Stereoselectivity of 6-Exo Cyclization of α-Carbamoyl Radicals

Article abstract of DOI:10.1021/acs.joc.6b00008

The stereoselectivity in the 6-exo cyclization of α-carbamoyl radicals was investigated experimentally and theoretically. The BEt₃/O₂-initiated iodine-atom-transfer radical cyclization reactions of substituted N-(but-3-en-1-yl)-N-(tert-butyl)-2-iodoalkanamides were carried out, which led to the predominant formations of 3,4-cis, 4,5-trans, or 4,6-trans substituted δ-lactams. Density functional calculations at the B3LYP/6-31G? level revealed that the 6-exo radical cyclization proceeds via boat-conformational transition states. Furthermore, a mechanistic insight into the stereoselectivity was provided and the calculation results were in excellent agreement with the experimental observations.

Full text of DOI:10.1021/acs.joc.6b00008

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Article
On the Stereoselectivity of 6-Exo Cyclization of alpha-Carbamoyl Radicals
Liyan Song, Xinqiang Fang, Zijia Wang, Kun Liu, and Chaozhong Li
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.6b00008 • Publication Date (Web): 29 Feb 2016
Downloaded from http://pubs.acs.org on March 3, 2016
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The Journal of Organic Chemistry
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On the Stereoselectivity of 6ꢀExo Cyclization of αꢀ
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Carbamoyl Radicals
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Liyan Song, b Xinqiang Fang,b Zijia Wang,b Kun Liu,*, c and Chaozhong Li*, a
a School of Chemical Engineering, Ningbo University of Technology, No. 89 Cuibai Road, Ningbo
315016, P. R. China, b Key Laboratory of Organofluorine Chemistry and Collaborative Innovation
Center of Chemistry for Life Sciences, Shanghai Institute of Organic Chemistry, Chinese Academy of
Sciences, 345 Lingling Road, Shanghai 200032, P. R. China and c College of Chemistry, Tianjin
Normal University, Tianjin 300387, P. R. China
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clig@mail.sioc.ac.cn; bnulk@foxmail.com
RECEIVED DATE (to be automatically inserted)
Abstract: The stereoselectivity in the 6ꢀexo cyclization of αꢀcarbamoyl radicals was investigated
experimentally and theoretically. The BEt3/O2ꢀinitiated iodineꢀatomꢀtransfer radical cyclization
reactions of substituted Nꢀ(butꢀ3ꢀenꢀ1ꢀyl)ꢀNꢀ(tertꢀbutyl)ꢀ2ꢀiodoalkanamides were carried out, which led
to the predominant formations of 3,4ꢀcis, 4,5ꢀtrans or 4,6ꢀtrans substituted δꢀlactams. Density functional
calculations at B3LYP/6ꢀ31G* level revealed that the 6ꢀexo radical cyclization proceeds via boatꢀ
conformational transition states. Furthermore, a mechanistic insight into the stereoselectivity was
provided and the calculation results were in excellent agreement with the experimental observations.
Introduction
Radical cyclizations provide a facile entry to various carboꢀ and heterocycles with unique chemoꢀ,
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regioꢀ and stereoselectivities and thus have gained increasing popularity in organic synthesis in the past
decades.1 Among various modes of radical cyclization, 5ꢀexo and 6ꢀexo cyclizations are perhaps the
most extensively studied types of reactions. In particular, the 6ꢀexo cyclization of αꢀcarbamoyl radicals
has been demonstrated to be a viable means for the construction of δꢀlactam skeletons and thus of great
potential in organic synthesis.2–9 For example, Bonjoch and coworkers studied extensively the 6ꢀexo
cyclization of unsaturated trichloroacetamides leading to the construction of 2ꢀazabicyclo[3.3.1]nonanes
and perhydroisoquinolines.2 This strategy was successfully applied to the total synthesis of indole
alkaloids (±)ꢀmelinonineꢀE and (±)ꢀstrychnoxanthine.2d
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Despite the extensive study on the 6ꢀexo cyclization of αꢀcarbamoyl radicals, we were surprised to
find that little was known on the general pattern of stereoselectivity in this type of cyclization. Yang et
al. reported the Lewis acidꢀpromoted phenylselenoꢀgroupꢀtransfer reaction of amide 1 in which the 3,4ꢀ
transꢀsubstituted product 2 was obtained as the only product in high yield (Equation 1).8 Curran et al.
also observed the same 3,4ꢀtransꢀselectivity in the Bu3SnHꢀmediated reactions of Nꢀ(2ꢀvinylphenyl)ꢀ2ꢀ
bromoalkanamide derivatives.9 Clark and coworkers reported the Cu(I)ꢀcatalyzed cyclization of
trichloroaetamide 3 leading to the exclusive formation of the 4,5ꢀtransꢀsubstituted δꢀlactam 4 in
quantitative yield (Equation 2).3a
We have long been interested in the cyclization of αꢀcarbonyl and αꢀcarbamoyl radicals.10–13 During
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The Journal of Organic Chemistry
our recent investigation10 on the behaviors of αꢀcarbamoyl radical reactions, we found that, in the
presence of Mg(ClO4)2 and a bis(oxazoline) ligand (L), the Nꢀethoxycarbonylꢀsubstituted Nꢀallylꢀ2ꢀ
iodoalkanamides 5 underwent efficient and stereoselective 5ꢀexo iodineꢀatomꢀtransfer radical
cyclization14–15 to afford exclusively the 3,4ꢀtransꢀconfigued γꢀlactams 6. Furthermore, the analogous 8ꢀ
endo cyclization reactions (7 to 8) also proceeded in high stereoselectivities (Scheme 1).10 It is certainly
interesting to see if this remarkable Lewis acid effect could be extended to control the stereoselectivity
of 6ꢀexo cyclization. Herein we report that efficient and highly stereoselective 6ꢀexo cyclization
reactions can be successfully implemented for αꢀcarbamoyl radicals. The control of stereoselectivity is
further analyzed by our theoretical calculations.
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Scheme 1. Lewis AcidꢀPromoted Stereoselective 5ꢀExo and 8ꢀEndo Cyclization
Results and Discussion
The Nꢀethoxycarbonylꢀsubstituted iodoamide 9 was chosen as the model substrate to examine the
effect of Lewis acid on the control of stereoselectivity. With the presence of Mg(ClO4)2/L, the BEt3/O2ꢀ
initiated reaction of 9 proceeded smoothly in dichloromethane at room temperature to give the expected
6ꢀexo cyclization product 10 in 85% yield (Equation 3). However, the stereoselectivity was only 3:1 in
favor of the cis isomer.
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The above results prompted us to examine the Nꢀsubstituent effect. Several substituents were thus
screened without the presence of a Lewis acid (Table 1). The cyclization of substrate 9 at room
temperature gave the product 10 in 79% yield as a 1:1 mixture of stereoisomers. The reaction did not
proceed at ꢀ78 oC (entries 1–2, Table 1). With an Nꢀparaꢀmethoxyphenyl (PMP) group, amide 11 failed
to give any cyclized product at room temperature. When its reaction was carried out in refluxing
benzene, the corresponding cyclization product 12 was obtained as a 2:1 mixture of two stereoisomers
in favor of the 3,4ꢀcis isomer (entries 3ꢀ4, Table 1). Apparently the PMP group is not bulky enough to
direct the substrate to the Zꢀconformation required for cyclization. Raising the reaction temperature
helps the interconversion.16 We then prepared Nꢀtosyl iodoamide 13. Surprisingly, the reaction of 13 at
room temperature yielded no cyclized product while all the starting material was consumed (entry 5,
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Table 1). When the cyclization was performed at ꢀ78 C, the expected lactam 14 was observed by the
crude NMR as the mixture of two isomers in about 9:1 ratio in favor of the cis isomer (entry 6, Table 1).
However, the 3,4ꢀtrans isomer decomposed during the purification step. Thus the ratio might not reflect
the true stereoselectivity of cyclization. Finally, we turned to the Nꢀtertꢀbutyl group. The reaction of
substrate 15a at room temperature afforded the corresponding δꢀlactam 16a in about quantitative yield
as a 72:28 mixture of two isomers (entry 7, Table 1). Again the 3,4ꢀcis isomer predominated. When the
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temperature was lowered to ꢀ78 C, the cyclization also proceeded smoothly and the stereoselectivity
was improved to 82:18 (entry 8, Table 1).
Table 1. Effect of NꢀSubstituent on the Stereoselectivity of 6ꢀExo Cyclization
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The Journal of Organic Chemistry
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entrya substrate
R
product
temp
rt
yield (%)b cis/transc
1
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8
CO2Et
CO2Et
PMP
PMP
Ts
79
0
50:50
–
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ꢀ78 oC
rt
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–
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15a
15a
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refluxd
rt
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dece
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–
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Ts
ꢀ78 oC
rt
~ 90:10
72:28
82:18
14
tꢀBu
tꢀBu
16a
16a
ꢀ78 oC
a Reaction conditions: iodoamide (0.3 mmol), BEt3 (0.09 mmol), air (3 × 10 mL) , CH2Cl2 (10 mL), 1
h. b Isolated yield based on the corresponding iodoamide substrate. c Determined by the crude 1H NMR
(400 MHz). d Benzene was used as the solvent. e Decomposed.
We then screened a number of Nꢀtertꢀbutylꢀsubstituted substrates on 6ꢀexo cyclization (Table 2).
Clean reactions were observed in all cases and the desired cyclization products were secured in
moderate to excellent yields. The stereochemistry of δꢀlactams was unambiguously assigned either by
1H NMR or by 2D NOESY experiments. It is noteworthy that the αꢀcarbonyl substituents R in substrates
15 exhibited an impact on the stereoselectivity. The stereochemical control was enhanced as the size of
R increased, resulting in the predominance of 3,4ꢀcis isomers (entries 1–6, Table 2). As a comparison,
for substrates 17 with the R group at the allylic position, the stereoselectivity of cyclization was
improved and the 4,5ꢀtrans isomers prevailed (entries 7–9, Table 2). Furthermore, for iodoamides 19
having a substituent at the homoallylic position, the cyclization also exhibited an excellent
stereoselectivity to give predominantly the 4,6ꢀtrans isomers 20 (entries 10–12, Table 2). The structure
of 20c was further confirmed by its Xꢀray diffraction analysis (See the Supporting Information).
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Table 2. 6ꢀExo Cyclization of Nꢀ(tertꢀButyl)ꢀsubstituted Iodoamides
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yield
(%)b
cis :
entrya
substrate
O
product
O
transc
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R
tBu
R
tBu
I
N
N
I
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4
15a
(R = Me)
(R = Et)
16a
16b
16c
16d
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90
81
93
82 : 18
92 : 8
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15d
(R = n-Bu)
(R = i-Pr)
> 95 : 5
> 95 : 5
5
6
15e
15f
(R = c-Hex)
(R = t-Bu)
16e
16f
87
72
> 95 : 5
> 95 : 5
O
O
I
tBu
tBu
N
N
I
R
R
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8
9
17a
(R = Me)
18a
18b
18c
81
89
82
12 : 88
< 5 : 95
< 5 : 95
17b
17c
(R = n-Pr)
(R = Ph)
O
O
I
tBu
tBu
R
N
N
I
R
10d
11d
12d
19a
19b
19c
(R = Me)
20a
20b
20c
62
60
42
9 : 91
< 5 : 95
< 5 : 95
(R = n-Bu)
(R = Ph)
a
Reaction conditions: iodoamide (0.3 mmol), BEt3 (0.09 mmol), air (3 × 10 mL), CH2Cl2 (10 mL), ꢀ
78 oC, 1 h. b Isolated yield based on the starting iodoamide. c Determined by 1H NMR (400 MHz). d The
reaction was run at rt.
We then went on to examine the stereoselectivity of 6ꢀexo cyclization of multiꢀsubstituted substrates.
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The Journal of Organic Chemistry
As shown in Equation 4, the iodineꢀatomꢀtransfer cyclization of iodoamide 21 led to the formation of
two stereoisomers 22 and 23 in the ratio of 91:9. Both isomers have the 3,5ꢀtrans configuration. In
another experiment, substrate 24 bearing two methyl groups was subjected to the above reaction
conditions, from which only two stereoisomers 25 and 26 were isolated. Both isomers have the 3,4ꢀcis
configuration (Equation 5). When the reaction of 24 was carried out at room temperature, the ratio of 25
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to 26 was 84:16. When the reaction temperature was lowered to ꢀ78 C, the ratio was raised to 94:6.
Again, the stereochemistry of cyclized products was unambiguously determined by their NOESY
experiments.
It is thus clear that the 6ꢀexo cyclization of αꢀcarbamoyl radicals can be highly stereoselective even
without the help of Lewis acids. The excellent stereoselectivity in favor of 3,4ꢀcis, 4,5ꢀtrans and 4,6ꢀ
trans configurations was clearly observed. To understand this unique stereoselectivity pattern, we
carried out density functional calculations on model radicals Rꢀ15a, Rꢀ17a and Rꢀ19a derived from
representative substrates 15a, 17a and 19a. All the calculations were performed at UB3LYP/6ꢀ31G*
level using the Gaussian09 suite of program,17 a widely used and fairly accurate method for treating
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radical reactions.18 The computed transition state structures and the calculated activation free energies
were thus obtained and grouped in Figure 1 and Table 3, respectively.
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Table 3. Relative Free Energies (kcal/mol) Calculated at UB3LYP/6ꢀ31G* Level
entry
radical
Rꢀ15a
Rꢀ17a
Rꢀ19a
Zꢀrotamer
Eꢀrotamer
2.7
transition states
1
2
3
0
0
0
11.6 (TSꢀ15aꢀcis), 12.1 (TSꢀ15aꢀtrans)
8.7 (TSꢀ17aꢀcis), 7.3 (TSꢀ17aꢀtrans)
8.9 (TSꢀ19aꢀcis), 7.6 (TSꢀ19aꢀtrans)
2.9
1.5
O
tBu
N
I
Me
cisꢀ16a
cisꢀ18a
cisꢀ20a
TSꢀ15aꢀcis
TSꢀ17aꢀcis
TSꢀ19aꢀcis
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TSꢀ15aꢀtrans
TSꢀ17aꢀtrans
TSꢀ19aꢀtrans
O
tBu
N
I
Me
transꢀ16a
transꢀ18a
transꢀ20a
Figure 1. Computed (UB3LYP/6ꢀ31G*) Transition State Structures and Corresponding Products.
The calculations indicate that the Zꢀrotamer is at least 1.5 kcal/mol lower in energy than the
corresponding Eꢀrotamer for all the substrate radicals, which should be attributed to the steric hindrance
of the bulky tertꢀbutyl group. This allows the αꢀcarbamoyl radicals readily undergo cyclization even at
low temperature. The calculations also indicate that all the transition states are in boatꢀlike
conformations. For the cyclization of radical Rꢀ15a, two transition states, TSꢀ15aꢀcis and TSꢀ15aꢀtrans
were computed. The pseudoequatorial configuration of the C=C bond in TSꢀ15aꢀtrans results in the
steric hindrance between the methylene moiety and the two flagpole hydrogen atoms, their distances
being estimated to be 3.021 Å and 3.720 Å. Such steric interactions are not observed in TSꢀ15aꢀcis in
which the C=C bond is at the pseudoaxial position. As a result, TSꢀ15aꢀcis is slightly lower in energy
(0.5 kcal/mol) than TSꢀ15aꢀtrans, in good agreement with the cis/trans ratio of stereoisomers in the
cyclized product 16a.
For the cyclization of radical Rꢀ17a, two transition states, TSꢀ17aꢀcis and TSꢀ17aꢀtrans, were also
computed. The vinylic methylene moiety and the allylic methyl group are much closer in TSꢀ17aꢀcis
(2.939 Å) than in TSꢀ17aꢀtrans (3.459 Å). Thus, TSꢀ17aꢀcis would face more steric hindrance and its
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free energy is higher. This is consistent to the predominant 4,5ꢀtrans stereoselectivity observed in the
cyclization of 17a.
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In the cyclization of radical Rꢀ19a, two transition states, TSꢀ19aꢀcis and TSꢀ19aꢀtrans, were also
obtained. In both structures the methyl substituent is at the pseudoaxial position in order to ease steric
congestion caused by the adjacent Nꢀtertꢀbutyl group. In TSꢀ19aꢀcis the vinylic methylene moiety is at
the pseudoequatorial position, suffering steric interactions not only with the flagpole hydrogen atom but
also with the flagpole methyl group. Such a steric congestion is not observed in TSꢀ19aꢀtrans with the
vinylic methylene moiety at the pseudoaxial position. Therefore, TSꢀ19aꢀtrans is of lower energy than
TSꢀ19aꢀcis, in excellent agreement with our experimental observations.
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The boatꢀlike conformational transition states nicely explains the preference of 3,4ꢀcis, 4,5ꢀtrans, 4,6ꢀ
trans configuration in the 6ꢀexo cyclization products. It is assumed that as the substituent gets more
bulky, the corresponding transitionꢀstate conformations become more rigid, leading to the increased
steric instability of the disfavored transition states. As a result, the energy difference is enlarged and
improved stereoselectivity is anticipated. These analyses are in excellent qualitative agreement with the
experimental data.
Conclusion
In summary, the experiments detailed above in combination with theoretical calculations have clearly
demonstrated that the introduction of Nꢀtertꢀbutyl group to the radical precursor not only significantly
elevates the efficiency of 6ꢀexo radical cyclization but also pushes the αꢀcarbamoyl radicals to cyclize
via fixed Zꢀconformational transition states. The boatꢀlike conformational transition states are
responsible for the predominant 3,4ꢀcis, 4,5ꢀtrans or 4,6ꢀtrans configurations and a high degree of
stereochemical control. The calculations furnish a quantitative view of on the mechanism of 6ꢀexo
cyclization of αꢀcarbamoyl radicals. These understanding should be of significance in the further
development of αꢀcarbamoyl radicalꢀbased strategy in organic synthesis.
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The Journal of Organic Chemistry
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Experimental Section
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General Information. Melting points were measured with a melting point instrument and were
uncorrected. H and 13C NMR spectra were recorded using a 400 MHz NMR spectrometer. The
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chemical shifts are referenced to CDCl3 (signals at 7.26 and 77.0 ppm, respectively) with TMS as the
internal standard. IR spectra were obtained either as potassium bromide pellets or as liquid films
between two potassium bromide pellets with a spectrometer. Highꢀresolution mass spectrometry (HRMS)
was performed on a TOF MS instrument with an ESI source.
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Ethyl butꢀ3ꢀenyl(2ꢀiodopropanoyl)carbamate (9). Typical Procedure: A 50 mL twoꢀnecked flask
equipped with a condensor was charged with LiAlH4 (456 mg, 12 mmol) and dry ether (20 mL) under
nitrogen. Allyl cyanide (0.67 g, 10 mmol) dissolved in ether (10 mL) was added dropwise. After the
addition was completed, the mixture was heated to reflux overnight. The reaction mixture was cooled to
0 oC with an iceꢀwater bath and quenched carefully with H2O (0.5 mL), 10% aqueous solution of NaOH
(1.0 mL) and H2O (1.5 mL). The resulting mixture was then filtered and the filtrate was dried with
anhydrous MgSO4 to afford the solution of 3ꢀbutenamine in ether. To the solution was added
triethylamine (2.10 mL, 15 mmol) and 4ꢀdimethylamino pyridine (DMAP, 122 mg, 1.0 mmol). The
resulting solution was cooled to 0 oC with an iceꢀwater bath and ethyl chloroformate (0.95 mL, 10.0 mol)
was added dropwise under nitrogen. After the completion of addtion, the resulting mixture was allowed
to warm to room termperature and stirred overnight. The reaciton mixture was quenched by addtion of
water (20 mL). The organic fractions were collected and the aqueous phase was extracted with ether (3
× 20 mL). The combined organic fractions were washed with 1M citric acid (10 mL), sat. NaHCO3 (10
mL) and brine, dried over anhydrous MgSO4 and concentrated under reduced pressure. The residue was
purified by flash chromatography on silica gel using petroleum ether/ethyl acetate (5:1) to afford ethyl
3ꢀbutenylcarbamate (900 mg, 63% yield over 2 steps) as a colorless oil.
o
To a solution of ethyl 3ꢀbutenylcarbamate (900 mg, 6.3 mmol) in dry THF (5 mL) at 0 C was added
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nꢀButyllithium (3.9 mL, 1.6 M in hexane, 6.24 mmol) under nitrogen. The resulting mixture was stirred
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for 5 min at 0 C. Then 2ꢀiodopropanoyl chloride (1.38 g, 6.3 mmol) dissolved in dry THF (5 mL) was
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added dropwise and the mixture was stirred for additional 30 minutes at 0 C. The reaction was
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quenched with saturated aqueous NH4Cl (10 mL). The organic fractions were collected and the aqueous
phase was extracted with ethyl acetate (3 × 10 mL). The combined organic fractions were washed with
brine, dried over anhydrous Na2SO4 and concentrated under reduced pressure. The residue was purified
by flash chromatography on silica gel using petroleum ether/ethyl acetate (50:1) to give 9 (1.10 g, 54%
yield) as a yellowish oil. IR (neat): ν (cmꢀ1) 2978, 2922, 1736, 1694, 1447, 1372, 1356, 1199, 1152,
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1020. H NMR (400 MHz, CDCl3) δ 1.37 (3H, t, J = 7.2 Hz), 1.99 (3H, d, J = 6.8 Hz), 2.28ꢀ2.38 (2H,
m), 3.72ꢀ3.78 (1H, m), 3.85ꢀ3.92 (1H, m), 4.25ꢀ4.36 (2H, m), 5.02ꢀ5.10 (2H, m), 5.72ꢀ5.82 (1H, m),
5.90 (1H, q, J = 6.8 Hz). 13C NMR (100 MHz, CDCl3) δ 14.2, 17.6, 23.5, 32.4, 44.2, 63.3, 117.1, 134.6,
153.9, 174.1. EIMS: m/z (rel intensity) 325 (M+, 1), 198 (77), 183 (38), 155 (34), 116 (48), 102 (100),
84 (27), 56 (41), 55 (32). HRMS calcd for C10H16INO3 (M): 325.0175. Found: 325.0180.
Nꢀ(Butꢀ3ꢀenyl)ꢀ2ꢀiodoꢀNꢀtosylpropanamide (13). Flash chromatography on silica gel using petroleum
ether/ethyl acetate (100:1) to give the product (928 mg, 76% yield) as a colorless oil. IR (neat): ν (cmꢀ1)
2976, 2921, 1693, 1596, 1445, 1355, 1205, 1168, 1086. 1H NMR (400 MHz, CDCl3) δ 1.90 (3H, d, J =
6.8 Hz), 2.39ꢀ2.53 (5H, m), 3.70ꢀ3.77 (1H, m), 3.90ꢀ3.97 (1H, m), 5.08ꢀ5.17 (3H, m), 5.70ꢀ5.80 (1H,
m), 7.36 (2H, d, J = 8.0 Hz), 7.82 (2H, d, J = 8.0 Hz). 13C NMR (100 MHz, CDCl3) δ 15.2, 21.7, 23.3,
33.7, 46.8, 118.2, 127.9, 129.9, 133.7, 135.9, 145.2, 171.4. EIMS: m/z (rel intensity) 407 (M+, 1), 366
(20), 280 (27), 236 (26), 184 (74), 183 (34), 155 (100), 91 (81), 56 (21). HRMS calcd for C14H18INO3S
(M): 407.0052. Found: 407.0050.
Nꢀ(Butꢀ3ꢀenyl)ꢀNꢀtertꢀbutylꢀ2ꢀiodopropanamide (15a). Typical Procedure: To a solution of tert-
butylamine (8.0 mL, 75 mmol) in dimethylformamide (DMF, 40 mL) was added sodium carbonate
(5.30 g, 50 mmol) and sodium iodide (0.30 g, 2 mmol) and the mixture was stirred at room temperature
for additional 5 min. 4ꢀBromoꢀ1ꢀbutene (6.75 g, 50 mmol) dissolved in DMF (5 mL) was added
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dropwise. After the completion of addtion, the resulting mixture was allowed to stirred at room
termperature for 48 hours. Water (100 mL) was added to quench the reaction. The aqueous phase was
extracted with ether (3 × 100 mL). The combined organic fractions were concentrated and treated with
excess 5% hydrochloric acid. The aqueous phase was extracted with ether (3 × 20 mL) and the organic
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fractions were discarded. The aqueous phase was cooled to 0 C with an iceꢀwater bath and alkalized
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with saturated aqueous NaOH. The aqueous phase was extracted with ether (3 × 30 mL). The combined
organic fractions were washed with brine and dried with anhydrous MgSO4 and concentrated under
reduced pressure to give Nꢀ(tertꢀbutyl)ꢀ3ꢀbutenꢀ1ꢀamine (2.16 g, 34% yield) as a yellowish liquid.
To a solution of Nꢀ(tertꢀbutyl)ꢀ3ꢀbutenꢀ1ꢀamine (254 mg, 2 mmol) in dry CH2Cl2 (10 mL) were added
triethylamine (0.56 mL, 4 mmol) and DMAP (25 mg, 0.2 mmol). The resulting solution was cooled to 0
oC with an iceꢀwater bath and then 2ꢀiodopropanoyl chloride (460 mg, 2.1 mmol) dissolved in dry
CH2Cl2 (2 mL) was added dropwise. After the completion of addition, the reaction mixture was allowed
to warm to room temperature and stirred overnight. The reaciton mixture was quenched by addtion of
water (10 mL). the organic fractions were collected and the aqueous phase was extracted with CH2Cl2 (3
× 10 mL). The combined organic fractions were washed successively with 1M citric acid (10 mL),
saturated aqueous NaHCO3 and brine, dried over anhydrous Na2SO4 and concentrated under reduced
pressure. The residue was purified by flash chromatography on silica gel using petroleum ether/ethyl
acetate (50:1) to afford 15a (501 mg, 81% yield) as a yellowish oil. IR (neat): ν (cmꢀ1) 2973, 2918,
1
1649, 1448, 1397, 1362, 1193, 1108, 919. H NMR (400 MHz, CDCl3) δ 1.45 (9H, s), 1.94 (3H, d, J =
6.8 Hz), 2.16ꢀ2.25 (1H, m), 2.45ꢀ2.54 (1H, m), 3.28ꢀ3.43 (2H, m), 4.57 (1H, q, J = 6.8 Hz), 5.10ꢀ5.15
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(2H, m), 5.69ꢀ5.79 (1H, m). C NMR (100 MHz, CDCl3) δ 18.4, 24.2, 28.5, 36.7, 44.9, 57.7, 117.7,
133.8, 171.2. EIMS: m/z (rel intensity) 309 (M+, 1), 268 (79), 212 (100), 112 (26), 86 (14), 85 (13), 57
(65), 55 (14), 41 (17). HRMS calcd for C11H20INO (M): 309.0590. Found: 309.0594.
Nꢀ(Butꢀ3ꢀenyl)ꢀ2ꢀiodoꢀNꢀ(4ꢀmethoxyphenyl)propanamide (11). Flash chromatography on silica
gel using petroleum ether/ethyl acetate (50:1) to give the product (481 mg, 67% yield) as a yellowish
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oil. IR (neat): ν (cmꢀ1) 2968, 2931, 2835, 1659, 1509, 1444, 1397, 1249, 1036. H NMR (400 MHz,
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CDCl3) δ 1.86 (3H, d, J = 6.8 Hz), 2.27ꢀ2.32 (2H, m), 3.72 (2H, t, J = 3.2 Hz), 3.85 (3H, s), 4.25 (1H, q,
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J = 6.8 Hz), 5.03ꢀ5.10 (2H, m), 5.72ꢀ5.82 (1H, m), 6.93ꢀ7.22 (4H, m). C NMR (100 MHz, CDCl3) δ
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15.3, 23.9, 31.7, 49.2, 55.5, 115.0, 116.9, 129.1, 134.1, 135.0, 159.4, 171.3. EIMS: m/z (rel intensity)
359 (M+, 11), 359 (11), 318 (15), 162 (9), 137 (9), 136 (100), 135 (26), 120 (21), 55 (10). HRMS calcd
for C14H18INO2 (M): 359.0382. Found: 359.0385.
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Nꢀ(Butꢀ3ꢀenyl)ꢀNꢀtertꢀbutylꢀ2ꢀiodobutanamide (15b). Flash chromatography on silica gel using
petroleum ether/ethyl acetate (50:1) to give the product (504 mg, 78% yield) as a yellowish oil. IR
1
(neat): ν (cmꢀ1) 2970, 2930, 2874, 1651, 1455, 1400, 1362, 1282, 1192, 1109. H NMR (400 MHz,
CDCl3) δ 0.92 (3H, t, J = 7.2 Hz), 1.45 (9H, s), 2.02ꢀ2.16 (2H, m), 2.18ꢀ2.27 (1H, m), 2.46ꢀ2.55 (1H,
13
m), 3.36ꢀ3.44 (2H, m), 4.31 (1H, t, J = 7.2 Hz), 5.10ꢀ5.16 (2H, m), 5.70ꢀ5.80 (1H, m). C NMR (100
MHz, CDCl3) δ 14.2, 27.2, 28.5, 30.5, 36.8, 44.8, 57.8, 117.5, 133.9, 170.6. EIMS: m/z (rel intensity)
323 (M+, 1), 282 (65), 226 (100), 112 (37), 86 (49), 70 (19), 57 (85), 55 (26), 41 (40). HRMS calcd for
C12H22INO (M): 323.0746. Found: 323.0745.
Nꢀ(Butꢀ3ꢀenyl)ꢀNꢀtertꢀbutylꢀ2ꢀiodohexanamide (15c). Flash chromatography on silica gel using
petroleum ether/ethyl acetate (50:1) to give the product (527 mg, 75% yield) as a yellowish oil. IR
1
(neat): ν (cmꢀ1) 2959, 2928, 2872, 1654, 1399, 1362, 1192, 1112, 919. H NMR (400 MHz, CDCl3) δ
0.91 (3H, t, J = 7.2 Hz), 1.26ꢀ1.40 (4H, m), 1.45 (9H, s), 1.99ꢀ2.13 (2H, m), 2.16ꢀ2.26 (1H, m), 2.46ꢀ
13
2.55 (1H, m), 3.26ꢀ3.42 (2H, m), 4.37 (1H, t, J = 7.2 Hz), 5.10ꢀ5.15 (2H, m), 5.70ꢀ5.80 (1H, m). C
NMR (100 MHz, CDCl3) δ 13.9, 22.1, 25.6, 28.5, 31.6, 36.8, 44.9, 57.8, 117.5, 133.9, 170.6. EIMS: m/z
(rel intensity) 351 (M+, 1), 310 (53), 254 (95), 112 (41), 86 (93), 69 (33), 57 (100), 55 (58), 41 (47).
HRMS calcd for C14H26INO (M): 351.1059. Found: 351.1058.
Nꢀ(Butꢀ3ꢀenyl)ꢀNꢀtertꢀbutylꢀ2ꢀiodoꢀ3ꢀmethylbutanamide (15d). Flash chromatography on silica gel
using petroleum ether/ethyl acetate (50:1) to give the product (533 mg, 79% yield) as a yellowish oil. IR
(neat): ν (cmꢀ1) 2962, 2929, 2870, 1654, 1469, 1399, 1363, 1193, 1113. 1H NMR (400 MHz, CDCl3) δ
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0.99 (3H, d, J = 6.8 Hz), 1.18 (3H, d, J = 6.8 Hz), 1.45 (9H, s), 2.20ꢀ2.38 (2H, m), 2.47ꢀ2.56 (1H, m),
3.23ꢀ3.40 (2H, m), 4.11 (1H, d, J = 10.0 Hz), 5.10ꢀ5.15 (2H, m), 5.71ꢀ5.81 (1H, m). 13C NMR (100
MHz, CDCl3) δ 19.4, 24.0, 28.4, 33.2, 36.5, 36.8, 44.9, 57.9, 117.3, 134.0, 170.7. EIMS: m/z (rel
intensity) 337 (M+, 1), 296 (42), 240 (40), 112 (29), 86 (100), 69 (16), 57 (62), 55 (34), 41 (28). HRMS
calcd for C13H24INO (M): 337.0903. Found: 337.0899.
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Nꢀ(Butꢀ3ꢀenyl)ꢀNꢀtertꢀbutylꢀ2ꢀcyclohexylꢀ2ꢀiodoacetamide (15e). Flash chromatography on silica gel
using petroleum ether/ethyl acetate (50:1) to give the product (558 mg, 74% yield) as a yellowish oil. IR
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(neat): ν (cmꢀ1) 2973, 2926, 2852, 1651, 1447, 1398, 1361, 1188, 917. H NMR (400 MHz, CDCl3) δ
0.76ꢀ0.92 (2H, m), 1.05ꢀ1.16 (1H, m), 1.23ꢀ1.36 (2H, m), 1.45 (9H, s), 1.59ꢀ1.65 (2H, m), 1.76ꢀ1.80
(1H, m), 1.88ꢀ2.04 (2H, m), 2.16ꢀ2.29 (2H, m), 2.46ꢀ2.56 (1H, m), 3.22ꢀ3.39 (2H, m), 4.12 (1H, d, J =
13
10.0 Hz), 5.10ꢀ5.15 (2H, m), 5.70ꢀ5.81 (1H, m). C NMR (100 MHz, CDCl3) δ 26.0, 26.2, 26.4, 28.4,
30.8, 34.3, 36.0, 36.8, 41.7, 44.8, 57.9, 117.3, 134.0, 170.5. EIMS: m/z (rel intensity) 377 (M+, 1), 336
(16), 280 (12), 112 (17), 95 (25), 86 (100), 57 (30), 55 (18), 41 (16). HRMS calcd for C16H28INO (M):
377.1216. Found: 377.1219.
Nꢀ(Butꢀ3ꢀenyl)ꢀNꢀtertꢀbutylꢀ2ꢀiodoꢀ3,3ꢀdimethylbutanamide (15f). Flash chromatography on silica
gel using petroleum ether/ethyl acetate (50:1) to give the product (534 mg, 76% yield) as a yellowish
1
oil. IR (neat): ν (cmꢀ1) 2959, 2929, 2867, 1656, 1479, 1389, 1362, 1281, 1196, 1097. H NMR (400
MHz, CDCl3) δ 1.21 (9H, s), 1.44 (9H, s), 2.25ꢀ2.35 (1H, m), 2.48ꢀ2.58 (1H, m), 3.27ꢀ3.40 (2H, m),
4.40 (1H, s), 5.10ꢀ5.16 (2H, m), 5.72ꢀ5.82 (1H, m). 13C NMR (100 MHz, CDCl3) δ 28.2, 28.5, 35.6,
36.6, 41.3, 45.3, 57.9, 117.3, 134.1, 170.8. EIMS: m/z (rel intensity) 351 (M+, 1), 310 (38), 254 (19),
198 (11), 197 (10), 112 (19), 86 (100), 57 (32), 55 (10). HRMS calcd for C14H26INO (M): 351.1059.
Found: 351.1054.
NꢀtertꢀButylꢀ2ꢀiodoꢀNꢀ(2ꢀmethylbutꢀ3ꢀenyl)acetamide (17a). Flash chromatography on silica gel
using petroleum ether/ethyl acetate (50:1) to give the product (451 mg, 73% yield) as a yellowish oil. IR
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(neat): ν (cmꢀ1) 2964, 2926, 1645, 1456, 1423, 1392, 1362, 1198, 1060, 919. H NMR (400 MHz,
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CDCl3) δ 1.03 (3H, d, J = 6.4 Hz), 1.44 (9H, s), 2.42ꢀ2.53 (1H, m), 3.12ꢀ3.32 (2H, m), 3.75 (2H, AB, J
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= 10.0 Hz), 5.08ꢀ5.13 (2H, m), 5.64ꢀ5.73 (1H, m). C NMR (100 MHz, CDCl3) δ 3.3, 17.0, 28.4, 39.7,
52.5, 57.6, 116.2, 139.9, 168.6. EIMS: m/z (rel intensity) 309 (M+, 1), 254 (75), 198 (100), 126 (8), 70
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(10), 57 (96), 55 (11), 42 (9), 41 (29). HRMS calcd for C11H20INO (M): 309.0590. Found: 309.0586.
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NꢀtertꢀButylꢀ2ꢀiodoꢀNꢀ(2ꢀvinylpentyl)acetamide (17b). Flash chromatography on silica gel using
petroleum ether/ethyl acetate (50:1) to give the product (555 mg, 77% yield) as a yellowish oil. IR
(neat): ν (cmꢀ1) 3076, 2959, 2928, 2871, 1644, 1456, 1424, 1393, 1362, 1195, 1150, 1073, 917. 1H NMR
(400 MHz, CDCl3) 0.91 (3H, t, J = 6.8 Hz), 1.23ꢀ1.44 (13H, m), 2.25ꢀ2.34 (1H, m), 3.13 (1H, dd, J =
15.6, 9.6 Hz), 3.28 (1H, dd, J = 16.0, 4.8 Hz), 3.72 (2H, AB, J = 9.6 Hz), 5.06ꢀ5.16 (2H, m), 5.45ꢀ5.54
(1H, m). 13C NMR (100 MHz, CDCl3) δ 3.3, 14.0, 20.3, 28.5, 34.2, 46.2, 51.8, 57.7, 118.1, 139.1,
168.8. ESIꢀMS m/z 360 (M+Na)+. HRMS calcd for C13H24INNaO (M+Na) 360.0795, found 360.0801.
NꢀtertꢀButylꢀ2ꢀiodoꢀNꢀ(2ꢀphenylbutꢀ3ꢀenyl)acetamide (17c). Flash chromatography on silica gel
using petroleum ether/ethyl acetate (50:1) to give the product (591 mg, 75% yield) as a yellowish oil. IR
(neat): ν (cmꢀ1) 3061, 3027, 2975, 2925, 1647, 1492, 1453, 1424, 1392, 1362, 1190, 1150, 1076, 1028,
1002, 921, 759, 702. 1H NMR (400 MHz, CDCl3) δ 1.47 (9H, s), 3.25ꢀ3.68 (5H, m), 5.15ꢀ5.24 (2H, m),
5.99ꢀ6.07 (1H, m), 7.20ꢀ7.37 (5H, m). 13C NMR (100 MHz, CDCl3) δ 3.0, 28.6, 51.6, 52.5, 58.0, 117.5,
127.4, 127.8, 129.1, 137.8, 141.0, 168.8. ESIꢀMS m/z 372 (M+H)+. HRMS calcd for C16H22INNaO
(M+Na) 394.0638, found 394.0640.
NꢀtertꢀButylꢀ2ꢀiodoꢀNꢀ(pentꢀ4ꢀenꢀ2ꢀyl)acetamide (19a). Flash chromatography on silica gel using
petroleum ether/ethyl acetate (50:1) to give the product (415 mg, 67% yield) as a yellowish oil. IR
(neat): ν (cmꢀ1) 2963, 2925, 2853, 1639, 1431, 1363, 1340, 1314, 1195. 1H NMR (400 MHz, CDCl3) δ
1.38ꢀ1.45 (12H, m), 2.41ꢀ2.49 (1H, m), 2.53ꢀ2.60 (1H, m), 3.76ꢀ3.87 (3H, m), 5.07ꢀ5.14 (2H, m), 5.71ꢀ
5.81 (1H, m). 13C NMR (100 MHz, CDCl3) δ 4.6, 20.7, 29.4, 41.2, 51.6, 58.7, 117.4, 135.4, 169.6.
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EIMS: m/z (rel intensity) 309 (M+, 1), 268 (37), 212 (100), 84 (8), 58 (7), 57 (33), 44 (24), 42 (6), 41
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(16). HRMS calcd for C11H20INO (M): 309.0590. Found: 309.0591.
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NꢀtertꢀButylꢀ2ꢀiodoꢀNꢀ(octꢀ1ꢀenꢀ4ꢀyl)acetamide (19b). Flash chromatography on silica gel using
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petroleum ether/ethyl acetate (50:1) to give the product (487 mg, 65% yield) as a yellowish oil. IR
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(neat): ν (cmꢀ1) 3076, 2958, 2929, 2871, 1639, 1431, 1361, 1329, 1192, 1157, 1086, 996, 916. H NMR
(400 MHz, CDCl3) δ 0.92 (3H, t, J = 6.8 Hz), 1.25ꢀ1.50 (13H, m), 1.71ꢀ1.76 (2H, m), 2.42ꢀ2.62 (2H,
m), 3.53ꢀ3.92 (3H, m), 5.06ꢀ5.13 (2H, m), 5.71ꢀ5.81 (1H, m). 13C NMR (100 MHz, CDCl3) δ 4.5, 14.0,
22.6, 29.6, 30.1, 34.9, 40.1, 56.7, 58.6, 117.4, 135.6, 169.4. ESIꢀMS m/z 352 (M+H)+. HRMS calcd for
C14H26INNaO (M+Na) 374.0951, found 374.0948.
NꢀtertꢀButylꢀ2ꢀiodoꢀNꢀ(1ꢀphenylbutꢀ3ꢀenyl)acetamide (19c). Flash chromatography on silica gel
using petroleum ether/ethyl acetate (50:1) to give the product (497 mg, 63% yield) as a yellowish oil. IR
(neat): ν (cmꢀ1) 3062, 2965, 2925, 2860, 1647, 1496, 1447, 1424, 1362, 1303, 1192, 1158, 1088, 1032,
1
997, 918, 744, 699. H NMR (400 MHz, CDCl3) δ 1.52 (9H, s), 2.75ꢀ2.83 (1H, m), 3.13ꢀ3.20 (1H, m),
3.41ꢀ3.58 (2H, m), 5.03 (1H, t, J = 6.8 Hz), 5.20ꢀ5.30 (2H, m), 5.93ꢀ6.03 (1H, m), 7.26ꢀ7.40 (5H, m).
13C NMR (100 MHz, CDCl3) δ 4.7, 29.2, 39.6, 58.1, 59.5, 118.1, 126.1, 127.2, 129.0, 135.4, 141.9,
169.6. ESIꢀMS m/z 372 (M+H)+. HRMS calcd for C16H22INNaO (M+Na) 394.0638, found 394.0633.
NꢀtertꢀButylꢀ2ꢀiodoꢀ3ꢀmethylꢀNꢀ(2ꢀmethylbutꢀ3ꢀenyl)butanamide (21). Flash chromatography on
silica gel using petroleum ether/ethyl acetate (50:1) to give the product (569 mg, 81% yield) as a
yellowish oil. IR (neat): ν (cmꢀ1) 2962, 2927, 2870, 1650, 1470, 1398, 1363, 1197, 1101, 918. 1H NMR
(400 MHz, CDCl3) δ 0.98ꢀ1.06 (6H, m), 1.17 (3H, t, J = 6.8 Hz), 1.44 (9H, d, J = 10.0 Hz), 2.14ꢀ2.32
(1H, m), 2.38ꢀ2.54 (1H, m), 3.08ꢀ3.14 (1H, m), 3.22ꢀ3.31 (1H, m), 4.21ꢀ4.25 (1H, m), 5.05ꢀ5.15 (2H,
m), 5.68ꢀ5.78 (1H, m). 13C NMR (100 MHz, CDCl3) δ 17.3/17.4, 20.0/20.1, 24.0/24.1, 28.4/28.5,
33.0/33.1, 38.2/38.7, 39.6/40.4, 51.1/51.7, 58.0/58.1, 115.4/116.3, 140.2/140.9, 170.9. EIMS: m/z (rel
intensity) 351 (M+, 1), 296 (51), 240 (56), 183 (13), 86 (100), 69 (14), 57 (48), 55 (21), 41 (22). HRMS
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calcd for C14H26INO (M): 351.1059. Found: 351.1054.
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NꢀtertꢀButylꢀ2ꢀiodoꢀNꢀ(pentꢀ4ꢀenꢀ2ꢀyl)propanamide (24). Flash chromatography on silica gel using
petroleum ether/ethyl acetate (50:1) to give the product (451 mg, 65% yield) as a yellowish oil. IR
(neat): ν (cmꢀ1) 3076, 2972, 2925, 1737, 1651, 1447, 1422, 1364, 1339, 1196, 1152, 1119, 918. 1H NMR
(400 MHz, CDCl3) δ 1.26ꢀ1.44 (12H, m), 1.93ꢀ1.96 (3H, m), 2.31ꢀ2.65 (2H, m), 3.72ꢀ3.74 (1H, m), 4.78
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(1H, q, J = 6.8 Hz), 5.06ꢀ5.17 (2H, m), 5.68ꢀ5.82 (1H, m). C NMR (100 MHz, CDCl3) δ 20.6, 22.1,
23.8/24.0, 29.0, 41.4/41.6, 51.2, 58.4, 117.4/117.6, 135.4, 174.2. ESIꢀMS m/z 346 (M+Na)+. HRMS
calcd for C12H22INNaO (M+Na) 346.0638, found 346.0635.
Typical Procedure for the 6ꢀExo Cyclization of αꢀCarbamoyl Radicals. A dry Schlenk tube with
nitrogen atmosphere was charged with iodoamide 15a (93 mg, 0.30 mmol) and dry CH2Cl2 (10 mL).
The solution was cooled to ꢀ78 oC and Et3B (0.09 mL, 1 M in hexane, 0.09 mmol) was added. Dry air (3
× 10 mL) was injected in 10 minutes. The mixture was then warmed up to room temperature and
concentrated under reduced pressure. The residue was purified by flash chromatography on silica gel
using petroleum ether/ethyl acetate (20/1) to give separately the pure cisꢀ16a (70 mg, 75% yield) and
transꢀ16a (16 mg, 17% yield). (3R*,4R*)ꢀ1ꢀtertꢀButylꢀ3ꢀmethylꢀ4ꢀ(iodomethyl)piperidinꢀ2ꢀone (cisꢀ
16a): yellowish oil. IR (neat): ν (cmꢀ1) 2972, 1639, 1456, 1425, 1362, 1318, 1203, 1050, 1018. 1H NMR
(400 MHz, CDCl3) δ 1.12 (3H, d, J = 7.2 Hz), 1.42 (9H, s), 1.69ꢀ1.79 (1H, m), 1.92ꢀ1.99 (1H, m), 2.17ꢀ
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2.26 (1H, m), 2.60ꢀ2.67 (1H, m), 2.99 (1H, t, J = 9.6 Hz), 3.18ꢀ3.26 (2H, m), 3.39ꢀ3.45 (1H, m). C
NMR (100 MHz, CDCl3) δ 8.2, 12.4, 26.9, 28.3, 38.7, 42.0, 42.3, 57.2, 173.3. EIMS: m/z (rel intensity)
309 (M+, 67), 309 (67), 294 (45), 266 (63), 166 (37), 70 (41), 57 (100), 41 (58), 40 (60). HRMS calcd
for
C11H20INO (M):
309.0590.
Found:
309.0594.
(3R*,4S*)ꢀ1ꢀtertꢀButylꢀ3ꢀmethylꢀ4ꢀ
(iodomethyl)piperidinꢀ2ꢀone (transꢀ16a): yellowish oil. IR (neat): ν (cmꢀ1) 2960, 2929, 2970, 1639,
1478, 1426, 1361, 1322, 1203. 1H NMR (400 MHz, CDCl3) δ 1.22 (3H, d, J = 6.8 Hz), 1.37ꢀ1.48 (10 H,
m), 1.52ꢀ1.61 (1H, m), 1.95ꢀ2.06 (1H, m), 2.10ꢀ2.17 (1H, m), 3.13 (1H, dd, J = 10.0, 7.2 Hz), 3.25ꢀ3.32
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(1H, m), 3.36ꢀ3.42 (2H, m). 13C NMR (100 MHz, CDCl3) δ 13.3, 16.2, 28.3, 30.0, 40.4, 42.0, 44.0,
57.2, 173.1. EIMS: m/z (rel intensity) 309 (M+, 48), 309 (48), 294 (38), 266 (49), 166 (34), 70 (37), 57
(100), 55 (35), 41 (53). HRMS calcd for C11H20INO (M): 309.0590. Found: 309.0588.
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(3R*,4R*)ꢀEthyl
4ꢀ(iodomethyl)ꢀ3ꢀmethylꢀ2ꢀoxopiperidineꢀ1ꢀcarboxylate
(cisꢀ10).
Flash
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chromatography on silica gel using petroleum ether/ethyl acetate (20:1) to give the product (39 mg, 40%
yield) as a yellowish oil. IR (neat): ν (cmꢀ1) 2979, 2934, 1767, 1705, 1531, 1456, 1384, 1257, 1175,
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1037. H NMR (400 MHz, CDCl3) δ 1.20 (3H, d, J = 7.2 Hz), 1.34 (3H, t, J = 6.8 Hz), 1.79ꢀ1.90 (1H,
m), 2.05ꢀ2.13 (1H, m), 2.32ꢀ2.40 (1H, m), 2.81ꢀ2.88 (1H, m), 2.99 (1H, t, J = 10.0 Hz), 2.24 (1H, dd, J
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= 10.0, 6.0 Hz), 3.50ꢀ3.57 (1H, m), 3.95ꢀ4.01 (1H, m), 4.30 (2H, q, J = 7.2 Hz). C NMR (100 MHz,
CDCl3) δ 7.1, 12.1, 14.2, 26.9, 38.8, 42.5, 44.1, 63.3, 154.2, 173.4. EIMS: m/z (rel intensity) 325 (M+,
10), 198 (100), 102 (29), 83 (27), 81 (25), 69 (32), 56 (32), 55 (67), 41 (36). HRMS calcd for
C10H16INO3 (M): 325.0175. Found: 325.0177.
(3R*,4S*)ꢀEthyl 4ꢀ(iodomethyl)ꢀ3ꢀmethylꢀ2ꢀoxopiperidineꢀ1ꢀcarboxylate (transꢀ10). Flash
chromatography on silica gel using petroleum ether/ethyl acetate (20:1) to give the product (38 mg, 39%
yield) as a yellowish oil. IR (neat): ν (cmꢀ1) 2978, 2933, 1771, 1716, 1464, 1368, 1287, 1229, 1181,
1
1024. H NMR (400 MHz, CDCl3) δ 1.24 (3H, d, J = 6.8 Hz), 1.35 (3H, t, J = 7.2 Hz), 1.42ꢀ1.50 (1H,
m), 1.68ꢀ1.77 (1H, m), 1.98ꢀ2.09 (1H, m), 2.36ꢀ2.43 (1H, m), 3.26 (1H, dd, J = 10.0, 5.2 Hz), 3.42 (1H,
dd, J = 10.0, 2.8 Hz), 3.72ꢀ3.86 (2H, m), 4.31 (2H, q, J = 6.8 Hz). 13C NMR (100 MHz, CDCl3) δ 13.9,
14.5, 29.2, 29.7, 39.5, 43.8, 44.3, 63.6, 154.1, 173.2. EIMS: m/z (rel intensity) 325 (M+, 7), 198 (100),
83 (34), 81 (33), 70 (24), 69 (48), 56 (38), 55 (83), 41 (54). HRMS calcd for C10H16INO3 (M): 325.0175.
Found: 325.0179.
(3R*,4R*)ꢀ4ꢀ(Iodomethyl)ꢀ1ꢀ(4ꢀmethoxyphenyl)ꢀ3ꢀmethylpiperidinꢀ2ꢀone
(cisꢀ12).
Flash
chromatography on silica gel using petroleum ether/ethyl acetate (20:1) to give the product (39 mg, 36%
yield) as a colorless oil. IR (neat): ν (cmꢀ1) 2936, 2835, 1651, 1607, 1510, 1430, 1296, 1246, 1184,
1
1035, 829. H NMR (400 MHz, CDCl3) δ 1.24 (3H, d, J = 7.2 Hz), 1.94ꢀ2.10 (2H, m), 2.37ꢀ2.46 (1H,
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m), 2.85ꢀ2.92 (1H, m), 3.15ꢀ3.27 (2H, m), 3.55ꢀ3.68 (2H, m), 3.80 (3H, s), 6.90 (2H, d, J = 8.8 Hz),
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7.12 (2H, d, J = 8.8 Hz). C NMR (100 MHz, CDCl3) δ 7.3, 12.3, 25.6, 39.4, 40.6, 50.0, 55.5, 114.5,
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127.4, 135.8, 158.2, 172.8. EIMS: m/z (rel intensity) 359 (M+, 78), 359 (78), 204 (22), 176 (29), 149
(20), 136 (100), 135 (19), 134 (18), 120 (26). HRMS calcd for C14H18INO2 (M): 359.0382. Found:
359.0383.
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(3R*,4S*)ꢀ4ꢀ(Iodomethyl)ꢀ1ꢀ(4ꢀmethoxyphenyl)ꢀ3ꢀmethylpiperidinꢀ2ꢀone
(transꢀ12).
Flash
chromatography on silica gel using petroleum ether/ethyl acetate (20:1) to give the product (20 mg, 18%
yield) as a colorless oil. IR (neat): ν (cmꢀ1) 2963, 2931, 2830, 1651, 1510, 1430, 1328, 1296, 1246,
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1033, 830. H NMR (400 MHz, CDCl3) δ 1.33 (3H, d, J = 7.2 Hz), 1.57ꢀ1.65 (1H, m), 1.82ꢀ1.92 (1H,
m), 2.07ꢀ2.14 (1H, m), 2.34ꢀ2.42 (1H, m), 3.27 (1H, dd, J = 10.0, 7.2 Hz), 3.49 (1H, dd, J = 10.0, 3.2
Hz), 3.58ꢀ3.72 (2H, m), 3.80 (3H, s), 6.90 (2H, d, J = 8.8 Hz), 7.13 (2H, d, J = 8.8 Hz). 13C NMR (100
MHz, CDCl3) δ 13.1, 15.4, 29.2, 40.9, 42.4, 49.4, 55.5, 114.5, 127.2, 136.2, 158.1, 171.9. EIMS: m/z
(rel intensity) 359 (M+, 100), 360 (17), 359 (100), 176 (15), 149 (18), 136 (66), 135 (18), 134 (16), 120
(23). HRMS calcd for C14H18INO2 (M): 359.0382. Found: 359.0376.
(3R*,4R*)ꢀ4ꢀ(Iodomethyl)ꢀ3ꢀmethylꢀ1ꢀtosylpiperidinꢀ2ꢀone (cisꢀ14). Flash chromatography on
silica gel using petroleum ether/ethyl acetate (20:1) to give the product (75 mg, 61% yield) as a
colorless oil. IR (neat): ν (cmꢀ1) 2977, 2923, 1693, 1596, 1477, 1352, 1272, 1167, 1091, 1026. 1H NMR
(400 MHz, CDCl3) δ 1.11 (3H, d, J = 7.6 Hz), 1.89ꢀ1.99 (1H, m), 2.07ꢀ2.16 (1H, m), 2.22ꢀ2.31 (1H, m),
2.43 (3H, s), 2.68ꢀ2.75 (1H, m), 2.88 (1H, t, J = 9.6 Hz), 3.13 (1H, dd, J = 10.4, 6.4 Hz), 3.64ꢀ3.71 (1H,
m), 4.16ꢀ4.22 (1H, m), 7.31 (2H, d, J = 8.0 Hz), 7.90 (2H, d, J = 8.0 Hz). 13C NMR (100 MHz, CDCl3)
δ 6.5, 11.8, 21.7, 26.8, 38.4, 42.1, 44.5, 128.7, 129.4, 135.9, 144.9, 172.7. ESIꢀMS m/z 430 (M+Na)+.
HRMS calcd for C14H19INO3S (M+H) 408.0125, found 408.0125.
(3R*,4R*)ꢀ1ꢀtertꢀButylꢀ3ꢀethylꢀ4ꢀ(iodomethyl)piperidinꢀ2ꢀone (cisꢀ16b). Flash chromatography on
silica gel using petroleum ether/ethyl acetate (20:1) to give the product (81 mg, 83% yield) as a
yellowish oil. IR (neat): ν (cmꢀ1) 2959, 2933, 2873, 1646, 1456, 1423, 1360, 1307, 1201. 1H NMR (400
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MHz, CDCl3) δ 0.99 (3H, t, J = 7.2 Hz), 1.33ꢀ1.45 (10H, m), 1.78ꢀ1.90 (2H, m), 1.95ꢀ2.03 (1H, m),
2.28ꢀ2.39 (2H, m), 2.87 (1H, t, J = 10.0 Hz), 3.20ꢀ3.32 (2H, m), 3.39ꢀ3.45 (1H, m). 13C NMR (100
MHz, CDCl3) δ 8.2, 12.5, 20.2, 28.4, 29.0, 36.9, 40.9, 48.9, 57.1, 172.3. EIMS: m/z (rel intensity) 323
(M+, 26), 308 (31), 280 (35), 180 (33), 168 (31), 70 (43), 57 (100), 55 (43), 41 (58). HRMS calcd for
C12H22INO (M): 323.0746. Found: 323.0741.
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(3R*,4S*)ꢀ1ꢀtertꢀButylꢀ3ꢀethylꢀ4ꢀ(iodomethyl)piperidinꢀ2ꢀone (transꢀ16b). Flash chromatography on
silica gel using petroleum ether/ethyl acetate (20:1) to give the product (7.0 mg, 7% yield) as a
yellowish oil. IR (neat): ν (cmꢀ1) 2961, 2928, 2875, 1638, 1457, 1423, 1362, 1321, 1198. 1H NMR (400
MHz, CDCl3) δ 0.88 (3H, t, J = 7.2 Hz), 1.42ꢀ1.73 (12H, m), 1.89ꢀ2.06 (2H, m), 2.10ꢀ2.14 (1H, m), 3.07
(1H, dd, J = 10.0, 8.0 Hz), 3.22ꢀ3.28 (1H, m), 3.34ꢀ3.43 (2H, m). 13C NMR (100 MHz, CDCl3) δ 10.2,
12.5, 23.3, 28.2, 29.8, 36.9, 42.1, 50.2, 57.5, 172.2. EIMS: m/z (rel intensity) 323 (M+, 28), 308 (36),
180 (35), 168 (47), 112 (36), 70 (45), 57 (100), 55 (40), 41 (60). HRMS calcd for C12H22INO (M):
323.0746. Found: 323.0744.
(3R*,4R*)ꢀ1ꢀtertꢀButylꢀ3ꢀbutylꢀ4ꢀ(iodomethyl)piperidinꢀ2ꢀone (cisꢀ16c). Flash chromatography on
silica gel using petroleum ether/ethyl acetate (20:1) to give the product (86 mg, 81% yield) as a
yellowish oil. IR (neat): ν (cmꢀ1) 2955, 2930, 2870, 1646, 1455, 1423, 1360, 1308, 1200. 1H NMR (400
MHz, CDCl3) δ 0.91 (3H, t, J = 6.8 Hz), 1.32ꢀ1.37 (5H, m), 1.41 (9H, s), 1.77ꢀ1.87 (2H, m), 1.95ꢀ2.01
(1H, m), 2.28ꢀ2.41 (2H, m), 2.87 (1H, t, J = 10.4 Hz), 3.20ꢀ3.26 (1H, m), 3.30 (1H, dd, J = 10.4, 4.8
Hz), 3.39ꢀ3.45 (1H, m). 13C NMR (100 MHz, CDCl3) δ 8.3, 14.0, 22.9, 26.9, 28.4, 29.0, 30.1, 37.2,
40.8, 47.3, 57.1, 172.5. EIMS: m/z (rel intensity) 351 (M+, 2), 295 (20), 208 (14), 168 (100), 112 (55),
70 (22), 57 (52), 55 (27), 41 (31). HRMS calcd for C14H26INO (M): 351.1059. Found: 351.1061.
(3R*,4R*)ꢀ1ꢀtertꢀButylꢀ4ꢀ(iodomethyl)ꢀ3ꢀisopropylpiperidinꢀ2ꢀone (cisꢀ16d). Flash chromatography
on silica gel using petroleum ether/ethyl acetate (20:1) to give the product (94 mg, 93% yield) as a
yellowish oil. IR (neat): ν (cmꢀ1) 2959, 2870, 1658, 1458, 1408, 1361, 1329, 1308, 1200, 1124. 1H NMR
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(400 MHz, CDCl3) δ 0.97 (3H, d, J = 6.0 Hz), 1.03 (3H, d, J = 6.0 Hz), 1.42 (9H, s), 1.56ꢀ1.65 (1H, m),
2.01ꢀ2.12 (3H, m), 2.49ꢀ2.56 (1H, m), 2.74 (1H, dd, J = 11.6, 9.6 Hz), 3.17ꢀ3.24 (1H, m), 3.33 (1H, dd,
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J = 9.6, 3.6 Hz), 3.48ꢀ3.54 (1H, m). C NMR (100 MHz, CDCl3) δ 10.5, 21.0, 22.7, 25.3, 28.8, 30.8,
37.0, 40.7, 53.9, 57.0, 171.8. EIMS: m/z (rel intensity) 337 (M+, 17), 210 (34), 194 (40), 168 (92), 112
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(71), 70 (35), 57 (100), 55 (33), 41 (54). HRMS calcd for C13H24INO (M): 337.0903. Found: 337.0906.
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(3R*,4R*)ꢀ1ꢀtertꢀButylꢀ3ꢀcyclohexylꢀ4ꢀ(iodomethyl)piperidinꢀ2ꢀone (cisꢀ16e). Flash chromatography
on silica gel using petroleum ether/ethyl acetate (20:1) to give the product (99 mg, 87% yield) as a
yellowish oil. IR (neat): ν (cmꢀ1) 2923, 2850, 1655, 1448, 1407, 1361, 1320, 1200, 1185. 1H NMR (400
MHz, CDCl3) δ 0.83ꢀ0.93 (1H, m), 1.02ꢀ1.21 (2H, m), 1.24ꢀ1.37 (2H, m), 1.41 (9H, s), 1.54ꢀ1.61 (1H,
m), 1.63ꢀ1.78 (5H, m), 1.99ꢀ2.06 (2H, m), 2.09 (1H, dd, J = 8.4, 5.2 Hz), 2.46ꢀ2.55 (1H, m), 2.74 (1H,
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dd, J = 11.2, 10.0 Hz), 3.16ꢀ3.23 (1H, m), 3.29 (1H, dd, J = 9.6, 3.6 Hz), 3.47ꢀ3.53 (1H, m). C NMR
(100 MHz, CDCl3) δ 10.7, 26.3, 26.5, 26.7, 28.8, 30.5, 31.2, 33.2, 34.8, 36.4, 40.8, 52.8, 57.0, 171.8.
EIMS: m/z (rel intensity) 377 (M+, 2), 295 (23), 169 (13), 168 (100), 112 (98), 98 (15), 57 (35), 55 (21),
41 (25). HRMS calcd for C16H28INO (M): 377.1216. Found: 377.1214.
(3S*,4R*)ꢀ1,3ꢀdiꢀtertꢀButylꢀ4ꢀ(iodomethyl)piperidinꢀ2ꢀone (cisꢀ16f). Flash chromatography on
silica gel using petroleum ether/ethyl acetate (20:1) to give the product (76 mg, 72% yield) as a
yellowish oil. IR (neat): ν (cmꢀ1) 2956, 2869, 1654, 1481, 1420, 1392, 1364, 1300, 1204, 1182, 1156. 1H
NMR (400 MHz, CDCl3) δ 1.15 (9H, s), 1.41 (9H, s), 1.87ꢀ2.04 (2H, m), 2.20 (1H, d, J = 4.4 Hz), 2.51ꢀ
2.68 (1H, m), 2.96 (1H, dd, J = 12.4, 9.6 Hz), 3.17ꢀ3.24 (1H, m), 3.36ꢀ3.43 (1H, m), 3.68 (1H, dd, J =
13
9.6, 2.8 Hz). C NMR (100 MHz, CDCl3) δ 9.8, 28.5, 30.1, 31.2, 33.6, 36.7, 39.8, 56.5, 57.0, 171.5.
EIMS: m/z (rel intensity) 351 (M+, 11), 336 (22), 295 (27), 208 (38), 168 (100), 112 (82), 70 (16), 57
(69), 41 (26). HRMS calcd for C14H26INO (M): 351.1059. Found: 351.1061.
(4S*,5S*)ꢀ1ꢀtertꢀButylꢀ4ꢀ(iodomethyl)ꢀ5ꢀmethylpiperidinꢀ2ꢀone (cisꢀ18a). Flash chromatography
on silica gel using petroleum ether/ethyl acetate (20:1) to give the product (9.5 mg, 10% yield) as a
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yellowish oil. IR (neat): ν (cmꢀ1) 2959, 2922, 1643, 1479, 1428, 1360, 1325, 1281, 1204, 1186. 1H NMR
1
2
3
(400 MHz, CDCl3) δ 0.90 (3H, d, J = 7.2 Hz), 1.42 (9H, s), 2.12ꢀ2.28 (3H, m), 2.51ꢀ2.61 (1H, m), 3.05
4
5
6
13
(2H, d, J = 7.2 Hz), 3.23 (1H, dd, J = 12.0, 4.0 Hz), 3.32 (1H, dd, J = 12.0, 4.0 Hz). C NMR (100
MHz, CDCl3) δ 7.7, 11.1, 28.2, 31.3, 37.5, 39.0, 50.2, 57.4, 169.0. EIMS: m/z (rel intensity) 309 (M+,
63), 309 (63), 266 (62), 166 (72), 126 (53), 71 (42), 57 (83), 55 (47), 41 (100). HRMS calcd for
C11H20INO (M): 309.0590. Found: 309.0591.
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(4S*,5R*)ꢀ1ꢀtertꢀButylꢀ4ꢀ(iodomethyl)ꢀ5ꢀmethylpiperidinꢀ2ꢀone (transꢀ18a). Flash chromatography
on silica gel using petroleum ether/ethyl acetate (20:1) to give the product (66 mg, 71% yield) as a
yellowish oil. IR (neat): ν (cmꢀ1) 2959, 2923, 1644, 1479, 1434, 1363, 1328, 1292, 1246, 1205. 1H NMR
(400 MHz, CDCl3) δ 1.00 (3H, d, J = 6.8 Hz), 1.24ꢀ1.32 (1H, m), 1.43 (9H, s), 1.62ꢀ1.73 (1H, m), 2.24
(1H, dd, J = 16.8, 10.4 Hz), 2.45 (1H, dd, J = 16.8, 5.2 Hz), 2.92 (1H, dd, J = 12.0, 10.0 Hz), 3.19ꢀ3.29
13
(2H, m), 3.38 (1H, dd, J = 12.0, 4.8 Hz). C NMR (100 MHz, CDCl3) δ 12.9, 16.5, 28.3, 34.6, 38.8,
40.8, 49.9, 57.1, 170.2. EIMS: m/z (rel intensity) 309 (M+, 18), 86 (50), 84 (100), 70 (20), 57 (30), 51
(22), 49 (71), 43 (58), 41 (31). HRMS calcd for C11H20INO (M): 309.0590. Found: 309.0586. The
structure was further confirmed by its 2D NOESY experiments.
(4S*,5R*)ꢀ1ꢀtertꢀButylꢀ4ꢀ(iodomethyl)ꢀ5ꢀpropylpiperidinꢀ2ꢀone (transꢀ18b). Flash chromatography
on silica gel using petroleum ether/ethyl acetate (20:1) to give the product (90 mg, 89% yield) as a
colorless oil. IR (neat): ν (cmꢀ1) 2958, 2927, 2872, 1650, 1480, 1457, 1433, 1360, 1331, 1297, 1249,
1
1205, 1157. H NMR (400 MHz, CDCl3) 0.96 (3H, t, J = 7.2 Hz), 1.20ꢀ1.52 (14H, m), 1.56ꢀ1.64 (1H,
m), 2.27 (1H, dd, J = 16.4, 9.2 Hz), 2.45 (1H, dd, J = 16.4, 5.6 Hz), 3.01 (1H, dd, J = 12.8, 7.6 Hz),
13
3.20ꢀ3.27 (2H, m), 3.40 (1H, dd, J = 12.8, 4.8 Hz). C NMR (100 MHz, CDCl3) δ 13.3, 14.2, 19.9,
28.4, 34.1, 37.9, 39.2, 40.6, 46.6, 57.0, 170.6. EIMS: m/z (rel intensity) 337 (M+, 35), 322 (50), 294
(77), 210 (39), 154 (100), 112 (48), 57 (62), 55 (44), 41 (77). HRMS calcd for C13H24INO (M):
337.0903. Found: 337.0902.
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(4S*,5S*)ꢀ1ꢀtertꢀButylꢀ4ꢀ(iodomethyl)ꢀ5ꢀphenylpiperidinꢀ2ꢀone (transꢀ18c). Flash chromatography
on silica gel using petroleum ether/ethyl acetate (20:1) to give the product (91 mg, 82% yield) as a
colorless oil. IR (neat): ν (cmꢀ1) 3028, 2958, 2923, 2853, 1647, 1496, 1475, 1454, 1431, 1362, 1318,
1
2
3
4
5
6
7
8
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1294, 1199, 1153, 765, 723, 701. H NMR (400 MHz, CDCl3) 1.42 (9H, s), 1.89ꢀ1.98 (1H, m), 2.40
9
(1H, dd, J = 17.2, 11.2 Hz), 2.65 (1H, dd, J = 17.2, 5.6 Hz), 2.76 (1H, td, J = 10.8, 5.2 Hz), 2.84 (1H,
dd, J = 10.0, 6.0 Hz), 3.09 (1H, dd, J = 10.0, 3.2 Hz), 3.28 (1H, dd, J = 12.4, 10.8 Hz), 3.53 (1H, dd, J =
12.0, 5.2 Hz), 7.25ꢀ7.38 (5H, m). 13C NMR (100 MHz, CDCl3) δ 13.0, 28.3, 37.7, 41.2, 47.0, 50.4, 57.5,
127.7, 128.1, 129.1, 139.6, 169.9. EIMS: m/z (rel intensity) 371 (M+, 37), 371 (37), 188 (33), 117 (100),
115 (34), 91 (37), 84 (40), 57 (37), 41 (36). HRMS calcd for C16H22INO (M): 371.0746. Found:
371.0747.
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(4R*,6R*)ꢀ1ꢀtertꢀButylꢀ4ꢀ(iodomethyl)ꢀ6ꢀmethylpiperidinꢀ2ꢀone (transꢀ20a). Flash chromatography
on silica gel using petroleum ether/ethyl acetate (20:1) to give the product (58 mg, 62% yield) as a
yellowish oil. IR (neat): ν (cmꢀ1) 2973, 2926, 1635, 1427, 1409, 1378, 1364, 1318, 1193. 1H NMR (400
MHz, CDCl3) δ 1.24 (3H, d, J = 6.8 Hz), 1.46ꢀ1.55 (10H, m), 1.86ꢀ1.91 (1H, m), 2.06 (1H, dd, J = 17.2,
10.4 Hz), 2.14ꢀ2.24 (1H, m), 2.61 (1H, ddd, J = 17.2, 6.8, 1.6 Hz), 3.05ꢀ3.17 (2H, m), 3.93ꢀ4.00 (1H,
13
m). C NMR (100 MHz, CDCl3) δ 13.1, 22.8, 28.9, 30.7, 38.0, 40.4, 48.6, 57.4, 169.0. EIMS: m/z (rel
intensity) 309 (M+, 78), 309 (78), 294 (66), 266 (86), 238 (64), 84 (49), 70 (51), 57 (100), 41 (94).
HRMS calcd for C11H20INO (M): 309.0590. Found: 309.0593. The structure was further confirmed by
its 2D NOESY experiments.
(4R*,6R*)ꢀ1ꢀtertꢀButylꢀ6ꢀbutylꢀ4ꢀ(iodomethyl)piperidinꢀ2ꢀone (transꢀ20b). Flash chromatography on
silica gel using petroleum ether/ethyl acetate (20:1) to give the product (63 mg, 60% yield) as a
colorless oil. IR (neat): ν (cmꢀ1) 2957, 2930, 2870, 1635, 1455, 1427, 1409, 1361, 1318, 1198, 1143. 1H
NMR (400 MHz, CDCl3) δ 0.92 (3H, t, J = 6.8 Hz), 1.14ꢀ1.37 (5H, m), 1.39ꢀ1.52 (10H, m), 1.60ꢀ1.69
(1H, m), 2.01ꢀ2.19 (3H, m), 2.58ꢀ2.64 (1H, m), 3.05 (1H, dd, J = 9.6, 6.4 Hz), 3.16 (1H, dd, J = 9.6, 5.6
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13
Hz), 3.67ꢀ3.72 (1H, m). C NMR (100 MHz, CDCl3) δ 13.0, 14.0, 22.6, 28.3, 29.0, 30.5, 33.3, 34.8,
40.3, 53.2, 57.6, 168.9. EIMS: m/z (rel intensity) 351 (M+, 6), 294 (44), 238 (100), 224 (22), 195 (20),
168 (26), 57 (29), 55 (13), 41 (33). HRMS calcd for C14H26INO (M): 351.1059. Found: 351.1057.
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(4R*,6S*)ꢀ1ꢀtertꢀButylꢀ4ꢀ(iodomethyl)ꢀ6ꢀphenylpiperidinꢀ2ꢀone (transꢀ20c). Flash chromatography
on silica gel using petroleum ether/ethyl acetate (20:1) to give the product (47 mg, 42% yield) as a white
solid. m.p. 128ꢀ130 oC. IR (KBr): ν (cmꢀ1) 3026, 2949, 2926, 1616, 1454, 1423, 1408, 1348, 1325, 1302,
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1
1260, 1194, 1183, 1160, 1127, 995, 955, 779, 749, 703. H NMR (400 MHz, CDCl3) δ 1.38 (9H, s),
1.70ꢀ1.85 (2H, m), 1.96ꢀ2.00 (1H, m), 2.18 (1H, dd, J = 17.6, 10.0 Hz), 2.69ꢀ2.75 (1H, m), 2.97ꢀ3.04
13
(2H, m), 5.02ꢀ5.04 (1H, m), 7.15ꢀ7.38 (5H, m). C NMR (100 MHz, CDCl3) δ 13.1, 28.6, 29.3, 39.7,
40.7, 57.9, 58.8, 126.3, 127.4, 128.6, 143.2, 170.1. EIMS: m/z (rel intensity) 371 (M+, 81), 371 (81), 314
(72), 146 (65), 132 (96), 130 (64), 104 (98), 91 (68), 58 (100). HRMS calcd for C16H22INO (M):
371.0746. Found: 371.0743. The structure was further confirmed by its Xꢀray diffractional analysis.
(3R*,4R*,5R*)ꢀ1ꢀtertꢀButylꢀ4ꢀ(iodomethyl)ꢀ3ꢀisopropylꢀ5ꢀmethylpiperidinꢀ2ꢀone
(22).
Flash
chromatography on silica gel using petroleum ether/ethyl acetate (20:1) to give the product (75 mg, 71%
yield) as a yellowish oil. IR (neat): ν (cmꢀ1) 2960, 2921, 2868, 1660, 1458, 1407, 1362, 1288, 1204,
1
1143. H NMR (400 MHz, CDCl3) δ 0.90 (3H, d, J = 6.8 Hz), 1.03 (6H, d, J = 6.8 Hz), 1.41 (9H, s),
1.71ꢀ1.78 (1H, m), 1.87 (1H, dd, J = 10.0, 4.8 Hz), 2.05ꢀ2.13 (2H, m), 2.65 (1H, dd, J = 12.0, 9.6 Hz),
13
2.80 (1H, dd, J = 13.6, 11.2 Hz), 3.29 (1H, dd, J = 9.6, 2.4 Hz), 3.52 (1H, dd, J = 13.6, 2.4 Hz). C
NMR (100 MHz, CDCl3) δ 10.8, 19.4, 20.1, 23.2, 24.7, 29.0, 37.3, 44.2, 47.6, 52.7, 56.7, 172.0. EIMS:
m/z (rel intensity) 351 (M+, 12), 336 (50), 224 (98), 208 (30), 182 (100), 168 (35), 126 (60), 57 (43), 41
(28). HRMS calcd for C14H26INO (M): 351.1059. Found: 351.1057. The structure was further confirmed
by its 2D NOESY experiments.
(3R*,4S*,5R*)ꢀ1ꢀtertꢀButylꢀ4ꢀ(iodomethyl)ꢀ3ꢀisopropylꢀ5ꢀmethylpiperidinꢀ2ꢀone
(23).
Flash
chromatography on silica gel using petroleum ether/ethyl acetate (20:1) to give the product (7.5 mg, 7%
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yield) as a yellowish oil. IR (neat): ν (cmꢀ1) 2958, 2926, 2875, 1640, 1463, 1427, 1362, 1286, 1245,
1206. 1H NMR (400 MHz, CDCl3) δ 0.91ꢀ0.98 (7H, m), 1.11 (3H, d, J = 6.8 Hz), 1.41 (9H, s), 1.57ꢀ1.65
(1H, m), 1.91ꢀ2.03 (1H, m), 2.13 (1H, dd, J = 7.2, 4.0 Hz), 2.94 (1H, dd, J = 12.0, 10.8 Hz), 3.27ꢀ3.36
1
2
3
4
5
6
7
13
(3H, m). C NMR (100 MHz, CDCl3) δ 15.0, 16.8, 19.2, 21.4, 28.3, 31.5, 35.7, 42.6, 49.3, 55.3, 57.2,
8
9
172.3. EIMS: m/z (rel intensity) 351 (M+, 9), 182 (57), 126 (40), 86 (68), 84 (46), 57 (100), 55 (35), 49
(38), 41 (48). HRMS calcd for C14H26INO (M): 351.1059. Found: 351.1056. The structure was further
confirmed by its 2D NOESY experiments.
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(3R*,4R*,6R*)ꢀ1ꢀtertꢀButylꢀ4ꢀ(iodomethyl)ꢀ3,6ꢀdimethylpiperidinꢀ2ꢀone (25). Flash chromatography
on silica gel using petroleum ether/ethyl acetate (20:1) to give the product (65 mg, 67% yield) as a
colorless oil. IR (neat): ν (cmꢀ1) 2973, 2928, 1637, 1467, 1413, 1377, 1362, 1316, 1200, 1167, 1049. 1H
NMR (400 MHz, CDCl3) δ 1.09 (3H, d, J = 7.2 Hz), 1.24 (3H, d, J = 6.4 Hz), 1.44 (9H, s), 1.67ꢀ1.71
(1H, m), 1.82 (1H, td, J = 12.4, 5.2 Hz), 2.41ꢀ2.51 (1H, m), 2.61ꢀ2.68 (1H, m), 3.03ꢀ3.12 (2H, m), 3.89ꢀ
13
3.96 (1H, m). C NMR (100 MHz, CDCl3) δ 9.2, 12.9, 23.4, 28.8, 33.0, 35.0, 41.9, 48.5, 57.0, 173.9.
EIMS: m/z (rel intensity) 323 (M+, 57), 323 (57), 308 (76), 280 (79), 252 (81), 196 (57), 99 (65), 57
(100), 41 (74). HRMS calcd for C12H22INO (M): 323.0746. Found: 323.0744. The structure was further
confirmed by its 2D NOESY experiments.
(3R*,4R*,6S*)ꢀ1ꢀtertꢀButylꢀ4ꢀ(iodomethyl)ꢀ3,6ꢀdimethylpiperidinꢀ2ꢀone
(26).
Flash
chromatography on silica gel using petroleum ether/ethyl acetate (20:1) to give the product (13 mg, 13%
yield) as a colorless oil. IR (neat): ν (cmꢀ1) 2960, 2926, 2868, 1648, 1458, 1416, 1377, 1360, 1280,
1247, 1203. 1H NMR (400 MHz, CDCl3) δ 1.14 (3H, d, J = 6.8 Hz), 1.31 (3H, d, J = 6.8 Hz), 1.35ꢀ1.48
(11H, m), 2.15ꢀ2.25 (2H, m), 3.23 (1H, dd, J = 10.0, 6.0 Hz), 3.39 (1H, dd, J = 10.0, 2.4 Hz), 3.95ꢀ4.03
(1H, m). 13C NMR (100 MHz, CDCl3) δ 13.6, 15.6, 25.3, 29.0, 36.4, 39.1, 42.1, 46.5, 57.2, 173.9.
EIMS: m/z (rel intensity) 323 (M+, 35), 323 (35), 308 (53), 280 (55), 252 (67), 84 (38), 57 (100), 55
(44), 41 (62). HRMS calcd for C12H22INO (M): 323.0746. Found: 323.0749. The structure was further
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confirmed by its 2D NOESY experiments.
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Acknowledgments: This project was supported by the National Natural Science Foundation of China
(Grant Nos. 21532008, 21472220, 21272259, and 21361140377) and by the Natural Science Foundation
of Tianjin (No. 15JCYBJC48200).
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Author Information
Corresponding Author
*Eꢀmail: clig@mail.sioc.ac.cn (C.L.); bnulk@foxmail.com (K.L.).
Notes
The authors declare no competing financial interest.
1
Supporting Information Available. Copies of H, 13C NMR and 2D NOESY spectra, DFT
calculation data, crystallographic data in CIF format and complete reference 17. This material is
available free of charge via the Internet at http://pubs.acs.org.
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