technology, Chicago, IL, USA.
E-mail: Chong@iit.edu; Fax: +1 312-567-3494; Tel: +1 312-567-3235
β-halo amines, and ring opening of aziridinium ions was used
for efficient synthesis of nitrogen-containing optically active
molecules with potential biomedical applications.7 Although
the synthetic methods of secondary β-halo amines including
mesylation and halogenation of β-amino alcohols and N-alkyl-
†Electronic supplementary information (ESI) available: A copy of 1H and 13C
NMR spectra of all new compounds and HPLC chromatograms of all chiral com-
pounds and a Crystallographic Information Framework (CIF) file for the X-ray
structure of compound 5a. CCDC 999697. For ESI and crystallographic data in
CIF or other electronic format see DOI: 10.1039/c5ob01692d
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Scheme 1 Formation and reactions of β-haloamines and aziridinium ions derived from β-alaninol.
ation of aziridines are known, the preparation of both optically
Results and discussion
One-pot halogenation and ring opening of aziridinium ions by
halides for the preparation of optically active β-halo amines
Using N,N-dibenzylated β-alaninol (S)-1a9 (R = Bn) as the model
active secondary β-halo amines and aziridinium ions and their
synthetic applications have been limitedly reported in the lit-
erature, and characterization of the labile species is often
unclear.8
In the present paper, we describe the preparation and the system, enantiomerically enriched β-halo amines 3–8 were pre-
experimental and theoretical aspects of optically active second- pared using different halogenating agents (Table 1). N,N-Dibenz-
ary β-halo amines and aziridinium ions and their application ylated β-alaninol (S)-1a (1 equiv.) in CH2Cl2 at 0 °C was treated
in nucleophilic substitution reactions (Scheme 1). Optically with diethylaminosulfur trifluoride (DAST, 1.2 equiv.), and the
active β-halo amines were prepared by one-pot halogenation of resulting mixture was reacted for 4 h at 0 °C and 20 h at room
β-alaninols and ring opening of aziridinium ions by halides. temperature. The reaction of (S)-1a with DAST provided second-
Optically active β-halo amines and aziridinium ions were ary β-fluoro amine (R)-3a as the major product, which is formed
characterized by NMR and X-ray crystallographic and from the nucleophilic attack of the fluoride counter ion at the
computational analyses. The stereospecific ring opening of more hindered methine carbon (C2) in aziridinium ion 2a
aziridinium ions by halides was computationally studied formed by intramolecular rearrangement (Table 1, entry 1). A
using DFT and highly-accurate DLPNO-CCSD(T) methods. The small amount of primary β-fluoro amine (S)-4a as the minor
highly regioselective and stereoselective ring opening of aziri- product was formed from ring opening of aziridinium ion 2a at
dinium ions was used for efficient one-pot conversion of β-ala- the less hindered carbon (C1) by fluoride.
ninols to enantiomerically enriched small molecules including
β-amino alcohols, β-amino nitriles, and vicinal diamine (1 equiv.) in CHCl3 at 0 °C was sequentially reacted with PPh3
derivatives. (1.2 equiv.) and N-halosuccinimide (NXS, X = Cl or Br, 1.2
(S)-1a was studied for chlorination and bromination. (S)-1a
Table 1 Formation and ring opening of aziridinium ions: synthesis of optically active β-halo amines
Entry
Substrate
Halogenating agent
Product
Ratio of isomersa
5 : 1
Yield (%)
1
2
3
4
5
6
1a
1a
1a
1b
1c
1a
DASTb
3a/4a
5a
6a
6b
6c
71
70
86
63
44
73
NCS/PPh3
NBS/PPh3
NBS/PPh3
NBS/PPh3
I2/PPh3/imidazole
7a/8a
6 : 1
a Determined by 1H NMR. b Diethylaminosulfur trifluoride (DAST).
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equiv.), and the resulting mixture was reacted for 4 h at 0 °C Formation of isolable aziridinium ions
and 20 h at room temperature. Halogenation of 1a with NCS/
Optically active aziridinium ions 2aa (X = BF4) and 2ab (X =
OTf) were directly prepared by treatment of β-chloro amine
(R)-5a with halo-sequestering silver salts containing weakly
nucleophilic counter anions, AgBF4 and AgOTf, respectively
(Scheme 2). β-Chloro amine (R)-5a was rapidly converted to the
corresponding aziridinium ion (S)-2ab containing triflate as a
counter anion (25 min, −10 °C), while the formation of azirid-
inium ion (S)-2aa containing tetrafluoroborate from (R)-5a took
longer (1 h, −10 °C). Enantiomerically enriched aziridinium
ions (S)-2aa and (S)-2ab remained stable at least for several
PPh3 and NBS/PPh3 followed by ring opening of aziridinium
ions by halides afforded secondary β-chloro amine (R)-5a10
(Table 1, entry 2) and secondary β-bromo amine (R)-6a8b
(Table 1, entry 3) as the regiospecific isomer, respectively. The
structure of β-chloro amine (R)-5a was unambiguously con-
firmed via X-ray crystallography (Fig. 1) and NMR analysis
(Fig. 2). The inverted stereochemistry in (R)-5a indicates
that aziridinium ion (S)-2a was formed by intramolecular
rearrangement of activated β-amino alcohol (S)-1a and a sub-
sequent stereospecific and regiospecific reaction of (S)-2a
with the counter anion chloride at the methine carbon
afforded β-chloro amine 5a. N,N-Dibenzyl groups in 1a were
replaced with an electron withdrawing group (1b) or a bulky
piperazine ring (1c) for the study of the N-substitution effect
on the formation of β-halo amines (Table 1, entries 4 and 5).
Bromination of 1b and 1c provided the corresponding
regiospecific isomers 6b and 6c in a slightly lower isolated
yield (63% and 44%), respectively. β-Chloro amine (R)-5a
and β-bromo amine (R)-6a were promptly isolated by
column chromatography and remained stable at −20 °C for
months.
Lastly, iodination of (S)-1a was conducted to understand
regioselectivity in the ring opening of aziridinium ions. (S)-1a
(1 equiv.) in CHCl3 at 0 °C was sequentially reacted with PPh3
(1.2 equiv.) and imidazole (1.2 equiv.), and I2 (1.2 equiv.), and
the resulting mixture was reacted for 4 h at 0 °C and 20 h at
room temperature. The reaction of (S)-1a with I2/PPh3
provided β-iodo amine (R)-7a as the major ring opening
product along with a small amount of the regioisomer (S)-8a
(Table 1, entry 6). Overall, halogenation of N,N-dibenzylated
β-alaninol 1a was highly regioselective and provided (R)-halo
amines as the major regioisomer from the attack of halides at
the more substituted carbon of aziridinium ions in a SN2
pathway.
1
hours at room temperature and were characterized by H and
13C and 2D HMQC (Heteronuclear Multiple-Quantum Corre-
lation) NMR and optical rotation. 1H NMR spectra of azirid-
inium ions 2aa or 2ab were clearly distinguished from those of
β-chloro amine 5a (Fig. 2). As expected, the methine protons in
aziridinium ions 2aa or 2ab (δ 3.5–3.7 ppm) are more shielded
than those in β-chloro amine 5a (δ 4.1 ppm). The methylene
protons in aziridinium ions 2aa and 2ab (δ 3.2 and 3.3 ppm)
are shifted downfield compared to those in β-chloro amine 5a
(δ 2.7 and 2.8 ppm) due to the positively charged nitrogen. The
diastereotopic methylene protons in β-chloro amine 5a
produce two sharp and distinctive doublets. The nonequiva-
lent N-benzyl protons in aziridinium ions 2aa and 2ab give rise
to four different resonance signals. Although
a slightly
different pattern in proton NMR was observed with aziridi-
nium ions 2aa and 2ab, possibly due to the counter ion effect,
2aa and 2ab produced essentially identical 13C NMR signals.
The methine carbon (C2) in β-chloro amine 5a (δ 56 ppm) and
aziridinium ions 2aa or 2ab (δ 48 ppm) were clearly shown to
resonate in different fields. The diastereotopic N-benzyl
carbons in aziridinium ions 2aa and 2ab gave two different
signals (δ 56 and 61 ppm) with a large difference in chemical
shift. The two magnetically nonequivalent phenyl rings in azir-
idinium ions 2aa and 2ab are clearly shown in 13C NMR.
Nucleophilic ring opening reactions of aziridinium ions
Nucleophilic reactions of aziridinium ions were initially
studied using N-protected β-bromo amines (R)-6 and cyanide
as a common carbon nucleophile (Table 2). The reaction of
(R)-6a (R = Bn) with sodium cyanide in CH3CN provided the
primary β-amino nitrile (S)-9aa as the major ring opening
product along with a tiny amount of the secondary β-amino
nitrile (R)-10aa (Table 2, entry 1, ESI†). Both of the regio-
isomeric substitution products were isolated and characterized
by 1H and 13C NMR, optical rotation, and chiral HPLC. The
formation of the two regioisomers (9 and 10) clearly indicates
that the reaction involved formation and ring opening of aziri-
dinium ion 2a. Ring opening of aziridinium ion 2a at the less
hindered methylene carbon (C-3) provided (S)-9aa (82.2% iso-
lated yield, >97.4% ee), while nucleophilic attack by the
cyanide ion at the more substituted methine carbon (C-2) in 2a
provided the minor regioisomer (R)-10aa (5.8% isolated yield,
>99% ee). The nearly absolute stereoselectivity in (S)-9aa and
(R)-10aa indicates that both formation and ring opening of
Fig. 1 X-ray crystallographic structure of β-chloroamine (R)-5a.
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Fig. 2 1H and 13C NMR spectra of β-chloroamine and aziridinium ions.
aziridinium ions proceeded with inverted stereochemistry in a solvent to DMSO or a mixture of CH3CN and H2O (Table 2,
SN2 pathway. The ring opening reaction was significantly faster entry 2) made a minimal impact on the preferential formation
in CH3CN/H2O (10 min) or DMSO (30 min) as compared to of the regioisomer (S)-9aa over (R)-10aa, although both regio-
CH3CN (4 days). The slow reaction observed in CH3CN is isomers were produced in excellent stereoselectivity (>98% ee).
related to poor solubility of NaCN in CH3CN. Change of The effect of N-substitution on the ring opening reaction was
investigated. Interestingly, replacement of the N-protecting
group from benzyl to p-NO2-Bn (6b, Table 2, entry 4) and piper-
azine ring (6c, Table 2, entry 5) as a bulky and/or electron-
withdrawing group led to the formation of the exclusive regio-
isomers 9b and 9c in excellent isolated yield and ee (>93%,
>99% ee). Other regioisomeric ring opening products (R)-10b
or (R)-10c that are expected from the nucleophilic attack of the
cyanide ion at the more hindered methine carbon in aziridi-
nium ion (S)-2 were not formed from the reaction. The exclu-
Scheme 2 Synthesis of enantiomerically enriched aziridinium ions.
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Table 2 Ring opening of aziridiniums: synthesis of optically active β-amino nitriles
Reaction
time
Product
(yield %)
Ratio of
ee (%) of
Entry
Substrate
Nu
Solvent
(S)-9/(R)-10a
(S)-9/(R)-10b
1
2
3
4
5
6a
6a
6a
6b
6c
CN
CN
CN
CN
CN
CH3CN
DMSO
CH3CN/H2O
DMSO
CH3CN/H2O
4 d
9aa/10aa (82/6)
9aa/10aa (76/7)
9aa/10aa (80/7)
9b (92.8)
14 : 1
11 : 1
11 : 1
97.4/>99
97.5/>97.9
97.9/98.6
>99
30 min
10 min
4 h
30 min
9c (98.5)
>99
a Determined by isolated yield of the regioisomers by prep-TLC. b Determined by chiral HPLC.
sive regioselectivity observed in nucleophilic ring opening reac- 2a with sodium borohydride was prompt to provide a mixture
tions of aziridinium ions 6b and 6c with cyanide can be of regioisomers 9ab and 10ab in a ratio of 2.4 to 1, with the
explained by changes in steric hindrance and/or electron with- preferred formation of the kinetic product (Table 3, entry 1).
drawal due to N-substitution. 6b and 6c were relatively slower Relatively less nucleophilic azide as compared to cyanide and
in reaction with the cyanide ion than 6a. Overall, the nucleo- hydride led to the formation of 10ac as the major product
philic attack at the less hindered carbon to provide (S)-9 from ring opening of 2a at the more hindered carbon (Table 3,
was highly favored in ring opening of all aziridinium ions (S)-2 entry 2). Both n-propyl amine and n-propane thiolate prefer to
by cyanide nucleophile. No clear solvent effect on the attack at the less substituted carbon (C3) of 2a to afford the
preferred formation of the major ring opening products was kinetic products 9ad and 9ae, respectively (Table 3, entries 3
observed. It should be noted that nucleophilic ring opening and 4). Particularly, ring opening of 2a at C3 by the strongly
reactions of aziridinium ions 2 with cyanide provided the nucleophilic but bulky thiolate was highly favored over C2.
regioisomeric β-amino nitriles 9 and 10 in almost absolute Aziridinium ion 2a was sluggish in the reaction with the steri-
stereoselectivity.
cally hindered nucleophiles n-PrNH2 or n-PrSNa. The for-
With the high regioselectivity and stereospecificity observed mation of the major regioisomers 9ab, 9ad, and 9ae is
in the ring opening of 2a with cyanide, we extended our expected from the kinetically controlled reaction of 2a at the
investigation to other nucleophiles (Table 3). The reaction of less substituted carbon with a strong nucleophile (hydride,
Table 3 Ring opening of aziridinium ions: synthesis of optically active molecules
Product
Ratio of
Entry
Reagent (Nu)
Solvent
Additive
Time
Temp
(yield %)a
(S)-9/(R)-10b
1
2
3
4
5
6
7
8
9
NaBH4
NaN3
n-PrNH2
n-PrSH
H2O
CH3OH
n-PrOH
H2O
CH3CN
CH3CN/H2O
CH3CN
CH3CN
CH3CN/H2O
CH3OH
CH3CN/n-PrOH
CH3CN/H2O
CH3CN/CH3OH
15 min
10 min
4 h
4 h
5 h
1 h
3 h
3 h
1.5 h
RT
RT
RT
RT
9ab/10ab (93)
9ac/10ac (96)
9ad/10ad (96)
9ae/10ae (90)
9af/10af (91)
9ag/10ag (96)
9ah/10h (90)
9af/10af (92)
9ag/10ag (97)
2.4/1
1/2
2/1
5.7/1
1/8.6
1/6.4
1/5.9
1.2/1
1.6/1
1 M NaOH
RT
Reflux
Reflux
RT
1 M NaOH
1 M NaOH
CH3OH
RT
a A mixture of the regioisomeric products was isolated via flash column chromatography. b Determined by 1H NMR.
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amine, or thiolate). The reaction of 2a with a relatively weak selectivity (Table 4, entry 1, 74%, >99% ee, 1 h). (S)-2a was
oxygen nucleophile H2O, CH3OH, or n-PrOH provided the reacted with AgCN in a mixture of CH3CN and H2O to provide
thermodynamic products 10af, 10ag, and 10ah as the major secondary β-amino alcohol (R)-9af11 (Table 4, entry 2, 70%,
regioisomers (Table 3, entries 5–7). The attack of the oxygen 80% ee) from the nucleophilic attack of the aziridinium ion at
nucleophiles at the more hindered C2 of 2a was highly favored the more hindered methine carbon. β-Amino nitrile (S)-9aa
over C3 to produce the more stable product 10 from the reac- was not formed from the substitution reaction, and this seems
tion wherein formation and ring opening of the aziridinium to reflect poor solubility of silver cyanide in CH3CN, and a
ion are predicted to be in equilibrium. To understand the sluggish reaction (24 h) of 2a with water instead of cyanide pro-
nature of the oxygen nucleophiles better, a reaction of 2a with vided the hydrolysis product (R)-9af. The significant loss of
H2O and CH3OH in the presence of a base (aq. NaOH) was stereoselectivity observed in (R)-9af (80% ee) can be explained
conducted as control runs. Under the basic reaction con- by possible formation of the secondary carbenium ion which
ditions, the back formation of aziridinium ions 2a from the is in equilibrium with aziridinium ion (S)-2a. Interestingly,
ring opening products 9af and 9ag is nearly not feasible due to treatment of aziridinium ion 2a with succinimide/1 M NaOH
the disfavorable departure of the hydroxyl and methoxy groups or succinimide/Ag2CO3 led to the formation of β-amino succin-
in 9af and 9ag and thus regiochemistry of aziridinium imide (S)-11 in excellent stereoselectivity (>99% ee) (Table 4,
opening is more likely controlled by sterics. As predicted, entries 3 and 4). This unexpected formation of 11 resulted
reaction of 2a with H2O or CH3OH produced the kinetic from direct reaction of 2a with the succinimide (Su) counter-
products 9af and 9ag as the major isomer (Table 3, entries 8 anion present in the reaction mixture under basic conditions.
and 9).
Steric hindrance seems to control the regioselectivity of the
reaction which produced (S)-11 from ring opening of 2a at the
less hindered methylene carbon. When 2a was treated with
AgNO3 in the presence of water, β-amino nitrate (R)-12 was
obtained from ring opening of 2a at the methine carbon by
One pot bromination and nucleophilic ring opening of
aziridinium ions
Regioselective and stereoselective ring opening of aziridinum the nitrate ion (Table 4, entry 5, 67% isolated yield, >99% ee).
ions with a nucleophile was applied for a convenient one-pot The stereochemistry in (R)-12 was confirmed by conversion of
synthesis of enantiomerically enriched building blocks from (R)-12 to the known compound (R)-9af. The favored formation
β-amino alcohol (S)-1a (Table 4). (S)-1a was subjected to bromi- of the more stable regioisomer (R)-12 is expected from the heat
nation followed by a nucleophilic substitution reaction in the promoted ring opening of aziridinium ion 2a in equilibrium
presence or the absence of a halo-sequestering agent (Ag2CO3, with (R)-12 containing the nitrate ion as a leaving group.
AgNO3, or AgCN). When bromination of β-alaninol (S)-1a to Unlike (R)-9af formed from the reaction of 2a with AgCN, an
provide (R)-6a was complete as monitored by TLC analysis, a almost absolute stereoselectivity was observed with (R)-12,
nucleophilic reagent (Table 4) was added to the reaction probably due to a significantly shorter reaction time (1 h vs.
mixture. The reaction of aziridinium ion (S)-2a with NaCN in 24 h). It is noteworthy that the one-pot bromination and
the presence of water and CH3CN as a co-solvent gave β-amino nucleophilic ring opening reactions of aziridinium ions pro-
nitrile (S)-9aa as the major product in excellent stereo- vided the nucleophilic substitution products in excellent
Table 4 One-pot synthesis of N-protected β-amino nitrile, β-amino alcohol, and vicinal diamine from primary β-amino alcohol (S)-1a
Entry
Nu/reagent
Time
Product
ee (%)
1
2
3
4
5
NaCN/H2O
AgCN/H2O
1 M NaOH
Ag2CO3
1 h
24 h
2 h
24 h
1 h
(S)-9aa (74%)
(R)-9af (70%)
(S)-11 (58%)
(S)-11 (52%)
(R)-12 (67%)
>99
80
>99
>99
>99
AgNO3/H2O
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enantioselectivity (>99% ee, Table 4, entries 1 and 3–5). opening products, (R)-β-halo amines (3a, 5a, 6a, and 7a) (Table 5).
The one-pot bromination and nucleophilic substitution reac- Based on the X-ray crystallographic parameters of β-chloro-
tions of aziridinium ions with carbon and nitrogen nucleo- amine 5a, the geometrical optimization of 5a was achieved.
philes provided the kinetic products from ring opening of The bond length between the methine carbon (C2) and halide
aziridinium ions at the less hindered carbon, while the aziridi- (X = Cl) in 5a is in excellent agreement with the bond distance
nium ions reacted with oxygen nucleophiles at the more shown in the X-ray crystal structure of 5a (calc: 1.814 Å vs. exp:
hindered carbon as expected from the reactions controlled by 1.815 Å). A small deviation in the C1–C2 distance for X-ray and
thermodynamics.
computational structure of 5a was observed (calc: 1.527 Å vs.
To confirm the regiochemistry and stereochemistry in exp: 1.522 Å). The length of the N–C1 bond in the X-ray crystal
(S)-9aa and (S)-11 obtained from ring opening of aziridinium structure of 5a was slightly longer than that of DFT-optimized
ions, syntheses of (S)-9aa and (S)-11 were independently 5a (calc: 1.457 Å vs. exp: 1.467 Å). Structural optimization of
carried out as outlined in Scheme 3. Activation of N-Boc pro- other halo amines 3a, 6a, and 7a was conducted by replacing
tected β-amino alcohol 1312 afforded β-amino mesylate 14, the chlorine atom in the optimized structure of 5a with other
which was reacted with sodium cyanide to provide β-amino halides. As expected from electrostatic interaction and orbital
nitrile 15.13 Removal of the N-Boc group in 15 using TFA fol- overlap considerations, β-fluoro amine 3a containing fluorine
lowed by N-alkylation with benzyl bromide provided the auth- (X = F) has the shortest X–C2 bond (1.395 Å), while β-iodo
entic product (S)-9aa. The structure and stereochemistry of the amine 7a (X = I) is calculated to have the longest bond length
N-protected vicinal diamine (S)-11 prepared from the ring of X–C2 (2.194 Å). All (R)-β-halo amines are calculated to have a
opening reaction of (S)-2a (Table 4) were confirmed by prepar- similar bond length of N–C1 (1.455–1.458 Å) and C1–C2
ing (S)-11 starting from 13 by a modification of the literature (1.523–1.527 Å). β-Fluoro amine 3a has the longest N–C2 bond
procedure (Scheme 3).14 The reaction of β-amino mesylate 14 (2.489 Å), while no significant difference in the bond was
with succinimide and subsequent removal of the N-Boc group observed with other halo amines (∼2.47 Å). The atomic
in 16 provided 17 which was further alkylated to afford (S)-11. charges were calculated within a framework of natural popu-
1H and 13C NMR spectra and optical rotation data of (S)-9aa lation analysis (NPA). In all halo amines, nitrogen (−0.57) is
and (S)-11 prepared starting from 13 (Scheme 3) were the most negatively charged atom in β-halo amines, and the
essentially identical to (S)-9aa and (S)-13 prepared from the methine carbon (C2) in β-fluoro amine 3a (0.24) is positively
ring opening of aziridinium ions (S)-2a, respectively (Tables 2 charged, while C2 in other β-halo amines 5a (−0.20), 6a
and 3). The optical rotation data of (S)-9aa and (S)-11 suggest (−0.27), and 7a (−0.35) bears a negative charge. As expected,
that stereospecific rearrangement of β-bromo amine (R)-6a to β-fluoro amine 3a has the largest difference in charge between
aziridinium ions proceeds through
a SN2 pathway with C2 and X (0.64) which is reduced for 5a (0.10), 6a (0.23), and
inversion of the chiral center and subsequent reaction of aziri- 7a (0.39). The methine carbon (C2) attached to the most electro-
dinium ions at the less hindered methylene carbon with negative halogen in 3a (X = F) is significantly more positive
cyanide or succinimide provided the nucleophilic substitution than C1. A similar partial charge is calculated for the less hin-
products.
dered carbon (C1) in all β-halo amines (−0.28 for 3a and −0.26
for 5a, 6a, and 7a). The calculations show that the optimized
structures of β-halo amines have similar parameters, except a
Computational studies
Formation and ring opening of aziridinium ions were theoreti- high positive charge on C2 in 3a (X = F).
cally studied by DFT (PBE0/cc-pVTZ) and DLPNO-CCSD(T) cal-
Next, we optimized the geometries of aziridinium ions 3a′,
culations. To understand the thermodynamic parameters, we 5a′, 6a′, and 7a′ (Table 6). In all aziridinium ions, the more
initially optimized equilibrium geometries of the major ring hindered carbon (C2) is more positive than the less hindered
Scheme 3 Structural determination of 9aa and 11.
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Table 5 Selected geometrical parameters of (R)-β-halo amines 3a, 5a, 6a, and 7a (PBE0/cc-pVTZ)
(R)-3a
(X = F)
(R)-5a
(X = Cl)
(R)-5a
(X = Cl, X-ray)
(R)-6a
(X = Br)
(R)-7a
(X = I)
Parameter
X–C1a
X–C2a
N–C1a
N–C2a
C1–C2a
Xb
2.338
1.395
1.455
2.489
1.523
−0.40
−0.57
−0.28
0.24
2.702
1.814
1.457
2.474
1.527
−0.10
−0.57
−0.26
−0.20
2.837
1.974
1.458
2.470
1.526
−0.04
−0.57
−0.26
−0.27
3.031
2.194
1.458
2.467
1.526
0.04
−0.57
−0.26
−0.35
1.815
1.467
1.522
—
—
—
—
Nb
C1b
C2b
a All bond lengths are in Ångstrom. b Atomic charges are calculated within the NPA framework.
carbon (C3) regardless of the counter anions, and the N–C2 shorter than the X–C2 bond in the transition structures. The
bond (average 1.53 Å) is longer than the N–C3 bond (average N–C2 bond in aziridinium ions is partially dissociated in the
1.49 Å) and the C2–C3 bond (average 1.47 Å). As compared to transition state (average bond length from 1.52 Å to 1.74 Å),
β-halo amines, the aziridinium ions have shorter C2–C3 and while the distance of the N–C3 bond remains almost
N–C3 bonds by on average 0.06 Å and 0.03 Å, respectively. The unchanged along the pathway (average distance: 1.49 Å vs.
counter-anion halides are more closely located to C2 than 1.48 Å). In all transition structures, the methine carbon (C2) is
C3 in the aziridinium rings (X–C2: 2.18–3.07 Å vs. X–C3: more positively charged than C3, and the N–C2 bond (average
2.93–3.44 Å). It is noteworthy that the counter anion halide is 1.74 Å) is much longer than the N–C3 bond (1.48 Å). The
shown to form hydrogen bonding with the proton in the more change in bond length between atoms along the intrinsic reac-
substituted carbon (C2) and one of the benzylic protons tion coordinates (IRC) is well reflected on progressive develop-
leading to the construction of a six-membered ring. The hydro- ment of charges on the atoms. More positive charge is built on
gen bonding interaction is predicted to further weaken the C2 in transition states relative to the aziridinium ion, and no
N–C2 bond and build up more positive charge in C2 that can substantial change in charge on C3 and nitrogen is observed
facilitate ring opening by the halide. The calculated charge on with the conversion of aziridinium ions to transition
the ring carbons and the length of ring bonds explain the high structures.
regioselectivity observed in the ring opening reactions of aziri-
dinium ions by halide (Table 1).
Relative energies of aziridinium ions, transition states (TS),
and (R)-β-halo amines involved in the ring opening reaction of
We calculated the structures of the transition states for the aziridinium ions (Az+) with halides via a SN2 pathway were cal-
stereospecific ring opening of aziridinium ions by the halide culated (Table 7). While using the PBE0 functional for all geo-
ion, leading to the formation of (R)-β-halo amines with metric manipulations and electronic structure analysis, the
inverted stereochemistry at C2 (Table 6). Intrinsic reaction energetics were evaluated, with the help of the DLPNO-CCSD
coordinate (IRC) calculations confirm the connection of (T) method15 (using DFT-optimized geometries), as providing
aziridinium ions and (R)-β-halo amines through transition more reliable estimations. The ring opening of aziridinium
structures. Transition states of the ring opening reactions are ions at the more substituted carbon (C2) for the formation of
shown to have reactant-like structures as supported by the cal- the major β-halo amines is calculated to be thermodynamically
culated parameters (Tables 5 and 6) and energy profiles favored (Table 8). The activation barrier (24 kcal mol−1) was
(Table 7). The X–C2 bond (average 3.18 Å) in aziridinium ions the highest for the ring opening of aziridinium ion 3a′ by flu-
is shown to be elongated in the transition structures (average oride being the least efficient nucleophile. The formation of
bond length 2.70 Å) as expected from the partial bond between β-fluoro amine 3a (−49.7 kcal mol−1) was significantly more
the approaching nucleophilic halide and electrophilic C2. The exothermic than other halo amines 5a (−33.3 kcal mol−1), 6a
X–C2 bond (average 1.84 Å) in β-halo amines is significantly (−29.0 kcal mol−1), and 7a (−24.9 kcal mol−1). Given the extre-
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Table 6 Optimized geometries and selected parameters of (S)-aziridinium ions 3a’, 5a’, 6a’, and 7a’ and transition states (TS) for the formation of
(R)-β-halo amines 3a, 5a, 6a, and 7a from ring opening reactions of aziridinium ions (Az+) with halides via a SN2 pathway (PBE0/cc-pVTZ)
Parameter
(S)-3a′
(X = F)
(S)-3a-TS
(X = F)
(S)-5a′
(X = Cl)
(S)-5a-TS
(X = Cl)
(S)-6a′
(X = Br)
(S)-6a-TS
(X = Br)
(S)-7a′
(X = I)
(S)-7a-TS
(X = I)
X–C2a
X–C3a
N–C2a
N–C3a
C2–C3a
Xb
2.610
3.228
1.527
1.487
1.473
−0.75
−0.38
−0.06
−0.21
2.184
2.931
1.813
1.474
1.460
−0.68
−0.46
−0.05
−0.23
3.184
3.434
1.517
1.494
1.469
−0.82
−0.38
−0.04
−0.20
2.705
3.086
1.693
1.485
1.453
−0.82
−0.43
0.00
3.351
3.564
1.516
1.494
1.469
−0.82
−0.38
−0.04
−0.20
2.846
3.217
1.715
1.482
1.454
−0.80
−0.43
0.00
3.591
3.779
1.515
1.494
1.469
−0.84
−0.38
−0.03
−0.20
3.068
3.445
1.749
1.477
1.457
−0.79
−0.43
0.00
Nb
C2b
C3b
−0.21
−0.22
−0.22
a All bond lengths are in Ångstrom. b Atomic charges are calculated within the NPA framework.
mely high activation barrier (74 kcal mol−1), the back reaction
of fluoro amine 3a to aziridinium ion 3a′ traversing the highly
labile transition state is shown to be nearly impossible. The
calculation predicts that the reaction is kinetically controlled
to produce the major regioisomer 3a which is estimated to be
more stable than the minor regioisomer 4a (Table 8). The ring
opening reactions of other aziridinium ions 5a′, 6a′, and 7a′
have a smaller activation barrier (11–13 kcal mol−1) as
compared to that of 3a′ (X = F). The barrier in the back reaction
of the ring opening products 5a, 6a, and 7a to aziridinium
ions 5a′, 6a′, and 7a′ is not too large to overcome. The energy
released in the formation of the ring opening products might
be also used to surmount the kinetic barrier required for the
back reaction. The ring opening reaction of 5a′, 6a′, and 7a′ is
Table 7 Relative energies of aziridinium ions, transition states (TS), and
(R)-β-halo amines involved in ring opening reactions of aziridinium ions
with halides in a SN2 pathway (DLPNO-CCSD(T)/cc-pVTZ)
Energies (kcal mol−1
)
Aziridinium
ion
Transition
state
(R)-β-Halo
amine
X
F
(S)-3a′
0.0
(S)-5a′
0.0
(S)-6a’
0.0
(S)-7a′
0.0
3a-TS
24.0
5a-TS
13.3
6a-TS
12.1
7a-TS
11.1
(R)-3a
−49.7
(R)-5a
−33.3
(R)-6a
−29.0
(R)-7a
−24.9
Cl
Br
I
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Table 8 Difference in electronic energies (kcal mol−1) between regio-
isomeric ring opening products (R or S isomer) from the reaction of
(S)-2a with the nucleophile (DLPNO-CCSD(T)/cc-pVTZ)
A smaller difference in energy between two isomers was
calculated for ring opening products containing hydride (ΔE =
1.52 kcal mol−1), succinimide (ΔE = 1.67 kcal mol−1), and
cyanide (ΔE = 2.03 kcal mol−1). Given the small difference in
stability of the isomers, sterics involving interactions of aziridi-
nium ions and the relatively stronger nucleophiles in the pres-
ence of bromide counter anions is predicted to be a major
factor in controlling regiochemistry in the ring opening of azir-
idinium ions, leading to the preferred formation of (S)-9aa,
(S)-9ab, and (S)-11 from the respective nucleophilic attack at
the less hindered carbon of cyanide, hydride, and succinimide.
(R)-Isomers formed from the reaction of 2a with the nitrogen
nucleophiles azide and n-propyl amine were calculated to be
more stable than (S)-isomers by ∼5 kcal mol−1. A smaller
difference in relative energy between the regioisomers was cal-
culated with the ring opening product containing a thio propyl
group ((S)-9ae/(R)-10ae, ΔE = 3.41 kcal mol−1) as compared to
an amino propyl group ((S)-9ad/(R)-10ad, ΔE = 5.28 kcal mol−1).
The highly preferred formation of (S)-9ae as experimentally
observed appeared to be the outcome of a kinetically con-
trolled reaction due to a negatively charged but sterically
hindered thiolate. The formation of (R)-9af, (R)-9ag, (R)-9ah
and (R)-12 over the regioisomeric counterparts from ring
opening at the more hindered carbon by oxygen nucleophiles
is thermodynamically favored (ΔE = 5.65, 3.96, 2.56, and
4.70 kcal mol−1, respectively). Indeed, the reaction of 2a with
all oxygen nucleophiles provided more stable regioisomers as
the major products (Table 3). This can be explained by the for-
mation and ring opening of aziridinium ions in thermodyn-
amic equilibrium that is achieved by a weak or neutral oxygen
nucleophile. With the oxygen nucleophile in steric demand,
the back reaction of the less stable (S)-ring opening product
for the formation of aziridinium ions becomes less feasible,
and thus the regiochemistry of ring opening is partly con-
trolled by the activation barrier. The steric effect of oxygen
nucleophiles (Nu = OH, OCH3, or n-PrO) on regiochemistry is
well reflected in both the experimental and theoretical
results (entries 5–7, Tables 3 and 8) and evidenced by the
decreased regioselectivity in the reaction 2a with more hin-
dered n-propanol. Under basic reaction conditions, the ring
opening reaction of aziridinium ions with oxygen nucleo-
philes produced the less stable but kinetically favorable (R)-
isomers as the major products (entries 8 and 9, Table 3). This
experimental finding demonstrates that the steric factor is
more important in controlling ring opening of aziridinium
ions with oxygen nucleophiles, as the activation barrier for
the back formation of aziridinium ions from the less stable
(S)-isomers containing a poor leaving hydroxyl or methoxy
group becomes too high to overcome.
Major
Minor
ΔE = E(S)−E(R)
Nu
isomerb
isomerb
(kcal mol−1
)
F
Cl
Br
I
CN
H
N3
n-PrNH
n-PrS
OH
CH3O
n-PrO
Sua
ONO2
(R)-3a
(R)-5a
(R)-6a
(R)-7a
(S)-9aa
(S)-9ab
(R)-9ac
(S)-9ad
(S)-9ae
(R)-9af
(R)-9ag
(R)-9ah
(S)-11
(S)-4a
6.31
4.94
4.50
3.81
2.03
1.52
5.04
5.28
3.41
5.65
3.96
2.56
1.67
4.70
(S)-8a
(R)-10aa
(R)-10ab
(S)-10ac
(R)-10ad
(S)-10ae
(S)-10af
(S)-10ag
(S)-10ah
(R)-12
a Succinimidyl. b Isolated.
predicted to be dominantly controlled by stability of the pro-
ducts to favor the formation of the thermodynamic products
5a, 6a, and 7a.
The major ring opening products (R)-β-halo amines 3a, 5a,
6a, and 7a are more stable than the regioisomeric minor pro-
ducts by 6.31, 4.94, 4.50, and 3.81 kcal mol−1, respectively
(Table 8). The difference in relative energies between the fluor-
ine-containing isomers was the largest (ΔE = 6.31 kcal mol−1).
While the reaction of chloride and bromide with the aziridi-
nium ion provided the more stable (R)-5a and (R)-6a as the
exclusive regioisomers, small amounts of less stable regio-
isomers (S)-4a (X = F) and (S)-8a (X = I) were formed from the
attack of fluoride and iodide at the less hindered carbon (C3)
of the aziridinium ions. The minor ring opening product (S)-
8a (X = I) is less stable than the major regioisomer (R)-7a by
3.81 kcal mol−1. This relatively small difference in energy
between the regioisomers containing iodide as an efficient and
bulky leaving group is expected to dilute the regiocontrol
dominated by stability of the product, leading to the formation
of the less stable regioisomer (S)-8a. The formation of the
minor product 4a (X = F) may be ascribed to the unusually
large positive charge on C2 in 3a (Table 5) that can facilitate
direct isomerization of (R)-3a to (S)-4a through back formation
of the aziridinium ion.
The regioisomeric products that can be obtained in nucleo-
philic reactions of aziridinium ions as outlined in Tables 2–4
were compared for relative energies (Table 8). For all ring
opening products, the (S)-isomers produced from the nucleo-
philic attack at C2 of aziridinium ions are estimated to be
Conclusion
Optically active β-halo amines and aziridinium ions were pre-
pared starting from β-alaninols and characterized and experi-
mentally and theoretically studied for the nucleophilic
more stable than the (R)-isomers by ΔE = 1.5–5.7 kcal mol−1
.
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substitution reactions. Ring opening of aziridinium ions by temperature and stirred for 24 h. The reaction mixture was fil-
halides was highly regioselective and occurred preferably at tered and concentrated in vacuo. The residue was purified by
the more hindered carbon to provide more stable β-halo column chromatography on silica gel (60–230 mesh) eluted
amines. The high regioselectivity experimentally observed in with 30% ethyl acetate in hexanes to afford pure (S)-1b
the ring opening reactions in a SN2 pathway was rationalized (254 mg, 55%) as a yellow waxy solid. [α]2D5 = −25.0° (c = 1.0,
1
by optimized geometries and relative stability of aziridinium CHCl3). H NMR (CDCl3, 300 MHz) δ 1.05 (d, J = 6.6 Hz, 3H),
ions, transition states, and the ring opening products using 2.48 (s, br, 1H), 2.87–3.02 (m, 1H), 3.45 (dd, J = 10.5, 4.2 Hz,
DFT and DLPNO-CCSD(T) methods. Ring opening at the less 1H), 3.54–3.63 (m, 3H), 3.85 (d, J = 14.1 Hz, 2H), 7.48 (d, J =
hindered carbon of aziridinium ions by cyanide, hydride, thio- 8.1 Hz, 4H), 8.13 (d, J = 8.1 Hz, 4H); 13C NMR (CDCl3, 75 MHz)
late, amine and succinimide as relatively stronger nucleophiles δ 9.6 (q), 53.1 (t), 55.5 (d), 63.4 (t), 123.8 (d), 129.5 (d), 147.0
was shown to be kinetically more favorable and provided less (s), 147.2 (s). HRMS (positive ion ESI) Calcd for C17H20N3O5
stable ring opening products as the major regioisomers. Azide [M + H]+ m/z 346.1397. Found: [M + H]+ m/z 346.1399.
and oxygen nucleophiles reacted at the more hindered carbon
2-{Bis[(4-nitrophenyl)methyl]amino}propan-1-ol ((rac)-1b).
of aziridinium ions leading to the formation of thermo- To a stirred solution of (rac)-alaninol (300 mg, 3.99 mmol) in
dynamically favored β-amino azide, β-amino alcohol, β-amino CH3CN (5 mL) was added K2CO3 (1.21 g, 8.79 mmol) at 0 °C.
ether, and β-amino nitrate analogues as the major ring To the mixture was added dropwise a solution of 4-nitrobenzyl
opening products. One-pot halogenation of primary β-amino bromide (1.90 g, 8.79 mmol) in CH3CN (10 mL) at 0 °C. The
alcohol and nucleophilic ring opening of aziridinium ions was reaction mixture was gradually warmed to room temperature
demonstrated to provide β-amino nitrile, β-amino alcohol, and stirred for 24 h. The reaction mixture was filtered and con-
and vicinal diamine derivatives in excellent stereoselectivity centrated in vacuo. The residue was purified by column chromato-
(>99% ee).
graphy on silica gel (60–230 mesh) eluted with 40% ethyl
acetate in hexanes to afford pure (rac)-1b (900 mg, 65.3%) as a
yellow waxy solid.
(2S)-2-{4-[(4-Methylbenzene)sulfonyl]piperazin-1-yl}propan-
1-ol ((S)-1c). To a stirred solution of (S)-alaninol (108 mg,
1.44 mmol) in CH3CN (8 mL) was added Na2CO3 (1.52 g,
Experimental section
General information
1H and 13C NMR spectra were obtained using a Bruker 300 14.4 mmol) at 0 °C. To the mixture was added dropwise a solu-
instrument and chemical shifts are reported in ppm on the tion of tritosyldiethanolamine16 (817 mg, 1.44 mmol) in
δ scale relative to TMS or solvent. Electrospray ionization (ESI) CH3CN (6.5 mL) at 0 °C. The reaction mixture was refluxed for
high resolution mass spectra (HRMS) were recorded on a JEOL 26 h. The reaction mixture was filtered, and the filtrate was
double sector JMS-AX505HA mass spectrometer (University of concentrated in vacuo. The residue was purified by column
Notre Dame, IN). Structure determination of compound 5a was chromatography on silica gel (60–230 mesh) eluted with 2%
conducted using SMART V5.054 (Bruker Analytical X-ray CH3OH in CH2Cl2 to afford pure (S)-1c (259 mg, 60%) as a
Systems, Madison, WI) at the X-Ray Crystallographic Labora- white waxy solid. [α]2D5 = −15.6° (c = 1.0, CHCl3). 1H NMR
tory (Department of Chemistry, University of Minnesota). (CDCl3, 300 MHz) δ 0.90 (d, J = 6.6 Hz, 3H), 1.60 (s, br, 1H),
Analytical chiral HPLC was performed on an Agilent 1200 2.40–2.54 (m, 5H), 2.70–2.89 (m, 3H), 2.90–3.10 (m, 4H), 3.28
(Agilent, Santa Clara, CA) equipped with a diode array detector (dd, J = 10.2, 10.2 Hz, 1H), 3.38 (dd, J = 11.1, 5.4 Hz, 1H), 7.35
and a column (Chiralpak® AD-H, 4.6 × 150 mm, 80 Å). Enantio- (d, J = 7.8 Hz, 2H), 7.64 (d, J = 8.1 Hz, 2H); 13C NMR (CDCl3,
meric excess of optically active compounds (20 µL, 1 mg of 75 MHz) δ 9.7 (q), 21.5 (q), 46.4 (t), 47.0 (t), 60.2 (d), 62.1 (t),
the sample in 1 mL of hexanes) was determined by chiral 127.8 (d), 129.7 (d), 132.2 (s), 143.8 (s). HRMS (positive ion
HPLC (isocratic, 230 nm) using the following chromatographic ESI) Calcd for C14H23N2O3S [M + H]+ m/z 299.1424. Found:
conditions: method A (1/99 = i-PrOH/hexanes at a flow rate of [M + H]+ m/z 299.1433.
0.5 mL min−1, 30 min); method B (1/99 = i-PrOH/hexanes at a
2-{4-[(4-Methylbenzene)sulfonyl]piperazin-1-yl}propan-1-ol
flow rate of 1 mL min−1, 15 min); method C (10/90 = i-PrOH/ ((rac)-1c). To a stirred solution of (rac)-alaninol (200 mg,
hexanes at a flow rate of 0.5 mL min−1, 60 min); method D 2.66 mmol) in CH3CN (3 mL) was added Na2CO3 (2.82 g,
(8/92 = i-PrOH/hexanes at a flow rate of 0.5 mL min−1
,
26.6 mmol) at 0 °C. To the resulting mixture was added drop-
160 min); method E (0.2/99.8 = i-PrOH/hexanes at a flow rate wise a solution of tritosyldiethanolamine16 (1.66 g, 2.93 mmol)
of 0.5 mL min−1, 15 min); method F (3/97 = i-PrOH/hexanes at in CH3CN (5 mL) at 0 °C. The reaction mixture was refluxed for
a flow rate of 1 mL min−1, 15 min). The optical rotation was 22 h. The reaction mixture was filtered and concentrated
determined using a JASCO P-2000 polarimeter.
in vacuo. The residue was purified by column chromatography
(2S)-2-{Bis[(4-nitrophenyl)methyl]amino}propan-1-ol ((S)-1b). on silica gel (60–230 mesh) eluted with 2% CH3OH in CH2Cl2
To a stirred solution of (S)-alaninol (100 mg, 1.33 mmol) in to afford pure (rac)-1c (250 mg, 31.5%) as a white waxy solid.
CH3CN (2 mL) was added K2CO3 (405 mg, 2.93 mmol) at 0 °C. 1H and 13C NMR data were essentially identical to those of
To the resulting mixture was added dropwise a solution of (R)-1c as described above.
4-nitrobenzyl bromide (605 mg, 2.80 mmol) in CH3CN (1 mL)
(2R)-N,N-Dibenzyl-2-fluoropropan-1-amine ((R)-3a). To
a
at 0 °C. The reaction mixture was gradually warmed to room solution of (S)-1a9 (50 mg, 0.196 mmol) in CH2Cl2 (3 mL) in an
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ice-bath maintained at 0 °C was added dropwise (diethyl- The resulting mixture was stirred for 4 h at 0 °C. The ice bath
amino)sulfur trifluoride (DAST, 37.9 mg, 0.235 mmol) in CH2Cl2 was removed and the reaction mixture was warmed to room
(2 mL) over 10 min. The resulting mixture was stirred for 4 h at temperature and stirred for 20 h before being evaporated to
0 °C. The ice bath was removed, and the reaction mixture was dryness. The residue was purified by silica gel column chromato-
warmed to room temperature and stirred for 20 h. Then the graphy eluted with 5% ethyl acetate in hexanes to afford
reaction mixture was treated with 10% Na2CO3 aqueous solution (R)-7a as an inseparable mixture with (S)-8a (52 mg, 72.6%,
1
(10 mL) and extracted with CH2Cl2 (2 × 10 mL) to provide a 7a/8a = 6.3 : 1, as determined by H NMR) as a light yellow oil.
crude mixture (49 mg), which was sequentially purified by 1H NMR (CDCl3, 300 MHz) δ 1.85 (d, J = 7.2 Hz, 3H), 2.59 (dd,
silica gel column chromatography eluted with 3% ethyl acetate J = 13.5, 8.1 Hz, 1H), 2.94 (dd, J = 13.2, 6.9 Hz, 1H), 3.50–3.74
in hexanes to afford (R)-3a in an inseparable mixture with (m, 4H), 4.11–4.18 (m, 1H), 7.25–7.45 (m, 10H); 13C NMR
1
(S)-4a (35.6 mg, 71%, 3a/4a = 5 : 1, as determined by H NMR) (CDCl3, 75 MHz) δ 25.9 (q), 26.7 (d), 58.8 (t), 64.3 (t), 127.2 (d),
1
as a yellow oil. H NMR (CDCl3, 300 MHz) δ 1.26 (dd, J = 24.0, 128.3 (d), 129.1 (d), 139.0 (s). HRMS (ESI) Calcd for C17H22NO:
+
6.3 Hz, 3H), 2.51–2.78 (m, 2H), 3.72 (s, 4H), 4.83 (dm, J = 49.2, [M − I + H2O]+ m/z 256.1696. Found: [M − I + H2O] m/z
1H), 7.23–7.40 (m, 10H); 13C NMR (CDCl3, 75 MHz) δ 19.3 (dq, 256.1682.
J = 22.5 Hz), 58.5 (dt, J = 22.5 Hz), 59.1 (t), 89.9 (dd, J = 165.0
[(2R)-2-Bromopropyl]bis[(4-nitrophenyl)methyl]amine ((R)-6b).
Hz), 127.0 (d), 128.2 (d), 128.8 (d), 139.5 (s). HRMS (ESI) Calcd To a solution of (S)-1b (500 mg, 1.23 mmol) and PPh3 (386 mg,
+
for C17H21FN: [M + H]+ m/z 258.1653. Found: [M + H] m/z 1.47 mmol) in CHCl3 (10 mL) maintained at 0 °C was added
258.1642.
NBS (262 mg, 1.47 mmol). The resulting mixture was stirred
(2R)-N,N-Dibenzyl-2-chloropropan-1-amine ((R)-5a).10 To a for 4 h at 0 °C. The ice bath was removed, and the reaction
solution of (S)-1a9 (50 mg, 0.196 mmol) and PPh3 (61.7 mg, mixture was warmed to room temperature and stirred for 20 h
0.235 mmol) in CHCl3 (5 mL) maintained at 0 °C was added and evaporated to dryness. The residue was purified by silica
NCS (31.4 mg, 0.235 mmol). The resulting mixture was stirred gel column chromatography eluted with 15% ethyl acetate
for 4 h at 0 °C. The ice bath was removed, and the reaction in hexanes to afford (R)-6b (314 mg, 63%) as a yellow solid.
mixture was warmed to room temperature and stirred for 20 h M.P. 125.1–127.8 °C. [α]2D6 = −9.1° (c = 1.0, CHCl3). 1H NMR
before being evaporated to dryness. The residue was purified (CDCl3, 300 MHz) δ 1.64 (d, J = 6.9 Hz, 3H), 2.69 (dd, J = 13.8,
by silica gel column chromatography eluted with 5% ethyl 6.0 Hz, 1H), 2.86 (dd, J = 13.8, 8.1 Hz, 1H), 3.69 (d, J = 14.4 Hz,
acetate in hexanes to afford (R)-5a (38 mg, 70%) as a white 2H), 3.78 (d, J = 14.4 Hz, 2H), 4.11–4.18 (m, 1H), 7.58 (d, J =
solid. M.P. 37.1–40.1 °C. [α]2D6 = +16.5° (c = 1.0, CHCl3). [Lit.10 8.7 Hz, 2H), 8.20 (d, J = 8.7 Hz, 2H); 13C NMR (CDCl3, 75 MHz)
[α]2D2 = +19.3° (c = 0.8, CHCl3)]. 1H NMR (CDCl3, 300 MHz) δ 23.9 (q), 46.8 (d), 58.4 (t), 62.8 (t), 123.7 (d), 129.5 (d), 146.2
δ 1.44 (d, J = 6.6 Hz, 3H), 2.66 (dd, J = 13.2, 7.8 Hz, 1H), 2.82 (s), 147.4 (s). HRMS (positive ion ESI) Calcd for C17H20N3O5:
+
(dd, J = 6.3, 3.0 Hz, 1H), 3.59 (d, J = 13.5 Hz, 2H), 3.71 (d, J = [M − Br + H2O]+ m/z 346.1397. Found: [M − Br + H2O] m/z
13.5 Hz, 2H), 4.00–4.06 (m, 1H), 7.24–7.40 (m, 10H); 13C NMR 346.1375.
(CDCl3, 75 MHz) δ 23.1 (q), 55.5 (d), 59.2 (t), 62.1 (t), 127.1 (d),
128.3 (d), 128.9 (d), 139.1 (s). 1H and 13C NMR data were essen- To a solution of (rac)-1b (400 mg, 1.158 mmol) and PPh3
tially identical to those of (R)-5a previously reported.10
(455.6 mg, 1.737 mmol) in CHCl3 (6 mL) maintained at 0 °C
(2-Bromopropyl)bis[(4-nitrophenyl)methyl]amine ((rac)-6b).
(2R)-N,N-Dibenzyl-2-bromopropan-1-amine ((R)-6a).8b To a was added NBS (309.3 mg, 1.737 mmol). The resulting mixture
solution of (S)-1a9 (50 mg, 0.196 mmol) and PPh3 (61.6 mg, was stirred for 4 h at 0 °C. The ice bath was removed, and the
0.235 mmol) in CHCl3 (5 mL) maintained at 0 °C was added reaction mixture was warmed to room temperature and stirred
NBS (45.3 mg, 0.235 mmol). The resulting mixture was stirred for 20 h and evaporated to dryness. The residue was purified
for 4 h at 0 °C. The ice bath was removed, and the reaction by silica gel column chromatography eluted with 15% ethyl
mixture was warmed to room temperature and stirred for 20 h acetate in hexanes to afford (rac)-6b (360 mg, 76.7%) as a
before being evaporated to dryness. The residue was purified yellow solid. 1H and 13C NMR data were essentially identical to
by silica gel column chromatography eluted with 5% ethyl those of (R)-6b as described above.
acetate in hexanes to afford (R)-6a (54 mg, 86%) as a white
1-[(2R)-2-Bromopropyl]-4-[(4-methylbenzene)sulfonyl]piper-
solid. M.P. 37.3–38.3 °C. [α]2D6 = +15.1° (c = 1.0, CHCl3). azine ((R)-6c)). To a solution of (S)-1c (180 mg, 0.603 mmol)
1H NMR (CDCl3, 300 MHz) δ 1.67 (d, J = 6.6 Hz, 3H), 2.75 (dd, and PPh3 (189.9 mg, 0.724 mmol) in CHCl3 (5 mL) at 0 °C was
J = 13.2, 8.1 Hz, 1H), 2.94 (dd, J = 13.2, 6.0 Hz, 1H), 3.61 (d, J = added NBS (139.6 mg, 0.784 mmol) and stirred for 4 h while
13.5 Hz, 2H), 3.72 (d, J = 13.5 Hz, 2H), 4.09–4.16 (m, 1H), being maintained at 0 °C. The ice bath was removed, and the
7.30–7.44 (m, 10H); 13C NMR (CDCl3, 75 MHz) δ 24.0 (q), reaction mixture was warmed to room temperature and stirred
47.9 (d), 59.1 (t), 62.7 (t), 127.2 (d), 128.3 (d), 129.0 (d), 139.1 for 20 h and evaporated to dryness. The residue was purified
(s). H and 13C NMR data were essentially identical to those of by silica gel column chromatography eluted with 20% ethyl
1
(R)-6a previously reported.8b
acetate in hexanes to afford (R)-6c (106 mg, 44%) as a light
(2R)-N,N-Dibenzyl-2-iodopropan-1-amine ((R)-7a). To a solu- yellow solid. M.P. 102.0–104.3 °C. [α]2D6 = −26.8° (c = 1.0,
tion of (S)-1a9 (50 mg, 0.196 mmol) and PPh3 (61.6 mg, CHCl3). H NMR (CDCl3, 300 MHz) δ 1.64 (d, J = 6.3 Hz, 3H),
1
0.235 mmol) in CHCl3 (6 mL) maintained at 0 °C was added 2.44 (s, 3H), 2.59 (s, 4H), 2.74 (dd, J = 13.2, 7.2 Hz, 2H), 3.03
imidazole (16 mg, 0.235 mmol) and I2 (59.6 mg, 0.235 mmol). (s, 4H), 4.04–4.06 (m, 1H), 7.33 (d, J = 7.8 Hz, 2H), 7.63 (d, J =
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8.1 Hz, 2H); 13C NMR (CDCl3, 75 MHz) δ 21.5 (q), 24.0 (q), 46.0 room temperature. The resulting mixture was evaporated and
(t), 46.3 (d), 52.5 (t), 66.3 (t), 127.8 (d), 129.7 (d), 132.6 (s), dissolved in CH2Cl2 and filtered, and the filtrate was concen-
143.7 (s). HRMS (ESI) Calcd for C14H23N2O3S [M + H]+ m/z trated in vacuo. The residue was purified by silica gel column
299.1424. Found: [M + H]+ m/z 299.1428.
1-(2-Bromopropyl)-4-[(4-methylbenzene)sulfonyl]piperazine afford (S)-9 and (R)-10.
chromatography eluted with 2–4% ethyl acetate in hexanes to
((rac)-6c)). To a solution of (rac)-1c (200 mg, 0.650 mmol) and
(S)-3-(Dibenzylamino)butanenitrile ((S)-9aa) and (R)-3-
PPh3 (255.7 mg, 0.975 mmol) in CHCl3 (3 mL) at 0 °C was (dibenzylamino)-2-methylpropanenitrile ((R)-10aa). From the
added NBS (173.6 mg, 0.975 mmol) and stirred for 4 h at 0 °C. reaction of 6a in CH3CN. To the stirred solution of (R)-6a
The ice bath was removed, and the reaction mixture was (60 mg, 0.188 mmol) in CH3CN (1.5 mL) was added NaCN
warmed to room temperature and stirred for 20 h and evapor- (18.4 mg, 0.38 mmol). The reaction mixture was stirred at
ated to dryness. The residue was purified by silica gel column room temperature for 4 d. The resulting mixture was evapor-
chromatography eluted with 20% ethyl acetate in hexanes to ated and dissolved in CH2Cl2 and filtered. The filtrate was con-
1
afford (rac)-6c (140 mg, 59.6%) as a light yellow solid. H and centrated and dried in vacuo. A mixture of (S)-9aa and (R)-10aa
13C NMR data were essentially identical to those of (R)-6c pre- (49.7 mg, 100%) was obtained. The regioisomeric mixture was
viously reported.
separated by preparative thin layer chromatography (Prep-TLC,
SiO2) eluted with 2–4% ethyl acetate in hexanes to provide
(S)-9aa (40.8 mg, 82.2%) as a white solid and (R)-10aa (2.9 mg,
5.8%) as a colorless oil.
General synthesis of isolable aziridinium ions
To a solution of β-halo amine in CDCl3 (0.8 mL) at −10 °C was
added silver tetrafluoroborate (1 equiv.) or silver triflate (5
equiv.). The resulting mixture was continuously stirred at
−10 °C, while the reaction progress was monitored using TLC.
After completion of the reaction, silver halide was filtered, and
the resulting solution was immediately characterized by 1H
and 13C NMR and HMQC.
1
(S)-9aa: M.P. 95.6–98.5 °C. [α]2D6 = +4.0° (c = 1.0, CHCl3). H
NMR (CDCl3, 300 MHz) δ 1.21 (d, J = 6.9 Hz, 3H), 2.36 (dd, J =
16.5, 6.6 Hz, 1H), 2.56 (dd, J = 16.8, 8.1 Hz, 1H), 3.22–3.28 (m,
1H), 3.55 (d, J = 13.8 Hz, 2H), 3.70 (d, J = 13.8 Hz, 2H),
7.26–7.45 (m, 10H); 13C NMR (CDCl3, 75 MHz) δ 14.0 (q), 21.9
(t), 50.4 (d), 53.4 (t), 118.8 (s), 127.2 (d), 128.4 (d), 128.6 (d),
139.1 (s). HRMS (positive ion ESI) Calcd for C18H21N2 [M + H]+
m/z 265.1699. Found: [M + H]+ m/z 265.1707. Chiral HPLC
(method A): tR = 15.4 min (S, major), tR = 16.8 min (R, minor),
97.4% e.e.
(2S)-1,1-Dibenzyl-2-methyl-aziridinium
tetrafluoroborate
((S)-2aa). The general procedure was followed for the
reaction of (R)-5a (40 mg, 0.15 mmol) and AgBF4 (28.4 mg,
0.15 mmol) in CDCl3 (0.8 mL) for 1 h. After completion of the
reaction, silver chloride was filtered, and the filtrate was
1
(R)-10aa: [α]2D5 = −17.2° (c = 0.15, CHCl3). H NMR (CDCl3,
300 MHz) δ 1.19 (d, J = 6.6 Hz, 3H), 2.52 (dd, J = 12.0, 5.7 Hz,
1H), 2.63–2.84 (m, 2H), 3.59 (d, J = 13.5 Hz, 2H), 3.69 (d, J =
13.5 Hz, 2H), 7.26–7.41 (m, 10H); 13C NMR (CDCl3, 75 MHz) δ
15.8 (q), 25.0 (t), 56.9 (d), 59.0 (d), 127.3 (d), 128.4 (d), 128.9
(d), 138.6 (s). HRMS (positive ion ESI) Calcd for C18H21N2 [M +
H]+ m/z 265.1699. Found: [M + H]+ m/z 265.1728. Chiral HPLC
(method B): tR = 4.6 min (R, major), tR = 5.9 min (S, minor),
>99% e.e.
immediately characterized by NMR and optical rotation. [α]D26
=
1
+ 22.8° (c = 1.0, CHCl3). H NMR (CDCl3, 300 MHz) δ 1.77 (d,
J = 6.3 Hz, 3H), 3.17 (dd, J = 8.4, 3.9 Hz, 1H), 3.27 (dd, J = 7.2,
3.9 Hz, 1H), 3.51–3.58 (m, 1H), 4.12 (d, J = 13.5 Hz, 1H), 4.19
(d, J = 14.4 Hz, 1H), 4.33 (d, J = 9.9 Hz, 1H), 4.38 (d, J = 10.8
Hz, 1H), 7.21 (d, J = 6.3 Hz, 2H), 7.30–7.47 (m, 8H); 13C NMR
(CDCl3, 75 MHz) δ 11.6 (q), 42.9 (t), 47.8 (d), 56.1 (t), 61.0 (t),
128.3 (s), 129.2 (s), 129.6 (d), 129.7 (d), 130.0 (d), 130.1 (d),
130.6 (d), 131.0 (d).
From reaction of (R)-6a in DMSO. To a solution of (R)-6a
(60 mg, 0.188 mmol) in DMSO (2 mL) was added NaCN
(18.4 mg, 0.38 mmol). The reaction mixture was continuously
stirred at room temperature for 30 min. The resulting mixture
was treated with H2O (25 mL) and extracted with diethyl ether
(3 × 25 mL). The combined organic layer was treated with
MgSO4 and concentrated in vacuo. A mixture of (S)-9aa and (R)-
10aa (49 mg, 98.8%) was obtained. The regioisomeric mixture
was separated by Prep-TLC (SiO2) eluted with 2–4% ethyl
acetate in hexanes to provide (S)-9aa (37.8 mg, 76.2%) as a
white solid and (R)-10aa (3.5 mg, 7.1%) as a colorless oil.
(2S)-1,1-Dibenzyl-2-methyl-aziridinium trifluoromethanesul-
fonate ((S)-2ab). The general procedure was followed for the
reaction of (R)-5a (40 mg, 0.15 mmol) and AgOTf (187.8 mg,
0.75 mmol) in CDCl3 (0.8 mL) for 25 min. After completion of
the reaction, silver chloride was filtered, and the filtrate was
immediately characterized by NMR. [α]2D6 = +16.0° (c = 1.0,
1
CHCl3). H NMR (CDCl3, 300 MHz) δ 1.77 (d, J = 6.0 Hz, 3H),
3.25–3.38 (m, 2H), 3.61–3.72 (m, 1H), 4.14 (d, J = 14.1 Hz, 1H),
4.19 (d, J = 14.1 Hz, 1H), 4.30 (d, J = 5.7 Hz, 1H), 4.35 (d, J =
5.1 Hz, 1H), 7.22 (d, J = 6.6 Hz, 2H), 7.30–7.48 (m, 8H);
13C NMR (CDCl3, 75 MHz) δ 11.8 (q), 43.4 (t), 48.4 (d), 55.8 (t),
61.2 (t), 120.5 (q, J = 322.5 Hz), 128.5 (s), 129.2 (s), 129.4 (d),
129.9 (d), 130.3 (d), 130.8 (d).
1
(S)-9aa: [α]2D6 = +3.5° (c = 1.0, CHCl3). H and 13C NMR data
of (S)-9aa were identical to those of (S)-9aa obtained from the
reaction described above. Chiral HPLC (method A): tR
=
15.2 min (S, major), tR = 16.9 min (R, minor), 97.5% e.e.
1
(R)-10aa: [α]2D6 = −13.2° (c = 0.18, CHCl3). H and 13C NMR
General procedure for nucleophilic reaction of 6 with NaCN
data of (S)-10aa were identical to those of (S)-10aa obtained
To a stirred solution of (R)-6 (0.1 mmol) in the solvent was from the reaction described above. Chiral HPLC (method B): tR
added NaCN (0.12 mmol). The reaction mixture was stirred at = 4.6 min (R, major), tR = 5.9 min (S, minor), 97.9% e.e.
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From the reaction of (R)-6a in CH3CN/H2O. To a stirred H2O (1.25 mL/0.25 mL) was added NaCN (12 mg,
solution of (R)-6a (60 mg, 0.188 mmol) in CH3CN/H2O 0.245 mmol). The reaction mixture was continuously stirred at
(1.25 mL/0.25 mL) was added NaCN (18.4 mg, 0.38 mmol). room temperature for 8 h. The resulting mixture was treated
The reaction mixture was stirred at room temperature for with H2O (25 mL) and extracted with CH2Cl2 (3 × 25 mL).
10 min. The resulting mixture was evaporated and dissolved in The combined organic layer was treated with MgSO4 and con-
CH2Cl2 and filtered. The filtrate was concentrated and dried centrated in vacuo to provide (rac)-9b (41 mg, 92.5%) as a color-
in vacuo. A mixture of (S)-9aa and (R)-10aa (49.3 mg, 99.3%) less oil. 1H and 13C NMR data of (rac)-9b were identical to
was obtained. The regioisomeric mixture was separated by (S)-9b. Chiral HPLC (method C): tR = 49.0 min (R) and
Prep-TLC (SiO2) eluted with 2–4% ethyl acetate in hexanes to 51.7 min (S).
provide (S)-9aa (39.6 mg, 79.8%) as a white solid and (R)-10aa
(3.5 mg, 7.1%) as a colorless oil.
(3S)-3-{4-[(4-Methylbenzene)sulfonyl]piperazin-1-yl}butane-
nitrile ((S)-9c). To a solution of (R)-6c (30 mg, 0.083 mmol) in
(S)-9aa: [α]D26 = +3.0° (c = 1.0, CHCl3). Chiral HPLC (method CH3CN (1.25 mL) and H2O (0.25 mL) was added NaCN
A): tR = 15.2 min (S, major), tR = 17.0 min (R, minor), 97.9% (8.1 mg, 0.17 mmol). The reaction mixture was continuously
1
e.e. H and 13C NMR data of (S)-9aa were identical to those of stirred at room temperature for 30 min. The resulting mixture
(S)-9aa obtained from the above reaction.
was evaporated to dryness and the residue was treated with
(R)-10aa: [α]D26 = −15.1° (c = 0.18, CHCl3). Chiral HPLC H2O (15 mL) and extracted with CH2Cl2 (3 × 15 mL). The com-
(method B): tR = 4.7 min (R, major), tR = 6.0 min (S, minor), bined organic layer was treated with MgSO4 and concentrated
1
98.6% e.e. H and 13C NMR data of (S)-10aa were identical to under vacuum to provide (S)-9c which was purified by column
those of (S)-10aa obtained from the reaction described above.
chromatography eluting with 10% ethyl acetate in hexane to
3-(Dibenzylamino)butanenitrile ((rac)-9aa)17 and 3-(dibenzyl- afford pure (S)-9c (25.1 mg, 98.5%) as a white solid. M.P.
amino)-2-methylpropanenitrile ((rac)-10aa). To a solution of 101.4–103.9 °C. [α]2D6 = +3.32° (c = 1.0, CHCl3). 1H NMR (CDCl3,
(rac)-6a (150 mg, 0.471 mmol) in CH3CN/H2O (2.5 mL/0.5 mL) 300 MHz) δ 1.13 (d, J = 6.6 Hz, 3H), 2.31–2.43 (m, 5H),
was added NaCN (46 mg, 0.95 mmol). The reaction mixture 2.60–2.62 (m, 4H), 2.91–3.09 (m, 4H), 7.32 (d, J = 8.1 Hz, 2H),
was continuously stirred at room temperature for 10 min. The 7.62 (d, J = 8.1 Hz, 2H); 13C NMR (CDCl3, 75 MHz) δ 15.0 (q),
resulting mixture was evaporated and dissolved in CH2Cl2 and 21.5 (d), 21.7 (t), 46.2 (t), 47.6 (t), 56.0 (d), 118.3 (s), 127.8 (d),
filtered. The filtrate was concentrated and dried in vacuo. A 129.7 (d), 132.3 (s), 143.8 (s). HRMS (positive ion ESI) Calcd
mixture of (rac)-9aa and (rac)-10aa (123.0 mg, 98%) was for C15H22N3O2S [M + H]+ m/z 308.1427. Found: [M + H]+ m/z
obtained. The regioisomeric mixture was separated by Prep- 308.1424. Chiral HPLC (method D): tR = 85.7 min (R, minor)
TLC (SiO2) eluted with 2–4% ethyl acetate in hexanes to and 89.4 min (S, major), >99% ee.
provide (rac)-9aa (93.4 mg, 75.3%) as a white solid and (rac)-
3-{4-[(4-Methylbenzene)sulfonyl]piperazin-1-yl}butanenitrile
10aa (9.6 mg, 7.7%) as a colorless oil. 1H and 13C NMR data of ((rac)-9c). To a solution of (rac)-6c (25 mg, 0.069 mmol) in
(rac)-9aa and (rac)-10aa were identical to those of (S)-9aa and CH3CN (1.25 mL) and H2O (0.25 mL) was added NaCN
(S)-10aa obtained from the reaction described above. Chiral (6.8 mg, 0.138 mmol). The reaction mixture was continuously
HPLC: tR = 15.4 min (S) and 16.8 min (R) (method A) for 9aa stirred at room temperature for 2 h. The resulting mixture was
and tR = 4.6 min (R) and 5.9 min (S) (method B) for 10aa.
evaporated to dryness and the residue was treated with H2O
(3S)-3-{Bis[(4-nitrophenyl)methyl]amino}butanenitrile ((S)- (15 mL) and extracted with CH2Cl2 (3 × 15 mL). The combined
9b). To a solution of (R)-6b (30 mg, 0.074 mmol) in DMSO organic layer was treated with MgSO4 and concentrated under
1
(1.5 mL) was added NaCN (7.2 mg, 0.15 mmol). The reaction vacuum to afford (rac)-9c (21 mg, 98.6%) a white solid. H and
mixture was continuously stirred at room temperature for 4 h. 13C NMR data of (rac)-9c were identical to (S)-9c. Chiral HPLC
The resulting mixture was treated with H2O (25 mL) and (method D): tR = 85.7 min (R) and 90.1 min (S).
extracted with diethyl ether (3 × 25 mL). The combined
(S)-3-(dibenzylamino)butanenitrile ((S)-9aa). From one-pot
organic layer was dried over MgSO4 and concentrated in vacuo reaction of (S)-1a with NaCN (Table 4, entry 1). To a solution of
to provide (S)-9b which was purified by column chromato- (S)-1a (100 mg, 0.392 mmol) and PPh3 (123.3 mg, 0.470 mmol)
graphy eluting with 25% ethyl acetate in hexane to afford pure in CH3CN (5 mL) at 0 °C was added NBS (83.6 mg,
9b (24.3 mg, 92.8%) as a colorless oil. [α]2D6 = −40.2° (c = 1.0, 0.470 mmol) over 5 min. The resulting mixture was stirred for
1
CHCl3). H NMR (CDCl3, 300 MHz) δ 1.23 (d, J = 6.6 Hz, 3H), 4 h at 0 °C. The ice bath was removed, and the reaction
2.45 (dd, J = 16.8, 5.4 Hz, 1H), 2.61 (dd, J = 17.1, 9.3 Hz, 1H), mixture was warmed to room temperature and stirred for 1 h.
3.14–3.19 (m, 1H), 3.65 (d, J = 14.7 Hz, 2H), 3.81 (d, J = 14.7 NaCN (23 mg, 0.470 mmol) was added to the reaction mixture
Hz, 2H), 7.61 (d, J = 8.7 Hz, 2H), 8.20 (d, J = 8.6 Hz, 2H); 13C followed by the addition of H2O (0.5 mL). The reaction mixture
NMR (CDCl3, 75 MHz) δ 13.8 (q), 22.5 (t), 51.2 (d), 53.1 (t), was stirred for 1 h at room temperature. The residue was puri-
118.1 (s), 123.9 (d), 129.3 (d), 146.1 (s), 147.5 (s). HRMS (posi- fied by column chromatography on silica gel (60–230 mesh)
tive ion ESI) Calcd for C18H19N4O4 [M + H]+ m/z 355.1401. eluting with 5% ethyl acetate in hexanes to afford (S)-9aa
Found: [M + H]+ m/z 355.1401. Chiral HPLC (method C): tR
49.0 min (R, minor) and 51.2 min (S, major), >99% ee.
=
(76.2 mg, 73.6%) as a white solid. [α]2D6 = +3.13° (c = 1.0,
CHCl3). 1H and 13C NMR data were essentially identical to
3-{Bis[(4-nitrophenyl)methyl]amino}butanenitrile
((rac)- those described above. Chiral HPLC (method A): tR = 15.0 min
9b). To a solution of (rac)-6b (50 mg, 0.122 mmol) in CH3CN/ (S, major) and 16.8 min (R, minor), >99% ee.
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From synthesis of the authentic sample for structure deter- 7.24–7.46 (m, 20H); 13C NMR (CDCl3, 75 MHz) δ 11.8 (q), 18.0
mination (Scheme 3). To a solution of 18 (60 mg, 0.33 mmol) (q), 53.0 (d), 53.8 (t), 54.2 (t), 56.1 (d), 59.2 (t), 59.7 (t), 127.0
in CHCl3 (3 mL) at 0 °C was added dropwise trifluoroacetic (d), 127.1 (d), 128.3 (d), 128.7 (d), 128.9 (d), 139.0 (s), 139.8 (s).
acid (3 mL). The resulting mixture was stirred for 3 h at room HRMS (ESI) Calcd for C17H21N4 [M + H]+ m/z 281.1761. Found:
temperature. The reaction mixture was concentrated to dryness [M + H]+ m/z 281.1757.
to provide (3S)-3-aminobutanenitrile as a waxy yellowish solid.
The compound was directly used for the next step without [(2R)-1-(dibenzylamino)propan-2-yl](propyl)amine ((R)-10ad).
purification. To the stirred solution of (R)-6a (60 mg, 0.188 mmol) in
To solution of (3S)-3-aminobutanenitrile (38 mg, CH3CN (0.75 mL) was added propan-1-amine (0.75 mL), and
[(2S)-2-(Dibenzylamino)propyl](propyl)amine ((S)-9ad) and
a
0.24 mmol) and K2CO3 (220.8 mg, 1.6 mmol) in CH3CN (1 mL) the reaction mixture was stirred at room temperature for 4 h.
was added benzyl bromide (107.8 mg, 0.63 mmol). The result- The resulting mixture was evaporated to dryness. The residue
ing mixture was stirred at 60 °C for 24 h. The resulting mixture was treated with buffer (Et3N/AcOH, 0.05 M, pH 6, 15 mL) and
was filtered and concentrated in vacuo. The residue was puri- then extracted with DCM (3 × 15 mL). The combined organic
fied by column chromatography on silica gel (60–230 mesh) layer was dried over MgSO4, filtered, and concentrated in vacuo
eluting with 3–5% ethyl acetate in hexanes to afford (S)-9aa to provide a regioisomeric mixture of (S)-9ad and (R)-10ad
(53.1 mg, 83.8%) as a white solid. [α]2D6 = +4.6° (c = 1.0, CHCl3). (55.3 mg, 99.2%) as a colorless oil which was further purified
1H and 13C NMR data were essentially identical to those by column chromatography on silica gel (60–220 mesh)
described above. Chiral HPLC (method A): tR = 7.8 min (S, eluting with 5% methanol in DCM to 30% methanol in DCM
major) and 8.6 min (R, minor), >99% ee.
containing 1% Et3N to provide a mixture of (S)-9ad and
(2S)-N,N-dibenzyl-2-propanamine (9ab)24 and N,N-dibenzyl- (R)-10ad (53.6 mg, 96.2%, 9ad/10ad = 2.1/1, as determined by
1-propanamine (10ab).25 To the stirred solution of (R)-6a 1H NMR) as a colorless oil. H NMR (CDCl3, 300 MHz) δ 0.82
1
(60 mg, 0.188 mmol) in CH3CN (1.25 mL) was added NaBH4 (t, J = 7.5 Hz, 3H), 0.89 (t, J = 7.2 Hz, 3H), 1.04–1.08 (m, 6H),
(14.3 mg, 0.377 mmol), and the reaction mixture was stirred at 1.44–1.56 (m, 4H), 2.15–2.24 (m, 3H), 2.39–2.44 (m, 1H),
room temperature for 15 min. The resulting mixture was evap- 2.49–2.57 (m, 2H), 2.66–2.80 (m, 3H), 3.07–3.16 (m, 1H), 3.40
orated to dryness. The residue was treated with a buffer (Et3N/ (d, J = 13.2 Hz, 2H), 3.54 (d, J = 13.5 Hz, 2H), 3.66 (d, J =
AcOH, 0.05 M, pH 6, 15 mL) and then extracted with DCM (3 × 13.5 Hz, 2H), 3.75 (d, J = 13.5 Hz, 2H), 5.92 (s, br, 2H),
15 mL). The combined organic layer was dried over MgSO4, fil- 7.22–7.34 (m, 20H); 13C NMR (CDCl3, 75 MHz) δ 10.6 (q),
tered, and concentrated in vacuo to provide a regioisomeric 11.4 (q), 11.6 (q), 16.8 (q), 21.8 (t), 22.1 (t), 47.7 (t), 50.0 (t),
mixture of 9ab and 10ab (43.5 mg, 96.5%) as a colorless oil 51.1 (d), 51.3 (d), 51.5 (t), 53.5 (t), 59.4 (t), 59.7 (t), 127.2 (d),
which was further purified by column chromatography on 128.1 (d), 128.5 (d), 129.0 (d), 139.0 (s), 139.7 (s). HRMS (posi-
silica gel (60–220 mesh) eluting with 5% ethyl acetate in tive ion ESI) Calcd for C20H29N2 [M + H]+ m/z 297.2331. Found:
hexane to provide an inseparable mixture of 9ab and 10ab [M + H]+ m/z 297.2333.
1
(41.8 mg, 92.7%, 9ab/10ab = 2.4/1, as determined by H NMR)
Dibenzyl[(2S)-1-(propylsulfanyl)propan-2-yl]amine ((S)-9ae)
dibenzyl[(2R)-2-(propylsulfanyl)propyl]amine ((R)-
1
as a colorless oil. H NMR (CDCl3, 300 MHz) δ 0.89 (t, J = 7.2 and
Hz, 3H), 1.09 (d, J = 6.6 Hz, 6H), 1.53–1.60 (m, 2H), 2.41 (t, J = 10ae). To the stirred solution of (R)-6a (60 mg, 0.188 mmol) in
7.2 Hz, 2H), 2.91–3.00 (m, 1H), 3.59 (s, 8H), 7.21–7.43 (m, CH3CN (0.75 mL) was added propane-1-thiol (0.75 mL), and
20H); 13C NMR (CDCl3, 75 MHz) δ 11.8 (q), 17.6 (q), 20.2 (t), the reaction mixture was stirred at room temperature for
48.2 (d), 53.2 (t), 55.4 (t), 58.3 (t), 126.6 (d), 126.7 (d), 128.1 (d), 10 min. After which, 1 M NaOH aqueous solution (0.38 mL)
128.3 (d), 128.5 (d), 128.8 (d), 140.1 (s), 141.0 (s).
was added and the resulting mixture was stirred at room temp-
[(2S)-1-Azidopropan-2-yl]dibenzylamine ((S)-9ac) and [(2R)-2- erature for 4 h. The resulting mixture was evaporated to
azidopropyl]dibenzylamine ((R)-10ac). To the stirred solution dryness. The residue was treated with buffer (Et3N/AcOH, 0.05
of (R)-6a (60 mg, 0.188 mmol) in CH3CN (1.25 mL) was added M, pH 6, 15 mL) and then extracted with DCM (3 × 15 mL).
the solution of NaN3 (24.5 mg, 0.377 mmol) in H2O (0.25 mL), The combined organic layer was dried over MgSO4, filtered,
and the reaction mixture was stirred at room temperature for and concentrated in vacuo to provide a regioisomeric mixture
10 min. The resulting mixture was evaporated and dissolved in of (S)-9ae and (R)-10ae (56.2 mg, 95.1%) as a colorless oil
CH2Cl2 and filtered. The filtrate was concentrated and dried which was further purified by column chromatography on
in vacuo to provide a regioisomeric mixture of (S)-9ac and silica gel (60–220 mesh) eluting with 4% ethyl acetate in
(R)-10ac (52.3 mg, 98.9%) as a colorless oil which was further hexane to provide the mixture of (S)-9ae and (R)-10ae (53.4 mg,
purified by column chromatography on silica gel (60–220 mesh) 90.4%, 9ae/10ae = 5.7/1, as determined by 1H NMR) as a color-
1
eluting with 5% ethyl acetate in hexane to provide a mixture of less oil. H NMR (CDCl3, 300 MHz) δ 0.93–1.01 (m, 6H), 1.17
(S)-9ac and (R)-10ac (50.7 mg, 95.8%, 9ac/10ac = 1/2, as deter- (d, J = 6.3 Hz, 3H), 1.27 (d, J = 6.6 Hz, 3H), 1.49–1.60 (m, 4H),
mined by 1H NMR). 1H NMR showed that the ratio of (S)-9ac to 2.31–2.48 (m, 6H), 2.85–3.00 (m, 4H), 3.47–3.55 (m, 4H), 3.72
(R)-10ac is 1/2. 1H NMR (CDCl3, 300 MHz) δ 1.10–1.15 (m, 6H), (d, J = 14.1 Hz, 4H), 7.22–7.47 (m, 20H); 13C NMR (CDCl3,
2.47 (dd, J = 13.2, 5.1 Hz, 1H), 2.64 (dd, J = 13.2, 7.8 Hz, 1H), 75 MHz) δ 13.4 (q), 13.5 (q), 13.7 (q), 19.7 (q), 22.9 (t), 23.3 (t),
3.05–3.17 (m, 2H), 3.44 (dd, J = 12.3, 7.2 Hz, 1H), 3.52–3.62 (m, 32.4 (t), 34.5 (t), 36.3 (t), 38.1 (d), 52.7 (d), 53.4 (t), 59.1 (t), 60.4
5H), 3.71 (d, J = 13.5 Hz, 2H), 3.79 (d, J = 13.8 Hz, 2H), (t), 126.8 (d), 127.0 (d), 128.2 (d), 128.7 (d), 129.0 (d), 139.5 (s),
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140.3 (s). HRMS (positive ion ESI) Calcd for C20H28NS [M + H]+ was dried over MgSO4, filtered, and concentrated in vacuo to
m/z 314.1942. Found: [M + H]+ m/z 314.1937.
provide a regioisomeric mixture of (S)-9ag and (R)-10ag
(2S)-2-(Dibenzylamino)propan-1-ol ((S)-9af)11 and (2R)-1- (49.8 mg, 98.4%) as a colorless oil which was further purified
(dibenzylamino)propan-2-ol ((R)-10af).7b From the reaction of by column chromatography on silica gel (60–220 mesh) eluting
(R)-6a and H2O with NaOH. To the stirred solution of (R)-6a with 5% ethyl acetate in hexane to provide a mixture of (S)-9ag
(60 mg, 0.188 mmol) in CH3CN (0.75 mL) was added H2O and (R)-10ag (49.0 mg, 96.8%, 9ag/10ag = 1.6/1, as determined
(0.75 mL), and the reaction mixture was stirred at room temp- by 1H NMR) as a colorless oil. For the preparation of analytical
erature for 10 min. After this, 1 M NaOH aqueous solution samples, the regioisomeric mixture was separated by Prep-TLC
(0.38 mL) was added and the resulting mixture was stirred at (SiO2) eluted with 1–2% ethyl acetate in hexanes.
room temperature for 3 h. The resulting mixture was evapor-
(S)-9ag. [α]2D5 = −4.9° (c = 0.5, CHCl3). 1H NMR (CDCl3,
ated to dryness. The residue was treated with buffer (Et3N/ 300 MHz) δ 1.08 (d, J = 6.6 Hz, 3H), 3.02 (q, J = 6.6 Hz, 1H),
AcOH, 0.05 M, pH 6, 15 mL) and then extracted with DCM (3 × 3.30 (s, 3H), 3.33–3.36 (m, 1H), 3.54–3.62 (m, 3H), 3.72 (d, J =
15 mL). The combined organic layer was dried over MgSO4, fil- 13.8 Hz, 2H), 7.19–7.32 (m, 6H), 7.40 (d, J = 7.2 Hz, 4H); 13C
tered, and concentrated in vacuo to provide a regioisomeric NMR (CDCl3, 75 MHz) δ 12.1 (q), 52.1 (q), 54.1 (t), 58.8 (d),
mixture of (S)-9af and (R)-10af (47.3 mg, 98.3%) as a colorless 75.8 (t), 126.7 (d), 128.1 (d), 128.5 (d), 140.7 (s). HRMS (posi-
oil which was further purified by column chromatography on tive ion ESI) Calcd for C18H24NO [M + H]+ m/z 270.1858.
silica gel (60–220 mesh) eluting with 8% ethyl acetate in Found: [M + H]+ m/z 270.1867.
hexane to provide the mixture of (S)-9af and (R)-10af (44.4 mg,
(R)-10ag. [α]2D5 = +13.0° (c = 0.5, CHCl3). 1H NMR (CDCl3,
1
1
92.3%, 9af/10af = 1.2/1, as determined by H NMR). H NMR 300 MHz) δ 1.10 (d, J = 6.0 Hz, 3H), 2.41 (dd, J = 12.9, 6.0 Hz,
(CDCl3, 300 MHz) δ 1.00 (d, J = 6.6 Hz, 3H), 1.08 (d, J = 6.0 Hz, 1H), 2.58 (dd, J = 13.2, 5.7 Hz, 1H), 3.31 (s, 3H), 3.45 (q, J =
3H), 2.43 (d, J = 6.6 Hz, 2H), 2.98–3.05 (m, 1H), 3.30 (s, 1H), 14.7 Hz, 1H), 3.54 (d, J = 13.5 Hz, 2H), 3.69 (d, J = 13.8 Hz, 2H),
3.35–3.44 (m, 7H), 3.85–3.91 (m, 5H), 7.26–7.38 (m, 20H); 13C 7.21–7.39 (m, 10H); 13C NMR (CDCl3, 75 MHz) δ 17.9 (q), 56.3
NMR (CDCl3, 75 MHz) δ 8.7 (q), 20.0 (q), 53.0 (t), 54.3 (d), 58.5 (q), 58.9 (t), 59.3 (t), 75.9 (d), 126.8 (d), 128.1 (d), 128.9 (d),
(t), 61.5 (t), 62.8 (t), 63.2 (d), 127.2 (d), 127.3 (d), 128.5 (d), 139.7 (s). HRMS (positive ion ESI) Calcd for C18H24NO [M +
128.6 (d), 129.0 (d), 129.1 (d), 138.6 (s), 139.3 (s).
H]+ m/z 270.1858. Found: [M + H]+ m/z 270.1865.
From the reaction of (R)-6a and H2O without NaOH. To the
From the reaction of (R)-6a and MeOH without NaOH. (R)-
stirred solution of (R)-6a (60 mg, 0.188 mmol) in CH3CN 6a (60 mg, 0.188 mmol) was dissolved in MeOH (1.5 mL), and
(0.75 mL) was added H2O (0.75 mL), and the reaction mixture the reaction mixture was refluxed for 1 h. The resulting
was stirred at room temperature for 5 h. The resulting mixture mixture was evaporated to dryness. The residue was treated
was evaporated to dryness. The residue was treated with buffer with buffer (Et3N/AcOH, 0.05 M, pH 6, 15 mL) and then
(Et3N/AcOH, 0.05 M, pH 6, 15 mL) and then extracted with extracted with DCM (3 × 15 mL). The combined organic layer
DCM (3 × 15 mL). The combined organic layer was dried over was dried over MgSO4, filtered, and concentrated in vacuo to
MgSO4, filtered, and concentrated in vacuo to provide a regio- provide a regioisomeric mixture of (S)-9ag and (R)-10ag
isomeric mixture of (S)-9af and (R)-10af (45.1 mg, 93.8%) as a (49.6 mg, 98.0%) as a colorless oil which was further purified
colorless oil which was further purified by column chromato- by column chromatography on silica gel (60–220 mesh) eluting
graphy on silica gel (60–220 mesh) eluting with 5% ethyl with 5% ethyl acetate in hexane to provide the mixture of (S)-
acetate in hexane to provide a mixture of (S)-9af and (R)-10af 9ag and (R)-10ag (48.8 mg, 96.4%, 9ag/10ag = 1/6.3, as deter-
1
(43.6 mg, 90.6%, 9af/10af = 1/8.6, as determined by H NMR) mined by 1H NMR) as a colorless oil. 1H NMR (CDCl3,
1
as a colorless oil. H NMR (CDCl3, 300 MHz) δ 1.00 (d, J = 6.3 300 MHz) δ 1.09–1.13 (m, 6H), 2.44 (dd, J = 13.2, 6.3 Hz, 1H),
Hz, 3H), 1.08 (d, J = 6.0 Hz, 3H), 2.43 (d, J = 6.3 Hz, 2H), 2.60 (dd, J = 12.9, 5.4 Hz, 1H), 3.01–3.10 (m, 1H), 3.32–3.36 (m,
2.98–3.05 (m, 1H), 3.26–3.52 (m, 8H), 3.82–3.89 (m, 5H), 7H), 3.38–3.77 (m, 10H), 7.23–7.41 (m, 20H); 13C NMR (CDCl3,
7.27–7.33 (m, 20H); 13C NMR (CDCl3, 75 MHz) δ 8.7 (q), 19.9 75 MHz) δ 12.1 (q), 17.9 (q), 52.1 (q), 54.1 (t), 56.4 (q), 58.9 (t),
(q), 52.9 (t), 54.2 (d), 58.5 (t), 61.4 (t), 62.7 (t), 63.1 (d), 127.2 59.3 (t), 75.8 (t), 75.9 (d), 126.7 (d), 126.9 (d), 128.2 (d), 128.6
(d), 127.3 (d), 128.5 (d), 128.6 (d), 129.0 (d), 129.1 (d), 138.6 (s), (d), 128.9 (d), 139.8 (s), 140.7 (s).
139.3 (s).
Dibenzyl[(2S)-1-propoxypropan-2-yl]amine ((S)-9ah) and
Dibenzyl[(2S)-1-methoxypropan-2-yl]amine ((S)-9ag) and dibenzyl[(2R)-2-propoxypropyl]amine ((R)-10ah). To the stirred
dibenzyl[(2R)-2-methoxypropyl]amine ((R)-10ag). From the solution of (R)-6a (60 mg, 0.188 mmol) in CH3CN (0.75 mL)
reaction of (R)-6a and MeOH with NaOH. To the stirred solu- was added propan-1-ol (0.75 mL), and the reaction mixture was
tion of (R)-6a (60 mg, 0.188 mmol) in CH3CN (0.75 mL) was refluxed for 3 h. The resulting mixture was evaporated to
added MeOH (0.75 mL), and the reaction mixture was stirred dryness. The residue was treated with buffer (Et3N/AcOH, 0.05
at room temperature for 10 min. After this, 1 M NaOH M, pH 6, 15 mL) and then extracted with DCM (3 × 15 mL).
aqueous solution (0.38 mL) was added and the resulting The combined organic layer was dried over MgSO4, filtered,
mixture was stirred at room temperature for 1.5 h. The result- and concentrated in vacuo to provide a regioisomeric mixture
ing mixture was evaporated to dryness. The residue was treated of (S)-9ah and (R)-10ah (51.8 mg, 92.3%) as a colorless oil
with buffer (Et3N/AcOH, 0.05 M, pH 6, 15 mL) and then which was further purified by column chromatography on
extracted with DCM (3 × 15 mL). The combined organic layer silica gel (60–220 mesh) eluting with 5% ethyl acetate in
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hexane to provide the mixture of (S)-9ah and (R)-10ah for 1 h. 1 M NaOH (0.5 mL) was added to the reaction mixture.
1
(50.6 mg, 90.2%, 9ah/10ah = 1/5.9, as determined by H NMR) The reaction mixture was stirred at room temperature for 2 h.
1
as a colorless oil. H NMR (CDCl3, 300 MHz) δ 0.89–0.97 (m, The residue was purified by column chromatography on silica
6H), 1.08–1.12 (m, 6H), 1.53–1.63 (m, 4H), 2.43 (dd, J = 12.9, gel (60–230 mesh) eluting with 15% ethyl acetate in hexanes to
6.0 Hz, 1H), 3.40 (dd, J = 12.9, 5.7 Hz, 1H), 3.01–3.07 (m, 1H), afford (S)-11 (77 mg, 58%) as a colorless oil. [α]2D6 = +99.3° (c =
3.32–3.47 (m, 4H), 3.53–3.73 (m, 11H), 7.21–7.42 (m, 20H); 13C 1.0, CHCl3). 1H and 13C NMR data were essentially identical to
NMR (CDCl3, 75 MHz) δ 10.7 (q), 12.4 (q), 18.5 (q), 23.0 (t), those described above. Chiral HPLC (method F): tR = 10.4 min
23.4 (t), 52.3 (d), 54.1 (t), 59.2 (t), 59.3 (t), 70.6 (t), 72.8 (t), 73.7 (S, major) and 9.4 min (R, minor), >99% ee.
(t), 74.3 (d), 126.6 (d), 126.8 (d), 128.1 (d), 128.6 (d), 128.9 (d),
From one-pot reaction using Ag2CO3 (Table 4, entry 4). To a
139.9 (s), 140.9 (s). HRMS (positive ion ESI) Calcd for solution of (S)-1a (100 mg, 0.392 mmol) and PPh3 (123.3 mg,
C20H28NO [M + H]+ m/z 298.2171. Found: [M + H]+ m/z 0.470 mmol) in CH3CN (5 mL) at 0 °C was added NBS
298.2176.
(83.6 mg, 0.470 mmol) over 5 min. The resulting mixture was
(2R)-1-(Dibenzylamino)propan-2-ol ((R)-9af).11 From one- stirred for 4 h at 0 °C. The ice bath was removed, and the reac-
pot reaction using AgCN/H2O (Table 4, entry 2). To a solution tion mixture was warmed to room temperature and stirred for
of (S)-1a (100 mg, 0.392 mmol) and PPh3 (123.3 mg, 1 h. Ag2CO3 (129.6 mg, 0.470 mmol) was added to the reaction
0.470 mmol) in CH3CN (5 mL) at 0 °C was added NBS mixture. The reaction mixture was stirred at room temperature
(83.6 mg, 0.470 mmol) over 5 min. The resulting mixture was for 24 h. The residue was purified by column chromatography
stirred for 4 h at 0 °C. The ice bath was removed, and the reac- on silica gel (60–230 mesh) eluting with 15% ethyl acetate in
tion mixture was warmed to room temperature and stirred for hexanes to afford (S)-11 (69 mg, 52%) as a colorless oil. [α]D26
=
1
1 h. Then AgCN (62.9 mg, 0.470 mmol) was added to the reac- +89.7° (c = 1.0, CHCl3). H NMR (CDCl3, 300 MHz) δ 1.12 (d,
tion mixture followed by the addition of H2O (0.5 mL). The J = 6.6 Hz, 3H), 2.44–2.59 (m, 4H), 3.12–3.16 (m, 2H), 3.29 (d,
reaction mixture was stirred at room temperature for 24 h and J = 13.2 Hz, 2H), 3.72–3.91 (m, 3H), 7.22–7.38 (m, 10H); 13C NMR
evaporated to dryness. The residue was purified by column (CDCl3, 75 MHz) δ 11.1 (q), 28.0 (t), 41.3 (t), 51.1 (d), 53.0 (t),
chromatography on silica gel (60–230 mesh) eluting with 10% 126.9 (d), 128.1 (d), 129.1 (d), 140.1 (s), 177.0 (s). HRMS (posi-
ethyl acetate in hexanes to afford (R)-9af (70 mg, 70%) as a tive ion ESI) Calcd for C21H25N2O2 [M + H]+ m/z 337.1911.
colorless oil. [α]2D5 = –75.1° (c = 1.0, CHCl3). [Lit.11 [α]D20 = –92.2° Found: [M + H]+ m/z 337.1911. Chiral HPLC (method F): tR
(c = 1.0, CHCl3)]. H NMR (CDCl3, 300 MHz) δ 1.10 (d, J = 6.3 10.4 min (S, major) and 9.4 min (R, minor), >99% ee.
=
1
Hz, 3H), 2.45 (d, J = 6.9 Hz, 2H), 3.29 (s, 1H), 3.43 (d, J = 13.5
Preparation of the authentic sample for structure determi-
Hz, 2H), 3.88 (d, J = 13.5 Hz, 2H), 7.26–7.40 (m, 10H); 13C NMR nation (Scheme 3). To a solution of 17 (30 mg, 0.19 mmol) and
(CDCl3, 75 MHz) δ 20.0 (q), 58.5 (t), 61.4 (t), 63.2 (d), 127.3 (d), K2CO3 (131.1 mg, 0.95 mmol) in CH3CN (3 mL) was added
128.5 (d), 129.1 (d), 138.6 (s). 1H and 13C NMR data were essen- benzyl bromide (65.7 mg, 0.38 mmol). The resulting mixture
tially identical to those previously reported.11 Chiral HPLC was warmed to 60 °C and continuously stirred for 40 h. The
(method E): tR = 6.6 min (S, minor) and 8.0 min (R, major), resulting mixture was concentrated in vacuo, and the residue
90% ee.
was purified by column chromatography on silica gel
From the acidification of (R)-12 (Table 4). (R)-12 (30 mg, (60–230 mesh) eluting with 15% ethyl acetate in hexanes to
0.010 mmol) was treated dropwise with 4 M HCl in 1,4-dioxane afford (S)-11 (43.4 mg, 68%) as a colorless oil. [α]2D6 = +83.2°
(5 mL) at 0 °C. The reaction mixture was heated to 50 °C and (c = 1.0, CHCl3). 1H and 13C NMR spectra of the compound
stirred for 2 d. H2O (20 mL) and 2 M NaOH (aq) (10 mL) were were essentially identical to (S)-13 reported above. Chiral HPLC
added to the reaction mixture. The resulting mixture was (method F): tR = 10.4 min (S, major) and 9.4 min (R, minor),
extracted with ethyl acetate (3 × 30 mL). The combined organic >99% ee.
layers were dried over MgSO4, filtered, and concentrated to
1-[2-(Dibenzylamino)propyl]pyrrolidine-2,5-dione((rac)-
dryness in vacuo. The residue was purified by column chromato- 11). To a solution of (rac)-1a (100 mg, 0.392 mmol) and PPh3
graphy on silica gel (60–230 mesh) eluting with 10% ethyl (123.3 mg, 0.470 mmol) in CH3CN (5 mL) at 0 °C was added
acetate in hexanes to afford (R)-9af (16 mg, 61%) as a colorless NBS (83.6 mg, 0.470 mmol) over 5 min. The resulting mixture
oil. [α]2D5 = –65.6° (c = 0.8, CHCl3). Chiral HPLC (method E): was stirred for 4 h at 0 °C. The ice bath was removed, and the
tR = 6.7 min (S) and 8.3 min (R). Chiral HPLC (method E): tR
6.6 min (S, minor) and 8.0 min (R, major), 81% ee. 1H and 13
=
C
reaction mixture was warmed to room temperature and stirred
for 1 h. Then 1 M NaOH (0.5 mL) was added to the reaction
NMR data of (R)-9af were essentially identical to those mixture. The reaction mixture was stirred at room temperature
described above. for 2 h. The residue was purified by column chromatography
1-[(2S)-2-(Dibenzylamino)propyl]pyrrolidine-2,5-dione ((S)- on silica gel (60–230 mesh) eluting with 15% ethyl acetate in
1
11). From one-pot reaction using 1 M NaOH (Table 4, entry 3). hexanes to afford (rac)-11 (50 mg, 37.7%) as a colorless oil. H
To a solution of (S)-1a (100 mg, 0.392 mmol) and PPh3 and 13C NMR data of (rac)-11 were identical to (S)-11. Chiral
(123.3 mg, 0.470 mmol) in CH3CN (5 mL) at 0 °C was added HPLC (method F): tR = 9.4 (R) and 10.6 min (S).
NBS (83.6 mg, 0.470 mmol) over 5 min. The resulting mixture
(2R)-1-(Dibenzylamino)propan-2-yl nitrate ((R)-12). To a
was stirred for 4 h at 0 °C. The ice bath was removed, and the solution of (S)-1a (100 mg, 0.392 mmol) and PPh3 (123.3 mg,
reaction mixture was warmed to room temperature and stirred 0.470 mmol) in CH3CN (5 mL) at 0 °C was added NBS
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1
(83.6 mg, 0.470 mmol) over 5 min. The resulting mixture was = 1.0, CHCl3). [Lit.13 [α]D20 = −89.3° (c = 0.96, CHCl3)]. H NMR
stirred for 4 h at 0 °C. The ice bath was removed, and the reac- (CDCl3, 300 MHz) δ 1.28 (d, J = 6.9 Hz, 3H), 1.40 (s, 9H), 2.50
tion mixture was warmed to room temperature and stirred for (dd, J = 16.8, 4.2 Hz, 1H), 2.71 (dd, J = 16.5, 4.8 Hz, 1H),
1 h. Then AgNO3 (80 mg, 0.470 mmol) was added to the reac- 3.85–3.98 (m, 1H), 4.81 (d, J = 5.4 Hz, 1H); 13C NMR (CDCl3,
tion mixture followed by the addition of H2O (0.5 mL). The 75 MHz) δ 19.4 (q), 25.1 (t), 28.3 (q), 43.2 (d), 80.0 (s), 117.4 (s),
1
reaction mixture was stirred at room temperature for 1 h. The 154.8 (s). H and 13C NMR data of (S)-15 were essentially iden-
residue was purified by column chromatography on silica gel tical to those previously reported.13
(60–230 mesh) eluting with 3% ethyl acetate in hexanes to
tert-Butyl N-[(2S)-1-(2,5-dioxopyrrolidin-1-yl)propan-2-yl]carb-
amate (16).14 To a solution of (S)-14 (150 mg, 0.59 mmol) in
afford (R)-12 (80 mg, 67%) as a colorless oil.
1
[α]2D6 = +25.1° (c = 1.0, CHCl3). H NMR (CDCl3, 300 MHz) δ DMF (3 mL) was added K2CO3 (162.8 mg, 1.18 mmol) and suc-
1.27 (d, J = 6.6 Hz, 3H), 2.58 (dd, J = 13.8, 5.4 Hz, 1H), 2.78 (dd, cinimide (58.5 mg, 0.59 mmol) at room temperature. The reac-
J = 13.8, 7.2 Hz, 1H), 3.64 (d, J = 13.8 Hz, 2H), 3.71 (d, J = 13.5 tion mixture was stirred at 90 °C for 1 h. The resulting mixture
Hz, 2H), 5.23–5.25 (m, 1H), 7.28–7.38 (m, 10H); 13C NMR was washed with H2O (50 ml) and extracted with ethyl acetate
(CDCl3, 75 MHz) δ 16.8 (q), 56.8 (t), 59.3 (t), 78.9 (d), 127.3 (d), (3 × 20 mL). The organic layers were combined, dried over
128.4 (d), 128.9 (d), 138.8 (s). HRMS (positive ion ESI) Calcd MgSO4, filtered and concentrated in vacuo. The residue was
for C17H21N2O3 [M + H]+ m/z 301.1547. Found: [M + H]+ m/z purified by column chromatography on silica gel
301.1562. Chiral HPLC (method E): tR = 8.7 min (S, minor) and (60–220 mesh) eluting with 15% ethyl acetate in hexanes to
9.2 min (R, major), >99% ee.
1-(Dibenzylamino)propan-2-yl nitrate ((rac)-12). To a solu-
provide (S)-16 (90.7 mg, 60%) as a white solid. [α]2D6 = +19.1° (c
1.0, CHCl3). [α]D26
+18.3° (c 0.9, CHCl3). M.P.
=
=
=
tion of (rac)-6a (50 mg, 0.106 mmol) in CH3CN (1 mL) was 117.2–120.5 °C. 1H NMR (CDCl3, 300 MHz) δ 1.11 (d, J = 6.6
added AgNO3 (32.7 mg, 0.192 mmol) followed by the addition Hz, 3H), 1.34 (s, 9H), 2.64–2.70 (m, 4H), 3.39–3.50 (m, 2H),
of H2O (0.1 mL). The reaction mixture was stirred at room 3.90–4.05 (m, 1H), 4.65 (d, J = 7.5 Hz, 1H); 13C NMR (CDCl3,
temperature overnight. The residue was purified by column 75 MHz) δ 18.5 (q), 28.3 (q), 44.5 (d), 44.9 (t), 79.1 (s), 155.6 (s),
chromatography on silica gel (60–230 mesh) eluting with 5% 177.6 (s). HRMS (positive ion ESI) Calcd for C12H20N2O4Na [M
ethyl acetate in hexanes to afford (rac)-12 (30 mg, 59%) as a + H]+ m/z 279.1315. Found: [M + H]+ m/z 279.1326.
colorless oil. 1H and 13C NMR data of (rac)-12 were identical to
(S)-12. Chiral HPLC (method E): tR = 8.7 min (S) and 9.3 min containing 16 (60 mg, 0.23 mmol) was added 4 M HCl in 1,4-
1-[(2S)-2-Aminopropyl]pyrrolidine-2,5-dione (17). To a flask
(R).
tert-Butyl
dioxane (2 mL) at 0 °C. The resulting mixture was stirred at
N-[(2S)-1-(methanesulfonyloxy)propan-2-yl]carb- room temperature for 18 h. Ethyl ether (20 mL) was added to
amate (14).14 To a solution of 1312 (300 mg, 1.71 mmol) and the mixture, and the resulting mixture was stirred for 15 min.
triethylamine (207.1 mg, 2.05 mmol) in CH2Cl2 (10 mL) at 0 °C The resulting mixture was filtered, and the slurry on the filter
was added methanesulfonyl chloride (216.4 mg, 1.89 mmol) funnel was immediately treated with H2O (30 mL). The
over 5 min. The resulting mixture was stirred for 3 h at 0 °C. aqueous solution was concentrated in vacuo. The residue was
The reaction mixture was concentrated to dryness, treated with purified by column chromatography on silica gel
H2O (30 mL), and extracted with CH2Cl2 (3 × 20 mL). The (60–220 mesh) eluting with 5% ethyl acetate in hexanes to
organic layers were combined, dried over MgSO4, filtered, and provide product (S)-17 (37.8 mg, 84.1%) as a white solid. [α]D26
1
evaporated. The residue was purified by column chromato- = +16.4. M.P. 226.3–228.9 °C. H NMR (D2O, 300 MHz) δ 1.15
graphy on silica gel (60–220 mesh) eluting with 5% ethyl (d, J = 5.7 Hz, 3H), 2.68 (s, 4H), 3.45–3.70 (m, 3H); 13C NMR
acetate in hexanes to provide (S)-14 (406 mg, 93.8%) as a waxy (D2O, 75 MHz) δ 15.6 (t), 28.1 (q), 41.4 (d), 46.6 (t), 181.4 (s).
solid. [α]2D6 = –26.4° (c = 1.0, CHCl3). 1H NMR (CDCl3, HRMS (positive ion ESI) Calcd for C18H19N4O4 [M + H]+ m/z
300 MHz) δ 1.14 (d, J = 6.9 Hz, 3H), 1.35 (s, 9H), 2.96 (s, 3H), 157.1000. Found: [M + H]+ m/z 157.0972.
3.80–3.95 (m, 1H), 4.07–4.09 (m, 2H), 4.84 (d, J = 6.9 Hz, 1H);
Calculation details
13C NMR (CDCl3, 75 MHz) δ 17.0 (q), 28.2 (q), 37.2 (d), 45.4 (t),
72.1(t), 79.6 (s), 155.1 (s). The compound was not very stable Geometry optimizations were performed at the Density Func-
and directly used for the next step without further tional Theory (DFT) level of theory using the Perdew–Burke–
purification.
Erzenhof parameter-free exchange–correlation functional
tert-Butyl N-[(2S)-1-cyanopropan-2-yl]carbamate (15).13 To a (PBE0).18 All atoms were described by correlation-consistent
solution of (S)-14 (150 mg, 0.59 mmol) in DMF (1.5 mL) was basis sets of triple-ζ quality (cc-pVTZ). The basis set for heavy
added NaCN (43.6 mg, 0.89 mmol) at room temperature. The iodine was augmented by effective core potential (so-called cc-
reaction mixture was stirred at 90 °C for 1 h. The resulting pVTZ-pp). In all cases, no symmetry restrictions were applied.
mixture was washed with H2O (50 ml) and extracted with ethyl All calculated structures were found to be minima on PES (no
acetate (3 × 20 mL). The organic layers were combined, dried negative elements of the Hessian matrix and, consequently, no
over MgSO4, filtered and concentrated in vacuo. The residue imaginary frequencies) unless otherwise noted. Transition
was purified by column chromatography on silica gel states were found to possess only one imaginary frequency,
(60–220 mesh) eluting with 10% ethyl acetate in hexanes to corresponding to the transition between reactants and pro-
provide (S)-15 (93.6 mg, 86%) as a white solid. [α]2D6 = −81.6° (c ducts intended. The nature of transition states was probed
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through IRC (intrinsic reaction coordinate) technique that led
directly to the target products or reactants. All computations
were performed by using the Firefly 8.1.0 program package.19
In the next step, optimized geometries were used to get
insight into the electronic structure of our target systems in
terms of natural bond orbitals (NBO).20 Bond orders quoted
are those from the Wiberg formulation21 (so-called Wiberg
bond indexes) incorporated into the NBO analysis. All compu-
tations were performed with the NBO 6.0 program,22 using the
converged wavefunctions generated by the Firefly program.
In order to obtain a more reliable evaluation on reaction
energetics, single-point calculations (for DFT-optimized geo-
metries) were performed for all minimum structures and tran-
sition states with the help of a highly-accurate single-reference
corrBrienelated method, DLPNO-CCSD(T)15 (domain-based
local pair natural orbitals coupled-cluster with single, double
and perturbative triple corrections) with the same basis sets.
This method was recently proposed by the group of Neese and
was found to be very accurate, providing accuracy comparable
with that of CCSD(T), which has the reputation of serving as a
benchmarking method. To accelerate these calculations, the
resolution-of-identity (RI) algorithm was applied using the
chain-of-sphere approach (RIJCOSX).23 All these high-level cal-
culations were carried out by using the ORCA program suite
(version 3.1.0).
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X-ray crystal determination of (R)-5a
Crystals for structure determination were obtained by slow
evaporation of 5a from a mixture of CH2Cl2/hexanes. The struc-
ture was solved using SIR-92 and refined using Bruker
SHELXTL. Crystallographic data for 5a have been deposited
with the Cambridge Crystallographic Data Centre as sup-
plementary publication no. CCDC 999697.
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