Synthesis of polyhydroxylated piperidine and pyrrolidine peptidomimetics via one-pot sequential lactam reduction/Joullié-Ugi reaction

Article abstract of DOI:10.1021/acs.joc.5b00335

A direct approach to the synthesis of polyhydroxylated piperidine and pyrrolidine peptidomimetics is described. The presented strategy is based on one-pot reduction of sugar-derived lactams with Schwartzs reagent followed by a multicomponent Ugi-Joullié reaction.

Full text of DOI:10.1021/acs.joc.5b00335

Article
pubs.acs.org/joc
Synthesis of Polyhydroxylated Piperidine and Pyrrolidine
Peptidomimetics via One-Pot Sequential Lactam
́
Reduction/Joullie−Ugi Reaction
Piotr Szczesniak, Elzbieta Maziarz, Sebastian Stecko,* and Bartłomiej Furman*
́
̇
Institute of Organic Chemistry, Polish Academy of Sciences Kasprzaka 44/52, 01-224 Warsaw, Poland
S
* Supporting Information
ABSTRACT: A direct approach to the synthesis of poly-
hydroxylated piperidine and pyrrolidine peptidomimetics is
described. The presented strategy is based on one-pot reduc-
tion of sugar-derived lactams with Schwartz’s reagent followed
́
by a multicomponent Ugi−Joullie reaction.
INTRODUCTION
■
Peptides and proteins play a key role in the biological functions
of living organisms. Therefore, these molecules are excellent
candidates for novel drugs. In recent decades, the investigation
of peptide mimics (peptidomimetics) has received much atten-
tion.1 In many cases, peptidomimetics have shown enhanced
pharmacological properties over their natural peptide ana-
logues. Particularly interesting examples of peptidomimetics are
peptide analogues into which cyclic structural elements have
been incorporated. By reducing their conformational flexibility,
in many cases their affinity for certain receptors is enhanced.
Another result of reduced flexibility is better defined secondary
and tertiary peptide structure.1
Figure 1. Potent inhibitors of α- and β-N-acetylhexosaminidases
(HexNAcases).
Among various amino acids, proline and pipecolic acid as
well as their derivatives have become particularly important
structural elements responsible for constraining the structural
and conformational features of biologically active peptides.1,2
They have a tremendous effect on peptide folding and bioactive
conformations.3 As a result, these amino acids and their deriv-
atives find application as β-turn mimetics3c and, therefore, as an
element of several pharmaceutically relevant compounds.2,3
Proline and pipecolic acid themselves also display important
bioactivity, as do their derivatives. In particular, polyhydroxy-
lated pipecolic acid amides and proline amides, also known as
iminosugar C-glycosides, have received much attention in
recent decades.2 Such aza-C-glycosides have become impor-
tant targets in the quest for iminosugar-type glycosidase and
glycosyltransferase inhibitors for the use in medical treatment.4
Several piperidine and pyrrolidine amides (Figure 1) have been
found to be potent inhibitors of α- and β-N-acetylhexosami-
nidases (HexNAcases). Their deficiencies in the human body
can lead to lysosomal storage disorders (LSDs) such as Tay−
Sachs and Sandhoff syndromes5 and to Alzheimer’s disease.6
Moreover, some of them exhibit specific inhibition of α-N-
acetylgalactosaminidases (α-GalNAcases) which are crucial
targets in the treatment of the Schindler−Kanzaki LSD7 and
cancer by preventing the degradation of the macrophage-
activating factor.8
Very recently, Ayers, Fleet, and Kato reported a series of
polyhydroxylated proline amides (e.g., 1 or 2, Figure 2) that
Figure 2. Examples of polyhydroxylated proline amides, pipecolic
amide, and azetidine amide derivatives that display high bioactivity
against hexosaminidases.
Received: February 12, 2015
© XXXX American Chemical Society
A
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Scheme 1
displayed low to submicromolar inhibition of β-N-acetylhex-
osaminidases.9 In addition, the same group has also reported
that certain hydroxylated pipecolic amide (e.g., 3)10 and
azetidine amide derivatives (e.g., 4)11 also display high
bioactivity against hexosaminidases (Figure 2).
The reported bioactivity of compounds of types 1−3 as well
as our long-term interest in the stereocontrolled synthesis of
bioactive compounds, such as β-lactams,12 iminosugars,13 and
alkaloids,14 prompted us to search for an attractive method of
the synthesis of such polyhydroxylated cyclic amino amides.
A particularly attractive pathway of the synthesis of such
́
proline and pipecolic acid derivatives is the Joullie−Ugi reac-
tion,2,15 which involves the reaction of cyclic imines with
isocyanides and carboxylic acids.16,3b,c,17 Although the multi-
component Ugi reactions15,18 enable preparation of broad
libraries of peptides in a fast and efficient manner, it has rather
limited applicability in the preparation of cyclic peptides due to
the limited accessibility of cyclic imines. The reasons for that
are the low stability of cyclic imines and difficulties in their
synthesis. Typical methods of cyclic imine synthesis involve (1)
N-chlorination/elimination of secondary amines,19 (2) deoxy-
genation of cyclic nitrones,20,21 or (3) cyclization of azido-
aldehydes through Staudinger/aza-Wittig reaction.16c,d,g,22
None of these methods is universal, and each of them has
serious drawbacks, such as difficulties in regioselective
formation of the CN bond, long and multistep preparation
of starting materials, or low stability.
Recently, we demonstrated that upon treatment with
Cp2Zr(H)Cl (Schwartz’s reagent), five- and six-membered
lactams, including sugar- and hydroxy acid-derived lactams,20,23
can be easily converted into imines under mild conditions. In
addition, as was also shown, in situ generated cyclic imines can
be directly subjected to further reactions with nucleophilic
reagents such as allyltributylstannane,23 Grignard reagents,23
enolates,23 or Danishefsky’s diene20 to afford α-functionalized
pyrrolidines and piperidines in a one-pot manner.
the reaction mixture from an initial white suspension into a
clear solution indicates the end of the reduction (ca. 0.5−
1.5 h). The resulting imine was directly subjected to
́
the Joullie−Ugi reaction. Thus, TFA (4 equiv) and isocyanide
(1.2 equiv) were added at −78 °C, and the reaction mixture
was allowed to warm to room temperature. As shown in
Table 1, the reaction proceeded smoothly either with aliphatic
(ent 1, 2) or aromatic isocyanides (ent 3). In all three cases, the
reaction proceeded diastereoselectively to provide predom-
inantly products 10−12 (dr > 95:5 according to NMR)
regardless of the isocyanide structure. The assignment of
configuration of 10 by the analysis of NMR spectra was difficult
due to the existence of this compound as a complex mixture of
rotamers. Therefore, to simplify its spectra, compound 10 was
hydrolyzed to afford amide 30. Thus, the assignment of the
absolute configuration at the newly formed stereogenic center
did not present any difficulties and was unambiguously achieved
by the analysis of coupling constants and NOE experiments.
Following the same procedure, lactams 2−9 were converted
into the corresponding cyclic trifluoroacetamides 11−29. As
presented in Table 1, their formation proceeded efficiently and
in most cases stereoselectively. As in the case of compound 10,
amides 11−29 were hydrolyzed to provide compounds 31−49
(Table 2). The absolute configuration of obtained products was
assigned by the analysis of NMR spectra and NOE experiments
of N-deprotected products. In some cases, those assignments
were confirmed by X-ray analysis (compounds 2-epi-23, 24, and
28) (Figures 3−5).
Excellent results of our recent studies on one-pot reduction/
functionalization of lactams encouraged us to check whether
under the same conditions the deoxygenative reduction of lactams
́
and the Joullie−Ugi reaction sequence can be performed without
isolation of the intermediate imine, as outlined in Scheme 1.
In particular, we focused our attention on the synthesis of
polyhydroxylated cyclic amides starting with carbohydrate-
derived lactams.
As we have already shown, the course of the addition to five-
and six-membered imines is not as straightforward and intuitive
as one could expect.20 The rationalization of the stereochemical
outcome cannot be based only on steric effects but must
also consider stereoelectronic effects and conformational
preferences, as in the case of C-allylation of furanosyl- and
pyranosyloxycarbenium ions investigated in detail by Woerpel
and co-workers.25
The experimental data collected in Tables 1 and 2 indicates
that, although the Ugi reaction is a complex process involving
imine activation, addition of an isocyanate ion, carboxylate
addition, and Mumm rearrangement,2,26,18 its stereochemical
RESULTS AND DISCUSSION
■
As in the previous studies, five- and six-membered poly-
hydroxylated lactams 1−9 were prepared starting with
commercially available sugars and tartaric and malic acid
following the previously reported methods.20,23,24
With the chiral lactams in hand, we began the investigation of
the synthesis of pyrrolidine and piperidine derivatives via a se-
́
quential one-pot lactam reduction/Joullie−Ugi reaction. Treat-
ment of gluco-lactam 1 with Cp2Zr(H)Cl (1.6 equiv) in THF
provided the corresponding imine. As reported previously,23
the progress of this step can be easily followed; the transition of
B
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a
Table 1. Sequential Lactam Reduction/Joullie−Ugi Three-Component Reaction
́
a
Reaction conditions: (step 1) Cp2Zr(H)Cl (1.6 equiv) in THF for 30 min; (step 2) TFA (4.0 equiv), isocyanide (1.25 equiv) at −78 °C to rt for
b
c
24 h. Isolated yield (overall after two steps). Yield was assigned by 1H NMR of crude reaction mixture. Isomeric products could not be separated
by column chromatography; the crude mixture of products was subjected directly to hydrolysis. Determined by H NMR of the crude reaction
d
1
mixture after hydrolysis of a mixture of isomeric trifluoroacetates.
course is determined by the isocyanide addition step and can be
rationalized by Woerpel’s model of allylation of oxycarbenium
ions.25
The above rules explain the marked preference of forma-
tion of 2,3-cis-pyrrolidine derivatives in the case of lactam 9
(product 29), D-ribo-lactam 4 (products 18 and 19), and
erythronolactam 7, as well as the formation of 2,4-cis products
27 and 28 from lactam 8 (Scheme 2). The same high cis-selectivity
In the case of allylation of furanosyloxycarbenium ions,
Woerpel’s model assumes that the relative stabilities of the
oxycarbenium ion envelope conformers is dictated by the
preferences of orientation of the substituents attached to the
ring. Alkoxy groups at the C-3 and C-4 positions preferentially
adopt the equatorial and axial position, respectively, and the
nucleophile approaches the intermediate oxycarbenium ion
from “inside”, syn to the carbon atom which is located out of
envelope plane (Figure 6). The effect of the C-5 group is
minor.25a−e,h
was also observed by Codee
́
and co-workers16h during the Ugi
reaction involving D-lyxo-imine generated through the
Staudinger/aza-Wittig reaction.
The low selectivity of isocyanide addition to the imines
generated from lactams 5 and 6 can be explained in the same
manner. In the case of arabino-imine 50, obtained from lactam
5, the adapting of the preferred pseudoaxial orientation by C-4
alkoxy group generates unfavorable syn-butanol interactions27
C
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a
Table 2. Hydrolysis of Trifluoroacetamides 10−29
a
b
c
1
Reaction conditions: substrate (0.5 mmol), 2.5 M NaOH in MeOH (2 mL), H2O (0.1 mL), rt. Determined by H NMR. Mixture of isomers
d
(crude reaction mixture from previous step) were subjected to hydrolysis. Overall yield of both isomers; PMP = 4-methoxyphenyl, Cy = cyclohexyl.
D
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Scheme 2
Figure 3. ORTEP plot of 2-epi-23 with 30% probability ellipsoids.
The formation of 2,3-cis product 10 results from an axial
4
attack of the nucleophile to the all-equatorial H3 conformer
(Scheme 4). The 3H4 conformer, which bears the stereo-
electronically more preferred axially oriented C-3 and C-4
groups, is strongly destabilized by 1,3-diaxial interactions. The
observed stereochemical outcome corresponds well with our
previous studies of allylation23 and tandem Mannich/Michael
reaction20 of in situ generated sugar-derived imines as well as
allylation of gluco-oxycarbenium ion.25b,c,f
Figure 4. ORTEP plot of 24 with 30% probability ellipsoids.
The same stereochemical outcome was observed in the case
of isocyanide addition to galacto-imine obtained from lactam 2.
The same course of addition has been observed previously in
the case of C-allylation of the same imine.23 However, this
stands in opposition to the result of the reaction of galacto-
imine with Danishefsky’s diene that led to the formation of
2,3-trans products predominantly.20 This result again confirms
our conclusion that the stereochemical outcome of nucleophilic
addition to cyclic imines is governed not only by the imine’s
structure but also by the structure of the nucleophile.
The addition of isocyanides to D-arabino-imine obtained
from lactam 3 resulted in the formation of 2,3-trans-substituted
piperidine derivatives as the major products (15−17). The
observed stereochemical course of the addition is similar to the
outcome observed for the addition of Danishefsky’s diene to
the same imine20 but is opposite to the result of its C-allylation
with allyltributylstannane.23 This result again confirms our
previous assumptions that the course of the addition to cyclic
imines is ruled not only by stereoelectronic and steric factors
resulting from the structure of the imine but depends also on
the structure of the nucleophile.20
Figure 5. ORTEP plot of 28 with 30% probability ellipsoids.
Figure 6. Stereochemical course of nucleophilic addition to furanyl
oxycarbenium ions according to Woerpel’s model.23
CONCLUSIONS
■
due to pseudoaxial arrangement of all substituents in E4 con-
In conclusion, an attractive method for the formation of
polyhydroxylated piperidine and pyrrolidine peptidomimetic
scaffolds was developed. The presented strategy is based on the
former (Scheme 3). As a result, the alternative reaction course
4
via the all-equatorially substituted conformer E should also be
possible and as a consequence lead to a poorly selective reac-
tion. Such prediction is in agreement with our experimental
observations (see Table 1, entries 12 and 13) as well as
experimental results and computational predictions reported by
others.16h
́
one-pot, sugar-derived lactam reduction/Joullie−Ugi reaction.
The key advantage of the presented approach is the simplicity
and convenience of generation of sugar-derived imines from
readily available starting materials: sugar-derived lactams. As
demonstrated, the developed strategy enables not only the
synthesis of proline amides but also pipecolic acid amides. The
use of sugar-derived lactams as cyclic imine precursors is crucial
to the efficiency of the described synthetic method. These
compounds are more readily prepared, handled, and stored
Following the analogous rules developed by Woerpel et al.25b,f,g
for C-allylation of pyranosyl oxycarbenium ions (Figure 7), the
course of the isocyanide addition to six-membered imines can
be explained similarly.
E
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Scheme 3
(2S,3S,4S,5R,6R)-3,4,5-Tris(benzyloxy)-6-[(benzyloxy)methyl)]-N-
tert-butyl-1-(2,2,2 trifluoroacetyl)piperidine-2-carboxamide (10):
mixture of rotamers; colorless oil; isolated yield 173 mg (69%)
starting from 187 mg (0.35 mmol) of compound 1; dr > 95:5
1
(determined by H NMR of crude reaction mixture after hydrolysis);
TLC Rf 0.74 (2:3 AcOEt/hexanes); flash column chromatography
23
1
(1:9 AcOEt/hexanes); [α]D −11.1 (c 0.43, CHCl3); H NMR (600
MHz, toluene, 75 °C, mixture of rotamers) δ: 7.22−7.18 (m, 2H),
7.15−6.95 (m, 18H), 6.73 (s, 1H), 4.73 (d, J 6.0 Hz, 1H), 4.62 (dd,
J 13.9, 6.9 Hz, 1H), 4.57 (d, J 11.5 Hz, 1H), 4.49−4.44 (m, 1H), 4.33−
4.18 (m, 7H), 4.15−4.07 (m, 1H), 4.00 (d, J 6.8 Hz, 1H), 3.78 (d, J 5.9
Hz, 1H), 3.74−3.70 (m, 1H), 1.18 (s, 9H); 13C NMR (151 MHz,
toluene, 75 °C) δ 165.1, 158.4 (d, J 36.1 Hz), 137.9, 137.7 (2×),
137.6, 128.6−127.2 (aromatic overlap), 116.5 (q, J 290.0 Hz), 78.6,
76.7, 76.2, 73.9, 73.3, 71.6, 70.9, 67.8, 59.3, 56.1, 50.8, 28.3; HRMS
(ESI-TOF) m/z calcd for C41H45N2O6NaF3 [M + Na+] 741.3127,
found 741.3115; IR (film) ν 3369, 3032, 2965, 2927, 2869, 1708,
1680, 1534, 1454, 1200, 1149, 1091, 1074, 738, 698 cm−1.
Figure 7. Stereochemical course of nucleophilic addition to pyranosyl
oxycarbenium ions according to Woerpel’s model.23
Scheme 4
(2S,3S,4S,5R,6R)-3,4,5-Tris(benzyloxy)-6-[(benzyloxy)methyl)]-N-
cyclohexyl-1-(2,2,2-trifluoroacetyl)piperidine-2-carboxamide (11:).
mixture of rotamers; colorless oil; isolated yield 180 mg (74%) starting
from 176 mg (0.33 mmol) of compound 1; dr > 95:5 (determined
1
by H NMR of crude reaction mixture after hydrolysis); TLC Rf 0.72
(2:3 AcOEt/hexanes); flash column chromatography (1:9 AcOEt/
hexanes); [α]D23 −5.9 (c 0.42, CHCl3); 1H NMR (600 MHz, toluene,
75 °C) δ 7.23−7.19 (m, 2H), 7.16−6.96 (m, 18H), 6.78 (d, J 7.6 Hz,
1H), 4.84 (d, J 6.1 Hz, 1H), 4.66−4.59 (m, 2H), 4.50−4.44 (m, 1H),
4.36−4.21 (m, 6H), 4.19 (d, J 11.5 Hz, 1H), 4.03 (d, J 6.9 Hz, 1H),
3.80 (d, J 6.1 Hz, 1H), 3.79−3.72 (m, 3H), 1.71−1.65 (m, 1H), 1.64−
1.58 (m, 1H), 1.43−1.34 (m, 2H), 1.33−1.24 (m, 1H), 1.13−1.01 (m,
2H), 0.93−0.71 (m, 3H); 13C NMR (151 MHz, toluene, 75 °C) δ
164.9, 158.4 (d, J 35.8 Hz), 138.0, 137.66, 137.65, 137.6, 128.6−127.2
(aromatic overlap), 116.5 (q, J 289.5 Hz), 78.5, 76.7, 76.3, 73.9, 73.4,
71.7, 71.0, 68.0, 59.1, 56.2, 48.0, 32.5, 32.3, 25.3, 24.5, 24.4; HRMS
(ESI-TOF) m/z calcd for C43H47N2O6NaF3 [M + Na+] 767.3284,
found 767.3265; IR (film) ν 3364, 3031, 2930, 2855, 1705, 1676,
1534, 1454, 1202, 1149, 1092, 1075, 737, 698 cm−1.
than the alternative precursors of cyclic imines such as nitrones,
N-chloroamines, or azido aldehydes. As demonstrated, there is
no need to isolate the imines generated in situ as they can be
directly used in the subsequent reaction with isocyanide and
carboxylic acid.
(2S,3S,4S,5R,6R)-3,4,5-Tris(benzyloxy)-6-[(benzyloxy)methyl)]-N-
(4-methoxyphenyl)-1-(2,2,2-trifluoroacetyl)piperidine-2-carboxamide
(12): mixture of rotamers; coloress oil; isolated yield 175 mg (86%)
starting from 142 mg (0.26 mmol) of compound 1; TLC Rf 0.38
(1:4 AcOEt/hexanes); flash column chromatography (1:9 than 1:4
EXPERIMENTAL SECTION
■
General Procedure for One-Pot Lactam Reduction/Ugi−
23
1
́
Joullie Reaction. A solution of lactam (0.5 mmol) in THF (5 mL)
AcOEt/hexanes); [α]D −4.7 (c 0.19, CHCl3); H NMR (600 MHz,
PhMe-d7, at 75 °C) δ 8.71 (s, 1H), 7.32−7.25 (m, 2H), 7.20−6.95 (m,
20H), 6.60−6.56 (m, 2H), 4.96 (d, J 6.2 Hz, 1H), 4.74 (dd, J 13.4,
6.8 Hz, 1H), 4.61 (d, J 11.5 Hz, 1H), 4.49 (d, J 11.4 Hz, 1H), 4.32 (d,
J 11.4 Hz, 1H), 4.30−4.23 (m, 5H), 4.18 (d, J 11.5 Hz, 1H), 4.14−
4.03 (m, 2H), 3.84 (d, J 6.1 Hz, 1H), 3.77−3.70 (m, 1H), 3.35 (s,
3H); 13C NMR (151 MHz, PhMe-d7, at 75 °C) δ 164.0, 158.5 (d,
J 36.2 Hz), 156.5, 138.0−136.7 (aromatic overlap), 131.6, 128.7−
127.2 (aromatic overlap), 121.2, 116.5 (q, J 289.2 Hz), 114.0, 79.1,
77.1, 75.9, 74.0, 73.4, 71.9, 71.0, 67.9, 59.1, 55.9, 54.5; HRMS (ESI-
TOF) m/z calcd for C44H43N2O7NaF3 [M + Na+] 791.2920, found
791.2914; IR (film) ν 3334, 3031, 2931, 2869, 2837, 1705, 1687, 1538,
1511, 1454, 1245, 1202, 1148, 1089, 1074, 1030, 738, 698 cm−1.
(3S,4S,5S,6R)-3,4,5-Tris(benzyloxy)-6-[(benzyloxy)methyl)]-N-tert-
butyl-1-(2,2,2-trifluoroacetyl)piperidine-2-carboxamide (13/2-epi-13):
mixture of rotamers 4:1 and diastereoisomers; colorless oil; isolated
yield 161 mg (63%) starting from 191 mg (0.36 mmol) of compound
was added to a solution of Cp2Zr(H)Cl (Schwartz’s reagent; 1.6 equiv,
206 mg, 0.8 mmol) in THF (5 mL). The initially formed white
suspension disappeared during the reaction progress; formation of
a clear solution indicated the end of the reaction (ca. 1.5 h, TLC
monitoring). The solution was then cooled to −78 °C, trifluoroacetic
acid (4.0 equiv, 2.0 mmol, 228 mg, 155 μL) and isocyanide
(1.25 equiv., 0.625 mmol) were successively added, and the reaction
mixture was allowed to warm to room temperature and stirred over-
night. The reaction was quenched with saturated aqueous NaHCO3
(5 mL) and diluted with Et2O (5 mL). The organic layer was separated,
and the aqueous layer was washed with Et2O (3 × 5 mL). The com-
bined organic layers were dried over anhydrous Na2SO4, and the
solvent was removed. The residue was purified by chromatography
on silica gel to give the corresponding product. In cases when the
isomeric products could not be separated by column chromatography,
the crude mixture of trifluoroacetates was submitted directly to the
next step.
1
2; dr 86:14 (determined by H NMR of crude reaction mixture after
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23
hydrolysis); TLC Rf 0.75 (1:2 AcOEt/hexanes); HRMS (ESI-TOF)
m/z calcd for C41H45N2O6NaF3 [M + Na+] 741.3127, found 741.3107.
Products were not isolated but directly submitted to the hydrolysis step.
(3S,4S,5S,6R)-3,4,5-Tris(benzyloxy)-6-[(benzyloxy)methyl)]-N-cyclohexyl-
1-(2,2,2-trifluoroacetyl)piperidine-2-carboxamide (14/2-epi-14): mixture
of rotamers and diastereoisomers; colorless oil; isolated yield 147 mg
(67%) starting from 158 mg (0.29 mmol) of compound 2; dr 82:18
[α]D +3.9 (c 2.6, CHCl3); major rotamer 1H NMR (400 MHz,
CDCl3) δ 7.39−7.23 (m, 13H), 7.23−7.17 (m, 2H), 6.39 (s, 1H),
4.66−4.49 (m, 7H), 4.46−4.42 (m, 2H), 4.05 (d, J 4.1 Hz, 1H), 3.69
(dd, J 10.2, 4.7 Hz, 1H), 3.55 (dd, J 10.2, 2.6 Hz, 1H), 1.11 (s, 9H);
13C NMR (101 MHz, CDCl3) δ 166.5, 137.6, 137.3, 136.9, 128.51,
128.49, 128.38, 128.2, 128.1, 128.0, 127.9, 127.5, 78.9, 76.5, 73.5, 72.8,
72.1, 67.0, 64.0, 51.2, 28.2; HRMS (ESI-TOF) m/z calcd for
C33H37N2O5NaF3 [M + Na+] 621.2552, found 621.2540; IR (film)
ν 3376, 3063, 3032, 2965, 2921, 2868, 1691, 1514, 1453, 1363, 1197,
1145, 1023, 958, 738, 699 cm−1.
(2R,3S,4R,5R)-3,4-Bis(benzyloxy)-5-[(benzyloxy)methyl)]-N-tert-butyl-
1-(2,2,2-trifluoroacetyl)pyrrolidine-2-carboxamide (2-epi-18): mixture
of rotamers; colorless oil; isolated yield 23 mg (12%) starting from
135 mg (0.32 mmol) of compound 4; TLC Rf 0.56 (1:4 AcOEt/hexanes);
1
(determined by H NMR of crude reaction mixture after hydrolysis);
TLC Rf 0.74 (1:2 AcOEt/hexanes); HRMS (ESI-TOF) m/z calcd for
C43H47N2O6NaF3 [M + Na+] 767.3284, found 767.3257. Products
were not isolated but directly submitted to the hydrolysis step.
(3R,4R,5R)-3,4,5-Tris(benzyloxy)-N-tert-butyl-1-(2,2,2-
trifluoroacetyl)piperidine-2-carboxamide (15/2-epi-15): mixture of
rotamers 2.5:1 and diastereoisomers; colorless oil; isolated yield 132 mg
(76%) starting from 121 mg (0.29 mmol) of compound 3; dr 75:25
23
flash column chromatography (10% AcOEt in hexanes); [α]D −7.1
1
(determined by H NMR of crude reaction mixture after hydrolysis);
(c 0.5, CHCl3); major rotamer: 1H NMR (400 MHz, CDCl3) δ 7.38−
7.27 (m, 1H), 4.61−4.58 (m, 2H), 4.54−4.50 (m, 2H), 4.43−4.40 (m,
2H), 4.29 (s, 1H), 4.27−4.21 (m, 1H), 4.12−4.08 (m, 1H), 3.82−3.75
(m, 1H), 3.55 (dd, J 10.1, 2.5 Hz, 1H), 1.26 (s, 1H); HRMS (ESI-
TOF) m/z calcd for C33H37N2O5NaF3 [M + Na+] 621.2552, found
621.2552; IR (film) ν 3335, 3064, 2926, 28671694, 1454, 1204, 1146,
1027, 737, 698 cm−1.
TLC Rf 0.85 (1:2 AcOEt/hexanes); HRMS (ESI-TOF) m/z calcd for
C33H37N2O5NaF3 [M + Na+] 621.2552, found 621.2544. Products were
not isolated but directly submitted to the hydrolysis step.
(2S,3R,4R,5R)-3,4,5-Tris(benzyloxy)-N-cyclohexyl-1-(2,2,2-
trifluoroacetyl)piperidine-2-carboxamide (16/2-epi-16:). mixture of
rotamers and diastereoisomers; colorless oil; isolated yield 161 mg
(84%) starting from 128 mg (0.31 mmol) of compound 3; dr 80:20
(2S,3S,4R,5R)-3,4-Bis(benzyloxy)-5-[(benzyloxy)methyl)]-N-cyclohexyl-
1-(2,2,2-trifluoroacetyl)pyrrolidine-2-carboxamide (19:). mixture of
rotamers 3:1; colorless oil; isolated yield 143 mg (63%) starting
from 152 mg (0.36 mmol) of compound 4; dr > 95:5 (determined
by H NMR of crude reaction mixture after hydrolysis); TLC Rf 0.78
(1:4 AcOEt/hexanes); flash column chromatography (12% AcOEt in
hexanes); [α]D −9.4 (c 4.7, CHCl3); H NMR (500 MHz, CDCl3)
δ 7.40−7.14 (m, 15H), 4.76−4.72 (m, 1H), 4.67−4.54 (m, 4H), 4.53−
4.48 (m, 2H), 4.45−4.40 (m, 2H), 4.03 (d, J 4.2 Hz, 1H), 3.69 (dd,
J 10.2, 4.7 Hz, 2H), 3.67−3.62 (m, 1H), 3.55 (dd, J 10.2, 2.6 Hz, 1H),
1.70−1.57 (m, 2H), 1.53−1.41 (m, 3H), 1.28−1.13 (m, 2H), 1.05−
0.95 (m, 1H), 0.91−0.78 (m, 2H); 13C NMR (126 MHz, CDCl3)
δ 166.9, 137.5, 137.1, 136.8, 128.5, 128.5, 128.4, 128.2, 128.0, 127.5,
78.8, 76.3, 73.4, 72.9, 71.9, 66.9, 63.9, 61.81, 61.79, 48.5, 32.3,
32.2, 25.5, 24.4; HRMS (ESI-TOF) m/z calcd for C35H39N2O5NaF3
[M + Na+] 647.2709, found 647.2703; IR (film) ν 3361, 2930, 2855,
1686, 1538, 1452, 1198, 1146, 735, 698 cm−1.
1
(determined by H NMR of crude reaction mixture after hydrolysis);
TLC Rf 0.85 (1:2 AcOEt/hexanes); HRMS (ESI-TOF) m/z calcd
for C35H39N2O5NaF3 [M + Na+] 647.2709, found 647.2708. Products
were not isolated but directly submitted to the hydrolysis step.
(2S,3R,4R,5R)-3,4,5-Tris(benzyloxy)-N-(4-methoxyphenyl)-1-
(2,2,2-trifluoroacetyl)piperidine-2-carboxamide (17): mixture of
rotamers; colorless oil; isolated yield 78 mg (40%) starting from
125 mg (0.30 mmol) of compound 3; TLC Rf 0.42 (1:4 hexanes/
AcOEt); column chromatography (1:9 AcOEt/hexanes); [α]D23 −65.3
1
23
1
1
(c 0.34, CHCl3); H NMR (600 MHz, pyridine-d5) δ 11.36 (s, 1H),
7.84−7.80 (m, 2H), 7.56−7.53 (m, 2H), 7.50−7.43 (m, 4H), 7.37−
7.23 (m, 9H), 6.96−6.92 (m, 2H), 6.04 (d, J 6.9 Hz, 1H), 4.97 (d,
J 11.6 Hz, 2H), 4.92 (d, J 11.6 Hz, 2H), 4.87 (s, 2H), 4.78−4.71 (m,
3H), 4.58 (dd, J 10.0, 6.9 Hz, 1H), 4.50 (d, J 13.6 Hz, 1H), 4.36 (d,
J 14.1 Hz, 1H), 4.26 (s, 1H), 3.60 (s, 3H); 13C NMR (151 MHz,
pyridine-d5) δ 168.1, 158.9 (d, J 35.5 Hz), 158.1, 140.6, 140.2, 140.1,
133.7, 130.1−128.8 (aromatic overlap), 123.6, 118.5 (q, J 288.2 Hz),
115.7, 80.8, 76.5, 75.4, 74.6, 74.1, 74.0, 58.4, 56.5, 47.8; HRMS (ESI-
TOF) m/z calcd for C36H35N2O6NaF3 [M + Na+] 671.2345, found
671.2344; IR (film) ν 3438, 2935, 1677, 1511, 1455, 1203, 1097, 1027,
735, 698 cm−1.
(2R,3R,4R,5R)-3,4-Bis(benzyloxy)-5-[(benzyloxy)methyl)]-N-tert-butyl-
1-(2,2,2-trifluoroacetyl)pyrrolidine-2-carboxamide (20): mixture of
rotamers and diastereoisomers; colorless oil; isolated yield 149 mg
(83%) starting from 125 mg (0.30 mmol) of compound 5; dr 57:43
1
(determined by H NMR of crude reaction mixture after hydrolysis);
(2S,3R,4R,5R)-3,4,5-Tris(benzyloxy)-N-(4-methoxyphenyl)-1-
(2,2,2-trifluoroacetyl)piperidine-2-carboxamide (2-epi-17): mixture
of rotamers (1:0.7); colorless oil; isolated yield 54 mg (28%) starting
from 125 mg (0.30 mmol) of compound 3; TLC Rf 0.38 (1:4 AcOEt/
TLC Rf 0.55 (1:4 AcOEt/hexanes); HRMS (ESI-TOF) m/z calcd
for C33H37N2O5NaF3 [M + Na+] 621.2552, found 621.2543, found
647.2708. Products were not isolated but directly submitted to the
hydrolysis step.
(2R,3R,4R,5R)-3,4-Bis(benzyloxy)-5-[(benzyloxy)methyl)]-N-cyclohexyl-
1-(2,2,2-trifluoroacetyl)pyrrolidine-2-carboxamide (21:). mixture of
rotamers and diastereoisomers; colorless oil; isolated yield 135 mg
(75%) starting from 120 mg (0.29 mmol) of compound 5; dr > 63:37
23
hexanes); column chromatography (1:9 AcOEt/hexanes); [α]D
1
−38.3 (c 0.21, CHCl3); H NMR (600 MHz, pyridine-d5) δ 10.04
(s, 0.7H), 10.00* (s, 1H), 6.89−6.83* (m, 3.4H), 6.80−6.45* (m,
25.5H), 6.16−6.09* (m, 3.4H), 5.27* (s, 1H), 4.47 (s, 0.7H), 4.42−
4.39 (m, 0.7H), 4.32−4.29* (m, 1H), 4.23−4.11* (m, 3.4H), 4.07* (d,
J 12.0 Hz, 1H), 3.96−3.77* (m, 6.5H), 3.72* (d, J 11.4 Hz, 1H),
3.63−3.59* (m, 1H), 3.56 (d, J 3.4 Hz, 0.7H), 3.52* (ddd, J 11.3, 4.5,
2.4 Hz, 1H), 3.47−3.42 (m, 0.7H), 3.41−3.39* (m, 1.7H), 2.83 (s,
2.1H), 2.82* (s, 3H); *major rotamer; 13C NMR** (151 MHz,
pyridine-d5) δ 166.7, 158.4, 158.0, 140.13, 140.08, 140.04, 140.01,
139.44, 139.42, 133.5, 133.2, 130.2−129.1 (aromatic overlap), 125.3,
124.7, 116.6 (q, J 269.9 Hz), 115.6, 115.5, 78.2, 77.7, 75.8, 75.5, 74.6,
74.4, 74.3, 73.6, 73.5, 73.3, 72.6, 72.4, 61.1, 58.2, 56.54, 56.52, 44.1,
41.4; **both rotamers; HRMS (ESI-TOF) m/z calcd for
C36H35N2O6NaF3 [M + Na+] 671.2345, found 671.2339; IR (film)
ν 3320, 3032, 2933, 2870, 1698, 1512, 1455, 1200, 1145, 1029, 738,
698 cm−1.
1
(determined by H NMR of crude reaction mixture after hydrolysis);
TLC Rf 0.55 (1:4 AcOEt/hexanes); HRMS (ESI-TOF) m/z calcd for
C35H39N2O5NaF3 [M + Na+] 647.2709, found 647.2706. Products
were not isolated but directly submitted to the hydrolysis step.
(2S,3R,4R)-3,4-Bis(benzyloxy)-N-tert-butyl-1-(2,2,2-trifluoroacetyl)-
pyrrolidine-2-carboxamide (22): mixture of rotamers 3:1; colorless
oil; isolated yield 95 mg (38%) starting from 156 mg (0.52 mmol) of
compound 6; TLC Rf 0.72 (1:2 AcOEt/hexanes); flash column
23
chromatography (18% AcOEt in hexanes); [α]D +29.8 (c 2.7,
CHCl3); major rotamer: H NMR (500 MHz, pyridine-d5) δ 7.79−
1
7.62 (m, 1H), 5.35−4.89 (m, 7H), 4.68 (dd, J 10.2, 5.8 Hz, 1H), 4.52
(dd, J 10.3, 6.1 Hz, 1H), 4.29 (dd, J 11.1, 5.6 Hz, 1H), 1.71 (s, 9H);
major rotamer: 13C NMR (126 MHz, pyridine-d5) δ 168.0, 138.3,
138.3, 128.9, 128.4, 128.4, 84.0, 81.3, 72.5, 72.3, 67.2, 51.5, 28.7;
HRMS (ESI-TOF) m/z calcd for C25H29N2O4NaF3 [M + Na+]
501.1977, found 501.1969; IR (film) ν 3333, 3064, 3030, 2968, 2929,
2873, 1697, 1531, 1455, 1365, 1207, 1207, 1179, 1146, 1098, 739, 698 cm−1.
(2S,3S,4R,5R)-3,4-Bis(benzyloxy)-5-[(benzyloxy)methyl)]-N-tert-
butyl-1-(2,2,2-trifluoroacetyl)pyrrolidine-2-carboxamide (18): mix-
ture of rotamers 5:1; colorless oil; isolated yield 116 mg (60%) starting
from 135 mg (0.32 mmol) of compound 4; TLC Rf 0.53 (1:4 AcOEt/
hexanes); flash column chromatography (12% AcOEt in hexanes);
G
DOI: 10.1021/acs.joc.5b00335
J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Article
(2R,3R,4R)-3,4-Bis(benzyloxy)-N-tert-butyl-1-(2,2,2-trifluoroacetyl)-
pyrrolidine-2-carboxamide (2-epi-22): mixture of rotamers; colorless
oil; isolated yield 55 mg (22%) starting from 156 mg (0.52 mmol) of
compound 6; TLC Rf 0.68 (1:2 AcOEt/hexanes); flash column
chromatography (21% AcOEt in hexanes); [α]D23 +3.2 (c 1.2, CHCl3);
δ 7.4 (s, 1H), 7.39−7.22 (m, 12H), 6.80−6.76 (m, 2H), 4.74−4.71 (m,
1H), 4.67 (d, J 11.9 Hz, 1H), 4.63−4.56 (m, 2H), 4.52 (d, J 11.9 Hz,
1H), 4.35 (dd, J 9.7, 4.5 Hz, 1H), 4.32−4.29 (m, 1H), 4.08 (dd, J 11.3,
5.5 Hz, 1H), 3.77 (s, 3H), 3.75−3.72 (m, 1H); 13C NMR (126 MHz,
CDCl3) δ 167.0, 160.0 (d, J 37.8 Hz), 159.3, 139.7, 139.6, 132.8, 131.3,
131.2, 130.90, 130.85, 130.7, 130.4, 124.7, 118.6 (q, J 287.6 Hz), 116.7,
82.8, 82.1, 76.1, 75.0, 66.7, 58.1, 53.2; HRMS (ESI-TOF) m/z calcd
for C28H27N2O5NaF3 [M + Na+] 551.1770, found 551.1762; IR (film,
CH2Cl2) ν 3278, 3033, 2935, 2838, 1693, 1512, 1454, 1243, 1146,
1031, 740, 699 cm−1.
(2S,3S,4R)-3,4-Bis(benzyloxy)-N-tert-butyl-1-(2,2,2-trifluoroacetyl)-
pyrrolidine-2-carboxamide (25:). mixture of rotamers; yellowish oil;
isolated yield 60%; Rf 0.3 (3:2 hexanes/AcOEt); HRMS (ESI-TOF)
m/z calcd for C25H29N2O4NaF3 [M + Na+] 501.1977, found 501.1979.
Products were not isolated but used directly in the hydrolysis step.
(2S,3S,4R)-3,4-Bis(benzyloxy)-N-(4-methoxyphenyl)-1-(2,2,2-
trifluoroacetyl)pyrrolidine-2-carboxamide (26:). mixture of two
rotamers; colorless oil; isolated yield 68%; TLC Rf 0.28 (3:2 hexanes/
AcOEt); HRMS (ESI-TOF) m/z calcd for C28H27N2O5NaF3 [M + Na+]
551.1770, found 551.1775. Products were not isolated but used directly in
the hydrolysis step.
1
major rotamer H NMR (500 MHz, pyridine-d5) δ 6.14−6.10 (m,
2H), 6.00−5.94 (m, 2H), 5.93−5.83 (m, 6H), 3.77 (d, J 7.1 Hz, 1H),
3.51 (d, J 11.9 Hz, 1H), 3.41 (d, J 11.8 Hz, 1H), 3.30 (dd, J 11.2, 5.4
Hz, 1H), 3.19 (d, J 11.8 Hz, 1H), 3.13 (d, J 11.8 Hz, 1H), 3.00 (dd,
J 7.1, 5.5 Hz, 1H), 2.86 (dd, J 11.2, 6.1 Hz, 1H), 2.33 (dd, J 10.8,
4.4 Hz, 1H), 0.00 (s, 9H); major rotamer 13C NMR (126 MHz,
pyridine-d5) δ 164.9, 137.1, 137.0, 127.4, 127.3, 126.75, 126.6, 79.6,
78.8, 71.7, 70.9, 62.2, 50.1, 27.4; HRMS (ESI-TOF) m/z calcd for
C25H29N2O4NaF3 [M + Na+] 501.1977, found 501.1974; IR (film)
ν 3322, 2969, 2929, 2870, 1690, 1551, 1455, 1147, 1105, 738, 698 cm−1.
(2S,3R,4R)-3,4-Bis(benzyloxy)-N-cyclohexyl-1-(2,2,2-trifluoroacetyl)-
pyrrolidine-2-carboxamide (23:). mixture of rotamers 2:1; white
crystals; mp 143−144 °C; isolated yield 89 mg (34%) starting from
155 mg (0.52 mmol) of compound 6; TLC Rf 0.80 (1:2 AcOEt/
hexanes); flash column chromatography (15% AcOEt in hexanes);
23
1
[α]D +29.5 (c 2.8, CHCl3); major rotamer H NMR (500 MHz,
pyridine-d5) δ 6.67−6.45 (m, 10H), 4.20 (d, J 3.1 Hz, 1H), 4.08 (s,
1H), 3.98 (d, J 6.1 Hz, 1H), 3.95 (t, J 3.5 Hz, 1H), 3.91−3.88 (m, 1H),
3.80 (d, J 11.5 Hz, 1H), 3.55 (dd, J 9.5, 5.0 Hz, 1H), 3.38 (dd, J 11.0,
5.8 Hz, 1H), 3.21−3.12 (m, 3H), 1.15−1.08 (m, 1H), 1.02 (d, J 10.4
Hz, 1H), 0.74−0.60 (m, 2H), 0.58−0.49 (m, 1H), 0.37−0.17 (m, 4H),
0.08−0.04 (m, 1H); major rotamer 13C NMR (126 MHz, pyridine-d5)
δ 166.0, 136.8, 127.41, 127.39, 127.0, 126.82, 126.80, 82.3, 79.7, 70.9,
70.7, 65.7, 47.6, 31.6, 31.5, 24.3, 23.9, 23.9; HRMS (ESI-TOF) m/z
calcd for C27H31N2O4NaF3 [M + Na+] 527.2134, found 527.2123; IR
(film) ν 3285, 2931, 2854, 1700, 1659, 1591, 1453, 1145, 732, 696 cm−1.
(2R,3R,4R)-3,4-Bis(benzyloxy)-N-cyclohexyl-1-(2,2,2-trifluoroacetyl)-
pyrrolidine-2-carboxamide (2-epi-23): mixture of rotamers 2:1; white
crystal; mp 128−129 °C; isolated yield 68 mg (26%) starting from 155
mg (0.52 mmol) of compound 6; TLC Rf 0.73 (1:2 AcOEt/hexanes);
flash column chromatography (19% AcOEt in hexanes); [α]D23 +13.9
(c 2.4, CHCl3); major rotamer 1H NMR (500 MHz, pyridine-d5)
δ 7.57−7.50 (m, 2H), 7.43−7.26 (m, 8H), 5.22 (d, J 7.0 Hz, 1H),
5.00−4.93 (m, 1H), 4.85 (d, J 11.9 Hz, 1H), 4.77 (dd, J 10.8, 5.3 Hz,
1H), 4.66 (d, J 11.8 Hz, 1H), 4.61 (d, J 11.8 Hz, 1H), 4.49 (dd, J 6.9,
5.3 Hz, 1H), 4.32 (dd, J 11.4, 5.9 Hz, 1H), 4.11−4.02 (m, 1H), 3.80
(dd, J 11.3, 4.5 Hz, 1H), 2.06−1.94 (m, 1H), 1.60−1.45 (m, 2H),
1.43−1.33 (m, 1H), 1.32−1.06 (m, 4H), 0.98−0.86 (m, 1H); major
rotamer 13C NMR (126 MHz, pyridine-d5) δ 164.7, 137.1, 137.0, 127.4,
126.7, 126.6, 79.5, 78.7, 71.7, 70.8, 62.2, 47.6, 31.9, 31.9, 24.3, 23.9, 23.9;
HRMS (ESI-TOF) m/z calcd for C27H31N2O4NaF3 [M + Na+]
527.2134., found 527.2128; IR (film) ν 3292, 3064, 3032, 2932, 2856,
1698, 1660, 1551, 1453, 1181, 1146, 1103, 737, 698 cm−1.
(2R,4R)-4-(Benzyloxy)-N-tert-butyl-1-(2,2,2-trifluoroacetyl)-
pyrrolidine-2-carboxamide (27). mixture of rotamers and diaster-
eosiomers; colorless oil; isolated yield 165 mg (58%) starting from
1
146 mg (0.76 mmol) of compound 8; dr 77:23 (determined by H
NMR of crude reaction mixture after hydrolysis); TLC Rf 0.3 (2:3
AcOEt/hexanes); HRMS (ESI-TOF) m/z calcd for C18H23N2O3NaF3
[M + Na+]: 395.1558; found 395.1555; Products were not isolated but
used directly in the hydrolysis step.
(2R,4R)-4-(Benzyloxy)-N-cyclohexyl-1-(2,2,2-trifluoroacetyl)-
pyrrolidine-2-carboxamide (28): mixture of rotamers; colorless
crystals; mp 115−116 °C; isolated yield 162 mg (54%) starting
from 144 mg (0.75 mmol) of compound 8; dr 74:26 (determined by
1H NMR of crude reaction mixture after hydrolysis); TLC Rf 0.26
(2:3 AcOEt/hexanes); column chromatography (1:4 than 3:7 AcOEt/
hexanes); [α]D23 −37.0 (c 0.2, CHCl3); 1H NMR (500 MHz, CDCl3)
δ 7.36−7.26 (m, 6.75H), 6.02* (d, J 6.9 Hz, 1H), 5.76 (d, J 8.0 Hz,
0.35H), 4.66 (d, J 9.4 Hz, 0.35H), 4.60−4.54* (m, 2H), 4.50 (d, J 11.4
Hz, 0.35H), 4.44−4.38* (m, 1.35H), 4.25−4.21* (m, 1H), 4.20−4.17
(m, 0.35H), 3.91−3.78* (m, 2.7H), 3.70−3.58* (m, 1.35H), 2.74 (d,
J 14.1 Hz, 0.35H), 2.67* (d, J 14.0 Hz, 1H), 2.32−2.22 (m, 0.35H),
2.17* (ddd, J 14.1, 9.7, 4.7 Hz, 1H), 1.96−1.89 (m, 0.35H), 1.84−
1.76* (m, 1H), 1.74−1.68 (m, 0.35H), 1.68−1.57* (m, 2H), 1.57−
1.49* (m, 2H), 1.48−1.38 (m, 0.7H), 1.35−1.14* (m, 3.05H), 1.13−
0.93* (m, 2.7H), 0.93−0.83* (m, 1H), 0.76 (ddd, J 15.0, 11.7, 3.0 Hz,
0.35H); * major rotamer 13C NMR (126 MHz, CDCl3) δ 169.2,
168.2*, 157.2 (d, J 37.4 Hz), 156.7* (d, J 37.5 Hz), 136.91*, 136.85,
128.5−128.0 (aromatic overlap), 116.3* (q, J 286.6 Hz), 115.5 (q,
J 288.0 Hz), 76.6*, 74.2, 71.0*, 70.8, 61.4*, 60.8, 55.4, 53.4*, 48.5,
48.2*, 36.5, 32.60, 32.55*, 32.5*, 32.3*, 32.1, 25.4*, 25.3, 24.79, 24.75,
24.5* (2×); * major rotamer; HRMS (ESI-TOF) m/z calcd for
C20H25N2O3NaF3 [M + Na+] 421.1715, found 421.1707; IR (film)
ν 3308, 2932, 2855, 1696, 1544, 1452, 1249, 1208, 1147, 1004,
(2R,3S,4S)-3,4-Bis(benzyloxy)-N-(4-methoxyphenyl)-1-(2,2,2-
trifluoroacetyl)pyrrolidine-2-carboxamide (24): mixture of rotamers;
white crystals; mp 139−140 °C; isolated yield 105 mg (38%) starting
from 156 mg (0.52 mmol) of compound 6; TLC Rf 0.71 (2:3 AcOEt/
23
hexanes); flash column chromatography (1:9 AcOEt/hexanes); [α]D
1
732, 698 cm−1
.
+49.6 (c 0.19, CHCl3); H NMR (500 MHz, CDCl3) δ 7.8 (s, 1H),
7.39−7.32 (m, 5H), 7.30−7.25 (m, 3H), 7.23−7.19 (m, 2H), 7.17−
7.13 (m, 2H), 6.79−6.74 (m, 2H), 4.77 (s, 1H), 4.72 (d, J 11.8 Hz,
1H), 4.63−4.56 (m, 3H), 4.43 (d, J 11.2 Hz, 1H), 4.16−4.14 (m, 1H),
4.03 (dd, J 11.5, 4.3 Hz, 1H), 3.96 (d, J 11.3 Hz, 1H), 3.77 (s, 3H);
13C NMR (126 MHz, CDCl3) δ 165.1, 157.5 (d, J 37.8 Hz), 156.6,
136.7, 136.4, 130.1, 128.7, 128.6, 128.28, 128.27, 128.2, 128.0, 122.0,
116.0 (q, J 287.4 Hz), 114.0, 80.7, 80.3, 72.0, 71.8, 67.7, 55.5, 52.1;
HRMS (ESI-TOF) m/z calcd for C28H27N2O5NaF3 [M + Na+]
551.1770, found 551.1761; IR (film, CH2Cl2) ν 3299, 3032, 2910,
2836, 1703, 1673, 1512, 1455, 1238, 1147, 1030, 733, 697 cm−1.
(2S,3S,4S)-3,4-Bis(benzyloxy)-N-(4-methoxyphenyl)-1-(2,2,2-
trifluoroacetyl)pyrrolidine-2-carboxamide (2-epi-24). mixture of
rotamers; white crystals; mp 116−117 °C; isolated yield 71 mg
(26%) starting from 156 mg (0.52 mmol) of compound 6; TLC
Rf 0.60 (2:3 AcOEt/hexanes); Column chromatography (3:7 AcOEt/
hexanes); [α]D23 +15.9 (c 0.63, CHCl3); 1H NMR (500 MHz, CDCl3)
(2S,3R)-3-(Benzyloxy)-N-isopropyl-1-(2,2,2-trifluoroacetyl)-
pyrrolidine-2-carboxamide (29): mixture of rotamers 3:1; colorless
oil; isolated yield 112 mg (39%) starting from 148 mg (0.77 mmol) of
compound 9; TLC Rf 0.35 (1:4 AcOEt/hexanes); column chro-
23
matography (22% AcOEt in hexanes); [α]D +13.4 (c 1.9, CHCl3);
1
major rotamer H NMR (400 MHz, CDCl3) δ 7.38−7.29 (m, 1H),
5.46 (s, 1H), 4.64−4.53 (m, 1H), 4.39 (d, J 6.9 Hz, 1H), 4.27 (dd,
J 13.6, 6.6 Hz, 1H), 4.02−3.94 (m, 1H), 3.71 (dd, J 17.6, 7.6 Hz, 1H),
2.34 (dq, J 12.5, 7.9 Hz, 1H), 2.19−2.11 (m, 1H), 1.30 (s, 9H); 13C
NMR (101 MHz, CDCl3) δ 165.6, 137.3, 128.5, 128.0, 127.7, 72.4,
64.3, 51.7, 28.6; HRMS (ESI-TOF) m/z calcd for C18H23N2O3NaF3
[M + Na+] 395.1558, found 395.1560; IR (film) ν 3333, 2969, 1687,
1546, 1454, 1364, 1244, 1206, 1146, 756, 736, 698 cm−1.
(2R,3R)-3-(Benzyloxy)-N-isopropyl-1-(2,2,2-trifluoroacetyl)-
pyrrolidine-2-carboxamide (2-epi-29): mixture of rotamers 8:1; colorless
oil; isolated yield 52 mg (18%) starting from 148 mg (0.77 mmol) of
H
DOI: 10.1021/acs.joc.5b00335
J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Article
compound 9; Rf 0.42 (1:4 AcOEt/hexanes); column chromatography
(15% AcOEt in hexanes); [α]D23 −13.4 (c 0.9, CHCl3); major rotamer
1H NMR (400 MHz, CDCl3) δ 7.40−7.28 (m, 1H), 6.07 (s, 1H),
4.57−4.54 (m, 1H), 4.44−4.42 (m, J 5.7 Hz, 1H), 4.31 (dd, J 2.7, 1.3
Hz, 1H), 3.85 (dd, J 9.6, 4.8 Hz, 2H), 2.41−2.30 (m, 1H), 2.22−2.15
(m, 1H), 1.31 (s, 9H).; 13C NMR (101 MHz, CDCl3) δ 167.0, 137.3,
128.6, 128.1, 127.8, 79.0, 71.4, 67.8, 51.7, 28.6; HRMS (ESI-TOF)
m/z calcd for C18H23N2O3NaF3 [M + Na+] 395.1558, found 395.1555;
IR (film) ν 3357, 2967, 1680, 1547, 1455, 1364, 1245, 1205, 1147,
756, 734, 698 cm−1.
1H, C(6)-CHHOBn), 3.54 (dd, J 9.6, 5.8 Hz, 1H, C(6)-CHHOBn),
3.45 (dd, J 9.4, 7.0 Hz, 1H, H-5), 3.11 (ddd, J 9.4, 5.8, 2.8 Hz, 1H,
H-6); 13C NMR (101 MHz, CDCl3) δ 169.1, 156.2, 138.3, 138.2,
138.1, 137.3, 131.2, 128.7, 128.5, 128.39, 128.37, 128.3, 128.2, 128.1,
128.0, 127.82, 127.80, 127.68, 127.67, 121.3, 114.1, 82.4, 79.6, 79.4,
74.6, 74.28, 74.26, 73.1, 69.9, 56.7, 55.5, 54.8; HRMS (ESI-TOF) m/z
calcd for C42H45N2O6 [M + H+] 673.3278, found 673.3272; IR (film)
ν 3311, 3061, 3030, 2908, 2864, 1678, 1512, 1435, 1244, 1069, 829,
738, 698 cm−1.
(2S,3S,4S,5S,6R)-3,4,5-Tris(benzyloxy)-6-[(benzyloxy)methyl)]-N-
tert-butylpiperidine-2-carboxamide (33): major isomer; yellow oil;
isolated yield 67 mg (50%) starting from 155 mg (0.22 mmol) of
mixture of 13/2-epi-13; TLC Rf 0.53 (1:2 AcOEt/hexanes); column
Hydrolysis of Trifluoroacetates 10−29. General Procedure.
The product (or crude postreaction mixture) of Ugi−Joullie reaction
́
(0.5 mmol) was dissolved in 2 mL of (2.5 M NaOH solution in
MeOH), and H2O (100 μL) was added. The reaction mixture was
stirred at room temperature for (ca. 0.5 h, TLC monitoring). When
hydrolysis was completed, the reaction mixture was diluted with H2O
(3 mL) and Et2O (3 mL). The organic layer was separated, and the
aqueous layer was washed with Et2O (3 × 3 mL). The combined
organic layers were dried over anhydrous Na2SO4, and the solvent was
removed. The residue was purified by chromatography on silica gel to
give the corresponding product.
23
chromatography (1:5 AcOEt/hexanes); [α]D −45.7 (c 0.8, CHCl3);
1H NMR (400 MHz, CDCl3) δ 7.34−7.21 (m, 18H), 7.15−7.12 (m,
2H), 4.67 (dd, J 3.7, 1.5 Hz, 1H), 4.63 (d, J 13.0 Hz, 1H), 4.58 (d,
J 12.2 Hz, 1H), 4.55−4.47 (m, 2H), 4.43 (d, J 12.2 Hz, 1H), 4.38 (d,
J 13.0 Hz, 1H), 4.28 (d, J 11.5 Hz, 1H), 4.21 (d, J 11.5 Hz, 1H), 3.88−
3.75 (m, 3H), 3.54 (dd, J 9.1, 2.5 Hz, 1H), 3.40 (d, J 1.2 Hz, 1H), 3.26
(dt, J 9.9, 2.6 Hz, 1H), 1.28 (s, 9H); 13C NMR (101 MHz, CDCl3)
δ 169.1, 156.2, 138.3, 138.1, 137.3, 128.7, 128.5, 128.4, 128.4, 128.2,
128.0, 127.8, 127.7, 127.7, 121.3, 114.1, 79.6, 74.6, 74.3, 74.3, 73.1,
69.9, 56.7, 55.5, 54.8; HRMS (ESI-TOF) m/z calcd for C39H47N2O5
[M + H+] 623.3485, found 623.3478; IR (film) ν 3347, 3030, 2961,
2924, 2865, 1673, 1514, 1454, 1364, 1103, 1028, 736, 698 cm−1.
(2R,3S,4S,5S,6R)-3,4,5-Tris(benzyloxy)-6-[(benzyloxy)methyl)]-N-
tert-butylpiperidine-2-carboxamide (2-epi-33): minor isomer; yellow
oil; isolated yield 11 mg (8%) starting from 155 mg (0.22 mmol)
of mixture of 13/2-epi-13; TLC Rf 0.39 (1:2 AcOEt/hexanes); flash
(2S,3S,4S,5R,6R)-3,4,5-Tris(benzyloxy)-6-[(benzyloxy)methyl)]-N-
tert-butylpiperidine-2-carboxamide (30): yellow oil; isolated yield
88 mg (59%) starting from 172 mg (0.24 mmol) of compound 10:
TLC Rf 0.30 (2:3 AcOEt/hexanes); column chromatography (3:7 to
23
1
2:3 AcOEt/hexanes); [α]D +54.5 (c 0.33, CHCl3); H NMR (600
MHz, CDCl3) δ 7.49 (s, 1H, CONH), 7.35−7.26 (m, 18H), 7.19−
7.17 (m, 2H), 4.83 (d, J 11.2 Hz, 1H, OCHHPh), 4.79−4.73 (m, 3H,
3 × OCHHPh), 4.68 (d, J 11.2 Hz, 1H, OCHHPh), 4.58 (d, J 12.1 Hz,
1H, OCHHPh), 4.48 (d, J 11.1 Hz, 1H, OCHHPh), 4.46 (d, J 12.4 Hz,
1H, OCHHPh), 4.03 (dd, J 8.6, 5.1 Hz, 1H, H-3), 3.64 (t, J 8.2 Hz,
1H, H-2), 3.62 (dd, J 9.6, 2.8 Hz, 1H, C(6)−CHHOBn), 3.60 (d, J 5.1
Hz, 1H, H-2), 3.51 (dd, J 9.6, 5.9 Hz, 1H, C(6)−CHHOBn), 3.43 (dd,
J 9.4, 7.7 Hz, 1H, H-5), 3.02 (ddd, J 9.4, 5.9, 2.8 Hz, 1H, H-6), 1.28 (s,
9H); 13C NMR (151 MHz, CDCl3) δ 172.4, 141.0, 140.9, 140.8,
140.1, 131.2, 131.1, 131.02, 130.98, 130.8, 130.74, 130.73, 130.6 (2×),
130.4, 130.3, 130.2, 85.1, 82.3 (2×), 77.3, 77.2, 76.7, 75.8, 72.6, 59.0,
57.7, 53.6, 31.5; HRMS (ESI-TOF) m/z calcd for C39H47N2O5
[M + H+] 623.3485, found 623.3475; IR (film) ν 3341, 3030, 2961,
2904, 2867, 1671, 1535, 1454, 1363, 1114, 1087, 1070, 737, 697 cm−1.
(2S,3S,4S,5R,6R)-3,4,5-Tris(benzyloxy)-6-[(benzyloxy)methyl)]-N-
cyclohexylpiperidine-2-carboxamide (31): yellow oil; isolated yield
81 mg (61%) starting from 152 mg (0.20 mmol) of compound 11;
TLC Rf 0.25 (2:3 AcOEt/hexanes); column chromatography on silica
23
column chromatography (1:5 AcOEt: hexanes); [α]D +30.9 (c 0.7,
CHCl3); 1H NMR (400 MHz, CDCl3) δ 7.38−7.17 (m, 20H), 4.67−
4.46 (m, 8H), 4.23 (dd, J 6.8, 3.6 Hz, 1H), 3.90 (dd, J 4.1, 2.9 Hz, 1H),
3.76−3.68 (m, 1H), 3.62−3.59 (m, 2H), 3.56 (dd, J 9.8, 4.3 Hz, 1H),
3.27 (dt, J 8.3, 4.0 Hz, 1H), 1.26 (s, 9H); 13C NMR (101 MHz,
CDCl3) δ 170.4, 138.5, 138.4, 138.3, 138.0, 128.4, 128.3, 128.2, 128.0,
127.9, 127.62, 127.56, 127.53, 74.5, 74.0, 73.2, 72.5, 54.7 50.9, 28.7;
HRMS (ESI-TOF) m/z calcd for C39H47N2O5 [M + H+] 623.3485,
found 623.3476; IR (film) ν 3348, 2925, 2868, 1672, 1519, 1454,
1364, 1095, 1028, 737, 697 cm−1.
(2S,3S,4S,5S,6R)-3,4,5-Tris(benzyloxy)-6-[(benzyloxy)methyl)]-N-
cyclohexylpiperidine-2-carboxamide (34): major isomer; colorless
oil; isolated yield 62 mg (50%) starting from 142 mg (0.19 mmol) of
mixture of 14/2-epi-14; TLC Rf 0.55 (1:2 AcOEt/hexanes); flash
23
column chromatography (25% AcOEt in hexanes); [α]D −32.3
(c 2.1, CHCl3); 1H NMR (400 MHz, CDCl3) δ 7.37−7.22 (m, 18H),
7.21−7.13 (m, 2H), 4.71 (dd, J 3.5, 1.5 Hz, 1H), 4.63 (d, J 12.3 Hz,
1H), 4.60 (d, J 12.2 Hz, 1H), 4.56−4.44 (m, 3H), 4.37 (d, J 12.3 Hz,
1H), 4.33 (d, J 11.7 Hz, 1H), 4.26 (d, J 11.6 Hz, 1H), 3.87−3.81 (m,
3H), 3.73−3.63 (m, 1H), 3.56 (dd, J 9.2, 2.6 Hz, 1H), 3.45 (s, 1H),
3.24 (d, J 9.8 Hz, 1H), 1.89−1.77 (m, 1H), 1.75−1.48 (m, 5H), 1.40−
1.01 (m, 6H); 13C NMR (101 MHz, CDCl3) δ 168.8, 138.44, 138.42,
138.37, 138.36, 128.4, 128.3, 128.24, 128.19, 128.09, 128.02, 127.6,
127.54, 127.50, 127.3, 74.7, 73.3, 72.8, 72.2, 71.7, 71.3, 70.9, 69.2, 57.1,
50.5, 47.4, 32.9, 32.8, 25.6, 24.7, 24.6; HRMS (ESI-TOF) m/z calcd
for C41H49N2O5 [M + H+] 649.3641, found 649.3637; IR (film)
ν 3349, 3030, 2927, 2854, 1666, 1513, 1452, 1103, 1027, 736, 698 cm−1.
(2R,3S,4S,5S,6R)-3,4,5-Tris(benzyloxy)-6-[(benzyloxy)methyl)]-N-
cyclohexylpiperidine-2-carboxamide (2-epi-34): minor isomer;
compound was not isolated in pure form; colorless oil; isolated
yield 14 mg (11%) starting from 142 mg (0.19 mmol) of mixture of
14/2-epi-14; TLC Rf 0.38 (1:2 AcOEt/hexanes); HRMS (ESI-TOF)
m/z calcd for C41H49N2O5 [M + H+] 649.3641, found 649.3639
(2S,3R,4R,5R)-3,4,5-Tris(benzyloxy)-N-tert-butylpiperidine-2-car-
boxamide (35): major isomer; colorless oil; isolated yield 54 mg
(51%) starting from 125 mg (0.21 mmol) of mixture of 15/2-epi-15;
TLC Rf 0.35 (1:1 AcOEt/hexanes); flash column chromatography
23
gel (1:4 AcOEt/hexanes); yellow oil; [α]D +33.7 (c 0.47, CHCl3);
1H NMR (600 MHz, CD3OD) δ 7.34−7.23 (m, 18H), 7.18−7.15 (m,
2H), 4.84−4.82 (m, 2H), 4.73−4.69 (m, 3H), 4.51 (d, J 11.9 Hz, 1H),
4.46 (d, J 11.2 Hz, 1H), 4.40 (d, J 11.9 Hz, 1H), 3.97 (t, J 8.1 Hz, 1H),
3.84 (dd, J 8.5, 5.6 Hz, 1H), 3.76 (d, J 5.5 Hz, 1H), 3.67 (ddd, J 13.9,
10.1, 3.8 Hz, 1H), 3.60 (dd, J 9.5, 2.8 Hz, 1H), 3.46 (dd, J 9.5, 6.1 Hz,
1H), 3.34 (dd, J 9.6, 7.7 Hz, 1H), 3.27−3.23 (m, 1H), 1.80−1.74
(m, 2H), 1.67−1.59 (m, 2H), 1.59−1.52 (m, 1H), 1.37−1.26 (m, 3H),
1.21−1.09 (m, 3H); 13C NMR (151 MHz, CD3OD) δ 170.9, 138.5,
138.3, 138.0, 137.9, 128.98, 127.95, 127.91, 127.87, 127.77, 127.70,
127.63, 127.60, 127.5, 127.3, 127.2, 81.6, 79.6, 79.1, 74.3, 73.9, 73.02,
72.7, 69.4, 56.0, 54.4, 32.3, 32.1, 25.2, 24.2; HRMS (ESI-TOF) m/z
calcd for C41H49N2O5 [M + H+] 649.3641, found 649.3633; IR (film)
ν 3341, 3030, 2928, 2854, 1663, 1453, 1091, 1069, 736, 697 cm−1.
(2S,3S,4S,5R,6R)-3,4,5-Tris(benzyloxy)-6-[(benzyloxy)methyl)]-N-
(4-methoxyphenyl)piperidine-2-carboxamide (32). waxy solid; iso-
lated yield 75 mg (58%) starting from 148 mg (0.19 mmol) of
compound 12; TLC Rf 0.36 (2:3 AcOEt/hexanes); column
23
chromatography on silica gel (1:9 than 3:7 AcOEt/hexanes); [α]D
1
+72.9 (c 0.24, CHCl3); H NMR (400 MHz, CDCl3) δ 9.44 (s, 1H,
CONH), 7.37−7.22 (m, 20H, 4 × Ph), 7.19−7.13 (m, 2H, PMP),
6.84−6.79 (m, 2H, PMP), 4.82 (d, J 11.2 Hz, 1H, OCHHPh), 4.80 (d,
J 11.2 Hz, 1H, OCHHPh), 4.76−4.69 (m, 3H, 3 × OCHHPh), 4.59
(d, J 12.0 Hz, 1H, OCHHPh), 4.48−4.44 (m, 2H, 2 × OCHHPh),
4.12 (dd, J 8.2, 5.0 Hz, 1H, H-3), 3.79 (d, J 5.0 Hz, 1H, H-2), 3.77 (s,
3H, OCH3), 3.74 (dd, J 8.2, 7.0 Hz, 1H, H-4), 3.65 (dd, J 9.6, 2.8 Hz,
23
(35% AcOEt in hexanes); colorless oil; [α]D −2.24 (c 0.7, CHCl3);
1H NMR (600 MHz, CDCl3) δ 7.41−7.17 (m, 15H, 3 × Ph), 6.77 (s,
1H, CONH), 4.66 (d, J 12.0 Hz, 1H, CHHOBn), 4.63 (d, J 12.0 Hz,
1H, CHHOBn), 4.60 (d, J 11.3 Hz, 1H, CHHOBn), 4.45−4.42 (m, 3H,
I
DOI: 10.1021/acs.joc.5b00335
J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Article
3 × CHHOBn), 4.28 (dd, J 4.2, 1.8 Hz, 1H, H-3), 3.81 (dd, J 4.2, 2.8
Hz, 1H, H-4), 3.66 (ddd, J 9.3, 6.8, 2.8 Hz, 1H, H-5), 3.56 (d, J 1.8 Hz,
1H, H-2), 3.00−2.92 (m, 2H, H-6′ and H-6″), 1.33 (s, 9H, (CH3)3C);
13C NMR (101 MHz, CDCl3) δ 170.3, 138.50, 138.45, 138.42, 128.36,
128.29, 128.28, 128.0, 127.8, 127.7, 127.60, 127.56, 127.55, 75.5, 74.4,
73.6, 73.2, 72.6, 70.7, 58.7, 50.7, 44.6, 28.7; HRMS (ESI-TOF) m/z
calcd for C31H39N2O4 [M + H+] 503.2910, found 503.2910; IR (film) ν
3370, 3031, 2963, 2929, 2871, 1673, 1518, 1454, 1364, 1227, 1116,
1092, 1064, 736, 698 cm−1.
553.2702, found 553.2693; IR (film) ν 3333, 3030, 2931, 2870, 1682,
1514, 1454, 1245, 1091, 1029, 829, 739, 698 cm−1.
(2R,3R,4R,5R)-3,4,5-Tris(benzyloxy)-N-(4-methoxyphenyl)piperidine-
2-carboxamide (2-epi-37): white crystals; mp 152−153 °C; isolated
yield 30 mg (69%) starting from 51 mg (0.08 mmol) of compound
2-epi-17; TLC Rf 0.64 (100% AcOEt); flash column chromatography
23
1
(60% AcOEt in hexanes); [α]D −5.9 (c 0.13, CHCl3); H NMR
(600 MHz, C6D6) δ 8.31 (s, 1H), 7.21−7.16 (m, 2H), 7.13−7.06 (m,
2H), 7.05−6.99 (m, 2H), 6.95−6.72 (m, 11H), 6.47−6.40 (m, 2H),
4.43−4.38 (m, 2H), 4.24−4.19 (m, 2H), 4.11 (d, J 11.4 Hz, 1H), 4.07
(d, J 12.3 Hz, 1H), 4.04 (d, J 12.3 Hz, 1H), 3.45 (d, J 4.1 Hz, 1H), 3.30
(dd, J 5.0, 2.9 Hz, 1H), 2.98 (s, 3H), 2.89 (dd, J 13.6, 8.3 Hz, 1H),
2.85 (d, J 4.4 Hz, 1H), 2.13 (dd, J 13.6, 3.3 Hz, 1H); 13C NMR (151
MHz, C6D6) δ 167.7, 156.1, 139.0, 138.8, 138.6, 131.8, 128.8−126.7
(aromatic overlap), 120.9, 113.9, 77.0, 76.3, 72.9 (2×), 71.6, 70.2, 59.5,
54.5, 42.6; HRMS (ESI-TOF) m/z calcd for C34H37N2O5 [M + H+]
553.2702, found 553.2702; IR (film) ν 3298, 3033, 2907, 2859, 1654,
1512, 1453, 1244, 1100, 1031, 828, 736, 697 cm−1.
(2R,3R,4R,5R)-3,4,5-Tris(benzyloxy)-N-tert-butylpiperidine-2-car-
boxamide (2-epi-35): minor isomer; colorless oil; isolated yield 18 mg
(17%) starting from 125 mg (0.21 mmol) of compound 15; TLC
Rf 0.12 (1:1 AcOEt/hexanes); flash column chromatography (25%
23
hexanes in AcOEt); colorless oil; [α]D −18.4 (c 1.6, CHCl3);
1H NMR (400 MHz, CDCl3) δ 7.36−7.22 (m, 15H, 3 × Ph), 6.34 (s,
1H, CONH), 4.77 (d, J 11.1 Hz, 1H, CHHOBn), 4.65−4.51 (m, 5H,
5 × CHHOBn), 4.25 (m, 1H, H-3), 3.72 (dt, J 5.8, 2.7 Hz, 1H, H-5),
3.61 (dd, J 7.3, 2.2 Hz, 1H, H-4), 3.13 (dd, J 14.0, 6.1 Hz, 1H, H-6′),
3.05 (d, J 6.5 Hz, 1H, H-2), 2.58 (dd, J 14.0, 1.9 Hz, 1H, H-6″), 1.29
(s, 9H); 13C NMR (101 MHz, CDCl3) δ 169.4, 138.5, 138.4, 128.4,
128.3, 128.3, 127.8, 127.69, 127.66, 127.65, 127.57, 127.5, 73.1, 71.4,
71.0, 50.9, 28.6; HRMS (ESI-TOF) m/z calcd for C31H39N2O4 [M + H+]
503.2910. Found 503.2910; IR (film) ν 3321, 3030, 2964, 2924, 2869,
1669, 1452, 1363, 1226, 1093, 1027, 737, 698 cm−1.
(2S,3S,4R,5R)-3,4-Bis(benzyloxy)-5-[(benzyloxy)methyl)]-N-tert-
butylpyrrolidine-2-carboxamide 38. colorless oil; isolated yield
65 mg (74%) starting from 105 mg (0.18 mmol) of compound 18;
TLC Rf 0.38 (1:1 AcOEt/hexanes); flash column chromatography
23
(35% AcOEt in hexanes); colorless oil; [α]D +41.9 (c 1.6, CHCl3);
1H NMR (400 MHz, CDCl3) δ 7.39−7.21 (m, 15H), 4.72 (d, J 11.6
Hz, 1H, OCHHPh), 4.67 (d, J 11.6 Hz, 1H, OCHHPh), 4.47 (d, J 9.9
Hz, 1H, OCHHPh), 4.45 (d, J 9.9 Hz, 1H, OCHHPh), 4.41 (d, J 12.0
Hz, 1H, OCHHPh), 4.37 (t, J 4.0 Hz, 1H, H-3), 4.29 (d, J 12.0 Hz,
1H, OCHHPh), 3.79 (dd, J 9.2, 3.7 Hz, 1H, H-4), 3.77 (d, J 4.2 Hz,
1H, H-2), 3.63 (dd, J 10.0, 3.1 Hz, 1H, C(5)-CHHOBn), 3.54 (dd,
J 10.0, 3.3 Hz, 1H, C(5)-CHHOBn), 3.46 (dt, J 9.2, 3.2 Hz, 1H, H-5),
1.31 (s, 9H); 13C NMR (101 MHz, CDCl3) δ 170.2, 138.7, 138.03,
137.96, 128.4, 128.3, 128.1, 128.0, 127.8, 127.73, 127.70, 127.67,
127.4, 80.4, 78.1, 73.9, 73.2, 72.1, 68.1, 63.5, 59.9, 50.4, 28.7; HRMS
(ESI-TOF) m/z calcd for C31H39N2O4 [M + H+] 503.2910, found
503.2910; IR (film) ν 3333, 3030, 2964, 2914, 2866, 1669, 1521, 1453,
1362, 1130, 1065, 737, 697 cm−1.
(2S,3S,4R,5R)-3,4-Bis(benzyloxy)-5-[(benzyloxy)methyl)]-N-cyclo-
hexylpyrrolidine-2-carboxamide (39): colorless oil; isolated yield
66 mg (58%) starting from 135 mg (0.22 mmol) of compound 19;
TLC Rf 0.60 (100% AcOEt); flash column chromatography (50%
AcOEt in hexanes); [α]D23 +50.3 (c 1.8, CHCl3); 1H NMR (600 MHz,
CDCl3) δ 7.51 (d, J 8.2 Hz, 1H, CONH), 7.36−7.20 (m, 15H, 3 ×
Ph), 4.68 (d, J 11.5 Hz, 1H, OCHHPh), 4.65 (d, J 11.5 Hz, 1H,
OCHHPh), 4.49 (d, J 11.9 Hz, 1H, OCHHPh), 4.46 (d, J 11.9 Hz, 1H,
OCHHPh), 4.44−4.40 (m, 2H, OCHHPh, H-3), 4.30 (d, J 11.9 Hz,
1H, OCHHPh), 3.87 (d, J 4.1 Hz, 1H, H-2), 3.80 (dd, J 9.2, 3.7 Hz,
1H, H-4), 3.77−3.70 (m, 1H), 3.63 (dd, J 10.0, 3.0 Hz, 1H, C(5)-
CHHOBn), 3.53 (dd, J 10.0, 3.5 Hz, 1H, C(5)-CHHOBn), 3.47 (dt,
J 9.0, 3.2 Hz, 1H, H-5), 1.86−1.50 (m, 6H), 1.37−1.24 (m, 2H),
1.18−1.02 (m, 2H); 13C NMR (101 MHz, CDCl3) δ 170.1, 138.6,
138.0, 137.9, 128.42, 128.35, 128.04, 128.00, 127.79, 127.76, 127.74,
127.69, 127.4, 80.4, 78.2, 73.9, 73.2, 72.1, 68.2, 63.1, 59.9, 47.6,
33.00, 32.97, 25.58, 24.85, 24.76; HRMS (ESI-TOF) m/z calcd for
C33H41N2O4 [M + H+] 529.3066, found 529.3062; IR (film) ν 3343,
3030, 2929, 2854, 1667, 1520, 1453, 1363, 1209, 1133, 1065, 1028,
736, 698 cm−1.
(2S,3R,4R,5R)-3,4,5-Tris(benzyloxy)-N-cyclohexylpiperidine-2-car-
boxamide (36): major isomer; white crystals; mp 67−68 °C; isolated
yield 74 mg (60%) starting from 145 mg (0.23 mmol) of compound
16; TLC Rf 0.53 (100% AcOEt); flash column chromatography
23
1
(40% AcOEt in hexanes); [α]D −3.85 (c 2.8, CHCl3); H NMR
(500 MHz, CDCl3) δ 7.38−7.27 (m, 13H), 7.24−7.19 (m, 2H), 6.82
(d, J 7.9 Hz, 1H), 4.65 (d, J 12.1 Hz, 1H), 4.62−4.58 (m, 2H), 3.80−
3.73 (m, 3H), 3.68 (ddd, J 9.1, 6.2, 2.8 Hz, 1H), 3.64 (d, J 1.3 Hz, 1H),
3.00−2.95 (m, 2H), 1.91−1.81 (m, 2H), 1.74−1.63 (m, 2H), 1.59 (dd,
J 9.0, 4.0 Hz, 1H), 1.41−1.24 (m, 2H), 1.21−1.07 (m, 2H); 13C NMR
(101 MHz, CDCl3) δ 170.1, 138.50, 138.45, 138.4, 128.4, 128.31,
128.28, 128.0, 127.82, 127.75, 127.61, 127.57, 127.55, 75.5, 74.4, 73.6,
73.4, 72.7, 70.7, 58.3, 47.8, 44.6, 33.1, 32.9, 25.6, 24.8; HRMS (ESI-
TOF) m/z calcd for C33H41N2O4 [M + H+] 529.3066, found
529.3062; IR (film) ν 3377, 3030, 2928, 2853, 1668, 1514, 1452, 1092,
1063, 736, 698 cm−1.
(2R,3R,4R,5R)-3,4,5-Tris(benzyloxy)-N-cyclohexylpiperidine-2-car-
boxamide (2-epi-36): minor isomer; white crystals; mp 72−73 °C;
isolated yield 18 mg (15%) starting from 145 mg (0.23 mmol) of com-
pound 16; TLC Rf 0.35 (100% AcOEt); flash column chromato-
23
graphy (50% AcOEt in hexanes); [α]D −11.1 (c 0.9, CHCl3);
1H NMR (600 MHz, CDCl3) δ 7.35−7.23 (m, 13H), 6.48 (s, 1H),
4.78 (d, J 11.2 Hz, 1H), 4.61−4.57 (m, 3H), 4.53 (d, J 12.0 Hz, 1H),
4.32−4.24 (m, 1H), 3.79−3.76 (m, 1H), 3.75−3.67 (m, 1H), 3.62 (d,
J 5.5 Hz, 1H), 3.23 (d, J 6.7 Hz, 1H), 3.18 (dd, J 14.0, 5.6 Hz, 1H),
2.68 (d, J 12.3 Hz, 1H), 1.85−1.78 (m, 2H), 1.65−1.58 (m, 2H),
1.58−1.52 (m, 1H), 1.33−1.22 (m, 2H), 1.15−0.99 (m, 3H); 13C
NMR (101 MHz, CDCl3) δ 170.1, 138.5, 138.4, 128.4, 128.2, 127.8,
127.72, 127.67, 127.66, 127.58, 127.5, 73.1, 71.5, 70.9, 48.0, 32.9, 25.5,
24.7; HRMS (ESI-TOF) m/z calcd for C33H41N2O4 [M + H+]
529.3066, found 529.3062; IR (film) ν 3424, 3316, 3053, 2931, 2855,
1666, 1519, 1453, 1265, 1093, 1075, 738, 700 cm−1.
(2R,3R,4R,5R)-3,4-Bis(benzyloxy)-5-[(benzyloxy)methyl)]-N-tert-
butylpyrrolidine-2-carboxamide (40): major isomer; colorless oil;
isolated yield 49 mg (43%) starting from 137 mg (0.23 mmol) of
mixture of 20/2-epi-20; TLC Rf 0.36 (1:1 AcOEt/hexanes); flash
(2S,3R,4R,5R)-3,4,5-Tris(benzyloxy)-N-(4-methoxyphenyl)piperidine-
2-carboxamide (37): colorless oil; isolated yield 56 mg (88%) starting
from 75 mg (0.12 mmol) of compound 17; TLC Rf 0.29 (3:2 AcOEt/
hexanes); flash column chromatography (30% AcOEt in hexanes);
23
column chromatography (35% AcOEt in hexanes); [α]D +30.5
23
1
1
[α]D +7.7 (c 0.22, CHCl3); H NMR (600 MHz, C6D6) δ 8.56 (s,
1H), 7.59−7.49 (m, 2H), 7.3−7.21 (m, 4H), 7.19−6.98 (m, 11H),
6.73−6.67 (m, 2H), 4.63 (d, J 11.3 Hz, 1H), 4.58 (d, J 12.0 Hz, 1H),
4.52−4.48 (m, 2H), 4.44 (d, J 11.3 Hz, 1H), 4.28−4.22 (m, 2H), 3.81
(s, 1H), 3.69 (d, J 1.3 Hz, 1H), 3.61−3.55 (m, 1H), 3.22 (s, 3H),
3.03−2.95 (m, 1H), 2.77 (dd, J 12.5, 4.7 Hz, 1H); 13C NMR (151
MHz, C6D6) δ 168.4, 156.1, 138.9, 138.8, 138.7, 131.8, 128.3−127.3
(aromatic overlap), 120.5, 114.0, 75.6, 74.7, 73.6, 73.5, 72.7, 70.4, 58.9,
54.5, 44.6; HRMS (ESI-TOF) m/z calcd for C34H37N2O5 [M + H+]
(c 0.8, CHCl3); H NMR (600 MHz, CDCl3) δ 7.35−7.21 (m, 15H,
3 × Ph), 4.60 (d, J 11.8 Hz, 1H, OCHHPh), 4.53 (d, J 12.1 Hz,
OCHHPh), 4.49 (d, J 12.1 Hz, OCHHPh), 4.47 (d, J 5.8 Hz,
OCHHPh), 4.44 (d, J 5.8 Hz, 1H, OCHHPh), 4.39 (d, J 11.8 Hz, 1H,
OCHHPh), 4.24 (dd, J 5.5, 1.7 Hz, 1H, H-3), 4.01 (d, J 5.5 Hz, 1H,
H-2), 3.83 (br s, 1H, H-4), 3.55−3.45 (m, 3H, H-5, C(5)-CH2OBn),
1.30 (s, 9H); 13C NMR (101 MHz, CDCl3) δ 170.0, 138.3, 138.2,
137.9, 128.4, 128.4, 128.2, 127.8, 127.72, 127.66, 127.62, 127.6,
127.5, 83.8, 83.2, 73.2, 72.9, 72.5, 71.4, 65.3, 62.5, 50.5, 28.7;
J
DOI: 10.1021/acs.joc.5b00335
J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Article
HRMS (ESI-TOF) m/z calcd for C31H39N2O4 [M + H+] 503.2910,
found 503.2915; IR (film) ν 3425, 3352, 3031, 2965, 2925, 2864,
1668, 1523, 1454, 1362, 1227, 1093, 1072, 737, 697 cm−1.
(2R,3R,4R)-3,4-Bis(benzyloxy)-N-tert-butylpyrrolidine-2-carboxamide
(2-epi-42): isolated yield 32 mg (84%) starting from 47 mg
(0.10 mmol) of compound 2-epi-22; TLC Rf 0.12 (1:1 AcOEt/hexanes);
column chromatography (50% AcOEt in hexanes); colorless oil;
[α]D23 −13.1 (c 0.8, CHCl3); 1H NMR (400 MHz, CDCl3) δ 7.41 (s,
1H, NH), 7.34−7.21 (m, 10H, 2 × Ph), 4.65 (d, J 11.9 Hz, 1H,
CHHOBn), 4.52 (d, J 11.9 Hz, 1H, CHHOBn), 4.44 (d, J 11.9 Hz,
1H, CHHOBn), 4.37−4.29 (m, 2H, CHHOBn, H-3), 3.99 (d, J 5.0
Hz, 1H, H-2), 3.91−3.86 (m, 1H, H-4), 3.18 (dd, J 12.2, 3.6 Hz, 1H,
H-5′), 3.04 (d, J 12.2 Hz, 1H, H-5″), 1.34 (s, 9H, (CH3)3C);
13C NMR (101 MHz, CDCl3) δ 171.0, 138.2, 137.9, 128.5, 128.2,
127.9, 127.8, 127.6, 82.8, 82.3, 73.3, 71.0, 65.1, 50.8, 50.4, 28.8; HRMS
(ESI-TOF) m/z calcd for C23H31N2O3 [M + H+] 383.2335, found
383.2331; IR (film) ν 3425, 3352, 3031, 2965, 2925, 2864, 1668, 1523,
1454, 1362, 1227, 1093, 1072, 737, 697 cm−1.
(2S,3R,4R,5R)-3,4-Bis(benzyloxy)-5-[(benzyloxy)methyl)]-N-tert-
butylpyrrolidine-2-carboxamide (2-epi-40): colorless oil; isolated
yield 37 mg (32%) starting from 137 mg (0.23 mmol) of mixture of
20/2-epi-20; TLC Rf 0.45 (1:1 AcOEt/hexanes); flash column
23
chromatography on silica gel (20% AcOEt in hexanes); [α]D +8.6
1
(c 1.5, CHCl3); H NMR (400 MHz, CDCl3) δ 7.37−7.22 (m, 15H,
3 × Ph), 4.76 (d, J 11.8 Hz, 1H, OCHHPh), 4.61 (d, J 11.8 Hz, 1H,
OCHHPh), 4.55 (d, J 11.7 Hz, 1H, OCHHPh), 4.51 (d, J 11.9 Hz,
OCHHPh), 4.48 (d, J 11.9 Hz, OCHHPh), 4.44 (d, J 11.7 Hz, 1H,
OCHHPh), 4.34 (t, J 3.0 Hz, 1H, H-3), 3.88 (dd, J 5.5, 3.1 Hz, 1H,
H-4), 3.65 (d, J 2.6 Hz, 1H, H-2), 3.60−3.51 (m, 2H, C(5)-CH2OBn),
3.24 (m, 1H, H-5), 1.32 (s, 9H); 13C NMR (101 MHz, CDCl3)
δ 171.2, 138.3, 138.0, 137.9, 128.4, 128.34, 128.29, 127.87, 127.85,
127.76, 127.7, 127.62, 127.55, 87.4, 85.0, 73.2, 71.8, 71.6, 69.1, 66.1,
62.4, 50.3, 28.7; HRMS (ESI-TOF) m/z calcd for C31H39N2O4
[M + H+] 503.2910, found 503.2921; IR (film) ν 3330, 3062, 3031,
2964, 2920, 2866, 1671, 1516, 1454, 1363, 1092, 1074, 736, 698 cm−1.
(2R,3R,4R,5R)-3,4-Bis(benzyloxy)-5-[(benzyloxy)methyl)]-N-cyclo-
hexylpyrrolidine-2-carboxamide (41). major isomer; white crystals;
mp 72−73 °C; isolated yield 44 mg (43%) starting from 122 mg
(0.20 mmol) of mixture of 21/2-epi-21; TLC Rf 0.43 (1:1 AcOEt/
hexanes); flash column chromatography on silica gel (40% AcOEt in
hexanes); [α]D23 +18.7 (c 2.3, CHCl3); 1H NMR (600 MHz, CDCl3)
δ 7.39−7.16 (m, 15H), 4.58 (d, J 11.7 Hz, 1H), 4.53−4.46 (m, 3H),
4.44 (d, J 11.7 Hz, 1H), 4.40 (d, J 11.8 Hz, 1H), 4.27 (d, J 4.7 Hz, 1H),
4.11 (d, J 4.7 Hz, 1H), 3.84 (mi, 1H), 3.79−3.72 (m, 1H), 3.55−3.45
(m, 3H), 1.83 (d, J 9.5 Hz, 1H), 1.74 (d, J 10.1 Hz, 1H), 1.69−1.63
(m, 1H), 1.61−1.52 (m, 2H), 1.40−1.24 (m, 2H), 1.17−1.10 (m, 2H),
1.08−1.00 (m, 1H); 13C NMR (101 MHz, CDCl3) δ 169.9, 138.3,
138.1, 137.9, 128.41, 128.39, 128.2, 127.8, 127.73, 127.67, 127.64,
127.5, 83.5, 83.2, 73.2, 72.9, 72.4, 71.4, 64.7, 62.5, 47.5, 33.0, 32.9,
25.6, 24.8, 24.6; HRMS (ESI-TOF) m/z calcd for C33H41N2O4
[M + H+] 529.3066, found 529.3071; IR (film) ν 3332, 2928, 2854,
1663, 1523, 1452, 1093, 1027, 737, 698 cm−1.
(2S,3R,4R)-3,4-Bis(benzyloxy)-N-cyclohexylpyrrolidine-2-carboxamide
(43): white crystals; mp 67−68 °C; isolated yield 47 mg (78%) starting
from 75 mg (0.15 mmol) of compound 23; TLC Rf 0.26 (1:1 AcOEt/
23
hexanes); column chromatography (35% AcOEt in hexanes); [α]D
1
+0.48 (c 0.5, CHCl3); H NMR (600 MHz, CDCl3) δ 7.46 (d, J 7.5
Hz, 1H), 7.39−7.22 (m, 10H, 2 × Ph), 4.72 (d, J 11.8 Hz, 1H,
CHHOBn), 4.60 (d, J 11.8 Hz, 1H, CHHOBn), 4.46 (d, J 11.6 Hz,
1H, CHHOBn), 4.39−4.35 (m, 2H, CHHOBn, H-3), 3.97−3.94 (m,
1H, H-4), 3.78 (s, 1H, H-2), 3.69−3.63 (m, 1H), 3.32 (dd, J 11.5, 5.1
Hz, 1H, H-5′), 3.03 (dd, J 11.5, 2.3 Hz, 1H, H-5″), 1.85−182 (m, 1H),
1.70−1.62 (m, 2H), 1.61−1.52 (m, 2H), 1.37−1.22 (m, 2H), 1.18−
1.08 (m, 2H), 1.05−0.96 (m, 1H); 13C NMR (101 MHz, CDCl3)
δ 170.8, 138.0, 137.9, 128.43, 128.42, 128.3, 127.92, 127.85, 127.74,
127.6, 85.6, 82.7, 71.4, 71.2, 66.1, 50.9, 47.6, 32.9, 32.8, 25.6, 24.8,
24.7; HRMS (ESI-TOF) m/z calcd for C25H33N2O3 [M + H+]
409.2491, found 409.2498; IR (film) ν 3329, 3062, 3031, 2929, 2853,
1664, 1518, 1453, 1098, 737, 698 cm−1.
(2R,3R,4R)-3,4-Bis(benzyloxy)-N-cyclohexylpyrrolidine-2-carboxamide
(2-epi-43): isolated yield 35 mg (75%) starting from 57 mg
(0.11 mmol) of compound 2-epi-23; TLC Rf 0.17 (100% AcOEt);
flash column chromatography (60% AcOEt in hexanes); white crystals;
23
1
mp 71−72 °C; [α]D −1.0 (c 0.7, CHCl3); H NMR (600 MHz,
CDCl3) δ 7.52 (s, 1H, NH), 7.36−7.19 (m, 10H, 2 × Ph), 4.63 (d,
J 11.8 Hz, 1H, CHHOBn), 4.50 (d, J 11.8 Hz, 1H, CHHOBn), 4.45
(d, J 11.9 Hz, 1H, CHHOBn), 4.39 (br s, 1H, H-3), 4.35 (d, J 11.8 Hz,
1H, CHHOBn), 4.12 (d, J 3.9 Hz, 1H, H-4), 3.88 (d, J 3.2 Hz, 1H,
H-2), 3.80−3.73 (m, 1H), 3.19 (dd, J 12.2, 3.6 Hz, 1H, H-5′), 3.08 (d,
J 12.2 Hz, 1H, H-5′), 1.90−1.77 (m, 2H), 1.72−1.60 (m, 2H), 1.60−
1.53 (m, 1H), 1.39−1.27 (m, 2H), 1.22−1.07 (m, 3H); 13C NMR
(101 MHz, CDCl3) δ 170.1, 138.2, 137.8, 128.5, 128.2, 127.81, 127.80,
127.6, 82.8, 82.3, 73.3, 71.0, 64.7, 50.8, 47.5, 33.2, 32.9, 25.6, 24.8,
24.7; HRMS (ESI-TOF) m/z calcd for C25H33N2O3 [M + H+]
409.2491, found 409.2504; IR (film) ν 3302, 3062, 3031, 2930, 2854,
1651, 1526, 1453, 1098, 737, 698 cm−1.
(2S,3R,4R,5R)-3,4-Bis(benzyloxy)-5-[(benzyloxy)methyl)]-N-cyclo-
hexylpyrrolidine-2-carboxamide (2-epi-41). minor isomer; white
crystals; mp 78−79 °C; isolated yield 34 mg (32%) starting from
122 mg (0.20 mmol) of mixture of 21/2-epi-21; TLC Rf 0.55 (1:1
AcOEt/hexanes); flash column chromatography on silica gel (25%
AcOEt in hexanes); [α]D23 +8.4 (c 0.8, CHCl3); 1H NMR (600 MHz,
C6D6) δ 7.15−6.99 (m, 15H), 4.66 (d, J 11.9 Hz, 1H), 4.52 (d, J 11.9
Hz, 1H), 4.41 (t, J 2.5 Hz, 1H), 4.36 (d, J 11.6 Hz, 1H), 4.23 (d, J 11.8
Hz, 1H), 4.19 (d, J 3.5 Hz, 2H), 3.78 (dd, J 4.9, 2.9 Hz, 1H),
3.71 (dt, J 14.9, 7.0 Hz, 1H), 3.56 (s, 1H), 3.34−3.28 (m, 2H), 3.21
(dd, J 9.0, 4.4 Hz, 1H), 1.75 (dd, J 12.6, 3.2 Hz, 1H), 1.61 (dd, J 12.5,
3.3 Hz, 1H), 1.50−1.37 (m, 2H), 1.37−1.29 (m, 1H), 1.24−1.04 (m,
2H), 0.99−0.82 (m, 4H); 13C NMR (101 MHz, CDCl3) δ 170.9,
138.2, 138.0, 137.9, 128.43, 128.35, 128.26, 128.0, 127.9, 127., 127.76,
127.62, 127.60, 87.2, 84.9, 73.2, 71.8, 71.6, 69.0, 65.7, 62.4, 47.7, 33.0,
25.6, 24.8; HRMS (ESI-TOF) m/z calcd for C33H41N2O4 [M + H+]
529.3066, found 529.3067; IR (film) ν 3334, 3062, 3031, 2928, 2854,
1665, 1516, 1452, 1094, 1074, 737, 698 cm−1.
(2R,3S,4S)-3,4-Bis(benzyloxy)-N-(4-methoxyphenyl)pyrrolidine-2-
carboxamide (44): isolated yield 67 mg (95%) starting from 86 mg
(0.16 mmol) of compound 24; TLC Rf 0.27 (3:2 AcOEt/hexane);
column chromatography (30% AcOEt in hexanes); white crystals; mp
55−56 °C; [α]D23 −2.1 (c 0.22, CHCl3); 1H NMR (600 MHz, C6D6)
δ 9.43 (s, 1H), 7.60−7.55 (m, 2H), 7.33−7.29 (m, 2H), 7.18−7.13 (m,
2H), 7.08−7.05 (m, 3H), 7.01−6.93 (m, 3H), 6.70−6.66 (m, 2H),
4.60 (d, J 11.9 Hz, 1H), 4.56 (s, 1H), 4.46 (d, J 11.9 Hz, 1H), 4.23 (d,
J 11.5 Hz, 1H), 4.03 (d, J 11.5 Hz, 1H), 3.73−3.70 (m, 1H), 3.60 (s,
1H), 3.22 (s, 3H), 2.88 (dd, J 11.0, 4.5 Hz, 1H), 2.84 (dd, J 11.0, 1.8
Hz, 1H); 13C NMR (151 MHz, C6D6) δ 169.2, 156.0, 138.4, 138.0,
132.0, 128.3−127.2 (aromatic overlap), 120.3, 114.0, 85.1, 82.2, 71.0,
70.9, 66.2, 54.5, 50.7; HRMS (ESI-TOF) m/z calcd for C26H29N2O4
[M + H+] 433.2127, found 433.2125; IR (film) ν 3280, 3031, 2931,
2868, 1675, 1523, 1455, 1245, 1098, 1032, 830, 739, 698 cm−1.
(2S,3S,4S)-3,4-Bis(benzyloxy)-N-(4-methoxyphenyl)pyrrolidine-2-
carboxamide (2-epi-44): isolated yield 50 mg (95%) starting from
64 mg (0.12 mmol) of compound 2-epi-24; TLC Rf 0.14 (3:2 AcOEt/
hexane); flash column chromatography on silica gel (30% AcOEt in
(2S,3R,4R)-3,4-Bis(benzyloxy)-N-tert-butylpyrrolidine-2-carboxamide
(42): colorless oil; isolated yield 55 mg (79%) starting from 87 mg
(0.18 mmol) of compound 22; TLC Rf 0.24 (1:1 AcOEt/hexanes);
flash column chromatography (35% AcOEt in hexanes); colorless oil;
23
1
[α]D +9.38 (c 1.7, CHCl3); H NMR (400 MHz, CDCl3) δ 7.44
(s, 1H, NH), 7.37−7.23 (m, 10H, 2 × Ph), 4.71 (d, J 11.8 Hz, 1H,
CHHOBn), 4.60 (d, J 11.8 Hz, 1H, CHHOBn), 4.51 (d, J 11.9 Hz,
1H, CHHOBn), 4.40 (d, J 11.9 Hz, 1H, CHHOBn), 4.36 (s, 1H, H-3),
3.99−3.94 (m, 1H, H-4), 3.68 (d, J 1.1 Hz, 1H, H-2), 3.31 (dd, J 11.5,
5.2 Hz, 1H, H-5′), 3.03 (dd, J 11.5, 2.6 Hz, 1H, H-5″), 1.28 (s, 9H,
(CH3)3C); 13C NMR (101 MHz, CDCl3) δ 171.0, 138.0, 137.9, 128.4,
128.3, 127.82, 127.76, 127.71, 127.6, 85.7, 82.8, 71.4, 71.2, 66.5, 50.9,
50.3, 28.6; HRMS (ESI-TOF) m/z calcd for C23H31N2O3 [M + H+]
383.2335, found 383.2330; IR (film) ν 3321, 2964, 2926, 2869, 1667,
1520, 1454, 1363, 1227, 1096, 736, 697 cm−1.
23
1
hexanes); colorless oil; [α]D −35.4 (c 0.26, CHCl3); H NMR (600
MHz, C6D6) δ 9.34 (s, 1H), 7.70−7.61 (m, 2H), 7.26−6.88 (m, 12H),
K
DOI: 10.1021/acs.joc.5b00335
J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Article
6.79−6.66 (m, 2H), 4.55 (d, J 11.7 Hz, 1H), 4.38−4.33 (m, 2H), 4.12
(d, J 12.0 Hz, 1H), 4.03−3.99 (m, 2H), 3.62 (d, J 3.0 Hz, 1H), 3.21 (s,
3H), 3.00 (dd, J 12.1, 3.4 Hz, 1H), 2.65 (d, J 12.1 Hz, 1H); 13C NMR
(151 MHz, C6D6) δ 168.3, 156.0, 138.29, 138.27, 132.1, 128.3−127.2
(aromatic overlap), 120.4, 114.0, 82.6, 82.5, 73.2, 70.4, 65.5, 54.5, 50.4;
HRMS (ESI-TOF) m/z calcd for C26H29N2O4 [M + H+] 433.2127,
found 433.2118; IR (film) ν 3288, 3030, 2931, 2869, 1674, 1514,
1454, 1244, 1096, 1032, 829, 738, 698 cm−1.
17 mg (14%) starting from 155 mg (0.39 mmol) of the mixture 28/2-
epi-28; TLC Rf 0.11 (100% AcOEt); H NMR (500 MHz, CDCl3) δ
1
7.54 (d, J 7.6 Hz, 1H, NH), 7.38−7.27 (m, 5H, Ph), 4.56 (d, J 11.7 Hz,
1H, CHHOBn), 4.50 (d, J 11.3 Hz, 1H, CHHOBn), 4.35 (ddd, J 10.4,
7.0, 3.7 Hz, 1H, H-4), 4.16−4.09 (m, 1H, H-2), 4.03−3.96 (m, 1H),
3.61 (dd, J 10.4, 6.4 Hz, 1H, H-5′), 3.44 (dd, J 10.4, 3.0 Hz, 1H, H-5″),
2.57 (dd, J 17.3, 6.9 Hz, 1H, H-3′), 2.46 (dd, J 17.3, 4.0 Hz, 1H, H-3″),
1.87−1.51 (m, 5H), 1.39−1.05 (m, 5H); selected signals 13C NMR
(151 MHz, C6D6) δ 178.2, 140.0, 131.1, 130.5, 130.3, 76.4, 73.6, 51.1,
39.6; HRMS (ESI-TOF) m/z calcd for C18H27N2O2 [M + H+]
303.2073, found 303.2070; IR (film) ν 3266, 2929, 2854, 1675, 1530,
1451, 1348, 1096, 1071, 737, 698 cm−1.
(2S,3S,4R)-3,4-Bis(benzyloxy)-N-tert-butylpyrrolidine-2-carboxamide
(45): isolated yield 14 mg (75%) starting from 24 mg (0.05 mmol) of
compound 25; TLC Rf 0.09 (100% AcOEt); column chromatography
1
(60−100% AcOEt in hexanes); [α]D +4.4 (c 1.31, CHCl3); H NMR
(2S,3R)-3-(Benzyloxy)-N-tert-butylpyrrolidine-2-carboxamide
(49): isolated yield 52 mg (71%) starting from 98 mg (0.26 mmol) of
compound 29; colorless oil; TLC Rf 0.15 (100% acetone); flash column
(600 MHz, C6D6) δ 7.49−7.42 (m, 2H), 7.33 (s, 1H), 7.22−7.00 (m,
8H), 4.81 (d, J 11.5 Hz, 1H, CHHOBn), 4.77 (d, J 11.5 Hz, 1H,
CHHOBn), 4.25 (d, J 12.2 Hz, 1H, CHHOBn), 4.15 (dd, J 4.7, 3.6
Hz, 1H, H-3), 4.10 (d, J 12.2 Hz, 1H, CHHOBn), 3.42 (d, J 4.7 Hz,
1H, H-2), 3.30 (ddd, J 9.4, 7.1, 3.6 Hz, 1H, H-4), 3.06 (t, J 9.8 Hz, 1H,
H-5′), 2.57 (dd, J 10.2, 7.1 Hz, 1H, H-5″), 1.28 (s, 9H, t-Bu);
13C NMR (151 MHz, C6D6) δ 169.4, 139.2, 138.6, 128.2, 128.0, 128.0,
127.4, 127.2, 127.2, 80.8, 78.5, 73.9, 71.6, 63.9, 49.8, 48.0, 28.5; HRMS
(ESI-TOF) m/z calcd for C23H31N2O3 [M + H+] 383.2335, found
383.2328; IR (film) ν 3298, 3033, 2907, 2859, 1654, 1512, 1453, 1244,
1100, 1031, 828, 736, 697 cm−1.
23
1
chromatography (100% acetone); [α]D +49.1 (c 0.8, CHCl3); H
NMR (400 MHz, CDCl3) δ 7.35−7.25 (m, 5H, Ph), 4.58 (d, J 12.0 Hz,
1H, CHHOBn), 4.54 (d, J 12.0 Hz, 1H, CHHOBn), 4.35 (td, J 4.9,
2.1 Hz, 1H, H-3), 3.71 (d, J 5.1 Hz, 1H, H-2), 3.19−3.11 (m, 1H,
H-5′), 3.06−3.02 (m, 1H, H-5″), 2.02−1.96 (m, 1H, H-4′), 1.85−1.75
(m, 1H, H-4″), 1.33 (s, 9H, (CH3)3C); 13C NMR (101 MHz, CDCl3)
δ 170.2, 138.6, 128.1, 127.6, 127.3, 80.5, 72.2, 66.9, 50.4, 44.7, 33.0,
28.8; HRMS (ESI-TOF) m/z calcd for C16H25N2O2 [M + H+]
277.1916, found 277.1910; IR (film) ν 3332, 2962, 2926, 2872, 1659,
1523, 1454, 1362, 1228, 1118, 1065, 1026, 737, 698 cm−1.
(2S,3S,4R)-3,4-Bis(benzyloxy)-N-(4-methoxyphenyl)pyrrolidine-2-
carboxamide (46): isolated yield 59 mg (79%) starting from 92 mg
(0.18 mmol) of compound 27: white crystals; Rf 0.2 (100% AcOEt);
(2R,3R)-3-(Benzyloxy)-N-tert-butylpyrrolidine-2-carboxamide (2-
epi-49): isolated yield 22 mg (69%) starting from 43 mg (0.12 mmol)
of compound 2-epi-29; colorless oil; TLC Rf 0.23 (100% AcOEt);
Flash column chromatography (75% AcOEt in hexanes); [α]D23 −19.8
25
column chromatography (50% AcOEt in hexanes); [α]D −12.4
1
(c 1.57, CHCl3); H NMR (600 MHz, C6D6) δ 9.24 (s, 1H, NH),
7.45−7.41 (m, 2H), 7.30−7.16 (m, 7H), 7.14−7.06 (m, 3H), 6.80−
6.74 (m, 2H), 4.71 (d, J 11.5 Hz, 1H, CHHOBn), 4.67 (d, J 11.5 Hz,
1H, CHHOBn), 4.45 (d, J 12.0 Hz, 1H, CHHOBn), 4.34 (d, J 12.0 Hz,
1H, CHHOBn), 4.26 (dd, J 5.0, 3.7 Hz, 1H, H-3), 3.72 (d, J 5.0 Hz, 1H,
H-2), 3.70−3.66 (ddd, J 8.8, 7.0, 3.7 Hz, 1H, H-4), 3.57 (s, 3H, OCH3),
3.06 (dd, J 10.4, 8.8 Hz, 1H, H-5′), 2.90 (dd, J 10.4, 7.0 Hz, 1H, H-5″);
13C NMR (151 MHz, CDCl3) δ 169.1, 156.1, 138.3, 138.0, 131.1,
1
(c 0.2, CHCl3); H NMR (400 MHz, CDCl3) δ 7.37−7.23 (m, 5H,
Ph), 4.65 (d, J 11.8 Hz, 1H, CHHOBn), 4.57 (d, J 11.9 Hz, 1H,
CHHOBn), 4.29 (d, J 5.3 Hz, 1H, H-3), 3.69 (m, 1H, H-2), 3.20 (td,
J 9.7, 6.9 Hz, 1H, H-5′), 2.95 (ddd, J 9.8, 7.9, 3.4 Hz, 1H, H-5″), 1.95−
1.87 (m, 1H, H-4′), 1.79−1.73 (m, 1H, H-4″), 1.33 (s, 9H, (CH3)3C);
13C NMR (101 MHz, CDCl3) δ 170.2, 138.6, 128.4, 127.7, 127.3, 80.5,
72.1, 79.0, 51.2, 45.3, 33.5, 28.7; HRMS (ESI-TOF) m/z calcd for
C16H25N2O2 [M + H+] 277.1916, found 277.1915; IR (film) ν 3322,
2964, 2928, 2869, 1667, 1520, 1454, 1363, 1228, 1097, 736, 697 cm−1.
128.4, 128.1, 127.8, 127.7, 127.5, 127.4, 121.2, 114.0, 80.2, 79.0, 74.0,
72.1, 63.8, 55.5, 48.1; HRMS (ESI-TOF) m/z calcd for C26H29N2O4
[M + H+] 433.2127, found 433.2128; IR (film) ν 3288, 3030, 2931, 2881,
2836, 1674, 1514, 1454, 1246, 1140, 1090, 1031, 829, 739, 698 cm−1.
(2R,4R)-4-(Benzyloxy)-N-tert-butylpyrrolidine-2-carboxamide
(47): isolated yield 72 mg (65%) starting from 148 mg (0.4 mmol) of
compound 27; TLC Rf 0.36 (1:1 acetone/hexanes); flash column
ASSOCIATED CONTENT
■
S
* Supporting Information
Copies of 1H and 13C NMR spectra, stereochemical proofs and
X-ray crystallographic data (CIF file) for compounds 2-epi-23,
24 and 28. This material is available free of charge via the
Internet at http://pubs.acs.org
23
chromatography (3:7 then 3:2 acetone/hexanes); colorless oil; [α]D
1
−8.2 (c 0.27, CHCl3); H NMR (600 MHz, CDCl3) δ 7.40 (s, 1H),
7.34−7.22 (m, 5H, Ph), 4.50 (d, J 11.8 Hz, 1H, CHHOBn),
4.39 (d, J 11.8 Hz, 1H, CHHOBn), 4.04 (ddd, J 8.6, 5.1, 3.8 Hz, 1H,
H-4), 3.63 (dd, J 8.8, 5.6 Hz, 1H, H-2), 3.11 (dd, J 11.1, 5.1 Hz, 1H,
H-5′), 3.05 (dd, J 11.1, 3.0 Hz, 1H, H-5″), 2.23−2.19 (m, 2H, H-3′/
H-3″), 1.27 (s, 9H, (CH3)3C); 13C NMR (151 MHz, CDCl3) δ 176.4,
140.9, 130.9, 130.3, 130.2, 81.3, 73.5, 62.6, 55.0, 52.7, 38.5, 31.3;
HRMS (ESI-TOF) m/z calcd for C16H25N2O2 [M + H+] 277.1916.
Found 277.1913; IR (film) ν 3316, 2966, 2929, 2868, 1658, 1522,
1453, 1362, 1227, 1111, 1094, 1071, 737, 698 cm−1.
AUTHOR INFORMATION
Corresponding Authors
*E-mail: sebastian.stecko@icho.edu.pl.
*E-mail: bartlomiej.furman@icho.edu.pl.
■
Notes
The authors declare no competing financial interest.
(2R,4R)-4-(Benzyloxy)-N-cyclohexylpyrrolidine-2-carboxamide
(48): major isomer; compound was not isolated in pure form; yield 47
mg (40%) starting from 155 mg (0.39 mmol) of mixture 28/2-epi-28;
Rf 0.13 (100% AcOEt); flash column chromatography (2:3 acetone/
hexanes); colorless oil; 1H NMR (600 MHz, C6D6) δ 7.36 (d, J 7.3 Hz,
1H, NH), 7.27−7.13 (m, 5H, Ph), 4.39 (d, J 11.6 Hz, 1H, CHHOBn),
4.29 (d, J 11.6 Hz, 1H, CHHOBn), 3.98−3.94 (m, 1H, H-4), 3.63 (t,
J 7.1 Hz, 1H, H-2), 3.61−3.54 (m, 1H), 3.02 (dd, J 11.0, 5.0 Hz, 1H,
H-5′), 2.97 (dd, J 11.0, 2.9 Hz, 1H, H-5″), 2.16−2.13 (m, 2H, H-3′/
H-3″), 1.76−1.70 (m, 1H), 1.64−1.54 (m, 2H), 1.52−1.43 (m, 2H),
1.26−1.13 (m, 2H), 1.06−0.97 (m, 2H), 0.96−0.87 (m, 1H); 13C
NMR (151 MHz, C6D6) δ 176.2, 140.7, 130.8, 130.3, 130.1, 81.2, 73.4,
62.0, 54.9, 49.9, 38.5, 35.6, 35.4, 28.1, 27.4, 27.3; HRMS (ESI-TOF) m/z
calcd for C18H27N2O2 [M + H+] 303.2073, found 303.2070; IR (film)
ν 3316, 2928, 2853, 1652, 1523, 1451, 1349, 1108, 1068, 737, 698 cm−1.
(2S,4R)-4-(Benzyloxy)-N-cyclohexylpyrrolidine-2-carboxamide (2-
epi-48): minor isomer; compound was not isolated in pure form; yield
ACKNOWLEDGMENTS
■
Financial support by the European Union within the European
Regional Development Fund, Project POIG.01.01.02.-14-102/
09, is gratefully acknowledged. We are also grateful to The
Regional Council of Mazovia and the European Union within
the European Regional Development Fund for a Ph.D. student
scholarship (P.Sz.).
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