Modular access to N-substituted cis-3,5-diaminopiperidines

Article abstract of DOI:10.1021/jo401994y

A sequence of oxidative cleavage/reductive amination/hydrogenolysis enables the preparation of N-substituted cis-3,5-diaminopiperidines from a readily available bicyclic hydrazine. This new synthetic route provides a simple and general access to RNA-friendly fragments with a good chemical diversity.

Full text of DOI:10.1021/jo401994y

Note
pubs.acs.org/joc
Modular Access to N‑Substituted cis-3,5-Diaminopiperidines
́
Aurelie Blond, Paul Dockerty, Raquel Alvarez, Serge Turcaud, Thomas Lecourt, and Laurent Micouin*
́
Laboratoire de Chimie et de Biochimie Pharmacologiques et Toxicologiques, Faculte
́ ́
des Sciences Fondamentales et Biomedicales,
UMR8601, CNRS-Paris Descartes University, 45 rue des Saints Peres, 75006 Paris, France
̀
S
* Supporting Information
ABSTRACT: A sequence of oxidative cleavage/reductive amination/
hydrogenolysis enables the preparation of N-substituted cis-3,5-
diaminopiperidines from a readily available bicyclic hydrazine. This
new synthetic route provides a simple and general access to RNA-
friendly fragments with a good chemical diversity.
he design of small molecular RNA ligands is a growing
with 4-methoxybenzylamine led to the expected product 7a in
1
Tfield since the recent understanding of the key role of 82% yield. An alternative strategy is to conduct an ozonolysis of
RNA in many cellular regulation processes.2 Among the
compound 5, followed by the reductive amination. Using this
procedure, compound 7a was obtained in 76% overall yield.
Beside a better yield, this pathway avoids the use of osmium
salts and aqueous conditions for the oxidative cleavage. In both
cases, all attempts to isolate in good yield the bis-aldehyde
intermediate failed. The scope of this double amination
reaction is rather large, as exemplified in Scheme 1. Aliphatic
(7a−e) or aromatic (7f−j) amines but also diamines (7m)
provide moderate to good yields for this transformation.
Interestingly, this method enables the introduction of a
stereogenic center α to the piperidine nitrogen without
racemization (compounds 7k,l).9
different strategies used to design such ligands, one of the
most successful is to build libraries from a ″RNA friendly″ small
molecular scaffold.3 This approach has been recently illustrated
by the group of Hermann, who showed that the cis-3,5-
diaminopiperidine moiety 1 can lead either to antibacterial
compounds 2 targeting the 16S bacterial rRNA4 or binders of
hepatitis C virus internal ribosome entry site (IRES) 3 with
antiviral properties (Figure 1).5
As a structural mimetic of 2-deoxystreptamine (DOS), the
central core of aminoglycosides, the meso cis-3,5-diaminopiper-
idine scaffold is indeed a very simple and cleverly designed
building block, which enables the preparation of libraries by
functionalization of the piperidine nitrogen atom. However, as
recognized by the authors themselves,5 the access to the
protected building block 4, obtained in 3 steps from 2-chloro-
3,5-dinitropyridine in 38% yield, is hampered by a problematic
high-pressure hydrogenation step. Furthermore, the selective
functionalization of the piperidine nitrogen in the presence of
the two NHBoc functional groups can also be expected to be
problematic under certain experimental conditions. Herein, we
describe a general approach for the preparation of diversely N-
substituted cis-3,5-diaminopiperidines that can overcome these
synthetic limitations.
In our ongoing work on the fragment-based design of small
molecular RNA binders, we have shown that bicyclic hydrazine
5 is a powerful building block for the preparation of substituted
cis-1,3-diaminocyclopentanes.6 As a Diels−Alder adduct, this
heterocycle is routinely prepared on a large scale (30−40g) and
obtained in a quantitative yield by a simple precipitation.7 The
large availability of this starting material prompted us to
investigate the access to cis-3,5-diaminopiperidines by an
oxidative cleavage-reductive amination sequence8 that would
deliver a direct precursor of compounds 1 after hydrogenolysis
(Scheme 1).
As the double reductive amination cannot be conducted with
amides, access to acylated triazabicyclo[3,2,1]octanes was
investigated. Compound 7n, prepared in 54% yield from 5
using pathway B, was deprotected to provide compound 8. This
bicyclic heterocycle can be functionalized by acylation, peptidic
coupling, or carbamoylation (Scheme 2).
The reductive cleavage and deprotection of bicyclic
compounds was conducted under hydrogen atmosphere using
Pd or Pt. Experimental conditions had to be tuned in order to
avoid catalyst poisoning by some final polyamines or the over-
reduction of heteroaromatic rings. In most of the cases, the final
diamines could be obtained in good to quantitative yields
(Scheme 3).
Finally, our strategy can also provide a simple access to the
building block 4 in 58% from compound 13a (Scheme 4). This
synthetic route allows the preparation of Hermann’s
intermediate 4 from cyclopentadiene in six steps and 44%
overall yield with only two column purification steps. Although
this route is longer than the three-step synthesis of Hermann,
the overall yield is in the same range and this method avoids the
high-pressure hydrogenation step.
In summary, we have established a simple and general access
to N-substituted cis-3,5-diaminopiperidines in 3−5 steps
starting from a readily available precursor. The functional
The preparation of triazabicyclo[3,2,1]octane 7a (Scheme 1)
was first investigated using a two-step approach. Dihydrox-
ylation of compound 5 led to bicyclic hydrazine 6 in 86% yield.
Oxidative cleavage followed by a double reductive amination
Received: September 11, 2013
Published: October 30, 2013
© 2013 American Chemical Society
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Note
Figure 1. Selected examples of diaminopiperidines.
a
Scheme 1. Synthetic Pathways for the Preparation of Compounds 7
a
Reagents and conditions: (a) K2OsO4·2H2O (0.8%), NMO (1.2 equiv), THF/H2O 90:10, 18 h, 86%. (b) (i) NaIO4 (2.3 equiv), MeOH/H2O or
NaIO4 (1.4 equiv), SiO2/H2O/CH2Cl2; (ii) RNH2, NaBH(OAc)3, AcOH, CH2Cl2, 3−22 h. (c) (i) O3, Me2S, CH2Cl2, −78 °C; (ii) RNH2,
NaBH(OAc)3, AcOH, CH2Cl2, 3−22 h. *Obtained with pathway B.
until disappearance of the initial product. The reaction mixture was
filtered on a sintered glass packed with Na2SO4, concentrated, and
dissolved in CH2Cl2 (7 mL). 4-Methoxybenzylamine (217 mg, 1.58
mmol) was added, followed by NaBH(OAc)3 (915 mg, 4.32 mmol)
and acetic acid (0.15 mL). After stirring for 16 h at room temperature,
the reaction was quenched with saturated aqueous NaHCO3 and
extracted with CH2Cl2, and the combined organic layers were dried
over MgSO4, filtered, and concentrated. Flash chromatography
(CH2Cl2/ethyl acetate 95:5) afforded 7a (592 mg, 1.18 mmol, 82%).
Dibenzyl 3-(4-Methoxybenzyl)-3,6,7-triazabicyclo[3.2.1]-
group tolerance of the key reductive amination step enables the
introduction of a broad chemical diversity. We have also shown
that Hermann’s key intermediate can be obtained using this
strategy, without any high pressure reduction step. The access
to the polypiperidine skeleton such as 13i through an iterative
synthesis is also noteworthy.
EXPERIMENTAL SECTION
■
Representative Preparation of 7a (Pathway A, Using NaIO4
on Silica). To a vigorously stirred suspension of silica (3.1 g) in
CH2Cl2 (49 mL) was added a 0.65 M aqueous solution of NaIO4 (3
mL, 1.95 mmol) dropwise. Diol 66d,f (574 mg, 1.44 mmol) in CH2Cl2
(47 mL) was then added, and the reaction was monitored by TLC
1
octane-6,7-dicarboxylate 7a. Colorless oil; H NMR (300 MHz,
(CD3)2SO, 72 °C) δ 1.85 (s, 2H), 2.15 (d, J = 10.9 Hz, 2H), 3.06 (br
s, 2H), 3.41 (s, 2H), 3.72 (s, 3H), 4.35 (br s, 2H), 5.11 (AB system,
Δδ = 0.07, J = 12.6 Hz, 4H), 6.81 (d, J = 8.2 Hz, 2H), 7.12 (d, J = 8.2
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Note
a
Scheme 2. Synthetic Pathways for the Preparation of Acylated Triazabicyclo[3,2,1]octanes
a
Reagents and conditions: (a) Pd(PPh3)4 (1%), 1,3-dimethylbarbituric acid (3 equiv), CH2Cl2, reflux, 5 h. (b) RCOCl (1.5 equiv), Et3N (3 equiv),
1,2-dichloroethane, reflux. (c) Boc2O (1.1 equiv), Et3N (1.1 equiv), CH2Cl2, 2 h. (d) Boc-Lys(Z)-OH (1.1 equiv), EDC (1.5 equiv), Et3N (7 equiv),
CH2Cl2, 5 h.
a
Scheme 3. Preparation of N-Substituted Diaminopiperidines
a
Reagents and conditions: (a) Method A, H2, Pd/C 10%, MeOH. Method B, H2, Pd/C 10%, Pd black, MeOH. Method C, H2, Pd/C 10%, Pd black,
MeOH/HCl. Method D, H2, PtO2, AcOH.
Hz, 2H), 7.32 (s, 10H); 13C NMR (75 MHz, (CD3)2SO, 75 °C) δ
36.1, 54.9, 55.6, 56.4, 60.2, 67.4, 114.1, 127.9, 128.2, 128.7, 130.1,
136.8, 157.0, 159.0; HRMS (ESI-TOF) [M + H]+ calcd for
C29H32N3O5 502.2342, found 502.2331.
J = 8.1 Hz, 1H), 6.76 (s, 1H), 6.82 (d, J = 8.1 Hz, 1H), 7.29−7.34 (m,
10H); 13C NMR (75 MHz, (CD3)2SO, 70 °C) δ 32.7, 36.2, 55.2, 56.3,
56.5, 58.4, 67.3, 113.4, 113.9, 121.0, 127.9, 128.2, 128.5, 133.6, 137.0,
148.0, 149.6, 157.2; HRMS (ESI-TOF) [M + H]+ calcd for
C31H36N3O6 546.2604, found 546.2588.
D i b e n z y l 3 - ( 3 , 4 - D i m e t h o x y p h e n e t h y l ) - 3 , 6 , 7 -
triazabicyclo[3.2.1]octane-6,7-dicarboxylate 7d. Yield 84 mg,
Dibenzyl 3-(4-(4-Chlorobenzamido)-3-hydroxyphenyl)-
3,6,7-triazabicyclo[3.2.1]octane-6,7-dicarboxylate 7f. Yield 80
1
62%, pale yellow oil; H NMR (300 MHz, (CD3)2SO, 72 °C) δ 1.86
1
(s, 2H), 2.24 (d, J = 10.4 Hz, 2H), 2.47−2.61 (m, 4H), 3.17 (br s,
2H), 3.72 (s, 3H), 3.75 (s, 3H), 4.38 (br s, 2H), 5.12 (s, 4H), 6.68 (d,
mg, 70%, pale yellow oil; H NMR (500 MHz, (CD3)2SO, 70 °C) δ
2.00−2.16 (m, 2H), 2.96 (s, 2H), 3.91 (br s, 2H), 4.66 (s, 2H), 5.10−
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Note
a
Scheme 4. Preparation Hermann’s Building Block 4
a
Reagents and conditions: (a) Boc2O (4.5 equiv), THF/NaOHaq, 1 h. (b) CAN (2.6 equiv), SiO2/H2O/CH2Cl2, 1 h.
5.25 (m, 4H), 6.33 (d, J = 8.5 Hz, 1H), 6.43 (s, 1H), 7.20−7.50 (m,
11H), 7.60 (d, J = 8.6 Hz, 2H), 8.05 (d, J = 8.6 Hz, 2H), 9.28 (s, 1H),
9.48 (s, 1H); 13C NMR (125 MHz, (CD3)2SO, 70 °C) δ 36.0, 52.1,
57.4, 69.0, 104.1, 106.8, 119.1, 127.0, 129.2, 129.5, 130.2, 130.3, 131.3,
135.4, 138.2, 138.2, 150.5, 152.4, 158.3, 166.3; HRMS (ESI-TOF) [M
+ Na]+ calcd for C34H31N4O6ClNa 649.1830, found 649.1827.
Dibenzyl 3-(Isoquinolin-5-yl)-3,6,7-triazabicyclo[3.2.1]-
octane-6,7-dicarboxylate 7h. Yield 247 mg, 28%, pale yellow oil;
1H NMR (300 MHz, (CD3)2SO, 70 °C) δ 2.00−2.12 (m, 1H), 2.16
(d, J = 11.5 Hz, 1H), 3.04 (br d, J = 9.7 Hz, 2H), 3.51 (br d, J = 9.7
Hz, 2H), 4.60 (s, 2H), 4.97−5.29 (m, 4H), 7.05−7.47 (m, 11H), 7.56
(t, J = 7.8 Hz, 1H), 7.79 (d, J = 7.8 Hz, 1H), 8.04 (d, J = 5.5 Hz, 1H),
8.30 (br s, 1H), 9.24 (s, 1H); 13C NMR (75 MHz, (CD3)2SO, 70 °C)
δ 36.1, 55.6, 56.7, 67.6, 116.6, 121.7, 123.6, 127.8, 128.2, 128.6, 130.0,
131.8, 136.6, 142.9, 147.3, 153.0, 157.3; HRMS (ESI-TOF) [M + Na]+
calcd for C30H28N4O4Na 531.2008, found 531.2003.
137.0, 153.7, 157.1; HRMS (ESI-TOF) [M + H]+ calcd for
C32H35N4O5 555.2608, found 555.2594.
Dibenzyl 3-(1H-Indol-5-yl)-3,6,7-triazabicyclo[3.2.1]octane-
1
6,7-dicarboxylate 7g. Yield 102 mg, 57%, colorless oil; H NMR
(300 MHz, (CD3)2SO, 75 °C) δ 1.92−2.11 (m, 2H), 2.89 (d, J = 10.7
Hz, 2H), 3.80 (br s, 2H), 4.58 (s, 2H), 5.14 (s, 4H), 6.29 (s, 1H), 6.70
(d, J = 9.3 Hz, 1H), 6.92 (s, 1H), 7.17−7.38 (m, 12H), 10.53 (br s,
1H); 13C NMR (75 MHz, (CD3)2SO, 75 °C) δ 35.3, 52.6, 56.4, 67.4,
101.2, 106.3, 112.0, 113.1, 125.7, 127.8, 128.1, 128.7, 128.8, 131.7,
136.8, 144.1, 157.1; HRMS (ESI-TOF) [M + H]+ calcd for
C29H29N4O4 497.2189, found 497.2185.
D i b e n z y l 3 - ( 3 , 4 , 5 - T r i m e t h o x y p h e n y l ) - 3 , 6 , 7 -
triazabicyclo[3.2.1]octane-6,7-dicarboxylate 7i. Yield 135 mg,
1
38%, colorless oil; H NMR (400 MHz, (CD3)2SO, 75 °C) δ 2.03−
2.10 (m, 2H), 2.90 (br s, 2H), 3.61 (s, 3H), 3.72 (s, 6H), 3.83 (br s,
2H), 4.61 (s, 2H), 5.17 (s, 4H), 6.02 (s, 2H), 7.32 (br s, 10H); 13C
NMR (75 MHz, (CD3)2SO, 70 °C) δ 34.6, 50.9, 55.9, 56.5, 60.6, 67.5,
93.5, 127.7, 128.2, 128.7, 131.7, 136.7, 146.9, 153.8, 157.0 ; HRMS
(ESI-TOF) [M + Na]+ calcd for C30H33N3O7Na 570.2216, found
570.2218.
Dibenzyl 3-(9, 9 ′-Spirobi[ fluoren]-2-yl)-3, 6, 7-
triazabicyclo[3.2.1]octane-6,7-dicarboxylate 7j. Yield 192 mg,
67%, white amorphous solid; 1H NMR (400 MHz, (CD3)2SO, 70 °C)
δ 1.88−1.94 (m, 1H), 1.99 (d, J = 11.1 Hz, 1H), 2.80 (br s, 2H), 3.64
(br s, 2H), 4.48 (br s, 2H), 4.76−5.15 (m, 4H), 6.01 (s, 1H), 6.49 (d, J
= 7.5 Hz, 1H), 6.61 (d, J = 7.5 Hz, 2H), 6.81 (d, J = 7.2 Hz, 1H), 6.99
(t, J = 7.5 Hz, 1H), 7.10 (t, J = 7.4 Hz, 2H), 7.26 (br s, 10H), 7.32 (t, J
= 7.5 Hz, 1H), 7.37 (t, J = 7.5 Hz, 2H), 7.81 (t, J = 8.6 Hz, 2H), 7.96
(d, J = 7.5 Hz, 2H); 13C NMR (125 MHz, (CD3)2SO, 70 °C) δ 35.7,
52.1, 57.2, 67.8, 68.9, 109.9, 115.4, 120.9, 122.1, 122.2, 122.8, 124.9,
125.0, 125.3, 125.4, 127.9, 129.2, 129.6, 129.8, 130.2, 133.8, 138.1,
143.1, 143.2, 143.8, 149.8, 150.8, 151.7, 152.2, 158.1; HRMS (ESI-
Orbitrap) [M + H]+ calcd for C46H38N3O4 696.2857, found 696.2820.
Tetrabenzyl 3,3′-((3S,5R)-1-(3,4-Dimethoxyphenethyl)-
piperidine-3,5-diyl)bis(3,6,7-triazabicyclo[3.2.1]octane-6,7-di-
Dibenzyl 3-((R)-1-Methoxy-1-oxo-3-phenylpropan-2-yl)-
3,6,7-triazabicyclo[3.2.1]octane-6,7-dicarboxylate 7k. Yield
1
106 mg, 39%, colorless oil; H NMR (300 MHz, (CD3)2SO, 70 °C)
δ 1.86 (s, 2H) ; 2.45−2.63 (m, 2H), 2.67 (dd, J = 4.9 Hz, 1H), 2.94
(dd, J = 13.5 Hz, J = 10.0 Hz, 1H), 3.10−3.28 (m, 2H), 3.43 (dd, J =
10.0 Hz, J = 4.9 Hz, 1H), 3.51 (s, 3H), 4.40 (br s, 2H), 5.12 (s, 4H),
7.08−7.40 (m, 15H); 13C NMR (75 MHz, (CD3)2SO, 70 °C) δ 35.4,
35.9, 49.8, 51.2, 54.0, 56.3, 56.6, 67.3, 67.4, 67.7, 126.7, 127.9, 128.3,
128.7, 128.7, 129.2, 136.9, 138.4, 157.1, 171.4; HRMS (ESI-TOF) [M
+ Na]+ calcd for C31H33N3O6Na 566.2267, found 566.2267; [α]20
D
+21.1 (c 1.0, CHCl3).
1
carboxylate) 7m. Yield 136 mg, 73%, colorless oil; H NMR (400
Dibenzyl 3-((S)-1-Methoxy-1-oxo-3-phenylpropan-2-yl)-
3,6,7-triazabicyclo[3.2.1]octane-6,7-dicarboxylate 7l. Yield 147
mg, 49%, colorless oil. NMR and MS data are similar to enantiomer
7k; [α]20 −19.5 (c 1.0, CHCl3).
MHz, (CD3)2SO, 75 °C) δ 1.01 (q, J = 11.1 Hz, 1H), 1.63−1.72 (m,
3H), 1.85 (s, 4H), 2.30−2.53 (m, 8H), 2.55−2.62 (m, 2H), 2.75−2.81
(br d, J = 9.5 Hz, 2H), 2.84−3.15 (m, 4H), 3.73 (s, 6H), 4.34 (br s,
4H), 5.13 (AB system, Δδ = 0.06, J = 12.6 Hz, 8H), 6.68 (d, J = 8.0
Hz, 1H), 6.78 (s, 1H), 6.84 (d, J = 8.0 Hz, 1H), 7.33 (s, 20H); 13C
NMR (75 MHz, (CD3)2SO, 75 °C) δ 31.2, 34.3, 37.7, 53.3, 57.2, 57.8,
57.9, 58.0, 60.4, 61.5, 68.7, 114.9, 115.5, 122.5, 129.3, 129.6, 130.2,
135.2, 138.4, 149.4, 151.0, 158.8; HRMS (ESI-TOF) [M + H]+ calcd
for C57H66N7O10 1008.4871, found 1008.4862.
Representative Preparation of 7e (Pathway A, Using NaIO4
in MeOH/H2O). To a solution of 6 (233 mg, 0.58 mmol) in MeOH/
H2O (70:30, 7.7 mL) was added NaIO4 (288 mg, 1.35 mmol). The
solution was stirred for 1 h at room temperature, diluted with CH2Cl2
(5 mL), and filtered through a Celite pad. The filtrate was
concentrated and dissolved in CH2Cl2 (4 mL). 5-Methoxytryptamine
(111 mg, 0.58 mmol) was added, and the reductive amination was
conducted according to the preparation of 7a. Flash chromatography
(cyclohexane/ethyl acetate 65:35) afforded 7e (96 mg, 0.17 mmol,
30%).
RepreDsentative Preparation of 7b (Pathway B). Ozone was
bubbled into a solution of 57 (753 mg, 2.07 mmol) in dry CH2Cl2 (10
mL) at −78 C until it became light blue, at which point argon was
bubbled to remove excess ozone. The ozonide was quenched by Me2S
(1.5 mL), and the reaction mixture was warmed to room temperature,
concentrated, and dissolved in CH2Cl2 (9 mL). Benzylamine (244 mg,
2.28 mmol) was added, and the reductive amination was conducted
according to the preparation of 7a. Flash chromatography (CH2Cl2/
ethyl acetate 98:2 up to 95:5) afforded 7b (481 mg, 1.02 mmol, 49%).
Dibenzyl 3-Benzyl-3,6,7-triazabicyclo[3.2.1]octane-6,7-di-
1
carboxylate 7b. Colorless oil; H NMR (500 MHz, (CD3)2SO, 70
°C) δ 1.87 (s, 2H), 2.20 (br s, 2H), 3.06 (br s, 2H), 3.50 (s, 2H), 4.37
(br s, 2H), 5.05−5.18 (m, 4H), 7.20−7.35 (m, 15H); 13C NMR (125
MHz, (CD3)2SO, 70 °C) δ 36.2, 55.1, 56.4, 60.8, 67.4, 127.3, 127.9,
128.2, 128.5, 128.7, 128.9, 136.8, 138.5, 157.0; HRMS (ESI-Orbitrap)
[M + H]+ calcd for C28H30N3O4 472.2236, found 472.2221.
Dibenzyl 3-(2-(5-Methoxy-1H-indol-3-yl)ethyl)-3,6,7-
triazabicyclo[3.2.1]octane-6,7-dicarboxylate 7e. Colorless oil;
1H NMR (400 MHz, (CD3)2SO, 75 °C) δ 1.88 (s, 2H), 2.28 (br s,
Dibenzyl 3-(3,4-Dimethoxybenzyl)-3,6,7-triazabicyclo-
[3.2.1]octane-6,7-dicarboxylate 7c. Yield 218 mg, 76%, colorless
1
oil; H NMR (500 MHz, (CD3)2SO, 70 °C) δ 1.80−1.95 (m, 2H),
2H), 2.61−2.74 (m, 4H), 3.11 (br s, 2H), 3.76 (s, 3H), 4.40 (br s,
2H), 5.13 (s, 4H), 6.72 (d, J = 8.8 Hz, 1H), 6.94 (s, 1H), 7.06 (s, 1H),
7.22 (d, J = 8.8 Hz, 1H), 7.25−7.40 (m, 10H), 10.4 (br s, 1H); 13C
NMR (75 MHz, (CD3)2SO, 75 °C) δ 22.8, 36.2, 55.1, 56.2, 56.6, 57.3,
67.3, 101.3, 111.4, 112.3, 112.8, 123.6, 127.9, 128.2, 128.7, 132.2,
2.17 (d, J = 10.2 Hz), 3.05 (br s, 2H), 3.41 (br s, 2H), 3.73 (s, 3H),
3.76 (s, 3H), 4.37 (br s, 2H), 4.99−5.18 (m, 4H), 6.75 (d, J = 8.2 Hz,
1H), 6.83 (d, J = 8.2 Hz, 1H), 6.89 (s, 1H), 7.32 (s, 10H); 13C NMR
(125 MHz, (CD3)2SO, 70 °C) δ 37.7, 56.6, 57.7, 57.8, 57.9, 61.9, 68.8,
114.3, 115.3, 122.7, 129.4, 129.7, 130.2, 132.8, 138.3, 150.2, 151.1,
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Note
158.4; HRMS (ESI-Orbitrap) [M + H]+ calcd for C30H34N3O6
532.2447, found 532.2419.
δ 29.9, 35.9, 48.5, 56.7, 69.1, 81.0, 129.3, 129.7, 130.2, 138.0, 156.4;
HRMS (ESI-Orbitrap) [M + H]+ calcd for C26H32N3O6 482.2291,
found 482.2300.
Dibenzyl 3-Allyl-3,6,7-triazabicyclo[3.2.1]octane-6,7-dicar-
boxylate 7n. Yield 955 mg, 54%, colorless oil; 1H NMR (500
MHz, (CD3)2SO, 70 °C) δ 1.80−1.89 (m, 2H), 2.17 (br s, 2H), 2.96
(br d, J = 6.1 Hz, 2H), 3.09 (br s, 2H), 4.38 (br s, 2H), 5.06 (d, J =
10.2 Hz, 1H), 5.10−5.19 (m, 5H), 5.62 (ddt, J = 6.1 Hz, J = 10.2 Hz, J
= 16.3 Hz, 1H), 7.30−7.37 (m, 10H); 13C NMR (125 MHz,
(CD3)2SO, 70 °C) δ 37.6, 56.6, 57.9, 60.6, 68.7, 118.8, 129.4, 129.7,
130.1, 136.9, 138.4, 158.6; HRMS (ESI-Orbitrap) [M + H]+ calcd for
C24H27N3O4 422.2079, found 422.2073.
Dibenzyl 3,6,7-Triazabicyclo[3.2.1]octane-6,7-dicarboxylate
8. Compound 7n (900 mg, 2.13 mmol), N,N-dimethylbarbituric acid
(998 mg, 6.39 mmol), and Pd(PPh3)4 (25 mg, 21 μmol) were
dissolved in CH2Cl2 (6.3 mL) under an argon atmosphere. The
solution was refluxed for 5 h, quenched with saturated aqueous
NaHCO3, and extracted with CH2Cl2. The combined organic layers
were dried over MgSO4, filtered, and concentrated. Flash chromatog-
raphy (CH2Cl2/MeOH 97:3) afforded 8 (673 mg, 1.76 mmol, 83%).
Yellow oil; 1H NMR (250 MHz, CDCl3) δ 1.91 (d, J = 11.3 Hz, 1H),
1.99−2.12 (m, 1H), 2.43 (br s, 1H), 2.70 (br d, J = 11.8 Hz, 2H), 3.06
(br s, 2H), 4.34 (br s, 2H), 5.22 (s, 4H), 7.34 (s, 10H); 13C NMR
(125 MHz, CDCl3) δ 37.5, 50.4, 58.5, 69.5, 129.5, 129.7, 130.0, 137.3,
158.0; HRMS (ESI-Orbitrap) [M + H]+ calcd for C21H24N3O4
382.1767, found 382.1779.
Dibenzyl 3-(2-(3,4-Dimethoxyphenyl)acetyl)-3,6,7-
triazabicyclo[3.2.1]octane-6,7-dicarboxylate 9. To a solution of
8 (41 mg, 0.11 mmol) in dry 1,2-dichloroethane (1.2 mL) were added
triethylamine (44 μL, 0.32 mmol) and 3,4-dimethoxyphenylacetyl-
chloride (28 μL, 0.16 mmol). The solution was stirred for 1.5 h at
room temperature and then at 45 °C, quenched with saturated
aqueous NH4Cl, and extracted with CH2Cl2, and the combined
organic layers were dried over MgSO4, filtered, and concentrated.
Flash chromatography (CH2Cl2/MeOH 98:2) afforded 9 (60 mg,
quantitative). Colorless oil; 1H NMR (500 MHz, (CD3)2SO, 70 °C) δ
2.02−2.08 (m, 1H), 2.21 (d, J = 11.7 Hz, 1H), 2.98 (s, 2H), 3.30 (br s,
2H), 4.54 (s, 2H), 5.14 (AB system, Δδ = 0.10, J = 12.5 Hz, 4H), 7.32
(s, 10H), 8.51 (s, 2H), 8.83 (s, 1H); 13C NMR (125 MHz, (CD3)2SO,
70 °C) δ 36.6, 57.2, 69.3, 121.0, 129.1, 129.3, 129.8, 130.2, 137.8,
140.8, 150.2, 157.9, 168.4; HRMS (ESI-Orbitrap) [M + H]+ calcd for
C28H26N5O9 576.1731, found 576.1731.
Dibenzyl 3-(6-(((Benzyloxy)carbonyl)amino)-2-((tert-
butoxycarbonyl)amino)hexanoyl)-3,6,7-triazabicyclo[3.2.1]-
octane-6,7-dicarboxylate 12. To a solution of 8 (68 mg, 0.18
mmol) in anhydrous CH2Cl2 (1.75 mL) were added Boc-Lys(Z)-OH
(75 mg, 0.20 mmol), Et3N (173 mL, 1.25 μmol), and EDC (51 mg,
0.27 mmol). The solution was stirred for 5 h, quenched with saturated
aqueous NaHCO3, and extracted with CH2Cl2. The combined organic
layers were dried over MgSO4, filtered, and concentrated. Flash
chromatography (CH2Cl2/MeOH 97:3) afforded 12 (107 mg, 0.14
mmol, 81%). Colorless oil; 1H NMR (500 MHz, (CD3)2SO, 70 °C) δ
1.17−1.62 (m, 15H), 1.92−2.01 (m, 1H), 2.12 (d, J = 11.7 Hz, 1H),
2.87 (br s, 1H), 2.93−3.02 (m, 2H), 3.33 (br s, 1H), 4.03 (br s, 1H),
4.23 (br s, 1H), 4.34 (br s, 1H), 4.49 (s, 1H), 4.54 (s, 1H), 5.03 (s,
2H), 5.12 (br s, 4H), 6.05−6.50 (m, 1H), 6.86 (br s, 1H), 7.07−7.55
(m, 15H); 13C NMR (75 MHz, (CD3)2SO, 70 °C) δ 23.1, 28.7, 29.6,
31.7, 34.6, 41.0, 51.1, 55.4, 65.7, 67.8, 78.6, 127.8, 128.0, 128.1, 128.3,
128.7, 128.8, 136.6, 137.9, 155.6, 156.5, 173.2; HRMS (ESI-Orbitrap)
[M + H]+ calcd for C40H50N5O9 744.3608, found 744.3596; [α]20
D
−7.6 (c 1.0, CHCl3).
General Procedures for Hydrogenolysis. A solution of bicyclic
hydrazine in solvent (Methods A and B: MeOH; Method C: MeOH/
HCl pH 3; Method D: distilled acetic acid) was stirred in the presence
of catalyst (A: 10% palladium on activated charcoal (0.2 equiv); B and
C: 10% palladium on activated charcoal (0.2 equiv) and palladium
black (0.01 equiv); D: PtO2 (0.15 equiv)) under hydrogen atmosphere
(1 atm). If needed, 0.1 equiv of catalyst can be added after 24 h to
reach completion. The reaction mixture was filtered through a Celite
pad and concentrated to afford the final diamine.
(3S,5R)-1-(4-Methoxybenzyl)piperidine-3,5-diamine 13a
1
(Method A). Yield 40 mg, quantitative, colorless oil; H NMR (250
MHz, CD3OD) δ 0.84 (q, J = 11.6 Hz, 1H), 1.62 (t, J = 10.4 Hz, 2H),
2.09 (d, J = 11.6 Hz, 1H), 2.75−2.87 (m, 2H), 2.94 (dd, J = 10.4 Hz, J
= 4.4 Hz, 2H), 3.50 (s, 2H), 3.77 (s, 3H), 6.86 (d, J = 8.5 Hz, 2H),
7.23 (d, J = 8.5 Hz, 2H); 13C NMR (125 MHz, CD3OD) δ 43.3, 48.1,
55.8, 61.5, 63.0, 114.8, 130.4, 131.9, 160.6; HRMS (ESI-Orbitrap) [M
+ H]+ calcd for C13H22N3O 236.1762, found 236.1756.
(3S,5R)-1-(3,4-Dimethoxyphenethyl)piperidine-3,5-diamine
1
13b (Method B). Yield 62 mg, 88%, colorless oil; H NMR (400
Dibenzyl 3-(3,5-Dinitrobenzoyl)-3,6,7-triazabicyclo[3.2.1]-
octane-6,7-dicarboxylate 10. To a solution of 8 (200 mg, 0.52
mmol) in dry 1,2-dichloroethane (5 mL) were added triethylamine
(216 μL, 1.57 mmol) and 3,5-dinitrobenzoylchloride (183 mg, 0.79
mmol). The solution was stirred for 6 h at 80 °C, quenched with
saturated aqueous NaHCO3, and extracted with CH2Cl2. The
combined organic layers were dried over MgSO4, filtered, and
concentrated. Flash chromatography (CH2Cl2/Ethyl acetate 90:10)
afforded 10 (280 mg, 0.49 mmol, 92%). Pale yellow oil; 1H NMR (500
MHz, (CD3)2SO, 70 °C) δ 1.93−2.00 (m, 1H), 2.10 (d, J = 11.7 Hz,
1H) ; 2.87 (br s, 1H), 3.23 (br s, 1H), 3.46 (s, 1H), 3.52 (s, 1H), 3.73
(s, 6H), 4.12 (br s, 1H), 4.45 (br s, 2H), 4.51 (s, 2H), 5.10 (AB
system, Δδ = 0.04, J = 12.3 Hz, 4H), 6.67 (d, J = 8.2 Hz, 1H), 6.77 (s,
1H), 6.84 (d, J = 8.2 Hz, 1H), 7.34 (s, 10H); 13C NMR (125 MHz,
(CD3)2SO, 70 °C) δ 36.0, 41.1, 56.8, 57.7, 57.8, 69.1, 114.6, 115.8,
123.1, 129.4, 129.8, 129.9, 130.2, 138.0, 149.8, 150., 157.9, 172.8;
HRMS (ESI-Orbitrap) [M + H]+ calcd for C31H34N3O7 560.2397,
found 560.2403.
MHz, CDCl3) δ 0.89 (q, J = 11.7 Hz, 1H), 1.25 (br s, 4H), 1.71 (t, J =
10.1 Hz, 2H), 2.17 (d, J = 11.7 Hz, 1H), 2.60−2.71 (m, 2H), 2.75−
2.85 (m, 2H), 2.92−3.03 (m, 2H), 3.06 (d, J = 10.1 Hz, 2H), 3.90 (s,
3H), 3.91 (s, 3H), 6.77−6.85 (m, 3H); 13C NMR (100 MHz, CDCl3)
δ 33.1, 44.9, 47.6, 55.8, 55.9, 60.3, 62.3, 111.1, 111.9, 120.5, 132.8,
147.2, 148.7; HRMS (ESI-TOF) [M + H]+ calcd for C15H26N3O2
280.2025, found 280.2029.
(3S,5R)-1-(2-(5-Methoxy-1H-indol-3-yl)ethyl)piperidine-3,5-
diamine 13c (Method B). Yield 29 mg, quantitative, colorless oil; 1H
NMR (400 MHz, CDCl3) δ 0.90 (q, J = 11.4 Hz, 1H), 1.30 (br s, 4H),
1.75 (t, J = 10.3 Hz, 2H), 2.19 (d, J = 11.4 Hz, 1H), 2.74−2.81 (m,
2H), 2.95−3.07 (m, 4H), 3.13 (dd, J = 10.3 Hz, J = 3.2 Hz, 2H), 3.90
(s, 3H), 6.90 (d, J = 8.8 Hz, 1H), 7.04 (s, 1H), 7.08 (s, 1H), 7.30 (d, J
= 8.8 Hz, 1H), 8.30 (s, 1H); 13C NMR (100 MHz, CDCl3) δ 22.9,
45.0, 47.7, 56.0, 58.9, 62.4, 100.6, 111.9, 112.1, 113.9, 122.4, 127.8,
131.4, 153.9; HRMS (ESI-TOF) [M + H]+ calcd for C16H25N4O
289.2028, found 289.2021.
N-(4-((3S,5R)-3,5-Diaminopiperidin-1-yl)-2-hydroxyphenyl)-
1
benzamide 13d (Method A). Yield 21 mg, 95%, orange oil; H
6,7-Dibenzyl 3-tert-Butyl 3,6,7-Triazabicyclo[3.2.1]octane-
3,6,7-tricarboxylate 11. To a solution of 8 (81 mg, 0.21 mmol)
in CH2Cl2 (0.6 mL) were added Et3N (32 μL, 233 μmol) and Boc2O
(51 mg, 0.23 mmol), and the mixture was stirred for 2 h. The reaction
was quenched with saturated aqueous NaHCO3 and extracted with
CH2Cl2, and the combined organic layers were dried over MgSO4,
filtered, and concentrated. Flash chromatography (CH2Cl2/MeOH
NMR (300 MHz, CD3OD) δ 1.45 (q, J = 11.0 Hz, 1H), 2.26 (d, J =
11.0 Hz, 1H), 2.74 (dd, J = 11.9 Hz, J = 9.2 Hz, 2H), 3.22 (m, 2H),
3.66 (dd, J = 11.9 Hz, J = 2.9 Hz, 2H), 6.57 (dd, J = 8.8 Hz, J = 2.3 Hz,
1H), 6.62 (d, J = 2.3 Hz, 1H), 7.52−7.60 (m, 4H), 7.97 (d, J = 8.0 Hz,
2H); 13C NMR (75 MHz, CD3OD) δ 36.4, 46.3, 54.6, 105.1, 108.4,
118.8, 124.3, 127.2, 128.4, 131.6, 134.2, 149.5, 150.2, 167.3; HRMS
(ESI-TOF) [M + H]+ calcd for C18H23N4O2 327.1821, found
327.1821.
1
99:1) afforded 11 (95 mg, 0.2 mmol, 93%). Colorless oil; H NMR
(500 MHz, (CD3)2SO, 70 °C) δ 1.38 (s, 9H), 1.95 (s, 1H), 2.03 (d, J
= 11.5 Hz, 1H), 2.98 (br s, 2H), 4.10 (br s, 2H), 4.45 (s, 2H), 5.09−
5.17 (m, 4H), 7.34 (s, 10H); 13C NMR (125 MHz, (CD3)2SO, 70 °C)
(3S,5R)-1-(1H-Indol-5-yl)piperidine-3,5-diamine 13e (Meth-
od B). Yield 22 mg, 79%, colorless oil; 1H NMR (300 MHz, CDCl3) δ
12240
dx.doi.org/10.1021/jo401994y | J. Org. Chem. 2013, 78, 12236−12242

The Journal of Organic Chemistry
Note
0.96 (q, J = 11.6 Hz, 1H), 1.39 (br s, 4H), 2.24 (d, J = 11.6 Hz, 1H),
2.33 (dd, J = 11.1 Hz, J = 10.3 Hz, 2H), 3.12 (m, 2H), 3.60 (dd, J =
11.1 Hz, J = 4.4 Hz, 2H), 6.48 (br s, 1H), 6.97 (dd, J = 8.8 Hz, J = 2.4
Hz, 1H), 7.17 (t, J = 2.7 Hz, 1H), 7.19 (d, J = 2.4 Hz, 1H), 7.29 (d, J =
8.8 Hz, 1H), 8.34 (br s, 1H); 13C NMR (75 MHz, CDCl3) δ 44.7,
47.8, 61.3, 102.3, 108.5, 111.5, 116.4, 124.7, 128.3, 131.4, 145.6;
HRMS (ESI-TOF) [M + H]+ calcd for C13H19N4 231.1610, found
231.1606.
dried over MgSO4, filtered, and concentrated to afford 14 (115 mg,
quantitative). White amorphous solid; 1H NMR (500 MHz,
(CD3)2SO, 70 °C) δ 1.12 (q, J = 11.8 Hz, 1H), 1.37 (s, 18H), 1.69
(br s, 2H), 1.91 (d, J = 11.8 Hz, 1H), 2.81 (d, J = 9.7 Hz, 2H, H′2 and
H′6), 3.37−3.48 (m, 4H), 3.76 (s, 3H), 6.44 (broad s, 2H), 6.88 (d, J =
8.2 Hz, 2H), 7.20 (d, J = 8.2 Hz, 2H);13C NMR (125 MHz,
(CD3)2SO, 70 °C) δ 30.2, 39.0, 48.6, 57.0, 59.3, 62.8, 79.6, 115.6,
131.6, 131.8, 156.8, 160.4; HRMS (ESI-TOF) [M + H]+ calcd for
C23H38N3O5 436.2812, found 436.2809.
(3S,5R)-1-(3,4,5-Trimethoxyphenyl)piperidine-3,5-diamine
1
Di-tert-butyl (3S,5R)-Piperidine-3,5-diyldicarbamate 4. A
solution of CAN (351 mg, 0.64 mmol) in water (0.32 mL) was
added dropwise to a flask charged with silica (753 mg). CH2Cl2 (3.1
mL) was added, and 14 (0.25 mmol) dissolved in CH2Cl2 (1.5 mL)
was added to the stirred reaction mixture. The suspension was stirred
for 1 h at room temperature and filtered. Flash chromatography
(CH2Cl2/(MeOH/NH4OH 30% aq 90:10) 95:5) of the residual
13f (Method A). Yield 45 mg, 88%, colorless oil; H NMR (300
MHz, CD3OD) δ 1.06 (q, J = 11.4 Hz, 1H), 2.20 (br d, J = 11.4 Hz,
1H), 2.35 (dd, J = 11.6 Hz, J = 10.4 Hz, 2H), 2.95 (m, 2H), 3.65 (dd, J
= 11.6 Hz, J = 4.3 Hz, 2H), 3.71 (s, 3H), 3.84 (s, 6H), 6.27 (s, 2H);
13C NMR (75 MHz, CD3OD) δ 41.9, 46.8, 55.1, 57.5, 59.9, 95.0,
131.5, 148.2, 153.4; HRMS (ESI-TOF) [M + H]+ calcd for
C14H24N3O3 282.1818, found 282.1815.
1
afforded 4 (45 mg, 0.14 mmol, 58%). White amorphous solid; H
(3S,5R)-1-(9,9′-Spirobi[fluoren]-2-yl)piperidine-3,5-diamine
1
NMR (500 MHz, (CD3)2SO) δ 1.12 (q, J = 11.9 Hz, 1H), 1.38 (s,
18H), 1.90 (d, J = 11.9 Hz, 1H), 2.02 (t, J = 10.8 Hz, 2H), 2.82 (d, J =
10.8 Hz, 2H), 3.15−3.20 (m, 2H), 6.72 (d, J = 8.0 Hz, 2H); 13C NMR
(125 MHz, (CD3)2SO) δ 30.1, 39.8, 49.6, 52.3, 79.4, 156.8; HRMS
(ESI-Orbitrap) [M + H]+ calcd for C15H30N3O4 316.2236, found
316.2239.
13g (Method D). Yield 78 mg, 85%, yellow amorphous solid; H
NMR (300 MHz, CD3OD) δ 1.58 (q, J = 11.0 Hz, 1H), 2.44 (d, J =
10.0 Hz, 1H), 2.62 (t, J = 11.0 Hz, 2H), 3.28−3.34 (m, 2H), 3.69 (d, J
= 10.0 Hz, 2H), 6.31 (s, 1H), 6.54 (d, J = 7.6 Hz, 1H), 6.62 (d, J = 7.6
Hz, 2H), 7.02 (t, J = 7.6 Hz, 1H), 7.09 (t, J = 7.6 Hz, 3H), 7.28−7.40
(m, 3H), 7.83 (t, J = 8.5 Hz, 2H), 7.90 (d, J = 7.6 Hz, 2H); 13C NMR
(75 MHz, CD3OD) δ 22.4, 34.0, 46.1, 53.4, 65.9, 112.6, 117.1, 119.1,
119.8, 120.6, 123.3, 123.6, 126.5, 127.6, 135.1, 141.1, 141.6, 148.3,
148.9, 150.2, 150.6; HRMS (APCI-Orbitrap) [M + H]+ calcd for
C30H28N3 430.2283, found 430.2276.
ASSOCIATED CONTENT
■
S
* Supporting Information
1
Copies of H, 13C NMR spectra. Copies of chiral HPLC of
(S)-Methyl 2-((3S,5R)-3,5-Diaminopiperidin-1-yl)-3-phenyl-
compounds 7k,l. This material is available free of charge via the
Internet at http://pubs.acs.org.
1
propanoate 13h (Method B). Yield 39 mg, 98%, colorless oil; H
NMR (400 MHz, CDCl3) δ 0.85 (q, J = 11.4 Hz, 1H), 1.47 (br s, 4H),
1.89 (t, J = 10.3 Hz, 1H), 2.05 (t, J = 10.3 Hz, 1H), 2.12 (d, J = 11.4
Hz, 1H), 2.80−2.99 (m, 4H), 3.04−3.15 (m, 2H), 3.50 (dd, J = 7.9
Hz, J = 7.0 Hz, 1H), 3.64 (s, 3H), 7.15−7.35 (m, 5H); 13C NMR (75
MHz, CDCl3) δ 35.6, 44.8, 47.7, 47.9, 51.1, 56.3, 61.2, 69.1, 126.4,
128.3, 129.1, 138.1, 171.7; HRMS (ESI-TOF) [M + H]+ calcd for
AUTHOR INFORMATION
Corresponding Author
*E-mail: laurent.micouin@parisdescartes.fr.
■
Notes
C15H24N3O2 278.1869, found 278.1864; [α]20 −19.0 (c 1.0,
D
The authors declare no competing financial interest.
CH3OH).
(3S,3′R,3″S,5R,5′S,5″R)-1′-(3,4-Dimethoxyphenethyl)-
[1,3′:5′,1″-terpiperidine]-3,3″,5,5″-tetraamine 13i (Method C).
Yield 44 mg, quantitative, colorless oil; 1H NMR (500 MHz, CD3OD)
δ 1.55−1.70 (m, 3H), 2.12 (d, J = 10.9 Hz, 1H), 2.45−2.56 (m, 6H),
2.60−2.69 (m, 2H), 2.95−3.11 (m, 6H), 3.15−3.26 (m, 4H), 3.30−
3.37 (m, 6H), 3.82 (s, 3H), 3.86 (s, 3H), 6.84 (d, J = 8.5 Hz, 1H), 6.91
(d, J = 8.5 Hz, 1H), 6.94 (s, 1H); 13C NMR (125 MHz, CD3OD) δ
28.7, 32.3, 34.5, 48.0, 48.1, 52.8, 53.5, 55.2, 56.7, 60.0, 60.8, 113.5,
114.0, 122.2, 132.4, 149.4, 150.6; HRMS (ESI-TOF) [M + Na]+ calcd
for C25H45N7O2Na 498.3532, found 498.3526.
ACKNOWLEDGMENTS
■
Financial support from CNRS, MRT (grant to A.B.) and
́
Consejeria de Educacion
́
de la Junta de Castilla y Leon
́
(grant
to R.A.) is acknowledged. A. Hessani is acknowledged for mass
spectroscopy analyses.
REFERENCES
■
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dimethoxyphenyl)ethanone 13j (Method B). Yield 16 mg, 76%,
1
colorless oil; H NMR (500 MHz, CD3OD) δ 1.43 (q, J = 11.8 Hz,
1H), 2.21 (d, J = 11.8 Hz, 1H), 2.80−2.87 (m, 2H), 2.95−3.10 (m,
2H), 3.76 (d, J = 4.9 Hz, 2H), 3.81 (s, 3H), 3.82 (s, 3H), 3.99 (d, J =
13.5 Hz, 1H), 4.41 (d, J = 13.5 Hz, 1H), 6.82 (d, J = 8.2 Hz, 1H), 6.84
(s, 1H), 6.86 (d, J = 8.2 Hz, 1H); 13C NMR (125 MHz, CD3OD) δ
38.2, 41.0, 47.0, 47.5, 48.0, 52.4, 56.7, 113.4, 114.0, 122.5, 128.9, 149.8,
150.9, 173.2; HRMS (ESI-Orbitrap) [M + H]+ calcd for C15H24N3O3
294.1817, found 294.1815.
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(3S,5R)-tert-Butyl 3,5-diaminopiperidine-1-carboxylate 13k
(Method A,. Flash chromatography (CH2Cl2/MeOH 97:3 then
CH2Cl2/(MeOH/NH4OH 30% aq 90:10) 90:10): 17 mg, 67%,
1
(5) Carnevali, M.; Parsons, J.; Wyles, D. L.; Hermann, T.
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colorless oil; H NMR (500 MHz, CD3OD) δ 0.93 (q, J = 11.5 Hz,
1H), 1.36 (s, 9H), 2.03−2.06 (m, 1H), 2.23 (br s, 2H), 2.55−2.62 (m,
2H), 4.00 (dd, J = 11.5 Hz, J = 4.5 Hz, 2H); 13C NMR (125 MHz,
CD3OD) δ 27.3, 42.6, 46.8, 50.0, 50.6, 79.9, 154.9; HRMS (ESI-
Orbitrap) [M + H]+ calcd for C10H22N3O2 216.1712, found 216.1713.
Di-tert-butyl ((3S,5R)-1-(4-Methoxybenzyl)piperidine-3,5-
diyl)dicarbamate 14. Compound 13a (58 mg, 0.25 mmol) was
dissolved in THF/H2O (50:50, 5.2 mL). Boc2O (242 mg, 1.11 mmol)
was added. The solution was stirred for 1 h at room temperature and
extracted with ethyl acetate, and the combined organic layers were
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́
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2011, 76, 5137−5142. (e) Lombes
̀
, T.; Moumne,
́
R.; Larue, V.; Prost,
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(8) For a similar approach for closely related systems, see: (a) Fray,
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(b) Kiss, L.; Kazi, B.; Forro, E.; Fulop, F. Tetrahedron Lett. 2008, 49,
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(9) See Supporting Information.
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