Enantioselective Synthesis of 2-Aminomethyl and 3-Amino Pyrrolidines and Piperidines through 1,2-Diamination of Aldehydes

Article abstract of DOI:10.1021/acs.joc.8b00933

An efficient method for the synthesis of 1,2-diamines from aldehydes through proline-catalyzed asymmetric α-amination followed by reductive amination is reported. The products resemble those obtained through direct asymmetric diamination of terminal alkenes. The methodology is used to synthesize 2-aminomethyl and 3-amino pyrrolidines and piperidines in high yields and with a good enantioselectivity. The usefulness of the method is demonstrated through the synthesis of a 2-aminomethyl iminocyclitol.

Full text of DOI:10.1021/acs.joc.8b00933

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Article
Enantioselective Synthesis of 2-Aminomethyl and 3-Amino
Pyrrolidines and Piperidines through 1,2-Diamination of Aldehydes
Anas Ansari, and Ramesh Ramapanicker
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.8b00933 • Publication Date (Web): 13 Jul 2018
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Enantioselective Synthesis of 2ꢀAminomethyl and 3ꢀAmino Pyrrolidines
and Piperidines through 1,2ꢀDiamination of Aldehydes
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Anas Ansari and Ramesh Ramapanicker*
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Department of Chemistry, Indian Institute of Technology Kanpur, Kanpur, UPꢀ208016, India
TOC Graphic
Abstract: An efficient method for the synthesis of 1,2ꢀdiamines from aldehydes through prolineꢀ
catalyzed asymmetric αꢀamination followed by reductive amination is reported. The products
resemble those obtained through direct asymmetric diamination of terminal alkenes. The
methodology is used to synthesize 2ꢀaminomethyl and 3ꢀamino pyrrolidines and piperidines in
high yields and with good enantioselectivity. The usefulness of the method is demonstrated
through the synthesis of a 2ꢀaminomethyl iminocyclitol.
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Introduction
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1,2ꢀdiamino units are widely found in natural products and in a number of biologically active
synthetic compounds.1 In addition to being used as synthetic building blocks for heterocyclic
compounds; they are also used as chiral ligands and catalysts.2 A wide range of approaches are
available in the literature towards the synthesis of this ubiquitous motif. While metalꢀcatalyzed
diamination reactions3ꢀ5 are the most common approach towards their synthesis, methods based
on the functionalization of nitro alkanes,6 amino acids,7 aziridines,8 βꢀchloro amines9 and
aldehydes through umpolung reactions10 are also available. Recently, Masson and coworkers
have reported an efficient method for the asymmetric synthesis of 1,2ꢀdiamines through
amination of enecarbamates.11 1,2ꢀdiamines are often part of azaꢀheterocyclic compounds as
masked units, eg. natural products such as balanol and pseudodistomins and azasugars containing
2ꢀaminomethyl groups (Figure 1). We envisaged that a general method for the synthesis of such
heterocyclic compounds can be achieved through intramolecular SN2 displacement of a leaving
group by one of the 2ꢀamino groups introduced by αꢀamination followed by reductive amination
of an aldehyde (Scheme 1).
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Figure 1. Azaꢀheterocyclic compounds containing 1,2ꢀdiamino units
Prolineꢀcatalyzed αꢀamination of aldehydes using dibenzyl azodicarboxylate (DBAD) is a widely
used synthetic strategy that allows the stereoselective introduction of an amino group in the αꢀ
position of aldehydes.12 The intermediate, an αꢀhydrazino aldehyde obtained from the initial
reaction is prone to racemization and hence is reduced in situ into an alcohol or is functionalized
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further by aldol,13 Wittig,14 Barbier15 or Passerini16 reactions in oneꢀpot. Reductive amination of
this αꢀhydrazino aldehyde to get a 2ꢀhydrazino amine, which could then be converted to a
terminal 1,2ꢀdiamine has not been explored yet. However, the αꢀhydroxylation of aldehydes
followed by reductive amination to get βꢀamino alcohols has already been reported17 and we
have used this method for the synthesis of hydroxy diamino acid derivatives.18 Here we report
enantioselective syntheses of four compounds (Figure 2), viz. (R)ꢀ3ꢀaminopiperidine (1), (R)ꢀ3ꢀ
aminopyrrolidine (2), (R)ꢀ2ꢀaminomethylpyrrolidine (3) and (R)ꢀ2ꢀaminomethylpiperidine (4)
using the strategy outlined in Scheme 1.
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Figure 2. Molecules synthesized in this study
Although, we carried out the synthesis of compounds 1ꢀ4 to establish the usefulness of the
methodology reported here, a literature search revealed that enantioselective synthesis of these
targets are of importance. These compounds also have the potential to be used as chiral ligands
for transition metals and as oragnocatalysts. A general method that can be used to synthesize
compounds 1ꢀ4 is not available. Zhang et al. have recently reported the synthesis of 1 as its
hydrochloride salt, which is a synthetic intermediate for linagliptin and alogliptin. The synthesis
was achieved by the cyclization followed by reduction of an ornithine derivative, which in turn
was synthesized from asymmetric reduction of a dehydroamino ester derivative.19 Compound 1
has been used as a component in the design of hybrid molecules for the inhibition of dipeptidyl
peptidaseꢀ4.20 Davies et al. have reported a general method for the synthesis of 3ꢀ
aminopyrrolidines, including compound 2, by the conjugate addition of homochiral lithium
amides to methyl 4ꢀ(NꢀbenzylꢀNꢀallylamino)butꢀ2ꢀenoates followed by cyclization, enolate
functionalization and deprotection.21 The reaction proceeds in essentially four steps with
stereoselectivity achieved in excess of 98%. An earlier report on the synthesis of 2 used optically
pure Nꢀbenzylꢀ3ꢀpyrrolidinol as the starting material.22 Recently, 2 was incorporated on to
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known glutaminase isomerase C inhibitors, resulting in molecules with nanomolar potency and
improved ClogP values.23 Compound 2 has also been incorporated as a structural unit to design
histamine H4 receptor antagonists.24 Compound 3 is probably the easiest to prepare using
methods other than we have reported here. The synthesis of 3 can be achieved by reduction of
prolinamides25 or from glutamic acid.26 As our method relies on the incorporation of an amino
function enantioselectively; it has the potential to be used for the synthesis of substituted
derivatives of 3, which may not be possible on using commercially available chiral derivatives of
amino acids. 3 has been used to develop inhibitors targeting calciumꢀdependent protein kinaseꢀ
1.27 Quirion, Husson and coworkers have reported an interesting strategy for the synthesis of 4
and other 2ꢀaminomethyl piperidines using (ꢀ)ꢀ2ꢀcyanoꢀ6ꢀphenyloxazolopiperidine, which in turn
is prepared from (R)ꢀ(ꢀ)ꢀphenylglycinol, glutaraldehyde and KCN.28 O’Hagan and coworkers
have reported a rather straight forward route to 4 through the cyclization of lysine.29
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Thus, most of the available syntheses of 1ꢀ4 rely on the use of enantiomerically pure starting
materials, which are commercially available. This limits their application to the synthesis of
those derivatives, for which an exact chiron is available. Therefore, a general method that
depends on the enantioselective installation of amino groups to synthesize 1,2ꢀdiamines is very
relevant.
Results and Discussion
(R)ꢀ3ꢀaminopiperidine (1) was synthesized from the aldehyde 5a, which in turn can be derived
from 1,5ꢀpentanediol.30 The aldehyde 5a was subjected to αꢀhydrazination using DBAD in the
presence of Lꢀproline (0 ºC – r. t., 3 h, CH3CN). The crude product was subjected to reductive
amination using benzylamine and triacetoxy sodium borohydride (NaBH(OAc)3, 0 ºC – r. t., 2.5
h). Under the reaction conditions the hydrazino amine intermediate, A underwent cyclization to
give the 3ꢀhydrazinopiperidine derivative 6a in 79% yield over the two steps. HPLC analysis of
6a was carried out and the peaks were compared with those obtained for a racemic mixture of 6a
derived from 5a through αꢀfunctionalization using DLꢀproline. The Lꢀprolineꢀcatalyzed reaction
yielded 6a with a moderate ee of 68%. The reduced ee in comparison with Lꢀproline catalyzed αꢀ
amination reactions in general, may be attributed to partial racemization of the aldehyde or the
imine before it is reduced to the benzylamine derivative. Carrying out the reaction at lower
temperatures substantially reduced the rate of conversion and a significant improvement in
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enantioselectivity could not be achieved. To our surprise, when sodium borohydride (NaBH4)
was used instead of NaBH(OAc)3 for reductive amination, the enantioselectivity of the reaction
improved substantially and 6a was isolated in 81% yield and with 92% ee (Scheme 2).
Hydrogenolysis of 6a, first using RaneyꢀNi® and then with 5% Pd/C yielded 1 in 82% yield.
Thus, the synthesis of 1 from 5a was achieved in an overall yield of 66% and with high
enantioselectivity.
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Scheme 1. Strategy for the synthesis of amino azaꢀheterocycles
Scheme 2: Synthesis of (R)ꢀ3ꢀaminopiperidine (1)
Encouraged by the success achieved in the synthesis of 1, we assumed that a similar sequence of
reactions would yield (R)ꢀ3ꢀaminopyrrolidine (2) from 5b, the lower homologue of 5a. However,
the aldehyde 5b did not give the expected product 6b, on Lꢀproline catalyzed αꢀhydrazination
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followed by reductive amination. A complex reaction mixture was obtained and no products
could be isolated and characterized after multiple attempts at different conditions (Scheme 3).
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CbzHN
NCbz
9
1. L-Proline, DBAD
TsO
CHO
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N
2. BnNH2, NaBH4
5b
Bn
6b
Scheme 3. An unsuccessful attempt towards the synthesis of 2 from 5b
CbzHN
NCbz
1. L-Proline, DBAD
TBDPSO
CHO
TBDPSO
2. BnNH2, NaBH4
3. (Boc)2O, NaHCO3
7a
N
Boc
Bn
8a (85%), er 97.5:2.5
1. H2, Raney-Ni, CH3OH
2. CbzCl, NaHCO3, THF
NHCbz
NHCbz
N
1. TBAF, THF, 0 ºC - r.t.
2. MsCl, Et3N, 0 ºC, CH2Cl2
MsO
TBDPSO
N
Boc
10 (81%)
Bn
Boc
9 (78%)
Bn
1. TFA, 0 ºC, CH2Cl2
2. K2CO3, r. t., CH3OH
NHCbz
NH2
H2, Pd(OH)2, CH3OH
N
N
H
Bn
11 (78%)
2 (82%)
Scheme 4: Synthesis of (R)ꢀ3ꢀaminopyrrolidine (2)
It was realized that 2 could be prepared from a slightly longer route from the aldehyde 7a31
(Scheme 4). Lꢀprolineꢀcatalyzed αꢀhydrazination followed by reductive amination and Bocꢀ
protection of 7a yielded 8a in 85% yield over the 3 steps and with an ee of 95%. Hydrogenolysis
of the N–N bond with RaneyꢀNi® and protection of the resultant amine with CbzCl gave the
diamine derivative 9 (78%). The silyl protecting group in 9 was removed using TBAF (0 ºC –
r.t., THF) and the primary hydroxyl group was mesylated (MsCl, Et3N, 0 ºC, CH2Cl2) to get 10.
Removal of the NꢀBoc protection using TFA (50% in CH2Cl2) and treatment of the crude TFA
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salt of the amine with K2CO3 (CH3OH, r.t.) gave the 3ꢀaminopyrrolidine derivative 11, which on
hydrogenolysis using Pd(OH)2 in CH3OH yielded 2 in 64% yield over the three steps.
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Scheme 5. Synthesis of (R)ꢀ2ꢀaminomethylpyrrolidine (3) and (R)ꢀ2ꢀaminomethylpiperidine (4)
(R)ꢀ2ꢀaminomethylpyrrolidine (3) and (R)ꢀ2ꢀaminomethylpiperidine (4) were prepared from
aldehydes 7b and 7c, respectively (Scheme 5). 7b and 7c were subjected to Lꢀprolineꢀcatalyzed
αꢀhydrazination and subsequently to reductive amination using benzylamine and NaBH4. The
resultant amines were treated with Boc anhydride to get the Bocꢀderivatives 8b and 8c in 87%
and 90% yields over the three steps and with 97% and 98% ee, respectively. The OꢀTBDPS
groups were deprotected (TBAF, THF, 0 ºC – r.t.) to get primary alcohols 12a (92%) and 12b
(92%), which were then converted to the mesylates 13a (90%) and 13b (88%) by treating with
MsCl (Et3N, 0 ºC, CH2Cl2). Hydrogenolysis of the N–N bond using RaneyꢀNi® and subsequent
Bocꢀprotection (Boc2O, NaHCO3, THF) of the free amine directly, yielded the corresponding
cyclized products 14a (76%) and 14b (77%). The NꢀBoc groups were removed by acidolysis
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(HCl in EtOAc, 0 ºC) and the Nꢀbenzyl groups were removed by hydrogenolysis (H2, Pd/C,
CH3OH) to get 3 and 4 in 86% and 82% yields from 14a and 14b, respectively (Scheme 5).
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In order to demonstrate the applicability of the current methodology for the synthesis of highly
functionalized molecules, we prepared a 2ꢀaminomethyl iminocyclitol using αꢀamination
followed by reductive amination of an aldehyde as the key step (Scheme 6). The unsaturated
ester derivative 15 was prepared from Dꢀribose following a reported procedure.32 Reduction of
the double bond and the ester group and mesylation of the hydroxyl group yielded the aldehyde
16 in 69% yield. Lꢀprolineꢀcatalyzed αꢀhydrazination followed by reductive amination and Boc
protection of 16 yielded 17 in 71% yield and in 9:1 diastereomeric ratio. Multiple attempts at
different conditions towards improving the diastereoselectivity for this reaction were not
successful. The reaction of the aldehyde function with benzylamine was found to be slower than
those observed for the unhindered aldehydes 5a and 7aꢀc. The increased reaction time in this
case may have resulted in partial stereo randomization of the newly generated chiral center.
Hydrogenolysis of 17 and treatment of the resulting amine with K2CO3 in methanol resulted in
the piperidine derivative 18 in very good yield. Acidolysis of 18 yielded 19 (87%), which was
subjected to hydrogenation to remove the Nꢀbenzyl group to get the desired 2ꢀ
aminomethylpiperidine derivative 20 in 80% yield over the two steps.
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Scheme 6. Synthesis of a 2ꢀaminomethyl iminocyclitol (20)
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Conclusion
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In conclusion, we have developed a reliable method for the enantioselective synthesis of terminal
1,2ꢀdiamines from aldehydes through prolineꢀcatalyzed asymmetric amination followed by
reductive amination. High enantioselectivity and very good yields are achieved in these
reactions. This methodology is successfully explored in the synthesis of 2ꢀaminomethyl and 3ꢀ
amino pyrrolidines and piperidines. The methodology will be useful for the synthesis of natural
products containing 1,2ꢀdiamino units in them, which was demonstrated by the synthesis of a 2ꢀ
aminomethyl iminocyclitol.
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EXPERIMENTAL SECTION
All the chemicals were purchased from commercial sources. The 1H NMR spectra of compounds
containing the hydrazino group were complex at r. t. due to the presence of rotamers. They were
therefore recorded at 80 °C in DMSOꢀd6. Column chromatography was done with silica gel
(particle size 60ꢀ120 and 100ꢀ200 mesh) purchased from Merck. The enantiomeric ratios were
determined by chiral HPLC analysis using Daicel chiralpak ODꢀH and IC columns with a
mixture of hexane and isopropanol as eluent at 25 °C. Optical rotation was measured using a 5.0
mL cell with 10 dm path length and is reported as [α]D25 (c in g per 100 mL solvent).
(R)ꢀdibenzyl 1ꢀ(1ꢀbenzylpiperidinꢀ3ꢀyl)hydrazineꢀ1,2ꢀdicarboxylate (6a). To a stirred solution of
the aldehyde 5a (1.10 g, 4.29 mmol) in CH3CN (13 mL) dibenzylazodicarboxylate (DBAD, 1.53
g, 5.14 mmol) and Lꢀproline (0.043 g, 10 mol%) were added at 0 °C and was stirred for 2 h. The
stirring was continued at room temperature until the solution turned colorless from yellow. The
reaction mixture was again cooled to 0 °C and benzyl amine (0.46 mL, 4.29 mmol) and sodium
borohydride (0.32 g, 8.58 mmol) were added and was stirred for 30 min at 0 °C and further for 2
h at r. t. The reaction was quenched with saturated NH4Cl solution (15 mL) at 0 ºC. The product
was extracted with EtOAc (3 × 40 mL); organic layers were combined and dried over anhydrous
Na2SO4. The solution was concentrated under reduced pressure and the product was isolated by
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column chromatography (60:40 petroleum ether/EtOAc) as a colorless oil (1.64 g, 81%); [α]D
̶
1
19.935 (c 0.26, CH2Cl2, 92% ee); H NMR (DMSOꢀd6 400 MHz, 80 °C) δ 9.23 (s, 1H), 7.41ꢀ
7.13 (m, 15H), 5.04 (s, 4H), 4.04 (s, 1H), 3.43 (m, 2H), 2.84 (s, 1H), 2.68 (d, J = 10.8 Hz, 1H),
13
1.91 (s, 1H), 1.83ꢀ1.69 (m, 2H), 1.61 (d, J = 12.2 Hz, 1H), 1.47 (m, 1H), 1.29 (m, 1H) ppm; C
NMR (DMSOꢀd6, 100 MHz, rotamers) δ 157.2, 155.4, 138.9, 138.7, 136.9, 136.8, 129.2, 128.9,
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128.6, 128.5, 128.2, 127.8, 127.7, 127.3, 67.3, 66.6, 62.7, 56.4, 54.8, 53.1, 27.9, 27.4, 24.48,
24.41; IR (thin film): 3290, 3030, 3032, 2937, 2807, 1755, 1713, 1496, 1454, 1408, 1348, 1300,
1257, 1224, 1173 cmꢀ1. HRMS (ESIꢀTOF) m/z: [M + H]+ calcd. for C28H32N3O4 474.2393, found
474.2377; HPLC (Diacel IC column, 90:10 hexane/IPA, detection wavelength λ = 254 nm, flow
rate of 1 mL/min) retention times: 21.5 min (major isomer, 96%) and 27.2 min (minor isomer,
4%).
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(R)ꢀ3ꢀaminopiperidine (1). To a stirred solution of 6a (1.00 g, 2.11 mmol) in CH3OH (15 mL),
RaneyꢀNi® (0.80 g, prewashed with absolute ethanol) and 0.10 mL of acetic acid were added and
the stirring was continued for 14 h at r. t. under a hydrogen atmosphere. The reaction mixture
was filtered through a celite pad and concentrated under reduced pressure to get 1ꢀbenzylꢀ3ꢀ
aminopiperidine, which was dissolved in CH3OH (5 mL) and 10% Pd/C (0.05 g) was added. The
mixture was stirred for 14 h at r. t. under a hydrogen atmosphere. The reaction mixture was
filtered through a celite pad and the solvents were removed under reduced pressure to get 1 as a
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colorless oil (0.17 g, 82%); [α]D +3.880 (c 0.30, CH3OH); H NMR (D2O, 500 MHz) δ 3.74
(m, 1H), 3.70ꢀ3.62 (m, 1H), 3.54ꢀ3.45 (m, 1H), 3.11 (m, 1H), 3.04 (m, 1H), 2.30 (d, J = 12.9 Hz,
1H), 2.20ꢀ2.09 (m, 1H), 1.94ꢀ1.81 (m, 1H), 1.74 (m, 1H) ppm; 13C NMR (D2O, 125 MHz) δ
44.9, 44.6, 43.4, 26.2, 20.1 ppm; IR (thin film): 3426, 2958, 2031, 1619, 1513, 1454, 1302, 1164
cmꢀ1. HRMS (ESIꢀTOF) m/z: [M + H]+ calcd. for C5H13N2 101.1079, found 101.1074.
General procedure for αꢀhydrazination followed by reductive amination of 7 to 8. To a
stirred solution of the aldehyde 7a (0.88 g, 2.69 mmol) at 0 °C in CH3CN (20 mL),
dibenzylazodicarboxylate (DBAD) (0.96 g, 3.22 mmol) and LꢀProline (0.031 g, 10 mol%) were
added. The reaction mixture was stirred for 2 h at 0 °C and then at r. t. until the solution turned
colorless from yellow. After the colour change, the reaction mixture was again cooled to 0 °C
and benzyl amine (0.29 mL, 2.69 mmol) and sodium borohydride (0.20 g, 5.38 mmol) were
added one after the other. The reaction mixture was stirred for 30 min at 0 °C and further for 2 h
at r. t. and then Boc anhydride (0.74 mL, 3.22 mmol) and NaHCO3 (0.45 g, 5.38 mmol) were
added and the mixture was stirred for an additional 4 h. The reaction mixture was quenched with
saturated NH4Cl solution (15 mL) and the product was extracted with EtOAc (3 × 50 mL), the
extractions were pooled, dried over Na2SO4 and concentrated under reduced pressure. The crude
product was purified by column chromatography to get 8a. The same procedure was used to
convert 7b and 7c to 8b and 8c, respectively.
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(R)ꢀdibenzyl
1ꢀ(9ꢀbenzylꢀ2,2,12,12ꢀtetramethylꢀ10ꢀoxoꢀ3,3ꢀdiphenylꢀ4,11ꢀdioxaꢀ9ꢀazaꢀ3ꢀ
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silatridecanꢀ7ꢀyl)hydrazineꢀ1,2ꢀdicarboxylate (8a). column chromatography (90:10 petroleum
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ether/EtOAc); clear oil (1.86 g, 85%); [α]D + 5.738 (c 0.36, CH2Cl2, 95% ee); H NMR
(DMSOꢀd6, 500 MHz, 80 °C) δ 7.58 (s, 4H), 7.43ꢀ7.18 (m, 19H), 7.12 (s, 2H), 5.04 (s, 4H), 4.65
(s, 1H), 4.32 (s, 2H), 3.77 (s, 1H), 3.69 (s, 1H), 3.21 (s, 1H), 1.74 (s, 1H), 1.58 (s, 1H), 1.32 (s,
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9H), 0.97 (s, 9H) ppm; C NMR (DMSOꢀd6, 125 MHz, rotamers) δ 156.5, 156.3, 156.1, 138.8,
138.7, 138.5, 136.8, 135.5, 133.8, 133.7, 130.2, 128.9, 128.9, 128.8, 128.7, 128.5, 128.3, 128.1,
128.0, 127.9, 127.6, 127.3, 127.1, 79.5, 67.9, 67.4, 66.8, 60.4, 50.4, 47.5, 32.3, 32.0, 31.8, 28.7,
28.4, 27.1, 19.2 ppm; IR (thin film): 3302, 3067, 3032, 2959, 2930, 2856, 1755, 1718, 1676,
1472, 1454, 1424, 1392, 1366, 1337, 1249, 1218, 1140, 1111 cmꢀ1. HRMS (ESIꢀTOF) m/z: [M +
H]+ calcd. for C48H58N3O7Si 816.4044, found 816.4045, HPLC (Diacel ODꢀH column, 98:2
hexane/IPA, detection wavelength λ = 254 nm, flow rate of 1 mL/min) retention times: 9.0 min
(minor isomer, 2.5%) and 20.8 min (major isomer, 97.5%).
(R)ꢀdibenzyl
1ꢀ(10ꢀbenzylꢀ2,2,13,13ꢀtetramethylꢀ11ꢀoxoꢀ3,3ꢀdiphenylꢀ4,12ꢀdioxaꢀ10ꢀazaꢀ3ꢀ
silatetradecanꢀ8ꢀyl)hydrazineꢀ1,2ꢀdicarboxylate (8b). column chromatography (90:10 petroleum
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ether/EtOAc); clear oil (1.99 g, 87%); [α]D +8.429 (c 0.22, CH2Cl2, 97% ee); H NMR
(DMSOꢀd6, 500 MHz, 80 °C) δ 7.58 (d, J = 6.4 Hz, 4H), 7.39 (m, 6H), 7.33ꢀ7.23 (m, 11H),
7.22ꢀ7.16 (m, 2H), 7.13 (s, 2H), 5.06 (s, 4H), 4.33 (s, 3H), 3.57 (d, J = 23.6 Hz, 2H), 3.20 (s,
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2H), 1.69 (s, 1H), 1.45 (s, 3H), 1.31 (s, 9H), 0.98 (s, 9H) ppm; C NMR (DMSOꢀd6, 125 MHz,
rotamers) δ 156.9, 156.1, 156.0, 138.9, 138.8, 136.8, 135.5, 134.2, 130.1, 128.8, 128.4, 128.2,
128.1, 127.6, 127.4, 79.9, 67.6, 66.8, 64.0, 50.9, 48.9, 29.4, 28.5, 27.3, 25.7, 19.3 ppm; IR (thin
film): 3302, 3067, 3032, 2959, 2930, 2856, 1755, 1718, 1676, 1496, 1426, 1392, 1337, 1248,
1208, 1140, 1111 cmꢀ1. HRMS (ESIꢀTOF) m/z: [M + H]+ calcd. for C49H60N3O7Si 830.4201,
found 830.4202, HPLC (Diacel ODꢀH column, 98:2 hexane/IPA, detection wavelength λ = 254
nm, flow rate of 1 mL/min) retention times: 15.7 min (minor isomer, 1.5%) and 21.6 min (major
isomer, 98.5%).
(R)ꢀdibenzyl
1ꢀ(11ꢀbenzylꢀ2,2,14,14ꢀtetramethylꢀ12ꢀoxoꢀ3,3ꢀdiphenylꢀ4,13ꢀdioxaꢀ11ꢀazaꢀ3ꢀ
silapentadecanꢀ9ꢀyl)hydrazineꢀ1,2ꢀdicarboxylate (8c). column chromatography (90:10 petroleum
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ether/EtOAc); clear oil (2.1 g, 90%); [α]D +14.262 (c 0.30, CH2Cl2, 98% ee); H NMR
(DMSOꢀd6, 500 MHz, 80 °C) δ 7.62 (d, J = 6.7 Hz, 4H), 7.48ꢀ7.37 (m, 6H), 7.31 (s, 11H), 7.21
(m, 4H), 5.09 (s, 4H), 4.57ꢀ4.07 (m, 3H), 3.60 (s, 2H), 3.22 (s, 1H), 1.47 (s, 4H), 1.35 (s, 9H),
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1.26 (s, 2H), 1.01 (s, 9H) ppm; 13C NMR (DMSOꢀd6, 125 MHz, rotamers) δ 155.9, 155.5, 136.9,
136.8, 135.5, 133.8, 130.2, 128.9, 128.7, 128.5, 128.3, 128.2, 127.5, 79.5, 67.3, 66.7, 63.9, 55.4,
50.7, 32.3, 28.7, 28.4, 27.1, 22.6, 19.3 ppm; IR (thin film): 3292, 3031, 2931, 2931, 2856, 1756,
1716, 1676, 1472, 1426, 1366, 1337, 1288, 1249, 1218, 1160, 1111 cmꢀ1. HRMS (ESIꢀTOF)
m/z: [M + NH4]+ calcd. for C50H65N4O7Si 861.4623, found 861.4627, HPLC (Diacel ODꢀH
column, 98:2 hexane/IPA, detection wavelength λ = 254 nm, flow rate of 1 mL/min) retention
times: 14.1 min (minor isomer, 1%) and 21.6 min (major isomer, 99%).
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Tertꢀbutyl
(R)ꢀbenzyl(2ꢀ(((benzyloxy)carbonyl)amino)ꢀ4ꢀ((tertꢀ
butyldiphenylsilyl)oxy)butyl)carbamate (9). To a stirred solution of 8a (1.10 g, 1.34 mmol) in
CH3OH (15 mL), RaneyꢀNi® (0.90 g, prewashed with absolute ethanol) and 0.1 mL of acetic acid
were added and the stirring was continued for 14 h at r. t. under a hydrogen atmosphere. The
reaction mixture was then filtered on a celite pad and concentrated under reduced pressure. The
crude amine was dissolved in THF (10 mL) and cooled to 0 °C. NaHCO3 (0.34 g, 4.02 mmol)
and benzyl chloroformate (50% solution in toluene 0.57 mL, 2.01 mmol) were added to the
solution. The reaction mixture was stirred for 5 h and then filtered, concentrated and purified by
column chromatography (80:20 petroleum ether/EtOAc) to get 9 as a colorless oil (0.696 g,
78%). [α]D25 +6.832 (c 0.44, CH2Cl2); 1H NMR (CDCl3, 500 MHz) δ = 7.62 (d, J = 6.7 Hz, 4H),
7.45ꢀ7.15 (m, 16H), 5.52 (s, 1H), 5.08 (s, 2H), 4.61 (d, J = 15.5 Hz, 1H), 4.44ꢀ4.20 (m, 1H), 4.04
(s, 1H), 3.76 (s, 1H), 3.68 (m, 1H), 3.56 (s, 1H), 3.14 (d, J = 10.4 Hz, 1H), 1.74 (s, 1H), 1.68 (s,
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1H), 1.42 (d, J = 25.5 Hz, 9H), 1.02 (s, 9H) ppm; C NMR (CDCl3, 100 MHz) δ 156.8, 156.4,
138.2, 136.8, 136.7, 135.6, 133.5, 133.4, 133.4, 133.3, 129.7, 128.5, 128.5, 127.9, 127.7, 127.3,
127.2, 80.2, 66.4, 61.0, 50.6, 49.3, 48.6, 35.3, 28.4, 26.8, 19.1 ppm; IR (thin film): 3340, 3068,
2959, 2931, 2857, 1720, 1696, 1514, 1497, 1454, 1427, 1392, 1365, 1248, 1168, 1111 cmꢀ1.
HRMS (ESIꢀTOF) m/z: [M + H]+ calcd. for C40H51N2O5Si 667.3567, found 667.3563.
(R)ꢀ4ꢀ(benzyl(tertꢀbutoxycarbonyl)amino)ꢀ3ꢀ(((benzyloxy)carbonyl)amino)butyl
methanesulfonate (10). To a stirred solution of 9 (0.70 g, 1.05 mmol) at 0 °C in dry THF (10
mL), TBAF (1 M solution in THF, 1.36 mL, 1.3 equiv.) was added and the reaction mixture was
stirred for 2 h. After the complete disappearance of starting material on TLC, the reaction was
quenched with saturated NH4Cl solution (12 mL) and the product was extracted with EtOAc (2 ×
20 mL) and dried over Na2SO4. Solvents were removed under reduced pressure and the alcohol
was purified through column chromatography (60:40 petroleum ether/EtOAc) to get tertꢀbutyl
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(R)ꢀbenzyl(2ꢀ(((benzyloxy)carbonyl)amino)ꢀ4ꢀhydroxybutyl)carbamate as an oil (0.404 g, 90%).
[α]D25 +16.455 (c 0.38, CH2Cl2); 1H NMR (CDCl3, 500 MHz) δ 7.41ꢀ7.11 (m, 10H), 5.92 (d, J =
6.6 Hz, 1H), 5.10 (d, J = 8.9 Hz, 2H), 4.66 (m, 1H), 4.23 (d, J = 15.7 Hz, 1H), 3.98 (d, J = 7.2
Hz, 1H), 3.74ꢀ3.56 (m, 3H), 2.91 (d, J = 12.2 Hz, 1H), 1.67 (s, 1H), 1.45 (d, J = 45.3 Hz, 10H)
ppm; 13C NMR (CDCl3, 100 MHz) δ 158.1, 157.5, 137.8, 136.6, 128.7, 128.5, 128.1, 127.9,
127.5, 127.2, 80.8, 66.8, 58.4, 51.0, 49.7, 48.1, 36.4, 28.3 ppm; IR (thin film): 3338, 3031, 2973,
2931, 1696, 1523, 1496, 1454, 1415, 1365, 1248, 1168 cmꢀ1. HRMS (ESIꢀTOF) m/z: [M + Na]+
calcd. for C24H32N2NaO5 451.2209, found 451.2209.
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To a stirred solution of the primary alcohol obtained as above (0.41 g, 0.95 mmol) in dry CH2Cl2
(5 mL) at 0 °C, triethylamine (0.26 mL, 1.86 mmol) and methanesulfonyl chloride (0.11 mL,
1.40 mmol) were added and the reaction mixture was stirred for 3 h. Reaction was monitored
through TLC and after the complete disappearance of the alcohol, reaction mixture was
quenched with saturated citric acid solution (5 mL), extracted with CH2Cl2 (3 × 10 mL) and
dried over Na2SO4. Solvents were removed under reduced pressure and the crude product was
purified through column chromatography (70:30 petroleum ether/EtOAc) to get 10 as a colorless
oil (0.435 g, 91%). [α]D25 +4.146 (c 0.58, CH2Cl2); 1H NMR (CDCl3, 500 MHz) δ 7.56ꢀ7.05 (m,
10H), 5.53 (d, J = 6.3 Hz, 1H), 5.07 (s, 2H), 4.60 (d, J = 15.2 Hz, 1H), 4.24 (d, J = 13.9 Hz, 3H),
3.95 (s, 1H), 3.72 – 3.53 (m, 1H), 3.11–2.95 (m, 1H), 2.93 (s, 3H), 1.89 (m, 1H), 1.80ꢀ1.68 (m,
1H), 1.45 (d, J = 44.1 Hz, 9H). ppm; 13C NMR (CDCl3, 125 MHz) δ 157.1, 156.7, 137.8, 136.6,
128.7, 128.5, 128.1, 127.9, 127.5, 127.3, 80.8, 67.1, 66.7, 50.9, 49.4, 47.9, 37.2, 33.0, 28.3 ppm;
IR (thin film): 3338, 3031, 2973, 2931, 1696, 1523, 1496, 1454, 1415, 1365, 1248, 1168 cmꢀ1.
HRMS (ESIꢀTOF) m/z: [M + NH4]+ calcd. for C25H38N3O7S 524.2430, found 524.2434.
Benzyl (R)ꢀ(1ꢀbenzylpyrrolidinꢀ3ꢀyl)carbamate (11). To a stirred solution of 10 (0.15 g, 0.30
mmol), trifluoroacetic acid (0.30 mL) in CH2Cl2 (4 mL) was added at 0 °C. After the complete
disappearance of the starting material on TLC, reaction mixture was concentrated under reduced
pressure and K2CO3 (0.06 g, 0.44 mmol) was added in CH3OH (3 mL) and stirred for 14 h. The
reaction mixture was filtered through a celite pad and the solvents were removed under reduced
pressure and the crude product was purified by column chromatography (40:60 petroleum
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ether/EtOAc). 11 was obtained as an oil (0.071 g, 78%). [α]D
̶ 3.006 (c 0.20, CH2Cl2); H
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NMR (CDCl3, 500 MHz) δ 7.33 (m, 8H), 7.31ꢀ7.26 (m, 2H), 5.34 (s, 1H), 5.08 (s, 2H), 4.28 (s,
1H), 3.66 (s, 2H), 2.92 (s, 1H), 2.72ꢀ2.60 (m, 2H), 2.38 (m, 1H), 2.29 (s, 1H), 1.70 (s, 1H) ppm;
13C NMR (CDCl3, 125 MHz) δ 155.8, 136.6, 129.0, 128.5, 128.5, 128.1, 127.5, 66.6, 60.5, 59.8,
52.5, 50.3, 32.4 ppm; IR (thin film): 3326, 3029, 2974, 2922, 2851, 1717, 1528, 1453, 1377,
1344, 1253 cmꢀ1. HRMS (ESIꢀTOF) m/z: [M + H]+ calcd. for C19H23N2O2 311.1760, found
311.1768.
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(R)ꢀ3ꢀaminopyrrolidine (2). To a stirred solution of 11 (0.120 g, 0.386 mmol) in CH3OH (5 mL),
Pd(OH)2/C (0.05 g) was added along with a few drops of acetic acid and the reaction and the
mixture was stirred for 14 h at r. t. under a hydrogen atmosphere. The reaction mixture was
filtered through celite pad and the solvents were removed under reduced pressure to get 2 as a
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wax (0.027 g, 82%). [α]D
̶
1.046 (c 0.46, CH3OH); 1H NMR (D2O, 500 MHz) δ 4.25ꢀ4.17 (m,
1H), 3.86 (m, 1H), 3.68ꢀ3.59 (m, 1H), 3.56ꢀ3.45 (m, 2H), 3.07 (s, 1H), 2.61 (m, 1H), 2.24 (m,
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1H) ppm; C NMR (D2O, 125 MHz) δ 48.7, 47.7, 44.6, 28.5 ppm; IR (thin film): 3429, 2987,
1600, 1476, 1446, 1401, 1295, 1245, 1224 cmꢀ1. HRMS (ESIꢀTOF) m/z: [M + H]+ calcd. for
C4H11N2 87.0922, found 87.0928.
Dibenzyl (R)ꢀ1ꢀ(1ꢀ(benzyl(tertꢀbutoxycarbonyl)amino)ꢀ5ꢀhydroxypentanꢀ2ꢀyl)ꢀ2λ2ꢀdiazaneꢀ1,2ꢀ
dicarboxylate (12a). To a stirred solution of 8b (1.21 g, 1.47 mmol) at 0 °C in dry THF (15 mL),
TBAF (1 M solution in THF, 1.91 mL, 1.3 equiv.) was added and the stirring was continued for
2 h. After the complete disappearance of 8b on TLC, the reaction was quenched with saturated
NH4Cl solution (15 mL) and the product was extracted with EtOAc (3 × 20 mL) and the solution
was dried over Na2SO4. Solvents were removed under reduced pressure and column
chromatography (60:40 petroleum ether/EtOAc) was performed to get 12a as colorless oil (0.80
g, 92%). [α]D25 +8.558 (c 0.20, CH2Cl2); 1H NMR (DMSOꢀd6, 500 MHz, 80 °C) δ 7.33 (s, 12H),
7.25 (d, J = 7.0 Hz, 1H), 7.18 (s, 2H), 5.10 (s, 4H), 4.35 (s, 3H), 4.07 (s, 1H), 3.36 (s, 2H), 3.20
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(s, 1H), 1.60 (s, 1H), 1.43 (s, 3H), 1.36 (s, 9H) ppm; C NMR (DMSOꢀd6, 125 MHz) δ 156.4,
155.9, 155.5, 139.0, 136.8, 128.9, 128.8, 128.5, 128.4, 128.2, 127.8, 127.6, 127.5, 79.6, 67.8,
67.4, 66.7, 61.0, 50.7, 47.9, 29.7, 28.4, 25.7 ppm; IR (thin film): 3503, 3288, 3032, 2974, 1752,
1714, 1672, 1496, 1478, 1420, 1366, 1338, 1249, 1162 cmꢀ1. HRMS (ESIꢀTOF) m/z: [M + H]+
calcd. for C33H42N3O7 592.3023, found 592.3027.
12b was prepared from 8c using the same procedure.
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Dibenzyl
(R)ꢀ1ꢀ(1ꢀ(benzyl(tertꢀbutoxycarbonyl)amino)ꢀ6ꢀhydroxyhexanꢀ2ꢀyl)ꢀ2λ2ꢀdiazaneꢀ1,2ꢀ
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dicarboxylate (12b). Column chromatography (60:40 petroleum ether/EtOAc); clear oil (0.675 g,
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92%); [α]D +5.980 (c 0.30, CH2Cl2); H NMR (DMSOꢀd6, 500 MHz, 80 °C) δ 7.45ꢀ7.06 (m,
15H), 5.10 (s, 4H), 4.35 (s, 3H), 4.06 (s, 1H), 3.35 (s, 2H), 3.21 (s, 1H), 1.49ꢀ1.24 (m, 15H) ppm;
13C NMR (DMSOꢀd6, 125 MHz) δ 156.4, 155.9, 155.5, 136.9, 136.8, 136.7, 128.9, 128.8, 128.5,
128.2, 128.1, 128.0, 127.8, 127.7, 127.6, 127.5, 80.0, 79.6, 67.7, 67.3, 66.7, 61.1, 50.8, 32.9,
28.9, 28.4, 22.7 ppm; IR (thin film): 3503, 3290, 3064, 3032, 2968, 2932, 1753, 1715, 1674,
1496, 1478, 1420, 1366, 1339, 1284, 1224, 1137 cmꢀ1. HRMS (ESIꢀTOF) m/z: [M + H]+ calcd.
for C34H44N3O7 606.3179, found 606.3171.
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Dibenzyl (R)ꢀ1ꢀ(1ꢀ(benzyl(tertꢀbutoxycarbonyl)amino)ꢀ5ꢀ((methylsulfonyl)oxy)pentanꢀ2ꢀyl)ꢀ2λ2ꢀ
diazaneꢀ1,2ꢀdicarboxylate (13a). To a solution of 12a (0.78 g, 1.31 mmol) in dry CH2Cl2 (10
mL) at 0 °C, triethylamine (0.36 mL, 2.62 mmol) and methanesulfonyl chloride (0.15 mL, 1.97
mmol) were added and the reaction mixture was stirred for 3 h. Reaction was monitored through
TLC and after the complete disappearance of 12a, reaction was quenched with saturated citric
acid solution (10 mL), product was extracted with CH2Cl2 (3 × 20 mL) and dried over Na2SO4.
Solvents were removed under reduced pressure and the crude product was purified further
through column chromatography (70:30 petroleum ether/EtOAc) to get 13a as oil (0.790 g,
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90%). [α]D
̶ 0.594 (c 0.24, CH2Cl2); H NMR (DMSOꢀd6, 500 MHz, 80 °C) δ 7.45ꢀ7.09 (m,
15H), 5.12 (s, 4H), 4.37 (s, 3H), 4.13 (s, 2H), 3.26 (s, 2H), 3.09 (s, 3H), 1.89 (s, 1H), 1.66 (s,
1H), 1.48 (s, 2H), 1.38 (s, 9H) ppm; 13C NMR (DMSOꢀd6, 125 MHz) δ 156.5, 155.9, 155.5,
138.9, 136.7, 128.9, 128.8, 128.6, 128.6, 128.4, 128.3, 127.9, 127.9, 127.8, 127.6, 127.5, 127.4,
80.3, 70.8, 67.5, 66.9, 55.2, 50.6, 47.9, 37.0, 28.4, 28.4, 28.3, 25.3, 25.0 ppm; IR (thin film):
3285, 3032, 2974, 1752, 1716, 1672, 1496, 1478, 1420, 1353, 1296, 1247, 1057 cmꢀ1. HRMS
(ESIꢀTOF) m/z: [M + NH4]+ calcd. for C34H47N4O9S 687.3064, found 687.3060.
13b was prepared from 12b using the same procedure.
Dibenzyl (R)ꢀ1ꢀ(1ꢀ(benzyl(tertꢀbutoxycarbonyl)amino)ꢀ6ꢀ((methylsulfonyl)oxy)hexanꢀ2ꢀyl)ꢀ 2λ2ꢀ
diazaneꢀ1,2ꢀdicarboxylate (13b). Column chromatography (70:30 petroleum ether/EtOAc); oil
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(1.292 g, 88%); [α]D +0.363 (c 0.38, CH2Cl2); 1H NMR (DMSOꢀd6, 500 MHz, 80 °C) δ 7.44ꢀ
7.07 (m, 15H), 5.11 (s, 4H), 4.35 (s, 3H), 4.12 (s, 2H), 3.24 (s, 2H), 3.10 (s, 3H), 1.59 (s, 2H),
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1.46 (d, J = 10.0 Hz, 2H), 1.37 (s, 9H), 1.27 (m, 2H) ppm; C NMR (DMSOꢀd6, 125 MHz) δ
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156.4, 156.4, 136.8, 136.8, 136.7, 128.9, 128.8, 128.5, 128.3, 127.9, 127.8, 127.6, 127.5, 79.6,
70.8, 67.8, 67.4, 66.8, 60.2, 55.4, 50.8, 37.1, 28.9, 28.4, 22.3, 21.2, 14.6 ppm; IR (thin film):
3287, 3031, 2936, 2932, 1753, 1715, 162, 1496, 1467, 1420, 1353, 1289, 1220, 1028 cmꢀ1.
HRMS (ESIꢀTOF) m/z: [M + NH4]+ calcd. for C35H49N4O9S 701.3220, found 701.3222.
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tꢀButyl (R)ꢀ2ꢀ((benzyl(tertꢀbutoxycarbonyl)amino)methyl)pyrrolidineꢀ1ꢀcarboxylate (14a). To a
solution of 13a (1.25 g, 1.86 mmol) in CH3OH (20 mL), RaneyꢀNi® (1.30 g, prewashed with
absolute ethanol) was added followed by 0.10 mL of acetic acid and stirred for 14 h at r. t. under
a hydrogen atmosphere. The reaction mixture was then filtered through a celite pad and the
solution was concentrated under reduced pressure. The crude product was dissolved in THF (10
mL) and NaHCO3 (0.408 g, 4.86 mmol) and (Boc)2O (0.55 mL, 2.43 mmol) were added to the
solution. The reaction mixture was stirred for 5 h and then filtered, concentrated and purified by
column chromatography (90:10 petroleum ether/EtOAc) to get 14a as a white solid (0.55 g,
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76%). [α]D
̶ 2.377 (c 0.24, CH2Cl2); m.p.: 89 °C; H NMR (CDCl3, 500 MHz,) δ 7.30 (d, J =
4.3 Hz, 2H), 7.24 (s, 2H), 7.18 (s, 1H), 4.64ꢀ4.34 (m, 2H), 3.96 (d, J = 54.6 Hz, 1H), 3.63ꢀ3.06
(m, 4H), 1.94 (s, 1H), 1.84 (s, 3H), 1.52ꢀ1.36 (m, 18H) ppm; 13C NMR (CDCl3, 125 MHz) δ
156.3, 154.5, 128.5, 128.3, 127.4, 127.1, 126.7, 80.0, 79.7, 55.5, 50.9, 50.0, 46.2, 28.7, 28.6,
28.4, 28.3, 23.6, 22.7 ppm; IR (thin film): 2974, 2931, 2862, 1693, 1496, 1478, 1454, 1392,
1365, 1343, 1251, 1162, 1111 cmꢀ1. HRMS (ESIꢀTOF) m/z: [M + H]+ calcd. for C22H35N2O4
391.2597, found 391.2598.
14b was prepared from 13b using the same procedure.
tꢀButyl (R)ꢀ2ꢀ((benzyl(tertꢀbutoxycarbonyl)amino)methyl)piperidineꢀ1ꢀcarboxylate (14b). column
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chromatography (90:10 petroleum ether/EtOAc); white solid (0.363 g, 77%); [α]D +4.600 (c
1
0.24, CH2Cl2); m.p.: 97 °C; H NMR (DMSOꢀd6, 500 MHz, 80 °C) δ 7.34 (t, J = 7.5 Hz, 2H),
7.28ꢀ7.18 (m, 3H), 4.44ꢀ4.32 (m, 3H), 3.87 (d, J = 13.0 Hz, 1H), 3.48 (s, 1H), 3.21ꢀ3.12 (m, 1H),
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2.87 (t, J = 12.7 Hz, 1H), 1.52 (s, 4H), 1.41 (d, J = 10.6 Hz, 20H) ppm; C NMR (DMSOꢀd6,
125 MHz): δ 155.3, 154.5, 139.1, 128.9, 128.9, 127.7, 127.5, 127.4, 79.0, 78.9, 49.0, 45.3, 45.2,
28.6, 28.4, 25.5, 19.5, 19.4 ppm; IR (thin film): 2975, 2933, 2865, 1693, 1495, 1476, 1453, 1391,
1365, 1340, 1271, 1246, 1161, 1104 cmꢀ1. HRMS (ESIꢀTOF) m/z: [M + H]+ calcd. for
C23H37N2O4 405.2753, found 405.2755.
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(R)ꢀ2ꢀaminomethylpyrrolidine (3). 4N HCl in EtOAc (1.5 mL) was added to 14a (0.14 g, 0.36
mmol) and the solution was stirred for 1 h. After the complete disappearance of the starting
material on TLC, the solvent was decanted carefully and the crude product was washed with
EtOAc (3 × 5 mL). The solution was concentrated (to approximately 3 mL) and NaHCO3 (0.08 g,
0.95 mmol) was added and the mixture was stirred for 10 min to neutralize any residual acids
present. The solids were filtered off and the solution was concentrated and the residue was
dissolved in CH3OH (4 mL). The solution was stirred with 10% Pd/C (0.05 g) for 14 h in a
hydrogen atmosphere at r. t., filtered through a celite pad and the solvents were removed under
reduced pressure to get 3 as a clear oil (0.030 g, 86%). [α]D25 +5.034 (c 0.34, CH3OH); 1H NMR
(D2O, 500 MHz) δ 4.00ꢀ3.89 (m, 1H), 3.55ꢀ3.35 (m, 4H), 2.39 (m, 1H), 2.23ꢀ2.14 (m, 1H), 2.13ꢀ
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2.04 (m, 1H), 1.86 (m, 1H); C NMR (D2O, 125 MHz) δ 57.1, 46.0, 39.8, 28.2, 22.8; IR (thin
film): 2974, 2931, 1693, 1496, 1478, 1454, 1392, 1365, 1343, 1251, 1162, 1111 cmꢀ1. HRMS
(ESIꢀTOF) m/z: [M + H]+ calcd. for C5H13N2 101.1079, found 101.1076.
(R)ꢀ2ꢀaminomethylpiperidine (4). 4 was prepared from 14b using the same procedure that was
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used for the preparation of 3 from 14a. Oil (0.05 g, 82%); [α]D +1.380 (c 0.60, CH3OH); H
NMR (D2O, 500 MHz) δ 3.53 (d, J = 11.3 Hz, 1H), 3.49 (d, J = 2.1 Hz, 1H), 3.35 (m, 1H), 3.24
(m, 1H), 3.06 (m, 1H), 2.09 (d, J = 9.3 Hz, 1H), 1.92 (d, J = 15.3 Hz, 2H), 1.75ꢀ1.64 (m, 1H),
13
1.63ꢀ1.50 (m, 2H); C NMR (D2O, 125 MHz) δ 53.8, 45.2, 41.1, 26.0, 21.4, 20.9 ppm; IR (thin
film): 2974, 2931, 1693, 1496, 1478, 1454, 1392, 1365, 1343, 1251, 1162, 1111 cmꢀ1. HRMS
(ESIꢀTOF) m/z: [M + H]+ calcd. for C6H15N2 115.1235, found 115.1238.
(R)ꢀ2ꢀ((tertꢀbutyldimethylsilyl)oxy)ꢀ1ꢀ((4S,5S)ꢀ2,2ꢀdimethylꢀ5ꢀ(3ꢀoxopropyl)ꢀ1,3ꢀdioxolanꢀ4ꢀ
yl)ethyl methanesulfonate (16). To a stirred solution of the α,βꢀunsaturated ester 15 (1.50 g, 4.01
mmol) in CH3OH (30 mL), Pd/C (0.10 g) was added and the reaction was stirred for 1 h at r. t.
under a hydrogen atmosphere. The reaction mixture was filtered through a celite pad and the
solvents were removed under reduced pressure. The crude product was dissolved in dry CH2Cl2
(30 mL) and at 0 °C, triethyl amine (1.09 mL, 7.85 mmol) and methane sulfonyl chloride (0.45
mL, 5.88 mmol) were added and the reaction mixture was stirred for 2 h. After complete
disappearance of the alcohol, reaction was quenched with citric acid solution (15 mL), extracted
with CH2Cl2 (3 x 20 mL) and dried over Na2SO4. Solvents were removed under reduced pressure
and the compound was purified through column chromatography (90:10 petroleum ether/EtOAc)
to get the mesyl derivative (1.63 g, 90%). The mesyl derivative (1.63 g, 3.59 mmol) was
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dissolved in dry CH2Cl2, at ꢀ78 °C and DIBALꢀH (1 M solution in toluene, 5.38 mL, 1.5 equiv.)
was added and the reaction mixture was stirred for 0.5 h. Reaction was monitored through TLC
and after the complete disappearance of the ester, it was quenched with saturated NH4Cl (15 mL)
and the product was extracted with CH2Cl2 (3 x 20 mL) and was dried over Na2SO4. Solvents
were removed under reduced pressure and the aldehyde was purified through column
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chromatography (85:15 petroleum ether/EtOAc) to give an aldehyde (1.13 g, 77%). [α]D
+6.666 (c 0.30, CH2Cl2); 1H NMR (CDCl3, 500 MHz) δ 9.79 (s, 1H), 4.72 (m, 1H), 4.26 (dd, J =
7.3, 5.9 Hz, 1H), 4.19 (m, 1H), 4.04 (dd, J = 12.1, 2.3 Hz, 1H), 3.89 (dd, J = 12.1, 5.4 Hz, 1H),
3.13 (s, 3H), 2.64 (q, J = 7.0 Hz, 2H), 2.08 (m, 1H), 1.87 (m, 1H), 1.39 (s, 3H), 1.30 (s, 3H), 0.90
(s, 9H), 0.09 (s, 3H), 0.09 (s, 3H) ppm; 13C NMR (CDCl3, 100 MHz) δ 201.7, 108.6, 81.1, 76.4,
75.0, 62.8, 40.7, 39.4, 27.8, 25.9, 25.4, 22.5, 18.4, ꢀ5.3, ꢀ5.4 ppm; IR (thin film): 2986, 2954,
2858, 1725, 1463, 1413, 1359, 1255, cmꢀ1. HRMS (ESIꢀTOF) m/z: [M + NH4]+ calcd. for
C17H38NO7SSi 428.2138, found 428.2136.
dibenzyl
1ꢀ((R)ꢀ1ꢀ(benzyl(tertꢀbutoxycarbonyl)amino)ꢀ3ꢀ((4S,5S)ꢀ5ꢀ((R)ꢀ2ꢀ((tertꢀ
butyldimethylsilyl)oxy)ꢀ1ꢀ((methylsulfonyl)oxy)ethyl)ꢀ2,2ꢀdimethylꢀ1,3ꢀdioxolanꢀ4ꢀyl)propanꢀ2ꢀ
yl)hydrazineꢀ1,2ꢀdicarboxylate (17). 17 was prepared from 16 using the same procedure that was
used for the preparation of 8 from 7. column chromatography (85:15 petroleum ether/EtOAc);
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clear oil (1.30 g, 71%); [α]D + 10.082 (c 0.21, CH2Cl2, 90:10 dr); H NMR (DMSOꢀd6, 400
MHz, 80 °C) δ 7.36 – 7.17 (m, 13H), 7.13 (s, 2H), 5.07 (s, 4H), 4.64 – 4.07 (m, 6H), 3.90 (d, J =
11.9 Hz, 1H), 3.79 (dd, J = 11.5, 5.1 Hz, 1H), 3.27 (bs, 1H), 3.12 (s, 1H), 3.07 (s, 3H), 1.93 (s,
1H), 1.73 (s, 1H), 1.45 (s, 3H), 1.32 (s, 9H), 1.21 (s, 3H), 0.85 (d, J = 4.4 Hz, 9H), 0.03 (s, 6H)
ppm; 13C NMR (DMSOꢀd6, 100 MHz, rotamers) δ 155.6, 155.5, 146.7, 138.7, 136.7, 128.9,
128.8, 128.5, 128.4, 128.3, 127.5, 127.4, 127.1, 126.9, 112.3, 108.0, 103.4, 86.8, 86.1, 84.0, 81.5,
81.2, 80.3, 79.8, 75.3, 73.8, 70.2, 67.7, 67.6, 67.3, 67.0, 62.7, 50.5, 37.3, 31.8, 28.7, 28.3, 27.8,
27.3, 26.6, 18.5, ꢀ5.0 ppm; IR (thin film): 3290, 3065, 2930, 2856, 1715, 1677, 1472, 1454,
1424, 1392, 1366, 1252, 1218, 1174 cmꢀ1. HRMS (ESIꢀTOF) m/z: [M ꢀ H]+ calcd. for
C45H64N3O12SSi 898.3980, found 898.3989, HPLC (Diacel IC column, 90:10 hexane/IPA,
detection wavelength λ = 250 nm, flow rate of 1 mL/min) retention times: 8.4 min (major
isomer, 90%) and 16.3 min (minor isomer, 10%).
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tertꢀbutyl
benzyl(((3aR,4S,6R,7aS)ꢀ4ꢀ(((tertꢀbutyldimethylsilyl)oxy)methyl)ꢀ2,2ꢀ
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dimethylhexahydroꢀ[1,3]dioxolo[4,5ꢀc]pyridinꢀ6ꢀyl)methyl)carbamate (18). To a stirred solution
of 17 (1.30 g, 1.44 mmol) in CH3OH (30 mL), RaneyꢀNi® (1.00 g, prewashed with absolute
ethanol) and 0.10 mL of acetic acid were added and the reaction mixture was stirred for 14 h at r.
t. under a hydrogen atmosphere. The reaction mixture was filtered through a celite pad and
concentrated under reduced pressure, the crude mixture obtained was dissolved in CH3OH (20
mL) and K2CO3 (0.39 g, 2.88 mmol) was added. The mixture was refluxed for 3 h and was
filtered through a celite pad and the solvents were removed under reduced pressure. The crude
product obtained was purified through column chromatography (80:20 petroleum ether/EtOAc)
to get 18 as a colorless oil (0.63 g, 84%). [α]D25 ꢀ10.031 (c 0.42, CH2Cl2); 1H NMR (CDCl3, 400
MHz) δ 7.32 – 7.26 (m, 2H), 7.21 (dd, J = 13.4, 5.9 Hz, 3H), 4.72 – 4.53 (m, 1H), 4.45 (dd, J =
16.9, 7.9 Hz, 2H), 4.23 (dd, J = 7.7, 1.9 Hz, 1H), 3.54 (m, 2H), 3.30 (d, J = 31.7 Hz, 2H), 3.16 –
2.92 (m, 2H), 2.82 (d, J = 18.4 Hz, 1H), 1.83 (d, J = 16.2 Hz, 1H), 1.59 (s, 1H), 1.47 (s, 3H),
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1.45 (s, 3H), 1.40 (s, 6H), 1.31 (s, 3H), 0.88 (s, 9H), 0.05 (d, J = 0.9 Hz, 6H) ppm; C NMR
(CDCl3, 100 MHz) δ 156.2, 128.5, 127.8, 127.2, 127.1, 107.8, 79.8, 71.7, 71.6, 63.6, 52.3, 51.5,
51.2, 46.5, 46.3, 28.5, 26.5, 26.0, 24.2, 18.4, ꢀ5.2, ꢀ5.3 ppm; IR (thin film): 3330, 2929, 2857,
1696, 1495, 1462, 1365, 1249, 1164, cmꢀ1. HRMS (ESIꢀTOF) m/z: [M + H]+ calcd. for
C28H49N2O5Si 521.3411, found 521.3414.
(2S,3R,4S,6R)ꢀ6ꢀ((benzylammonio)methyl)ꢀ3,4ꢀdihydroxyꢀ2ꢀ(hydroxymethyl)piperidinꢀ1ꢀium
chloride (19). 4N HCl in EtOAc (5 mL) was added to 18 (0.30 g, 0.57 mmol) at 0 °C and the
reaction mixture was stirred for 24 h at r. t. The reaction mixture was concentrated under reduced
pressure and the solid was washed with EtOAc (5 x 3 mL) and dried under reduced pressure to
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get 19 as a wax (0.17 g, 87%). [α]D ꢀ18.750 (c 0.16, CH3OH); H NMR (D2O, 400 MHz) δ
7.36 (d, J = 7.1 Hz, 5H), 4.20 (s, 2H), 3.96 (d, J = 13.3 Hz, 2H), 3.89 – 3.82 (m, 1H), 3.75 (m,
13
2H), 3.49 – 3.37 (m, 3H), 2.17 – 2.06 (m, 1H), 1.89 – 1.81 (m, 1H) ppm; C NMR (D2O, 100
MHz) δ 130.0, 129.9, 129.8, 129.3, 65.6, 63.8, 58.8, 56.2, 52.0, 48.9, 45.5, 27.0 ppm; IR (thin
film): 3390, 2958, 2795, 1619, 1457, 1446 cmꢀ1. HRMS (ESIꢀTOF) m/z: [M + H]+ calcd. for
C14H23N2O3 267.1709, found 267.1700.
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(2S,3R,4S,6R)ꢀ6ꢀ(ammoniomethyl)ꢀ3,4ꢀdihydroxyꢀ2ꢀ(hydroxymethyl)piperidinꢀ1ꢀium
chloride
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(20). To a solution of 19 (0.10 g, 0.29 mmol) in CH3OH (3 mL), Pd/C (0.020 g) was added and
the reaction mixture was stirred for 20 h at r. t. under a hydrogen atmosphere. The reaction
mixture was filtered through a celite pad and the solvents were removed under reduced pressure
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to get 20 as a wax (0.66 g, 91%). [α]D ꢀ9.328 (c 0.16, CH3OH); H NMR (D2O, 500 MHz) δ
3.95 (s, 1H), 3.91 (d, J = 10.7 Hz, 1H), 3.85 (d, J = 4.4 Hz, 1H), 3.78 – 3.73 (m, 2H), 3.39 – 3.29
(m, 3H), 2.15 – 2.04 (m, 1H), 1.85 (d, J = 14.4 Hz, 1H) ppm; 13C NMR (D2O, 125 MHz) δ 66.0,
64.1, 59.3, 55.9, 49.4, 38.3, 26.9 ppm; IR (thin film): 3390, 2922, 2852, 1457 cmꢀ1. HRMS (ESIꢀ
TOF) m/z: [M + H]+ calcd. for C7H16N2O3 177.1239, found 177.1700.
ASSOCIATED CONTENT
Supporting Information
The Supporting Information is available free of charge on the ACS Publications website
1H and 13C spectra for all the compounds
HPLC data for 6a, 8a, 8b and 8c
AUTHOR INFORMATION
Corresponding Author
*Eꢀmail: rameshr@iitk.ac.in
ORCID
R. Ramapanicker: 0000ꢀ0002ꢀ7717ꢀ6843
Notes
The authors declare no competing financial interest.
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ACKNOWLEDGEMENTS
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We thank Prof. Manas K. Ghorai for the chiral HPLC facility that was essential for the
completion of this work. AA thanks Council of Scientific and Industrial Research (India), New
Delhi for a Senior Research Fellowship.
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F. E. Enantioselective PalladiumꢀCatalyzed Diamination of Alkenes Using Nꢀ
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Rosewall, C. F.; Swartz, R. D.; Michael, F. E. Mechanism of NꢀFluorobenzenesulfonimide
Promoted Diamination and Carboamination Reactions: Divergent Reactivity of a Pd(IV) Species.
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(4) For Cu(I) and Cu(II)ꢀCatalyseddiamination reactions, see: (a) Wang, Y.ꢀF.; Zhu, X.; Chiba,
S. CopperꢀCatalyzed Aerobic [3+2]ꢀAnnulation of NꢀAlkenyl Amidines. J. Am. Chem. Soc.
2012, 134, 3679−3682. (b) Zhang, H. W.; Pu, W. Y.; Xiong, T.; Li, Y.; Zhou, X.; Sun, K.; Liu,
Q.; Zhang, Q. CopperꢀCatalyzed Intermolecular Aminocyanation and Diamination of Alkenes.
Angew. Chem., Int. Ed. 2013, 52, 2529−2533. (c) Turnpenny, B. W.; Chemler, S. R. Copperꢀ
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catalyzed alkene diamination: synthesis of chiral 2ꢀaminomethyl indolines and pyrrolidines.
Chem. Sci. 2014, 5, 1786−1793. (d) Wen, Y.; Zhao, B.; Shi, Y. Cu(I)ꢀCatalyzed Diamination of
Disubstituted Terminal Olefins: An Approach to Potent NK1 Antagonist. Org. Lett. 2009, 11,
2365−2368. (e) Zhao, B. G.; Yuan, W. C.; Du, H. F.; Shi, Y. A. Cu(I)ꢀCatalyzed Intermolecular
Diamination of Activated Terminal Olefins. Org. Lett. 2007, 9, 4943−4945.
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