Transition Metal-Free Selective Double sp3 C-H Oxidation of Cyclic Amines to 3-Alkoxyamine Lactams

Article abstract of DOI:10.1021/acs.joc.6b01566

The first chemical method for selective dual sp³ C-H functionalization at the alpha-and beta positions of cyclic amines to their corresponding 3-alkoxyamine lactams is reported. Unlike traditional C_α-H oxidation of amines to amides mediated by transition metals, the present protocol, which involves the use of NaClO₂/TEMPO/NaClO in either aqueous or organic solvent, not only allows the C_α-H oxidation but also the subsequent functionalization of the unreactive β-methylene group in an unprecedented tandem fashion and using environmentally friendly reactants.

Full text of DOI:10.1021/acs.joc.6b01566

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Note
Transition Metal-Free Selective Double sp3 C-H
Oxidation of Cyclic Amines to 3-Alkoxyamine lactams
Urbano Osorio-Nieto, Delfino Chamorro-Arenas, Leticia Quintero, Herbert Höpfl, and Fernando Sartillo-Piscil
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.6b01566 • Publication Date (Web): 26 Aug 2016
Downloaded from http://pubs.acs.org on August 29, 2016
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The Journal of Organic Chemistry
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Transition MetalꢀFree Selective Double sp3 C−H
Oxidation of Cyclic Amines to 3ꢀAlkoxyamine lactams
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Urbano OsorioꢀNieto,a Delfino ChamorroꢀArenas,a Leticia Quintero,a Herbert Höpfl,b and Fernando
SartilloꢀPiscil.a*
aCentro de Investigación de la Facultad de Ciencias Químicas, Benemérita Universidad Autónoma de
Puebla (BUAP). 14 Sur Esq. San Claudio, Col. San Manuel. 72570, Puebla, México.
bCentro de Investigaciones Químicas, Instituto de Investigación en Ciencias Básicas y Aplicadas,
Universidad Autónoma del Estado de Morelos. Avenida Universidad 1001, Col. Chamilpa. 62209,
Cuernavaca, México.
*To whom correspondence should be addressed. Telephone:+52 222 2955500 ext. 7391. Fax number: +
52 222 2454972
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ABSTRACT. The first chemical method for selective dual sp3 C−H functionalization at the alphaꢀand
beta positions of cyclic amines to their corresponding 3ꢀalkoxyamine lactams is reported. Unlike
traditional Cα−H oxidation of amines to amides mediated by transition metals, the present protocol,
which involves the use of NaClO2/TEMPO/NaClO in either aqueous or organic solvent, not only allows
the Cα−H oxidation but also the subsequent functionalization of the unreactive βꢀmethylene group in an
unprecedented tandem fashion and using environmentally friendly reactants.
The Cα−H oxidation reaction of cyclic amines mediated by transitionꢀmetals is becoming a powerful
methodology for preparing lactams.1 Since complex and expensive transition metalꢀcatalysts are
employed, direct Cα−H functionalization is frequently not attractive from an economic and
environmental point of view, albeit dehydrogenation of cyclic amines in water mediated by ruthenium
pincer complex might offer some green chemistry features.1a Because most of the oxidizing agents based
on nonꢀtransition metals react at the nitrogen atom to furnish Nꢀoxides rather than the desired Cα−H
bond, one of the challenges is to evade the premature oxidation at the nitrogen atom.2 Therefore,
developing synthetic methodologies that could permit Cα−H functionalization of amines under
transitionꢀmetal free conditions is imperative.
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The Journal of Organic Chemistry
In 2012, a chemical method for the preparation of 2,3ꢀepoxyamides (glycidic amides) from tertiary
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allyl amines was reported (Scheme 1).3 Since the NaClO2 was the sole oxidizing reagent used in the
tandem Cα−H oxidation/olefinic epoxidation, this methodology represents an environmentalꢀfriendly
and economic approach for the synthesis of highly oxygenated compounds.4 Interestingly, NaClO2,
which is considered a strong oxidizing agent for organic materials,5 does not oxidize the nitrogen atom.
However, the synthesis of the glycidic amides was not diastereoselective even when employing chiral
auxiliaries such as the (S)ꢀαꢀmethylbenzylamine or the (R)ꢀ2ꢀphenylglycinol.3
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Scheme 1. Direct Chemical Method for the Synthesis of Glycidic Amides from Tertiary Amines
Searching for an efficient chiral auxiliary for this direct synthesis of glycidic amides, allyl amines
derived from Lꢀdiphenylprolinol were thought to be suitable candidates. However, treatment of 1 with
NaClO2 under the previously established conditions did not afford the expected glycidic amide 2 but
benzophenone 3 and γꢀlactone 4 (eq 1, Scheme 2). The C−C bond cleavage of 1 can be explained by a βꢀ
fragmentation reaction of radical cation A to the resonanceꢀstabilized radical B and the iminium cation
C,6 of which the former is further oxidized to benzophenone 3, while the latter is transformed into γꢀ
lactam 4 in two sequential steps: nucleophilic attack of a chlorite anion (5) to form D followed by
elimination of hypochlorous acid.7 Since the electronic effect of phenyl groups in 1 seems to provide the
driving force for the C−C bond cleavage, the protected Lꢀprolinol 6 was prepared and tested under the
same reaction conditions as for 1. But again, the formation of glycidic amide was not observed and now
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cinnamic acid 7 and the starting prolinol 8 were isolated, illustrating that the C−N bond cleavage is
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3
favored over C−C bond rupture.
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Scheme 2. Attempts for Diastereoselective Oxidation of Allyl Amine 1 to Glycidic Amide 2 in the
8
9
Absence of TEMPO (eq 1), and in the Presence of TEMPO (eq 2)
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In an attempt to evidence the presence of radicals, compound 6 was exposed to 5 equivalents of
TEMPO (radical scavenger), which inhibited the C−N bond cleavage (22% of 7). Unexpectedly,
diastereomeric 3ꢀalkoxyamine pyrrolidinones 9a and 9b were obtained in 30% yield as an equimolar
mixture (eq 2, Scheme 2). The accidental incorporation of TEMPO in the βꢀsite of 6 to form 9a and 9b
inspired the development of a new chemical reaction for the selective double Cα−H/Cβ−H oxidation of
pyrrolidines to 3ꢀalkoxyamine pyrrolidinones under transitionꢀmetalꢀfree conditions.
Table 1. Optimization for the Selective Double Cα−H/Cβ−H Oxidation of NꢀBenzyl Piperidinesꢀ
and Pyrrolidinesa
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The Journal of Organic Chemistry
1
2
( )n
O
N
( )n
3
4
5
6
7
8
N
Conditions
O
N
Ph
n = 1; 10
n = 2; 11
n = 1; 12
n = 2; 13
Ph
time
entry cyclic NaClO2/TEMPO/NaOCl
solvent
product
(yield %)b
9
amine
(equiv)
(h)
(ratio v/v)
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13 (0)c
12 (0)c
THF/H2O/tꢀBuOH
1
2
11
5/5/0
4
(3/7/7)
10
5/5/0
THF/H2O/tꢀBuOH
4
(3/7/7)
3
4
11
10
5/5/1.5
5/5/1.5
THF/H2O/tꢀBuOH
1
2
13 (80)
12 (45)
(3/7/7)
THF/H2O/tꢀBuOH
(3/7/7)
5
6
7
8
11
10
11
11
3/5/1.5
3/5/1.5
0/3/1.5
5/5/1.5
THF/H2O/tꢀBuOH
1
2
2
2
13 (85)
12 (55)
13 (0)c
13 (80)
(3/7/7)
THF/H2O/tꢀBuOH
(3/7/7)
THF/H2O/tꢀBuOH
(3/7/7)
MeCN
9
11
11
11
10
3/3/4.5
3/3/1.5
MeCN
MeCN
MeCN
MeCN
1
2
4
4
13 (0)c
13 (85)
13 (85)
12 (60)
10
11
12
2/1.5/1.5
2/1.5/1.5
aReactions were performed using 0.3 mmol of cyclic amine warming from 0 °C to room
b
temperature and using 10 equiv of NaH2PO4 as buffer keeping a pH ~5. Unless noted,
c
yields are reported after silica gel chromatography. Starting material remains unchanged
Benzyl pyrrolidine 10 and benzyl piperidine 11 represent suitable substrates for testing the apparent
selectivity in the double C−H functionalization and were selected for screening a variety of reaction
conditions (Table 1). Both benzyl amines 10 and 11 were treated under the same reaction conditions as
for 6 (entries 1 and 2), but the expected 3ꢀalkoxyamine lactams 12 and 13 were not observed. With the
knowledge that in some cases the oxidative capacity of NaClO2 and TEMPO is reinforced by the use of
NaClO,8 the reactions were performed also in the presence of 1.5 equiv of NaOCl. To our delight, the
reaction now proceeded in good yield for 3ꢀalkoxyamineꢀ2ꢀpiperidone 13 (80%) and moderate yield
(45%) for 3ꢀalkoxyamineꢀ2ꢀpyrrolidinone 12 (entries 3 and 4). By reducing the amount of NaClO2 from
5 to 3 equivalents, the yields of 13 and 12 were slightly increased (entries 5 and 6). As expected, in the
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absence of NaClO2 the reaction did not proceed (entry 7). By using only MeCN as solvent, the yield of
13 was identical to that isolated from the THF/H2O/tꢀBuOH mixture (entry 8). However, with an excess
of NaOCl (4.5 equiv) the reaction did not proceed, and the starting materials remained almost
unchanged (entry 9). These results establish that the use of 1.5 equiv of NaOCl is determinant for this
unprecedented dual sp3 C−H functionalization, and that at least 3 equivalents of NaClO2 and TEMPO
are necessary to obtain 13 in good yield (entry 10). Finally, upon reduction of the stoichiometric
amounts of NaClO2 and TEMPO, the reaction conditions could be further optimized (2 equiv of
NaClO2, and 1.5 equiv of both NaOCl and TEMPO) to give 12 (60%) and 13 (85%), using MeCN as
solvent (entries 11 and 12).
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To explore the scope of the reaction, a series of substrates were selected in order to evaluate the
selectivity of the double C−H oxidation that would allow to synthesize 3ꢀalkoxyamine lactams of
potential use in total synthesis. Thus, chiral tertiary pyrrolidines (14, 16, 18 and 20) and tertiary
piperidines (23, 254a and 27) were prepared from their corresponding Lꢀprolinol derivatives and
piperidine, respectively. As determined after column chromatographic purification, pyrrolidinone 14 was
transformed to an equimolar diastereomeric mixture of 15a and 15b in good yields, even though these
oxidative reaction conditions are known to oxidize the hydroxyl groups to carboxylic acids (entry 1).9 A
slight reaction improvement was observed when the hydroxyl group was protected by the typical silyl
group (16 to 17a and 17b), illustrating the mildness of the reaction conditions (entry 2). As noted above
for 1, the presence of phenyl groups at the carbinol position of Lꢀprolinol (1) favours dealkylation, and
hence, only moderate yields were obtained for diastereomeric mixture of 19aꢀb and 21aꢀb (entries 3 and
4). With prolinol 1, 66% of the corresponding diastereomeric mixture of the 3ꢀalkoxyamine lactam 22aꢀ
b were obtained (entry 5). For the Nꢀalkyl substituted piperidine 23, the reaction was less successful,
giving 24 only in 14% yield.
Table 2. Dual sp3 C−H Oxidation of a Series of LꢀProlinol and Piperidine Derivativesa
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The Journal of Organic Chemistry
( )n
YO
R
1
2
3
4
( )n
NaClO2/TEMPO/NaOCl
R
N
P
Y =
N
CH3CN
0 °C to room temperature
O
N
P
5
yield (%)b
76c,d
6
7
8
9
entry
1
substrate
time (h)
0.5
product
YO
O
OH
N
10
11
12
13
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N
OH
Bn
Bn
15(a+b)
14
YO
OTBS
2
3
4
0.5
0.3
0.3
81c
52c
61c
N
O
N
OTBS
Bn
Bn
17(a+b)
16
YO
O
Ph
Ph
Ph
Ph
N
N
OH
Bn
OH
Bn
18
19(a+b)
YO
pꢀFꢀPh
pꢀFꢀPh
pꢀFꢀPh
pꢀFꢀPh
N
O
N
OH
20
Bn
OH
Bn
21(a+b)
Ph
Ph
Ph
YO
Ph
OH
OH
5
0.5
66c
N
N
O
22(a+b)
Ph
Ph
1
Ph
YO
N
O
N
6
7
1
1
14
23
24
Ph
O
71e
N
N
O
Ph
25
Ph
26(a+b)
OY
N
N
8
3
78
O
N
N
28
27
BOC
Boc
aReactions were carry out in 10 mL of CH3CN using 2 equiv of NaClO2, 1.5 equiv of TEMPO
b
and 1.5 equiv of
NaOCl, and 0.3 mmol of cyclic amines. Yields reported after silica gel
c
d
chromatography. Diastereomeric ratio (a+b) ~ 50:50. Both diastereomers were structurally
characterized by Xꢀray crystallographic studies. eDiastereomeric ratio (a+b) = 71:29.
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The chiral dihydropiperidine 25 was tested expecting to achieve C−H oxidation at both the Cꢀ5 and Cꢀ6
positions; however, the expected lactam was not observed, but instead the glycidic amide 264a (71%)
was formed with good yield and with moderate diastereoselectivity (71:26) (entry 7). Since the reported
direct method for the synthesis of glycidic amides occurs without any stereoselectivity,3,4a this result
might provide a significant improvement for the stereocontrolled construction of the 3,4ꢀepoxyꢀ2ꢀ
piperidone motif, which is a common skeleton encountered in numerous biologically active
compounds.10 A final remarkable result was obtained from the indole piperidine derivative 27 (entry 8),
which not only features the high C−H oxidation selectivity and the compatibility of the Boc protecting
group with the reaction conditions, but also the high stability of the indole ring against the inherent
electrophilic species delivered from the oxidizing reagents employed. Thus, this later result represents a
convenient way for the C−H functionalization of piperidines containing indole moiety, which is relevant
for the total synthesis of indole alkaloids.11
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Based on the αꢀaminoxylation of aldehydes12 with enamines and TEMPO+X−, a mechanistic proposal
for this double C−H oxidation is centered on the formation of enamine E, which might be generated by
following the sequential transformation depicted in Scheme 3. TEMPO radical is first oxidized to
oxammonium cation F that reacts with the cyclic amine8,13 to give either G or G’, and after an
eliminationꢀlike reaction, the iminium intermediate H is formed and rapidly transformed to enamine E.
The reaction of enamine E with oxammonium cation F (which the latter is probably regenerated by
oxidation of TEMPOH13,15) allows the incorporation of TEMPO14 forming iminium I which is attacked
by chlorite ion7 to form K, and after elimination of HOCl provides the corresponding 3ꢀalkoxyamine
lactam (eq 3, Scheme 3). It is important to mention that the formation of enamine E (e. g., R = Ph) from
6
radical cation L via an electron transfer reaction with ClO2 might be not feasible because it would
afford benzylic C−H oxidation (M), and after reacting with chlorite ion, benzoyl piperidine would be
obtained as the major product (eq 4, Scheme 3).3
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The Journal of Organic Chemistry
Scheme 3. Proposed Reaction Mechanism
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2
3
4
5
6
7
8
[O]
N OH
TEMPOH
N O
TEMPO
[O]
9
Bn
N
H
R
10
11
12
13
14
15
16
17
18
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O
N
O
N
+
O
N
N
or
N
cyclic amine
H
F
R
G
G'
O
O
N
N
ꢀH
(eq. 3)
N
O
N
N
Cl
I
O
R
H
R
R
E
O
O
O
O
N
N
ꢀ HOCl
N
N
H
Cl
R
O
R
3ꢀalkoxyamine lactam
K
Ph
Ph
Ph
Ph
ClO2
(eq. 4)
ꢀ HOCl
N
ꢀH
N
N
N
ClO2
O
O
M
L
Cl
O
cyclic amine
benzoyl piperidine
Scheme 4. Preparation of 3ꢀHydroxylactams
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Finally, starting from the 3ꢀalkoxylamine lactams, the respective 3ꢀhydroxy lactams can be liberated
by reduction with Zn.15 This has been evidenced representatively for 13, 12 and 28 to give 29, 30 and
31, respectively, in good yields (Scheme 4).
1
2
3
4
5
6
7
8
9
In summary, an unprecedented chemical method for the selective double C−H functionalization of
cyclic amines to 3ꢀalkoxyamine lactams is reported. Since this unprecedented dual sp3 C−H
functionalization is performed in the absence of a transitionꢀmetal catalyst, and cheap and nontoxic
oxidizing reagents such as NaClO2 and NaOCl are employed, this protocol represents a promising
environmentalꢀfriendly method for the access to a number of pyrrolidineꢀand piperidine derivedꢀ
alkaloids. Additionally, this new methodology represents a suitable methodology for αꢀoxygenation of
lactams.16
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EXPERIMENTAL SECTION
Commercially available reagents were used without further purification. Column chromatography
(CC) was performed using silica gel (200ꢀ300 mesh) with solvents indicated on the text. Melting points
were determined on an open capillary tube and are uncorrected. Optical rotations were measured in a
digital polarimeter in the sodium D line (589 nm) and are reported as degrees at 20 °C and concentration
1
13
is expressed as g/100 mL. Unless otherwise stated, H NMR and C NMR spectra were obtained in a
500 MHz and 125 MHz spectrometer, respectively. All samples were analyzed in CDCl3 with TMS as
internal reference using a relative scale in parts per million (ppm) for the chemical shift (δ) and Hz for
coupling constants (J). Splitting patterns are designated as follow: s, singlet; d, doublet; t, triplet; q,
quartet; qu, quintet; m, multiple; and br, broad. High resolution mass spectra (HRMS) were acquired in
electronꢀimpact (EI) mode using a TOF mass analyzer or in fastꢀatomꢀbombardment (FAB) mode using
a QMS mass analyzer.
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The Journal of Organic Chemistry
NꢀCinnamylꢀα,αꢀdiphenylꢀLꢀprolinol (1)
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To a solution of Lꢀproline (2.0 g, 17.37 mmol) in CH3OH (20 mL) at 0 °C was dropwise added SOCl2
(2.53 mL, 4.13 g, 34.7 mmol). The reaction mixture was stirred over 5h at reflux temperature, and after
the reaction was complete, the mixture was cooled and the solvent was removed under reduced pressure
to obtain the corresponding methyl ester hydrochloride salt, which was dissolved in 30 mL of dry
CH2Cl2 and treated with 4ꢀdimethylaminopyridine (1.06 g, 8.68 mmol) and NEt3 (3.512 g, 34.74
mmol,). The reaction mixture was stirred for 15 min before to add cinnamyl bromide (4.10 g, 20.84
mmol) dissolved in CH2Cl2 (5 mL). The mixture was stirred under argon atmosphere at room
temperature for 16 h, then 5 mL of concentrated aqueous solution of NaHCO3 and 10 mL of H2O were
added. The organic phase was separated using an extraction funnel and the aqueous phase was extracted
with ethyl acetate (3 x 15 mL). The organic portions were joined and concentrated just after passing on
sodium sulfate to obtain methylꢀNꢀcinnamylꢀLꢀprolinate (4.018 g). The reaction crude was submitted to
the next reaction without further purification. To a solution of methyl Lꢀprolinate (2.87 g, 17.32 mmol)
in dry CH2Cl2 (30 mL) was added benzyl bromide (2.47 mL, 20.84 mmol, 3.56 g) and DMAP (3.18 g,
25.05 mmol). The mixture was stirred at room temperature over 18 h to obtain methyl NꢀbenzylꢀLꢀ
prolinate (3.7 g) that was submitted to the next reaction without purification. To a solution of methyl Nꢀ
cinnamylꢀLꢀprolinate (1.0 g, 4.06 mmol) in dry THF (30 ml) at 0 °C was added a 1.0 M solution in THF
of phenylmagnesium bromide (10.15 mL, 10.15 mmol). The reaction mixture was stirred over 3 h in
argon atmosphere at 0 °C and after the reaction was completed, a saturated solution of ammonium
chloride was dropwise added until salts formation was observed. The solvent was removed by
distillation at reduced pressure; the solids were washed with AcOEt (5 x 10 mL), then the liquids
portions were dried over Na2SO4 and evaporated under reduced pressure. The residue was purified by
flash column chromatography on silica gel (eluent: hexane/EtOAc, 6/1) to yield 1 (1.276 g, 85%) as a
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withe crystalline solid. Mp = 96ꢀ98 °C; [α]D20 = + 49.9 (c = 1.0, CHCl3); 1H NMR (400 MHz, CDCl3)
δ:
7.40ꢀ7.64 (m, 5H), 7.10ꢀ7.34 (m, 10H), 6.15 (d, J = 15.6 Hz, 1H), 6.00 (ddd, J = 15.6, 8.0, 5.2 Hz, 1H),
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4.84 (s, 1H), 3.88 (dd, J = 9.2, 4.0 Hz, 1H), 3.14ꢀ3.18 (m, 1H), 2.76 (ddd, J = 14.0, 5.2, 1.2 Hz, 1H),
2.64 (dd, J = 14.0, 8.4 Hz, 1H), 2.51 (dt, J = 6.4, 9.2 Hz, 1H), 1.87ꢀ1.92 (m, 1H), 1.60ꢀ1.74 (m, 4H); 13C
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NMR (100 MHz, CDCl3) δ: 148.0, 146.4, 131.7, 128.7, 128.5, 128.0, 128.0, 127.3, 127.2, 127.1, 126.9,
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C26H27NO, 369.2093).
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NꢀBenzylꢀα,αꢀdiphenylꢀLꢀprolinol (18)
Following the above procedure, but using methyl NꢀbenzylꢀLꢀprolinate (1.0 g, 4.56 mmol) and
phenylmagnesium bromide (9.12 mL, 9.12 mmol) as substrate, prolinol 18 (1.31 g, 84%) was obtained
as white crystals. Mp =119ꢀ122 °C; [α]D20 = + 79.6 (c = 1.0, CHCl3); lit17 [α]D = + 91.5 (c = 1.0,
22
CHCl3); 1H NMR (500 MHz, CDCl3)
δ: 7.72 (d, J = 8.5 Hz, 2H), 7.57 (d, J = 8.5 Hz, 2H), 7.31ꢀ7.14 (m,
8H), 7.09 (td, J = 7.0, 1.0 Hz, 1H), 7.04 (d, J = 7.5 Hz, 2H), 4.93 (br, 1H), 3.97 (dd, J = 9.5, 4.5 Hz,
1H), 3.21 (d, J = 12.5 Hz, 1H), 3.02 (d, J = 13.0 Hz, 1H), 2.93ꢀ2.89 (m, 1H), 2.37ꢀ2.32 (m, 1H), 1.96
(dq, J = 13.0, 9.0 Hz, 1H), 1.78ꢀ1.73 (m, 1H), 1.66ꢀ1.58 (m, 2H); 13C NMR (125 MHz, CDCl3)
δ: 147.9,
146.6, 139.6, 128.5, 128.1, 128.0, 128.0, 126.8, 126.3, 126.2, 125.5, 125.5, 77.9, 70.6, 60.5, 55.5, 29.7,
24.1.
NꢀBenzylꢀα,αꢀbis(4ꢀfluorophenyl)ꢀLꢀprolinol (20)
Following the above procedure but using 4ꢀfluorophenylmagnesium bromide (2.85 mL, 1.14 g, 5.7
mmol) as Grignard reagent, prolinol 20 (0.679 g, 78.5%) was obtained as white crystals. Mp = 150ꢀ152
°C; [α]D20 = + 71.4 (c = 1.0, CHCl3); lit17 [α]22D = + 94.4 (c 1.0, CHCl3); 1H NMR (500 MHz, CDCl3)
δ: 7.69ꢀ7.65 (m, 2H), 7.55ꢀ7.51 (m, 2H), 7.28ꢀ7.20 (m, 3H), 7.07ꢀ6.96 (m, 6H), 5.01 (br, 1H), 3.93 (dd,
J = 9.5, 5.0 Hz, 1H), 3.27 (d, J = 12.5 Hz, 1H), 3.09 (d, J = 12.5 Hz, 1H), 2.95 (ddd, J = 10.0, 6.0, 4.5
Hz, 1H), 2.39 (dt, J = 9.0, 8.0 Hz, 1H), 1.95 (apparent dq, J = 12.5, 9.0 Hz, 1H), 1.75ꢀ1.69 (m, 1H),
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1.68ꢀ1.62 (m, 1H); C NMR (125 MHz, CDCl3)
δ
: 161.4 (d, JCꢀF = 244.0 Hz), 161.2 (d, JCꢀF = 243.5
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Hz), 143.7 (d, JCꢀF = 3.1 Hz), 142.4 (d, JCꢀF = 3.2 Hz), 139.3, 128.4, 128.2, 127.1 (d, JCꢀF = 7.7 Hz),
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127.0 (d, JCꢀF =7.7 Hz), 127.0, 115.1 (d, JCꢀF = 21.1 Hz), 114.9 (d, JCꢀF = 21.0 Hz), 77.3, 70.6, 60.6,
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NꢀCinnamylꢀOꢀterꢀbutyldimethylsilylꢀLꢀprolinol (6)
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To a suspension of LiAlH4 (0.464 g, 12.22 mmol) in dry THF (20 ml) at 0 °C was added a solution of
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methyl NꢀcinnamylꢀLꢀprolinate (2.0 g, 8.15 mmol) in dry THF (10 ml). The solution was allowed
stirring over 3 h at 0 °C, after this time, aqueous solution of NaHCO3 (5 mL) was dropwise aggregated
until salts formation are observed. Then the resulting solids were filtered off, washed with AcOEt and
the organic phase was dried over Na2SO4, concentrated and purified by flash chromatography on silica
gel (eluent hexane/EtOAc: 1:2) to obtain the corresponding NꢀcinnamylꢀLꢀprolinol (1.32 g, 75%) as a
viscous liquid. [α]D20 = ꢀ 35.8 (c = 1.0, CHCl3); 1H NMR (500 MHz, CDCl3)
δ: 7.38ꢀ7.36 (m,2H), 7.32ꢀ
7.29 (m, 2H), 7.23 (tt, J = 7.5, 1.0 Hz, 1H), 6.52 (d, J = 16.0 Hz, 1H), 6.28 (ddd, J = 16.0, 7.5, 6.0 Hz,
1H), 3.67 (dd, J = 10.5, 3.5 Hz, 1H), 3.56 (ddd, J = 13.5, 6.0, 1.5 Hz, 1H), 3.43 (dd, J = 10.5, 2.5 Hz,
1H), 3.15 (apparent qu, J = 5.0 Hz, 1H), 3.09 (ddd, J = 13.5, 8.0, 1.5 Hz, 1H), 2.69 (dddd, J = 5.5, 3.5,
3.0, 2.5 Hz, 1H), 2.36 (apparent q, J = 8.5 Hz, 1H), 1.91 (ddt, J = 12.5, 9.0, 8.5 Hz 1H), 1.83ꢀ 1.77 (m,
13
1H), 1.76ꢀ1.70 (m, 2H); C NMR (125 MHz, CDCl3)
δ: 136.9, 131.8, 128.5, 127.5, 127.4, 126.2, 63.8,
62.0, 56.4, 54.4, 27.8, 23.5. To a solution of tꢀBu(CH3)2SiCl (0.754 g, 5.00 mmol) and imidazole (0.426
g, 6.26 mmol) in dry CH2Cl2 (15 mL) at 0 °C was dropwise added a solution of NꢀcinnamylꢀLꢀprolinol
(0.904 g, 4.17 mmol) in CH2Cl2 (10 ml). The reaction mixture was stirred at room temperature over 3 h
and then 5 mL of aqueous solution of NaHCO3 was added. Both phases were separated and the aqueous
phase was extracted with EtOAc (3 x 10 ml). The combined organic phases were dried over Na2SO4 and
the solvent was removed under reduced pressure. The residue was purified by flash chromatography on
silica gel (eluent hexane/EtOAc: 9:1) to obtain 618 (1.17 g, 85%) as a greenish yellow liquid. [α]D20 = ꢀ
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45.8 (c = 1.0, CHCl3); lit17 [α]D = ꢀ 59.0 (c = 0.8, CHCl3); H NMR (500 MHz, CDCl3)
δ: 7.38ꢀ7.36
(m, 2H), 7.31ꢀ7.28 (m, 2H), 7.21 (tt, J = 7.0, 1.5 Hz, 1H), 6.52 (d, J = 16.0 Hz, 1H), 6.33 (ddd, J = 16.0,
8.0, 6.5 Hz, 1H), 3.73ꢀ3.69 (m, 2H), 3.47 (dd, J = 10.0, 7.0 Hz, 1H), 3.15ꢀ3.09 (m, 2H), 2.64 (qu, J = 6.5
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Hz, 1H), 2.31 (dt, J = 9.0, 7.0 Hz, 1H), 1.91 (ddt, J = 12.5, 8.5, 8.0 Hz, 1H), 1.80ꢀ1.67 (m, 2H), 1.63ꢀ
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1.57 (m, 1H), 0.89 (s, 9H), 0.05 (s, 6H); CꢀNMR (125 MHz, CDCl3)
δ: 137.0, 131.8, 128.4, 127.8,
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NꢀBenzylꢀLꢀprolinol (14)
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A solution of methyl Nꢀbenzylprolinate (2.0 g, 9.12 mmol) in dry THF (10 mL) was added to a
suspension of LiAlH4 (0.693 g, 18.25 mmol) in dry THF (20 ml). The mixture was stirred over 2 h
before to add dropwise an aqueous solution of NaHCO3 (5 mL) until salts formation are observed. Then
the resulting solids were filtered off, washed with AcOEt and the organic phase was dried over Na2SO4.
Organic phase was concentrated under reduced pressure and purified by flash chromatography on silica
gel (eluent hexane/EtOAc: 1:1) to give 1419 (1.517 g, 87%) as a yellow oil. [α]D20 = ꢀ 46.3 (c = 1.15,
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CHCl3); H NMR (500 MHz, CDCl3)
δ: 7.34ꢀ7.24 (m, 5H), 3.99 (d, J = 13.0 Hz, 1H), 3.66 (dd, J =
11.0, 3.5 Hz, 1H), 3.44 (dd, J = 11.0, 2.5 Hz, 1H), 3.38 (d, J = 13.0 Hz, 1H), 3.03ꢀ2.97 (m, 2H), 2.76
(ddd, J = 12.0, 6.0, 3.0 Hz, 1H), 2.31 (dt, J = 8.0, 9.5 Hz, 1H), 1.93 (apparent dq, J = 13.0, 9.0 Hz, 1H),
1.87ꢀ1.80 (m, 1H), 1.73ꢀ1.66 (m, 2H); 13C NMR (125 MHz, CDCl3)
61.6, 58.5, 54.3, 27.6, 23.4.
δ: 138.8, 128.7, 128.3, 127.1, 64.3,
NꢀBenzylꢀOꢀtertꢀButyldimethylsilylꢀLꢀprolinol (16)
To a solution of imidazole (0.408 g, 6.00 mmol) and tꢀBu(CH3)2SiCl (0.723 g, 4.80 mmol) in 20 mL of
dry CH2Cl2 was added a solution of 14 (0.765 g, 4.00 mmol) in dry CH2Cl2 (5 mL). The reaction
mixture was stirred at room temperature over 2 h and then 5 mL of aqueous solution of NaHCO3 was
added. Both phases were separated, and the aqueous phase was extracted with EtOAc (3 x 10 mL). The
combined organic phases were dried over Na2SO4, and the solvent was removed under reduced pressure.
The residue was purified by flash chromatography on silica gel (eluent hexane/EtOAc: 12:1) to obtain
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1620 (1.03 g, 84%) as a greenish yellow liquid. [α]D20 = ꢀ 46.9 (c = 1.0, CHCl3); H NMR (500 MHz,
CDCl3)
δ: 7.33ꢀ7.27 (m, 4H), 7.22 (tt, J = 7.5, 1.5 Hz, 1H), 4.11 (d, J = 13.0 Hz, 1H), 3.64 (dd, J = 10.0,
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5.5 Hz, 1H), 3.46 (dd, J = 10.0, 6.5 Hz, 1H), 3.41 (d, J = 13.0 Hz, 1H), 2.90 (ddd, J = 9.0, 7.0, 2.5 Hz,
1H), 2.67 (ddd, J = 12.5, 8.5, 6.0 Hz, 1H), 2.21 (dt, J =9.0, 7.5 Hz, 1H), 1.90 (dq, J = 12.5, 8.5 Hz, 1H),
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CDCl3) δ: 139.9, 128.9, 128.0, 126.6, 67.1, 65.0, 60.4, 54.8, 28.04, 25.9, 22.8, 18.2, ꢀ5.3, ꢀ5.3.
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1ꢀCinnamylpiperidine (23)
To a suspension of Na2CO3 (1.58 g, 15 mmol) in dry MeCN (20 mL) at room temperature was added
piperidine (0.98 ml, 10. 0 mmol) and a solution of cinnamyl bromide (1.97 g, 10 mmol) in CH2Cl2 (10
mL). Then, the mixture was heated to reflux temperature over 4 h. After the reaction was completed, the
solvent was removed under reduced pressure and the resulting solids were washed with EtOAc (5 x 10
ml). The organic portion was dried over Na2SO4, concentrated and purified by flash chromatography on
silica gel (eluent hexane/EtOAc: 2/1) to obtain 2321 (1.12 g, 56%) as a black brownish liquid. H NMR
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(500 MHz, CDCl3) δ: 7.38ꢀ7.36 (m, 2H), 7.31ꢀ7.28 (m, 2H), 7.21 (tt, J = 7.5, 1.5 Hz 1H), 6.49 (d, J =
15.5 Hz, 1H), 6.30 (dt, J = 16.0, 7.0 Hz, 1H), 3.11 (dd, J = 7.0, 1.5 Hz, 2H), 2.43 (br, 4H), 1.60 (qu, J =
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6.0 Hz, 4H), 1.44 (br, 2H); C NMR (125 MHz, CDCl3)
δ: 137.0, 132.5, 128.4, 127.3, 126.2, 61.8,
54.5, 25.9, 24.2.
tertꢀButyl 3ꢀ[2ꢀ(piperidinꢀ1ꢀyl)ethyl]ꢀ1Hꢀindoleꢀ1ꢀcarboxylate (27)
To a suspension of K2CO3 (0.704 g, 5.09 mmol) in dry MeCN (20 mL) at room temperature was added
piperidine (0.325 g, 1.46 mmol) and NꢀBocꢀ2ꢀbromoethylindole (0.826 g, 2.54 mmol). Then, the
mixture was allowed to react over 4 h. After the reaction was completed, the solvent was removed under
reduced pressure and the resulting solids were washed with EtOAc (5 x 10 ml). The organic portion was
concentrated, dried over Na2SO4, and purified by flash chromatography on silica gel (eluent
hexane/EtOAc: 1/1) to obtain 27 (1.20 g, 90%) as a light yellow oil. 1H NRM (500 MHz, CDCl3) δ: 8.11
(br, 1H), 7.54 (d, J = 7.5 Hz, 1H), 7.40 (br, 1H), 2.51 (br, 4H), 7.30 (ddd, J = 8.5, 7.5, 1.0 Hz, 1H), 7.23
(ddd, J = 8.5, 8.0, 1.0 Hz, 1H), 2.91ꢀ2.88 (m, 2H), 2.67ꢀ2.64 (m, 2H), 1.66 (s, 9H), 1.63 (m, 4H), 1.48
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(br, 2H); 13C NMR (125 MHz, CDCl3) δ: 149.8, 135.3, 130.7, 124.2, 122.5, 122.2, 119.1, 118.9, 115.2,
83.2, 59.0, 54.5, 28.1, 25.9, 24.3, 22.5; HRMSꢀESI m/z 328.2151 (calcd 328.2151 for C20H28N2O2).
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Oxidation with TEMPOꢀNaClO2ꢀNaClO in a mixture of tꢀbutanol/H2O/THF
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of THF/H2O/tꢀBuOH (3/7/7) at 0 °C was added 0.3 mmol of pyrrolidine or piperidine dissolved in 1.0
mL of THF. Immediately, 1.5 mL of a solution of NaClO (aq, 3%) was dropwise added. The mixture
was allowed to stir until reaction was completed. Finally, the reaction was quenched by adding few
drops of NaOH (aq) until the redꢀwine color was turned into a clearꢀred color. The resulting phases were
separated; the organic layer was washed with brine (2 x 3 mL), whereas the aqueous phase was extracted
with AcOEt (3 x 5 ml). Organic portions were concentrated and purified by flash chromatography on
silica gel using hexanes/AcOEt as eluent.
Oxidation with TEMPOꢀNaClO2ꢀNaClO in MeCN
To a suspension of 3 mmol of NaH2PO4, 0.90 mmol of NaClO2 and 0.60 mmol of TEMPO in 5 mL of
MeCN was added 1.5 mL of a solution of NaClO (aq, 3%) at 0 °C, then 0.3 mmol of pyrrolidine or
piperidine in 1.0 mL of MeCN was added. The mixture was stirred and monitored by TLC until the
starting material reacted totally. Finally, 0.3 mL of NaOH (aq) was added dropwise to quench the
reaction until the redꢀwine color was turned into a clearꢀred color. The resulting phases were separated
in a separatory funnel, then solids were washed with AcOEt (3 x 5 mL) while the liquid was washed
with brine (2 x 3 mL). The organic portions were concentrated at vacuum and purified by flash
chromatography on silica gel using hexanes/AcOEt as eluent. Chiral pyrrolidines and piperidinas yielded
diastereomeric equimolar mixture of 3ꢀalkoxyamine lactams.
(5S,3S*)ꢀ5ꢀ[((tertꢀButyldimethylsilyl)oxy)methyl)]ꢀ1ꢀcinnamylꢀ3ꢀ((2,2,6,6ꢀtetramethylpiperidinꢀ1ꢀ
yl)oxy)pirrolydinꢀ2ꢀone (9a). Eluent hexanes/EtOAc: 19/1. Isolated 0.024 g (16%) as a greenish viscous
liquid. [α]D20 = + 42.9 (c = 1.0, CHCl3); 1HꢀNMR (500 MHz, CDCl3)
δ: 7.33ꢀ7.31 (m, 2H), 7.28 (t, J =
7.0 Hz, 2H), 7.21 (tt, J = 7.5, 2.0 Hz, 1H), 6.49 (d, J = 16.0 Hz, 1H), 6.10 (ddd, J = 16.0, 8.0, 5.5 Hz,
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1H), 4.80 (t, J = 9.0 Hz, 1H), 4.64 (ddd, J = 15.0, 5.5, 1.5 Hz, 1H), 3.69ꢀ3.65 (m, 2H), 3.58ꢀ3.55 (m,
1H), 3.52 (dd, J = 10.5, 3.5 Hz, 1H), 2.38 (dd, J = 12.5, 8.5 Hz, 1H), 2.10 (dt, J = 12.5, 9.5 Hz, 1H),
1.43ꢀ1.41 (m, 9H), 1.22 (br, 3H), 1.11 (br, 3H), 1.07 (br, 3H), 0.85 (s, 9H), 0.02 (s, 3H), 0.00 (s, 3H);
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13CꢀNMR (125 MHz, CDCl3)
δ: 172.5, 136.2, 133.2, 128.4, 127.6, 126.2, 124.0, 82.5, 63.3, 60.8, 58.7,
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(calcd. for C29H48N2O3Si, 500.3434).
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(5S,3R*)ꢀ5ꢀ[((tertꢀButyldimethylsilyl)oxy)methyl)]ꢀ1ꢀcinnamylꢀ3ꢀ((2,2,6,6ꢀtetramethylpiperidinꢀ1ꢀ
yl)oxy)pirrolydinꢀ2ꢀone (9b). Isolated 0.021g (14%) as a greenish viscous liquid. [α]D20 = + 46.1 (c =
1.0, CHCl3); 1HꢀNMR (500 MHz, CDCl3)
δ: 7.35ꢀ7.21 (m, 5H), 6.53 (d, J = 16.0 Hz, 1H), 6.15 (dt, J =
15.5, 7.0 Hz, 1H), 4.57 (t, J = 8.5 Hz, 1H), 4.43 (dd, J = 15.0, 6.0 Hz, 1H), 3.88 (dd, J = 15.0, 7.5 Hz,
1H), 3.74 (dd, J = 10.5, 3.5 Hz, 1H), 3.69 (dd, J = 10.5, 5.0 Hz, 1H), 3.50ꢀ 3.46 (m, 1H), 2.46 (ddd, J =
12.5, 7.0, 6.0 Hz, 1H), 1.82 (dt, J = 12.5, 8.5 Hz, 1H), 1.47 (br, 4H), 1.43 (br, 3H), 1.31 (br, 2H), 1.24
(br, 3H), 1.16 (br, 3H), 1.10 (br, 3H), 0.90 (s, 9H), 0.70 (s, 6H); 13CꢀNMR (125 MHz, CDCl3)
δ: 172.3,
136.3, 132.7, 128.3, 127.4, 126.2, 124.2, 82.3, 64.4, 54.9, 43.2, 40.2, 40.1, 34.3, 32.4, 31.5, 25.6, 20.1,
20.0, 18.0, 16.9, ꢀ5.5, ꢀ5.6; HRMSꢀEI m/z 500.3433 (calcd. for C29H48N2O3Si, 500.3434).
1ꢀBenzylꢀ3ꢀ((2,2,6,6ꢀtetramethylpiperidinꢀ1ꢀyl)oxy)pyrrolidinꢀ2ꢀone (12). Eluent hexanes/EtOAc: 2/1.
Isolated 0.059 g (60%) as a yellow viscous liquid. 1HꢀNMR (500 MHz, CDCl3)
δ: 7.34ꢀ7.23 (m, 5H),
4.64 (dd, J = 9.5, 8.0 Hz, 1H), 4.55 (d, J = 14.5 Hz, 1H), 4.33 (d, J = 14.5 Hz, 1H), 3.13 (t, J = 9.5 Hz,
1H), 3.00 (dt, J = 9.5, 6.5 Hz, 1H), 2.46 (dt, J = 12.5, 6.5 Hz, 1H), 2.00 (tt, J = 12.5, 9.5 Hz, 1H), 1.57
13
(br, 1H), 1.46 (br, 4H), 1.44 (br, 3H), 1.32 (br, 1H), 1.28 (br, 3H), 1.15 (br, 3H), 1.11 (br, 3H); Cꢀ
NMR (125 MHz, CDCl3) δ: 172.0, 136.0, 128.5, 128.2, 127.5, 83.1, 61.0, 59.0, 46.9, 41.9, 40.4, 40.2,
34.3, 32.4, 28.9, 20.3, 20.1, 17.11; HRMSꢀEI m/z 330.2306 (calcd. for C20H30N2O2, 330.2307).
1ꢀBenzylꢀ3ꢀ((2,2,6,6ꢀtetramethylpiperidinꢀ1ꢀyl)oxy)piperidinꢀ2ꢀone (13). Eluent hexanes/EtOAc: 3/1.
1
Isolated 0.087 g (85%) as a yellow and viscous liquid. HꢀNMR (500 MHz, CDCl3)
δ: 7.32ꢀ7.24 (m,
5H), 4.76 (d, J = 15.0 Hz, 1H), 4.40ꢀ4.38 (m, 1H), 4.38 (d, J = 15.0 Hz, 1H), 3.29 (ddd, J = 12.5, 6.5,
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5.5 Hz, 1H), 3.11 (dt, J = 12.5, 6.5 Hz, 1H), 2.11ꢀ2.04 (m, 1H), 2.02ꢀ1.92 (m, 2H), 1.70ꢀ1.62 (m, 1H),
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1.48 (br, 6H), 1.25 (br, 3H), 1.20 (s, 6H), 1.13 (br, 3H); CꢀNMR 125 (MHz, CDCl3)
δ: 169.3, 137.0,
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128.4, 128.1, 127.1, 80.5, 60.5, 59.7, 49.9, 45.9, 40.1, 34.1, 33.0, 27.1, 20.4, 20.1, 18.7, 17.0. HRMSꢀEI
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m/z 344.2493 (calcd. for C21H32N2O2, 344.2464).
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(3S,5S)ꢀ1ꢀBenzylꢀ5ꢀ(hydroxymethyl)ꢀ3ꢀ((2,2,6,6ꢀtetramethylpiperidinꢀ1ꢀyl)oxy)pyrrolidinꢀ2ꢀone (15a).
Eluent hexanes/EtOAc: 2/12. Isolated 0.041 g (38 %) as a colorless crystal; mp = 129ꢀ131 °C. [α]D20 = +
12.3 (c = 1.0, CHCl3); 1HꢀNMR (500 MHz, CDCl3)
δ: 7.35ꢀ7.26 (m, 5H), 4.64 (d, J = 8.5 Hz, 1H), 4.63
(d, J = 15.0 Hz, 1H) 4.43 (d, J = 15.0 Hz, 1H), 3.77 (ddd, J = 12.0, 4.5, 3.5 Hz, 1H), 3.50 (ddd, J = 12.0,
7.0, 3.0 Hz, 1H), 3.36 (ddt, J = 4.5, 3.5, 3.0 Hz, 1H), 2.43 (ddd, J = 13.0, 8.0, 6.5 Hz, 1H), 2.00 (dt, J =
13.0, 8.0 Hz, 1H), 1.62ꢀ1.60 (m, 2H), 1.48 (br, 6H), 4.40ꢀ1.33 (m, 2H), 1.24 (br, 3H), 1.19 (br, 3H), 1.12
(br, 2H); 13CꢀNMR (125 MHz, CDCl3)
δ: 173.2, 137.0, 128.8, 127.9, 127.7, 82.6, 62.1, 61.1, 59.3, 55.3,
45.3, 40.4, 34.4, 32.6, 30.9, 20.3, 20.2, 17.1; HRMSꢀEI m/z 360.2418 (calcd. for C21H32N2O3,
360.2413).
(3R,5S)ꢀ1ꢀBenzylꢀ5ꢀ(hydroxymethyl)ꢀ3ꢀ((2,2,6,6ꢀtetramethylpiperidinꢀ1ꢀyl)oxy)pyrrolidinꢀ2ꢀone (15b).
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Isolated 0.040 g (38 %) of a colorless crystal; mp = 134ꢀ136 °C; [α]D20 = +39.5 (c = 1.0, CHCl3); Hꢀ
NMR (500 MHz, CDCl3) δ: 7.34ꢀ7.26 (m, 5H), 4.87 (t, J = 9.0 Hz, 1H), 4.81 (dd, J = 15.0, 6.0 Hz, 1H),
4.24 (dd, J = 15.0, 12.0 Hz, 1H), 3.62 (dd, J = 11.0, 2.5 Hz, 1H), 3.49 (d, J = 11.0 Hz, 1H), 3.46ꢀ3.43
(m, 1H), 2.44 (ddd, J = 12.5, 8.5, 1.0 Hz, 1H), 2.17ꢀ2.10 (m, 1H), 1.89 (br, 1H), 1.71ꢀ1.58 (m, 1H), 1.46
(br, 7H), 1.32ꢀ1.27 (m, 4H), 1.14 (br, 3H), 1.11 (br, 3H); 13CꢀNMR (125 MHz, CDCl3)
δ: 173.0, 136.5,
128.7, 128.1 127.6, 82.3, 62.6, 62.5, 61.1, 59.0, 55.1, 55.1, 45.2, 45.1, 40.4, 40.3, 34.3, 33.0, 32.3, 20.4,
20.2, 17.1; HRMSꢀEI m/z 360.2408 (calcd. for C21H32N2O3, 360.2413).
(5S,3R)ꢀ1ꢀBenzylꢀ5ꢀ(((tertꢀbutyldimethylsilyl)oxy)methyl)ꢀ3ꢀ((2,2,6,6ꢀtetramethylpiperidinꢀ1ꢀ
yl)oxy)pyrrolidinꢀ2ꢀone (17a). Absolute configuration at Cꢀ3 was determined by chemical correlation.
Eluent hexanes/EtOAc: 19/1. Isolated 0.056 g (40%) as a yellow pale liquid; [α]D20 = + 54.1 (c = 1.0,
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CHCl3); HꢀNMR (500 MHz, CDCl3) δ: 7.33ꢀ7.25 (m, 5H), 4.95 (d, J = 15.0 Hz, 1H), 4.87 (t, J = 9.0
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Hz, 1H), 4.05 (d, J = 15.0 Hz, 1H), 3.61 (dd, J = 10.5, 3.5 Hz, 1H), 3.46 (dd, J = 11.0, 3.5 Hz, 1H), 3.38
(dt, J = 8.5, 3.5 Hz, 1H), 2.38 (dd, J = 8.0, 12.0 Hz, 1H), 2.07 (dt, J = 12.0, 9.0 Hz, 1H), 1.57 (br, 2H),
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1.45 (br, 7H), 1.27 (br, 3H), 1.13 (br, 3H) 1.10 (br, 3H), 0.88 (s, 9H), 0.02 (s, 3H), 0.00 (s, 3H); Cꢀ
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NMR (125 MHz, CDCl3)
δ: 172.7, 136.2, 128.3, 128.0, 127.2, 82.4, 62.9, 60.7, 58.6, 54.5, 44.7, 40.3,
40.1, 34.2, 33.1, 32.2, 25.6, 20.1, 19.9, 17.9, 16.9, ꢀ5.7, ꢀ5.8; HRMSꢀEI m/z 474.3247 (calcd. for
C27H46N2O3Si, 474.3278).
(5S,3S)ꢀ1ꢀBenzylꢀ5ꢀ(((tertꢀbutyldimethylsilyl)oxy)methyl)ꢀ3ꢀ((2,2,6,6ꢀtetramethylpiperidinꢀ1ꢀ
yl)oxy)pyrrolidinꢀ2ꢀone (17b). Isolated 0.058 g (41%) as a yellow pale liquid. [α]D20 = + 40.5 (c = 1.0,
CHCl3); 1H NMR (500 MHz, CDCl3)
δ: 7.32ꢀ7.22 (m, 5H), 4.98 (d, J = 15 Hz, 1H), 4.59 (t, J = 8.5 Hz,
1H), 4.16 (d, J = 15 Hz, 1H), 3.66 (dd, J = 11.0, 4.0 Hz, 1H), 3.61 (dd, J = 11.0, 5.0 Hz, 1H), 3.34ꢀ3.30
(m, 1H), 2.39 (ddd, J = 12.5, 8.0, 6.5 Hz, 1H), 1.88 (dt, J = 12.5, 8.5 Hz, 1H), 1.77 (br, 1H), 1.57 (br,
1H), 1.47ꢀ1.45 (m, 7H), 1.25 (br, 3H), 1.17 (br, 3H), 1.11 (br, 3H), 0.87 (s, 9H), 0.03 (s, 3H), 0.02 (s,
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3H); C NMR (125 MHz, CDCl3)
δ: 172.8, 136.9, 128.4, 128.0, 127.2, 82.5, 64.1, 61.0, 59.1, 54.5,
44.8, 40.3, 34.4, 32.6, 31.4, 25.8, 20.1, 18.2, 17.1, ꢀ5.4, ꢀ5.5; HRMSꢀEI m/z 474.3275 (calcd. for
C27H46N2O3Si, 474.3278).
(5S,3S*ꢀand5S,3R*)ꢀ1ꢀBenzylꢀ5ꢀ(hydroxydiphenylmethyl)ꢀ3ꢀ((2,2,6,6ꢀtetramethylpiperidinꢀ1ꢀ
yl)oxy)pyrrolidinꢀ2ꢀone (19a and 19b). Eluent hexanes/EtOAc: 19/1. Isolated 0.079 g (52%) as a yellow
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and very viscous liquid. Reported as a mixture of diastereoisomers. RMN (500 MHz, CDCl3)
δ: 7.55
(br, 2H), 7.49 (d, J = 8.5 Hz, 2H), 7.36ꢀ7.19 (m, 23H), 7.16 (tt, J = 7.5, 1.0 Hz, 1H), 6.93 (d, J = 7.0 Hz,
2H), 6.70 (dd, J = 7.5, 3.5 Hz, 2H), 5.03 (d, J = 15.5 Hz, 1H), 4.82 (d, J = 15.0 Hz, 1H), 4.57 (dd, J =
8.0, 2.0 Hz, 1H), 4.52 (t, J = 9.0, 1H), 4.48 (dd, J = 8.0, 2.5 Hz, 1H), 4.39 (d, J = 9.0 Hz, 1H), 4.14 (s,
1H), 2.98 (d, J = 15.0 Hz, 1H), 2.96 (d, J = 15.0 Hz, 1H), 2.51 (dd, J = 13.0, 8.0 Hz, 1H), 2.45 (s, 1H),
2.20 (dt, J = 15.0, 8.0 Hz, 1H), 2.11ꢀ2.04 (m, 2H), 1.66 (br, 3H), 1.47ꢀ1.39 (m, 12H), 1.33 (br, 3H),
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1.27ꢀ1.24 (m, 9H), 1.07 (br, 6H), 0.99 (br, 3H); C RMN (125 MHz, CDCl3)
δ: 175.1, 173.0, 146.7,
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145.0, 144.7, 144.3, 136.4, 136.1, 128.6, 128.4, 128.4, 128.4, 128.3, 127.8, 127.7, 127.5, 127.4, 127.2,
126.9, 126.8,, 126.0, 125.9, 125.6, 125.3, 81.9, 81.8, 80.0, 76.9, 61.9, 60.9, 60.0, 58.8, 45.7, 45.0, 40.5,
40.2, 34.3, 34.2, 32.3, 31.4, 29.6, 20.3, 20.1, 17.1, 17.0; HRMSꢀEI m/z 512.3049 (calcd. for
C33H40N2O3, 512.3039).
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(5S,3R*)ꢀ1ꢀBenzylꢀ5ꢀ(bis(4ꢀfluorophenyl)(hydroxy)methyl)ꢀ3ꢀ((2,2,6,6ꢀtetramethylpiperidinꢀ1ꢀ
yl)oxy)pyrrolidinꢀ2ꢀone (21a). Eluent hexanes/EtOAc: 7/1. Isolated 0.053 g (32%) as a colorless
viscous oil. [α]D20 = + 63.2 (c = 1.0, CHCl3); 1H NMR (500 MHz, CDCl3)
δ: 7.32ꢀ7.24 (m, 7H), 6.96 (t,
J = 8.5 Hz, 4H), 6.90 (d, J = 7.0 Hz, 2H), 4.98 (d, J = 15.0 Hz, 1H), 4.47 (t, J = 7.0 Hz, 1H), 4.35 (d, J =
9.0 Hz, 1H), 3.07 (d, J = 15.0 Hz, 1H), 3.01 (br, 1H), 2.42 (dd, J = 13.0, 8.0 Hz, 1H), 2.07 (dt, J = 12.5,
9.5 Hz, 1H), 1.53 (br, 1H), 1.42ꢀ1.40 (m, 5H), 1.32 (br, 3H), 1.23 (br, 4H), 1.08 (br, 3H), 1.00 (br, 3H);
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13CꢀNMR (125 MHz, CDCl3)
δ: 174.8, 161.8 (d, JCꢀF = 246.1 Hz), 161.6 (d, JCꢀF = 245.7 Hz), 140.2
(d, 4JCꢀF = 2.6 Hz), 140.0 (d, 4JCꢀF = 2.8 Hz), 135.6, 128.4, 127.6 (d, 3JCꢀF = 7.7 Hz), 127.6 (d, 3JCꢀF = 7.6
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Hz), 127.4, 127.2, 115.2 (d, JCꢀF = 21.1 Hz), 115.1 (d, JCꢀF = 21.1 Hz), 81.4, 79.1, 60.8, 59.8, 58.7,
45.7, 40.2, 40.0, 34.1, 33.6, 32.2, 20.1, 20.0, 16.9; HRMSꢀFAB m/z [M+H]+ 549.2919 (calcd. for
C33H39F2N2O3, 549.2929).
(5S,3S*)ꢀ1ꢀBenzylꢀ5ꢀ(bis(4ꢀfluorophenyl)(hydroxy)methyl)ꢀ3ꢀ((2,2,6,6ꢀtetramethylpiperidinꢀ1ꢀ
yl)oxy)pyrrolidinꢀ2ꢀone (21b). Isolated 0.047 g (29%) as a colorless viscous oil. [α]D20 = + 78.6 (c = 0.9,
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CHCl3); H NMR (500 MHz, CDCl3)
δ: 7.47ꢀ7.44 (m, 4H), 7.22 (br, 3H), 6.97 (dd, J = 12.5, 7.5 Hz,
4H), 6.71 (d, J = 3.0 Hz, 2H), 4.86 (d, J = 15.0 Hz, 1H), 4.53ꢀ4.49 (m, 2H), 4.30 (br, 1H), 2.99 (d, J =
15.0 Hz, 1H), 2.24ꢀ2.17 (m, 1H), 2.07 (d, J = 14.5 Hz, 1H), 1.49ꢀ1.47 (m, 8H), 1.27ꢀ1.22 (m, 4H), 1.08ꢀ
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1.05 (m, 3H), 0.91ꢀ0.87 (m, 3H); 13C NMR (125 MHz, CDCl3)
δ
: 171.3, 160.2 (d, JCꢀF = 245.0
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Hz),159.9 (d, 1JCꢀF = 244.8 Hz), 141.0 (d, JCꢀF = 2.7 Hz), 139.2 (d, 4JCꢀF = 2.7 Hz), 134.5, 126.9, 126.0,
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125.9, 125.8 (d, JCꢀF = 7.7 Hz), 125.4 (d, JCꢀF = 7.7 Hz), 113.7 (d, JCꢀF = 21.1 Hz), 113.6 (d, JCꢀF
=
21.1 Hz), 80.2, 74.8, 60.2, 59.4, 58.6, 44.1, 38.9, 32.5, 31.5, 29.9, 18.9, 18.8, 15.4; HRMSꢀFAB m/z
[M+H]+ 549.2898 (calcd. for C33H39F2N2O3, 549.2929).
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(5S,3R*)ꢀ1ꢀCinnamylꢀ5ꢀ(hydroxydiphenylmethyl)ꢀ3ꢀ((2,2,6,6ꢀtetramethylpiperidinꢀ1ꢀ
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yl)oxy)pyrrolidinꢀ2ꢀone (22a). Eluent hexanes/EtOAc: 6/1. Isolated 0.056 g (36%) as a yellow viscous
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oil. [α]D20 = + 53.3 (c = 1.0, CHCl3); H NMR (500 MHz, CDCl3)
δ: 7.46ꢀ7.42 (m, 4H), 7.37ꢀ7.34 (m,
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2H), 7.33ꢀ7.28 (m, 7H), 7.27ꢀ7.23 (m, 2H), 6.05 (dd, J = 16.0, 1.0 Hz, 1H), 5.89 (ddd, J = 16.0, 9.0, 4.5
Hz, 1H), 4.63 (d, J = 9.0 Hz, 1H), 4.52 (t, J = 9.0 Hz, 1H), 4.43 (dd, J = 14.5, 4.0, 2.0 Hz, 1H), 2.62 (dd,
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J = 15.0, 9.0 Hz, 1H), 2.55ꢀ2.50 (m, 2H), 2.16 (dt, J = 13.0, 9.5 Hz, 1H), 1.55ꢀ1.36 (m, 6H), 1.32 (br,
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3H), 1.22 (br, 3H), 1.05 (br, 3H), 0.99 (br, 3H); C NMR (125 MHz, CDCl3)
δ: 174.7, 144.6, 144.3,
136.3, 133.9, 128.5, 128.4, 127.7, 127.5, 124.4, 126.3, 125.9, 123.8, 81.9, 79.8, 60.9, 60.4, 58.8, 44.7,
40.4, 40.1, 34.2, 34.2, 32.2, 20.3, 20.1, 17.0; HRMSꢀEI m/z 538.3166 (calcd. for C35H42N2O3,
538.3195).
(5S,3R*)ꢀ1ꢀCinnamylꢀ5ꢀ(hydroxydiphenylmethyl)ꢀ3ꢀ((2,2,6,6ꢀtetramethylpiperidinꢀ1ꢀ
yl)oxy)pyrrolidinꢀ2ꢀone (22b). Isolated 0.048 g (30%) as a yellow and viscous oil. [α]D20 = + 45.0 (c =
1
0.7, CHCl3); H NMR (500 MHz, CDCl3)
δ: 7.68 (d, J = 7.0 Hz, 2H), 7.55 (dd, J = 9.0, 1.5 Hz, 2H),
7.35 (t, J = 7.5 Hz, 2H), 7.32ꢀ7.23 (m, 8H), 7.18 (tt, J = 7.5, 1.5 Hz, 1H), 5.82ꢀ5.73 (m, 2H), 4.75 (dd, J
= 8.0, 3.0 Hz, 1H), 4.43 (dd, J = 7.5, 3.0 Hz, 1H), 4.23 (dd, J = 14.5, 3.5 Hz, 1H), 4.03 (s, 1H), 2.78 (dd,
J = 14.5, 6.5 Hz, 1H), 2.24 (dt, 14.5, 8.0 Hz, 1H), 2.07 (dt, J = 15.0, 3.0 Hz, 1H), 1.45 (br, 8H), 1.23 (br,
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4H), 1.05 (br, 3H), 0.88 (br, 3H); C NMR (125 MHz, CDCl3)
δ: 172.8, 146.5, 145.2, 136.2, 133.6,
128.5, 128.3, 128.2, 127.7, 127.0, 126.8, 126.3, 125.7, 125.2, 123.3, 81.9, 76.9, 61.8, 61.0, 59.9, 44.3,
40.4, 33.9, 33.0, 31.5, 20.5, 20.3, 16.9; HRMSꢀFAB m/z [M+H]+ 539.3299 (calcd. for C35H43N2O3,
539.3274).
1ꢀCinnamylꢀ3ꢀ((2,2,6,6ꢀtetramethylpiperidinꢀ1ꢀyl)oxy)piperidinꢀ2ꢀone (24). Eluent hexanes/EtOAc:
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10/1. Isolated 0.015 g (14%) as a yellow oil; H NMR (500 MHz, CDCl3)
δ: 7.36 (d, J = 7.5 Hz, 2H),
7.31 (t, J = 7.5 Hz, 2H), 7.23 (t, J = 7.5 Hz, 1H), 6.50 (d, J = 16 Hz, 1H), 6.17 (dt, J = 16.0, 7.0 Hz, 1H),
4.35 (dd, J = 5.5, 3.5 Hz, 1H), 4.15 (ddd, J = 14.5, 6.5, 1.0 Hz, 1H), 4.11 (ddd, J = 14.5, 8.0, 1.5 Hz,
1H), 3.37 (ddd, J = 12.0, 6.5, 5.5 Hz, 1H), 3.21 (ddd, J = 12.0, 6.5, 4.5 Hz, 1H), 2.08ꢀ1.97 (m, 3H),
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1.77ꢀ1.70 (m, 1H), 1.47 (br, 6H), 1.25 (br, 3H), 1.20 (s, 6H), 1.13 (br, 3H); 13CꢀNMR (125 MHz,
CDCl3) : 169.2, 136.5, 133.0, 128.5, 127.6, 126.3 124.3, 80.5, 60.6, 59.8, 48.8, 46.1, 40.2, 34.2, 33.0,
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tertꢀButylꢀ3ꢀ(2ꢀ(2ꢀoxoꢀ3ꢀ((2,2,6,6ꢀtetramethylpiperidinꢀ1ꢀyl)oxy)piperidinꢀ1ꢀyl)ethyl)ꢀ1Hꢀindoleꢀ1ꢀ
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carboxylate (28). Eluent hexanes/EtOAc: 4/1. Isolated 0.116 g (78%) as a colorless oil; H NMR (500
MHz, CDCl3) δ: 8.13 (br, 1H), 7.61 (d, 7.5 Hz), 7.41 (s, 1H), 7.31 (ddd, J = 8.5, 7.5, 1.0 Hz, 1H), 7.24
(ddd, J = 8.0, 7.5, 1.0 Hz, 1H), 4.33 (dd, J = 5.5, 4.0 Hz, 1H), 3.66 (ddd, J = 13.0, 9.0, 6.0 Hz, 1H), 3.55
(ddd, J = 13.0, 9.0, 6.0 Hz, 1H), 3.34 (ddd, J = 12.0, 7.0, 5.5 Hz, 1H), 3.12 (dt, J = 12.0, 6.0 Hz, 1H),
3.03ꢀ2.91 (m, 2H), 2.03ꢀ1.88 (m, 4H), 1.66 (s, 9H), 1.47 (br, 4H), 1.26 (m, 3H), 1.20 (s, 6H), 1.13 (br,
3H); 13C NMR (125 MHz, CDCl3) δ: 169.3, 149.6, 130.4, 124.3, 123.0, 122.4, 119.0, 118.0, 115.1, 83.3,
80.4, 60.5, 59.7, 47.9, 47.6, 40.2, 34.1, 33.0, 28.1, 27.1, 22.7, 20.5, 20.2, 18.9, 17.1; HRMSꢀEI m/z
497.3263 (calcd. for C29H43N3O4, 497.3254).
General procedure for preparation of 3ꢀhydroxylactams
1ꢀBenzylꢀ3ꢀhydroxypyrrolidinꢀ2ꢀone (29). To a solution of 11 (0.055 g, 0.166 mmol) in acetic acid (2.0
mL), water (3.0 mL) and THF (2.0 mL) was added Zn powder (0.261 g), which was previously activated
into an oven at 150 °C. The suspension was allowed to react for 1 h at 70 °C. Then the solution was
cooled down to room temperature and quenched by adding a saturated solution of NaOH (3.0 mL). The
organic component was extracted with AcOEt (5 x 5 ml) and concentrated at reduced pressure. Crude
was purified by flash chromatography on silica gel (eluent hexane/EtOAc: 1/2) to obtain 2922 (0.0238 g,
75%) as a white solid. Mp. 69ꢀ71 °C; lit23 69ꢀ70 °C; 1H NMR (500 MHz, CDCl3) δ: 7.35ꢀ7.22 (m, 5H),
4.50ꢀ4.42 (m, 3H), 3.25 (ddd, J = 9.5, 9.0, 2.0 Hz, 1H), 3.20ꢀ3.14 (m, 1H), 2.44ꢀ2.38 (m, 1H), 1.99ꢀ1.91
(m, 1H); 13C NMR (125 MHz, CDCl3) δ: 175.0, 135.6, 128.7, 128.0, 127.7, 69.9, 46.9, 43.0, 27.6.
1ꢀBenzylꢀ3ꢀhydroxypiperidinꢀ2ꢀone (30). Eluent hexane/EtOAc: 1/1. Isolated 0.207 g (78%) as a
1
colorless oil; H NMR (500 MHz, CDCl3)
δ
: 7.35ꢀ7.23 (m, 5H), 4.64 (d, J = 15.0 Hz, 1H), 4.52 (d, J =
15.0 Hz, 1H), 4.10 (dd, J = 10.5, 6.5 Hz, 1H), 3.90 (br, 1H), 3.26ꢀ3.19 (m, 2H), 2.31ꢀ2.25 (m, 1H), 1.93ꢀ
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1.87 (m, 1H), 1.86ꢀ1.78 (m, 1H), 1.73 (dtd, J = 12.5, 12.0, 4 Hz, 1H). C NMR (125 MHz, CDCl3) δ:
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172.4, 136.3, 128.6, 128.0, 127.5, 68.0, 50.3, 47.0, 28.2, 19.8. HRMSꢀEI m/z 205.1087 (calcd. 205.1103
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for C12H15N1O2).
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tertꢀButylꢀ3ꢀ(2ꢀ(3ꢀhydroxyꢀ2ꢀoxopiperidinꢀ1ꢀyl)ethyl)ꢀ1Hꢀindoleꢀ1ꢀcarboxylate
(31).
Eluent
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hexane/EtOAc: 1/1. Isolated 0.0211 g (70%) as a colorless oil; 1H NMR (500 MHz, CDCl3) δ: 8.13 (br,
1H), 7.58 (d, J = 7.5 Hz, 1H), 7.42 (s, 1H), 7.34 (ddd, J = 8.5, 7.5, 1.0 Hz, 1H), 7.28 (ddd, J = 8.5, 8.0,
1.0 Hz, 1H), 4.04 (dd, J = 11.0, 6.0 Hz, 1H), 3.82 (s, 1H), 3.72 (dt, J = 13.5, 7.5 Hz, 1H), 3.59 (dt, J
=13.5, 7.5 Hz, 1H), 3.28 (td, J = 12.0, 5.0 Hz, 1H), 3.21 (ddd, J = 11.0, 5.0, 3.5 Hz, 1H), 3.00 (t, J = 7.5
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Hz, 2H), 2.27ꢀ2.23 (m, 1H), 1.88ꢀ1.84 (m, 1H), 1.79ꢀ1.70 (m, 2H), 1.68 (s, 9H); C NMR (125 MHz,
CDCl3) δ: 172.2, 149.7, 135.4, 130.3, 124.5, 123.1, 122.5, 118.9, 117.5, 115.2, 83.5, 68.0, 48.5, 47.8,
28.2, 28.1, 22.7, 20.0; HRMSꢀFAB m/z [M+H]+ 359.1975 (calcd. 359.1971 for C20H27N2O4).
ASSOCIATED CONTENT
The supporting information is available free of charge on the ACS Publications website at:
1H and 13C NMR spectra of new and relevant products. Xꢀray crystallographic data for 15a (and
for 15b.
AUTHOR INFORMATION
*Eꢀmail: fernando.sartillo@correo.buap.mx
Notes
The authors declare no competing financial interest
ACKNOWLEDGMENTS
We gratefully acknowledge financial support provided by CONACyT (project number 179074) and
Benemérita Universidad Autónoma de Puebla (BUAPꢀVIEP). U.O.N acknowledges CONACyT for
graduate scholarship (grant number: 383339).
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